WO2021109704A1 - 慢性伤口愈合组合物及其应用 - Google Patents

慢性伤口愈合组合物及其应用 Download PDF

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WO2021109704A1
WO2021109704A1 PCT/CN2020/118933 CN2020118933W WO2021109704A1 WO 2021109704 A1 WO2021109704 A1 WO 2021109704A1 CN 2020118933 W CN2020118933 W CN 2020118933W WO 2021109704 A1 WO2021109704 A1 WO 2021109704A1
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pharmaceutical composition
present
wound
composition
borneol
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PCT/CN2020/118933
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English (en)
French (fr)
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罗胥恩
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罗胥恩
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Priority to KR1020227022973A priority Critical patent/KR20220118446A/ko
Priority to CN202080057131.7A priority patent/CN114555093A/zh
Priority to EP20895228.3A priority patent/EP4070798A4/en
Priority to MX2022006884A priority patent/MX2022006884A/es
Priority to AU2020397401A priority patent/AU2020397401A1/en
Priority to BR112022010966A priority patent/BR112022010966A2/pt
Application filed by 罗胥恩 filed Critical 罗胥恩
Priority to CA3168280A priority patent/CA3168280A1/en
Priority to JP2022534305A priority patent/JP7551752B2/ja
Priority to US17/782,348 priority patent/US20230059230A1/en
Publication of WO2021109704A1 publication Critical patent/WO2021109704A1/zh
Priority to TW110136366A priority patent/TW202228667A/zh
Priority to ZA2022/07234A priority patent/ZA202207234B/en

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    • 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
    • A61K31/7032—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/29—Antimony or bismuth compounds
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to a composition with chronic wound healing effect and its application.
  • Chronic wounds refer to wounds that have undergone appropriate treatment for a predetermined period of time, but still cannot achieve general wound healing in terms of structure and appearance, and there is still no effective treatment agent.
  • Types of chronic wounds include bedsores or pressure ulcers caused by long-term bed rest, wound ulcers of diabetic patients, gangrene of peripheral blood vessels, ulcers caused by arterial or venous disorders, unhealed wounds of cancer patients, and chronic wounds caused by acute wound infections. Poor healing and so on.
  • Acteoside is an active ingredient in Chinese herbal medicine. It has a lipase inhibitory effect and is known to have antibacterial, anti-inflammatory, antiviral, antioxidant, and neuroprotective activities.
  • Cimicifuga glycosides have been reported as effective antimicrobial ingredients and are known to have good antibacterial effects against Staphylococcus aureus (Guillermo et al., 1999, Journal of Ethnopharmacology 66(1): 75-8). Cimicifugaoside also has a good anti-inflammatory effect (Speranza et al., 2009, Journal of biological regulators and homeostatic agents 23(3): 189-95.).
  • the Chinese Patent Grant Announcement No. 103816169B announced on January 6, 2016 reveals that cimicifugaoside can be used to prepare and prevent vascular dementia, and has protective and therapeutic effects on cell ischemia and hypoxia caused by low glucose and hypoxia.
  • the present invention provides a novel composition, which has chronic wound healing effect and is mainly composed of the following three components: (1) An anti-inflammatory agent selected from the group consisting of cohodoside, cohodoside and combinations thereof The group consisting of (2) an astringent selected from the group consisting of gallic acid, hypogallic acid, its salts and combinations thereof, and (3) a cooling agent selected from the group consisting of borneol, menthol and combinations thereof If necessary, it can be combined with one or more pharmaceutically acceptable carriers.
  • the present invention provides the use of this composition for preparing a medicament for treating chronic wounds.
  • chronic wounds refer to diabetic wounds.
  • the equivalent ratio of the three components is (1) anti-inflammatory agent: (2) astringent: (3) cooling agent 1:0.1-10:0.1-10.
  • the equivalent ratio of the three components is (1) anti-inflammatory agent: (2) astringent: (3) cooling agent 1:0.5-5:0.5-5.
  • the equivalent ratio of the three components is (1) anti-inflammatory agent: (2) astringent: (3) cooling agent is about 1:1:1.
  • the anti-inflammatory agent is a xylogen-like glycoside having the structure of the following formula I or an isomer thereof:
  • astringent is gallic acid having the structure of the following formula II:
  • the astringent is a salt of gallic acid or hypogallic acid, preferably a bismuth salt.
  • the astringent is bismuth hypogallate with the structure of the following formula IIa:
  • cooling agent is borneol having the structure of the following formula IIIa:
  • cooling agent is menthol having the structure of the following formula IIIb:
  • the present invention provides a pharmaceutical composition with the effect of treating chronic wound healing, which is mainly composed of the following three components: (1) cohodoside, (2) bismuth subgallate, and (3) dragon Brain, and optionally combined with one or more pharmaceutically acceptable carriers.
  • the equivalent ratio of the three components in the pharmaceutical composition is (1) cimicifugaoside: (2) bismuth subgallate: (3) borneol is 1:0.1-10:0.1-10 ; Preferably it is 1:0.5-5:0.5-5.
  • the equivalent ratio of the three components in the pharmaceutical composition is (1) cimicifugaoside: (2) bismuth subgallate: (3) borneol is about 1:1: 1.
  • the pharmaceutical composition comprises (1) 0.05%-10% luteolin, (2) 0.05%-10% bismuth subgallate, and (3) 0.02%-5% by weight Borneol, and a pharmaceutically acceptable carrier.
  • Figure 1 shows the results of the composition of the present invention for promoting cell proliferation by culturing HaCaT cells for 48 hours in a high glucose (20mM) environment
  • Figure 2 shows the comparison of the composition of the present invention (All, A 16.0 ⁇ M + BO 18.8 ⁇ M + BSG 14.2 ⁇ M) against the 48-hour cell proliferation of HaCaT cells cultured in low-sugar (5mM) and high-sugar (25mM) environments, *shows significant differences, p ⁇ 0.05 (5: 5mM glucose; 25: 25mM glucose; 5+All: 5mM glucose with addition of the composition of the invention (A 16.0 ⁇ M+BO18.8 ⁇ M+BSG 14.2 ⁇ M);; 25+All: 25mM glucose with addition of the invention Composition (A 16.0 ⁇ M + BO 18.8 ⁇ M + BSG 14.2 ⁇ M)).
  • Figure 3A shows the image of cell migration of HaCaT cells cultured in the composition of the present invention (All) and the control group equal to high glucose (25mM) for 48 hours (Con: control group; BO 18.8 ⁇ M; BSG 14.2 ⁇ M; BO 18.8 ⁇ M+A 16.0 ⁇ M ; BSG 14.2 ⁇ M+A 16.0 ⁇ M; BO 18.8 ⁇ M+BSG 14.2 ⁇ M; All(A 16.0 ⁇ M+BO 18.8 ⁇ M+BSG 14.2 ⁇ M)).
  • Figure 3B shows the comparison between the composition of the present invention (All) and the control group in a high-glycemic (25mM) environment equal to HaCaT cells for 48 hours, with a cell proliferation ratio of 1.0 compared to other experimental groups (Con: Control group; A 16.0 ⁇ M; BO 18.8 ⁇ M; BSG 14.2 ⁇ M; BO 18.8 ⁇ M+A 16.0 ⁇ M; BSG 14.2 ⁇ M+A 16.0 ⁇ M; BO 18.8 ⁇ M+BSG 14.2 ⁇ M; All(A16.0 ⁇ M+BO 18.8 ⁇ M+BSG 14.2 ⁇ M)).
  • Figure 4 shows the comparison of the changes in the protein concentration of Collagen III, MMP-1, Collagen I, TFG- ⁇ and the like on HDF cells treated with IL-1 ⁇ by the composition of the present invention and the control group.
  • Figure 5 shows the wound healing process of Case 1 (diabetes and stroke patient, male, 77 years old).
  • the wound size was 4cm x 3cm x 0.5cm (A), and the wound obviously began to close on day 18 (B), and day 33
  • the wound was 1.5cm x 0.5cm x 0.2cm ( Figure C), and the wound was completely healed on the 79th day (D).
  • Figure 6 shows the wound healing process of Case 2 (diabetes and stroke patient, male, 77 years old).
  • the wound size on the 0th day is 15cm x 11cm x 2cm (A)
  • the wound on the 75th day is 5.5cm x11cm x1cm (B)
  • the 103rd day The wound was 3cm x 2cm x 0.5cm (C), and the wound healed completely on the 140th day (D).
  • Figure 7 shows Case 3 (a patient with diabetes and lung cancer, female, 82 years old).
  • the wound size on day 0 was 2.5cm x 1cm x 0.5cm (A), and the wound size on day 17 was 1.5cm x 1cm x 0.2cm (B).
  • chronic wound refers to a wound that has been treated appropriately for a predetermined period of time, but it still fails to heal the structure and appearance of the general wound.
  • Types of chronic wounds include bedsores or pressure ulcers caused by long-term bed rest, diabetic wound ulcers, gangrene of peripheral blood vessels, ulcers caused by arterial or venous disorders, unhealed wounds of cancer patients, and chronic poor healing caused by acute wound infections .
  • the composition of the present invention has a healing effect on chronic wounds with skin symptoms, and is particularly effective for diabetic wounds.
  • treatment used in this article includes the meaning of “treating” or “promoting”, which means to improve symptoms.
  • patient as used herein includes humans, and animals, especially mammals.
  • the term "pharmaceutically acceptable carrier” refers to diluents, excipients, and the like that can be used to prepare pharmaceutical compositions by techniques commonly used in medicine. According to the present invention, it can be adjusted into the form of medicine, cosmetics or medical materials. According to the present invention, it can be made into a form of topical application, for example, a spray form.
  • the spray form includes spray and liquid; or semi-solid or solid form, preferably a solid form with a dynamic viscosity greater than water.
  • Appropriate formulations include, but are not limited to, suspensions, emulsions, creams, ointments, liniments and the like. Preferably, it is in the form of an ointment. No matter what form the pharmaceutical composition of the present invention is in, it can also contain emollients, fragrances or pigments to improve its acceptability for various uses.
  • terapéuticaally effective dose means a dose that can effectively treat wounds in the management of symptoms.
  • the appropriate dosage can be used according to the needs of the patient or wound, according to common medical techniques or clinical knowledge, and can be adjusted according to the method of administration and treatment, including age, weight, symptoms, treatment effect, administration method, and treatment time. .
  • the present invention provides a composition with chronic wound healing effect, which is mainly composed of the following three components: (1) An anti-inflammatory agent selected from the group consisting of cohodosides, cohodosides and combinations thereof , (2) an astringent, selected from the group consisting of gallic acid, hypogallic acid, its salts and combinations thereof, and (3) a cooling agent, selected from the group consisting of borneol, menthol and their combinations , And optionally combined with one or more pharmaceutically acceptable carriers.
  • the present invention also provides the use of the composition for preparing a medicament for treating chronic wounds, especially diabetic wounds.
  • the composition of the present invention has a significant effect on promoting cell proliferation and migration in a high-glycemic environment, but a single component or any two combination has no effect.
  • the composition of the present invention is relatively ineffective for culture in a low-sugar environment, showing that the composition of the present invention has a special effect on diabetic wound healing, and can further support its chronic wound healing effect.
  • composition with an appropriate content can be prepared according to general traditional techniques, wherein the examples can include the equivalent range of each ingredient:
  • Anti-inflammatory agent 1;
  • Astringent 0.1-10; preferably 0.5-5.
  • Cooling agent 0.1-10; preferably 0.5-5.
  • the equivalent ratio of the three components is (1) anti-inflammatory agent: (2) astringent: (3) cooling agent is about 1:1:1.
  • the subject of the present invention provides a medicinal composition with the healing effect of treating chronic wounds, which is mainly composed of the following three components: (1) cimicifugaoside, (2) bismuth subgallate, and (3) borneol, and If necessary, it can be combined with one or more pharmaceutically acceptable carriers. That is to say, a product whose trademark is Tangzule 7 TM (NuDFC7 TM ) has not yet been launched.
  • the equivalent ratio of the three components in the pharmaceutical composition is (1) cimicifugaoside: (2) bismuth subgallate: (3) borneol is 1:0.1-10:0.1-10 ; Preferably it is 1:0.5-5:0.5-5.
  • the specific example therein is about 1:1:1.
  • the pharmaceutical composition comprises (1) 0.05%-10% cimicifuga glycosides, (2) 0.05%-10% bismuth subgallate, and (3) 0.02%-5% by weight. Brain, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises (1) 0.1%-5% by weight of xylogenin, (2) 0.06%-6% bismuth subgallate, and (3) 0.03 %-3% borneol, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises (1) 0.3%-5% cimicifugain, (2) 0.5%-5% bismuth subgallate, and (3) 0.5% %-1% Borneol, and a pharmaceutically acceptable carrier.
  • the composition may contain an appropriate excipient to prepare a composition in the form of external pharmaceuticals, cosmetics or medical materials.
  • the composition further contains a therapeutic agent, such as other anti-inflammatory agents, antibacterial agents or other therapeutic agents.
  • a therapeutic agent such as other anti-inflammatory agents, antibacterial agents or other therapeutic agents.
  • Acteoside Acteoside, code name A: purchased from Sigma-Aldrich (St. Louis, MO, USA).
  • composition can be prepared according to the following composition:
  • Cimicifugaoside (A) 16.0 ⁇ M (0.01 ⁇ g/ ⁇ l), that is, 0.1%;
  • HDF cells human dermal fibroblast
  • HaCaT cells skin keratinocytes
  • DMEM Dulbecco's Modified Eagle Medium
  • NEAA non-essential amino acid
  • the medium is changed every two days.
  • the cells were collected and re-cultured at a ratio of 1:10 after being treated with a 0.1% Trypsin-EDTA mixture.
  • the cells used in the study are between 12 and 40 generations. 24 hours before the drug treatment, the cells were planted and left for 24 hours. The control group was maintained in the medium and added with drugs. Under this culture condition, cell growth and differentiation are not affected.
  • HaCaT cells were cultured at 3 ⁇ 10 5 with 25 mM glucose, and cultured in a 12-well petri dish for 48 hours. Cell growth and viability were analyzed with CCK-8 reagent kit (Dojindo Molecular Technologies, Kumamoto, Japan). 5 ⁇ L of CCK-8 solution was added to each cell and incubated at 37°C for one hour, and then microplate reader was used. (SpectraMax, Molecular Device, USA) Measure the 450nm absorbance, and compare the sample with the control group to analyze the experimental results.
  • the experimental groups tested include:
  • Figure 1 The results of cell proliferation after 48 hours of culture are shown in Figure 1, which shows that the composition of the present invention (All; A16.0 ⁇ M+BO18.8 ⁇ M+BSG 14.2 ⁇ M) is the best, providing an unexpectedly significant effect of promoting cell proliferation (p ⁇ 0.05), but A single group of ingredients has no effect, or the combination of any two is not as effective as a combination of the three.
  • HaCaT cells were cultured in 3 ⁇ 10 5 with 5mM, 25mM glucose, cultured in a 12-well petri dish for 48 hours, and the composition of the present invention (All:A 16.0 ⁇ M+BO 18.8 ⁇ M+BSG 14.2 ⁇ M) was added to observe the cell proliferation situation.
  • Fig. 2 shows that the composition of the present invention (A16.0 ⁇ M+BO 18.8 ⁇ M+BSG 14.2 ⁇ M) has a significant synergistic effect on cell growth in high-glucose culture (25mM), but is effective for low-glucose (5mM) cell proliferation has no significant effect on promoting cell proliferation.
  • HaCaT cells were cultured at 1 ⁇ 10 5 with 25 mM glucose, cultured in a 24-well petri dish for 48 hours, and the following drugs were added to observe the cell migration status:
  • composition of the present invention A 16.0 ⁇ M+BO 18.8 ⁇ M+BSG 14.2 ⁇ M
  • High-glucose culture 25mM
  • the composition of the present invention has an unexpected treatment for diabetes wound healing Effect, and further support its chronic wound healing effect.
  • HDF cells (1 X 10 5 /well) were added with the cellular inflammatory factor IL-1 ⁇ (10ng/mL) to evaluate the inhibition of IL-1 ⁇ -induced inflammation by these drugs.
  • the cells were cultured in a 24-well culture dish for 48 hours, and the following drugs were added at the same time to observe how the cells affect protein expression in the inflammatory state.
  • These proteins contain matrix metalloproteinases (such as MMP-1 or MMP- 9); and the expression of collagen (collagen I or Collagen 9) controlled by the down-regulated TGF- ⁇ factor and its downstream information pathways:
  • control group no IL-1 ⁇ treatment
  • control group (IL-1 ⁇ treatment);
  • BO+A BO 18.8 ⁇ M+A 16.0 ⁇ M
  • BO+BSG BO 18.8 ⁇ M+BSG 14.2 ⁇ M;
  • composition of the present invention (A 16.0 ⁇ M + BO 18.8 ⁇ M + BSG 14.2 ⁇ M) was applied to different patients daily to observe the wound healing situation.
  • the wound healing results of the three patients are shown in Figures 5, 6 and 7. And the results are as follows.
  • the original wound size on day 0 was 15cm x 11cm x 2cm (A), and the wound was reduced to 5.5cm x 11cm x 1cm (B) on the 75th day of treatment, and the wound healed on day 103 ,
  • the size of the wound is 3cm x 2cm x 0.5cm (C), and the wound is completely healed on the 140th day (D), which shows that the composition of the present invention has a significant therapeutic effect on diabetic wounds, and the treatment is ongoing.

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Abstract

一种具有慢性伤口愈合功效的组合物，尤指糖尿病伤口愈合，其主要由下列三组分组成：(1)一种抗发炎剂，选自类叶升麻苷、异类叶升麻苷及其组合组成的群，(2)一种收敛剂，选自没食子酸、次没食子酸、其盐类及其组合组成的群，以及(3)一种清凉剂，选自龙脑、薄荷脑及其组合组成的群，并视需要与一种或以上医药上可接受的载剂组合。该组合物用于制备治疗慢性伤口药剂的用途，尤指糖尿病伤口。

Description

慢性伤口愈合组合物及其应用 技术领域
本发明涉及具有慢性伤口愈合功效的组合物及其应用。
背景技术
随着人口结构老化，慢性疾病已成为健康照护的主轴，其中慢性伤口的照护是非常重要的一环。慢性伤口是指伤口在经过合宜治疗经一预定的时间后，仍无法达到一般伤口结构上和外观上的愈合，迄今仍无有效的治疗药剂。慢性伤口种类包括长期卧床所造成的褥疮或压疮、糖尿病人的伤口溃疡、末梢血管阻塞的肢体坏疽、动脉或静脉障碍所引起的溃疡、癌症病人的不愈伤口、急性伤口感染所引起的慢性愈合不良等等。
类叶升麻苷(acteoside)存在于中草药的一种活性成分，具有脂肪酶抑制功效，已知具有抗菌、抗发炎、抗病毒、抗氧化、神经保护等活性。
类叶升麻苷被报导为有效的抗微生物成分，已知对于金黄葡萄球菌(Staphylococcus aureus)具有良好的抗菌功效(Guillermo等人，1999，Journal of Ethnopharmacology 66(1)：75-8)。类叶升麻苷亦具有良好的抗发炎效果(Speranza等人，2009，Journal of biological regulators and homeostatic agents 23(3)：189-95.)。此外，2016年01月06日公告的中国专利授权公告第103816169B号，揭示类叶升麻苷可用于制备防治血管性痴呆，对低糖低氧造成的细胞缺血缺氧具保护和治疗作用。又，2016年01月16日公开的中国台湾专利公开号第201601739号，提供一种桂花萃取物的制备方法，以类叶升麻苷为主要活性成分，具有抗氧化、皮肤保养、抗微生物及抗发炎等功效。但并未有任何报导可用于治疗慢性伤口愈合。
发明内容
本发明提供一种新颖的组合物，其具有慢性伤口愈合功效，主要由下列三组分组成：(1)一种抗发炎剂，选自类叶升麻苷、异类叶升麻苷及其组合组成的群，(2)一种收敛剂，选自没食子酸、次没食子酸、其盐类及其组合组成的群，以及(3)一种清凉剂，选自龙脑、薄荷脑及其组合组成的群，并视需要与一种或以上医药上可接受的载剂组合。
另一方面，本发明提供此组合物用于制备治疗慢性伤口药剂的用途。
根据本发明的一实施例，慢性伤口指糖尿病伤口。
根据本发明的一实施例，其中三组分的当量配比为(1)抗发炎剂：(2)收敛剂：(3)清凉剂为1:0.1-10:0.1-10。
根据本发明的一较佳实施例，其中三组分的当量配比为(1)抗发炎剂：(2)收敛剂：(3)清凉剂为1:0.5-5:0.5-5。
根据本发明的一特定实施例，其中三组分的当量配比为(1)抗发炎剂：(2)收敛剂：(3)清凉剂为约1:1:1。
根据本发明的实施例，其中该抗发炎剂为具有下列式I结构的类叶升麻苷或其异构物：
Figure PCTCN2020118933-appb-000001
根据本发明的实施例，其中该收敛剂为具有下列式II结构的没食子酸：
Figure PCTCN2020118933-appb-000002
根据本发明的实施例，其中该收敛剂为没食子酸或次没食子酸的盐类，较佳为铋盐。
根据本发明的最佳实施例，其中该收敛剂为具有下列式IIa结构的次没食子酸铋：
Figure PCTCN2020118933-appb-000003
根据本发明的实施例，其中该清凉剂为具有下列式IIIa结构的龙脑：
Figure PCTCN2020118933-appb-000004
根据本发明的实施例，其中该清凉剂为具有下列式IIIb结构的薄荷脑：
Figure PCTCN2020118933-appb-000005
再一方面，本发明提供一种具有治疗慢性伤口愈合功效的医药组合物，主要由下列三组分组成：(1)类叶升麻苷，(2)次没食子酸铋，以及(3)龙脑，并视需要与一种或以上医药上可接受的载剂组合。
根据本发明，其中该医药组合物中三组分的当量配比为(1)类叶升麻苷：(2)次没食子酸铋：(3)龙脑为1:0.1-10:0.1-10；较佳为1:0.5-5:0.5-5。
根据本发明的一实施例，其中该医药组合物中三组分的当量配比为(1)类叶升麻苷：(2)次没食子酸铋：(3)龙脑为约1:1:1。
根据本发明，该医药组合物包含重量比(1)0.05％-10％的类叶升麻苷，(2)0.05％-10％的次没食子酸铋，及(3)0.02％-5％的龙脑，以及医药上可接受载体。
本发明的这些及其它方面，可藉由以下的较佳具体实施例的描述以及图式，得以更为明晰；即便其中可能会有变化或修饰，但不背离 本发明所揭示的新颖观念的精神及范畴。
附图说明
前文所述以及实施方式可通过附图达到更好的说明效果。为了加强本发明的说明，将适当的实施例的图式列举于此。
图1显示本发明组合物针对高糖(20mM)环境培养HaCaT细胞48小时促进细胞增生的结果(Con:对照组；A 16.0μM；BO 18.8μM；BSG 14.2μM；BO 18.8μM+A 16.0μM；BSG 14.2μM+A 16.0μM；BO 18.8μM+BSG 14.2μM；All(A 16.0μM+BO 18.8μM+BSG 14.2μM)；*显示差异显著，p<0.05)。
图2显示本发明组合物(All,A 16.0μM+BO 18.8μM+BSG 14.2μM)针对低糖(5mM)与高糖(25mM)环境培养HaCaT细胞48小时细胞增生的比较，*显示差异显著，p<0.05(5:5mM葡萄糖；25:25mM葡萄糖；5+All:5mM葡萄糖并添加本发明组合物(A 16.0μM+BO18.8μM+BSG 14.2μM)；；25+All:25mM葡萄糖并添加本发明组合物(A 16.0μM+BO 18.8μM+BSG 14.2μM))。
图3A显示本发明组合物(All)与对照组等于高糖(25mM)环境培养HaCaT细胞48小时细胞迁移的影像(Con:对照组；BO 18.8μM；BSG 14.2μM；BO 18.8μM+A 16.0μM；BSG 14.2μM+A 16.0μM；BO 18.8μM+BSG 14.2μM；All(A 16.0μM+BO 18.8μM+BSG 14.2μM))。
图3B显示本发明组合物(All)与对照组等于高糖(25mM)环境培养HaCaT细胞48小时，以对造组组胞细胞为1.0，相对于其他实验组胞细胞增生比的比较(Con:对照组；A 16.0μM；BO 18.8μM；BSG 14.2μM；BO 18.8μM+A 16.0μM；BSG 14.2μM+A 16.0μM；BO 18.8μM+BSG 14.2μM；All(A 16.0μM+BO 18.8μM+BSG 14.2μM))。
图4显示本发明组合物与对照组对HDF细胞以IL-1β处理测定Collagen III、MMP-1、Collagen I、TFG-β等蛋白浓度变化的比较。
图5显示病例1(糖尿病及中风病人，男，77岁)伤口愈合过程，第0天伤口大小为4cm x 3cm x 0.5cm(A)，第18天伤口明显开始收口(B)，第33天伤口为1.5cm x0.5cm x 0.2cm(图C)，第79天伤口完全愈合(D)。
图6显示病例2(糖尿病及中风病人，男，77岁)伤口愈合过程，第0天伤口大小为15cm x 11cm x 2cm(A)，第75天伤口为5.5cm x11cm x1cm(B)，第103天伤口为3cm x2cm x0.5cm(C)，第140天伤口完全 愈合(D)。
图7显示病例3(糖尿病及肺癌病人，女，82岁)，第0天伤口大小为2.5cm x 1cm x 0.5cm(A)，第17天伤口为1.5cm x1cm x 0.2cm(B)，第90天伤口完全愈合(C)。
具体实施方式
本发明说明中的用词通常具有在本技术领域中、在本发明内容中、及各用语所在的特定内容中的原始意义。
本文所使用的「一」一词，如未特别指明，是指至少一个(一个或一个以上)的数量。
于本文中所使用的名词「慢性伤口」指伤口在经过合宜治疗经一预定的时间后，仍无法达到一般伤口结构上和外观上的愈合。慢性伤口种类包括长期卧床所造成的褥疮或压疮、糖尿病伤口溃疡、末梢血管阻塞的肢体坏疽、动脉或静脉障碍所引起的溃疡、癌症病人的不愈伤口、急性伤口感染所引起的慢性愈合不良。根据本发明，本发明组合物显示对于慢性伤口的皮肤症状伤口具有愈合的效果，尤其是对糖尿病伤口特别有效。
于本文中所使用的名词「治疗」，包括「处理」或「促进」的意思，意指改善症状。
于本文中所使用的名词「患者」包含人类、及动物，特别是哺乳动物。
于本文中所使用的名词「医药上可接受的载剂」指一般医药上常用的技术可用于制备医药组合物的稀释剂、赋形剂及其类似物。根据本发明，可调制成药品、化妆品或医药材料的形式。根据本发明，可制成局部方式涂敷的形式，例如，喷雾形式。喷雾形式包含喷剂及液剂；或半固体或固体形式，较佳为具有动态黏度大于水者的固体形式。适当配方包括但不限于悬浮液、乳化液、乳膏、软膏、擦剂等。较佳者，呈软膏形式。本发明医药组合物不论呈何种形式，亦可含有润肤剂、香料或颜料，以提高其对于各种用途的可接受性。
于本文中所使用的名词「治疗有效量」，意指在症状处理上可有效治疗伤口的剂量。可依患者或伤口之需，依一般医药上常用的技术或临床知识使用适当剂量，并可依照施予的方式及治疗的情况，包括年龄、体重、症状、治疗效果、施用方式及治疗时间调整。
本发明提供一种具有慢性伤口愈合功效的组合物，主要由下列三 组分组成：(1)一种抗发炎剂，选自类叶升麻苷、异类叶升麻苷及其组合组成的群，(2)一种收敛剂，选自没食子酸、次没食子酸、其盐类及其组合组成的群，以及(3)一种清凉剂，选自龙脑、薄荷脑及其组合组成的群，并视需要与一种或以上医药上可接受的载剂组合。本发明亦提供此组合物用于制备治疗慢性伤口药剂的用途，尤指糖尿病伤口。
根据本发明的实施例显示，本发明组合物对于高糖环境下培养的细胞增生及迁移具有显著的增进功效，但单一组成分或任二组合则并无功效。尤其本发明组合物对于低糖环境培养相对并无增进功效，显示本发明组合物对于糖尿病伤口愈合的特殊功效，进一步可支持其慢性伤口愈合的功效。
根据本发明，可依一般传统技术制备适当含量的组合物，其中实施例可包括各成分的当量范围是：
(1)抗发炎剂：1；
(2)收敛剂：0.1-10；较佳为0.5-5。
(3)清凉剂：0.1-10；较佳为0.5-5。
根据本发明的一特定实施例，其中三组分的当量配比为(1)抗发炎剂：(2)收敛剂：(3)清凉剂为约1:1:1。
本发明议题提供一种具有治疗慢性伤口愈合功效的医药组合物，主要由下列三组分组成：(1)类叶升麻苷，(2)次没食子酸铋，以及(3)龙脑，并视需要与一种或以上医药上可接受的载剂组合。即如商标为糖足乐7 TM(NuDFC7 TM)尚未上市的商品。
根据本发明，其中该医药组合物中三组分的当量配比为(1)类叶升麻苷：(2)次没食子酸铋：(3)龙脑为1:0.1-10:0.1-10；较佳为1:0.5-5:0.5-5。其中的特定实施例为约1:1:1。
根据本发明，其中该医药组合物包含重量比(1)0.05％-10％类叶升麻苷，(2)0.05％-10％的次没食子酸铋，(3)0.02％-5％的龙脑，以及医药上可接受载体。
根据本发明的一实施例，其中该医药组合物包含重量比(1)0.1％-5％的类叶升麻苷，(2)0.06％-6％的次没食子酸铋，及(3)0.03％-3％的龙脑，以及医药上可接受载体。
根据本发明的一较佳实施例，其中该医药组合物包含(1)0.3％-5％的类叶升麻苷，(2)0.5％-5％的次没食子酸铋，及(3)0.5％-1％的龙脑，以及医药上可接受载体。
根据本发明，其中该组合物可包含一适当赋形剂而制成外用药剂 形式、化妆品形式或医药材料形式的组合物。
根据本发明，其中该组合物尚包含一治疗剂，例如其他抗发炎剂、抗菌剂或其他治疗药剂。
以上述发明说明以及下列实施例说明本发明，但并非用以限制本发明的范围。
实施例
药剂：(1)类叶升麻苷(Acteoside,以A为代号)：购自美国Sigma-Aldrich(St.Louis,MO,USA)。
(2)次没食子酸铋(Bismuth subgallate,以BSG为代号)：美国Sigma-Aldrich(St.Louis,MO,USA)。
(3)龙脑(Borneal,以BO为代号)：美国Sigma-Aldrich(St.Louis,MO,USA)。
根据本发明可依下列组成制备组合物：
Figure PCTCN2020118933-appb-000006
进行以下细胞实验的本发明组合物各组分含量为：
(1)类叶升麻苷(A)16.0μM(0.01μg/μl)，即0.1％；
(2)次没食子酸铋(BSG)14.2μM(0.0056μg/μl)，即0.056％；及
(3)龙脑(BO)18.8μM(0.0029μg/μl)，即0.029％。
细胞培养(Cell culture)：
将人类皮肤原纤细胞(human dermal fibroblast,HDF cells)或皮肤角质细胞(human keratinocytes,HaCaT cells)，培养于37℃的潮湿培养箱中，在空气为5％二氧化碳及95％氧气的环境下，放置在Dulbecco氏修饰Eagle培养基(DMEM)中，并添加葡萄糖、10％胎牛血清、100IU/mL盘尼西林、100μg/mL链霉素、2mM丙酮酸钠和1％非必须胺基酸(NEAA)。该培养基每两天更换一次。进行继代培养时，在以0.1％胰蛋白酶(Trypsin)-EDTA混合液作用后，收集细胞并以1:10的比例稀释重新培养。使用于研究中的细胞，代数介于12至40代之间。在以药物处理前24小时，开始种植细胞并放置24小时。对照组维持于培养基并添加药物。在此培养条件下，不影响细胞生长与分化。
实例1细胞生长分析(Cell Proliferation Assay)
以HaCaT细胞3 X 10 5培养于标添加25mM的葡萄糖，培养于12孔的培养皿培养48小时。细胞生长及存活状态以CCK-8试剂套组(Dojindo Molecular Technologies,Kumamoto,Japan)进行分析，在每格中加入5μL CCK-8溶液并于37℃下培养一小时，再用分亮度计Microplate reader(SpectraMax,Molecular Device,USA)测定450nm吸收，样本与对照组数值相比进行实验结果分析。测试的实验组包括：
(1)Con:对照组；
(2)A 16.0μM；
(3)BO 18.8μM；
(4)BSG 14.2μM；
(5)BO 18.8μM+A 16.0μM；
(6)BSG 14.2μM+A 16.0μM；
(7)BO 18.8μM+BSG 14.2μM；
(8)All(A 16.0μM+BO 18.8μM+BSG 14.2μM)。
培养48小时候的细胞增生结果如图1，显示本发明组合物(All；A16.0μM+BO 18.8μM+BSG 14.2μM)最佳，提供不可预期的显著促进细胞增生功效(p<0.05)，但单一组成分则无效果，或任二者的组合效果不如三者的组合。
实例2低糖与高糖环境细胞培养分析比较(Comparison in Cell Proliferation Assay)
以HaCaT细胞3 X 10 5培养于添加5mM、25mM的葡萄糖，培养于12孔的培养皿48小时，添加本发明组合物(All:A 16.0μM+BO 18.8μM+BSG 14.2μM)观察其细胞增生状况。
培养48小时候的细胞增生结果如图2，显示本发明组合物(A16.0μM+BO 18.8μM+BSG 14.2μM)对高糖培养(25mM)的细胞增长有显著的相乘增进功效，但对低糖(5mM)的细胞增生并无显著促进功效。
实例3细胞迁移分析(Cell Migration Assay)
以HaCaT细胞1 X 10 5培养于添加25mM的葡萄糖，培养于24孔的培养皿48小时，添加如下列的药物，观察其细胞迁移状态：
Con:对照组；
BO 18.8μM+A 16.0μM；
BSG 14.2μM+A 16.0μM；
BO 18.8μM+BSG 14.2μM；
All:A 16.0μM+BO 18.8μM+BSG 14.2μM。
48小时培养后的各组细胞迁移结果影像如图3A，并以对照组结果为1，与其他组比较如图3B，显示本发明组合物(A 16.0μM+BO 18.8μM+BSG 14.2μM)对高糖培养(25mM)的细胞迁移有促进功效，但BO18.8μM、BSG 14.2μM、或三组分的任二组合则无促进功效，可推知本发明组合物对于糖尿伤口愈合具有不可预期的治疗效果，并进一步支持其慢性伤口愈合的效果。
实例4发炎反应实验分析
抑制IL-1β诱导的发炎反应分析
培养的HDF细胞(1 X 10 5/well)，添加细胞发炎因子IL-1β(10ng/mL)以评估这些药物抑制IL-1β诱导发炎的情形。细胞培养于24孔的培养皿48小时，并同时添加如下列的药物，观察细胞在发炎状态影响蛋白质表达的情形，这些蛋白质包含受发炎状态而上调的基质金属蛋白酶(如MMP-1或MMP-9)；以及受发炎而下调的TGF-β因子以及其下游信息路径所控制的胶原蛋白(collagen I或Collagen 9)的表达：
Con:对照组(无IL-1β处理)；
Con:对照组(IL-1β处理)；
BO:18.8μM；
BSG:14.2μM；
A:16.0μM
BO+A:BO 18.8μM+A 16.0μM；
BSG+A:BSG 14.2μM+A 16.0μM；
BO+BSG:BO 18.8μM+BSG 14.2μM；
All:BO 18.8μM+BSG 14.2μM+16.0μM。
其结果如图4，显示各组分及其组合对于添加IL-1β诱导发炎反应下，不同组分的组合个蛋白质分泌量的影响，显示三组分的组合对于TGF-β因子以及其下游的胶原蛋白(Collgen I和Collgen III)有明显的促进功效，并对受发炎诱导的MMP-1具有明显的抑制功效，显示三组分的组合对于伤口愈合的功效远优于任一组分或其二组分的组合。
实例5人体临床结果
将本发明组合物(A 16.0μM+BO 18.8μM+BSG 14.2μM)对不同病人进行每日敷药，观察伤口愈合情形，三位病人伤口愈合的结果如图5、6和7。并整理结果如下。
(1)病例1
糖尿病及中风病人，男，77岁。经治疗，左脚跟伤口愈合过程照片如图5，第0天原伤口大小为4cm x 3cm x 0.5cm(A)，经治疗第18天伤口明显开始收口(B)，第33天伤口缩小为1.5cm x0.5cm x 0.2cm(C)，第79天伤口完全愈合(D)，显示本发明组合物对于糖尿病伤口有明显的治疗效果。
(2)病例2
糖尿病病人，男，77岁。经治疗，右脚跟伤口愈合过程照片如图6，第0天原伤口大小为15cm x 11cm x 2cm(A)，经治疗第75天伤口缩小为5.5cm x11cm x1cm(B)，第103天伤口愈合，伤口大小为3cm x2cm x0.5cm(C)，第140天伤口完全愈合(D)，显示本发明组合物对于糖尿病伤口有明显的治疗效果，持续治疗中。
(3)病例3
糖尿病及肺癌病人，女，82岁，长期卧床有褥疮。经治疗，伤口愈合过程照片如图7，第0天原伤口大小为2.5cm x 1cm x 0.5cm(A)，经治疗第17天伤口明显开始收口，伤口缩小为1.5cm x1cm x 0.2cm(B)，第90天伤口完全愈合(C)，显示本发明组合物对于褥疮有明显的治疗效果。
虽然本发明以较佳实施例披露如上，然其并非用以限定本发明，任何熟习本发明技术者，当可在不脱离本发明的精神和范围内，作些许的更动与润饰，则应属本发明权利要求所界定的保护范围。

Claims (15)

  1. 一种具有慢性伤口愈合功效的医药组合物，主要由下列三组分组成：(1)一种抗发炎剂，选自类叶升麻苷、异类叶升麻苷及其组合组成的群，(2)一种收敛剂，选自没食子酸、次没食子酸、其盐类及其组合组成的群，以及(3)一种清凉剂，选自龙脑、薄荷脑及其组合组成的群，并视需要与一种或以上医药上可接受的载剂组合；其中该三组分的当量配比为(1)抗发炎剂：(2)收敛剂：(3)清凉剂为1:0.1-10:0.1-10。
  2. 如权利要求1所述的医药组合物，其中该慢性伤口为糖尿病伤口。
  3. 如权利要求1所述的医药组合物，其中该三组分的当量配比为(1)抗发炎剂：(2)收敛剂：(3)清凉剂为1:0.5-5:0.5-5。
  4. 如权利要求1所述的医药组合物，其中该抗发炎剂为类叶升麻苷或其异构物。
  5. 如权利要求1所述的医药组合物，其中该收敛剂为没食子酸或次没食子酸的盐类。
  6. 如权利要求5所述的医药组合物，其中该盐类为铋盐。
  7. 如权利要求1所述的医药组合物，其中该收敛剂为次没食子酸铋。
  8. 如权利要求1所述的医药组合物，其中该清凉剂为龙脑或薄荷脑。
  9. 如权利要求1所述的医药组合物，其中该组合物的三组分为(1)类叶升麻苷，(2)次没食子酸铋，及(3)龙脑。
  10. 如权利要求9所述的医药组合物，其包含重量比(1)0.05％-10％类叶升麻苷，(2)0.05％-10％的次没食子酸铋，(3)0.02％-5％的龙脑，以及医药上可接受载体。
  11. 如权利要求10所述的医药组合物，其包含重量比(1)0.1％-5％类叶升麻苷，(2)0.06％-6％的次没食子酸铋：(3)0.03％-3％的龙脑，以及医药上可接受载体。
  12. 如权利要求11所述的医药组合物，其包含重量比(1)0.3％-5％的类叶升麻苷，(2)0.5％-5％的次没食子酸铋，及(3)0.5％-1％的龙脑，以及医药上可接受载体。
  13. 一种如权利要求1或9中任一项所述的组合物用于制备治疗慢性伤口药剂的用途。
  14. 如权利要求13所述的用途，其中该慢性伤口为糖尿病伤口。
  15. 如权利要求1所述的医药组合物，另包含一适当赋形剂而制成外用药剂形式、化妆品形式或医药材料形式。
PCT/CN2020/118933 2019-12-06 2020-09-29 慢性伤口愈合组合物及其应用 WO2021109704A1 (zh)

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EP20895228.3A EP4070798A4 (en) 2019-12-06 2020-09-29 COMPOSITION FOR HEALING CHRONIC WOUNDS AND USE THEREOF
MX2022006884A MX2022006884A (es) 2019-12-06 2020-09-29 Composicion para cicatrizacion de heridas cronicas y aplicaciones de la misma.
AU2020397401A AU2020397401A1 (en) 2019-12-06 2020-09-29 Chronic wound healing composition and application thereof
BR112022010966A BR112022010966A2 (pt) 2019-12-06 2020-09-29 Composição farmacêutica com eficácia para promover a proliferação e migração celular, promover a expressão de colágeno e melhorar a cicatrização, e, uso de uma composição farmacêutica
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CA3168280A CA3168280A1 (en) 2019-12-06 2020-09-29 Chronic wound healing composition and application thereof
JP2022534305A JP7551752B2 (ja) 2019-12-06 2020-09-29 慢性創傷治癒組成物およびその適用
US17/782,348 US20230059230A1 (en) 2019-12-06 2020-09-29 Chronic wound healing composition and application thereof
TW110136366A TW202228667A (zh) 2019-12-06 2021-09-29 慢性傷口癒合之二組分組合物
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