CA2182038A1 - Therapeutic agents containing thyroid hormones - Google Patents
Therapeutic agents containing thyroid hormonesInfo
- Publication number
- CA2182038A1 CA2182038A1 CA002182038A CA2182038A CA2182038A1 CA 2182038 A1 CA2182038 A1 CA 2182038A1 CA 002182038 A CA002182038 A CA 002182038A CA 2182038 A CA2182038 A CA 2182038A CA 2182038 A1 CA2182038 A1 CA 2182038A1
- Authority
- CA
- Canada
- Prior art keywords
- thyroid hormone
- dosage form
- agent
- mass
- pharmaceutically acceptable
- Prior art date
- Legal status (The legal status 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 status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—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
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
Abstract
There is disclosed a solid fast dispersing dosage form of a pharmaceutical composition suitable for oral administration comprising: a therapeutic agent which comprises one or more compound thyroid hormone or hormones; from about 80 % to about 99.9 % of disintegrating agent by mass; from about 0.01 % to about 10 % of flavouring agent by mass: and from about 0.1 % to about 5 % mass of lubricating agent by mass; which has utility in the treatment of disorders associated with the improvement of the thyroid hormone function in animals including human beings.
Description
Wo~5l20953 2 ~ 8~3~ tJ ,5A.
THERAPEUTIC AGENTS C~NTAINING THYROIG HORMONES
This invention relates to novel pharmaceutical compositions comprisi.~g one or more thyroid hormones, and to their use in the treatment of disorders 5 associated with impairment of tl~e thyroid hormone functions in animals including human beings.
Pharmaceutical c~mpositions comprising solid fast dispersing dosage forms for oral administration have recently become avaiiable. The dosage forms are 10 prepared by freeze drying, a relatively slow process, which involves the use of expensive and complicated equipment. Furthermore, fast dispersing dosage forms produced by f reeze dryLng are very friable and extremely moisture sensitive, which lilakes them difficult to 15 package. For example, when presented in a conventional blister pack they are not sufficiently hard to retain their integrity when ~ force is applied to break the package seal and eject them from the blister. Such tablets are also uns~litable for conventional packing ~0 into bottles. Known f~-eeze dried fast dispersing dosage forms have the furt~ler disadvantage that the~ are difficult to prepare other thall as large tablets.
Therefore it is an object of the invention to provide a solid fast dispersing oral dosage form for a 75 pharm2ceutical composition as described herein which avoids all or some of ~ he disadvantages of known freeze dried rapidly dispersing dGsage forms whilst retaining all or some of the advantages or fast dispersing dosage forms o~er more conventional solid oral dosage forms.
3~ These advantages ib1clude good patient compliance as fast dispersing dosage forms are easy to ingest as they _ _ . _ . . .. .
Wogs/209~3 ~ ~ ~38 disintegrate readily and quickly in the mouth within seconds imparting a pleasant sensation to the mouth.
This can be partlcularly uselul for patients such as children or the elderly who have difficulty in 5 swallowing, as no extra liquid (eg water) is required to take these oral dosage forms. Fast dispersing oral dosage forms have the further advantage that the thyroid hormone active ingredient is presented to the gastro-intestinal tract in a f inely divided particulate form 10 which favours optimal and consistent absorption into the body .
To impro~e convenience and patient compliance the oral dosage forms of the present invention may be made of a mass typically ten times smaller than possible for i5 free7e-dried dosage forms. Small oral dosage forms have the further advantage of minimising the amount of diluents ingested particularly when the therapeutic agent is present in very small amounts, for example the microgram ~uantities per unit dose required if the 20 therapeutic agent is thyroid hormone.
Thyroid hormones as described are useful in the treatment of disorders associated with improvement of the thyroid hormone function in animals including human beings for example myxedema, cretinism or obesity.
~5 Thyroid hormones can be prepared synthetically as the biologically active 1-enantiomer or can be isolated direct from the thyroid gland of animals.
Therefore the present invention provides a solid fast dispersing dosage form of a pharmaceutical 30 composition suitable for oral administration comprising:
a therapeutlc agent which comprises at least one thyroid hormone; from about 80~ to about 99.996 of disintegrating agent; from about 0.01S'6 to about 10~ of flavouring W0 95/20953 Z( f3~ r~ 't- -agent; and from about 0.1% ~o 2bout 5% of lubricating agent, all percenta~les being percentage mass of ingre~lent by total mass of the composition (known hereinafter as 'by mass ~ ) .
~;urprisingly, the present invention provides pharmaceutical compositions giving the above stated ad~antages of fast dis~ersing oral dosage forms without freeze drying. Freeze drying is a time consuming and expensive process requiring significant capital investment in specialised plant and machinery and high maintenance and operat-;ng costs. The production of the solid fast dispersing oral dosage form of the present invention by using si.mple formulation and processing technolog~ results in r~lajor cost savings over production of known rapidly dispersing oral ~osage forms. The lubricating agent is added to the composition to aid compresslon of the solid dosage form In order to improve palatability arld patient corr,pliance it has also been found that the composition must comprise a flavouring agent. sOlid fast disE~ersing oral dosage forms of the inventioll are less friable than freeze-dried formulations and may be made into smaller dosage forms than is possible with freeze-dried formulations.
Compositions of the present invention have a suitably '5 long shelf life, and disperse in the mouth rapidly in a fine particulate form with no gritty texture. They are easy and pleasant to administer.
Thyroid hormones c~mprise the fcllowing:
L-3,5,3~,5'-tetraiodothyronine (levothyroxine or LT4);
30 L-3,5,3'-triiodothyronine (liothyronine or LT3);
L-3, 3 ~, 5 ' -triiodothyronine (Lrq'3 );
L-3,5-diiodothyronine (LT7); or mixtures thereof. As used herein the term thyroid hormone should be wo s~/20ss3 understood to include all pharmaceutically acceptable salts thereof, preferably sodium salts.
Thyroid hormones may e.Yist as one or more polymorphic forms (for example one or more crystalline 5 forms, amorphous forms, phases, solid solutions andtor mixtures thereof ) and the therapeutic agent ma~ include each pharmaceutically acceptable polymorphic form of thyroid hormones and~or mixtures thereof.
Thyroid hormones may also exist in the form of 10 solvates (for example hydrates) and the therapeutic agent may include each solvate of thyroid ho}mones and~or mixtures thereof.
Preferably the therapeutic agent is present in the composition in an amount per unit dose from about 0.1 llg 15 to about lO, 300 llg, more preferably from about 1 llg to about lO00 ,ug, most preferably, if the therapeutic agent is LT4, from about 25 llg to about 300 llg.
It may be benef icial for any of the insredients of compositions of the present invention ~including the 20 therapeutic agent) to be in the form of particles of very small size, for example as obtained by fluid energy milling. Alternativel~ the therapeutic agent may be bound (for example by sorption, incorporation andfor chemically) to nanoparticles which are collodial 25 polymeric particles of a si e typically less than 1 micron. The dlstribution of such nanoparticles in the body and hence tne sites of delivery of the therapeutic agent can be effected by coating the surface of the nanoparticles appropriately (for examp~e with 30 surfactants or antibodies). The therapeutic agent in the solid dosage form of the present invention ma~y, if Wo 95/20953 ;~ r r ~ s desired, be associated with other compatible, pharmacologically active ingredient~;.
Preferably the disintegratin~ agent comprises a blend of at least two components and each component may 5 independently comprise one or mcre of the followins insredients- pharmac~utical grade starch (eg maize starch), modified starch (eg pre-gelled starch and,or sodium starch glycollate), agar, bentonite, cellulose, microcrystalline cellulose, methylcellulose, carmellose, lO croscarmellose sodium, alginic acid, guar gum, silicon dioxide and sodium lallryl sulphate; more preferably one or more of pharmaceutical grade starch and microcrystalline cellulose. Preferably the disintegrating agent is p}esent in an amount from about 80% to about 99%, mc,re preferably from about 85% to about g8g by mass of the composition.
Preferably the flavourirlg agent comprises one or more of the following:
a sweetening agent w~ich may be a nutritive or non-~G nutritive sweetener preferably sodium saccharin or aspartame i a peppermint oil and/or fruit flavour;
a f lavour enhancing agent; or an ingredient or ingredients whi.ch may induce the ~5 formation of saliva, preferably a pharmaceutically acceptable acid, more preEerably ar~ organic acid, most preferably an acid selected from citric and malic acid.
Preferably the flavouring agerlt is presen.t in an amount from 2bout G.l~ to about 5%, more prerferably from 30 about 1% to about 3%, oy mass of the composition.
Preferably the lubricating agent is selected from one or more of the following ingredients: magnesium Wo 9v2n9~ 8~ 3~
stearate, calciun~ stearate, stearlc acid and mixtures thereof; more preferably magnesium stearate. Preferably the lubricating agent is present in an amount from about 0.1% to about 1% by n,ass of the composition.
The dlsintegrating agent may be the sole diluent in the composition, or the composition may also comprise one or more additional inert diluent or diluent:s, which may be selected from one or more of the following ingredients: lactose, powdered sugar, sucrose, pharmaceutical grade starch, kaolin, talc, and pharmaceutically acceptable calcium salts; more preferably selected from sucrose and pharmaceutical grade starch, talc, calcium phosphate and calcium sulphate . The total amount of diluent ( including the 15 disintegrating agenti may be present in an amount from about gO% to about 99 . 9%, preferably from about 95% to about 99%, more preferably from about 95% to about 98%, by mass of the composition.
The solid oral dosage forms of the invention may 2G further comprise one or more of the following optional ingredients which are pharmaceutically acceptable:
binders, for example starch, gelatin, sugars ~such as sucrose, molasses or lactose), and/or natural and synthetic gums (such as acacia, sodium alginate, extract 25 of Irish moss, carboxymethylcellulose, methylcellulose, ethylcellulose, polyethylene glycol, waxes, microcrystalline cellulose or polyvinylpyrrolidione~;
colouring agents, for example con~entional pharmaceutically acceptable dyes;
30 orally acceptable preservatives;
ant i -oxi dan t s; and one or more pharmaceutically acceptable effervescent couple o~ couples Isuch as an acid and a carbonate, ~ woss/2o9s3 ~1 ~38 r~"~
preferably sodium car~onate and~or sodium bicarbonate~
to aid disi~tegration ~nd improve mouth feel.
T}le optional ingredients may be present in an amount from a trace ar.~ount to about 10~ by mass of the 5 cornposition.
Preferably solid oral dosage forms of the present invention may have a hardness in the range from about 1 to about 6 kp, more preferably from about 1 to about 5 kp . It will be appr~ciated by a person - skilled in the 10 art that these rang~s should not be considered as limiting, because the actual hardness of a specific solid dosage form of the present invention will vary according to the particular formulation anc equipment used to prepare the dosage form. The practical limits 15 for the hardness of solid dosage form~i of the invention are governed by the minimum hardness requirec to survive production, packaging, trânsport ar.d removal from the packaging and the ma:~i]num hardness which stil~ provides an ac~ eptable mouth fe~l .
A further aspect ~f the present inventicn provides use of a thyroid hormone in the preparation of the pharmaceutical compositions described herel.. for the treating of disorders associated hith an im.pairment of the t~lyroid hormone function in anima~.s including human 2 5 beings .
A still further aspect of th~ preserlt invention provides a method of t -eat ing disorder s asscci2ted with an impairment of the thyroid hormone fllnction in animals including human beings, which comprises administering to 30 a patient in need t~-e~eof a therapeutice'~ ly and/or prophylactically effective amount of a composition according to the present invention.
W095/20953 2~ `3~ r~ S
~ hilst the 2recise amount of the therapeutic agent administered in the treatment described abo~le will depend on a number of factors, for example the severity of the condition, the age and past medical history of 5 the patient, and aiways lies within the sound discretion of the administering medical practitioner or veterinary a suitable daily dose of a thyroid hormone or administra.ion to animals, including human beings, may generally be from about 0 .1 ~Lg to about 10, 000 ~Lg, preferably from about 1 llg to about 1000 ~Lg, more preferably if the thyroid hormone is LT4 from about 25 llg to about 300 ~lg 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 15 unit dosage form, therefore each solid oFal dosage form may comprise from about 0.1 llg to about 10,000 llg, preferably from about 1 llg to about 1000 llg, more preferably, if the therapeutic agent is LT4, from about 25 ~Lg to about 300 !lg (for example 25 llg, 50 ~Lg, 75 llg 20 or 100 ~g) of a thyroid hormone.
Pharmaceutical 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 25 hormone function in animals including human beings. It will be appreciated that the term treatment as used herein includes prophylactic use of the pharmaceutical compositicn of the present invention for example to protect against conditions such as hypothyroidism, in 30 animals ir.cluding human beings.
The coF~positions of the present invention may be prepared by blending of the components or by wet or dr~
granulation. The blend or granulation is then compressec into tablets.
~ W0~5/20g53 ~ 3~
g ~ yet further aspect of the presen.t lnvention provides a method for the man~lfacture of th~ solid oral dosage fonr.s of the in~.~ention comprising the steps of:
(a) forming a first mixture by blending in intimate admixture one or more disintegrant or disintegrants with a therapeuti.c agent comprising cne or more thyroid hormone or hormones;
(b~ forming a second mixture by blending in intimate admixture one or ~lore disintegrant or disintegrants with a flavouring agent and a lubricating agent;
(c) combining the first and second mixtures to form a pharmaceutical co~r,position; and (d) compressing the composition from step (c) to form a fast dispersing solid oral dosage form.
The invention will now be illustrated by the following non-limiting examples in which ~ mim indicates the amount of ingredierlt is given as percen.age by mass of the ingredient per total mass of the composition.
The y~rce~g~ may no~ Cot-i l009~ dae ~c r~.rdirg.
V~oss/209s3 ~ r~llr~
ExamD l e Fa~t disDersina fonr~ul2tiGn Inaredien~ ~6 m/m Mai~e starch powder 33.15 (disintegrant) A Microcrystalline cellulose 15.00 ~Avicel PH101) (disintegrant) L-thyroxine therapeutically effective [llg~
amount s Ma i z e s t a rch powde r 3 4 .1 5 ~dlsil~tegrant ) Microcr~stalline cellulose 15 . 00 (A-Jicel PH101) (disintegrant~
B Citric acid powder (saliva 2.00 inducing agent ) Aspartame (sweetener) 0.2 Magnesium stearate powder 0 . 5 Q ( lubricant ) The ingredients marked A were mixed together and granulated. The powders marked B were mixed together and the resultant powder was mixed with the granuies from A to coat them. Optionally permitted colours may ~5 be added at this stage. The coated granules were then compressed into tablets each containing 50 llg levothyroxine sodium on an anhydrous basis, each tablet having a hardness in the range froml 1 to 3 kp. The resulting tablets were hard enough to survive in 30 con~entional packaging systems such as bottles or blister packs, were insoluble and dispersed completely Wog5/2ns~ r.I/E-,5r as fine particles ln t:he mouth within lO to 15 seconds with a pleasant taste ~nd 2 good mouth feel.
Exam~le 2 Inclre~ ent 's rn~m Microcrysalline cellulose 20 . 00 (Avicel PHlOl) A Le~othyroxine sodium Therapeutically ef Eective amounts (llg) B M~ize starch powder 67.75 Microcrystalline cellulose 10 . 00 (~.vicel PHl 01 ) Citric acid monohydrate ~! . 50 powder C Pe~mitted colour qs powder 20 D Magnesium stearate powder 0 . 50 The ingredients rnarked A were triturated. The tritur~ed material was mixed the irlgredients marked B.
The mixture of .~. and B was granulated with purified water and dried to form granules, which were 25 (optionally) mixed with the permitted colour (ingredient C) . ~;Ais mixture was finally blended with the magnesium stearate (in~3redient D) . The final mixture was compressed into taclets each containing 25 ~Lg levoth~rcxine sodium on an anhydrous basis, each tablet 30 having a hardness in the range from 2 to 6 kp. The resultant tablets were stron~ enough to survive in conventional packaging systems such as a bottle or W0 9~/~09~3 ';;~
_2 blister packs. The tablets were insoluble and dispersed completely as f ine particles in the mouth within 10 to 15 seconds with a pleasant taste and mout~ feel.
THERAPEUTIC AGENTS C~NTAINING THYROIG HORMONES
This invention relates to novel pharmaceutical compositions comprisi.~g one or more thyroid hormones, and to their use in the treatment of disorders 5 associated with impairment of tl~e thyroid hormone functions in animals including human beings.
Pharmaceutical c~mpositions comprising solid fast dispersing dosage forms for oral administration have recently become avaiiable. The dosage forms are 10 prepared by freeze drying, a relatively slow process, which involves the use of expensive and complicated equipment. Furthermore, fast dispersing dosage forms produced by f reeze dryLng are very friable and extremely moisture sensitive, which lilakes them difficult to 15 package. For example, when presented in a conventional blister pack they are not sufficiently hard to retain their integrity when ~ force is applied to break the package seal and eject them from the blister. Such tablets are also uns~litable for conventional packing ~0 into bottles. Known f~-eeze dried fast dispersing dosage forms have the furt~ler disadvantage that the~ are difficult to prepare other thall as large tablets.
Therefore it is an object of the invention to provide a solid fast dispersing oral dosage form for a 75 pharm2ceutical composition as described herein which avoids all or some of ~ he disadvantages of known freeze dried rapidly dispersing dGsage forms whilst retaining all or some of the advantages or fast dispersing dosage forms o~er more conventional solid oral dosage forms.
3~ These advantages ib1clude good patient compliance as fast dispersing dosage forms are easy to ingest as they _ _ . _ . . .. .
Wogs/209~3 ~ ~ ~38 disintegrate readily and quickly in the mouth within seconds imparting a pleasant sensation to the mouth.
This can be partlcularly uselul for patients such as children or the elderly who have difficulty in 5 swallowing, as no extra liquid (eg water) is required to take these oral dosage forms. Fast dispersing oral dosage forms have the further advantage that the thyroid hormone active ingredient is presented to the gastro-intestinal tract in a f inely divided particulate form 10 which favours optimal and consistent absorption into the body .
To impro~e convenience and patient compliance the oral dosage forms of the present invention may be made of a mass typically ten times smaller than possible for i5 free7e-dried dosage forms. Small oral dosage forms have the further advantage of minimising the amount of diluents ingested particularly when the therapeutic agent is present in very small amounts, for example the microgram ~uantities per unit dose required if the 20 therapeutic agent is thyroid hormone.
Thyroid hormones as described are useful in the treatment of disorders associated with improvement of the thyroid hormone function in animals including human beings for example myxedema, cretinism or obesity.
~5 Thyroid hormones can be prepared synthetically as the biologically active 1-enantiomer or can be isolated direct from the thyroid gland of animals.
Therefore the present invention provides a solid fast dispersing dosage form of a pharmaceutical 30 composition suitable for oral administration comprising:
a therapeutlc agent which comprises at least one thyroid hormone; from about 80~ to about 99.996 of disintegrating agent; from about 0.01S'6 to about 10~ of flavouring W0 95/20953 Z( f3~ r~ 't- -agent; and from about 0.1% ~o 2bout 5% of lubricating agent, all percenta~les being percentage mass of ingre~lent by total mass of the composition (known hereinafter as 'by mass ~ ) .
~;urprisingly, the present invention provides pharmaceutical compositions giving the above stated ad~antages of fast dis~ersing oral dosage forms without freeze drying. Freeze drying is a time consuming and expensive process requiring significant capital investment in specialised plant and machinery and high maintenance and operat-;ng costs. The production of the solid fast dispersing oral dosage form of the present invention by using si.mple formulation and processing technolog~ results in r~lajor cost savings over production of known rapidly dispersing oral ~osage forms. The lubricating agent is added to the composition to aid compresslon of the solid dosage form In order to improve palatability arld patient corr,pliance it has also been found that the composition must comprise a flavouring agent. sOlid fast disE~ersing oral dosage forms of the inventioll are less friable than freeze-dried formulations and may be made into smaller dosage forms than is possible with freeze-dried formulations.
Compositions of the present invention have a suitably '5 long shelf life, and disperse in the mouth rapidly in a fine particulate form with no gritty texture. They are easy and pleasant to administer.
Thyroid hormones c~mprise the fcllowing:
L-3,5,3~,5'-tetraiodothyronine (levothyroxine or LT4);
30 L-3,5,3'-triiodothyronine (liothyronine or LT3);
L-3, 3 ~, 5 ' -triiodothyronine (Lrq'3 );
L-3,5-diiodothyronine (LT7); or mixtures thereof. As used herein the term thyroid hormone should be wo s~/20ss3 understood to include all pharmaceutically acceptable salts thereof, preferably sodium salts.
Thyroid hormones may e.Yist as one or more polymorphic forms (for example one or more crystalline 5 forms, amorphous forms, phases, solid solutions andtor mixtures thereof ) and the therapeutic agent ma~ include each pharmaceutically acceptable polymorphic form of thyroid hormones and~or mixtures thereof.
Thyroid hormones may also exist in the form of 10 solvates (for example hydrates) and the therapeutic agent may include each solvate of thyroid ho}mones and~or mixtures thereof.
Preferably the therapeutic agent is present in the composition in an amount per unit dose from about 0.1 llg 15 to about lO, 300 llg, more preferably from about 1 llg to about lO00 ,ug, most preferably, if the therapeutic agent is LT4, from about 25 llg to about 300 llg.
It may be benef icial for any of the insredients of compositions of the present invention ~including the 20 therapeutic agent) to be in the form of particles of very small size, for example as obtained by fluid energy milling. Alternativel~ the therapeutic agent may be bound (for example by sorption, incorporation andfor chemically) to nanoparticles which are collodial 25 polymeric particles of a si e typically less than 1 micron. The dlstribution of such nanoparticles in the body and hence tne sites of delivery of the therapeutic agent can be effected by coating the surface of the nanoparticles appropriately (for examp~e with 30 surfactants or antibodies). The therapeutic agent in the solid dosage form of the present invention ma~y, if Wo 95/20953 ;~ r r ~ s desired, be associated with other compatible, pharmacologically active ingredient~;.
Preferably the disintegratin~ agent comprises a blend of at least two components and each component may 5 independently comprise one or mcre of the followins insredients- pharmac~utical grade starch (eg maize starch), modified starch (eg pre-gelled starch and,or sodium starch glycollate), agar, bentonite, cellulose, microcrystalline cellulose, methylcellulose, carmellose, lO croscarmellose sodium, alginic acid, guar gum, silicon dioxide and sodium lallryl sulphate; more preferably one or more of pharmaceutical grade starch and microcrystalline cellulose. Preferably the disintegrating agent is p}esent in an amount from about 80% to about 99%, mc,re preferably from about 85% to about g8g by mass of the composition.
Preferably the flavourirlg agent comprises one or more of the following:
a sweetening agent w~ich may be a nutritive or non-~G nutritive sweetener preferably sodium saccharin or aspartame i a peppermint oil and/or fruit flavour;
a f lavour enhancing agent; or an ingredient or ingredients whi.ch may induce the ~5 formation of saliva, preferably a pharmaceutically acceptable acid, more preEerably ar~ organic acid, most preferably an acid selected from citric and malic acid.
Preferably the flavouring agerlt is presen.t in an amount from 2bout G.l~ to about 5%, more prerferably from 30 about 1% to about 3%, oy mass of the composition.
Preferably the lubricating agent is selected from one or more of the following ingredients: magnesium Wo 9v2n9~ 8~ 3~
stearate, calciun~ stearate, stearlc acid and mixtures thereof; more preferably magnesium stearate. Preferably the lubricating agent is present in an amount from about 0.1% to about 1% by n,ass of the composition.
The dlsintegrating agent may be the sole diluent in the composition, or the composition may also comprise one or more additional inert diluent or diluent:s, which may be selected from one or more of the following ingredients: lactose, powdered sugar, sucrose, pharmaceutical grade starch, kaolin, talc, and pharmaceutically acceptable calcium salts; more preferably selected from sucrose and pharmaceutical grade starch, talc, calcium phosphate and calcium sulphate . The total amount of diluent ( including the 15 disintegrating agenti may be present in an amount from about gO% to about 99 . 9%, preferably from about 95% to about 99%, more preferably from about 95% to about 98%, by mass of the composition.
The solid oral dosage forms of the invention may 2G further comprise one or more of the following optional ingredients which are pharmaceutically acceptable:
binders, for example starch, gelatin, sugars ~such as sucrose, molasses or lactose), and/or natural and synthetic gums (such as acacia, sodium alginate, extract 25 of Irish moss, carboxymethylcellulose, methylcellulose, ethylcellulose, polyethylene glycol, waxes, microcrystalline cellulose or polyvinylpyrrolidione~;
colouring agents, for example con~entional pharmaceutically acceptable dyes;
30 orally acceptable preservatives;
ant i -oxi dan t s; and one or more pharmaceutically acceptable effervescent couple o~ couples Isuch as an acid and a carbonate, ~ woss/2o9s3 ~1 ~38 r~"~
preferably sodium car~onate and~or sodium bicarbonate~
to aid disi~tegration ~nd improve mouth feel.
T}le optional ingredients may be present in an amount from a trace ar.~ount to about 10~ by mass of the 5 cornposition.
Preferably solid oral dosage forms of the present invention may have a hardness in the range from about 1 to about 6 kp, more preferably from about 1 to about 5 kp . It will be appr~ciated by a person - skilled in the 10 art that these rang~s should not be considered as limiting, because the actual hardness of a specific solid dosage form of the present invention will vary according to the particular formulation anc equipment used to prepare the dosage form. The practical limits 15 for the hardness of solid dosage form~i of the invention are governed by the minimum hardness requirec to survive production, packaging, trânsport ar.d removal from the packaging and the ma:~i]num hardness which stil~ provides an ac~ eptable mouth fe~l .
A further aspect ~f the present inventicn provides use of a thyroid hormone in the preparation of the pharmaceutical compositions described herel.. for the treating of disorders associated hith an im.pairment of the t~lyroid hormone function in anima~.s including human 2 5 beings .
A still further aspect of th~ preserlt invention provides a method of t -eat ing disorder s asscci2ted with an impairment of the thyroid hormone fllnction in animals including human beings, which comprises administering to 30 a patient in need t~-e~eof a therapeutice'~ ly and/or prophylactically effective amount of a composition according to the present invention.
W095/20953 2~ `3~ r~ S
~ hilst the 2recise amount of the therapeutic agent administered in the treatment described abo~le will depend on a number of factors, for example the severity of the condition, the age and past medical history of 5 the patient, and aiways lies within the sound discretion of the administering medical practitioner or veterinary a suitable daily dose of a thyroid hormone or administra.ion to animals, including human beings, may generally be from about 0 .1 ~Lg to about 10, 000 ~Lg, preferably from about 1 llg to about 1000 ~Lg, more preferably if the thyroid hormone is LT4 from about 25 llg to about 300 ~lg 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 15 unit dosage form, therefore each solid oFal dosage form may comprise from about 0.1 llg to about 10,000 llg, preferably from about 1 llg to about 1000 llg, more preferably, if the therapeutic agent is LT4, from about 25 ~Lg to about 300 !lg (for example 25 llg, 50 ~Lg, 75 llg 20 or 100 ~g) of a thyroid hormone.
Pharmaceutical 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 25 hormone function in animals including human beings. It will be appreciated that the term treatment as used herein includes prophylactic use of the pharmaceutical compositicn of the present invention for example to protect against conditions such as hypothyroidism, in 30 animals ir.cluding human beings.
The coF~positions of the present invention may be prepared by blending of the components or by wet or dr~
granulation. The blend or granulation is then compressec into tablets.
~ W0~5/20g53 ~ 3~
g ~ yet further aspect of the presen.t lnvention provides a method for the man~lfacture of th~ solid oral dosage fonr.s of the in~.~ention comprising the steps of:
(a) forming a first mixture by blending in intimate admixture one or more disintegrant or disintegrants with a therapeuti.c agent comprising cne or more thyroid hormone or hormones;
(b~ forming a second mixture by blending in intimate admixture one or ~lore disintegrant or disintegrants with a flavouring agent and a lubricating agent;
(c) combining the first and second mixtures to form a pharmaceutical co~r,position; and (d) compressing the composition from step (c) to form a fast dispersing solid oral dosage form.
The invention will now be illustrated by the following non-limiting examples in which ~ mim indicates the amount of ingredierlt is given as percen.age by mass of the ingredient per total mass of the composition.
The y~rce~g~ may no~ Cot-i l009~ dae ~c r~.rdirg.
V~oss/209s3 ~ r~llr~
ExamD l e Fa~t disDersina fonr~ul2tiGn Inaredien~ ~6 m/m Mai~e starch powder 33.15 (disintegrant) A Microcrystalline cellulose 15.00 ~Avicel PH101) (disintegrant) L-thyroxine therapeutically effective [llg~
amount s Ma i z e s t a rch powde r 3 4 .1 5 ~dlsil~tegrant ) Microcr~stalline cellulose 15 . 00 (A-Jicel PH101) (disintegrant~
B Citric acid powder (saliva 2.00 inducing agent ) Aspartame (sweetener) 0.2 Magnesium stearate powder 0 . 5 Q ( lubricant ) The ingredients marked A were mixed together and granulated. The powders marked B were mixed together and the resultant powder was mixed with the granuies from A to coat them. Optionally permitted colours may ~5 be added at this stage. The coated granules were then compressed into tablets each containing 50 llg levothyroxine sodium on an anhydrous basis, each tablet having a hardness in the range froml 1 to 3 kp. The resulting tablets were hard enough to survive in 30 con~entional packaging systems such as bottles or blister packs, were insoluble and dispersed completely Wog5/2ns~ r.I/E-,5r as fine particles ln t:he mouth within lO to 15 seconds with a pleasant taste ~nd 2 good mouth feel.
Exam~le 2 Inclre~ ent 's rn~m Microcrysalline cellulose 20 . 00 (Avicel PHlOl) A Le~othyroxine sodium Therapeutically ef Eective amounts (llg) B M~ize starch powder 67.75 Microcrystalline cellulose 10 . 00 (~.vicel PHl 01 ) Citric acid monohydrate ~! . 50 powder C Pe~mitted colour qs powder 20 D Magnesium stearate powder 0 . 50 The ingredients rnarked A were triturated. The tritur~ed material was mixed the irlgredients marked B.
The mixture of .~. and B was granulated with purified water and dried to form granules, which were 25 (optionally) mixed with the permitted colour (ingredient C) . ~;Ais mixture was finally blended with the magnesium stearate (in~3redient D) . The final mixture was compressed into taclets each containing 25 ~Lg levoth~rcxine sodium on an anhydrous basis, each tablet 30 having a hardness in the range from 2 to 6 kp. The resultant tablets were stron~ enough to survive in conventional packaging systems such as a bottle or W0 9~/~09~3 ';;~
_2 blister packs. The tablets were insoluble and dispersed completely as f ine particles in the mouth within 10 to 15 seconds with a pleasant taste and mout~ feel.
Claims (14)
1. A solid fast dispersing dosage form of a pharmaceutical composition suitable for oral administration, the dosage form comprising: a therapeutic agent which comprises one or more thyroid hormone or hormones; from about 80% to about 99.9% of disintegrating agent by mass; from about 0.01% to about by mass 10% of flavouring agent by mass; and from about 0.1% to about 5% of lubricating agent by mass.
2. A dosage form as claimed in claim 1; in which the thyroid hormone comprises L-3,5,3',5' -tetraiodothyronine;
L-3,5,3'-triiodothyronine;
L-3,3',5'-triiodothyronine;
L-3,5-diiodothyronine;
pharmaceutically acceptable salts thereof;
or any mixtures thereof.
L-3,5,3'-triiodothyronine;
L-3,3',5'-triiodothyronine;
L-3,5-diiodothyronine;
pharmaceutically acceptable salts thereof;
or any mixtures thereof.
3. A dosage form as claimed in either claim 1 or 2, in which the disintegrating agent comprises a blend of at least two components.
4. A dosage form as claimed in claim 3, in which each component independently comprises an ingredient selected from pharmaceutically acceptable starch, modified starch, methyl cellulose, agar, bentonite, cellulose, microcrystalline cellulose, alginic acid, guar gum, carboxymethylcellulose and sodium lauryl sulphate.
5. A dosage form as claimed in any preceding claim, in which composition comprises an ingredient or ingredients which induces the formation of saliva.
6. Use of thyroid hormone in the preparation of dosage forms as claimed in any preceding claim, for the treatment of disorders associated with impairment of the thyroid hormone function in animals including human beings.
7. A method of treating disorders associated with an impairment of the thyroid hormone function in animals including human beings, which comprises the administration to a patient in need thereof a therapeutically effective amount of a solid oral dosage form as claimed in any of claims 1 to 5.
8. A method for the manufacture of a solid oral dosage form, comprising the steps of:-(a) forming a first mixture by blending in intimate admixture one or more disintegrant or disintegrants with a therapeutic agent comprising one or more thyroid hormone or hormones;
(b) forming a second mixture by blending in intimate admixture one or more disintegrant or disintegrants with a flavouring agent and a lubricating agent;
(c) combining the first and second mixtures to form a pharmaceutical composition; and (d) compressing the composition from step (c) to form a fast dispersing solid oral dosage form.
(b) forming a second mixture by blending in intimate admixture one or more disintegrant or disintegrants with a flavouring agent and a lubricating agent;
(c) combining the first and second mixtures to form a pharmaceutical composition; and (d) compressing the composition from step (c) to form a fast dispersing solid oral dosage form.
9. A method of preparing a solid fast dispersing dosage form of a pharmaceutical composition suitable for oral administration, the method comprising: combining a therapeutic agent which comprises one or more compound thyroid hormone or hormones, with; from about 80% to about 99.9% by mass of disintegrating agent and from about 0.01% to about 10% by mass of flavouring agent;
followed by from about 0.1% to about 5% by mass of lubricating agent.
followed by from about 0.1% to about 5% by mass of lubricating agent.
10. A method as claimed in claim 9; in which the thyroid hormone comprises L-3,5,3',5'-tetraiodothyronine;
L-3,5,3'-triiodothyronine;
L-3,3',5'-triiodothyronine;
L-3,5-diiodothyronine;
pharmaceutically acceptable salts thereof;
or any mixtures thereof.
L-3,5,3'-triiodothyronine;
L-3,3',5'-triiodothyronine;
L-3,5-diiodothyronine;
pharmaceutically acceptable salts thereof;
or any mixtures thereof.
11. A method as claimed in either claim 9 or 10, in which the disintegrating agent comprises a blend of at least two components.
12. A method as claimed in claim 11, in which each component independently comprises an ingredient selected from pharmaceutically acceptable starch, modified starch, methyl cellulose, agar, bentonite, cellulose, microcrystalline cellulose, alginic acid, guar gum, carboxymethylcellulose and sodium lauryl sulphate.
13. A method as claimed in any of claims 9 to 12, in which an ingredient or ingredients which induces the formation of saliva is added to the composition.
14. Use of thyroid hormone in a method as claimed in any of claims 9 to 13, for preparing a pharmaceutical composition for treating disorders associated with impairment of the thyroid hormone function in animals including human beings.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9401892A GB9401892D0 (en) | 1994-02-01 | 1994-02-01 | Therapeutic agents |
| GB9401892.6 | 1994-02-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2182038A1 true CA2182038A1 (en) | 1995-08-10 |
Family
ID=10749669
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002182038A Abandoned CA2182038A1 (en) | 1994-02-01 | 1995-01-30 | Therapeutic agents containing thyroid hormones |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US5753254A (en) |
| EP (1) | EP0732920B1 (en) |
| AT (1) | ATE252899T1 (en) |
| AU (1) | AU1537095A (en) |
| CA (1) | CA2182038A1 (en) |
| DE (1) | DE69532031T2 (en) |
| ES (1) | ES2210282T3 (en) |
| GB (1) | GB9401892D0 (en) |
| IL (1) | IL112518A0 (en) |
| WO (1) | WO1995020953A1 (en) |
| ZA (1) | ZA95741B (en) |
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| DE69224809T2 (en) * | 1991-12-30 | 1998-07-09 | Akzo Nobel Nv | Thyroactive composition with controlled release |
-
1994
- 1994-02-01 GB GB9401892A patent/GB9401892D0/en active Pending
-
1995
- 1995-01-30 CA CA002182038A patent/CA2182038A1/en not_active Abandoned
- 1995-01-30 AT AT95907000T patent/ATE252899T1/en not_active IP Right Cessation
- 1995-01-30 DE DE69532031T patent/DE69532031T2/en not_active Expired - Fee Related
- 1995-01-30 WO PCT/EP1995/000321 patent/WO1995020953A1/en active IP Right Grant
- 1995-01-30 EP EP95907000A patent/EP0732920B1/en not_active Expired - Lifetime
- 1995-01-30 AU AU15370/95A patent/AU1537095A/en not_active Abandoned
- 1995-01-30 ES ES95907000T patent/ES2210282T3/en not_active Expired - Lifetime
- 1995-01-30 US US08/682,783 patent/US5753254A/en not_active Expired - Lifetime
- 1995-01-31 ZA ZA95741A patent/ZA95741B/en unknown
- 1995-02-01 IL IL11251895A patent/IL112518A0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ES2210282T3 (en) | 2004-07-01 |
| US5753254A (en) | 1998-05-19 |
| IL112518A0 (en) | 1995-12-08 |
| AU1537095A (en) | 1995-08-21 |
| DE69532031T2 (en) | 2004-07-22 |
| WO1995020953A1 (en) | 1995-08-10 |
| ATE252899T1 (en) | 2003-11-15 |
| GB9401892D0 (en) | 1994-03-30 |
| ZA95741B (en) | 1995-08-01 |
| EP0732920B1 (en) | 2003-10-29 |
| DE69532031D1 (en) | 2003-12-04 |
| EP0732920A1 (en) | 1996-09-25 |
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| Date | Code | Title | Description |
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| EEER | Examination request | ||
| FZDE | Discontinued |