WO1995020954A1 - Comprimes contenant des hormones thyroidiennes - Google Patents

Comprimes contenant des hormones thyroidiennes Download PDF

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Publication number
WO1995020954A1
WO1995020954A1 PCT/EP1995/000322 EP9500322W WO9520954A1 WO 1995020954 A1 WO1995020954 A1 WO 1995020954A1 EP 9500322 W EP9500322 W EP 9500322W WO 9520954 A1 WO9520954 A1 WO 9520954A1
Authority
WO
WIPO (PCT)
Prior art keywords
mass
thyroid hormone
agent
dosage form
oral dosage
Prior art date
Application number
PCT/EP1995/000322
Other languages
English (en)
Inventor
Karrar Ahmad Khan
Alan Smith
Original Assignee
Knoll Ag
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 Knoll Ag filed Critical Knoll Ag
Priority to AU16630/95A priority Critical patent/AU1663095A/en
Publication of WO1995020954A1 publication Critical patent/WO1995020954A1/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
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals

Definitions

  • This invention relates to novel pharmaceutical compositions comprising at least one thyroid hormone, and to their use in the treatment of disorders associated with impairment of the thyroid hormone functions in animals including human beings.
  • compositions comprising solid fast dispersing dosage forms for oral administration have recently become available.
  • the dosage forms are prepared by freeze drying, a relatively slow process, which involves the use of expensive and complicated equipment.
  • fast dispersing dosage forms produced by freeze drying are very friable and extremely moisture sensitive, which makes them difficult to package.
  • When presented in a conventional blister pack they are not sufficiently hard to retain their integrity when a force is applied to break the package seal and eject them from the blister.
  • Such tablets are also unsuitable for conventional packing into bottles.
  • Known freeze dried fast dispersing dosage forms have the further disadvantage that they are difficult to prepare other than as large tablets.
  • Liquid oral dosage forms such as solutions, syrups and suspensions which comprise thyroid hormones are difficult to dose accurately due to small (microgra ) quantities of active ingredient.
  • Thyroid hormones are also known to be unstable in solucion and not very soluble in aqueous media. For these reasons a product comprising an oral liquid dosage form containing thyroid hormones is not currently available. It would be advantageous to provide an oral dosage formulation comprising thyroid hormone, which has good patient compliance and is suitable for general use by almost all patients.
  • a suckable, swallowable, chewable, solid, oral dosage form for a pharmaceutical composition as described herein which avoids all or some of the disadvantages of liquid oral dosage forms or known freeze dried fast dispersing dosage forms whilst retaining all or some of the advantages associated with oral dosage forms that disperse readily in the mouth.
  • These advantages include good patient compliance as such oral dosage forms are easy and pleasant to ingest.
  • Such oral dosage forms can be particularly useful for patients such as children or the elderly that have difficulty in swallowing, as no extra liquid (eg water) is required to take these oral dosage forms.
  • a readily soluble oral dosage form has the further advantage that the thyroid hormone active ingredient is presented to the gastro-intestinal tract in a finely divided particulate form which favours optimal and consistent absorption into the body.
  • the present invention provides a solid oral dosage form of a pharmaceutical composition suitable for oral administration comprising: a therapeutic agent which comprises at least one thyroid hormone; from about 60% to about 90% of an inert diluent which is a sugar or sugar alcohol; from about 5% to about 35% of disintegrating agent; and from about 0.1% to about 5% of a lubricating agent, all percentages being percentage mass of ingredient by total mass of the composition (known hereinafter as 'by mass') .
  • the present invention provides pharmaceutical compositions suitable for almost all patients, easy and pleasant to administer and giving the advantages of a readily dispersed oral dosage form without freeze drying. Freeze drying is a time consuming and expensive process.
  • compositions of the present invention are less friable than freeze-dried formulations and may be made into smaller dosage units than possible with freeze-dried formulations.
  • Compositions of the present invention have a suitably long shelf life, and disperse in the mouth, gradually with sucking and rapidly with chewing, in a fine particulate form with a pleasant taste and no gritty texture.
  • Thyroid hormones as described herein are useful in the treatment of disorders associated with improvement of the thyroid hormone function in animals including human beings for example, yxedema, cretinism or obesity.
  • Thyroid hormones can be prepared synthetically as the biologically active 1-enantiomer or can be isolated directly from the thyroid gland of animals.
  • Thyroid hormones comprise the following:
  • thyroid hormone should be understood to include all pharmaceutically acceptable salts thereof, preferably sodium salts.
  • Thyroid hormones may exist as one or more polymorphic forms (for example one or more crystalline forms, amorphous forms, phases, solid solutions and/or mixtures thereof) , and the therapeutic agent may include each pharmaceutically acceptable polymorphic form of thyroid hormone and/or mixtures thereof.
  • Thyroid hormones may also exist in the form of solvates (for example hydrates) and the therapeutic agent may include each solvate of thyroid hormones and/or mixtures thereof.
  • the therapeutic agent is present in an amount from about 0.1 ⁇ g to about 10,000 ⁇ g, more preferably from about 1 ⁇ g to about 1000 ⁇ g, most preferably if the therapeutic agent is LT ⁇ from about 25 ⁇ g to about 300 ⁇ g.
  • any of the ingredient of compositions of the present invention may be in the form of particles of very small size, for example as obtained by fluid energy milling.
  • the therapeutic agent may be bound (for example by sorption, incorporation and/or chemically) to nanoparticles which are collodial polymeric particles of a size typically less than 1 micron.
  • the distribution of such nanoparticles in the body and hence the sites of delivery of the therapeutic agent can be effected by coating the surface of the nanoparticles appropriately (for example with surfactants or antibodies) .
  • the therapeutic agent in - - the solid dosage form of the present invention may, if desired, be associated with other compatible, pharmacologically active ingredients.
  • the sugar or sugar alcohol comprises sucrose and/or mannitol.
  • the disintegrating agent comprises one or more of the following ingredients: pharmaceutically acceptable starch, such as maize starch, modified starch (eg pregelled starch and/or sodium starch glycolate) , methyl cellulose, agar, bentonite, alginic acid, guar gum, cellulose, microcrystalline cellulose, carboxymethylcellulose, methylcellulose, carmellose, croscarmellose sodium, silicon dioxide and sodium lauryl sulphate; more preferably one or more of maize starch and microcrystalline cellulose.
  • pharmaceutically acceptable starch such as maize starch, modified starch (eg pregelled starch and/or sodium starch glycolate)
  • methyl cellulose agar
  • bentonite alginic acid, guar gum, cellulose, microcrystalline cellulose, carboxymethylcellulose, methylcellulose, carmellose, croscarmellose sodium, silicon dioxide and sodium lauryl sulphate
  • more preferably one or more of maize starch and microcrystalline cellulose are examples of the following
  • the disintegrating agent is present in an amount from about 10% to about 30%, more preferably from about 15% to about 25% by mass of the composition.
  • the flavouring agent comprises one or more of the following: a sweetening agent which may be a nutritive or non- nutritive sweetener preferably sodium saccharin or aspartame; a peppermint oil or fruit flavour; a flavour enhancing agent; or an ingredient or ingredients which may induce the formation of saliva, preferably a pharmaceutically acceptable acid, more preferably an organic acid, most preferably an acid selected from citric and malic acid.
  • a sweetening agent is present in an amount from about 0.1% to about 5%, more preferably from about 1% to about 3%, by mass of the composition.
  • the lubricating agent is selected from one or more of the following ingredients: magnesium stearate, calcium stearate, stearic acid and mixtures thereof; more preferably magnesium stearate.
  • the lubricating agent is present in an amount from about 0.1% to about 1% by mass of the composition.
  • the solid oral dosage forms of the invention may further comprise one or more of the following ingredients which are pharmaceutically acceptable: binders, for example starch, gelatin, or natural and synthetic gums (such as acacia, sodium alginate, extract of Irish moss, carboxymethylcellulose, methylcellulose, ethylcellulose , polyethylene glycol, waxes, microcrystalline cellulose or polyvinylpyrrolidione) ; colouring agents, for example conventional pharmaceutically acceptable dyes; preservatives ; anti-oxidar.ts; and one or more pharmaceutically acceptable effervescent couple or couples (such as an acid and a carbonate, preferably sodium carbonate or sodium bicarbonate) to aid disintegration, and improve mouth feel.
  • binders for example starch, gelatin, or natural and synthetic gums (such as acacia, sodium alginate, extract of Irish moss, carboxymethylcellulose, methylcellulose, ethylcellulose , polyethylene glycol, waxes, microcrystalline cellulose or polyvinyl
  • the optional ingredients may each be present in an or in total amount from a trace amount to about 10% by mass of the composition.
  • solid oral dosage forms of the present invention may have a hardness in the range from about 1 to about 10 kp, more preferably from abou 1 to about 7 kp . It will be appreciated by a person skilled in the art that these ranges should not be considered as limiting, because the actual hardness of a specific solid dosage form of t. e present invention will vary according to the particular formulation and equipment used to prepare the dose form. The practical limits for the hardness of solid dosage forms of the invention are governed by the minimum hardness required to survive production, packaging, transport and removal from the packaging and the maximum hardness which still provides an acceptable mouth feel .
  • a further aspect of the present invention provides use of at least one thyroid hormone in the preparation of the pharmaceutical compositions described herein for the treatment of disorders associated with an impairment of the thyroid hormone function in animals including human beings .
  • a still further aspect of the present invention provides a method of treating disorders associated with an impairment of the thyroid hormone function in animals including human beings, which comprises the administration to patient in need thereof a therapeutically and/or prophylactically effective amount of the pharmaceutical compositions described herein in the form of a solid oral dosage form as described herein.
  • a suitable daily dose of a thyroid hormone for administration to human beings may generally be from about 0.1 ⁇ g to about 10,000 ⁇ g, preferably from about 0.1 ⁇ g to about 1,000 ⁇ g, more preferably if the thyroid hormone is LT 4 from about 25 ⁇ g to about 300 ⁇ g given in a single dose or in divided doses at one or more times during the day.
  • compositions of the present invention may be prepared in unit dosage form, therefore each solid oral dosage form may comprise from about 0.1 ⁇ g to about 10,000 ⁇ g, preferably from about 1 ⁇ g to about: 1000 ⁇ g, more preferably, if the therapeutic agent is LT 4 , from about 25 ⁇ g to about 300 ⁇ g (for example 25 ⁇ g, 50 ⁇ g, 75 ⁇ g or 100 ⁇ g) of a thyroid hormone.
  • compositions of the present invention may be used in adjunctive therapy with one or more other compounds having activity in the treatment of disorders associated with an impairment of the thyroid hormone function in animals including human beings.
  • treatment includes prophylactic use of the pharmaceutical composition of the present invention for example to protect against conditions such as hypothyroidism, in animals including human beings .
  • % m/m indicates the amount of ingredient is given as a percentage by mass of ingredient per total mass of the composition. The percentage may not total 100%, due to rounding.
  • the l-thyroxine ingredients were triturated with the microcrystalline cellulose followed by the sucrose, starch and citric acid and finally the magnesium stearate.
  • the mixture was compressed into tablets each containing 50 ⁇ g levothyroxine sodium on an anhydrous basis, each tablet having a hardness in the range from 1 to 6 kp.
  • the resulting tablets were hard enough to survive conventional packaging systems, such as bottles or blister packs.
  • the tablets were suckable and chewable in the mouth, and dissolved slowly. They were easily swallowed and tasted slightly of citrus.
  • Example 2 was prepared from the ingredients in the ratios listed in Example 1, except the l-thyroxine ingredient was present in an amount to produce 25 ⁇ g per tablet.
  • the levothyroxine sodium was triturated with the microcrystalline cellulose then the maize starch and citric acid.
  • the mixture was granulated with sucrose in purified water, and a permitted colour was mixed in followed by magnesium stearate.
  • the resulting granules were compressed into tablets comprising 25 ⁇ g levothyroxine sodium on an anhydrous basis, each tablet having a hardness in the range from 1 to 3 kp.
  • the resulting tablets were suitable for packaging and administration as example 1.
  • the above ingredients were combined by triturating; firstly levothyroxine sodium with microcrystalline cellulose; then the following ingredients: mannitol, citric acid, aspartame, croscarmellose sodium, orange flavour and permitted colouring (which ingredients may ⁇ be mixed together and the mixture added gradually or each ingredient may be added separately) ; and finally the magnesium stearate.
  • the mixture was compressed into tablets each containing 100 ⁇ g levothyroxine sodium on an anhydrous basis, each tablet having a hardness in the range from 2 to 6 kp.
  • the resulting tablets were suitable for packaging and administration as above, and had a cool, citrus fruit flavour in the mouth.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Zoology (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention se rapporte à des formes galéniques s'administrant par voie buccale et aptes à être sucées, avalées et mâchées, obtenues à partir d'une composition pharmaceutique appropriée pour être administrée par voie buccale à pratiquement tous les patients. Cette composition comprend: un agent thérapeutique contenant au moins une hormone thyroïdienne; d'environ 60 % à environ 90 % en volume d'un diluant inerte qui est un sucre ou un alcool de sucre; d'environ 5 % à environ 35 % en volume d'un agent de désintégration; et d'environ 0,1 % à environ 5 % en volume d'un agent lubrifiant. Cette composition est utilisée dans le traitement de troubles associés à l'amélioration de la fonction hormonale thyroïdienne chez les animaux, y compris chez les êtres humains.
PCT/EP1995/000322 1994-02-01 1995-01-30 Comprimes contenant des hormones thyroidiennes WO1995020954A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU16630/95A AU1663095A (en) 1994-02-01 1995-01-30 Tablets containing thyroid hormones

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9401879A GB9401879D0 (en) 1994-02-01 1994-02-01 Therapeutic agents
GB9401879.3 1994-02-01

Publications (1)

Publication Number Publication Date
WO1995020954A1 true WO1995020954A1 (fr) 1995-08-10

Family

ID=10749659

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1995/000322 WO1995020954A1 (fr) 1994-02-01 1995-01-30 Comprimes contenant des hormones thyroidiennes

Country Status (5)

Country Link
AU (1) AU1663095A (fr)
GB (1) GB9401879D0 (fr)
IL (1) IL112517A0 (fr)
WO (1) WO1995020954A1 (fr)
ZA (1) ZA95742B (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997017951A1 (fr) * 1995-11-14 1997-05-22 Knoll Pharmaceutical Company Preparations d'hormones thyroidiennes stabilisees et procede de fabrication correspondant
WO2005004849A2 (fr) * 2003-07-10 2005-01-20 Glaxo Group Limited Formulation pharmaceutique
WO2005009433A1 (fr) * 2003-07-24 2005-02-03 Fernando Goglia Utilisation de la 3,5 diiodothyronine en tant que regulateur du metabolisme lipidique
WO2014029464A1 (fr) * 2012-08-20 2014-02-27 Merck Patent Gmbh Préparation pharmaceutique solide contenant de la lévothyroxine
CN112930212A (zh) * 2018-10-17 2021-06-08 桑多斯股份公司 包含左甲状腺素和二羧酸的共晶体

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3689669A (en) * 1970-10-09 1972-09-05 Univ Of North Carolina The Antidepressant method and composition
GB1296510A (fr) * 1971-05-28 1972-11-15
EP0550108A1 (fr) * 1991-12-30 1993-07-07 Akzo Nobel N.V. Composition thyroactive à libération contrôlée
DE4318577A1 (de) * 1993-06-04 1994-12-08 Merck Patent Gmbh Schmiermittelfreie, arzneimittelhaltige Tabletten

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3689669A (en) * 1970-10-09 1972-09-05 Univ Of North Carolina The Antidepressant method and composition
GB1296510A (fr) * 1971-05-28 1972-11-15
EP0550108A1 (fr) * 1991-12-30 1993-07-07 Akzo Nobel N.V. Composition thyroactive à libération contrôlée
DE4318577A1 (de) * 1993-06-04 1994-12-08 Merck Patent Gmbh Schmiermittelfreie, arzneimittelhaltige Tabletten

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997017951A1 (fr) * 1995-11-14 1997-05-22 Knoll Pharmaceutical Company Preparations d'hormones thyroidiennes stabilisees et procede de fabrication correspondant
US5955105A (en) * 1995-11-14 1999-09-21 Knoll Pharmaceutical Company Stabilized thyroid hormone preparations and methods of making same
US6056975A (en) * 1995-11-14 2000-05-02 Basf Corporation Stabilized thyroid hormone preparations and methods of making same
WO2005004849A2 (fr) * 2003-07-10 2005-01-20 Glaxo Group Limited Formulation pharmaceutique
WO2005004849A3 (fr) * 2003-07-10 2005-05-06 Glaxo Group Ltd Formulation pharmaceutique
CN100430051C (zh) * 2003-07-10 2008-11-05 葛兰素集团有限公司 包含左甲状腺素钠的药物制剂
US7955621B2 (en) 2003-07-10 2011-06-07 Aspen Global Incorporated Pharmaceutical formulation comprising levothyroxine sodium
WO2005009433A1 (fr) * 2003-07-24 2005-02-03 Fernando Goglia Utilisation de la 3,5 diiodothyronine en tant que regulateur du metabolisme lipidique
WO2014029464A1 (fr) * 2012-08-20 2014-02-27 Merck Patent Gmbh Préparation pharmaceutique solide contenant de la lévothyroxine
CN104582731A (zh) * 2012-08-20 2015-04-29 默克专利股份有限公司 含有左甲状腺素的固体药物制剂
JP2015525802A (ja) * 2012-08-20 2015-09-07 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングＭｅｒｃｋ Ｐａｔｅｎｔ Ｇｅｓｅｌｌｓｃｈａｆｔ ｍｉｔ ｂｅｓｃｈｒａｅｎｋｔｅｒ Ｈａｆｔｕｎｇ レボチロキシンを含有する固形医薬調製物
EA027189B1 (ru) * 2012-08-20 2017-06-30 Мерк Патент Гмбх Твердый фармацевтический препарат, который содержит левотироксин
CN104582731B (zh) * 2012-08-20 2020-01-10 默克专利股份有限公司 含有左甲状腺素的固体药物制剂
US11298331B2 (en) 2012-08-20 2022-04-12 Merck Patent Gmbh Solid pharmaceutical preparation containing levothyroxine
CN112930212A (zh) * 2018-10-17 2021-06-08 桑多斯股份公司 包含左甲状腺素和二羧酸的共晶体
US12043590B2 (en) 2018-10-17 2024-07-23 Sandoz Ag Co-crystals comprising levothyroxine and a dicarboxylic acid

Also Published As

Publication number Publication date
ZA95742B (en) 1995-08-01
GB9401879D0 (en) 1994-03-30
IL112517A0 (en) 1995-12-08
AU1663095A (en) 1995-08-21

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