CN109248159A - The monthly preparation method of a needle Exenatide control-release microsphere - Google Patents
The monthly preparation method of a needle Exenatide control-release microsphere Download PDFInfo
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- CN109248159A CN109248159A CN201811168429.6A CN201811168429A CN109248159A CN 109248159 A CN109248159 A CN 109248159A CN 201811168429 A CN201811168429 A CN 201811168429A CN 109248159 A CN109248159 A CN 109248159A
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- microballoon
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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
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
Abstract
The invention discloses a kind of preparation methods of a monthly needle Exenatide control-release microsphere.The present invention is using biodegradable polymer as the controlled release matrix of microballoon, add the leading portion Exenatide rate of release based on flooding mechanism in perforating agent regulation microballoon, addition acid-base modifier regulates and controls the back segment Exenatide rate of release degraded based on microsphere polymer skeleton, the biodegradable polymer, perforating agent, acid-base modifier and Exenatide are shaped to by microballoon using film emulsification infall process, it is close to Zero order release, technique is provided to produce monthly a needle uniform particle diameter, encapsulation rate height, the good Exenatide microballoon of release profiles and supports.Compared with prior art, the present invention has been successfully prepared monthly a needle high encapsulation rate, uniform particle diameter, the good Exenatide release microsphere of release profiles.
Description
Technical field
The present invention relates to a kind of preparation methods of a monthly needle Exenatide control-release microsphere.
Background technique
Medicinal industry passes through long-term development, and biopharmaceutical macromolecular drug just at a high speed develops and occupy pharmaceutical market, closely
For the average growth rate per annum of biopharmaceutical macromolecular drug up to 12%~16%, sales volume has reached the half of total market over year.It is biological big
Molecular drug also has significant limitation, it is oral do not absorb lead to not oral administration, Half-life in vivo it is short and need to frequently to
Medicine, medication cycle be generally very long and the administration mode of common liquid drugs injection injection to patient medication brings greatly pain and inconvenient
Deng.
Polymer microballoon, which refers to, is wrapped up drug with the high molecular polymer that has good biocompatibility, can degrade in vivo
Get up to form tiny spherical solid, into body after high molecular polymer slowly degrade, spherical shell is gradually thinning, generates hole, from
And slowly release the drug of encapsulated inside.By screening suitable macromolecule polymer material, adjustment microspherulite diameter and drugloading rate,
Can obtain is suitable for controllable drug release rate, while can protect the high molecular weight protein drug maximum journey of fragile structure mutability
Degree exempts to be affected by the external environment, and plays drug effect to greatest extent.Due to its outstanding sustained-release and controlled release ability with to the strong of entrapped drug
Protective effect, polymer microballoon are a kind of ideal high molecular weight protein drug conveying carriers, generally through intramuscular injection or subcutaneous note
Penetrate administration.Poly lactide-glycolide acid (PLGA) microballoon due to preferable biocompatibility and biodegradability,
It is to apply and study one of widest drug carrier material.
The releasing mechanism of polymer microballoon can be divided into three classes, i.e. superficial degradation mechanism, bulk degradation mechanism and diffusion control
Release mechanism.(1) superficial degradation mechanism: medicaments uniformity is distributed in formation monolith system in degradation polymer, when degradation speed is higher than
When diffusion velocity, rate of release is mainly related with degradation speed.When the seepage velocity of water is less than the degradation speed of polymer, this is poly-
The degradation for closing object only carries out on surface, then drug releasing rate is influenced by microsphere surface product with volume ratio and shape.Medicine
Object is discharged from microsphere surface, superficial degradation occurs, and as microsphere surface product is smaller and smaller, drug releasing rate is slower and slower.(2)
Bulk degradation mechanism: when the seepage velocity of water is greater than the degradation speed of polymer, microsphere surface and inside hydrolyze simultaneously, most
Occurs the phenomenon that skeleton disintegration eventually.If the degradation mode of the polymer is bulk degradation, degradation speed and controlled release system
Surface-to-volume ratio it is unrelated, in the incipient stage of degradation, rate of release is slow, with the rapid dissolution of polymer, releases
Medicine speed is greatly speeded up.(3) diffusion-controlled theory: it is assumed that when degradation speed is much smaller than diffusion velocity, drug release is mainly to expand
Scattered mode carries out, and degradation polymer, which is formed by total system, can indicate rate of releasing drug with Higuchi equation.Drug is molten first
Solution from preparation at diffusing out after solution into body fluid again, control of the drug release by diffusion rate.
Release in vitro behavioral study is to be able to the preferably drug release situation of reflection microballoon in vivo, is conducive to filter out
More preferably prescription and technique.The strong-hydrophobicity of polymer, the acidity of catabolite and acid cause autoacceleration bulk degradation feature
It is easy to cause cohesion or the inactivation of polypeptide drugs and the drug of other acid labile, showing for " burst release " or " lag " release is presented
As this is unfavorable for the constant release of drug.It is relatively high to prepare main matrix material PLGA molecular weight used in microballoon, institute
The micro-sphere structure of formation is finer and close, and the release of drug is relatively slow, depends primarily on the degradation of polymer, i.e. ontology
Degradation.Microspheres swell is generated compared with multichannel, and dissolution medium is entered inside microballoon by channel, accelerates high-molecular bone frame material drop
Solution, it is lower in this stage release amount of medicine.
Summary of the invention
In the above context, the purpose of the present invention is to provide a kind of preparation sides of a monthly needle Exenatide control-release microsphere
Method.The present invention is based on flooding mechanism in addition perforating agent regulation microballoon using biodegradable polymer as the controlled release matrix of microballoon
Leading portion Exenatide rate of release, the back segment Exenatide release that addition acid-base modifier regulation degrade based on microballoon skeleton is fast
The biodegradable polymer, perforating agent, acid-base modifier and Exenatide are shaped to by rate using film emulsification infall process
Microballoon can be very good the behavior for improving drug release lag, be close to Zero order release, and it is bent to obtain more preferably release
Line.
The purpose of the present invention is achieved through the following technical solutions:
The present invention relates to a kind of preparation methods of a monthly needle Exenatide control-release microsphere, which comprises
A) using biodegradable polymer as the controlled release matrix of microballoon；
B) the leading portion Exenatide rate of release based on flooding mechanism in addition perforating agent regulation microballoon；
C) addition acid-base modifier regulates and controls the back segment Exenatide rate of release degraded based on microsphere polymer skeleton；
D) infall process is emulsified for the biodegradable polymer, perforating agent, acid-base modifier and Ai Saina using film
Peptide is shaped to microballoon.
Preferably, the perforating agent based on flooding mechanism regulation leading portion Exenatide rate of release is selected from medicinal small molecule carbohydrate
Auxiliary material.
Preferably, the medicinal small molecule carbohydrate auxiliary material is selected from one of trehalose, glucose, lactose, sucrose or several
The mixture of kind.
It is furthermore preferred that the medicinal small molecule carbohydrate auxiliary material is trehalose.
It is furthermore preferred that the mass ratio that the trehalose accounts for the gross weight of the Exenatide control-release microsphere is 0.01~3%.
Preferably, the acid-base modifier based on microsphere polymer skeleton degrading and regulating back segment Exenatide rate of release is selected from
The mixture of one or both of zinc hydroxide, magnesium hydroxide.
It is furthermore preferred that the acid-base modifier is magnesium hydroxide.
It is furthermore preferred that the mass ratio that the magnesium hydroxide accounts for the gross weight of the Exenatide control-release microsphere is 0.5~11%.
Preferably, the average grain diameter of the Exenatide control-release microsphere is 40.102~55.465 μm.
Preferably, the drugloading rate of the Exenatide control-release microsphere is 2wt%~8wt%.
Preferably, the film emulsification sedimentation includes the following steps:
S1, perforated membrane limit molding: by the biodegradable polymer containing Exenatide, perforating agent and acid-base modifier
Solution is transferred in perforated membrane, is crossed film by nitrogen pressure and is formed embryo's microballoon；
S2, settling leg guiding carry out microballoon solidification: embryo's microballoon through settling leg natural subsidence to bottom when collect microballoon, clearly
It washes, freeze-drying.
Preferably, the material of the perforated membrane is glass or stainless steel.
Preferably, the aperture of the perforated membrane is 5~40um.
Preferably, the height of the settling leg is 820~1600mm, and diameter is 44~84mm, 3~4mm of wall thickness.
Preferably, the settling leg is provided with the poly-vinyl alcohol solution of pre-cooling.
Preferably, in step S2, the microballoon of bottom collection enters purge tank under siphonage and is cleaned.
Compared with prior art, the present invention is wrapped up trehalose, magnesium hydroxide into Ai Saina using film emulsification infall process
In peptide microballoon, the long-acting slow-release microballoon of preparation one month carries out the observation of microsphere surface form with scanning electron microscope, using efficient liquid
Phase chromatography tests and analyzes the encapsulation rate of microballoon, using the release in vitro of microballoon remaining method measurement microballoon；More identical magnesium hydroxide
Under content, Exenatide microsphere surface form, the difference of encapsulation rate and release profiles of different content of trehalose are closed by addition
The trehalose and magnesium hydroxide of suitable content, have been successfully prepared the good Exenatide of high encapsulation rate, uniform particle diameter, release profiles
Sustained-release micro-spheres.
Detailed description of the invention
Upon reading the detailed description of non-limiting embodiments with reference to the following drawings, other feature of the invention,
Objects and advantages will become more apparent upon:
Fig. 1 is Exenatide microballoon preparation facilities figure；Wherein, 1 is microballoon preparation facilities, and 2 be fluid reservoir, and 3 be perforated membrane,
4 be settling leg, and 5 be microballoon collecting tank, and 6 be purge tank, and 7 be refrigeration unit, and 8 be high-pressure bottle, and 9 be rocking equipment, and 10 be total
Power supply；
Fig. 2 is the scanning electron microscope (SEM) photograph of different content of trehalose Exenatide microsphere surfaces；Wherein, Fig. 2-1 magnesium hydroxide contains
Amount 5%, content of trehalose 0%, Fig. 2-2 magnesium hydroxide content 5%, content of trehalose 1%, Fig. 2-3 magnesium hydroxide content 5%,
Content of trehalose 2%, Fig. 2-4 magnesium hydroxide content 5%, content of trehalose 3%；
Fig. 3 is the encapsulation rate figure of different content of trehalose Exenatide microballoons；Wherein, one magnesium hydroxide content 5% of prescription,
Content of trehalose 0%, prescription magnesium dihydroxide content 5%, content of trehalose 1%, three magnesium hydroxide content 5% of prescription, seaweed
Sugared content 2%, four magnesium hydroxide content 5% of prescription, content of trehalose 3%；
Fig. 4 is the cumulative release curve graph of different trehaloses, magnesium hydroxide content Exenatide microballoon；Wherein, prescription one
Magnesium hydroxide and content of trehalose equal 0%, prescription magnesium dihydroxide content 5%, content of trehalose 0%, three magnesium hydroxide of prescription
Content 5%, content of trehalose 1%, four magnesium hydroxide content 5% of prescription, content of trehalose 2%, five magnesium hydroxide content of prescription
5%, content of trehalose 3%.
Specific embodiment
The following describes the present invention in detail with reference to examples.Following embodiment will be helpful to those skilled in the art
The present invention is further understood, but the invention is not limited in any way.It should be pointed out that those skilled in the art
For, without departing from the inventive concept of the premise, it can also make certain adjustments and improvements.These belong to guarantor of the invention
Protect range.
In system of the invention, the perforating agent based on flooding mechanism regulation leading portion Exenatide rate of release of microballoon selection
Material:
For the drilling agent material that the present invention uses for trehalose, trehalose is the irreducibility being widely present in a kind of nature
Disaccharide has no toxic side effect, and chemical property is sufficiently stable, and trehalose is soluble easily in water, and solubility with temperature variation in water is more
Obviously, solubility is 55.3 at 10 DEG C；It is 140.1 at 50 DEG C；It is 602.9 at 90 DEG C.Exenatide microballoon phase before releasing,
High molecular material is not yet degraded, and microballoon relies primarily on drug diffusion and enters dissolution medium release, but because thin inside microballoon
Aqueous nature, so that dissolution medium is difficult to enter inside microballoon, therefore early period, rate of release was slower；To release later period, macromolecule material
Material is degraded, so that drug releasing rate is accelerated.The present invention adds trehalose as perforating agent on the basis of bulk degradation,
So that microsphere surface, which is formed, forms some ducts inside some holes and microballoon, dissolution medium passes through these holes and duct very
Fast to immerse microballoon, drug passes through these ducts and spreads rapidly.It is continuous inside microballoon to be formed as trehalose constantly dissolves
Duct regulates and controls the leading portion Exenatide rate of release based on flooding mechanism in microballoon.Content by regulating and controlling trehalose, which adjusts, to expand
Dissipate the quantity and distribution in duct.The release performance of drug especially burst drug release is related with the surface property of microballoon in microballoon, micro-
The surface topography of ball is an important factor for determining microballoon release performance, and the micropore of microsphere surface is more, and aperture is bigger, and body fluid is to micro-
The diffusion of infiltration and drug to outside microballoon in ball is easier to, and can improve the lag period of Exenatide microballoon release.
The acid-base modifier based on microsphere polymer skeleton degrading and regulating back segment Exenatide rate of release that microballoon is selected:
The acid-base modifier magnesium hydroxide that the present invention uses regulates and controls the Exenatide rate of release degraded based on microballoon skeleton,
Since dissolution medium immerses microballoon, degradation, which occurs, for PLGA can generate lactic acid and hydroxyacetic acid, these monomers and the general band of oligomer
There is carboxylic acid group to be gathered in inside microballoon, reduces the pH value of microenvironment inside microballoon.Magnesium hydroxide is added, acid-base neutralization makes pH value
Increase.The carboxyl that PLGA degradation generates occurs dissociation and generates carboxylic acid ion, so that the degree of ionization of catabolite increases, it is interior
Portion's osmotic pressure increases.Under the action of osmotic pressure, hydrone is easier to immerse inside microballoon, promotes polymer degradation quickening and medicine
Object diffusion is accelerated.The prescription that magnesium hydroxide is not added is relatively slow during the release in later period, and the magnesium hydroxide of alkalinity is added
Can degrade the substance reaction with carboxylic acid group-COOH generated with PLGA, thus it is possible to vary discharge the pH value of environment, release to increase
The degradation rate of later period PLGA is put, microballoon release is promoted.The addition of magnesium hydroxide, which can be played, to be adjusted outside Exenatide microsphere
The purpose of release, the amount of magnesium hydroxide appropriate promote later period release, have the function of optimizing microballoon release profiles, improve microballoon
Cumulative release amount.
The biodegradable polymer material that microballoon is selected:
The polymer material poly lactide-glycolide acid (PLGA) that the present invention uses is with its good bio-compatible
Property, hypotoxicity and degradability are widely used in drug delivery system.PLGA has good biodegradability, in vivo may be used
It is degraded to participate in the lactic acid and hydroxyacetic acid of internal tricarboxylic acid cycle, ultimately generates water and carbon dioxide and excrete.
PLGA is not accumulated in vivo and its in degradation process, non-immunogenicity, and non-carcinogenesis can be absorbed by organisms, no pollution to the environment.
There are good compatibility in PLGA and human tissue cell, can be reduced inflammatory reaction, promote cell attachment growth.
The molding film of microballoon emulsifies infall process:
The molding film emulsification infall process of microballoon is prepared containing Exenatide, dimethyl sulfoxide, trehalose, methylene chloride
With the polymer solution of magnesium hydroxide, polymer solution is transferred in perforated membrane, it is micro- to cross film formation embryo by nitrogen pressure
Ball collects microballoon when embryo's microballoon natural subsidence to microballoon collects pot bottom, cleans and dispense freeze-drying microballoon.This technique
Advantage first is that reduce protein and peptide drugs caused by the shearing forces such as magnetic agitation be lost, the collision adhesion of microballoon；Another party
Face, integrated design concept application without mixing industrially make the simple operations such as sterile, achievableization of mass production.
The release in vitro method of microballoon:
The release in vitro method of microballoon -- microballoon remaining method, precision weigh 10mg microballoon and PBS (pH=7.4) buffer are added
In, it is placed in 100r/min, 37 DEG C of constant-temperature tables, guarantees after taking out supernatant, to supplement same amount of fresh daily in the same time
PBS buffer solution；After sample stops shaking after the predetermined time, microballoon residual in bottle is frozen after blotting supernatant
It is dry；Microballoon after freeze-drying carries out efficient liquid phase chromatographic analysis；The drug concentration in each sample is calculated according to standard curve, according to
The Cumulative release profile of different time point-rendering drug.
By being fitted to the In-vitro release curves for being not added with trehalose Exenatide microballoon, the hydrophobicity because of PLGA is obtained
So that dissolution medium hardly enters inside microballoon, so microballoon discharges drug early period almost without release.Before microballoon release
The releasing mechanism of phase is occupied an leading position with flooding mechanism, and drug cannot be released inside microballoon by flooding mechanism.
Addition trehalose causes the hole of Exenatide microsphere surface to increase, as shown in the microballoon electron microscope in Fig. 2, high power
Lower observation microsphere features smooth surface, with the increase of content of trehalose, the hole of microsphere surface obviously increases and becomes larger, the reason is that extra large
Dissolution of algae sugar during preparing microballoon makes microsphere surface form many apertures.Dissolution medium can lead to during release
It crosses these ducts and immerses microballoon quickly, at this moment drug can be diffused out rapidly by these ducts.By to microspheres swell behavior
The study found that addition trehalose particle microballoon the swelling time started obviously earlier than the microballoon for being not added with trehalose particle.
The present invention investigates release conditions outside Exenatide microsphere, and different trehaloses and magnesium hydroxide is selected to contain
The microballoon of amount carries out release in vitro assessment.Under conditions of no addition magnesium hydroxide and trehalose, the release of Exenatide microballoon
Slowly.In the case where no addition trehalose, the band carboxylic acid group-that the magnesium hydroxide of alkalinity can be generated with PLGA degradation is added
The substance reaction of COOH, thus it is possible to vary discharge the pH value of environment, to increase the degradation rate of release later period PLGA, promote Ai Sai
The release of that peptide microballoon.On the basis of fixed magnesium hydroxide content, the trehalose of different content is added, as content of trehalose is got over
More, more in the hole that microsphere surface is formed, hydrone permeates faster, and the hole of formation can be bigger, therewith drug diffusion
Speed it is also faster, therefore with the increase of content of trehalose, early period, drug releasing rate was continuously increased.From the present invention, we are obtained
Know, the release behavior of drug, addition can be adjusted by the content of trehalose and magnesium hydroxide in control Exenatide microballoon
Perforating agent regulates and controls the leading portion Exenatide rate of release based on flooding mechanism in microballoon, and addition acid-base modifier regulation is based on microballoon
The back segment Exenatide rate of release of polymer backbone degradation.
Disclose the particle diameter distribution of microballoon in the present invention, 40.102-55.465 μm of average grain diameter.
Concrete application is shown in following embodiment:
The preparation of 1 Exenatide microballoon of embodiment
As shown in Figure 1, being first turned on general supply 10 using microballoon preparation facilities 1, refrigeration unit 7 is opened, sterile is gathered
Glycohol solution is added in settling leg 4 and is pre-chilled.Then it will contain Exenatide, dimethyl sulfoxide, trehalose, magnesium hydroxide and two
Polymer (PLGA) medical fluid of chloromethanes is transferred in the perforated membrane 3 of fluid reservoir 2, is opened rocking equipment 9, is passed through high-pressure bottle 8
There is provided nitrogen pressure cross film formed embryo's microballoon, when embryo's microballoon natural subsidence arrive microballoon 5 bottom of collecting tank when, opening transfer pipe
Valve, microballoon enters purge tank 6 under siphonage, the pre- milli-Q water for being cooled to 4 DEG C is added, after cleaning, after packing
Freeze-drying is to get microspheres product.
By the shortcut microballoon preparation facilities, obtained microballoon has carried out particle size distribution measuring using laser particle analyzer,
Test result shows 40.102-55.465 μm of average grain diameter of finished product microballoon, show the particle size of the microballoon being prepared with
Particle diameter distribution is uniform.
The encapsulation rate of 2 Exenatide microballoon of embodiment is investigated
The Exenatide microballoon that precision weighs 10mg is placed in centrifuge tube, and suitable DMSO is added, and vortex dissolves microballoon,
By 100 μ l of centrifuging and taking supernatant, injects high performance liquid chromatography and tested and analyzed, record the chromatography main peak area of sample.
Drugloading rate=(actual content/microballoon quality of albumen in microballoon) * 100%
Encapsulation rate=(the practical drugloading rate of microballoon/microballoon theory drugloading rate) * 100%
From the figure 3, it may be seen that the encapsulation rate that addition trehalose and the Exenatide microballoon of magnesium hydroxide preparation obtain is 90%
Above.
The release dynamics of 3 Exenatide microballoon of embodiment
Release in vitro research is carried out using microballoon remaining method, the Exenatide microballoon that every group of prescription precision weighs 10mg is put into
It discharges in bottle, 1mlPBS (pH=7.4) buffer is added, be placed in 100r/min, 37 DEG C of constant-temperature tables, guarantee daily in same a period of time
Between, after taking out supernatant, supplement same amount of fresh PBS buffer solution, sample respectively at the 1st, 4,7,10,13,16,19,22,
25, after stopping shaking after 28,30 days, microballoon residual in bottle is lyophilized after blotting supernatant.Microballoon after freeze-drying is added
DMSO is vortexed after thoroughly dissolution, and centrifuging and taking supernatant carries out efficient liquid phase chromatographic analysis into liquid phase bottle.According to standard curve meter
The drug concentration in each sample is calculated, according to drug one month Cumulative release profile of different time point-rendering.
Chromatographic condition determines
Chromatographic column: Agilent TC-C18 chromatographic column (4.6 × 250mm, 5 μm)；
Mobile phase: A phase: the aqueous solution containing 0.05% trifluoroacetic acid；B phase: the acetonitrile solution containing 0.05% trifluoroacetic acid；B
Phase content changes with time ratio, 30%-55% (0-20min), 55%-30% (20-26min)；
Flow velocity: 1.0mlmin-1；Detection wavelength: 214nm；Column temperature: 25 degree；Sample volume: 100 μ l；
The Exenatide microballoon preparation curve of different trehaloses and magnesium hydroxide content is calculated, as a result
It has been shown that, the addition of trehalose and magnesium hydroxide have promoted the release of Exenatide microballoon close, do not lag and phenomenon of burst release, in surrounding
Accumulative release reaches 100%.This explanation, the present invention is under the premise of guaranteeing encapsulation rate and uniform particle diameter, addition perforating agent regulation
Leading portion Exenatide rate of release in microballoon based on flooding mechanism, addition acid-base modifier regulation are based on microsphere polymer skeleton
The back segment Exenatide rate of release of degradation emulsifies infall process for the biodegradable polymer, perforating agent, acid using film
Alkali regulator and Exenatide are shaped to microballoon, and drug can be made to release from microballoon with the speed of uniform, controllable, and
Do not cause lag and phenomenon of burst release, obtains the microballoon for having excellent controlled-release effect, concrete outcome is shown in Fig. 4.
Specific embodiments of the present invention are described above.It is to be appreciated that the invention is not limited to above-mentioned
Particular implementation, those skilled in the art can make various deformations or amendments within the scope of the claims, this not shadow
Ring substantive content of the invention.
Claims (10)
1. a kind of preparation method of a monthly needle Exenatide control-release microsphere, which is characterized in that described method includes following steps:
A) using biodegradable polymer as the controlled release matrix of microballoon；
B) the leading portion Exenatide rate of release based on flooding mechanism in addition perforating agent regulation microballoon；
C) addition acid-base modifier regulates and controls the back segment Exenatide rate of release degraded based on microsphere polymer skeleton；
D) using film emulsification infall process by the biodegradable polymer, perforating agent, acid-base modifier and Exenatide at
Type is microballoon.
2. preparation method according to claim 1, which is characterized in that based on flooding mechanism regulation leading portion Exenatide release
The perforating agent of rate is selected from medicinal small molecule carbohydrate auxiliary material.
3. preparation method according to claim 2, which is characterized in that the medicinal small molecule carbohydrate auxiliary material is selected from seaweed
The mixture of one or more of sugar, glucose, lactose, sucrose.
4. preparation method according to claim 3, which is characterized in that the medicinal small molecule carbohydrate auxiliary material is trehalose.
5. the preparation method according to claim 4, which is characterized in that the trehalose accounts for the Exenatide control-release microsphere
Gross weight mass percent be 0.01~3%.
6. preparation method according to claim 1, which is characterized in that ended based on microsphere polymer skeleton degrading and regulating back segment
The acid-base modifier for filling in that peptide rate of release is selected from the mixture of one or both of zinc hydroxide, magnesium hydroxide.
7. preparation method according to claim 6, which is characterized in that the acid-base modifier is magnesium hydroxide.
8. preparation method according to claim 7, which is characterized in that it is micro- that the magnesium hydroxide accounts for the Exenatide controlled release
The mass percent of the gross weight of ball is 0.5~11%.
9. preparation method according to claim 1, which is characterized in that the biodegradable polymer is polylactic acid-glycolic
Acetic acid copolymer.
10. preparation method according to claim 1, which is characterized in that the film emulsification sedimentation includes the following steps:
S1, perforated membrane limit molding: by the biodegradable polymer solution containing Exenatide, perforating agent and acid-base modifier
It is transferred in perforated membrane, film is crossed by nitrogen pressure and forms embryo's microballoon；
S2, settling leg guiding carry out microballoon solidification: embryo's microballoon through settling leg natural subsidence arrive bottom when collect microballoon, cleaning,
Freeze-drying.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114712312A (en) * | 2020-12-18 | 2022-07-08 | 浙江圣兆药物科技股份有限公司 | Method for controlling release of microsphere active ingredient |
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| CN101536984A (en) * | 2008-03-20 | 2009-09-23 | 江苏先声药物研究有限公司 | Injection-use recombinant human Endostatin porous sustained-release microsphere and preparation method thereof |
| CN102488619A (en) * | 2011-12-05 | 2012-06-13 | 上海交通大学 | Device for continuously producing exenatide microspheres and method for controlling release rate of microspheres |
| CN103585114A (en) * | 2013-11-25 | 2014-02-19 | 深圳翰宇药业股份有限公司 | Improved method for preparing exenatide sustained release microspheres |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101536984A (en) * | 2008-03-20 | 2009-09-23 | 江苏先声药物研究有限公司 | Injection-use recombinant human Endostatin porous sustained-release microsphere and preparation method thereof |
| CN102488619A (en) * | 2011-12-05 | 2012-06-13 | 上海交通大学 | Device for continuously producing exenatide microspheres and method for controlling release rate of microspheres |
| CN103585114A (en) * | 2013-11-25 | 2014-02-19 | 深圳翰宇药业股份有限公司 | Improved method for preparing exenatide sustained release microspheres |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114712312A (en) * | 2020-12-18 | 2022-07-08 | 浙江圣兆药物科技股份有限公司 | Method for controlling release of microsphere active ingredient |
| CN114712312B (en) * | 2020-12-18 | 2023-10-24 | 浙江圣兆药物科技股份有限公司 | Method for controlling release of microsphere active ingredients |
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