CN103622902A - A temperature-sensitive gel medicine preparation and a preparation method thereof - Google Patents
A temperature-sensitive gel medicine preparation and a preparation method thereof Download PDFInfo
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Abstract
The invention discloses a temperature-sensitive gel medicine preparation and a preparation method thereof. A raw material formula of the temperature-sensitive gel medicine preparation comprises a medicine, a temperature-sensitive gel composition, and an auxiliary material C. The auxiliary material C is one or more selected from a metal salt, a carbohydrate and a hydrophilic polymer used for injection medicines. The metal salt is a pharmaceutically acceptable metal salt which can dissociate divalent metal cation in a water solution. The medicine is a compound A which exists in an anion state in a water solution. The compound A is one or more selected from a protein type medicine, a polypeptide type medicine and a glycopeptides type antibiotic. The preparation method comprises a step of dissolving the medicine into the temperature-sensitive gel composition existing in a solution form according to the raw material formula. The temperature-sensitive gel medicine preparation is especially suitable for water-soluble medicines, and is capable of diminishing burst release effects and releasing the medicine slowly, thus achieving an objective of slow release.
Description
Technical field
The present invention relates to a kind of thermosensitive hydrogel pharmaceutical preparation and preparation method thereof.
Background technology
Exendin (claiming again exenatide or exendin-4) is separated from the salivation thing of Monster (Heloderm suspectum) and go out at first, to contain 39 amino acid whose polypeptide (Eng, J. etc., J.Biol.Chem., 1990 (265): 20259-20262; Or J.Biol.Chem., 1992 (267): 7402-7405), have an appointment 53% same composition of its aminoacid sequence and glucagon-like (glucagon-like peptide-1, GLP-1).Pharmaceutical research discovery, exendin has the effect similar with GLP-1, can stimulating pancreas β emiocytosis insulin.Exendin can act on GLP-1 receptor on the cell of some excreting insulin in vitro, act on from the distribution acinous cell of Cavia porcellus pancreas or act on the parietal cell from stomach; Report that in addition exendin can stimulate somatostatin to discharge and the gastrin that suppresses in separated stomach discharges (Goke etc., J.Biol.Chem., 1993 (268): 19650-19655; Schepp7, Eur.J.PharrrLacol., 1994 (69): 183-191; Eissele etc., Life Sci., 1994 (55): 629-634).Effect and GLP-1 that exendin induces cAMP to produce in the basic receptor system of the mankind and rat are basic identical, and the most significant receptor binding site is at pancreas islets of langerhans position.
Medicine exendin is developed cooperatively by He Lilai company of U.S. Amylin company, its listing of FDA approved, trade name Byetta, for failing to obtain the type ii diabetes patient's of good control auxiliary treatment to independent use metformin, sulfonylurea drugs or metformin and sulfonylurea drugs coupling treatment.The clinical treatment for type ii diabetes of exendin injection, existing scheme is each administration 5-10 microgram, every day, administration was 2-3 time, more than life cycle reaches half a year.Therefore the long-acting injection that, prepare a kind of slow release, facilitates patient's administration is extremely important for the clinical practice of exendin.
Microsphere is that a kind of medicine is dispersed in to Biodegradable material is the spherical of skeleton or entity that class is spherical, before use, add after suspending agent, can inject smoothly as subcutaneous or intramuscular, micro-balloon injection has following advantage: (1) can be injected to the subcutaneous or intramuscular of patient by ordinary syringe, and medication is convenient; (2) medicine slowly discharges with constant speed in vivo, maintains lasting drug effect in body; (3) microballoon skeleton material has biodegradable and biocompatibility, in vivo, medicine can slowly discharge from microsphere, and framework material can be constantly for body absorbs, because material has good biocompatibility, be unlikely to produce the advantages such as toxic and side effects (Li Kun, Liu Xiaojun, Chen Qinghua, the progress of biodegradable long-acting injection drug-supplying system, Chinese industrial magazine, 2012,43 (3): 34).
In the micro-balloon injection kind of having gone on the market, micro-balloon injection with polyester material is occupied an leading position, wherein artificial synthetic polypeptide---luteinizing hormone-releasing hormone (luteinisin hormone releasing hormones, LHRH) analog microsphere is to develop and obtained a successful class polypeptide long-acting injection product nineties in last century.In July, 2011 European Union's approval Li Lai company
(exendin micro-balloon injection) listing (Chinese patent, CN200580019229.9), at present
be first be also a unique long-acting injection for type ii diabetes treatment, within one week, inject once.Clinical data shows, uses
after 6 months, glycolated hemoglobin index is compared decline 1.5%-1.9% with baseline, and patient's blood glucose can be well controlled.
But still there is following shortcoming as long-acting injection agent carrier in microsphere: (1) complicated process of preparation, there is the complicated procedures of forming of driving away organic solvent, the production cycle is longer, and cost is higher; (2) in microsphere preparation, often have the problem of entrapment efficiency, medicament contg is difficult to improve; (3) processing of sterilizing is very difficult etc.
In recent years, responsive to temperature type biodegradable polymer has received increasing concern as the carrier of drug administration by injection system.This base polymer is very responsive to ambient temperature, when ambient temperature is during lower than minimum critical phase temperature (LCST), polymer water soluble forms free-pouring liquid, and when ambient temperature is greater than LCST, aqueous solutions of polymers forms the physical crosslinking gel of semi-solid state, completes the phase transformation from colloidal sol to gel.Polyester (abbreviation is designated as A)/Polyethylene Glycol (abbreviation is designated as B) triblock copolymer is the most frequently used a kind of responsive to temperature type polymer, by polymerization methods, is divided into two types of ABA and BAB; Hydrophilic Polyethylene Glycol (PEG) is inserted into hydrophilic and the degradation rate of scalable copolymer in biodegradable polyester chain.Under the condition of special ratios, this analog copolymer water soluble, when concentration is greater than critical micelle concentration, copolymer micelle state with nucleocapsid structure in water exists, be that hydrophobicity block A forms kernel, hydrophilic B block is distributed in the shell of hydrone interface formation micelle; When ambient temperature > LCST, micelle is assembled the hydrogel that forms physical crosslinking.Thus, the release of medicine from Biodegradable temperature responsive type ABA or BAB triblock copolymer is mainly by drug diffusion, and the degraded of polymer and these two kinds of mechanism of corrosion (both are referred to as degradation behavior) or both are in conjunction with control.Rate of release is one of key index of evaluating gel injection quality.Therefore thermosensitive hydrogel can be used as the carrier of long-acting injection, is expected to solve microsphere as the above-mentioned shortcoming of drug administration system carrier, so its successful research and development are subject to chemical industry, the generally attention in the fields such as pharmacy.
that MacroMed company is as the proprietary temperature sensitive type in-situ gel product having of first hand.The gel of this not medicine carrying is that the phosphate buffer that is dissolved in pH7.4 by low-molecular-weight ABA type PLGA-PEG-PLGA triblock copolymer is made, and PLGA refers to Poly(D,L-lactide-co-glycolide herein.This gel systems has following characteristics: 1.
from the preparation that is synthesized to product of polymer all without adopting organic solvent, at low temperatures can filtration sterilization, guaranteed thus the safety of product.2. the anti-phase thermosensitive hydrogel characteristic of " cryosol, high temperature gel " has facilitated the preparation of preparation, has improved the chemical stability of medicine when storing and transporting.3. good biological degradability and biocompatibility, avoided Operation, improved safety and the compliance of medication.4. amphipathic nature polyalcohol aqueous solution has improved the dissolubility of a lot of hydrophobic drugs, can not only transmit water soluble drug, also can be applicable to low dose of poorly water soluble drugs, has widened the scope of transmitting medicine.5. with the internal medium of the micelle state gentleness of nucleocapsid structure, improve the chemical stability of a lot of medicines, be more suitable for transmitting the polypeptide protein class medicine day by day increasing.6. there is the slow-release capability of 1～6 week and the keeping life of 2 years, possessed the basis that is developed to long-acting injection.Except above-mentioned advantage, in system, the rate of release of medicine can regulate by changing hydrophobic/hydrophilic constituent content, polymer concentration, molecular weight and the polydispersity of triblock polymer, when design prescription, can make applicable prescription according to different application requirements, have a wide range of applications space.
OncoGel
tMthat paclitaxel is dissolved in
in make the long-acting injection that dosage is 2mg/g, said preparation can be used for treating esophageal carcinoma, at present in the U.S. in II phase clinical research, be also the kind of first thermosensitive hydrogel injection.According to the advantage of this carrier, can find out as the dosage form for the treatment of have good research and development space and application prospect.Yet through research, find,
the shortcoming existing is as follows: 1. polymeric material exceeds certain block and forms (as the lactic acid in GA/LA and hydroxyacetic acid unit mol ratio surpass the A/B ratio in polymer unit ABA in certain ratio or PLGA/PEG, surpassing certain ratio), and it is big or small to exceed certain block copolymer amount, just can only completely water-soluble or partly become precipitation even completely, thereby lost sol-gel transition performance, and the performance of temperature sensitive gelatine; Even if 2. sensitive characteristic appears in partial polymer, but its gelatinization temperature is not suitable for human body application; 3. the range of accommodation of the degradation rate of this gel and dynamic process have certain limitation, have limited its application at field of medicaments.
Chinese Patent Application No. is that mixed gel that 200910049664.6 reports are comprised of two or more PLGA-PEG-PLGA block polymer has single polymers gel and do not have temperature sensitive characteristic.This mixed polymer gel has sensitive, reversible, suitable gelatinization temperature, has broken through
the yoke of patent, can regulate the character such as gelatinization temperature, degradation speed of gel more neatly by adjusting the ratio of each polymer, have application potential.Yet, aqueous environments due to thermosensitive hydrogel, preparation water soluble drug thermosensitive hydrogel time, water soluble drug is easy to spread out by gel internal water dissolubility passage, cause the medication initial stage to discharge most medicine, after medication, start a period of time and there will be serious burst drug release effect (Burst effect), and do not reach the slow release effect of preparation, or slow release effect is not obvious, limited the application of water soluble drug thermosensitive hydrogel.There is the burst effect that reduces medicine by increasing temperature sensitive polymer concentration present stage, but DeGrain is seldom seen so far and studied the report successfully addressing this problem.
Summary of the invention
Technical problem to be solved by this invention is that the water soluble drug having overcome in water soluble drug thermosensitive hydrogel is easy to spread out by gel internal water dissolubility passage, cause the medication initial stage to discharge most of medicine, after medication, starting a period of time there will be serious burst drug release effect, do not reach the defects such as slow release effect of preparation, and provide a kind of water soluble drug that is particularly suitable for, lowering dashes forward releases effect, can discharge lentamente thermosensitive hydrogel pharmaceutical preparation of medicine and preparation method thereof.
Thermosensitive hydrogel pharmaceutical preparation of the present invention, its composition of raw materials contains medicine, thermosensitive hydrogel compositions, and adjuvant C; Described adjuvant C is one or more in the hydrophilic polymer used of slaine, glucide and injection drug; Described slaine is the slaine of dissociation divalent metal in pharmaceutically acceptable and aqueous solution; The substance A of described medicine for existing with anionic form in aqueous solution, described substance A is one or more in protein medicaments, polypeptide drug and glycopeptide antibiotics.
In the present invention, described medicine is preferably glucagon-like-peptide-1 (GLP-1 analog), luteinising hormone-releasing hormo (p-GLU-HIS-TRP-SER-TYR-D-TRP-LEU-ARG-PRO-GLY-NH2), growth hormones material, better one or more in Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37], exendin, GLP-1 (7-37), leuprorelin, Supprelin, goserelin, recombinant human somatropin, bovine growth hormone recombinant, RPST, people's somatostatin, octreotide, C peptide (claiming again connection peptides), calcitonin, vancomycin, norvancomycin and teicoplanin, further better is exendin.
In the present invention, the content of described medicine can be by this area conventional amount used, and preferably, for accounting for thermosensitive hydrogel pharmaceutical preparation weight 0.01%～5%, better is 0.2%～2%.When described medicine is exendin, the consumption of described medicine is preferably for to count 0.01%～2% by thermosensitive hydrogel pharmaceutical preparation weight, and better is 0.05%～0.5%, and further better is 0.2%～0.5%.
In the present invention, described thermosensitive hydrogel compositions is the conventional thermosensitive hydrogel compositions of using in this area, is preferably according to Chinese patent application, and application number is 200910049664.6 said thermosensitive hydrogel compositionss.Described thermosensitive hydrogel compositions preferably contains polymer; Described polymer comprises hydrophobicity block polymer and hydrophilic block polymer; Wherein, described hydrophobicity block polymer and hydrophilic block polymer include Polyethylene Glycol hydrophilic block A and polyester hydrophobic block B (block being introduced to A and B sign herein so that for hereinafter quoting) separately.Those skilled in the art all know according to this area general knowledge, and the ratio of adjusting between Polyethylene Glycol hydrophilic block A and polyester hydrophobic block B obtains respectively hydrophobicity block polymer and hydrophilic block polymer.
Wherein, the total amount of described hydrophobicity block polymer and hydrophilic block polymer is preferably for accounting for the weight percentage 3%～50% of thermosensitive hydrogel total composition; Described hydrophobicity block polymer and the consumption weight ratio of hydrophilic block polymer are preferably 0.5: 1～3: 1, and better is 1: 1.
Wherein, the percentage by weight of described Polyethylene Glycol hydrophilic block A is preferably 10wt%～90wt%.Described Polyethylene Glycol hydrophilic block A is preferably for having the Polyethylene Glycol block of 400 to 8000 number-average molecular weight.
Wherein, the percentage by weight of described polyester hydrophobic block B is preferably 10wt%～90wt%.Described polyester hydrophobic block B is preferably for having the polyester block of 500～40000 number-average molecular weight.
Wherein, polyester in described polyester hydrophobic block B is preferably poly DL-lactide, poly-D-lactide, PLLA, PGA, poe, polycaprolactone, poly-alkyl replacement caprolactone, poly-δ-valerolactone, polyesteramide, Merlon, polyacrylate or polyether ester, and the formed copolymer of two or more polyester in above-mentioned each kind polyester.
In the present invention, described polymer is preferably the triblock copolymer of ABA block configuration, the segmented copolymer of the diblock copolymer of the triblock copolymer of BAB block configuration, BA block configuration, A (BA) n block configuration or the segmented copolymer of B (AB) n block configuration, and wherein n is 2 to 10 integer.Described polymer preferably at least one polymer does not have the character of heat-convertible gel.
In the present invention, described hydrophobicity block polymer is preferably PLGA-PEG-PLGA copolymer; Wherein the number-average molecular weight of PLGA block is 1000～2000, and better is 1571; In PLGA block, the mol ratio of lactic acid units and hydroxyacetic acid unit is 1～10, and better is 4; The number-average molecular weight of PEG block is 1400～1600, and better is 1500.The molecular weight distribution coefficient of described hydrophobicity block polymer is 1.01～1.40, and better is 1.23.
In the present invention, described hydrophilic block polymer is preferably PLGA-PEG-PLGA copolymer, and wherein the number-average molecular weight of PLGA block is 800～1600, and better is 1255; In PLGA block, the mol ratio of lactic acid units and hydroxyacetic acid unit is 1～10, and better is 4; The number-average molecular weight of PEG block is 1000～2000, and better is 1500.The molecular weight distribution coefficient of described hydrophilic block polymer is preferably 1.01～1.50, and better is 1.15.
In the present invention, solvent in described thermosensitive hydrogel compositions is conventional by this area, be generally body fluid, tissue culture medium or the cell culture fluid of pure water, normal saline, buffer solution, animals and plants or human body, and other aqueous solution and the organic solvent of the not take medium that is main body, preferably for water, etc. ooze normal saline or etc. the pH that the oozes PBS solution that is 7.4.
As previously mentioned, the adjuvant C in the thermosensitive hydrogel pharmaceutical preparation described in the present invention is one or more in the hydrophilic polymer used of slaine, glucide and injection drug; Described slaine is the slaine of dissociation divalent metal in pharmaceutically acceptable and aqueous solution.
In the present invention, described divalent metal is preferably zinc ion, calcium ion or magnesium ion.What described slaine was better is zinc acetate.
In the present invention, the consumption of described slaine is preferably for accounting for thermosensitive hydrogel composition weight percentage ratio 0.1%～10%, and better is 1%～3%, and further better is 0.5%～2.5%.
In the present invention, described glucide is the conventional acceptable glucide of pharmacy using in this area, is preferably one or more in sucrose, lactose, fructose, glucose, maltose and trehalose; The consumption of described glucide is this area conventional amount used, and preferably, for to account for 0.1%～20% of thermosensitive hydrogel composition weight, better is 2%～5%, and further better is 2.5%～5%.
In the present invention, to be that this area is conventional use the hydrophilic polymer that described injection drug is used, and its biocompatibility is good and in hydrogel, have a thickening power; Be preferably Polyethylene Glycol, better is Polyethylene Glycol number-average molecular weight 200～6000, and further better is PEG number-average molecular weight 200.The consumption of the hydrophilic polymer that described injection drug is used is preferably for to account for 0.1%～20% of thermosensitive hydrogel composition weight, and better is 2%～5%, and better is 2.5%～5%.
In the present invention, a preferred embodiments, the zinc acetate that described adjuvant C is 1.25%, 5% sucrose and 5% PEG number-average molecular weight 200, percentage ratio is for accounting for thermosensitive hydrogel composition weight meter.
The present invention also provides a kind of preparation method of aforesaid thermosensitive hydrogel pharmaceutical preparation, and it comprises the steps: by composition of raw materials, each composition is dissolved in to the thermosensitive hydrogel compositions existing with solution form;
When described adjuvant C contains slaine, slaine is uniformly dissolved and is mixed in aqueous solution with medicine, then lyophilization, evenly mixes with thermosensitive hydrogel compositions afterwards again;
When described adjuvant C contains glucide, glucide is directly dissolved in to thermosensitive hydrogel compositions; Or be uniformly dissolved and mix in aqueous solution with medicine, then lyophilization, evenly mixes with thermosensitive hydrogel compositions afterwards again.
Thermosensitive hydrogel pharmaceutical preparation of the present invention preferably, for being injected in the subcutaneous or intramuscular of human body, is controlled water soluble drug with constant speed, slowly the biodegradable thermosensitive hydrogel pharmaceutical preparation of sustained release.As exendin thermosensitive hydrogel pharmaceutical preparation treatment type ii diabetes works very well.
Agents useful for same of the present invention and raw material be commercially available obtaining all.
Meeting on the basis of this area general knowledge, in the present invention, the optimum condition of each above-mentioned technical characterictic can combination in any obtain preferred embodiments of the present invention.
Positive progressive effect of the present invention is: thermosensitive hydrogel pharmaceutical preparation of the present invention can improve the prominent problem of releasing of polypeptide, protide water soluble drug and glycopeptide antibiotics preferably, discharges lentamente medicine, to reach the object of slow releasing pharmaceutical; The thermosensitive hydrogel pharmaceutical preparation of particularly treating type ii diabetes medicine GLP-1 analog can evenly discharge 9 days in vitro, and in Mice Body, effective blood sugar lowering is 5 to 9 days, thereby has improved the medication compliance of diabetic; This research and development to the long-acting injection of polypeptide, protide macromolecular drug, will have good reference value and application value.
Accompanying drawing explanation
Fig. 1 is the drug release in vitro curve chart of the thermosensitive hydrogel pharmaceutical preparation that makes of comparative example 1-7.
Fig. 2 is the drug release in vitro curve chart of the thermosensitive hydrogel pharmaceutical preparation that makes of comparative example 8-9.
Fig. 3 is the drug release in vitro curve chart of the thermosensitive hydrogel pharmaceutical preparation that makes of embodiment 1-2.
Fig. 4 is the drug release in vitro curve chart of the thermosensitive hydrogel pharmaceutical preparation that makes of embodiment 3-4.
Fig. 5 is the drug release in vitro curve chart of the thermosensitive hydrogel pharmaceutical preparation that makes of embodiment 5-6.
Fig. 6 is the drug release in vitro curve chart of the thermosensitive hydrogel pharmaceutical preparation that makes of embodiment 7.
Fig. 7 is the drug release in vitro curve chart of the thermosensitive hydrogel pharmaceutical preparation that makes of embodiment 8.
Fig. 8 is the drug release in vitro curve chart of the thermosensitive hydrogel pharmaceutical preparation that makes of embodiment 9.
Fig. 9 is the affect graph of a relation of effect embodiment 1 exendin gel preparation on ICR mouse blood sugar.
Figure 10 is the affect graph of a relation of effect embodiment 1 exendin gel preparation on ICR mouse blood sugar; * * p < 0.001, * * p < 0.01, * p < 0.05vs NaCl.
Figure 11 is the affect graph of a relation of effect embodiment 1 exendin gel preparation on ICR mouse blood sugar; * * p < 0.001, * * p < 0.01, * p < 0.05vs NaCl.
Figure 12 is the affect graph of a relation of effect embodiment 1 exendin gel preparation on ICR mouse blood sugar; * * p < 0.001, * * p < 0.01, * p < 0.05vs NaCl.
Figure 13 is the affect graph of a relation of effect embodiment 1 exendin gel preparation on ICR mouse blood sugar; * * p < 0.001, * * p < 0.01, * p < 0.05vs NaCl.
Figure 14 is the affect graph of a relation of effect embodiment 1 exendin gel preparation on ICR mouse blood sugar; * * p < 0.001, * * p < 0.01, * p < 0.05vs NaCl.
Figure 15 is the affect graph of a relation of effect embodiment 1 exendin gel preparation on ICR mouse blood sugar; * * p < 0.001, * * p < 0.01, * p < 0.05vs NaCl.
Figure 16 is the affect graph of a relation of effect embodiment 1 exendin gel preparation on ICR mouse blood sugar; * * p < 0.001, * * p < 0.01, * p < 0.05vs NaCl.
Figure 17 is the affect graph of a relation of effect embodiment 1 exendin gel preparation on ICR mouse blood sugar; * * p < 0.001, * * p < 0.01, * p < 0.05vs NaCl.
Figure 18 is the affect graph of a relation of effect embodiment 1 exendin gel preparation on ICR mouse blood sugar.
Figure 19 is the affect graph of a relation of effect embodiment 1 exendin gel preparation on ICR mouse blood sugar.
The specific embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.
Comparative example 1-7
The preparation of 1.1 comparative example 1-7 thermosensitive hydrogel pharmaceutical preparatioies (not containing adjuvant C)
Block polymer in table 1～3 is respectively according to Chinese patent application, and application number is that in 200910049664.6 embodiment 1～3, method is synthetic, and concrete proportioning is recorded in table 1 and 2.
Wherein the block copolymer of table 1 is hydrophilic block polymer (just can dissolve in water), and the block copolymer of table 2 is hydrophobicity block polymer (can not be dissolved in water or can not be dissolved in water completely); And the block copolymer of table 3 itself just has the performance of hot reversible gelling.
Comparative example 1-7 for choosing one or more block copolymers from table 1, in conjunction with choosing one or more block copolymers to be mixed in proportion from table 2 and/or table 3, according to finite concentration, be dissolved in deionized water, obtain the gel solution with hot reversible gelling.
The concrete proportioning raw materials of comparative example 1-7 is as described in Table 4.Exendin medicine dissolution, in gel solution, is stirred and makes medicine dissolution, and 0.22 μ m membrane filtration sterilizing, makes thermosensitive hydrogel pharmaceutical preparation.
The drug release in vitro experiment of 1.2 comparative example 1-7 thermosensitive hydrogel pharmaceutical preparatioies
Each about 0.5g of the thermosensitive hydrogel pharmaceutical preparation that comparative example 1-7 is made is placed in respectively 10ml tool plug scale test tube, in 37 ℃ of Tempeerature-constant air shaking tables, place 15min after polymer solution complete gelation, add equality of temperature phosphate buffer (PBS) solution of 10ml pH=7.4 as release medium, release area is 0.18cm
2, rotating speed is 50rpm.After release starts, within 1,3,5,7 and 9 day, take out respectively whole release medium, measure the medicament contg in the remaining gel in bottom, indirect calculation release amount of medicine, 3 parts of operation repetitives.With accumulative total release amount of medicine, the time is mapped, obtain release profiles, the results are shown in Figure 1.
The HPLC method of measuring exendin is as follows: chromatographic column: Sepax Technologies Inc.C
4bonded silica gel chromatographic column (4.6*150mm, 5um), the PBS-acetonitrile of mobile phase A: pH=1.9 (potassium dihydrogen phosphate 11.58g, 85% phosphatase 11 0.9g, adds water to 1000ml) (468: 26, w/w), the PBS-acetonitrile of Mobile phase B: pH=1.9 (potassium dihydrogen phosphate 11.58g, 85% phosphatase 11 0.9g, adds water to 1000ml) (536: 338, w/w), elution program: 0～6min, mobile phase A is down to 28%, 6～33min from 35%, it is 28% constant that mobile phase A ratio keeps, detect wavelength: 214nm, column temperature, 55 ℃, flow velocity 1.0ml/min, sample size 50 μ l.
As shown in Figure 1, the thermosensitive hydrogel pharmaceutical preparation of comparative example 1-7, medicine first day in hydrogel matrix is prominent release all more serious, the cumulative release amount of first 5 days basic medicine-feeding things is all over 80%, the cumulative release of the 24th hour surpasses 60%, drug release rate is too fast, and the data of burst drug release clearly.
Table 1
Table 2
Table 3
Table 4
| Numbering | Polymer ratio (w/w) | Polymer percentage ratio (wt%) | Drug loading (wt%) |
| Comparative example 1 | Polymer 1/2/8=1/1/2 | 25 | 0.2 |
| Comparative example 2 | Polymer 3/9=1/1 | 25 | 0.2 |
| Comparative example 3 | |
25 | 0.2 |
| Comparative example 4 | |
25 | 0.2 |
| Comparative example 5 | |
25 | 0.2 |
| Comparative example 6 | Polymer 3/8/12=4/5/1 | 25 | 0.2 |
| Comparative example 7 | |
25 | 0.2 |
Comparative example 8-9
The preparation of 1, comparative example 8-9 thermosensitive hydrogel pharmaceutical preparation (not containing adjuvant C)
The polymer A of comparative example 8-9, the synthesis technique of B are with reference to Chinese patent application, and application number is method in 200910049664.6 said embodiment 1 and 3.
Get hydrophilic PLGA-PEG-PLGA copolymer (polymer A, 1571-1500-1571, the molecular weight of block is number-average molecular weight, block mol ratio LA/GA=4, molecular weight distribution coefficient is 1.15) and the appropriate (polymer B of hydrophobicity PLGA-PEG-PLAG copolymer, 1255-1500-1255, the molecular weight of block is number-average molecular weight, block mol ratio LA/GA=4, molecular weight distribution coefficient is 1.23), add deionized water, under magnetic agitation, dissolve, be configured to the solution that polymer A/B part by weight is respectively 25% (w/w) of 1/1 (comparative example 8) and 1/2 (comparative example 9), cross after 0.22um filter membrane standby.Precision weighing exendin 15mg, is dissolved in respectively the above-mentioned polymer solution of 7.5g, stirs and makes medicine dissolution, makes medicine carrying gel solution.
2, the drug release in vitro of comparative example 8-9 thermosensitive hydrogel pharmaceutical preparation experiment
The about 0.5g of thermosensitive hydrogel pharmaceutical preparation that comparative example 8-9 is made is placed in 10ml tool plug scale test tube, in 37 ℃ of Tempeerature-constant air shaking tables, place 15min after polymer solution complete gelation, add equality of temperature phosphate buffer (PBS) solution of 10mlpH=7.4 as release medium, release area is 0.18cm
2, rotating speed is 50rpm.After release starts, within 1,3,5,7 and 9 day, take out respectively whole release medium, measure the medicament contg in the remaining gel in bottom, indirect calculation release amount of medicine, 3 parts of operation repetitives.With accumulative total release amount of medicine, the time is mapped, obtain release profiles, the results are shown in Figure 2.
As can be seen from Figure 2, comparative example 8 thermosensitive hydrogel pharmaceutical preparatioies, medicine first day in hydrogel matrix is prominent releases all more seriously, and the cumulative release amount of first 5 days basic medicine-feeding things is all over 80%, and drug release rate is too fast.Although the gel rate of release of comparative example 9 preparations is slow, experiment discovery, its gel solution gelation temperature is lower, gelling when room temperature (25 ℃), unfavorable gel preparation technology's operation.
Embodiment 1-2
Polymer A: hydrophilic PLGA-PEG-PLGA copolymer (molecular weight of block is number-average molecular weight for polymer A, 1571-1500-1571, block mol ratio LA/GA=4, molecular weight distribution coefficient is 1.15); Polymer B: hydrophobicity PLGA-PEG-PLAG copolymer appropriate (molecular weight of block is number-average molecular weight for polymer B, 1255-1500-1255, block mol ratio LA/GA=4, molecular weight distribution coefficient is 1.23).
Wherein, the synthesis technique of polymer A, B is with reference to Chinese patent application, and application number is that in 200910049664.6 said embodiment 1 and 3, method is synthetic.
Get polymer A and polymer B, add deionized water, under magnetic agitation, dissolve, be configured to polymer, polymer A/polymer B part by weight is 1/1, total polymer concentration is the aqueous solution of 25% (w/w), excessively standby after 0.22 μ m filter membrane, is designated as polymer solution 1 (being thermosensitive hydrogel compositions).
Afterwards, precision weighing exendin 15mg, be dissolved in 7.5g polymer solution 1, add respectively with respect to 2.5% (w/w) (embodiment 1) of polymer solution 1 and the sucrose of 5% (w/w) (embodiment 2), stirring makes medicine and sucrose dissolved, makes thermosensitive hydrogel pharmaceutical preparation.
The thermosensitive hydrogel pharmaceutical preparation that embodiment 1-2 is made separately about 0.5g is placed in respectively 10ml tool plug scale test tube, in 37 ℃ of Tempeerature-constant air shaking tables, place 15min after polymer solution complete gelation, add the equality of temperature PBS solution of 10ml pH=7.4 as release medium, release area is 0.18cm
2, rotating speed is 50rpm.After release starts, within 1,3,5,7 and 9 day, take out respectively whole release medium, measure the medicament contg (with 1.2 in comparative example 1-7) in the remaining gel in bottom, indirect calculation release amount of medicine, 3 parts of operation repetitives.With accumulative total release amount of medicine, the time is mapped, obtain release profiles, the results are shown in Figure 3.
As shown in Figure 3, the sucrose of difference 2.5% and 5.0% in the product exendin thermosensitive hydrogel compositions of embodiments of the invention 1-2, all can reduce prominent the releasing of the first day of exendin medicine, medicine rate of releasing drug declines to some extent, the group of sucrose 5.0% is more more than 2.5% group decline, within the 24th hour, is respectively 57.57% and 54.00%.
Embodiment 3-4
Polymer A: hydrophilic PLGA-PEG-PLGA copolymer (molecular weight of block is number-average molecular weight for polymer A, 1571-1500-1571, block mol ratio LA/GA=4, molecular weight distribution coefficient is 1.15); Polymer B: hydrophobicity PLGA-PEG-PLAG copolymer appropriate (molecular weight of block is number-average molecular weight for polymer B, 1255-1500-1255, block mol ratio LA/GA=4, molecular weight distribution coefficient is 1.23).
Wherein, the synthesis technique of polymer A, B is with reference to Chinese patent application, and application number is that in 200910049664.6 said embodiment 1 and 3, method is synthetic.
Get polymer A and polymer B, add deionized water, under magnetic agitation, dissolve, be configured to polymer, polymer A/polymer B part by weight is respectively 1/1, total polymer concentration is the aqueous solution of 25% (w/w), excessively standby after 0.22 μ m filter membrane, is designated as polymer solution 1 (being thermosensitive hydrogel compositions).
Afterwards, precision weighing exendin 15mg, be dissolved in 7.5g polymer solution 1, add respectively the PEG200 (number-average molecular weight) with respect to polymer solution 2.5% (w/w) (embodiment 3) and 5% (w/w) (embodiment 4), stirring is dissolved medicine and PEG200, makes thermosensitive hydrogel pharmaceutical preparation.
The thermosensitive hydrogel pharmaceutical preparation that embodiment 3-4 is made separately about 0.5g is placed in respectively 10ml tool plug scale test tube, in 37 ℃ of Tempeerature-constant air shaking tables, place 15min after polymer solution complete gelation, add the equality of temperature PBS solution of 10ml pH=7.4 as release medium, release area is 0.18cm
2, rotating speed is 50rpm.After release starts, within 1,3,5,7 and 9 day, take out respectively whole release medium, measure the medicament contg (with 1.2 in comparative example 1-7) in the remaining gel in bottom, indirect calculation release amount of medicine, 3 parts of operation repetitives.With accumulative total release amount of medicine, the time is mapped, obtain release profiles, the results are shown in Figure 4.
As shown in Figure 4, in the product exendin thermosensitive hydrogel pharmaceutical preparation of embodiments of the invention 3-4, add respectively the PEG200 (number-average molecular weight) of 2.5% (w/w) and 5% (w/w) all can reduce prominent the releasing of the first day of exendin medicine, and the later stage of medicine is discharged and affected not quite.
Embodiment 5-6
Polymer A: hydrophilic PLGA-PEG-PLGA copolymer (molecular weight of block is number-average molecular weight for polymer A, 1571-1500-1571, block mol ratio LA/GA=4, molecular weight distribution coefficient is 1.15); Polymer B: hydrophobicity PLGA-PEG-PLAG copolymer appropriate (molecular weight of block is number-average molecular weight for polymer B, 1255-1500-1255, block mol ratio LA/GA=4, molecular weight distribution coefficient is 1.23).
Wherein, the synthesis technique of polymer A, B is with reference to Chinese patent application, and application number is that in 200910049664.6 said embodiment 1 and 3, method is synthetic.
Get polymer A and polymer B, add deionized water, under magnetic agitation, dissolve, be configured to polymer, polymer A/polymer B part by weight is respectively 1/1, total polymer concentration is the aqueous solution of 25% (w/w), excessively standby after 0.22 μ m filter membrane, is designated as polymer solution 1 (being thermosensitive hydrogel compositions).
Afterwards, precision weighing exendin 15mg, be dissolved in 0.5ml aqueous solution, add respectively with respect to 1.25% (w/w) (embodiment 5) of polymer solution 1 and the zinc acetate of 2.5% (w/w) (embodiment 6), regulate pH to 7.4, under 4 ℃ of conditions, place 24h, lyophilization obtains medicine zinc complexes respectively.Medicine zinc complexes is added respectively to 7.5g polymer solution 1 separately, stir medicine zinc complexes is mixed, make thermosensitive hydrogel pharmaceutical preparation.
The thermosensitive hydrogel pharmaceutical preparation that embodiment 5-6 is made separately about 0.5g is placed in respectively 10ml tool plug scale test tube, in 37 ℃ of Tempeerature-constant air shaking tables, place 15min after polymer solution complete gelation, add the equality of temperature PBS solution of 10ml pH=7.4 as release medium, release area is 0.18cm
2, rotating speed is 50rpm.After release starts, within 1,3,5,7 and 9 day, take out respectively whole release medium, measure the medicament contg (with 1.2 in comparative example 1-7) in the remaining gel in bottom, indirect calculation release amount of medicine, 3 parts of operation repetitives.With accumulative total release amount of medicine, the time is mapped, obtain release profiles, the results are shown in Figure 5.
As shown in Figure 5, the zinc acetate that adds respectively 1.25% (w/w) and 2.5% (w/w) in the product exendin thermosensitive hydrogel pharmaceutical preparation of embodiments of the invention 5-6, the prominent phenomenon of releasing of medicine is obviously declined, its release of 24 hours never adds being respectively greater than of Zn and 60% drops to 29.32% and 11.57%, the later stage of medicine discharges slightly inhomogeneous, but is obviously better than comparative example.
Embodiment 7
Polymer A: hydrophilic PLGA-PEG-PLGA copolymer (molecular weight of block is number-average molecular weight for polymer A, 1571-1500-1571, block mol ratio LA/GA=4, molecular weight distribution coefficient is 1.15); Polymer B: hydrophobicity PLGA-PEG-PLAG copolymer appropriate (molecular weight of block is number-average molecular weight for polymer B, 1255-1500-1255, block mol ratio LA/GA=4, molecular weight distribution coefficient is 1.23).
Wherein, the synthesis technique of polymer A, B is with reference to Chinese patent application, and application number is that in 200910049664.6 said embodiment 1 and 3, method is synthetic.
Get polymer A and polymer B, add deionized water, under magnetic agitation, dissolve, be configured to polymer, polymer A/polymer B part by weight is respectively 1/1, total polymer concentration is the aqueous solution of 25% (w/w), excessively standby after 0.22 μ m filter membrane, is designated as polymer solution 1 (being thermosensitive hydrogel compositions).
Afterwards, precision weighing exendin 15mg, adds the zinc acetate with respect to 1.25% (w/w) of polymer solution 1, regulates pH to 7.4, under 4 ℃ of conditions, places 24h, and lyophilization becomes medicine zinc complexes.Medicine zinc complexes is added to 7.5g polymer solution 1, stirring mixes medicine zinc complexes, add sucrose, 5% (w/w) PEG200 (number-average molecular weight) with respect to 5% (w/w) of polymer solution 1, agitating solution is even, makes thermosensitive hydrogel pharmaceutical preparation again.
The about 0.5g of thermosensitive hydrogel pharmaceutical preparation that embodiment 7 is made is placed in 10ml tool plug scale test tube, in 37 ℃ of Tempeerature-constant air shaking tables, place 15min after polymer solution complete gelation, add the equality of temperature PBS solution of 10mlpH=7.4 as release medium, release area is 0.18cm
2, rotating speed is 50rpm.After release starts, within 1,3,5,7 and 9 day, take out respectively whole release medium, measure the medicament contg in the remaining gel in bottom, indirect calculation release amount of medicine, 3 parts of operation repetitives.With accumulative total release amount of medicine, the time is mapped, obtain release profiles, the results are shown in Figure 6.
As shown in Figure 6, the product exendin thermosensitive hydrogel pharmaceutical preparation of embodiments of the invention 7 exendin first day under sucrose, PEG200 and zinc acetate three's coordinative role is prominent release lower, the rate of release rule that becomes, later stage discharges more even, the release amount of medicine of the 24th hour is about 20%, within 5th, be 60% to 70%, the 9 day be more than 80%; Burst drug release effect is little, and rate of release is even, meets especially the transmission polypeptide of one week slow release and the requirement of protein medicaments.
Get listed polymer 12 in table 3, add deionized water, under magnetic agitation, dissolve, be configured to 25% (w/w) polymer solution, excessively standby after 0.22 μ m filter membrane, be designated as polymer solution 2 (being thermosensitive hydrogel compositions).
Afterwards, precision weighing leuprorelin acetate (Shanghai Lizhu Pharmaceutical Co., ltd., purity > 98%) 45mg, be dissolved in 1.5ml aqueous solution, add the zinc acetate with respect to 1% (w/w) of polymer solution 2, regulate pH to 7.4, under 4 ℃ of conditions, place 24h, lyophilization obtains medicine zinc complexes.Medicine zinc complexes is added to 7.5g polymer solution 2, stir medicine zinc complexes is mixed, make thermosensitive hydrogel pharmaceutical preparation.
Each about 0.5g of the thermosensitive hydrogel pharmaceutical preparation that embodiment 8 is made is placed in respectively 10ml tool plug scale test tube, in 37 ℃ of Tempeerature-constant air shaking tables, place 15min after polymer solution complete gelation, add the equality of temperature PBS solution of 10ml pH=7.4 as release medium, release area is 0.18cm
2, rotating speed is 50rpm.In certain intervals after release starts, take out respectively whole release medium (with 1.2 in comparative example 1-7), measure the medicament contg in the remaining gel in bottom, indirect calculation release amount of medicine, 3 parts of operation repetitives.With accumulative total release amount of medicine, the time is mapped, obtain release profiles, the results are shown in Figure 7.
The HPLC method of measuring leuprorelin acetate is as follows: chromatographic column: C
18bonded silica gel chromatographic column (4.6*150mm, 5um), mobile phase: 100mmol/L phosphoric acid triethylamine solution: acetonitrile=78: 22.Detect wavelength: 225nm, column temperature, 35 ℃, flow velocity 1.0ml/min, sample size 20 μ l.
As shown in Figure 7, add respectively the zinc acetate zinc of 1% (w/w) in the pharmaceutical preparation of leuprorelin acetate thermosensitive hydrogel, medicine can slowly discharge about 3 weeks uniformly.
Embodiment 9
Get in table 1 polymer 8 in polymer 1 and table 2, add deionized water, under magnetic agitation, dissolve, being configured to polymer 1/ polymer 8 part by weight is 1/1.5, total polymer concentration is the aqueous solution of 25% (w/w), cross after 0.22 μ m filter membrane standbyly, be designated as polymer solution 3 (being thermosensitive hydrogel compositions).
Afterwards, (Animal Husbandary and Veterinary Inst., Shanghai Academy of Agricultural Science is synthetic for precision weighing bovine growth hormone recombinant 40mg, purity > 90%), be dissolved in 1ml aqueous solution, add the zinc acetate with respect to 0.5% (w/w) of polymer solution 3, regulate pH to 7.4, under 4 ℃ of conditions, place 24h, lyophilization obtains medicine zinc complexes.Medicine zinc complexes is added to 2g polymer solution 3, stir medicine zinc complexes is mixed, make thermosensitive hydrogel pharmaceutical preparation.
The about 0.5g of thermosensitive hydrogel pharmaceutical preparation that embodiment 9 is made is placed in respectively 10ml tool plug scale test tube, in 37.In ℃ Tempeerature-constant air shaking table, place 15min after polymer solution complete gelation, add the equality of temperature PBS solution of 10ml pH=7.4 as release medium, release area is 0.18cm
2, rotating speed is 50rpm.In certain intervals after release starts, take out a certain amount of release medium, BSA method is measured medicament contg, calculates release amount of medicine, 3 parts of operation repetitives.With accumulative total release amount of medicine, the time is mapped, obtain release profiles, the results are shown in Figure 8.
As shown in Figure 8, add respectively the zinc acetate of 0.5% (w/w) in the pharmaceutical preparation of bovine growth hormone recombinant thermosensitive hydrogel, medicine can slowly discharge about 3～4 weeks uniformly.
Effect embodiment
1, experimental principle and object
Because the blood sugar reducing function of GLP-1 class medicine has significant dependence on the glucose, so adopt normal ICR mouse stomach to give glucose, investigate pharmacologically active and the action time of the pharmaceutical preparation of exendin thermosensitive hydrogel, thereby evaluate hypoglycemic effect (Li Yikui in its body, Jin Ruomin, Wang Qinmao. herbal pharmacology experimental methodology, 1 edition, Shanghai: Shanghai science tech publishing house, 2006:608-610 page)
2, laboratory animal
Normal ICR mice, male, body weight 20～30g.Before experiment, all animals are divided into 4 groups (n=6) at random according to body weight, are respectively Normal group (Nor), blank normal saline group (NaCl), positive control exendin aqueous solution (Sol), gel group (Gel).
3, medicine preparation
1) gel group (Gel): embodiment 7 products.
2) positive control exendin aqueous solution (Sol): by the acetate buffer of exendin solution and pH4.5, make 1mg/ml standard mother solution, use before use 5 times of ice-cold normal saline dilutions, stand-by.
3) glucose: 2g/kg.
4, experimental technique
Each treated animal overnight fasting (freely drinking water), subcutaneous injection administration (0.1ml/10g after tail point blood sampling next day, Normal group gives normal saline), after 15min, gavage gives glucose (2g/kg, 0.1ml/10g), and respectively at after glucose load 30,60, the blood sampling of 120min tail point, measure blood glucose.After administration 4h again gavage give glucose (the same), equally respectively after glucose load 30,60, the blood sampling of 120min tail point, measure blood glucose (blood sugar detection adopts glucose oxidase method, lower with).
Afterwards, each treated animal respectively after administration the 2nd, 3,4,5,6,7,8,9,10 and 11 days 9:00am start fasting (freely drinking water) 4h, then tail point blood sampling, and gavage gives glucose (the same), respectively after glucose load 30, the blood sampling of 60min tail point, measure blood glucose.
5, result of the test, is recorded in Fig. 9 to 19.
From the resistance to sugar test of mice, finally to write out a prescription under 5mg/kg dosage, after single-dose, the 1st to 5 days (Fig. 9-Figure 13) can both significantly reduce the blood glucose after normal ICR mice oral glucose load, and has good hypoglycemic effect.After single-dose, the 6th to 9 days (Figure 14-Figure 17) weakens the blood sugar reducing function after mice oral glucose load, the 10th to 11 days (Figure 18-Figure 19) do not have a significant effect to the blood glucose after mice oral glucose load, and the prompting exendin blood sugar reducing function in body of finally writing out a prescription after single-dose can continue 5-9 days; Duration of test mice is without any abnormal phenomena, and this thermosensitive hydrogel pharmaceutical preparation is long-acting as can be seen here, safety is good.
Claims (10)
1. a thermosensitive hydrogel pharmaceutical preparation, is characterized in that, its composition of raw materials contains medicine, thermosensitive hydrogel compositions, and adjuvant C; Described adjuvant C is one or more in the hydrophilic polymer used of slaine, glucide and injection drug; Described slaine is the slaine of dissociation divalent metal in pharmaceutically acceptable and aqueous solution; The substance A of described medicine for existing with anionic form in aqueous solution, described substance A is one or more in protein medicaments, polypeptide drug and glycopeptide antibiotics.
2. thermosensitive hydrogel pharmaceutical preparation as claimed in claim 1, is characterized in that, described divalent metal is zinc ion, calcium ion or magnesium ion; Described slaine is preferably zinc acetate; The consumption of described slaine, for accounting for thermosensitive hydrogel composition weight percentage ratio 0.1%～10%, is preferably 1%～3%, and better is 0.5%～2.5%.
3. thermosensitive hydrogel pharmaceutical preparation as claimed in claim 1, is characterized in that, described glucide is one or more in sucrose, lactose, fructose, glucose, maltose and trehalose; The consumption of described glucide is to account for 0.1%～20% of thermosensitive hydrogel composition weight, is preferably 2%～5%, and better is 2.5%～5%.
4. thermosensitive hydrogel pharmaceutical preparation as claimed in claim 1, is characterized in that, the hydrophilic polymer that described injection drug is used is Polyethylene Glycol, is preferably Polyethylene Glycol number-average molecular weight 200～6000, and better is PEG number-average molecular weight 200; The consumption of the hydrophilic polymer that described injection drug is used is to account for 0.1%～20% of thermosensitive hydrogel composition weight, is preferably 2%～5%, and better is 2.5%～5%.
5. thermosensitive hydrogel pharmaceutical preparation as claimed in claim 1, is characterized in that, the content of described medicine, for accounting for thermosensitive hydrogel pharmaceutical preparation weight 0.01%～5%, is preferably 0.2%～2%; When described medicine is exendin, the consumption of described medicine, for to count 0.01%～2% by thermosensitive hydrogel pharmaceutical preparation weight, is preferably 0.05%～0.5%, and better is 0.2%～0.5%.
6. thermosensitive hydrogel pharmaceutical preparation as claimed in claim 1, it is characterized in that, described medicine is glucagon-like-peptide-1, luteinising hormone-releasing hormo or growth hormones material, is preferably one or more in Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37], exendin, GLP-1 (7-37), leuprorelin, Supprelin, goserelin, recombinant human somatropin, bovine growth hormone recombinant, RPST, people's somatostatin, octreotide, C peptide, calcitonin, vancomycin, norvancomycin and teicoplanin; Described adjuvant C is preferably 1.25% zinc acetate, 5% sucrose and 5% PEG number-average molecular weight 200, and percentage ratio is for accounting for thermosensitive hydrogel composition weight meter.
7. thermosensitive hydrogel pharmaceutical preparation as claimed in claim 1, is characterized in that, described thermosensitive hydrogel compositions contains polymer; Described polymer comprises hydrophobicity block polymer and hydrophilic block polymer; Wherein, described hydrophobicity block polymer and hydrophilic block polymer include Polyethylene Glycol hydrophilic block A and polyester hydrophobic block B separately.
8. thermosensitive hydrogel pharmaceutical preparation as claimed in claim 7, is characterized in that, described hydrophobicity block polymer and the total amount of hydrophilic block polymer are the weight percentage 3%～50% that accounts for thermosensitive hydrogel total composition; Described hydrophobicity block polymer and the consumption weight ratio of hydrophilic block polymer are 0.5: 1～3: 1, are preferably 1: 1;
The percentage by weight of described Polyethylene Glycol hydrophilic block A is 10wt%～90wt%; Described Polyethylene Glycol hydrophilic block A is the Polyethylene Glycol block with 400 to 8000 number-average molecular weight;
The percentage by weight of described polyester hydrophobic block B is 10wt%～90wt%; Described polyester hydrophobic block B is the polyester block with 500～40000 number-average molecular weight;
Polyester in described polyester hydrophobic block B is poly DL-lactide, poly-D-lactide, PLLA, PGA, poe, polycaprolactone, poly-alkyl replacement caprolactone, poly-δ-valerolactone, polyesteramide, Merlon, polyacrylate or polyether ester, and the formed copolymer of two or more polyester in above-mentioned each kind polyester.
9. thermosensitive hydrogel pharmaceutical preparation as claimed in claim 7, it is characterized in that, described polymer is preferably the triblock copolymer of ABA block configuration, the segmented copolymer of the diblock copolymer of the triblock copolymer of BAB block configuration, BA block configuration, A (BA) n block configuration or the segmented copolymer of B (AB) n block configuration, and wherein n is 2 to 10 integer; At least one polymer of described polymer does not have the character of heat-convertible gel;
Described hydrophobicity block polymer is preferably PLGA-PEG-PLGA copolymer; Wherein the number-average molecular weight of PLGA block is 1000～2000, and better is 1571; In PLGA block, the mol ratio of lactic acid units and hydroxyacetic acid unit is 1～10, and better is 4; The number-average molecular weight of PEG block is 1400～1600, and better is 1500; The molecular weight distribution coefficient of described hydrophobicity block polymer is 1.01～1.40, and better is 1.23;
Described hydrophilic block polymer is preferably PLGA-PEG-PLGA copolymer, and wherein the number-average molecular weight of PLGA block is 800～1600, and better is 1255; In PLGA block, the mol ratio of lactic acid units and hydroxyacetic acid unit is 1～10, and better is 4; The number-average molecular weight of PEG block is 1000～2000, and better is 1500; The molecular weight distribution coefficient of described hydrophilic block polymer is 1.01～1.50, and better is 1.15.
10. a preparation method for the thermosensitive hydrogel pharmaceutical preparation as described in claim 1-9 any one, is characterized in that, it comprises the steps: by composition of raw materials, each composition is dissolved in to the thermosensitive hydrogel compositions existing with solution form;
When described adjuvant C contains slaine, slaine is uniformly dissolved and is mixed in aqueous solution with medicine, then lyophilization, evenly mixes with thermosensitive hydrogel compositions afterwards again;
When described adjuvant C contains glucide, glucide is directly dissolved in to thermosensitive hydrogel compositions; Or be uniformly dissolved and mix in aqueous solution with medicine, then lyophilization, evenly mixes with thermosensitive hydrogel compositions afterwards again.
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| CN105982845A (en) * | 2015-02-17 | 2016-10-05 | 复旦大学 | Thermotropic hydrogel hypoglycemic drug preparation and preparing method thereof |
| CN107281502A (en) * | 2016-04-05 | 2017-10-24 | 上海市肿瘤研究所 | The compound development thermo-sensitive gel suppository of one kind, preparation method and applications |
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| CN105982845A (en) * | 2015-02-17 | 2016-10-05 | 复旦大学 | Thermotropic hydrogel hypoglycemic drug preparation and preparing method thereof |
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| CN111286204A (en) * | 2020-03-12 | 2020-06-16 | 复旦大学 | Polymer compound capable of being rapidly dissolved or dispersed in aqueous solvent and preparation method and application thereof |
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| WO2023230720A1 (en) * | 2022-05-31 | 2023-12-07 | Everbond Interface Technologies, Inc. | Reactive gel material for sustained water-based reactions |
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