WO2005004849A2 - Pharmaceutical formulation comprising levothyroxine sodium - Google Patents
Pharmaceutical formulation comprising levothyroxine sodium Download PDFInfo
- Publication number
- WO2005004849A2 WO2005004849A2 PCT/EP2004/007667 EP2004007667W WO2005004849A2 WO 2005004849 A2 WO2005004849 A2 WO 2005004849A2 EP 2004007667 W EP2004007667 W EP 2004007667W WO 2005004849 A2 WO2005004849 A2 WO 2005004849A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutical formulation
- formulation
- levothyroxine sodium
- microcrystalline cellulose
- total weight
- Prior art date
Links
- 229960003918 levothyroxine sodium Drugs 0.000 title claims abstract description 43
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 37
- XUIIKFGFIJCVMT-LBPRGKRZSA-N L-thyroxine Chemical compound IC1=CC(C[C@H]([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-LBPRGKRZSA-N 0.000 title abstract description 6
- 239000000203 mixture Substances 0.000 claims abstract description 38
- 238000009472 formulation Methods 0.000 claims abstract description 34
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 26
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 26
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 26
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 26
- 229920000881 Modified starch Polymers 0.000 claims abstract description 19
- 239000002245 particle Substances 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 15
- 235000019359 magnesium stearate Nutrition 0.000 claims description 9
- 239000000454 talc Substances 0.000 claims description 9
- 229910052623 talc Inorganic materials 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 229940036555 thyroid hormone Drugs 0.000 claims description 7
- 239000005495 thyroid hormone Substances 0.000 claims description 7
- 238000011282 treatment Methods 0.000 claims description 7
- AUYYCJSJGJYCDS-LBPRGKRZSA-N Thyrolar Chemical class IC1=CC(C[C@H](N)C(O)=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 AUYYCJSJGJYCDS-LBPRGKRZSA-N 0.000 claims description 6
- 239000000314 lubricant Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 239000000377 silicon dioxide Substances 0.000 claims description 5
- 241000124008 Mammalia Species 0.000 claims description 4
- 238000007906 compression Methods 0.000 claims description 4
- 230000006835 compression Effects 0.000 claims description 4
- 230000007423 decrease Effects 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 238000013160 medical therapy Methods 0.000 claims description 2
- 150000004686 pentahydrates Chemical group 0.000 claims description 2
- JMHCCAYJTTWMCX-QWPJCUCISA-M sodium;(2s)-2-amino-3-[4-(4-hydroxy-3,5-diiodophenoxy)-3,5-diiodophenyl]propanoate;pentahydrate Chemical compound O.O.O.O.O.[Na+].IC1=CC(C[C@H](N)C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 JMHCCAYJTTWMCX-QWPJCUCISA-M 0.000 claims 4
- 238000002360 preparation method Methods 0.000 abstract description 5
- YDTFRJLNMPSCFM-YDALLXLXSA-M levothyroxine sodium anhydrous Chemical compound [Na+].IC1=CC(C[C@H](N)C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 YDTFRJLNMPSCFM-YDALLXLXSA-M 0.000 description 61
- 239000003826 tablet Substances 0.000 description 19
- 235000012222 talc Nutrition 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 5
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 229920002472 Starch Polymers 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 230000037396 body weight Effects 0.000 description 3
- 238000007907 direct compression Methods 0.000 description 3
- 208000003532 hypothyroidism Diseases 0.000 description 3
- 230000002989 hypothyroidism Effects 0.000 description 3
- 229950008325 levothyroxine Drugs 0.000 description 3
- 238000011321 prophylaxis Methods 0.000 description 3
- 239000007909 solid dosage form Substances 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000011888 foil Substances 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007916 tablet composition Substances 0.000 description 2
- 210000001685 thyroid gland Anatomy 0.000 description 2
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 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
- 229920000856 Amylose Polymers 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- XUIIKFGFIJCVMT-GFCCVEGCSA-N D-thyroxine Chemical compound IC1=CC(C[C@@H](N)C(O)=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-GFCCVEGCSA-N 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 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 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 235000019759 Maize starch Nutrition 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010028665 Myxoedema Diseases 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical class [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000007897 gelcap Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229920001903 high density polyethylene Polymers 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000004700 high-density polyethylene Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 238000002657 hormone replacement therapy Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000000266 injurious effect Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229920001684 low density polyethylene Polymers 0.000 description 1
- 239000004702 low-density polyethylene Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- NFMIISUHNXYECR-UHFFFAOYSA-K magnesium sodium dodecyl sulfate Chemical compound [Na+].[Mg++].CCCCCCCCCCCCOS([O-])(=O)=O.CCCCCCCCCCCCOS([O-])(=O)=O.CCCCCCCCCCCCOS([O-])(=O)=O NFMIISUHNXYECR-UHFFFAOYSA-K 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 208000003786 myxedema Diseases 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- -1 polypropylene Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- OKODKVMXHLUQSW-JITBQSAISA-M sodium;(e)-4-hydroxy-4-oxobut-2-enoate;octadecanoic acid Chemical compound [Na+].OC(=O)\C=C\C([O-])=O.CCCCCCCCCCCCCCCCCC(O)=O OKODKVMXHLUQSW-JITBQSAISA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000006104 solid solution Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229940034208 thyroxine Drugs 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 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
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
-
- 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
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
Definitions
- the present invention relates to stable pharmaceutical formulations of levothyroxine sodium, useful in the treatment of thyroid hormone disorders in mammals, including humans.
- the invention also relates to a process for preparing such a formulation.
- Levothyroxine sodium is widely used in the treatment and/or prophylaxis of thyroid hormone disorders.
- Levothyroxine sodium is presently commercially available under the trademark EltroxinTM in the form of 50 ⁇ g and 100 ⁇ g tablets. These tablets contain levothyroxine sodium, lactose, magnesium stearate, acacia powder, sodium citrate and maize starch. Whilst levothyroxine sodium is relatively stable in pure form, pharmaceutical formulations containing levothyroxine sodium exhibit a relatively short shelf life, particularly under conditions of high light, heat, air and humidity (see " Kinetics of Degradation of Levothyroxin Sodium in Aqueous solution and in Solid State" , Chong Min Won , Pharmaceutical Research, Vol.
- the present invention is therefore directed at providing a stable solid dosage form of levothyroxine sodium. It is also desired that the solid dosage form disintegrates rapidly, thereby ensuring rapid release of the active ingredient, and is aesthetically acceptable and palatable to the patient.
- the present inventors have found that a pharmaceutical formulation comprising levothyroxine sodium, microcrystalline cellulose with a mean particle size less than 125 ⁇ m and pregelatinised starch provides a solid dosage form with improved stability and disintegration characteristics that is aesthetically acceptable and palatable to the patient.
- the present invention provides a pharmaceutical formulation comprising (a) an effective amount of levothyroxine sodium, (b) microcrystalline cellulose which has a mean particle size of less than 125 ⁇ m and is present in an amount of 60 to 85% w/w based upon the total weight of the formulation and (c) pregelatinised starch present in an amount of 5 to 30% w/w based upon total weight of the formulation.
- the pharmaceutical formulations of the present invention have improved stability such that they are stable to the extent that potency decreases by less than 5%, preferably less than 4%, more preferably less than 3% when the pharmaceutical formulation is stored at 25°C and 60% relative humidity for 12 months.
- the pharmaceutical formulations of the present invention have improved disintegration characteristics such that they have a disintegration time of less than 6 minutes, preferably less than 5 minutes, more preferably less than 4 minutes when tested in the disintegration test as described in the Examples section below.
- levothyroxine sodium is sodium (S)-2-amino-3-[4-(4-hydroxy-3,5- diiodophenoxy)-3,5-diiodophenyl]propionate.
- Levothyroxine sodium is the monosodium salt of the levo-rotatory isomer of thyroxine.
- Levothyroxine sodium may exist as one or more polymorphic forms, for example one or more crystalline forms, amorphous forms, phases, solid solutions and/or mixtures thereof. All such forms of levothyroxine sodium and/or mixtures thereof are encompassed by the present invention.
- the levothyroxine sodium for use in pharmaceutical formulations of the present invention is in hydrated form. More preferably, the levothyroxine sodium for use in pharmaceutical formulations of the present invention is in the pentahydrate form.
- the levothyroxine sodium is present in an amount less than 1% w/w based upon the total weight of the formulation, more preferably 0.01-0.30% w/w, even more preferably 0.03-0.25% w/w, most preferably 0.06-0.20% w/w.
- the minimum amount of levothyroxine sodium can vary, so long as an effective amount is utilised to cause the desired pharmacological effect.
- the microcrystalline cellulose has a mean particle size of ⁇ 100 ⁇ m, more preferably ⁇ 75 ⁇ m, even more preferably ⁇ 50 ⁇ m.
- the microcrystalline cellulose is selected from microcrystalline cellulose grade 101, 102, or 103, more preferably grade 101 or 102, most preferably grade 101.
- the term 'Grade 101' as used herein means material with nominal mean particle size 50 ⁇ m and moisture content ⁇ 5.0% in accordance with the European Pharmacopeia (2002).
- the term 'Grade 102' as used herein means material with nominal mean particle size 100 ⁇ m and moisture content
- the term 'Grade 103' as used herein means material with nominal mean particle size 50 ⁇ m and moisture content ⁇ 3.0% in accordance with the European Pharmacopeia (2002).
- the term 'Grade 200' as used herein means material with nominal mean particle size 180 ⁇ m and moisture content
- microcrystalline cellulose is sourced from FMC Corporation, JRS Rettenmaier or Sahne (Germany) or Wei Ming (Taiwan), more preferably Wei Ming (Taiwan).
- the microcrystalline cellulose is present in an amount of 60 to 85% w/w based on the total weight of the formulation, more preferably 65 to 80% w/w, most preferably 70 to 80% w/w.
- pregelatinised starch as used herein means partially pregelatinised starch typically containing about 5% of free amylose, 15% of free amylop ⁇ clin and 80% unmodified starch. It is produced by subjecting moistened starch to mechanical pressure in order to rupture some or all of the starch granules. The resultant material is ground and it's moisture content adjusted such that it possesses good flow and compression characteristics. Typical cold water solubility of partially pregelatinised starch, e.g. Starch 1500 (Colorcon) is 10-20%. Pregelatinised starch is further defined in the European Pharmacopea (2002) which is included herein by reference. Preferably, the pregelatinised starch is present in an amount of 5 to 30% w/w based on the total weight of the formulation, more preferably 10 to 30% w/w, most preferably 15 to 25% w/w.
- the ratio of microcrystalline cellulose:pregelatinised starch is in the range of 2:1 to 15:1 , more preferably 2.5:1 to 8:1 , most preferably 3:1 to 5:1.
- the microcrystalline cellulose and pregelatinised starch contain water.
- the water comprises 3-6% w/w based on the total weight of the formulation, more preferably about 4.5% (e.g. 4.5% - 5.0%).
- the pharmaceutical formulation includes one or more glidants/lubricants.
- Suitable glidants/lubricants for use in the present invention include colloidal silicon dioxide, talc, magnesium stearate, zinc stearate, calcium stearate, sodium stearate fumarate and sodium magnesium lauryl sulphate.
- the glidants/lubricants are selected from one or more of: colloidal silicon dioxide, talc and magnesium stearate.
- the glidant/lubricant is present in an amount 1-10% of the total weight of the formulation, more preferably 2-9% of the total weight of the formulation, most preferably 3- 8% of the total weight of the formulation.
- talc is present in an amount 1-5% of the total weight of the formulation, more preferably 2-4% of the total weight of the formulation, most preferably 2.5-3.5% of the total weight of the formulation.
- colloidal anhydrous silica is present in an amount 1-5% of the total weight of the formulation, more preferably 1-3% of the total weight of the formulation, most preferably 1.5-2.5% of the total weight of the formulation.
- magnesium stearate is present in an amount 0.1-5% of the total weight of the formulation, more preferably 0.5-4% of the total weight of the formulation, most preferably 0.8-1.5% of the total weight of the formulation.
- the pH of the pharmaceutical formulation is in the range pH 6.8 to 8.2, preferably pH 7.2 to 7.8 when suspended in water in a ratio wate ⁇ pharmaceutical formulation of 10:1.
- the formulations of the invention may, if desired, further include one or more pharmaceutically acceptable excipients. All such excipients must be “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
- Pharmaceutically acceptable excipients may include colours, flavours e.g. menthol, sweeteners e.g. mannitol, preservatives, stabilisers, antioxidants and any other excipients known to those skilled in the art.
- the present invention covers all combinations of particular and preferred groups described hereinabove.
- the present invention provides a pharmaceutical formulation for use in medical therapy, e.g. in the treatment of thyroid hormone disorders in an animal, e.g. a mammal such as a human.
- Levothyroxine and other thyroid hormones are known to serve as hormone replacement therapy when the thyroid function has been reduced or is completely absent for a variety of disease states, including, hypothyroidism, myxedema, cretinism and obesity, preferably hypothyroidism.
- the amount required of levothyroxine sodium will depend on a number of factors including the severity of the condition to be treated and the identity of the recipient and will ultimately be at the discretion of the attendant physician or veterinarian.
- a physician will determine the actual dosage which will be most suitable for an individual subject.
- the specific dose level and frequency of dosage for any particular individual may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy.
- a suitable effective dose will be in the range 1.0 to 6.0 ⁇ g per kilogram bodyweight of recipient per day, preferably in the 1.5 to 5.0 ⁇ g per kilogram bodyweight per day (unless otherwise indicated, all weights are calculated with respect to the free base active ingredient).
- the desired dose is preferably presented as one, two, three or four sub-doses administered at appropriate intervals throughout the day.
- These sub-doses may be administered in unit dosage forms, for example, containing about 10 to 300 ⁇ g, preferably 10-200 ⁇ g, more preferably 25-150 ⁇ g, of active ingredient per unit dose form, most preferably 50 ⁇ g or 100 ⁇ g of active ingredient per unit dose form.
- a 50 ⁇ g tablet may comprise 0.0425-0.0575mg levothyroxine sodium, 50- 60mg microcrystalline cellulose, 12-17mg pregelatinised starch, 2-3mg talc, 1-2mg colloidal anhydrous silica and 0.5-1 mg magnesium stearate.
- a 100 ⁇ g tablet may comprise 0.085-0.115mg levothyroxine sodium, 100-120mg microcrystalline cellulose, 24-34 pregelatinised starch, 4-6mg talc, 2-4 mg colloidal anhydrous silica and 1-2mg magnesium
- the pharmaceutical formulation is preferably administered orally and is preferably in the form of a tablet.
- the composition according to the present invention may also be administered in the form of capsules, caplets, gelcaps, pills, and any other oral dosage forms known in the pharmaceutical art.
- treatment and derivatives such as “treating” as used herein includes both treatment and prophylaxis. Prophylaxis is relevant in relation to protection against such conditions such as hypothyroidism.
- a further aspect of the invention provides a process for preparing a pharmaceutical formulation according to the invention.
- the tablet may be prepared either by a wet granulation or by a direct compression process.
- a direct compression process is used, e.g. using a conventional high speed rotary press.
- the pharmaceutical formulation is prepared by making an initial preparation of a triturate of levothyroxine sodium and subsequently incorporating the triturate into the tablet formulation.
- a triturate of levothyroxine sodium comprises levothyroxine sodium and a suitable carrier, e.g. microcrystalline cellulose, wherein the levothyroxine sodium is present in a greater concentration in the triturate than in the final tablet formulation.
- the triturate comprises 2-3% w/w levothyroxine sodium of total weight of triturate. Preparation using a triturate improves distribution of the low concentration of drug throughout the blend and uniformity in the tablets i.e. homogeneous incorporation.
- the process comprises the steps of: (a) preparing a triturate of levothyroxine sodium and microcrystalline cellulose, (b) mixing the triturate with the remaining components of the pharmaceutical formulation, and (c) compression.
- Levothyroxine sodium can be obtained from the thyroid gland of domesticated animals, or alternatively the hormone can be prepared synthetically.
- Methods for making active ingredient are disclosed in Hagers Handbuch der pharmazeutician für fürtechnik, - 5., vollst. Neubearb., Bd. ⁇ .Stoffe: E-O / F... Von Bruchhausen; (Hrgs.).Bearb... von M. Albinus - 1993, Springer-Verlag Berlin Heidelberg 1993, pages 733 - 734; S. Rolski, Chemia srodk ⁇ w leczniczych, str. 654-655, PZWL, Warszawa 1968. The contents of which are incorporated herein by reference.
- the formulation may be introduced into a container which is then closed.
- the container may be sealed, e.g. by LDPE tamper-evident snap fit closures. It may be a single-dose or multi-dose container.
- the container may be bottles, jars, bags or sachets. Sachets, especially foil sachets (foil-foil blisters), are particularly suitable for single dose packaging. Bottles, particularly high density polyethylene (HOPE) or polypropylene (PP) bottles are particularly suitable for multi-dose packaging.
- HOPE high density polyethylene
- PP polypropylene
- Example 1 (b) differed from Example 1 (a) in that a preblend of the remainder of microcrystalline cellulose and colloidal silicon dioxide was made before blending with the levothyroxine sodium triturate and pregelatinised starch.
- Example 2 Stability of Levothyroxine Sodium Tablets. Comparative stability studies of levothyroxine sodium tablets were based on testing of levothyroxine sodium and total impurities contents after storage of tablets at (i) 40°C/75%RH, (ii) 30°C/60%RH, and (iii) 25°C/60%RH. Suitable HPLC methods were applied. Stability was measured in terms of levothyroxine sodium content and total impurities content:
- Total impurities contents were determined using the assay method for levothyroxine sodium tablets in the British Pharmacopoeia 2002 with a sample concentration of 50 ⁇ g/ml, sample solvent: methanol and 0.02 M aqueous NaOH (1 :1 ), an injection volume of 10O ⁇ l and a phase flow rate of 1.5ml/min.
- Levothyroxine sodium contents were determined using the assay method for levothyroxine sodium tablets in the British Pharmacopoeia 2002 using a sample concentration of 50 ⁇ g/ml, sample solvent: methanol and 0.02 M aqueous NaOH (1 :1) and phase flow rate of 1.5 ml/min.
- the data shows that at 3-9 months after storage a higher levothyroxine sodium content is maintained in tablets according to Example 1 (b) than in the marketed formulation of Eltroxin TM and total impurities are lower in tablets according to Example 1(b) than in marketed formulation of Eltroxin TM.
- the data shows that a higher levothyroxine sodium content is maintained and the total impurities are lower when microcrystalline cellulose with a mean particle size of 50 ⁇ m or 100 ⁇ m compared to 180 ⁇ m is used in the levothyroxine sodium formulation.
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- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Diabetes (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
Claims
Priority Applications (16)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NZ544174A NZ544174A (en) | 2003-07-10 | 2004-07-08 | Pharmaceutical formulation comprising levothyroxine sodium |
KR1020067000484A KR101136655B1 (en) | 2003-07-10 | 2004-07-08 | Pharmaceutical formulation comprising levothyroxine sodium |
CA2531853A CA2531853C (en) | 2003-07-10 | 2004-07-08 | Pharmaceutical formulation comprising levothyroxine sodium |
BRPI0412391A BRPI0412391B8 (en) | 2003-07-10 | 2004-07-08 | pharmaceutical formulation comprising levothyroxine sodium, its use and process for its preparation and |
EP04740922A EP1643976B1 (en) | 2003-07-10 | 2004-07-08 | Pharmaceutical formulation comprising levothyroxine sodium |
DE602004018142T DE602004018142D1 (en) | 2003-07-10 | 2004-07-08 | PHARMACEUTICAL FORMULATION WITH LEVOTHYROXINE SODIUM |
JP2006518170A JP4880457B2 (en) | 2003-07-10 | 2004-07-08 | Pharmaceutical formulations containing levothyroxine sodium |
MXPA06000353A MXPA06000353A (en) | 2003-07-10 | 2004-07-08 | Pharmaceutical formulation comprising levothyroxine sodium. |
US10/564,148 US7955621B2 (en) | 2003-07-10 | 2004-07-08 | Pharmaceutical formulation comprising levothyroxine sodium |
PL04740922T PL1643976T3 (en) | 2003-07-10 | 2004-07-08 | Pharmaceutical formulation comprising levothyroxine sodium |
DK04740922T DK1643976T3 (en) | 2003-07-10 | 2004-07-08 | Pharmaceutical formulation comprising levothyroxine sodium |
AU2004255466A AU2004255466B2 (en) | 2003-07-10 | 2004-07-08 | Pharmaceutical formulation comprising levothyroxine sodium |
IL172619A IL172619A (en) | 2003-07-10 | 2005-12-15 | Pharmaceutical formulations comprising (a) levothyroxine sodium, (b) micro crystalline cellulose, and (c) pregelatinised starch, use thereof in the manufacture of medicaments for the treatment of thyroid hormone disorders in a mammal and a process for preparing said pharmaceutical formulations |
NO20060208A NO338465B1 (en) | 2003-07-10 | 2006-01-13 | A pharmaceutical composition comprising levothyroxine sodium, method of preparation and use thereof |
IS8287A IS2616B (en) | 2003-07-10 | 2006-02-07 | A pharmaceutical composition containing levothyroxine sodium |
HK06109617.8A HK1089094A1 (en) | 2003-07-10 | 2006-08-29 | Pharmaceutical formulation comprising levothyroxine sodium |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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GB0316206.2 | 2003-07-10 | ||
GBGB0316206.2A GB0316206D0 (en) | 2003-07-10 | 2003-07-10 | Pharmaceutical formulation |
Publications (2)
Publication Number | Publication Date |
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WO2005004849A2 true WO2005004849A2 (en) | 2005-01-20 |
WO2005004849A3 WO2005004849A3 (en) | 2005-05-06 |
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Application Number | Title | Priority Date | Filing Date |
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PCT/EP2004/007667 WO2005004849A2 (en) | 2003-07-10 | 2004-07-08 | Pharmaceutical formulation comprising levothyroxine sodium |
Country Status (29)
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US (1) | US7955621B2 (en) |
EP (1) | EP1643976B1 (en) |
JP (2) | JP4880457B2 (en) |
KR (1) | KR101136655B1 (en) |
CN (1) | CN100430051C (en) |
AR (1) | AR045719A1 (en) |
AT (1) | ATE415949T1 (en) |
AU (1) | AU2004255466B2 (en) |
BR (1) | BRPI0412391B8 (en) |
CA (1) | CA2531853C (en) |
CO (1) | CO5700710A2 (en) |
DE (1) | DE602004018142D1 (en) |
DK (1) | DK1643976T3 (en) |
ES (1) | ES2319193T3 (en) |
GB (1) | GB0316206D0 (en) |
HK (1) | HK1089094A1 (en) |
IL (1) | IL172619A (en) |
IS (1) | IS2616B (en) |
MA (1) | MA27898A1 (en) |
MX (1) | MXPA06000353A (en) |
MY (1) | MY140127A (en) |
NO (1) | NO338465B1 (en) |
NZ (1) | NZ544174A (en) |
PL (1) | PL1643976T3 (en) |
PT (1) | PT1643976E (en) |
RU (1) | RU2349345C2 (en) |
TW (1) | TWI329026B (en) |
WO (1) | WO2005004849A2 (en) |
ZA (1) | ZA200510224B (en) |
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WO2007077252A1 (en) * | 2006-01-06 | 2007-07-12 | Intervet International B.V. | Concentrated liquid thyroid hormone composition |
WO2014098886A1 (en) * | 2012-12-21 | 2014-06-26 | Mylan Inc. | Levothyroxine formulation with carrageenan |
WO2014098887A1 (en) * | 2012-12-21 | 2014-06-26 | Mylan Inc. | Levothyroxine formulation with acacia |
US9012438B2 (en) | 2002-11-13 | 2015-04-21 | Aldo Pinchera | 3,5,3′ -triiodothronine sulfate as thyromimetic agent and pharmaceutical formulations thereof |
US9271951B2 (en) | 2012-12-21 | 2016-03-01 | Mylan Inc. | Levothyroxine formulation with acacia |
US9890116B2 (en) | 2002-11-13 | 2018-02-13 | Bracco Imaging S.P.A. | Process for the preparation of a sulfated derivative of 3,5-diiodo-O-[3-iodophenyl]-L-tyrosine |
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IT1395454B1 (en) * | 2009-03-24 | 2012-09-21 | Altergon Sa | PHARMACEUTICAL COMPOSITIONS AND FORMS FOR ORAL ADMINISTRATION OF THYROID ORMONS ABLE TO COUNTER THE ACTION OF SEQUESTRANT AGENTS IN THE GASTROINTESTINAL TRACT |
ITMI20112066A1 (en) * | 2011-11-14 | 2013-05-15 | Altergon Sa | SINGLE-DOSE ORAL PHARMACEUTICAL PREPARATION OF THYROID ORMONS T3 AND T4 |
EP2932963A1 (en) | 2014-04-16 | 2015-10-21 | Uni-Pharma Kleon Tsetis Pharmaceutical Laboratories S.A. | Stable pharmaceutical dosage forms comprising Levothyroxine sodium |
WO2017061621A1 (en) | 2015-10-07 | 2017-04-13 | 協和発酵キリン株式会社 | Pharmaceutical composition containing aryl alkyl amine compound |
JP6168673B2 (en) | 2015-10-07 | 2017-07-26 | 協和発酵キリン株式会社 | Arylalkylamine compound-containing pharmaceutical composition |
WO2018069805A2 (en) | 2016-10-10 | 2018-04-19 | Ftf Pharma Private Limited | Method for preparation of liquid oral composition of l-thyroxin |
SG11201906890TA (en) * | 2017-02-03 | 2019-08-27 | Berlin Chemie Ag | Oral thyroid therapeutic agent |
IT201800003615A1 (en) * | 2018-03-15 | 2019-09-15 | Altergon Sa | Highly stable formulations of thyroid hormone in soft capsules |
CN109988076A (en) * | 2019-05-05 | 2019-07-09 | 上海葆隆生物科技有限公司 | A kind of Levothyroxine sodium impurity and its preparation |
KR20220085086A (en) | 2020-12-14 | 2022-06-22 | 메디케어제약 주식회사 | Pharmaceutical composite formulation for treating metabolic syndrome with hypothyroidism |
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- 2004-07-08 EP EP04740922A patent/EP1643976B1/en not_active Expired - Lifetime
- 2004-07-08 KR KR1020067000484A patent/KR101136655B1/en active IP Right Grant
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- 2004-07-08 RU RU2006104009/15A patent/RU2349345C2/en active
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- 2004-07-08 DK DK04740922T patent/DK1643976T3/en active
- 2004-07-08 NZ NZ544174A patent/NZ544174A/en unknown
- 2004-07-08 DE DE602004018142T patent/DE602004018142D1/en not_active Expired - Lifetime
- 2004-07-08 US US10/564,148 patent/US7955621B2/en active Active
- 2004-07-08 AR ARP040102405A patent/AR045719A1/en not_active Application Discontinuation
- 2004-07-08 AU AU2004255466A patent/AU2004255466B2/en not_active Expired
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US9012438B2 (en) | 2002-11-13 | 2015-04-21 | Aldo Pinchera | 3,5,3′ -triiodothronine sulfate as thyromimetic agent and pharmaceutical formulations thereof |
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