CN102370624A - Exendin-4 sustained release microsphere, its injection and preparation method - Google Patents
Exendin-4 sustained release microsphere, its injection and preparation method Download PDFInfo
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Abstract
The invention relates to a sustained release microsphere containing exendin-4, prepared by using emulsion-crosslinking technology. The sustained release microsphere has a W/O/W structure, wherein, the inner water phase contains exendin-4 as the main drug, the medium oil phase contains polylactic acid-glycolic acid copolymer (PLGA), and the outer water phase contains polyvinyl alcohol (PVA). The obtained microsphere has a smooth surface, the particle size of the microsphere is between 40-100 mu m, and the drug-loading rate of the microsphere is between 0.4-0.8 %. The invention also relates to an injection prepared from the sustained release microsphere. The invention further relates to a preparation method of the sustained release microsphere. The sustained release microsphere has the advantages of high drug-loading rate, high entrapment rate, stable releasing rate, long continuous release time (more than 4 weeks), biodegradable property and the like, so that the administration frequency can be reduced obviously, and surgical implantation and removal before and after administration are avoided, thus the invention is benefit for clinic application, greatly improves patient compliance. According to the invention, the therapeutic effect of long-acting anti-diabetes is achieved.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, particularly, the present invention relates to comprise the long-acting slow-release microsphere of insulin secretion accelerating element (Exendin-4), and the method for preparing of this sustained-release micro-spheres and the injection that makes by this sustained-release micro-spheres.
Background technology
Estimate that according to Epidemiological study present global diabetics sum has exceeded 1.2 hundred million, wherein about 90% is type ii diabetes, and this numeral also will rise steadily, and estimate 2025, and world wide will have 300,000,000 people to suffer from diabetes.This shows that the market of treatment diabetes medicament is not only huge but also still have great development space.
Insulin secretion accelerating plain (Exendin-4) is a kind of 39 amino acid whose polypeptide of from the Monster oral secretion, separating; Its aminoacid sequence and glucagon-like peptide (glucagon-like peptide; GLP-1) 53% homology is arranged, and in several animal models, shown similar antidiabetic effect with GLP-1.But different with GLP-1, do not receive after exendin-4 gets in the body that dipeptides is zymolytic to be influenced, so the half-life is than the obvious prolongation of GLP-1 .Pharmacology&Therapeutics 2007 (113) 546-593 such as () M á ire E.Exendin-4 reduces the speed of gastric emptying through stimulating the propagation and the differentiation of beta Cell of islet, and mechanism such as promotion satietion reach the effect of reduction, blood sugar control, are having broad prospects aspect the treatment type 2 diabetes mellitus.
The similar medicine of external exploitation is the Exenatide (synthetic insulin secretion accelerating is plain) of U.S. Amylin company and the cooperative development of Lilly company at present.The insulin secretion accelerating element (for example can also utilize the gene engineering method preparation; Referring to ZL 200410052039.4): through the DNA sequence of synthetic exendin-4; Then sequence is inserted into expression plasmid pET32a (+), transformed into escherichia coli DH5 α makes up and forms again.It is stable that the product that makes is like this deposited at low temperatures (2～8 ℃).
Compare with existing antidiabetic drug; The maximum advantage of exendin-4 is the mechanism of action that it is unique, and it can stimulate secretion of insulin when hyperglycemia, and does not stimulate secretion of insulin during hypoglycemia; So just effectively prevented hypoglycemic generation; Improved the safety of medication greatly, reduced the consumption of insulin, the quality of life and the medication that have effectively improved the patient are dangerous.
The aminoacid sequence of Exendin-4 is:
His?Gly?Glu?Gly?Thr?Phe?Thr?Ser?Asp?Leu?Ser?Lys?Gln?Met?GluGlu?Glu?Ala?Val?Arg?Leu?Phe?Ile?Glu?Trp?Leu?Lys?Asn?Gly?Gly?Pro?SerSer?Gly?Ala?Pro?Pro?Pro?Ser
Be abbreviated as: HGEGTFTSDL SKQMEEEAVR LFIEWLKNGGPSSGAPPPS
Controlled drug delivery system is meant: medicine is processed certain dosage form, and the control medicine is at the intravital release degree of people, make medicine according to the dosage of design, in the time range that requires, slowly discharge in vivo, to reach the purpose of treatment disease with certain speed.This drug delivery system comprise injectable oil, emulsion, suspension, liposome, microgranule (microcapsule or microsphere), implantation or gel systems etc. (.Plenmu such as Baker R W, NewYork, 1974,15-71).
Biodegradable in recent years macromolecular material is widely used in the preparation of protein and peptide class prolonged drug sustained-release micro-spheres; Make the sustained-release micro-spheres ejection preparation of carrier with Biodegradable material; Comply with galenic pharmacy to direction long-acting, efficient, the low toxicity development, become a focus of pharmaceutics research over 30 years.The sustained-release micro-spheres ejection preparation has the following advantages: 1. compare with the normal injection agent, long-acting injection microsphere significant prolongation dosing interval has improved the compliance of patient's medication greatly; 2. can continue to keep MEC, thereby can reduce total dosage, alleviate some side effect.Dosage like the leuprorelin microsphere can be reduced to 1/4～1/8 of dosage every day; 3. the biodegradable micro-balloon injection implantation of need not performing the operation, only intramuscular injection, carrier is biodegradable after the release, and its degradation product is absorbed by body, has overcome the inconvenience on implant uses in the past, for the patient provides a kind of good administering mode.
Polylactic acid-glycolic guanidine-acetic acid copolymer (PLGA) is the high-molecular copolymer that under the effect of catalyst, is polymerized by lactide (LA) and two kinds of monomers of Acetic acid, hydroxy-, bimol. cyclic ester (GA).PLGA has excellent biological compatibility and biological degradability; Can be degraded into lactic acid, water and carbon dioxide (Anderson JM Shive MS.Adv Drug Deliv Rev1997,28 (1): 5-24), participate in intravital metabolism in vivo; Can not cause any toxic reaction in vivo; Can be widely used in biomedical tissue engineering (Okada, H.Adv.Drug Deliver.Rev.1997,28; 43), like controlled drug delivery system, organism suture material, the fixing tissue renovation material etc. that reaches of orthopaedics.This material has been that medicinal high polymer adjuvant uses by drugs approved by FDA.Like the leuprorelin microsphere Lupron Depot of Takeda company, the octreotide microsphere Sandostatin Depot of the triptorelin microsphere Trelstar Depot of Debiopharm company and Novartis company etc.Medicine through the PLGA embedding, is processed sustained-release micro-spheres, can improve the bioavailability of medicine, reduce administration number of times and dose, alleviate patient's misery, reduce medicine to greatest extent the whole body toxic and side effects of liver, kidney particularly.
Summary of the invention
The purpose of this invention is to provide a kind of exendin-4 sustained-release micro-spheres.
The present invention also aims to provide a kind of injection that makes by said exendin-4 sustained-release micro-spheres.
The present invention also aims to provide a kind of method for preparing of exendin-4 sustained-release micro-spheres.
In order to realize the object of the invention, the present invention provides a kind of exendin-4 sustained-release micro-spheres, comprises:
(1) interior water, water comprises exendin-4 in this;
(2) seal said in the middle oil phase of water, oil phase comprises polylactic acid-glycolic guanidine-acetic acid copolymer (PLGA) in this; And
(3) seal said in the outer water of oil phase, this outer water comprises polyvinyl alcohol (PVA); The weight proportion of wherein said exendin-4, PLGA, PVA is (22-44): (1000-20000): (2000-30000).
Preferably, the weight proportion of said exendin-4, PLGA, PVA is 33: (1800-17200): (2500-20000).
Preferably, the particle diameter of said exendin-4 sustained-release micro-spheres is 40～100 μ m.
Preferably, the molecular weight of PLGA is 5000～100000 in the said middle oil phase, and wherein the mass percent of polylactic acid and polyglycolic acid is 25: 75～85: 15; More preferably, the molecular weight of said PLGA is 6000, and wherein the mass percent of polylactic acid and polyglycolic acid is 40: 60～60: 40.
Preferably, exendin-4 prepares for the method through gene recombinaton or synthetic.
The present invention also provides a kind of injection, and it is with exendin-4 sustained-release micro-spheres of the present invention, makes through the known injection method for preparing of those skilled in the art.
The present invention also provides a kind of method for preparing of exendin-4 sustained-release micro-spheres, and this method comprises the following steps:
1), makes interior aqueous phase solution with exendin-4 dissolving or to be suspended in pH be in 5 to 7 the aqueous buffer solution;
2) PLGA is dissolved in the organic solvent, makes middle oil-phase solution;
3) PVA being dissolved in pH is in 5 to 7 the aqueous buffer solution, makes outer aqueous phase solution;
4) in the middle oil-phase solution preparation colostrum (emulsifying): the interior aqueous phase solution in the step 1) is joined step 2), carry out emulsifying, make colostrum;
5) preparation emulsion (second emulsifying): the colostrum that step 4) is made joins under stirring condition in the outer aqueous phase solution in the step 3), carries out the emulsifying second time, makes emulsion;
6) solvent evaporates: make organic solvent volatilization, obtain the present invention's exendin-4 sustained-release micro-spheres that hardens.
The microsphere that makes adopts centrifuging to collect, and washs microsphere with water for injection, and lyophilizing after suspending with low amounts of water is then preserved in exsiccator.Microsphere is time spent not for a long time, need be positioned over 4 ℃ of preservations.
Preferably; In preparation in the said step 1) of aqueous phase solution; Also add in the following material one or more: the polysorbas20 of the zinc carbonate and 0.001%～1.0% (g/ml) of the trehalose, 0.5%～10% (g/ml) of the polyvinyl alcohol, 0.1%～10% (g/ml) of the glycine of 0.5%～10% (g/ml), 0.1%～10% (g/ml), to increase the stability of reorganization exendin-4 when sealing and/or discharge.
Preferably, said step 2) the PLGA molecular weight in the middle oil-phase solution in is 5000～100000, and wherein the mass percent of polylactic acid and polyglycolic acid is 25: 75～85: 15; More preferably, the molecular weight of said PLGA is 6000, and wherein the mass percent of polylactic acid and polyglycolic acid is 40: 60～60: 40.
The organic solvent of the middle oil-phase solution preferably, said step 2) is the mixed liquor of dichloromethane (DCM) or dichloromethane and ethyl acetate (EA), and wherein the volume ratio of DCM and EA is 60: 40～100: 0.
Preferably, interior aqueous phase solution in the wherein said step 1) and said step 2) in the volume ratio of middle oil-phase solution be 2～10: 100.
Preferably, the concentration of PVA is 0.1%～5% (g/ml) in the outer aqueous phase solution that makes in the said step 3).
Preferably, in the said step 3) of aqueous phase solution, also adding one or more concentration is 0～10% (g/ml) inorganic salt outside preparation, and to increase the envelop rate of reorganization exendin-4, wherein inorganic salt is preferably NaCl.
Preferably, in the step 4) of preparation colostrum, emulsification method for adopt batch (-type) ultrasonic (135W, 40KHz) method is carried out emulsifying, ultransonic total time is 1～4 minute; Or adopt alr mode emulsifying.
Preferably, in the step 5) of preparation emulsion, emulsification method is a high-speed stirred, and mixing speed is 1000～4000rpm, and emulsification times is 1～5 minute.
Preferably, in the step 6) of solvent evaporates, the method that the organic solvent volatilization is adopted is a paddling process, and wherein mixing speed is 400-600rpm, and temperature is a room temperature, and the solvent evaporates time is 3～4 hours.
The method for preparing of Exendin-4 sustained-release micro-spheres of the present invention is as shown in Figure 1.
The prepared microsphere features smooth surface of the present invention, outward appearance is even, and regular particles does not have adhesion; Mean diameter is at 40～100 μ m, and drug loading, envelop rate are high, and slow-release period is about 30 days; Biodegradable, good biocompatibility can be used for non-vein form administrations such as subcutaneous, muscle.
The standard dose scope of Exendin-4 administration is 10-20 μ g (microgram) for each person every day.Therefore; When using Exendin-4 sustained-release micro-spheres of the present invention to treat type 2 diabetes mellitus; Can be administered once weekly or per two weeks are administered once, preferred dosage is everyone weekly 1-140 μ g exendin-4, more preferably everyone weekly 10-100 μ g exendin-4.
Description of drawings
The method for preparing flow chart of Fig. 1 .Exendin-4 sustained-release micro-spheres.
The external release degree of Fig. 2 .Exendin-4 sustained-release micro-spheres cumulative release curve chart.
Fig. 3. be loaded with the stereoscan photograph of the PLGA microsphere of exendin-4.
Fig. 4. the situation of change of db/db mouse blood sugar after each test group administration.
The specific embodiment
Below through the specific embodiment description and combine accompanying drawing that the present invention is described further; But this is not to be limitation of the present invention; Those skilled in the art are according to basic thought of the present invention; Can make various modifications or improvement, but only otherwise break away from basic thought of the present invention, all within scope of the present invention.
Exendin-4 produces for self-control among the embodiment, and its preparation technology is referring to Chinese patent 200410052039.4; All the other reagent are and are purchased:
PLGA purchases the handle of the Big Dipper bio tech ltd in the Mount Tai, Jinan, lot number 20080625, molecular weight 6000;
PVA purchases in Chemical Reagent Co., Ltd., Sinopharm Group, lot number T20071227, molecular weight 1750;
NaCl purchases in Jinhuada Chemical Agent Co., Ltd., Guangzhou City, lot number 20080701;
Glycine is purchased the consor thing Science and Technology Ltd. in the source, Shanghai, lot number 20040726;
Dichloromethane is purchased the chemical reagent engineering and technological research development centre in Guangdong Province, lot number 20061107.
The mensuration that relates to particle diameter, envelop rate, drug loading among the embodiment, list of references " Tang Peifu, etc.; the preparation and the evaluation of BMP-4 2 sustained-release micro-spheres; Chinese Tissue Engineering Study and clinical rehabilitation, 2008,12 (6): 1001-1004 " in assay method.
Embodiment 1:
With 0.1ml concentration is exendin-4 solution (the 0.02M phosphate buffer of 8.25mg/ml; PH6.5) be added in the dichloromethane solution that 4.3ml concentration is 100mg/ml PLGA; Ultrasonic under condition of ice bath (135W, 40KHz) emulsifying is 2 minutes, obtains the W/O emulsion with above-mentioned mixed liquor.This emulsion drop is added to 100ml contains in the 0.02M phosphate buffer (PH6.5) of 0.5% (g/ml) PVA, stir with the rotating speed of 2000rpm and made W/O/W emulsion in 3 minutes, then with rotational speed regulation to 600rpm; Stir 3-4h under the room temperature; Remove organic solvent, microsphere solidifies the centrifugal collection in back, distilled water washing three times; Lyophilization, cryopreservation.
The thus obtained microsphere mean diameter is 56 μ m, and envelop rate is 87.5%, and drug loading is 0.67% (g/g).
Embodiment 2:
With 0.2ml concentration is exendin-4 solution (the 0.02M phosphate buffer of 8.25mg/ml; PH6.5) be added in the dichloromethane solution that 4.2ml concentration is 100mg/ml PLGA; Ultrasonic under condition of ice bath (135W, 40KHz) emulsifying is 2 minutes, obtains the W/O emulsion with above-mentioned mixed liquor.This emulsion drop is added to 100ml contains in the 0.02M phosphate buffer (pH6.5) of 0.5% (g/ml) PVA and 5% (g/ml) NaCl, stir with the rotating speed of 2000rpm and made W/O/W emulsion in 3 minutes, then with rotational speed regulation to 600rpm; Stir 3-4h under the room temperature; Remove organic solvent, microsphere solidifies the centrifugal collection in back, distilled water washing three times; Lyophilization, cryopreservation.
The thus obtained microsphere mean diameter is 58.4 μ m, and envelop rate is 85.4%, and drug loading is 0.63% (g/g).
Embodiment 3:
With 0.4ml concentration is exendin-4 solution (the 0.02M phosphate buffer that contains 3% (g/ml) glycine of 8.25mg/ml; PH6.5) be added in the dichloromethane solution that 4.0ml concentration is 100mg/mlPLGA; With above-mentioned mixed liquor ultrasonic (135W under condition of ice bath; 40KHz) emulsifying is 2 minutes, obtains the W/O emulsion.This emulsion drop is added to 100ml contains in the 0.02M phosphate buffer (PH6.5) of 0.5% (g/ml) PVA, stir with the rotating speed of 2000rpm and made W/O/W emulsion in 3 minutes, then with rotational speed regulation to 600rpm; Stir 3-4h under the room temperature; Remove organic solvent, microsphere solidifies the centrifugal collection in back, distilled water washing three times; Lyophilization, cryopreservation.
The thus obtained microsphere mean diameter is 72 μ m, and envelop rate is 78.1%, and drug loading is 0.59% (g/g).
Embodiment 4:
With 0.8ml concentration is exendin-4 solution (the 0.02M phosphate buffer that contains 3% (g/ml) glycine of 8.25mg/ml; PH6.5) be added in the dichloromethane solution that 3.6ml concentration is 100mg/mlPLGA; With above-mentioned mixed liquor ultrasonic (135W under condition of ice bath; 40KHz) emulsifying is 2 minutes, obtains the W/O emulsion.This emulsion drop is added to 100ml contains in the 0.02M phosphate buffer (pH6.5) of 0.5% (g/ml) PVA and 5% (g/ml) NaCl, stir with the rotating speed of 2000rpm and made W/O/W emulsion in 3 minutes, then with rotational speed regulation to 600rpm; Stir 3-4h under the room temperature; Remove organic solvent, microsphere solidifies the centrifugal collection in back, distilled water washing three times; Lyophilization, cryopreservation.
The thus obtained microsphere mean diameter is 80.3 μ m, and envelop rate is 72.9%, and drug loading is 0.52% (g/g).
The result of the test of above embodiment 1-4 shows that exendin-4 sustained-release micro-spheres of the present invention is along with the increase of PLGA content, and the mean diameter of microsphere reduces, and simultaneously, envelop rate and drug loading improve.
Embodiment 5:
The accurate respectively microsphere 50mg that takes by weighing embodiment 1-4 preparation, placing volume is the 5ml PA tube, and adds release medium (phosphate buffer of pH7.4) 2ml.PA tube is placed the water bath with thermostatic control oscillator; Isothermal vibration under 37 ℃ of conditions with 75rpm; Took a sample in 0,1,2,3,5,7,10,14,18,21,25,28,35 day: during sampling PA tube is taken out, centrifugal 10 minutes of 5000rpm gets supernatant 1ml as test liquid.After the sampling, discard remaining supernatant in the PA tube, add blank release medium (phosphate buffer of pH7.4) 2ml again, then PA tube is put into the water bath with thermostatic control agitator and continue concussion.Measure the concentration of exendin-4 in each time point test liquid respectively with HPLC, calculate exendin-4 cumulative release degree.Result of the test is seen table 1 and Fig. 2.
The external release degree of table 1Exendin-4 sustained-release micro-spheres result of the test
Above result of the test shows that exendin-4 sustained-release micro-spheres of the present invention can effectively delay the rate of release of exendin-4, discharges the 28th day accumulative total and reaches 90%, has the effect of long-acting slow-release; And along with the raising of the reducing of microspherulite diameter, envelop rate, rate of release slows down.
Embodiment 6:
The exendin-4 sustained-release micro-spheres of embodiment 3 preparations is placed on the metal pillar that posts double faced adhesive tape, and metal spraying is processed the scanning electron microscope BIAO and BEN, under scanning electron microscope, observes its profile, sees Fig. 3 (scale is 100 μ m).The scanning electron microscope result shows exendin-4 sustained-release micro-spheres smooth surface of the present invention, and outward appearance is even, and regular particles does not have adhesion.
The pharmacodynamic experiment of embodiment 7:Exendin-4 sustained-release micro-spheres
The exendin-4 sustained-release micro-spheres of experimental drug: embodiment 3 preparations uses the water for injection dissolving.
Laboratory animal: the db/db mice in 6 ages in week, totally 30.
Experiment is divided into groups: 30 mices are divided into 5 groups at random, that is:
Exendin-4 matched group (exendin-4 dosage 0.2 μ g/kg, be administered once every day, is called for short matched group);
PLGA microsphere group (no exendin-4 is administered once weekly, is called for short the microsphere group);
The heavy dose of group of Exendin-4 microsphere (exendin-4 dosage 4 μ g/kg, per two weeks are administered once, and are called for short heavy dose of group);
Dose groups in the Exendin-4 microsphere (exendin-4 dosage 2 μ g/kg, per two weeks are administered once, dose groups in the abbreviation);
Exendin-4 microsphere small dose group (exendin-4 dosage 1 μ g/kg, per two weeks are administered once, and are called for short small dose group).
Experimental technique: with laboratory animal at 25 ℃ of temperature, relative humidity 60%, freely drink water, raise a week at regular time and quantity the environment, subcutaneous injection administration then, fasting is 4 hours before each administration.Get mouse tail vein blood in 0h, 8h, 1d, 3d, 5d, 7d, 10d, 13d, 16d, 20d, 25d, 30d after the administration and carry out rapid blood sugar mensuration (used blood glucose meter and blood sugar test paper are Johson & Johnson and produce).
Experimental result: the result sees Fig. 4, wherein the equal obvious blood sugar lowering of exendin-4 microsphere group; Compare with matched group, exendin-4 microsphere group blood sugar lowering is slow slightly, but can reach the effect of remarkable blood sugar lowering about 8 hours, and blood glucose maintains normal level always afterwards, does not have significant difference between three dose groups; The animal blood glucose of microsphere group does not have significant change.
Claims (9)
1. exendin-4 sustained-release micro-spheres comprises:
(1) interior water, water comprises exendin-4 in this;
(2) seal said in the middle oil phase of water, to comprise molecular weight be 5000～100000 polylactic acid-glycolic guanidine-acetic acid copolymer (PLGA) to oil phase in this; And
(3) seal said in the outer water of oil phase, this outer water comprises polyvinyl alcohol (PVA);
The weight proportion of wherein said exendin-4, PLGA, PVA is (22-44): (1000-20000): (2000-30000); And the particle diameter of said exendin-4 sustained-release micro-spheres is 40～100 μ m.
2. exendin-4 sustained-release micro-spheres according to claim 1, the weight proportion of wherein said exendin-4, PLGA, PVA are 33: (1800-17200): (2500-20000).
3. exendin-4 sustained-release micro-spheres according to claim 1, the molecular weight of PLGA is 6000 in the wherein said middle oil phase.
4. according to each described exendin-4 sustained-release micro-spheres among the claim 1-3, wherein said exendin-4 prepares for the method through gene recombinaton or synthetic.
5. injection that makes by each described exendin-4 sustained-release micro-spheres in the claim 1 to 4.
6. the method for preparing of each described exendin-4 sustained-release micro-spheres in the claim 1 to 4, this method comprises the following steps:
1), makes interior aqueous phase solution with exendin-4 dissolving or to be suspended in pH be in 5 to 7 the aqueous buffer solution;
2) PLGA is dissolved in the organic solvent, makes middle oil-phase solution;
3) PVA being dissolved in pH is in 5 to 7 the aqueous buffer solution, makes outer aqueous phase solution;
4) the interior aqueous phase solution in the step 1) is joined step 2) in middle oil-phase solution in, carry out emulsifying, make colostrum;
5) colostrum that step 4) is made joins under stirring condition in the outer aqueous phase solution in the step 3), carries out the emulsifying second time, makes emulsion;
6) make the organic solvent volatilization, make sclerosis exendin-4 sustained-release micro-spheres.
7. the organic solvent method according to claim 6, wherein said step 2) is the mixed liquor of dichloromethane or dichloromethane and ethyl acetate.
8. method according to claim 6, the emulsification method in the wherein said step 4) are the batch (-type) ultrasonic method, supersonic frequency 40KHz, and ultrasonic total time is 1～4 minute.
9. method according to claim 6, the emulsification method in the wherein said step 5) are high-speed mixing method, and mixing speed is 1000～4000rpm, and emulsification times is 1～5 minute.
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| WO2017107906A1 (en) * | 2015-12-22 | 2017-06-29 | 四川科伦药物研究院有限公司 | Exenatide microsphere preparation and preparation method thereof |
| CN114867470A (en) * | 2019-11-08 | 2022-08-05 | 丸仁制药株式会社 | Microspheres for sustained release and method of making same |
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