CN116173044A - Composition containing mesalamine, preparation method and application thereof - Google Patents
Composition containing mesalamine, preparation method and application thereof Download PDFInfo
- Publication number
- CN116173044A CN116173044A CN202310299419.0A CN202310299419A CN116173044A CN 116173044 A CN116173044 A CN 116173044A CN 202310299419 A CN202310299419 A CN 202310299419A CN 116173044 A CN116173044 A CN 116173044A
- Authority
- CN
- China
- Prior art keywords
- parts
- mesalamine
- bioadhesive
- mpa
- wetting agent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- KBOPZPXVLCULAV-UHFFFAOYSA-N mesalamine Chemical compound NC1=CC=C(O)C(C(O)=O)=C1 KBOPZPXVLCULAV-UHFFFAOYSA-N 0.000 title claims abstract description 176
- 229960004963 mesalazine Drugs 0.000 title claims abstract description 176
- 239000000203 mixture Substances 0.000 title claims abstract description 91
- 238000002360 preparation method Methods 0.000 title claims abstract description 85
- 239000000080 wetting agent Substances 0.000 claims abstract description 68
- 239000000227 bioadhesive Substances 0.000 claims abstract description 66
- 239000003814 drug Substances 0.000 claims abstract description 15
- 239000004480 active ingredient Substances 0.000 claims abstract description 7
- 239000002245 particle Substances 0.000 claims description 67
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 45
- 239000000243 solution Substances 0.000 claims description 36
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 30
- 239000000725 suspension Substances 0.000 claims description 27
- 230000003204 osmotic effect Effects 0.000 claims description 25
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 23
- 229920002125 Sokalan® Polymers 0.000 claims description 23
- 229960001631 carbomer Drugs 0.000 claims description 23
- 238000009472 formulation Methods 0.000 claims description 23
- -1 polyoxyethylene Polymers 0.000 claims description 23
- 229920000148 Polycarbophil calcium Polymers 0.000 claims description 20
- 239000004359 castor oil Substances 0.000 claims description 20
- 235000019438 castor oil Nutrition 0.000 claims description 20
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 20
- 229950005134 polycarbophil Drugs 0.000 claims description 20
- 239000000872 buffer Substances 0.000 claims description 18
- 239000002202 Polyethylene glycol Substances 0.000 claims description 14
- 229920001223 polyethylene glycol Polymers 0.000 claims description 14
- 239000000230 xanthan gum Substances 0.000 claims description 14
- 229920001285 xanthan gum Polymers 0.000 claims description 14
- 229940082509 xanthan gum Drugs 0.000 claims description 14
- 235000010493 xanthan gum Nutrition 0.000 claims description 14
- 239000008187 granular material Substances 0.000 claims description 13
- 229920001519 homopolymer Polymers 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 13
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 12
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 12
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 12
- 239000000843 powder Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical group O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 239000008367 deionised water Substances 0.000 claims description 11
- 229910021641 deionized water Inorganic materials 0.000 claims description 11
- 229920006316 polyvinylpyrrolidine Polymers 0.000 claims description 11
- 101100248253 Arabidopsis thaliana RH40 gene Proteins 0.000 claims description 10
- 229920001661 Chitosan Polymers 0.000 claims description 10
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 10
- 229930195725 Mannitol Natural products 0.000 claims description 10
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical group C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 10
- 239000000594 mannitol Substances 0.000 claims description 10
- 235000010355 mannitol Nutrition 0.000 claims description 10
- 229940075508 carbomer homopolymer type b Drugs 0.000 claims description 9
- 229920001983 poloxamer Polymers 0.000 claims description 9
- 229960000502 poloxamer Drugs 0.000 claims description 9
- 229940049638 carbomer homopolymer type c Drugs 0.000 claims description 8
- 238000012377 drug delivery Methods 0.000 claims description 8
- 229910000402 monopotassium phosphate Inorganic materials 0.000 claims description 8
- 235000019796 monopotassium phosphate Nutrition 0.000 claims description 8
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 7
- 150000001413 amino acids Chemical class 0.000 claims description 7
- 229920001400 block copolymer Polymers 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 229920001993 poloxamer 188 Polymers 0.000 claims description 7
- 229940044519 poloxamer 188 Drugs 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 239000008186 active pharmaceutical agent Substances 0.000 claims description 6
- 239000006172 buffering agent Substances 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 229920001577 copolymer Polymers 0.000 claims description 6
- 150000004676 glycans Chemical class 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 229920000058 polyacrylate Polymers 0.000 claims description 6
- 229920001282 polysaccharide Polymers 0.000 claims description 6
- 239000005017 polysaccharide Substances 0.000 claims description 6
- 239000000375 suspending agent Substances 0.000 claims description 6
- 239000003002 pH adjusting agent Substances 0.000 claims description 5
- 238000005550 wet granulation Methods 0.000 claims description 5
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 4
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 claims description 4
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical class C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 4
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 4
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 4
- 229960002303 citric acid monohydrate Drugs 0.000 claims description 4
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 239000008101 lactose Substances 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000003381 stabilizer Substances 0.000 claims description 4
- 239000007983 Tris buffer Substances 0.000 claims description 3
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 2
- 229960004106 citric acid Drugs 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims description 2
- 239000000347 magnesium hydroxide Substances 0.000 claims description 2
- 229910001862 magnesium hydroxide Inorganic materials 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- LJSOLTRJEQZSHV-UHFFFAOYSA-L potassium;sodium;hydron;hydroxide;phosphate Chemical compound [OH-].[Na+].[K+].OP(O)([O-])=O LJSOLTRJEQZSHV-UHFFFAOYSA-L 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- 230000000968 intestinal effect Effects 0.000 abstract description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- 241000792859 Enema Species 0.000 description 25
- 229940095399 enema Drugs 0.000 description 25
- 239000007920 enema Substances 0.000 description 25
- 230000000052 comparative effect Effects 0.000 description 15
- 230000000694 effects Effects 0.000 description 10
- 238000012360 testing method Methods 0.000 description 9
- 229940079593 drug Drugs 0.000 description 8
- 238000004062 sedimentation Methods 0.000 description 7
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 description 6
- 210000004877 mucosa Anatomy 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 238000005259 measurement Methods 0.000 description 5
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 5
- LWIHDJKSTIGBAC-UHFFFAOYSA-K potassium phosphate Substances [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 5
- 239000006185 dispersion Substances 0.000 description 4
- 239000000829 suppository Substances 0.000 description 4
- 230000001133 acceleration Effects 0.000 description 3
- 230000002209 hydrophobic effect Effects 0.000 description 3
- 229940047969 mesalamine enema Drugs 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 2
- SGHZXLIDFTYFHQ-UHFFFAOYSA-L Brilliant Blue Chemical compound [Na+].[Na+].C=1C=C(C(=C2C=CC(C=C2)=[N+](CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=2C(=CC=CC=2)S([O-])(=O)=O)C=CC=1N(CC)CC1=CC=CC(S([O-])(=O)=O)=C1 SGHZXLIDFTYFHQ-UHFFFAOYSA-L 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 2
- 229960002233 benzalkonium bromide Drugs 0.000 description 2
- KHSLHYAUZSPBIU-UHFFFAOYSA-M benzododecinium bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 KHSLHYAUZSPBIU-UHFFFAOYSA-M 0.000 description 2
- 239000003364 biologic glue Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000001055 blue pigment Substances 0.000 description 2
- 230000000112 colonic effect Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 210000005081 epithelial layer Anatomy 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 210000004347 intestinal mucosa Anatomy 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- RWPGFSMJFRPDDP-UHFFFAOYSA-L potassium metabisulfite Chemical compound [K+].[K+].[O-]S(=O)S([O-])(=O)=O RWPGFSMJFRPDDP-UHFFFAOYSA-L 0.000 description 2
- 229940043349 potassium metabisulfite Drugs 0.000 description 2
- 235000010263 potassium metabisulphite Nutrition 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- 206010000050 Abdominal adhesions Diseases 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 201000010927 Mucositis Diseases 0.000 description 1
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000003431 cross linking reagent Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000013100 final test Methods 0.000 description 1
- 238000009477 fluid bed granulation Methods 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 210000003405 ileum Anatomy 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 150000002617 leukotrienes Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 230000002572 peristaltic effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/606—Salicylic acid; Derivatives thereof having amino groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0031—Rectum, anus
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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- A—HUMAN NECESSITIES
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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Abstract
The invention discloses a composition containing mesalamine, a preparation method and application thereof. The mesalamine-containing composition comprises the following components in parts by weight: 4-14 parts of a pharmaceutical active ingredient, 0.1-15 parts of a bioadhesive, 0.1-15 parts of a wetting agent and 0-5 parts of a pH regulator; wherein the medicine active ingredient is mesalamine; the bioadhesive comprises a crosslinked structure; the wetting agent comprises a linear structure. The composition containing mesalamine and the preparation thereof have higher uniform dispersivity, stability and safety, and excellent intestinal adhesiveness, can stay at the focus of the intestinal canal for a long time by combining a local administration mode of anorectal administration, and are convenient to use, safe and effective and high in patient compliance.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a composition containing mesalamine, a preparation method and application thereof.
Background
Mesalamine (mesalazine) is a common name of 5-aminosalicylic acid (5-aminosalicylic acid, 5-ASA) and has a molecular formula of CH 7 NO 3 Molecular weight is 153.14, its structural formula is shown below, -OH and-NH 2 Is in para position, unstable and easy to be oxidized and degraded.
Experiments show that the stability of mesalamine is related to the pH, and the mesalamine has better stability in a solution with the pH of 4-5. The stability investigation result of the bulk drug shows that: the high temperature and strong light can increase related substances, which shows that the preparation needs to avoid high temperature and strong light when being stored. Mesalamine has been recognized for the last 30 years as a first line drug to induce and sustain relief from light-medium ulcerative colitis (Ulcerative Colitis, UC). Mesalamine has remarkable inhibition effect on intestinal mucosa inflammation by mainly controlling synthesis and release of inflammatory factor leukotriene in local intestinal tissues, eliminating the generation of free radicals, reducing the synthesis of arachidonic acid. The medicine has high safety and relatively less adverse reaction, and is easy to be accepted by patients.
Currently, mesalamine is mainly used for treating UC by two routes of oral administration and rectal administration, and the dosage forms on the market mainly comprise enteric tablets, slow release particles, slow release tablets, suppositories and enema. However, the oral preparation is generally released at the terminal ileum and colon, has the problems of unstable drug release position caused by long gastrointestinal tract transport distance and a plurality of influencing factors, large change of local drug concentration of focus and the like, and is difficult to achieve ideal curative effect. The suppository and the enema can be applied to focus positions through rectal administration positioning, so that symptoms are relieved rapidly, and compared with an oral preparation, the suppository and the enema have greater advantages in the aspect of positioning treatment of local lesions. However, the suppository has smaller diffusion area after melting, is difficult to widely contact with the focus of UC scattered distribution, and the enema has wider distribution, is easy to leak, can not well control the acting time and dosage of the medicine, and is inconvenient to use. Mesalamine temperature-sensitive gel enema has also been developed to further extend the residence time of the drug in the colorectal, increase local AUC, and reduce the risk of leakage by increasing adhesion in vivo.
However, in all these semisolid preparations, on one hand, due to the insoluble active ingredient, it is difficult to ensure the uniformity of the raw materials, and the effect of uniform and rapid dispersion is achieved; on the other hand, to increase the stability of mesalazine, the stability of the formulation and the control of microbial limits, preservatives, antioxidants or stabilizers such as SDS, benzalkonium bromide, potassium metabisulfite, etc. are added, which, although in safe amounts, have significant cytotoxicity to mucosal cells, especially in patients with UC.
Therefore, from the clinical requirement and safety of mesalamine in treating UC, it is very necessary to continue to develop related work in terms of formulation innovation and development, so as to pointedly solve the current shortages.
Disclosure of Invention
Aiming at the problems of poor dispersibility, poor stability and low safety of mesalamine enema in the prior art, the invention provides a mesalamine-containing composition, a preparation method and application thereof. The mesalamine composition and the mesalamine preparation have good uniform dispersibility, and can ensure good stability and safety.
In order to achieve the above purpose, the present invention adopts the following scheme:
one of the schemes of the invention provides a composition containing mesalamine, which comprises the following components in parts by weight: 4-15 parts of a pharmaceutical active ingredient, 0.1-15 parts of a bioadhesive, 0.1-15 parts of a wetting agent and 0-5 parts of a pH regulator; wherein,,
the medicine active ingredient is mesalamine; the bioadhesive comprises a crosslinked structure; the wetting agent includes a linear structure.
In the present invention, the mesalamine may be 4 to 10 parts by weight, for example, 4 parts by weight.
In the present invention, the crosslinked structure in the molecular chain of the bioadhesive may be a crosslinked structure formed by a crosslinking agent, or may be a crosslinked structure in which a three-dimensional space is formed by intramolecular or intermolecular hydrogen bonds.
In the present invention, the cross-linked structure means a three-dimensional network structure in the molecular chain of the polymer compound, and those skilled in the art can know the obvious difference between the three-dimensional network structure and the linear structure or the branched structure. The three-dimensional network structure can interact with and stably connect with the mucosa glycoprotein, can keep longer adhesion time, and can not irritate the mucosa.
In the present invention, the bioadhesive may be selected from acrylic polymers and/or polysaccharides having a crosslinked structure.
When the bioadhesive is an acrylic polymer, the acrylic polymer may be one or more of carbomer homopolymer type a, carbomer homopolymer type B, carbomer copolymer type B, carbomer interpolymer type B, carbomer homopolymer type C, and polycarbophil. The viscosity of the carbomer homopolymer type A may be 4000-11000 mPa.s. The viscosity of the carbomer homopolymer type B may be 25000-39000 mPa.s. The viscosity of the carbomer copolymer type B may be 1700-4500 mPa.s. The viscosity of the carbomer type B may be 47000-77000 mPa.s. The carbomer homopolymer type C may have a viscosity of 40000-60000 mPa.s. The viscosity of the polycarbophil may be 2000-12000 mPa-s.
When the bioadhesive is a polysaccharide, the polysaccharide may be chitosan and/or xanthan gum. The viscosity of the chitosan may be 80-160 mpa.s. The viscosity of the xanthan gum may be 700-1300 mpa.s.
In the invention, the viscosity is obtained by adopting a rotary viscometer measuring method according to the operating rules of viscosity inspection of Chinese pharmacopoeia of 2020 edition.
In the present invention, the bioadhesive may be in the range of 0.2 to 14.5 parts by weight, for example 0.2 parts, 1 part, 2 parts or 14.1 parts.
In the invention, the wetting agent can reduce the contact angle of the hydrophobic material and water, and increase the hydrophilicity of the hydrophobic material, so as to realize better dissolution or dispersion of the hydrophobic material in an aqueous phase environment.
In the present invention, the wetting agent may be selected from one or more of polyoxyethylene derivatives having a linear structure, povidone derivatives, polyethylene glycol, polylactic acid-glycolic acid copolymers, amino acid block copolymers, and linear acrylic acid.
Wherein the polyoxyethylene derivative may be a poloxamer and/or polyoxyethylene hydrogenated castor oil, such as poloxamer 188 and/or polyoxyethylene hydrogenated castor oil RH40.
Wherein the povidone derivative may be polyvinylpyrrolidone, such as polyvinylpyrrolidone K15 or polyvinylpyrrolidone K30.
In the present invention, the wetting agent may be 0.2 to 15 parts by weight, for example, 0.2 parts, 0.57 parts, 1.2 parts, 4.6 parts, 5 parts, 13.1 parts or 15 parts.
In the present invention, the wetting agent may be a powder having a particle diameter of not more than 250 μm.
In the present invention, the pH adjustor may be a pH adjustor conventionally used in the art, preferably one or more selected from the group consisting of amino acids, sodium hydroxide, potassium hydroxide, magnesium hydroxide and sodium bicarbonate, for example sodium hydroxide.
In the present invention, the weight part of the pH adjuster may be 0.1 to 0.6 part, for example, 0.1 part, 0.14 part, 0.32 part, 0.4 part, or 0.51 part.
In certain embodiments, the bioadhesive is polycarbophil.
In certain embodiments, the bioadhesive is polycarbophil and xanthan gum. The ratio of the parts by weight of polycarbophil to the xanthan gum may be 3:1.
In certain embodiments, the bioadhesives are carbomer homopolymer type a and polycarbophil. The weight fraction ratio of carbomer homopolymer form A to polycarbophil may be 1:1.
In certain embodiments, the bioadhesive is carbomer homopolymer type B and chitosan. The weight fraction ratio of carbomer homopolymer type B to chitosan may be 0.1:14.
In certain embodiments, the bioadhesive is carbomer homopolymer type C and xanthan gum. The weight fraction ratio of carbomer homopolymer type C to xanthan gum may be 1:1.
In certain embodiments, the wetting agent is polyoxyethylated hydrogenated castor oil RH40.
In certain embodiments, the wetting agent is polyethylene glycol and a polylactic acid-glycolic acid copolymer. The weight fraction ratio of the polyethylene glycol and the polylactic acid-glycolic acid copolymer can be 3:2.
In certain embodiments, the wetting agents are poloxamer 188 and polyvinylpyrrolidone K15. The weight part ratio of poloxamer 188 to polyvinylpyrrolidone K15 may be 4:1.
In certain embodiments, the wetting agent is an amino acid block copolymer and linear acrylic acid. The weight fraction ratio of the amino acid block copolymer to the linear acrylic acid may be 1:1.
In certain embodiments, the wetting agent is polyoxyethylene hydrogenated castor oil RH40, polyethylene glycol, and polyvinylpyrrolidone K15. The weight portion ratio of the polyoxyethylene hydrogenated castor oil RH40, the polyethylene glycol and the polyvinylpyrrolidone K15 can be 1:0.3:1.
In certain embodiments, the wetting agent is polyoxyethylene hydrogenated castor oil RH40, polyethylene glycol, polyvinylpyrrolidone K15, and poloxamer 188. The weight parts ratio of polyoxyethylene hydrogenated castor oil RH40, polyethylene glycol, polyvinylpyrrolidone K15 and poloxamer 188 may be 4:3:3.01:3.
In the present invention, the mesalamine-containing composition may further include a solvent. The solvent is deionized water, which plays a dispersing role in the mesalamine-containing composition.
In the present invention, the mesalamine-containing composition may also include no solvent.
In the present invention, the mesalamine-containing composition may not include a stabilizer. Wherein the stabilizer comprises an antioxidant and a preservative which have significant cytotoxicity to mucosal cells, such as SDS, benzalkonium bromide and potassium metabisulfite.
In the invention, the composition containing mesalamine can also comprise pharmaceutically acceptable auxiliary materials; the pharmaceutically acceptable excipients may include one or more of buffers, tonicity adjusting agents, suspending agents and solubilizing agents.
Wherein the buffer may be a buffer conventional in the art, preferably selected from one or more of citric acid and salts thereof, phosphoric acid and salts thereof, tris (Tris) hydroxymethyl aminomethane), carbonic acid, acetic acid and barbituric acid, such as one or more of potassium dihydrogen phosphate, potassium dihydrogen phosphate-sodium hydroxide, disodium hydrogen phosphate and citric acid monohydrate. The buffer may be present in an amount of 0.1 to 5 parts by weight, for example 0.68 parts, 0.79 parts or 2.68 parts.
Wherein the osmolality adjusting agent may be an osmolality adjusting agent conventional in the art, preferably selected from one or more of mannitol, lactose and trehalose. The osmolality adjusting agent may be 0.1 to 10 parts, for example 0.7 parts, 0.8 parts, 1 part or 6 parts.
In a specific embodiment, based on 20 parts by weight of the mesalamine-containing composition, the following parts by weight of each component may be used: 4 parts of mesalamine, 1 part of bioadhesive, 13.01 parts of wetting agent, 0.68 part of buffer, 0.51 part of pH regulator and 0.8 part of osmotic pressure regulator.
In a specific embodiment, based on 20 parts by weight of the mesalamine-containing composition, the following parts by weight of each component may be used: 4 parts of mesalamine, 14.1 parts of bioadhesive, 0.2 parts of wetting agent, 0.79 parts of buffering agent and 1 part of osmotic pressure regulator.
In a specific embodiment, the following components are calculated according to the weight part of the mesalamine-containing composition being 5.71 parts: 4 parts of mesalamine, 1 part of bioadhesive, 0.57 part of wetting agent and 0.14 part of pH regulator.
In a specific embodiment, based on 20 parts by weight of the mesalamine-containing composition, the following parts by weight of each component may be used: 4 parts of mesalamine, 2 parts of bioadhesive, 5 parts of wetting agent, 2.68 parts of buffer, 0.32 part of pH regulator and 6 parts of osmotic pressure regulator.
In a specific embodiment, the following components are calculated according to the weight part of the mesalamine-containing composition being 6.6 parts: 4 parts of mesalamine, 1 part of bioadhesive, 1.2 parts of wetting agent and 0.4 part of pH regulator.
In a specific embodiment, based on 20 parts by weight of the mesalamine-containing composition, the following parts by weight of each component may be used: 4 parts of mesalamine, 0.2 part of bioadhesive, 15 parts of wetting agent, 0.1 part of pH regulator and 0.7 part of osmotic pressure regulator.
In a specific embodiment, based on 10 parts by weight of the mesalamine-containing composition, the following parts by weight of each component may be used: 4 parts of mesalamine, 1 part of bioadhesive, 4.6 parts of wetting agent and 0.4 part of pH regulator.
In a second aspect of the invention there is provided a mesalamine formulation comprising a mesalamine-containing composition as described above.
In the invention, the mesalamine preparation can be in the form of granules or powder.
Wherein, when the mesalamine preparation is a granule, the particle size of the granule is not more than 250 μm, preferably not more than 150 μm.
Wherein, when the mesalamine preparation is a powder, the particle size of the powder does not exceed 250 μm.
In the present invention, the mesalamine formulation may have a pH of 4 to 9, such as 4.5, 4.9, 6.8, 7.3, 7.4, or 8.
In the present invention, the mesalamine formulation may have a viscosity of 500-8000 mPa-s, for example 800 mPa-s, 1100 mPa-s, 3100 mPa-s, 4500 mPa-s, 6100 mPa-s, 7400 mPa-s or 7600 mPa-s.
In the invention, the mesalamine preparation can be rapidly dispersed in deionized water to form uniform solution or suspension, and the sedimentation rate is not more than 5% within 100 min.
The third aspect of the present invention provides a method for preparing a mesalamine preparation as described above, which adopts the following one or two modes:
mode one: when the mesalamine-containing composition includes the active pharmaceutical ingredient, the bioadhesive, and the wetting agent, the preparation method includes the steps of: mixing the active pharmaceutical ingredient, the bioadhesive and the wetting agent to prepare granules or powder;
mode two: when the mesalamine-containing composition further includes one or more of the pH adjuster, the buffer, the suspending agent, the osmotic pressure adjuster, and the solubilizing agent, the preparation method includes the steps of: mixing the active pharmaceutical ingredient, the bioadhesive and the wetting agent further with one or more of the pH adjustor, the buffering agent, the suspending agent, the osmotic pressure adjustor and the solubilizing agent to prepare granules or powder.
In the present invention, when the mesalamine preparation is a granule, the preparation method may further include wet granulation and drying after the mixing.
Wherein the wet granulation conditions may be conventional in the art, such as fluid bed granulation.
Wherein the wet granulation solvent may be an aqueous ethanol solution, such as 90% ethanol or 95% ethanol, wherein% represents the volume ratio in the entire aqueous ethanol solution.
Wherein the wet granulation temperature may be conventional in the art, e.g., 30-70 ℃.
Wherein the drying conditions may be conventional in the art, for example, 37-45 ℃ drying.
The fourth scheme of the invention provides an application of the composition containing mesalamine or the mesalamine preparation in preparing medicines for treating ulcerative colitis.
In the present invention, the use may comprise dispersing the mesalamine-containing composition or the mesalamine formulation with deionized water to form a solution or suspension before administration. Wherein the pH of the suspension may range from 4 to 9; the viscosity of the suspension is not more than 10000 mPa.s; the particle size of the suspension is not more than 250 μm.
In the present invention, the step of administering may include delivering the mesalamine-containing composition or the formulation to the anorectal site in one continuous or fractional delivery with an anorectal applicator.
In the present invention, the anorectal applicator may be an integrated applicator, or an applicator and a preparation separated from each other, preferably an applicator and a preparation separated from each other;
in the invention, the administration mode can be manual push injection or automatic administration mode realized by external force, preferably automatic administration mode realized by external force.
On the basis of conforming to the common knowledge in the field, the above preferred conditions can be arbitrarily combined to obtain the preferred examples of the invention.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that:
the composition containing mesalamine and the mesalamine preparation have the following effects:
(1) The uniform dispersity is high, and the particle size is uniform and controllable;
(2) The stability and the safety are high;
(3) Excellent intestinal adhesion, more durable residence time at a specific intestinal site;
(4) Can directly act on the focus part of the intestinal canal to realize targeted drug delivery;
(5) The administration times and adverse reactions are reduced, and the treatment effect and the compliance of patients are improved;
(6) Avoiding the discomfort of patients and the waste of medicines caused by the traditional short-term large-dose administration, and fully and effectively playing the role of the medicine treatment or the auxiliary treatment.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
As shown in Table 1, the raw materials used in the examples and comparative examples of the present invention are all commercially available except those listed in the tables.
Wherein, according to the conventional method (if no special mark exists, the viscosity of each raw material refers to the viscosity inspection operation rule of 2020 edition of Chinese pharmacopoeia, obtained by adopting a rotary viscometer measuring method) and conditions in the field, or according to the commodity specification, the viscosity data of the corresponding raw material can be obtained. In the table "/" is viscosity data of the raw material with no relevant information or without measurement.
The commercially available mesalamine enema used in the examples was salfu and the manufacturer thereof was switzerland Vifor AG Zweigniederlassung Medichemie Ettingen.
TABLE 1 information about the raw materials used in examples and comparative examples
In the following examples, the procedure used to disperse the particles of the mesalamine formulation in solution was as follows, except as specifically described: the prepared particles were introduced into 100mL deionized water over 90s and stirred mechanically with a leaf machine at a rotational speed: 200rpm/min,2min.
The following examples are given as criteria for particle sizes below 250 μm after dispersion in solution: and (3) passing through a 60-mesh (corresponding to the aperture of 250 μm) pharmacopoeia sieve, and observing whether the agglomerate passes through the sieve mesh or not.
Example 1
An enema composition containing mesalamine comprises the following components in parts by weight of the composition as 20 parts: 4 parts of mesalamine, 1 part of bioadhesive, 13.01 parts of wetting agent, 0.68 part of buffer and 0.51 part of pH regulator; 0.8 part of osmotic pressure regulator, wherein,
the bioadhesive consists of 0.5 parts of carbomer homopolymer type A and 0.5 parts of polycarbophil;
the wetting agent consists of 3.01 parts of polyvinylpyrrolidone K15,4 parts of polyoxyethylene hydrogenated castor oil RH40,3 parts of poloxamer 188,3 parts of PEG 4000.
The preparation method of the enema preparation containing the mesalamine composition comprises the following steps:
(1) Taking 4 parts of mesalamine, 1 part of bioadhesive, 13.01 parts of wetting agent, 0.68 part of monopotassium phosphate, 0.8 part of osmotic pressure regulator (mannitol), 0.51 part of pH regulator (sodium hydroxide), granulating by a 95% ethanol fluidized bed, and preparing particles with the particle size not exceeding 250 mu m at the air inlet temperature of 40 ℃;
(2) Before anorectal administration, dispersing the particles of the mesalamine preparation in the solution to prepare uniform solution or suspension for later use;
the particles of the mesalamine preparation are dispersed in a solution, the pH range is 4-9, the particle size of the obtained suspension is not more than 250 mu m, and the viscosity of the system is not more than 10000 mPa.s.
Example 2
An enema composition containing mesalamine comprises the following components in parts by weight of the composition as 20 parts: 4 parts of mesalamine, 14.1 parts of bioadhesive, 0.2 parts of wetting agent and 0.79 parts of buffer; 1 part of osmotic pressure regulator, wherein,
the bioadhesive consists of 0.1 part of carbomer homopolymer type B and 14 parts of chitosan;
the wetting agent is polyoxyethylene hydrogenated castor oil RH40 with the weight of 0.2 part;
the buffer consists of 0.68 part of monopotassium phosphate and 0.11 part of sodium hydroxide
The preparation method of the enema preparation containing the mesalamine composition comprises the following steps:
(1) Taking 4 parts of mesalamine, 14.1 parts of bioadhesive, 0.2 parts of wetting agent, 0.79 parts of buffer (0.68 parts of monopotassium phosphate and 0.11 parts of sodium hydroxide), 1 part of osmotic pressure regulator (mannitol), granulating by a 95% ethanol fluidized bed, and preparing particles with the particle diameter not exceeding 250 μm at the air inlet temperature of 45 ℃;
(2) Before anorectal administration, dispersing the particles of the mesalamine preparation in the solution to prepare uniform solution or suspension for later use;
the particles of the mesalamine preparation are dispersed in a solution, the pH range is 4-9, the particle size of the obtained suspension is not more than 250 mu m, and the viscosity of the system is not more than 10000 mPa.s.
Example 3
An enema composition containing mesalamine, which comprises the following components in parts by weight of the composition being 5.71 parts: 4 parts of mesalamine, 1 part of bioadhesive, 0.57 part of wetting agent and 0.14 part of pH regulator; wherein,,
the bioadhesive consists of 1 part of carbomer homopolymer type B, carbomer copolymer type B, carbomer interpolymer type b=0.4:0.3:0.3;
the wetting agent consists of 0.57 parts of polyoxyethylene hydrogenated castor oil RH40.
The preparation method of the enema preparation containing the mesalamine composition comprises the following steps:
(1) Taking 4 parts of mesalamine, 1 part of bioadhesive, 0.57 part of wetting agent, 0.14 part of pH regulator (sodium hydroxide), granulating by a 95% ethanol fluidized bed, and preparing particles with the particle size not exceeding 250 μm at the air inlet temperature of 37 ℃;
(2) Before anorectal administration, dispersing the particles of the mesalamine preparation in the solution to prepare uniform solution or suspension for later use;
the particles of the mesalamine preparation are dispersed in a solution, the pH range is 4-9, the particle size of the obtained suspension is not more than 250 mu m, and the viscosity of the system is not more than 10000 mPa.s.
Example 4
An enema composition containing mesalamine comprises the following components in parts by weight of the composition as 20 parts: 4 parts of mesalamine, 2 parts of bioadhesive, 5 parts of wetting agent, 2.68 parts of buffer and 0.32 part of pH regulator; 6 parts of osmotic pressure regulator, wherein,
the bioadhesive consists of 1.5 parts of polycarbophil and 0.5 part of xanthan gum;
the wetting agent consists of 3 parts of PLGA and 2 parts of PEG 4000;
the osmotic pressure regulator consists of 2 parts of mannitol, 2 parts of lactose and 2 parts of trehalose;
the buffer consisted of 2.2 parts disodium hydrogen phosphate and 0.48 parts citric acid monohydrate.
The preparation method of the enema preparation containing the mesalamine composition comprises the following steps:
(1) Taking 4 parts of mesalamine, 2 parts of a bioadhesive, 5 parts of a wetting agent, 2.68 parts of a buffering agent (2.2 parts of disodium hydrogen phosphate and 0.48 part of citric acid monohydrate), 6 parts of an osmotic pressure regulator (2 parts of mannitol, 2 parts of lactose and 2 parts of trehalose), 0.32 part of a pH regulator (sodium hydroxide), granulating by a 95% ethanol fluidized bed, and preparing particles with the particle size of not more than 250 mu m at the inlet air temperature of 42 ℃;
(2) Before anorectal administration, dispersing the particles of the mesalamine preparation in the solution to prepare uniform solution or suspension for later use;
the particles of the mesalamine preparation are dispersed in a solution, the pH range is 4-9, the particle size of the obtained suspension is not more than 250 mu m, and the viscosity of the system is not more than 10000 mPa.s.
Example 5
An enema composition containing mesalamine, which comprises the following components in parts by weight of 6.6 parts: 4 parts of mesalamine, 1 part of bioadhesive, 1.2 parts of wetting agent and 0.4 part of pH regulator; wherein,,
the biological adhesive consists of 1 part of polycarbophil;
the wetting agent consists of 0.6 parts of an amino acid block copolymer and 0.6 parts of linear acrylic acid.
The preparation method of the enema preparation containing the mesalamine composition comprises the following steps:
(1) Taking 4 parts of mesalamine, 1 part of bioadhesive, 1.2 parts of wetting agent, 0.4 part of pH regulator (sodium hydroxide), granulating by a 90% ethanol fluidized bed, and preparing particles with the particle size not exceeding 250 μm at the air inlet temperature of 40 ℃;
(2) Before anorectal administration, dispersing the particles of the mesalamine preparation in the solution to prepare uniform solution or suspension for later use;
the particles of the mesalamine preparation are dispersed in a solution, the pH range is 4-9, the particle size of the obtained suspension is not more than 250 mu m, and the viscosity of the system is not more than 10000 mPa.s.
Example 6
An enema composition containing mesalamine comprises the following components in parts by weight of the composition as 20 parts: 4 parts of mesalamine, 0.2 part of bioadhesive, 15 parts of wetting agent and 0.1 part of pH regulator; 0.7 part of osmotic pressure regulator, wherein,
the bioadhesive consists of 0.1 part of carbomer homopolymer type C and 0.1 part of xanthan gum;
the wetting agent consists of 3 parts of polyvinylpyrrolidone K15 and 12 parts of poloxamer 188.
The preparation method of the enema preparation containing the mesalamine composition comprises the following steps:
(1) Taking 4 parts of mesalamine, 0.2 part of bioadhesive, 15 parts of wetting agent, 0.7 part of osmotic pressure regulator (mannitol), 0.1 part of pH regulator (sodium hydroxide), granulating by a 95% ethanol fluidized bed, and preparing particles with the particle size not exceeding 250 μm at the air inlet temperature of 40 ℃;
(2) Before anorectal administration, dispersing the particles of the mesalamine preparation in the solution to prepare uniform solution or suspension for later use;
the particles of the mesalamine preparation are dispersed in a solution, the pH range is 4-9, the particle size of the obtained suspension is not more than 250 mu m, and the viscosity of the system is not more than 10000 mPa.s.
Example 7
An enema composition containing mesalamine comprises the following components in parts by weight of 10 parts: 4 parts of mesalamine, 1 part of bioadhesive, 4.6 parts of wetting agent and 0.4 part of pH regulator; wherein,,
the biological adhesive consists of 1 part of polycarbophil;
the wetting agent consists of 2 parts of polyvinylpyrrolidone K15,2 parts of polyoxyethylene hydrogenated castor oil RH40 and 0.6 part of PEG 4000.
The preparation method of the enema preparation containing the mesalamine composition comprises the following steps:
(1) Taking 4 parts of mesalamine, 1 part of bioadhesive, 4.6 parts of wetting agent, 0.4 part of pH regulator (sodium hydroxide), granulating by a 95% ethanol fluidized bed, and preparing particles with the particle diameter not more than 250 μm at the air inlet temperature of 40 ℃;
(2) Before anorectal administration, dispersing the particles of the mesalamine preparation in the solution to prepare uniform solution or suspension for later use;
the particles of the mesalamine preparation are dispersed in a solution, the pH range is 4-9, the particle size of the obtained suspension is not more than 250 mu m, and the viscosity of the system is not more than 10000 mPa.s.
Comparative example 1
Compared with example 1, the difference is that no bioadhesive agent exists, and the dosage of the pH regulator is correspondingly adjusted;
an enema composition containing mesalamine, which comprises the following components in parts by weight of 18.6 parts: 4 parts of mesalamine, 0 part of bioadhesive, 13.01 parts of wetting agent, 0.68 part of buffer and 0.11 part of pH regulator; 0.8 part of osmotic pressure regulator, wherein,
the wetting agent consists of 3.01 parts of polyvinylpyrrolidone K15,4 parts of polyoxyethylene hydrogenated castor oil RH40,3 parts of poloxamer 188,3 parts of PEG 4000.
The preparation method of the enema preparation containing the mesalamine composition comprises the following steps:
(1) Taking 4 parts of mesalamine, 13.01 parts of wetting agent, 0.68 parts of monopotassium phosphate, 0.8 parts of osmotic pressure regulator (mannitol), 0.11 parts of pH regulator (sodium hydroxide), granulating by a 95% ethanol fluidized bed, and preparing particles with the particle size not exceeding 250 μm at the air inlet temperature of 40 ℃;
(2) Before anorectal administration, dispersing the particles of the mesalamine preparation in the solution to prepare uniform solution or suspension for later use;
the particles of the mesalamine preparation are dispersed in a solution, the pH range is 4-9, the particle size of the obtained suspension is not more than 250 mu m, and the viscosity of the system is not more than 10000 mPa.s.
Comparative example 2
In comparison with example 1, the difference is that no wetting agent is present;
an enema composition containing mesalamine, which comprises the following components in parts by weight of 6.99 parts: 4 parts of mesalamine, 1 part of bioadhesive, 0 part of wetting agent, 0.68 part of buffer and 0.51 part of pH regulator; 0.8 part of osmotic pressure regulator, wherein,
the bioadhesive consisted of 0.5 parts of carbomer homopolymer type A and 0.5 parts of polycarbophil.
The preparation method of the enema preparation containing the mesalamine composition comprises the following steps:
(1) Taking 4 parts of mesalamine, 1 part of a bioadhesive, 0.68 part of potassium dihydrogen phosphate, 0.8 part of an osmotic pressure regulator (mannitol), 0.51 part of a pH regulator (sodium hydroxide), granulating by a 95% ethanol fluidized bed, and preparing particles with the particle size not exceeding 250 μm at the air inlet temperature of 40 ℃;
(2) Before anorectal administration, the particles of the mesalamine preparation are dispersed in a solution to prepare suspension with the viscosity of about 5900 mPa.s, but due to lack of a wetting agent, the particles are unevenly dispersed and aggregated into agglomerates, the particles do not meet the requirement that the particle size is not more than 250 mu m, and the particles are unsuitable for rectal infusion and stop subsequent experiments.
Comparative example 3
Compared with example 1, the difference is that the proportion of the bioadhesive exceeds 15 parts, and the dosage of the pH regulator is correspondingly adjusted;
an enema composition containing mesalamine, which comprises the following components in parts by weight of the composition being 37.8 parts: 4 parts of mesalamine, 18 parts of bioadhesive, 13.01 parts of wetting agent, 0.68 parts of buffer and 1.31 parts of pH regulator; 0.8 part of osmotic pressure regulator, wherein,
the bioadhesive consists of 1 part of carbomer homopolymer A and 2 parts of polycarbophil and 15 parts of chitosan;
the wetting agent consists of 3.01 parts of polyvinylpyrrolidone K15,4 parts of polyoxyethylene hydrogenated castor oil RH40,3 parts of poloxamer 188,3 parts of PEG 4000.
The preparation method of the enema preparation containing the mesalamine composition comprises the following steps:
(1) 4 parts of mesalamine, 18 parts of a bioadhesive, 13.01 parts of a wetting agent, 0.68 part of monopotassium phosphate, 0.8 part of an osmotic pressure regulator (mannitol), 1.31 parts of a pH regulator (sodium hydroxide), granulating by a 95% ethanol fluidized bed, and preparing particles with the particle size not exceeding 250 mu m at the air inlet temperature of 40 ℃;
(2) Before anorectal administration, the particles of the mesalamine preparation are dispersed in the solution to obtain gel with a viscosity of about 34500 mpa.s, which is too high to be suitable for rectal infusion and stop the subsequent experiments.
Effect example 1pH and viscosity test
The mesalamine formulations obtained in examples 1-7 and comparative examples 1-3 were tested for pH and viscosity. The viscosity test conditions were: the above pellets were added to 80mL of deionized water and the viscosity measured using a Brosh viscometer at 25℃and 20rpm. The test results are shown in Table 1.
TABLE 1pH and viscosity of mesalamine formulations of the different examples and comparative examples
| Examples or comparative examples | pH | Viscosity (mPa. S) |
| Example 1 | 7.4 | 6100 |
| Example 2 | 6.8 | 1100 |
| Example 3 | 4.5 | 4500 |
| Example 4 | 4.9 | 3100 |
| Example 5 | 6.8 | 7600 |
| Example 6 | 8.0 | 800 |
| Example 7 | 7.3 | 7400 |
| Comparative example 1 | 7.1 | 250 |
| Comparative example 2 | 7.3 | 5900 |
| Comparative example 3 | 7.3 | 34500 |
Effect example 2 adhesion test
The mesalamine formulations obtained in examples 1-7 and comparative example 1 were tested for intestinal mucoadhesion testing. The test methods for mesalamine formulations of examples 1-7 and comparative example 1 were: taking particles prepared by 4g of mesalamine, dispersing the particles in 80mL of deionized water, and uniformly stirring the particles. On a U-shaped groove with a flat bottom, fixing a physiological saline treated colonic mucosa epithelial layer (2 cm multiplied by 5cm multiplied by 0.3mm is respectively the width multiplied by length multiplied by thickness of the pig colonic mucosa epithelial layer) at one end of the groove, and dripping water-soluble brilliant blue pigment into a mesalamine preparation (convenient for observation); then 1mL of mesalamine preparation is loaded on intestinal mucosa, the distances between all mesalamine preparations and the bottom end of the mucosa are ensured to be equal, the mesalamine preparation is horizontally stood for 1 minute, the U-shaped groove is inclined by 30 degrees, and the mesalamine preparation is at the uppermost end; starting peristaltic pump, uniformly flushing mesalamine preparation with deionized water at 37+ -1deg.C from top, and stopping timing when color completely disappears from mucosa.
Setting a negative blank group as deionized water containing only water-soluble brilliant blue pigment; each group of samples was tested in parallel 6 times and the average was taken as the final test value and the test data is shown in table 2.
TABLE 2 adhesion Property intestinal mucoadhesion
| Test group | Adhesion (min) |
| Example 1 | 60±2.1 |
| Example 2 | 36±1.7 |
| Example 3 | 67±2.6 |
| Example 4 | 92±3.1 |
| Example 5 | 86±2.3 |
| Example 6 | 28+0.8 |
| Example 7 | 83±2.2 |
| Comparative example 1 | 4±0.3 |
| Negative blank | <2 |
From the above table, it is clear that the mesalamine formulations obtained in examples 1 to 7 have better adhesion properties than comparative example 1.
Effect example 3 accelerated test for determining total impurity content of mesalamine preparation
The granules prepared in examples 1-7 were packed in double aluminium bags (mesalamine content 4 g/bag) and placed under 60 ℃ acceleration conditions; commercially available mesalazine Qin Guanchang solution was placed in parallel under 60 ℃ acceleration conditions. Measuring the total impurities of mesalamine in the product at 0d,5d and 10d respectively, and examining the stability; (test methods refer to the measurement of mesalamine impurity in the Chinese pharmacopoeia), and the measurement results of mesalamine impurity are shown in table 3 below.
TABLE 3 determination of total impurity content of mesalamine preparation
As shown in the table above, the stability of the mesalamine preparation is superior to that of the commercially available mesalamine enema through the high-temperature acceleration experiment test.
Effect example 4 sedimentation rate measurement results
Pellets of mesalamine formulations prepared in examples 1-7 were introduced into 100mL deionized water over 90s and mechanically stirred with a leaf machine at a speed: 200rpm/min,2min. Transferring the dispersion liquid into a graduated cylinder, and standing for 100min at room temperature, wherein the ratio of the volume of supernatant to the total volume is the sedimentation rate:
sedimentation rate (%) = supernatant volume/total volume.
As shown in Table 4, the results of the sedimentation rate measurement of the mesalamine preparations prepared in examples 1 to 7 revealed that the sedimentation rate of the mesalamine preparation was not more than 10% when the particles of the mesalamine preparation were dispersed as a solution or suspension, and the preparation was left to stand at room temperature for 100 min.
TABLE 4 Mesalazine preparation sedimentation Rate determination results
Claims (10)
1. A mesalamine-containing composition, which is characterized by comprising the following components in parts by weight: 4-15 parts of a pharmaceutically active ingredient, 0.1-15 parts of a bioadhesive, 0.1-15 parts of a wetting agent and 0-5 parts of a pH regulator; wherein,,
the medicine active ingredient is mesalamine; the bioadhesive comprises a crosslinked structure; the wetting agent includes a linear structure.
2. The mesalamine-containing composition according to claim 1, wherein the parts by weight of mesalamine is 4 to 10 parts, such as 4 parts;
and/or the bioadhesive is an acrylic polymer and/or polysaccharide having a cross-linked structure;
when the bioadhesive is an acrylic polymer, the acrylic polymer is one or more of carbomer homopolymer type a, carbomer homopolymer type B, carbomer copolymer type B, carbomer interpolymer type B, carbomer homopolymer type C, and polycarbophil; the viscosity of the carbomer homopolymer type A may be 4000-11000 mPa.s; the viscosity of the carbomer homopolymer type B can be 25000-39000 mPa.s; the viscosity of the carbomer copolymer type B can be 1700-4500 mPa.s; the viscosity of the carbomer type B may be 47000-77000 mPa.s; the viscosity of the carbomer homopolymer type C can be 40000-60000 mPa.s; the viscosity of the polycarbophil can be 2000-12000 mPa.s;
when the bioadhesive is a polysaccharide, the polysaccharide is chitosan and/or xanthan gum; the viscosity of the chitosan can be 80-160 mPa.s; the viscosity of the xanthan gum can be 700-1300 mPa.s;
and/or the bioadhesive is 0.2 to 14.5 parts by weight, for example 0.2 parts, 1 part, 2 parts or 14.1 parts;
and/or the wetting agent is selected from one or more of polyoxyethylene derivatives with linear structures, povidone derivatives, polyethylene glycol, polylactic acid-glycolic acid copolymers, amino acid block copolymers and linear acrylic acid;
wherein the polyoxyethylene derivative is poloxamer and/or polyoxyethylene hydrogenated castor oil, such as poloxamer 188 and/or polyoxyethylene hydrogenated castor oil RH40;
wherein the povidone derivative is polyvinylpyrrolidone, such as polyvinylpyrrolidone K15 or polyvinylpyrrolidone K30;
and/or the wetting agent is 0.2-15 parts by weight, for example 0.2 parts, 0.57 parts, 1.2 parts, 4.6 parts, 5 parts, 13.1 parts or 15 parts;
and/or the wetting agent is a powder having a particle size of not more than 250 μm;
and/or the pH adjuster is selected from one or more of amino acids, sodium hydroxide, potassium hydroxide, magnesium hydroxide and sodium bicarbonate, for example sodium hydroxide; the pH adjuster is 0.1-0.6 parts by weight, for example 0.1, 0.14, 0.32, 0.4 or 0.51 parts.
3. The mesalamine-containing composition of claim 2, wherein the bioadhesive is polycarbophil;
alternatively, the bioadhesive is polycarbophil and xanthan gum; the weight part ratio of the polycarbophil to the xanthan gum is 3:1;
alternatively, the bioadhesive is carbomer homopolymer type a and polycarbophil; the weight part ratio of the carbomer homopolymer A to the polycarbophil is 1:1;
alternatively, the bioadhesive is carbomer homopolymer type B and chitosan; the weight part ratio of the carbomer homopolymer B type to the chitosan is 0.1:14;
alternatively, the bioadhesive is carbomer homopolymer type C and xanthan gum; the weight part ratio of the carbomer homopolymer C type to the xanthan gum is 1:1;
and/or, the wetting agent is polyoxyethylene hydrogenated castor oil;
or the wetting agent is polyethylene glycol and polylactic acid-glycolic acid copolymer; the weight part ratio of the polyethylene glycol to the polylactic acid-glycolic acid copolymer is 3:2;
or, the wetting agent is poloxamer and polyvinylpyrrolidone; the weight part ratio of the poloxamer to the polyvinylpyrrolidone is 4:1;
alternatively, the wetting agent is an amino acid block copolymer and linear acrylic acid; the weight part ratio of the amino acid block copolymer to the linear acrylic acid is 1:1;
or, the wetting agent is polyoxyethylene hydrogenated castor oil, polyethylene glycol and polyvinylpyrrolidone; the weight part ratio of the polyoxyethylene hydrogenated castor oil to the polyethylene glycol to the polyvinylpyrrolidone is 1:0.3:1;
or, the wetting agent is polyoxyethylene hydrogenated castor oil, polyethylene glycol, polyvinylpyrrolidone and poloxamer; the weight part ratio of the polyoxyethylene hydrogenated castor oil, the polyethylene glycol, the polyvinylpyrrolidone and the poloxamer is 4:3:3.01:3.
4. The mesalamine-containing composition of claim 1, wherein the mesalamine-containing composition further comprises a solvent; the solvent is deionized water;
alternatively, the mesalamine-containing composition does not include a solvent;
and/or the mesalamine-containing composition does not include a stabilizer.
5. The mesalamine-containing composition of claim 1, further comprising pharmaceutically acceptable excipients; the pharmaceutically acceptable auxiliary materials are one or more of buffering agents, osmotic pressure regulators, suspending agents and solubilizers; wherein,,
the buffering agent is selected from one or more of citric acid and its salts, phosphoric acid and its salts, tris, carbonic acid, acetic acid and barbituric acid, for example, one or more of potassium dihydrogen phosphate, potassium dihydrogen phosphate-sodium hydroxide, disodium hydrogen phosphate and citric acid monohydrate; the buffer is 0.1 to 5 parts by weight, for example 0.68 parts, 0.79 parts or 2.68 parts;
the osmotic pressure regulator is selected from one or more of mannitol, lactose and trehalose; the osmolality adjusting agent is 0.1 to 10 parts, for example 0.7 parts, 0.8 parts, 1 part or 6 parts by weight.
6. A mesalamine formulation comprising a mesalamine-containing composition of any of claims 1-5.
7. The mesalamine formulation of claim 6, wherein the dosage form of the mesalamine formulation is a granule or powder; wherein,,
when the mesalamine preparation is a granule, the particle size of the granule is not more than 250 μm;
when the mesalamine preparation is a powder, the particle size of the powder is not more than 250 μm;
preferably, the mesalamine formulation has a pH of 4 to 9, such as 4.5, 4.9, 6.8, 7.3, 7.4, or 8;
preferably, the mesalamine formulation has a viscosity of 500-8000 mPa-s, for example 800 mPa-s, 1100 mPa-s, 3100 mPa-s, 4500 mPa-s, 6100 mPa-s, 7400 mPa-s or 7600 mPa-s.
8. A process for the preparation of mesalamine formulations according to claim 6 or 7, characterized in that it is carried out in one or two of the following ways:
mode one: when the mesalamine-containing composition includes the active pharmaceutical ingredient, the bioadhesive, and the wetting agent, the preparation method includes the steps of: mixing the active pharmaceutical ingredient, the bioadhesive and the wetting agent to prepare granules or powder;
mode two: when the mesalamine-containing composition further includes one or more of the pH adjuster, the buffer, the suspending agent, the osmotic pressure adjuster, and the solubilizing agent, the preparation method includes the steps of: mixing the active pharmaceutical ingredient, the bioadhesive and the wetting agent further with one or more of the pH adjustor, the buffering agent, the suspending agent, the osmotic pressure adjustor and the solubilizing agent to prepare granules or powder.
9. The method of manufacture of claim 8, wherein when the mesalamine formulation is a granule, the method of manufacture further comprises wet granulation, drying after the mixing.
10. Use of a mesalamine-containing composition according to any one of claims 1 to 5 or a mesalamine formulation according to claim 6 or 7 in the manufacture of a medicament for the treatment of ulcerative colitis;
wherein the application comprises dispersing the mesalamine-containing composition or the mesalamine preparation with deionized water to form a solution or suspension, and then administering; the pH range of the suspension is 4-9; the viscosity of the suspension is not more than 10000 mPa.s; the particle size of the suspension is not more than 250 μm;
wherein the step of administering comprises delivering the mesalamine-containing composition or the mesalamine formulation to the anorectal site in one continuous or fractional delivery with an anorectal applicator;
wherein the anorectal drug delivery device is a drug delivery device with a drug delivery device and a preparation combined into a whole, or a drug delivery device with a drug delivery device and a preparation separated, preferably a drug delivery device with a drug delivery device and a preparation separated;
wherein, the mode of dosing is manual bolus injection or automatic mode of dosing that relies on external force to realize, preferably relies on external force to realize automatic mode of dosing.
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| CN105658205A (en) * | 2013-12-20 | 2016-06-08 | 迪斯法国际私人有限责任公司 | Dry enema product |
| CN105878177A (en) * | 2016-05-12 | 2016-08-24 | 中国人民解放军***武汉总医院 | Mesalazine temperature-sensitive gel enema and preparation method thereof |
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| CN105658205A (en) * | 2013-12-20 | 2016-06-08 | 迪斯法国际私人有限责任公司 | Dry enema product |
| CN105878177A (en) * | 2016-05-12 | 2016-08-24 | 中国人民解放军***武汉总医院 | Mesalazine temperature-sensitive gel enema and preparation method thereof |
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