CN113121832A - PVA-g-mPEG graft polymer for preventing drug abuse and preparation method thereof - Google Patents
PVA-g-mPEG graft polymer for preventing drug abuse and preparation method thereof Download PDFInfo
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- CN113121832A CN113121832A CN202110260140.2A CN202110260140A CN113121832A CN 113121832 A CN113121832 A CN 113121832A CN 202110260140 A CN202110260140 A CN 202110260140A CN 113121832 A CN113121832 A CN 113121832A
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- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G81/00—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers
- C08G81/02—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers at least one of the polymers being obtained by reactions involving only carbon-to-carbon unsaturated bonds
- C08G81/024—Block or graft polymers containing sequences of polymers of C08C or C08F and of polymers of C08G
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
Abstract
The invention discloses a PVA-g-mPEG graft polymer for preventing drug abuse and a preparation method thereof, relating to the technical field of high molecular materials, wherein the PVA-g-mPEG graft polymer with a novel structure is successfully prepared through molecular design, and is prepared by carrying out etherification reaction on mPEG with terminal hydroxyl groups being subjected to epichlorohydrin and PVA under an alkaline condition; the grafted polymer can effectively prevent the extraction of the drugs in water by forming gel when meeting water, thereby preventing the drugs from being abused through intravenous injection, being an innovative potential auxiliary material for developing an abuse-proof preparation and providing a new idea for the abuse-proof research.
Description
The technical field is as follows:
the invention relates to the technical field of high polymer materials, in particular to a PVA-g-mPEG graft polymer for preventing drug abuse and a preparation method thereof.
Background art:
despite the general safety and addiction problems associated with opioid analgesics, there is an increasing need for analgesia. Surveys showed that the global analgesic market size was $ 710 billion in 2019, and is expected to grow to $ 920 billion by 2027. Chinese analgesics are relatively small in market size, about $ 5.3 billion in 2017, and are mostly used for surgical analgesia.
Drug abusers tamper with drug products by altering the dosage form to make them suitable for abusive routes of administration, such as bulk oral or chewing, snuff or powder, intravenous injection, etc., thereby producing a euphoric effect, the common practice consisting essentially of crushing the tablets and solvent extracting the active ingredient.
Abuse deterrent Agents (ADFs) have emerged as a result of the increasing abuse of opioids. ADFs opioid drugs are mainly modified in a series to reduce the abuse desirability of the opioid drugs, and the specific measures include adding a physical barrier to make the tablets difficult to grind and crush, setting a chemical barrier to reduce the extraction efficiency of a drug solvent by forming a viscous gel, adding an antagonist or an aversion agent, preparing a prodrug and the like to eliminate the euphoria of the drugs.
Currently approved ADFs products on the market primarily deter drug abuse by adding a physicochemical barrier, and high molecular weight polyethylene oxide (PEO) is widely used in such commercial products. PEO is a non-ionic, non-toxic hydrophilic polymer with a molecular weight between 10 and 700 million that, when contacted with water, rapidly hydrates to form a viscous gel that can deter injection abuse. The glass transition temperature of PEO is between-50 ℃ and-57 ℃, and the lower glass transition temperature causes the PEO to be subjected to plastic deformation rather than brittle fracture under the action of mechanical stress, so that the tablets are effectively prevented from being crushed when being crushed by external force.
Because of its unique properties, PEO is widely used in the development of ADFs, but the conditions for preparing PEO with high molecular weight are more severe, the catalytic system is complex, expensive or dangerous, the technical requirements for process implementation are high, the difficulty is high, and the market is basically monopolized by the american enterprises such as the dow chemical company and the like.
Zhang Mei et al (Proc. Chem. of higher school, 2005,26(1): 170) use graft copolymerization to graft PEG with phase transition characteristics onto the main chain of polyvinyl alcohol (PVA) with higher melting point to obtain PVA-g-PEG high molecular solid-solid phase transition material with stable performance (toluene diisocyanate reacts with the hydroxyl group of PEG first and then with PVA to undergo graft reaction). The synthesized PVA-g-PEG high molecular solid-solid phase transition material can be widely used for refrigeration and cold accumulation of refrigerators and air conditioners, automatic constant temperature devices of intelligent buildings, preservation boxes, heat-proof shells of electric appliances and the like.
Kollicoat IR, a product of BASF, Germany chemical company, is a PVA-g-PEG graft copolymer, which is prepared by firstly generating active free radicals on a polyethylene glycol (PEG) chain to initiate vinyl acetate polymerization to form side branch chain-polyvinyl acetate, and then hydrolyzing the side branch chain-polyvinyl acetate into PVA; the final copolymer, which is composed of approximately 75% PVA units and 25% PEG units, is strictly PEG-g-PVA, is used primarily as a film-forming agent in foods, tablets and pellet immediate release coatings.
The invention content is as follows:
the invention aims to solve the technical problem of providing a PVA-g-mPEG graft polymer for preventing drug abuse, which is prepared by carrying out etherification reaction on mPEG with terminal hydroxyl groups being epichlorohydrized and PVA under an alkaline condition, and the graft polymer can effectively prevent the extraction of drugs in water by forming gel in water, thereby preventing the drugs from being abused through intravenous injection.
The technical problem to be solved by the invention is realized by adopting the following technical scheme:
a PVA-g-mPEG graft polymer for preventing drug abuse, which has a structural formula as follows:
the preparation method of the PVA-g-mPEG graft polymer for preventing drug abuse comprises the following steps:
(1) epichlorohydrin of mPEG: melting mPEG, adding a Lewis acid catalyst at the temperature lower than 60 ℃, then slowly dropwise adding ECH (epichlorohydrin), reacting for 3-6 h at the temperature of 55-70 ℃, quenching the reaction after the reaction is finished, and removing excessive ECH by rotary evaporation to obtain an epichlorohydrin intermediate (mPEG-Cl) of mPEG;
(2) preparation of PVA-g-mPEG graft Polymer: uniformly stirring the prepared mPEG-Cl and a PVA aqueous solution, then dropwise adding an alkali liquor at 70-90 ℃, reacting for 3-10 h, after the reaction is finished, adjusting the pH to be neutral by using hydrochloric acid, performing Soxhlet extraction to separate unreacted mPEG-Cl, filtering, performing vacuum drying on a precipitate to obtain a PVA-g-mPEG crude graft polymer, then dialyzing by using purified water, and performing vacuum drying to obtain a purified PVA-g-mPEG graft polymer.
The molecular weight of mPEG in the step (1) is not less than 800, and is preferably 4000-50000.
In the step (1), mPEG is melted at the temperature of 100-160 ℃ and decompressed for 4-6 h to remove water.
The Lewis acid catalyst in the step (1) is AlCl3、BF3、SbCl5、FeBr3、FeCl3、SnCl4、TiCl4、ZnCl2At least one Lewis acid catalyst, wherein the weight percentage of the Lewis acid catalyst is 0.5-2% of mPEG.
The molar ratio of mPEG to ECH in the step (1) is 1: 1-5.
The types of the PVA in the step (2) comprise PVA1792, 1788 and 1799.
The mPEG-Cl intermediate in the step (2) is 10-20% (w/v) of aqueous solution or molten state.
The molar ratio of PVA to mPEG-Cl in the step (2) is 1: 25-100.
The alkali liquor in the step (2) is NaOH, KOH or NaHCO3、KHCO3、Na2CO3、K2CO3The molar ratio of the alkali to the mPEG-Cl is 1: 1-12; the concentration of the alkali liquor is 5-10% (w/w).
The solvent for Soxhlet extraction in the step (2) is at least one of methanol, ethanol, ethylene glycol, acetone, dichloroethane and ethyl acetate.
The invention has the beneficial effects that: the invention successfully prepares a PVA-g-mPEG graft polymer with a novel structure through molecular design, the graft polymer is prepared by the etherification reaction of mPEG with terminal hydroxyl being epichlorohydrized and PVA under the alkaline condition, the preparation method has simple process, stable and reliable preparation process, and the adopted raw materials are abundant and easy to obtain; the grafted polymer can effectively prevent the extraction of the drugs in water by forming gel when meeting water, thereby preventing the drugs from being abused through intravenous injection, being an innovative potential auxiliary material for developing an abuse-proof preparation and providing a new idea for the abuse-proof research.
Description of the drawings:
FIG. 1 is an infrared spectrum of the raw materials mPEG, PVA, intermediate mPEG-Cl and graft polymer PVA-g-mPEG of the present invention;
FIG. 2 is a diagram showing the states of the mPEG, mPEG-Cl, PVA and PVA-g-mPEG of the present invention dissolved and dispersed in water;
wherein, a: mPEG; b: mPEG-Cl; c: PVA; d: PVA-g-mPEG.
The specific implementation mode is as follows:
in order to make the technical means, the original characteristics, the achieved purposes and the effects of the invention easy to understand, the invention is further explained by combining the specific embodiments and the drawings.
Example 1
50g of mPEG (Mw: 4000) was poured into a four-necked flask equipped with a mechanical stirrer, a thermometer and a reflux condenser, and 0.4g of BF was added to the flask at 55 deg.C3-Et2O, 3.92mL ECH, reacted for 5h, then excess ECH was removed by rotary evaporation to give mPEG-Cl.
23.5g of mPEG-Cl and 100g of 8% (w/w) PVA-1788 aqueous solution are stirred uniformly, then 12mL of 10% (w/w) NaOH aqueous solution is added at 90 ℃, the mixture is stirred and reacted for 5 hours, after the reaction is finished, the solution is adjusted to be neutral by hydrochloric acid, and the mPEG-Cl is precipitated and eluted by ethanol, thus obtaining the crude product of the PVA-g-mPEG graft polymer. The crude product was dried under vacuum at 50 ℃ to give PVA-g-mPEG graft polymer.
Example 2
10.93g mPEG-Cl was stirred well with 100g of 8% (w/w) aqueous PVA-1788 solution, then 12mL of 10% (w/w) aqueous NaOH solution was added and the reaction was continued at 70 ℃ for 10 h. After the reaction is finished, hydrochloric acid is used for adjusting the solution to be neutral, and acetone is used for Soxhlet extraction of unreacted side chain mPEG-Cl to obtain a crude product of the PVA-g-mPEG graft polymer. Followed by thorough dialysis against purified water (60 h in a 2L vessel with water change every 12 h) to remove small NaCl molecules and vacuum drying at 50 ℃ to obtain purified PVA-g-mPEG graft polymer.
Example 3
50g mPEG (Mw 1000) was poured into a four-necked flask equipped with a mechanical stirrer, a thermometer and a reflux condenser. 0.3g BF was added to the flask at 70 deg.C3-Et2O, 5.88mL ECH, reacted for 3 h. Excess ECH was then removed by rotary evaporation to give mPEG-Cl.
55mL of 10% (w/v) aqueous solution of the prepared mPEG-Cl intermediate was added to a four-necked flask containing 50g of 8% (w/w) PVA-1788 aqueous solution, and after stirring, 12mL of 10% (w/w) NaOH aqueous solution was added and reacted at 70 ℃ for 10 hours. After the reaction is finished, hydrochloric acid is used for adjusting the solution to be neutral, and acetone is used for Soxhlet extraction of unreacted side chain mPEG-Cl to obtain a crude product of the PVA-g-mPEG graft polymer. Followed by thorough dialysis with purified water (dialysis in a 2L vessel for 60h, water change every 12 h) to remove small molecular NaCl and vacuum drying at 50 ℃ to obtain purified PVA-g-mPEG graft polymer.
As can be seen from FIG. 1, the spectrum of the intermediate mPEG-Cl has a characteristic peak of C-Cl bonds at a wave number of 740cm < -1 >, and the reaction belongs to end group reaction, so that the content of the C-Cl bonds is low, and the vibration intensity of the C-Cl bonds in the spectrum is weak. The main characteristic bands of the starting PVA and mPEG were observed in the IR spectrum of the PVA-g-mPEG graft polymer. The PVA-g-mPEG graft polymer shows a stretching vibration peak of a hydroxyl group at 3326cm-1, and a very strong characteristic peak at 1095cm-1 is attributed to stretching vibration of an ether bond C-O-C, indicating that mPEG is grafted to a PVA main chain. Meanwhile, the characteristic peak of the C-Cl bond of the mPEG-Cl is not found in the infrared spectrum of the graft, which indicates that the C-Cl group is completely consumed in the grafting reaction, and the product is not a mixture of the mPEG-Cl and PVA, but is PVA-g-mPEG graft polymer formed by ether oxygen bond.
As can be seen from FIG. 2, the raw materials and intermediates have good solubility in water, and can form a uniform aqueous solution; the graft forms gel when meeting water, and further can effectively prevent the extraction of the medicine in the water.
The foregoing shows and describes the general principles and broad features of the present invention and advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (10)
1. A PVA-g-mPEG graft polymer protected from drug abuse, wherein the PVA-g-mPEG graft polymer has the formula:
2. the method for preparing the PVA-g-mPEG graft polymer according to claim 1, which comprises the following steps:
(1) epichlorohydrin of mPEG: melting mPEG, adding a Lewis acid catalyst at the temperature lower than 60 ℃, then slowly dropwise adding ECH, reacting for 3-6 h at the temperature of 55-70 ℃, quenching the reaction after the reaction is finished, and removing excessive ECH by rotary evaporation to obtain mPEG-Cl;
(2) preparation of PVA-g-mPEG graft Polymer: uniformly stirring the prepared mPEG-Cl and a PVA aqueous solution, then dropwise adding an alkali liquor at 70-90 ℃, reacting for 3-10 h, after the reaction is finished, adjusting the pH to be neutral by using hydrochloric acid, performing Soxhlet extraction to separate unreacted mPEG-Cl, filtering, performing vacuum drying on a precipitate to obtain a PVA-g-mPEG crude graft polymer, then dialyzing by using purified water, and performing vacuum drying to obtain a purified PVA-g-mPEG graft polymer.
3. The method for preparing a PVA-g-mPEG graft polymer according to claim 2, characterized in that: the molecular weight of mPEG in the step (1) is not less than 800.
4. The method for preparing a PVA-g-mPEG graft polymer according to claim 2, characterized in that: in the step (1), mPEG is melted at the temperature of 100-160 ℃ and decompressed for 4-6 h to remove water.
5. The method for preparing a PVA-g-mPEG graft polymer according to claim 2, characterized in that: the Lewis acid catalyst in the step (1) is AlCl3、BF3、SbCl5、FeBr3、FeCl3、SnCl4、TiCl4、ZnCl2At least one Lewis acid catalyst, wherein the weight percentage of the Lewis acid catalyst is 0.5-2% of mPEG.
6. The method for preparing a PVA-g-mPEG graft polymer according to claim 2, characterized in that: the types of the PVA in the step (2) comprise PVA1792, 1788 and 1799.
7. The method for preparing a PVA-g-mPEG graft polymer according to claim 2, characterized in that: the mPEG-Cl intermediate in the step (2) is 10-20% (w/v) of aqueous solution or molten state.
8. The method for preparing a PVA-g-mPEG graft polymer according to claim 2, characterized in that: the molar ratio of mPEG to ECH in the step (1) is 1: 1-5; the molar ratio of PVA to mPEG-Cl in the step (2) is 1: 25-100.
9. The method for preparing a PVA-g-mPEG graft polymer according to claim 2, characterized in that: the alkali liquor in the step (2) is NaOH, KOH or NaHCO3、KHCO3、Na2CO3、K2CO3In an aqueous solution of (1: 1E) base to mPEG-Cl in a molar ratio of 1:112; the concentration of the alkali liquor is 5-10% (w/w).
10. The method for preparing a PVA-g-mPEG graft polymer according to claim 2, characterized in that: the solvent for Soxhlet extraction in the step (2) is at least one of methanol, ethanol, ethylene glycol, acetone, dichloroethane and ethyl acetate.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100038297A1 (en) * | 2006-06-14 | 2010-02-18 | Julian Xiao-Xia Zhu | Poly (Vinyl Alcohol) Polymers, Uses and Preparation Thereof |
| CN102492112A (en) * | 2011-11-22 | 2012-06-13 | 吉林大学 | Method for preparing polyethylene glycol-polyvinyl alcohol temperature sensing hydrogel |
| CN107988737A (en) * | 2017-12-30 | 2018-05-04 | 绍兴恒钧环保科技有限公司 | Pure-cotton fabric short-flow pre-treating process |
| CN110437456A (en) * | 2019-07-31 | 2019-11-12 | 华中科技大学 | A kind of self-healing polymer and the preparation method and application thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100038297A1 (en) * | 2006-06-14 | 2010-02-18 | Julian Xiao-Xia Zhu | Poly (Vinyl Alcohol) Polymers, Uses and Preparation Thereof |
| CN102492112A (en) * | 2011-11-22 | 2012-06-13 | 吉林大学 | Method for preparing polyethylene glycol-polyvinyl alcohol temperature sensing hydrogel |
| CN107988737A (en) * | 2017-12-30 | 2018-05-04 | 绍兴恒钧环保科技有限公司 | Pure-cotton fabric short-flow pre-treating process |
| CN110437456A (en) * | 2019-07-31 | 2019-11-12 | 华中科技大学 | A kind of self-healing polymer and the preparation method and application thereof |
Non-Patent Citations (1)
| Title |
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| 张梅: ""聚乙二醇/聚乙烯醇高分子固-固相变材料的合成与性能研究"", 《中国博士学位论文全文数据库 工程科技Ⅰ辑》 * |
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