CN115068413A - Adriamycin hydrochloride/epirubicin hydrochloride sustained-release gel - Google Patents
Adriamycin hydrochloride/epirubicin hydrochloride sustained-release gel Download PDFInfo
- Publication number
- CN115068413A CN115068413A CN202210933631.3A CN202210933631A CN115068413A CN 115068413 A CN115068413 A CN 115068413A CN 202210933631 A CN202210933631 A CN 202210933631A CN 115068413 A CN115068413 A CN 115068413A
- Authority
- CN
- China
- Prior art keywords
- sustained
- release
- release gel
- hydrochloride
- drug
- 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.)
- Granted
Links
- 238000013268 sustained release Methods 0.000 title claims abstract description 37
- 239000012730 sustained-release form Substances 0.000 title claims abstract description 37
- MWWSFMDVAYGXBV-FGBSZODSSA-N (7s,9s)-7-[(2r,4s,5r,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydron;chloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-FGBSZODSSA-N 0.000 title claims abstract description 27
- 229960003265 epirubicin hydrochloride Drugs 0.000 title claims abstract description 27
- MWWSFMDVAYGXBV-RUELKSSGSA-N Doxorubicin hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-RUELKSSGSA-N 0.000 title claims abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 55
- 229940079593 drug Drugs 0.000 claims abstract description 48
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 21
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 21
- 229960002918 doxorubicin hydrochloride Drugs 0.000 claims abstract description 12
- 229920002873 Polyethylenimine Polymers 0.000 claims abstract description 9
- 108010039918 Polylysine Proteins 0.000 claims abstract description 9
- 229920000656 polylysine Polymers 0.000 claims abstract description 9
- 238000011065 in-situ storage Methods 0.000 claims abstract description 5
- 238000004132 cross linking Methods 0.000 claims abstract description 4
- 239000000243 solution Substances 0.000 claims description 22
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 125000003172 aldehyde group Chemical group 0.000 claims description 8
- 239000007853 buffer solution Substances 0.000 claims description 7
- 230000003073 embolic effect Effects 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 6
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 6
- 229920000858 Cyclodextrin Polymers 0.000 claims description 5
- 239000001116 FEMA 4028 Substances 0.000 claims description 4
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims description 4
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims description 4
- 229960004853 betadex Drugs 0.000 claims description 4
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 4
- 229920000053 polysorbate 80 Polymers 0.000 claims description 4
- 230000000259 anti-tumor effect Effects 0.000 claims description 3
- 230000002792 vascular Effects 0.000 claims description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 150000003934 aromatic aldehydes Chemical group 0.000 claims description 2
- 239000004202 carbamide Substances 0.000 claims description 2
- 238000012377 drug delivery Methods 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 239000003623 enhancer Substances 0.000 claims 1
- 150000002334 glycols Chemical class 0.000 abstract 1
- 239000000499 gel Substances 0.000 description 34
- 239000000017 hydrogel Substances 0.000 description 12
- 206010028980 Neoplasm Diseases 0.000 description 10
- 230000010102 embolization Effects 0.000 description 9
- 210000004204 blood vessel Anatomy 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 230000001737 promoting effect Effects 0.000 description 4
- 239000000654 additive Substances 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 230000010109 chemoembolization Effects 0.000 description 3
- 201000007270 liver cancer Diseases 0.000 description 3
- 208000014018 liver neoplasm Diseases 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 229940044683 chemotherapy drug Drugs 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 229960001904 epirubicin Drugs 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 239000004005 microsphere Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 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 description 1
- -1 F127 Substances 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 229910021538 borax Inorganic materials 0.000 description 1
- 150000001642 boronic acid derivatives Chemical group 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000003759 clinical diagnosis Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 238000009116 palliative therapy Methods 0.000 description 1
- 230000006320 pegylation Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000003014 reinforcing effect Effects 0.000 description 1
- 238000002271 resection Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 239000012890 simulated body fluid Substances 0.000 description 1
- 239000004328 sodium tetraborate Substances 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 239000007779 soft material Substances 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000005909 tumor killing Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- 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
- 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
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- 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
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
-
- 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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- 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
- A61K47/40—Cyclodextrins; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Inorganic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses doxorubicin hydrochloride/epirubicin hydrochloride sustained-release gel which is formed by in-situ crosslinking of polyethylene glycol derivatives, polyethyleneimine and polylysine. The gel can quickly load doxorubicin hydrochloride/epirubicin hydrochloride, and realizes slow release of the drug.
Description
Technical Field
The invention relates to the field of biological medicine, in particular to doxorubicin hydrochloride/epirubicin hydrochloride sustained-release gel.
Background
Hepatocellular carcinoma (HCC) is a high-incidence malignant tumor worldwide, seriously threatening human life health. Liver cancer has the characteristics of occult morbidity, high malignancy degree, rapid progress and the like, which causes that more than 75 percent of patients are in the middle and late stages in clinical diagnosis and lose the best time of surgical resection, only can select palliative therapies such as radiotherapy, chemotherapy, interventional therapy and the like, and the clinical response strategy is very limited. For the middle and late stage liver cancer patients, the interventional comprehensive treatment based on Transcatheter Arterial Chemoembolization (TACE) shows excellent anti-tumor curative effect, and gradually becomes an important treatment means for middle and late stage liver cancer in clinic at present. TACE is inserted into the blood-supply target artery of tumor selectively or super-selectively through a catheter, and a proper amount of embolic agent is injected to block the blood vessel of tumor, so that the ischemic necrosis of tumor tissue is caused, and the chemoembolization effect can be achieved by mixing the anti-cancer drug and the embolic agent for embolization.
The traditional transcatheter arterial chemoembolization is mainly characterized in that iodized oil and chemotherapeutics are mixed and injected, and gelatin sponge is used for reinforcing embolization, and the defects that the release speed of the drugs in an iodized oil emulsion is high, the concentration of the drugs for effectively killing tumors is difficult to maintain locally, and the systemic reaction is obvious; meanwhile, after partial tumor embolization, the iodine oil is fast in diffusion and difficult to completely embolize the tumor, so that the tumor killing effect is limited. The drug-loaded microspheres solve the problems of fast diffusion of the iodine oil and reduction of systemic reaction, increase of embolization effect, and still have the risks of blocking a catheter, ectopic embolization and incapability of completely embolizing a target blood vessel and recanalization of the blood vessel.
Therefore, the application of embolic materials in tumor therapy still faces significant challenges. Desirable characteristics of the embolic agent should include: (1) biocompatibility; (2) easy delivery; (3) biodegradability (depending on the application of the material); (4) visibility and traceability on common imaging modalities (e.g. CT, MRI); (5) the price is low. Generally, the dispersibility and catheter passability of liquid-gel embolization agents are incomparable with solid embolization agents such as microspheres. The new liquid-gel drug loaded embolic agents require a phase change of the material both at the time of administration (in the syringe and catheter) and after operation (in vivo), i.e. a lower viscosity is desired to pass through the delivery system, forming a more robust structure in the blood vessel according to the vascular structure to achieve embolization.
The hydrogel is a soft material containing a large amount of moisture, which is obtained by crosslinking a hydrophilic polymer. The hydrogel has excellent physical and chemical properties and biological characteristics, such as high water content, high elasticity, softness, biocompatibility and the like, and has important application value in the biomedical research fields of drug delivery, tissue engineering and the like. Injectable hydrogels are hydrogels having a certain fluidity, which can be applied by an injection method, exhibit phase transition between sol and gel for external stimuli (changes in temperature, temperature/pH, etc.), are in a liquid state or a semi-solid state having shear thinning properties before being injected into a human body, and can form gel in situ after being injected into the human body, thereby eliminating the need for invasive surgery, effectively avoiding the risk of infection, and reducing the pain of patients.
Polyethylene glycol (PEG) is a class of nonionic polymers, and is a class of synthetic polymers approved by the U.S. Food and Drug Administration (FDA) for clinical applications in humans due to its good biocompatibility and safety. The PEG can be used as a pharmaceutic adjuvant, and can also be used for modifying (pegylating) the medicine by using the PEG containing the terminal active functional group. The pegylation technology has more advantages, and particularly has the characteristics of prolonging the in vivo circulation time, enhancing the biological activity, avoiding proteolysis and reducing the immune response in the aspect of modifying protein and polypeptide medicaments.
The polyethylene glycol hydrogel can load and slowly release a plurality of water-soluble chemotherapeutic drugs, but for some chemotherapeutic drugs with poor water solubility or high drug concentration requirement, the problem of low drug release concentration exists. The addition of the sustained-release drug into the polyethylene glycol hydrogel system is a method for effectively increasing the release amount of the drug.
Disclosure of Invention
The invention provides a novel adriamycin hydrochloride/epiadriamycin hydrochloride sustained-release gel capable of increasing the sustained-release amount of a medicament on the basis of the research of the existing medical hydrogel, and the novel adriamycin hydrochloride/epiadriamycin hydrochloride sustained-release gel has good injectability, medicament loading and medicament sustained-release capacity. In-vitro drug release results prove that the gel can be used for quickly loading the drug, can realize slow release for several days to several months, maintains the drug concentration for a long time and continuously inhibits the growth of tumor cells.
The specific technical scheme of the invention is as follows:
the slow release gel is formed by in-situ crosslinking of aldehyde-group-terminated star-shaped multi-arm polyethylene glycol, polyethyleneimine and polylysine, and contains the doxorubicin hydrochloride/epirubicin hydrochloride and a drug release promoter, wherein the drug release promoter is selected from one or more of tween 80, beta cyclodextrin, dimethyl sulfoxide and polyvinylpyrrolidone (PVP).
The sustained-release gel can form gel in situ in blood vessels to release the medicine.
Preferably, the concentration of the doxorubicin hydrochloride or the epirubicin hydrochloride in the sustained-release gel is 10 mg/mL-50 mg/mL.
Preferably, the concentration of the drug release promoting agent in the sustained-release gel is 0.1 mg/mL-100 mg/mL, and more preferably 10-50 mg/mL.
Preferably, when the drug release promoter is beta-cyclodextrin and tween 80, the concentration of the beta-cyclodextrin in the sustained-release gel is 10-50 mg/mL.
Preferably, when the drug release promoting agent is dimethyl sulfoxide, the concentration of the dimethyl sulfoxide in the sustained-release gel is 10 mg/mL.
Preferably, when the drug release promoter is polyvinylpyrrolidone, the concentration of the polyvinylpyrrolidone in the sustained-release gel is 20-50 mg/mL.
The sustained-release gel is prepared by the following method: dissolving the aldehyde-terminated star-shaped multi-arm polyethylene glycol in a buffer solution with the pH value of 4-10, and adding a drug release promoter to prepare a solution A; dissolving polyethyleneimine and polylysine in a buffer solution with the pH value of 4-10 to prepare a solution B; dissolving doxorubicin hydrochloride or epirubicin hydrochloride in normal saline or 5% glucose solution, adding into solution A or solution B, and mixing solution A or solution B to obtain the sustained-release gel.
Preferably, the buffer solution of the solution A is phosphate buffer solution with the pH of 4-6, and the buffer solution of the solution B is borate buffer solution with the pH of 8-10.
Preferably, the final concentration of the aldehyde-terminated star-shaped multi-arm polyethylene glycol in the sustained-release gel is 2-40% (w/v), preferably 3-30% (w/v), and more preferably 5-15% (w/v); the concentration of polyethyleneimine and polylysine in the sustained-release gel is 0.5-20%, more preferably 1-5% (w/v).
Preferably, the aldehyde group of the aldehyde-terminated star-shaped multi-arm polyethylene glycol is connected with the star-shaped multi-arm polyethylene glycol through an ester bond, an ether bond, an amide bond, an urethane bond, an imine bond or a urea bond. More preferably with amide or ester linkages.
Preferably, the arm number of the star-shaped multi-arm polyethylene glycol is 2-8, and the single-arm molecular weight is 1000-5000 Da.
The aldehyde group is selected from one or more of aromatic aldehyde group and alkyl aldehyde group.
The invention also aims to provide the application of the sustained-release gel in preparing anti-tumor vascular embolization agents and drug release carriers.
The invention has the advantages that:
although the doxorubicin hydrochloride/epirubicin hydrochloride is wrapped in the water inlet gel and is arranged near/in the tumor, the drug slow-release effect of the gel can effectively improve the residence time of the drug near the tumor. However, the present inventors have found that the release amount of the drug from the gel is too low at a high concentration, and the therapeutic effect is significantly affected. The invention overcomes the problems, and through adding the drug release promoter, the doxorubicin hydrochloride/epirubicin hydrochloride gel not only can locally release the drug, but also has high drug release amount so as to meet the clinical requirement on the effective drug dose.
Detailed Description
The following examples are provided to illustrate specific steps of the present invention, but are not intended to limit the scope of the invention.
Terms used in the present invention generally have meanings commonly understood by those of ordinary skill in the art, unless otherwise specified.
The invention is described in further detail below with reference to specific examples and data, it being understood that these examples are intended to illustrate the invention and are not intended to limit the scope of the invention in any way.
In the following examples, various procedures and methods not described in detail are conventional methods well known in the art.
EXAMPLE 1 preparation of epirubicin hydrochloride sustained-release gel with different drug release promoters
Step 1: preparing a hydrogel precursor solution: 200mg of ester-linked benzaldehyde-terminated 8-arm polyethylene glycol (molecular weight 15kDa) was dissolved in 1mL of phosphate buffer (pH5.6), and a drug releasing accelerator (Table 1) was added as solution A. A borax buffer solution (pH9.2) of polylysine and polyethyleneimine (M.W.1.8K) was prepared as a solution B in a molar ratio of 1:0.9:1 between the aldehyde group of polyethylene glycol and the amino group of polyethyleneimine and polylysine.
Step 2: preparing medicine-carrying hydrogel: calculating the using amount of epirubicin hydrochloride by taking the relative gel concentration of the epirubicin hydrochloride as 25mg/mL, and dissolving the weighed epirubicin hydrochloride in a certain amount of physiological saline to prepare an epirubicin hydrochloride solution; and adding the epirubicin hydrochloride solution into the solution A to form a uniform mixed solution, and mixing and injecting the mixed solution and the solution B to obtain the epirubicin hydrochloride-loaded hydrogel.
Investigating the drug slow-release performance of different epirubicin hydrochloride drug-loaded gels in simulated body fluid
Accurately weighing the prepared different epirubicin hydrochloride drug-loaded gels, placing the epirubicin hydrochloride drug-loaded gels in a release tube containing PBS solution with the mass 10 times that of the drug-loaded gels, and placing the epirubicin hydrochloride drug-loaded gels at a constant temperature of 37 ℃. Samples were taken at preset time points, and each time the PBS in the release tube was taken out in its entirety and weighed and added again with 10 times the mass of the drug-loaded hydrogel of PBS fresh release medium. And (3) measuring the concentration of the epirubicin hydrochloride in the extracted PBS sample by using an ultraviolet spectrophotometry, and measuring the in-vitro release condition of the epirubicin hydrochloride in the gel.
TABLE 1
The hydrogels with different additives were tested for drug release over 3 days, giving the results in table 1. From analysis of the test results, it was found that different additives have different abilities to promote drug release. Wherein, the cyclodextrin, the Tween 80, the DMSO and the PVP have the capability of promoting the drug release amount, the drug release amount can be improved from 18.33 percent to 44.59 percent at most, and the capability of promoting the drug release amount has obvious concentration dependence. For example, for DMSO, the drug release was 42% at 1% concentration, while only 29% and 25.7% at 2% and 5% concentrations. In addition, additives including F127, ethanol and hyaluronic acid do not have a significant ability to promote drug release at different concentrations.
Claims (10)
1. The doxorubicin hydrochloride/epirubicin hydrochloride sustained-release gel is characterized in that the sustained-release gel is formed by in-situ crosslinking of aldehyde-group-terminated star-shaped multi-arm polyethylene glycol, polyethyleneimine and polylysine, and the sustained-release gel contains the doxorubicin hydrochloride/epirubicin hydrochloride and a drug release promoter, wherein the drug release promoter is selected from one or more of tween 80, beta cyclodextrin, dimethyl sulfoxide and polyvinylpyrrolidone.
2. The sustained-release gel according to claim 1, wherein the concentration of doxorubicin hydrochloride or epirubicin hydrochloride in the sustained-release gel is 10mg/mL to 50 mg/mL.
3. The sustained-release gel according to claim 1, wherein the concentration of the drug release enhancer in the sustained-release gel is 0.1mg/mL to 100 mg/mL.
4. The sustained-release gel according to claim 1, characterized by being prepared by the following method: dissolving doxorubicin hydrochloride or epirubicin hydrochloride in normal saline or 5% glucose solution, and adding into star-shaped multi-arm polyethylene glycol solution dissolved with drug release promoter to form solution A; dissolving polyethyleneimine and polylysine in a buffer solution to prepare a solution B; the solution A, B was mixed to give a sustained release gel.
5. The sustained-release gel according to any one of claims 1 to 4, wherein the aldehyde group is chemically linked to the star-shaped multi-armed polyethylene glycol via an ester bond, an ether bond, an amide bond, a urethane bond, an imine bond or a urea bond.
6. The sustained-release gel of claim 5, wherein the aldehyde group is connected with the star-shaped multi-arm polyethylene glycol through an amide bond or an ester bond.
7. The sustained-release gel according to claim 5, wherein the number of arms of the star-shaped multi-arm polyethylene glycol is 2-8, and the molecular weight of the single arm is 1000-5000 Da.
8. The sustained-release gel according to claim 1, wherein the aldehyde group is selected from one or more of aromatic aldehyde group and alkyl aldehyde group.
9. The sustained-release gel according to claim 5, wherein the concentration of star-shaped multi-arm polyethylene glycol in the sustained-release gel is 2-40%, w/v, and the concentration of polyethyleneimine and polylysine is 0.5-20%, w/v.
10. Use of a sustained release gel according to any one of claims 1 to 9 in the preparation of an anti-tumour vascular embolic agent and a drug delivery vehicle.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210933631.3A CN115068413B (en) | 2022-08-04 | 2022-08-04 | Doxorubicin hydrochloride/epirubicin hydrochloride sustained-release gel |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210933631.3A CN115068413B (en) | 2022-08-04 | 2022-08-04 | Doxorubicin hydrochloride/epirubicin hydrochloride sustained-release gel |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115068413A true CN115068413A (en) | 2022-09-20 |
| CN115068413B CN115068413B (en) | 2024-02-23 |
Family
ID=83244932
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210933631.3A Active CN115068413B (en) | 2022-08-04 | 2022-08-04 | Doxorubicin hydrochloride/epirubicin hydrochloride sustained-release gel |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115068413B (en) |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109646723A (en) * | 2019-02-02 | 2019-04-19 | 上海瑞凝生物科技有限公司 | Medical aquogel with Study On The Radioprotective |
| CN109939065A (en) * | 2018-08-10 | 2019-06-28 | 上海瑞凝生物科技有限公司 | Medical aquogel |
| CN111150702A (en) * | 2019-12-04 | 2020-05-15 | 复旦大学 | Gel drug sustained release preparation and preparation method and application thereof |
| CN112225912A (en) * | 2020-10-19 | 2021-01-15 | 上海瑞凝生物科技有限公司 | Degradable medical hydrogel |
| WO2022022369A1 (en) * | 2020-07-29 | 2022-02-03 | 中国科学院上海药物研究所 | Sustained-release formulation of tofacitinib or salt thereof and preparation method therefor |
| CN114369354A (en) * | 2021-08-05 | 2022-04-19 | 上海瑞凝生物科技有限公司 | Injectable hydrogels for vascular embolization |
-
2022
- 2022-08-04 CN CN202210933631.3A patent/CN115068413B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109939065A (en) * | 2018-08-10 | 2019-06-28 | 上海瑞凝生物科技有限公司 | Medical aquogel |
| CN109646723A (en) * | 2019-02-02 | 2019-04-19 | 上海瑞凝生物科技有限公司 | Medical aquogel with Study On The Radioprotective |
| CN111150702A (en) * | 2019-12-04 | 2020-05-15 | 复旦大学 | Gel drug sustained release preparation and preparation method and application thereof |
| WO2022022369A1 (en) * | 2020-07-29 | 2022-02-03 | 中国科学院上海药物研究所 | Sustained-release formulation of tofacitinib or salt thereof and preparation method therefor |
| CN112225912A (en) * | 2020-10-19 | 2021-01-15 | 上海瑞凝生物科技有限公司 | Degradable medical hydrogel |
| CN114369354A (en) * | 2021-08-05 | 2022-04-19 | 上海瑞凝生物科技有限公司 | Injectable hydrogels for vascular embolization |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115068413B (en) | 2024-02-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5894022A (en) | Embolic material for endovascular occlusion of abnormal vasculature and method of using the same | |
| US9844597B2 (en) | Biocompatible in situ hydrogel | |
| EP1128816B1 (en) | Polyvinyl alcohol microspheres, and methods for making of the same | |
| JP7339267B2 (en) | Thermoresponsive hydrogels for intratumoral administration as a treatment for solid tumor cancers | |
| CN109646723B (en) | Medical hydrogel with radiation protection effect | |
| US11426450B2 (en) | Shear-thinning compositions as an intravascular embolic agent | |
| US20110033548A1 (en) | Degradable crosslinked aminated dextran microspheres and methods of use | |
| JP2003500114A (en) | Novel high viscosity embolization composition | |
| JP2002519364A (en) | Vascular embolization-forming composition containing ethyl lactate and method of using the same | |
| WO2015179997A1 (en) | Polyhydroxyl polymer embolic microsphere and preparation process therefor | |
| KR102479259B1 (en) | Injectable Hydrogels into injured tissue sites and uses thereof | |
| KR20130010402A (en) | Drug delivery system based on interventional injection of temperature and ph-sensitive injectable hydrogel | |
| US20200030238A1 (en) | Microspheres containing therapeutic agents and related methods of use | |
| CN114369354A (en) | Injectable hydrogels for vascular embolization | |
| CN115068413B (en) | Doxorubicin hydrochloride/epirubicin hydrochloride sustained-release gel | |
| US11229604B2 (en) | Microspheres containing therapeutic agents and related methods of use | |
| US20230272142A1 (en) | Non-degradable embolisation microsphere | |
| Yan et al. | Doxorubicin-loaded in situ gel combined with biocompatible hydroxyethyl cellulose hemostatic gauze for controlled release of drugs and prevention of breast cancer recurrence postsurgery | |
| CN111686075B (en) | In-situ hydrogel composition taking nano-micelle as cross-linking agent and application thereof | |
| Hu et al. | Temperature-responsive hydrogel for tumor embolization therapy | |
| CN114533937B (en) | Biodegradable temperature-sensitive embolic gel and preparation method and application thereof | |
| CN117883366A (en) | Preparation method and application of docetaxel micelle-loaded temperature-sensitive hydrogel | |
| CN116370643A (en) | Nanometer assembly, preparation method and application thereof | |
| CN113197866A (en) | Radiopaque drug-loaded embolism microsphere for interventional therapy and preparation method thereof |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |