CN116568272A - 聚合双胍杀微生物剂与糖胺聚糖的可溶性聚电解质复合物 - Google Patents
聚合双胍杀微生物剂与糖胺聚糖的可溶性聚电解质复合物 Download PDFInfo
- Publication number
- CN116568272A CN116568272A CN202180080319.8A CN202180080319A CN116568272A CN 116568272 A CN116568272 A CN 116568272A CN 202180080319 A CN202180080319 A CN 202180080319A CN 116568272 A CN116568272 A CN 116568272A
- Authority
- CN
- China
- Prior art keywords
- phmb
- soluble
- biguanide
- soluble polyelectrolyte
- gag
- 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.)
- Pending
Links
- 229920000867 polyelectrolyte Polymers 0.000 title claims abstract description 44
- 229920002683 Glycosaminoglycan Polymers 0.000 title claims abstract description 21
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 title claims abstract description 9
- 229940123208 Biguanide Drugs 0.000 title claims abstract description 9
- 230000003641 microbiacidal effect Effects 0.000 title description 3
- 229920002413 Polyhexanide Polymers 0.000 claims abstract description 44
- 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 claims abstract description 38
- 229920002674 hyaluronan Polymers 0.000 claims abstract description 38
- 229960003160 hyaluronic acid Drugs 0.000 claims abstract description 38
- 229920001090 Polyaminopropyl biguanide Polymers 0.000 claims abstract description 13
- 229920002567 Chondroitin Polymers 0.000 claims abstract description 6
- DLGJWSVWTWEWBJ-HGGSSLSASA-N chondroitin Chemical compound CC(O)=N[C@@H]1[C@H](O)O[C@H](CO)[C@H](O)[C@@H]1OC1[C@H](O)[C@H](O)C=C(C(O)=O)O1 DLGJWSVWTWEWBJ-HGGSSLSASA-N 0.000 claims abstract description 6
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical compound FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229920001287 Chondroitin sulfate Polymers 0.000 claims abstract description 5
- 229940059329 chondroitin sulfate Drugs 0.000 claims abstract description 5
- 239000004599 antimicrobial Substances 0.000 claims abstract description 4
- VAZJLPXFVQHDFB-UHFFFAOYSA-N 1-(diaminomethylidene)-2-hexylguanidine Polymers CCCCCCN=C(N)N=C(N)N VAZJLPXFVQHDFB-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000004480 active ingredient Substances 0.000 claims abstract description 3
- 229940093424 polyaminopropyl biguanide Drugs 0.000 claims abstract 2
- 239000000243 solution Substances 0.000 claims description 23
- 239000000203 mixture Substances 0.000 claims description 11
- 238000009472 formulation Methods 0.000 claims description 9
- 229920000642 polymer Polymers 0.000 claims description 3
- 208000002874 Acne Vulgaris Diseases 0.000 claims description 2
- 206010000496 acne Diseases 0.000 claims description 2
- 239000003889 eye drop Substances 0.000 claims description 2
- 229940012356 eye drops Drugs 0.000 claims description 2
- 239000000499 gel Substances 0.000 claims description 2
- 208000015181 infectious disease Diseases 0.000 claims description 2
- 230000004054 inflammatory process Effects 0.000 claims description 2
- 239000006210 lotion Substances 0.000 claims description 2
- 239000002324 mouth wash Substances 0.000 claims description 2
- 239000002674 ointment Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000006254 rheological additive Substances 0.000 claims description 2
- 206010061218 Inflammation Diseases 0.000 claims 1
- 210000001508 eye Anatomy 0.000 claims 1
- 210000002200 mouth mucosa Anatomy 0.000 claims 1
- 210000003932 urinary bladder Anatomy 0.000 claims 1
- 210000001215 vagina Anatomy 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 3
- 238000000502 dialysis Methods 0.000 description 8
- 241000191967 Staphylococcus aureus Species 0.000 description 7
- 241000191963 Staphylococcus epidermidis Species 0.000 description 7
- 238000010790 dilution Methods 0.000 description 7
- 239000012895 dilution Substances 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 230000000845 anti-microbial effect Effects 0.000 description 6
- 206010052428 Wound Diseases 0.000 description 5
- 208000027418 Wounds and injury Diseases 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 235000010633 broth Nutrition 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 230000029663 wound healing Effects 0.000 description 4
- 241000186427 Cutibacterium acnes Species 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 229920001448 anionic polyelectrolyte Polymers 0.000 description 3
- 230000032770 biofilm formation Effects 0.000 description 3
- 125000002091 cationic group Chemical group 0.000 description 3
- 210000002510 keratinocyte Anatomy 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000001974 tryptic soy broth Substances 0.000 description 3
- 206010069408 Acanthamoeba keratitis Diseases 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 239000003792 electrolyte Substances 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 230000017423 tissue regeneration Effects 0.000 description 2
- 108010050327 trypticase-soy broth Proteins 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 1
- 241000928573 Cutibacterium Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 208000034693 Laceration Diseases 0.000 description 1
- 206010065764 Mucosal infection Diseases 0.000 description 1
- 206010028116 Mucosal inflammation Diseases 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- -1 alkali metal cations Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004283 biguanides Chemical class 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000012292 cell migration Effects 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000009918 complex formation Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000002781 deodorant agent Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 230000001172 regenerating effect Effects 0.000 description 1
- 238000000518 rheometry Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000007259 schaedler broth Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 239000006150 trypticase soy agar Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
- C08L5/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/73—Polysaccharides
- A61K8/735—Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
- A61Q17/005—Antimicrobial preparations
-
- 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
-
- 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
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- 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
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Materials Engineering (AREA)
- Dermatology (AREA)
- Birds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
公开了聚合双胍抗微生物剂如聚六亚甲基双胍或聚氨丙基双胍与糖胺聚糖如透明质酸、软骨素或硫酸软骨素及其衍生物的可溶性聚电解质复合物，及其作为药物组合物或医学装置的活性成分的用途。
Description
本发明涉及聚合双胍杀微生物剂与糖胺聚糖的可溶性聚电解质复合物以及含有它们的制剂。
现有技术
聚电解质是在其结构上具有多个可电离官能团的聚合物。在溶液中，电离的聚电解质可以与带相反电荷的聚电解质形成复合物；所述复合物在溶液中的行为基于阴离子聚电解质当量和阳离子聚电解质当量之间的化学计量。
通过以非化学计量比(在实践中涉及一种比另一种大大过量)混合阴离子和阳离子聚电解质可以形成水溶性聚电解质复合物；然而，当所述比例接近1时，获得不溶性聚电解质复合物。
阳离子聚电解质类别包括聚六亚甲基双胍抗微生物剂(也称为PHMBs)和聚氨丙基双胍(也称为PAPBs)，而GAGs是阴离子聚电解质。
PHMBs和PAPBs(统称为ABPs，即抗菌双胍聚合物)是合成聚电解质，在外科和卫生领域用作抗菌剂。PHMBs用于治疗棘阿米巴角膜炎(Acanthamoeba keratitis)、用作接触镜清洁产品的成分以及用于美容化妆品、祛臭剂和兽医学产品中。
GAGs是天然阴离子聚电解质，因其组织再生性质和流变学特性而用于药物和美容化妆领域。GAGs的实例有透明质酸(HA)、软骨素(C)和硫酸软骨素(CS)。
双胍抗菌盐的已知制剂并不完全令人满意，特别是不允许延迟/控制释放形式，所述延迟/控制释放形式在各种应用中是期望的。将GAGs典型的组织修复和伤口愈合作用与双胍化合物已知的抗菌和防腐性质相结合的制剂也将是令人感兴趣的。
发明描述
现已发现，ABPs和GAGs之间的相互作用形成了聚电解质复合物，其特性取决于形成复合物的化学计量。特别地，只有GAG和ABP之间的当量比大于10，才能获得可溶性聚电解质复合物；这意味着，就当量而言，聚阳离子ABP必须少于与GAG相互作用的正电荷的十分之一，主要由单价碱金属阳离子组成。用所述可溶性聚电解质复合物(缩写为GAG/ABP)治疗感染部位是特别有利的，因为ABP和GAG同时、受控、逐渐和/或延迟释放，使ABP的抗微生物作用与GAG典型的伤口愈合和组织修复性质协同作用。由于应用部位存在的其它阳离子在GAG表面的竞争，ABP从GAG/ABP中释放出来。
鉴于所述特征，构成本发明目的的GAGs/ABPs可特别用于配制药物组合物和医学装置。
GAG选自HA、C和CS及其混合物、如EP2614090中所述获得的混合协作复合物、和如WO2013/164782A1中所述的交联形式。
聚电解质的平均分子量Mn宽泛地为2×103至5×106Da的范围。
控制GAG和ABP之间的当量比能够调控GAG/ABP聚电解质复合物的溶解度。
本发明的化合物可以在水性溶液中通过将GAG或其盐与ABP的盐以所需的化学计量比混合来容易地制备。
当GAG当量和ABP当量之间的比例>10时，获得了可溶性聚电解质复合物，而在较小的比例下，获得不溶性聚电解质复合物。
GAG/ABP聚电解质复合物的形成反应在室温下立即发生。如果复合物是不溶的，可以通过过滤或离心进行分离，如果是可溶的，可以通过干燥、冷冻干燥或膜法进行分离。
本发明的可溶性GAG/ABP聚电解质复合物可以以滴眼剂、凝胶、漱口剂、洗剂、软膏、溶液剂、含药贴剂或任何适于局部施用的形式使用。
含有可溶性GAG/ABP聚电解质复合物的药物组合物或医学装置是本发明的另一个目的。
所述组合物可用于治疗痤疮以及膀胱、阴道、眼和口腔粘膜感染或炎症。
含有可溶性GAG/ABP聚电解质复合物的制剂的流变学和功效可以通过使用流变学改性剂和其它活性成分或赋形剂来优化。
在制剂中，可溶性GAG/ABP聚电解质复合物的浓度可以在宽范围内变化，这取决于所讨论的应用。广义而言，浓度范围将为总制剂重量的0.001至10％。
以下实施例更详细地描述了本发明。
实施例1—GAGs与PHMB的聚电解质复合物的形成
制备了浓度为9.96mEq/100的200mL的以下GAG钠盐溶液(溶液A)，其中GAG为HA Mw700KDa或HA Mw 100KDa或软骨素35KDa，PHMB盐酸盐Mw 2.2KDa的溶液的浓度为45.77mEq/100mL(溶液B)。在搅拌下将不同量的溶液B加入到10mL溶液A中，用蒸馏水定容至20mL，继续搅拌4小时。如果形成沉淀，则将样品离心，通过离心回收沉淀物并用5mL水洗涤，在真空下烘箱干燥并称重。如表1所示，对于GAG当量/PHMB当量比值>10，普遍形成了可溶性聚电解质复合物，而当比值<2时不溶性聚电解质复合物是主要物质；在2-10的范围，不溶性和可溶性聚电解质复合物之间存在平衡。
表1—GAG/PHMB系统的行为作为化学计量比GAG mEq/PHMB mEq(1.1，HA Mw700KDa；1.2，HA Mw 100KDa；1.3，软骨素Mw 35KDa)的函数。数据显示在不同GAG结构特征时的行为非常相似。
1.1—*将用水预稀释至10mL的溶液B加到10mL GAG溶液(HA Mw 700KDa0.996mEq/10ml)中。
| B*mL | H2O(mL) | PHMB(mEq) | mEq GAG/mEq PHMB | 沉淀物(mg) |
| 3.84 | 6.16 | 1.76 | 0.56 | 590 |
| 1.52 | 8.46 | 0.70 | 1.42 | 296 |
| 0.77 | 9.23 | 0.35 | 2.81 | 98 |
| 0.38 | 9.62 | 0.18 | 5.72 | 40 |
| 0.22 | 9.78 | 0.10 | 10.00 | 22 |
| 0.11 | 9.89 | 0.05 | 19.91 | 2 |
| 0.05 | 9.95 | 0.03 | 39.82 | 0 |
1.2—*将用水预稀释至10mL的溶液B加至10mL GAG溶液(HA Mw 100KDa0.996mEq)中。
| B*mL | H2O(mL) | PHMB(mEq) | mEq GAG/mEq PHMB | 沉淀物(mg) |
| 3.84 | 6.16 | 1.76 | 0.56 | 530 |
| 1.52 | 8.46 | 0.70 | 1.42 | 300 |
| 0.77 | 9.23 | 0.35 | 2.81 | 95 |
| 0.38 | 9.62 | 0.18 | 5.72 | 48 |
| 0.22 | 9.78 | 0.10 | 10.00 | 10 |
| 0.11 | 9.89 | 0.05 | 19.91 | 1 |
| 0.05 | 9.95 | 0.03 | 39.82 | 0 |
1.3—*将用水预稀释至10mL的溶液B加至10mL GAG溶液(软骨素Mw35KDa0.996mEq)中。
| B*mL | H2O(mL) | PHMB(mEq) | mEq GAG/mEq PHMB | 沉淀物(mg) |
| 3.84 | 6.16 | 1.76 | 0.56 | 570 |
| 1.52 | 8.46 | 0.70 | 1.42 | 280 |
| 0.77 | 9.23 | 0.35 | 2.81 | 91 |
| 0.38 | 9.62 | 0.18 | 5.72 | 33 |
| 0.22 | 9.78 | 0.10 | 10.00 | 11 |
| 0.11 | 9.89 | 0.05 | 19.91 | 0 |
| 0.05 | 9.95 | 0.03 | 39.82 | 0 |
实施例2—当GAG mEq/PHMB mEq比例为10时，PHMB从实施例1.1的可溶性聚电解质复合物中的缓慢释放
制备了200mL mEq HA 700KDa/mEq PHMB等于10的实施例1.1的样品，将50ml溶液转移到截留值为5KDa的透析管中，在搅拌下用500mL盐水溶液进行透析。随时间在240nm处测定透析管中溶液的吸收度。平行监测含有相同浓度的PHMB的溶液的透析动力学(20mLPHMB盐水溶液用200mL盐水透析)。表2显示了240nm处的吸收数据，表明在单独PHMB的情况下在约12小时内达到透析平衡，而在HA的存在下，在24小时后仍未达到平衡。这种行为表明，可溶性聚电解质复合物HA/PHMB的行为类似于PHMB缓释系统，确保了随时间推移的逐渐、连续的抗微生物作用。
表2—如实施例1.1所述制备了200mL聚电解质复合物HA/PHMB，其中mEq HA/mEqPHMB比例为10。将50mL溶液转移到截断值为5KDa的透析管中，在搅拌下用500mL盐水溶液进行透析。随时间在240nm处测定透析管中溶液的吸收度。平行监测含有相同量PHMB的溶液的透析动力学(20mL PHMB盐水溶液用200mL盐水透析)。吸收数据表明，在单独PHMB的情况下在约12小时内达到透析平衡，而在HA的存在下，在24小时后仍未达到平衡。
表2
| 10min | 1h | 6h | 12h | 24h | |
| HA/PHMB* | 2.35 | 1.85 | 0.99 | 0.81 | 0.50 |
| PHMB | 2.28 | 1.33 | 0.40 | 0.21 | 0.21 |
*按照表1.1的mEq HA/mEq PHMB 10进行准备，但规模高10倍。
实施例3
各种可溶性HA Mw 500KDa/ABP聚电解质复合物对抗Cutibacterium acnes的抗微生物活性
将Cutibacterium acnes菌株(12827)在Schaedler肉汤中于37℃厌氧培养48小时。将培养后得到的培养肉汤稀释至约1.0-5.0×108CFU/ml的浓度。该测定于37℃厌氧进行48小时，在培养后评估每个孔中细菌生长的存在。向各孔加入不同稀释度(0.01、0.005、0.001和0.0005)的溶液，所述溶液在10mL中含有0.1mEq PHMB或0.1mEq PAPB或1mEqHA Mw 500KDa/0.1mEq PHMB或1mEq HA Mw 500KDa/0.1mEq PAPB。表3显示了获得的结果。直到0.001的稀释度，两种可溶性聚电解质复合物都证明有效对抗Cutibacterium acnes11827。
表3—在可溶性聚电解质复合物HA Mw 500KDa/PHMB和HA Mw500KDa/PAPB的存在下对Cutibacterium acnes 11827生长的抑制，其中HA/ABP的当量比为10。
+＝存在增长；-＝无生长；
实施例4—各种可溶性聚电解质复合物HA/PHMB对抗金黄色葡萄球菌(Staphylococcus aureus)和表皮葡萄球菌(Staphylococcus epidermidis)的抗微生物活性
评价了含有在10mL中的0.1mEq PHMB或1mEq PAPB或1mEq HA Mw500KDa/0.1mEqPHMB或1mEq HA Mw 500KDa/0.1mEq PAPB的溶液的抗微生物活性。
生物膜形成测定—将金黄色葡萄球菌和表皮葡萄球菌的菌株解冻并在胰蛋白酶大豆肉汤(Tryptic Soy Broth)中培养过夜。将培养过夜后获得的培养肉汤稀释至107CFU/mL的浓度，按照确定的稀释度添加物质并在96孔多孔聚苯乙烯板中于37℃培养过夜。通过用1％结晶紫将染色并于550nm读取吸光度，测定了生物膜形成。没有观察到生物膜形成。
抗菌活性测定—将浓度为107CFU/mL的金黄色葡萄球菌和表皮葡萄球菌培养肉汤与含有在10mL中的0.1mEq PHMB或0.1mEq PAPB或1mEq HA Mw500KDa/0.1mEq PHMB或1mEqHA Mw 500KDa/0.1mEq PAPB的溶液一起培养24小时，稀释度为1:2、1:5和1:10。
然后将如此处理的样品的标量稀释液接种在胰蛋白酶大豆琼脂上以计算活CFUs，于37℃培养12小时。对于直到1:10稀释的任何样品都没有观察到细菌生长。
实施例5—高和低分子量HA与PHMB和PAPB的混合协作复合物对表皮葡萄球菌和金黄色葡萄球菌的抗微生物活性
按照EP2614090B1中的报道，使用等量的HA 1400KDa和HA 220KDa制备了高和低分子量HA的混合协作复合物。
将表皮葡萄球菌和金黄色葡萄球菌这两种微生物在TSB培养基中培养12小时。将两种培养肉汤稀释至0.5OD的浓度，借助缓冲液将100μl接种在琼脂化培养基的板上。在接种板中设置孔，向其中插入100μL的以下可溶性GAG/ABP电解质复合物，其中当量比等于10，并且其中GAG是混合协作复合物HA 1400KDa+HA 220KDa(1:1)和ABP在一种情况中是PHMB，在另一种情况中是PAPB。表4显示了获得的结果。
表4—在可溶性GAG/ABP电解质复合物存在下的表皮葡萄球菌和金黄色葡萄球菌的生长抑制，其中当量比等于10，并且其中GAG是混合协作复合物HA 1400KDa+HA 220KDa(1:1)和ABP在一种情况中是PHMB，在另一种情况中是PAPB。
实施例6—对人角质形成细胞的伤口愈合测定
采用微速摄影视频显微镜，在体外伤口愈合试验中评估了实施例2的可溶性聚电解质复合物的生物学应答。具体而言，将永生化人角质形成细胞(HaCat)单层划伤以模拟伤口，将1:8稀释的待测样品添加到受损细胞中。通过观察细胞迁移和对随时间修复速度的定量分析，实时监测了伤口闭合。使用适宜的软件(Okolab)，对每块板的不同观察区域(对象)和每个处理在增加的实验时间下评估修复区域。分析自动和手动进行。表5显示了与未处理样品(对照)中量化的修复相比的修复伤口区域(划伤)的百分比结果以及每个样品的修复速率。
表5—对人角质形成细胞的伤口愈合测定。此表显示了与未处理样品(对照)中量化的修复相比的修复伤口区域(划伤)的百分比结果以及每个样品的修复速率。
Claims (8)
1.糖胺聚糖与双胍聚合物衍生物的可溶性聚电解质复合物。
2.根据权利要求1所述的可溶性聚电解质复合物，其中所述聚合双胍抗微生物剂是聚六亚甲基双胍或聚氨丙基双胍。
3.根据权利要求1所述的可溶性聚电解质复合物，其中所述糖胺聚糖选自软骨素、硫酸软骨素和透明质酸，以及它们的复合物和交联产物。
4.根据权利要求1至3所述的可溶性聚电解质复合物，其中所述聚电解质的平均分子量Mn为2×103至5×106Da的范围。
5.根据权利要求1至4任一项所述的聚电解质复合物，其中糖胺聚糖与聚合双胍抗微生物剂之间的当量比为＞10。
6.含有权利要求1的可溶性聚电解质复合物以及赋形剂和任选的其它活性成分和流变添加剂的制剂。
7.根据权利要求6的制剂，为滴眼剂、凝胶、漱口剂、洗剂、软膏或溶液剂的形式。
8.用于治疗痤疮以及膀胱、阴道、眼和口腔粘膜感染或炎症的根据权利要求6和7的制剂。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT102020000029288 | 2020-12-01 | ||
| IT102020000029288A IT202000029288A1 (it) | 2020-12-01 | 2020-12-01 | Sali di microbiocidi biguanidinici con glicosamminoglicani |
| PCT/IB2021/061053 WO2022118163A1 (en) | 2020-12-01 | 2021-11-29 | Soluble polyelectrolytic complexes of polymeric biguanidine microbiocides with glycosaminoglicans |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116568272A true CN116568272A (zh) | 2023-08-08 |
Family
ID=74669290
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202180080319.8A Pending CN116568272A (zh) | 2020-12-01 | 2021-11-29 | 聚合双胍杀微生物剂与糖胺聚糖的可溶性聚电解质复合物 |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US20240000955A1 (zh) |
| EP (1) | EP4255939A1 (zh) |
| CN (1) | CN116568272A (zh) |
| CA (1) | CA3200312A1 (zh) |
| IT (1) | IT202000029288A1 (zh) |
| WO (1) | WO2022118163A1 (zh) |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3468898A (en) | 1966-05-26 | 1969-09-23 | Sterling Drug Inc | Bridged bis-biguanides and bis-guanidines |
| US4022834A (en) | 1972-03-16 | 1977-05-10 | A/S Farmaceutisk Industri | Antibacterially active hexamethylene-bis-biguanides |
| GB8312663D0 (en) | 1983-05-09 | 1983-06-15 | Ici Plc | Bisbiguanide compounds |
| US4567174A (en) | 1984-05-07 | 1986-01-28 | Imperial Chemical Industries Plc | Bis(1-substituted biguanide) derivatives |
| US4952704A (en) | 1989-05-12 | 1990-08-28 | Gaf Chemicals Corporation | Bis-(pyrrolidonyl alkylene) biguanides |
| US5180577A (en) | 1990-10-09 | 1993-01-19 | Colgate-Palmolive | Stabilized bis biguanide/anionic active ingredient compositions |
| JP3493692B2 (ja) | 1993-09-09 | 2004-02-03 | 三菱マテリアル株式会社 | ビスビグアナイド系化合物およびそれを含む殺菌剤 |
| US20100234319A1 (en) * | 2009-03-11 | 2010-09-16 | Abbott Medical Optics Inc. | Complex of Polymeric Quaternary Ammonium and Anionic Polymers as a New Antimicrobial Agent for Ophthalmic Compositions |
| US8501200B2 (en) | 2010-04-26 | 2013-08-06 | Bausch & Lomb Incorporated | Ophthalmic compositions with biguanide and PEG-glycerol esters |
| IT1402382B1 (it) | 2010-09-09 | 2013-09-04 | Ibsa Inst Biochimique Sa | Complessi cooperativi ibridi di acido ialuronico |
| ITMI20120019A1 (it) | 2012-01-10 | 2013-07-11 | Restituta Castellaccio | Colluttorio |
| ITMI20120732A1 (it) | 2012-05-03 | 2013-11-04 | B S Srl | Polisaccaridi reticolati a memoria di forma |
| WO2017203550A1 (ja) | 2016-05-26 | 2017-11-30 | 株式会社オフテクス | 加水分解ヒアルロン酸誘導体及びカチオン系殺菌剤を含有するコンタクトレンズ用液剤 |
| CN107412049A (zh) * | 2017-07-12 | 2017-12-01 | 贵州九立德生物制药有限公司 | 一种用于皮肤清洁和护理的制剂及其制备方法 |
| IE87094B1 (en) | 2017-08-04 | 2020-05-13 | Laboratorios Kin S A | Gel comprising chlorhexidine |
-
2020
- 2020-12-01 IT IT102020000029288A patent/IT202000029288A1/it unknown
-
2021
- 2021-11-29 US US18/254,864 patent/US20240000955A1/en active Pending
- 2021-11-29 CN CN202180080319.8A patent/CN116568272A/zh active Pending
- 2021-11-29 WO PCT/IB2021/061053 patent/WO2022118163A1/en active Application Filing
- 2021-11-29 EP EP21830498.8A patent/EP4255939A1/en active Pending
- 2021-11-29 CA CA3200312A patent/CA3200312A1/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| CA3200312A1 (en) | 2022-06-09 |
| IT202000029288A1 (it) | 2022-06-01 |
| EP4255939A1 (en) | 2023-10-11 |
| WO2022118163A1 (en) | 2022-06-09 |
| US20240000955A1 (en) | 2024-01-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP7054212B2 (ja) | 有効な創傷ケア処置としての新規高速付着薄膜形成組成物 | |
| CN110448722B (zh) | 一种可注射含单宁酸的温敏复合抗菌水凝胶材料及其制备和应用 | |
| Kim et al. | Antimicrobial hydrogels based on PVA and diphlorethohydroxycarmalol (DPHC) derived from brown alga Ishige okamurae: An in vitro and in vivo study for wound dressing application | |
| CN103191461B (zh) | 一种含透明质酸的伤口护理用敷料 | |
| CN1089587C (zh) | 稳定的交联聚乙烯吡咯烷酮和碘的配合物以及制备该配合物的方法 | |
| US8658192B2 (en) | Integrated antimicrobial and low fouling materials | |
| KR101155884B1 (ko) | 하이드로카르빌 설톤 화합물에 의해 화학적으로 변형된폴리아미노사카라이드 | |
| EP2231761A2 (en) | Disinfectant alcohol-soluble quaternary ammonium polymers | |
| CN102970995A (zh) | 稳定的抗菌组合物及方法 | |
| CN107929232B (zh) | 一种多效抑菌杀菌修复凝胶及其制备方法与应用 | |
| Akca et al. | Comparison of different types and sources of chitosan for the treatment of infections in the oral cavity | |
| Parwani et al. | Evaluation of Moringa oleifera seed biopolymer-PVA composite hydrogel in wound healing dressing | |
| US6521243B2 (en) | Ionic chitosan -iodine complexes: antiseptic hydrogels and wound healing promoters | |
| RU2485938C1 (ru) | Гель-основа для ранозаживляющих и косметических средств и способ его получения | |
| RU2636530C2 (ru) | Фармацевтическая композиция для лечения ран и ожогов | |
| CN116568272A (zh) | 聚合双胍杀微生物剂与糖胺聚糖的可溶性聚电解质复合物 | |
| CN111991417A (zh) | 一种具有生理响应性的次氯酸凝胶及其在皮肤创面中的应用 | |
| CN114381083B (zh) | 一种角膜接触镜用抗菌抗氧化水凝胶及其制备方法 | |
| CN109157505A (zh) | 抗菌保湿凝胶及其制备方法 | |
| JP3054758B2 (ja) | 外傷用組成物 | |
| RU2562113C1 (ru) | Катионный антисептик на основе композиций l-цистеин-серебряного раствора и пищевого хитозана | |
| Sim et al. | Harnessing the benefits of utilizing the optimal pH in conjunction with a hydrogel for wound care | |
| CN117815440A (zh) | 一种含重组胶原蛋白的修复消炎保湿组合物及其应用 | |
| CN112048083A (zh) | 促进糖尿病溃疡皮肤修复的含胍基抗菌聚合物及制备方法 | |
| CN114259503A (zh) | 一种人用聚维酮碘溶液及其制备方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |