CN106729717A - The analogs of GLP 1 and ziconotide composition sustained-release microsphere preparation - Google Patents
The analogs of GLP 1 and ziconotide composition sustained-release microsphere preparation Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/1767—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/26—Glucagons
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
Abstract
The present invention relates to the analogs of GLP 1 and ziconotide composition sustained-release microsphere preparation and preparation method thereof.Sustained release microsphere agents include the analogs of GLP 1, ziconotide, biodegradable and tool biocompatibility macromolecular material, stabilizer and freeze drying protectant.Its preparation method is comprised the following steps：1) GLP l analogs and ziconotide are added water and is made into drug solution A；By biodegradable and tool biocompatibility macromolecular material added with machine solvent solution-forming B；2) solution A and solution B are mixed and is ultrasonically formed colostrum, colostrum is added in the stabilizer aqueous solution crossed with organic mixed solvent saturation, and emulsifying obtains emulsion；3) emulsion was stirred at room temperature after 1 hour and is warming up to 40 DEG C~45 DEG C and is kept for 1 hour, then be cooled to 10 DEG C, add freeze drying protectant, particle is collected in sieving, is freezed, and is sterilized via radiation.Using technology of the present invention, it is possible to achieve the effect of long-term treatment diabetes and its pain diabetic neuropathy (PDN) complication, and mitigate patient suffering, patient medication compliance is improved, with clinical reality meaning.
Description
Technical field
The present invention relates to GLP-1 analogs and ziconotide composition sustained-release microsphere preparation and preparation method thereof, belong to medicine
Thing formulation art.
Background technology
With the development of society, the incidence of disease of diabetes is in obvious increased trend in world wide, is once estimated within 2000
It is 2.8%, 4.3% was expected to be by 2025, diabetic's number will also increases to 2025 from 1.71 hundred million in 2000
3.8 hundred million.The complication of diabetes is more, it has also become cause the main cause that patient is lethal, disable, and drastically influence the mankind and is good for
Health.Diabetic complication includes diabetic ketoacidosis, diabetic nephropathy, hypertension, pain diabetic neuropathy
(Painful diabetic neuropathy, PDN) etc., wherein PDN is that diabetes are most common, one of most serious complication.
Chronic disease is common in PDN, main to invade four limbs and foot.Patient is mainly shown as acrodynia, Burning Pain, cut sample, tears
Fragility, acupuncture sample pain.PDN is one of diabete peripheral herve pathology clinically most complicated, most refractory at present.
Most of in diabetic is diabetes B patient, accounts for 90-95%.GLP-1 analogs are that occur 21 century
New types of therapeutic agents, has good hypoglycemic effect because of such medicine, can reduce the risk of hypoglycemia, at the same have it is appropriate
The advantages such as loss of weight effect are always the focus of Remedies for diabetes research.GLP-1 analog hypoglycemic medicine bags main at present
Include Liraglutide, Exenatide, degree and draw glycopeptide, albiglutide etc., the main subcutaneous injection administration of such medicine.However, clinical
Although upper Exenatide, degree drawing glycopeptide, albiglutide etc. have durative action preparation, when being used alone, to the therapeutic effect of diabetes
It is still unsatisfactory, it is impossible to alleviate the pain of PDN complication.Liraglutide needs daily hypodermic injection, is brought greatly to patient
Administration pain.
The medicine for being clinically used to treat PDN mainly has anticonvulsive drug, antidepressants, opiates medicine, aldose reductase to press down
Preparation, ACEI, calcium ion antagonist and prostaglandin etc..But opium kind analgesicses are to chronic god
Therapeutic effect through pain such as source property is unsatisfactory, and has additive, and (i.e. curative effect gradually drops tachyphylaxis after medication several times
It is low), cause the serious bad hair such as constipation and respiration inhibition to be answered.
Ziconotide is the artificial synthesized A conotoxins of ω-M VII, reversibly blocks N-type calcium channel, as the
A kind of new Neurotherapeutic medicine-N-type calcium ion channel blockor (NCCB).As a kind of non-opioid analgesic agents, examine together
Promise peptide and security and validity that the difference of other analgesics is its clinical practice, so that predictive of it in severe chronic
Important potential value in pain therapy, and do not find that patient develops immunity to drugs to ziconotide in clinical studies yet.Mesh
Preceding ziconotide is administered by the way of intrathecal instillation, and intrathecal drug delivery system needs implantation, and very big inconvenience is brought to patient, while
Clinical management requirement is also relatively stricter.
Clinically hypoglycemic and complications Treatment scheme is separate administration, and the pain of multiple dosing is brought to patient.Mesh
Before, not yet find the report of both use in conjunction.
GLP-1 analogs and ziconotide are combined, diabetes and its PDN complication can be effectively treated, hence it is evident that town
Bitterly, mitigate patient suffering, improve patient medication compliance.
The content of the invention
Based on this, it is necessary to provide a kind of GLP-1 analogs with slow release effect and ziconotide composition sustained-release is micro-
Ball preparation, to realize treating the effect of diabetes and its PDN complication, and mitigates patient suffering, improves patient medication compliance,
With clinical reality meaning.
To achieve the above object, the present invention provides following technical scheme：
A kind of GLP-1 analogs and ziconotide composition sustained-release microsphere preparation, comprising GLP-1 analogs, ziconotide,
Biodegradable and tool biocompatibility macromolecular material, stabilizer and freeze drying protectant；
Wherein in one embodiment, the GLP-1 analogs be selected from Liraglutide or its salt, Exenatide or its salt,
Degree draws the one kind in glycopeptide or its salt, A Bilutai or its salt；
Wherein in one embodiment, the GLP-1 analogs are 1 with the mass ratio of ziconotide:1~1:25.
Wherein in one embodiment, the sustained release microsphere agents are made up of the composition of following weight percent content：
GLP-1 analogs 0.02~1.35%, ziconotide 0.02~1.58%, biodegradable and tool biocompatibility macromolecule
Material 60.00~92.00%, stabilizer 0.05~25% and freeze drying protectant 0.21~28.54%；The GLP-1 analogs
It is 1 with the mass ratio of ziconotide:8~1:20.
Wherein in one embodiment, the sustained release microsphere agents are made up of the composition of following weight percent content：
GLP-1 analogs 0.05~1.25%, ziconotide 0.06~1.58%, biodegradable and tool biocompatibility macromolecule
Material 75.00~92.00%, stabilizer 0.05~20.00% and freeze drying protectant 0.35~20.30%；The GLP-1 is similar to
Thing is 1 with the mass ratio of ziconotide:10~1:20.
Wherein in one embodiment, described biodegradable and tool biocompatibility macromolecular material is selected from poly- third and hands over
One or more in ester-glycolide, PHBV, poly lactic-co-glycolic acid, polylactic acid-polyglycol, point
Son amount is 5000~90000 dalton.
Wherein in one embodiment, described biodegradable and tool biocompatibility the preferred autohemagglutination third of macromolecular material
Lactide-glycolide, PHBV, poly lactic-co-glycolic acid (50: 50~85: 15), polylactic acid-polyglycol (5
: 1~20: one or more in 1), molecular weight is 8000~80000 dalton.
Wherein in one embodiment, the average grain diameter of the sustained-release micro-spheres is 10 μm~100 μm.
Wherein in one embodiment, the stabilizer is polyvinyl alcohol, polyvinylpyrrolidone, polymethylacrylic acid
At least one in sodium, Sodium Polyacrylate；The freeze drying protectant is selected from sorbierite, mannitol, lactose, sucrose, trehalose, pool
At least one in Luo Shamu.
Wherein in one embodiment, the stabilizer is preferably at least in polyvinyl alcohol, polyvinylpyrrolidone
Kind；The freeze drying protectant preferably is selected from least one in mannitol, lactose, poloxamer.
A kind of preparation method of GLP-1 analogs and ziconotide composition sustained-release microsphere preparation, it is characterised in that including
Following steps：
Step 1) GLP-l analogs and ziconotide add water is made into drug solution A；By biodegradable and tool biofacies
The macromolecular material of capacitive is added with machine solvent solution-forming B；
Step 2) solution A and solution B are mixed it is ultrasonically formed colostrum, colostrum is added to be crossed with organic mixed solvent saturation
In the stabilizer aqueous solution, emulsifying obtains emulsion；
Step 3) emulsion was stirred at room temperature after 1 hour it is warming up to 40 DEG C~45 DEG C and is kept for 1 hour, then it is cooled to 10 DEG C, plus
Enter freeze drying protectant, particle is collected in sieving, is freezed, and is sterilized via radiation.
Wherein in one embodiment, step 1) in organic solvent be selected from ethyl acetate, phenmethylol mixed solution or two
One kind in chloromethanes, phenmethylol mixed solution.
Wherein in one embodiment, step 1) in organic solvent ethyl acetate and the volume ratio of phenmethylol be 2.5~8
∶1；The volume ratio of dichloromethane and phenmethylol is 2.5~7: 1.
Wherein in one embodiment, step 2) in organic mixed solvent be phenmethylol and ethyl acetate, organic mixing
The concentration of solvent is 1%~3%.
Wherein in one embodiment, step 3) in emulsion be stirred at room temperature 1 hour after be warming up to 45 DEG C and kept for 1 hour,
10 DEG C are cooled to again.
Described GLP-1 analogs and ziconotide composition sustained-release microsphere preparation, for treating diabetes and its pain
Diabetic neuropathy complication.
Brief description of the drawings
Fig. 1 is the external release profiles of sustained-release micro-spheres prepared by embodiment 1,3,7,9.
Specific embodiment
Following examples are further illustrated to of the invention, but are never limited the scope of the present invention.Referring to
Embodiment is further elaborated on the present invention, it should be appreciated to those skilled in the art that the present invention is not limited to these implementations
Example and the preparation method for using.And, those skilled in the art's description of the invention can be equal to the present invention
Replace, combine, improve or modify, but these are intended to be included in the scope of the present invention.
The GLP-1 analogs and ziconotide composition sustained-release microsphere preparation of one implementation method, including GLP-1 analogs,
Ziconotide, biodegradable and tool biocompatibility macromolecular material, stabilizer and freeze drying protectant.
Wherein, GLP-1 analogs are selected from Liraglutide or its salt, Exenatide or its salt, degree draw glycopeptide or its salt, A Bi
One kind in Shandong Thailand or its salt.For example, GLP-1 analogs can be the vinegar of Liraglutide, acetic acid Liraglutide or Liraglutide
Hydrochlorate.
GLP-1 analogs and ziconotide are mixed to form the kernel of sustained-release micro-spheres, biodegradable and tool biocompatibility
Macromolecular material be coated on kernel surface formed sustained-release micro-spheres coating.
Biodegradable and tool biocompatibility macromolecular material is used as coating so that the GLP-1 analogs and Qi Kao
Promise peptide combinations sustained-release micro-spheres have preferable sustained release performance, can overcome common GLP-1 analog formulations administration number of times it is many,
It is unfavorable for the shortcoming that patient receives.
GLP-1 analogs can treat diabetes.Ziconotide can effectively mitigate significant chronic pain.GLP-1 is similar to
Thing and ziconotide are used in combination, and can effectively treat diabetes and its PDN complication, hence it is evident that mitigate chronic ache without producing
Drug resistance, mitigates patient suffering, improves patient medication compliance.
Preferably, the mass ratio of GLP-1 analogs and ziconotide is 1:1~1:25, to give full play to GLP-1 analogs
With the advantage of ziconotide, preferable coordinative role is played, preferably to treat diabetes and its PDN complication.
Preferably, GLP-1 analogs and ziconotide composition sustained-release microsphere preparation are mainly contained by following percentage by weight
The composition composition of amount：GLP-1 analogs 0.02~1.35%, ziconotide 0.02~1.58%, biodegradable and tool biology
The macromolecular material 60.00~92.00% of compatibility, stabilizer 0.05~2.84% and freeze drying protectant 0.21~28.54%；
The GLP-1 analogs are 1 with the mass ratio of ziconotide:8~1:20.
It is highly preferred that GLP-1 analogs and ziconotide composition sustained-release microsphere preparation are main by following percentage by weight
The composition composition of content：GLP-1 analogs 0.05~1.25%, ziconotide 0.06~1.58%, biodegradable and tool life
The macromolecular material 75.00~92.00% of thing compatibility, stabilizer 0.05~2.00% and freeze drying protectant 0.35~
20.30%；The GLP-1 analogs are 1 with the mass ratio of ziconotide:10~1:20.
Using above-mentioned percentage by weight, curative effect associated with active component GLP-1 analogs and ziconotide can be played,
And cause that the GLP-1 analogs and ziconotide composition sustained-release microsphere have preferable slow release effect, can not only significantly subtract
Few administration number of times, facilitates Clinical practice and patient to receive, and can eliminate the drug concentration of ordinary preparation multiple dosing generation
Peak valley phenomenon, is conducive to obtaining steady prolonged valid density, reduces toxic and side effect.
Preferably, biodegradable and tool biocompatibility macromolecular material is selected from polylactide-glycolide, poly- hydroxyl
One or more in base butyric acid valerate, poly lactic-co-glycolic acid, polylactic acid-polyglycol, molecular weight be 5000~
90000 dalton.
It is highly preferred that biodegradable and tool biocompatibility macromolecular material is selected from polylactide-glycolide, gathers
In hydroxybutyric acid valerate, poly lactic-co-glycolic acid (50: 50~85: 15), polylactic acid-polyglycol (5: 1~20: 1) one
Plant or various, molecular weight is 8000~80000 dalton.
The biocompatibility of above-mentioned biodegradable and tool biocompatibility macromolecular material preferably, and biological can drop
Solution so that the security of the GLP-1 analogs and ziconotide composition sustained-release microsphere preparation is preferable.
Preferably, the average grain diameter of above-mentioned sustained-release micro-spheres is 10 μm~100 μm so that the GLP-1 analogs and Qi Kaonuo
Peptide combinations sustained release microsphere agents are conducive to effective diffusion in vivo, can efficiently control internal blood-sugar content and mitigation
PDN complication pain, reduces administration number of times and drug tolerance, improves the compliance of patient, facilitates Clinical practice and patient to use
Medicine.
Preferably, stabilizer is in polyvinyl alcohol, polyvinylpyrrolidone, sodium polymethacrylate, Sodium Polyacrylate
It is at least one；Freeze drying protectant is selected from least one in sorbierite, mannitol, lactose, sucrose, trehalose, poloxamer.
It is highly preferred that stabilizer is at least one in polyvinyl alcohol, polyvinylpyrrolidone；Freeze drying protectant is selected from sweet
At least one in dew alcohol, lactose, poloxamer.
The GLP-1 analogs and ziconotide composition sustained-release microsphere preparation can effectively treat diabetes and its PDN simultaneously
Hair disease.Due to having used sustained-release micro-spheres so that the GLP-1 analogs and ziconotide composition sustained-release microsphere preparation have sustained release
Effect, can significantly play the coordinating effect of GLP-1 analogs and ziconotide, improve curative effect.
GLP-1 analogs and ziconotide composition sustained-release microsphere preparation subcutaneous injection are administered, and our experiments show that, discharge
For up to 1 month, accumulative releasing degree was up to more than 90%.
It is administered by the above-mentioned GLP-1 analogs of a hypodermic injection and ziconotide composition sustained-release microsphere preparation,
The administration of GLP-1 analogs and ziconotide is realized simultaneously, clinical administration inconvenience when solving the problems, such as to be administered alone.
The preparation method of a kind of GLP-1 analogs and ziconotide composition sustained-release microsphere preparation, comprises the following steps：
Step 1) GLP-l analogs and ziconotide add water is made into drug solution A；By biodegradable and tool biofacies
The macromolecular material of capacitive is added with machine solvent solution-forming B；
Step 2) solution A and solution B are mixed it is ultrasonically formed colostrum, colostrum is added to be crossed with organic mixed solvent saturation
In the stabilizer aqueous solution, emulsifying obtains emulsion；
Step 3) emulsion was stirred at room temperature after 1 hour it is warming up to 40 DEG C~45 DEG C and is kept for 1 hour, then it is cooled to 10 DEG C, plus
Enter freeze drying protectant, particle is collected in sieving, is freezed, and is sterilized via radiation.
Preferably, step 1) in organic solvent be selected from ethyl acetate, phenmethylol mixed solution or dichloromethane, phenmethylol
One kind in mixed solution.
Preferably, step 1) in organic solvent ethyl acetate and phenmethylol volume ratio be 2.5~8: 1；Dichloromethane
It is 2.5~7: 1 with the volume ratio of phenmethylol.
Preferably, step 2) in organic mixed solvent be phenmethylol and ethyl acetate, the concentration of organic mixed solvent is
1%~3%.
Preferably, step 3) in emulsion be stirred at room temperature 1 hour after be warming up to 45 DEG C and kept for 1 hour, then be cooled to 10 DEG C.
By the method can solve the problem that common multi-emulsion method prepare during water soluble drug it is most common it is prominent release problem and
The caused drug loss problem when washing outside microballoon；The smoothness of microsphere surface can be improved so that blood concentration more
Plus stabilization is smooth.
It is expanded on further below by way of specific embodiment.
Embodiment 1
Weigh 0.2mg Liraglutides and 0.2mg ziconotides add water the drug solution for being made into that concentration is 40%, by 1g poly- third
Lactide-co-glycolides are dissolved with 25mL ethyl acetate and 10mL phenmethylols, and the two is mixed into ultrasound 2min, at the beginning of forming white homogeneous
Breast.Colostrum is added to the poly- second of 6 DEG C of 1000mL 0.01% (w/v) under the homogeneous of 1600rpm by syringe
In the enol aqueous solution (containing 1% phenmethylol and 1% ethyl acetate), emulsifying 2min obtains emulsion.Emulsion is moved into cantilever stirring
On machine, rotating speed is 600rpm, stirs 1h, is then warmed up to 40 DEG C and is kept for 1 hour, then is reduced to 10 DEG C, addition sorbierite 0.1g
Mixture is obtained, screen filtration freezes to obtain powdered microballoon.Observed through JSM-5600 types SEM, microballoon hole connects
Continuous complete, microballoon is in spherical shape, and uniform in size regular, 10~40 μm of particle size range, 18 μm of average grain diameter.Through Zeta potential
Analysis-e/or determining, the Zeta potential of microballoon is set to (- 28.5 ± 1.23) mV, and it is negative electrical charge that its surface institute is electrically charged.
Embodiment 2
Weigh 0.25mg Exenatides and 0.3mg ziconotides add water the drug solution for being made into that concentration is 20%, 1g is gathered
Hydroxybutyric acid valerate is dissolved with 30mL ethyl acetate and 10mL phenmethylols, and the two is mixed into ultrasound 2min, forms white homogeneous
Colostrum.The poly-vinyl alcohol solution that colostrum is added to 6 DEG C of 1000mL 0.02% under the homogeneous of 1600rpm by syringe (contains
0.5% phenmethylol and 1% ethyl acetate) in, emulsifying 2min obtains emulsion.Emulsion is moved on cantilever mixer, rotating speed is
600rpm, stirs 1h, is then warmed up to 45 DEG C and is kept for 1 hour, then is reduced to 10 DEG C, adds lactose 0.1g to obtain mixture, screen cloth
Filtering, freezes to obtain powdered microballoon.Observed through JSM-5600 types SEM, microballoon hole is continuous whole, and microballoon is equal
In spherical shape, and uniform in size regular, 10~55 μm of particle size range, 25 μm of average grain diameter.It is micro- through Zeta potential analysis-e/or determining
The Zeta potential of ball is set to (- 33.2 ± 1.06) mV, and it is negative electrical charge that its surface institute is electrically charged.
Embodiment 3
Weigh 5mg Liraglutides and 0.1g ziconotides add water the drug solution for being made into that concentration is 18%, 6g poly- third is handed over
Ester-glycolide is dissolved with 25mL dichloromethane and 10mL phenmethylols, and the two is mixed into ultrasound 2min, forms white homogeneous colostrum.
The polyvinylpyrrolidonesolution solution that colostrum is added to 6 DEG C of 1000mL0.2% under the homogeneous of 1600rpm by syringe (contains
1% phenmethylol and 1.5% ethyl acetate) in, emulsifying 2min obtains emulsion.Emulsion is moved on cantilever mixer, rotating speed is
600rpm, stirs 1h, is then warmed up to 42 DEG C and is kept for 1 hour, then is reduced to 10 DEG C, adds mannitol 0.5g to obtain mixture, sieves
Net filtration, freezes to obtain powdered microballoon.Observed through JSM-5600 types SEM, microballoon hole is continuous whole, microballoon
In spherical shape, and uniform in size regular, 12~70 μm of particle size range, 20 μm of average grain diameter.Through Zeta potential analysis-e/or determining,
The Zeta potential of microballoon is set to (- 26.1 ± 1.27) mV, and it is negative electrical charge that its surface institute is electrically charged.
Embodiment 4
Weighing 4mg degree draws glycopeptide and 90mg ziconotides to add water the drug solution for being made into that concentration is 18%, by 8g PLAs
Hydroxyacetic acid (50:50) dissolved with 40mL dichloromethane and 10mL phenmethylols, the two is mixed into ultrasound 2min, form white homogeneous
Colostrum.Colostrum is added to the sodium polyacrylate solution of 6 DEG C of 1000mL 0.1% under the homogeneous of 1600rpm by syringe
In (containing 1.5% phenmethylol and 1.5% ethyl acetate), emulsifying 2min obtains emulsion.Emulsion is moved on cantilever mixer, is turned
Speed is 600rpm, stirs 1h, is then warmed up to 40 DEG C and is kept for 1 hour, then is reduced to 10 DEG C, adds poloxamer 2g to mix
Thing, screen filtration freezes to obtain powdered microballoon.Observed through JSM-5600 types SEM, microballoon hole is continuous whole,
Microballoon is in spherical shape, and uniform in size regular, 27~78 μm of particle size range, 35 μm of average grain diameter.Through Zeta potential analyzer
Determine, the Zeta potential of microballoon is set to (- 29.4 ± 1.54) mV, and it is negative electrical charge that its surface institute is electrically charged.
Embodiment 5
Weigh 1g albiglutides and 1g ziconotides add water the drug solution for being made into that concentration is 20%, by 50g PLAs-poly-
Ethylene glycol (280:50) dissolved with 50mL ethyl acetate and 20mL phenmethylols, the two is mixed into ultrasound 2min, form white homogeneous
Colostrum.Colostrum is added to the poly-vinyl alcohol solution of 6 DEG C of 1000mL 1% (containing 1% under the homogeneous of 1600rpm by syringe
Phenmethylol and 1.5% ethyl acetate) in, emulsifying 2min obtains emulsion.Emulsion is moved on cantilever mixer, rotating speed is
600rpm, stirs 1h, is then warmed up to 45 DEG C and is kept for 1 hour, then is reduced to 10 DEG C, adds sucrose 12g to obtain mixture, screen cloth mistake
Filter, freezes to obtain powdered microballoon.Observed through JSM-5600 types SEM, microballoon hole is continuous whole, and microballoon is in
Spherical shape, and uniform in size regular, 15~40 μm of particle size range, 25 μm of average grain diameter.Through Zeta potential analysis-e/or determining, microballoon
Zeta potential be set to (- 22.4 ± 1.68) mV, it is negative electrical charge that its surface institute is electrically charged.
Embodiment 6
Weigh 80mg Exenatides and 120mg ziconotides add water the drug solution for being made into that concentration is 25%, by 48g poly- third
Lactide-co-glycolides are dissolved with 80mL ethyl acetate and 15mL phenmethylols, and the two is mixed into ultrasound 2min, at the beginning of forming white homogeneous
Breast.The polyvinylpyrrolidone that colostrum is added to 6 DEG C of 1000mL 0.15% under the homogeneous of 1600rpm by syringe is molten
In liquid (containing 0.5% phenmethylol and 1.5% ethyl acetate), emulsifying 2min obtains emulsion.Emulsion is moved on cantilever mixer,
Rotating speed is 600rpm, stirs 1h, is then warmed up to 50 DEG C and is kept for 1 hour, then is reduced to 10 DEG C, adds mannitol 5g to mix
Thing, screen filtration freezes to obtain powdered microballoon.Observed through JSM-5600 types SEM, microballoon hole is continuous whole,
Microballoon is in spherical shape, and uniform in size regular, 15~60 μm of particle size range, 30 μm of average grain diameter.Through Zeta potential analyzer
Determine, the Zeta potential of microballoon is set to (- 29.3 ± 1.61) mV, and it is negative electrical charge that its surface institute is electrically charged.
Embodiment 7
Weighing 20mg degree draws glycopeptide and 0.5g ziconotides to add water the drug solution for being made into that concentration is 30%, by the poly- hydroxyls of 80g
Base butyric acid valerate is dissolved with 50mL ethyl acetate and 12mL phenmethylols, and the two is mixed into ultrasound 2min, at the beginning of forming white homogeneous
Breast.The polyvinylpyrrolidone that colostrum is added to 6 DEG C of 1000mL 0.15% under the homogeneous of 1600rpm by syringe is molten
In liquid (containing 1.5% phenmethylol and 1.5% ethyl acetate), emulsifying 2min obtains emulsion.Emulsion is moved on cantilever mixer,
Rotating speed is 600rpm, stirs 1h, is then warmed up to 50 DEG C and is kept for 1 hour, then is reduced to 10 DEG C, adds lactose 12g to obtain mixture,
Screen filtration, freezes to obtain powdered microballoon.Observed through JSM-5600 types SEM, microballoon hole is continuous whole, micro-
Ball is in spherical shape, and uniform in size regular, 10~90 μm of particle size range, 35 μm of average grain diameter.Surveyed through Zeta potential analyzer
Fixed, the Zeta potential of microballoon is set to (- 27.2 ± 1.39) mV, and it is negative electrical charge that its surface institute is electrically charged.
Embodiment 8
Weigh 50mg albiglutides and 0.8g ziconotides add water the drug solution for being made into that concentration is 25%, by the poly- breasts of 80g
Acid-hydroxyacetic acid (75:15) dissolved with 30mL dichloromethane and 12mL phenmethylols, the two is mixed into ultrasound 2min, form white
Homogeneous colostrum.Colostrum is added to the poly-vinyl alcohol solution of 6 DEG C of 1000mL 0.2% under the homogeneous of 1600rpm by syringe
In (containing 0.8% phenmethylol and 1.5% ethyl acetate), emulsifying 2min obtains emulsion.Emulsion is moved on cantilever mixer, is turned
Speed is 600rpm, stirs 1h, is then warmed up to 50 DEG C and is kept for 1 hour, then is reduced to 10 DEG C, adds lactose 5g to obtain mixture, is sieved
Net filtration, freezes to obtain powdered microballoon.Observed through JSM-5600 types SEM, microballoon hole is continuous whole, microballoon
In spherical shape, and uniform in size regular, 15~70 μm of particle size range, 25 μm of average grain diameter.Through Zeta potential analysis-e/or determining,
The Zeta potential of microballoon is set to (- 32.0 ± 1.34) mV, and it is negative electrical charge that its surface institute is electrically charged.
Embodiment 9
Weigh 0.5g Exenatides and 8g ziconotides add water the drug solution for being made into that concentration is 25%, by the poly- breasts of 500g
Acid-polyethylene glycol (18:2) dissolved with 60mL ethyl acetate and 12mL phenmethylols, the two is mixed into ultrasound 2min, form white
Matter colostrum.The poly-vinyl alcohol solution that colostrum is added to 6 DEG C of 1000mL 10% under the homogeneous of 1600rpm by syringe (contains
2% phenmethylol and 1% ethyl acetate) in, emulsifying 2min obtains emulsion.Emulsion is moved on cantilever mixer, rotating speed is
600rpm, stirs 1h, is then warmed up to 50 DEG C and is kept for 1 hour, then is reduced to 10 DEG C, adds trehalose 40g to obtain mixture, screen cloth
Filtering, freezes to obtain powdered microballoon.Observed through JSM-5600 types SEM, microballoon hole is continuous whole, and microballoon is equal
In spherical shape, and uniform in size regular, 10~80 μm of particle size range, 30 μm of average grain diameter.It is micro- through Zeta potential analysis-e/or determining
The Zeta potential of ball is set to (- 23.6 ± 1.97) mV, and it is negative electrical charge that its surface institute is electrically charged.
The measure of the vitro cumulative release of embodiment 10
Clip length is about the bag filter (8000-14000) of 5cm, is put into the beaker for filling suitable quantity of water, and heating is boiled
5min (timing since boiling water), bag filter one end after boiling is tightened with fine rule, leak detection.Carried out using dynamic dialysis method
The measure of vitro cumulative release.
Precision claims sustained-release micro-spheres 40mg prepared by embodiment 1,3,7,9 to insert in bag filter, adds 2mL PBSs
(0.1M, pH=7.4, containing 0.02% sodium azide), sealing, is placed in the conical flask with cover equipped with 48mL PBSs, puts
Enter the water bath with thermostatic control shaking table of (37.0 ± 0.5) DEG C, with rotating speed as 100rmin-1Speed shaking, respectively at 0,5,10,15,
20,25,30d respectively take out 5mL, while adding the PBS of the fresh equality of temperature of equivalent, extinction are determined with UV detector
Degree, calculates cumulative release percentage, draws release profiles as shown in Figure 1.
The release profiles of Fig. 1 can be seen that the release medicine of sustained release microsphere agents of the invention sustainable stabilization in 30 days
Thing, it is ensured that the stabilization of blood concentration, has reached the purpose of the present invention.
Sustained release microsphere agents obtained in Example 2,4,5,6,8 carry out drug release determination, as a result with embodiment 1,3,7,
10 results for measuring are close, show that equally there is the sustained release microsphere agents that embodiment 2,4,5,6,8,9 is provided obvious sustained release to make
With, it is ensured that the stabilization of blood concentration, reach the purpose of the present invention.
Pharmacodynamics in the body of embodiment 11
Animal Model and packet
210 (180 ± 20) g of cleaning grade male SD rat, after adaptability is fed 1 week, 30 are taken by body weight level at random,
It is divided into three groups, respectively 2w, 4w, 8w Normal group (every group 10), remaining 180 rat modeling.Model group is raised with sugar high
High lipid food (adds sucrose, refining lard and yolk, heat content 21.6kJ/kg) on the basis of standard full price mixed fodder.
After high glucose and high fat feed group is fed 4 weeks, intraperitoneal injection Streptozotocin citrate buffer (is dissolved in pH=4.0's before use
In 0.1mmol/L citrate buffers, 25mg/kg, 1 time/d, continuous 2d)；Normal group normal diet is fed 4 weeks, then is noted
Penetrate equivalent citrate buffer, 1 time/d, continuous 2d.Injection medicine is spaced 1d blood glucose monitoring systems and checks and examine rat limosis blood two days later
Sugar (fasting 12h before test), that is, blood sugar after injecting, is diabetes rat model criterion with blood-sugar content 16.7mmol/L,
Rat more than 16.7mmol/L as the object of observation, is continued to raise to be determined after 4 weeks with normal diet using Vonfrey fibers
PDN modelings success is thought in the mechanical pain threshold of rat hindleg, decline.By the successful rat of modeling press blood sugar level with
Machine is divided into 2w, 4w, 8w model group (every group 10), the sustained-release micro-spheres group of 2w, 4w, 8w the present embodiment 1,3,5,7,9 (every group 10).
Medication
Normal group：By physiological saline 10mL/kg/d hypodermic injections；Model group：By the subcutaneous notes of physiological saline 10mL/kg/d
Penetrate；Sustained-release micro-spheres group：5mg/kg monthly property hypodermic injections, microballoon first uses supensoid agent (3% sodium carboxymethylcellulose before injection
+ 0.1%Tween20) it is suspended；All groups all from after the establishment of PDN rat models, except sustained-release micro-spheres group, start daily hypodermic injection
Once, until each group experiment terminates.Each group rat is raised under the same terms during experiment.
Statistical procedures
Statistical procedures are carried out using SPSS13.0 softwares, measurement data is represented with x ± s, compare between group and use single factor test
Variance analysis and t are checked, and P ＜ 0.05 represent statistically significant, and P ＜ 0.01 indicate significant difference.
Blood sugar detection
Respectively at 2 weekends, 4 weekends, three time points of 8 weekend after treatment, each group takes 8 rats at random, using steady type
Blood glucose meter determines rat tail vein fasting blood-glucose.Change of each group blood sugar at each time point, as shown in table 1.
Change of each group rat blood sugar (mmol/L) of table 1 at each time point(n=8)
| Group | 2w | 4w | 8w |
| Normal group | 5.21±1.24 | 5.14±0.56 | 5.32±0.45 |
| Model group | 21.34±4.45** | 24.25±3.12** | 28.98±2.91** |
| Embodiment 1 | 12.65±0.87**△ | 6.84±1.23*△△ | 6.65±0.54△△ |
| Embodiment 3 | 11.45±0.25**△ | 7.33±0.71*△△ | 6.27±1.26△△ |
| Embodiment 5 | 10.35±0.51**△ | 7.45±0.73*△△ | 5.93±0.26△△ |
| Embodiment 7 | 10.01±0.41**△ | 8.02±0.66*△△ | 7.01±0.26△△ |
| Embodiment 9 | 10.25±0.12**△ | 7.65±0.27*△△ | 6.15±0.54△△ |
Note：Compare with normal group, * P ＜ 0.05, * * P ＜ 0.01；Compare with model group, △ P ＜ 0.05, △ △ P ＜
0.01。
During experiment, as time went on, model group rats tail vein blood sugar is significantly raised, compares with normal group, 2 weeks, 4
There is the difference (P ＜ 0.01) of conspicuousness when week and 8 weeks, and during testing, treatment group's rats tail vein blood glucose value is in
The trend of reduction, compared with model group, (P ＜ 0.05) statistically significant at 2 weeks, and at 4 weeks and 8 weeks, the difference with conspicuousness
Different (P ＜ 0.01), compared with normal group, has the difference (P ＜ 0.01) of conspicuousness, (P ＜ statistically significant at 4 weeks at 2 weeks
0.05), 8 weeks when not statistically significant (P ＞ 0.05).Illustrate that sustained-release microspherical composition of the invention can substantially suppress blood sugar liter
Effect high.
Mechanicalness Determination of Pain Threshold
Respectively at 2 weekends, 4 weekends, 8 weekends after treatment, each group takes 8 rats at random, and the Vonfrey using standard is fine
Dimension, the mechanical pain threshold (MPT) of rat hindleg is detected using up-down methods.The each group rat mechanicalness threshold of pain (MPT) exists
The change at each time point, as shown in table 2.
Change of each group rat MPT (g) of table 2 at each time point(n=10)
Note：Compare with normal group, * P ＜ 0.05, * * P ＜ 0.01；Compare with model group, △ P ＜ 0.05, △ △ P ＜
0.01。
It can be seen that model group extends with experimental period, rat mechanical pain threshold is presented substantially reduces trend, with normal group
Compare, 2 weeks, 4 weeks, there is the difference (P ＜ 0.01) of conspicuousness at 8 weeks；And during testing, treatment group's rat mechanicalness threshold of pain
Value is in elevated trend, compared with model group, (P ＜ 0.05) statistically significant at 2 weeks, at 4 weeks and 8 weeks, with conspicuousness
Difference (P ＜ 0.01), compared with normal group, (P ＜ 0.05) statistically significant at 2 weeks and 4 weeks, at 8 weeks without statistics anticipate
Adopted (P ＞ 0.05).Illustrate that sustained-release microspherical composition of the invention can significantly improve diabetic rat mechanical pain threshold.
Claims (14)
1. a kind of GLP-1 analogs and ziconotide composition sustained-release microsphere preparation, it is characterised in that comprising GLP-1 analogs,
Ziconotide, biodegradable and tool biocompatibility macromolecular material, stabilizer and freeze drying protectant；
The GLP-1 analogs are selected from Liraglutide or its salt, Exenatide or its salt, degree draw glycopeptide or its salt, A Bilutai
Or the one kind in its salt；
The GLP-1 analogs are 1 with the mass ratio of ziconotide:1~1:25.
2. GLP-1 analogs according to claim 1 and ziconotide composition sustained-release microsphere preparation, it is characterised in that
The sustained release microsphere agents are mainly made up of the composition of following weight percent content：It is GLP-1 analogs 0.02~1.35%, neat
Examine promise peptide 0.02~1.58%, biodegradable and tool biocompatibility macromolecular material 60.00~92.00%, stabilizer
0.05~25% and freeze drying protectant 0.21~28.54%；The GLP-1 analogs are 1 with the mass ratio of ziconotide:8~
1:20。
3. GLP-1 analogs according to claim 1 and 2 and ziconotide composition sustained-release microsphere preparation, its feature exist
In the sustained release microsphere agents are mainly made up of the composition of following weight percent content：GLP-1 analogs 0.05~
1.25%th, ziconotide 0.06~1.58%, it is biodegradable and tool biocompatibility macromolecular material 75.00~
92.00%th, stabilizer 0.05~20.00% and freeze drying protectant 0.35~20.30%；The GLP-1 analogs and Qi Kaonuo
The mass ratio of peptide is 1:10~1:20.
4. GLP-1 analogs according to claim 1 and ziconotide composition sustained-release microsphere preparation, it is characterised in that
Described biodegradable and tool biocompatibility macromolecular material is selected from polylactide-glycolide, poly butyric valeric acid
One or more in ester, poly lactic-co-glycolic acid, polylactic acid-polyglycol, molecular weight is 5000~90000 dalton.
5. according to claim 4 biodegradable and tool biocompatibility macromolecular material, it is characterised in that be selected from
Polylactide-glycolide, PHBV, poly lactic-co-glycolic acid (50: 50~85: 15), PLA-poly- second two
One or more in alcohol (5: 1~20: 1), molecular weight is 8000~80000 dalton.
6. GLP-1 analogs according to claim 1 and ziconotide composition sustained-release microsphere preparation, it is characterised in that
The average grain diameter of the sustained-release micro-spheres is 10 μm~100 μm.
7. according to claim 1 biodegradable and tool biocompatibility macromolecular material, it is characterised in that described
Stabilizer is at least one in polyvinyl alcohol, polyvinylpyrrolidone, sodium polymethacrylate, Sodium Polyacrylate；The jelly
Dry protective agent is selected from least one in sorbierite, mannitol, lactose, sucrose, trehalose, poloxamer.
8. according to claim 7 biodegradable and tool biocompatibility macromolecular material, it is characterised in that described
Stabilizer is at least one in polyvinyl alcohol, polyvinylpyrrolidone；The freeze drying protectant is selected from mannitol, lactose, pool
At least one in Luo Shamu.
9. the preparation method of a kind of GLP-1 analogs and ziconotide composition sustained-release microsphere preparation, it is characterised in that including such as
Lower step：
Step 1) GLP-l analogs and ziconotide add water is made into drug solution A；By biodegradable and tool biocompatibility
Macromolecular material added with machine solvent solution-forming B；
Step 2) solution A and solution B mixing are ultrasonically formed colostrum, colostrum is added to the stabilization crossed with organic mixed solvent saturation
In the agent aqueous solution, emulsifying obtains emulsion；
Step 3) emulsion was stirred at room temperature after 1 hour it is warming up to 40 DEG C~45 DEG C and is kept for 1 hour, then it is cooled to 10 DEG C, add and freeze
Particle is collected in dry protective agent, sieving, is freezed, and is sterilized via radiation.
10. the preparation method of GLP-1 analogs according to claim 9 and ziconotide composition sustained-release microsphere preparation,
Characterized in that, step 1) in organic solvent be selected from ethyl acetate, phenmethylol mixed solution or dichloromethane, phenmethylol mix
One kind in solution.
The preparation method of 11. GLP-1 analogs according to claim 9 and ziconotide composition sustained-release microsphere preparation,
Characterized in that, step 1) in organic solvent ethyl acetate and phenmethylol volume ratio be 2.5~8: 1；Dichloromethane and benzene
The volume ratio of methyl alcohol is 2.5~7: 1.
The preparation method of 12. GLP-1 analogs according to claim 9 and ziconotide composition sustained-release microsphere preparation,
Characterized in that, step 2) in organic mixed solvent be phenmethylol and ethyl acetate, the concentration of organic mixed solvent for 1%~
3%.
The preparation method of 13. GLP-1 analogs according to claim 9 and ziconotide composition sustained-release microsphere preparation,
Characterized in that, step 3) in emulsion be stirred at room temperature 1 hour after be warming up to 45 DEG C and kept for 1 hour, then be cooled to 10 DEG C.
The 14. GLP-1 analogs and ziconotide composition sustained-release microsphere preparation according to any one of claim 1~13,
Characterized in that, for treating diabetes and its pain diabetic neuropathy complication.
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