Film for medicine packaging and method of preparing the same

Abstract

The present invention discloses a film for a medicine packaging and a method of preparing the same. The film for the medicine packaging includes a polymer film layer, a graphene composite layer and a light-curable adhesive, wherein the polymer film layer is bonded with a graphene composite layer by a light-curable adhesive, the graphene composite layer includes multiple graphene layers bonded by the light-curable adhesive; and the light-curable adhesive includes a hyperbranched cationic mussel-imitated polymer including a multi-hydroxylbenzoylbenzamide ene amide monomer, a cationic monomer and a photo-responsive monomer. The present invention provides strong adhesion with reduced adhesive layer, allowing greatly increasing the number of the graphene layers in the graphene composite layer without obvious increase in the total thickness and mass. This can meet the requirements of the medicine packaging material, as it obviously lowers the film's permeation to water vapor and oxygen and significantly enhances the tensile strength.

Claims

1. A method of preparing a film for a medicine packaging, comprising a polymer film layer, wherein the polymer film layer is bonded with a graphene composite layer by a light-curable adhesive, the graphene composite layer comprises a plurality of graphene layers, and two adjacent graphene layers of the plurality of the graphene layers are bonded by the light-curable adhesive; and the light-curable adhesive comprises a hyperbranched cationic mussel-imitated polymer, and the hyperbranched cationic mussel-imitated polymer comprises a multi-hydroxylbenzoylbenzamide ene amide monomer, a cationic monomer, and a photo-responsive monomer, the method comprising the following steps: (A) using a reversible addition fragmentation chain transfer polymerization method to prepare the hyperbranched cationic mussel-imitated polymer, and formulating the prepared hyperbranched cationic mussel-imitated polymer into an aqueous solution of the light-curable adhesive; (B) preparing a reduced graphene oxide solution; (C) spraying the aqueous solution of the light-curable adhesive prepared in the step (A) on the polymer film layer to form a first adhesive layer, then spraying the reduced graphene oxide solution prepared in the step (B) on the first adhesive layer to form one of the plurality of the graphene layers, and curing the first adhesive layer under a light condition; (D) spraying the aqueous solution of the light-curable adhesive prepared in the step (A) on the one of the plurality of the graphene layers prepared in the step (C) to form a second adhesive layer, then spraying the reduced graphene oxide solution prepared in the step (B) on the second adhesive layer to form another one of the plurality of the graphene layers, and then curing the second adhesive layer under the light condition; and (E) repeating the step (D) until a desired number of layers of the plurality of the graphene layers in the graphene composite layer are achieved.

2. The method of claim 1, wherein the step (A) comprises the following steps: (A1) adding an initiator, a RAFT agent, and a first reaction mixture to a vessel containing DMF to form a second reaction mixture; (A2) stirring the second reaction mixture until homogenous, and introducing argon to a reaction system to remove oxygen therein; (A3) heating and stirring the second reaction mixture to carry out a reaction; (A4) after a product with a desired molecular weight is produced, the reaction system being exposed to air and cooled rapidly in a cold water bath to terminate the reaction; (A5) purifying the product to obtain the hyperbranched cationic mussel-imitated polymer; and (A6) formulating the hyperbranched cationic mussel-imitated polymer into the aqueous solution of the light-curable adhesive having a concentration of 0.5-5 mg/mL; wherein the first reaction mixture comprises the multi-hydroxylbenzoylbenzamide ene amide monomer, the cationic monomer, the photo-responsive monomer, poly(ethylene glycol) diolefine acid ester, and poly(ethylene glycol) olefine acid ester.

3. The method of claim 2, wherein the multi-hydroxylbenzoylbenzamide ene amide monomer has a molar percentage of 20-40%, the cationic monomer has a molar percentage of 30-40%, the photo-responsive monomer has a molar percentage of 1-5%, poly(ethylene glycol) olefine acid ester has a molar percentage of 20-40%, and poly(ethylene glycol) diolefine acid ester has a molar percentage of 5-10%.

4. The method of claim 2, wherein in the step (A1), the initiator, the RAFT agent, and the first reaction mixture are in a molar ratio of 1:2:100.

5. The method of claim 2, wherein the initiator is 1,1-azobis(cyclohexanecarbonitrile), 2,2′-azobis(2-methylpropionitrile), or 4,4′-azobis(4-cyanovaleric acid); and the RAFT agent is any one of 2-(dodecyltrithiocarbonate)-2-methylpropionic acid, 4-cyano-4-(phenylthioformylthio)pentanoic acid, and 2-cyano-2-propyl-4-cyanobenzene dithiocarbonate.

6. The method of claim 1, wherein the step (B) comprises the following steps: (B1) adding graphite powder to concentrated sulfuric acid, stirring until homogenous in an ice water bath and then adding potassium permanganate, controlling a temperature of the ice water bath within a range of 10-15° C., and reacting for 2 hours; (B2) transferring a reaction solution obtained in step (B1) to a water bath to react at a constant temperature of 35° C. for 30 minutes, continually stirring the reaction solution and adding distilled water to the reaction solution, and thereafter reacting at a temperature of 80° C. for 15 minutes; (B3) adding a certain amount of 15 wt % hydrogen peroxide to the reaction solution until generation of bubbles, hot filtering the reaction solution, washing a filter cake with hydrochloric acid and deionized water until a filtrate is neutral, and obtaining an aqueous solution of graphene oxide; (B4) diluting the aqueous solution of graphene oxide with deionized water, and ultrasonically treating the aqueous solution of graphene oxide for 1 hour to obtain a graphene oxide solution having a concentration of 0.1-5.0 mg/mL; and (B5) mixing the prepared graphene oxide solution and a reducing agent at a mass ratio of 1:3, reacting at a room temperature for 2 minutes, and diluting to obtain the reduced graphene oxide solution with a required concentration.

Description

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

(1) In order to make the objects, the technical solutions and the advantages of the present invention clearer, the present invention is now further described in details below with reference to the embodiments or examples. The illustrative embodiments of the present invention and the description thereof are merely for purpose of illustration, and are not intended to limit the invention to the precise embodiments disclosed.

(2) All the raw materials of the present invention are not particularly limited in their sources, and are commercially available or can be prepared in accordance with the conventional methods known to those skilled in the art. For example, the photo-responsive monomer can be synthesized by the esterification reaction, and the multi-hydroxylbenzoylbenzamide acylamide monomer can be synthesized according to the method disclosed in [J] Polymer Bulletin, 2012, 68, 441-452, and in [J] Tetrahedron Letters, 2008, 49, 1336-1339.

(3) All the raw materials of the present invention are not particularly limited in their purity. The present invention preferably employs the analytical purity or the conventional purity in the field of binder preparation.

(4) The expressions of the substitutes in the present invention are not particularly limited, and use the expressions known to those skilled in the art. Based on the common sense, those skilled in the art can correctly understand the meanings of expressions of the substitutes.

(5) All the brands and abbreviations of all the raw materials of the present invention belong to the conventional brands and abbreviations in the field. Each of the brands and abbreviations is clear in its relative fields. The raw materials may be purchased or prepared with the conventional methods by those skilled in the art according to their brands, abbreviations and corresponding use.

Example 1

Preparation of the Hyperbranched Cationic Mussel-Imitated Polymer P1

(6) N-(2-acrylamidoethyl)-3-(2,3,4-trihydroxybenzoyl)benzamide, N-(2-aminoethyl)methacrylamide hydrochloride, N-(2-acrylamidoethyl)-4-azido-2,3,5,6-tetrafluorobenzamide, poly(ethylene glycol)methyl ether acrylate (i.e. PEGMEA), poly(ethylene glycol) diacrylate (i.e. PEGDEA) and the RAFT agent are added to a solution of N,N-dimethylformamide containing the initiator to form a second reaction mixture, wherein the initiator is 4,4′-azobis(4-cyanovaleric acid) and has a concentration of 0.012M. The polymerization of ethylene glycol in the PEGMEA is 15, and the polymerization of ethylene glycol in the PEGDEA is 22. 4,4′-azobis(4-cyanovaleric acid), the raft agent and the first reaction mixture formed by all the monomers involved in the polymerization are in a molar ratio of 1:2:100. The molar percentages of N-(2-acrylamidoethyl)-3-(2,3,4-trihydroxybenzoyl)benzamide, N-(2-aminoethyl)methacrylamide hydrochloride, N-(2-acrylamidoethyl)-4-azido-2,3,5,6-tetrafluorobenzamide, PEGDEA and PEGMEA are respectively 40%, 30%, 5%, 15% and 10%. After the second reaction mixture is stirred uniformly, the argon is introduced to the reaction system for 20-25 minutes to remove the oxygen. Then the reaction system is stirred at a stirring speed of 700 rmp and reacted at a temperature of 70° C. until an expected conversion is reached and a product with a desired molecular weight is obtained. Later, the reaction system is exposed to air and cooled in a cold water bath to terminate the reaction. The product is further purified with dichloromethane and diethyl ether to obtain a light brown hyperbranched cationic mussel-imitated polymer P1. Thereafter, the hyperbranched cationic mussel-imitated polymer P1 is dissolved in ethanol and water (volume ratio is 1:1) to obtain an aqueous solution of the light-curable adhesive S1 having a concentration of 15 wt %.

(7) The structure of the hyperbranched cationic mussel-imitated polymer P1 is as follows:

(8) ##STR00005##

(9) The detection result of the map for the structure of P1 is as follows:

(10) .sup.1H NMR (400 MHz, DMSO-D.sub.6) δ(ppm) 7.90-8.2 (—NHCOC.sub.6H.sub.4CO—) 6.6-7.2 (C.sub.6H.sub.2(OH).sub.3), 5.35 (—C.sub.6H.sub.3(OH).sub.2), 4.32 (CH.sub.2OOC—), 3.50-3.8 (—CH.sub.2CH.sub.2O—, —OCNHCH.sub.2CH.sub.2—), 3.22 (CH.sub.3O—), 3.03 (—OCNHCH.sub.2CH.sub.2NH.sub.3Cl), 2.16 (—CH.sub.2CHCO—), 1.25-1.96 (—CH.sub.2CHCO—);

(11) .sup.19F NMR (188 MHz, DMSO-D.sub.6) δ(ppm) −134.69˜−134.88(2F), −147.58˜−147.71(2F).

Example 2

Preparation of the Hyperbranched Cationic Mussel-Imitated Polymer P2

(12) N-(2-acrylamidoethyl)-4-(2,3,4-trihydroxybenzoyl)benzamide, N-(3-aminopropyl) acrylamide hydrochloride, N-(2-acrylamidoethyl)-4-azido-2,3,5,6-tetrafluorobenzamide, poly(ethylene glycol)methyl ether acrylate (i.e. PEGMEA), poly(ethylene glycol) diacrylate (i.e. PEGDEA) and the RAFT agent are added to a solution of N,N-dimethylformamide containing the initiator to form a second reaction mixture, wherein the initiator is 2,2′-azobis(2-methylpropionitrile) and has a concentration of 0.012M. The polymerization of ethylene glycol in the PEGMEA is 45, and the polymerization of ethylene glycol in the PEGDEA is 10. 2,2′-azobis(2-methylpropionitrile), the raft agent and the first reaction mixture formed by all the monomers involved in the polymerization are in a molar ratio of 1:2:100. The molar percentages of N-(2-acrylamidoethyl)-4-(2,3,4-trihydroxybenzoyl)benzamide, N-(3-aminopropyl) acrylamide hydrochloride, N-(2-acrylamidoethyl)-4-azido-2,3,5,6-tetrafluorobenzamide, PEGDEA and PEGMEA are respectively 20%, 33%, 2%, 35% and 10%. After the second reaction mixture is stirred uniformly, the argon is introduced to the reaction system for 20-25 minutes to remove the oxygen. Then the reaction system is stirred at a stirring speed of 700 rmp and reacted at a temperature of 70° C. until an expected conversion is reached and a product with a desired molecular weight is obtained. Later, the reaction system is exposed to air and cooled in a cold water bath to terminate the reaction. The product is further purified with dichloromethane and diethyl ether to obtain a light brown hyperbranched cationic mussel-imitated polymer P2. Thereafter, the hyperbranched cationic mussel-imitated polymer P2 is dissolved in ethanol and water (volume ratio is 1:1) to obtain an aqueous solution of the light-curable adhesive S2 having a concentration of 15 wt %.

(13) The structure of the hyperbranched cationic mussel-imitated polymer P2 is as follows:

(14) ##STR00006##

(15) The detection result of the map for the structure of P2 is as follows:

(16) .sup.1H NMR (400 MHz, DMSO-D.sub.6) δ(ppm):

(17) 7.90-8.2 (—NHCOC.sub.6H.sub.4CO—) 6.6-7.2 (C.sub.6H.sub.2(OH).sub.3), 5.35 (C.sub.6H.sub.2(OH).sub.3), 4.32 (CH.sub.2OOC—), 3.50-3.8 (—CH.sub.2CH.sub.2O—, —OCNHCH.sub.2CH.sub.2—), 3.22 (CH.sub.3O—), 3.03 (—OCNHCH.sub.2CH.sub.2NH.sub.3Cl), 2.16 (—CH.sub.2CHCO—), 1.25-1.96 (—CH.sub.2CHCO—);

(18) .sup.19F NMR (188 MHz, DMSO-D.sub.6) δ(ppm); −134.69˜−134.88(2F), −147.58˜−147.71(2F).

Example 3

Preparation of the Hyperbranched Cationic Mussel-Imitated Polymer P3

(19) N-(2-acrylamidoethyl)-4-(3,4-dihydroxybenzoyl)benzamide, N-(4-aminobutyl) acrylamide hydrochloride, N-(2-acrylamidoethyl)-4-azidobenzamide, poly(ethylene glycol)methyl ether acrylate (i.e. PEGMEA), poly(ethylene glycol) diacrylate (i.e. PEGDEA) and the RAFT agent are added to a solution of N,N-dimethylformamide containing the initiator to form a second reaction mixture, wherein the RAFT agent is 2-(dodecyltrithiocarbonate)-2-methylpropionic acid, and the initiator is 2,2′-azobis(2-methylpropionitrile) and has a concentration of 0.012M. The polymerization of ethylene glycol in the PEGMEA is 5, and the polymerization of ethylene glycol in the PEGDEA is 8. 2,2′-azobis(2-methylpropionitrile), the raft agent and the first reaction mixture formed by all the monomers involved in the polymerization are in a molar ratio of 1:2:100. The molar percentages of N-(2-acrylamidoethyl)-4-(3,4-dihydroxybenzoyl)benzamide, N-(4-aminobutyl) acrylamide hydrochloride, N-(2-acrylamidoethyl)-4-azidobenzamide, PEGDEA and PEGMEA are respectively 25%, 35%, 5%, 30% and 5%. After the second reaction mixture is stirred uniformly, the argon is introduced to the reaction system for 20-25 minutes to remove the oxygen. Then the reaction system is stirred at a stirring speed of 700 rmp and reacted at a temperature of 70° C. until an expected conversion is reached and a product with a desired molecular weight is obtained. Later, the reaction system is exposed to air and cooled in a cold water bath to terminate the reaction. The product is further purified with dichloromethane and diethyl ether to obtain a light brown hyperbranched cationic mussel-imitated polymer P3. Thereafter, the hyperbranched cationic mussel-imitated polymer P3 is dissolved in ethanol and water (volume ratio is 1:1) to obtain an aqueous solution of the light-curable adhesive S3 having a concentration of 15 wt %.

(20) The structure of the hyperbranched cationic mussel-imitated polymer P3 is as follows:

(21) ##STR00007##

(22) The detection result of the map for the structure of P3 is as follows:

(23) .sup.1H NMR (400 MHz, DMSO-D.sub.6) δ(ppm) 7.90-8.2 (—NHCOC.sub.6H.sub.4CO—) 6.6-7.5 (N.sub.3C.sub.6H.sub.4CO—, —C.sub.6H.sub.3(OH).sub.2), 5.35 (—C.sub.6H.sub.3(OH).sub.3), 4.32 (CH.sub.2OOC—), 3.50-3.8 (—CH.sub.2CH.sub.2O—, —OCNHCH.sub.2CH.sub.2—), 3.22 (CH.sub.3O—), 3.03 (—OCNHCH.sub.2CH.sub.2NH.sub.3Cl), 2.16 (—CH.sub.2CHCO—), 1.25-1.96 (—CH.sub.2CHCO—).

Example 4

Preparation of the Films for Medicine Packaging M1, M2 and M3

(24) At first, the graphene oxide solution with a concentration of 15 mg/mL is prepared by the existing Hummers method. Thereafter, the prepared graphene oxide solution and 98 wt % hydrazine hydrate solution are mixed at a mass ratio of 1:3, and reacted at the room temperature for 2 minutes. Then the product is diluted to obtain the reduced graphene oxide solutions with various concentrations for subsequent use.

(25) Next, three PET films are cleaned and ultrasonically treated to remove the contaminants from the surfaces of the PET films.

(26) The aqueous solutions of the light-curable adhesive S1 to S3 prepared in Examples 1-3 are respectively sprayed on the three PET films to form the first adhesive layer. Thereafter, the reduced graphene oxide solution is sprayed on the first adhesive layer to form the graphene layer. Then the first adhesive layer is cured under a light condition, wherein the light condition is that the film is exposed at a distance of 25 cm under a 1000 W medium pressure mercury lamp for 10 seconds.

(27) Later the corresponding aqueous solutions of the light-curable adhesive and the reduced graphene oxide solution are sprayed alternatively on the film. After each time the reduced graphene oxide solution is sprayed, the film is placed at a distance of 25 cm under a 1000 W medium pressure mercury lamp for 10 seconds to cure the second adhesive layer. Finally, films M1, M2 and M3 that each has 30 graphene layers are obtained.

Example 5

(28) Comparative example 1 uses PVC sheet for packing solid medicine, and comparative example 2 uses PVDC sheet for packing solid medicine.

(29) The physical parameters of the films for medicine packaging M1, M2, M3, comparative example 1 and comparative example 2 of the same thickness and mass are measured according to national standards, and the obtained physical parameters are shown in Table 1:

(30) TABLE-US-00001 TABLE 1 physical parameters of the films for medicine packaging Comparative Comparative Items Unit M1 M2 M3 example 1 example 2 Water Vapor g/m.sup.2 .Math. atm .Math. day 0.32 0.38 0.39 1.01 0.42 Transmission Oxygen cc/m.sup.2 .Math. atm .Math. day 0.21 0.33 0.35 12.27 0.523 Transmission Tensile Strength MPa 65.3/64.7 63.9/62.7 64.1/63.4 66.2/65.3 56.7/55.7 (vertical/horizontal) Hear-sealing N/15 mm 10.9 11.1 10.8 11.5 10.8 Strength Heavy Metals % <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 Readily Oxidizable ml <1.5 <1.5 <1.5 <1.5 <2 Substance Nonvolatile mg <25 <30 <30 <30 <30 Matter Total Bacterial unit/cm.sup.2 <1000 <1000 <1000 <1000 <1000 Count Total Mold Count unit/cm.sup.2 <100 <100 <100 <100 <100 Colibacillus unit/cm.sup.2 0 0 0 0 0

(31) Table 1 indicates that, with the same mass and thickness, compared with the comparative example land comparative example 2, the films for medicine packaging prepared in Examples 1-3 have remarkably lower water vapor transmission and oxygen transmission, and effectively inhibit small molecules such as oxygen and water vapor from penetrating into the packaging material, which avoids the oxidative deterioration of the active ingredients in the drugs and inhibits the propagation of microorganisims, thereby prolonging the shelf life of the drugs.

Example 6

(32) On the basis of Example 4, the preparation method of the reduced graphene oxide solution is improved.

(33) 1 g of graphite power is added to 23 ml of concentrated sulfuric acid. The reaction system is stirred until homogenous in an ice water bath. Then 2.5 g of potassium permanganate is added to the reaction system. The temperature of the water bath is controlled within a range of 10-15° C., and the reaction lasts for 2 hours. Thereafter, the reaction solution of the reaction system is transferred to a water bath to react at a constant temperature of 35° C. for 30 minutes. The reaction solution is stirred during reaction. Next, 80 ml of distilled water is added to the reaction solution, and the reaction last for 15 minutes at a temperature of 80° C. Then a certain amount of 15 wt % hydrogen peroxide is added to the reaction solution until generation of bubbles. The reaction solution is hot filtered, and the filter cake is washed with hydrochloric acid and deionized water until the filtrate is neutral. An aqueous solution of graphene oxide is prepared for subsequent use. Prior to using the aqueous solution of graphene oxide, the aqueous solution of graphene oxide is diluted with deionized water and then ultrasonically treated for 1 hour to obtain a graphene oxide solution having a concentration of 0.1-5 mg/mL.

(34) Next, the prepared graphene oxide solution having a concentration of 5 mg/mL and 98 wt % hydrazine hydrate solution are mixed at a mass ratio of 1:3, and reacted at the room temperature for 2 minutes. Then the product is diluted to obtain the reduced graphene oxide solutions with various concentrations.

(35) In such technical solution, the total reaction time is less than 3 hours which is far less than that of the existing Hummers method, and the steps such as standing step and drying step can be removed, effectively improving the production efficiency. On the other hand, the entire reaction process uses water as the solvent so that the preparation conditions are environmentally friendly, and the post-treatment process is simpler, lowering the production cost.

(36) The aforementioned embodiments and examples further illustrate the purposes, technical solutions and beneficial effects of the present invention in detail. It is to be understood that the foregoing is only the embodiments of the present invention, and is not intended to limit the scope of the present invention. Any modifications, equivalent substitutes, improvements and the like made within the spirit and principle of the present invention should all be included in the scope of the present invention.