WO2014098887A1 - Formulation de lévothyroxine avec de la gomme arabique - Google Patents

Formulation de lévothyroxine avec de la gomme arabique Download PDF

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Publication number
WO2014098887A1
WO2014098887A1 PCT/US2012/071184 US2012071184W WO2014098887A1 WO 2014098887 A1 WO2014098887 A1 WO 2014098887A1 US 2012071184 W US2012071184 W US 2012071184W WO 2014098887 A1 WO2014098887 A1 WO 2014098887A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
acacia
thyroxine
propyl gallate
mannitol
Prior art date
Application number
PCT/US2012/071184
Other languages
English (en)
Inventor
Baris E. POLAT
John Kirsch
Ramakrishna NALLAMOTHU
Original Assignee
Mylan Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mylan Inc. filed Critical Mylan Inc.
Priority to EP12814094.4A priority Critical patent/EP2941272A1/fr
Priority to PCT/US2012/071184 priority patent/WO2014098887A1/fr
Publication of WO2014098887A1 publication Critical patent/WO2014098887A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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

Definitions

  • Thyroxine active drugs are known for both therapeutic and prophylactic treatment of thyroid disorders.
  • levothyroxine sodium is prescribed for thyroid hormone replacement therapy in cases of reduced or absent thyroid function in, for example, ailments such as myxedema, cretinism and obesity.
  • Levothyroxine sodium is quite unstable, hygroscopic, and degrades rapidly when subjected to high humidity, light, or high temperature. See, for example, Won, Pharm. Res, 9(1):131-137, 1992.
  • U.S. Pat. No. 5,225,204 issued July 6, 1993, to Chen, et al, discloses a complex of levothyroxine sodium and a cellulose, polyvinylpyrrolidone or Poloxamer.
  • the formulation may be prepared by dissolving the drug complex in a polar organic solvent, adding a cellulose carrier to the liquid, and drying the resulting mixture to obtain a complex of levothyroxine sodium and polyvinylpyrrolidone or Poloxamer adsorbed on the cellulose carrier.
  • a pharmaceutical composition comprising thyroxine, acacia, and an antioxidant selected from propyl gallate, butylated hydroxyanisol, and butylated hydroxytoluene is disclosed.
  • the pharmaceutical composition has an improved shelf life.
  • the composition additionally comprises sucrose, microcrystalline cellulose, and mannitol.
  • the pharmaceutical composition may be used for treating thyroid disorders by orally administering the composition to a patient in need thereof.
  • a pharmaceutical composition comprising thyroxine, acacia, and an antioxidant selected from propyl gallate, butylated hydroxyanisol, and butylated hydroxytoluene is disclosed.
  • the pharmaceutical composition has an improved shelf life. Because the shelf life of thyroxine is improved, the dosage of thyroxine is maintained at a predictable level for a longer period of time.
  • the composition additionally comprises sucrose, microcrystalline cellulose, and mannitol.
  • thyroxine is understood to encompass levothyroxine (L-thyroxine),
  • levothyroxine sodium and other thyroid hormone medications of the general formula:
  • Ri and R 3 may be the same or different and are selected from hydrogen; halogen; alkyl; aryl; cycloalkyl; heterocycloalkyl; amide; alcohol; acid; ester; ether; acyl; alkenyl; and alkynyl; wherein R 2
  • R4 and R 5 may be the same or different and are selected from hydrogen; halogen; alkyl; aryl; cycloalkyl; heterocycloalkyl; amide; alcohol; acid; ester; ether; acyl; alkenyl; and alkynyl.
  • the thyroxine can be in the form of a free acid, a free base, an organic salt, an inorganic salt, or a hydrate.
  • Liothyronine is an example of a drug encompassed by the above-mentioned general formula.
  • Formulations of thyroxine with greatly increased resistance to degradation can be produced by providing excipients which reduce or eliminate degradation of the active substance.
  • excipients which reduce or eliminate degradation of the active substance.
  • the prior art indicates that reactions between levothyroxine sodium and certain carbohydrate, monosaccharide, or disaccharide excipients is responsible for the poor stability of the drug, the described formulation achieves surprisingly stable thyroxine dosage forms even when these previously disfavored excipients are included. Additionally, in some embodiments, formulations are maintained at a pH of less than about 10.
  • Stabilized pharmaceutical compositions may be produced by blending thyroxine with acacia and an antioxidant selected from propyl gallate, butylated hydroxyanisol, and butylated hydroxytoluene to form a granulation intermediate. Addition of any additional pharmaceutical excipients, diluents, or granulation aids is optional. Generally, further pharmaceutical excipients may optionally be added to produce final dosage forms such as tablets or capsules.
  • Acacia is a natural gum also known as gum arabic or gum acacia. It is a mixture of glycoproteins and polysaccharides, and acts as a binder.
  • the acacia is able to be dissolved in water relatively fast, such as an instant soluble or spray dried grade.
  • the pharmaceutical composition comprises from about 0.1% to about 10% acacia, from about 0.25% to about 2.5%, from about 0.4% to about 2.0%, or from about 1.0% to about 2.0%.
  • the pharmaceutical composition comprises an antioxidant selected from propyl gallate, butylated hydroxyanisol, and butylated hydroxytoluene.
  • Antioxidants are compounds which decrease the potential for oxidation, including for example, the oxidation of thyroxine.
  • the pharmaceutical composition may comprise additional antioxidants known to a person of ordinary skill in the art.
  • Propyl gallate is propyl 3,4,5- trihydroxybenzoate.
  • the pharmaceutical composition comprises from about 0.001%) to about 1% propyl gallate, for example, from about 0.005% to about 0.5%, or from about 0.01% to about 0.1%.
  • the pharmaceutical composition comprises from about 0.001% to about 1% butylated hydroxyanisol, for example, from about 0.005%) to about 0.5%>, or from about 0.01%) to about 0.1%. In one embodiment, the pharmaceutical composition comprises from about 0.001% to about 1% butylated hydroxytoluene, for example, from about 0.005%) to about 0.5%, or from about 0.01%) to about 0.1 %>. In one embodiment, the pharmaceutical composition comprises a combination of propyl gallate and butylated hydroxyanisol, or propyl gallate and butylated hydroxytoluene.
  • the active ingredient in the composition is levothyroxine sodium.
  • the pharmaceutical comprises a therapeutically effective amount.
  • the dose will be adjusted to the individual requirements in each particular case. That dosage can vary within wide limits depending upon numerous factors such as the severity of the disease to be treated, the age and general health condition of the patient, other medicaments with which the patient is being treated, any side effects, and the preferences and experience of the medical practitioner involved.
  • a therapeutically effective dosage amount for thyroxine generally ranges from about 0.1 ⁇ g to about 5000 ⁇ g, such as from about 25 ⁇ g to about 300 ⁇ g.
  • Exemplary dosages therefore include, but are not limited to 20 ⁇ g, 25 ⁇ g, 50 ⁇ g, 75 ⁇ g, 88 ⁇ g, 100 ⁇ g, 112 ⁇ g, 125 ⁇ g, 137 ⁇ g, 150 ⁇ g, 175 ⁇ g, 200 ⁇ g, and 300 ⁇ g.
  • the solid dosage forms contain the following compounds: levothyroxine sodium (active drug substance); mannitol; microcrystalline cellulose (diluent); sucrose; a disintegrant (such as crospovidone or croscarmellose sodium); propyl gallate; magnesium stearate (lubricant); and colloidal silicon dioxide (glidant).
  • the solid dosage forms contain the following compounds: levothyroxine sodium (active drug substance); mannitol;
  • the solid dosage forms contain the following compounds: levothyroxine sodium (active drug substance);
  • mannitol mannitol
  • microcrystalline cellulose disintegrant
  • sucrose a disintegrant
  • the solid dosage forms contain the following compounds: levothyroxine sodium (active drug substance); mannitol; microcrystalline cellulose (diluent); sucrose; a disintegrant (such as crospovidone or croscarmellose sodium); butylated hydroxytoluene; magnesium stearate (lubricant); and colloidal silicon dioxide (glidant).
  • the composition comprises about 0.1 ⁇ g to about 5000 ⁇ g thyroxine, such as about 1 ⁇ g to about 1000 ⁇ g, about 25 ⁇ g to about 300 ⁇ g.
  • alditols comprise from about 5% to about 90% (by weight) of the final composition, such as about 15% to about 80%, or about 20% to about 70%.
  • the alditol is mannitol.
  • filler such as carbohydrates (starch or cellulose polymer) and microcrystalline cellulose, comprises about 5% to about 90%, such as about 15% to about 80%, or about 25% to about 70%, by weight of the final formulations.
  • the final dosage forms comprises about 5% to about 70%, such as about 10% to about 60%, about 15% to about 50%, or about 15% to about 40% saccharide, by weight.
  • the saccharide is sucrose.
  • Further optional ingredients in the final dosage form may include a disintegrant, which if present, generally forms about 2% to about 30%, such as about 2% to about 15%, or about 3% to about 10% of the final formulation by weight.
  • lubricants are present in the final composition formulation at about 0.1% to about 5%, such as about 0.2% to about 3%, or about 0.5% to about 2.5% by weight.
  • glidants are present in the final composition at about 0.05% to about 2%, such as about 0.075% to about 1%, or about 0.1% to about 0.5% by weight.
  • surfactants are present in the final composition at about 0.005% to about 1%, such as about 0.01% to about 0.5%, or about 0.01% to about 0.2% by weight.
  • binders are present in the final composition at about 0.1% to about 10%, such as about 0.5% to about 5%, or about 1% to about 3% by weight.
  • Alditols which may be used in pharmaceutical compositions are well known in the art. Such alditols include, but are not limited to, one or more of the following:
  • saccharides for use in pharmaceutical compositions are well known in the art. Such saccharides include, but are not limited to, one or more monosaccharides, disaccharides, and oligosaccharides composed of 2-10 monosaccharides. Monosaccharides, also known as reducing sugars, include, but are not limited to, aldoses, hemiacetals, and cyclic hemiacetals. Disaccharides are generally defined as two monosaccharide units joined together by a glycoside linkage.
  • Oligosaccharides are generally defined as carbohydrates that hydro lyze to yield 2 to 10 molecules of a monosaccharide.
  • Monosaccharides, disaccharides, and oligosaccharides include, but are not limited to, sucrose, maltose, cellobiose, lactose, trehalose, glucose, fructose, galactose, ribose, or deoxyribose.
  • the saccharide is a monosaccharide or a disaccharide.
  • the saccharide is a disaccharide.
  • the saccharide is sucrose.
  • Exemplary surfactants and surface active agents may be selected from known pharmaceutical excipients such as, for example, gelatin, casein, lecithin, stearic acid or other fatty acids, benzalkonium chloride, calcium stearate, glyceryl monostearate or other fatty acid salts, polyethylene glycols, silicon dioxide, methylcelluloses or
  • carboxymethylcelluloses sodium stearyl fumarate, magnesium stearate, alginate, or any other surface modifying compounds known in the art.
  • Compounds which function as wetting agents such as, for example, pharmaceutically acceptable detergents and cetyl alcohols also are contemplated for use.
  • Examples of lubricants include, but are not limited to, talc, calcium stearate, sodium stearyl fumarate, stearic acid, magnesium stearate, solid polyethylene glycols, and cocoa butter.
  • Examples of binders, fillers, or extenders include, but are not limited to, carrageenan, starches, lactose or other sugars, polyvinylpyrrolidone, sodium citrate, dicalcium phosphate and other alkaline inorganic salts, carboxylmethylcellulose and other cellulose polymers, alginates, gelatins, microcrystalline cellulose, sorbitol, sodium chloride, chitosan, hydrogenated vegetable oil, kaolin, glycerol palmitostearate, magnesium carbonate, and calcium carbonate.
  • compositions may be made according to the following general steps. Those of skill in the art are aware of equivalent methods and variations which produce the same general result. Therefore, the general instructions and the example, which follows, should not be considered to be strictly limiting.
  • a portion or all of the acacia is dissolved in water.
  • Propyl gallate, butylated hydroxyanisol, butylated hydroxytoluene, or any combination thereof is dissolved in alcohol.
  • An alditol such as mannitol, a saccharide such as sucrose, and a granulation aid such as microcrystalline cellulose are screened or passed through a mill. The dry mixture is then blended with the thyroxine ingredient, for example, levothyroxine sodium.
  • the mixture is then granulated by adding the propyl gallate, butylated hydroxyanisol, or butylated hydroxytoluene, and acacia solutions.
  • the granulated mixture is dried, cooled, then passed through a mill.
  • the acacia and thyroxine are blended together as dry ingredients.
  • excipients such as microcrystalline cellulose or dicalcium phosphate may also be incorporated into the granulation, but need not be added until the active ingredient is intimately mixed with the alditol and/or the sucrose.
  • microcrystalline cellulose or other diluent functions as a granulation aid and compression enhancer (for tablet or capsule formulations) and not as a specific carrier for the thyroxine active drug.
  • the wet granulation is dried, milled, and optionally further blended.
  • the granulation intermediate then may be stored or directly mixed with further ingredients such as excipients to form a composition suitable for compression into tablets, filling into capsules, or dissolved or suspended to form a liquid dosage form.
  • compositions may be prepared for administration orally, rectally, vaginally, transmucosally, transdermally, parenterally, subcutaneously, and
  • excipients which are suitable for use in compositions for these methods of administration are known to those of skill in the art.
  • excipients contemplated for use in these compositions may include, but are not limited to, adjuvants, preservatives, buffers, fillers, extenders, carriers, binders, diluents, glidants, lubricants, surfactants, wetting agents, surface active agents, suspending agents, and solvents.
  • Compounds such as dyes and colorants, sweeteners, flavorings, perfuming agents, and taste-masking ingredients also may be included in compositions.
  • Any pharmaceutically acceptable excipient, such as ingredients to aid in processing, to improve taste, or to improve appearance are contemplated for use in this composition.
  • other active ingredients may be included to produce a dual or multiple active ingredient composition.
  • solid dosage forms examples include, but are not limited to, tablets, capsules, rectal or vaginal suppositories, pills, dragees, lozenges, granules, beads, microspheres, pellets, powders, or any combination thereof.
  • Formulations also may be prepared in the form of solutions, suspensions, emulsions, syrups, and elixirs. These liquid dosage forms may include liquid diluents in addition to the solid ingredients discussed above.
  • Such diluents may include, but are not limited to, solvents, solubilizing agents, suspending agents and emulsifiers, water or saline solutions, ethanol and other pharmaceutically acceptable alcohols, ethyl carbonate, ethyl acetate, propylene glycol, dimethyl formamide, pharmaceutically acceptable oils such as cottonseed, corn, olive, castor, and sesame, fatty acid esters of sorbitan, polyoxyethylene sorbitol, and agar-agar.
  • Formulations can be either immediate or modified release.
  • the composition may be used for any convenient dosage amount of the active ingredient. Generally, the level of the active ingredient may be increased or decreased according to the judgment of the physician, pharmacist, pharmaceutical scientist, or other person of skill in the art. The amount of the remaining non-active ingredients can be adjusted as needed. [0027] After the solid ingredients of the composition are blended, the composition may be compressed into tablets. Alternatively, the composition may be used to fill capsules such as hard gelatin capsules or used to prepare any other convenient solid dosage form.
  • compositions may be stored in the form of powders, granulates, intermediates, suspensions, or solutions prior to addition of additional desired pharmaceutical excipients for the production of final dosage forms such as tablets or solid-filled capsules, or final liquid dosage forms such as solutions, syrups, suspensions, emulsions and the like.
  • the pharmaceutical composition comprising thyroxine, acacia, and an antioxidant selected from propyl gallate, butylated hydroxyanisol, butylated hydroxytoluene, or combinations thereof has improved stability. Under accelerated testing conditions of 40°C at 75% relative humidity, the compositions retained about 95% to about 105% Theoretical Drug Content (TDC) after 6 months. In one embodiment, under accelerated testing conditions, the decrease in potency after 6 months is less than 5% such as less than 4%), less than 3%, or less than 2.5%. In another embodiment, the composition retained about 99% TDC after 6 months.
  • the stability of the pharmaceutical composition may also be tested at room temperature (25°C) at 60% relative humidity. In one embodiment, under the room temperature testing conditions the composition retained 95% to 105% TDC after 2 years.
  • microcrystalline cellulose, mannitol, and sucrose were screened or milled and then blended with levothyroxine sodium for about 6 minutes.
  • the wet granulation was dried at a temperature below 60°C until the moisture content was less than about 4%.
  • the dried granulation was sized by passing it through a mill, and then blended with the additional ingredients listed in the table below using conventional mixing equipment.
  • Levothyroxine 100 ⁇ g tablets were prepared using the following ingredients:
  • Tablets were made according to Example 1 , except half the mass of the propyl gallate has been substituted with butylated hydroxyanisol.
  • Tablets were made according to Example 1 , except all the propyl gallate has been substituted with butylated hydroxyanisol.
  • Tablets made according to Examples 1 to 3 were stored at 40°C for 24 weeks at 75% relative humidity. The tablets were then analyzed for drug potency using an HPLC standard assay. The change in potency of the tablets of Example 1 was -2.1%.
  • Example 1 Evaluation of the potency of Example 1 shows that the new composition yields a product which demonstrates improved stability. Stability testing at 40°C and 75% relative humidity

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une composition pharmaceutique comprenant de la thyroxine, de la gomme arabique, et un antioxydant choisi parmi le gallate de propyle, l'hydroxyanisol butylé et de l'hydroxytoluène butylé. La composition pharmaceutique a une durée de conservation améliorée. Dans un mode de réalisation, la composition comprend en outre du saccharose, de la cellulose microcristalline et du mannitol. La composition pharmaceutique peut être utilisée pour traiter des troubles de la thyroïde par administration par voie orale de la composition à un patient nécessitant cela.
PCT/US2012/071184 2012-12-21 2012-12-21 Formulation de lévothyroxine avec de la gomme arabique WO2014098887A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP12814094.4A EP2941272A1 (fr) 2012-12-21 2012-12-21 Formulation de lévothyroxine avec de la gomme arabique
PCT/US2012/071184 WO2014098887A1 (fr) 2012-12-21 2012-12-21 Formulation de lévothyroxine avec de la gomme arabique

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Application Number Priority Date Filing Date Title
PCT/US2012/071184 WO2014098887A1 (fr) 2012-12-21 2012-12-21 Formulation de lévothyroxine avec de la gomme arabique

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005004849A2 (fr) * 2003-07-10 2005-01-20 Glaxo Group Limited Formulation pharmaceutique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005004849A2 (fr) * 2003-07-10 2005-01-20 Glaxo Group Limited Formulation pharmaceutique

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SHAH R B ET AL: "Stability indicating validated HPLC method for quantification of levothyroxine with eight degradation peaks in the presence of excipients", INTERNATIONAL JOURNAL OF PHARMACEUTICS, ELSEVIER BV, NL, vol. 360, no. 1-2, 6 August 2008 (2008-08-06), pages 77 - 82, XP022853129, ISSN: 0378-5173, [retrieved on 20080420], DOI: 10.1016/J.IJPHARM.2008.04.018 *

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