CN103804684B - A kind of poe pharmaceutic adjuvant and slow releasing pharmaceutical novel formulation thereof - Google Patents
A kind of poe pharmaceutic adjuvant and slow releasing pharmaceutical novel formulation thereof Download PDFInfo
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- CN103804684B CN103804684B CN201210436124.5A CN201210436124A CN103804684B CN 103804684 B CN103804684 B CN 103804684B CN 201210436124 A CN201210436124 A CN 201210436124A CN 103804684 B CN103804684 B CN 103804684B
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Abstract
The present invention relates to the synthetic method of a kind of surface-etched poe polyamide copolymer (POEAd), and this delivery vector and comprise the controlled release pharmaceutical compositions of activating agent, belong to polymer support and slow controlled-release material technical field.This pharmaceutical composition could be for the partial controllable delivery of this activating agent or injectable dosage form.
Description
Technical field
The present invention relates to the synthetic method of a kind of surface-etched poe-polyamide copolymer, and this delivery vector and comprise the controlled release pharmaceutical compositions of activating agent.This pharmaceutical composition could be for the partial controllable delivery of this activating agent or injectable dosage form.Belong to polymer support and slow controlled-release material technical field.
Background technology
The erosion of biodegradable material mainly has two kinds: mass erosion and surface erosion.There is the entirety at material in mass erosion, not only material surface is degraded, and inside occurs the most simultaneously, and by dispersal events out, rate of release is uncontrollable for the medicine of loading.The degraded of surface erosion only occurs in material surface, and the release of medicine meets first order kinetics process, and the rate of release of medicine is controlled well.Poe backbone structure very hydrophobic, the original acid ester key contained facile hydrolysis under mildly acidic conditions, is a kind of Biodegradable material meeting surface erosion, and traditional synthesis technique has ester-interchange method and addition addition polymerization method, uses polymerization to produce original acid ester key.Both approaches severe reaction conditions, ester-interchange method needs reaction (United States Patent (USP) 4079038 the most for a long time；United States Patent (USP) 4108646), the monomer that the synthesis of addition addition polymerization method needs, to light, moisture-sensitive, is prepared and stores difficulty, poor (the Chinese patent 101052376A of the further functionalization of polymer；Chinese patent 1726043A；United States Patent (USP) 4304767；United States Patent (USP) 4957998) although addition polymerization process achieves bigger success, but need a kind of two (Ketenyl glycol) monomer (DETOSU) (Chinese patent 1726177A；United States Patent (USP) 4513143；United States Patent (USP) 4532335), this monomer is very sensitive to light and dampness, and preparing, storing and using needs exacting terms.
Inventor's early stage the present inventor's early stage is it has been reported that the synthetic method of a kind of diamido ortho-ester monomer and be applied to R&D work (the Rupei Tang in slow releasing pharmaceutical novel formulation field as pharmaceutical carrier, et al., Biomacromolecules 2009,10,722-727；Chinese Patent Application No.: 201010195605.2,201010195627.9), the DETOSU monomer of the addition polymerization effectively overcoming poe material prepares the shortcomings such as difficulty and poor stability, and it is applied to the surface-etched controllable release of activating agent, achieve preferable medicine sustained and controlled release effect.
Summary of the invention
It is an object of the invention to provide a kind of simple, economical, the synthetic method of efficient surface-etched poe-polyamide copolymer (POEAd) of new generation.
Shown in the following Formula I of poe-polyamide copolymer (POEAd) structure of present invention synthesis:
X represents numerical value 2,6 and 10.
Synthetic method of the present invention step in greater detail is as follows:
Under nitrogen atmosphere, one diamido ortho-ester monomer and organic base are dissolved in organic solvent, are subsequently adding aliphatic diacid active ester or aliphatic diacid chloride, stirring reaction 8-24 hour；After reaction terminates, reactant liquor being added dropwise in ether precipitation, filter, after ether washes three times, vacuum drying obtains pure poe-polyamide copolymer (POEAd).
The synthetic method of poe-polyamide copolymer, it is characterised in that: diamido ortho-ester monomer used is the 4 of Formulae II, 4 '-dimethylene oxygen-two-(2-amino ethoxy-1,3-dioxolane):
The synthetic method of poe-polyamide copolymer, it is characterised in that: organic solvent used is second cyanogen, dioxane, oxolane, dichloromethane, chloroform, DMF or dimethyl sulfoxide；Aliphatic diacid active ester used is succinyl weight amido succinate, succinyl weight amido suberate or succinyl weight amido 12 acid esters；Aliphatic diacid chloride used is succinyl chloride, suberoyl chlorine or 12 diacid chlorides, and organic base is triethylamine, DIPEA or pyridine, and reaction temperature is-70-25 DEG C.
A kind of slow releasing pharmaceutical novel formulation, including a kind of activating agent and as the poe-polyamide copolymer of carrier, the number-average molecular weight of polymer is 1000-50000, and described active agents mark accounts for the 1% to 30% of described composition weight, and polymer support weight content is 10-80%；The preparation method of its slow releasing pharmaceutical novel formulation includes using the organic solvent such as ethanol, chloroform to dissolve chatted polymer support and active substance, and solvent is removed in volatilization of reducing pressure；Or in the absence of a solvent, under temperature 40-100 DEG C scope and blanket of nitrogen, described activating agent is dissolved in described polymer support, to obtain being uniformly distributed of described component；By above-mentioned polymer-drug compositions through mould compression molding.
A kind of slow releasing pharmaceutical novel formulation, wherein said activating agent is selected from anti-infective, antibacterial, steroid, therapeutical peptide or albumen, anti-inflammatory agent, cancer chemotherapeutic drug, anesthetics, Bendectin, and wherein said compositions is local or injectable forms.
A kind of method that controlled release topical by activating agent treats disease, including the described activating agent of sustained release pharmaceutical composition form topical treatment effective dose；A kind of prevention or the method alleviating mammal local pain, including being administered the local anesthetic of described site treatment effective dose, described anesthetis selects the group that free bupivacaine, lignocaine, first croak caine, pyrrocaine river prilocaine form；Wherein said activating agent is to select free 5-HT3Antagonist, dopamine antagonist, anticholinergic agent, GABABReceptor stimulating agent, NK1Receptor antagonist and GABAAα2And/or α3The group of receptor stimulating agent composition；Wherein 5-HT3Antagonist selects free ondansetron, granisetron and the group of tropisetron composition.
A kind of method of eye treatment, including any copolymer and the activating agent for eye treatment of therapeutic dose, wherein said activating agent includes the cAMP regulator of therapeutically effective amount, Forskolin, adenyl cyclase activator, stimulates the macrophage-derived factors of cAMP, macrophage activation agent, Calcium ionophore, membrane depolarization agent, phosphodiesterase inhibitor, special phosphodiesterase IV inhibitors, beta-2-adrenoreceptor inhibitor or vasoactive intestinal peptide and neurotrophic factor.
A kind of cancer chemotherapeutic drug, wherein said cancer chemotherapeutic drug is line cancer therapy drugs such as paclitaxel, docetaxel amycin, ciclosporin, carmustine, capecitabine, 5-fluorouracil, camptothecine, hydroxy camptothecin.
A kind of sustained release pharmaceutical composition, wherein said activating agent is antibiotic, anti-inflammatory agent, antiangiogenic agent, also can farther include one or more vitamin.
Detailed description of the invention
Example below will be explained in detail present disclosure, but present disclosure is not limited solely to the following examples.
Embodiment 1
Under nitrogen atmosphere, weigh 0.979g diamine monomer (4,4 '-dimethylene oxygen-two-(2-amino ethoxy-1,3-dioxolane) in bis-mouthfuls of reaction bulbs of 50mL, add 5mLDMF to dissolve, add 1.36mL triethylamine, be subsequently adding 1.348g succinyl weight amido 12 acid esters, add 5mLDMF and react 1-5 days；After completion of the reaction, reactant liquor is added dropwise in the 100mL ethyl acetate containing triethylamine, after dripping off, stands 10min, filtering, ethyl acetate is washed 3 times, and vacuum drying obtains 1.04g white solid powder, i.e. poe-polyamide copolymer (POEd-1), productivity is 65%.
Embodiment 2
The preparation of slow releasing pharmaceutical novel formulation
1) using bupivacaine as the pharmaceutical composition preparation method of activating agent: after a selected amount of poe-polyamide copolymer (POEAd) and bupivacaine mechanical mixture, it is heated to 50-90 DEG C of dissolving under nitrogen atmosphere and stirring, then this solution is made naturally to be cooled to the solid composite medicament that room temperature is uniformly mixed, the wherein weight content 5% to 30% of activating agent.
2) using bupivacaine as the pharmaceutical composition preparation method of activating agent: after a selected amount of poe-polyamide copolymer (POEAd), bupivacaine and poly glycol monomethyl ether mechanical mixture, it is heated to 50-90 DEG C of dissolving under nitrogen atmosphere and stirring, then this solution is made naturally to be cooled to the solid composite medicament that room temperature is uniformly mixed, the wherein weight content 5% to 30% of activating agent, the weight content of poly glycol monomethyl ether is 10-30%.
3) using bupivacaine as the pharmaceutical composition preparation method of activating agent: after a selected amount of poe-polyamide copolymer (POEAd), bupivacaine and PBS (PH7.4) mechanical mixture, it is heated to 50-80 DEG C of dissolving under nitrogen atmosphere and stirring, then this solution is made naturally to be cooled to the pharmaceutical hydrogel compositions that room temperature is uniformly mixed, wherein the weight content of the weight content 5% to 30% of activating agent, polymer and activating agent is 20-90%.
4) with 5-HT3Antagonist is as the pharmaceutical composition preparation method of activating agent: by a selected amount of poe-polyamide copolymer (POEAd) and 5-HT3After antagonist mechanical mixture, under nitrogen atmosphere and stirring, it is heated to 50-90 DEG C of dissolving, then makes this solution naturally be cooled to the solid composite medicament that room temperature is uniformly mixed, the wherein weight content 1% to 20% of activating agent.
5) with 5-HT3Antagonist is as the pharmaceutical composition preparation method of activating agent: by a selected amount of poe-polyamide copolymer (POEAd), 5-HT3After antagonist and poly glycol monomethyl ether mechanical mixture, it is heated to 50-90 DEG C of dissolving under nitrogen atmosphere and stirring, then this solution is made naturally to be cooled to the solid composite medicament that room temperature is uniformly mixed, the wherein weight content 5% to 30% of activating agent, the weight content of poly glycol monomethyl ether is 10-30%.
6) with 5-HT3Antagonist is as the pharmaceutical composition preparation method of activating agent: by a selected amount of poe-polyamide copolymer (POEAd), 5-HT3After antagonist and PBS (PH7.4) mechanical mixture, it is heated to 50-80 DEG C of dissolving under nitrogen atmosphere and stirring, then this solution is made naturally to be cooled to the pharmaceutical hydrogel compositions that room temperature is uniformly mixed, wherein the weight content of activating agent is 1% to 20%, and the weight content of polymer and activating agent is 20-90%.
Embodiment 3
The releasing properties of pharmaceutical composition
The pharmaceutical composition of embodiment of weighing 2, is placed in the bottle of lid.50ml50mMPBS (PH7.4) is joined in each bottle, cultivates with rotating speed 60rpm concussion in 37 DEG C of calorstats.At selected time point, take out about 2ml culture fluid and analyze active agent content by HPLC.Remove the culture fluid of residual quantity and supplement the fresh buffer of same volume.There is the pharmaceutical composition of identical active agent content and copolymer, its drug release rate: organize 3 ＞ group 2 ＞ groups 1；Organize 6 ＞ group 5 ＞ groups 4；For having the pharmaceutical composition 1 of identical active agent content, drug release rate: POEAd-1 ＞ POEAd-2 ＞ POEAd-3.
Experimental result confirms, the pharmaceutical composition of the present invention can regulate in many ways, the drug release rate of control composition, such as change main chain parent/hydrophobic property, categories of excipients and the concentration etc. of copolymer, or the combination of all of these factors taken together regulates rate of release, to adapt to required Curing circumstance and effect.
Each raw material of the present invention and the bound value of pharmaceutical composition and interval value, and cited each raw material can realize the present invention, does not the most enumerate embodiment at this.
Claims (8)
1. the poe of a Formula I-polyamide copolymer pharmaceutic adjuvant (POEAd):
X represents numerical value 2,6 or 10.
2. a synthetic method for the poe of claim 1-polyamide copolymer pharmaceutic adjuvant, is characterized in that:
In a nitrogen atmosphere, one diamido ortho-ester monomer and organic base are dissolved in organic solvent, are subsequently adding aliphatic diacid active ester or aliphatic diacid chloride, stirring reaction 8-24 hour；After reaction terminates, reactant liquor being added dropwise in ether precipitation, filter, after ether washes three times, vacuum drying obtains pure poe-polyamide copolymer；
Diamido ortho-ester monomer used is 4,4 '-dimethylene oxygen-two-(2-amino ethoxy-1,3-dioxolane) of Formulae II:
。
The synthetic method of poe the most according to claim 2-polyamide copolymer pharmaceutic adjuvant, it is characterized in that: organic solvent used is second cyanogen, dioxane, oxolane, dichloromethane, chloroform, DMF or dimethyl sulfoxide；Aliphatic diacid active ester used is succinyl weight amido succinate or succinyl weight amido suberate；Aliphatic diacid chloride used is succinyl chloride or suberoyl chlorine, and organic base is triethylamine, DIPEA or pyridine, and reaction temperature is-70-25 DEG C.
4. a sustained release pharmaceutical formulation, including a kind of activating agent and as the poe described in the claim 1 of carrier-polyamide copolymer pharmaceutic adjuvant, the number-average molecular weight of copolymer is 1000-50000, described activating agent mark accounts for the 1% to 30% of composition weight, copolymerization carrier weight content is 10-80%, wherein, content sum is absolutely；The preparation method of its sustained release pharmaceutical formulation includes using ethanol, chloroform organic solvent to dissolve described copolymerization carrier and activating agent, and solvent is removed in volatilization of reducing pressure；Or in the absence of a solvent, under temperature 40-100 DEG C scope and blanket of nitrogen, described activating agent is dissolved in described copolymerization carrier, to obtain being uniformly distributed of described component；Component will be obtained through mould compression molding.
Sustained release pharmaceutical formulation the most according to claim 4, wherein said activating agent is selected from anti-infective, antibacterial, steroid, therapeutical peptide or albumen, anti-inflammatory agent, cancer chemotherapeutic drug, anesthetics, Bendectin；Described compositions is local or injectable forms.
Sustained release pharmaceutical formulation the most according to claim 4, wherein said activating agent is antibiotic, anti-inflammatory agent, antiangiogenic agent, moreover it is possible to farther include one or more vitamin.
7. the pharmaceutical composition of an eye treatment, including any copolymer and the activating agent for eye treatment of therapeutic dose of the sustained release pharmaceutical formulation described in claim 5, wherein said activating agent includes the cAMP regulator of therapeutically effective amount, Forskolin, adenyl cyclase activator, stimulates the macrophage-derived factors of cAMP, macrophage activation agent, Calcium ionophore, membrane depolarization agent, phosphodiesterase inhibitor, special phosphodiesterase IV inhibitors, beta-2-adrenoreceptor inhibitor or vasoactive intestinal peptide and neurotrophic factor.
Pharmaceutical composition the most according to claim 7, wherein said activating agent is cancer chemotherapeutic drug, and wherein said cancer chemotherapeutic drug is paclitaxel, docetaxel amycin, ciclosporin, carmustine, capecitabine, 5-fluorouracil, camptothecine, hydroxy camptothecin.
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| DE102014226194A1 (en) * | 2014-12-17 | 2016-06-23 | Henkel Ag & Co. Kgaa | Orthoformic acid ester as a perfume precursor |
| CN106075460B (en) * | 2016-07-01 | 2021-03-23 | 安徽大学 | Novel ortho-ester cross-linking agent monomer and method for preparing acid-sensitive nano-drug carrier by using same |
| CN106432715B (en) * | 2016-07-19 | 2020-09-15 | 安徽大学 | Preparation method and application of alternating copolymer P (OE-alt-CL) |
| CN108144067B (en) * | 2017-12-27 | 2020-11-24 | 安徽大学 | Tetravalent platinum compound-bicyclic double-bond amphiphilic polymer prodrug, nano micelle, preparation method and application thereof |
| CN109161022A (en) * | 2018-07-26 | 2019-01-08 | 安徽大学 | Tetravalence platinum complex-ortho esters polymeric prodrugs, its micella and preparation method and application |
| CN109796445B (en) * | 2019-02-19 | 2020-07-14 | 安徽大学 | Indometacin dimer prodrug and preparation method and application thereof |
| CN114366711A (en) * | 2021-12-09 | 2022-04-19 | 安徽大学 | Orthoester miscible medicine medicinal auxiliary material, preparation method and local sustained-release administration preparation containing auxiliary material |
| CN114848585B (en) | 2022-05-20 | 2023-03-28 | 安徽大学 | Improved low-toxicity high-efficiency orthoester miscible medicinal adjuvant, preparation method and local sustained-release drug delivery preparation containing adjuvant |
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| CN101870686A (en) * | 2010-06-09 | 2010-10-27 | 江南大学 | Synthesis method of diamido ortho-ester monomer |
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| CN101870686A (en) * | 2010-06-09 | 2010-10-27 | 江南大学 | Synthesis method of diamido ortho-ester monomer |
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| 生物可降解高分子材料--聚原酸酯;魏民等;《北京生物医学工程》;19990331;第18卷(第1期);60-64 * |
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