CN104940145B - A kind of method for improving drug bearing microsphere controlled release ability - Google Patents
A kind of method for improving drug bearing microsphere controlled release ability Download PDFInfo
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- CN104940145B CN104940145B CN201510319273.7A CN201510319273A CN104940145B CN 104940145 B CN104940145 B CN 104940145B CN 201510319273 A CN201510319273 A CN 201510319273A CN 104940145 B CN104940145 B CN 104940145B
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Abstract
The present invention relates to a kind of method for improving drug bearing microsphere controlled release ability, belong to pharmaceutical technology field, this method first carries out active surface processing using technique for atomic layer deposition to drug bearing microsphere, then by atomic deposition successively, drug bearing microsphere surface is set to form the sedimentary of controllable thickness, by the accurate control to deposit thickness, to realize the slow release of medicine.The medicine can maintain certain blood concentration in a long time, and so as to reduce administration number of times, and blood concentration can be maintained in the steady lasting effective range of comparison, advantageously reduce the adverse reaction of medicine, curative effect is lasting, safety.
Description
Technical field
The present invention relates to a kind of method for improving drug bearing microsphere controlled release ability, belong to pharmaceutical technology field.
Background technology
Traditional drug delivery system, medicine disposably discharge in vivo after being taken in by human body, cause drug in blood serum dense
Degree fluctuates in very large range, unexpected side effect can be not only brought to human body, and can cause the decline of curative effect of medication.
Thus center of gravity has been transferred to the research to medicament slow release by people.Early in the beginning of the seventies in last century, foreign countries have begun to sustained release, control
The research and development of release formulation, the so far existing history in more than 50 years.Because such medicine can maintain certain blood in a long time
Concentration, so as to reduce administration number of times, and blood concentration can be maintained in the steady lasting effective range of comparison, be advantageous to subtract
The adverse reaction of few medicine, curative effect persistently, safety, it the advantages of increasingly paid attention to by clinic.Slow-release controlled-release system in recent years
Agent research and development is very rapid.The sustained-release preparation of domestic listing is of less types at present, and quality is also unstable.Chinese patent mandate
Notification number is the B of CN 101810583, authorized announcement date 2013.09.11, entitled：HIV fusion inhibitor slow-releases are micro-
Ball, the microspherulite diameter are 1~1000 μm, can be sustained in vivo 0.5~3 month or for more time, there is preferable slow release effect, but
Because drug bearing microsphere support layer thickness is difficult to control, and some drugs are scattered in carrying layer surface, so preceding 8h after the tablet has been ingested,
Drug release rate is still very fast, and Cumulative release amount reaches more than 50%.Chinese patent Authorization Notice No. CN 102579368A, it is public
Accuse day 2012.07.18, denomination of invention：Mei-Tuo Luoer sustained-release micro-spheres, slow-releasing medicated composition and preparation method thereof, the invention
Pharmaceutical composition low toxicity, envelop rate is high, and burst drug release rate is less than the requirement of general water soluble drug 30%, but it is to keep blood
Concentration is steady in a long-term, very high to the slow-released carrier layer material requirement for preparing microballoon, and carrier layer materials need to mix with inert matter
Uniformly, it is available for the material that it is selected very little.
The content of the invention
Problem be present for above-mentioned, it is an object of the invention to provide a kind of method for improving drug bearing microsphere controlled release ability.
To achieve these goals, technical solution of the invention is：
A kind of method for improving drug bearing microsphere controlled release ability, methods described is using technique for atomic layer deposition to drug bearing microsphere
The outer surface of carrier layer carries out layer by layer deposition, forms sedimentary in the outer surface of the carrier layer of drug bearing microsphere, its method is by following
Step is carried out：
Drug bearing microsphere is placed in the reaction cavity of atomic deposition, keep the temperature in atomic deposition reaction cavity 20~
50 DEG C, pressure in 40~50pa, vapor is passed through in reaction cavity, keeps 30~90s, toward reaction cavity in be passed through nitrogen,
10~20s is kept, remaining vapor in cleaning reaction cavity, then oxalyl chlorine body is passed through in reaction cavity, keeps 30
~90s, again toward nitrogen is passed through in reaction cavity, keep 10~20s, remaining oxalyl chlorine body in cleaning reaction cavity, then
Ethylene glycol gas is passed through in reaction cavity, 30~90s is kept, nitrogen is passed through in reaction cavity again, holding 10~
20s, remaining ethylene glycol gas in cleaning reaction cavity, thickness is formed in 0.1nm in the outer surface of the carrier layer of drug bearing microsphere
Sedimentary.
It is alternately repeated above-mentioned steps 500~800 times, it is micro- to carry medicine that molal weight is passed through before final step is passed through nitrogen
The ethylene glycol gas of 7~8 times of the molal weight of the carrier layer of ball, 30~90s is kept, obtains forming thickness in the outer surface of carrier layer
Spend for the drug bearing microsphere of 50~80nm sedimentaries.
Wherein, vapor in atomic deposition reaction cavity, oxalyl chlorine body, ethylene glycol gas, the speed of nitrogen are passed through
It is 100~150ml/s.
The vapor that is passed through in the reaction cavity of atomic deposition, the molal weight of oxalyl chlorine body and ethylene glycol gas are
2~3 times of the molal weight of the carrier layer of drug bearing microsphere.
The material of the carrier layer of described drug bearing microsphere is PLA or chitosan or gelatin or Arabic gum or collagen egg
In vain.
Technical scheme as a result of more than, a kind of method of raising drug bearing microsphere controlled release ability of the invention is using logical
Cross water and active surface processing is carried out to microballoon, then by oxalyl chlorine body introducing reative cell be allowed to that chemisorbed occurs.Until micro-
Ball surface reaches saturation, is passed through inert nitrogen gas and removes superfluous reactant and accessory substance, then ethylene glycol gas is put into instead
Room is answered, is allowed to react with the material adsorbed on microballoon.After saturation, be passed through inert nitrogen gas remove remaining reactant and
Byproduct.Successively grown by so circulating to realize, so as to realize the control to deposit thickness.
The drug bearing microsphere prepared with this method, its prominent features are the sedimentaries with one layer of controllable thickness, deposit layer choosing
By the use of the oxalyl chloride and ethylene glycol of 2-2 systems as reactant, with covalent bond keyed alternating copolymerization, therefore the homogeneous friendship of structure can be formed
For copolymer.And reaction condition relaxes, and the degree of polymerization of alternate copolymer by the control to reaction times size, can be changed,
Accurately change deposit thickness, regulating medicine release way, so as to obtain that there is the structure of different pharmaceutical releasability.Therefore make
The microballoon pair prepared with this method can effectively avoid the higher and insoluble drug release later stage blood medicine of insoluble drug release blood concentration early stage dense
Spend the problem of relatively low.Can steadily blood concentration, reduction toxic side effect, extension drug treating time, and then improve patient in disease
Drug effect under state, have administration number of times is few, facilitate medication and it is safe the characteristics of.
For the inventive method using technique for atomic layer deposition, this is that one kind can be by material with monatomic one layer of form membrane
One layer of the method for being plated in substrate surface.In atomic layer deposition process, the chemical reaction of new one layer of atomic film is directly therewith
What preceding layer was associated, this mode makes every secondary response only deposit one layer of atom, accurately controls the thickness of sedimentary.
The polymer that drug bearing microsphere sedimentary prepared by the inventive method is formed by oxalyl chloride and glycol reaction only has carbon
Three kinds of elements of hydrogen-oxygen, will not produce harmful substance, good biocompatibility, therefore small to the excitant of human body, advantageously reduce medicine
Adverse reaction there is good biocompatibility, have no toxic side effect.
Brief description of the drawings
Fig. 1 is control-release microsphere cross-sectional view of the present invention.
Wherein, 1- medicine layers, 2- carrier layers, 3- sedimentaries.
Embodiment
Done further in detail with reference to the specific embodiment method for improving drug bearing microsphere controlled release ability a kind of to the present invention
Thin description：
A kind of method for improving drug bearing microsphere controlled release ability, sedimentary 3 is accurately controlled by using atomic deposition layer technology
Thickness, the insoluble drug release path in regulation drug bearing microsphere medicine layer 1, the effect slowly discharged so as to the medicine reached.With this
Drug bearing microsphere prepared by method, its biocompatibility is good, steadily blood concentration, reduction toxic side effect, extension medicine can act on
Time, and then improve drug effect of the patient under morbid state, have administration number of times is few, facilitate medication and it is safe the characteristics of, choosing
By the use of the oxalyl chloride and ethylene glycol of 2-2 systems as reactant, with covalent bond keyed alternating copolymerization, therefore the homogeneous friendship of structure can be formed
For copolymer.And reaction condition relaxes, and the degree of polymerization of alternate copolymer by the control to reaction times size, can be changed,
Accurately change the thickness of sedimentary 3, so as to obtain that there is the structure of different pharmaceutical releasability.
A kind of method for improving drug bearing microsphere controlled release ability, methods described is using technique for atomic layer deposition to drug bearing microsphere
The outer surface of carrier layer 2 carries out layer by layer deposition, forms sedimentary 3 in the outer surface of the carrier layer 2 of drug bearing microsphere, its method press with
Lower step is carried out：
It is PLA or chitosan or gelatin or Arabic gum or collagen by the material of carrier layer 2, the medicine of drug-loaded layer 1
Thing is that acetylsalicylic acid or the drug bearing microsphere of water soluble vitamin or clindamycin are placed in the reaction cavity of atomic deposition, is kept
Temperature in atomic deposition reaction cavity is in 20~50 DEG C, pressure in 40~50pa, the carrier by molal weight for drug bearing microsphere
2~3 times of vapor of the molal weight of layer 2 is passed through in reaction cavity with 100~150ml/s speed, keeps 30~90s,
With 100~150ml/s speed toward nitrogen is passed through in reaction cavity, 10~20s is kept, it is remaining in cleaning reaction cavity
Vapor, then by molal weight for drug bearing microsphere carrier layer 2 molal weight 2~3 times of oxalyl chlorine body
It is passed through with 100~150ml/s speed in reaction cavity, 30~90s of holding, its reaction equation is as follows：Led to again with 100~150ml/s speed toward in reaction cavity
Enter nitrogen, keep 10~20s, remaining oxalyl chlorine body in cleaning reaction cavity, then by load that molal weight is drug bearing microsphere
2~3 times of ethylene glycol gas of the molal weight of body layer 2 is passed through in reaction cavity with 100~150ml/s speed, keeps 30s
~90s, reaction equation are as follows：Again
Nitrogen is passed through in reaction cavity with 100~150ml/s speed, 10~20s of holding, remaining second two in cleaning reaction cavity
Alcohol gas, sedimentary 3 of the thickness in 0.1nm is formed in the outer surface of the carrier layer 2 of drug bearing microsphere.
It is alternately repeated above-mentioned steps 500~800 times, the reaction equation being directed to is as follows：
At last
Step will be passed through ethylene glycol gas of the molal weight for 7~8 times of the molal weight of the carrier layer 2 of drug bearing microsphere before being passed through nitrogen, protect
30~90s is held, obtains forming the drug bearing microsphere that thickness is 50~80nm sedimentaries 3 in the outer surface of carrier layer 2.
Specific embodiment:
Embodiment one
By the material of carrier layer be PLA, drug-loaded layer medicine be that the drug bearing microsphere of acetylsalicylic acid is placed in atomic deposition
Reaction cavity in, keep the temperature in atomic deposition reaction cavity in 20 DEG C, pressure in 40pa, molal weight is micro- to carry medicine
2 times of vapor of the molal weight of the carrier layer of ball is passed through in reaction cavity with 150ml/s speed, keeps 90s, with
150ml/s speed keeps 20s toward nitrogen is passed through in reaction cavity, remaining vapor in cleaning reaction cavity, will then rub
Your quality is that 2 times of oxalyl chlorine body of the molal weight of the carrier layer of drug bearing microsphere is passed through reaction chamber with 150ml/s speed
In vivo, holding 90s, its reaction equation are as follows：Again with
150ml/s speed keeps 20s toward nitrogen is passed through in reaction cavity, remaining oxalyl chlorine in cleaning reaction cavity
Body, then by molal weight for drug bearing microsphere carrier layer molal weight 2 times of ethylene glycol gas with
100ml/s~150ml/s speed is passed through in reaction cavity, holding 90s, and reaction equation is as follows：Again with 150ml/s speed by nitrogen
Be passed through in reaction cavity, keep 20s, remaining ethylene glycol gas in cleaning reaction cavity, drug bearing microsphere carrier layer it is outer
Surface forms sedimentary of the thickness in 0.1nm.
It is alternately repeated above-mentioned steps 500 times, the reaction equation being directed to is as follows：
At last
Step will be passed through ethylene glycol gas of the molal weight for 7 times of the molal weight of the carrier layer of drug bearing microsphere before being passed through nitrogen, keep
90s, obtain forming the drug bearing microsphere that thickness is 50nm sedimentaries in the outer surface of carrier layer.
Embodiment two
By the material of carrier layer be PLA, drug-loaded layer medicine be that the drug bearing microsphere of water soluble vitamin is placed in atom and sunk
In long-pending reaction cavity, keep the temperature in atomic deposition reaction cavity in 35 DEG C, pressure in 45pa, by molal weight to carry medicine
2.5 times of vapor of the molal weight of the carrier layer of microballoon is passed through in reaction cavity with 135ml/s speed, keeps 60s, with
135ml/s speed keeps 15s toward nitrogen is passed through in reaction cavity, remaining vapor in cleaning reaction cavity, will then rub
Your quality is that 2.5 times of oxalyl chlorine body of the molal weight of the carrier layer of drug bearing microsphere is passed through reaction with 135ml/s speed
In cavity, 60s is kept, its reaction equation is as follows：Again with
135ml/s speed keeps 15s toward nitrogen is passed through in reaction cavity, remaining grass in cleaning reaction cavity
Acyl chlorides gas, then by molal weight for drug bearing microsphere carrier layer molal weight 2.5 times of ethylene glycol gas with
135ml/s speed is passed through in reaction cavity, holding 60s, and reaction equation is as follows：Again with 135ml/s speed by nitrogen
Be passed through in reaction cavity, keep 15s, remaining ethylene glycol gas in cleaning reaction cavity, drug bearing microsphere carrier layer it is outer
Surface forms sedimentary of the thickness in 0.1nm.
It is alternately repeated above-mentioned step 650 times, the reaction equation being directed to is as follows：
At last
Step will be passed through ethylene glycol gas of the molal weight for 7.5 times of the molal weight of the carrier layer of drug bearing microsphere before being passed through nitrogen, keep
60s, obtain forming the drug bearing microsphere that thickness is 65nm sedimentaries in the outer surface of carrier layer.
Embodiment three
By the material of carrier layer be PLA, drug-loaded layer medicine be that the drug bearing microsphere of clindamycin is placed in atomic deposition
In reaction cavity, it in 50 DEG C, pressure is drug bearing microsphere by molal weight in 50pa to keep the temperature in atomic deposition reaction cavity
3 times of the vapor of molal weight of carrier layer be passed through with 100ml/s speed in reaction cavity, 30s is kept, with 100ml/
S speed keeps 10s toward nitrogen is passed through in reaction cavity, remaining vapor in cleaning reaction cavity, then by molal weight
It is passed through in reaction cavity, is protected with 100ml/s speed for 3 times of oxalyl chlorine body of the molal weight of the carrier layer of drug bearing microsphere
30s is held, its reaction equation is as follows：Again with 100ml/s's
Speed keeps 10s toward nitrogen is passed through in reaction cavity, remaining oxalyl chlorine body in cleaning reaction cavity, then by molal weight
It is passed through in reaction cavity, is protected with 100ml/s speed for 3 times of ethylene glycol gas of the molal weight of the carrier layer of drug bearing microsphere
30s is held, reaction equation is as follows：Again with
Nitrogen is passed through in reaction cavity by 100ml/s speed, holding 10, remaining ethylene glycol gas in cleaning reaction cavity, is being carried
The outer surface of the carrier layer of medicine microballoon forms sedimentary of the thickness in 0.1nm.
It is alternately repeated above-mentioned steps 800 times, the reaction equation being directed to is as follows：
At last
Step will be passed through ethylene glycol gas of the molal weight for 8 times of the molal weight of the carrier layer of drug bearing microsphere before being passed through nitrogen, keep
30s, obtain forming the drug bearing microsphere that thickness is 80nm sedimentaries in the outer surface of carrier layer.
Example IV
By the material of carrier layer be chitosan, drug-loaded layer medicine be that the drug bearing microsphere of acetylsalicylic acid is placed in atomic deposition
Reaction cavity in, keep the temperature in atomic deposition reaction cavity in 20 DEG C, pressure in 40pa, molal weight is micro- to carry medicine
2 times of vapor of the molal weight of the carrier layer of ball is passed through in reaction cavity with 150ml/s speed, keeps 90s, with
150ml/s speed keeps 20s toward nitrogen is passed through in reaction cavity, remaining vapor in cleaning reaction cavity, will then rub
Your quality is that 2 times of oxalyl chlorine body of the molal weight of the carrier layer of drug bearing microsphere is passed through reaction chamber with 150ml/s speed
In vivo, holding 90s, its reaction equation are as follows：Again with
150ml/s speed keeps 20s toward nitrogen is passed through in reaction cavity, remaining oxalyl chloride in cleaning reaction cavity
Gas, then by molal weight for drug bearing microsphere carrier layer molal weight 2 times of ethylene glycol gas with
100ml/s~150ml/s speed is passed through in reaction cavity, holding 90s, and reaction equation is as follows：Again with 150ml/s speed by nitrogen
Be passed through in reaction cavity, keep 20s, remaining ethylene glycol gas in cleaning reaction cavity, drug bearing microsphere carrier layer it is outer
Surface forms sedimentary of the thickness in 0.1nm.
It is alternately repeated above-mentioned steps 500 times, the reaction equation being directed to is as follows：
At last
Step will be passed through ethylene glycol gas of the molal weight for 7 times of the molal weight of the carrier layer of drug bearing microsphere before being passed through nitrogen, keep
90s, obtain forming the drug bearing microsphere that thickness is 50nm sedimentaries in the outer surface of carrier layer.
Embodiment five
By the material of carrier layer be chitosan, drug-loaded layer medicine be that the drug bearing microsphere of water soluble vitamin is placed in atom and sunk
In long-pending reaction cavity, keep the temperature in atomic deposition reaction cavity in 35 DEG C, pressure in 45pa, by molal weight to carry medicine
2.5 times of vapor of the molal weight of the carrier layer of microballoon is passed through in reaction cavity with 135ml/s speed, keeps 60s, with
135ml/s speed keeps 15s toward nitrogen is passed through in reaction cavity, remaining vapor in cleaning reaction cavity, will then rub
Your quality is that 2.5 times of oxalyl chlorine body of the molal weight of the carrier layer of drug bearing microsphere is passed through reaction with 135ml/s speed
In cavity, 60s is kept, its reaction equation is as follows：Again with
135ml/s speed keeps 15s toward nitrogen is passed through in reaction cavity, remaining in cleaning reaction cavity
Oxalyl chlorine body, then 2.5 times of the second two by molal weight for the molal weight of the carrier layer of drug bearing microsphere
Alcohol gas is passed through in reaction cavity with 135ml/s speed, holding 60s, and reaction equation is as follows：Again with 135ml/s speed by nitrogen
Be passed through in reaction cavity, keep 15s, remaining ethylene glycol gas in cleaning reaction cavity, drug bearing microsphere carrier layer it is outer
Surface forms sedimentary of the thickness in 0.1nm.
It is alternately repeated above-mentioned step 650 times, the reaction equation being directed to is as follows：
In final step
Ethylene glycol gas of the molal weight for 7.5 times of the molal weight of the carrier layer of drug bearing microsphere is passed through before being passed through nitrogen, is kept
60s, obtain forming the drug bearing microsphere that thickness is 65nm sedimentaries in the outer surface of carrier layer.
Embodiment six
By the material of carrier layer be chitosan, drug-loaded layer medicine be that the drug bearing microsphere of clindamycin is placed in atomic deposition
In reaction cavity, it in 50 DEG C, pressure is drug bearing microsphere by molal weight in 50pa to keep the temperature in atomic deposition reaction cavity
3 times of the vapor 100ml/s speed of molal weight of carrier layer be passed through in reaction cavity, 30s is kept, with 100ml/s
Speed toward nitrogen is passed through in reaction cavity, keep 10s, remaining vapor in cleaning reaction cavity, then by molal weight
It is passed through in reaction cavity, is protected with 100ml/s speed for 3 times of oxalyl chlorine body of the molal weight of the carrier layer of drug bearing microsphere
30s is held, its reaction equation is as follows：Again with 100ml/s's
Speed keeps 10s toward nitrogen is passed through in reaction cavity, remaining oxalyl chlorine body in cleaning reaction cavity, then by molal weight
It is passed through in reaction cavity, is protected with 100ml/s speed for 3 times of ethylene glycol gas of the molal weight of the carrier layer of drug bearing microsphere
30s is held, reaction equation is as follows：Again
Nitrogen is passed through in reaction cavity with 100ml/s speed, holding 10, remaining ethylene glycol gas in cleaning reaction cavity,
The outer surface of the carrier layer of drug bearing microsphere forms sedimentary of the thickness in 0.1nm.
It is alternately repeated above-mentioned steps 800 times, the reaction equation being directed to is as follows：
At last
Step will be passed through ethylene glycol gas of the molal weight for 8 times of the molal weight of the carrier layer of drug bearing microsphere before being passed through nitrogen, keep
30s, obtain forming the drug bearing microsphere that thickness is 80nm sedimentaries in the outer surface of carrier layer.
Embodiment seven
By the material of carrier layer be gelatin, drug-loaded layer medicine be that the drug bearing microsphere of acetylsalicylic acid is placed in atomic deposition
In reaction cavity, it in 20 DEG C, pressure is drug bearing microsphere by molal weight in 20pa to keep the temperature in atomic deposition reaction cavity
2 times of the vapor of molal weight of carrier layer be passed through with 150ml/s speed in reaction cavity, 90s is kept, with 150ml/
S speed keeps 20s toward nitrogen is passed through in reaction cavity, remaining vapor in cleaning reaction cavity, then by molal weight
It is passed through in reaction cavity, is protected with 150ml/s speed for 2 times of oxalyl chlorine body of the molal weight of the carrier layer of drug bearing microsphere
90s is held, its reaction equation is as follows：Again with 150ml/s's
Speed keeps 20s toward nitrogen is passed through in reaction cavity, remaining oxalyl chlorine in cleaning reaction cavity
Body, then by molal weight for drug bearing microsphere carrier layer molal weight 2 times of ethylene glycol gas with
100ml/s~150ml/s speed is passed through in reaction cavity, holding 90s, and reaction equation is as follows：Again with 150ml/s speed by nitrogen
Be passed through in reaction cavity, keep 20s, remaining ethylene glycol gas in cleaning reaction cavity, drug bearing microsphere carrier layer it is outer
Surface forms sedimentary of the thickness in 0.1nm.
It is alternately repeated above-mentioned steps 500 times, the reaction equation being directed to is as follows：
Last
One step will be passed through ethylene glycol gas of the molal weight for 7 times of the molal weight of the carrier layer of drug bearing microsphere before being passed through nitrogen, keep
90s, obtain forming the drug bearing microsphere that thickness is 50nm sedimentaries in the outer surface of carrier layer.
Embodiment eight
By the material of carrier layer be gelatin, drug-loaded layer medicine be that the drug bearing microsphere of water soluble vitamin is placed in atomic deposition
Reaction cavity in, keep the temperature in atomic deposition reaction cavity in 35 DEG C, pressure in 45pa, molal weight is micro- to carry medicine
2.5 times of vapor of the molal weight of the carrier layer of ball is passed through in reaction cavity with 135ml/s speed, keeps 60s, with
135ml/s speed keeps 15s toward nitrogen is passed through in reaction cavity, remaining vapor in cleaning reaction cavity, will then rub
Your quality is that 2.5 times of oxalyl chlorine body of the molal weight of the carrier layer of drug bearing microsphere is passed through reaction with 135ml/s speed
In cavity, 60s is kept, its reaction equation is as follows：Again with
135ml/s speed keeps 15s toward nitrogen is passed through in reaction cavity, remaining grass in cleaning reaction cavity
Acyl chlorides gas, then 2.5 times of the ethylene glycol gas by molal weight for the molal weight of the carrier layer of drug bearing microsphere
It is passed through with 135ml/s speed in reaction cavity, holding 60s, reaction equation is as follows：Again with 135ml/s speed by nitrogen
Be passed through in reaction cavity, keep 15s, remaining ethylene glycol gas in cleaning reaction cavity, drug bearing microsphere carrier layer it is outer
Surface forms sedimentary of the thickness in 0.1nm.
It is alternately repeated above-mentioned step 650 times, the reaction equation being directed to is as follows：
Last
One step will be passed through ethylene glycol gas of the molal weight for 7.5 times of the molal weight of the carrier layer of drug bearing microsphere before being passed through nitrogen, protect
60s is held, obtains forming the drug bearing microsphere that thickness is 65nm sedimentaries in the outer surface of carrier layer.
Embodiment nine
By the material of carrier layer be gelatin, drug-loaded layer medicine be that the drug bearing microsphere of clindamycin is placed in the anti-of atomic deposition
Answer in cavity, keep the temperature in atomic deposition reaction cavity in 50 DEG C, pressure in 50pa, be drug bearing microsphere by molal weight
3 times of vapor of the molal weight of carrier layer is passed through in reaction cavity with 100ml/s speed, 30s is kept, with 100ml/s
Speed toward nitrogen is passed through in reaction cavity, keep 10s, remaining vapor in cleaning reaction cavity, then by molal weight
It is passed through in reaction cavity, is protected with 100ml/s speed for 3 times of oxalyl chlorine body of the molal weight of the carrier layer of drug bearing microsphere
30s is held, its reaction equation is as follows：Again with 100ml/s's
Speed keeps 10s toward nitrogen is passed through in reaction cavity, remaining oxalyl chlorine body in cleaning reaction cavity, then by molal weight
It is passed through in reaction cavity, is protected with 100ml/s speed for 3 times of ethylene glycol gas of the molal weight of the carrier layer of drug bearing microsphere
30s is held, reaction equation is as follows：Again with
Nitrogen is passed through in reaction cavity by 100ml/s speed, holding 10, remaining ethylene glycol gas in cleaning reaction cavity, is being carried
The outer surface of the carrier layer of medicine microballoon forms sedimentary of the thickness in 0.1nm.
It is alternately repeated above-mentioned steps 800 times, the reaction equation being directed to is as follows：
Last
One step will be passed through ethylene glycol gas of the molal weight for 8 times of the molal weight of the carrier layer of drug bearing microsphere before being passed through nitrogen, keep
30s, obtain forming the drug bearing microsphere that thickness is 80nm sedimentaries in the outer surface of carrier layer.
Embodiment ten
By the material of carrier layer be Arabic gum, drug-loaded layer medicine be that the drug bearing microsphere of acetylsalicylic acid is placed in atom and sunk
In long-pending reaction cavity, keep the temperature in atomic deposition reaction cavity in 20 DEG C, pressure in 40pa, by molal weight to carry medicine
2 times of vapor of the molal weight of the carrier layer of microballoon is passed through in reaction cavity with 150ml/s speed, keeps 90s, with
150ml/s speed keeps 20s toward nitrogen is passed through in reaction cavity, remaining vapor in cleaning reaction cavity, will then rub
Your quality is that 2 times of oxalyl chlorine body of the molal weight of the carrier layer of drug bearing microsphere is passed through reaction chamber with 150ml/s speed
In vivo, holding 90s, its reaction equation are as follows：Again with
150ml/s speed keeps 20s toward nitrogen is passed through in reaction cavity, remaining oxalyl chloride in cleaning reaction cavity
Gas, then by molal weight for drug bearing microsphere carrier layer molal weight 2 times of ethylene glycol gas with
100ml/s~150ml/s speed is passed through in reaction cavity, holding 90s, and reaction equation is as follows：Again with 150ml/s speed by nitrogen
Be passed through in reaction cavity, keep 20s, remaining ethylene glycol gas in cleaning reaction cavity, drug bearing microsphere carrier layer it is outer
Surface forms sedimentary of the thickness in 0.1nm.
It is alternately repeated above-mentioned steps 500 times, the reaction equation being directed to is as follows：
Last
One step will be passed through ethylene glycol gas of the molal weight for 7 times of the molal weight of the carrier layer of drug bearing microsphere before being passed through nitrogen, keep
90s, obtain forming the drug bearing microsphere that thickness is 50nm sedimentaries in the outer surface of carrier layer.
Embodiment 11
By the material of carrier layer be Arabic gum, drug-loaded layer medicine be that the drug bearing microsphere of water soluble vitamin is placed in atom
In the reaction cavity of deposition, keep the temperature in atomic deposition reaction cavity in 35 DEG C, pressure in 45pa, by molal weight to carry
2.5 times of vapor of the molal weight of the carrier layer of medicine microballoon is passed through in reaction cavity with 135ml/s speed, keeps 60s,
With 135ml/s speed toward nitrogen is passed through in reaction cavity, 15s is kept, remaining vapor in cleaning reaction cavity, then will
Molal weight is passed through instead for 2.5 times of oxalyl chlorine body of the molal weight of the carrier layer of drug bearing microsphere with 135ml/s speed
Answer in cavity, holding 60s, its reaction equation is as follows：Again
With 135ml/s speed toward nitrogen is passed through in reaction cavity, 15s is kept, remaining oxalyl chlorine body in cleaning reaction cavity, then
2.5 times of ethylene glycol gas of the molal weight for the molal weight of the carrier layer of drug bearing microsphere is passed through with 135ml/s speed
In reaction cavity, 60s is kept, reaction equation is as follows：
Nitrogen is passed through in reaction cavity with 135ml/s speed again, holding 15s, remaining ethylene glycol in cleaning reaction cavity
Gas, sedimentary of the thickness in 0.1nm is formed in the outer surface of the carrier layer of drug bearing microsphere.
It is alternately repeated above-mentioned step 650 times, the reaction equation being directed to is as follows：
Last
One step will be passed through ethylene glycol gas of the molal weight for 7.5 times of the molal weight of the carrier layer of drug bearing microsphere before being passed through nitrogen, protect
60s is held, obtains forming the drug bearing microsphere that thickness is 65nm sedimentaries in the outer surface of carrier layer.
Embodiment 12
By the material of carrier layer be Arabic gum, drug-loaded layer medicine be that the drug bearing microsphere of clindamycin is placed in atomic deposition
Reaction cavity in, keep the temperature in atomic deposition reaction cavity in 50 DEG C, pressure in 50pa, molal weight is micro- to carry medicine
3 times of vapor of the molal weight of the carrier layer of ball is passed through in reaction cavity with 100ml/s speed, keeps 30s, with
100ml/s speed keeps 10s toward nitrogen is passed through in reaction cavity, remaining vapor in cleaning reaction cavity, will then rub
Your quality is that 3 times of oxalyl chlorine body of the molal weight of the carrier layer of drug bearing microsphere is passed through reaction chamber with 100ml/s speed
In vivo, holding 30s, its reaction equation are as follows：Again with
100ml/s speed keeps 10s toward nitrogen is passed through in reaction cavity, remaining in cleaning reaction cavity
Oxalyl chlorine body, then by molal weight for drug bearing microsphere carrier layer molal weight 3 times of second two
Alcohol gas is passed through in reaction cavity with 100ml/s speed, holding 30s, and reaction equation is as follows：Again with 100ml/s speed by nitrogen
It is passed through in reaction cavity, holding 10, remaining ethylene glycol gas in cleaning reaction cavity, in the appearance of the carrier layer of drug bearing microsphere
Face forms sedimentary of the thickness in 0.1nm.
It is alternately repeated above-mentioned steps 800 times, the reaction equation being directed to is as follows：
At last
Step will be passed through ethylene glycol gas of the molal weight for 8 times of the molal weight of the carrier layer of drug bearing microsphere before being passed through nitrogen, keep
30s, obtain forming the drug bearing microsphere that thickness is 80nm sedimentaries in the outer surface of carrier layer.
Embodiment 13
By the material of carrier layer be collagen, drug-loaded layer medicine be that the drug bearing microsphere of acetylsalicylic acid is placed in atom and sunk
In long-pending reaction cavity, keep the temperature in atomic deposition reaction cavity in 20 DEG C, pressure in 40pa, by molal weight to carry medicine
2 times of vapor of the molal weight of the carrier layer of microballoon is passed through in reaction cavity with 150ml/s speed, keeps 90s, with
150ml/s speed keeps 20s toward nitrogen is passed through in reaction cavity, remaining vapor in cleaning reaction cavity, will then rub
Your quality is that 2 times of oxalyl chlorine body of the molal weight of the carrier layer of drug bearing microsphere is passed through reaction chamber with 150ml/s speed
In vivo, holding 90s, its reaction equation are as follows：Again with
150ml/s speed keeps 20s toward nitrogen is passed through in reaction cavity, remaining in cleaning reaction cavity
Oxalyl chlorine body, then by molal weight for drug bearing microsphere carrier layer molal weight 2 times of ethylene glycol gas with
100ml/s~150ml/s speed is passed through in reaction cavity, holding 90s, and reaction equation is as follows：Again with 150ml/s speed by nitrogen
Be passed through in reaction cavity, keep 20s, remaining ethylene glycol gas in cleaning reaction cavity, drug bearing microsphere carrier layer it is outer
Surface forms sedimentary of the thickness in 0.1nm.
It is alternately repeated above-mentioned steps 500 times, the reaction equation being directed to is as follows：
At last
Step will be passed through ethylene glycol gas of the molal weight for 7 times of the molal weight of the carrier layer of drug bearing microsphere before being passed through nitrogen, keep
90s, obtain forming the drug bearing microsphere that thickness is 50nm sedimentaries in the outer surface of carrier layer.
Embodiment 14
By the material of carrier layer be collagen, drug-loaded layer medicine be that the drug bearing microsphere of water soluble vitamin is placed in atom
In the reaction cavity of deposition, keep the temperature in atomic deposition reaction cavity in 35 DEG C, pressure in 45pa, by molal weight to carry
2.5 times of vapor of the molal weight of the carrier layer of medicine microballoon is passed through in reaction cavity with 135ml/s speed, keeps 60s,
With 135ml/s speed toward nitrogen is passed through in reaction cavity, 15s is kept, remaining vapor in cleaning reaction cavity, then will
Molal weight is passed through instead for 2.5 times of oxalyl chlorine body of the molal weight of the carrier layer of drug bearing microsphere with 135ml/s speed
Answer in cavity, holding 60s, its reaction equation is as follows：Again
With 135ml/s speed toward nitrogen is passed through in reaction cavity, 15s is kept, it is remaining in cleaning reaction cavity
Oxalyl chlorine body, then 2.5 times of the ethylene glycol gas by molal weight for the molal weight of the carrier layer of drug bearing microsphere
Body is passed through in reaction cavity with 135ml/s speed, holding 60s, and reaction equation is as follows：Again with 135ml/s speed by nitrogen
Be passed through in reaction cavity, keep 15s, remaining ethylene glycol gas in cleaning reaction cavity, drug bearing microsphere carrier layer it is outer
Surface forms sedimentary of the thickness in 0.1nm.
It is alternately repeated above-mentioned step 650 times, the reaction equation being directed to is as follows：
At last
Step will be passed through ethylene glycol gas of the molal weight for 7.5 times of the molal weight of the carrier layer of drug bearing microsphere before being passed through nitrogen, keep
60s, obtain forming the drug bearing microsphere that thickness is 65nm sedimentaries in the outer surface of carrier layer.
Embodiment 15
By the material of carrier layer be collagen, drug-loaded layer medicine be that the drug bearing microsphere of clindamycin is placed in atomic deposition
Reaction cavity in, keep the temperature in atomic deposition reaction cavity in 50 DEG C, pressure in 50pa, molal weight is micro- to carry medicine
3 times of vapor of the molal weight of the carrier layer of ball is passed through in reaction cavity with 100ml/s speed, keeps 30s, with
100ml/s speed keeps 10s toward nitrogen is passed through in reaction cavity, remaining vapor in cleaning reaction cavity, will then rub
Your quality is that 3 times of oxalyl chlorine body of the molal weight of the carrier layer of drug bearing microsphere is passed through reaction chamber with 100ml/s speed
In vivo, holding 30s, its reaction equation are as follows：Again with
100ml/s speed keeps 10s toward nitrogen is passed through in reaction cavity, remaining in cleaning reaction cavity
Oxalyl chlorine body, then 3 times of the ethylene glycol gas by molal weight for the molal weight of the carrier layer of drug bearing microsphere
It is passed through with 100ml/s speed in reaction cavity, holding 30s, reaction equation is as follows：Again with 100ml/s speed by nitrogen
It is passed through in reaction cavity, holding 10, remaining ethylene glycol gas in cleaning reaction cavity, in the appearance of the carrier layer of drug bearing microsphere
Face forms sedimentary of the thickness in 0.1nm.
It is alternately repeated above-mentioned steps 800 times, the reaction equation being directed to is as follows：
At last
Step will be passed through ethylene glycol gas of the molal weight for 8 times of the molal weight of the carrier layer of drug bearing microsphere before being passed through nitrogen, keep
30s, obtain forming the drug bearing microsphere that thickness is 80nm sedimentaries in the outer surface of carrier layer.
Claims (1)
- A kind of 1. method for improving drug bearing microsphere controlled release ability, it is characterised in that：Methods described utilizes technique for atomic layer deposition pair The carrier layer of drug bearing microsphere（2）Outer surface carry out layer by layer deposition, in the carrier layer of drug bearing microsphere（2）Outer surface formed deposition Layer（3）, its method carries out according to the following steps：Drug bearing microsphere is placed in the reaction cavity of atomic deposition, keeps the temperature in atomic deposition reaction cavity 20~50 DEG C, pressure in 40~50Pa, vapor is passed through in reaction cavity, keeps 30~90s, toward reaction cavity in be passed through nitrogen, guarantor Hold 10~20s, remaining vapor in cleaning reaction cavity, then oxalyl chlorine body is passed through in reaction cavity, keep 30~ 90s, again toward nitrogen is passed through in reaction cavity, keep 10~20s, remaining oxalyl chlorine body in cleaning reaction cavity, then will Ethylene glycol gas is passed through in reaction cavity, keeps 30~90s, nitrogen is passed through in reaction cavity again, keeps 10~20s, Remaining ethylene glycol gas in cleaning reaction cavity, in the carrier layer of drug bearing microsphere（2）Outer surface formed thickness 0.1nm's Sedimentary（3）；It is alternately repeated above-mentioned steps 500~800 times, molal weight is passed through before final step is passed through nitrogen as drug bearing microsphere Carrier layer（2）7~8 times of molal weight ethylene glycol gas, keep 30~90s, obtain in carrier layer（2）Outer surface formed Thickness is 50~80nm sedimentaries（3）Drug bearing microsphere；Wherein, the vapor that is passed through in atomic deposition reaction cavity, oxalyl chlorine body, ethylene glycol gas, the speed of nitrogen are 100~150ml/s；The molal weight of the vapor, oxalyl chlorine body and the ethylene glycol gas that are passed through in the reaction cavity of atomic deposition is load medicine The carrier layer of microballoon（2）2~3 times of molal weight；Wherein, the carrier layer of described drug bearing microsphere（2）Material be PLA or chitosan or gelatin or Arabic gum or glue Former albumen.
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| 原子层沉积方法制备核-壳型纳米材料研究;李勇等;《物理学报》;20131231;第62卷(第19期);参见全文 * |
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