CN103191417A - Long-effect blood-glucose-control medicine-controlled-release system loading insulin aggregate, and preparation method thereof - Google Patents
Long-effect blood-glucose-control medicine-controlled-release system loading insulin aggregate, and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a long-effect blood-glucose-control medicine-controlled-release system loading insulin aggregate. The system is composed of a substrate, and a polymer layer with pH sensitivity and an insulin aggregate layer superposed or coated on the substrate, wherein the substrate, the polymer layer with pH sensitivity, and the insulin aggregate layer are integrated through an electrostatic effect. Or, the system is composed of a substrate, a polymer layer with pH sensitivity, a protein layer, and an insulin aggregate layer superposed or coated on the substrate, wherein the substrate, the polymer layer with pH sensitivity, the protein layer, and the insulin aggregate layer are integrated through an electrostatic effect. A preparation method of the invention comprises the steps that: 1, a raw material solution or suspension liquid is prepared; 2, a substrate surface is treated or a substrate is prepared; and 3, the coating layer or an encapsulation layer is assembled on the substrate.
Description
Technical field
The invention belongs to biomaterial and pharmaceutics crossed technical, particularly can store and control system and preparation method that the insulin aggregation discharges.
Background technology
Studies show that, to glycosuria animal pattern single subcutaneous injection bovine insulin aggregation (being called for short B-SIA) 200 μ g, can control normal 120 days of the interior blood sugar concentration of its body, to diabetes model animal single subcutaneous injection recombinant human insulin aggregation (being called for short rH-SIA) 200 μ g, can control volume normal 140 days of blood sugar concentration in it, but to diabetes model animal single subcutaneous injection insulin aggregation 400 μ g, then can cause excessive hypoglycemia (to see Gupta, S., Chattopadhyay, T., Singh, M.P., et al., Supramolecular insulin assembly II for a sustained treatment of type 1 diabetes mellitus.Proc.Natl.Acad.Sci.USA 2010,107:13246-13251.); To diabetes model animal single subcutaneous injection Iletin II (Lilly) aggregation (being called for short P-SIA) 200 μ g, can control normal 129 days of the interior blood sugar concentration of its body.Research also shows, greatly sickness rate and the fatality rate of the various cancers of increase (are seen Smith because the insulin dose that a variety of causes (control of for example lack of wisdom response discharges) causes is controlled improper meeting, U., Gale, E.A.M., Does diabetes therapy influence the risk of cancer? Diabetologia 2009,52:1699-1708.).The case report shows, the long-term position of insulin of directly using might produce the deposition of insulin and cause amyloid distortion disease (to see Dische, F.E., Wernstedt, C., Westermark, G.T., et al., Insulin as an amyloid-fibril protein at sites of repeated insulin injection in a diabetic patient.Diabetologia 1988,31:158-161.).Thereby, be necessary very much to make up the energy load and control the intelligent response system that the insulin aggregation discharges.
Summary of the invention
The objective of the invention is to overcome the deficiencies in the prior art, medicine controlled releasing system and the preparation method of the long-acting control blood sugar concentration that is loaded with the insulin aggregation are provided, described medicine controlled releasing system not only can prolong the normal time of blood sugar concentration in the diabetes model animal body, and the release of the contained insulin of intelligent response control.
The medicine controlled releasing system that is loaded with the long-acting control blood sugar concentration of insulin aggregation of the present invention has following two types.
1, first type: substrate is the non-insulin aggregation
The medicine controlled releasing system of this type is made up of substrate and polymeric layer and insulin aggregation layer overlapping or that be coated on the suprabasil pH of having sensitivity, and substrate, the polymeric layer with pH sensitivity, insulin aggregation layer are combined into one by electrostatic interaction each other; Or formed by substrate and polymeric layer, protein layer and insulin aggregation layer overlapping or that be coated on the suprabasil pH of having sensitivity, substrate, the polymeric layer with pH sensitivity, protein layer, insulin aggregation layer are combined into one by electrostatic interaction each other; Described substrate is flat board, microsphere or medical apparatus and instruments, and described flat board or microsphere are by a kind of making in lucite, quartz, the Muscovitum.
The above-mentioned medicine controlled releasing system that is loaded with the long-acting control blood sugar concentration of insulin aggregation, having the polymeric layer of pH sensitivity and insulin aggregation layer can be the polymeric layer with pH sensitivity, all compound modes of insulin aggregation layer in suprabasil coating order, or polymeric layer, protein layer and insulin aggregation layer with pH sensitivity can be all compound modes of polymeric layer with pH sensitivity, protein layer, insulin aggregation layer in suprabasil coating order.
2, second type: substrate is the insulin aggregation
This kind is loaded with the medicine controlled releasing system of the long-acting control blood sugar concentration of insulin aggregation, be made up of substrate and the polymeric layer and the protein layer that are coated on the suprabasil pH of having sensitivity, substrate, the polymeric layer with pH sensitivity, protein layer are combined into one by electrostatic interaction each other; Or formed by substrate and the polymeric layer, protein layer, the insulin aggregation layer that are coated on the suprabasil pH of having sensitivity, substrate, the polymeric layer with pH sensitivity, protein layer, insulin aggregation layer are combined into one by electrostatic interaction each other; Described substrate is the insulin aggregate particle.
The above-mentioned medicine controlled releasing system that is loaded with the long-acting control blood sugar concentration of insulin aggregation, having the polymeric layer of pH sensitivity and protein layer can be the polymeric layer with pH sensitivity, all compound modes of protein layer in suprabasil coating order, or polymeric layer, protein layer and insulin aggregation layer with pH sensitivity can be all compound modes of polymeric layer with pH sensitivity, protein layer, insulin aggregation layer in suprabasil coating order.
In the medicine controlled releasing system of above-mentioned two kinds of long-acting control blood sugar concentrations that are loaded with the insulin aggregation, described insulin aggregation is a kind of in bovine insulin aggregation, recombinant human insulin's aggregation, the Iletin II (Lilly) aggregation.The polymer of the described pH of having sensitivity is polymethylacrylic acid-N, a kind of in N-dimethylaminoethyl, PMAm propyl-dimethyl amine, polyacrylic acid dimethylaminoethyl, polymethacrylates, the chitosan, and molecular weight is 1～1000kda.Described protein is glucoseoxidase or catalase.
The preparation method of the medicine controlled releasing system of the long-acting control blood sugar concentration that is loaded with the insulin aggregation of the present invention has following two kinds:
1, first method
First method is for the preparation of the medicine controlled releasing system of the above-mentioned first type long-acting control blood sugar concentration that is loaded with the insulin aggregation, and processing step is as follows:
(1) preparation raw material solution or suspension
Material solution or suspension are polymer solution and the insulin aggregation suspension with pH sensitivity, or polymer solution, insulin aggregation suspension and protein solution with pH sensitivity;
The polymer of the described pH of having sensitivity is polymethylacrylic acid-N, a kind of in N-dimethylaminoethyl, PMAm propyl-dimethyl amine, polyacrylic acid dimethylaminoethyl, polymethacrylates, the chitosan, and molecular weight is 1～1000kda; Be that to become concentration be the solution of 0.015～100mg/mL for polymer formulation that 1～7 aqueous hydrochloric acid solution, acetic acid solution or deionized water will have pH sensitivity with pH value, if having the polymer of pH sensitivity is polymethylacrylic acid-N, N-dimethylaminoethyl, PMAm propyl-dimethyl amine, polyacrylic acid dimethylaminoethyl or polymethacrylates, then add NaCl again, the addition of NaCl reaches 0.01～5mol/L with its concentration in mixed liquor and is limited;
Described insulin aggregation is a kind of in bovine insulin aggregation, recombinant human insulin's aggregation, the Iletin II (Lilly) aggregation; Be that 3～8 aqueous hydrochloric acid solution, acetic acid aqueous solution, phosphate aqueous solution or deionized water are mixed with the suspension that concentration is 0.015～100mg/mL with the insulin aggregation with pH value;
Described protein is glucoseoxidase or catalase; Be that 3～8 aqueous hydrochloric acid solution, acetic acid aqueous solution, phosphate aqueous solution or deionized water are mixed with the solution that concentration is 0.015～100mg/mL with protein with pH value;
(2) handling substrate surface makes it electrically charged;
(3) assembling overlapping layer or clad
Polymer solution, insulin aggregation suspension and/or the protein solution that will have pH sensitivity is overlapping or be coated in the substrate and the preceding on the overlapping or coating according to the structure of described medicine controlled releasing system with the method for spin coating, dip-coating or spraying, when each ply of preparation or coating, leave standstill 0-100min, and will form that the redundant solution of described overlapping or coating or suspension remove with deionized water rinsing, method centrifugal or dialysis and dry, namely obtain being loaded with the medicine controlled releasing system of the long-acting control blood sugar concentration of insulin aggregation;
Described substrate is flat board, microsphere or medical apparatus and instruments, and described flat board or microsphere are by a kind of making in lucite, quartz, the Muscovitum.
2, second method
Second method is for the preparation of the medicine controlled releasing system of the above-mentioned second type long-acting control blood sugar concentration that is loaded with the insulin aggregation, and processing step is as follows:
(1) preparation raw material solution or suspension
Material solution or suspension are polymer solution and the protein solution with pH sensitivity, or have polymer solution, protein solution and the insulin aggregation suspension of pH sensitivity;
The polymer of the described pH of having sensitivity is polymethylacrylic acid-N, a kind of in N-dimethylaminoethyl, PMAm propyl-dimethyl amine, polyacrylic acid dimethylaminoethyl, polymethacrylates, the chitosan, and molecular weight is 1～1000kda; Be that to become concentration be the solution of 0.015～100mg/mL for polymer formulation that 1～7 aqueous hydrochloric acid solution, acetic acid solution or deionized water will have pH sensitivity with pH value, if having the polymer of pH sensitivity is polymethylacrylic acid-N, N-dimethylaminoethyl, PMAm propyl-dimethyl amine, polyacrylic acid dimethylaminoethyl or polymethacrylates, then add NaCl again, the addition of NaCl reaches 0.01～5mol/L with its concentration in mixed liquor and is limited;
Described insulin aggregation is a kind of in bovine insulin aggregation, recombinant human insulin's aggregation, the Iletin II (Lilly) aggregation; Be that 3～8 aqueous hydrochloric acid solution, acetic acid aqueous solution, phosphate aqueous solution or deionized water are mixed with the suspension that concentration is 0.015～100mg/mL with the insulin aggregation with pH value;
Described protein is glucoseoxidase or catalase; Be that 3～8 aqueous hydrochloric acid solution, acetic acid aqueous solution, phosphate aqueous solution or deionized water are mixed with the solution that concentration is 0.015～100mg/mL with protein with pH value;
(2) preparation insulin aggregation substrate
It is 1～100mg/mL suspension that the insulin aggregation is mixed with concentration with the acetic acid of pH 2～5 or hydrochloric acid solution, regulate pH value to 6～10 of aggregation suspension then with NaOH solution, add NaCl then, the addition of NaCl reaches 0.5～5mol/L with the concentration of NaCl in the mixed liquor, under room temperature, normal pressure, mix 1～20h, continue after centrifugalize, obtain electronegative graininess insulin aggregation substrate;
(3) assembling clad
To have the polymer solution of pH sensitivity and protein solution adopts the method for mixing with substrate and mixing with coating the preceding to be coated in the substrate according to the structure of described medicine controlled releasing system and the preceding on the coating, the polymer solution that maybe will have pH sensitivity, protein solution and insulin aggregation suspension adopt the method for mixing with substrate and mixing with coating the preceding to be coated in the substrate according to the structure of described medicine controlled releasing system and the preceding on the coating, when each layer of preparation coating, stir 10min at least, and will form redundant solution or the suspension deionized water rinsing of described coating, method centrifugal or dialysis is removed, and namely obtains being loaded with the medicine controlled releasing system of the long-acting control blood sugar concentration of insulin aggregation.
In the method for the invention, the preparation method of bovine insulin aggregation, recombinant human insulin's aggregation is stated document as follows:
1、Gupta，S.，Chattopadhyay，T.，Singh，M.P.，et?al.，Supramolecular?insulin?assembly?II?for?a?sustained?treatment?of?type?1?diabetes?mellitus.Proc.Natl.Acad.Sci.USA?2010，107：13246-13251.
In the method for the invention, the preparation method of Iletin II (Lilly) aggregation is as follows:
Iletin II (Lilly) is mixed with the solution of concentration between 0.01mg/mL-400mg/mL with solution, place reaction vessel under agitation in normal pressure, 5～60 ℃ of reaction 1～300h this solution, after response time expires, get Iletin II (Lilly) aggregation suspension, then the lyophilization of Iletin II (Lilly) aggregation suspension is namely obtained the Iletin II (Lilly) aggregation; Described solution is aqueous hydrochloric acid solution, or aqueous acetic acid, or the mixed aqueous solution of hydrochloric acid and acetic acid, or is phosphate buffer, or is citrate buffer solution, or is sodium hydrate aqueous solution, and their pH value is between 1～14.
The present invention has following beneficial effect:
1, test shows, medicine controlled releasing system of the present invention is imbedded under the diabetes model animal skins, can control the interior euglycemia concentration of its body and reach 295 days (seeing embodiment 7), compared with prior art, prolong the time of euglycemia concentration in the single medication control volume greatly.
2, medicine controlled releasing system of the present invention has the concentration of glucose response performance, is a kind of insulin control delivery systme of intelligent response.
3, the polymer in the medicine controlled releasing system of the present invention and the protein material that is avirulence, good biocompatibility, thereby its good biocompatibility has no side effect to body.
4, the method for the invention is simple to operate, is convenient to suitability for industrialized production.
Description of drawings
Fig. 1 is a kind of structural representation of the medicine controlled releasing system of the long-acting control blood sugar concentration that is loaded with the insulin aggregation of the present invention, among the figure, and 1: substrate; 2: the polymeric layer with pH sensitivity; 3: insulin aggregation layer; 4: glucose oxidase layer; 5: the catalase layer.
Fig. 2 is laser scanning co-focusing microscope (CLSM) picture of medicine controlled releasing system intelligent response in glucose solution of the prepared long-acting control blood sugar concentration that is loaded with the insulin aggregation of embodiment 1, wherein, laser scanning co-focusing microscope (CLSM) picture that Fig. 2 (a) closes for intelligence in concentration 0g/L glucose solution, laser scanning co-focusing microscope (CLSM) picture that Fig. 2 (b) opens for intelligence in concentration 5g/L glucose solution.
Fig. 3 be medicine controlled releasing system heeling-in with the long-acting control blood sugar concentration that is loaded with the insulin aggregation of the present invention in the diabetes model animal body, the change curve of blood sugar concentration in its body.
The specific embodiment
Below by embodiment medicine controlled releasing system of the long-acting control blood sugar concentration that is loaded with the insulin aggregation of the present invention and its preparation method and application is described further.
The processing step of present embodiment is as follows:
(1) preparation Iletin II (Lilly) aggregation
Be that 6.5 phosphate buffered solution is mixed with the solution that concentration is 10mg/mL with the Iletin II (Lilly) pH value, place reaction vessel under agitation in normal pressure, 35 ℃ of reaction 26h this solution, after response time expires, get Iletin II (Lilly) aggregation suspension, then Iletin II (Lilly) aggregation suspension is namely obtained Iletin II (Lilly) aggregation (being called for short P-SIA in following description) at-80 ℃ of lyophilization 15h;
(2) preparation raw material solution or suspension
Be the star-type polymer of 120kda: polymethylacrylic acid-N with molecular weight, N-dimethylaminoethyl (being called for short Star-PDMAEMA in following description) is that 5 aqueous hydrochloric acid solution is mixed with the solution that concentration is 0.5mg/mL with pH value, add NaCl then, the addition of NaCl reaches 0.2mol/L with its concentration in mixed liquor and is limited;
The P-SIA of step (1) preparation is mixed with the P-SIA suspension that concentration is 2mg/mL with deionized water;
Be that 6 aqueous hydrochloric acid solution is mixed with the GOD solution that concentration is 3mg/mL with glucoseoxidase (in following description, being called for short GOD) powder pH value; Catalase (being called for short CAT in following description) powder is mixed with the CAT solution that concentration is 2mg/mL with deionized water;
(3) handle substrate
Substrate is the lucite sheet, and its length is that 2cm, width are that 2cm, thickness are 2mm.At first use washed with de-ionized water 3 times, in volume ratio is the mixed liquor of 1: 1 deionized water and isopropyl alcohol, soaked 15 minutes then, put into deionized water/mass concentration 30%H of 5: 1: 1 of volume ratio again
2O
2In the mixed solution of/mass concentration 29% ammonia, under 70 ℃ of water bath condition, soaked 10 minutes, dry after the back is with deionized water rinsing, namely obtain surperficial electronegative lucite sheet.
(4) assembling cover layer
In the medicine controlled releasing system of the long-acting control blood sugar concentration that is loaded with the insulin aggregation of present embodiment preparation, Star-PDMAEMA layer, P-SIA layer, GOD layer, CAT layer in suprabasil overlapping order are: { (Star-PDMAEMA/P-SIA)
2+ (Star-PDMAEMA/CAT)
1+ (Star-PDMAEMA/GOD)
2}
2+ Star-PDMAEMA, its structure is seen Fig. 1.
According to said structure, at first the Star-PDMAEMA solution 150 μ L that under room temperature, normal pressure step (2) prepared are coated on surface treated lucite sheet surface, and absorption 30min uses the deionized water clean surface then, and dries up with nitrogen; P-SIA suspension 200 μ L with step (2) preparation are coated on the Star-PDMAEMA laminar surface again, and absorption 40min uses the deionized water clean surface then, and dries up with nitrogen; Repeat aforesaid operations, obtain 2 Star-PDMAEMA/P-SI bilayers.Star-PDMAEMA 150 μ L solution with step (2) preparation under room temperature, normal pressure are coated on the P-SIA laminar surface, absorption 30min, use the deionized water clean surface then, and dry up with nitrogen, CAT solution 150 μ L with step (2) preparation are coated on the Star-PDMAEMA laminar surface again, and absorption 40min uses the deionized water clean surface then, and dry up with nitrogen, obtain 1 Star-PDMAEMA/CAT bilayer.Star-PDMAEMA solution 150 μ L with step (2) preparation under room temperature, normal pressure are coated on the CAT laminar surface, absorption 30min, use the deionized water clean surface then, and dry up with nitrogen, GOD solution 200 μ L with step (2) preparation are coated on the Star-PDMAEMA laminar surface again, absorption 40min uses the deionized water clean surface then, and dries up with nitrogen; Repeat aforesaid operations, obtain 2 Star-PDMAEMA/GOD bilayers.So far, substrate formed following covering order " (Star-PDMAEMA/P-SIA)
2+ (Star-PDMAEMA/CAT)
1+ (Star-PDMAEMA/GOD)
2" 10 layers of cover layer.Repeat aforesaid operations, obtain having formed in the substrate following covering order " { (Star-PDMAEMA/P-SIA)
2+ (Star-PDMAEMA/CAT)
1+ (Star-PDMAEMA/GOD)
2}
2" 20 layers of cover layer.At last, under room temperature, the normal pressure 150 μ L Star-PDMAEMA solution are being coated on the GOD layer, use the deionized water clean surface then, and dry up with nitrogen, namely obtain the medicine controlled releasing system of the long-acting control blood sugar concentration that is loaded with the insulin aggregation of the described structure of Fig. 1.
Under room temperature, normal pressure, the medicine controlled releasing system that is loaded with the insulin aggregation that present embodiment is prepared is put into the glucose solution of concentration 0g/L glucose solution and 5g/L respectively, its laser scanning co-focusing microscope (CLSM) picture is seen Fig. 2, as can be seen from Figure 2, body series is in closed condition in the 0g/L glucose solution, and body series is in open state in the glucose solution of 5g/L.
The processing step of present embodiment is as follows:
(1) preparation bovine insulin aggregation
Be that 5.9 aqueous hydrochloric acid solution is mixed with the solution that concentration is 0.01mg/mL with the bovine insulin pH value, place reaction vessel under agitation in normal pressure, 25 ℃ of reaction 43h this solution, after response time expires, get bovine insulin aggregation suspension, then bovine insulin aggregation suspension is namely obtained bovine insulin aggregation (being called for short B-SIA in following description) at-60 ℃ of lyophilization 18h;
(2) preparation raw material solution
Be the star-type polymer of 170kda: polymethylacrylic acid-N with molecular weight, N-dimethylaminoethyl (being called for short Star-PDMAEMA in following description) is that 6.2 aqueous hydrochloric acid solution is mixed with the solution that concentration is 10mg/mL with pH value, add NaCl then, the addition of NaCl reaches 0.1mol/L with its concentration in mixed liquor and is limited;
Be that 6 aqueous hydrochloric acid solution is mixed with the GOD solution that concentration is 10mg/mL with glucoseoxidase (in following description, being called for short GOD) powder pH value; Be that 6 aqueous hydrochloric acid solution is mixed with the CAT solution that concentration is 10mg/mL with catalase (in following description, being called for short CAT) powder pH value;
(3) preparation insulin aggregation substrate
Be that 3 hydrochloric acid solution is mixed with the B-SIA suspension that concentration is 100mg/mL with the B-SIA pH value of step (1) preparation, regulate the pH value to 6 (more than the bovine insulin isoelectric point, IP) of B-SIA suspension then with the NaOH solution of concentration 1mol/L, add NaCl again, the addition of NaCl reaches 0.5mol/L with the concentration of NaCl in the mixed liquor and is limited, under room temperature, normal pressure, mix 1h, continue after with the centrifugal 5min of 1000 rev/mins rotating speed, obtain electronegative graininess B-SIA substrate.
(4) assembling clad
In the medicine controlled releasing system of the long-acting control blood sugar concentration that is loaded with the insulin aggregation of present embodiment preparation, Star-PDMAEMA layer, GOD layer, CAT layer in the suprabasil coating of graininess B-SIA are in proper order: (Star-PDMAEMA/GOD)
2+ (Star-PDMAEMA/CAT)
1+ (Star-PDMAEMA/GOD)
2+ Star-PDMAEMA.
According to said structure, graininess B-SIA substrate 20mg with step (3) preparation under room temperature, normal pressure mixes by the mode that stirs with the Star-PDMAEMA solution 5mL of step (2) preparation, mixing time 20min, after mixing time expires, with the centrifugal 5min of 1000 rev/mins rotating speed, then with obtain precipitation with the NaCl mixed liquor of the HCl of concentration 1mM and concentration 0.5M wash, centrifugal 2 times, obtain the microgranule that is coated with the Star-PDMAEMA layer; The microgranule that will be coated with the Star-PDMAEMA layer under room temperature, normal pressure mixes by the mode that stirs with the GOD solution 3mL of step (2) preparation, mixing time 20min, after mixing time expires, with the centrifugal 5min of 1000 rev/mins rotating speed, then with obtain precipitation with the NaCl mixed liquor of the HCl of concentration 1mM and concentration 0.5M wash, centrifugal 2 times, obtain the microgranule that is coated with Star-PDMAEMA, GOD layer successively, i.e. 1 Star-PDMAEMA/GOD bilayer.Repeat aforesaid operations, obtain 2 Star-PDMAEMA/GOD bilayers.
The microgranule that will be coated with Star-PDMAEMA, GOD layer, Star-PDMAEMA, GOD layer under room temperature, normal pressure successively mixes by the mode that stirs with the Star-PDMAEMA solution 5mL of step (2) preparation, mixing time 20min, after mixing time expires, with the centrifugal 5min of 1000 rev/mins rotating speed, then with obtain precipitation with the NaCl mixed liquor of the HCl of concentration 1mM and concentration 0.5M wash, centrifugal 2 times; Under room temperature, normal pressure, the CAT solution 1mL of aforementioned microgranule with step (2) preparation mixed by the mode that stirs, mixing time 20min, after mixing time expires, with the centrifugal 5min of 1000 rev/mins rotating speed, then with obtain precipitation with the NaCl mixed liquor of the HCl of concentration 1mM and concentration 0.5M wash, centrifugal 2 times, obtain 1 Star-PDMAEMA/CAT bilayer.So far, substrate formed following coating order " (Star-PDMAEMA/GOD)
2+ (Star-PDMAEMA/CAT)
1" 6 layers of clad.Repeat aforesaid operations, substrate formed following coating order " (Star-PDMAEMA/GOD)
2+ (Star-PDMAEMA/CAT)
1+ (Star-PDMAEMA/GOD)
2" 10 layers of clad.At last, the microgranule of above-mentioned 10 layers of clad mixes by the mode that stirs with the Star-PDMAEMA solution 2mL of step (2) preparation under room temperature, normal pressure, mixing time 20min, after mixing time expires, with the centrifugal 5min of 1000 rev/mins rotating speed, then with obtain precipitation with the NaCl mixed liquor of the HCl of concentration 1mM and concentration 0.5M wash, centrifugal 2 times, namely obtain the medicine controlled releasing system of the long-acting control blood sugar concentration that is loaded with the insulin aggregation of the described structure of present embodiment, with prepared microspheroidal medicine controlled releasing system at-60 ℃ of lyophilization 17h.
Embodiment 3
The processing step of present embodiment is as follows:
(1) preparation recombinant human insulin aggregation
Be that 4.9 aqueous acetic acid is mixed with the solution that concentration is 400mg/mL with the recombinant human insulin with pH value, place reaction vessel under agitation in normal pressure, 5 ℃ of reaction 48h this solution, after response time expires, get recombinant human insulin's aggregation suspension, then recombinant human insulin's aggregation suspension is namely obtained recombinant human insulin's aggregation (being called for short rH-SIA in following description) at-80 ℃ of lyophilization 9h;
(2) preparation raw material solution
Be that the chitosan pH value of 10kda is that 6.2 acetic acid aqueous solution is mixed with the chitosan solution that concentration is 1mg/mL with molecular weight; Be that 5 aqueous hydrochloric acid solution is mixed with the GOD solution that concentration is 3mg/mL with glucoseoxidase (in following description, being called for short GOD) powder pH value.
(3) preparation insulin aggregation substrate
Be that 5 hydrochloric acid solution is mixed with the rH-SIA suspension that concentration is 1mg/mL with the rH-SIA pH value of step (1) preparation, regulate the pH value to 10 of rH-SIA suspension then with the NaOH solution of concentration 0.1N, add NaCl then, the addition of NaCl reaches 5mol/L with the concentration of NaCl in the mixed liquor and is limited, under room temperature, normal pressure, mix 20h, continue after with the centrifugal 15min of 3000 rev/mins rotating speed, obtain electronegative graininess rH-SIA substrate.
(4) assembling clad
In the medicine controlled releasing system of the long-acting control blood sugar concentration that is loaded with the insulin aggregation of present embodiment preparation, chitosan layer, GOD layer in the suprabasil coating of graininess rH-SIA are in proper order: (chitosan/GOD)
10
According to said structure, graininess rH-SIA substrate 10mg with step (3) preparation under room temperature, normal pressure mixes by the mode that stirs with the chitosan solution 5mL of step (2) preparation, mixing time 60min, after mixing time expires, with the centrifugal 5min of 3000 rev/mins rotating speed, then with obtain precipitation with the NaCl mixed liquor of the HCl of concentration 2mM and concentration 0.7M wash, centrifugal 2 times, obtain the microgranule that is coated with the chitosan layer; The microgranule that will be coated with the chitosan layer under room temperature, normal pressure mixes by the mode that stirs with the GOD solution 1mL of step (2) preparation, mixing time 10min, after mixing time expires, with the centrifugal 5min of 3000 rev/mins rotating speed, then with obtain precipitation with the NaCl mixed liquor of the HCl of concentration 2mM and concentration 0.7M wash, centrifugal 2 times, obtain the microgranule that is coated with chitosan layer, GOD layer successively, i.e. 1 chitosan/GOD bilayer.Repeat aforesaid operations, formed the " (chitosan/GOD) of following coating order in substrate
10" 20 layers of clad, i.e. the medicine controlled releasing system of the long-acting control blood sugar concentration that is loaded with the insulin aggregation of the described structure of present embodiment, with prepared microspheroidal medicine controlled releasing system at-80 ℃ of lyophilization 9h.
The processing step of present embodiment is as follows:
(1) preparation recombinant human insulin aggregation
Be that 6 aqueous citric acid solution is mixed with the solution that concentration is 200mg/mL with the recombinant human insulin with pH value, place reaction vessel under agitation in normal pressure, 30 ℃ of reaction 30h this solution, after response time expires, get recombinant human insulin's aggregation suspension, then recombinant human insulin's aggregation suspension is namely obtained recombinant human insulin's aggregation (being called for short rH-SIA in following description) at-70 ℃ of lyophilization 12h;
(2) preparation raw material solution
Be the linear polymer of 1kda with molecular weight: polyacrylic acid dimethylaminoethyl (being called for short PDMAEA in following description) is that 5 aqueous hydrochloric acid solution is mixed with the solution that concentration is 0.5mg/mL with pH value, add NaCl then, the addition of NaCl reaches 0.6mol/L with its concentration in mixed liquor and is limited;
Just the rH-SIA of step (1) preparation is mixed with the rH-SIA suspension that concentration is 1mg/mL with deionized water;
Be that 6 aqueous hydrochloric acid solution is mixed with the GOD solution that concentration is 2mg/mL with glucoseoxidase (in following description, being called for short GOD) powder pH value;
(3) handle substrate
Substrate is mica sheet, and its length is that 2cm, width are that 2cm, thickness are 2mm, and processing method is identical with embodiment 1.
(4) assembling cover layer
In the medicine controlled releasing system of the long-acting control blood sugar concentration that is loaded with the insulin aggregation of present embodiment preparation, PDMAEA layer, rH-SIA layer, GOD layer in suprabasil overlapping order are: (PDMAEA/rH-SIA/PDMAEA/GOD)
2
According to said structure, the PDMAEA solution 100 μ L with step (2) preparation under room temperature, normal pressure are spun on surface treated mica sheet surface, absorption 60min, the unnecessary PDMAEA solution of dialysis treatment then; The rH-SIA suspension 100 μ L of step (2) preparation are coated on the PDMAEA laminar surface, and absorption 5min uses the deionized water clean surface then, and dries up with nitrogen; The PDMAEA solution 100 μ L of step (2) preparation are spun on the rH-SIA laminar surface, absorption 20min, the unnecessary PDMAEA solution of dialysis treatment then; The GOD solution 200 μ L of step (2) preparation are spun on the PDMAEA laminar surface, absorption 10min, the unnecessary GOD solution of centrifugal treating obtains 1 PDMAEA/rH-SIA/PDMAEA/GOD four molecular layer then.Repeat aforesaid operations, obtain having formed in the substrate following covering order " (PDMAEA/rH-SIA/PDMAEA/GOD)
2" 8 layers of cover layer, i.e. the medicine controlled releasing system of the long-acting control blood sugar concentration that is loaded with the insulin aggregation of the described structure of present embodiment.
Embodiment 5
The processing step of present embodiment is as follows:
(1) preparation Iletin II (Lilly) aggregation
The preparation method of Iletin II (Lilly) aggregation (being called for short P-SIA in following description) is identical with embodiment 1.
(2) preparation raw material solution
Be the linear polymer of 1000kda with molecular weight: polyacrylic acid dimethylaminoethyl (being called for short PDMAEA in following description) is the solution that 5.2 aqueous hydrochloric acid solution is mixed with concentration 1.5mg/mL with pH value, add NaCl then, the addition of NaCl reaches 0.3mol/L with its concentration in mixed liquor and is limited;
Just the P-SIA of step (1) preparation is mixed with the P-SIA suspension that concentration is 2mg/mL with deionized water;
Be that 6 aqueous hydrochloric acid solution is mixed with the GOD solution that concentration is 2mg/mL with glucoseoxidase (in following description, being called for short GOD) powder pH value;
(3) handle substrate
Substrate is the catheter surface of polyurethane material, and processing method is with embodiment 1.
(4) assembling cover layer
In the medicine controlled releasing system of the long-acting control blood sugar concentration that is loaded with the insulin aggregation of present embodiment preparation, PDMAEA layer, P-SIA layer, GOD layer in suprabasil overlapping order are: PDMAEA/P-SIA/PDMAEA/GOD.
According to said structure, the PDMAEA solution 150 μ L with step (2) preparation under room temperature, normal pressure are spun on surface treated catheter surface, absorption 20min, the unnecessary PDMAEA solution of dialysis treatment then; The P-SIA suspension 100 μ L of step (2) preparation are spun on the PDMAEA laminar surface, and absorption 15min uses the deionized water clean surface then, and dries up with nitrogen; The PDMAEA solution 200 μ L of step (2) preparation are spun on the P-SIA laminar surface, absorption 10min, the unnecessary PDMAEA solution of dialysis treatment then; The GOD solution 200 μ L of step (2) preparation are spun on the PDMAEA laminar surface, absorption 10min, the unnecessary GOD solution of centrifugal treating then.Obtain having formed in the substrate 4 layers of cover layer of following covering " PDMAEA/P-SIA/PDMAEA/GOD " in proper order, i.e. the medicine controlled releasing system of the long-acting control blood sugar concentration that is loaded with the insulin aggregation of the described structure of present embodiment.
Embodiment 6
The processing step of present embodiment is as follows:
(1) preparation Iletin II (Lilly) aggregation
The preparation method of Iletin II (Lilly) aggregation (being called for short P-SIA in following description) is identical with embodiment 1.
(2) preparation raw material solution
Be that the chitosan of 25kda is with being that 5.2 acetic acid aqueous solutions are mixed with the chitosan solution that concentration is 2mg/mL with pH value with molecular weight;
Be the P-SIA suspension that 5 hydrochloric acid solution is mixed with concentration 1mg/mL with the P-SIA pH value of step (1) preparation;
Glucoseoxidase (being called for short GOD in following description) powder dissolution in pH is 5 hydrochloric acid solution, is made into the solution that concentration is 1mg/mL.
(3) preparation insulin aggregation substrate
Be that 5 hydrochloric acid solution is mixed with the P-SIA suspension that concentration is 25mg/mL with the P-SIA pH value of step (1) preparation, regulate the pH value to 8 of B-SIA suspension then with the NaOH solution of concentration 2N, add NaCl then, the addition of NaCl reaches 4N with the concentration of NaCl in the mixed liquor and is limited, under room temperature, normal pressure, mix 8h, continue after with the centrifugal 5min of 3000 rev/mins rotating speed, obtain electronegative graininess P-SIA substrate.
(4) assembling clad
In the medicine controlled releasing system of the long-acting control blood sugar concentration that is loaded with the insulin aggregation of present embodiment preparation, chitosan layer, P-SIA layer, GOD layer in the suprabasil coating of graininess P-SIA are in proper order: (chitosan/GOD/ chitosan/P-SIA)
4
According to said structure, graininess P-SIA substrate 10mg with step (3) preparation under room temperature, normal pressure mixes by the mode that stirs with the chitosan solution 5mL of step (2) preparation, mixing time 60min, after mixing time expires, with the centrifugal 5min of 3000 rev/mins rotating speed, then with obtain precipitation with the NaCl mixed liquor of the HCl of concentration 2mM and concentration 0.7M wash, centrifugal 2 times, obtain the microgranule that is coated with the chitosan layer; The microgranule that will be coated with the chitosan layer under room temperature, normal pressure mixes by the mode that stirs with the GOD solution 3mL of step (2) preparation, mixing time 10min, after mixing time expires, with the centrifugal 5min of 3000 rev/mins rotating speed, then with obtain precipitation with the NaCl mixed liquor of the HCl of concentration 2mM and concentration 0.7M wash, centrifugal 2 times, obtain the microgranule that is coated with chitosan layer, GOD layer successively; The microgranule that will be coated with chitosan layer, GOD layer under room temperature, normal pressure mixes by the mode that stirs with the chitosan solution 5mL of step (2) preparation, mixing time 20min, after mixing time expires, with the centrifugal 5min of 3000 rev/mins rotating speed, then with obtain precipitation with the NaCl mixed liquor of the HCl of concentration 2mM and concentration 0.7M wash, centrifugal 2 times, obtain the microgranule that is coated with chitosan layer, GOD layer, chitosan layer successively; The microgranule that will be coated with chitosan layer, GOD layer, chitosan layer under room temperature, normal pressure mixes by the mode that stirs with the P-SIA suspension 2mL of step (2) preparation, mixing time 15min, after mixing time expires, with the centrifugal 5min of 3000 rev/mins rotating speed, then with obtain precipitation with the NaCl mixed liquor of the HCl of concentration 2mM and concentration 0.7M wash, centrifugal 2 times, obtain 1 chitosan/GOD/ chitosan/P-SIA four molecular layers.Repeat aforesaid operations, formed the " (chitosan/GOD/ chitosan/P-SIA) of following coating order in substrate
4" 16 layers of clad, i.e. the medicine controlled releasing system of the long-acting control blood sugar concentration that is loaded with the insulin aggregation of the described structure of present embodiment, with prepared microspheroidal medicine controlled releasing system at-80 ℃ of lyophilization 10h.
Embodiment 7
Healthy 8 all SD rats, body weight 210～240g are adopted in zoopery.Totally 20 of SD rats are divided into two groups at random, and 10 every group, wherein one group is test group, and one group is the normal healthy controls group.
With the streptozotocin of rats in test groups fasting 12h pneumoretroperitoneum injection citrate buffer solution with the concentration ice bath dissolving of 4mg/mL, make up diabetes rat model by body weight 50mg/kg injection on an empty stomach, one week of injection the back fasting blood sugar (=300mg/dl) rat is for suffering from rats with diabetes greater than 16.7mmol/L.In the medicine controlled releasing system that is loaded with the Iletin II (Lilly) aggregation of suffering from diabetes rat subdermal implantation embodiment 1 preparation, all rat whole days are freely fetched water and feedstuff.
The method of monitoring rat blood sugar be blood that rat tail vein is taken out with a touch blood glucose monitoring system (
UltraEasy
TM, LifeScan, Inc.Milpitas CA.) measures.
Result of the test is seen Fig. 3, as can be seen from Figure 3, uses medicine controlled releasing system of the present invention, and the single medication can be controlled the euglycemia concentration of suffering from the diabetes rat body and reach 295 days.
Claims (9)
1. medicine controlled releasing system that is loaded with the long-acting control blood sugar concentration of insulin aggregation, it is characterized in that being made up of substrate and polymeric layer and insulin aggregation layer overlapping or that be coated on the suprabasil pH of having sensitivity, substrate, the polymeric layer with pH sensitivity, insulin aggregation layer are combined into one by electrostatic interaction each other;
Or formed by substrate and polymeric layer, protein layer and insulin aggregation layer overlapping or that be coated on the suprabasil pH of having sensitivity, substrate, the polymeric layer with pH sensitivity, protein layer, insulin aggregation layer are combined into one by electrostatic interaction each other;
Described substrate is flat board, microsphere or medical apparatus and instruments, and described flat board or microsphere are by a kind of making in lucite, quartz, the Muscovitum.
2. according to the described medicine controlled releasing system that is loaded with the long-acting control blood sugar concentration of insulin aggregation of claim 1, the polymeric layer and the insulin aggregation layer that it is characterized in that having pH sensitivity can be the polymeric layer with pH sensitivity, all compound modes of insulin aggregation layer in suprabasil coating order, or polymeric layer, protein layer and insulin aggregation layer with pH sensitivity can be all compound modes of polymeric layer with pH sensitivity, protein layer, insulin aggregation layer in suprabasil coating order.
3. medicine controlled releasing system that is loaded with the long-acting control blood sugar concentration of insulin aggregation, it is characterized in that being made up of substrate and the polymeric layer and the protein layer that are coated on the suprabasil pH of having sensitivity, substrate, the polymeric layer with pH sensitivity, protein layer are combined into one by electrostatic interaction each other;
Or formed by substrate and the polymeric layer, protein layer, the insulin aggregation layer that are coated on the suprabasil pH of having sensitivity, substrate, the polymeric layer with pH sensitivity, protein layer, insulin aggregation layer are combined into one by electrostatic interaction each other;
Described substrate is the insulin aggregate particle.
4. according to the described medicine controlled releasing system that is loaded with the long-acting control blood sugar concentration of insulin aggregation of claim 3, the polymeric layer and the protein layer that it is characterized in that having pH sensitivity can be the polymeric layer with pH sensitivity, all compound modes of protein layer in suprabasil coating order, or polymeric layer, protein layer and insulin aggregation layer with pH sensitivity can be all compound modes of polymeric layer with pH sensitivity, protein layer, insulin aggregation layer in suprabasil coating order.
5. according to the described medicine controlled releasing system that is loaded with the long-acting control blood sugar concentration of insulin aggregation of arbitrary claim in the claim 1 to 4, it is characterized in that the insulin aggregation is a kind of in bovine insulin aggregation, recombinant human insulin's aggregation, the Iletin II (Lilly) aggregation.
6. according to the described medicine controlled releasing system that is loaded with the long-acting control blood sugar concentration of insulin aggregation of arbitrary claim in the claim 1 to 4, the polymer that it is characterized in that having pH sensitivity is polymethylacrylic acid-N, a kind of in N-dimethylaminoethyl, PMAm propyl-dimethyl amine, polyacrylic acid dimethylaminoethyl, polymethacrylates, the chitosan, molecular weight is 1～1000kda.
7. according to the described medicine controlled releasing system that is loaded with the long-acting control blood sugar concentration of insulin aggregation of arbitrary claim in the claim 1 to 4, it is characterized in that protein is glucoseoxidase or catalase.
8. the preparation method of the medicine controlled releasing system of a claim 1 or the 2 described long-acting control blood sugar concentrations that are loaded with the insulin aggregation is characterized in that processing step is as follows:
(1) preparation raw material solution or suspension
Material solution or suspension are polymer solution and the insulin aggregation suspension with pH sensitivity, or polymer solution, insulin aggregation suspension and protein solution with pH sensitivity;
The polymer of the described pH of having sensitivity is polymethylacrylic acid-N, a kind of in N-dimethylaminoethyl, PMAm propyl-dimethyl amine, polyacrylic acid dimethylaminoethyl, polymethacrylates, the chitosan, and molecular weight is 1～1000kda; Be that to become concentration be the solution of 0.015～100mg/mL for polymer formulation that 1～7 aqueous hydrochloric acid solution, acetic acid solution or deionized water will have pH sensitivity with pH value, if having the polymer of pH sensitivity is polymethylacrylic acid-N, N-dimethylaminoethyl, PMAm propyl-dimethyl amine, polyacrylic acid dimethylaminoethyl or polymethacrylates, then add NaCl again, the addition of NaCl reaches 0.01～5mol/L with its concentration in mixed liquor and is limited;
Described insulin aggregation is a kind of in bovine insulin aggregation, recombinant human insulin's aggregation, the Iletin II (Lilly) aggregation; Be that 3～8 aqueous hydrochloric acid solution, acetic acid aqueous solution, phosphate aqueous solution or deionized water are mixed with the suspension that concentration is 0.015～100mg/mL with the insulin aggregation with pH value;
Described protein is glucoseoxidase or catalase; Be that 3～8 aqueous hydrochloric acid solution, acetic acid aqueous solution, phosphate aqueous solution or deionized water are mixed with the solution that concentration is 0.015～100mg/mL with protein with pH value;
(2) handling substrate surface makes it electrically charged;
(3) assembling overlapping layer or clad
Polymer solution, insulin aggregation suspension and/or the protein solution that will have pH sensitivity is overlapping or be coated in the substrate and the preceding on the overlapping or coating according to the structure of described medicine controlled releasing system with the method for spin coating, dip-coating or spraying, when each ply of preparation or coating, leave standstill 0-100min, and will form that the redundant solution of described overlapping or coating or suspension remove with deionized water rinsing, method centrifugal or dialysis and dry, namely obtain being loaded with the medicine controlled releasing system of the long-acting control blood sugar concentration of insulin aggregation;
Described substrate is flat board, microsphere or medical apparatus and instruments, and described flat board or microsphere are by a kind of making in lucite, quartz, the Muscovitum.
9. the preparation method of the medicine controlled releasing system of a claim 3 or the 4 described long-acting control blood sugar concentrations that are loaded with the insulin aggregation is characterized in that processing step is as follows:
(1) preparation raw material solution or suspension
Material solution or suspension are polymer solution and the protein solution with pH sensitivity, or have polymer solution, protein solution and the insulin aggregation suspension of pH sensitivity;
The polymer of the described pH of having sensitivity is polymethylacrylic acid-N, a kind of in N-dimethylaminoethyl, PMAm propyl-dimethyl amine, polyacrylic acid dimethylaminoethyl, polymethacrylates, the chitosan, and molecular weight is 1～1000kda; Be that to become concentration be the solution of 0.015～100mg/mL for polymer formulation that 1～7 aqueous hydrochloric acid solution, acetic acid solution or deionized water will have pH sensitivity with pH value, if having the polymer of pH sensitivity is polymethylacrylic acid-N, N-dimethylaminoethyl, PMAm propyl-dimethyl amine, polyacrylic acid dimethylaminoethyl or polymethacrylates, then add NaCl again, the addition of NaCl reaches 0.01～5mol/L with its concentration in mixed liquor and is limited;
Described insulin aggregation is a kind of in bovine insulin aggregation, recombinant human insulin's aggregation, the Iletin II (Lilly) aggregation; Be that 3～8 aqueous hydrochloric acid solution, acetic acid aqueous solution, phosphate aqueous solution or deionized water are mixed with the suspension that concentration is 0.015～100mg/mL with the insulin aggregation with pH value;
Described protein is glucoseoxidase or catalase; Be that 3～8 aqueous hydrochloric acid solution, acetic acid aqueous solution, phosphate aqueous solution or deionized water are mixed with the solution that concentration is 0.015～100mg/mL with protein with pH value;
(2) preparation insulin aggregation substrate
It is 1～100mg/mL suspension that the insulin aggregation is mixed with concentration with the acetic acid of pH 2～5 or hydrochloric acid solution, regulate pH value to 6～10 of aggregation suspension then with NaOH solution, add NaCl then, the addition of NaCl reaches 0.5～5mol/L with the concentration of NaCl in the mixed liquor, under room temperature, normal pressure, mix 1～20h, continue after centrifugalize, obtain electronegative graininess insulin aggregation substrate;
(3) assembling clad
To have the polymer solution of pH sensitivity and protein solution adopts the method for mixing with substrate and mixing with coating the preceding to be coated in the substrate according to the structure of described medicine controlled releasing system and the preceding on the coating, the polymer solution that maybe will have pH sensitivity, protein solution and insulin aggregation suspension adopt the method for mixing with substrate and mixing with coating the preceding to be coated in the substrate according to the structure of described medicine controlled releasing system and the preceding on the coating, when each layer of preparation coating, stir 10min at least, and will form redundant solution or the suspension deionized water rinsing of described coating, method centrifugal or dialysis is removed, and namely obtains being loaded with the medicine controlled releasing system of the long-acting control blood sugar concentration of insulin aggregation.
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| CN2012100021901A CN103191417A (en) | 2012-01-05 | 2012-01-05 | Long-effect blood-glucose-control medicine-controlled-release system loading insulin aggregate, and preparation method thereof |
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| CN2012100021901A CN103191417A (en) | 2012-01-05 | 2012-01-05 | Long-effect blood-glucose-control medicine-controlled-release system loading insulin aggregate, and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111419825A (en) * | 2020-06-03 | 2020-07-17 | 烟台大学 | Intelligent response type sustained and controlled release microsphere and preparation method thereof |
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|---|---|---|---|---|
| US4364385A (en) * | 1981-03-13 | 1982-12-21 | Lossef Steven V | Insulin delivery device |
| WO1984004932A1 (en) * | 1983-06-10 | 1984-12-20 | Washington Res Found | Biochemical detection and/or treatment process |
| US4764364A (en) * | 1986-02-25 | 1988-08-16 | S R I International | Method of preparing bioerodible polymers having pH sensitivity in the acid range and resulting product |
| US4855132A (en) * | 1986-02-25 | 1989-08-08 | S R I International | Method of preparing bioerodible polymers having pH sensitivity in the acid range and resulting product |
| CN101951957A (en) * | 2008-01-04 | 2011-01-19 | 百达尔公司 | Insulin discharges the insulin preparation as the function of the glucose level of tissue |
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2012
- 2012-01-05 CN CN2012100021901A patent/CN103191417A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4364385A (en) * | 1981-03-13 | 1982-12-21 | Lossef Steven V | Insulin delivery device |
| WO1984004932A1 (en) * | 1983-06-10 | 1984-12-20 | Washington Res Found | Biochemical detection and/or treatment process |
| US4764364A (en) * | 1986-02-25 | 1988-08-16 | S R I International | Method of preparing bioerodible polymers having pH sensitivity in the acid range and resulting product |
| US4855132A (en) * | 1986-02-25 | 1989-08-08 | S R I International | Method of preparing bioerodible polymers having pH sensitivity in the acid range and resulting product |
| CN101951957A (en) * | 2008-01-04 | 2011-01-19 | 百达尔公司 | Insulin discharges the insulin preparation as the function of the glucose level of tissue |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111419825A (en) * | 2020-06-03 | 2020-07-17 | 烟台大学 | Intelligent response type sustained and controlled release microsphere and preparation method thereof |
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