CN102228696B - Polyethylene glycol-polyvinyl alcohol copolymer-metaxalone prodrug and synthesis method thereof - Google Patents
Polyethylene glycol-polyvinyl alcohol copolymer-metaxalone prodrug and synthesis method thereof Download PDFInfo
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- CN102228696B CN102228696B CN 201110162519 CN201110162519A CN102228696B CN 102228696 B CN102228696 B CN 102228696B CN 201110162519 CN201110162519 CN 201110162519 CN 201110162519 A CN201110162519 A CN 201110162519A CN 102228696 B CN102228696 B CN 102228696B
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Abstract
The invention discloses a polyethylene glycol-polyvinyl alcohol copolymer-metaxalone (PEG-PVA-Met) prodrug which is shown as a structural general formula (I), wherein R is a formula which is shown in the specification; n is 10-100; and X is an integer from 3 to 10. Through the PEG-PVA-Met macromolecular prodrug synthesized by the invention, the water solubility of the small molecular drug of metaxalone can be improved, the half-life period of the prodrug is prolonged, and the release of the prodrug in a human body can also be effectively controlled. The prodrug is undoubtedly good for many chronic patients.
Description
Technical field
The present invention relates to a kind of polyethylene glycol-ethenol copolymer as metaxalone prodrug and the synthetic method thereof of carrier, belong to technical field of medicine synthesis.
Background technology
Development along with polymer science and modern medicine, Polymer Materials for Controlled Drug Release (PDDS) has become popular research field, according to the model of action between medicine and the macromolecule carrier, PDDS can be divided into two classes, a kind of be medicine with physics mode by the sustained release system of macromolecule carrier embedding, the drug controlled release system that namely adopts encapsulation or complex technique to obtain.Another kind is to adopt the covalent bond interconnection technique that macromolecule carrier is connected with small-molecule drug with covalent chemical bond and the macromolecular prodrug that obtains, also claims polymeric prodrugs.Prodrug is a kind of special medicament forms, and this medicine is keeping nonactive before transhipment arrives action site, just can discharge active medicine after activating by specific condition at target site.Although low-molecule drug curative effect in the past is high, and is easy to use, many kinds wherein but exist very large side effect.General low-molecule drug all is to enter human body by oral or injection, and in the short time after advancing medicine, the concentration of blood Chinese medicine is considerably beyond the required concentration for the treatment of, too high concentration may make the people poison, irritated etc.Simultaneously they rate of metabolism is fast in vivo, the half-life is short, easily drain, so along with the putting off of time, the very fast reduction of the concentration of medicament and affecting the treatment.On the other hand, appointed part also lacks selectivity to low-molecule drug in the body to entering, and this also is to increase into dose, one of reason that curative effect is lower.The advantages such as that macromolecular drug has is long-acting, efficient, low toxicity, slow release, selectivity is good, side effect is little.A kind of effective method that improves curative effect of medication is exactly that the low molecule medicine that will have pharmacologically active changes into inactive derivant (namely macromolecular prodrug) by chemical method, and in general the synthetic of macromolecular prodrug is will hang down the molecule medicine by covalent bond to be connected on the suitable macromole.This macromolecular prodrug can become low molecule medicine and macromole by hydrolysis or enzymolysis in human body.Macromolecular prodrug on the one hand can reduce side effects of pharmaceutical drugs effectively, reduces consumption release time that on the other hand can prolong drug, increases dissolubility.If use the targeting poly compound to be combined with low-molecule drug, this macromolecular prodrug may be gathered on the cell of pathological changes, and does not affect other normal cell, has both reached the purpose for the treatment of, can not cause large side effect to the people again.This shows that the macromole medical instrument has very large practical significance.
The rhythm of life that modern society is fast and keen competition, make most people bear huge life stress, therefore, the diseases such as anxiety, lumbago and backache, skelalgia, arthralgia become common health problem, especially sprain, dampen and make the people more painful, cause live in straitened circumstances cisco unity malfunction and study.According to document announcement, there is 70%～85% adult to suffer the puzzlement of backache, worldwide, myalgia becomes second largest disease.
Metaxalone (chemical name: 5-[(3,5-dimethyl benzene oxygen) methyl]-the 2-oxazolidone, metaxalone, be called for short: Met) be the central muscle-relaxing drug, spinal cord polysynaptic pathway capable of blocking has sedation, also has cholinolytic and antipyretic effect.Clinically be mainly used in treating the local myalgia that inflammation, wound etc. cause.Drugs approved by FDA listing in 2002.Metaxalone is glucuronide at liver metabolism, discharges through kidney.Although metaxalone is as novel nondepolarizing type muscle relaxant, have advantage clearly, but also have some untoward reaction, such as drowsiness, anorexia, feel sick, vomiting, dizziness, xerostomia, urine retention, anemia and jaundice, pyuria and renal calculus can appear in severe patient.The poorly water-soluble of metaxalone, the half-life only has 2～3h, makes its application be subject to certain restriction.
The water-soluble macromolecule material is extraordinary medicine control release vehicle, if with small-molecule drug by being hydrolyzed or the covalent bond of enzymolysis is connected with them and is prepared into macromolecular prodrug, can effectively prolong the half-life of micromolecule medicine, increase dissolubility, improve the therapeutic effect of medicine, reduce side effect etc.
Polyethylene Glycol (Polyethylene glycol, PEG) has good water solublity, can increase the blood plasma anelasticity, reduces protein immunization, improves therapeutic index, and therefore, PEG becomes the first-selected polymer support of synthetic macromolecule prodrug.The appearance of Pegylation technology in 1989 is polyethyleneglycol modified bioactive molecule, or macromolecular prodrug synthetic provides necessary technical guarantee.Over more than 30 year, scientist has developed many technology, in order to making up Polyethylene Glycol and medicine, or the junctional complex of other bioactive molecule.Polyethylene Glycol as the Heterosis of carrier following some: (1) PEG has amphipathic, both can be water-soluble, can be dissolved in again most organic solvents.(2) nontoxic, without teratogenecity, non-immunogenicity, have fine biocompatibility.(3) with other polymer phase ratio, the molecular weight of PEG not only distributes wide, and lower, is suitable as very much the carrier of synthetic macromolecule prodrug.(4) its many advantageous properties can be given biomolecule after the modification.Although Polyethylene Glycol has the clear superiority as the macromolecular carrier of prodrug, but because the peg molecule end of the chain only has 1～2 activity hydroxy, cause its struck capacity low, the active drug molecule that is connected on the polymer chain is few, often is difficult to obtain high charging ratio.The activated group of polyvinyl alcohol is many, and each has a hydroxyl above the construction unit, all can be connected with medicine, and drug loading can change according to condition, but its rate of dissolution in water is slow, needs suitable heating just can reach quick dissolving.If the copolymer of polyvinyl alcohol and Polyethylene Glycol as pharmaceutical carrier, might both can be guaranteed the water solublity that polymer is good, can increase again the activated group of polymer support, prepare the macromolecular prodrug of high drug load, this is innovation of the present invention place just.
For the metaxalone poorly water-soluble, the problems such as the half-life is short, the inventor utilizes the copolymer of polyvinyl alcohol and Polyethylene Glycol to make carrier, be connected with metaxalone by covalent bond, the synthetic macromolecule prodrug, improve the water solublity of small-molecule drug metaxalone, prolong its half-life, make it in human body, can effectively control the release of its medicine.
Summary of the invention
The object of the present invention is to provide a kind of good biocompatibility, good water solubility, have the PEG-PVA-Met macromolecular prodrug of control slow-release function.
Another object of the present invention is to provide the synthetic method of PEG-PVA-Met prodrug.
Implementation procedure of the present invention is as follows:
PEG-PVA-Met prodrug shown in the general structure (I),
Wherein, R is
, n is 10-100, X is the integer of 3-10.
The synthetic method of above-mentioned PEG-PVA-Met prodrug comprises the steps:
(1) reaction of 5-aryloxy methyl-2-oxazolidone and chloracetyl chloride obtains N-chloracetyl-5-[(3,5-dimethyl benzene oxygen) methyl]-the 2-oxazolidone;
(2) polyethylene glycol-ethenol copolymer and N-chloracetyl-5-[(3,5-dimethyl benzene oxygen) methyl]-2-oxazolidone reaction obtains the PEG-PVA-Met prodrug, reaction is carried out at 40～70 ℃, is preferably in 55～65 ℃ and carries out; Reaction dissolvent adopts DMF.
The concrete synthesis step that the present invention adopts is as follows:
(1) N-chloracetyl-5-[(3,5-dimethyl benzene oxygen) methyl]-the 2-oxazolidone
In four-hole bottle, add 5-aryloxy methyl-2-oxazolidone, triethylamine and toluene stir, and when treating that temperature rises to 50 ℃, drip chloracetyl chloride, react 3 h, are cooled to room temperature, add suitable quantity of water, stir, and crystallization gets white needle-like crystals.
(2) PEG-PVA-Met (PEG-PVA-Met) prodrug is synthetic
In four-hole bottle, add PEG-PVA, DMF and N-chloracetyl-5-[(3,5-dimethyl benzene oxygen) methyl]-the 2-oxazolidone, 40～70 ℃ were reacted 8-20 hour, then were cooled to room temperature, filtered, and drying obtains white PEG-PVA-Met solid.
The present invention also provides the rate of releasing drug of PEG-PVA-Met in pH=1.1, pH=7.4 and pH=10.0 buffer solution.The result shows: PEG-PVA-Met can slowly release the female medicine metaxalone of micromolecule; PEG-PVA-Met is in pH=1.1 buffer solution, and the rate of release of metaxalone is the slowest; In the buffer solution of pH=10.0, the rate of release of metaxalone is the fastest.Along with buffer solution alkalescence increases, the hydrolysis rate of macromolecular prodrug increases, and is consistent with the hydrolysis situation of amido link.Amido link is easily hydrolysis under alkali condition, and the namely easily fracture under alkali condition of the amido link in the PEG-PVA-Met macromole easily discharges the small-molecule drug metaxalone.
The PEG-PVA-Met macromolecular prodrug that the present invention synthesizes can not only increase the water solublity of small-molecule drug metaxalone, prolongs its half-life, and can also effectively control the release of its medicine in human body, and this is undoubtedly a lot of chronics' Gospel.
Description of drawings
[0003] Fig. 1 is synthetic route chart of the present invention;
The DSC collection of illustrative plates of Fig. 2 Met and PEG-PVA-Met;
The IR collection of illustrative plates of Fig. 3 PEG-PVA and PEG-PVA-Met;
The release curve of Fig. 4 PEG-PVA-Met in different buffer solution;
The release curve of Fig. 5 PEG-PVA-Met when Chymetin exists and do not exist.
The specific embodiment
The invention will be further described below in conjunction with specific embodiment.
The reagent specification that the present invention adopts is as follows: polyethylene glycol-ethenol copolymer (on the grand chemical industry company limited of transporting by sea provide, the husband of BASF Aktiengesellschaft produces, polyvinyl alcohol and Polyethylene Glycol mole are than being 3:1, molecular weight 45000); DMF; Acetone (traditional Chinese medicines group, CP); DMF (DMF Tianjin Fu Yu Fine Chemical Co., Ltd, AR); The chloracetyl metaxalone.
The synthetic synthetic route of polyethylene glycol-vinyl alcohol-metaxalone as shown in Figure 1.
Embodiment 1:PEG-PVA-Na's is synthetic
Adding successively new steaming of 25ml DMF(in the 50ml three-necked bottle of thermometer, condensing tube is housed dewaters), 3.0g PEG-PVA, slowly heating and vigorous stirring are to fully dissolving (about 110 ℃), be cooled to 60 ℃, add 0.25g sodium, keep the system temperature 60 C, reaction 4h, sucking filtration is removed insoluble matter, gets the pale red clear solution.
Embodiment 2:N-chloracetyl-5-[(3,5-dimethyl benzene oxygen) methyl]-2-oxazolidone synthetic
In the 100mL four-hole bottle of mechanical agitator, condensing tube, thermometer and Dropping funnel is housed, add 0.002mol 5-aryloxy methyl-2-oxazolidone, 0.002mol triethylamine and 15mL toluene stir.When treating that temperature rises to 50 ℃, drip the mixed liquor of 0.0032mol chloracetyl chloride and 10mL toluene, and the control rate of addition makes reaction temperature be no more than 50 ℃.After dropwising, be heated to backflow, react 3 h, be cooled to room temperature, add 5mL water, stir, crystallization, filtration and with water wash 3 times get white needle-like crystals.Mother solution water extracting twice merges organic layer, the toluene that distilling under reduced pressure is excessive, and crystallization is filtered, and gets target product chloracetyl-metaxalone.
Embodiment 3: polyethylene glycol-vinyl alcohol-metaxalone synthetic
In the mother solution (1) of embodiment 1, add 1.8g chloracetyl-metaxalone that embodiment 2 synthesizes, stir, and keep 60 ℃ of reaction temperatures, reaction 6h.React complete; distilling under reduced pressure goes out most of DMF; add precipitant acetone under the vigorous stirring, produce in a large number precipitation, sucking filtration; fully embathe precipitation three times with acetone; until do not contain the chloracetyl metaxalone in the washing liquid, put into the dry 2d of exsiccator, get pale solid; be PEG-PVA-Met, 2.8g weighs to get.
The synthetic PEG-PVA-Met prodrug that obtains has been carried out DSC and IR analysis, and the result is as follows:
As shown in Figure 2, can find out from the DSC thermal analysis curve that the fusing point of metaxalone is 124.6 ℃.And in the DSC collection of illustrative plates of synthetic PEG-PVA-Met prodrug, there is not obvious endothermic peak to occur near this temperature, two endothermic peaks of PEG-PVA-Met are 108 ℃ and 215 ℃, it can be said that bright: (1) metaxalone and PEG-PVA are generating the PEG-PVA-Met macromolecular prodrug after the reaction under the condition of determining; (2) illustrate do not have unreacted metaxalone to exist in the product.
Can find out from the infrared spectrum curve of Fig. 3 PEG-PVA and PEG-PVA-Met, at 3420cm
-1Near strong absworption peak is the hydroxyl stretching vibration absworption peak in the PEG-PVA strand; 2923 cm
-1With 2856 cm
-1Absworption peak is methylene asymmetrical stretching vibration and symmetrical stretching vibration absworption peak near two places; 1457 cm
-1The place is methylene in-plane deformation vibration absorption peak; 1089 cm
-1The place is C-O-C ehter bond stretching vibration peak in the peg molecule chain; Contrasting two collection of illustrative plates differences is: in the PEG-PVA-Met spectrogram at 3035 cm
-1It is to connect the proton hydrogen stretching vibration peak on the phenyl ring in the medicine metaxalone molecule, 1652 cm that there is absworption peak at the place
-1The place is the carbonylic stretching vibration peak, and showing has amido link to generate 1731 cm in the macromolecular prodrug that is synthesized
-1Stretching vibration peak for ester carbonyl group in the five-membered ring in the Met molecule.Contrast by two figure can find out that Met has been connected on the PEG-PVA copolymer.
The present invention has also studied the impact of differential responses temperature on drug loading, as shown in table 1, during synthesizing polyethylene glycol-polyvinyl alcohol-metaxalone during metaxalone, metaxalone and PEG-PVA rate of charge are the 1:1(mass ratio), along with reaction temperature rises to 60 ℃ from 40 ℃, its drug loading also constantly increasing, reaches maximum 22.8%; After temperature was elevated to 70 ℃, drug loading began to descend.So selecting best reaction temperature is 60 ℃.The reason that the temperature high drug load descends may be: the one, and female medicine metaxalone is failed to be connected with carrier and is just had decomposition partly under alkali condition; The 2nd, solvent itself has some side reactions and occurs under hot conditions.
As can be seen from Table 1, the present invention adopts the PEG-PVA copolymer, and drug loading is compared existing PEG medicine carrying and is greatly improved.
Embodiment 4: the external control release experiment of polyethylene glycol-vinyl alcohol polymer-metaxalone prodrug
PEG-PVA-Met is respectively charged into the long bag filter (molecular cut off 3500) of 4cm and sealing, puts into respectively pH=1.1 (KCl-glycine/HCl), the pH=7.4 (Na of 40mL
2HPO
4/ KH
2PO
4), pH=8.0(tris/ CaCl
2), pH=10.0(Na
2CO
3/ NaHCO
3) buffer solution in, constant temperature to 37 ℃ carries out release experiment.The 5.0mL that takes a sample at a certain time interval carries out ultraviolet test, quantitatively determines the amount of medicine that this interval discharges, simultaneously to the additional 5.0mL fresh buffer of delivery systme, take the solution of keeping delivery systme as 40 mL.The Cumulative release amount of medicine is calculated as follows.
Cumulative release amount (%)=100 * (40.0C
n+ 5.0 ∑ C (n-1))/W
0
In the formula: W
0The quality (mg) of Met in the-macromolecular prodrug to be measured;
C
n-t discharges the concentration (mg/mL) of Met in the liquid when measuring for the n time in the time, the formula that its value press the working curve match by ultraviolet spectra is definite;
C
N-1Discharge the concentration (mg/mL) of Met in the liquid when measuring for-the n-1 time;
The Met concentration sum that ∑ C (n-1)-front measures for n-1 time.
Fig. 4 has shown that the PEG-PVA-Met macromolecular prodrug is respectively the releasing effect in the 31.5h in three kinds of buffer solution of 1.1,7.4,10.0 at pH.PEG-PVA-Met is very fast in front 5.5h rate of release, and burst size reaches 25.7%, 33.5%, 45.1% of total amount in three kinds of buffer solution; When burst size reaches 50%, the about institute 6.5h that is required to be, 19h and greater than 31.5h respectively; 31.5 total burst size reaches 46.4%, 58.1%, 76 % in the h, the grand mean burst size is: 1.5%/h, 1.8%/h, 2.4%/h.
Embodiment 5: the enzymolysis release experiment of polyethylene glycol-vinyl alcohol polymer-metaxalone prodrug
PEG-PVA-Met is respectively charged into the long bag filter (molecular cut off 3500) of 4cm and sealing, put into respectively pH=8.0(2-amino-2-methylol-1,3-propylene glycol/calcium chloride) contain among the buffer solution 40mL of Chymetin (concentration is the 0.001M HCl solution of 20 μ L * 10-5M), and constant temperature to 37 ℃ carries out releasing research, the 5.0mL that takes a sample at a certain time interval carries out the ultraviolet test, quantitatively determine the amount of medicine that this interval discharges, replenish the 5.0mL fresh buffer to delivery system simultaneously, take the solution of keeping delivery systme as 40mL.
As shown in Figure 5, polyethylene glycol-vinyl alcohol polymer-metaxalone macromolecular prodrug is in the presence of Chymetin, and in the same time interval, the Met that the Met that discharges all discharges when not existing is many, but the amount that increases and little.
Claims (4)
1. the PEG-PVA-Met prodrug shown in the general structure (I),
Wherein, R is
N is 10-100, and X is the integer of 3-10.
2. the synthetic method of PEG-PVA-Met prodrug claimed in claim 1 comprises the steps:
(1) reaction of 5-aryloxy methyl-2-oxazolidone and chloracetyl chloride obtains N-chloracetyl-5-[(3,5-dimethyl benzene oxygen) methyl]-the 2-oxazolidone;
(2) polyethylene glycol-ethenol copolymer and N-chloracetyl-5-[(3,5-dimethyl benzene oxygen) methyl]-the 2-oxazolidone obtains the PEG-PVA-Met prodrug 40～70 ℃ of reactions.
3. the synthetic method of PEG-PVA-Met prodrug according to claim 2 is characterized in that: react and carry out at 55～65 ℃.
4. the synthetic method of PEG-PVA-Met prodrug according to claim 2, it is characterized in that: in the step (2), reaction dissolvent is DMF.
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| 薄澜."连接基在大分子前药合成中的应用及药物缓释研究".《中国优秀硕士学位论文全文数据库》.2006,摘要部分，第17－19页. |
| 薄澜."连接基在大分子前药合成中的应用及药物缓释研究".《中国优秀硕士学位论文全文数据库》.2006,摘要部分,第17-19页. * |
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