CN101244259B - Thymus gland peptide alpha1sustained-release microsphere preparation for injection and preparation thereof - Google Patents
Thymus gland peptide alpha1sustained-release microsphere preparation for injection and preparation thereof Download PDFInfo
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Abstract
The invention provides a slow release microsphere agents, comprising thymosin Alpha 1 of 0.5% to 10% of the microsphere weight, degradable pharmaceutical macromolecular accessories with a molecular weight of 5,000 to 500,000 Dalton and of 70% to 99.5% of the macroshpere weight, and 0% to 10% of other pharmaceutically acceptable accessories. The invention also provides the preparation method of the slow release microsphere agents. The slow release microsphere agent of thymosin Alpha 1 for injection has the advantages that the poison and side effect of thymosin Alpha 1 is reduced; the bioavailability is enhanced; times for drug taking is reduced and the drug can be conveniently taken by patients.
Description
Technical field
The present invention relates to a kind of injection Thymosin alpha
1Sustained release microsphere agents belongs to drug world.
Background technology
Thymosin alpha
1(thymosin α
1, be called for short T α
1) be that a kind of polypeptide with immunologic function is used for the treatment of viral hepatitis clinically, its aminoacid sequence is
A?C-Ser-Asp-Ala-Ala-Val-Asp-Thr-Ser-Ser-Glu-Ile-Thr-Thr-Lys-Asp-Leu-lys-Glu-Lys-Lys-Glu-Val-Val-Glu-Glu-Ala-Glu-Asn_-OH
Molecular formula: C
129H
215N
33O
55-
Molecular weight: 3108.37
Existing T α
1Preparation since short treatment time of half-life the long frequent drug administration that needs, shortcoming such as the relatively poor and bioavailability of patient compliance is low.
At present about Thymosin alpha
1The report of microsphere is more, as: He Yi etc., the preparation of thymosin polylactic acid microsphere and Release Performance research, Chinese Journal of Pharmaceuticals, 2006,37 (3), disclose with emulsion-solvent evaporation method and prepared the thymosin polylactic acid microsphere, be carrier wherein, with the microsphere of emulsifying volatility process preparation with polymeric polyglycolide-polylactide (PLGA).Zou Liang etc., the preparation of thymosin gelatine microsphere and the feature of external release, the Chinese Hospitals pharmaceutical journal was rolled up for the 9th phase in 2004 the 24th, disclosed a kind of gelatine microsphere of thymosin.With the thymosin gelatine microsphere of emulsion-crosslinking method preparation, be the capsule material with medicine A type gelatin.Zhang Haisong, Chen Yangshu, Hu Jungao, etc., the research of oral thymus microsphere, China Dispensary, 1999,10 (2); 58; Number of patent application: 200310119386.X discloses the method that a kind of PLGA of utilization (poly (glycolide-lactide)) extracts, synthesizes thymosin microcapsule controlled-release pin.It is to be organic facies with PLGA, and thymosin is dissolved in the water yield water, makes the internal layer water, will restraint shell material PLGA again and be dissolved in the organic solution, makes organic facies; The internal layer water is dispersed in the organic facies, forms water-in-oil emulsion, add the outer aqueous phase that contains dispersant again, stir down and form double-deck emulsion, make water/oil/water double emulsion; Under agitation make the organic solvent volatilization at last and polymeric layer is solidified, form solid microsphere, thymosin is wrapped in the microsphere.Zhu Yan etc., Thymosin alpha under the microball preparation condition
1Estimation of stability, the The 2nd Army Medical College journal, 2005,26 (5), reported Thymosin alpha under the capsule ball preparation process condition
1Stability.Adopt HPLC, the research Thymosin alpha
1At different temperatures (20 ℃, 6-8 ℃, 60 ℃), the stability under different ultrasonic time (10-60s) and different pH value (4.0,7.0, the 10.0) condition.Zhu Yan etc., Thymosin alpha
1The preparation of microsphere and evaluation thereof, pharmaceutical services and research, 2005,5 (3), Thymosin alpha is disclosed
1The preparation of microsphere and evaluation methodology.Be carrier material wherein, adopt multi-emulsion method (w/o/w) preparation Thymosin alpha with polylactic acid-glycollic acid block copolymer (PLGA)
1Long-acting injection microsphere is investigated its size, physicochemical properties such as outward appearance, envelop rate; Adopt the RP-HPLC method to measure Thymosin alpha in the microsphere
1Content.
Thymosin alpha
1Crude drug is expensive, and the price of 1g is about 8000 yuans.At Thymosin alpha
1Under the lower situation of microsphere envelop rate, a large amount of Thymosin alphas
1Be dissolved in the water, cause the huge waste and the raising of cost; So this moment, an important indicator of microsphere technique for packing is high envelop rate.
Thymosin alpha
1Half-life short, need frequent administration, it is 1～3 month long-acting slow-release preparation that above-mentioned technology discloses various complete release times, can satisfy part patient's needs, makes treatment convenient.But because the complexity and the variation of disease usually various demand can occur clinically.As: the patient in the ICU (intensive care unit) usually needs to use Thymosin alpha
1Treatment Deng immunostimulant; But because a large amount of uses of antibiotic etc, part patient very likely allergy such as allergy, erythra can occur, re-uses Thymosin alpha this moment
1To be unfavorable for the further treatment of patient disease Deng immunostimulant; Especially when these allergy be when being difficult to tolerate, except using Claritin, need stop the immunostimulant Thymosin alpha
1Immunity rise effect.And for example: using Thymosin alpha
1Deng the patient of immunostimulant, unpredictable when strong inflammatory reaction having occurred, be subjected to serious damage for preventing organ and tissue, the function of armour and tissue needs to suppress the propagation and the differentiation of immunocyte; If accepted 3 months long-acting thymulin α of lasting release before the patient
1The treatment of microball preparation, the process that will be difficult to control inflammation reaction this moment, patient's histoorgan might be subjected to irreversible damage.For another example: the patient of infective virus herpes only needs to use one month sometimes with the interior immunostimulant adjusting time.Therefore, a kind of release time is suitable, discharges 10～15 days as continuing, perhaps 10～25 days Thymosin alpha
1Microsphere sustained-release preparation has huge demand space clinically.
Common Thymosin alpha through the PLGA preparation
1Microsphere, be 1～3 month (seeing above-mentioned document) its release time, the PLGA viscosity of this moment is bigger.If will realize 10～15 days or 10～25 shorter releasing effect, need to reduce the viscosity of PLGA, but the reduction of viscosity must be followed the reduction of envelop rate, a large amount of expensive Thymosin alphas
1To run off in water, cause the huge waste and the rising of cost.The Thymosin alpha that to seal through PLGA how
1Microsphere is controlled in 10～25 days the shorter relatively scope release time, keeps high envelop rate simultaneously again, saves manufacturing cost, and is the clinical slow release Thymosin alpha that variation is provided, is badly in need of
1Preparation satisfies the demand of medium slow-release time, is that vast pharmacy work person wishes the difficult problem that solves always.
Summary of the invention
Technical scheme of the present invention provided a kind of can be even, stable in 10～20, discharge Thymosin alpha completely
1Sustained release microsphere agents, another technical scheme of the present invention has provided Thymosin alpha
1The preparation method of sustained release microsphere agents.
The invention provides a kind of injection Thymosin alpha
1Sustained release microsphere agents, it is 0.5%～10% a Thymosin alpha by microsphere weight
1With 70%～99.5% degradable molecular weight of microsphere weight be the preparation that 5,000～500,000 daltonian medicinal high polymer adjuvant and 0%～10% other acceptable accessories that accounts for microsphere weight are prepared from.
Wherein, medicinal high polymer adjuvant is selected from one or more the mixture in polymeric polyglycolide-polylactide, gelatin, polylactic acid, polylactic acid-glycollic acid, polyglycolic acid, polyvinyl alcohol, Polyethylene Glycol, hydroxyacetic acid, polylactic acid-polyglycol, the poly butyric ester-hydroxyl pentanoate copolymer.
Wherein, medicinal high polymer adjuvant is selected from one or more the mixture in polymeric polyglycolide-polylactide, polylactic acid, polyvinyl alcohol, Polyethylene Glycol, hydroxyacetic acid, poly butyric ester-hydroxyl pentanoate copolymer, the polylactic acid-polyglycol.
Further preferably, the molecular weight of described medicinal high polymer adjuvant is 10,000～400,000 dalton, and weight percentage is: 78%～99.5%.
Still more preferably, the molecular weight of described medicinal high polymer adjuvant is 10,000～300,000 dalton.
Wherein, medicinal high polymer adjuvant is selected from polymeric polyglycolide-polylactide, and described polymeric polyglycolide-polylactide molecular weight is 5,000～500,000 dalton, and Acetic acid, hydroxy-, bimol. cyclic ester and lactide ratio are 50: 50, and the intrinsic viscosity scope is 0.15dl/g～0.90dl/g.
Polymeric polyglycolide-polylactide is because nontoxic, safe and good physicochemical properties are widely used in the preparation of medicine microspheres; Through the microsphere of its parcel preparation, be 1～3 month the release time of lot of documents report, belongs to long-acting delivery formulations.PLGA is a polymer substance, the molecular weight that its particular viscosity is corresponding specific; Those skilled in the art can inquire about the synopsis of viscosity and molecular weight very easily.
Wherein, described medicinal high polymer adjuvant polymeric polyglycolide-polylactide molecular weight is 10,000～400,000 dalton, and Acetic acid, hydroxy-, bimol. cyclic ester and lactide ratio are 50: 50, and the intrinsic viscosity scope is 0.30dl/g～0.90dl/g.
Described polymeric polyglycolide-polylactide is that the polymeric polyglycolide-polylactide by two kinds of different viscosities mixes the back and uses, and weight ratio low, full-bodied polymeric polyglycolide-polylactide is 1: 0.5～3.Wherein, described low viscosity is " 0.3～0.65dl/g, high viscosity is 0.5～0.9dl/g ".During each the use, all select the PLGA of two kinds of different viscosities for use, when inferior viscosity high be called high viscosity PLGA, when inferior viscosity low be called the low viscosity polymeric polyglycolide-polylactide.
Further preferably, low, full-bodied polymeric polyglycolide-polylactide weight ratio is 1: 1～2.Described intrinsic viscosity scope is 0.30dl/g～0.90dl/g.Described low high viscosity polymeric polyglycolide-polylactide weight ratio is 1: 1,1: 1.5,1: 2,1: 1.8,1: 1.7.
Sustained-release micro-spheres of the present invention is by 1.5% Thymosin alpha 1 of total inventory, accounts for the PEG-6000 of total inventory 2.4% and account for 95.9% the polymeric polyglycolide-polylactide of always feeding intake (0.65dl/g: 0.89dl/g=1: 1.7) the preparation w/o microsphere that feeds intake respectively, concentration at PVA is 2% again, and the concentration of NaCl is the microsphere that w/o/w is finished in preparation in 2% the aqueous solution.
Wherein, the particle diameter of described sustained-release micro-spheres is 1～200 μ m mean diameter, 20～150 μ m.Preferable particle size is 1～150 μ m mean diameter, 32.5～86.3 μ m.
Described preparation is subcutaneous injection or intramuscular injectable formulations.
Wherein, described preparation is the subcutaneous injection preparation.
The present invention also provides a kind of preparation injection Thymosin alpha
1The method of sustained release microsphere agents comprises the steps:
The first step at first is dissolved into oil phase with organic solvent with degradable adjuvant, will be dissolved with Thymosin alpha in addition then
1Interior water add wherein, with oil phase and water put with agitator in, changeed high-speed stirred 5～8 minutes with per minute 2000～3000, form the w/o emulsion, the outer aqueous phase of PVA that afterwards the w/o emulsion droplets is joined 0-8 ℃ ice bath 1%--5% forms the W/O/W emulsion and stirred 3-5 minute;
Second step will add the PVA contain 1-5% again, contain 1～5%NaCl aqueous solution in the above-mentioned gained W/O/W emulsion, organic solvent volatilizees under the stirring at low speed that per minute 400-700 changes; After microsphere solidifies, filter, filter bulky grain, sucking filtration, wash, be drying to obtain microsphere.
The organic solvent that wherein forms organic facies is for having enough volatility, lower boiling organic solvent, for example can be selected from a kind of in dichloromethane, chloroform, ethyl acetate, ether, acetone, the ethanol or two or more mixture wherein.The concentration of above-mentioned degradable adjuvant in organic solvent is preferably 10～1000mg/ml.
Interior water is made Thymosin alpha with the dissolving of aqueous solutions such as gelatin, mannitol, Polyethylene Glycol
1Aqueous solution, make Thymosin alpha
1Concentration at water reaches 10～500mg/ml.
Outer water adopts one or both in polyvinyl alcohol, polyvinylpyrrolidone, sodium polymethacrylate, the sodium-chloride water solution, and concentration is 0.5%～15% (w/v).
The present invention also provides a kind of detection injection Thymosin alpha
1The catabolite of sustained-release micro-spheres and the method for content adopt high performance liquid chromatography, and its chromatographic condition is chromatographic column C18 (300
, 4.6 * 250mm) mobile phases are PH7.0 phosphate buffered solution-isopropyl alcohol (volume ratios 95: 5), detect wavelength 215nm sampling volume 20 μ l.
The injection Thymosin alpha of formulation and technology preparation of the present invention
1Microsphere is the white powder of good fluidity, and mean diameter is about 20～100 μ m, and span is medicine between 0.1～2.0, envelop rate＞and more than 85%, prominent degree＜20% of releasing.
For with Thymosin alpha of the present invention
1Slow release microphere for injection make the finished product injection, after making microsphere, also should give sterilization, Thymosin alpha of the present invention
1Sustained-release micro-spheres can adopt the sterile working sterilizing methods and
60Co gamma-rays radioactive source carries out the radiation sterilization method, the sterilizing methods of preferred sterile working.
Injection Thymosin alpha of the present invention
1Sustained-release micro-spheres be that the microsphere sterilized powder that will prepare is at 0.1～1.0% aseptic sodium carboxymethyl cellulose, 1.0～5.0 mannitol, 0.01 suspendible in～0.05 Tween-80 solution, evenly after subcutaneous or intramuscular administration, be administered once in per 10 days, be administered once in per 15 days, be administered once in per 30 days.
Thymosin alpha of the present invention
1Sustained release microsphere agents is preferably sealed with polymeric polyglycolide-polylactide, provides a kind of important selection for satisfying clinical demand; Thymosin alpha according to the preparation of the technology of the present invention content
1Microsphere has the envelop rate height, discharges stable, uniform characteristics.Can reduce Thymosin alpha
1Toxic and side effects, improve bioavailability, reduce administration number of times simultaneously, make things convenient for patient's medication.By a large amount of evidences, fully utilize the characteristic of the polymeric polyglycolide-polylactide of two or more viscosity according to specific ratio, reached that a kind of prominent to release rate low, envelop rate is more than 90%, Thymosin alpha 1 steadily discharged microball preparation completely in 10-25 days, be Thymosin alpha
1Clinical practice a kind of new selection is provided.
Obviously, according to foregoing of the present invention,,, can also make modification, replacement or the change of other various ways not breaking away under the above-mentioned basic fundamental thought of the present invention prerequisite according to the ordinary skill and the customary means of this area.
The specific embodiment of form is described in further detail foregoing of the present invention again by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example, all technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Figure of description
Fig. 1: embodiment 1 made slow release microphere for injection sample sem photograph
Fig. 2: the embodiment 1 made slow release microphere for injection sample release in vitro line chart of writing music
Fig. 3: the embodiment 2 made slow release microphere for injection sample release in vitro line chart of writing music
Fig. 4: the embodiment 3 made slow release microphere for injection sample release in vitro line chart of writing music
Fig. 5: the embodiment 4 made slow release microphere for injection sample release in vitro line chart of writing music
Fig. 6: the embodiment 5 made slow release microphere for injection sample release in vitro line chart of writing music
Fig. 7: the embodiment 6 made slow release microphere for injection sample release in vitro line chart of writing music
Fig. 8: the embodiment 7 made slow release microphere for injection sample release in vitro line chart of writing music
Fig. 9: the embodiment 8 made slow release microphere for injection sample release in vitro line chart of writing music
Figure 10: the release in vitro curve chart that adopts the polymeric polyglycolide-polylactide microsphere sample of single (0.30dl/g) viscosity
The specific embodiment
Further specify injection Thymosin alpha of the present invention by following examples and experimental example
1The preparation method of sustained-release micro-spheres, particle diameter control, prominent mensuration (the envelop rate %=practical measurement T α that releases situation, slow release effect, reaches microsphere drug loading and envelop rate
1Amount ÷ T α
1Inventory * 100%).Wherein, the polymeric polyglycolide-polylactide intrinsic viscosity is as in " 0.45dl/g: 0.89dl/g=2: 3 ", 2: 3 expression weight ratios.All describe among the embodiment by this literary style.
The microsphere drug loading among the embodiment and the mensuration of envelop rate
Test method: precision takes by weighing the microsphere 12mg of preparation in the tool plug centrifuge tube of 10ml, add dichloromethane 0.5ml, the vortex dissolving, the 3 minutes centrifugal 10min of 2000r/m of buffer vortex extraction that add the PH7.4 of 2.5ml again collect whole supernatant, adding the 2.5ml buffer to centrifuge tube again operates with method, merge twice supernatant, sample introduction HPLC 20 μ l. calculate medicament contg and envelop rate.
High performance liquid chromatography: its chromatographic condition is chromatographic column C18 (300
, 4.6 * 250mm) mobile phases are PH7.0 phosphate buffered solution-isopropyl alcohol (volume ratios 95: 5), detect wavelength 215nm sampling volume 20 μ l.All the other carry out routinely.
The mensuration of microspherulite diameter:
Test specimen: the microsphere for preparing among the embodiment
Test apparatus: M α stersizer2000
Test method: the exsiccant microsphere powder that will prepare disperses with the distilled water of 1000ml, measures with M α stersizer2000, gets particle size distribution.
The Acetic acid, hydroxy-, bimol. cyclic ester of polymeric polyglycolide-polylactide and lactide ratio are selected test in the sustained-release micro-spheres adjuvant of the present invention:
Commercially available polymeric polyglycolide-polylactide PLGA has: PLGA (50: 50), PLGA (65: 35), PLGA (75: 25), PLGA (85: 15), and degradation time:
| The PLGA ratio | 50∶50 | 65∶35 | 75∶25 | 85∶15 |
| Degradation time (my god) | 30～60 | 90～120 | 120～150 | 150～180 |
The preferred PLGA of the present invention is: PLGA (50: 50).
Below by specific embodiment explanation in the above-mentioned range of choice, all can reach beneficial effect of the present invention.
Embodiment 1: the injection Thymosin alpha of emulsion-liquid drying method preparation
1Sustained-release micro-spheres
Thymosin alpha with 100mg
10.7g PEG-6000 be dissolved in the phosphate buffer of PH7.4 of 6ml, 3) and be dissolved in the 130ml dichloromethane polymeric polyglycolide-polylactide of 6g (Acetic acid, hydroxy-, bimol. cyclic ester: (intrinsic viscosity 0.45dl/g: 0.55dl/g=2: lactide=50: 50), under high shear dispersing emulsification machine rotating speed 2000r/m effect, water is poured in the oil phase, emulsifying 5-8min gets the w/o emulsion under the 2500r/m rotating speed, the w/o emulsion is poured into 1000ml ice bath contain 2%PVA, mixing speed 700r/m in the outer aqueous phase solution of 1%NaCl, time 2-3 minute, the outer aqueous phase solution that adds 1500ml again, mixing speed 550r/m stirred 4 hours, volatilize organic solvent, sucking filtration is used distilled water wash 3 times, lyophilization 4 days, get mobile white powder preferably, envelop rate 92.1%, microspherulite diameter 1～120 μ m microsphere average grain diameter 36.4 μ m, outward appearance rounding.
Embodiment 2: emulsion-liquid drying method prepares the injection Thymosin alpha
1Sustained-release micro-spheres
Thymosin alpha with 100mg
11.5g mannitol be dissolved in the phosphate buffer of PH7.4 of 6ml, the polymeric polyglycolide-polylactide of 6g (Acetic acid, hydroxy-, bimol. cyclic ester: lactide=50: 50, intrinsic viscosity 0.35dl/g: 0.89dl/g=1: 3) be dissolved in the 130ml dichloromethane, under high shear dispersing emulsification machine rotating speed 2000r/m effect, water is poured in the oil phase, emulsifying 5-8min gets the w/o emulsion under the 2500r/m rotating speed, the w/o emulsion is poured into 1000ml ice bath contain 2%PVA, mixing speed 700r/m in the outer aqueous phase solution of 1%NaCl, time 2-3 minute, the outer aqueous phase solution that adds 1500ml again, mixing speed 550r/m mixing time 4 hours volatilizes organic solvent, sucking filtration, with distilled water wash 3 times, lyophilization, mobile white powder preferably, envelop rate 90.2%, microspherulite diameter 1～104 μ m, microsphere average grain diameter 32.5 μ m, outward appearance rounding.
Embodiment 3: emulsion-liquid drying method prepares the injection Thymosin alpha
1Sustained-release micro-spheres
Thymosin alpha with 500mg
1Be dissolved in the phosphate buffer of PH7.4 of 20ml, the polymeric polyglycolide-polylactide of 33g (Acetic acid, hydroxy-, bimol. cyclic ester: lactide=50: 50, intrinsic viscosity 0.65dl/g: 0.80dl/g=1: 1) and PEG-60003g be dissolved in the 600ml dichloromethane, under high shear dispersing emulsification machine rotating speed 2000r/m effect, water is poured in the oil phase, emulsifying 5-8min gets the w/o emulsion under the 2500r/m rotating speed, the w/o emulsion is poured into 4000ml ice bath contain 2%PVA, mixing speed 700r/m in the outer aqueous phase solution of 1%NaCl, time 2-3 minute, the outer aqueous phase solution that adds 1000ml again, mixing speed 550r/m mixing time 5 hours volatilizes organic solvent, sucking filtration, with distilled water wash 3 times, lyophilization, mobile white powder preferably, envelop rate 92.6%, microspherulite diameter 1～120 μ m, microsphere average grain diameter 86.3, outward appearance rounding.
Embodiment 4: emulsion-liquid drying method prepares the injection Thymosin alpha
1Sustained-release micro-spheres
Thymosin alpha with 500mg
1The mannitol of 5g is dissolved in the phosphate buffer of PH7.4 of 21ml, 32.5g polymeric polyglycolide-polylactide (Acetic acid, hydroxy-, bimol. cyclic ester: lactide=50: 50, intrinsic viscosity 0.65dl/g: 0.80dl/g=1: 2) be dissolved in the 300ml dichloromethane, under high shear dispersing emulsification machine rotating speed 2000r/m effect, water is poured in the oil phase, emulsifying 5min gets the w/o emulsion under the 2500r/m rotating speed, the w/o emulsion is poured into 2500ml ice bath contain 2%PVA, mixing speed 700r/m in the outer aqueous phase solution of 1%NaCl, time 2-3 minute, the outer aqueous phase solution that adds 2000ml again, mixing speed 550r/m mixing time 4 hours volatilizes organic solvent, sucking filtration, with distilled water wash 3 times, lyophilization, mobile white powder preferably, envelop rate 93.2%, microspherulite diameter 1-126 μ m, microsphere average grain diameter 67.8 μ m, outward appearance rounding.
Embodiment 5: emulsion-liquid drying method prepares the injection Thymosin alpha
1Sustained-release micro-spheres
Thymosin alpha with 100mg
1Be dissolved in the water of 6ml, the polymeric polyglycolide-polylactide of 10g (Acetic acid, hydroxy-, bimol. cyclic ester: lactide=50: 50, intrinsic viscosity 0.65dl/g: 0.89dl/g=1: 1.8) and PEG-6000 3g be dissolved in the 120ml dichloromethane, under high shear dispersing emulsification machine rotating speed 2000r/m effect, water is poured in the oil phase, emulsifying 5min gets the w/o emulsion under the 2500r/m rotating speed, the w/o emulsion is poured into 3500ml ice bath contain 2%PVA, mixing speed 700r/m in the outer aqueous phase solution of 2%NaCl, time 2-3 minute, the outer aqueous phase solution that adds 1000ml again, mixing speed 550r/m mixing time 4 hours volatilizes organic solvent, sucking filtration, with distilled water wash 3 times, lyophilization, mobile white powder preferably, envelop rate 94.7%, microspherulite diameter 1-150 μ m, microsphere average grain diameter 55.4 μ m, outward appearance rounding.
Embodiment 6: emulsion-liquid drying method prepares the injection Thymosin alpha
1Sustained-release micro-spheres
Thymosin alpha with 100mg
1Be dissolved in the phosphate buffer of PH7.4 of 6ml, 10.5g polymeric polyglycolide-polylactide (Acetic acid, hydroxy-, bimol. cyclic ester: lactide=50: 50, intrinsic viscosity 0.65dl/g: 0.89dl/g=1: 0.5) and PEG-6000 3.2g be dissolved in the 120ml dichloromethane, under high shear dispersing emulsification machine rotating speed 2000r/m effect, water is poured in the oil phase, emulsifying 5min gets the w/o emulsion under the 2500r/m rotating speed, the w/o emulsion is poured into 3500ml ice bath contain 2%PVA, mixing speed 700r/m in the outer aqueous phase solution of 1.5%Nacl, time 2-3 minute, the outer aqueous phase solution that adds 1000ml again, mixing speed 550r/m mixing time 4 hours volatilizes organic solvent, sucking filtration, with distilled water wash 3 times, lyophilization, mobile white powder preferably, envelop rate 91.2%, microspherulite diameter 1-150 μ m, microsphere average grain diameter 62.3 μ m, outward appearance rounding.
Embodiment 7: emulsion-liquid drying method prepares the injection Thymosin alpha
1Sustained-release micro-spheres
Thymosin alpha with 1.55g
1Be dissolved in the phosphate buffer of PH7.4 of 57ml, the polymeric polyglycolide-polylactide of 90g (Acetic acid, hydroxy-, bimol. cyclic ester: lactide=50: 50, intrinsic viscosity 0.65dl/g: 0.89dl/g=1: 1.7) and PEG-6000 2.25g be dissolved in the 700ml dichloromethane, under high shear dispersing emulsification machine rotating speed 3500r/m effect, water is poured in the oil phase, emulsifying 8min gets the w/o emulsion under the 3500r/m rotating speed, the w/o emulsion is poured into 10l ice bath contain 2%PVA, mixing speed 700r/m in the outer aqueous phase solution of 2%NaCl, time 2-3 minute, the outer aqueous phase solution that adds 1000ml again, mixing speed 700r/m mixing time 4 hours volatilizes organic solvent, sucking filtration, with distilled water wash 3 times, lyophilization, mobile white powder preferably, envelop rate 98.6%, microspherulite diameter 1-150 μ m, microsphere average grain diameter 76.3 μ m, outward appearance rounding.
Embodiment 8: emulsion-liquid drying method prepares the injection Thymosin alpha
1Sustained-release micro-spheres
Thymosin alpha with 200mg
1Be dissolved in the phosphate buffer of PH7.4 of 12ml, the polymeric polyglycolide-polylactide of 12g (Acetic acid, hydroxy-, bimol. cyclic ester: lactide=50: 50, intrinsic viscosity 0.65dl/g: 0.90dl/g=2: 3) and PEG-60000.3g be dissolved in the 102ml dichloromethane, under high shear dispersing emulsification machine rotating speed 2500r/m effect, water is poured in the oil phase, emulsifying 5min gets the w/o emulsion under the 2500r/m rotating speed, the w/o emulsion is poured into 3500ml ice bath contain 2%PVA, mixing speed 700r/m in the outer aqueous phase solution of 2%NaCl, time 2-3 minute, the outer aqueous phase solution that adds 1000ml again, mixing speed 550r/m mixing time 4 hours volatilizes organic solvent, sucking filtration, with distilled water wash 3 times, lyophilization, mobile white powder preferably, envelop rate 96.2%, microspherulite diameter 1-150 μ m, microsphere average grain diameter 48.3 μ m, outward appearance rounding.
The inventor finds through a large amount of screening tests and to mean diameter, envelop rate, the prominent range analysis of releasing influence: the ratio of the concentration of interior water Thymosin alpha 1, the concentration of PLGA, mixing speed, emulsion strength, NaCl concentration and inside and outside water thereof has decisive influence to envelop rate, microsphere roundness, microspherulite diameter size and release.
When adopting preferred adjuvant of the present invention and technological process to prepare microsphere, can realize 10～25 days lasting releasing effect.
Below by release in vitro degree evidence beneficial effect of the present invention.
Test example 1: injection Thymosin alpha
1The test of the external release of sustained-release micro-spheres.
Test specimen: according to the sample of the embodiment of the invention 1 described method preparation.
Test reagent: the phosphate buffer that contains 0.2% Tween 80 PH7.4
Test apparatus: constant temperature water bath agitator, centrifuge.
Experimental condition: temperature: 37 ℃ ± 0.5 ℃
Test method: precision takes by weighing the tool plug centrifuge tube that the about 12mg of laboratory sample places 10ml, adds 5ml release medium (phosphate buffer that contains 0.2% Tween 80 PH7.4), places the constant temperature water bath agitator to keep certain temperature to take a sample on time.
Sampling method: centrifugal, abandon or adopt supernatant, dry 48h, press the content that content assaying method is measured remaining solid.(0.5h directly measures T α in the aqueous solution
1Content)
Sample time: 0.5h, 1d, 3d, 5d, 7d, 10d
Result of the test: microspheres prepared release in vitro degree 0.5h release of the present invention is 8.9%, 10 day cumulative release 94.5%, and release in vitro degree figure sees Fig. 2.Attached in addition: the slow release microphere for injection sample sem photograph of embodiment 1 preparation, see Fig. 1.
Test example 2: Thymosin alpha
1Slow release microphere for injection release in vitro degree test.
Test specimen: according to the sample of the embodiment of the invention 2 described method preparations.
Test reagent: the phosphate buffer that contains 0.2% Tween 80 PH7.4
Test apparatus: constant temperature water bath agitator, centrifuge.
Experimental condition: temperature: 37 ℃ ± 0.5 ℃
Test method: precision takes by weighing the tool plug centrifuge tube that the about 12mg of laboratory sample places 10ml, adds 5ml release medium (phosphate buffer that contains 0.2% Tween 80 PH7.4), places the constant temperature water bath agitator to keep certain temperature to take a sample on time.
Sampling method: centrifugal, abandon or adopt supernatant, dry 48h, press the content that content assaying method is measured remaining solid.(0.5h directly measures T α in the aqueous solution
1Content) sample time: 0.5h, 1d, 3d, 5d, 7d, 10d.
Result of the test: microspheres prepared release in vitro degree 0.5h release of the present invention is 12.6%, 10 day cumulative release 96.3%, and release in vitro degree figure sees Fig. 3.
Test example 3: Thymosin alpha
1Slow release microphere for injection release in vitro degree test.
Test specimen: according to the sample of the embodiment of the invention 3 described method preparations.
Test reagent: the phosphate buffer that contains 0.2% Tween 80 PH7.4
Test apparatus: constant temperature water bath agitator, centrifuge.
Experimental condition: temperature: 37 ℃ ± 0.5 ℃
Test method: precision takes by weighing the tool plug centrifuge tube that the about 12mg of laboratory sample places 10ml, adds 5ml release medium (phosphate buffer that contains 0.2% Tween 80 PH7.4), places the constant temperature water bath agitator to keep certain temperature to take a sample on time.
Sampling method: centrifugal, abandon or adopt supernatant, dry 48h, press the content that content assaying method is measured remaining solid.(0.5h directly measures T α in the aqueous solution
1Content)
Sample time: 0.5h, 1d, 3d, 5d, 7d, 10d
Result of the test: microspheres prepared release in vitro degree 0.5h release of the present invention is 6.8%, 10 day cumulative release 97.9%, and release in vitro degree figure sees Fig. 4.
Test example 4: Thymosin alpha
1Slow release microphere for injection release in vitro degree test.
Test specimen: according to the sample of the embodiment of the invention 4 described method preparations.
Test reagent: the phosphate buffer that contains 0.2% Tween 80 PH7.4
Test apparatus: constant temperature water bath agitator, centrifuge.
Experimental condition: temperature: 37 ℃ ± 0.5 ℃
Test method: precision takes by weighing the tool plug centrifuge tube that the about 12mg of laboratory sample places 10ml, adds 5ml release medium (phosphate buffer that contains 0.2% Tween 80 PH7.4), places the constant temperature water bath agitator to keep certain temperature to take a sample on time.
Sampling method: centrifugal, abandon or adopt supernatant, dry 48h, press the content that content assaying method is measured remaining solid.(0.5h directly measures T α in the aqueous solution
1Content)
Sample time: 0.5h, 1d, 3d, 5d, 7d, 10d
Result of the test: microspheres prepared release in vitro degree 0.5h release of the present invention is 5.6%, 10 day cumulative release 95.8%, and release in vitro degree figure sees Fig. 5.
Test example 5: Thymosin alpha
1Slow release microphere for injection release in vitro degree test.
Test specimen: according to the sample of the embodiment of the invention 5 described method preparations.
Test reagent: the phosphate buffer that contains 0.2% Tween 80 PH7.4
Test apparatus: constant temperature water bath agitator, centrifuge.
Experimental condition: temperature: 37 ℃ ± 0.5 ℃
Test method: precision takes by weighing the tool plug centrifuge tube that the about 12mg of laboratory sample places 10ml, adds 5ml release medium (phosphate buffer that contains 0.2% Tween 80 PH7.4), places the constant temperature water bath agitator to keep certain temperature to take a sample on time.
Sampling method: centrifugal, abandon or adopt supernatant, dry 48h, press the content that content assaying method is measured remaining solid.(0.5h directly measures T α in the aqueous solution
1Content)
Sample time: 0.5h, 1d, 5d, 7d, 10d, 15d
Result of the test: microspheres prepared release in vitro degree 0.5h release of the present invention is 3.2%, 15 day cumulative release 95.5%, and release in vitro degree figure sees Fig. 6.
Test example 6: Thymosin alpha
1Slow release microphere for injection release in vitro degree test.
Test specimen: according to the sample of the embodiment of the invention 6 described method preparations.
Test reagent: the phosphate buffer that contains 0.2% Tween 80 PH7.4
Test apparatus: constant temperature water bath agitator, centrifuge.
Experimental condition: temperature: 37 ℃ ± 0.5 ℃
Test method: precision takes by weighing the tool plug centrifuge tube that the about 12mg of laboratory sample places 10ml, adds 5ml release medium (phosphate buffer that contains 0.2% Tween 80 PH7.4), places the constant temperature water bath agitator to keep certain temperature to take a sample on time.
Sampling method: centrifugal, abandon or adopt supernatant, dry 48h, press the content that content assaying method is measured remaining solid.(0.5h directly measures T α in the aqueous solution
1Content)
Sample time 0.5h, 1d, 5d, 7d, 10d, 15d
Result of the test: microspheres prepared release in vitro degree 0.5h release of the present invention is 8.9%, 15 day cumulative release 94.5%, and release in vitro degree figure sees Fig. 7.
Test example 7: Thymosin alpha
1Slow release microphere for injection release in vitro degree test.
Test specimen: according to the sample of the embodiment of the invention 7 described method preparations.
Test reagent: the phosphate buffer that contains 0.2% Tween 80 PH7.4
Test apparatus: constant temperature water bath agitator, centrifuge.
Experimental condition: temperature: 37 ℃ ± 0.5 ℃
Test method: precision takes by weighing the tool plug centrifuge tube that the about 12mg of laboratory sample places 10ml, adds 5ml release medium (phosphate buffer that contains 0.2% Tween 80 PH7.4), places the constant temperature water bath agitator to keep certain temperature to take a sample on time.
Sampling method: centrifugal, abandon or adopt supernatant, dry 48h, press the content that content assaying method is measured remaining solid.(0.5h directly measures T α in the aqueous solution
1Content)
Sample time 0.5h, 1d, 5d, 10d, 15d, 21d
Result of the test: microspheres prepared release in vitro degree 0.5h release of the present invention is 4.5%, 21 day cumulative release 97.1%, and release in vitro degree figure sees Fig. 8.
Test example 8: Thymosin alpha
1Slow release microphere for injection release in vitro degree test.
Test specimen: according to the sample of the embodiment of the invention 8 described method preparations.
Test reagent: the phosphate buffer that contains 0.2% Tween 80 PH7.4
Test apparatus: constant temperature water bath agitator, centrifuge.
Experimental condition: temperature: 37 ℃ ± 0.5 ℃
Test method: precision takes by weighing the tool plug centrifuge tube that the about 12mg of laboratory sample places 10ml, adds 5ml release medium (phosphate buffer that contains 0.2% Tween 80 PH7.4), places the constant temperature water bath agitator to keep certain temperature to take a sample on time.
Sampling method: centrifugal, abandon or adopt supernatant, dry 48h, press the content that content assaying method is measured remaining solid.(0.5h directly measures T α in the aqueous solution
1Content)
Sample time 0.5h, 1d, 5d, 10d, 15d, 21d
Result of the test: microspheres prepared release in vitro degree 0.5h release of the present invention is 6.1%, 21 day cumulative release 96.8%, and release in vitro degree figure sees Fig. 9.
Test example 9 stable contrast tests
A, the single low viscous PLGA of employing prepare microsphere:
The Thymosin alpha 1 of 100mg is dissolved in the water of 6.25ml, (Acetic acid, hydroxy-, bimol. cyclic ester: lactide=50: 50) (intrinsic viscosity 0.30dl/g) and 0.3g mannitol are dissolved in the 110ml dichloromethane polymeric polyglycolide-polylactide of 8g, under high shear dispersing emulsification machine rotating speed 2000r/m effect, water is poured in the oil phase, emulsifying 5-8min gets the w/o emulsion under the 2500r/m rotating speed, the w/o emulsion is poured into the 2%PVA of the ice bath of 15ml, mixing speed 500r/m in the outer aqueous phase solution of 2%NaCl, time 2-3 minute, the outer aqueous phase solution that adds 1500ml again, mixing speed 550r/m stirred 4 hours, volatilize organic solvent, sucking filtration, with distilled water wash 3 times, lyophilization 4 days gets mobile white powder preferably.Envelop rate 59.8% as a result, and envelop rate is not high to cause great waste, and release reached 60% in 1 day, and be 10 days release time fully.Dashing forward, it is serious to release phenomenon.See Figure 10.
B, test example two: adopt single full-bodied PLGA to prepare microsphere
The Thymosin alpha 1 of 100mg is dissolved in the water of 6.25ml, (Acetic acid, hydroxy-, bimol. cyclic ester: lactide=50: 50) (intrinsic viscosity 0.89dl/g) and 0.3g mannitol are dissolved in the 110ml dichloromethane polymeric polyglycolide-polylactide of 8g, under high shear dispersing emulsification machine rotating speed 2000r/m effect, water is poured in the oil phase, emulsifying 5-8min gets the w/o emulsion under the 2500r/m rotating speed, the w/o emulsion is poured into the 2%PVA of the ice bath of 15ml, mixing speed 700r/m in the outer aqueous phase solution of 1%NaCl, time 2-3 minute, the outer aqueous phase solution that adds 1500ml again, mixing speed 550r/m stirred 4 hours, volatilize organic solvent, sucking filtration, with distilled water wash 3 times, lyophilization 4 days gets mobile white powder preferably.The result: envelop rate 67.3%, envelop rate be not high to cause great waste and release time long.
According to the experimental technique that provides herein, under the equal conditions, the experimental result of release time and envelop rate is as shown in the table when adopting single viscosity polymeric polyglycolide-polylactide:
| PLGA viscosity (dl/g) | 0.25 | 0.30 | 0.55 | 0.80 | 0.95 |
| Envelop rate % | 55 | 62 | 65 | 85 | 86 |
| Release time (my god) | 10 | 10 | 12 | 30 | 40 |
Above-mentioned test as can be known, the polymeric polyglycolide-polylactide of single employing viscosity higher can realize improving the microsphere envelop rate, drug loading also do not have the prominent existence of releasing problem, but the time that discharges is long; After the more low viscous polymeric polyglycolide-polylactide of single employing was sealed, the time that discharges completely was shorter, but envelop rate is not high, drug loading is low, and prominent to release phenomenon more serious.
Behind the solution of the common small molecule material that mixes variable concentrations, can obtain a kind of homogeneous system difference of steady concentration; The polymeric polyglycolide-polylactide that adopts two or more viscosity can form the mixture with intrinsic viscosity feature, specific physicochemical properties according to certain mixed; Because it is different that the molecule of the polymer of the polymeric polyglycolide-polylactide polymer substance of formation different viscosities itself constitutes, simultaneously to have a molecular weight big for polymer substance, the spatial configuration of molecules complicated factors, said mixture is diverse with the physicochemical characteristic of the polymeric polyglycolide-polylactide solution of the single average concentration that only calculates according to mathematic(al) mean, and can cause sealing the difference of the notable difference and the stablizing effect of effect, by result of the test as can be known, adopt the polymeric polyglycolide-polylactide of two kinds of different viscosities to mix, envelop rate is all more than 92%, and can be in 10-25 days steadily, discharge medicine fully.
Claims (7)
1. injection Thymosin alpha
1Sustained release microsphere agents is characterized in that: it is 0.5%～10% a Thymosin alpha by microsphere weight
1With 70%～99.5% degradable molecular weight of microsphere weight be the preparation that 5,000～500,000 daltonian medicinal high polymer adjuvant and 0%～10% other acceptable accessories that accounts for microsphere weight are prepared from; Wherein, Thymosin alpha
1, medicinal high polymer adjuvant and other acceptable accessories total amount be 100%; Described medicinal high polymer adjuvant is a polymeric polyglycolide-polylactide, Acetic acid, hydroxy-, bimol. cyclic ester and lactide ratio are 50: 50, described polymeric polyglycolide-polylactide is that the polymeric polyglycolide-polylactide by two kinds of different viscosities mixes the back and uses, wherein, described low viscosity is 0.3～0.65dl/g, and high viscosity is 0.5～0.9dl/g; Weight ratio low, full-bodied polymeric polyglycolide-polylactide is 1: 0.5～3.
2. injection Thymosin alpha according to claim 1
1Sustained release microsphere agents is characterized in that: the molecular weight of described medicinal high polymer adjuvant is 10,000～400,000 dalton, and weight percentage is: 78%～99.5%.
3. injection Thymosin alpha according to claim 1
1Sustained release microsphere agents is characterized in that: described weight ratio low, full-bodied polymeric polyglycolide-polylactide is 1: 1～2.
4. injection Thymosin alpha according to claim 3
1Sustained release microsphere agents, it is characterized in that: 1.55g Thymosin alpha 1,2.25gPEG-6000 and 90g polymeric polyglycolide-polylactide are fed intake respectively prepares the w/o microsphere, wherein, the weight proportion of the polymeric polyglycolide-polylactide of two kinds of viscosity is: 0.65dl/g: 0.89dl/g=1: 1.7; Concentration at PVA is 2% again, and the concentration of NaCl is the microsphere that is prepared into w/o/w in 2% the aqueous solution.
5. according to each described injection Thymosin alpha of claim 1-4
1Sustained release microsphere agents is characterized in that: the particle diameter of described sustained-release micro-spheres is 1～200 μ m, mean diameter 20～150 μ m.
6. according to each described injection Thymosin alpha of claim 1-4
1Sustained release microsphere agents is characterized in that: described preparation is subcutaneous injection or intramuscular injectable formulations.
7. one kind prepares the described injection Thymosin alpha of claim 1
1The method of sustained release microsphere agents comprises the steps:
The first step at first is dissolved into oil phase with dichloromethane with degradable medicinal high polymer adjuvant, will be dissolved with Thymosin alpha in addition then
1Interior water add wherein, oil phase and water are placed in the agitator, changeed high-speed stirred 5～8 minutes with per minute 2000～3000, form the w/o emulsion, the outer aqueous phase of PVA that afterwards the w/o emulsion droplets is joined 0-8 ℃ ice bath 1%--5% forms the W/O/W emulsion and stirred 3-5 minute;
Second step will add the PVA contain 1-5% again, contain 1～5%NaCl aqueous solution in the above-mentioned gained W/O/W emulsion, organic solvent volatilizees under the stirring at low speed that per minute 400-700 changes; After microsphere solidifies, filter, filter bulky grain, sucking filtration, wash, be drying to obtain microsphere.
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| CN102106828B (en) * | 2011-02-25 | 2013-04-24 | 深圳翰宇药业股份有限公司 | Thymalfasin sustained-release microsphere preparation and preparation method thereof |
| CN103405752A (en) * | 2013-08-22 | 2013-11-27 | 天津大学 | Oral thymosin alpha1 solid lipid nanoparticle absorption preparation and preparing method thereof |
| CN104984327A (en) * | 2015-06-15 | 2015-10-21 | 烟台海安药物研发有限公司 | Thymalfasin sustained release micro-sphere preparation and preparing method thereof |
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| CN1631437A (en) * | 2003-12-24 | 2005-06-29 | 刘金雪 | Method for extracting and synthesizing thymus microcapsule sustained release needle by PLGA |
| CN1965810A (en) * | 2006-11-17 | 2007-05-23 | 中国人民解放军第二军医大学 | Sustained release microsphere formulation of thymosin alpha-1, preparation process and use thereof |
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| CN1631437A (en) * | 2003-12-24 | 2005-06-29 | 刘金雪 | Method for extracting and synthesizing thymus microcapsule sustained release needle by PLGA |
| CN1965810A (en) * | 2006-11-17 | 2007-05-23 | 中国人民解放军第二军医大学 | Sustained release microsphere formulation of thymosin alpha-1, preparation process and use thereof |
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