WO2019241985A1 - Hydrogel, composition pharmaceutique le comprenant et son application - Google Patents

Hydrogel, composition pharmaceutique le comprenant et son application Download PDF

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Publication number
WO2019241985A1
WO2019241985A1 PCT/CN2018/092325 CN2018092325W WO2019241985A1 WO 2019241985 A1 WO2019241985 A1 WO 2019241985A1 CN 2018092325 W CN2018092325 W CN 2018092325W WO 2019241985 A1 WO2019241985 A1 WO 2019241985A1
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hydrogel
fgf
kgf
poloxamer
gel
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PCT/CN2018/092325
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English (en)
Chinese (zh)
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王晓杰
李校堃
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温州医科大学
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Priority to PCT/CN2018/092325 priority Critical patent/WO2019241985A1/fr
Priority to CN201880094459.9A priority patent/CN112512504A/zh
Publication of WO2019241985A1 publication Critical patent/WO2019241985A1/fr
Priority to AU2020100021A priority patent/AU2020100021A4/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • 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
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like

Definitions

  • the present invention belongs to the field of pharmaceutical preparations, and in particular, the present invention relates to a hydrogel and a pharmaceutical composition containing the same, and uses for treating diabetes-related concurrent injuries.
  • ROS activates inflammatory cells and produces excessive inflammatory factors, leading to prolonged inflammatory reactions.
  • the accumulation of inflammatory exudates destroys the wound microenvironment and causes cell damage (Nelson, CMand MJBissell. Of extracellular matrix, scaffolds, and signaling: architecture, developments, homeostasis, and cancer.Annu Rev Cell Dev. Biol 2006, 22: 287-309).
  • Excessive ROS also stimulates the intracellular signal cascade, regulates the expression of apoptosis-related genes, and induces excessive apoptosis (He, P., W. Mao, H. Zhang, et al.
  • Chinese patent applications CN1234071A and CN1372569A disclose a keratinocyte growth factor-2 (KGF-2) for promoting or accelerating wound healing; for example, Chinese patent Application CN104258456A discloses a wound repair gel containing hexagonal mesoporous silicon, which includes FGF-21 and a large number of auxiliary ingredients.
  • KGF-2 keratinocyte growth factor-2
  • Chinese patent application CN105708722 discloses a complex growth factor skin care gel, which includes a factor composition that promotes skin cell growth.
  • the composition includes EGF, bFGF and KGF;
  • Chinese patent application CN101417121A discloses a medicine for treating skin burns and frostbite, which includes a large number of complex components, including epidermal cell growth factor, fibroblast growth factor, keratinocyte growth factor, vascular endothelial growth Factors and cellular immune factors.
  • the wounds complicated by diabetes are more complicated and more difficult to treat than the common wounds.
  • the growth factor activity decreases, but also the relative or absolute number of growth factor receptors.
  • the deficiency is also the physiological and physiological basis for the difficult healing of diabetic skin ulcers (Rathsman, B., K. Jensen-Urstad, and T. Nystrom. Intensified Insulin treatment is associated with improvement, and ischaemic, and ischaemic, foot, ulcer, and patients : a long-term follow-up study. Diabetologia 2014, 57 (8): 1703-10).
  • keratinocyte growth factor-2 KGF-2
  • FGF-21 fibroblast growth factor-21
  • the present invention provides a new hydrogel, which can be used to prepare a pharmaceutical composition for treating diabetes-induced concurrent injuries, especially a pharmaceutical composition suitable for use in the early stage of the treatment of the injury.
  • the present invention provides a hydrogel including poloxamer, glycerin, and water, and a mass ratio of the poloxamer and the glycerin is preferably (8: 1) ⁇ (36: 1), more preferably (11.3: 1) to (18: 1), and most preferably 17: 1.
  • the hydrogel according to the first aspect of the present invention wherein the concentration of poloxamer is preferably 16 to 18% (w / w), preferably 17 to 18% (w / w), such as 17% (w / w ).
  • the type of poloxamer is preferably poloxamer 407.
  • the hydrogel according to the first aspect of the present invention wherein the concentration of glycerin is preferably 0.5 to 2.0% (w / w), preferably 1.0 to 1.5% (w / w), such as 1.0% (w / w).
  • w / w refers to the mass percentage of poloxamer or glycerol in a hydrogel
  • the numerator represents the mass of poloxamer or glycerol
  • the denominator represents the mass of the hydrogel
  • the hydrogel according to the first aspect of the present invention may further include heparin sodium, and the concentration of the heparin sodium is preferably 10 to 40 ⁇ g / ml, more preferably 15 to 25 ⁇ g / ml, such as 20 ⁇ g / ml.
  • the hydrogel according to the first aspect of the present invention is preferably composed of 16 to 18% (w / w) poloxamer, 10 to 40 ⁇ g / ml sodium heparin, 0.5 to 2.0% (w / w) glycerol, and Water composition; further preferably, it consists of 17-18% (w / w) poloxamer, 15-25 ⁇ g / ml sodium heparin, 1.0-1.5% (w / w) glycerol and water; more preferably, it Consists of 17% (w / w) poloxamer, 20 ⁇ g / ml sodium heparin, 1.0% (w / w) glycerol and water.
  • the preparation method of the hydrogel according to the first aspect of the present invention may be a conventional preparation method in the art, such as a cold solution stirring method.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an active ingredient and the aforementioned hydrogel, wherein the active ingredient is preferably an active ingredient for treating concurrent damage to diabetes, and more preferably KGF-2 and / or FGF-21.
  • the pharmaceutical composition according to the second aspect of the present invention wherein the concentration of KGF-2 is preferably 25 to 100 ⁇ g / ml, more preferably 40 to 60 ⁇ g / ml, such as 50 ⁇ g / ml.
  • the pharmaceutical composition according to the second aspect of the present invention wherein the concentration of FGF-21 is preferably 200 to 700 ⁇ g / ml, more preferably 350 to 400 ⁇ g / ml, such as 375 ⁇ g / ml.
  • the pharmaceutical composition according to the second aspect of the present invention is preferably composed of KGF-2, FGF-21, poloxamer, sodium heparin, glycerol, and water; further preferably, it is composed of 25-100 ⁇ g / ml KGF -2, 200-700 ⁇ g / ml FGF-21, 16-18% (w / w) poloxamer, 10-40 ⁇ g / ml sodium heparin, 0.5-2.0% (w / w) glycerol and water; more preferred Specifically, it consists of 40 to 60 ⁇ g / ml KGF-2, 350 to 400 ⁇ g / ml FGF-21, 17 to 18% (w / w) poloxamer, 15 to 25 ⁇ g / ml sodium heparin, 1.0 to 1.5% (w / w) glycerol and water; most preferably, it consists of 50 ⁇ g / ml KGF-2, 375 ⁇ g /
  • the preparation method of the pharmaceutical composition according to the second aspect of the present invention may be a conventional preparation method in the art, such as mixing the pharmaceutical composition to obtain a coagulated gel.
  • the present invention provides the hydrogel of the first aspect of the present invention and the pharmaceutical composition of the second aspect, which are used in the preparation of a medicament for treating concurrent damage to diabetes, preferably in the initial stage of the treatment of concurrent damage to diabetes Used drugs.
  • the present invention provides a method for treating concurrent damage of diabetes, comprising the step of applying the pharmaceutical composition of the second aspect of the present invention to a wound surface of a diabetic patient.
  • the present invention provides a composition for preparing a hydrogel comprising 17% (w / w) poloxamer 407, 20 ⁇ g / ml sodium heparin, 1.0% (w / w) glycerol and water composition.
  • the present invention provides a pharmaceutical composition for treating (especially, initial treatment) diabetic concomitant injury, its therapeutic or pharmaceutical application, an excipient composition therein, and the like.
  • a second aspect of the present invention provides a pharmaceutical composition for treating diabetes-induced concurrent injuries, wherein the active ingredient consists of KGF-2 and FGF-21.
  • the active ingredient consists of KGF-2 and FGF-21.
  • FGF-21 fibroblast growth factor-21
  • the FGF-21 in the hydrogel of the present invention is human FGF-21 (its gene sequence accession number is AB021975.1), and the FGF-21 may be produced by recombinant DNA technology, That is, recombinant human FGF-21.
  • Keratinocyte growth factor-2 (KGF-2) is a basic protein growth factor secreted by human subcutaneous tissue cells, which can specifically stimulate the physiological processes of epithelial cells, including cell regeneration, differentiation, and migration. Although there are many growth factors (eg, EGF, bFGF, aFGF, TGF, VEGF, PDGF, etc.) that can play a similar role, the hydrogel of the present invention uses KGF-2 as an active ingredient that complements FGF-21. In a specific embodiment of the present invention, the hydrogel of the present invention uses human KGF-2 (its gene sequence accession number: NM-004465.1). The KGF-2 can be produced by recombinant DNA technology, and recombinant human KGF -2.
  • hydrogels of the present invention use poloxamer 407, heparin sodium, glycerol and water as the excipients.
  • Poloxamer is a polyoxyethylene polyoxypropylene ether block copolymer, which is a high molecular non-ionic surfactant.
  • Heparin sodium is preferably enoxaparin sodium.
  • the hydrogel of the present invention uses poloxamer 407, which is formulated with glycerin and heparin sodium (eg, enoxaparin sodium) to form an excipient composition.
  • the auxiliary material of the hydrogel of the present invention has few ingredients and is easy to control costs.
  • the most preferred excipient is 17% (w / w) poloxamer 407, 20 ⁇ g / ml sodium heparin, 1.0% (w / w).
  • the hydrogel prepared by the auxiliary material composition has a gelling temperature suitable for being applied on the body surface, has good moisturizing property, and has good sustained-release properties.
  • the hydrogel of the present invention is used to treat the concurrent damage of diabetes, that is, the trauma caused on the skin of diabetic patients, including diabetic ulcers and burns, frostbite, mechanical violent injuries, chemical corrosion injuries, etc. Diabetic concomitant injuries are more difficult to heal and more difficult to treat than conventional injuries, and the hydrogel of the present invention can effectively treat this injury.
  • the pharmaceutical composition of the aqueous gel of the present invention can be a therapeutic drug for the concurrent damage of diabetes, that is, it can be used for treatment after the concurrent damage of diabetes appears.
  • the initial stage of the treatment of diabetic concomitant injury refers to the 0th to 14th days after the treatment of the diabetic concomitant injury, preferably the 0th to 10th day, such as the 0th to 7th day.
  • the hydrogel of the present invention uses KGF-2 and FGF-21 in combination, and in the early stage of the treatment of diabetic concomitant injury, the wound healing speed is significantly faster than a hydrogel loaded with KGF-2 or FGF-21 alone.
  • FGF-21 in the hydrogel-containing pharmaceutical composition of the present invention can regulate blood glucose through the wound in the early stage of the treatment of diabetes concurrent injuries, and effectively regulate the expression of inflammatory factors. Therefore, the hydrogel of the present invention is more advantageous in the early stage of the treatment of diabetes concurrent injuries.
  • the pharmaceutical composition of the aqueous gel of the present invention also has good curative effect after the initial stage of the treatment of diabetic concomitant injury, but the advantage is not as significant as that of the early use of the concomitant treatment of diabetes. Therefore, the hydrogel-containing pharmaceutical composition of the present invention can be used in the early stage of the treatment of diabetic concomitant injury, and replaced by other hydrogels with lower cost after the initial stage of the treatment of diabetic concomitant injury, such as only loading KGF-2 or FGF alone -21 hydrogel.
  • a hydrogel loaded with KGF-2 or FGF-21 alone is a hydrogel obtained by omitting only FGF-21 or KGF-2 in the hydrogel formulation of the present invention.
  • the hydrogel of the present invention can be used throughout the treatment period of diabetes-induced concurrent injuries.
  • a diabetic patient is a mammal, preferably a human, with diabetes.
  • experimental animal models are used to test the hydrogels of the invention.
  • the use manner of the hydrogel of the present invention is to be applied on the wound surface of a diabetic patient, especially to completely cover the wound surface of a diabetic patient.
  • the advantages of the hydrogel of the present invention are based on the combined application of FGF-21 and KGF-2, as well as the excellent properties of the excipient composition.
  • the hydrogel of the first aspect of the present invention is an intermediate product of the pharmaceutical composition of the second aspect of the present invention, but it is not limited to being only an intermediate product of the pharmaceutical composition of the second aspect of the present invention.
  • the hydrogel can also be used to load other active ingredients.
  • the beneficial effect of the present invention is that the hydrogel of the present invention can effectively treat the concurrent damage of diabetes, especially in the early stage of the treatment of the concurrent damage of diabetes. It has fewer types of active ingredients and excipients, stable quality and easy cost control.
  • the present invention refers to public documents, which are used to describe the present invention more clearly, and the entire contents thereof are incorporated herein by reference, as if their entire texts have been repeatedly described herein.
  • Figure 1 shows the release rate of vitamin B6 from hydrogels of different concentrations, where the abscissa is time, the ordinate is the percentage of cumulative release, NS is normal saline, and each concentration is the corresponding concentration of hydrogel.
  • Figure 2 shows a photograph of the skin wound of a GK rat burn model.
  • Figure 3 shows blood glucose measurements after GK rats were treated with different hydrogels, where the abscissa is time and the ordinate is blood glucose level. Compared with the KGF-2 treatment group, *: P ⁇ 0.05; **; P ⁇ 0.01.
  • Figure 4 shows the construction of wound tissue in each group of GK rats.
  • Figure a HE staining map, specifically including HE staining maps at 7d, 14d, 25d, and 31d after scald. Including global map (40x left) and enlarged map (100x right);
  • Figure b Masson staining chart, including Masson staining chart at 7d, 14d, 25d, and 31d after scald, in which the coloring chart of each day is in each group They include global (left 40x) and enlarged (100x right).
  • Figure 7 shows a-SMA and pan-keratin immunofluorescence results (31d), where a: a-SMA immunofluorescence staining (100x), a-SMA indicates the positive area after a-SMA staining, and DAPI indicates DAPI staining Post-live cell area, Merge indicates that the positive area after a-SMA staining is combined with the live-cell area after DAPI staining;
  • Figure c pan-keratin immunofluorescence staining Figure (100x), pan-keratin indicates the positive area after pan-keratin staining, DAPI indicates the living cell area after DAPI staining, and Merge indicates that the positive area after pan-keratin staining is combined with the living cell area after DAPI staining;
  • Hydrogels were prepared by cold-dissolving stirring methods with a mass concentration of 15.0%, 15.5%, 16.0%, 17.0%, and 18.0%.
  • Poloxamer 407 purchased from Xi'an Yuelai Biotechnology Co., Ltd.
  • hydrogel was used to determine the retention rate using an osmometer.
  • the quality of a 10 cm 2 petri dish in a precise urban area is precisely coated, and the test product prepared in Table 1 is evenly coated on the plane.
  • the total mass of the plane and the test product is accurately weighed every 1 h, and the mass difference between each weight loss is the mass of water loss. Calculate the ratio of water loss in 3h to the original mass as the water loss rate.
  • the gelation temperature and osmotic pressure of the unloaded hydrogel are shown in Tables 3 and 4, respectively.
  • the gelation temperature of the unloaded hydrogel decreases with increasing concentration, and its osmotic pressure increases with increasing concentration.
  • the properties of the unloaded hydrogel are equivalent to the properties of an unsterilized hydrogel with an increase of about 1%.
  • Hydrogels with a poloxamer mass concentration of 15.0% could not be gelled after cold dissolution, but gelation could be achieved after sterilization.
  • the osmotic pressure of 15.5% and 15.5% hydrogels are more suitable for in vivo use, considering the skin conditions, preliminary experiments on the body surface have found that 17.0% hydrogel characteristics are more suitable for body surface use.
  • Vb6 vitamin B6
  • 15.0%, 16.0%, 17.0%, and 18.0% poloxamer 407 hydrogel containing 20 ⁇ g / ml low molecular weight heparin sodium and 1.0% glycerol
  • the saline solution was placed in a 50 ml centrifuge tube, heated to 37 ° C until the gel solidified, then sealed with a 0.22 ⁇ m cellulose acetate membrane, poured into a large-caliber glass test tube containing 10 ml physiological saline, and placed in a 37 ° C constant temperature shaker Inside, spin at 120 rpm, measure 100 ⁇ l of the solution in the glass test tube every 1 h, add 100ul of physiological saline to the glass test tube, and measure the Vb6 content of the extraction solution with a UV spectrometer. Calculate the amount of Vb6 released. The total amount of original vitamins is the release of Vb6.
  • Example 3 Effect of the hydrogel containing KGF-2 and FGF-21 of the present invention on a diabetic scald model of GK rats
  • the hydrogel is composed of 17% (w / w) poloxamer 407, 20 ⁇ g / ml sodium heparin, 1.0% (w / w) glycerol, and water.
  • the method for preparing a hydrogel containing a pharmaceutically active ingredient is the same as in Example 2.
  • the concentration of the pharmaceutically active ingredient and the volume of the hydrogel are as follows.
  • GK Goto-Kakizaki
  • Rats were anesthetized with intraperitoneal injection of 10% chloral hydrate (dose 3.5ml / kg), fixed on the rat's fixed plate in a prone position, shaved off the hair on the center of the back, and locally disinfected with 75% alcohol to prepare a burn model.
  • the diameter of the scald wounds was 1.8mm at 1.0cm on each side of the spine.
  • the YLS-5Q scald instrument was used to scald a deep II degree scald wound with a diameter of 1.8cm on the back. 0.5kg for 12 seconds.
  • the skin ulcer wound administration time began on the day when the self-made surface was formed, and was administered in a single single dose per day for 7 days, 14 days, 25 days, and 31 days. According to 4 time points (7d, 14d, 25d and 31d), 6 animals at each time point (each time point: the control group and the KGF-2 Gel group are used in combination of 3 animals, the FGF-21 Gel group and the F21- K2 (Gel combination 3), a total of 24.
  • Photographs were taken on the burned skin at four times: 7d, 14d, 25d, and 31d after the model was made, and calibration was performed with a ruler. And calculate the healing rate at a time point, the formula is as follows:
  • 3 GK rats were randomly selected in each group, and the rats were anesthetized with 10% chloral hydrate at 0.4ml / 100g, and the skin of each treatment group was cut along the wound healing area with straight scissors. Cut in half, put 1/4 in a 1.5mlEp tube, mark it, and store it at -80 ° C; 1/4 in a 1.5mlEp tube, mark it, dehydrate it with a 20% sucrose solution overnight, and embed it in OCT embedding agent. Store at -80 °C in refrigerator.
  • Frozen sections are used for immunofluorescence staining (IF); the remaining 1/2 are fixed with 4% paraformaldehyde aqueous solution for later paraffin sections for HE, Masson and immunohistochemical staining (IHC) ).
  • IF immunofluorescence staining
  • IHC immunohistochemical staining
  • KGF-2 and FGF-21 hydrogels promote the healing rate of scalded skin wounds.
  • the combined use of KGF-2 and FGF-21 can speed up the healing rate in the early stage.
  • the results of healing rates of GK rat burn models in each group are shown in Table 7.
  • the healing speed of KGF-2, Gel, FGF-21, Gel, and F21-K2-Gel groups was faster than that of the control group (P ⁇ 0.05).
  • F21-K2-Gel group healed faster than FGF-21Gel group (P ⁇ 0.05).
  • the healing speed of the KGF-2, Gel, FGF-21, Gel, and F21-K2-Gel groups was faster than that of the control group (P ⁇ 0.05, P ⁇ 0.001); the healing speed of the F21-K2-Gel group was faster than that of KGF-
  • the 2Gel group was fast with statistical difference (P ⁇ 0.01).
  • n refers to the number of GK rats measuring the healing rate in each group and day.
  • FGF-21 hydrogel can make FGF-21 regulate the blood glucose of GK rats through the wound in the early stage
  • KGF-2 and FGF-21 hydrogels significantly improve the tissue construction of burn wounds
  • FGF-21 in the hydrogel can inhibit the expression of the pro-inflammatory factor IL-6 during the healing process of skin burns in GK rats. Expression, inhibits excessive inflammation in the wound; and, FGF-21 can increase the expression of post-inflammatory factor IL-10 in the early inflammatory phase, thereby promoting the progression of the inflammatory phase. Until 14 days, the skin wounds in the Control group and KGF-2 Gel group were still in the inflammatory phase.
  • KGF-2 and FGF-21 hydrogels promote the expression of Collagen III, and the combined use of KGF-2 and FGF-21 to promote the expression of Collagen III has a long-lasting effect and a good effect
  • KGF-2 and FGF-21 hydrogels had no significant effect on early expression of Collagen III in the wound, but as shown in Figure 6, at 25 days, compared with the Control group, the KGF-2 Gel group and the F21-K2-Gel group Collage III
  • the positive expression levels were significantly increased, and there was a statistical difference (P ⁇ 0.01), indicating that both groups could promote the expression of the collagen III protein in the extracellular matrix of scalded skin at 25 days; the control group and the FGF-21 Gel group at 25 days
  • P> 0.05 at 31 days, compared with the Control group, the positive expression of Collagen III in the KGF-2, Gel, FGF-21, and F21-K2-Gel groups Significantly increased, all with statistical differences (P ⁇ 0.001, P ⁇ 0.01, P ⁇ 0.001), indicating that the gel group can significantly promote the expression of collagen III protein in the extracellular matrix of scalded skin at the end of healing.
  • KGF-2 and FGF-21 hydrogels promote ⁇ -SMA and pan-keratin expression

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Abstract

L'invention concerne un hydrogel thermosensible pour le traitement d'une lésion compliquée du diabète, comprenant du KGF-2, du FGF-21, du poloxamère 407, de l'héparine sodique, de la glycérine et de l'eau. L'hydrogel est particulièrement approprié pour être utilisé au stade précoce de traitement de la lésion. De plus, l'invention concerne également une composition d'adjuvant pour préparer l'hydrogel, et analogue.
PCT/CN2018/092325 2018-06-22 2018-06-22 Hydrogel, composition pharmaceutique le comprenant et son application WO2019241985A1 (fr)

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PCT/CN2018/092325 WO2019241985A1 (fr) 2018-06-22 2018-06-22 Hydrogel, composition pharmaceutique le comprenant et son application
CN201880094459.9A CN112512504A (zh) 2018-06-22 2018-06-22 一种水凝胶、含其的药物组合物及其应用
AU2020100021A AU2020100021A4 (en) 2018-06-22 2020-01-07 Hydrogel, pharmaceutical composition comprising same, and application thereof

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CN113633756A (zh) * 2021-06-17 2021-11-12 温州医科大学 Fgf21温敏缓释载体和基因修饰方法以及其制备方法
CN114617839B (zh) * 2022-03-31 2023-07-07 温州医科大学 治疗冻结性冷损伤的凝胶搽剂及其制备方法

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