NO771765L - PROCEDURE FOR PREPARING A NEW PHARMACEUTICAL PREPARATION - Google Patents
PROCEDURE FOR PREPARING A NEW PHARMACEUTICAL PREPARATIONInfo
- Publication number
- NO771765L NO771765L NO771765A NO771765A NO771765L NO 771765 L NO771765 L NO 771765L NO 771765 A NO771765 A NO 771765A NO 771765 A NO771765 A NO 771765A NO 771765 L NO771765 L NO 771765L
- Authority
- NO
- Norway
- Prior art keywords
- stated
- preparation
- naphtho
- tetrahydro
- oxo
- Prior art date
Links
- 239000000825 pharmaceutical preparation Substances 0.000 title claims description 5
- 238000000034 method Methods 0.000 title claims 37
- 238000002360 preparation method Methods 0.000 claims description 41
- 239000004480 active ingredient Substances 0.000 claims description 28
- 150000001875 compounds Chemical class 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 15
- 239000013543 active substance Substances 0.000 claims description 15
- 239000000126 substance Substances 0.000 claims description 15
- 239000003085 diluting agent Substances 0.000 claims description 13
- 206010020751 Hypersensitivity Diseases 0.000 claims description 11
- 239000011230 binding agent Substances 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- 239000002360 explosive Substances 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 7
- IMZMKUWMOSJXDT-UHFFFAOYSA-N cromoglycic acid Chemical group O1C(C(O)=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C(O)=O)O2 IMZMKUWMOSJXDT-UHFFFAOYSA-N 0.000 claims description 7
- 230000000694 effects Effects 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 6
- 208000010668 atopic eczema Diseases 0.000 claims description 6
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 6
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 6
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 6
- 238000003892 spreading Methods 0.000 claims description 6
- 230000000172 allergic effect Effects 0.000 claims description 5
- 239000000043 antiallergic agent Substances 0.000 claims description 5
- 229960000265 cromoglicic acid Drugs 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 230000002009 allergenic effect Effects 0.000 claims description 4
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 4
- 239000000314 lubricant Substances 0.000 claims description 4
- 229920000609 methyl cellulose Polymers 0.000 claims description 4
- 239000001923 methylcellulose Substances 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims description 3
- 239000012530 fluid Substances 0.000 claims description 3
- 239000004615 ingredient Substances 0.000 claims description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 2
- 229920003086 cellulose ether Polymers 0.000 claims description 2
- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 2
- 229940095079 dicalcium phosphate anhydrous Drugs 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- 235000012239 silicon dioxide Nutrition 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- UYTRXNHKEBKEMK-UHFFFAOYSA-N 5-[3-(3-carboxy-4-oxochromen-5-yl)oxy-2-hydroxypropoxy]-4-oxochromene-3-carboxylic acid Chemical group C(=O)(O)C1=COC2=CC=CC(=C2C1=O)OCC(COC1=C2C(C(=COC2=CC=C1)C(=O)O)=O)O UYTRXNHKEBKEMK-UHFFFAOYSA-N 0.000 claims 1
- 239000003995 emulsifying agent Substances 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 6
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 6
- 206010002198 Anaphylactic reaction Diseases 0.000 description 5
- 235000021355 Stearic acid Nutrition 0.000 description 5
- 230000036783 anaphylactic response Effects 0.000 description 5
- 208000003455 anaphylaxis Diseases 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000008117 stearic acid Substances 0.000 description 5
- 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 description 4
- 239000005557 antagonist Substances 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 3
- OMOVVBIIQSXZSZ-UHFFFAOYSA-N [6-(4-acetyloxy-5,9a-dimethyl-2,7-dioxo-4,5a,6,9-tetrahydro-3h-pyrano[3,4-b]oxepin-5-yl)-5-formyloxy-3-(furan-3-yl)-3a-methyl-7-methylidene-1a,2,3,4,5,6-hexahydroindeno[1,7a-b]oxiren-4-yl] 2-hydroxy-3-methylpentanoate Chemical compound CC12C(OC(=O)C(O)C(C)CC)C(OC=O)C(C3(C)C(CC(=O)OC4(C)COC(=O)CC43)OC(C)=O)C(=C)C32OC3CC1C=1C=COC=1 OMOVVBIIQSXZSZ-UHFFFAOYSA-N 0.000 description 3
- HEUMNKZPHGRBKR-UHFFFAOYSA-N [Na].[Cr] Chemical compound [Na].[Cr] HEUMNKZPHGRBKR-UHFFFAOYSA-N 0.000 description 3
- 230000001078 anti-cholinergic effect Effects 0.000 description 3
- 239000000427 antigen Substances 0.000 description 3
- 102000036639 antigens Human genes 0.000 description 3
- 108091007433 antigens Proteins 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- 230000001713 cholinergic effect Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 229960001340 histamine Drugs 0.000 description 3
- 235000010981 methylcellulose Nutrition 0.000 description 3
- 229940032147 starch Drugs 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 150000003973 alkyl amines Chemical class 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000007908 dry granulation Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000008024 pharmaceutical diluent Substances 0.000 description 2
- 238000003825 pressing Methods 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 229940076279 serotonin Drugs 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 description 1
- 206010027654 Allergic conditions Diseases 0.000 description 1
- 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 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000004135 Bone phosphate Substances 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 208000011231 Crohn disease Diseases 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010036774 Proctitis Diseases 0.000 description 1
- 206010036783 Proctitis ulcerative Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000024780 Urticaria Diseases 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 125000005041 acyloxyalkyl group Chemical group 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 201000009961 allergic asthma Diseases 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 208000030961 allergic reaction Diseases 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000009172 bursting Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- OTAFHZMPRISVEM-UHFFFAOYSA-N chromone Chemical compound C1=CC=C2C(=O)C=COC2=C1 OTAFHZMPRISVEM-UHFFFAOYSA-N 0.000 description 1
- 150000004777 chromones Chemical class 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 229930003944 flavone Natural products 0.000 description 1
- 150000002213 flavones Chemical class 0.000 description 1
- 235000011949 flavones Nutrition 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229940014259 gelatin Drugs 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 210000003405 ileum Anatomy 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 201000010659 intrinsic asthma Diseases 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 150000002641 lithium Chemical class 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 238000009740 moulding (composite fabrication) Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002916 oxazoles Chemical class 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000005041 phenanthrolines Chemical class 0.000 description 1
- -1 pivaloyloxymethyl ester Chemical class 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229940066769 systemic antihistamines substituted alkylamines Drugs 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940033134 talc Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 150000007964 xanthones Chemical class 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
-
- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Description
Det har i en rekke år vært kjent å fremstille forskjellige anti-allergiske legemidler med forskjellige blandings-media eller eksipienser for å kunne presentere preparatene i en hensiktsmessig farmasoytisk form. Imidlertid har en rekke av disse blandemidler vist seg å være eller inneholde forbindelser som noen pasienter er allergiske for. Det har derfor oppstått den merkelige situasjon at en gruppe pasienter som er særlig utsatt for allergi behandles med anti-allergiske legemidler som er laget med forbindelser som kan fremkalle en allergisk reaksjon. It has been known for a number of years to produce different anti-allergic drugs with different mixing media or excipients in order to be able to present the preparations in an appropriate pharmaceutical form. However, a number of these admixtures have been found to be or contain compounds to which some patients are allergic. The strange situation has therefore arisen that a group of patients who are particularly prone to allergies are treated with anti-allergic drugs that are made with compounds that can cause an allergic reaction.
I henhold til oppfinnelsen tilveiebringes et farmasoytisk tablettpreparat som inneholder et anti-allergisk legemiddel med natriumkromglykat-lignende virkning, som aktiv bestanddel, i kombinasjon med et smøremiddel og et fortynningsmiddel som ikke inneholder stoffer som kan fremkalle allergiske reaksjoner hos allergiske pasienter. According to the invention, a pharmaceutical tablet preparation is provided which contains an anti-allergic drug with a sodium chromium glycate-like effect, as active ingredient, in combination with a lubricant and a diluent which does not contain substances that can cause allergic reactions in allergic patients.
Preparatet inneholder fortrinnsvis også et flytemiddel og/eller bindemiddel som ikke inneholder stoffer som kan fremkalle allergiske reaksjoner hos pasientene. The preparation preferably also contains a emollient and/or binder that does not contain substances that can cause allergic reactions in the patients.
Den forbindelse eller stoff som kan fremkalle allergiske reaksjoner hos pasienter kan være f.eks. laktose som kan gi enzym-mangel hos visse mennesker eller kan være stoffer som inneholder rester av antibiotika som penicillin eller kan inneholde et virkelig eller potensielt allergent materiale. The compound or substance that can cause allergic reactions in patients can be e.g. lactose which can cause enzyme deficiency in certain people or may be substances containing residues of antibiotics such as penicillin or may contain an actual or potential allergenic material.
Stoffer som ikke er reelt eller potensielt allergene er slike som ikke gir bket overfblsomhet eller hypersensitivitet hos de enkelte pasienter. Forbindelsen bor ikke kunne fremkalle en immunrespons enten gjennom antistoffer eller gjennom celler. Forbindelsene bor heller ikke kunne kombineres eller bindes til proteiner under dannelse av et hapten-bæresystem og bor ikke aktivere komplementær-veiene som danner C5a eller C3a. Substances that are not actually or potentially allergenic are those that do not cause excessive sensitivity or hypersensitivity in the individual patients. The compound must not be able to elicit an immune response either through antibodies or through cells. The compounds must also not be able to combine or bind to proteins during the formation of a hapten carrier system and must not activate the complementary pathways that form C5a or C3a.
Det er særlig foretrukket at det ikke finnes proteinholdige stoffer i preparatet. Eksempler på stoffer som bor utelukkes fra preparatet er gelatin, stivelse, stivelsesderivater (f.eks. natriumstivelsesglykollat) og akasiegummi. Stoffer som inneholder spor av protein etter deres opprinnelse, f.eks. laktose, eller etter deres fremstilling som f.eks. maltose-dekstrose-kombinasjoner fremstilt ved enzymbehandling (også^ forhandlet under varemerket "Emdex") bor også utelukkes fra preparatet. It is particularly preferred that there are no proteinaceous substances in the preparation. Examples of substances that should be excluded from the preparation are gelatin, starch, starch derivatives (eg sodium starch glycollate) and acacia gum. Substances containing traces of protein according to their origin, e.g. lactose, or according to their preparation such as e.g. maltose-dextrose combinations produced by enzyme treatment (also sold under the trademark "Emdex") should also be excluded from the preparation.
Fremstillingen av tabletterf kan bestå av ett eller flere av trinnene våtgranulering, torrgranulering, smelting, stbping, enterisk belegning, filmbelegning eller forming til preparater med forlenget utlbsningstid. Imidlertid foretrekkes preparater som kan presses til tabletter direkte uten et mellom-liggende trinn som f.eks. våtA~ eller torr granulering. The production of tabletsf can consist of one or more of the steps wet granulation, dry granulation, melting, stomping, enteric coating, film coating or forming into preparations with an extended release time. However, preparations which can be pressed into tablets directly without an intermediate step such as e.g. wetA~ or dry granulation.
Flytemidlet kan f.eks. være renset talkum eller silisiumdioksyd, og særlig kolloidal silisiumdioksyd med midlere partikkelstbrrelse ca. 12 nm. The fluid can e.g. be purified talc or silicon dioxide, and in particular colloidal silicon dioxide with average particle size approx. 12 nm.
Bindemidlet kan f.eks. være polyvinylpyrrolidon eller metylcellulose. The binder can e.g. be polyvinylpyrrolidone or methylcellulose.
Smbremidlet kan f.eks. være stearinsyre, et metall-stearat, polyetylenglykol med molvekt 4.000 eller mer, eller renset talkum. The spreader can e.g. be stearic acid, a metal stearate, polyethylene glycol with a molecular weight of 4,000 or more, or purified talc.
Fortynningsmidlet som også kan tjene som sprengmiddel kan være mikrokrystallinsk cellulose eller et cellulosederi-vat, f.eks. celluloseeter som metylcellulose eller natriumbi-karbonat eller tobasisk kalsiumfosfat. Preparatet kan også inneholde et sprengmiddel som en separat bestanddel. Hvis sprengmidlet er en separat bestanddel, skal det ikke inneholde stoffer som kan fremkalle allergiske reaksjoner hos allergiske pasienter. The diluent which can also serve as an explosive can be microcrystalline cellulose or a cellulose derivative, e.g. cellulose ethers such as methyl cellulose or sodium bicarbonate or dibasic calcium phosphate. The preparation may also contain an explosive as a separate component. If the explosive is a separate component, it must not contain substances that can cause allergic reactions in allergic patients.
Preparatet kan fremstilles ved å tbrrblande den aktive ingrediens med andre bestanddeler som f.eks. flytemiddel, bindemiddel, smbremiddel og fortynningsmiddel/sprengmiddel, f.eks. The preparation can be prepared by mixing the active ingredient with other ingredients such as e.g. flow agent, binder, spreader and diluent/explosive, e.g.
i en pulverblander. Blandingen kan skje i to trinn idet blandingen eller deler av den siktes gjennom en egnet sikt (f.eks. in a powder mixer. The mixing can take place in two stages, as the mixture or parts of it are sieved through a suitable sieve (e.g.
60 mesh = 250 mikron) som avslutning av et fbrste trinn for opp- deling av hårdnakkede klumper. Det siktede pulveret kan deretter blandes videre. Denne blanding kan så presses i en 60 mesh = 250 microns) as the end of a first step for breaking up stubborn lumps. The sieved powder can then be mixed further. This mixture can then be pressed into a
tabletteringsmaskin.tableting machine.
Den aktive bestanddel kan være ethvert anti-allergisk legemiddel med natriul^kromglykat-lignende virkning. En forbindelse med natriumkromglykatlignende virkning kan inhibere avgiv-else av farmakologiske mellomprodukter som dannes ved kombinasjon in vivo av visse typer antistoffer og spesifikk antigen, f.eks. kombinasjonen av reaginisk antistoff og spesifikk antigen (se eksempel 27 i britisk patent 1.292.601 - forsbk med passiv kutan anafylaksis hos rotte). The active ingredient can be any anti-allergic drug with sodium chromium glycate-like action. A compound with sodium chromium glycate-like action can inhibit the release of pharmacological intermediates which are formed by combination in vivo of certain types of antibodies and specific antigen, e.g. the combination of reaginic antibody and specific antigen (see example 27 in British patent 1,292,601 - experiment with passive cutaneous anaphylaxis in rats).
De aktive ingredienser kan karakteriseres ved de fblgende biologiske forsbk og deres resultater. The active ingredients can be characterized by the following biological tests and their results.
Forbindelsen testes forst i henhold til passiv kutan anafylaksis på rotte. Hvis forbindelsen ikke viser signifikant inhibering av allergiske reaksjoner i doser på 20 mg/kg intra-peritonealt (i.p.) eller intravenbst (i.v.) i dette forsbk, The compound is first tested according to passive cutaneous anaphylaxis in rats. If the compound does not show significant inhibition of allergic reactions in doses of 20 mg/kg intra-peritoneally (i.p.) or intravenously (i.v.) in this trial,
er aktiviteten generelt for lav. Forskjellige andre biologiske prover kan brukes for å vise at forbindelsen utover dens anti-allergiske virkning som inhibitor av anafylaksis-mellomprodukter (anafylaksis-mediator) og ikke f.eks. som organ-antagonist, cholinergisk eller anti-cholinergisk og adeny1-cyelase-stimula-tor. Derfor kan man bruke forsbk for å se om forbindelsen in-hiberer virkningen av histamin, serotonin, og den langsomt rea-gerende anafylakse-forbindelse (slow reacting substance of anaphylaxis = SRSA), dvs., om forbindelsen er en slutt-organ-antagonist for slike mellomprodukter. Slike forsbk er kjent og omfatter sammentrekning av marsvin-ileum i nærvær av metyl-sergid for påvisning av serotonin-aktivitet. Hvis man fremdeles finner aktivitet i disse systemer, skyldes dette histaminvirk-ning. En ytterligere prove på histamin er gjennom spektrafluor-imetriske forsbk beskrevet av Shore, Burkhalter and Cohn, Journal of Pharmacology and Experimental Therapeutics, bind 127, side 182. Aktive bestanddeler i henhold til foreliggende oppfinnelse er ikke slutt-organ-antagonister. is the activity generally too low. Various other biological tests can be used to show that the compound beyond its anti-allergic effect as an inhibitor of anaphylaxis intermediates (anaphylaxis mediator) and not e.g. as organ-antagonist, cholinergic or anti-cholinergic and adenyl-cyylase-stimulator. Forsbk can therefore be used to see if the compound inhibits the effects of histamine, serotonin, and the slow reacting substance of anaphylaxis (SRSA), i.e. if the compound is an end-organ antagonist for such intermediates. Such experiments are known and include contraction of guinea pig ileum in the presence of methylsergide for the detection of serotonin activity. If activity is still found in these systems, this is due to histamine action. A further test for histamine is through spectrofluorimetric experiments described by Shore, Burkhalter and Cohn, Journal of Pharmacology and Experimental Therapeutics, volume 127, page 182. Active ingredients according to the present invention are not end-organ antagonists.
Hvis resultatene av disse forsbk viser at den aktive ingrediens ikke er noen slutt-organ-antagonist, kan man gjennom-føre ytterligere prover for å vise at forbindelsen ikke opp-viser sin aktivitet gjennom cholinergisk eller anti-cholinergisk virkning, f.eks. ved en omvending av kontraksjon som skyl des acetylcholin på tracheal-kjeden hos marsvin. En aktiv ingrediens vil ikke være en cholinergisk eller anti-cholinergisk forbindelse. If the results of these tests show that the active ingredient is not an end-organ antagonist, further tests can be carried out to show that the compound does not exhibit its activity through cholinergic or anti-cholinergic action, e.g. by a reversal of contraction that flushes acetylcholine onto the tracheal chain in guinea pigs. An active ingredient will not be a cholinergic or anti-cholinergic compound.
Spesielle grupper av aktive stoffer finner man blant kromon-2-karboksylsyrer og egnede derivater, f.eks. beskrevet i british patent nr. 1.368.243, 1.144.905, 1.230.087 og vesttysk patent nr. 2.553.688. Andre aktive stoffer finner man blant xantoner, f.eks. ifblge belgisk patent nr. 759.292 og 787.843 og hollandsk patent 72.09622 og 73.06958, blant forbindelsene ifblge belgisk patent nr. 809.935, blant nitroindandioner f.eks. ifblge beltisk patent nr. 792.867, blant fenantroliner f.eks. i henhold til belgisk patent nr. 773.200, blant aza-puriner f.eks. ifblge belgisk patent nr. 770.683, oksazoler som i vesttysk utlegningsskrift nr. 2.459.380 og flavoner, f.eks. ifblge belgisk patent nr. 823.874. Special groups of active substances can be found among chromone-2-carboxylic acids and suitable derivatives, e.g. described in British Patent No. 1,368,243, 1,144,905, 1,230,087 and West German Patent No. 2,553,688. Other active substances can be found among xanthones, e.g. according to Belgian patent no. 759,292 and 787,843 and Dutch patent 72.09622 and 73.06958, among the compounds according to Belgian patent no. 809,935, among nitroindanions e.g. according to Belgian patent no. 792,867, among phenanthrolines e.g. according to Belgian Patent No. 773,200, among aza-purines e.g. according to Belgian patent no. 770,683, oxazoles as in West German specification no. 2,459,380 and flavones, e.g. according to Belgian patent no. 823,874.
Særlig foretrukket er kromoner og kromlignende forbindelser ifblge britisk patent nr. 1.144.905 og 1.230.087 og vesttysk patent nr. 2.553.688. Mer spesielt foretrukkes 1,3-bis-(2-karboksykromon-5-yloksy)propan-2-ol eller et farmasbytisk derivat av denne, f.eks. et salt som dinatriumsaltet, sistnevnte er. kjent som natriumkromoglykat eller kromolynnatrium. Andre foretrukne forbindelser er 6,7,8,9-tetrahydro-4-okso-10-propyl-4H-nafto/~2,3-b//Pyran-2-karboksylsyre og deres farmasøytiske derivater (kollektivt betegnet "aktive ingredienser B") og 6,7, 8,9-tetrahydro-5-hydroksy-4-okso-10-propyl-4H-nafto/2,3-b7pyran-2-karboksylsyre og deres farmasbytiske derivater (samlet betegnet "aktiv ingrediens A"). Når man bruker kromon og kromlignende forbindelser beskrevet i dette avsnitt foretrekkes at sammensetningen ikke inneholder di- eller tri-basiske kationer. Particularly preferred are chromones and chromium-like compounds according to British patent no. 1,144,905 and 1,230,087 and West German patent no. 2,553,688. More particularly preferred is 1,3-bis-(2-carboxychromon-5-yloxy)propan-2-ol or a pharmaceutical derivative thereof, e.g. a salt like the disodium salt, the latter being. known as sodium cromoglycate or cromolyn sodium. Other preferred compounds are 6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho/~2,3-b//Pyran-2-carboxylic acid and their pharmaceutical derivatives (collectively termed "active ingredients B ") and 6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho/2,3-b7pyran-2-carboxylic acid and their pharmaceutical derivatives (collectively termed "active ingredient A" ). When using chromone and chromium-like compounds described in this section, it is preferred that the composition does not contain di- or tri-basic cations.
Farmasbytiske derivater som omfattes av aktiv ingrediens A eller B er farmasbytisk anvendelige salter, estere og amider av 2-karboksylsyregruppen. Egnene salter er ammonium-, alkalimetall- (f.eks. natrium-, kalium- og litium-) salter og salter med egnede organiske baser, f.eks. salter med hydroksyl-amin, lavere alkylaminer som metylamin eller etylamin, med substituerte lavere alkylaminer som hydroksy-substituert alkylaminer av typen tris(hydroksymetyl)metylamin, eller med enkle monocykliske nitrogen-heterocykliske forbindelser, f.eks. piper-idin eller morfolin. Egnede estere er enkle lavere alkylestere etylestere, estere avledet fra alkoholer inneholdende basiske grupper, f.eks. di-lav-alkylamino-substituerte alkanoler som (3-(dietoksyamino)-etylester, og acyloksyalkylestere, f.eks. lav-acyl-lav-alkyl-estere som pivaloyloksymetylester,,eller en bis-ester avledet fra en dihydroksyforbindelse, f.eks. en di(hydroksy-lav-alkyl)eter, eksempelvis bis-2-oksapropan-l,3-diyl-ester. Farmasbytiske salter av de basiske estere, f.eks. hydro-kloridet, kan også brukes. Pharmaceutical derivatives that are covered by active ingredient A or B are pharmaceutically usable salts, esters and amides of the 2-carboxylic acid group. Suitable salts are ammonium, alkali metal (e.g. sodium, potassium and lithium) salts and salts with suitable organic bases, e.g. salts with hydroxylamine, lower alkylamines such as methylamine or ethylamine, with substituted lower alkylamines such as hydroxy-substituted alkylamines of the type tris(hydroxymethyl)methylamine, or with simple monocyclic nitrogen-heterocyclic compounds, e.g. piperidine or morpholine. Suitable esters are simple lower alkyl esters ethyl esters, esters derived from alcohols containing basic groups, e.g. di-lower alkylamino-substituted alkanols such as (3-(diethoxyamino)-ethyl ester, and acyloxyalkyl esters, e.g. lower acyl-lower alkyl esters such as pivaloyloxymethyl ester,, or a bis-ester derived from a dihydroxy compound, e.g. eg a di(hydroxy-lower alkyl) ether, eg bis-2-oxapropane-1,3-diyl ester Pharmaceutical salts of the basic esters, eg the hydrochloride, can also be used.
Det foretrkkes som aktiv ingrediens A eller B å be-nytte den fri karboksylsyre eller dens natriumsalt. Spesielt foretrekkes den fri karboksylsyre siden den er bedre egnet oralt enn dens derivater. It is preferred to use the free carboxylic acid or its sodium salt as active ingredient A or B. In particular, the free carboxylic acid is preferred since it is more suitable orally than its derivatives.
Fortrinnsvis inneholder preparatet mindre enn 50%,Preferably, the preparation contains less than 50%,
og fortrinnsvis mellom 0,5 og 18 vektprosent aktiv ingrediens A eller B. Selv med meget små relative mengder av aktiv bestanddel A eller B har. man uventet funnet at et smoremiddel er meget gunétig. Smbremidlet bor utgjore opptil 4,0% og fortrinnsvis 0,2 - 4,0 vektprosent av preparatet. Fortrinnsvis inneholder oppløsningen også mellom ca. 0,1 og 5,0%" flytmiddel, fortrinnsvis ca. 0, 5%. Bindemidlet bor utgjore ca. 0,5-5 vektprosent av preparatet og fortynningsmiddel/sprengmiddel fra ca. 80 - 99 vektprosent. and preferably between 0.5 and 18 weight percent active ingredient A or B. Even with very small relative amounts of active ingredient A or B have. one unexpectedly found that a lubricant is very harmful. The spreading agent should make up up to 4.0% and preferably 0.2 - 4.0% by weight of the preparation. Preferably, the solution also contains between approx. 0.1 and 5.0%" flow agent, preferably approx. 0.5%. The binder should make up approx. 0.5-5% by weight of the preparation and the diluent/explosive from approx. 80 - 99% by weight.
Fortrinnsvis inneholder tablettpreparater fra 3 -Preferably, tablet preparations contain from 3 -
15% aktivt stoff A og fortrinnsvis 4-10 vektprosent vann idet slike preparater har gunstige flyt- og presse-égenskaper. 15% active substance A and preferably 4-10% water by weight as such preparations have favorable flow and pressing properties.
I henhold til et ytterligere trekk ved oppfinnelsen tilveiebringes et farmasbytisk preparat som inneholder fra 2 - 12 mg (målt som fri syre) aktivt stoff A som doseringsenhet. Spesielt foretrekkes en doseringsenhet på 3 - 12 mg (målt som fri syre), fortrinnsvis 3 - 6 mg (målt som fri syre) av aktivt stoff A. Egnede doseringsenheter kan inneholde 3, 6 eller 12 According to a further feature of the invention, a pharmaceutical preparation is provided which contains from 2 - 12 mg (measured as free acid) of active substance A as a dosage unit. A dosage unit of 3 - 12 mg (measured as free acid), preferably 3 - 6 mg (measured as free acid) of active substance A is particularly preferred. Suitable dosage units may contain 3, 6 or 12
mg (målt som fri syre) aktiv ingrediens A.mg (measured as free acid) active ingredient A.
Det tilveiebringes også farmasbytiske preparater som inneholder fra 10 - 50 mg (fri syre) aktivt stoff B i form av doseringsenheter. Spesielt foretrekkes en doseringsenhet som inneholder fra 10 - 30 mg (målt som fri syre) aktivt stoff B. Pharmaceutical preparations containing from 10 - 50 mg (free acid) of active substance B in the form of dosage units are also provided. A dosage unit containing from 10 - 30 mg (measured as free acid) of active substance B is particularly preferred.
Doseringsenheter ifblge oppfinnelsen er gunstige ved at de representerer den dose som pasienten skal innta på et bestemt tidspunkt. Således behbver pasienten bare å ta én en- hetsdose (eller eventuelt to doseringsenheter avhengig av pasi-entens evne til å svelge de storre enhetsdoser) på et gitt tidspunkt, hvilket gir en sikker og hensiktsmessig behandling ved at doseringsfeil elimineres. Doser på over 20 mg aktivt stoff A (målt som fri syre) eller over 50 mg aktiv ingrediens B (målt som fri syre) på én gang har tendens til å forårsake en viss mageirritasjon hos noen pasienter og doser- på under 2 mg aktivt stoff A (målt som fri syre) eller under 10 mg aktivt stoff B (målt som fri syre) synes å gi manglende eller usikker reaksjon fra pasienten. Dosage units according to the invention are advantageous in that they represent the dose that the patient must take at a specific time. Thus, the patient only needs to take one unit dose (or possibly two dosage units depending on the patient's ability to swallow the larger unit doses) at a given time, which provides safe and appropriate treatment by eliminating dosing errors. Doses of more than 20 mg of active substance A (measured as free acid) or more than 50 mg of active ingredient B (measured as free acid) at one time tend to cause some stomach irritation in some patients and doses of less than 2 mg of active substance A (measured as free acid) or less than 10 mg of active substance B (measured as free acid) seems to give a missing or uncertain reaction from the patient.
I tillegg til aktiv ingrediens A eller B kan doseringsenhetene også inneholde (fortrinnsvis en storre del av) farmasbytiske fortynningsmidler eller bærere. Eksempler på slike fortynningsmidler, drbyningsmidler eller bærestoffer er: for tabletter og dragéer: mikrokrytallinsk cellulose, laktose, stivelse, talkum eller stearinsyre, for kapsler: vinsyre, stivelse, stearinsyre eller laktose. Doseringsenhetene kan også formes som preparater med kontrollert opplbsning (forsinket opplbsning). In addition to active ingredient A or B, the dosage units may also contain (preferably a larger part of) pharmaceutical diluents or carriers. Examples of such diluents, thickeners or carriers are: for tablets and dragees: microcrystalline cellulose, lactose, starch, talc or stearic acid, for capsules: tartaric acid, starch, stearic acid or lactose. The dosage units can also be formulated as preparations with controlled dissolution (delayed dissolution).
Det tilveiebringes også en fremgangsmåte for fremstilling av doseringsenheter i henhold til oppfinnelsen som be-står i å forme aktiv ingrediens A eller B, eventuelt i blanding med farmasbytiske fortynningsmidler eller bærere, til separate enheter sonrinneholder den bnskede dosering. Formingen til separate enheter vil normalt bestå i å fylle et passende volum (eller vekt) av finfordelt og granulert aktivt stoff eventuelt i kombinasjon med fortynningsmidler eller bærer i et bestemt rom som f.eks. en kapsel eller formingshulrommet i en tablettmaskin. A method for producing dosage units according to the invention is also provided, which consists in shaping active ingredient A or B, possibly in admixture with pharmaceutical diluents or carriers, into separate units containing the desired dosage. The forming into separate units will normally consist of filling a suitable volume (or weight) of finely divided and granulated active substance, possibly in combination with diluents or carrier in a specific space such as e.g. a capsule or the forming cavity in a tablet machine.
I henhold til oppfinnelsen tilveiebringes også farma-søytiske tablettpreparater som inneholder aktiv ingrediens A eller B i kombinasjon med et smbremiddel og fortynningsmiddel og fortrinnsvis også et flytemiddel, bindemiddel og sprengmiddel. According to the invention, pharmaceutical tablet preparations are also provided which contain active ingredient A or B in combination with a spreading agent and diluent and preferably also a fluidizing agent, binding agent and explosive.
Ingen av bestanddelene bor inneholde reelt eller potensielt allergene stoffer og spesielt ingen proteinholdige forbindelser. Det foretrekkes således de ovenfor beskrevne tablettpreparater inneholdende aktiv ingrediens A eller B. None of the ingredients should contain actual or potentially allergenic substances and especially no proteinaceous compounds. The above-described tablet preparations containing active ingredient A or B are thus preferred.
Tabletter ifblge oppfinnelsen har fortrinnsvis en diametral knusestyrke på minst 1,5 og fortrinnsvis 3 - 7 kP Tablets according to the invention preferably have a diametral crushing strength of at least 1.5 and preferably 3 - 7 kP
Schleuniger (Dr K Schleuniger & Co., Ztlrich, Sveits). Det foretrekkes også at tablettene ved opplbsningsforsbk i apparatur beskrevet i United States Pharmacopeia XIX, med vann som'opp-' lbsningsmedium, brytes opp eller opploses i lopet av under 30 minutter. Det foretrekkes også at tablettene har lav sprohets-grad. Særlig foretrekkes det at når 20 bbrstede og veide tabletter roteres på en Roche Friabilator-trommel (EGE Shafer, Schleuniger (Dr K Schleuniger & Co., Ztlrich, Switzerland). It is also preferred that the tablets break up or dissolve in the course of less than 30 minutes during a dissolution test in apparatus described in United States Pharmacopeia XIX, with water as the 'dissolving' medium. It is also preferred that the tablets have a low degree of friability. It is particularly preferred that when 20 broken and weighed tablets are rotated on a Roche Friabilator drum (EGE Shafer,
EG Wollish og CE Engel: Journal of the American Pharmaceuti-cal Association (1956) bind 45, side 114 - 116) ved 25 omdrei-ninger pr. 8 minutter og deretter borstes på nytt, skal tab-lett-vekttapet være under 3% og fortrinnsvis under 1%. EG Wollish and CE Engel: Journal of the American Pharmaceutical Association (1956) volume 45, pages 114 - 116) at 25 revolutions per 8 minutes and then brushed again, the tablet weight loss should be below 3% and preferably below 1%.
Doseringsenhetene og andre preparater ifblge oppfinnelsen og spesielt preparater som inneholder natriumkromoglykat eller aktiv ingrediens A eller B har indikasjon for bruk ved behandling av allergiske tilstander som astma (særlig allergisk astma) og sykdommer i magetarmkanalen som Crohn's sykdom, ulcer-colitis og proctitis. Doseringsenheter og andre preparater har også indikasjon for bruk ved behandling av "iboende astma" (hvor man ikke kan påvise fblsomhet for noe ytre antigen). Doseringsenheter og andre preparater kan også brukes for behandling av hbyfeber, urticaria og eksem. The dosage units and other preparations according to the invention and especially preparations containing sodium cromoglycate or active ingredient A or B are indicated for use in the treatment of allergic conditions such as asthma (particularly allergic asthma) and diseases of the gastrointestinal tract such as Crohn's disease, ulcerative colitis and proctitis. Dosing units and other preparations are also indicated for use in the treatment of "intrinsic asthma" (where susceptibility to any external antigen cannot be demonstrated). Dosage units and other preparations can also be used for the treatment of hay fever, urticaria and eczema.
Spesielt foretrekkes preparater som inneholder 1,3-bis(2-karboksy-kromon-5-yloksy)propan-2-ol eller 6,7,8,9-tetra-hydro-5-hydroksy-4-okso-10-propyl-4H-nafto^2,3-h7pyran-2-karboksylsyre eller deres farmasbytiske derivater. Particular preference is given to preparations containing 1,3-bis(2-carboxy-chromon-5-yloxy)propan-2-ol or 6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl -4H-naphtho^2,3-h7pyran-2-carboxylic acid or their pharmaceutical derivatives.
Oppfinnelsen illustreres uten begrensninger av de fblgende eksempler. The invention is illustrated without limitation by the following examples.
Eksempel 1 Example 1
Det finfordelte eller malte 6,7,8,9-tetrahydro-5- hydroksy-4-okso-10-propyl-4H-nafto/2,3-b7pyran-2-karboksylsyre ble blandet med kolloidal silisiumdioksyd, polyvinylpyrrolidon, stearinsyre og mikrokrystallinsk cellulose i hurtiggående pulverblander. Blanderveggene og slagrbrerbla:déne ble skrapt med spatel etter ca. 5 minutters blanding og blandingen derpå fortsatt til egnet blandegrad ble oppnådd. The finely divided or ground 6,7,8,9-tetrahydro-5-hydroxy-4-oxo-10-propyl-4H-naphtho/2,3-b7pyran-2-carboxylic acid was mixed with colloidal silicon dioxide, polyvinylpyrrolidone, stearic acid and microcrystalline cellulose in high-speed powder mixers. The mixer walls and beater blades were scraped with a spatula after approx. 5 minutes of mixing and the mixing then continued until a suitable degree of mixing was achieved.
For å bedre flyt- og presningsegenskaper og forbedre lagringsstabiliteten (med hensyn på knusestyrke og sprengtid) ble blandingens fuktighetsinnhold regulert til innenfor 3-15 vektprosent, fortrinnsvis 4-10 vektprosent. In order to improve flow and pressing properties and to improve storage stability (with regard to crushing strength and bursting time), the mixture's moisture content was regulated to within 3-15 weight percent, preferably 4-10 weight percent.
Den ferdige blanding ble presset i en tablettmaskin til en fasthet som gir diametral knusestyrke lik 5 kp Schleuniger. The finished mixture was pressed in a tablet machine to a firmness which gives a diametral crushing strength equal to 5 kp Schleuniger.
Eksempel 2 Example 2
Natriumkromoglykatet og natriumbikarbonatet ble torr-blandet i planetblander, fuktet med renset vann, idet ca. 20 deler vann ble tilsatt til 100 vektdeler faste stoffer. Det fuktede materiale ble presset gjennom en 16 mesh sikt og tbrket i fluidisert sjikt. Renset talkum ble tilblandet til de torre granulater og tablettene presset i 10 mm hullsenker i en roterende tablettmaskin til en diametral knusestyrke på 6 - 8 kp Schleuniger. The sodium cromoglycate and sodium bicarbonate were dry-mixed in a planetary mixer, moistened with purified water, as approx. 20 parts of water were added to 100 parts by weight of solids. The moistened material was pressed through a 16 mesh sieve and used in a fluidized bed. Purified talc was mixed into the dry granules and the tablets were pressed in 10 mm hole punches in a rotary tablet machine to a diametral crushing strength of 6 - 8 kp Schleuniger.
Eksempel 3 Example 3
6,7,8,9-tetrahydro-4-okso-10-propyl-4H-nafto/2,3-b7-pyran-2-karboksylsyre, halvparten av den mlkrokrystallinske cellulose og natriumbikarbonatet ble tbrrblandet og fuktet med 5% vandig metylcellulose, idet man tilsatte ca. 20 deler opplbsning til 100 vektdeler pulver. Det fuktede pulver ble granulert i en 16 mesh sikt (1000 mikron) og tbrket i fluidisert sjikt med en inngående lufttemperatur lik 60°C. De torre granulater ble fort gjennom en 16 mesh sikt (1000 mikron) og blandet med resten av den mikrokrystallinske cellulose og stea-rinsyren. Blandingen ble presset i tablettmaskin til en diametral knusestyrke lik 4 - 7 kp Schleuniger. 6,7,8,9-tetrahydro-4-oxo-10-propyl-4H-naphtho/2,3-b7-pyran-2-carboxylic acid, half of the microcrystalline cellulose and the sodium bicarbonate were mixed and moistened with 5% aqueous methylcellulose , adding approx. 20 parts solution to 100 parts by weight of powder. The wetted powder was granulated in a 16 mesh sieve (1000 microns) and used in a fluidized bed with an inlet air temperature equal to 60°C. The dry granules were passed through a 16 mesh sieve (1000 microns) and mixed with the rest of the microcrystalline cellulose and the stearic acid. The mixture was pressed in a tablet machine to a diametral crushing strength equal to 4 - 7 kp Schleuniger.
Claims (36)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB20984/76A GB1570993A (en) | 1976-05-21 | 1976-05-21 | Pharmaceutical tablet formulation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO771765L true NO771765L (en) | 1977-11-22 |
Family
ID=10155196
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO771765A NO771765L (en) | 1976-05-21 | 1977-05-20 | PROCEDURE FOR PREPARING A NEW PHARMACEUTICAL PREPARATION |
Country Status (17)
| Country | Link |
|---|---|
| JP (1) | JPS52143220A (en) |
| AU (1) | AU511269B2 (en) |
| BE (1) | BE854690A (en) |
| CA (1) | CA1105835A (en) |
| DE (1) | DE2722917A1 (en) |
| DK (1) | DK218777A (en) |
| FI (1) | FI771587A (en) |
| FR (1) | FR2426460A1 (en) |
| GB (1) | GB1570993A (en) |
| IE (1) | IE45282B1 (en) |
| IL (1) | IL52102A0 (en) |
| LU (1) | LU77369A1 (en) |
| NL (1) | NL7705560A (en) |
| NO (1) | NO771765L (en) |
| NZ (1) | NZ184141A (en) |
| SE (1) | SE7705850L (en) |
| ZA (1) | ZA772989B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1595220A (en) * | 1977-12-23 | 1981-08-12 | Fisons Ltd | Tablets containing 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane |
| US5447728A (en) * | 1992-06-15 | 1995-09-05 | Emisphere Technologies, Inc. | Desferrioxamine oral delivery system |
| CZ20032959A3 (en) | 2001-05-01 | 2004-01-14 | Pfizer Products Inc. | Process for preparing a pharmaceutical composition with low dosage of a medicament and having uniform distribution and efficiency of the medicament |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZA753210B (en) * | 1974-06-14 | 1976-04-28 | Upjohn Co | Novel dosing regimen for intal biologues |
| IE41922B1 (en) * | 1974-11-09 | 1980-04-23 | Fisons Ltd | Pharmaceutical compositions containing bis-chromones |
| AT351530B (en) * | 1974-11-30 | 1979-07-25 | Fisons Ltd | PROCESS FOR THE PREPARATION OF NEW PYRAN-2-CARBONIC ACIDS, THEIR SALT, ESTER, AMIDES AND OPTICAL ISOMERS |
-
1976
- 1976-05-21 GB GB20984/76A patent/GB1570993A/en not_active Expired
-
1977
- 1977-05-16 IL IL52102A patent/IL52102A0/en unknown
- 1977-05-16 FR FR7714858A patent/FR2426460A1/en active Granted
- 1977-05-16 BE BE177619A patent/BE854690A/en unknown
- 1977-05-17 SE SE7705850A patent/SE7705850L/en unknown
- 1977-05-17 AU AU25214/77A patent/AU511269B2/en not_active Expired
- 1977-05-18 NZ NZ184141A patent/NZ184141A/en unknown
- 1977-05-18 DK DK218777A patent/DK218777A/en not_active Application Discontinuation
- 1977-05-18 LU LU77369A patent/LU77369A1/xx unknown
- 1977-05-18 ZA ZA00772989A patent/ZA772989B/en unknown
- 1977-05-19 JP JP5712777A patent/JPS52143220A/en active Pending
- 1977-05-19 CA CA278,833A patent/CA1105835A/en not_active Expired
- 1977-05-19 FI FI771587A patent/FI771587A/fi not_active Application Discontinuation
- 1977-05-20 NO NO771765A patent/NO771765L/en unknown
- 1977-05-20 NL NL7705560A patent/NL7705560A/en not_active Application Discontinuation
- 1977-05-20 DE DE19772722917 patent/DE2722917A1/en not_active Ceased
- 1977-05-20 IE IE1038/77A patent/IE45282B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| GB1570993A (en) | 1980-07-09 |
| SE7705850L (en) | 1977-11-22 |
| NL7705560A (en) | 1977-11-23 |
| IL52102A0 (en) | 1977-07-31 |
| BE854690A (en) | 1977-11-16 |
| FI771587A (en) | 1977-11-22 |
| ZA772989B (en) | 1978-04-26 |
| LU77369A1 (en) | 1977-12-13 |
| DE2722917A1 (en) | 1977-12-01 |
| AU511269B2 (en) | 1980-08-07 |
| FR2426460A1 (en) | 1979-12-21 |
| DK218777A (en) | 1977-11-22 |
| AU2521477A (en) | 1978-11-23 |
| IE45282L (en) | 1977-11-21 |
| JPS52143220A (en) | 1977-11-29 |
| IE45282B1 (en) | 1982-07-28 |
| CA1105835A (en) | 1981-07-28 |
| NZ184141A (en) | 1979-06-19 |
| FR2426460B1 (en) | 1983-04-29 |
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