HUE035222T2 - Levotiroxint tartalmazó szilárd gyógyszerészeti készítmények - Google Patents
Levotiroxint tartalmazó szilárd gyógyszerészeti készítmények Download PDFInfo
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- HUE035222T2 HUE035222T2 HUE13747642A HUE13747642A HUE035222T2 HU E035222 T2 HUE035222 T2 HU E035222T2 HU E13747642 A HUE13747642 A HU E13747642A HU E13747642 A HUE13747642 A HU E13747642A HU E035222 T2 HUE035222 T2 HU E035222T2
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- pharmaceutical preparation
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- BYNVYIUJKRRNNC-UHFFFAOYSA-N docosanoic acid;propane-1,2,3-triol Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCCCCCCCC(O)=O BYNVYIUJKRRNNC-UHFFFAOYSA-N 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
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- 238000009501 film coating Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 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
- 239000012943 hotmelt Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000000905 isomalt Substances 0.000 description 1
- 235000010439 isomalt Nutrition 0.000 description 1
- HPIGCVXMBGOWTF-UHFFFAOYSA-N isomaltol Natural products CC(=O)C=1OC=CC=1O HPIGCVXMBGOWTF-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 239000007788 liquid Substances 0.000 description 1
- LSPWIBVVGBHFQW-UHFFFAOYSA-N magnesium lead(2+) oxygen(2-) Chemical compound [O--].[O--].[Mg++].[Pb++] LSPWIBVVGBHFQW-UHFFFAOYSA-N 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 description 1
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- 239000004014 plasticizer Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
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- 235000012015 potatoes Nutrition 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
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- 239000011780 sodium chloride Substances 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- 238000012430 stability testing Methods 0.000 description 1
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- 229940035722 triiodothyronine Drugs 0.000 description 1
- 238000001195 ultra high performance liquid chromatography Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
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Classifications
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- 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]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—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
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- 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
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1658—Proteins, e.g. albumin, gelatin
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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- A—HUMAN NECESSITIES
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Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Engineering & Computer Science (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Endocrinology (AREA)
- Diabetes (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
(12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) IntCI.: of the grant of the patent: A61K 47Ι12<2006 01> A61K 9l16<2006 01> 27.09.2017 Bulletin 2017/39 A61K 9Ι20<2006 01> A61K 9l48<2006 01> A61K 31l195<2006 01> A61K 31l198<200601> (21) Application number: 13747642.0 (86) International application number: (22) Date of filing: 01.08.2013 PCT/EP2013/002293 (87) International publication number: WO 2014/029464 (27.02.2014 Gazette 2014/09)
(54) SOLID PHARMACEUTICAL PREPARATION CONTAINING LEVOTHYROXINE FESTES PHARMAZEUTISCHES PRAPARAT MIT LEVOTHYROXIN PREPARATION PHARMACEUTIQUE SOLIDE CONTENANT DE LA LEVOTHYROXINE (84) Designated Contracting States: (72) Inventors: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB · LINDENBLATT, Hiltrud GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO 63329 Egelsbach (DE) PL PT RO RS SE SI SK SM TR · FRANK, Thomas T. 64331 Weiterstadt (DE) (30) Priority: 20.08.2012 EP 12005960 · VONDERSCHMITT, Reiner 64372 Ober-Ramstadt (DE) (43) Date of publication of application: 24.06.2015 Bulletin 2015/26 (56) References cited: WO-A1-95/20953 WO-A1-95/20954 (73) Proprietor: Merck Patent GmbH WO-A1-99/59551 WO-A1-2004/096177 64293 Darmstadt (DE) WO-A1-2010/108553 US-A- 5 958 979
Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).
Description [0001] The invention relates to a solid pharmaceutical preparation comprising levothyroxine sodium, gelatine, citric acid and a filler. The solid pharmaceutical preparation has an improved stability.
[0002] Levothyroxine sodium is used to treat thyroid hormone deficiency, and occasionally to prevent the recurrence of thyroid cancer. In treatment of thyroid hormone deficiency very low daily doses of levothyroxine sodium are used in the range from 25 to 30C^g. Due to its high potency it is very important to avoid dosage variations as this may cause serious symptoms of hypothyroidism such as as severe depression, fatigue, weight gain, constipation, cold intolerance, swelling, and difficulty concentrating, if levothyroxine sodium is underdosed, or of hypothyroidism, such as pain, heart palpitations, or cardiac arrhythmias, if levothyroxine sodium dosis is too high. Therefore, storage stability of pharmaceutical preparations containing levothyroxine sodium is a critical issue.
[0003] DE 195 41 128 teaches to stabilize thyroxine preparations by addition of sodium thiosulfate. However, the use of substances like sodium thiosulfate in pharmaceutical preparations is undesirable from the toxicological point of view. [0004] WO 2004/096177 A1 teaches to stabilize pharmaceutical preparations containing levothyroxine sodium by providing them with a water activity below 0.4. Disadvantageously the water activity of the formulations varies with the change of relative humidity during shelf life so that additional measures have to be taken such as moisture-tight packs, which result in additional costs and waste management problems.
[0005] Patel et al. examined the effect of various pH modifying additives on the stability of levothyroxine sodium tablets (Patel H. et al: The effect of excipients on stability of levothyroxine sodium pentahydrate tablets, Int J Pharm 264 (2003) 35-43). It was found that the basic pH modifying additives sodium carbonate, sodium bicarbonate and magnesium oxide lead to improvement of the stability of levothyroxine sodium tablets whereas acid pH modifying additives tartaric acid and citric acid lead to impairment of stability.
[0006] WO 99/59551 A1 teaches that storage stability of levothyroxine sodium containing solid pharmaceutical preparations can be improved by using gelatine as a binder. As described in the introduction such stabilized formulation has been developed in order to meet the increased requirements on stability as established by the Food and Drug Administration (FDA) in 1996. According to such FDA requirements levothyroxine sodium degradation in tablets throughout their shelf life has been fixed to 10% at the most.
[0007] In 2007 the FDA has raised its requirements on stability of levothyroxine sodium containing products to further diminish the risk caused this. In fact the limit of levothyroxine sodium degradation in tablets was lowered from 10 to 5% (FDA press release from 3 Oct 2007).
[0008] There is an ongoing demand for pharmaceutical preparations having an improved stability. The pharmaceutical preparations should ensure release of active compound in accordance with the requirements, should not comprise any toxicologically unacceptable adjuvants and should be capable of storage in a stable manner over an extended time. [0009] Surprisingly, it has been found that a solid pharmaceutical preparation which meets these requirements and has an improved storage stability can be provided if it comprises besides levothyroxine sodium, gelatine, citric acid and a filler. Therefore, when an object of the present invention is directed to a solid pharmaceutical preparation comprising levothyroxine sodium, gelatine, citric acid and a filler.
[0010] The improved stability of a solid pharmaceutical preparation is especially surprising in view of that the prior art teaching of Patel et al. (as cited above) according to which the addition of citric acid leads not only to no improvement but even to a deterioration of levothyroxine sodium in tablets.
[0011] US 6,649,186 B1 disclose effervescent granules which are prepared by hot melt extruding which may contain levothyroxine sodium. Such effervescent granules contain an acid component such as citric acid together with a basic component such as sodium carbonate or sodium bicarbonate which upon contact with water react under carbon dioxide development. The pharmaceutical preparation of the present invention is preferably not an effervescent preparation. Therefore, a further object of the present invention is directed to a solid pharmaceutical preparation, which is characterized in that it is not an effervescent preparation.
[0012] US 5,753,254 A discloses a solid fast dispersing dosage form containing thyroid hormone which may also comprise citric acid to induce the formation of saliva. Solid fast dispersing dosage forms are oral administration forms which disintegrate readily and quickly in the mouth within seconds upon contact with saliva when taken orally. The pharmaceutical preparation of the present invention is preferably not a solid fast dispersing dosage form.
[0013] Therefore, a further object of the invention is directed to a solid pharmaceutical preparation, which is characterized in that it is not a solid fast dispersing dosage form.
[0014] According to an appropriate embodiment of the invention solid pharmaceutical preparation contains 5 to 400 μg, preferably 10 to 300 μg, in particular 25 to 300 μg, of levothyroxine sodium. Preferably the solid pharmaceutical preparation contain 25, 50, 75, 88, 100, 112, 125, 137, 150, 175, 200 or 300 μg of levothyroxine sodium.
[0015] If levothyroxine sodium is present in micronized form, especially with a particle size from 5 μπι to 25 μπι, the dissolution of the solid pharmaceutical preparation improves. Therefore, a preferred object of the present invention is directed to a solid pharmaceutical preparation, which is characterized in that it contains levothyroxine sodium micronized with a particle size from 5 |im to 25 |im [0016] According to an appropriate embodiment of the present invention gelatine is present in the solid pharmaceutical preparation in an amount from 0.5 to 20% by weight, preferably from 1 to 10% by weight, particularly preferably from 2 to 10% by weight, most preferably at about 5% .
[0017] According to a further appropriate embodiment of the present invention citric acid is present in the solid pharmaceutical preparation in an amountfrom 0.1 to 5% by weight, preferably from 0.2 to 3% by weight, particularly preferably from 0.4 to 2% by weight.
[0018] According to a preferred embodiment of the invention the pharmaceutical preparation comprises besides levothyroxine sodium liothyronine sodium a as further active ingredient. Therefore, the invention is also directed to a solid pharmaceutical preparation, which is characterized in that it comprises liothyronine sodium.
[0019] A filler is an agent increasing the bulk of the pharmaceutical preparation by providing the quantity of material which is needed to form such pharmaceutical preparation. The filler being present in the solid preparation of the present invention is preferably a sugar alcohol, a sugar, a starch, a cellulose or a mixture thereof.
[0020] Sugar alcohol is taken to mean a monosaccharide whose reactive carbonyl group has been reduced to the alcohol group, such as, for example, a hexitol or a pentitol. The solid preparation according to the invention preferably comprises hexitols, such as, for example, mannitol, sorbitol, dulcitol, xylitol or ribitol, as sugar alcohol. Particular preference is given to the presence of mannitol and/or sorbitol, most particular preference is given to mannitol.
[0021] Sugar is taken to mean a monosaccharide such as, for example, a hexitol or a pentitol and a disaccharide consisting of two monosaccharides joined by aglycosidicbond. The solid preparation according to the invention preferably comprises glucose, fructose or mannose, as a monosaccharide or lactose, saccharose or maltose, as a disaccharide. Particular preference is given to lactose.
[0022] Starch is taken to mean a polysaccharide comprising helical amylose and branched amylopectin, it is produced by green plants such as potatoes, wheat, maize, rice, and cassava. The solid preparation according to the invention preferably comprises potato starch, rice starch, maize starch or precooked starch, i.e. pregelatinized starch. Particular preference is given to maize starch and pregelatinized starch, most particular preference is given to maize starch. [0023] Cellulose is taken to mean a polysaccharide consisting of a linear chain of several hundred to over ten thousand β(1 —>4) linked D-glucose. The solid preparation according to the invention preferably comprises powdered cellulose or microcrystalline cellulose, particular preferred is microcrystalline cellulose.
[0024] According to an appropriate embodiment of the present invention the solid pharmaceutical preparation is characterized in that the filler is a sugar alcohol such as sorbitol or mannitol dulcitol, xylitol or ribitol, preferably sorbitol or mannitol, particular preferably mannitol, a sugar such as glucose, fructose, mannose, lactose, saccharose or maltose, preferably lactose, saccharose or maltose, particular preferably lactose, a starch such as potato starch, rice starch, maize starch or pregelatinized starch, preferably maize starch or pregelatinized starch, particular preferably maize starch, a cellulose such as powdered cellulose or microcrystalline cellulose, preferably microcrystalline cellulose, or a mixture thereof.
[0025] According to a particularly preferred embodiment of the present invention solid pharmaceutical preparation is characterized in that the filler is mannitol and/or maize starch.
[0026] According to a appropriate embodiment of the present invention the filler is present in the solid pharmaceutical preparation in an amount from 70 to 98% by weight, preferably 80 to 98% by weight, particular preferably 85 to 95% by weight.
[0027] The stability of the solid pharmaceutical preparation can be further improved if it comprises an antioxidant selected from the group consisting of tocopherol, sodium ascorbate, propyl gallate, tertiary butylhydroquinone, butylated hydroxyanisole and butylated hydroxytoluene (BHT), preferably butylated hydroxyanisole or butylated hydroxytoluene, particular preferably butylated hydroxytoluene. Therefore, a preferred object of the invention is directed to a solid pharmaceutical preparation, which is characterized in that it further comprises an antioxidant selected from the group consisting of tocopherol, propyl gallate, tertiary butylhydroquinone, butylated hydroxyanisole and butylated hydroxytoluene, preferably hydroxyanisole or butylated hydroxytoluene, particular preferably butylated hydroxytoluene. The solid pharmaceutical preparation according to the invention comprises 0.01 to 2% by weight, preferably 0.05 to 0.5% by weight, particularly preferably 0.08 to 0.2 and most preferably 0.1 %-0.15% by weight of the antioxidant.
[0028] The solid pharmaceutical preparation can be in granule, pellet, capsule or tablet form. While capsules and tablets provide the amount of active compound intended to be taken in each case as a clearly defined individual dose, the amount of active compound required in each case can be adapted in a simple manner by means of pellets and granules. [0029] Granules can be prepared by granulation. Pellets are solid, small, spherical medicament forms, such as, for example, granule grains or microtablets, having a very narrow particle-size range. Granules and pellets represent an independent medicament form, but can also serve as intermediate product for the production of tablets. If it is intended that predetermined amounts of active compound can be administered by means of granules or pellets, these are, in order to ensure adequate dosage accuracy, also provided as portioned granules or introduced into capsules. The solid pharmaceutical preparation according to the invention is preferably in granule, pellet, capsule or tablet form, particular preferably in capsule or tablet form, very particular preferably in tablet form.
[0030] Therefore, a further object of the present invention is directed to a solid pharmaceutical preparation, which is characterised in that it is in granule, pellet, capsule or tablet form, particular preferably in capsule or tablet form. A very particularly preferred object of the present invention is directed to a solid pharmaceutical preparation, which is characterized in that it is a tablet.
[0031] The solid pharmaceutical preparation may contain a disintegrating agent in order to shorten the disintegration time of the tablet or granules, enabling the active compound to be released rapidly from the it. Therefore, a further object of the present invention is directed to a solid pharmaceutical preparation, which is characterised in that a disintegrating agent is present.
[0032] Appropriate disintegrating agent in the solid pharmaceutical preparation of the present invention are sodium starch glycolate, carboxymethylcellulose sodium, crosslinked carboxymethylcellulosesodiumora mixture thereof. Therefore, a further object of the present invention is directed to a solid pharmaceutical preparation which is characterized in that the disintegrating agent is sodium starch glycolate or carboxymethylcellulose sodium or a mixture thereof.
[0033] A preferred embodiment of the solid pharmaceutical preparation comprises as a disintegrating agent carboxymethylcellulose sodium, particular preferably crosslinked carboxymethylcellulose sodium. Accordingly, a preferred object of the present invention is directed to a solid pharmaceutical preparation which is characterized in that disintegrating agent is carboxymethylcellulose sodium, particular preferably crosslinked carboxymethylcellulose sodium.
[0034] Depending on the nature of the disintegrating agent, this may be present in the solid preparation according to the invention in a proportion by weight of 0.01 to 20% by weight. The solid preparation according to the invention preferably comprises 0.1 to 10% by weight, particularly preferably 1-5% by weight, of the disintegrating agent.
[0035] According to an appropriate embodiment of the invention the solid pharmaceutical preparation comprises 1 to 10% by weight of gelatine, 0.1 to 3% by weight citric acid, 50 to 80% by weight of mannitol or lactose and 10 to 30% by weightof maize starch. Therefore, afurtherobjectofthe present invention is directed to a solid pharmaceutical preparation, which is characterised in that it comprises 1 to 10% by weight of gelatine, 0.1 to 3% by weight citric acid, 50 to 80% by weight of mannitol or lactose, 10 to 30% by weight maize starch.
[0036] According to an preferred embodiment of the invention the solid pharmaceutical preparation comprises 0,05 to 0,5% by weight butylated hydroxytoluene. Therefore, a further object of the present invention is directed to a solid pharmaceutical preparation, which is characterised in that it comprises 0,05 to 0,5% by weight butylated hydroxy toluene. Preferably the 0,05 to 0,5% by weight butylated hydroxytoluene are is present in the solid pharmaceutical preparation, which is characterised in that it comprises 1 to 10% by weight of gelatine, 0.1 to 3% by weight citric acid, 50 to 80% by weight of mannitol or lactose, 10 to 30% by weight maize starch.
[0037] A particular preferred object of the invention is directed to a solid pharmaceutical preparation which is characterised in that it comprises 2 to 8% by weight of gelatine, 0.5 to 2% by weight citric acid, 60 to 75% by weight of mannitol or lactose, 15 to 25% by weight of maize starch and optionally 0,08 to 0,2% by weight butylated hydroxytoluene. [0038] If the solid pharmaceutical preparation according to the invention is a tablet, this may also comprise lubricants in order to reduce the sliding friction of the tableting material and ram in the mould during the tableting operation and to prevent sticking to the rams. Suitable lubricants are alkaline-earth metal salts of fatty acids, such as magnesium stearate or calcium stearate, fatty acids, such as stearic acid, higher fatty alcohols such al cetyl alcohol orstearyl alhohol, fats such as glyceryl dipalmitostearate, glyceryl distearate, stearin or glyceryl dibehenate, alkaline-earth metal salts of C16-C18 alkyl substituted dicarbonic acids such as sodium stearyl fumarate, hydrated vegetable oils such as hydrated castor oil or hydrated cotton seed oil, or minerals such as silica or talc. The solid preparation according to the invention preferably comprises magnesium stearate, stearic acid or sodium stearyl fumarate as lubricant, particular preferably magnesium stearate. Lubricants are preferably present in the solid preparation according to the invention in a proportion of 0.1 to 5% by weight, preferably 0.25 to 4% by weight, particularly preferably 0,5 to 3% by weight, most preferably about 1% by weight.
[0039] The solid preparation according to the invention can be prepared by methods known to the person skilled in the art.
[0040] Granules are produced by granulation, which can basically be carried out by the moist or dry route. In the case of moist granulation, for example, a granulation liquid, which preferably comprises a binder, is added to a powder mixture comprising the active compound together with the sugar alcohol and any further suitable adjuvants, the mixture is converted into aggregates of suitable size (granules) and subsequently dried. The active compound can also be introduced into the granules by suspension in the granulation liquid. The conversion of the powder mixture into aggregates of suitable size can be carried out, for example, by so-called build-up granulation, for example in coating pans, by means of plate granulation or in fluidised-bed methods, for example by the Glatt or Wurster method, or by so-called reduction granulation, in which the powder mixture is firstly moistened and converted into a plastically mouldable mass and subsequently converted into aggregates of the desired size, for example by extrusion through a screen having meshes of suitable size. In the case of dry granulation, the powder mixture is pressed, for example, by means of compaction between two counter-rotating compaction rolls to give flakes, which are subsequently comminuted to give granules.
[0041] Pellets can be produced by granulation and subsequent rounding-off (spheronisation), for example by means of plate granulation, or alternatively by pressing powders or granules to give microtablets.
[0042] The preparation according to the invention in the form of tablets can be produced by pressing powder mixtures (direct compression) or by pressing granules. In the simplest case of direct compression, the active compound is firstly mixed with the excipients and the resultant powder mixture is pressed directly to give the solid preparation according to the invention.
[0043] According to a preferred embodiment of the invention the solid pharmaceutical preparation is prepared by a process, which is characterized in that (a) levothyroxine sodium and optionally liothyronine sodium is/are suspended in an aqueous gelatine solution, (b) the suspension obtained by step (a) is sprayed onto the filler in a fluidized bed granulation and dried to form granules, (c) the granules obtained by step (b) are collected and optionally, (d) a disintegrant and optionally a lubricant is/are mixed with the granules obtained by step (c), and (e) the mixture obtained by step (d) is compressed to give tablets.
[0044] Accordingly, one object of the present invention is further directed to a process for the production of a solid pharmaceutical preparation, which is characterized in that (a) levothyroxine sodium and optionally liothyronine sodium is/are suspended in an aqueous gelatine solution, (b) the suspension obtained by step (a) is sprayed onto the filler in a fluidized bed granulation and dried to form granules, (c) the granules obtained by step (b) are collected and optionally, (d) a disintegrant and optionally a lubricant is/are mixed with the granules obtained by step (c), and (e) the mixture obtained by step (d) is compressed to give tablets.
[0045] The granules obtained by performing the steps (a) to (c) can be directly used as a medicament form without performing the optional steps (d) and (e). Ifthe granules are used they can be provided as portioned granules or introduced into capsules to ensure adequate dosage accuracy as described above.
[0046] According to a further appropriate embodiment of the invention the solid pharmaceutical preparation is prepared by a process, which is characterized in that citric acid and, if present, the antioxidant is dissolved in in the aqueous gelatine solution used in step (a) or is admixed with the granules in step (d). Therefore, a further object of the invention is directed to a process for the production of a solid pharmaceutical preparation, which is characterized in that citric acid and, if present, the antioxidant is dissolved in the aqueous gelatine solution used in step (a) or is admixed with the granules in step (d).
[0047] According to an appropriate embodiment of the invention the granules or the tablets are provided with a coating. Therefore, a further object of the invention is directed to a process for the production of a solid pharmaceutical preparation, which is characterized in that the granules or the tablets are provided with a coating.
[0048] Suitable coatings are film-forming polymers, such as, for example, those from the group of the cellulose derivatives, dextrins, starches, natural gums, such as, for example, gum arabic, xanthans, alginates, polyvinyl alcohol, polymethacrylates and derivatives thereof, such as, for example, eudragites, which may be applied to the tablet as solutions or suspensions by means of the various pharmaceutical conventional methods, such as, for example, film coating. Use is usually made here of solutions/suspensions which, besides the film-forming polymer, also comprise further adjuvants, such as hydrophilisers, plasticisers, surfactants, dyes and white pigments, such as, for example, titanium dioxide.
[0049] The examples illustrate the invention without being restricted thereto.
Example 1 [0050] Tablet (batch 015093) comprising 0.075 mg of levothyroxine sodium 68.525 mg of mannitol 20.00 mg of maize starch 5.00 mg of sodium starch glycolate 5.00 mg of gelatine 0.40 mg of citric acid 1.00 mg of magnesium stearate [0051] The gelatin is diluted in hot water (ca. 90% of total amount of water, temperature 90°C ± 10°C) under stirring. The levothyroxine sodium is suspended in cold water (10% of total amount of water) with Ultraturrax. When the gelatin solution has cooled down to 50°C ± 5°C, the levothyroxine sodium suspension is given to it, while the final temperature of the granulation fluid is 40-45°C.
[0052] The granulation fluid containing gelatin and active compound is sprayed onto the mannitol and maize starch in the fluidised bed. The temperature of the granulation fluid is kept at around 40°C. The granules are finalized as soon a outlet air temperature has raised up to 40°C.
[0053] Citric acid, sodium starch glycolate and magnesium stearate are admixed with the granules, the resultant mixture is pressed to give tablets. Instead of admixing with the granules citric acid can also be added by dissolving it during preparation of the levothyroxine sodium containing gelatine solution.
Example 2 [0054] Tablet (batch 015099) comprising 0.30 mg of levothyroxine sodium 68.20 mg of mannitol 20.00 mg of maize starch 3.50 mg of croscarmellose sodium 5.00 mg of gelatine 2.00 mg of citric acid 1.00 mg of magnesium stearate [0055] The tablets are produced analogous to Example 1.
Example 3 [0056] Tablet (batch 014916) comprising 0.105 mg of levothyroxine sodium 70.295 mg of mannitol 20.00 mg of maize starch 3.50 mg of croscarmellose sodium 5.00 mg of gelatine 0.10 mg of butylated hydroxytoluene 0.80 mg of citric acid 1.00 mg of magnesium stearate [0057] The tablets are produced analogous to Example 1. The butylated hydroxytoluene is diluted in hot water (ca. 90% of total amount of water, temperature 90°C ± 10°C) under stirring. Afterwards the gelatin is given to this solution under stirring. The Levothyroxine sodium is suspended in cold water (10% of total amount of water) with Ultraturrax. As soon the BHT-gelatin solution has cooled down to 50°C ± 5°C, the levothyroxine sodium suspension is given to it, while the final temperature of the granulation fluid now is 40-45°C.
Example 4 [0058] Tablet comprising 0.300 mg of levothyroxine sodium 73.100 mg of mannitol 20.00 mg of maize starch 3.50 mg of croscarmellose sodium 2.00 mg of gelatine 0.10 mg of butylated hydroxytoluene 0.80 mg of citric acid 1.00 mg of magnesium stearate [0059] The tablets are produced analogous to Example 3.
Example 5 [0060] Tablet comprising 0.025 mg of levothyroxine sodium 65.375 mg of mannitol 20.00 mg of maize starch 3.50 mg of croscarmellose sodium 10.00 mg of gelatine 0.10 mg of butylated hydroxytoluene 0.80 mg of citric acid 1.00 mg of magnesium stearate [0061] The tablets are produced analogous to Example 3.
Example 6 [0062] Tablet comprising 0.105 mg of levothyroxine sodium 70.395 mg of isomalt 20.00 mg of maize starch 3.50 mg of croscarmellose sodium 5.00 mg of gelatine 0.40 mg of citric acid 1.00 mg of magnesium stearate [0063] The tablets are produced analogous to Example 1.
Example 7 [0064] Tablet comprising 0.105 mg of levothyroxine sodium 81.645 mg of cellulose microcrystalline 3.50 mg of croscarmellose sodium 4.50 mg of gelatine 1.50 mg of citric acid 0.25 mg of magnesium stearate [0065] The tablets are produced analogous to Example 1.
Example 8 [0066] Tablet comprising 0.105 mg of levothyroxine sodium 70.295 mg of sorbitol 20.00 mg of maize starch 3.50 mg of croscarmellose sodium 5.00 mg of gelatine 0.10 mg of butylated hydroxytoluene 0.80 mg of citric acid 1.00 mg of magnesium stearate [0067] The tablets are produced analogous to Example 3.
Example 9 [0068] Tablet comprising 0.105 mg of levothyroxine sodium 70.295 mg of sucrose 20.00 mg of maize starch 3.50 mg of croscarmellose sodium 5.00 mg of gelatine 0.10 mg of butylated hydroxytoluene 0.80 mg of citric acid 1.00 mg of magnesium stearate [0069] The tablets are produced analogous to Example 3.
Example 10 [0070] Tablet comprising 0.105 mg of levothyroxine sodium 70.395 mg of mannitol 20.00 mg of maize starch 3.50 mg of croscarmellose sodium 5.00 mg of gelatine 2.00 mg of citric acid 0.10 mg of sodium ascorbate 1.00 mg of magnesium stearate [0071] The tablets are produced analogous to Example 1.
Example 11 [0072] Granules comprising 0.105 mg of levothyroxine sodium 70.295 mg of mannitol 20.00 mg of maize starch 5.00 mg of gelatine 0.10 mg of butylated hydroxytoluene 0.80 mg of citric acid [0073] The citric acid and the gelatin are diluted in hot water (ca. 90% of total amount of water, temperature 90°C ± 10°C) under stirring. The levothyroxine sodium is suspended in cold water (10% of total amount of water) with Ultraturrax. When the gelatin solution with the citric acid has cooled down to 50°C ± 5°C, the levothyroxine sodium suspension is given to it, while the final temperature of the granulation fluid is 40-45°C.
[0074] The granulation fluid containing gelatin and active compound is sprayed onto the mannitol and maize starch in the fluidised bed. The temperature of the granulation fluid is kept at around 40°C. The granules are finalized as soon a outlet air temperature has raised up to 40°C.
Example 12 [0075]
Capsules comprising granules
Granules of example 11 filled into capsules (gelatine or HPMC)
Comparison Example 1 [0076] Tablet (batch 127494) comprising 0.105 mg of levothyroxine sodium 65.895 mg of lactose 25.00 mg of maize starch 3.50 mg of crosscarmellose sodium 5.00 mg of gelatine 0.50 mg of magnesium stearate [0077] The tablets are produced analogous to Example 1.
Comparison Example 2 [0078] Tablet (batch 014698) comprising 0.105 mg of levothyroxine sodium 70.395 mg of mannitol 20.00 mg of maize starch 3.50 mg of crosscarmellose sodium 5.00 mg of gelatine 0.50 mg of magnesium stearate [0079] The tablets are produced analogous to Example 1.
Comparison Example 3 [0080] Tablet (batch 014842) comprising 0.105 mg of levothyroxine sodium 70.295 mg of mannitol 20.00 mg of maize starch 3.50 mg of crosscarmellose sodium 5.00 mg of gelatine 0.10 mg of butylated hydroxytoluene 1.00 mg of magnesium stearate [0081] The tablets are produced analogous to Example 1. Butylated hydroxytoluene was admixed as described in Example 3.
Stability testing [0082] To assess the influence of the ingredients, especially citric acid and/or antioxidant on storage stability the pharmaceutical preparations of Examples 1 to 4 and the Comparison Examples 1 and 2 were transferred into glass bottles without closure and stored under elevated temperature and humidity (60 degree Celsius and 75% relative humidity (r.h.)). Storage times and the amounts of active compound measured in each case are shown in Table 1.
Table 1
(continued)
[0083] As demonstrated by the data in table 1 the presence of citric acid leads to an improvement of stability which is further improved by the antioxidant. As no improvement of stability is obtained if the antioxidant is present without citric acid the antioxidant exhibits an antioxidant unexpectedly exhibits a synergistic stabilization effect in combination with citric acid.
[0084] The pharmaceutical preparations of Examples 3 and 4 and Comparison Examples were transferred into HDPE bottles, closed and stored at40°C and 75% r.h. Storage times and the amounts of active compound measured in each case are shown in Table 2.
Table 2
[0085] As apparent from table 2 the presence of an antioxidant does not exhibit a significant stabilisation effect without the presence of citric acid. Further and surprisingly the combination of citric acid with the antioxidant leads to such a good stabilization effect that after half year storage at elevated temperature and humidity (40°C and 75% r.h.) the content of levothyroxine sodium in the preparation decreased only 0.1 % by weight.
Analytical test methods: [0086] Identity, purity and assay of the solid pharmaceutical preparation comprising levothyroxine sodium are tested by high-performance liquid chromatography or ultra high performance liquid chromatography with UV detection using an reversed phase column and a gradient system after preparation and during the stability studies. The extraction medium and mobile phase used are mixtures of acetonitrile, water and phosphoric acid.
Claims 1. Solid pharmaceutical preparation comprising levothyroxine sodium, gelatine, citric acid and a filler. 2. Solid pharmaceutical preparation according to Claim 1, characterized in that it comprises liothyronine sodium. 3. Solid pharmaceutical preparation according to Claim 1 and/or 2, characterized in that the filler is a sugar alcohol such as sorbitol or mannitol dulcitol, xylitol or ribitol, preferably sorbitol or mannitol, particular preferably mannitol, a sugar such as glucose, fructose, mannose, lactose, saccharose or maltose, preferably lactose, saccharose or maltose, particular preferably lactose, a starch such as potato starch, rice starch, maize starch or pregelatinized starch, preferably maize starch or pregelatinized starch, particular preferably maize starch, a cellulose such as powdered cellulose or microcrystalline cellulose, preferably microcrystalline cellulose, or a mixture thereof. 4. Solid pharmaceutical preparation according to Claim 3, characterised in that the filler is mannitol and/or maize starch. 5. Solid pharmaceutical preparation according to one or more of Claims 1 to 4, characterized in that it further comprises an antioxidant selected from the group consisting of tocopherol, propyl gallate, tertiary butyl hydroquinone, butylated hydroxyanisole and butylated hydroxytoluene, preferably hydroxyanisole or butylated hydroxytoluene, particular preferably butylated hydroxytoluene. 6. Solid pharmaceutical preparation according to one or more of Claims 1 to 5, characterised in that it is in granule, pellet, capsule or tablet form. 7. Solid pharmaceutical preparation according to Claim 6, characterised in that it is a tablet. 8. Solid pharmaceutical preparation according to one or more of Claim 1 to 7, characterised in that at least one disintegrating agent is present. 9. Solid pharmaceutical preparation according to Claim 8, characterized in that the disintegrating agent is sodium starch glycolate, or carboxymethylcellulose sodium or a mixture thereof. 10. Solid pharmaceutical preparation according to Claim 9, characterized in that the disintegrating agent present is carboxymethylcellulose sodium. 11. Solid pharmaceutical preparation according to one or more of Claims 1 to 10, characterised in that it comprises 1 to 10% by weight of gelatine, 0.1 to 3% by weight citric acid, 50 to 80% by weight of mannitol or lactose, 10 to 30% by weight maize starch. 12. Solid pharmaceutical preparation according to Claim 11, characterised in that it comprises 0,05 to 0,5% by weight butylated hydroxytoluene. 13. Process for the production of a solid pharmaceutical preparation according to one or more of Claims 7 to 12, characterized in that (a) levothyroxine sodium and optionally liothyronine sodium is/are suspended in an aqueous gelatine solution, (b) the suspension obtained by step (a) is sprayed onto the filler in a fluidized bed granulation and dried to form granules, (c) the granules obtained by step (b) is collected and optionally, (d) a disintegrant and optionally a lubricant is/are mixed with the granules obtained by step (c), and (e) the mixture obtained by step (d) is compressed to give tablets. 14. Process for the production of a solid pharmaceutical preparation according to Claim 13, characterized in that citric acid and, if present, the antioxidant is dissolved in the aqueous gelatine solution used in step (a) or is admixed with the granules in step (d). 15. Process for the preparation of a solid pharmaceutical preparation according to Claims 13 and/or 14, characterised in that the granules or the tablets are provided with a coating.
Patentansprüche 1. Feste pharmazeutische Zubereitung enthaltend Levothyroxin-Natrium, Gelatine, Zitronensäure und ein Füllmittel. 2. Feste pharmazeutische Zubereitung nach Anspruch 1, dadurch gekennzeichnet, dass sie Liothyronin-Natrium enthält. 3. Feste pharmazeutische Zubereitung nach Anspruch 1 und/oder2, dadurch gekennzeichnet, dass es sich bei dem Füllmittel um einen Zuckeralkohol wie Sorbitol oder Mannitol Dulcitol, Xylitol oder Ribitol, bevorzugt Sorbitol oder Mannitol, besonders bevorzugt Mannitol, einen Zucker wie Glucose, Fructose, Mannose, Lactose, Saccharose oder Maltose, bevorzugt Lactose, Saccharose oder Maltose, besonders bevorzugt Lactose, eine Stärke wie Kartoffelstärke, Reisstärke, Maisstärke oder Quellstärke, bevorzugt Maisstärke oder Quellstärke, besonders bevorzugt Maisstärke, eine Cellulose wie pulverisierte Cellulose oder mikrokristalline Cellulose, bevorzugt mikrokristalline Cellulose, oder ein Gemisch davon handelt. 4. Feste pharmazeutische Zubereitung nach Anspruch 3, dadurch gekennzeichnet, dass es sich bei dem Füllmittel um Mannitol und/ oder Maisstärke handelt. 5. Feste pharmazeutische Zubereitung nach einem oder mehreren der Ansprüche 1 bis 4, dadurch gekennzeichnet, dass sie weiterhin ein Antioxidans enthält, das aus der Gruppe bestehend aus Tocopherol, Propylgallat, tertiärem Butylhydrochinon butyliertem Hydroxyanisol und butyliertem Hydroxytoluol, bevorzugt Hydroxyanisol oder butylier-tem Hydroxytoluol, besonders bevorzugt butyliertem Hydroxytoluol, ausgewählt ist. 6. Feste pharmazeutische Zubereitung nach einem oder mehreren der Ansprüche 1 bis 5, dadurch gekennzeichnet, dass sie in Granulat-, Pellet-, Kapsel- oder Tablettenform vorliegt. 7. Feste pharmazeutische Zubereitung nach Anspruch 6, dadurch gekennzeichnet, dass es sich um eine Tablette handelt. 8. Feste pharmazeutische Zubereitung nach einem oder mehreren der Anspruch 1 bis 7, dadurch gekennzeichnet, dass mindestens ein Sprengmittel vorhanden ist. 9. Feste pharmazeutische Zubereitung nach Anspruch 8, dadurch gekennzeichnet, dass es sich bei dem Sprengmittel um Natrium-Stärkeglykolat oder Carboxymethylcellulose-Natrium oderein Gemisch davon handelt. 10. Feste pharmazeutische Zubereitung nach Anspruch 9, dadurch gekennzeichnet, dass es sich bei dem vorhandenen Sprengmittel um Carboxymethylcellulose-Natrium handelt. 11. Feste pharmazeutische Zubereitung nach einem oder mehreren der Ansprüche 1 bis 10, dadurch gekennzeichnet, dass sie 1 bis 10 Gew.-% Gelatine, 0,1 bis 3 Gew.-% Zitronensäure, 50 bis 80 Gew.-% Mannitol oder Lactose, 10 bis 30 Gew.-% Maisstärke enthält. 12. Feste pharmazeutische Zubereitung nach Anspruch 11, dadurch gekennzeichnet, dass sie 0,05 bis 0,5 Gew.-% butyliertes Hydroxytoluol enthält. 13. Verfahren zur Herstellung einer festen pharmazeutischen Zubereitung nach einem oder mehreren der Ansprüche 7 bis 12, dadurch gekennzeichnet, dass man (a) Levothyroxin-Natrium und gegebenenfalls Liothyronin-Natrium in einer wässrigen Gelatinelösung suspendiert, (b) die aus Schritt (a) erhaltene Suspension in einer Fließbettgranulierung auf das Streckmittel aufsprüht und zu Granulat trocknet, (c) das aus Schritt (b) erhaltene Granulat gewinnt und gegebenenfalls (d) ein Sprengmittel und gegebenenfalls ein Gleitmittel mit dem aus Schritt (c) erhaltenen Granulat mischt, und (e) das aus Schritt (d) erhaltene Gemisch zu Tabletten verpresst. 14. Verfahren zur Herstellung einer festen pharmazeutischen Zubereitung nach Anspruch 13, dadurch gekennzeichnet, dass Zitronensäure und, wenn vorhanden, das Antioxidans in der in Schritt (a) verwendeten wässrigen Gelatinelösung gelöst oder mit dem Granulat in Schritt (d) vermischt wird. 15. Verfahren zur Herstellung einer festen pharmazeutischen Zubereitung nach den Ansprüchen 13 und/oder 14, dadurch gekennzeichnet, dass das Granulat oder die Tabletten mit einem Überzug versehen werden.
Revendications 1. Préparation pharmaceutique solide comprenant de la lévothyroxine sodique, de la gélatine, de l’acide citrique et une charge. 2. Préparation pharmaceutique solide selon la revendication 1, caractérisée en ce qu’elle comprend de la liothyronine sodique. 3. Préparation pharmaceutique solide selon la revendication 1 et/ou 2, caractérisée en ce que la charge est un alcool de sucre tel que le sorbitol ou le mannitol, le dulcitol, le xylitol ou le ribitol, préférablement le sorbitol ou le mannitol, particulièrement préférablement le mannitol, un sucre tel que le glucose, le fructose, le mannose, le lactose, le saccharose ou le maltose, préférablement le lactose, le saccharose ou le maltose, particulièrement préférablement le lactose, un amidon tel que l’amidon de pomme de terre, l’amidon de riz, l’amidon de maïs ou un amidon prégé-latinisé, préférablement l’amidon de maïs ou un amidon prégélatinisé, particulièrement préférablement l’amidon de maïs, une cellulose telle qu’une cellulose en poudre ou une cellulose microcristalline, préférablement une cellulose microcristalline, ou un mélange de ceux-ci. 4. Préparation pharmaceutique solide selon la revendication 3, caractérisée en ce que la charge est le mannitol et/ou l’amidon de maïs. 5. Préparation pharmaceutique solide selon l’une ou plusieurs parmi les revendications 1 à 4, caractérisée en ce qu’elle comprend en outre un antioxydant choisi dans le groupe constitué par le tocophérol, le gallate de propyle, la tertio-butylhydroquinone, l’hydroxyanisole butylé et l’hydroxytoluène butylé, préférablement l’hydroxyanisole ou l’hydroxy-toluène butylé, particulièrement préférablement l’hydroxytoluène butylé,. 6. Préparation pharmaceutique solide selon l’une ou plusieurs parmi les revendications 1 à 5, caractérisée en ce qu’elle se trouve sous forme de granulé, de pastille, de capsule ou de comprimé. 7. Préparation pharmaceutique solide selon la revendication 6, caractérisée en ce qu’il s’agit d’un comprimé. 8. Préparation pharmaceutique solide selon l’une ou plusieurs parmi les revendications 1 à 7, caractérisée en ce qu’au moins un agent délitant est présent. 9. Préparation pharmaceutique solide selon la revendication 8, caractérisée en ce que l’agent délitant est le glycolate d’amidon sodique, ou la carboxyméthylcellulose de sodium, ou un mélange de ceux-ci. 10. Préparation pharmaceutique solide selon la revendication 9, caractérisée en ce que l’agent délitant présent est la carboxyméthylcellulose de sodium. 11. Préparation pharmaceutique solide selon l’une ou plusieurs parmi les revendications 1 à 10, caractérisée en ce qu’elle comprend de 1à 10% en poids de gélatine, de 0,1 à 3% en poids d’acide citrique, de 50 à 80% en poids de mannitol ou de lactose, de 10 à 30% en poids d’amidon de maïs. 12. Préparation pharmaceutique solide selon la revendication 11, caractérisée en ce qu’elle comprend de 0,05 à 0,5% en poids d’hydroxy-toluène butylé. 13. Procédé de production d’une préparation pharmaceutique solide selon l’une ou plusieurs parmi les revendications 7 à 12, caractérisé en ce que (a) de la lévothyroxine sodique et éventuellement de la liothyronine sodique est/sont mise(s) en suspension dans une solution de gélatine aqueuse, (b) la suspension obtenue dans l’étape (a) est pulvérisée sur la charge par granulation en lit fluidisé pour et séchée afin de former des granulés, (c) les granulés obtenus dans l’étape (b) sont récupérés et éventuellement, (d) un agent délitant et éventuellement un lubrifiant est/sont mélangé(s) avec les granulés obtenus dans l’étape (c), et (e) le mélange obtenu dans l’étape (d) est mis sous forme de comprimés. 14. Procédé de production d’une préparation pharmaceutique solide selon la revendication 13, caractérisé en ce que l’acide citrique et, s’il est présent, l’antioxydant, est/sont dissous dans la solution de gélatine aqueuse utilisée dans l’étape (a) ou est/sont mélangé(s) avec les granulés dans l’étape (d). 15. Procédé de préparation d’une préparation pharmaceutique solide selon les revendications 13 et/ou 14, caractérisé en ce que les granulés ou les comprimés sont pourvus d’un revêtement.
REFERENCES CITED IN THE DESCRIPTION
This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.
Patent documents cited in the description • DE 19541128 [0003] · US 6649186 B1 [0011] • WO 2004096177 A1 [0004] · US 5753254 A [0012] • WO 9959551 A1 [0006]
Non-patent literature cited in the description • PATEL H. et al. The effect of excipients on stability of levothyroxine sodium pentahydrate tablets. Int J Pharm, 2003, vol. 264, 35-43 [0005]
Claims (6)
- Szabadalmi igénypoatok1, Szilárd.-gyögyszerészéél készgioéfíy, sipoly tartzltnsz ievötifoxln-tiátrltnoöt, zselatint, eitrönrssvat és töltőany'agob
- 2, Áz 1, igénypont Szerhsti szilárd gybgyszSíészei! készítmény, ozzsl jélloíttezve. begy WtalntM Ütá »·οοη··-ηόΐΑ»ϊί!«ΐ.
- 3, Az I. étvágy 2. Igénypontok szerinti szilárd gyógyszerészed Részvény, azzal jellemezve, hogy & söitöiiíivísg egy eukot&ikohöl, mint szerbit vagy mannií, dulctí, xilit vagy cibh, előnyösen szerbit vagy tmmnit, különösen előnyösen snanott, egy ««kor, mint glükóz, fruktöz, mán máz, l&któz, szacharóz vagy maltóz, okvoo-e * }?k\" wtríiAiv’ t igv utaitoz kik'U'Yjan , .öp.b^b skno '.s?· kenen\go ntnt p,agvn> jkutum-ttn rizskeményltő, kukoritakereéoyltft vagy eiőzselatinezett keményítő, előnyösen kokorleakensényítő vagy elözsel&tinozoít kernéoyiiö, különösé elbtsyöséo ktjkóÍ'ifcáksinénybö, egy pelíölóz. mini porttoft oelhtlőz vagy nnk^kristats os vetlnloz előnyösen «siMoküsadvx evlmlóz, \y,\ ezek Keverek? 4, A 3. ige bypönt szer isik szilárd gyógy szorászoii kászktoény, azzal jellemezve, hogy a. töltőanyag, manna ,", r,-.e\ Koko-naKemmsttó
- 5, Az Mi igénypontokteöl egy vagy több szerinti szilárd gyógyszerészet; készítmény,, azzal jölíéntozvo, hogy lattáknoz továbbá egy oxidápst a. kővetkezőkből álló esopőrthéi választva; toköfemi, pengik galiát, tercier bnulibtbá>ktoon; hnidezsii hldmíanizot és bntitezett kidPóxítohiöi, előnyösen hidzoxionízol vagy 'bölifozett hidroxllöiböl, különösé» előnyösen beikezeit bldrpxítnlböl,
- 6, Az 1 -5. igénypnntnk közití egy vagy több szerinti szilárd gyógyszsrésZóti készitPiény, azzal jehentezve, hogy gramilálam, paliét, kapszula vagy tabletta íbrtnájü. '?'. Λ ö. igénypont szerinti szilárd gyógyszerészeti készítmény, azzal, jellemezve, hogy tabletta, á i ίθθ!" οοο'ο\ \oz lown s'bi s,i·) » s tt.»' i'--. j-xeszttménv·. azzas jellemezve». hogy legalább egy dezintegráló szer van jelen. 4 \S η1 '0' p, »u vő ! s'dxt t «Sí\gs,i'fos t,i \ts,«tr rf' t /«l<dkne u :«ev a aezmtezfaio szar nátrinm-keménylté-gbkoiat vagy kartxíximetil'Celluléz-náttiom vagy ezek keveréke. lő λ u szent pora szenei! szered gs éys s/eraveh ke^mnem azzal redetnezte, hogy a kienböo dezintográlő .szer a karboxitnösikéeibalözntáö'iittó. :! Az i-1 ő sgrnspontok kozni egy rags tpob szedőn t/d.ud gyógyszerei zen ku'zmnms,azzal jellemezve·, hogy tártalínaz Mö töőiégH zselatnu. 0,1 -A t;ömeg% eitremsavaí,.50-80 tömegM mamutét vagy laktözt, 10-30 íbirsegbiktikprlnaKetöénylW,
- 12. All. Igénypont szórlníi szilául gyógyszérészeti készítmény, azzal jelienrezvs, hogy íarsaintaz hős n v te wa’s bu de et ,tm " t «1, >> t > pi a ’ ' \s\ \m >t, ’,e niav\) ' \M<b > o tn » > t o ,so io, u kss, tmui' előállítására.: azzal jelleméivé, hogy t a) levottrosio-nátnamoí és adott esetben hötironút-náirimnot szuszpsndálonk egy viz.es zselatin oldatba, Ao .sz <.d kgusbon kapóit sztiszpetiziót a töltőanyagra pernudezzük egy tinid ágyas grannlálás során. <-í. sz,ainak szemesek tonkd-nasára, (c) a (b) iépéslien kapott szemcséké} összegyűjtjük, és adott esetben !vö dectnsesyaíö s.w p·. aJott esubin teovamax^ V\?un>\ a npépben k«pet« s-ven „ fej a fd) lépésben, kapott keveréket tablettákká préseljük. * S {' i ·. -p , X t ;j < S ΐ\\ í ! > .>·>ί>..>Λ >', V ü! ·. nos Jo SÓ üt t Jv !'? ·. hogy citromsavat, és ha jelen van, antioxutóast okhmR az. (a) lépés szerinti vizes zselatin oldatban vagy a (dl tépésben kapoi.í szeíocsékké! követünk össze, Π, A-13¾ ész vagy 14. igénypont szerinti ebátás .Szilárd gyógySZéiéSéétí kéözittttóny elöálHiására, azzal, jellemezve, hogy a szemcséket vagy tablettákat fedőréteggel látjuk el.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP12005960 | 2012-08-20 |
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| Publication Number | Publication Date |
|---|---|
| HUE035222T2 true HUE035222T2 (hu) | 2018-05-02 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HUE13747642A HUE035222T2 (hu) | 2012-08-20 | 2013-08-01 | Levotiroxint tartalmazó szilárd gyógyszerészeti készítmények |
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| Country | Link |
|---|---|
| US (2) | US20150231101A1 (hu) |
| EP (1) | EP2885005B1 (hu) |
| JP (1) | JP6195424B2 (hu) |
| KR (1) | KR102184254B1 (hu) |
| CN (1) | CN104582731B (hu) |
| AR (1) | AR092151A1 (hu) |
| AU (1) | AU2013304795B2 (hu) |
| BR (1) | BR112015003116B1 (hu) |
| CA (1) | CA2882372A1 (hu) |
| CL (1) | CL2015000390A1 (hu) |
| CO (1) | CO7200278A2 (hu) |
| DK (1) | DK2885005T3 (hu) |
| EA (1) | EA027189B1 (hu) |
| EC (1) | ECSP15010550A (hu) |
| ES (1) | ES2654306T3 (hu) |
| HK (1) | HK1204961A1 (hu) |
| HR (1) | HRP20171784T1 (hu) |
| HU (1) | HUE035222T2 (hu) |
| IL (1) | IL237322A0 (hu) |
| LT (1) | LT2885005T (hu) |
| MX (1) | MX353618B (hu) |
| MY (1) | MY184400A (hu) |
| NO (1) | NO2885005T3 (hu) |
| NZ (1) | NZ703038A (hu) |
| PE (1) | PE20150597A1 (hu) |
| PH (1) | PH12014502856A1 (hu) |
| PL (1) | PL2885005T3 (hu) |
| PT (1) | PT2885005T (hu) |
| RS (1) | RS56745B1 (hu) |
| SG (1) | SG11201501122WA (hu) |
| SI (1) | SI2885005T1 (hu) |
| TW (1) | TWI603730B (hu) |
| UA (1) | UA115247C2 (hu) |
| WO (1) | WO2014029464A1 (hu) |
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| CN106267220B (zh) * | 2015-05-14 | 2019-06-28 | 北京科信必成医药科技发展有限公司 | 愈创甘油醚氢溴酸右美沙芬无水吞服掩味制剂 |
| EP3576795B1 (de) * | 2017-02-03 | 2021-04-07 | Berlin-Chemie AG | Orales schilddrüsentherapeutikum |
| IT201800003615A1 (it) * | 2018-03-15 | 2019-09-15 | Altergon Sa | Formulazioni altamente stabili di ormone tiroideo in capsule molli |
| BR112021001008A2 (pt) * | 2018-07-30 | 2021-04-20 | Daiichi Sankyo Company, Limited | comprimido de fármaco |
| CN109364043A (zh) * | 2018-12-10 | 2019-02-22 | 唐熠达 | 一种治疗甲状腺功能异常的缓控释药物组合物 |
| CN110075305A (zh) * | 2019-05-22 | 2019-08-02 | 上海葆隆生物科技有限公司 | 一种含有左甲状腺素钠的药物组合物 |
| CN115737576B (zh) * | 2022-11-14 | 2024-05-07 | 山东创新药物研发有限公司 | 一种左甲状腺素钠片剂及其制备方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| GB9401892D0 (en) * | 1994-02-01 | 1994-03-30 | Boots Co Plc | Therapeutic agents |
| GB9401879D0 (en) * | 1994-02-01 | 1994-03-30 | Boots Co Plc | Therapeutic agents |
| DE19541128C2 (de) | 1995-10-27 | 1997-11-27 | Henning Berlin Gmbh & Co | Stabilisierte schilddrüsenhormonhaltige Arzneimittel |
| US6017958A (en) * | 1996-06-04 | 2000-01-25 | Octamer, Inc. | Method of treating malignant tumors with thyroxine analogues having no significant hormonal activity |
| US6649186B1 (en) | 1996-09-20 | 2003-11-18 | Ethypharm | Effervescent granules and methods for their preparation |
| KR100569319B1 (ko) * | 1997-10-30 | 2006-04-07 | 모리시타 진탄 가부시키가이샤 | 불포화 지방산 또는 이들의 유도체를 내용물로 하는 캡슐제제 및 그의 제조방법 |
| DE19821625C1 (de) * | 1998-05-15 | 2000-01-05 | Merck Patent Gmbh | Pharmazeutische Zubereitung |
| US20030099699A1 (en) * | 2001-11-13 | 2003-05-29 | Hanshew Dwight D. | Storage stable thyroxine active drug formulations and methods for their production |
| ATE465718T1 (de) * | 2003-05-02 | 2010-05-15 | Globopharm Pharmazeutische Pro | Feste pharmazeutische zubereitung enthaltend levothyroxin- und/oder liothyroninsalze |
| US8293272B2 (en) | 2003-05-02 | 2012-10-23 | Globopharm Pharmazeutische Produktions-Und Handelsgesellschaft M.B.H. | Solid pharmaceutical preparation containing levothyroxine and/or liothyronine salts |
| IT1395454B1 (it) | 2009-03-24 | 2012-09-21 | Altergon Sa | Composizioni e forme farmaceutiche per somministrazione orale di ormoni tiroidei in grado di contrastare l'azione di agenti sequestranti nel tratto gastrointestinale |
| US20110206775A1 (en) * | 2010-01-27 | 2011-08-25 | Groenewoud Pieter J | Preparation of inert pharmaceutical excipients for stabilizing unstable pharmaceutical ingredients |
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