CN110063939B - Hollow hydroxyapatite drug-loaded particle for shock wave mediated release and preparation method thereof - Google Patents
Hollow hydroxyapatite drug-loaded particle for shock wave mediated release and preparation method thereof Download PDFInfo
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- 239000003814 drug Substances 0.000 title claims abstract description 74
- 229910052588 hydroxylapatite Inorganic materials 0.000 title claims abstract description 69
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 title claims abstract description 69
- 229940079593 drug Drugs 0.000 title claims abstract description 60
- 239000002245 particle Substances 0.000 title claims abstract description 59
- 230000035939 shock Effects 0.000 title claims abstract description 34
- 230000001404 mediated effect Effects 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims description 23
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 238000003760 magnetic stirring Methods 0.000 claims description 14
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- 238000007792 addition Methods 0.000 claims description 8
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- 230000001376 precipitating effect Effects 0.000 claims description 5
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- 238000000034 method Methods 0.000 claims description 4
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- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 claims description 4
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 claims description 3
- DBVJJBKOTRCVKF-UHFFFAOYSA-N Etidronic acid Chemical compound OP(=O)(O)C(O)(C)P(O)(O)=O DBVJJBKOTRCVKF-UHFFFAOYSA-N 0.000 claims description 3
- 229960004343 alendronic acid Drugs 0.000 claims description 3
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-N 0.000 claims description 2
- 229960005236 ibandronic acid Drugs 0.000 claims description 2
- 238000001125 extrusion Methods 0.000 claims 2
- DRFDPXKCEWYIAW-UHFFFAOYSA-M Risedronate sodium Chemical compound [Na+].OP(=O)(O)C(P(O)([O-])=O)(O)CC1=CC=CN=C1 DRFDPXKCEWYIAW-UHFFFAOYSA-M 0.000 claims 1
- 210000000988 bone and bone Anatomy 0.000 abstract description 11
- 230000004071 biological effect Effects 0.000 abstract description 5
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- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 description 6
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- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 6
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- 229910001873 dinitrogen Inorganic materials 0.000 description 3
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- 208000001132 Osteoporosis Diseases 0.000 description 2
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- 238000013459 approach Methods 0.000 description 2
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- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
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- 241001465754 Metazoa Species 0.000 description 1
- IIDJRNMFWXDHID-UHFFFAOYSA-N Risedronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CC1=CC=CN=C1 IIDJRNMFWXDHID-UHFFFAOYSA-N 0.000 description 1
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- 230000017074 necrotic cell death Effects 0.000 description 1
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- 230000001009 osteoporotic effect Effects 0.000 description 1
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0028—Disruption, e.g. by heat or ultrasounds, sonophysical or sonochemical activation, e.g. thermosensitive or heat-sensitive liposomes, disruption of calculi with a medicinal preparation and ultrasounds
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- 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
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- 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—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
- A61K9/1273—Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances
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- 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
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Abstract
The invention discloses a hollow hydroxyapatite drug-loaded particle for shock wave mediated release, which has a particle size of 150-220 nm and a wall thickness of 5-10 nm. Preparing a Tris alkali solution, adding PEG and a medicament into the Tris alkali solution, dissolving, sequentially dripping Tween80 and Triton-100 solution, and stirring for 20-60 min to form a nonionic surfactant vesicle solution; extruding the reaction liquid by using a screen membrane, and ultrasonically forming a hydroxyapatite hollow template solution; placing the solution in nitrogen environment, slowly and alternately adding CaCl2And Na2HPO4Centrifuging the solution, washing the precipitate, and drying in vacuum to obtain the desired nanoparticles. The medicine carrying particle prepared by the inventionThe uniformity is good, the wall of the sphere is thin, the rigidity is good, the shell is easy to break under the adaptive energy action with biological effect, the effective release of the medicine is realized, and the local medicine concentration of the bone is improved.
Description
Technical Field
The invention relates to the technical field of hydroxyapatite nano materials, in particular to hollow hydroxyapatite medicine carrying particles for shock wave mediated release and a preparation method thereof.
Background
With the general aging of the population, osteoporosis is an emerging public health problem of global concern. Local treatment strategies for specific bone regions susceptible to fracture may help reduce the incidence of osteoporotic fractures. The development of minimally invasive CT-guided Intradermal (IO) injections has made local intervention on specific target bones useful for preventing or treating osteoporotic fractures, so the IO approach is widely studied as an alternative to the venous approach.
The hydroxyapatite has very similar chemical components and crystal structures with human hard tissues, has unique biological activity and biocompatibility, has the advantage of greatly improving drug-loading rate, and is widely used in tissue engineering, bone repair and substitution, dental materials and the like. Yang et al [ Xiaoanyan Yang, et al, intra-bone mineral injection of trace elements co-doped calcium nanoparticles for the treatment of osteoporotic acid, [ J ]. J Biomed Mater Res A.2017105 (5): 1422-. However, after the hydroxyapatite is used as a drug carrier and enters a medullary cavity, the drug which is locally released is denatured or the release of the drug is limited to a certain extent under the influence of the environment in a body, so that the local drug concentration is reduced and the expected effect cannot be achieved.
Foreign scholars find that the ultrasonic wave can mediate the targeted drug release rate of the nano-carrier to be improved, so that the malignant tumor locally reaches the satisfactory blood concentration. The External Shock Wave (ESW) is also a sound wave capable of transmitting energy, has more characteristics than ultrasonic waves, acts on the body through the mechanical effect, the cavitation effect and the heat effect of the ESW, and achieves good curative effect on diseases such as femoral head necrosis, bone nonunion, osteoporosis and the like. However, in previous in vitro experiments on animals, the applicant found that when the hollow hydroxyapatite nanoparticles prepared according to the prior preparation method (such as the preparation method disclosed in the prior patent application 200710067822.1) are locally released in bones by using in vitro shock wave energy, the hollow hydroxyapatite nanoparticles cannot be broken by proper energy having biological effect on the bones, and satisfactory treatment and prevention effects cannot be achieved by releasing the encapsulated zoledronic acid drug.
Therefore, the existing drug-loaded hollow hydroxyapatite nanoparticles and the preparation method thereof obviously still have inconvenience and defects in structure, method and use, and further improvement is urgently needed. How to create a new shock wave mediated release hollow hydroxyapatite medicine-carrying particle and a preparation method thereof, the hollow hydroxyapatite medicine-carrying particle can realize the release of medicine in bone tissues under the in vitro shock wave mediation, meet the requirements of local medicine concentration, obtain satisfactory effect, and belong to one of the current important research and development subjects.
Disclosure of Invention
The invention aims to solve the technical problem of providing hollow hydroxyapatite drug-loaded particles for shock wave mediated release, which can realize the release of drugs in bone tissues under the in vitro shock wave mediated condition, meet the requirement of local drug concentration and obtain satisfactory effect, thereby overcoming the defects of the existing drug-loaded hollow hydroxyapatite nanoparticles.
In order to solve the technical problems, the invention provides hollow hydroxyapatite drug-loaded particles for shock wave mediated release, wherein the spherical particle diameter of the hollow hydroxyapatite drug-loaded particles is 150-220 nm, and the wall thickness of a spherical shell of the nanoparticles is 5-10 nm.
As an improvement of the invention, the spherical particle diameter of the hollow hydroxyapatite medicine-carrying particle is 170-200 nm, and the wall thickness of the spherical shell of the nano particle is 6-9 nm.
The invention also provides a preparation method of the hollow hydroxyapatite drug-loaded particles mediated and released by the shock wave, which comprises the following steps:
(1) and preparing a Tris solution, and adjusting the pH value to 11-12 to form a solution A.
(2) Adding polyethylene glycol and a water-soluble drug into the solution A, stirring until the polyethylene glycol and the water-soluble drug are completely dissolved, slowly dripping Tween80 and Triton-100 solution in sequence while stirring, and magnetically stirring for 20-60 min to form a solution B, namely a solution containing the drug-coated nonionic surface active vesicles; the Triton-100 solution in the step has the function of increasing the rigidity of the formed nonionic surface active vesicle, so that hydroxyapatite formed subsequently is conveniently precipitated on the surface of the vesicle.
(3) And extruding the liquid B by using a screen membrane with the diameter of a screen hole of 200nm to form vesicles with uniform sizes, collecting the liquid extruded through the membrane, and placing the liquid in an ultrasonic instrument for ultrasonic treatment for 5-15 min to form liquid C, namely the solution containing the hydroxyapatite hollow template with a certain particle size.
(4) Transferring the solution C into a double-neck round-bottom flask, continuously introducing nitrogen from the neck of one side flask under the condition of magnetic stirring to form a nitrogen environment inside the flask, and slowly and alternately adding CaCl2Solution and Na2HPO4And (3) forming a solution D by adjusting the molar ratio of Ca to P to be 1-1.67.
(5) And centrifuging the solution D, washing the precipitate with deionized water and absolute ethyl alcohol, performing vacuum drying on the obtained precipitate, and collecting to obtain the hollow hydroxyapatite medicine-carrying particles.
Further improved, the concentration of the Tris solution in the step (1) is 0.1-0.5M, and the pH value is adjusted by adopting 0.1NNaOH solution.
Further improvement, the step (2) is specifically as follows: adding 0.15-0.2 g of polyethylene glycol 4000 and a water-soluble drug into 5ml of the solution A, stirring by a small rotor until the polyethylene glycol 4000 is completely dissolved, sequentially and slowly dripping 1.5-2 g of Tween80 and 2ml of 1% Triton-100 solution while stirring, and magnetically stirring for 20-60 min to form a solution B.
Further improving, the ultrasonic conditions of the ultrasonic instrument in the step (3) are 40KHz and 100W; the screen membrane is a polycarbonate membrane.
Further improvement, the step (4) is specifically: transferring the solution C into a container containing 50ml of the solution AThe double-neck round-bottom flask is continuously filled with nitrogen from the neck of a flask on one side under the condition of magnetic stirring to form a nitrogen environment inside the flask, and then 1ml of 0.1-0.5M CaCl is slowly added2Continuously stirring the solution for 10min, and slowly adding 1ml of 0.1-0.8M Na2HPO4The solution is continuously stirred for 10min, and then 1ml of CaCl is slowly added2The solution was stirred for 8min, and 1ml of Na was slowly added2HPO4Continuously stirring the solution for 8min, repeating the steps, wherein the stirring time between the repeatedly added solutions is reduced by 2min for one time compared with the previous time, and the CaCl to be added2Solution and Na2HPO4And stopping dripping when the total amount of the solution reaches 5ml respectively, and continuously stirring for 2-12 h to form a solution D. The step can ensure that the hydroxyapatite deposited on the surface of the vesicle is uniform, and finally the spherical shell with thin thickness is formed.
In a further improvement, the magnetic stirring condition in the step (4) is 100rpm, wherein the CaCl is slowly added2Solution and Na2HPO4The speed of the solution was 1 drop/second.
And (3) further improving, washing and precipitating the solution D in the step (5) by using deionized water and absolute ethyl alcohol for 3 times, drying in a vacuum drying oven at 35-40 ℃ overnight, collecting, and storing the hollow hydroxyapatite medicine-carrying particles at normal temperature.
In a further improvement, the water-soluble medicine is zoledronic acid sodium, alendronate sodium, etidronate sodium, risedronate sodium or ibandronate sodium.
After adopting such design, the invention has at least the following advantages:
1. the preparation method comprises the steps of adding polyethylene glycol and a nonionic surfactant solution into a Tris alkali solution to form a medicine-coated nonionic surfactant vesicle solution, sieving and extruding to form uniform vesicles, and slowly and alternately adding CaCl in a nitrogen environment2Solution and Na2HPO4The solution ensures that the hydroxyapatite is uniformly deposited on the surface of the vesicle, and finally the hollow hydroxyapatite with thin thickness and mediated release of the shock wave is formedThe drug-loaded particles meet the effect of effectively releasing drugs under the mediation of in vitro shock waves.
2. According to the preparation method, the rigidity of the formed nonionic surface active vesicle is increased by adopting the Triton-100 solution, so that hydroxyapatite formed subsequently is conveniently precipitated on the surface of the vesicle.
3. The diameter of the spherical hollow hydroxyapatite drug-loaded particles prepared by the preparation method is 150-200 nm, the uniformity is good, the rigidity of the spherical shell wall of the nano particles is good, and the wall thickness is 5-10 nm, so that the shell can be easily broken under the action of proper shock wave energy with biological effect, the local drug concentration of bones is improved, and the purposes of preventing and treating diseases are met.
Drawings
The foregoing is only an overview of the technical solutions of the present invention, and in order to make the technical solutions of the present invention more clearly understood, the present invention is further described in detail below with reference to the accompanying drawings and the detailed description.
Fig. 1 is a particle size distribution diagram of hollow hydroxyapatite drug-loaded particles prepared by the invention.
Fig. 2 is a high-power scanning electron microscope image of the hollow hydroxyapatite drug-loaded particles prepared by the invention, wherein 2a is a 120-power scanning electron microscope image, and 2b is a 300-power scanning electron microscope image.
Fig. 3 is a high-power transmission electron microscope image of the hollow hydroxyapatite drug-loaded particles prepared by the invention.
Fig. 4 is a high-power scanning electron microscope image of the hollow hydroxyapatite drug-loaded particles prepared by the invention under the mediation of in vitro shock waves, wherein 4a is an electron microscope image under the mediation condition of 0bar of in vitro shock waves, 4b is an electron microscope image under the mediation condition of 2bar of in vitro shock waves, and 4c is an electron microscope image under the mediation condition of 3bar of in vitro shock waves.
Fig. 5 is a high-power scanning electron microscope image of hollow spherical hydroxyapatite nanoparticles prepared in the prior art under the mediation of in vitro shock waves, wherein 5a is an electron microscope image under the mediation condition that the in vitro shock waves are 0bar, 5b is an electron microscope image under the mediation condition that the in vitro shock waves are 2bar, and 5c is an electron microscope image under the mediation condition that the in vitro shock waves are 3 bar.
Detailed Description
Example 1
Preparing 0.1M Tris solution, and adjusting the pH value to be between 11 and 12 by using 0.1N NaOH solution to form A solution.
0.15g of PEG4000 and 0.5M sodium zoledronate are dissolved in 5ml of the solution A, a small rotor is placed into the solution A and stirred at 200rpm until the PEG4000 is completely dissolved, then 1.5g of Tween80 solution and 2ml of 1% Triton-100 solution are sequentially dropped into the solution A, and the solution B is formed by stirring the solution A for 20min at 100rpm under magnetic stirring.
Extruding the solution B with 200nm polycarbonate membrane, collecting the extruded solution, and subjecting to ultrasonic treatment in an ultrasonic instrument (ultrasonic condition: 40KHz, 100W) for 5min to synthesize hydroxyapatite hollow template with certain and uniform particle size to obtain solution C.
The whole amount of solution C was transferred to a two-necked round-bottomed flask containing 50ml of solution A, and nitrogen gas was continuously introduced from a neck of the one-side flask under magnetic stirring at 100rpm to form a nitrogen atmosphere inside the flask. Then slowly add (1 drop/second) 1ml0.1MCaCl2The solution was stirred at 100rpm for 10min, and 1ml of 0.1MNa was slowly added dropwise2HPO4The solution was stirred at 100rpm for 10min and then 1ml of 0.1MCaCl was slowly added dropwise2The solution was stirred for 8min, and then 1ml of 0.1MNa was slowly added dropwise2HPO4And (4) solution, and repeating the steps. The stirring time between the addition of the repeated solutions is reduced by 2min for one time compared with the previous time, and CaCl is added into the reaction system2Solution and Na2HPO4When the total amount of the solution reached 5ml, the dropwise addition was stopped and stirring was continued at 100rpm for 2 hours. And then centrifuging the reaction solution, washing and precipitating for 3 times by using deionized water and absolute ethyl alcohol, drying in a vacuum drying oven at 35 ℃ overnight, collecting the hollow hydroxyapatite drug-loaded particles 1, and storing at normal temperature.
Example 2
Preparing 0.5M Tris solution, and adjusting the pH value to be between 11 and 12 by using 0.1N NaOH solution to form A solution.
0.2g of PEG4000 and 0.5M alendronate sodium are dissolved in 5ml of solution A, the solution A is placed into a small rotor and stirred at 200rpm until the PEG4000 is completely dissolved, then 2g of Tween80 solution and 2ml of 1% Triton-100 solution are sequentially dropped, and the solution B is formed by stirring for 60min at 100rpm under magnetic stirring.
Extruding the liquid B by using a 200nm polycarbonate membrane, collecting the extruded liquid, and placing the liquid in an ultrasonic instrument (the ultrasonic condition is 40KHz and 100W) for ultrasonic treatment for 15min to synthesize a hydroxyapatite hollow template with a certain and uniform particle size to form a liquid C.
The whole amount of solution C was transferred to a two-necked round-bottomed flask containing 50ml of solution A, and nitrogen gas was continuously introduced from a neck of the one-side flask under magnetic stirring at 100rpm to form a nitrogen atmosphere inside the flask. Then, 1ml of 0.5MCaCl was slowly added dropwise (1 drop/sec)2The solution was stirred at 100rpm for 10min, and 1ml of 0.5MNa was slowly added dropwise2HPO4The solution was further stirred at 100rpm for 10min, and 1ml of 0.5MCaCl was slowly added dropwise2The solution was stirred for 8min, and 1ml of 0.5MNa was slowly added dropwise2HPO4And (4) solution, and repeating the steps. The stirring time between the addition of the repeated solutions is reduced by 2min for one time compared with the previous time, and CaCl is added into the reaction system2Solution and Na2HPO4When the total amount of the solution reached 5ml, the dropwise addition was stopped and stirring was continued at 100rpm for 12 hours. And then centrifuging the reaction solution, washing and precipitating for 3 times by using deionized water and absolute ethyl alcohol, drying in a vacuum drying oven at 40 ℃ overnight, collecting the hollow hydroxyapatite drug-loaded particles 2, and storing at normal temperature.
Example 3
Preparing 0.3M Tris solution, and adjusting the pH value to be between 11 and 12 by using 0.1N NaOH solution to form A solution.
0.2g of PEG4000 and 0.5M of etidronate sodium are dissolved in 5ml of solution A, the solution is placed into a small rotor and stirred at 200rpm until the PEG4000 is completely dissolved, then 1.5g of Tween80 solution and 2ml of 1% Triton-100 solution are sequentially dropped, and the solution is stirred for 50min under magnetic stirring at 100rpm, so that solution B is formed.
Extruding the liquid B by using a 200nm polycarbonate membrane, collecting the extruded liquid, and placing the liquid in an ultrasonic instrument (the ultrasonic condition is 40KHz and 100W) for ultrasonic treatment for 10min to synthesize a hydroxyapatite hollow template with a certain and uniform particle size to form a liquid C.
Transfer all solution C into a two-necked round-bottomed flask containing 50ml of solution A and magnetically stir bar at 100rpmUnder the condition, nitrogen gas was continuously introduced from the neck of the flask on one side to form a nitrogen atmosphere inside the flask. Then slowly add 1ml0.4MCaCl dropwise (1 drop/s)2The solution was stirred at 100rpm for 10min, and 1ml of 0.25MNa was slowly added dropwise2HPO4The solution was stirred at 100rpm for 10min and then 1ml of 0.4MCaCl was slowly added dropwise2Stirring the solution for 8min, and slowly adding 1ml of 0.25MNa dropwise2HPO4And (4) solution, and repeating the steps. The stirring time between the addition of the repeated solutions is reduced by 2min for one time compared with the previous time, and CaCl is added into the reaction system2Solution and Na2HPO4When the total amount of the solution reached 5ml, the dropwise addition was stopped and stirring was continued at 100rpm for 10 hours. And then centrifuging the reaction solution, washing and precipitating for 3 times by using deionized water and absolute ethyl alcohol, drying in a vacuum drying oven at 35 ℃ overnight, collecting the hollow hydroxyapatite drug-loaded particles 3, and storing at normal temperature.
Results examples
The particle size detection is carried out on the hollow hydroxyapatite medicine carrying particles 1, 2 and 3 obtained in the three embodiments, the result is shown in figure 1, the particle size of the hollow hydroxyapatite medicine carrying particles obtained by the preparation method is concentrated in the range of 150-220 nm, preferably 170-200 nm, the sizes are close, and the uniformity is good, as shown in figure 2.
Then, high-power transmission electron microscope analysis is carried out on the hollow hydroxyapatite medicine carrying particles 1, 2 and 3 obtained in the three embodiments, and the wall thickness of a spherical shell of the hollow hydroxyapatite medicine carrying particles is about 5-10 nm, preferably 6-9 nm.
Comparative examples
The hollow hydroxyapatite drug-loaded particles 1, 2 and 3 obtained in the above three embodiments and the hollow hydroxyapatite nanoparticles prepared by the existing preparation method (such as the preparation method disclosed in the existing patent application 200710067822.1) are subjected to morphological analysis of the nanoparticles after in vitro shock wave intervention mediation, and refer to fig. 4 and 5. Fig. 4 is a high-power scanning electron microscope image of hollow hydroxyapatite drug-loaded particles prepared by the invention under the mediation of in vitro shock waves, fig. 5 is a high-power scanning electron microscope image of hollow spherical hydroxyapatite nanoparticles prepared by the prior art under the mediation of in vitro shock waves, wherein a is an electron microscope image under the mediation condition that the in vitro shock waves are 0bar, b is an electron microscope image under the mediation condition that the in vitro shock waves are 2bar, and c is an electron microscope image under the mediation condition that the in vitro shock waves are 3 bar.
As can be seen from the attached figures 4 and 5, under the condition that the in vitro shock wave is 2bar and 3bar, the crushing degrees of the two types of nano-particles are different, the hollow hydroxyapatite medicine-carrying particle prepared by the invention is suitable for in vitro shock wave mediated drug release, can realize good crushing, and realizes effective release of the spherical drug carried.
In conclusion, the hollow hydroxyapatite drug-loaded particles for shock wave mediated release obtained by the preparation method have the advantages of good sphericity, good uniformity, thin sphere wall and good rigidity, are easy to generate shell breakage under the action of adaptive energy with biological effect, and achieve the purposes of effectively releasing the drugs and improving the local bone drug concentration.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the present invention in any way, and it will be apparent to those skilled in the art that the above description of the present invention can be applied to various modifications, equivalent variations or modifications without departing from the spirit and scope of the present invention.
Claims (11)
1. The hollow hydroxyapatite drug-loaded particles for shock wave mediated release are characterized in that the spherical particle size of the hollow hydroxyapatite drug-loaded particles is 150-220 nm, and the wall thickness of a spherical shell of the nanoparticles is 5-10 nm;
the preparation method of the hollow hydroxyapatite medicine-carrying particle comprises the following steps:
(1) preparing a Tris solution, and adjusting the pH to 11-12 to form a solution A;
(2) adding polyethylene glycol and a water-soluble drug into the solution A, stirring until the polyethylene glycol and the water-soluble drug are completely dissolved, slowly dripping Tween80 and Triton-100 solution in sequence while stirring, and magnetically stirring for 20-60 min to form a solution B, namely a solution containing the drug-coated nonionic surface active vesicles;
(3) extruding the liquid B by using a screen membrane with the diameter of a screen hole of 200nm, collecting the liquid after membrane extrusion, and placing the liquid in an ultrasonic instrument for ultrasonic treatment for 5-15 min to form a liquid C, namely a solution containing a hydroxyapatite hollow template with a certain particle size;
(4) transferring the solution C into a double-neck round-bottom flask, continuously introducing nitrogen from the neck of one side flask under the condition of magnetic stirring to form a nitrogen environment inside the flask, and slowly and alternately adding CaCl2Solution and Na2HPO4Forming a solution D by adjusting the molar ratio of Ca to P to be 1-1.67;
(5) and centrifuging the solution D, washing the precipitate with deionized water and absolute ethyl alcohol, performing vacuum drying on the obtained precipitate, and collecting to obtain the hollow hydroxyapatite medicine-carrying particles.
2. The hollow hydroxyapatite drug-loaded particle according to claim 1, wherein the spherical particle diameter of the hollow hydroxyapatite drug-loaded particle is 170 to 200nm, and the wall thickness of the spherical shell of the nanoparticle is 6 to 9 nm.
3. The hollow hydroxyapatite drug-loaded particle according to claim 1, wherein the concentration of the Tris solution in the step (1) is 0.1-0.5M, and the pH value is adjusted by using 0.1N NaOH solution;
the step (2) is specifically as follows: adding 0.15-0.2 g of polyethylene glycol 4000 and a water-soluble drug into 5ml of the solution A, stirring by a small rotor until the polyethylene glycol 4000 is completely dissolved, sequentially and slowly dripping 1.5-2 g of Tween80 and 2ml of 1% Triton-100 solution while stirring, and magnetically stirring for 20-60 min to form a solution B;
the ultrasonic conditions of the ultrasonic instrument in the step (3) are 40KHz and 100W; the screen membrane is a polycarbonate membrane;
the step (4) is specifically as follows: transferring the solution C into a double-neck round-bottom flask containing 50ml of the solution A, continuously introducing nitrogen from a neck of a side flask under the condition of magnetic stirring to form a nitrogen environment in the flask, and slowly adding 1ml of 0.1-0.5M CaCl2Continuously stirring the solution for 10min, and slowly adding 1ml of 0.1-0.8M Na2HPO4The solution is continuously stirred for 10min, and then 1ml of CaCl is slowly added2The solution was stirred for 8min, and 1ml of Na was slowly added2HPO4Continuously stirring the solution for 8min, repeating the steps, and reducing the stirring time between repeated solution additions by 2min for one time compared with the previous time to add the CaCl2Solution and Na2HPO4Stopping dripping when the total amount of the solution reaches 5ml respectively, and continuously stirring for 2-12 h to form a solution D;
wherein the magnetic stirring conditions are 100rpm, wherein the CaCl is slowly added2Solution and Na2HPO4The speed of the solution was 1 drop/second;
and (3) washing and precipitating the solution D in the step (5) by using deionized water and absolute ethyl alcohol for 3 times, drying in a vacuum drying oven at 35-40 ℃ overnight, collecting, and storing the hollow hydroxyapatite medicine-carrying particles at normal temperature.
4. The preparation method of the hollow hydroxyapatite drug-loaded particles through shock wave mediated release is characterized in that the spherical particle size of the hollow hydroxyapatite drug-loaded particles is 150-220 nm, the wall thickness of a spherical shell of the nanoparticles is 5-10 nm, and the preparation method comprises the following steps:
(1) preparing a Tris solution, and adjusting the pH to 11-12 to form a solution A;
(2) adding polyethylene glycol and a water-soluble drug into the solution A, stirring until the polyethylene glycol and the water-soluble drug are completely dissolved, slowly dripping Tween80 and Triton-100 solution in sequence while stirring, and magnetically stirring for 20-60 min to form a solution B, namely a solution containing the drug-coated nonionic surface active vesicles;
(3) extruding the liquid B by using a screen membrane with the diameter of a screen hole of 200nm, collecting the liquid after membrane extrusion, and placing the liquid in an ultrasonic instrument for ultrasonic treatment for 5-15 min to form a liquid C, namely a solution containing a hydroxyapatite hollow template with a certain particle size;
(4) transferring the solution C into a double-neck round-bottom flask, continuously introducing nitrogen from the neck of one side flask under the condition of magnetic stirring to form a nitrogen environment inside the flask, and slowly and alternately adding CaCl2Solution and Na2HPO4Forming a solution D by adjusting the molar ratio of Ca to P to be 1-1.67;
(5) and centrifuging the solution D, washing the precipitate with deionized water and absolute ethyl alcohol, performing vacuum drying on the obtained precipitate, and collecting to obtain the hollow hydroxyapatite medicine-carrying particles.
5. The preparation method of the hollow hydroxyapatite drug-loaded particle according to claim 4, wherein the concentration of the Tris solution in the step (1) is 0.1-0.5M, and the pH value is adjusted by using 0.1N NaOH solution.
6. The preparation method of the hollow hydroxyapatite drug-loaded particle according to claim 5, wherein the step (2) is specifically: adding 0.15-0.2 g of polyethylene glycol 4000 and a water-soluble drug into 5ml of the solution A, stirring by a small rotor until the polyethylene glycol 4000 is completely dissolved, sequentially and slowly dripping 1.5-2 g of Tween80 and 2ml of 1% Triton-100 solution while stirring, and magnetically stirring for 20-60 min to form a solution B.
7. The preparation method of the hollow hydroxyapatite drug-loaded particles according to claim 6, wherein the ultrasonic conditions of the ultrasonic instrument in the step (3) are 40KHz and 100W; the screen membrane is a polycarbonate membrane.
8. The preparation method of the hollow hydroxyapatite drug-loaded particle according to claim 6, wherein the step (4) is specifically: transferring the solution C into a double-neck round-bottom flask containing 50ml of the solution A, continuously introducing nitrogen from a neck of a side flask under the condition of magnetic stirring to form a nitrogen environment in the flask, and slowly adding 1ml of 0.1-0.5M CaCl2Continuously stirring the solution for 10min, and slowly adding 1ml of 0.1-0.8M Na2HPO4The solution is continuously stirred for 10min, and then 1ml of CaCl is slowly added2The solution was stirred for 8min, and 1ml of Na was slowly added2HPO4The solution is continuously stirred for 8min, and the process is repeated,the stirring time between repeated solution additions is reduced by 2min for one time compared with the previous time, and the CaCl to be added2Solution and Na2HPO4And stopping dripping when the total amount of the solution reaches 5ml respectively, and continuously stirring for 2-12 h to form a solution D.
9. The method for preparing hollow hydroxyapatite drug-loaded particles according to claim 8, wherein the magnetic stirring condition in the step (4) is 100rpm, wherein the CaCl is slowly added2Solution and Na2HPO4The speed of the solution was 1 drop/second.
10. The preparation method of the hollow hydroxyapatite drug-loaded particles according to claim 8, wherein the solution D in the step (5) is washed and precipitated for 3 times by using deionized water and absolute ethyl alcohol, and then dried in a vacuum drying oven at 35-40 ℃ overnight, collected, and stored at normal temperature.
11. The method for preparing hollow hydroxyapatite drug-loaded particles according to claim 4, wherein the water-soluble drug is zoledronic acid sodium, alendronic acid sodium, etidronic acid sodium, risedronic acid sodium or ibandronic acid sodium.
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