WO2024078559A1 - 一种药用辅料包衣膜及其制备方法 - Google Patents
一种药用辅料包衣膜及其制备方法 Download PDFInfo
- Publication number
- WO2024078559A1 WO2024078559A1 PCT/CN2023/124150 CN2023124150W WO2024078559A1 WO 2024078559 A1 WO2024078559 A1 WO 2024078559A1 CN 2023124150 W CN2023124150 W CN 2023124150W WO 2024078559 A1 WO2024078559 A1 WO 2024078559A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cellulose acetate
- coating film
- pharmaceutical excipient
- soybean oil
- modified cellulose
- Prior art date
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- 238000000576 coating method Methods 0.000 title claims abstract description 47
- 239000011248 coating agent Substances 0.000 title claims abstract description 43
- 239000000546 pharmaceutical excipient Substances 0.000 title claims abstract description 31
- 229940124531 pharmaceutical excipient Drugs 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 229920002301 cellulose acetate Polymers 0.000 claims abstract description 75
- 235000012424 soybean oil Nutrition 0.000 claims abstract description 33
- 239000003549 soybean oil Substances 0.000 claims abstract description 33
- 239000006087 Silane Coupling Agent Substances 0.000 claims abstract description 13
- 229920001661 Chitosan Polymers 0.000 claims abstract description 12
- 229920000747 poly(lactic acid) Polymers 0.000 claims abstract description 11
- 239000004626 polylactic acid Substances 0.000 claims abstract description 11
- 239000000203 mixture Substances 0.000 claims abstract description 7
- 150000001413 amino acids Chemical class 0.000 claims abstract description 4
- 239000003431 cross linking reagent Substances 0.000 claims abstract description 3
- 239000004014 plasticizer Substances 0.000 claims abstract description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 32
- 239000004593 Epoxy Substances 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 238000001035 drying Methods 0.000 claims description 12
- 239000012265 solid product Substances 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 10
- 239000008367 deionised water Substances 0.000 claims description 8
- 229910021641 deionized water Inorganic materials 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- 239000007822 coupling agent Substances 0.000 claims description 7
- 238000001125 extrusion Methods 0.000 claims description 7
- JPSKCQCQZUGWNM-UHFFFAOYSA-N 2,7-Oxepanedione Chemical compound O=C1CCCCC(=O)O1 JPSKCQCQZUGWNM-UHFFFAOYSA-N 0.000 claims description 6
- LEVWYRKDKASIDU-QWWZWVQMSA-N D-cystine Chemical compound OC(=O)[C@H](N)CSSC[C@@H](N)C(O)=O LEVWYRKDKASIDU-QWWZWVQMSA-N 0.000 claims description 6
- 229960003067 cystine Drugs 0.000 claims description 6
- 229920001223 polyethylene glycol Polymers 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 6
- FFEARJCKVFRZRR-SCSAIBSYSA-N D-methionine Chemical compound CSCC[C@@H](N)C(O)=O FFEARJCKVFRZRR-SCSAIBSYSA-N 0.000 claims description 5
- 229930182818 D-methionine Natural products 0.000 claims description 5
- 239000002202 Polyethylene glycol Substances 0.000 claims description 5
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 claims description 5
- OUPZKGBUJRBPGC-UHFFFAOYSA-N 1,3,5-tris(oxiran-2-ylmethyl)-1,3,5-triazinane-2,4,6-trione Chemical compound O=C1N(CC2OC2)C(=O)N(CC2OC2)C(=O)N1CC1CO1 OUPZKGBUJRBPGC-UHFFFAOYSA-N 0.000 claims description 4
- KOMNUTZXSVSERR-UHFFFAOYSA-N 1,3,5-tris(prop-2-enyl)-1,3,5-triazinane-2,4,6-trione Chemical compound C=CCN1C(=O)N(CC=C)C(=O)N(CC=C)C1=O KOMNUTZXSVSERR-UHFFFAOYSA-N 0.000 claims description 4
- 229920001747 Cellulose diacetate Polymers 0.000 claims description 4
- 229920002284 Cellulose triacetate Polymers 0.000 claims description 4
- NNLVGZFZQQXQNW-ADJNRHBOSA-N [(2r,3r,4s,5r,6s)-4,5-diacetyloxy-3-[(2s,3r,4s,5r,6r)-3,4,5-triacetyloxy-6-(acetyloxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6s)-4,5,6-triacetyloxy-2-(acetyloxymethyl)oxan-3-yl]oxyoxan-2-yl]methyl acetate Chemical compound O([C@@H]1O[C@@H]([C@H]([C@H](OC(C)=O)[C@H]1OC(C)=O)O[C@H]1[C@@H]([C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O1)OC(C)=O)COC(=O)C)[C@@H]1[C@@H](COC(C)=O)O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O NNLVGZFZQQXQNW-ADJNRHBOSA-N 0.000 claims description 4
- 230000021736 acetylation Effects 0.000 claims description 4
- 238000006640 acetylation reaction Methods 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- GYZLOYUZLJXAJU-UHFFFAOYSA-N diglycidyl ether Chemical class C1OC1COCC1CO1 GYZLOYUZLJXAJU-UHFFFAOYSA-N 0.000 claims description 4
- 239000012948 isocyanate Substances 0.000 claims description 4
- 150000002513 isocyanates Chemical class 0.000 claims description 4
- 235000001014 amino acid Nutrition 0.000 claims description 3
- 239000000155 melt Substances 0.000 claims description 3
- 239000000047 product Substances 0.000 claims description 3
- 230000008961 swelling Effects 0.000 claims description 3
- WYTZZXDRDKSJID-UHFFFAOYSA-N (3-aminopropyl)triethoxysilane Chemical compound CCO[Si](OCC)(OCC)CCCN WYTZZXDRDKSJID-UHFFFAOYSA-N 0.000 claims description 2
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 claims description 2
- XDLMVUHYZWKMMD-UHFFFAOYSA-N 3-trimethoxysilylpropyl 2-methylprop-2-enoate Chemical compound CO[Si](OC)(OC)CCCOC(=O)C(C)=C XDLMVUHYZWKMMD-UHFFFAOYSA-N 0.000 claims description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 2
- GTDPSWPPOUPBNX-UHFFFAOYSA-N ac1mqpva Chemical compound CC12C(=O)OC(=O)C1(C)C1(C)C2(C)C(=O)OC1=O GTDPSWPPOUPBNX-UHFFFAOYSA-N 0.000 claims description 2
- 150000001371 alpha-amino acids Chemical class 0.000 claims description 2
- 235000008206 alpha-amino acids Nutrition 0.000 claims description 2
- 150000001860 citric acid derivatives Chemical class 0.000 claims description 2
- 125000006159 dianhydride group Chemical group 0.000 claims description 2
- 239000004220 glutamic acid Substances 0.000 claims description 2
- 235000013922 glutamic acid Nutrition 0.000 claims description 2
- VANNPISTIUFMLH-UHFFFAOYSA-N glutaric anhydride Chemical compound O=C1CCCC(=O)O1 VANNPISTIUFMLH-UHFFFAOYSA-N 0.000 claims description 2
- 150000002978 peroxides Chemical class 0.000 claims description 2
- 238000007151 ring opening polymerisation reaction Methods 0.000 claims description 2
- 229940014800 succinic anhydride Drugs 0.000 claims description 2
- BPSIOYPQMFLKFR-UHFFFAOYSA-N trimethoxy-[3-(oxiran-2-ylmethoxy)propyl]silane Chemical compound CO[Si](OC)(OC)CCCOCC1CO1 BPSIOYPQMFLKFR-UHFFFAOYSA-N 0.000 claims description 2
- PHQOGHDTIVQXHL-UHFFFAOYSA-N n'-(3-trimethoxysilylpropyl)ethane-1,2-diamine Chemical compound CO[Si](OC)(OC)CCCNCCN PHQOGHDTIVQXHL-UHFFFAOYSA-N 0.000 claims 1
- 239000000463 material Substances 0.000 abstract description 7
- 230000008901 benefit Effects 0.000 abstract description 5
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 239000010408 film Substances 0.000 description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000003814 drug Substances 0.000 description 9
- 229940079593 drug Drugs 0.000 description 7
- 230000004048 modification Effects 0.000 description 7
- 238000012986 modification Methods 0.000 description 7
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 6
- 238000005507 spraying Methods 0.000 description 6
- 229920002678 cellulose Polymers 0.000 description 5
- 239000001913 cellulose Substances 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
- 230000003179 granulation Effects 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 238000009512 pharmaceutical packaging Methods 0.000 description 3
- 238000005292 vacuum distillation Methods 0.000 description 3
- -1 N-(β-aminoethyl)-γ-aminopropyltrimethoxy(ethyl)silane Chemical compound 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000004925 Acrylic resin Substances 0.000 description 1
- 229920000178 Acrylic resin Polymers 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 229920002101 Chitin Polymers 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 235000019504 cigarettes Nutrition 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 230000006196 deacetylation Effects 0.000 description 1
- 238000003381 deacetylation reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 229920005994 diacetyl cellulose Polymers 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000012567 medical material Substances 0.000 description 1
- 238000010128 melt processing Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000010525 oxidative degradation reaction Methods 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 239000011241 protective layer Substances 0.000 description 1
- 230000005588 protonation Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000019635 sulfation Effects 0.000 description 1
- 238000005670 sulfation reaction Methods 0.000 description 1
- 239000004753 textile Substances 0.000 description 1
- 238000005979 thermal decomposition reaction Methods 0.000 description 1
- 229920005992 thermoplastic resin Polymers 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- ILJSQTXMGCGYMG-UHFFFAOYSA-N triacetic acid Chemical compound CC(=O)CC(=O)CC(O)=O ILJSQTXMGCGYMG-UHFFFAOYSA-N 0.000 description 1
- 239000011850 water-based material Substances 0.000 description 1
- 238000004383 yellowing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B11/00—Preparation of cellulose ethers
- C08B11/02—Alkyl or cycloalkyl ethers
- C08B11/04—Alkyl or cycloalkyl ethers with substituted hydrocarbon radicals
- C08B11/10—Alkyl or cycloalkyl ethers with substituted hydrocarbon radicals substituted with acid radicals
- C08B11/12—Alkyl or cycloalkyl ethers with substituted hydrocarbon radicals substituted with acid radicals substituted with carboxylic radicals, e.g. carboxymethylcellulose [CMC]
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02W—CLIMATE CHANGE MITIGATION TECHNOLOGIES RELATED TO WASTEWATER TREATMENT OR WASTE MANAGEMENT
- Y02W90/00—Enabling technologies or technologies with a potential or indirect contribution to greenhouse gas [GHG] emissions mitigation
- Y02W90/10—Bio-packaging, e.g. packing containers made from renewable resources or bio-plastics
Definitions
- the invention belongs to the technical field of drug packaging and relates to a pharmaceutical excipient coating film and a preparation method thereof.
- Coating is a professional term in the field of pharmaceutical packaging, which refers to the process of spraying film-forming materials on the outer surface of solid pharmaceutical preparations using special equipment to form a thin film. Originated in the UK, the original purpose was to color the medicine. With the advancement of science and technology and the demand for controlled release performance of drugs, drug coating has become a drug packaging technology that integrates multiple functions, integrates multidisciplinary technologies, and has high technical content.
- Coating film refers to a protective layer of polymer material used as a tablet film on the surface of the drug. It is a new packaging material for drug tablets and has many advantages, such as shielding the special smell of some drugs, making it easier for patients to take, or giving drugs controlled release functions.
- Drug coating is one of the most core process technologies in the modern pharmaceutical industry. Common materials for coating films include cellulose derivatives, polyethylene glycols, acrylic resins, etc. These materials are non-toxic and harmless to the human body and are also good film-forming materials. Among them, cellulose derivatives are the most widely used.
- Cellulose acetate is a thermoplastic resin, a cellulose derivative obtained by acetylation of natural cellulose under the action of a catalyst. It was first prepared in 1865 and is the earliest commercially used cellulose derivative. The performance of cellulose acetate depends on the degree of acetylation of its hydroxyl groups during the production process. It can be divided into diacetate and triacetate, and has the advantages of good toughness, gloss, transparency, etc. At present, cellulose acetate is widely used in cigarette filters, textile fibers, medical materials, separation membranes and other fields.
- the melting temperature of cellulose acetate is close to its thermal decomposition temperature. Direct melt processing can easily cause cellulose acetate to undergo oxidative degradation, resulting in yellowing of the product and poor mechanical properties.
- grafting modification is not only simple and easy, does not require the introduction of new chemical reactions or other processes, is easy to control, and can give full play to the respective advantages of the components in the blend. It has become the most effective means of modifying cellulose acetate films.
- Spray coating process is the most common way to coat the surface of solid pharmaceuticals.
- the coating of most solid preparations is usually This is achieved through spray coating technology.
- the coating liquid Before spraying, the coating liquid must be prepared, and the prepared coating liquid is atomized into small droplets using a spray device, and then sprayed on the surface of the solid preparation. Under hot air or heating conditions, the solvent evaporates, and the polymer is wrapped on the surface of the solid preparation. Repeated spraying and drying complete the coating process.
- the problem is that the volatilization of organic solvents will cause environmental pollution.
- Polylactic acid is a new type of biodegradable material made from renewable plant resources such as corn starch, cassava starch, etc. It is absolutely harmless to the human body, has good gloss and transparency, mechanical and physical properties, good compatibility and degradability, and high tensile strength and ductility.
- Chitosan is a natural separation membrane material, which is obtained by deacetylation of chitin.
- the basic amino groups in the molecule lose their hydrogen bonding ability after protonation and are soluble in acidic solutions. Since chitosan molecules contain reactive hydroxyl and amino groups, they are easy to be chemically modified (acylation, sulfation, hydroxyethylation, carboxymethylation, etc.). After forming a membrane, it has good hydrophilicity and permeability, and is suitable for separating water-based materials.
- the object of the present invention is to provide a pharmaceutical excipient coating film and a preparation method thereof.
- the present invention provides a pharmaceutical excipient coating film, wherein the raw material composition comprises, by weight:
- the modified cellulose acetate is obtained by sequentially grafting and modifying cellulose acetate with epoxy soybean oil and a coupling agent.
- the preparation of the modified cellulose acetate is to first fully swell the cellulose acetate in acetone, pre-modify it with epoxy soybean oil through a ring-opening polymerization reaction, and obtain epoxy soybean oil pre-modified cellulose acetate; then use a silane coupling agent to graft-modify the epoxy soybean oil pre-modified cellulose acetate, and wash and dry the obtained product to obtain the modified cellulose acetate.
- the cellulose acetate is one of diacetyl cellulose and triacetyl cellulose, and the degree of acetylation is about 40%, such as 38-42%.
- the preparation of the modified cellulose acetate specifically comprises the following steps:
- step b) dispersing the epoxy soybean oil pre-modified cellulose acetate obtained in step a) in an acetone solvent, then slowly adding a silane coupling agent and deionized water in sequence, adjusting the pH to 8-9, stirring and reacting at room temperature for 4-12 hours, and finally distilling under reduced pressure, collecting the solid product, washing and drying, to obtain the modified cellulose acetate.
- the dosage ratio of each raw material is as follows:
- Acetone 35-50 parts by weight
- Epoxidized soybean oil 15-20 parts by weight
- Silane coupling agent 1 to 3 parts by mass
- Deionized water 3 to 20 parts by weight.
- the silane coupling agent is selected from one or more of ⁇ -aminopropyltriethoxysilane (KH550), ⁇ -glycidyloxypropyltrimethoxysilane, ⁇ -(methacryloyloxy)propyltrimethoxysilane (KH570), N-( ⁇ -aminoethyl)- ⁇ -aminopropyltrimethoxy(ethyl)silane (KH792) and N- ⁇ -(aminoethyl)- ⁇ -aminopropylmethyldimethoxysilane (DL602), preferably KH560.
- KH550 ⁇ -aminopropyltriethoxysilane
- KH570 ⁇ -glycidyloxypropyltrimethoxysilane
- KH570 ⁇ -(methacryloyloxy)propyltrimethoxysilane
- KH792 N-( ⁇ -aminoethyl
- an alkaline pH regulator is used to adjust the pH to 8-12 and pH to 8-9.
- the alkaline pH regulator includes but is not limited to sodium hydroxide, potassium hydroxide, triethanolamine, and ammonia water, preferably triethanolamine.
- the number average molecular weight of the polylactic acid is 3 ⁇ 10 5 -6 ⁇ 10 5 .
- the amino acid is selected from one or more of ⁇ -amino acids, glutamic acid, cystine and D-methionine, preferably D-methionine.
- the number average molecular weight of the chitosan is 3 ⁇ 10 5 -9 ⁇ 10 5 .
- the plasticizer is selected from one or more of epoxidized soybean oil, polyethylene glycol and citrate esters, preferably polyethylene glycol.
- the cross-linking agent is selected from one or more of isocyanates, glycidyl ethers, dianhydrides, and peroxides.
- the isocyanate is selected from triallyl isocyanurate and triglycidyl isocyanurate.
- the dianhydride is selected from succinic anhydride, glutaric anhydride, adipic anhydride, maleic anhydride One of the above, preferably maleic anhydride.
- the present invention also relates to a method for preparing a pharmaceutical excipient coating film; all raw materials are dried, dehydrated and blended uniformly, and then heated, melted, extruded, granulated and dried to obtain the pharmaceutical excipient coating film.
- the melt extrusion temperature is controlled at 160-190°C, preferably 180°C.
- the present invention has the following significant beneficial effects:
- the surface modification of cellulose acetate in the present invention is to pre-modify cellulose acetate with epoxy soybean oil and then graft-modify it with a coupling agent.
- the present invention further modifies cellulose acetate with a coupling agent on the basis of pre-modification with epoxy soybean oil, thereby improving the flexibility of cellulose acetate; at the same time, the compatibility and cross-linking properties between modified cellulose acetate and polylactic acid, amino acids and chitosan can be improved; and the comprehensive properties of the coating film such as strength, transparency and flexibility can be effectively improved.
- the present invention effectively reduces the melt extrusion temperature of cellulose acetate, avoids the degradation of cellulose acetate, and can also reduce the processing temperature and save energy.
- the present invention effectively expands the application scope of cellulose acetate, improves the economic added value of cellulose acetate, is beneficial to expand the application scope of pharmaceutical excipient coating film, reduces production costs, and has very important environmental significance.
- step b) Dispersing the epoxy soybean oil pre-modified cellulose acetate obtained in step a) in 20 g of acetone solvent, then slowly adding 3 g of KH560 silane coupling agent and 20 g of deionized water, adjusting the pH to 9 with sodium hydroxide, stirring at room temperature for 12 hours, finally distilling under reduced pressure, collecting the solid product, washing and drying to obtain the modified cellulose acetate.
- modified cellulose acetate 6 g of polylactic acid with a number average molecular weight of 3 ⁇ 10 5 , 10 g of D-methionine, 10 g of chitosan with a number average molecular weight of 9 ⁇ 10 5 , 15 g of polyethylene glycol, 1.5 g of triallyl isocyanurate and 1.5 g of maleic anhydride were dried. After dry dehydration and uniform blending, the mixture is heated at 180°C for melt extrusion, granulation and drying to obtain a pharmaceutical excipient coating film.
- step b) Dispersing the epoxy soybean oil pre-modified cellulose acetate obtained in step a) in 15 g of acetone solvent, then slowly adding 1 g of KH550 silane coupling agent and 3 g of deionized water, adjusting the pH to 8 with sodium hydroxide, stirring at room temperature for 4 hours, finally distilling under reduced pressure, collecting the solid product, washing and drying to obtain the modified cellulose acetate.
- modified cellulose acetate 15g of polylactic acid with a number average molecular weight of 6 ⁇ 10 5 , 5g of cystine, 10g of chitosan with a number average molecular weight of 3 ⁇ 10 5 , 10g of citrate, 1.0g of triglycidyl isocyanurate and 0.5g of adipic anhydride were dried and mixed to remove water, and then heated at 160°C for melt extrusion, granulation and drying to obtain a pharmaceutical excipient coating film.
- step b) Dispersing the epoxy soybean oil pre-modified cellulose acetate obtained in step a) in 16 g of acetone solvent, and then slowly adding 1.5 g of KH792 silane coupling agent and 10 g of deionized water, adjusting the pH to 8.5 with sodium hydroxide, stirring at room temperature for 2.5 hours, and finally distilling under reduced pressure, collecting the solid product, washing and drying to obtain the modified cellulose acetate.
- modified cellulose acetate 15g of polylactic acid with a number average molecular weight of 6 ⁇ 10 5 , 5g of cystine, 10g of chitosan with a number average molecular weight of 3 ⁇ 10 5 , 10g of citrate, 1.0g of glycidyl ether and 0.5g of adipic anhydride were dried to remove water and mixed evenly, and then heated at 160°C for melt extrusion, granulation and drying to obtain a pharmaceutical excipient coating film.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biochemistry (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
Abstract
本发明公开了一种药用辅料包衣膜及其制备方法；所述包衣膜具有如下组成及配比：改性醋酸纤维素60～70质量份，聚乳酸6～15质量份，氨基酸5～10质量份，壳聚糖5～10质量份，增塑剂10～15质量份，交联剂1.5～3.0质量份；所述改性醋酸纤维素是由醋酸纤维素依次经过环氧大豆油和硅烷偶联剂接枝改性而得。含有本发明所述的高柔韧性醋酸纤维素膜相较于传统的醋酸纤维素膜，具有优异的外观，光滑、平整、高柔韧，制备工艺简单，具有良好的环保性能，可以使用在生物功能材料中。
Description
本发明属于药物包装技术领域，涉及一种药用辅料包衣膜及其制备方法。
包衣是药物制剂包装领域的专业术语，指采用专门的设备将成膜材料喷涂在固体药物制剂的外表面形成薄膜的工艺。起源于英国，最初目的是对药剂上色。随着科技的进步与人类对于药物控释性能的需求，药物包衣已经是集齐多种功能于一身，多学科技术融合，高技术含量的一种药物包装技术。
包衣膜是指在包裹覆盖在药物表面以高分子材料作为片剂薄膜的保护层，是一种全新的药物片剂包装材料，具有很多的优点，例如是屏蔽一些药物的特殊气味，便于患者服用，或是赋予药物缓控释功能等。药物的包衣是现代制药行业最为核心的工艺技术之一。包衣膜常用材料有纤维素衍生物类、聚乙二醇类、丙烯酸树脂类等，这些材料在对人体无毒无害的同时也是良好的成膜材料，其中纤维素衍生物类使用最为广泛。
醋酸纤维素(celluloseacetate，CA)，是一种热塑性树脂，在催化剂作用下，天然纤维素通过乙酰化反应得到的一种纤维素衍生物。首次制备于1865年，是最早商业化应用的纤维素衍生物。醋酸纤维素的性能取决于其在生产过程中羟基的乙酰化程度，可分为二醋酸纤维和三醋酸纤维，具有良好的韧性、光泽性、透明性等优点。目前，醋酸纤维素被广泛应用于香烟过滤嘴、纺织纤维、医用材料、分离膜等领域。
醋酸纤维素的熔融温度与其热分解温度相近，直接熔融加工容易使醋酸纤维素发生氧化降解，导致产品发黄，力学性能差。目前制备醋酸纤维素的方法主要包括两种，接枝改性法和共混改性法，共混改性与接枝改性相比，不仅简单易行，无需引入新的化学反应或者其他过程，容易控制，而且可以发挥共混物中组分的各自优势，已成为醋酸纤维素膜改性的最有效的手段。
目前工业生产中常用的包衣工艺有喷雾包衣工艺，与干法包衣工艺等。干法包衣是目前比较新颖的包衣工艺，其优点是不使用溶剂，可节省成本，但对于设备要求较高。喷雾包衣工艺是最为常见的为固体药剂表面包衣的一种方式，绝大多数固体制剂的包衣通常是
通过喷雾包衣技术来实现的。在喷雾之前要进行包衣液的配制，将配制好的包衣液用喷雾装置雾化成小液滴，然后喷涂在固体制剂的表面，在热空气或加热条件下，溶剂蒸发，聚合物包裹在固体制剂的表面上，如此反复喷雾、干燥，完成包衣过程。存在的问题是有机溶剂的挥发，会对环境造成污染。
聚乳酸使用可再生的植物资源如玉米淀粉，木薯淀粉等为原料制成一种新型的生物降解材料，对人体绝对无害，拥有良好的光泽性和透明度，机械性能及物理性能，相容性与可降解性良好，抗拉强度及延展度较高。
壳聚糖是一类天然分离膜材料，由甲壳素脱乙酰化制得，分子中存在的碱性氨基基团，经质子化后失去氢键能力，可溶于酸性溶液。由于壳聚糖分子内含有反应活性的羟基、氨基，易进行化学修饰(酰基化、硫酸酯化、羟乙基化、羧甲基化等)，成膜后具有良好的亲水性、透过性，适合分离水系物料。
发明内容
针对现有技术存在的上述问题，本发明的目的是提供一种药用辅料包衣膜及其制备方法。
为实现上述发明目的，本发明采用的技术方案如下：
第一方面，本发明提供一种药用辅料包衣膜，按重量份计，原料组成包括：
所述改性醋酸纤维素是由醋酸纤维素依次经过环氧大豆油和偶联剂接枝改性而得。
作为一种实施方案，所述改性醋酸纤维素的制备，是先将醋酸纤维素充分溶胀于丙酮中，经过开环聚合反应进行环氧大豆油预改性，得到环氧大豆油预改性醋酸纤维素；然后采用硅烷偶联剂对环氧大豆油预改性醋酸纤维素进行偶联剂接枝改性，所得产物进行洗涤、干燥，即得所述改性醋酸纤维素。
作为一种实施方案，所述醋酸纤维素为二醋酸纤维素和三醋酸纤维素中的一种，乙酰化度为40％左右，如38-42％。
作为一种实施方案，所述改性醋酸纤维素的制备，具体包括如下步骤：
a)将醋酸纤维素充分溶胀于丙酮中；然后加入环氧大豆油，搅拌使之混合均匀；接着调节pH＝8～12，在80～105℃下搅拌反应2～4小时；最后减压蒸馏，收集固体产物，洗涤、干燥，得到环氧大豆油预改性醋酸纤维素；
b)将步骤a)得到的环氧大豆油预改性醋酸纤维素分散于丙酮溶剂中，然后依次缓慢加入硅烷偶联剂、去离子水，调节pH＝8～9，室温搅拌反应4～12小时后，最后减压蒸馏，收集固体产物，洗涤、干燥，得到所述改性醋酸纤维素。
作为一种实施方案，改性醋酸纤维素的制备过程中，各原料的用量配比如下：
醋酸纤维素：25～45质量份，
丙酮：35～50质量份，
环氧大豆油：15～20质量份，
硅烷偶联剂：1～3质量份，
去离子水：3～20质量份。
作为一种实施方案，所述硅烷偶联剂选自γ-氨丙基三乙氧基硅烷(KH550)、γ-缩水甘油醚氧丙基三甲氧基硅烷、γ-(甲基丙烯酰氧)丙基三甲氧基硅烷(KH570)、N-(β一氨乙基)-γ-氨丙基三甲(乙)氧基硅烷(KH792)和N-β-(氨乙基)-γ-氨丙基甲基二甲氧基硅烷(DL602)的一种或多种，优选KH560。
作为一种优选方案，改性醋酸纤维素的制备过程中，采用碱性pH调节剂调节pH＝8～12和pH＝8～9，碱性pH调节剂包括但不限于氢氧化钠、氢氧化钾、三乙醇胺、氨水，优选三乙醇胺。
作为一种实施方案，所述聚乳酸数均分子量大小为：3×105-6×105。
作为一种实施方案，所述氨基酸，选自α氨基酸、谷氨酸、胱胺酸和D-蛋氨酸中的一种或多种，优选D-蛋氨酸。
作为一种实施方案，所述壳聚糖数均分子量大小为：3×105-9×105。
作为一种实施方案，所述增塑剂选自环氧大豆油、聚乙二醇和柠檬酸酯类中的一种或多种，优选聚乙二醇。
作为一种实施方案，所述交联剂选自异氰酸酯类、缩水甘油醚、二酸酐类、过氧化物类中的一种或多种。
作为一种实施方案，所述异氰酸酯类选自三烯丙基异氰脲酸酯、异氰尿酸三缩水甘油酯中的一种。
作为一种实施方案，所述二酸酐类选自丁二酸酐、戊二酸酐、己二酸酐、马来酸酐中
的一种，优选马来酸酐。
第二方面，本发明还涉及一种药用辅料包衣膜的制备方法；将所有原料烘干除水共混均匀后，加热熔融挤出、造粒、干燥后得到所述的药用辅料包衣膜。
作为一种实施方案，熔融挤出温度控制在160～190℃，优选180℃。
与现有技术相比，本发明具有如下显著性有益效果：
1、本发明对醋酸纤维素的表面改性是先对醋酸纤维素进行环氧大豆油预改性，然后再进行偶联剂接枝改性，相较于传统的单纯接枝改性而言，本发明在环氧大豆油预改性的基础上，采用偶联剂进一步改性，可以提高醋酸纤维素的柔韧性能；同时，还可以提高改性醋酸纤维素与聚乳酸、氨基酸、壳聚糖之间的相容性能和交联性能；有效提高包衣膜的强度，透明性和柔韧性等各方面的综合性能。
2、本发明有效降低了醋酸纤维素熔融挤出温度，避免醋酸纤维素的降解，还可以降低加工温度，节约能源。
3、本发明有效扩大了醋酸纤维素的使用范围，提高了醋酸纤维素的经济附加值，有利于扩大药用辅料包衣膜的适用范围，降低生产成本，具有十分重要的环保意义。
下面结合实施例对本发明进行详细说明。以下实施例将有助于本领域的技术人员进一步理解本发明，但不以任何形式限制本发明。应当指出的是，对本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干调整和改进。这些都属于本发明的保护范围。
实施例1
一、改性醋酸纤维素的制备：
a)将45g二醋酸纤维素充分溶胀于30g丙酮中；然后加入20g环氧大豆油，搅拌使之混合均匀；接着使用三乙醇胺调节pH＝12，在105℃下搅拌反应4小时；最后减压蒸馏，收集固体产物，洗涤、干燥，得到环氧大豆油预改性醋酸纤维素；
b)将步骤a)得到的环氧大豆油预改性醋酸纤维素分散于20g丙酮溶剂中，然后依次缓慢加入3g KH560硅烷偶联剂、20g去离子水，使用氢氧化钠调节pH＝9，室温搅拌反应12小时后，最后减压蒸馏，收集固体产物，洗涤、干燥，得到所述改性醋酸纤维素。
二、药用辅料包衣膜的制备：
将70g改性醋酸纤维素、6g数均分子量为3×105的聚乳酸、10g D-蛋氨酸、10g数均分子量为9×105的壳聚糖、15g聚乙二醇、1.5g三烯丙基异氰脲酸酯和1.5g马来酸酐，烘
干除水共混均匀后，180℃下加热熔融挤出、造粒、干燥后得到药用辅料包衣膜。
实施例2
一、改性醋酸纤维素的制备：
a)将25g二醋酸纤维素充分溶胀于20g丙酮中；然后加入15g环氧大豆油，搅拌使之混合均匀；接着使用三乙醇胺调节pH＝8，在80℃下搅拌反应2小时；最后减压蒸馏，收集固体产物，洗涤、干燥，得到环氧大豆油预改性醋酸纤维素；
b)将步骤a)得到的环氧大豆油预改性醋酸纤维素分散于15g丙酮溶剂中，然后依次缓慢加入1g KH550硅烷偶联剂、3g去离子水，使用氢氧化钠调节pH＝8，室温搅拌反应4小时后，最后减压蒸馏，收集固体产物，洗涤、干燥，得到所述改性醋酸纤维素。
二、药用辅料包衣膜的制备：
将60g改性醋酸纤维素、15g数均分子量为6×105的聚乳酸、5g胱胺酸、10g数均分子量为3×105的壳聚糖、10g柠檬酸酯、1.0g异氰尿酸三缩水甘油酯和0.5g己二酸酐，烘干除水共混均匀后，160℃下加热熔融挤出、造粒、干燥后得到药用辅料包衣膜。
实施例3
一、改性醋酸纤维素的制备：
a)将30g三醋酸纤维素充分溶胀于25g丙酮中；然后加入18g环氧大豆油，搅拌使之混合均匀；接着使用三乙醇胺调节pH＝10，在90℃下搅拌反应2.5小时；最后减压蒸馏，收集固体产物，洗涤、干燥，得到环氧大豆油预改性醋酸纤维素；
b)将步骤a)得到的环氧大豆油预改性醋酸纤维素分散于16g丙酮溶剂中，然后依次缓慢加入1.5g KH792硅烷偶联剂、10g去离子水，使用氢氧化钠调节pH＝8.5，室温搅拌反应2.5小时后，最后减压蒸馏，收集固体产物，洗涤、干燥，得到所述改性醋酸纤维素。
二、药用辅料包衣膜的制备：
将60g改性醋酸纤维素、15g数均分子量为6×105的聚乳酸、5g胱胺酸、10g数均分子量为3×105的壳聚糖、10g柠檬酸酯、1.0g缩水甘油醚和0.5g己二酸酐，烘干除水共混均匀后，160℃下加热熔融挤出、造粒、干燥后得到药用辅料包衣膜。
对比例1
将70g未改性的醋酸纤维素、6g数均分子量为3×105的聚乳酸、10g D-蛋氨酸、10g数均分子量为9×105的壳聚糖、15g聚乙二醇、1.5g三烯丙基异氰脲酸酯和1.5g马来酸酐，烘干除水共混均匀后，180℃下加热熔融挤出、造粒、干燥后得到药用辅料包衣膜。
对比例2
一、偶联剂改性醋酸纤维素的制备：
a)将25g二醋酸纤维素充分溶胀于15g丙酮溶剂中，然后依次缓慢加入1g KH550硅烷偶联剂、3g去离子水，使用氢氧化钠调节pH＝8，室温搅拌反应4小时后，最后减压蒸馏，收集固体产物，洗涤、干燥，得到偶联剂改性醋酸纤维素。
二、药用辅料包衣膜的制备：
将60g偶联剂改性醋酸纤维素、15g数均分子量为6×105的聚乳酸、5g胱胺酸、10g数均分子量为3×105的壳聚糖、10g柠檬酸酯、1.0g异氰尿酸三缩水甘油酯和0.5g己二酸酐，烘干除水共混均匀后，160℃下加热熔融挤出、造粒、干燥后得到药用辅料包衣膜。
对比例3
一、环氧大豆油改性醋酸纤维素的制备：
将30g三醋酸纤维素充分溶胀于25g丙酮中；然后加入18g环氧大豆油，搅拌使之混合均匀；接着使用三乙醇胺调节pH＝10，在90℃下搅拌反应2.5小时；最后减压蒸馏，收集固体产物，洗涤、干燥，得到环氧大豆油改性醋酸纤维素；
二、药用辅料包衣膜的制备：
将60g环氧大豆油改性醋酸纤维素、15g数均分子量为6×105的聚乳酸、5g胱胺酸、10g数均分子量为3×105的壳聚糖、10g柠檬酸酯、1.0g缩水甘油醚和0.5g己二酸酐，烘干除水共混均匀后，160℃下加热熔融挤出、造粒、干燥后得到药用辅料包衣膜。
以上实施例和对比例制得的药用辅料包衣膜性能对比如下表1所示。
表1
最后需要在此指出的是：以上仅是本发明的部分优选实施例，不能理解为对本发明保
护范围的限制，本领域的技术人员根据本发明的上述内容做出的一些非本质的改进和调整均属于本发明的保护范围。
Claims (10)
- 一种药用辅料包衣膜，其特征在于，按重量份计，所述包衣膜原料组成包括：
所述改性醋酸纤维素是由醋酸纤维素依次经过环氧大豆油和偶联剂接枝改性而得。 - 根据权利要求1所述药用辅料包衣膜，其特征在于，所述改性醋酸纤维素的制备，是先将醋酸纤维素充分溶胀于丙酮中，经过开环聚合反应进行环氧大豆油预改性，得到环氧大豆油预改性醋酸纤维素；然后采用硅烷偶联剂对环氧大豆油预改性醋酸纤维素进行偶联剂接枝改性，所得产物进行洗涤、干燥，即得所述改性醋酸纤维素。
- 根据权利要求1或2所述药用辅料包衣膜，其特征在于，所述醋酸纤维素为二醋酸纤维素和三醋酸纤维素中的一种，乙酰化度为38-42％。
- 根据权利要求2所述药用辅料包衣膜，其特征在于，所述改性醋酸纤维素的制备，具体包括如下步骤：a)将醋酸纤维素充分溶胀于丙酮中；然后加入环氧大豆油，搅拌使之混合均匀；接着调节pH＝8～12，在80～105℃下搅拌反应2～4小时；最后减压蒸馏，收集固体产物，洗涤、干燥，得到环氧大豆油预改性醋酸纤维素；b)将步骤a)得到的环氧大豆油预改性醋酸纤维素分散于丙酮溶剂中，然后依次缓慢加入硅烷偶联剂、去离子水，调节pH＝8～9，室温搅拌反应4～12小时后，最后减压蒸馏，收集固体产物，洗涤、干燥，得到所述改性醋酸纤维素。
- 根据权利要求2或4所述药用辅料包衣膜，其特征在于，改性醋酸纤维素的制备过程中，各原料的用量配比如下：
醋酸纤维素：25～45质量份，
丙酮：35～50质量份，
环氧大豆油：15～20质量份，
硅烷偶联剂：1～3质量份，
去离子水：3～20质量份。 - 根据权利要求5所述药用辅料包衣膜，其特征在于，所述硅烷偶联剂选自γ-氨丙基三乙氧基硅烷、γ-缩水甘油醚氧丙基三甲氧基硅烷、γ-(甲基丙烯酰氧)丙基三甲氧基硅烷、N-(β一氨乙基)-γ-氨丙基三甲(乙)氧基硅烷和N-β-(氨乙基)-γ-氨丙基甲基二甲氧基硅烷的一种或多种。
- 根据权利要求1所述药用辅料包衣膜，其特征在于，所述聚乳酸数均分子量大小为：3×105-6×105；所述氨基酸，选自α氨基酸、谷氨酸、胱胺酸和D-蛋氨酸中的一种或多种；所述壳聚糖数均分子量大小为：3×105-9×105；所述增塑剂选自环氧大豆油、聚乙二醇和柠檬酸酯类等中的一种或多种；所述交联剂选自异氰酸酯类、缩水甘油醚、二酸酐类、过氧化物类中的一种或多种。
- 根据权利要求7所述药用辅料包衣膜，其特征在于，所述异氰酸酯类选自三烯丙基异氰脲酸酯、异氰尿酸三缩水甘油酯中的一种；所述二酸酐类选自丁二酸酐、戊二酸酐、己二酸酐、马来酸酐中的一种。
- 一种根据权利要求1-8中任一项所述药用辅料包衣膜的制备方法，其特征在于，将所有原料烘干除水共混均匀后，加热熔融挤出、造粒、干燥后得到所述药用辅料包衣膜。
- 根据权利要求9所述药用辅料包衣膜的制备方法，其特征在于，熔融挤出温度控制在160～190℃。
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