Bone targeted liposome, drugs and preparations thereof, and preparation method and application thereof

A technology of targeting liposomes and liposomes, applied in the field of medicine and chemical industry, can solve the problems of high cost, poor safety, inconvenient operation, etc.

Inactive Publication Date: 2017-10-31
BOARD OF RGT UNIV OF NEBRASKA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Whether it is autologous bone graft surgery or BMP protein intervention, there are problems such as inconvenient operation, high cost and poor safety, so it is difficult to meet the clinical needs
[0011] In view of the fact that the incidence rate of fracture healing disorder is not low and there is a lack of effective therapeutic drugs, further searching for simple, safe and effective fracture healing disorder drugs is another technical problem to be solved by the inventors of the present invention.

Method used

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  • Bone targeted liposome, drugs and preparations thereof, and preparation method and application thereof
  • Bone targeted liposome, drugs and preparations thereof, and preparation method and application thereof
  • Bone targeted liposome, drugs and preparations thereof, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Example 1 Synthesis of Bone Targeting Compound Molecules

[0059] The synthesis of the compound of formula 5 of the present invention can be prepared by referring to the synthesis method of compound 4, or the method of patent CN104274407, the difference is only in the length of the linking chain between pyrophosphate and cholesterol.

[0060] Taking compound 4 as an example, the bone-targeting compound molecule was synthesized according to the following synthetic route:

[0061]

[0062] (1) Synthetic intermediate product: triethylene glycol-cholesterol

[0063] Cholesterol (3.86g, 10mmol), triethylamine (Et 3 N, 2.02g, 20mmol), 4-dimethylaminopyridine (DMAP, 244mg, 2mmol) was dissolved in dichloromethane (DCM, 20mL), the solution was cooled to 0 degrees in an ice-water bath, and 4-p-toluenesulfonyl chloride ( TsCl, 2.85g, 15mmol), the solution was stirred and reacted at room temperature for 20 hours. After evaporating the solvent, the compound 1 was obtained by c...

Embodiment 2

[0075] The preparation of embodiment 2 Danshensu bone targeting liposome

[0076] Precisely weigh a certain proportion of lecithin, cholesterol and pyrophosphate-cholesterol, put the three into a round bottom evaporating flask, add a certain proportion of dichloromethane dissolving reagent, weigh an appropriate amount of danshensu and dissolve it in PBS with a pH value of 7.4 to prepare Danshen Danshensu solution was added to the round bottom flask, the two were mixed and shaken evenly, the mixed solution was stirred by magnetic force at 1500rpm / min for 10min, and then the emulsion formed by stirring was rotatively evaporated to remove the dichloromethane (500mpa , 2 hours; 250mpa, 1 hour), forming liposomes. The formed liposomes were repeatedly squeezed back and forth 11 times with an Avanti@mini Extruder with 0.2 μm and 0.4 μm filter membranes to obtain liposomes of the desired size, and then removed using a commercial PD-10 purification column Free drug not loaded in lipos...

Embodiment 3

[0081] The characterization of embodiment 3 Danshensu bone targeting liposome

[0082] 3.1 Average particle size, average dispersion coefficient and membrane surface Zeta potential of Danshensu bone-targeting liposome (Tan-BTL)

[0083] Dilute 1 ml of the liposome newly synthesized in Example 2 to one time with PBS, take 1 ml and put it into a dynamic light scattering particle size detector (Dynamic Light Scattering, DLS) to detect its particle size and Zeta potential. DLS test results showed that the average particle size of danshensu bone-targeted liposomes was 153nm, the average dispersion index (PDI) was 0.230, and the surface charge of the liposome membrane was -33.1mv, as shown in Table 1.

[0084] Table 1 Particle size, dispersion coefficient and Zeta potential of Danshensu bone targeting liposome (Tan-BTL)

[0085]

[0086] 3.2 Stability determination of Danshensu bone targeting liposome (Tan-BTL)

[0087] Put the Danshensu bone-targeting liposome prepared in Exampl...

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Abstract

The invention discloses a bone targeted liposome containing a compound of a structure in Formula 5, wherein n is selected from integers from 1 to 100, and the invention also discloses a bone targeted liposome drug containing the liposome and active drug molecules wrapped therein and preparations of the bone targeted liposome drug and a preparation method and application thereof. The bone targeted liposome uses pyrophosphoric acid to modify the liposome surface, has good bone affinity and good targeting, solves the problem that bonding between existing bone targeted drugs and a bone surface is insufficient, and can be targeted to various surfaces of bones: a bone absorption surface, a bone forming surface, a bone growth plate, the interior of cortical bone and a bone concave cavity, a bone targeting characteristic range is wider, and requirements for loading various drugs for treating bone diseases can be fully satisfied. The invention also discloses a tanshinol bone targeted liposome drug and application thereof in fracture healing disorders, and the drugs can promote formation of callus in an early stage, and promote transformation of the callus to normal bone in a later stage, thereby remarkably shortening fracture healing time and enhancing the mechanical property of bone after fracture healing.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a bone-targeting liposome, a medicine containing the liposome, a preparation, a preparation method, and an application thereof in preparation of a medicine for treating bone disease. Background technique [0002] Bone disease is a general term for bone and joint-related diseases, mainly including osteoporosis, fracture healing disorders, arthritis, and various acute and chronic neck, shoulder, waist, and leg pains. Although there have been some corresponding drug researches for various bone diseases, and some of them have been applied clinically, due to the high hardness of bone tissue, low blood flow, poor permeability, and special physiological and biochemical processes, the treatment of bone diseases Almost all of the drugs are difficult to be effectively transported to the site of action according to the general route of administration, and the curati...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/127A61K47/28A61K47/24A61K45/00A61K31/192A61P19/08A61P19/10A61P19/02A61P29/00
CPCA61K9/1271A61K31/192A61K45/00A61K47/24A61K47/28
Inventor 王东崔燎刘衍志贾振山
Owner BOARD OF RGT UNIV OF NEBRASKA
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