CN116492323A - New application of styreneic acid compound - Google Patents
New application of styreneic acid compound Download PDFInfo
- Publication number
- CN116492323A CN116492323A CN202210062778.XA CN202210062778A CN116492323A CN 116492323 A CN116492323 A CN 116492323A CN 202210062778 A CN202210062778 A CN 202210062778A CN 116492323 A CN116492323 A CN 116492323A
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- medicament
- skin cancer
- acid
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- JVTIXNMXDLQEJE-UHFFFAOYSA-N 2-decanoyloxypropyl decanoate 2-octanoyloxypropyl octanoate Chemical compound C(CCCCCCC)(=O)OCC(C)OC(CCCCCCC)=O.C(=O)(CCCCCCCCC)OCC(C)OC(=O)CCCCCCCCC JVTIXNMXDLQEJE-UHFFFAOYSA-N 0.000 description 2
- WLAMNBDJUVNPJU-UHFFFAOYSA-N 2-methylbutyric acid Chemical compound CCC(C)C(O)=O WLAMNBDJUVNPJU-UHFFFAOYSA-N 0.000 description 2
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- 206010027476 Metastases Diseases 0.000 description 2
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- 239000004698 Polyethylene Substances 0.000 description 2
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- 238000010521 absorption reaction Methods 0.000 description 2
- 239000004037 angiogenesis inhibitor Substances 0.000 description 2
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 2
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- 230000001186 cumulative effect Effects 0.000 description 2
- 238000009792 diffusion process Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 229920006267 polyester film Polymers 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000010839 reverse transcription Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 230000005747 tumor angiogenesis Effects 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- BMVXCPBXGZKUPN-UHFFFAOYSA-N 1-hexanamine Chemical class CCCCCCN BMVXCPBXGZKUPN-UHFFFAOYSA-N 0.000 description 1
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-M Aminoacetate Chemical compound NCC([O-])=O DHMQDGOQFOQNFH-UHFFFAOYSA-M 0.000 description 1
- 208000010837 Diabetic eye disease Diseases 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical class CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 208000001382 Experimental Melanoma Diseases 0.000 description 1
- WJYIASZWHGOTOU-UHFFFAOYSA-N Heptylamine Chemical class CCCCCCCN WJYIASZWHGOTOU-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
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- 229920000604 Polyethylene Glycol 200 Polymers 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 206010054094 Tumour necrosis Diseases 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical class CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 230000034303 cell budding Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 210000004207 dermis Anatomy 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 210000003414 extremity Anatomy 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000003941 n-butylamines Chemical class 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical class CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 229910021487 silica fume Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—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
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
- A61K9/7061—Polyacrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention provides a new application of a styreneic acid compound, and provides a new application of the compound shown in a formula I in preparing a medicine for treating skin cancer. The styracin compound can cause necrosis in melanoma, slow down tumor proliferation and play a role in resisting skin cancer. It can be made into topical preparation with pharmaceutically acceptable adjuvants, and can be used for percutaneous administrationThe composition can be absorbed by skin or body cavity to reduce toxic and side effects of the medicine, and can be used for treating or relieving diseases by selecting proper composition dosage forms containing the compound according to the position of skin cancer, thereby realizing targeted medicine treatment of skin cancer.
Description
Technical Field
The invention belongs to the field of biological medicine, and in particular relates to a new application of a styrene compound.
Background
Skin cancer is malignant tumor of skin, including squamous cell carcinoma, basal cell carcinoma, malignant melanoma, malignant lymphoma, idiopathic hemorrhagic sarcoma, sweat gland carcinoma, tumor of carina skin fibrosarcoma, angiosarcoma, etc. Malignant melanoma belongs to primary skin cancer, is a malignant tumor which is highly malignant and easy to cause tumor recurrence or metastasis, is mainly developed at the positions of head and neck, lower limbs, trunk skin, limb ends, mucous membrane and the like, is one of the most serious skin cancer types, has the effective rate of about 10% of advanced melanoma, has the median survival time of about 9 months and seriously threatens the life of patients.
For many years, researchers have made many efforts in the development of antitumor drugs in order to overcome the difficulty of malignant tumor treatment. Angiogenesis inhibitors have gained increasing attention in recent years in anti-tumor therapy. Angiogenesis, which is a distinct feature of tumor growth, is a messy and non-functional feature, and tumor cells acquire sufficient oxygen and nutrition through the newly generated blood vessels to meet the needs of their growth, proliferation and metastasis; the treatment effect of starving the tumor can be achieved by blocking tumor angiogenesis by angiogenesis inhibitors, or by destroying tumor blood vessels using drugs with vascular targeting. For example, chinese patent publication No. CN101074189B discloses that styrenes represented by formula a and derivatives thereof can be used for preparing vascular targeting drugs, and have anti-tumor potential.
It specifically discloses (E) -3- (3 '-hydroxy-4' -methoxyphenyl) -2- (3 ', 4', 5 '-trimethoxyphenyl) -2-propenoic acid glycinate, (E) -3- (3' -amino-4 '-methoxyphenyl) -2- (3', 4",5" -trimethoxyphenyl) -2-propenoic acid triethanolamine salt, (E) -3- (3 ',5' -dihydroxyphenyl) -2- (3 ",4",5 "-trimethoxyphenyl) -2-quinic acid ester inhibiting effect on lung cancer cells.
However, the different tumor angiogenesis modes (including budding angiogenesis, telescoping angiogenesis, angiogenesis youtai, mosaic angiogenesis, etc.) are different, and the key growth factors in the angiogenesis process are different, so that the vascular targeting and the inhibition effect of the styreneic compounds on different tumor cells are not known. Especially for melanoma, which is a highly malignant tumor, the angiogenesis mode is very complex, and a single action target point often has poor effect, so that the treatment is more difficult.
Furthermore, patent publication No. CN105566100B discloses that in the compound of formula A, R 1 、R 4 、R 5 Is hydrogen, R 2 Is hydroxy, R 3 Is methoxy, R 6 Compounds that are n-butyl: (E) Process for the preparation of n-butylamino-3- (3 ' -hydroxy-4 ' -methoxyphenyl) -2- (3 ', 4', 5' -trimethoxyphenyl) -2-propenoic acid and the use of R in the compounds of formula A 1 、R 4 、R 5 Is hydrogen, R 2 、R 3 Use of ethylammonium salt, n-propylammonium salt, n-butylaminium salt, n-hexylammonium salt and n-heptylammonium salt, which are methoxy groups, for the preparation of a medicament for the prevention and/or treatment of diabetic eye diseases.
However, the use of compounds of the formula A, in particular of n-butylamine salt of (E) -3- (3 ' -hydroxy-4 ' -methoxyphenyl) -2- (3 ', 4', 5' -trimethoxyphenyl) -2-propenoic acid, against melanoma has not been reported at present.
Disclosure of Invention
The invention aims to provide a new application of a styrene acid compound.
The invention provides application of a compound shown in a formula I in preparing a medicament for treating skin cancer;
wherein M is + Is Na (Na) + 、K + 、Li + Or organic ammonium ions.
Further, M is as described above + Is organic ammonium ion CH 3 (CH 2 ) n NH 3 + Wherein n is an integer of 0 to 5.
Further, n is 3, M + Is that
Further, the above-mentioned medicines for treating skin cancer are medicines for treating squamous cell carcinoma, basal cell carcinoma, malignant melanoma, malignant lymphoma, idiopathic hemorrhagic sarcoma, sweat gland carcinoma, carina-type skin fibrosarcoma or angiosarcoma.
Further, the medicament is a medicament for treating malignant melanoma.
Further, the medicine is a preparation prepared by taking a compound shown in a formula I as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
Further, the above preparation is a transdermal preparation for topical application to the skin or body cavity.
Further, the preparation is a patch, a cream, an ointment or a gel.
Further, the preparation contains at least one of a drug carrier, an adhesive, a thickener, a humectant, a filler, a crosslinking agent, a stabilizer, a transdermal enhancer, a pH regulator, a crosslinking regulator, an antifoaming agent, an opacifying agent, and a solvent.
Further, the drug carrier comprises at least one of polymer solid dispersion, polymer inclusion compound, polymer particles, polymer microspheres, liposome, micro silica gel, lactose, acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talcum powder, corn starch, keratin, colloidal silica, potato starch and urea;
the adhesive comprises: at least one of polyurethane, polystyrene, polyacrylate, ethylene-vinyl acetate copolymer, shellac, butyl rubber, vinyl acetate resin, acrylic resin, chlorinated rubber, epoxy resin, polyvinyl alcohol, carboxymethyl cellulose, synthetic resin, synthetic rubber, natural rubber, isoprene rubber, styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, silicone;
the thickener comprises at least one of starch, sodium alginate, agar, acacia, locust bean gum, soybean gum, casein, guar gum, alginic acid, sodium alginate, propylene glycol alginate, agar, acacia, tragacanth, pectin, chitosan, guar gum, xanthan gum, gelatin, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl starch, polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methacrylate, carboxyvinyl polymer, carbomer, polyacrylamide, sodium polyacrylate, polyethylene oxide, polyamine resin, epoxy resin, and polymaleic anhydride;
the humectant comprises at least one of glycerol, propylene glycol, glycerol, polyethylene glycol, sorbitol and the like;
the filler comprises at least one of kaolin, diatomite, superfine silica powder, kaolin, titanium dioxide and zinc oxide;
the cross-linking agent comprises at least one of a metal chelating agent, ferric trichloride, aluminum glycinate and high-valence metal oxide;
the pH regulator comprises at least one of triethanolamine, lactic acid, tartaric acid and citric acid;
the transdermal enhancer comprises at least one of sulfoxides, pyrrolidone, azone and analogues, fatty acid and esters thereof, surfactant, alcohols, polyalcohols, terpenes, amines, amides, cyclodextrins, amino acids and esters thereof, macrocyclic compounds, organic solvents and phospholipids;
the opacifier comprises at least one of titanium dioxide and ferric oxide;
the solvent comprises at least one of ethanol, propylene glycol, glycerol, butanediol, and water.
Experimental results show that the styracin compound can cause necrosis in melanoma, slow down tumor proliferation and play a role in resisting skin cancer. The composition is prepared into a preparation capable of being locally administrated by forming the composition with pharmaceutically acceptable auxiliary materials, can be absorbed through skin or body cavities, reduces toxic and side effects of the medicine, can achieve the purpose of treating or relieving diseases by selecting a proper composition dosage form containing the compound according to the position of skin cancer, and achieves the purpose of targeted medicine treatment of the skin cancer.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Drawings
FIG. 1 shows the HE staining results of melanoma tissues of mice in the control group and the experimental group using the drug of the present invention.
Detailed Description
The raw materials and equipment used in the invention are all known products and are obtained by purchasing commercial products. (E) -3- (3 '-hydroxy-4' -methoxyphenyl) -2- (3 ",4",5 "-trimethoxyphenyl) -2-propenoic acid n-butylamine salt can be prepared according to the preparation method disclosed in CN105566100B, having the structure:
example 1: preparation of gel of pharmaceutical composition containing (E) -3- (3 ' -hydroxy-4 ' -methoxyphenyl) -2- (3 ', 4', 5' -trimethoxyphenyl) -2-propenoic acid n-butyl ammonium salt
The medicine composition gel is prepared by taking (E) -3- (3 ' -hydroxy-4 ' -methoxyphenyl) -2- (3 ', 4', 5' -trimethoxyphenyl) -2-acrylic acid n-butyl ammonium salt as a main medicine according to the following proportion and operation.
The names and the dosage of the main medicine and the auxiliary materials
50g of main medicine
Carbomer 934 g 25g
45g of glycerol
Azone 15g
P-hydroxybenzoic acid ethyl ester 2g
Distilled water is added to 1000g
Preparation method
The steps are as follows:
(1) Mixing carbomer 934 with azone and 500ml distilled water, stirring to dissolve;
(2) Dissolving the main medicine in 75% ethanol solution, adding ethyl p-hydroxybenzoate and glycerol, and stirring to dissolve completely;
(3) And (3) adding the step (2) into the step (1), and stirring to uniformly mix the components.
(4) The pH value of the triethanolamine is regulated to 7.5, water is added to 1000g of the total amount, and the mixture is continuously stirred until the sample becomes gel;
example 2: preparation of gel of pharmaceutical composition containing (E) -3- (3 ' -hydroxy-4 ' -methoxyphenyl) -2- (3 ', 4', 5' -trimethoxyphenyl) -2-propenoic acid n-butyl ammonium salt
The medicine composition gel is prepared by taking (E) -3- (3 ' -hydroxy-4 ' -methoxyphenyl) -2- (3 ', 4', 5' -trimethoxyphenyl) -2-acrylic acid n-butyl ammonium salt as a main medicine according to the following proportion and operation.
The names and the dosage of the main medicine and the auxiliary materials
50g of main medicine
Carbomer 941 g20 g
Propylene glycol 50g
Azone 15g
P-hydroxybenzoic acid ethyl ester 2g
Distilled water is added to 1000g
Preparation method
The steps are as follows:
(1) Carbomer 941 was mixed with azone and 600ml distilled water and dissolved by stirring;
(2) Dissolving the main medicine in 75% ethanol solution, adding ethyl p-hydroxybenzoate and propylene glycol, and stirring to dissolve completely;
(3) And (3) adding the step (2) into the step (1), and stirring to uniformly mix the components.
(4) The pH value of the triethanolamine is regulated to 7.5, water is added to 1000g of the total amount, and the mixture is continuously stirred until the sample becomes gel;
example 3: preparation of pharmaceutical composition ointments containing (E) -3- (3 ' -hydroxy-4 ' -methoxyphenyl) -2- (3 ', 4', 5' -trimethoxyphenyl) -2-propenoic acid n-butylammonium salt
The pharmaceutical composition ointment of the invention is prepared by taking (E) -3- (3 ' -hydroxy-4 ' -methoxyphenyl) -2- (3 ', 4', 5' -trimethoxyphenyl) -2-acrylic acid n-butyl ammonium salt as a main medicine according to the following proportion and operation.
The preparation method comprises the following steps: pulverizing the main medicine, sieving with 100 mesh sieve, adding 5g main medicine into 50g PEG200, heating in water bath at 65deg.C to dissolve the main medicine, adding 43g PEG4000, 0.2g ethyl p-hydroxybenzoate and 1.8g azone into the above solution, heating in water bath until all the main medicine is dissolved, stirring and mixing uniformly until condensing to obtain the ointment containing the compound.
Example 4: preparation of pharmaceutical composition ointments containing (E) -3- (3 ' -hydroxy-4 ' -methoxyphenyl) -2- (3 ', 4', 5' -trimethoxyphenyl) -2-propenoic acid n-butylammonium salt
The pharmaceutical composition ointment of the invention is prepared by taking (E) -3- (3 ' -hydroxy-4 ' -methoxyphenyl) -2- (3 ', 4', 5' -trimethoxyphenyl) -2-acrylic acid n-butyl ammonium salt as a main medicine according to the following proportion and operation.
The preparation method comprises the following steps: pulverizing the main medicine, sieving with 100 mesh sieve, adding 5g main medicine into 55g PEG400, heating in 70deg.C water bath to dissolve the main medicine, adding 38g PEG4000, 0.2g ethyl p-hydroxybenzoate and 1.8g azone into the above solution, heating in water bath until all the main medicine is dissolved, stirring and mixing uniformly until condensation to obtain the ointment containing the compound.
Example 5: preparation of a pharmaceutical composition patch containing (E) -3- (3 ' -hydroxy-4 ' -methoxyphenyl) -2- (3 ', 4', 5' -trimethoxyphenyl) -2-propenoic acid n-butylammonium salt
The medicine composition emplastrum is prepared by taking (E) -3- (3 ' -hydroxy-4 ' -methoxyphenyl) -2- (3 ', 4', 5' -trimethoxyphenyl) -2-acrylic acid n-butyl ammonium salt as a main medicine according to the following proportion and operation.
A backing layer: nonwoven fabric
Anti-sticking layer: polyethylene film
The ointment-containing body layer comprises the following components in parts by weight:
the preparation method comprises the following steps: pulverizing main medicine, sieving with 100 mesh sieve, weighing main medicine, propylene glycol, PEG-400 and azone according to prescription, adding water, heating in water bath to dissolve, adding gelatin to dissolve into glue solution, mixing polyvinylpyrrolidone, sodium polyacrylate, differential silica gel and ethyl p-hydroxybenzoate uniformly, adding into the above glue solution, stirring to obtain paste, uniformly coating on non-woven fabric, drying, covering polyethylene film, and shearing.
Example 6: preparation of a pharmaceutical composition patch containing (E) -3- (3 ' -hydroxy-4 ' -methoxyphenyl) -2- (3 ', 4', 5' -trimethoxyphenyl) -2-propenoic acid n-butylammonium salt
The medicine composition emplastrum is prepared by taking (E) -3- (3 ' -hydroxy-4 ' -methoxyphenyl) -2- (3 ', 4', 5' -trimethoxyphenyl) -2-acrylic acid n-butyl ammonium salt as a main medicine according to the following proportion and operation.
A backing layer: nonwoven fabric
Anti-sticking layer: polyester film
The ointment-containing body layer comprises the following components in parts by weight:
the preparation method comprises the following steps: pulverizing main medicine, sieving with 100 mesh sieve, weighing main medicine, propylene glycol, PEG-400 and azone according to prescription, adding water, heating in water bath to dissolve, adding gelatin to dissolve into glue solution, mixing sodium carboxymethylcellulose, sodium polyacrylate, zinc oxide and ethyl p-hydroxybenzoate uniformly, adding into the above glue solution, stirring and mixing uniformly to obtain paste, uniformly coating on non-woven fabric, drying, covering with polyester film, and cutting.
The following experiments prove the beneficial effects of the invention.
Experimental example 1 in vitro transdermal experiments
The treated mouse skin is fixed around the edge of the diffusion cell by adopting an improved Franz diffusion cell, the dermis faces a receiving chamber, the cuticle faces a supply chamber, a self-made preparation (example) is stuck on the cuticle face, a magnetic stirrer is placed in the receiving cell, isotonic phosphate buffer solution with pH of 7.4 is added to the scale, an in-vitro transdermal device is placed in a constant-temperature water bath, the temperature is kept at (37+/-0.5) DEG C, a magnetic stirrer is started, and 2ml is sampled in a side tube at 1.0, 2.0, 4.0, 6.0, 8.0, 10.0, 12.0, 16.0 and 24.0h, and meanwhile, an equal volume of receiving solution is supplemented. Filtering the sample with a 0.45 μm microporous filter membrane to obtain the sample. The sample concentration was measured by HPLC method. The gel, ointment and cataplasm prepared in examples 2-7 were subjected to in vitro transdermal absorption tests, the results of the in vitro transdermal absorption tests conform to the zero order dynamic process, the cumulative transdermal amounts of 24 hours are all more than 50%, and the test results are shown in Table 1.
TABLE 1 cumulative percent release versus time
Therefore, the transdermal drug delivery preparation prepared by the embodiment of the invention has good transdermal effect, can be absorbed through skin or body cavities, reduces toxic and side effects of the drug, and can be used for targeted treatment of melanoma by local drug delivery.
Experimental example 2 animal experiment study for inhibiting melanoma
Taking commercial source B16 cell strain, culturing with RPMI-1640 culture solution containing 10% new born calf serum, penicillin (100U/ml) and streptomycin (100 μg/ml), and digesting logarithmic phase B16 cells with 0.25% trypsin, wherein the passage ratio is about 1: cells were washed 3 times with PBS and centrifuged at 1000RPM for 5min. Cell viability was measured by 0.4% trypan blue exclusion and required to be greater than 90% and cell concentration adjusted to 3 x 10 with PBS 6 /ml of B16 cell suspension. Each mouse (BALB/C mice (SPF grade), shanghai Sipulel-BiKai laboratory animal Co., ltd.) was injected intradermally with 0.1ml of the B16 cell suspension. Animals with oversized and undersized tumors were eliminated by regrouping them according to tumor size 10-14 days after inoculation, with the average tumor volumes of each group being substantially consistent. The test consisted of 2 groups of 5 mice each, 1) a blank, 2) 2mg/20g of the test drug (example 6) administered at a dose of 2mg/20g of body weight.
At different time points (2 h and 24 h) after administration, the mice are sacrificed to dissect tumor tissues, the tumor tissues are fixed by 10% formalin, pathological sections are made, HE staining is carried out, photographing is carried out, and the necrosis condition and the cell proliferation condition in the tumor are observed.
HE staining as shown in fig. 1, the results showed that necrosis began to occur inside tumor tissue 2 hours after transdermal administration of the test drug (2 mg/20 g), and that necrosis of a large area inside the tumor (light area) could be caused by 24 hours. Therefore, the (E) -3- (3 ' -hydroxy-4 ' -methoxyphenyl) -2- (3 ', 4', 5' -trimethoxyphenyl) -2-acrylic acid n-butyl ammonium salt can cause the internal proliferation slowing down of melanoma and tumor necrosis, and finally plays an anti-tumor role.
Tumor length a (mm) and perpendicular tumor length b (mm) were measured 2 times per week from day 10 of inoculation with digital electronic calipers, and the tumor volume calculation formula was: tv=ab 2 The calculation formula of the relative tumor volume is as follows: RT (reverse transcription) methodv=vt/Vo, vo is the tumor volume measured at the time of the split cage (i.e. d 1), vt is the tumor volume at each measurement. Tumor inhibition% = (control mean RTV-dosing mean RTV)/control mean RTV x 100%. Influence of test drugs on tumor volume of B16 melanoma cell strain transplanted to back of mouse and tumor inhibition rateUnits: mm (mm) 3 ) The results are shown in Table 2.
TABLE 2
It can be seen that the (E) -3- (3 ' -hydroxy-4 ' -methoxyphenyl) -2- (3 ', 4', 5' -trimethoxyphenyl) -2-acrylic acid n-butyl ammonium salt can remarkably reduce proliferation of melanoma, cause necrosis of the melanoma, remarkably reduce volume of the melanoma and has excellent effect of inhibiting the melanoma.
In summary, the invention provides a new application of a styreneic acid compound, which can cause necrosis in melanoma, slow down tumor proliferation and play a role in resisting skin cancer. The composition is prepared into a preparation capable of being locally administrated by forming the composition with pharmaceutically acceptable auxiliary materials, can be absorbed through skin or body cavities, reduces toxic and side effects of the medicine, can achieve the purpose of treating or relieving diseases by selecting a proper composition dosage form containing the compound according to the position of skin cancer, and achieves the purpose of targeted medicine treatment of the skin cancer.
Claims (10)
1. The application of a compound shown in a formula I in preparing a medicament for treating skin cancer;
wherein M is + Is Na (Na) + 、K + 、Li + Or organic ammonium ions.
2. The use according to claim 1, wherein M + Is organic ammonium ion CH 3 (CH 2 ) n NH 3 + Wherein n is an integer of 0 to 5.
3. The use according to claim 2, wherein n is 3, m + Is that
4. The use according to any one of claims 1 to 3, wherein the medicament for treating skin cancer is a medicament for treating squamous cell carcinoma, basal cell carcinoma, malignant melanoma, malignant lymphoma, idiopathic hemorrhagic sarcoma, sweat gland carcinoma, carina skin fibrosarcoma or angiosarcoma.
5. The use according to claim 4, wherein the medicament is a medicament for the treatment of malignant melanoma.
6. The use according to any one of claims 1 to 5, wherein the medicament is a preparation prepared by adding pharmaceutically acceptable auxiliary materials to the compound of formula I as active ingredient.
7. The use according to claim 6, wherein the formulation is a transdermal formulation for topical application to the skin or body cavity.
8. The use according to claim 7, wherein the formulation is a patch, a cream, an ointment or a gel.
9. The use according to claim 7 or 8, wherein the formulation comprises at least one of a pharmaceutical carrier, an adhesive, a thickener, a humectant, a filler, a cross-linking agent, a stabilizer, a transdermal enhancer, a pH adjusting agent, a cross-linking adjusting agent, an antifoaming agent, an opacifying agent, a solvent.
10. The use according to claim 9, wherein the pharmaceutical carrier comprises at least one of a polymeric solid dispersion, a polymeric clathrate, a polymeric microparticle, a polymeric microsphere, a liposome, a micro-powder silica gel, lactose, acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea;
the adhesive comprises: at least one of polyurethane, polystyrene, polyacrylate, ethylene-vinyl acetate copolymer, shellac, butyl rubber, vinyl acetate resin, acrylic resin, chlorinated rubber, epoxy resin, polyvinyl alcohol, carboxymethyl cellulose, synthetic resin, synthetic rubber, natural rubber, isoprene rubber, styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, silicone;
the thickener comprises at least one of starch, sodium alginate, agar, acacia, locust bean gum, soybean gum, casein, guar gum, alginic acid, sodium alginate, propylene glycol alginate, agar, acacia, tragacanth, pectin, chitosan, guar gum, xanthan gum, gelatin, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl starch, polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methacrylate, carboxyvinyl polymer, carbomer, polyacrylamide, sodium polyacrylate, polyethylene oxide, polyamine resin, epoxy resin, and polymaleic anhydride;
the humectant comprises at least one of glycerol, propylene glycol, glycerol, polyethylene glycol, sorbitol and the like;
the filler comprises at least one of kaolin, diatomite, superfine silica powder, kaolin, titanium dioxide and zinc oxide;
the cross-linking agent comprises at least one of a metal chelating agent, ferric trichloride, aluminum glycinate and high-valence metal oxide;
the pH regulator comprises at least one of triethanolamine, lactic acid, tartaric acid and citric acid;
the transdermal enhancer comprises at least one of sulfoxides, pyrrolidone, azone and analogues, fatty acid and esters thereof, surfactant, alcohols, polyalcohols, terpenes, amines, amides, cyclodextrins, amino acids and esters thereof, macrocyclic compounds, organic solvents and phospholipids;
the opacifier comprises at least one of titanium dioxide and ferric oxide;
the solvent comprises at least one of ethanol, propylene glycol, glycerol, butanediol, and water.
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CN101074189A (en) * | 2006-05-15 | 2007-11-21 | 雍智全 | Styrene acid derivative and use in preparation of various blood-vessels target agent medicine |
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CN105566100A (en) * | 2014-10-29 | 2016-05-11 | 东莞达信生物技术有限公司 | Styrene acid compound, composition containing same and application of styrene acid compound |
CN107773556A (en) * | 2016-08-26 | 2018-03-09 | 东莞达信生物技术有限公司 | A kind of combination medicine with antineoplastic effect |
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CN101074189A (en) * | 2006-05-15 | 2007-11-21 | 雍智全 | Styrene acid derivative and use in preparation of various blood-vessels target agent medicine |
CN101579328A (en) * | 2008-05-12 | 2009-11-18 | 浙江大德药业集团有限公司 | Application of combretastatin |
CN105566100A (en) * | 2014-10-29 | 2016-05-11 | 东莞达信生物技术有限公司 | Styrene acid compound, composition containing same and application of styrene acid compound |
CN107773556A (en) * | 2016-08-26 | 2018-03-09 | 东莞达信生物技术有限公司 | A kind of combination medicine with antineoplastic effect |
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