CN116650418A - Alendronate sodium liposome and preparation thereof - Google Patents
Alendronate sodium liposome and preparation thereof Download PDFInfo
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- CN116650418A CN116650418A CN202310657029.6A CN202310657029A CN116650418A CN 116650418 A CN116650418 A CN 116650418A CN 202310657029 A CN202310657029 A CN 202310657029A CN 116650418 A CN116650418 A CN 116650418A
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- Prior art keywords
- alendronate sodium
- liposome
- alendronate
- sodium
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- 229960004343 alendronic acid Drugs 0.000 title claims abstract description 159
- 239000002502 liposome Substances 0.000 title claims abstract description 114
- 238000002360 preparation method Methods 0.000 title claims abstract description 40
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 title abstract description 148
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims abstract description 38
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 claims abstract description 38
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims abstract description 21
- 235000012000 cholesterol Nutrition 0.000 claims abstract description 19
- 239000008347 soybean phospholipid Substances 0.000 claims abstract description 19
- 239000011259 mixed solution Substances 0.000 claims description 42
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- 239000007853 buffer solution Substances 0.000 claims description 25
- DCSBSVSZJRSITC-UHFFFAOYSA-M alendronate sodium trihydrate Chemical compound O.O.O.[Na+].NCCCC(O)(P(O)(O)=O)P(O)([O-])=O DCSBSVSZJRSITC-UHFFFAOYSA-M 0.000 claims description 24
- 238000002390 rotary evaporation Methods 0.000 claims description 24
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 22
- 239000002775 capsule Substances 0.000 claims description 15
- 150000002632 lipids Chemical class 0.000 claims description 14
- 239000012043 crude product Substances 0.000 claims description 13
- 238000001035 drying Methods 0.000 claims description 12
- 239000000047 product Substances 0.000 claims description 12
- 238000000265 homogenisation Methods 0.000 claims description 11
- 238000001471 micro-filtration Methods 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000008187 granular material Substances 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 3
- 239000007983 Tris buffer Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims description 2
- 229940083466 soybean lecithin Drugs 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims 2
- 239000000203 mixture Substances 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000000463 material Substances 0.000 abstract description 20
- 238000005538 encapsulation Methods 0.000 abstract description 15
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 239000003814 drug Substances 0.000 description 18
- 230000000052 comparative effect Effects 0.000 description 14
- 229940079593 drug Drugs 0.000 description 14
- 208000001132 Osteoporosis Diseases 0.000 description 10
- 239000002245 particle Substances 0.000 description 7
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- 239000003995 emulsifying agent Substances 0.000 description 5
- 229920002472 Starch Polymers 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
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- 229940122361 Bisphosphonate Drugs 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 150000004663 bisphosphonates Chemical class 0.000 description 3
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- 238000003908 quality control method Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 206010039984 Senile osteoporosis Diseases 0.000 description 2
- 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 2
- 239000011230 binding agent Substances 0.000 description 2
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
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- 235000015424 sodium Nutrition 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
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- 239000000661 sodium alginate Substances 0.000 description 2
- 229940005550 sodium alginate Drugs 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- 102000055006 Calcitonin Human genes 0.000 description 1
- 108060001064 Calcitonin Proteins 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 208000010191 Osteitis Deformans Diseases 0.000 description 1
- 208000027067 Paget disease of bone Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
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- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 208000016738 bone Paget disease Diseases 0.000 description 1
- 230000037182 bone density Effects 0.000 description 1
- 230000024279 bone resorption Effects 0.000 description 1
- 229960004015 calcitonin Drugs 0.000 description 1
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 235000019425 dextrin Nutrition 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
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000004821 effect on bone Effects 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
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- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229940001490 fosamax Drugs 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
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- 238000010438 heat treatment Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000009245 menopause Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229960002900 methylcellulose Drugs 0.000 description 1
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- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
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- 238000004321 preservation Methods 0.000 description 1
- 238000013441 quality evaluation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 229910021487 silica fume Inorganic materials 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1277—Processes for preparing; Proliposomes
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
- A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic 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
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- 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
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to alendronate sodium liposome and a preparation thereof. The alendronate sodium liposome comprises 10 parts by weight of alendronate sodium, 8-15 parts by weight of soybean phospholipid, 1-3 parts by weight of cholesterol and 0.4-0.8 part by weight of tetrabutylammonium bisulfate. The invention optimizes liposome materials such as soybean phospholipid, cholesterol, tetrabutylammonium bisulfate and the like, optimizes the preparation process, solves the problem of low encapsulation efficiency of alendronate sodium liposome in the prior art, and has encapsulation efficiency higher than 80 percent.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to alendronate sodium liposome and a preparation thereof.
Background
Osteoporosis is a worldwide health problem that is becoming more and more important. About 2 hundred million people worldwide suffer from osteoporosis, and the incidence rate of the osteoporosis is the seventh most common disease and frequently occurring disease. Currently, the prevention and treatment of geriatric diseases, particularly osteoporosis, is an important research topic. Senile osteoporosis is a common and frequently occurring disease of the elderly, especially women after menopause. Therefore, attention and importance are also drawn to medicaments for osteoporosis treatment.
Bisphosphonate drugs are new drugs developed in the last twenty years, and have paid attention to the prevention and treatment of senile osteoporosis abroad, and the bisphosphonate drugs have the following characteristics in clinic: (1) not only can inhibit bone resorption, but also can increase bone mass to recover lost bone tissue; (2) can promote the reconstruction of trabeculae and reduce the depth of absorption pit; (3) short-term administration and long-term effect. In addition, bisphosphonates are first-line therapeutic agents for hypercalcemia caused by malignant tumors and paget's disease of bone.
The alendronate sodium is created by Italy Instituto Gentili company, is marketed under the trade name Alendros in Italy in 1993, is marketed under the name Fosamax in 1995, is used for treating osteoporosis and osteoarthritis, and is approved again by FDA in 5 months in 1997 to prevent osteoporosis and prevent the expansion indication of fracture, so that the alendronate sodium becomes a non-hormone medicament approved by FDA for preventing osteoporosis for the first time, has the weight gain effect on bones similar to estrogen, is superior to calcitonin, can obviously increase bone density, reduces the occurrence rate of fracture, is orally effective, has lasting effect, and has good tolerance and higher safety.
The Chinese patent with publication number of CN103356506A discloses solid lipid nanoparticles of alendronate sodium and a preparation method thereof, wherein the solid lipid nanoparticles of alendronate sodium are prepared from the following components in percentage by weight: 0.05 to 0.5 percent of alendronate sodium, 5 to 30 percent of lipid material, 10 to 60 percent of emulsifier and the balance of water. The preparation method adopts a high-pressure homogenization method to pack alendronate sodium into solid lipid nanoparticles. However, the encapsulation rate of the prepared alendronate sodium liposome is only 69.7% at the highest.
The Chinese patent with publication number of CN106821984A discloses alendronate sodium solid lipid nanoparticles and a preparation method thereof, wherein the solid lipid nanoparticles comprise the following components in percentage by weight: 0.01 to 0.05 percent of alendronate sodium, 0.29 to 0.5 percent of solid lipid, 0.19 to 0.5 percent of fat-soluble emulsifier, 0.49 to 0.98 percent of water-soluble emulsifier and the balance of distilled water. The preparation method is a shearing-ultrasonic method, wherein alendronate sodium is firstly dissolved in a small amount of organic solvent, then mixed with solid lipid and fat-soluble emulsifier, heated and melted to obtain an oil phase; adding a water-soluble emulsifier into distilled water, and heating to the same temperature as the oil phase to form a water phase; and pouring the water phase into the oil phase, and performing high-speed shearing and ultrasonic crushing to obtain the alendronate sodium solid lipid nanoparticle. However, the encapsulation rate of the prepared alendronate sodium liposome is 62.65 percent on average.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides an alendronate sodium liposome with high encapsulation efficiency and an alendronate sodium preparation prepared by the same, and solves the problem of low encapsulation efficiency of the alendronate sodium liposome in the prior art.
Specifically, the technical scheme of the invention is as follows:
a first object of the present invention is to provide a sodium alendronate liposome including: alendronate sodium, soybean phospholipid, cholesterol, and tetrabutylammonium bisulfate.
In various embodiments, the alendronate sodium liposome includes: 10 parts by weight of alendronate sodium, 8-15 parts by weight of soybean lecithin, 1-3 parts by weight of cholesterol and 0.4-0.8 part by weight of tetrabutylammonium bisulfate.
In a preferred embodiment, the alendronate sodium liposome includes: 10 parts by weight of alendronate sodium, 11 parts by weight of soybean phospholipid, 2 parts by weight of cholesterol and 0.6 part by weight of tetrabutylammonium bisulfate.
The second object of the present invention is to provide a method for preparing the alendronate sodium liposome, which comprises the following steps:
(1) Dissolving tetrabutylammonium bisulfate in a buffer solution to form a mixed solution A;
(2) Dissolving soybean phospholipid, cholesterol and alendronate sodium in an organic solvent to form a mixed solution B;
(3) Placing the mixed solution B into a eggplant-shaped bottle, performing reduced pressure rotary evaporation in a water bath at 35-55 ℃ to obtain a lipid film, adding the mixed solution A, and continuously performing reduced pressure rotary evaporation in the water bath at 35-55 ℃ to obtain a crude product of alendronate sodium liposome:
(4) And (3) placing the crude alendronate sodium liposome product prepared in the step (3) into a constant temperature box, preserving the temperature for 3-5 hours at 35-45 ℃, and then carrying out high-pressure homogenization, microfiltration and drying steps to prepare the alendronate sodium liposome.
In various embodiments, the buffer solution is selected from one of a citric acid buffer solution, a phosphoric acid buffer solution, and a tris buffer solution.
In a preferred embodiment, the buffer solution is selected from the group consisting of citric acid buffer solutions.
In various embodiments, the buffer solution has a pH in the range of 5.2 to 6.2.
In a preferred embodiment, the pH of the buffer solution is in the range of 5.6.
In various embodiments, the organic solvent is selected from one of chloroform, ethanol, methanol.
In a preferred embodiment, the organic solvent is chloroform.
In a preferred embodiment, the temperature of the reduced pressure rotary evaporation of the water bath is 40-50 ℃.
A third object of the present invention is to provide a sodium alendronate preparation, which is composed of a sodium alendronate liposome as defined in claim 1 and pharmaceutically acceptable excipients.
Further, the preparation is tablets, granules and capsules.
Further, the pharmaceutically acceptable auxiliary materials can be fillers, lubricants, disintegrants, wetting agents, binders, flavoring agents and the like.
Compared with the prior art, the invention has the beneficial effects that:
the invention optimizes liposome materials and preparation process, solves the problem of low encapsulation efficiency of alendronate sodium liposome in the prior art, and has encapsulation efficiency higher than 80%.
In addition, the preparation process is improved, and the crude product of the alendronate sodium liposome is subjected to constant temperature and heat preservation, so that the leakage rate of the crude product is effectively reduced, the leakage of the medicine in the alendronate sodium liposome is avoided to a great extent, and the stability of the alendronate sodium liposome is improved.
Drawings
Fig. 1: examples 1 to 5 sodium alendronate liposomes, comparative examples 1 to 3 drug loading of sodium alendronate liposomes
Fig. 2: examples 1 to 5 sodium alendronate liposomes, comparative examples 1 to 3 encapsulation efficiency of sodium alendronate liposomes
Detailed Description
The present invention will be further described with reference to examples for the purpose of making the objects and technical aspects of the present invention more apparent, but the scope of the present invention is not limited to these examples, which are only for explaining the present invention. It will be understood by those skilled in the art that variations or equivalent substitutions that do not depart from the spirit of the invention are intended to be included within the scope of the invention.
1. Alendronate sodium liposome
Example 1 alendronate sodium liposomes
The preparation method comprises the following steps:
(1) Tetrabutylammonium bisulfate is dissolved in a citric acid buffer solution (ph=5.6) to form a mixed solution a;
(2) Dissolving soybean phospholipid, cholesterol and alendronate sodium in chloroform to form a mixed solution B;
(3) Placing the mixed solution B into a eggplant-shaped bottle, performing reduced pressure rotary evaporation in a water bath at 40-50 ℃ to obtain a lipid film, adding the mixed solution A, and continuously performing reduced pressure rotary evaporation in the water bath at 40-50 ℃ to obtain a crude product of alendronate sodium liposome:
(4) And (3) placing the crude alendronate sodium liposome product prepared in the step (3) into a constant temperature box, preserving the temperature for 3-5 hours at 35-45 ℃, and then carrying out high-pressure homogenization, microfiltration and drying steps to prepare the alendronate sodium liposome.
Example 2 alendronate sodium liposomes
The preparation method comprises the following steps:
(1) Tetrabutylammonium bisulfate is dissolved in a citric acid buffer solution (ph=5.6) to form a mixed solution a;
(2) Dissolving soybean phospholipid, cholesterol and alendronate sodium in chloroform to form a mixed solution B;
(3) Placing the mixed solution B into a eggplant-shaped bottle, performing reduced pressure rotary evaporation in a water bath at 40-50 ℃ to obtain a lipid film, adding the mixed solution A, and continuously performing reduced pressure rotary evaporation in the water bath at 40-50 ℃ to obtain a crude product of alendronate sodium liposome:
(4) And (3) placing the crude alendronate sodium liposome product prepared in the step (3) into a constant temperature box, preserving the temperature for 3-5 hours at 35-45 ℃, and then carrying out high-pressure homogenization, microfiltration and drying steps to prepare the alendronate sodium liposome.
EXAMPLE 3 alendronate sodium liposomes
The preparation method comprises the following steps:
(1) Tetrabutylammonium bisulfate is dissolved in a citric acid buffer solution (ph=5.6) to form a mixed solution a;
(2) Dissolving soybean phospholipid, cholesterol and alendronate sodium in chloroform to form a mixed solution B;
(3) Placing the mixed solution B into a eggplant-shaped bottle, performing reduced pressure rotary evaporation in a water bath at 40-50 ℃ to obtain a lipid film, adding the mixed solution A, and continuously performing reduced pressure rotary evaporation in the water bath at 40-50 ℃ to obtain a crude product of alendronate sodium liposome:
(4) And (3) placing the crude alendronate sodium liposome product prepared in the step (3) into a constant temperature box, preserving the temperature for 3-5 hours at 35-45 ℃, and then carrying out high-pressure homogenization, microfiltration and drying steps to prepare the alendronate sodium liposome.
EXAMPLE 4 alendronate sodium liposomes
The preparation method comprises the following steps:
(1) Tetrabutylammonium bisulfate is dissolved in a phosphoric acid buffer solution (ph=5.2) to form a mixed solution a;
(2) Dissolving soybean phospholipid, cholesterol and alendronate sodium in ethanol to form a mixed solution B;
(3) Placing the mixed solution B into a eggplant-shaped bottle, performing reduced pressure rotary evaporation in a water bath at the temperature of between 35 and 40 ℃ to obtain a lipid film, adding the mixed solution A, and continuously performing reduced pressure rotary evaporation in a water bath at the temperature of between 40 and 50 ℃ to obtain a crude product of alendronate sodium liposome:
(4) And (3) placing the crude alendronate sodium liposome product prepared in the step (3) into a constant temperature box, preserving the temperature for 3-5 hours at 35-45 ℃, and then carrying out high-pressure homogenization, microfiltration and drying steps to prepare the alendronate sodium liposome.
EXAMPLE 5 alendronate sodium liposomes
The preparation method comprises the following steps:
(1) Tetrabutylammonium bisulfate is dissolved in a buffer solution of tris (hydroxymethyl) aminomethane (ph=6.2) to form a mixed solution a;
(2) Dissolving soybean phospholipid, cholesterol and alendronate sodium in methanol to form a mixed solution B;
(3) Placing the mixed solution B into a eggplant-shaped bottle, performing reduced pressure rotary evaporation in a water bath at 50-55 ℃ to obtain a lipid film, adding the mixed solution A, and continuously performing reduced pressure rotary evaporation in the water bath at 40-50 ℃ to obtain a crude product of alendronate sodium liposome:
(4) And (3) placing the crude alendronate sodium liposome product prepared in the step (3) into a constant temperature box, preserving the temperature for 3-5 hours at 35-45 ℃, and then carrying out high-pressure homogenization, microfiltration and drying steps to prepare the alendronate sodium liposome.
Comparative example 1 alendronate sodium liposomes
11 parts by weight of soybean phospholipid
Tetrabutylammonium bisulfate 0.6 weight portions
Alendronate sodium 10 weight portions
The preparation method comprises the following steps:
(1) Tetrabutylammonium bisulfate is dissolved in a citric acid buffer solution (ph=5.6) to form a mixed solution a;
(2) Dissolving soybean phospholipid and alendronate sodium in chloroform to form a mixed solution B;
(3) Placing the mixed solution B into a eggplant-shaped bottle, performing reduced pressure rotary evaporation in a water bath at 40-50 ℃ to obtain a lipid film, adding the mixed solution A, and continuously performing reduced pressure rotary evaporation in the water bath at 40-50 ℃ to obtain a crude product of alendronate sodium liposome:
(4) And (3) placing the crude alendronate sodium liposome product prepared in the step (3) into a constant temperature box, preserving the temperature for 3-5 hours at 35-45 ℃, and then carrying out high-pressure homogenization, microfiltration and drying steps to prepare the alendronate sodium liposome.
Comparative example 2 alendronate sodium liposomes
11 parts by weight of soybean phospholipid
Cholesterol 2 weight portions
Alendronate sodium 10 weight portions
The preparation method comprises the following steps:
(1) Dissolving soybean phospholipid, cholesterol and alendronate sodium in chloroform to form a mixed solution A;
(2) Placing the mixed solution A in a eggplant-shaped bottle, performing reduced pressure rotary evaporation in a water bath at 40-50 ℃ to obtain a lipid film, adding a citric acid buffer solution (pH=5.6), and continuously performing reduced pressure rotary evaporation in the water bath at 40-50 ℃ to obtain a crude product of alendronate sodium liposome:
(3) And (3) placing the crude alendronate sodium liposome product prepared in the step (3) into a constant temperature box, preserving the temperature for 3-5 hours at 35-45 ℃, and then carrying out high-pressure homogenization, microfiltration and drying steps to prepare the alendronate sodium liposome.
Comparative example 3 alendronate sodium liposomes
The preparation method comprises the following steps:
(1) Tetrabutylammonium bisulfate is dissolved in a citric acid buffer solution (ph=5.6) to form a mixed solution a;
(2) Dissolving soybean phospholipid, cholesterol and alendronate sodium in chloroform to form a mixed solution B;
(3) Placing the mixed solution B into a eggplant-shaped bottle, performing reduced pressure rotary evaporation in a water bath at 40-50 ℃ to obtain a lipid film, adding the mixed solution A, and continuously performing reduced pressure rotary evaporation in the water bath at 40-50 ℃ to obtain a crude product of alendronate sodium liposome:
(4) And (3) placing the crude alendronate sodium liposome product prepared in the step (3) into a constant temperature box, preserving the temperature for 3-5 hours at 35-45 ℃, and then carrying out high-pressure homogenization, microfiltration and drying steps to prepare the alendronate sodium liposome.
Comparative example 4 alendronate sodium liposomes
The preparation method comprises the following steps:
(1) Tetrabutylammonium bisulfate is dissolved in a citric acid buffer solution (ph=5.6) to form a mixed solution a;
(2) Dissolving soybean phospholipid, cholesterol and alendronate sodium in chloroform to form a mixed solution B;
(3) Placing the mixed solution B into a eggplant-shaped bottle, performing reduced pressure rotary evaporation in a water bath at 40-50 ℃ to obtain a lipid film, adding the mixed solution A, and continuously performing reduced pressure rotary evaporation in the water bath at 40-50 ℃ to obtain a crude product of alendronate sodium liposome:
(4) And (3) directly homogenizing the crude alendronate sodium liposome product prepared in the step (3) under high pressure, micro-filtering and drying to obtain the alendronate sodium liposome.
2. Quality evaluation of alendronate sodium liposome
1. Drug loading rate
The percentage of the weight of the drug encapsulated in the alendronate sodium liposomes of examples 1 to 5 and comparative examples 1 to 3 (alendronate sodium) was measured, i.e., the drug loading amount of the alendronate sodium liposomes.
Fig. 1 shows the drug loading of the alendronate sodium liposome of examples 1 to 5 and the drug loading of the alendronate sodium liposome of comparative examples 1 to 3, and the drug loading of the alendronate sodium liposome of the invention is higher and the drug transfer rate is high compared with the drug loading of the alendronate sodium liposome of comparative example.
2. Encapsulation efficiency
The encapsulation efficiency of the alendronate sodium liposomes of examples 1 to 5 and the drug in the alendronate sodium liposomes of comparative examples 1 to 3 was measured as a weight percentage of the drug to the amount to be administered.
Fig. 2 shows the encapsulation efficiency of the alendronate sodium liposome of examples 1 to 5 and the alendronate sodium liposome of comparative examples 1 to 3, and the results show that the encapsulation efficiency of the alendronate sodium liposome of the invention is higher than 80% compared with that of the alendronate sodium liposome in the prior art, and the encapsulation efficiency of the alendronate sodium liposome of the invention is improved remarkably.
3. Leakage rate
The change in encapsulation efficiency during storage of the alendronate sodium liposomes of examples 1 to 5 and the alendronate sodium liposomes of comparative examples 1 to 4 was calculated, i.e., the leak rate of the alendronate sodium liposomes. The storage condition is that the temperature is 40+/-2 ℃, the relative humidity is 75+/-5%, and the storage time is 10 days, 20 days and 30 days.
TABLE 1 leakage Rate (%)
Table 1 shows the leakage rates of the alendronate sodium liposomes of examples 1 to 5 and the alendronate sodium liposomes of comparative examples 1 to 4, and shows that the alendronate sodium liposomes of the present invention have high stability and low leakage rate under the same storage conditions. Especially, the alendronate sodium liposome of comparative example 4 has a leakage rate up to 0.64% when stored for 30 days, which proves that the crude alendronate sodium liposome product prepared is kept at constant temperature for a certain time, and the drug leakage of the alendronate sodium liposome can be effectively avoided.
3. Alandronate sodium preparation
1. Alendronate sodium tablet
The alendronate sodium liposome of the example 1 and pharmaceutically acceptable auxiliary materials are prepared into the alendronate sodium tablet according to a conventional tablet preparation method.
The alendronate sodium liposome of the example 2 and pharmaceutically acceptable auxiliary materials are prepared into the alendronate sodium tablet according to a conventional tablet preparation method.
The alendronate sodium liposome of the example 3 and pharmaceutically acceptable auxiliary materials are prepared into the alendronate sodium tablet according to a conventional tablet preparation method.
The alendronate sodium liposome of the example 4 and pharmaceutically acceptable auxiliary materials are prepared into the alendronate sodium tablet according to a conventional tablet preparation method.
The alendronate sodium liposome of the example 5 and pharmaceutically acceptable auxiliary materials are prepared into the alendronate sodium tablet according to a conventional tablet preparation method.
The quality control of the alendronate sodium tablet shows that the appearance shape, the tablet weight difference, the hardness and the friability, the disintegration time limit, the dissolution rate, the content uniformity, related substances and the like of the alendronate sodium tablet accord with the related regulations of pharmacopoeia.
2. Alendronate sodium capsule
The alendronate sodium liposome of the embodiment 1 and pharmaceutically acceptable auxiliary materials are prepared into the alendronate sodium capsule according to a conventional capsule preparation method.
The alendronate sodium liposome of the example 2 and pharmaceutically acceptable auxiliary materials are prepared into the alendronate sodium capsule according to a conventional capsule preparation method.
The alendronate sodium liposome of the embodiment 3 and pharmaceutically acceptable auxiliary materials are prepared into the alendronate sodium capsule according to a conventional capsule preparation method.
The alendronate sodium liposome of the example 4 and pharmaceutically acceptable auxiliary materials are prepared into the alendronate sodium capsule according to a conventional capsule preparation method.
The alendronate sodium liposome of the example 5 and pharmaceutically acceptable auxiliary materials are prepared into the alendronate sodium capsule according to a conventional capsule preparation method.
The quality control of the alendronate sodium capsule shows that the water content, the loading difference, the disintegration time limit, related substances and the like of the alendronate sodium capsule accord with the related regulations of pharmacopoeia.
3. Alendronate sodium granules
The alendronate sodium liposome of the embodiment 1 and pharmaceutically acceptable auxiliary materials are prepared into alendronate sodium particles according to a conventional preparation method of granules.
The alendronate sodium liposome of the example 2 and pharmaceutically acceptable auxiliary materials are prepared into alendronate sodium particles according to a conventional preparation method of granules.
The alendronate sodium liposome of the embodiment 3 and pharmaceutically acceptable auxiliary materials are prepared into alendronate sodium particles according to a conventional preparation method of granules.
The alendronate sodium liposome of the example 4 and pharmaceutically acceptable auxiliary materials are prepared into alendronate sodium particles according to a conventional preparation method of granules.
The alendronate sodium liposome of the example 5 and pharmaceutically acceptable auxiliary materials are prepared into alendronate sodium particles according to a conventional preparation method of granules.
The quality control of the alendronate sodium particles shows that the granularity, the drying weight loss, the moisture, the dissolubility, the loading weight difference, the related substances and the like of the alendronate sodium particles accord with the related regulations of pharmacopoeia.
It should be noted that the pharmaceutically acceptable auxiliary materials may be one or more of a filler, a lubricant, a disintegrating agent, a wetting agent, an adhesive and a flavoring agent, but are not limited thereto, and may be modified according to actual needs, and the dosage thereof may be selected conventionally, and may be taken into consideration according to actual needs.
The filler may be one or more of starch, pregelatinized starch, dextrin, sucrose, lactose, microcrystalline cellulose, mannitol, and inorganic salts, but is not limited thereto, and may be selected according to practical needs.
The wetting agent may be distilled water, ethanol, or the like, but is not limited thereto, and may be selected according to actual needs.
The binder may be one or more selected from starch slurry, syrup, vitamin derivatives (methylcellulose, hypromellose, sodium carboxymethylcellulose, ethylcellulose), polyethylene glycol, gelatin, acacia, and sodium alginate, but is not limited thereto, and may be selected according to practical needs.
The disintegrating agent can be one or more of dry starch, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, alginic acid and sodium alginate, but is not limited thereto, and can be selected according to actual needs.
The lubricant may be one or more of magnesium stearate, talcum powder, hydrogenated vegetable oil, micro silica gel and polyethylene glycol, but is not limited thereto, and may be selected according to practical needs.
Claims (10)
1. A sodium alendronate liposome, characterized in that said sodium alendronate liposome comprises: alendronate sodium, soybean phospholipid, cholesterol, and tetrabutylammonium bisulfate.
2. The alendronate sodium liposome according to claim 1, wherein the alendronate sodium liposome comprises: 10 parts by weight of alendronate sodium, 8-15 parts by weight of soybean lecithin, 1-3 parts by weight of cholesterol and 0.4-0.8 part by weight of tetrabutylammonium bisulfate.
3. The alendronate sodium liposome according to claim 2, wherein the alendronate sodium liposome comprises: 10 parts by weight of alendronate sodium, 11 parts by weight of soybean phospholipid, 2 parts by weight of cholesterol and 0.6 part by weight of tetrabutylammonium bisulfate.
4. A process for preparing alendronate sodium liposomes according to claim 1 or 2 or 3, characterized in that said process is:
(1) Dissolving tetrabutylammonium bisulfate in a buffer solution to form a mixed solution A;
(2) Dissolving soybean phospholipid, cholesterol and alendronate sodium in an organic solvent to form a mixed solution B;
(3) Placing the mixed solution B into a eggplant-shaped bottle, performing reduced pressure rotary evaporation in a water bath at 35-55 ℃ to obtain a lipid film, adding the mixed solution A, and continuously performing reduced pressure rotary evaporation in the water bath at 35-55 ℃ to obtain a crude product of alendronate sodium liposome:
(4) And (3) placing the crude alendronate sodium liposome product prepared in the step (3) into a constant temperature box, preserving the temperature for 3-5 hours at 35-45 ℃, and then carrying out high-pressure homogenization, microfiltration and drying steps to prepare the alendronate sodium liposome.
5. The method according to claim 4, wherein the buffer solution is one selected from the group consisting of a citric acid buffer solution, a phosphoric acid buffer solution, and a tris buffer solution; preferably, the buffer solution is selected from citric acid buffer solutions.
6. The method according to claim 4, wherein the buffer solution has a pH in the range of 5.2 to 6.2; preferably, the pH of the buffer solution is in the range of 5.6.
7. The method according to claim 4, wherein the organic solvent is selected from one of chloroform, ethanol, and methanol; preferably, the organic solvent is chloroform.
8. The method according to claim 4, wherein the temperature of the reduced pressure rotary evaporation in the water bath is 40 to 50 ℃.
9. A sodium alendronate preparation, characterized by comprising a sodium alendronate liposome according to claim 1 and pharmaceutically acceptable excipients.
10. The formulation of claim 9, wherein the formulation is a tablet, granule, capsule.
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