CN104274407A - Tanshinol lipidosome bone-targeting pharmaceutical preparation and preparation method thereof - Google Patents
Tanshinol lipidosome bone-targeting pharmaceutical preparation and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a tanshinol lipidosome bone-targeting pharmaceutical preparation and a preparation method thereof. The preparation is prepared by jointing and carrying out surface modification on a lipidosome microparticle containing a tanshinol medicine molecule by using a bone-targeting jointer. The preparation method comprises the steps of jointing a bisphosphonate molecule with bone-targeting ability on one end of a polyethylene glycol molecule through synthetic reaction, and jointing a cholesterol molecule serving as a lipidosome raw material on the other end of the polyethylene glycol molecule through synthetic reaction to prepare a jointer with bone-targeting ability, namely bisphosphonate-polyethylene glycol-cholesterol (BP-PEG-CHOL); and then, preparing a lipidosome provided with the bone-targeting jointer on the surface from phospholipid, cholesterol and the bone-targeting jointer which serve as raw materials, adding tanshinol, and containing the tanshinol into the lipidosome to prepare the tanshinol lipidosome bone-targeting preparation. The preparation disclosed by the invention has the bone-targeting ability and can be used for remarkably increasing the concentration of medicines in a bone tissue, improving the curative effect and preventing and treating systemic metabolic bone diseases, osteoporosis and bone fracture.
Description
Technical field
The present invention relates to a kind of pharmaceutical preparation and preparation method thereof of Bone targeting that can be used for Bone targeting treatment and prevention of osteoporosis disease, fracture and generalized metabolic osteopathia, belong to the technical field of medicine manufacture.
Background technology
Osteoporosis is the common function degenerative disease of middle-aged and elderly people.Because osseous tissue hardness is large, poor permeability, physiological and biochemical procedure is special, and medicine is difficult to effectively be transported to site of action by general route of administration.Some drugs often needs Formulations for systemic administration, could reach and effectively treat concentration, not only reduce drug therapeutic indices in osseous tissue, and produces toxic and side effects to other organ-tissues of patient.
1986, Pierce proposed the concept of Bone targeting first: compound has and is deposited on bone and the trend of fusion in hydroxyapatite (HA) crystal, had i.e. tool " Bone targeting " affinity of binding ability with bone calcium.After this many scholars have made fruitful work in the development of bone target medicine, according to the difference of their used carrier molecule, roughly can be divided into following a few class: bis-phosphonic acids, Tetracyclines, Crude oil esters and small-molecule peptide.Wherein bis-phosphonic acids compounds (diphosphonate) is the analog of natural coal phosphoric acid, has specific affinity to osseous tissue and calcified tissue, effectively can suppress bone absorption, is mainly used in treatment osteoporosis and Paget ' s disease clinically.The main bis phosphoric acid salt osteosporosis resistant medicament of existing market is Allan sodium phosphate (trade name Fosamax), and market share is once up to 35%.But increasing report finds that Fosamax has obvious side effect in recent years.The side effect that patient occurs after taking this type of medicine is severe infections, swelling and odontoseisis.In addition have patient to occur the symptom such as skeleton, bone joint pain after oral this kind of medicine, some patients is even unable to leave the bed or wheelchair, crutch can only be relied on to walk.Visible single Bisphosphonates side effect is remarkable, limits its range of application.
Diphosphonate compounds due to Bone targeting obvious, foreign study tends to bis-phosphonic acids compounds for being connected with some drug molecules, for the targeted therapy of osteopathia.Researcher by bis-phosphonic acids compounds and some nonspecific medicines as estrogens, prostaglandin E 2, cisplatin, tyrosine protein kinase (Src) inhibitor, diclofenac and some radiopharmaceutical couplings, to reach object [the WANG Yi-han of targeted therapy, METCALF C A, SHAKESPEARE W C, et al.Bone-targeted2, 6.9-trisubstituted purines:Novel inhibitors of srctyrosine kinase for the treatment of bone diseases [J] .Bioorganic Medicinal Chemistry Letters, 2003, 13 (18): 3067-3070.].But this coupling is generally directly diphosphonate and drug molecule are combined by chemical bonded refractory, and enter blood circulation upon administration, drug molecule is exposed in the various enzymes of physiological environment, very soon by metabolism, have impact on the performance of drug effect.
Be a kind of new formulation method with liposome natural drug micromolecule, can effectively avoid small-molecule drug too early by metabolic inactivation.Have been reported [strict England Premier League such as having prepared silymarin liposome, Paclitaxel liposome, SOD from cactus liposome and podophyllin liposome, Dong Lei, merchant's pure white, Deng. the preparation of silibinin solid lipid nanoparticle and effect of anti hepatic fibrosis [J]. XI AN JIAOTONG UNIVERSITY Subject Index (medicine), 2007,28 (5): 517-20.].Treatment [the Guo Jia that Bone targeting flexible nano-liposomes can be used for metastatic tumor of bone is prepared according to the bone affinity of polynary phosphate compound ethylene diamine tetra methylene phosphonic acid, Zhang Miao, Li Yunfeng etc., Bone targeting flexible nano-liposomes [J], Peking University's journal (medicine), 2009,41 (2): 203-207].
Modern pharmacological research finds that the water soluble ingredient danshensu in Radix Salviae Miltiorrhizae can promote knitting, radix Salviae Miltiorrhizae water extract can prevent and treat rat alveolar bone osteoporosis, experiment in vitro finds that danshensu can increase alkali phosphatase (the alkaline phosphatase of rat osteoblast, and BGP content AIJP), improve the external mineralization ability of OB, OPG gene expression is increased; Impelling bone marrow stroma stem cell to while osteoblast differentiation, suppress it to Adipocyte Differentiation; Salvianolic acid B also has this to act on, and liposoluble constituent TANSHINONES does not have this to act on, zoopery shows the osteoporosis rat [Liu Yuyu that danshensu can effectively prevent glucocorticoid to cause, Cui is burned, Wu Tie. the direction [J] of drug regulation marrow stromal cell Osteoblast Differentiation and osteoporosis treatment. Chinese Clinical rehabilitation, 2005,9 (26): 184-5. open swallow dawn, Wu Tie, Cui is burned, Deng. radix Salviae Miltiorrhizae water extract is on the impact [J] of ovariectomized female rats alveolar bone bone amount. Chinese patent medicine, 2007,29 (2): 268-270].Danshensu can prevent the loss of alveolar bone bone amount.After ovariectomized female rats gives danshensu control, bone trabecula area percent raises 45.45%, bone trabecula thickness adds 36.21%, bone trabecula separating degree have dropped 30.66%, and the rising of bone trabecula area percent has significant, this result prompting danshensu can reverse the loss of ovariectomized female rats alveolar bone bone amount.This may be relevant to following factor: one. and Radix Salviae Miltiorrhizae promotes the synthesis of ossein.Ossein is type i collagen, is the main matter of bone matrix organic matter, and account for organic 90%-95%, calcium salt deposits on bone collagen matrix, forms bone lesser tubercle.There is report Radix Salviae Miltiorrhizae can promote the expression of I procollagen type gene mRNA, thus promote the synthesis of I procollagen type.This points out effective ingredient one danshensu as Radix Salviae Miltiorrhizae can prevent and treat alveolar bone osteoporosis may be relevant to the synthesis of its promotion ossein.Two. Radix Salviae Miltiorrhizae increases osteoclast number, activity and reduces osteoclast number, activity.The formation of bone and absorbing and the number of osteoblast and osteoclast and active closely related, the number of osteoclast is relative with activity when increasing, and bone resorption strengthens, and bone amount minimizing, osteoporosis appears in body.Danshensu, by suppressing brokenly osteoblast to the conversion of mature osteoclast thus the formation of suppression osteoclast, can promote that rat osteoblast is active.
Because the function of resisting osteoporosis of danshensu (or salvianolic acid B) is relevant with dosage, also relevant with danshensu (or salvianolic acid B) antioxidation, and salvia root polyphenol class medicine is easily oxidized, in blood, the half-life is of short duration, to play the osteoporotic effect of control, need the dosage or the administration number of times that strengthen danshensu (or salvianolic acid B).Because osseous tissue hardness is large, poor permeability, physiological and biochemical procedure is special, medicine is all difficult to effectively be transported to site of action as oral or intravenous injection by general route of administration, this not only lowers drug therapeutic indices, and also produces unnecessary toxic and side effects to patient non-bone tissue.In order to overcome this difficulty, need the problem of solution two aspect, one is that drug molecule targeting is transported to osteopathia position, avoid the side effect that Formulations for systemic administration causes, two is that drug molecule is high at osteopathia site concentration, and release time is long, strengthens the therapeutical effect of drug molecule.Therefore, when studying preparation, design is needed to be targeted to osseous tissue, simultaneously again can medicine carrying the dosage form of Co ntrolled release in a large number.Such designing requirement is met using Diphosphonate as the lipid physical ability of Bone targeting bullet.
Domestic market there is not yet the Bone targeting drug-delivery preparation of danshensu liposome, also have no the research report of this pharmaceutical preparation, therefore developing this kind of medicine not only has important clinical meaning, also has wide market prospect.
Summary of the invention
We devise a kind of new type bone target drug-carrying liposome, treatment small-molecule drug danshensu liposome loads, surface of liposome Bone targeting jointer is modified, and Bone targeting jointer molecule is Diphosphonate-PEG-CHOL (BP-PEG-CHOL), and molecular formula is shown in accompanying drawing 1.Namely the drug-loaded liposome of this surface modification has Bone targeting function.Cholesterol group in Bone targeting jointer molecule serves as the anchor fixed member of liposome bilayers, and Polyethylene Glycol is used as link interval molecule, and Diphosphonate stretches out outside liposome bilayers and serves as Bone targeting group.The drug-loaded liposome of this surface modification has and can be targeted to osseous tissue, simultaneously again can medicine carrying the characteristic of Co ntrolled release (Fig. 2) in a large number.
This danshensu liposome with Bone targeting, is characterized in that, using BP-PEG-CHOL as Bone targeting thing, being bonded on surface of liposome, liposome interior comprises drug molecule danshensu, by following step, BP-PEG-CHOL is as Bone targeting thing in synthesis, prepares Bone targeting danshensu liposome:
A. Bone targeting thing BP-PEG-CHOL is prepared:
(1) synthetic intermediate cholesterol methanesulfonate ester
Cholesterol is dissolved in dichloromethane, adds triethylamine and does acid binding agent, is cooled to-10 to spend, and slowly drips methylsufonyl chloride stirring reaction, and process washes with water and filters to obtain white powdery solids after completion of the reaction.
(2) synthetic intermediate cholesterol-poly(oxyethylene glycol) (CHOL-PEG)
After fully dry for PEG2000 also evacuation; under argon shield; add dry DMSO and THF; add sodium hydride rapidly subsequently, after room temperature activation, the cholesterol methanesulfonate ester being dissolved in THF is added dropwise in above-mentioned solution and reacts; reactant liquor is inclined people in frozen water; dichloromethane extraction, is spin-dried for, and is separated to obtain CHOL-PEG. through rapid column chromatography
(3) derivant (CHOL-PEG-NH2) of synthesizing polyethylene glycol terminal amino group
Above-mentioned product and methylsufonyl chloride are reacted the intermediate preparing methanesulfonate ester, is dissolved in DMF, the sodium azide added generates primary amine in 50-80 DEG C of reaction reduction.
(4) synthetic cholesterol-Polyethylene Glycol-two banks (CHOL-PEG-BP)
Bisphosphonic acid derivatives is dissolved in anhydrous THF, adds CHOL-PEG-NH2 under stirring, add DCC, be filled in THF suspension after room temperature reaction, filter, washing, anhydrous sodium sulfate drying, concentrate, through silica gel rapid column chromatography, obtains with methylene chloride/methanol gradient elution.
B. the preparation of the danshensu liposome of Bone targeting joint
Precision takes a certain proportion of lecithin, cholesterol and danshensu and appropriate vitamin E, and danshensu and vitamin E are dissolved in dehydrated alcohol, and the appropriate ether of lecithin, cholesterol is dissolved in round bottom evaporative flask, and different mixing jolting is even.On Rotary Evaporators, decompression rotation steaming becomes transparent membrane to bottle wall.Appropriate BP-PEG-CHOL is added in PBS buffer, abundant dissolving, join above-mentioned round-bottomed flask, rotate 0.5h and film is dissolved, inflated with nitrogen removing trace organic solvents, place 2.5h and make its abundant hydration, ultrasonic some minutes, cross 0.45 and 0.22um filter membrane successively, obtain uniform liposome turbid liquor sample, be separated the free danshensu (Fig. 3) of removing through gel filtration chromatography, obtain Bone targeting danshensu liposome.
The present invention has the following advantages:
1. preparation of the present invention is the danshensu of liposome, prevents from being eliminated by metabolism at absorption distributed process Chinese medicine molecule.
2. preparation of the present invention has Bone targeting, and can arrive appointed part release, target area drug level, higher than its hetero-organization, gives full play to the therapeutical effect of medicine.
Detailed description of the invention
Be described further content of the present invention by the following examples, but should do not think that scope of the present invention is only limitted to embodiment, all technology realized based on foregoing of the present invention all belong to scope of the present invention.
The Bone targeting drug-delivery preparation of danshensu liposome of the present invention is by the drug molecule enclose of danshensu in liposome particle, and the surface Bone targeting jointer of liposome particle is modified and made.
Bone targeting jointer adopts organic synthesis legal system standby, namely the two banks hydrochlorate molecule with Bone targeting is connected in one end of peg molecule by synthetic reaction, connect the cholesterol molecule as liposome raw material at the other end by synthetic reaction, preparation becomes the jointer diphosphonate-PEG-CHOL (BP-PEG-CHOL) with Bone targeting; Then with phospholipid, cholesterol, Bone targeting jointer raw material, be prepared into the liposome that surface has Bone targeting jointer, in preparation process, add danshensu, danshensu is included in liposome, thus the Bone targeting preparation of obtained danshensu liposome.
Prepare the preparation method of danshensu liposome Bone targeting preparation of the present invention, comprise the steps: the first step, with diphosphonate, Polyethylene Glycol and cholesterol for Material synthesis prepares Bone targeting jointer; Second step, with phospholipid, cholesterol and danshensu for danshensu liposome prepared by raw material, with Bone targeting jointer modified liposome; 3rd step, filters the Bone targeting preparation of danshensu liposome, granulate, and namely column chromatography for separation obtains Bone targeting preparation.
Bone targeting jointer is prepared as follows: cholesterol is dissolved in dichloromethane, adds triethylamine and does acid binding agent, be cooled to-10 DEG C, slowly drips methylsufonyl chloride stirring reaction, and process washes with water and filters to obtain white powdery solids after completion of the reaction.After fully dry for PEG2000 also evacuation; under argon shield; add dry DMSO and THF; add sodium hydride rapidly subsequently; after room temperature activation; the cholesterol methanesulfonate ester being dissolved in THF is added dropwise in above-mentioned solution and reacts; reactant liquor is inclined people in frozen water; dichloromethane extraction; be spin-dried for; be separated above-mentioned product and methylsufonyl chloride are reacted the intermediate preparing methanesulfonate ester by CHOL-PEG. through rapid column chromatography, be dissolved in DMF, the sodium azide added generates primary amine in 50-80 DEG C of reaction reduction.Bis phosphoric acid derivant is dissolved in anhydrous THF, CHOL-PEG-NH2 is added under stirring, add DCC, be filled in THF suspension after room temperature reaction, filter, washing, anhydrous sodium sulfate drying, concentrate, through silica gel rapid column chromatography, obtains Bone targeting jointer BP-PEG-CHOL with methylene chloride/methanol gradient elution.
Embodiment one
Take soybean lecithin 200mg, cholesterol 50mg, Bone targeting fairlead 80mg, be placed in 500ml eggplant-shape bottle, dissolve, 45 DEG C with 15ml dichloromethane, 60r/min rotary evaporation forms thin film, adds the aqueous solution 5ml containing danshensu 10mg.Room temperature, 60r/min places expansion 2h for 45 DEG C after revolving and steaming demoulding formation suspension.Successively by 0.8 μm, 0.45 μm, 0.22 μm microporous filter membrane granulate, gel column is separated the free danshensu of removing.
Embodiment two
Take soybean lecithin 200mg, cholesterol 50mg, Bone targeting fairlead 80mg, dissolve with 15ml dichloromethane, and add the aqueous solution 5ml containing danshensu 10mg.1000rpm stirs 10min, 45 DEG C, 60r/min rotary evaporation 60min.Successively by 0.8 μm, 0.45 μm, 0.22 μm microporous filter membrane granulate, gel column is separated the free danshensu of removing.
Embodiment three
Take soybean lecithin 200mg, cholesterol 50mg, Bone targeting fairlead 80mg, use 15ml ether dissolution, separately getting 10mg danshensu is dissolved in 5ml distilled water, stir under 60 DEG C of water bath condition, after danshensu solution arrives 60 DEG C, diethyl ether solution is slowly instilled in danshensu solution, after dropwising, continue 60 DEG C and stir 30min.Successively by 0.8 μm, 0.45 μm, 0.22 μm microporous filter membrane granulate, gel column is separated the free danshensu of removing.
Embodiment four
Take soybean lecithin 200mg, cholesterol 50mg, Bone targeting fairlead 80mg in triangular flask, dissolve with 20ml dichloromethane, add the aqueous solution 10ml containing danshensu 10mg, 1000rpm stirs 10mi n and forms colostrum, under 1000rpm stirs, colostrum is added drop-wise in 40ml distilled water, dropwise rear continuation and stir 15min, form W/O/W emulsion, 60r/min revolves and steams removing dichloromethane, successively by 0.8 μm, 0.45 μm, 0.22 μm microporous filter membrane granulate, gel column is separated the free danshensu of removing.
Accompanying drawing illustrates:
The chemical structural formula of accompanying drawing 1 Bone targeting jointer BP-PEG-CHOL
The structural representation of accompanying drawing 2 danshensu liposome Bone targeting preparation
The chromatographic fractionation figure of accompanying drawing 3 danshensu liposome and free danshensu.
Claims (5)
1. pharmaceutical preparation containing the liposome Bone targeting of danshensu and preparation method thereof.
2. a kind of preparation method of the liposome bone target medicine preparation containing danshensu is wrapped in liposome by danshensu as claimed in claim 1, surface of liposome Bone targeting jointer diphosphonate-PEG-CHOL (BP-PEG-CHOL) is modified, and accompanying drawing 1 be shown in the chemical structural formula of Bone targeting jointer.
3. Bone targeting jointer as claimed in claim 1 is with by following step, and BP-PEG-CHOL is as Bone targeting thing in synthesis:
(1) synthetic intermediate cholesterol methanesulfonate ester: cholesterol is dissolved in dichloromethane, adds triethylamine and does acid binding agent, is cooled to-10 to spend, and slowly drips methylsufonyl chloride stirring reaction, and process washes with water and filters to obtain white powdery solids after completion of the reaction;
(2) synthetic intermediate cholesterol-poly(oxyethylene glycol) (CHOL-PEG): after fully dry for PEG2000 also evacuation, under argon shield, add dry DMSO and THF, add sodium hydride rapidly subsequently, after room temperature activation, the cholesterol methanesulfonate ester being dissolved in THF is added dropwise in above-mentioned solution and reacts, reactant liquor is inclined people in frozen water, dichloromethane extraction, is spin-dried for, and is separated to obtain CHOL-PEG through rapid column chromatography;
(3) derivant (CHOL-PEG-NH2) of synthesizing polyethylene glycol terminal amino group: above-mentioned product and methylsufonyl chloride are reacted the intermediate preparing methanesulfonate ester, be dissolved in DMF, the sodium azide added generates primary amine in 50-80 DEG C of reaction reduction;
(4) synthetic cholesterol-Polyethylene Glycol-two banks (CHOL-PEG-BP): bis phosphoric acid derivant is dissolved in anhydrous THF, CHOL-PEG-NH2 is added under stirring, add DCC, be filled in THF suspension after room temperature reaction, filter, washing, anhydrous sodium sulfate drying, concentrate, through silica gel rapid column chromatography, obtains CHOL-PEG-BP with methylene chloride/methanol gradient elution.
4. as claim 1,2, the preparation method of the pharmaceutical preparation of the liposome Bone targeting containing danshensu described in 3, it prepares Bone targeting danshensu liposome is for raw material with phospholipid, cholesterol, Bone targeting jointer and danshensu, through mixing, revolve steaming, aquation preparation, cross 0.45 and 0.22um filter membrane granulate successively, be separated the free danshensu of removing through gel filtration chromatography and namely obtain Bone targeting danshensu liposome.
5. the liposome bone target medicine preparation containing danshensu as claimed in claim 1 is for Bone targeting treatment and prevention of osteoporosis disease, fracture and generalized metabolic osteopathia.
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Cited By (5)
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| CN106047935A (en) * | 2016-05-20 | 2016-10-26 | 中国科学院深圳先进技术研究院 | Targeting gene carrier as well as preparation method and applications thereof |
| CN106109399A (en) * | 2016-07-14 | 2016-11-16 | 广东药科大学 | Pharmaceutical composition and containing the gel of this pharmaceutical composition and preparation method |
| CN107028885A (en) * | 2017-03-23 | 2017-08-11 | 内蒙古自治区人民医院 | Bone targeting liposome for treating osteoporosis and preparation method thereof |
| CN107303277A (en) * | 2016-04-22 | 2017-10-31 | 内布拉斯加大学董事会 | Bone targeting liposome, its medicine and preparation and preparation method and application |
| CN110665058A (en) * | 2019-10-15 | 2020-01-10 | 上海纳米技术及应用国家工程研究中心有限公司 | Preparation method of bone cement containing zoledronic acid liposome |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107303277A (en) * | 2016-04-22 | 2017-10-31 | 内布拉斯加大学董事会 | Bone targeting liposome, its medicine and preparation and preparation method and application |
| CN107303277B (en) * | 2016-04-22 | 2020-10-02 | 内布拉斯加大学董事会 | Bone targeting liposome, medicine and preparation thereof, and preparation method and application thereof |
| CN106047935A (en) * | 2016-05-20 | 2016-10-26 | 中国科学院深圳先进技术研究院 | Targeting gene carrier as well as preparation method and applications thereof |
| WO2017197726A1 (en) * | 2016-05-20 | 2017-11-23 | 中国科学院深圳先进技术研究院 | Bone-targeted gene carrier, preparation method therefor and application thereof |
| CN106109399A (en) * | 2016-07-14 | 2016-11-16 | 广东药科大学 | Pharmaceutical composition and containing the gel of this pharmaceutical composition and preparation method |
| CN106109399B (en) * | 2016-07-14 | 2019-08-16 | 广东药科大学 | Pharmaceutical composition and gelling agent and preparation method containing the pharmaceutical composition |
| CN107028885A (en) * | 2017-03-23 | 2017-08-11 | 内蒙古自治区人民医院 | Bone targeting liposome for treating osteoporosis and preparation method thereof |
| CN107028885B (en) * | 2017-03-23 | 2022-05-13 | 内蒙古自治区人民医院 | Bone targeting liposome for treating osteoporosis and preparation method thereof |
| CN110665058A (en) * | 2019-10-15 | 2020-01-10 | 上海纳米技术及应用国家工程研究中心有限公司 | Preparation method of bone cement containing zoledronic acid liposome |
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Address after: 524023 Guangdong natural medicine research and development laboratory, Guangdong Medical College, 2 east civilization Road, Guangdong, Zhanjiang Applicant after: Guangdong Medical University Address before: 524023 Guangdong natural medicine research and development laboratory, Guangdong Medical College, 2 east civilization Road, Guangdong, Zhanjiang Applicant before: Guangdong Medical College |
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