CN118021765B - Taqniamycin tartrate nano-preparation and preparation method thereof - Google Patents
Taqniamycin tartrate nano-preparation and preparation method thereof Download PDFInfo
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- CN118021765B CN118021765B CN202410447553.5A CN202410447553A CN118021765B CN 118021765 B CN118021765 B CN 118021765B CN 202410447553 A CN202410447553 A CN 202410447553A CN 118021765 B CN118021765 B CN 118021765B
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- mixed solution
- telavancin
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- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 title claims abstract description 134
- 229940095064 tartrate Drugs 0.000 title claims abstract description 134
- 238000002360 preparation method Methods 0.000 title claims abstract description 115
- ONUMZHGUFYIKPM-MXNFEBESSA-N telavancin Chemical compound O1[C@@H](C)[C@@H](O)[C@](NCCNCCCCCCCCCC)(C)C[C@@H]1O[C@H]1[C@H](OC=2C3=CC=4[C@H](C(N[C@H]5C(=O)N[C@H](C(N[C@@H](C6=CC(O)=C(CNCP(O)(O)=O)C(O)=C6C=6C(O)=CC=C5C=6)C(O)=O)=O)[C@H](O)C5=CC=C(C(=C5)Cl)O3)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](NC(=O)[C@@H](CC(C)C)NC)[C@H](O)C3=CC=C(C(=C3)Cl)OC=2C=4)O[C@H](CO)[C@@H](O)[C@@H]1O ONUMZHGUFYIKPM-MXNFEBESSA-N 0.000 claims abstract description 94
- 229960005240 telavancin Drugs 0.000 claims abstract description 94
- 108010089019 telavancin Proteins 0.000 claims abstract description 94
- ICVKYYINQHWDLM-KBEWXLTPSA-N (2r,3r)-2,3-dihydroxybutanedioic acid;2-[(4r,5s,6s,7r,9r,11e,13e,15r,16r)-6-[(2r,3r,4r,5s,6r)-5-[(2s,4r,5s,6s)-4,5-dihydroxy-4,6-dimethyloxan-2-yl]oxy-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-16-ethyl-4-hydroxy-15-[[(2r,3r,4r,5r,6r)-5-hydroxy-3,4 Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.O([C@@H]1[C@@H](C)O[C@H]([C@@H]([C@H]1N(C)C)O)O[C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CC=O)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@H]1C[C@@](C)(O)[C@@H](O)[C@H](C)O1 ICVKYYINQHWDLM-KBEWXLTPSA-N 0.000 claims abstract description 48
- 229960001717 tylosin tartrate Drugs 0.000 claims abstract description 48
- 235000003599 food sweetener Nutrition 0.000 claims abstract description 47
- 239000003765 sweetening agent Substances 0.000 claims abstract description 47
- 239000000463 material Substances 0.000 claims abstract description 41
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims abstract description 37
- 239000002245 particle Substances 0.000 claims abstract description 12
- 239000013530 defoamer Substances 0.000 claims abstract description 4
- 239000011259 mixed solution Substances 0.000 claims description 118
- 239000000243 solution Substances 0.000 claims description 118
- 239000000203 mixture Substances 0.000 claims description 73
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 63
- 238000009472 formulation Methods 0.000 claims description 47
- 238000002156 mixing Methods 0.000 claims description 37
- 238000003756 stirring Methods 0.000 claims description 37
- 238000001694 spray drying Methods 0.000 claims description 35
- 239000002518 antifoaming agent Substances 0.000 claims description 31
- 239000000843 powder Substances 0.000 claims description 25
- 238000002347 injection Methods 0.000 claims description 20
- 239000007924 injection Substances 0.000 claims description 20
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 19
- 229930006000 Sucrose Natural products 0.000 claims description 19
- 239000005720 sucrose Substances 0.000 claims description 19
- 229920002472 Starch Polymers 0.000 claims description 16
- 239000008107 starch Substances 0.000 claims description 16
- 235000019698 starch Nutrition 0.000 claims description 16
- UDIPTWFVPPPURJ-UHFFFAOYSA-M Cyclamate Chemical compound [Na+].[O-]S(=O)(=O)NC1CCCCC1 UDIPTWFVPPPURJ-UHFFFAOYSA-M 0.000 claims description 14
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 claims description 13
- YIKYNHJUKRTCJL-UHFFFAOYSA-N Ethyl maltol Chemical compound CCC=1OC=CC(=O)C=1O YIKYNHJUKRTCJL-UHFFFAOYSA-N 0.000 claims description 13
- 239000000625 cyclamic acid and its Na and Ca salt Substances 0.000 claims description 13
- 229940093503 ethyl maltol Drugs 0.000 claims description 13
- 229940085605 saccharin sodium Drugs 0.000 claims description 13
- 229960001462 sodium cyclamate Drugs 0.000 claims description 13
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical group OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 11
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 11
- 239000001630 malic acid Substances 0.000 claims description 11
- 235000011090 malic acid Nutrition 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 10
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical group COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 claims description 6
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 claims description 6
- 235000012141 vanillin Nutrition 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 12
- 230000009286 beneficial effect Effects 0.000 abstract description 9
- 235000019658 bitter taste Nutrition 0.000 abstract description 6
- 235000019629 palatability Nutrition 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 4
- 230000007794 irritation Effects 0.000 abstract description 3
- 238000004090 dissolution Methods 0.000 description 16
- 238000012360 testing method Methods 0.000 description 16
- 239000000047 product Substances 0.000 description 14
- 230000000052 comparative effect Effects 0.000 description 11
- 239000013065 commercial product Substances 0.000 description 9
- 235000019640 taste Nutrition 0.000 description 9
- 239000002994 raw material Substances 0.000 description 6
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 4
- 229910052782 aluminium Inorganic materials 0.000 description 4
- 239000011888 foil Substances 0.000 description 4
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical group OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 3
- 241000204031 Mycoplasma Species 0.000 description 3
- 241000282898 Sus scrofa Species 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
- 230000005540 biological transmission Effects 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 229940048879 dl tartaric acid Drugs 0.000 description 3
- 230000000873 masking effect Effects 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 206010035664 Pneumonia Diseases 0.000 description 2
- 229930194936 Tylosin Natural products 0.000 description 2
- 239000004182 Tylosin Substances 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 235000009508 confectionery Nutrition 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 208000032625 disorder of ear Diseases 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229960004059 tylosin Drugs 0.000 description 2
- WBPYTXDJUQJLPQ-VMXQISHHSA-N tylosin Chemical compound O([C@@H]1[C@@H](C)O[C@H]([C@@H]([C@H]1N(C)C)O)O[C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CC=O)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@H]1C[C@@](C)(O)[C@@H](O)[C@H](C)O1 WBPYTXDJUQJLPQ-VMXQISHHSA-N 0.000 description 2
- 235000019375 tylosin Nutrition 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- OLLSDNUHBJHKJS-XKORHJEPSA-N [(2s,3s,4r,6s)-6-[(2r,3s,4r,5r,6r)-6-[[(4r,5s,6s,7r,9r,11e,13e,15r,16r)-4-acetyloxy-16-ethyl-15-[[(2r,3r,4r,5r,6r)-5-hydroxy-3,4-dimethoxy-6-methyloxan-2-yl]oxymethyl]-5,9,13-trimethyl-2,10-dioxo-7-(2-oxoethyl)-1-oxacyclohexadeca-11,13-dien-6-yl]oxy]-4-(d Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.O([C@@H]1[C@@H](C)O[C@H]([C@@H]([C@H]1N(C)C)O)O[C@@H]1[C@@H](C)[C@H](OC(C)=O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CC=O)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@H]1C[C@@](C)(O)[C@@H](OC(=O)CC(C)C)[C@H](C)O1 OLLSDNUHBJHKJS-XKORHJEPSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 238000006136 alcoholysis reaction Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229940109275 cyclamate Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000009326 ileitis Diseases 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 201000006509 pleuropneumonia Diseases 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 235000019633 pungent taste Nutrition 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 230000035943 smell Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- JTSDBFGMPLKDCD-XVFHVFLVSA-N tilmicosin Chemical compound O([C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CCN1C[C@H](C)C[C@H](C)C1)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@@H]1O[C@H](C)[C@@H](O)[C@H](N(C)C)[C@H]1O JTSDBFGMPLKDCD-XVFHVFLVSA-N 0.000 description 1
- 229960000223 tilmicosin Drugs 0.000 description 1
- 238000012876 topography 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5123—Organic compounds, e.g. fats, sugars
-
- 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
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Virology (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Communicable Diseases (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Physics & Mathematics (AREA)
- Biomedical Technology (AREA)
- Nanotechnology (AREA)
- Optics & Photonics (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a telavancin tartrate nano preparation and a preparation method thereof, wherein the telavancin tartrate nano preparation comprises the following components in parts by weight: 25 parts of tylosin tartrate, 15-25 parts of hydroxypropyl-beta-cyclodextrin, 3-5 parts of pH regulator, 0.5-1.5 parts of phagostimulant, 1-4 parts of sweetener, 42.5-55.5 parts of water-soluble auxiliary material and 0.3-0.8 part of defoamer, wherein the tylosin tartrate accounts for 25% of the total weight of the tylosin tartrate nano preparation. The tylosin tartrate nano preparation disclosed by the invention can mask the strong irritation and extremely bitter taste of the tylosin tartrate bulk drug, has good palatability, is beneficial to feeding, has smaller particle size, is simple in preparation method, has better drug solubility and stability, and is beneficial to large-scale cultivation.
Description
Technical Field
The invention relates to the technical field of veterinary medicine preparations, in particular to a telavancin tartrate nano preparation and a preparation method thereof.
Background
The tylosin tartrate (also called acetylisovaleryl tylosin tartrate) is a new generation of macrolide medicine, and is synthesized by taking tylosin as a raw material through acetylation, isovalerylation and alcoholysis reactions. The medicine is the only medicine which can really reach the bronchus cavity and kill mycoplasma, the antibacterial potency of the medicine is 5-10 times of that of tylosin, and 2-5 times of tilmicosin; the alkaline side chain can effectively change the intracellular pH value, inhibit the propagation of blue-ear virus, and is commonly used for preventing and treating mycoplasma diseases (swine enzootic pneumonia, chicken slow breathing), swine blue-ear diseases, swine proliferative ileitis, infectious pleuropneumonia, streptococcosis and other diseases of livestock and poultry. In addition, the novel compound bacterium has the functions of enhancing nonspecific immunity and inhibiting replication and growth promotion of blue-ear disease viruses in macrophages, is a totipotent antibiotic suitable for large-scale farms, and has wide market application prospect.
The tylosin tartrate dissolves slowly when being applied to cultivation, is easy to agglomerate, has poor water solubility and has great bitter taste and irritation. Although the existing commercial tylosin tartrate preparation is improved in terms of changing the solubility, stability and taste masking effect of the medicine, the taste masking effect of the existing prepared tylosin tartrate preparation cannot meet the actual requirements of farms because of extremely bitter taste of the tylosin tartrate, and is not beneficial to feeding. In addition, the particle size of the prepared telavancin tartrate preparation is larger, most of the particles are in a micron level, the preparation method is still required to be further simplified to better realize industrialization, and meanwhile, the stability and the water solubility are still required to be further improved.
Therefore, there is a need in the art for a tylosin tartrate preparation which combines drug solubility, stability and palatability, has smaller particle size, simple preparation process and easy realization of industrialization.
Disclosure of Invention
Aiming at the problems, the invention aims to provide the telavancin tartrate nano preparation which can mask the strong irritation and the extremely bitter taste of the telavancin tartrate raw material medicine, has good palatability, is beneficial to feeding, has smaller particle size, is simple in preparation method, has better medicine solubility and stability and is beneficial to large-scale cultivation.
Another object of the present invention is to provide a method for preparing the above-mentioned telavancin tartrate nano-formulation.
In order to achieve the aim, the invention provides a telavancin tartrate nano preparation, which comprises the following components in parts by weight:
Tylwanin tartrate: 25 parts of
Hydroxypropyl-beta-cyclodextrin: 15-25 parts
PH regulator: 3-5 parts
Phagostimulant: 0.5-1.5 parts
Sweetener: 1-4 parts
Water-soluble auxiliary materials: 42.5-55.5 parts
Defoaming agent: 0.3 to 0.8 part of a compound,
Wherein, the tylosin tartrate accounts for 25 percent of the total weight of the tylosin tartrate nano preparation.
In some embodiments, the telavancin tartrate nano-formulation consists of the following components by weight:
Tylwanin tartrate: 25 parts of
Hydroxypropyl-beta-cyclodextrin: 20-22 parts
PH regulator: 3.5-4.5 parts
Phagostimulant: 0.7-1 part
Sweetener: 1.5-3 parts
Water-soluble auxiliary materials: 44.5-49.3 parts
Defoaming agent: 0.4-0.6 parts.
In some embodiments, the telavancin tartrate nano-formulation consists of the following components by weight:
Tylwanin tartrate: 25 parts of
Hydroxypropyl-beta-cyclodextrin: 20 parts of
PH regulator: 3.7 parts of
Phagostimulant: 0.8 part
Sweetener: 3 parts of
Water-soluble auxiliary materials: 47.5 parts
Defoaming agent: 0.6 part.
In some embodiments, the phagostimulant and sweetener comprise 3.78% of the total weight of the telavancin tartrate nano-formulation.
In some embodiments, the pH adjuster is DL-tartaric acid or malic acid, the phagostimulant is vanillin or ethyl maltol, the sweetener is a mixture of sodium saccharin and sodium cyclamate, and the water-soluble excipient is a mixture of sucrose and soluble starch.
In some embodiments, the pH adjuster is malic acid, the phagostimulant is ethyl maltol, the weight ratio of saccharin sodium to sodium cyclamate in the sweetener is 1:1-1:4, and the weight ratio of sucrose to soluble starch in the water-soluble adjuvant is 2.5:1-4:1.
In some embodiments, the weight ratio of saccharin sodium to cyclamate in the sweetener is 1:3 and the weight ratio of sucrose to soluble starch in the water soluble excipient is 3:1.
In some embodiments, the telavancin tartrate nano-formulation is a soluble powder having a particle size of 50 nm or less.
The invention further provides a preparation method of the telavancin tartrate nano-preparation, which comprises the following steps:
Step a: mixing the telavancin tartrate, the hydroxypropyl-beta-cyclodextrin and water at room temperature, and stirring for 1.5-4 hours to obtain a mixed solution A;
Step b: mixing a pH regulator, a phagostimulant, a sweetener and water-soluble auxiliary materials with water under the water bath condition of 45-55 ℃ and stirring until the solid is completely dissolved to obtain a solution B;
step c: mixing and stirring the mixed solution A and the solution B, and adding a defoaming agent to obtain a mixed solution C;
step d: and (3) carrying out spray drying treatment on the mixed solution C to obtain the telavancin tartrate nano preparation, wherein the air inlet temperature of the spray drying treatment is 130-150 ℃, the air outlet temperature is 70-90 ℃, and the sample injection flow rate is 600-800 mL/h.
In some embodiments, the method of making comprises the steps of:
Step a: mixing the telavancin tartrate, the hydroxypropyl-beta-cyclodextrin and water at room temperature, and stirring for 2-3h to obtain a mixed solution A;
Step b: mixing a pH regulator, a phagostimulant, a sweetener and water-soluble auxiliary materials with water under the water bath condition of 45-55 ℃ and stirring until the solid is completely dissolved to obtain a solution B;
step c: mixing and stirring the mixed solution A and the solution B, and adding a defoaming agent to obtain a mixed solution C;
Step d: and (3) carrying out spray drying treatment on the mixed solution C to obtain the telavancin tartrate nano preparation, wherein the air inlet temperature of the spray drying treatment is 135-145 ℃, the air outlet temperature is 70-90 ℃, and the sample injection flow rate is 600-800mL/h.
In some embodiments, the method of making comprises the steps of:
Step a: mixing and stirring the telavancin tartrate, the hydroxypropyl-beta-cyclodextrin and water for 2 hours at room temperature to obtain a mixed solution A;
step b: mixing a pH regulator, a phagostimulant, a sweetener and water-soluble auxiliary materials with water under the water bath condition of 50 ℃ and stirring until the solid is completely dissolved to obtain a solution B;
step c: mixing and stirring the mixed solution A and the solution B, and adding a defoaming agent to obtain a mixed solution C;
Step d: and (3) carrying out spray drying treatment on the mixed solution C to obtain the telavancin tartrate nano preparation, wherein the air inlet temperature of the spray drying treatment is 140 ℃, the air outlet temperature is 80 ℃, and the sample injection flow rate is 700mL/h.
In some embodiments, the tylosin tartrate comprises 3.35-5.32% of the total weight of the mixed liquor A, and the hydroxypropyl-beta-cyclodextrin comprises 2.95-4.55% of the total weight of the mixed liquor A;
In the solution B, the pH regulator accounts for 1.30-4.07% of the total weight of the solution B, the phagostimulant accounts for 0.22-0.73% of the total weight of the solution B, the sweetener accounts for 0.43-3.25% of the total weight of the solution B, and the water-soluble auxiliary material accounts for 24.13-35.37% of the total weight of the solution B;
In the mixed solution C, the weight ratio of the mixed solution A to the solution B is 2.04:1-6.07:1, and the defoamer accounts for 0.04-0.09% of the total weight of the mixed solution C.
In some embodiments, the tylosin tartrate comprises 4.55-4.61% of the total weight of the mixed liquor a, and the hydroxypropyl-beta-cyclodextrin comprises 3.14-4.55% of the total weight of the mixed liquor a;
in the solution B, the pH regulator accounts for 2.08-2.18% of the total weight of the solution B, the phagostimulant accounts for 0.45-0.47% of the total weight of the solution B, the sweetener accounts for 1.69-1.76% of the total weight of the solution B, and the water-soluble auxiliary material accounts for 25-28.37% of the total weight of the solution B;
in the mixed solution C, the weight ratio of the mixed solution A to the solution B is 3.04:1-3.24:1, and the defoamer accounts for 0.04-0.09% of the total weight of the mixed solution C.
In some embodiments, in the mixed liquor a, the tylosin tartrate comprises 4.59% of the total weight of the mixed liquor a, and the hydroxypropyl-beta-cyclodextrin comprises 3.67% of the total weight of the mixed liquor a;
in the solution B, the pH regulator accounts for 2.11 percent of the total weight of the solution B, the phagostimulant accounts for 0.46 percent of the total weight of the solution B, the sweetener accounts for 1.71 percent of the total weight of the solution B, and the water-soluble auxiliary material accounts for 27.14 percent of the total weight of the solution B;
in the mixed solution C, the weight ratio of the mixed solution A to the solution B is 3.11:1, and the defoaming agent accounts for 0.08 percent of the total weight of the mixed solution C.
Compared with the existing tylosin tartrate preparation, the tylosin tartrate nano preparation provided by the invention has the following advantages:
1. The nano preparation of the tylosin tartrate prepared by the invention is soluble powder, not only can improve the bioavailability of the tylosin tartrate, but also can highly disperse the free tylosin tartrate in water to completely dissolve the tylosin tartrate, so that the solubility of the tylosin tartrate is effectively improved, the solubility of the tylosin tartrate in the nano preparation of the tylosin tartrate can reach 15000ppm, and the solubility is higher;
2. According to the invention, the preparation process parameters, the components and the proportions thereof are optimized and selected to prepare the telavancin tartrate nano preparation, so that a better effect is achieved in the aspect of covering the pungent taste and the stronger bitter taste of the telavancin tartrate, and the telavancin tartrate nano preparation has better palatability compared with the existing product and is beneficial to large-scale cultivation;
3. the components of the telavancin tartrate nano preparation prepared by the invention are synergistic mutually, so that the preparation has better stability compared with the existing product and meets the requirements of the quality standard of soluble powder;
4. According to the preparation method, the components, the proportion and the preparation process parameters are optimized, so that the particle size of the prepared telavancin tartrate nano preparation can reach below 50 nm (30-50 nm), and therefore, compared with the existing product, the preparation method has smaller particle size, improves the fluidity and the solubility of the product, and is beneficial to realizing the industrial production and the use of a cultivation terminal;
5. the preparation method provided by the invention is simple, easy to operate, low in cost and more beneficial to industrialization.
Drawings
FIG. 1 shows a powder schematic of a telavancin tartrate nano-formulation prepared by the method of the present invention;
FIG. 2 shows a transmission electron microscope picture of a telavancin tartrate nanoformulation prepared using the method of the present invention;
FIG. 3 shows a powder schematic of the telavancin tartrate nano-formulation of the present invention and a prior telavancin tartrate formulation;
FIG. 4 shows the relative sweetness comparison of a tavancin tartrate nanoformulation of the present invention with a prior tavancin tartrate formulation;
FIG. 5 shows photographs of the solution states of the telavancin tartrate nano-formulation prepared by the method of the present invention and the commercially available telavancin tartrate formulation after being dissolved in water;
Fig. 6 shows a schematic diagram of the state of the tavancomycin tartrate nano-preparation prepared by the method of the present invention after being wrapped by aluminum foil paper for 26 days at 40 ℃ in a 75% humidity environment.
Detailed Description
The invention is described below with reference to specific examples. It will be appreciated by those skilled in the art that these examples are for illustration of the invention only and are not intended to limit the scope of the invention in any way.
The experimental methods in the following examples are conventional methods unless otherwise specified. The raw materials of the medicines, the materials of the reagents, and the like used in the examples described below are commercially available products unless otherwise specified.
EXAMPLE 1 preparation of Taqnian tartrate nano-formulation 1
Mixing 25g of tylosin tartrate, 17g of hydroxypropyl-beta-cyclodextrin and 500g of water at room temperature and stirring for 2 hours to obtain a mixed solution A, wherein the tylosin tartrate accounts for 4.61% of the total weight of the mixed solution A, and the hydroxypropyl-beta-cyclodextrin accounts for 3.14% of the total weight of the mixed solution A;
Under the water bath condition of 45 ℃, 3.7g of pH regulator malic acid, 0.8g of phagostimulant ethyl maltol, 3g of sweetener (a mixture of saccharin sodium and sodium cyclamate with the weight ratio of 1:3), 50.5g of water-soluble auxiliary material (a mixture of sucrose and soluble starch with the weight ratio of 3:1) and 120g of water are mixed and stirred until the water is completely dissolved to obtain solution B, wherein the pH regulator accounts for 2.08 percent of the total weight of the solution B, the phagostimulant accounts for 0.45 percent of the total weight of the solution B, the sweetener accounts for 1.69 percent of the total weight of the solution B, and the water-soluble auxiliary material accounts for 28.37 percent of the total weight of the solution B;
Mixing and stirring the mixed solution A and the solution B, and adding 0.6g of an antifoaming agent (CAS accession number: 63148-62-9, available from New Material Co., ltd., buddha) to obtain a mixed solution C, wherein the weight ratio of the mixed solution A to the solution B is 3.04:1, and the antifoaming agent accounts for 0.08% of the total weight of the mixed solution C;
And (3) carrying out spray drying treatment on the mixed solution C to obtain the telavancin tartrate nano preparation powder, wherein the air inlet temperature of the spray drying treatment is 135 ℃, the air outlet temperature is 70 ℃, and the sample injection flow rate is 700 mL/h.
Example 2 preparation of telavancin tartrate nano-formulation 2
Mixing 25g of tylosin tartrate, 20g of hydroxypropyl-beta-cyclodextrin and 500g of water at room temperature and stirring for 2 hours to obtain a mixed solution A, wherein the tylosin tartrate accounts for 4.59% of the total weight of the mixed solution A, and the hydroxypropyl-beta-cyclodextrin accounts for 3.67% of the total weight of the mixed solution A;
under the water bath condition of 50 ℃, 3.7g of pH regulator malic acid, 0.8g of phagostimulant ethyl maltol, 3g of sweetener (a mixture of saccharin sodium and sodium cyclamate with the weight ratio of 1:3), 47.5g of water-soluble auxiliary material (a mixture of sucrose and soluble starch with the weight ratio of 3:1) and 120g of water are mixed and stirred until the water is completely dissolved to obtain solution B, wherein the pH regulator accounts for 2.11 percent of the total weight of the solution B, the phagostimulant accounts for 0.46 percent of the total weight of the solution B, the sweetener accounts for 1.71 percent of the total weight of the solution B, and the water-soluble auxiliary material accounts for 27.14 percent of the total weight of the solution B;
Mixing and stirring the mixed solution A and the solution B, and adding 0.6g of an antifoaming agent (CAS accession number: 63148-62-9, available from New Material Co., ltd., buddha) to obtain a mixed solution C, wherein the weight ratio of the mixed solution A to the solution B is 3.11:1, and the antifoaming agent accounts for 0.08% of the total weight of the mixed solution C;
and (3) carrying out spray drying treatment on the mixed solution C to obtain the telavancin tartrate nano preparation powder, wherein the air inlet temperature of the spray drying treatment is 140 ℃, the air outlet temperature is 80 ℃, and the sample injection flow rate is 700 mL/h.
Example 3 preparation of telavancin tartrate nano-formulation 3
Mixing 25g of tylosin tartrate, 25g of hydroxypropyl-beta-cyclodextrin and 500g of water at room temperature and stirring for 2 hours to obtain a mixed solution A, wherein the tylosin tartrate accounts for 4.55% of the total weight of the mixed solution A, and the hydroxypropyl-beta-cyclodextrin accounts for 4.55% of the total weight of the mixed solution A;
Under the water bath condition of 50 ℃, 3.7g of pH regulator malic acid, 0.8g of phagostimulant ethyl maltol, 3g of sweetener (a mixture of saccharin sodium and sodium cyclamate with the weight ratio of 1:3), 42.5g of water-soluble auxiliary material (a mixture of sucrose and soluble starch with the weight ratio of 3:1) and 120g of water are mixed and stirred until the water is completely dissolved to obtain solution B, wherein the pH regulator accounts for 2.18 percent of the total weight of the solution B, the phagostimulant accounts for 0.47 percent of the total weight of the solution B, the sweetener accounts for 1.76 percent of the total weight of the solution B, and the water-soluble auxiliary material accounts for 25 percent of the total weight of the solution B;
Mixing and stirring the mixed solution A and the solution B, and adding 0.6g of an antifoaming agent (CAS accession number: 63148-62-9, available from New Material Co., ltd., buddha) to obtain a mixed solution C, wherein the weight ratio of the mixed solution A to the solution B is 3.24:1, and the antifoaming agent accounts for 0.08% of the total weight of the mixed solution C;
and (3) carrying out spray drying treatment on the mixed solution C to obtain the telavancin tartrate nano preparation powder, wherein the air inlet temperature of the spray drying treatment is 140 ℃, the air outlet temperature is 80 ℃, and the sample injection flow rate is 700 mL/h.
Example 4 preparation of telavancin tartrate nano-formulation 4
At room temperature, 25g of tylosin tartrate, 15g of hydroxypropyl-beta-cyclodextrin and 430g of water are mixed and stirred for 1.5 hours to obtain a mixed solution A, wherein the tylosin tartrate accounts for 5.32% of the total weight of the mixed solution A, and the hydroxypropyl-beta-cyclodextrin accounts for 3.19% of the total weight of the mixed solution A;
Under the condition of a water bath at 55 ℃, 3g of pH regulator malic acid, 0.5g of phagostimulant vanillin, 1g of sweetener (a mixture of saccharin sodium and sodium cyclamate with the weight ratio of 1:1), 55.5g of water-soluble auxiliary material (a mixture of sucrose and soluble starch with the weight ratio of 3:1) and 170g of water are mixed and stirred until the water is completely dissolved to obtain solution B, wherein the pH regulator accounts for 1.3% of the total weight of the solution B, the phagostimulant accounts for 0.22% of the total weight of the solution B, the sweetener accounts for 0.43% of the total weight of the solution B, and the water-soluble auxiliary material accounts for 24.13% of the total weight of the solution B;
mixing and stirring the mixed solution A and the solution B, and adding 0.3g of an antifoaming agent (CAS accession number: 63148-62-9, available from New Material Co., ltd., buddha) to obtain a mixed solution C, wherein the weight ratio of the mixed solution A to the solution B is 2.04:1, and the antifoaming agent accounts for 0.04% of the total weight of the mixed solution C;
and (3) carrying out spray drying treatment on the mixed solution C to obtain the telavancin tartrate nano preparation powder, wherein the air inlet temperature of the spray drying treatment is 130 ℃, the air outlet temperature is 85 ℃, and the sample injection flow rate is 600 mL/h.
Example 5 preparation of telavancin tartrate nano-formulation 5
Mixing 25g of tylosin tartrate, 20g of hydroxypropyl-beta-cyclodextrin and 450g of water at room temperature, and stirring for 2.5 hours to obtain a mixed solution A, wherein the tylosin tartrate accounts for 5.05% of the total weight of the mixed solution A, and the hydroxypropyl-beta-cyclodextrin accounts for 4.04% of the total weight of the mixed solution A;
3.5g of a pH regulator DL-tartaric acid, 0.7g of a phagostimulant ethyl maltol, 1.5g of a sweetener (a mixture of saccharin sodium and sodium cyclamate in a weight ratio of 1:3) and 49.3g of a water-soluble auxiliary material (a mixture of sucrose and soluble starch in a weight ratio of 2.5:1) are mixed with 140g of water under the water bath condition of 50 ℃ and stirred until the water-soluble auxiliary material is completely dissolved to obtain a solution B, wherein the pH regulator accounts for 1.79 percent of the total weight of the solution B, the phagostimulant accounts for 0.36 percent of the total weight of the solution B, the sweetener accounts for 0.77 percent of the total weight of the solution B, and the water-soluble auxiliary material accounts for 25.28 percent of the total weight of the solution B;
mixing and stirring the mixed solution A and the solution B, and adding 0.4g of an antifoaming agent (CAS accession number: 63148-62-9, available from New Material Co., ltd., buddha) to obtain a mixed solution C, wherein the weight ratio of the mixed solution A to the solution B is 2.54:1, and the antifoaming agent accounts for 0.06% of the total weight of the mixed solution C;
and (3) carrying out spray drying treatment on the mixed solution C to obtain the telavancin tartrate nano preparation powder, wherein the air inlet temperature of the spray drying treatment is 145 ℃, the air outlet temperature is 90 ℃, and the sample injection flow rate is 700 mL/h.
Example 6 preparation of telavancin tartrate nano-formulation 6
At room temperature, 25g of tylosin tartrate, 21g of hydroxypropyl-beta-cyclodextrin and 660g of water are mixed and stirred for 3 hours to obtain a mixed solution A, wherein the tylosin tartrate accounts for 3.54% of the total weight of the mixed solution A, and the hydroxypropyl-beta-cyclodextrin accounts for 2.97% of the total weight of the mixed solution A;
Mixing 4.5g of pH regulator malic acid, 1g of phagostimulant ethyl maltol, 2.3g of sweetener (a mixture of saccharin sodium and sodium cyclamate with the weight ratio of 1:4), 44.5g of water-soluble auxiliary material (a mixture of sucrose and soluble starch with the weight ratio of 4:1) and 85g of water under the water bath condition of 50 ℃ and stirring until the water-soluble auxiliary material is completely dissolved to obtain solution B, wherein the pH regulator accounts for 3.28 percent of the total weight of the solution B, the phagostimulant accounts for 0.73 percent of the total weight of the solution B, the sweetener accounts for 1.68 percent of the total weight of the solution B, and the water-soluble auxiliary material accounts for 32.41 percent of the total weight of the solution B;
Mixing and stirring the mixed solution A and the solution B, and adding 0.5g of an antifoaming agent (CAS accession number: 63148-62-9, available from New Material Co., ltd., buddha) to obtain a mixed solution C, wherein the weight ratio of the mixed solution A to the solution B is 5.14:1, and the antifoaming agent accounts for 0.06% of the total weight of the mixed solution C;
And (3) carrying out spray drying treatment on the mixed solution C to obtain the telavancin tartrate nano preparation powder, wherein the air inlet temperature of the spray drying treatment is 150 ℃, the air outlet temperature is 80 ℃, and the sample injection flow rate is 800 mL/h.
EXAMPLE 7 preparation of Tawansin Tawann tartrate nano-formulation 7
Mixing 25g of tylosin tartrate, 22g of hydroxypropyl-beta-cyclodextrin and 700g of water at room temperature, and stirring for 4 hours to obtain a mixed solution A, wherein the tylosin tartrate accounts for 3.35% of the total weight of the mixed solution A, and the hydroxypropyl-beta-cyclodextrin accounts for 2.95% of the total weight of the mixed solution A;
5g of a pH regulator DL-tartaric acid, 1.5g of a phagostimulant ethyl maltol, 4g of a sweetener (a mixture of saccharin sodium and sodium cyclamate in a weight ratio of 1:3), 43.5g of a water-soluble auxiliary material (a mixture of sucrose and soluble starch in a weight ratio of 3:1) and 70g of water are mixed and stirred until the water is completely dissolved under the water bath condition at 50 ℃ to obtain a solution B, wherein the pH regulator accounts for 4.07 percent of the total weight of the solution B, the phagostimulant accounts for 0.41 percent of the total weight of the solution B, the sweetener accounts for 3.25 percent of the total weight of the solution B, and the water-soluble auxiliary material accounts for 35.37 percent of the total weight of the solution B;
Mixing and stirring the mixed solution A and the solution B, and adding 0.8g of an antifoaming agent (CAS accession number: 63148-62-9, available from New Material Co., ltd., buddha) to obtain a mixed solution C, wherein the weight ratio of the mixed solution A to the solution B is 6.07:1, and the antifoaming agent accounts for 0.09% of the total weight of the mixed solution C;
and (3) carrying out spray drying treatment on the mixed solution C to obtain the telavancin tartrate nano preparation powder, wherein the air inlet temperature of the spray drying treatment is 140 ℃, the air outlet temperature is 80 ℃, and the sample injection flow rate is 700 mL/h.
Comparative example 1 preparation of telavancin tartrate preparation
25G of telavancin tartrate and 500g of water are mixed and stirred for 2h at room temperature to obtain a mixed solution A;
3.7g of pH regulator malic acid, 0.8g of phagostimulant ethyl maltol, 3g of sweetener (a mixture of saccharin sodium and sodium cyclamate with the weight ratio of 1:3) and 67.5g of water-soluble auxiliary material (a mixture of sucrose and soluble starch with the weight ratio of 3:1) are mixed with 120g of water under the water bath condition of 50 ℃ and stirred until the solid is completely dissolved, so as to obtain solution B;
mixing and stirring the mixed solution A and the solution B, and adding 0.6g of an antifoaming agent (CAS registry number: 63148-62-9, available from New Material Co., ltd., buddha) to obtain a mixed solution C;
And (3) carrying out spray drying treatment on the mixed solution C to obtain the telavancin tartrate preparation powder, wherein the air inlet temperature of the spray drying treatment is 140 ℃, the air outlet temperature is 80 ℃, and the sample injection flow rate is 700 mL/h. ( And (3) injection: this comparative example is essentially the same as example 2, except that no hydroxypropyl-beta-cyclodextrin was added )
Comparative example 2 preparation of telavancin tartrate preparation
25G of telavancin tartrate, 20g of hydroxypropyl-beta-cyclodextrin and 500g of water are mixed and stirred for 2h at room temperature to obtain a mixed solution A;
3.7g of pH regulator malic acid, 0.8g of phagostimulant vanillin, 1.5g of sweetener (a mixture of saccharin sodium and sodium cyclamate with the weight ratio of 1:3) and 49g of water-soluble auxiliary material (a mixture of sucrose and soluble starch with the weight ratio of 3:1) are mixed with 120g of water under the water bath condition of 50 ℃ and stirred until the solid is completely dissolved, so as to obtain solution B;
mixing and stirring the mixed solution A and the solution B, and adding 0.6g of an antifoaming agent (CAS registry number: 63148-62-9, available from New Material Co., ltd., buddha) to obtain a mixed solution C;
And (3) carrying out spray drying treatment on the mixed solution C to obtain the telavancin tartrate preparation powder, wherein the air inlet temperature of the spray drying treatment is 140 ℃, the air outlet temperature is 80 ℃, and the sample injection flow rate is 700 mL/h. ( And (3) injection: this comparative example is essentially the same as example 2, except that the phagostimulant is changed from ethyl maltol to vanillin, the amount of sweetener is reduced by 50% )
Comparative example 3 preparation of telavancin tartrate preparation
25G of telavancin tartrate, 20g of hydroxypropyl-beta-cyclodextrin and 500g of water are mixed and stirred for 2h at room temperature to obtain a mixed solution A;
under the water bath condition of 50 ℃, 3.7g of pH regulator malic acid, 51.3g of water-soluble auxiliary material (a mixture of sucrose and soluble starch with the weight ratio of 3:1) and 120g of water are mixed and stirred until the solid is completely dissolved, so as to obtain solution B;
mixing and stirring the mixed solution A and the solution B, and adding 0.6g of an antifoaming agent (CAS registry number: 63148-62-9, available from New Material Co., ltd., buddha) to obtain a mixed solution C;
And (3) carrying out spray drying treatment on the mixed solution C to obtain the telavancin tartrate preparation powder, wherein the air inlet temperature of the spray drying treatment is 140 ℃, the air outlet temperature is 80 ℃, and the sample injection flow rate is 700 mL/h. ( And (3) injection: this comparative example is essentially the same as example 2, except that no phagostimulant and sweetener are added )
Test 1 flowability test of telavancin tartrate nano-formulations
The tavancomycin tartrate nano-formulation powder prepared in example 2 of the present invention was filled into vials (see fig. 1), and the vials were shaken to observe fluidity thereof.
Fig. 1 shows a powder schematic diagram of a telavancin tartrate nano-preparation prepared by the method of the present invention, and from the figure, it is seen that the telavancin tartrate nano-preparation prepared in example 2 of the present invention is white powder with good fluidity.
Test 2 surface topography test of telavancin tartrate nano-formulations
The surface morphology of the telavancin tartrate nano-formulation prepared in example 2 of the present invention was observed using a transmission electron microscope (HITACHI, HT 7700).
Figures 2A and 2B show transmission electron microscope pictures of a telavancin tartrate nano-formulation prepared using the method of the present invention. As shown in the figure, the nano preparation of the telavancin tartrate has smaller particle size, and the particles are uniformly dispersed within the range of 30-50 nm.
Test 3 taste test of telavancin tartrate nano-formulations
The respective 0.2g of the tavern tartrate nano-preparation powder prepared in example 2 (shown in fig. 3C), comparative example 2 and comparative example 3 of the present invention, the conventional commercially available 25% tavern tartrate soluble powder 1 (labeled as commercially available commodity 1 in zhejiang israel health products limited, as shown in fig. 3A), the conventional commercially available 25% tavern tartrate soluble powder 2 (labeled as commercially available commodity 2 in the case of the lozenges of the joint venture, as shown in fig. 3B) and the tavern tartrate preparation prepared according to the scheme of example 2 of the specification of chinese patent (CN 114469869 a) were taken, and the sweetness score was given by a tasting manner, wherein the sweetness score was evaluated based on "score" with sucrose as a standard, the sucrose was 10 minutes, and the tavern tartrate raw material was 0 minutes (extremely bitter). The relative sweetness of each of the tylwanin tartrate formulations relative to sucrose (wherein the relative sweetness of the tylwanin tartrate starting material is noted as 0) was additionally calculated and the test results are shown in table 1 and fig. 4.
Table 1 taste test scores for the tavancin tartrate nano-formulations of the present invention and existing tavancin tartrate formulations
As can be seen from table 1 and fig. 4, the tayloxacin tartrate nano-preparation prepared in the embodiment of the invention smells faint scent, has slightly sour and slightly bitter taste, the score is 9 minutes, the relative sweetness is 0.9, while the taste of the commercial products 1 and 2 and the tayloxacin tartrate preparation prepared according to patent (CN 114469869 a) is bitter, the score is less than 4 minutes, and the relative sweetness is less than 0.4, so that the tayloxacin tartrate nano-preparation prepared in the invention has greatly improved taste masking effect compared with the conventional tayloxacin tartrate preparation, has better palatability, and is more beneficial to large-scale cultivation.
In addition, the amount of sweetener was reduced by 50% from ethyl maltol to vanillin in comparative example 2, the sweetness score was 6, the relative sweetness was 0.6, and the sweetness score was reduced in comparison with the tavancomycin tartrate nano-preparation of example 2, indicating that the selection of the material of the phagostimulant and the amount of sweetener had a greater influence on the taste of the tavancomycin tartrate preparation.
In addition, compared with example 2, the sweet score of comparative example 3, in which no phagostimulant and sweetener were added, was 3, and the relative sweetness was 0.3, and compared with the tayloxacillin tartrate nano-preparation of example 2, the sweet score was significantly reduced, the taste was bitter, indicating that the selection of the amount of phagostimulant and sweetener had a large influence on the taste of the tayloxacillin tartrate preparation.
Test for solubility test of telavancin 4 tartrate nano-formulations
Test 1: 1g, 2g, 3g, 4g, 5g and 6g of the telavancin tartrate nano preparation powder prepared in the examples 1,2 and 3 of the invention, commercial product 1 and commercial product 2 are respectively taken and added into 100mL of water, and the mixture is immediately hand-operated for a certain time, then the mixture is stood to foam the solution, and after foam removal, the dissolution condition of each preparation is observed. The test results are shown in tables 2 and 3 (defoaming time in the tables is time from the start of standing of the solution to complete defoaming, and complete dissolution time is time from complete defoaming of the solution to complete dissolution of the sample).
TABLE 2 solubility data of the Tawansin tartrate nano-formulations of the invention and the existing Tawansin tartrate formulations at concentrations of 0.01-0.03g/mL
TABLE 3 solubility data of the Tawansin tartrate nano-formulations of the invention and the existing Tawansin tartrate formulations at concentrations of 0.04-0.06g/mL
As can be seen from tables 1 and 2, the defoaming time of the tylosin tartrate nano-formulations of examples 1 to 3 of the present invention at the concentrations of 0.01g/mL, 0.02g/mL, 0.03g/mL, 0.04g/mL, 0.05g/mL, 0.06g/mL were 4s, 5s, 7s, respectively, whereas the defoaming time of the commercially available product 1 at the concentrations of 0.01g/mL, 0.02g/mL, 0.03g/mL, 0.04g/mL were 10s, 15s, 30s, respectively, and the defoaming time of the commercially available product 2 at the concentrations of 0.01g/mL, 0.02g/mL, 0.03g/mL, 0.04g/mL, 0.05g/mL, 0.06g/mL was 5s, 8s, 11s, 15s, 21s, respectively, which is significantly shorter than that of the commercially available product.
In addition, the tylosin tartrate nano preparation of the embodiment 1-3 of the invention can realize complete dissolution when being hand-operated for 20s-1min at the concentration of 0.01-0.06g/mL, and the time required for complete dissolution at the concentrations of 0.01g/mL, 0.02g/mL, 0.03g/mL, 0.04g/mL, 0.05g/mL and 0.06g/mL is respectively 25-45s, 1-1.5min, 1.5-2min, 2-3min, 2.6-4.5min and 3.2-6min, while the solution is still relatively turbid when the commercial product 1 is hand-operated for 2-6min at the concentration of 0.02-0.04g/mL, and the time required for complete dissolution at the concentration of 0.01g/mL is 4-7.2 times of the time required for complete dissolution (25-45 s) of the tylosin tartrate nano preparation of the invention when being hand-operated for 20 s; when the commercial product 2 is hand-operated for 10-25min at the concentration of 0.05-0.06g/mL, the solution is still turbid and can not be completely dissolved, the time required for complete dissolution at the concentration of 0.01g/mL, 0.02g/mL, 0.03g/mL and 0.04g/mL is respectively 2min, 5min, 10min and 16min, which are far longer than the time required for complete dissolution of the telavancin tartrate nano preparation (25-45 s, 1-1.5min, 1.5-2min and 2-3 min) at the same concentration, and the time required for complete dissolution at the concentration of 0.01g/mL (2 min) is 2.7-4.8 times the time required for complete dissolution of the telavancin tartrate nano preparation (25-45 s). Therefore, under the same conditions, the time required for complete dissolution of the telavancin tartrate nano-preparation provided by the invention is obviously shortened compared with that of a commercially available product.
In conclusion, compared with the commercial products, the defoaming time and the complete dissolution time of the telavancin tartrate nano preparation are obviously shortened, and the solubility is obviously improved.
In addition, compared with example 2, the mixed solution C prepared in comparative example 1, to which no hydroxypropyl-beta-cyclodextrin was added, had much of the tayloxacin tartrate as a raw material, and the spray nozzle was blocked during spray drying, so that no preparation could be prepared, indicating that the amount of hydroxypropyl-beta-cyclodextrin had a large influence on the dissolution of the tayloxacin tartrate as a raw material of the preparation.
Comparing the solubility data of examples 1-3 of the present invention in tables 2 and 3, it can be seen that the tavancin tartrate nano-formulation prepared in example 2 has a shorter dissolution time and the best solubility under the same hand shaking time and concentration. The preferred telavancin tartrate nano-formulation prepared in the preferred embodiment 2 of the present invention is the preferred telavancin tartrate nano-formulation of the present invention.
Test 2: 1g, 3g and 6g of the telavancin tartrate nano-preparation powder prepared in the embodiment 2 of the invention, a commercial product 1 and a commercial product 2 are respectively taken and added into 100mL of water, and the mixture is respectively hand-operated for 20s, 35s and 60s, then respectively kept stand for 29s, 94s and 199s, and a picture of the dissolution state of each preparation is taken.
FIG. 5 shows photographs of the solution state of the telavancin tartrate nano-formulation (FIG. 5C) prepared in example 2 of the present invention after standing at 0.01g/mL for 29s, at 0.03g/mL for 94s, and at 0.06g/mL for 199s, respectively, with commercial article 1 (FIG. 5A) and commercial article 2 (FIG. 5B). As seen in FIG. 5, the telavancin tartrate nano-formulation of the present invention was completely dissolved when left to stand for 29s at a concentration of 0.01g/mL, the solution was clear and transparent, completely defoamed, while the solutions of commercial products 1 and 2 were slightly cloudy, not completely dissolved, and more air bubbles were present above the solution. When the nano preparation of the telavancin tartrate is stood for 94 seconds at the concentration of 0.03g/mL, the solution is clear and transparent and is completely defoamed, the solution of the commercial product 1 is cloudy and is not completely dissolved, more bubbles are arranged above the solution, the solution of the commercial product 2 is slightly cloudy and is not completely dissolved, and more bubbles are arranged above the solution. When the nano preparation of the telavancin tartrate is stood for 199 seconds at the concentration of 0.06g/mL, the solution is clear and transparent and is completely defoamed, the solutions of the commercial products 1 and 2 are turbid, the solution is not completely dissolved, and a few bubbles exist above the solution. Therefore, the solubility of the telavancin tartrate nano preparation provided by the invention under the same conditions is obviously superior to that of the commercial product.
Test example 5 stability test of telavancin tartrate nano-formulations
16.49G of the telavancin tartrate nano-preparation prepared in the example 2 of the present invention was wrapped with aluminum foil paper at 25 ℃, 65% humidity and 40 ℃ and 75% humidity for storage, and weighed on days 7, 12, 18 and 26, respectively, to test the weight change of the telavancin tartrate nano-preparation. The test results are shown in Table 4.
TABLE 4 weight changes of the tylosin tartrate nano-formulations of the present invention stored under different conditions
Fig. 6 shows a schematic diagram of the state of the tavancomycin tartrate nano-preparation prepared by the method of the present invention after being wrapped by aluminum foil paper for 26 days at 40 ℃ in a 75% humidity environment. As shown in FIG. 6, the tylosin tartrate nano preparation of the invention is white powder after being wrapped by aluminum foil paper for 26 days at 40 ℃ in a 75% humidity environment, particles are not agglomerated, and the state is almost no different from the state before storage. As can be seen from Table 4, the weight of the tavancin tartrate nano-preparation of the invention is hardly changed after being stored for 26 days at 25 ℃, 65% humidity and 75% humidity, which indicates that the tavancin tartrate nano-preparation of the invention has better storage stability.
While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. The following claims are intended to define the scope of the invention and their methods and structures and their equivalents are covered thereby.
Claims (9)
1. A telavancin tartrate nano-formulation, which consists of the following components by weight:
Tylwanin tartrate: 25 parts of
Hydroxypropyl-beta-cyclodextrin: 20-22 parts
PH regulator: 3.5-4.5 parts
Phagostimulant: 0.7-1 part
Sweetener: 1.5-3 parts
Water-soluble auxiliary materials: 44.5-49.3 parts
Defoaming agent: 0.4 to 0.6 part of a compound,
Wherein, the tylosin tartrate accounts for 25 percent of the total weight of the tylosin tartrate nano preparation; the phagostimulant and the sweetener account for 3.78% of the total weight of the telavancin tartrate nano-preparation; the pH regulator is malic acid, the phagostimulant is vanillin or ethyl maltol, the sweetener is a mixture of saccharin sodium and sodium cyclamate, the water-soluble auxiliary material is a mixture of sucrose and soluble starch, the weight ratio of the saccharin sodium to the sodium cyclamate in the sweetener is 1:3, and the weight ratio of the sucrose to the soluble starch in the water-soluble auxiliary material is 2.5:1-4:1; the particle size of the telavancin tartrate nano preparation is less than or equal to 50 nm;
The preparation method of the telavancin tartrate nano preparation comprises the following steps:
Step a: mixing the telavancin tartrate, the hydroxypropyl-beta-cyclodextrin and water at room temperature, and stirring for 1.5-4 hours to obtain a mixed solution A;
Step b: mixing a pH regulator, a phagostimulant, a sweetener and water-soluble auxiliary materials with water under the water bath condition of 45-55 ℃ and stirring until the solid is completely dissolved to obtain a solution B;
step c: mixing and stirring the mixed solution A and the solution B, and adding a defoaming agent to obtain a mixed solution C;
Step d: carrying out spray drying treatment on the mixed solution C to obtain a telavancin tartrate nano preparation, wherein the air inlet temperature of the spray drying treatment is 130-150 ℃, the air outlet temperature is 70-90 ℃, and the sample injection flow rate is 600-800 mL/h;
In the mixed solution A, the tylosin tartrate accounts for 4.55-4.61% of the total weight of the mixed solution A, and the hydroxypropyl-beta-cyclodextrin accounts for 3.14-4.55% of the total weight of the mixed solution A;
in the solution B, the pH regulator accounts for 2.08-2.18% of the total weight of the solution B, the phagostimulant accounts for 0.45-0.47% of the total weight of the solution B, the sweetener accounts for 1.69-1.76% of the total weight of the solution B, and the water-soluble auxiliary material accounts for 25-28.37% of the total weight of the solution B;
in the mixed solution C, the weight ratio of the mixed solution A to the solution B is 3.04:1-3.24:1, and the defoamer accounts for 0.04-0.09% of the total weight of the mixed solution C.
2. The telavancin tartrate nano-formulation according to claim 1, characterized in that it consists of the following components by weight:
Tylwanin tartrate: 25 parts of
Hydroxypropyl-beta-cyclodextrin: 20 parts of
PH regulator: 3.7 parts of
Phagostimulant: 0.8 part
Sweetener: 3 parts of
Water-soluble auxiliary materials: 47.5 parts
Defoaming agent: 0.6 part.
3. The nano-formulation of telavancin tartrate according to claim 1, wherein the phagostimulant is ethyl maltol.
4. The telavancin tartrate nano-formulation according to claim 1, wherein the weight ratio of sucrose to soluble starch in the water-soluble adjuvant is 3:1.
5. The telavancin tartrate nano-formulation of claim 1, wherein the telavancin tartrate nano-formulation is a soluble powder.
6. A process for the preparation of a telavancin tartrate nano-formulation according to any one of claims 1-5, comprising the steps of:
Step a: mixing the telavancin tartrate, the hydroxypropyl-beta-cyclodextrin and water at room temperature, and stirring for 1.5-4 hours to obtain a mixed solution A;
Step b: mixing a pH regulator, a phagostimulant, a sweetener and water-soluble auxiliary materials with water under the water bath condition of 45-55 ℃ and stirring until the solid is completely dissolved to obtain a solution B;
step c: mixing and stirring the mixed solution A and the solution B, and adding a defoaming agent to obtain a mixed solution C;
step d: and (3) carrying out spray drying treatment on the mixed solution C to obtain the telavancin tartrate nano preparation, wherein the air inlet temperature of the spray drying treatment is 130-150 ℃, the air outlet temperature is 70-90 ℃, and the sample injection flow rate is 600-800 mL/h.
7. The preparation method according to claim 6, characterized in that the preparation method comprises the steps of:
Step a: mixing the telavancin tartrate, the hydroxypropyl-beta-cyclodextrin and water at room temperature, and stirring for 2-3h to obtain a mixed solution A;
Step b: mixing a pH regulator, a phagostimulant, a sweetener and water-soluble auxiliary materials with water under the water bath condition of 45-55 ℃ and stirring until the solid is completely dissolved to obtain a solution B;
step c: mixing and stirring the mixed solution A and the solution B, and adding a defoaming agent to obtain a mixed solution C;
Step d: and (3) carrying out spray drying treatment on the mixed solution C to obtain the telavancin tartrate nano preparation, wherein the air inlet temperature of the spray drying treatment is 135-145 ℃, the air outlet temperature is 70-90 ℃, and the sample injection flow rate is 600-800mL/h.
8. The preparation method according to claim 7, characterized in that the preparation method comprises the steps of:
Step a: mixing and stirring the telavancin tartrate, the hydroxypropyl-beta-cyclodextrin and water for 2 hours at room temperature to obtain a mixed solution A;
step b: mixing a pH regulator, a phagostimulant, a sweetener and water-soluble auxiliary materials with water under the water bath condition of 50 ℃ and stirring until the solid is completely dissolved to obtain a solution B;
step c: mixing and stirring the mixed solution A and the solution B, and adding a defoaming agent to obtain a mixed solution C;
Step d: and (3) carrying out spray drying treatment on the mixed solution C to obtain the telavancin tartrate nano preparation, wherein the air inlet temperature of the spray drying treatment is 140 ℃, the air outlet temperature is 80 ℃, and the sample injection flow rate is 700mL/h.
9. The preparation method of claim 8, wherein in the mixed solution a, the tylosin tartrate accounts for 4.59% of the total weight of the mixed solution a, and the hydroxypropyl-beta-cyclodextrin accounts for 3.67% of the total weight of the mixed solution a;
in the solution B, the pH regulator accounts for 2.11 percent of the total weight of the solution B, the phagostimulant accounts for 0.46 percent of the total weight of the solution B, the sweetener accounts for 1.71 percent of the total weight of the solution B, and the water-soluble auxiliary material accounts for 27.14 percent of the total weight of the solution B;
in the mixed solution C, the weight ratio of the mixed solution A to the solution B is 3.11:1, and the defoaming agent accounts for 0.08 percent of the total weight of the mixed solution C.
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| CN113197864A (en) * | 2021-05-07 | 2021-08-03 | 江苏恒丰强生物技术有限公司 | Tylosin tartrate soluble powder and preparation method thereof |
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