NZ618332B2 - Liquid pharmaceutical composition comprising nitisinone - Google Patents
Liquid pharmaceutical composition comprising nitisinone Download PDFInfo
- Publication number
- NZ618332B2 NZ618332B2 NZ618332A NZ61833212A NZ618332B2 NZ 618332 B2 NZ618332 B2 NZ 618332B2 NZ 618332 A NZ618332 A NZ 618332A NZ 61833212 A NZ61833212 A NZ 61833212A NZ 618332 B2 NZ618332 B2 NZ 618332B2
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- NZ
- New Zealand
- Prior art keywords
- formulation according
- amount
- nitisinone
- formulation
- polysorbate
- Prior art date
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- OUBCNLGXQFSTLU-UHFFFAOYSA-N Nitisinone Chemical compound [O-][N+](=O)C1=CC(C(F)(F)F)=CC=C1C(=O)C1C(=O)CCCC1=O OUBCNLGXQFSTLU-UHFFFAOYSA-N 0.000 title claims abstract description 51
- 229960001721 nitisinone Drugs 0.000 title claims abstract description 50
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 8
- 239000007788 liquid Substances 0.000 title claims abstract description 7
- 239000000203 mixture Substances 0.000 claims abstract description 50
- 238000009472 formulation Methods 0.000 claims abstract description 47
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims abstract description 15
- 201000011296 tyrosinemia Diseases 0.000 claims abstract description 13
- 206010001689 Alkaptonuria Diseases 0.000 claims abstract description 8
- 206010061536 Parkinson's disease Diseases 0.000 claims abstract description 8
- 208000005793 Restless Legs Syndrome Diseases 0.000 claims abstract description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims abstract description 6
- 239000000725 suspension Substances 0.000 claims abstract description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol group Chemical group OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 33
- 239000003755 preservative agent Substances 0.000 claims description 20
- 230000002335 preservative Effects 0.000 claims description 19
- LXCFILQKKLGQFO-UHFFFAOYSA-N Methylparaben Chemical group COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 18
- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 claims description 13
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 13
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 13
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 13
- 229940068968 Polysorbate 80 Drugs 0.000 claims description 12
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 12
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 12
- 229920000053 polysorbate 80 Polymers 0.000 claims description 12
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims description 11
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 claims description 11
- WXMKPNITSTVMEF-UHFFFAOYSA-M Sodium benzoate Chemical group [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 10
- 235000010234 sodium benzoate Nutrition 0.000 claims description 10
- 239000004299 sodium benzoate Substances 0.000 claims description 10
- QELSKZZBTMNZEB-UHFFFAOYSA-N Propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 239000000796 flavoring agent Substances 0.000 claims description 9
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 claims description 9
- 229960002216 methylparaben Drugs 0.000 claims description 9
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 claims description 9
- 229960003415 propylparaben Drugs 0.000 claims description 9
- 235000003599 food sweetener Nutrition 0.000 claims description 8
- 239000004094 surface-active agent Substances 0.000 claims description 8
- 239000000375 suspending agent Substances 0.000 claims description 8
- 239000003765 sweetening agent Substances 0.000 claims description 8
- 229960002303 citric acid monohydrate Drugs 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 235000013355 food flavoring agent Nutrition 0.000 claims description 5
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K Trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 claims description 4
- 239000011778 trisodium citrate Substances 0.000 claims description 4
- 229940038773 trisodium citrate Drugs 0.000 claims description 4
- -1 2-(2-nitro 5 trifluoromethylbenzoyl)-1,3-cyclohexanedione Chemical compound 0.000 claims description 2
- 229960004106 citric acid Drugs 0.000 claims description 2
- 239000000470 constituent Substances 0.000 claims description 2
- 201000010099 disease Diseases 0.000 abstract description 10
- 108010068327 EC 1.13.11.27 Proteins 0.000 abstract description 7
- 102100017125 HPD Human genes 0.000 abstract description 7
- 230000002401 inhibitory effect Effects 0.000 abstract description 6
- 239000007857 degradation product Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 229940100692 Oral Suspension Drugs 0.000 description 7
- 229940079593 drugs Drugs 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 241000220223 Fragaria Species 0.000 description 4
- 235000016623 Fragaria vesca Nutrition 0.000 description 4
- 235000011363 Fragaria x ananassa Nutrition 0.000 description 4
- 201000008739 coronary artery disease Diseases 0.000 description 4
- 235000019634 flavors Nutrition 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- ANUFPVOYCMRMDS-UHFFFAOYSA-N C1=CC=C(C(F)(F)F)C([N+](=O)[O-])=C1C(=O)C1C(=O)CCCC1=O Chemical compound C1=CC=C(C(F)(F)F)C([N+](=O)[O-])=C1C(=O)C1C(=O)CCCC1=O ANUFPVOYCMRMDS-UHFFFAOYSA-N 0.000 description 3
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000007979 citrate buffer Substances 0.000 description 3
- 230000000875 corresponding Effects 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 238000003801 milling Methods 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 241000222122 Candida albicans Species 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- 102100014967 FAH Human genes 0.000 description 2
- VEAVWOKGOGQZIG-UHFFFAOYSA-N FC(C=1C=CC=C(C(=O)Cl)C=1[N+](=O)[O-])(F)F Chemical compound FC(C=1C=CC=C(C(=O)Cl)C=1[N+](=O)[O-])(F)F VEAVWOKGOGQZIG-UHFFFAOYSA-N 0.000 description 2
- 210000004185 Liver Anatomy 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N Oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 244000052616 bacterial pathogens Species 0.000 description 2
- 230000001925 catabolic Effects 0.000 description 2
- 230000035569 catabolism Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- HJSLFCCWAKVHIW-UHFFFAOYSA-N cyclohexane-1,3-dione Chemical compound O=C1CCCC(=O)C1 HJSLFCCWAKVHIW-UHFFFAOYSA-N 0.000 description 2
- 108010022687 fumarylacetoacetase Proteins 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 238000001907 polarising light microscopy Methods 0.000 description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate dihydrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- XMLFPUBZFSJWCN-UHFFFAOYSA-N 2-Hydroxy-4-trifluoromethyl benzoic acid Chemical compound OC(=O)C1=CC=C(C(F)(F)F)C=C1O XMLFPUBZFSJWCN-UHFFFAOYSA-N 0.000 description 1
- OMFWHSRZHVVVAL-UHFFFAOYSA-N 3,5-dioxooctanedioic acid Chemical compound OC(=O)CCC(=O)CC(=O)CC(O)=O OMFWHSRZHVVVAL-UHFFFAOYSA-N 0.000 description 1
- GACSIVHAIFQKTC-UPHRSURJSA-N 4-Maleylacetoacetic acid Chemical compound OC(=O)CC(=O)CC(=O)\C=C/C(O)=O GACSIVHAIFQKTC-UPHRSURJSA-N 0.000 description 1
- MWFMGBPGAXYFAR-UHFFFAOYSA-N Acetone cyanohydrin Chemical compound CC(C)(O)C#N MWFMGBPGAXYFAR-UHFFFAOYSA-N 0.000 description 1
- 240000000940 Araucaria angustifolia Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 108010028143 Dioxygenases Proteins 0.000 description 1
- 102000016680 Dioxygenases Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- GACSIVHAIFQKTC-OWOJBTEDSA-N Fumarylacetoacetic acid Chemical compound OC(=O)CC(=O)CC(=O)\C=C\C(O)=O GACSIVHAIFQKTC-OWOJBTEDSA-N 0.000 description 1
- 206010019663 Hepatic failure Diseases 0.000 description 1
- 210000003734 Kidney Anatomy 0.000 description 1
- 208000007903 Liver Failure Diseases 0.000 description 1
- 208000008466 Metabolic Disease Diseases 0.000 description 1
- 230000036740 Metabolism Effects 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229960003885 Sodium Benzoate Drugs 0.000 description 1
- WYEPBHZLDUPIOD-UHFFFAOYSA-N Succinylacetone Chemical compound CC(=O)CC(=O)CCC(O)=O WYEPBHZLDUPIOD-UHFFFAOYSA-N 0.000 description 1
- NWGKJDSIEKMTRX-HSACVWGTSA-N [(2R)-2-[(2R,3R,4S)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] (E)-octadec-9-enoate Chemical compound CCCCCCCC\C=C\CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-HSACVWGTSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000002860 competitive Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 201000009910 diseases by infectious agent Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000002708 enhancing Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 230000002068 genetic Effects 0.000 description 1
- 230000002363 herbicidal Effects 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 231100000835 liver failure Toxicity 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000035786 metabolism Effects 0.000 description 1
- 229940009674 methylparaben / propylparaben Drugs 0.000 description 1
- 230000000813 microbial Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000012088 reference solution Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 239000000273 veterinary drug 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
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
-
- 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
- A61K47/06—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
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- 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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
- A61K9/10—Dispersions; Emulsions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
Disclosed is a liquid pharmaceutical formulation suitable for oral administration, comprising a suspension of an effective amount of micronized 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (nitisinone); and a citric acid buffer having a pH in the range of 2.5 to 3.5. The formulation is useful in the treatment of disorders and diseases in which inhibition of 4-hydroxyphenylpyruvate dioxygenase (HPPD) is desirable, e.g. in hereditary tyrosinaemia type I and also in Parkinson's disease, depression, restless leg syndrome and alkaptonuria. useful in the treatment of disorders and diseases in which inhibition of 4-hydroxyphenylpyruvate dioxygenase (HPPD) is desirable, e.g. in hereditary tyrosinaemia type I and also in Parkinson's disease, depression, restless leg syndrome and alkaptonuria.
Description
– 1 –
LIQUID PHARMACEUTICAL COMPOSITION COMPRISING NITISINONE
TECHNICAL FIELD
This invention concerns generally pharmaceutical formulations comprising 2-(2-nitro
trifluoromethylbenzoyl)-1,3-cyclohexanedione (nitisinone) as an active agent. The
formulations are useful in the treatment of disorders and diseases in which inhibition of
4-hydroxyphenylpyruvate dioxygenase (HPPD) is desirable, e.g. in hereditary
tyrosinaemia type I.
BACKGROUND ART
The compound 2-(2-nitrotrifluoromethylbenzoyl)-1,3-cyclohexanedione, also known
as nitisinone or NTBC, was first disclosed as a herbicide (US 5,006,158; US 4,695,673;
US 5,668,089).
Nitisinone is used under the brand name Orfadin for the treatment of hereditary
tyrosinemia type I (HT-1), a rare paediatric disease. HT-1 is a genetic metabolic
disorder that results from an inability to break down the amino acid tyrosine. Because of
resulting liver failure and liver cancer, children with HT-1 rarely survive into their
twenties without a liver transplant.
As disclosed in e.g. US 5,550,165, nitisinone is a competitive inhibitor of 4-
hydroxyphenyl-pyruvate dioxygenase (HPPD), an enzyme upstream of
fumarylacetoacetate hydrolase (FAH) in the tyrosine catabolic pathway. By inhibiting
the normal catabolism of tyrosine in patients with HT-1, nitisinone prevents the
accumulation of the catabolic intermediates maleylacetoacetate and
fumarylacetoacetate. In patients with HT-1, these catabolic intermediates are converted
to the toxic metabolites succinylacetone and succinylacetoacetate, which are responsible
for the observed liver and kidney toxicity.
Further, nitisinone has been described as being useful in the treatment of other
disorders, such as Parkinson’s disease (); depression (WO
– 2 –
2008/020150); restless leg syndrome (); and alkaptonuria
(Sunwanarat, P. et al., Metabolism 54: 719-728, 2005). The use of nitisinone has also
been disclosed in a method for enhancing phagolysosomal fusion following infection of
a patient with a microorganism (U.S. patent application, publication No. 2010-
0227936).
Oral administration of drugs is one of the preferred routes for treatment, because of its
simplicity. While drugs are generally administered in the form of tablets or capsules,
such administration may be less preferred, for example when the dosage has to be finely
adapted to treated subject, or may be less convenient, for example in the case of
paediatric or veterinary drugs. The liquid dosage form may then be an advantageous
alternative.
Consequently, there is a need for stable liquid nitisinone compositions which are
adapted for administration to paediatric patients and overcome the drawbacks with solid
pharmaceutical compositions.
DISCLOSURE OF THE INVENTION
According to the invention it has been shown that liquid pharmaceutical formulation,
comprising a suspension of micronized nitisinone, and having a pH of about 3, has
surprisingly advantageous properties such as increased stability. Consequently, the
present invention relates to a liquid pharmaceutical formulation suitable for oral
administration, comprising
(a) a suspension of an effective amount of micronized 2-(2-nitro
trifluoromethylbenzoyl)-1,3-cyclohexanedione (nitisinone); and
(b) citric acid buffer having a pH in the range of 2.5 to 3.5. In one embodiment the
formulation has a pH of 3.0.
In another aspect the invention relates to a formulation according to the invention, for
use in the treatment of a medical condition selected from tyrosinaemia, Parkinson’s
disease, depression, restless leg syndrome, and alkaptonuria.
– 3 –
In another aspect the invention relates to the use of a formulation according to the
invention in the manufacture of a medicament for treating of a medical condition
selected from tyrosinaemia, Parkinson’s disease, depression, restless leg syndrome, and
alkaptonuria.
Certain statements that appear below are broader than what appears in the statements of
the invention above. These statements are provided in the interests of providing the
reader with a better understanding of the invention and its practice. The reader is
directed to the accompanying claim set which defines the scope of the invention.
The term “effective amount” of nitisinone should be understood as an amount effective
to inhibit 4-hydroxyphenypyruvate dioxygenase. Preferably, the amount of nitisinone is
1 to 10 mg/ml, more preferably 4 mg/ml.
Nitisinone may be obtained by conventional procedures of organic chemistry already
known for the production of structurally analogous materials. Thus, for example,
nitisinone may be conveniently obtained by reaction of 2-nitro
trifluoromethylbenzoyl chloride with cyclohexane-1,3-dione in the presence of acetone
cyanhydrin and a suitable base such as triethylamine, as disclosed in US 5,550,165. The
starting 2-nitrotrifluoromethylbenzoyl chloride may itself be obtained from the
corresponding benzoic acid, for example by reaction with thionyl chloride or oxalyl
chloride as is described in Reagents for Organic Synthesis, (J Wiley and Sons, 1967;
Vol. 1, pp. 767-769) and is generally used without special purification. Similarly, 2-
nitrotrifluroromethylbenzoic acid may be obtained, for example, as described by
Haupstein et al. in J. Amer. Chem. Soc., 1954, 76, 1051, or by one of the general
methods described in The Chemistry of Carboxylic Acids and Esters (J Wiley and Sons,
1969; editor: S. Patai) and Survey of Organic Synthesis (J Wiley and Sons, 1970; C. A.
Buehler and D. F. Pearson).
Preferably, the formulation according to the invention in addition comprises one or
more pharmaceutically acceptable constituents selected from the group consisting of
suspending agents, sweeteners, preservatives, surfactants, and flavoring agents.
– 4 –
A suitable suspending agent is e.g. hydroxypropyl methylcellulose (HPMC) in an
amount of 1 to 20 mg/ml, preferably 5 mg/ml.
A suitable sweetener is glycerol, in an amount which results in an acceptable taste. The
amount of glycerol is preferably 100 to 500 mg/ml, more preferably 500 mg/ml.
The formulation according to the invention preferably comprises at least one
preservative chosen from methyl paraben, propyl paraben and sodium benzoate.
Preferably, the preservatives are methyl paraben in an amount of 1 to 2 mg/ml, more
preferably 1.4 mg/ml; propyl paraben in an amount of 0.1 to 0.2 mg/ml, more preferably
0.14 mg/ml; and sodium benzoate in an amount of 0.2 to 5 mg/ml, more preferably 1.0
mg/ml.
The formulation according to the invention preferably comprises a surfactant, such as
polysorbate 80 (polyoxyethylene (80) sorbitan monooleate; common commercial brand
names include Alkest TW 80 and Tween 80). The amount of polysorbate 80 should
be sufficient to wet nitisinone particles to facilitate the dispersion of nitisinone during
manufacturing, as well as to avoid any agglomeration of the nitisinone particles during
storage of the final product. Preferably the formulation according to the invention
comprises Polysorbate 80 in an amount of 0.1 to 20 mg/ml, more preferably from 0.10
to 0.15 mg/ml, such as about 0.135 mg/ml.
The formulation according to the invention preferably comprises an aroma agent, such
as strawberry flavor. The amount of flavor should be sufficient to achieve an acceptable
taste of the formulation and preferably in an amount of 0.2 to 1.1 mg/ml, more
preferably 0.7 mg/ml.
In an especially preferred form, the formulation according to the invention comprises
(a) nitisinone (4 mg/ml);
(b) citric acid monohydrate (9 mg/ml);
(c) trisodium citrate dehydrate (2.1 mg/ml)
(d) hydroxypropyl methylcellulose (5 mg/ml);
(e) glycerol (500 mg/ml);
– 5 –
(f) methyl paraben (1.4 mg/ml);
(g) propyl paraben (0.14 mg/ml); and
(h) polysorbate 80 (0.14 mg/ml).
In another especially preferred form, the formulation according to the invention
comprises
(a) nitisinone (4 mg/ml);
(b) citric acid monohydrate (9 mg/ml);
(c) trisodium citrate dehydrate (2.1 mg/ml)
(d) hydroxypropyl methylcellulose (5 mg/ml);
(e) glycerol (500 mg/ml);
(f) sodium benzoate (1.0 mg/ml); and
(g) polysorbate 80 (0.14 mg/ml).
A further preferred form of the formulation comprises a flavoring agent such as:
(h) strawberry flavor (0.7 mg/ml).
The formulation according to the invention is useful for the treatment of medical
disorders and diseases wherein inhibition of 4-hydroxyphenyl-pyruvate dioxygenase
(HPPD) is desirable. Examples of such conditions include hereditary tyrosinaemia type
1 (HT-1), Parkinson’s disease, depression, restless leg syndrome and alkaptonuria.
The formulation according to the invention is particularly useful for paediatric use.
Specifically, is it suitable for newborn infants up to children 8-10 years of age,
representing a body weight span of approximately 3.5 to 40 kg. A daily dose of 1 mg/kg
thus corresponds to a dose range from 2x1.75 mg to 2x20 mg. A strength of 4 mg/ml
will achieve acceptable dosage volumes corresponding 0.44 to 5 ml administered twice
daily. An oral syringe is suitable as administration dispenser for accurate dosing in this
range.
– 6 –
EXAMPLES
EXAMPLE 1: Micronization of nitisinone
A lab-scale air-jet mill, 2 inches qualification model, Sturtevant Inc., was used to
micronize nitisinone obtained from the company Bachem, Switzerland. The mill was
operated with tangential flow (i.e. the air and drug are fed in the same direction in the
milling chamber). The unmilled drug was fed into the mill using a Venturi feed system,
Syncron®, Magnet Feeder model F-TO-C, where air was used to draw the feed material
into the milling chamber. A product filter bag was affixed to the outlet of the mill,
through which the exhausts and the milled drug collects. The milling conditions were
set as follows:
• Grind air: Dry nitrogen gas
• Grind pressure: 90 psi
• Feed pressure: 85 psi
• Room conditions: Ambient
g of the API was passed through the lab-scale micronizer and the resulting material
was collected (3.7 g). The material was analyzed for/by particle size diameter (PSD),
assay and purity by high performance liquid chromatography (HPLC), x-ray powder
diffraction (XRPD), differential scanning calorimetry (DSC) and polarized light
microscopy (PLM). The results for PSD from the micronization are shown in Table I.
Table I
Particle size diameter (microns)
d d d d d
20 50 80 90
Start material 20.50 33.10 60.01 94.42 115.11
Micronized material 0.30 0.47 1.29 2.59 3.59
EXAMPLE 2: Preparation of an oral suspension of micronized nitisinone containing
methyl and propyl parabens as preservatives
– 7 –
A formulation according to the invention, as shown in Table II, was prepared according
to standard procedures.
Table II
Ingredient Quantity (mg) Function
Nitisinone (micronized) 4.0 Active substance
Hydroxypropyl methylcellulose 5.0 Suspending agent
(HPMC)
Glycerol 500 Sweetener
Polysorbate 80 0.135 Surfactant
Methyl paraben 1.4
Preservatives
Propyl paraben 0.14
Citric acid monohydrate 8.98
Buffer (pH 3.0)
Trisodium citrate dihydrate 2.13
Water purified q.s. to 1.00 ml Solvent
EXAMPLE 3: Preparation of an oral suspension of micronized nitisinone containing
sodium benzoate as preservative and strawberry aroma as flavoring agent
A formulation according to the invention, as shown in Table III, was prepared according
to standard procedures.
Table III
Ingredient Quantity (mg) Function
Nitisinone (micronized) 4.0 Active substance
Hydroxypropyl methylcellulose 5.0 Suspending agent
(HPMC)
Glycerol 500 Sweetener
Polysorbate 80 0.135 Surfactant
Sodium benzoate 1.0 Preservative
Strawberry aroma 0.7 Flavor agent
Citric acid monohydrate 8.98
Buffer (pH 3.0)
Trisodium citrate dihydrate 2.13
– 8 –
Water purified q.s. to 1.00 ml Solvent
EXAMPLE 4: Preparation of a nitisinone solution for comparison
A nitisinone solution as shown in Table IV was prepared according to standard
procedures.
Table IV
Ingredient Quantity (mg) Function
Nitisinone 2.0 Active substance
Methyl paraben 1.8 Preservatives
Propyl paraben 0.2
KH PO 1.4 Buffer (pH 6.8)
. 2.9
Na HPO 2H O
2 4 2
NaOH (0.5M aqueous) Adjust to pH 6.8
Water purified q.s. to 1.00 ml Solvent
EXAMPLE 5: Optimization of the amounts of preservatives by microbial challenge
studies according to the Europena Pharmacopoeia (Ph Eur 5.1.3) and the United
States Pharmacopoeia (USP <51>)
The results of different amounts of preservatives are shown in Tables V and VI, below.
Table V
Oral suspension of micronized nitisinone prepared according to Example 2 containing
different amounts of methyl and propyl parabens as preservatives.
Methyl paraben/Propyl paraben (mg/mL) Limits
Microbe Days 0 1.0/0.1 1.4/0.14 1.7/0.17 2.0/0.2 Ph USP Units
Eur <51>
.1.3
S.aureus Initial 5.3-5.5 5.3-5.5 5.3-5.5 5.3-5.5 5.3-5.5 - - log
– 9 –
14 >3.5 >3.5 >3.5 >3.3 >3.5 ≥3 ≥1.0 log red
28 NI NI NI NI NI NI NI log red
Initial 5.3-5.5 5.3-5.5 5.3-5.5 5.3-5.5 5.3-5.5 - - log
P. aeruginosa 14 >3.3 >3.5 >3.5 >3.4 >3.5 ≥3 ≥1.0 log red
28 NI NI NI NI NI NI NI log red
Initial 5.2-5.6 5.2-5.6 5.2-5.6 5.2-5.6 5.2-5.6 - - log
E. coli 14 >3.7 >3.6 >3.6 >3.2 >3.6 ≥3 ≥1.0 log red
28 NI NI NI NI NI NI NI log red
Initial 5.3-5.6 5.3-5.6 5.3-5.6 5.3-5.6 5.3-5.6 - - log
C. albicans 14 1.4 >3.7 >3.7 >3.3 >3.7 ≥1 NI log red
28 2.2 NI NI NI NI NI NI log red
Initial 5.5-5.6 5.5-5.6 5.5-5.6 5.5-5.6 5.5-5.6 - - log
14 1.0 2.2 2.1 3.2 >3.6 ≥1 NI log red
brasiliensis
28 1.0 NI 3.3 3.3 NI NI NI log red
NI = No increase
Table VI
Oral suspension of micronized nitisinone prepared according to Example 3 containing
different amounts of sodium benzoate as preservative.
Sodium benzoate (mg/mL) Limits
Microbe Days 0.2 1.0 3.0 5.0 Ph Eur USP Units
.1.3 <51>
Initial 5.3 5.3 5.3 5.3 - - log
S.aureus 14 5 5 5 5 ≥3 ≥1 log red
28 NI NI NI NI NI NI log red
Initial 5.2 5.2 5.2 5.2 - - log
P. aeruginosa 14 5 5 5 5 ≥3 ≥1 log red
28 NI NI NI NI NI NI log red
Initial 5.4 5.4 5.4 5.4 - - log
E. coli 14 5 5 5 5 ≥3 ≥1 log red
28 NI NI NI NI NI NI log red
Initial 5.8 5.8 5.8 5.8 - - log
C. albicans 14 1.4 4.5 5 5 ≥1 NI log red
28 4.1 5 NI NI NI NI log red
Initial 5.6 5.6 5.6 5.6 - - log
A. brasiliensis 14 1 3.3 5 5 ≥1 NI log red
28 1.3 5 NI NI NI NI log red
– 10 –
NI = No increase
The results show that all the above formulations according to the invention comply with
the prescribed requirements for preservative effectiveness according to the European
Pharmacopoeia (Ph Eur) and the U.S. Pharmacopeia (USP), including the preservative-
free formulation indicating a self -preservative nature of the basic formulation.
EXAMPLE 6: Stability test
Samples from the oral suspension of micronized nitisinone prepared according to
Example 2, as well as the nitisinone solution prepared according to Example 4, were put
on stability at +5°C, +25°C and +40°C, respectively, for 12 months. The concentrations
of nitisinone and the degradation product 6-(trifluoromethyl)-3,4-dihydro-1H-
xanthenene-1,9(2H)-dione (oxotetrahydroxanthenone) were followed by HPLC with
UV-detection. The results, shown in Tables VII to X, below, are expressed as percent of
the nominal concentration of nitisinone (% of label claim).
Table VII
Oral suspension of micronized nitisinone prepared according to Example 2.
Nitisinone (% of label claim)
Months
Temperature
0 1 2 3 6 12
99,9 104,2 101,7 105,0 102,9 104,8
99,9 105,6 98,6 104,0 101,8 103,7
°C
99,9 105,6 102,0 102,7 101,0 100,1
40°C
Table VIII
Oral suspension of micronized nitisinone prepared according to Example 2 (nd= not
detected).
Oxotetrahydroxanthenone (% of label claim)
Months
Temperature 0 1 2 3 6 12
– 11 –
°C nd nd nd nd nd nd
°C nd nd nd nd 0,02 0,02
40°C nd nd 0,07 0,15 0,28 0,54
Table IX
Nitisinone solution prepared according to Example 4.
Nitisinone (% of label claim)
Months
Temperature
0 1 2 3 6 12
°C 96,6 99,8 95,3 100,4 99,7 99,3
°C 96,6 100,9 96,0 100,2 98,0 95,9
40°C 96,6 98,3 96,3 93,6 86,5 74,4
Table X
Nitisinone solution prepared according to Example 4 (nd= not detected).
Oxotetrahydroxanthenone (% of label claim)
Months
Temperature
0 1 2 3 6 12
°C nd nd nd nd 0,03 0,05
°C nd 0,01 nd 0,39 0,58 0,78
40°C nd 0,07 1,86 2,05 1,63 1,38
The results show that the formulation according to the invention (Tables VII and VIII)
is more stable than the solution for comparison (Tables IX and X) under all storage
conditions. In the solution for comparison, the main degradation product,
oxotetrahydroxanthenone, is further degraded to secondary degradation products. As a
consequence it is not possible to achieve a mass balance between nitisinone and
degradation products for the reference solution.
EXAMPLE 7: Stability of oxtetrahydroxanthenone
– 12 –
The stability study of the main degradation product in Example 6,
oxotetrahydroxanthenone, is performed under similar conditions as described in
Example 6. Samples of oxotetrahydroxanthenone (OTHX), 81 µg/ml in either citrate
buffer pH 3.0 or phosphate buffer pH 6.8, were put on stability at +5°C, +25°C and
+37°C, respectively, for 6 months. The concentrations of OTHX and the secondary
degradation products 1,3-cyclohexanedione (CHD) and 4-(trifluoromethyl)salicylic acid
(TSA) were analyzed by LC-MS. The results, shown in Table XI, below, are expressed
as percent of the initial concentration of OTHX. The mass balance expressed as the total
recovery of CHD+OTHX+TSA compared to the initial concentration of OTHX were
calculated from MmOTHX/(Mm CHD + MmTSA) x (CHDconc + TSAconc) +
OTHXconc expressed in µg/ml where MmOTHX, MmCHD and MmTSA are the
molecular masses corresponding to 282, 202 and 206 g/mol, respectively. The results
for the mass balance, expressed as percent of initial concentration of OTHX, are shown
in Table XII.
Table XI
Stability of solutions of oxotetrahydroxanthenone prepared according to Example 7.
Citrate buffer pH 3.0 Phosphate buffer pH 6.8
Months Months
Component Temp (°C) 1,8 3 6 1,8 3 6
96,7 96,9 91,6 96,7 91,0 83,1
OTHX 25 96,7 102,7 92,3 74,8 63,2 44,8
37 97,9 97,7 95,3 33,5 13,7 0,4
0,0 0,0 0,0 0,0 0,7 0,0
CHD 25 0,0 0,0 0,0 7,7 9,7 25,2
37 0,0 0,0 0,0 22,2 21,5 32,8
0,0 0,0 0,0 1,4 1,9 0,0
TSA 25 0,0 0,0 0,0 13,0 20,2 36,4
37 0,2 0,0 0,0 38,6 49,1 66,4
Table XII
Mass balance.
Citrate buffer pH 3.0 Phosphate buffer pH 6.8
Months Months
– 13 –
Temp (°C) 1,8 3 6 1,8 3 6
96,7 96,9 91,6 97,9 93,3 83,1
96,7 102,7 92,3 93,2 89,8 99,4
37 98,1 97,7 95,3 87,4 76,3 88,5
The results show that the formulation according to the invention is surprisingly stable
also with respect to the formation of secondary degradation products. The results, close
to 100% for the mass balance, confirm that the LC-MS method is capable detecting and
determining the majority of the secondary degradation products.
In this specification where reference has been made to patent specifications, other
external documents, or other sources of information, this is generally for the purpose of
providing a context for discussing the features of the invention. Unless specifically
stated otherwise, reference to such external documents is not to be construed as an
admission that such documents, or such sources of information, in any jurisdiction, are
prior art, or form part of the common general knowledge in the art.
The term “comprising” as used in this specification and claims means “consisting at
least in part of”. When interpreting statements in this specification, and claims which
include the term “comprising”, it is to be understood that other features that are
additional to the features prefaced by this term in each statement or claim may also be
present. Related terms such as “comprise” and “comprised” are to be interpreted in
similar manner.
– 14 –
Claims (30)
1. A liquid pharmaceutical formulation suitable for oral administration, comprising (a) a suspension of an effective amount of micronized 2-(2-nitro 5 trifluoromethylbenzoyl)-1,3-cyclohexanedione (nitisinone); and (b) citric acid buffer having a pH in the range of 2.5 to 3.5.
2. The formulation according to claim 1 having a pH of 3.0. 10
3. The formulation according to claim 1 or claim 2 wherein the amount of nitisinone is 1 to 10 mg/ml.
4. The formulation according to claim 3, wherein the amount of nitisinone is 4 mg/ml. 15
5. The formulation according to claim 1, in addition comprising one or more pharmaceutically acceptable constituents selected from the group consisting of suspending agents, sweeteners, preservatives, surfactants, and flavoring agents.
6. The formulation according to claim 5 wherein the suspending agent is 20 hydroxypropyl methylcellulose.
7. The formulation according to claim 6 wherein the suspending agent is hydroxypropyl methylcellulose in an amount of 1 to 20 mg/ml. 25
8. The formulation according to claim 6 or claim 7, wherein the suspending agent is hydroxypropyl methylcellulose in an amount of 5 mg/ml.
9. The formulation according to claim 5 wherein the sweetener is glycerol. 30
10. The formulation according to claim 9 wherein the sweetener is glycerol in an amount of 100 to 500 mg/ml. – 15 –
11. The formulation according to claim 9 or claim 10 wherein the sweetener is glycerol in an amount of 500 mg/ml.
12. The formulation according to claim 5 wherein the preservative is methyl paraben 5 and/or propyl paraben.
13. The formulation according to claim 12 wherein the preservatives are methyl paraben in an amount of 1 to 2 mg/ml, and propyl paraben in an amount of 0.1 to 0.2 mg/ml.
14. The formulation according to claim 12 or claim 13, wherein the preservatives are methyl paraben in an amount of 1.4 mg/ml, and propyl paraben in an amount of 0 0.14 mg/ml.
15 15. The formulation according to claim 5 wherein the preservative is sodium benzoate in an amount of 0.2 to 5 mg/ml.
16. The formulation according to claim 15 wherein the preservative is sodium benzoate in an amount of 1 mg/ml.
17. The formulation according to claim 5 wherein the surfactant is polysorbate 80.
18. The formulation according to claim 17 wherein the surfactant is polysorbate 80 in an amount of 0.1 to 20 mg/ml.
19. The formulation according to claim 18 wherein the surfactant is polysorbate 80 in an amount of 0.10 to 0.15 mg/ml.
20. The formulation according to any one of claims 1-14 and 17-19 comprising: 30 (a) nitisinone (4 mg/ml); (b) citric acid monohydrate (9 mg/ml); (c) trisodium citrate dehydrate (2.1 mg/ml) (d) hydroxypropyl methylcellulose (5 mg/ml); – 16 – (e) glycerol (500 mg/ml); (f) methyl paraben (1.4 mg/ml); (g) propyl paraben (0.14 mg/ml); and (h) polysorbate 80 (0.14 mg/ml).
21. The formulation according to any one of claims 1-11 and 15-18, comprising: (a) nitisinone (4 mg/ml); (b) citric acid monohydrate (9 mg/ml); (c) trisodium citrate dehydrate (2.1 mg/ml) 10 (d) hydroxypropyl methylcellulose (5 mg/ml); (e) glycerol (500 mg/ml); (f) sodium benzoate (1.0 mg/ml); and (g) polysorbate 80 (0.14 mg/ml). 15
22. The formulation according to claim 20 or claim 21, in addition comprising a flavoring agent.
23. The formulation according to any one of claims 1 to 22, for use in the treatment of a medical condition selected from tyrosinaemia, Parkinson’s disease, depression, 20 restless leg syndrome, and alkaptonuria.
24. The formulation according to claim 23, for use in the treatment of hereditary tyrosinaemia type 1 (HT-1).
25 25. The formulation according to claim 24, for use in the treatment of hereditary tyrosinaemia type 1 (HT-1) in a paediatric patient.
26. Use of a formulation according to any one of claims 1 to 22 in the manufacture of a medicament for treating of a medical condition selected from tyrosinaemia, 30 Parkinson’s disease, depression, restless leg syndrome, and alkaptonuria.
27. A use according to claim 26 in the manufacture of a medicament for treating hereditary tyrosinaemia type 1 (HT-1). – 17 –
28. A use according to claim 26 in the manufacture of a medicament for treating hereditary tyrosinaemia type 1 (HT-1) in a paediatric patient.
29. A formulation as defined in any one of claims 1-25 substantially as herein 5 described with reference to any example thereof.
30. A use as defined in any one of claims 26-28 substantially as herein described with reference to any example thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE1150585 | 2011-06-23 | ||
SE1150585-6 | 2011-06-23 | ||
PCT/SE2012/050681 WO2012177214A1 (en) | 2011-06-23 | 2012-06-20 | Liquid pharmaceutical composition comprising nitisinone |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ618332A NZ618332A (en) | 2015-06-26 |
NZ618332B2 true NZ618332B2 (en) | 2015-09-29 |
Family
ID=
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