CZ2001438A3 - Pharmaceutical compositions containing ibuprofen a domperidone - Google Patents

Abstract

A stable pharmaceutical composition comprising a mixture of (i) ibuprofen medicament is disclosed; (ii) a domperidone drug; and (iii) a carrier characterized in that the carrier is substantially free of povion and comprises at least one diluent combined with at least one release modifying agent.

Description

Pharmaceutical compositions comprising ibuprofen and domperidone

Area, techniques

The present invention relates to pharmaceutical compositions comprising an ibuprofen medicament and a domperidone medicament.

BACKGROUND OF THE INVENTION

Ibuprofen, i.e. 2- (4-isobutylphenyl) propionic acid, is a well known drug with analgesic, anti-inflammatory and antipyretic properties. It is usually sold in the form of racemic ibuprofen (equal amounts of the enantiomer of S (+) - ibuprofen and R (-) ibuprofen). It may also be in the form of a purified form of any isomer, particularly S (+) -ibuprofen, which has been found to be the active form of racemic ibuprofen. Ibuprofen is also available in the form of a salt, for example the sodium or lysine salt of ibuprofen. Ibuprofen is available on prescription (for example as Brufen (registered trademark)) primarily for the treatment of painful and inflammatory diseases including rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, postoperative pain, postpartum pain and soft tissue damage, generally at doses up to 32 00 mg per day. Ibuprofen is also available as a non-prescription medicine (such as Nurofen (registered trademark)), primarily for the treatment of symptoms of pain and fever, including headache, migraine, rheumatic pain, muscle pain, back pain, neuralgia, painful menstruation, toothache and cold and flu, usually in doses up to 1200 mg per day. Commercially available ibuprofen tablets usually contain ibuprofen or an enantiomer or salt thereof corresponding to 200 mg, 400 mg, 600 mg or 800 mg of racemic ibuprofen. Further, the term "ibuprofen" means any enantiomer of ibuprofen or a mixture of enantiomers, including a racemic mixture.

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Domperidone, i.e. 5-chloro-1- [1- [3- (2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) propyl-4-piperidinyl] -1,3-dihydro-2H Benzimidazol-2-one is a known drug with anti-emetic properties. Domperidone is available as a prescription [eg, Motilium (registered trademark)] as a tablet for the treatment of dyspepsia at doses up to 80 mg per day and is also available as tablets, suspensions or suppositories for the treatment of emesis (nausea or vomiting) in doses up to 120 mg per day. In place of domperidone itself, pharmaceutically acceptable salts such as domperidone maleate may be used. In this case, the amount of active agent is adjusted to administer an equivalent amount of domperidone base.

Administration of analgesic NSAIDs (such as ibuprofen) together with domperidone is useful in the treatment of migraine. for example GB 2313309 and CA 2020018. When two active agents are administered in combination therapy, it is preferable that they be present together in one dosage form rather than being administered sequentially in different dosage forms. The references cited above provide a general analysis of typical formulation ingredients suitable for the preparation of uniform dosage forms, but do not specifically illustrate a composition comprising ibuprofen and domperidone.

It has been found that when the ibuprofen and domperidone active ingredients are prepared as one pharmaceutical composition, the solid composition is unstable for storage.

A variety of ingredients may be used in the preparation of solid dosage forms of the active ingredients. They may be selected so as to obtain a composition that is sufficiently resistant to withstand production, shipping and storage. However, it is also important to ensure that the composition releases the active ingredient in the body at an appropriate rate after administration to the patient so that all active ingredients can be released in a precise amount and have the desired release profile. A medicament suitable for the treatment of the diseases for which they have been administered. Thus, components that meet both requirements must be selected. In the preparation of solid compositions, ingredients having cohesive properties holding the ingredients together are important. Other suitable additives are release agents such as disintegrants (disintegrants, disintegrants) used in conventional rapid release tablets and sustained release carriers that are suitable for drug release over a prolonged period of time. When the dosage form is exposed after use to an aqueous medium, these release-modifying ingredients cause the active ingredient to be released from the solid composition at a desired rate, for example, almost immediately or at a controlled rate. There are also carriers which allow homogeneous mixing of the active ingredients of the dosage form and which aid in the compressibility of the tablets. These carriers may have disintegrating and / or cohesive properties when used in a dosage form at a particular ratio. Other ingredients may also be added to certain drugs to aid in proper release and absorption into the body.

In the manufacture of solid dosage forms, there is often a granulation step in which the active ingredient is mixed with an inert ingredient and made into a free-flowing, homogeneous granular composition which can be mixed with other ingredients and formed into a solid dosage form. In this granulation step, usually the powdered ingredients are mixed and then granulated with a granulating liquid (for example water or a pharmaceutically acceptable organic solvent such as an alcoholic solvent) to form a granular composition. The granulating agent, which may be solid and which further imparts cohesive properties to the granulate, may be present either dissolved in the granulating liquid or mixed with the powder components. Povidone is the preferred granulating agent as it is readily soluble in both water and alcoholic solvents.

and provides good cohesive properties to the resulting granules. Povidone was previously used in the production of both ibuprofen granule compositions and domperidone granule compositions. Povidone is particularly advantageous in the manufacturing process because it allows the composition of the granulating liquid to be changed (for example, water can be replaced with an alcoholic solvent or the water and alcoholic solvent can be mixed in the desired ratio) without affecting the solid components of the composition. These changes in the granulating liquid may be necessary to optimize the quality of the granular product as it moves from the preparation of the solid composition on a laboratory scale to full industrial production. It is also advantageous to use polyvidone in the composition because its readily soluble properties contribute to the disintegration of the solid dosage form when it enters the gastrointestinal tract. Thus, povidone is a preferred substance for use in particular as a granulating agent in ibuprofen-containing compositions and is widely used.

However, compositions containing ibuprofen, domperidone and povidone have been found to be unstable for storage, for example, leading to a reduction in the amount of active ingredient available for absorption, particularly with respect to domperidone.

This is a very important factor in the above-mentioned combination of active ingredients, since povidone is such a widely used pharmaceutical additive especially in the preparation of tablets. Just as povidone affects compositions containing granulated ibuprofen together with domperidone, its presence will also be affected by other solid compositions containing this combination of active ingredients as well as any other compositions in which ibuprofen, domperidone and povidone, for example liquid and semi-solid compositions, are co-present.

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SUMMARY OF THE INVENTION

Thus, according to the present invention, a carrier has been found which provides stabilized compositions of ibuprofen and domperidone.

AND

Thus, the present invention provides a stable pharmaceutical composition comprising a mixture of:

(i) an ibuprofen medicament;

(ii) a domperidone drug; and (iii) carriers;

characterized in that the carrier is substantially free of povidone and comprises at least one diluent combined with at least one release modifying agent.

International patent application WO 98/34612 was published on August 13, 1998. It relates to combination therapy with ibuprofen drug and domperidone drug. Disclosed herein are pharmaceutical compositions comprising two active ingredients suitable for administration to patients, including solid compositions for oral administration, liquid fill compositions and oral liquid compositions, compositions for topical administration, rectal administration and parenteral administration, as well as spray compositions. Certain solid compositions which may contain a diluent, a lubricant, a disintegrating agent and optionally a binder and / or a glidant are disclosed. A preferred binder (which reflects the state of the art above) is polyvinylpyrrolidone and is used as an additive in many illustrative solid compositions. However, the scope of the illustrative examples omits the use of polyvinylpyrrolidone many times (see Examples 6 and 7, where the granules of ibuprofen and domperidone active ingredients are present with a carrier containing only corn starch (35-38% by weight) and dried corn starch (3-4%). Examples 8 and 9 disclose hard gelatin capsules comprising a carrier consisting solely of maize (corn). * '· · · · _Λ <· ···· ···· · · · * starch (in an amount of 15 to 20% by weight of the total capsule contents) and pre-gelled starch (at 5-6 percent by weight of the capsule contents); Examples 9 and 10 also disclose tablets containing granulated ibuprofen with a carrier consisting solely of microcrystalline cellulose (in an amount of 10 to 11% of the total weight of the tablet) in combination with croscarmellose sodium (in mn). an amount of 14 to 16% of the total weight of the tablet) and pregelatinized starch) in an amount of 10% of the total weight of the tablet); in Examples 15 and 16, all ingredients are compressed directly, without a granulation step, and the tablets comprise a carrier consisting only of microcrystalline cellulose (8-11% by weight) and lactose (5-6% by weight of the tablet).

However, there is no mention in the international patent application WO 98/134612 of the advantageous stability that is obtained with a single dosage form comprising ibuprofen medicament and domperidone medicament using a carrier substantially free of polyvinylpyrrolidone. The compositions specifically disclosed in the above-described examples of International Patent Application WO 98/134612 can be excluded from the scope of this patent application as they form the prior art. The following are excluded items:

(a) compressed tablets comprising granulated ibuprofen and a carrier consisting essentially of either corn starch in an amount of 35 to 38% of the total tablet weight in combination with dried corn starch in an amount of 3 to 4% of the total tablet weight or microcrystalline cellulose in an amount of 10 to 11% of the total weight of the tablet in combination with croscarmellose sodium at 14-16% of the total weight of the tablet and pregelatinized starch at 10% of the total weight of the tablet;

(b) a directly compressed tablet comprising a carrier consisting essentially of microcrystalline cellulose in an amount of 8 to 11% of the cell. 4 β 4 ·

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(c) a hard gelatin capsule containing a carrier consisting of maize starch in an amount of 15 to 20% of the total weight of the capsule content in combination with pregelatinized starch in an amount of 5 to 6% of the total weight of the capsule content.

Povidone is an internationally recognized term for a 1-ethenyl-2-pyrrolidone homopolymer, also known as polyvinylpyrrolidone.

The words "povidone and" polyvinylpyrrolidone can be used interchangeably. Povidone is water soluble. According to the invention, the term "povidone" includes crospovidone, which is a cross-linked homopolymer of N-vinyl-2-pyrrolidone. The chemical name of crospovidone is 1-ethenyl-2-pyrrolidone homopolymer. Crospovidone is insoluble in water. Crospovidone-containing compositions have been found to be more unstable than povidone-containing compositions.

The dosage forms of the present invention may be solid, semisolid or liquid forms. In a preferred aspect, the present invention provides a compressed tablet composition comprising an ibuprofen medicament, a domperidone medicament and a carrier comprising a compressed mixture:

(a) granulated ingredients comprising said ibuprofen medicament and at least a portion of said carrier; and (b) a powder component comprising a lubricant and optionally another portion of said carrier, said domperidone medicament may be present in both components (a) and (b), and the composition is characterized in that the carrier is substantially free of povidone and comprises at least one diluent. combined with at least one disintegrant.

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In another preferred aspect, the present invention provides a directly compressed tablet composition comprising (i) an ibuprofen medicament;

(ii) a domperidone medicament; and (iii) a carrier, wherein the carrier is substantially free of povidone and comprises at least one diluent combined with at least one disintegrating agent and a lubricant.

In another preferred aspect, the present invention provides a solid composition comprising a non-compressed mixture of (i) an ibuprofen medicament (ii) a domperidone medicament; and (iii) carriers;

characterized in that the carrier is substantially free of povidone and comprises at least one diluent combined with at least one release modifying agent.

In another preferred aspect, the present invention provides a liquid or semi-solid composition comprising (i) an ibuprofen medicament;

(ii) a domperidone medicament; and (iii) a carrier;

characterized in that the carrier is substantially free of povidone and comprises at least one diluent combined with at least one release modifying agent.

In yet another preferred aspect, the present invention provides a solid pharmaceutical composition comprising:

(a) an ibuprofen medicament;

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(B) domperidone drug; (b) domperidone drug; and (c) a carrier comprising a diluent combined with a disintegrant;

characterized in that the carrier is substantially free of water-soluble polyvinylpyrrolidone.

If the international patent application WO 98/34612 constitutes the prior art, it is possible to exclude:

(a) a composition wherein the carrier comprises a mixture of 15 to 38% by weight corn starch or 9 to 11% by weight microcrystalline cellulose in combination with a starch component comprising 3 to 6% by weight dried corn starch or 6 to 10% by weight pregelatinized starch;

(b) direct compression tablets containing 9 to 11% by weight of microcrystalline cellulose and 5 to 6% by weight of lactose. ‘

In yet another preferred aspect, the present invention provides a solid pharmaceutical composition formed by compressing a granular composition comprising:

(a) an ibuprofen medicament; (b) domperidone medicament; and (c) a carrier comprising at least one diluent and at least one disintegrant, said carrier being adapted to form a stable composition upon mixing the ingredients;

optionally in combination with other ingredients, wherein the granular composition is prepared by a granulation process in the absence of a water-soluble polyvinylpyrrolidone.

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The ibuprofen molecule exists in two enantiomeric forms and the term ibuprofen medicament according to the present invention includes the individual enantiomers, in particular S (+) -ibuprofen, and mixtures thereof in any ratio, including 1: 1, hereinafter referred to as racemic ibuprofen. The ibuprofen medicament may also be present in the form of any salt or derivative of ibuprofen or its enantiomers. If necessary, the ibuprofen medicament may comprise one or more ibuprofen active ingredients such as racemic ibuprofen and S (+) - ibuprofen in combination. However, it is preferred that the ibuprofen medicament comprises one ibuprofen active ingredient. Representative examples of racemic or S (+) -ibuprofen salts are alkali metal salts such as sodium or potassium salts of ibuprofen; alkaline earth metal salts, for example, calcium or magnesium salts of ibuprofen; metal salts such as ibuprofen aluminum salts; amino acid salts such as the lysine or arginine salt of ibuprofen; or amine salts, such as the meglumine salt of ibuprofen. The ibuprofen drug is preferably racemic ibuprofen, S (+) ibuprofen or its sodium or lysine salt, most preferably racemic ibuprofen.

It is generally desirable for the ibuprofen medicament to contain as much ibuprofen in the dosage form as possible to reduce the size of the solid dosage form. Representative dosage forms usually contain the ibuprofen medicament in an amount to achieve 35-90% by weight of the ibuprofen medicament in the composition, preferably 35-75% by weight, more preferably 40-70% by weight, and most preferably 50-65% by weight. Unit doses may contain ibuprofen drug in amounts of 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 500 mg, 600 mg and 800 mg. If salts or other derivatives are used, the exact dose is usually chosen to achieve a dose of ibuprofen corresponding to the above values, for example 256 mg of the dihydrate

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Sodium salt or 342 mg dl of lysine salt provides a dose equivalent to 200 mg ibuprofen. Suitably, the pharmaceutical compositions are administered in divided doses throughout the day such that the amount of ibuprofen (or the corresponding amount of its salt) to be administered at each dosing time is in the range of 50 to 800 mg (preferably 50 to 400 mg, more preferably 200 to 400 mg). Therefore, if two dosage forms are to be administered at any one time, the dosage form may contain 25 to 400 mg (preferably 50 to 300 mg, more preferably 100 to 200 mg) of the ibuprofen medicament.

The domperidone medicament may be in the form of domperidone or a pharmaceutically acceptable salt thereof, especially an acid addition salt such as a maleate. The domperidone drug is in the form of domperidone or a maleate salt thereof.

Representative compositions of the present invention may comprise domperidone drug in an amount of 0.1 to 20% by weight, suitably 0.5 to 15% by weight, preferably 1 to 10% by weight, and more preferably 1 to 5% by weight of the composition. Unit doses may contain domperidone drug in amounts of 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, and 50 mg. Suitably, the pharmaceutical compositions are administered in divided doses throughout the day such that the amount of domperidone (or equivalent amount of salt) administered at each dosing time is 5 to 50 mg (preferably 5 to 25'mg, more preferably 5 ' up to 20 mg). Therefore, if two dosage forms are to be administered at any one time, the dosage form may comprise 2.5 to 25 mg (preferably 2.5 to 12.5 mg, more preferably 2.5 to 10 mg) of domperidone drug.

Preferred compositions of the present invention are in unit dosage form containing 50 to 400 mg ibuprofen drug and 5 to 20 mg domperidone drug. More preferred compositions comprise 100-400 mg or 100-200 mg ibuprofen drug and 5-10 mg domperidone drug.

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The solid dosage form may be in the form of a controlled release tablet, a suppository, effervescent granules, chewable tablets and a soluble buccal dosage form, or in any other suitable form. The ibuprofen and domperidone medicaments may preferably be administered as a compressed solid dosage form, further preferably orally.

Preferred solid dosage forms are in the form of tablets for oral administration (conventional, retarded and mixed release profile), gelatin capsules (hard and soft), dispersible tablets, chewable tablets, effervescent powders and granules. More preferably, the solid dosage form is a tablet, either prepared by direct compression of the powdered ingredients or by granulation of the ibuprofen medicament, in which case it may be domperidone. drug in granular form or in powder form combined with granular form.

The unit dosage form preferably comprises one or two dosage forms, preferably tablets.

The composition of the present invention may be adapted for substantially immediate release, controlled release, or each active ingredient may be released at different rates. Thus, the composition may exhibit a variety of release profiles. For example, the time period for which each drug is released may begin shortly after ingestion, or, if the dosage form permits, controlled release after some time. The desired release profile is usually determined by a number of factors including the nature of the active ingredient, the type of treatment and the nature of the controlled release additive. Optionally, the composition may be prepared with one or two layers that substantially prevent release until the dosage form reaches a certain point in the digestive tract (e.g., pH) or that acts as a barrier and thus reduces the release rate. Optional layers may also be prepared which may also contribute to the release profile of the active ingredients.

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The carrier suitably constitutes up to 65% by weight of the dosage form. A preferred dosage form comprises 20 to 60% by weight of carrier, more preferably 25 to 60% by weight, and most preferably 30 to 50% by weight. The carrier is formulated to form a stable solid composition upon mixing the ingredients. The ibuprofen and domperidone may thus be combined in one dosage form, preferably as complete an la ₇ mixture with the carrier.

The carrier consists of ingredients not containing povidone. The carrier comprises at least one inert diluent, for example one or more sugar diluents, alkaline earth metal salts and oxides, cellulose diluents, methacrylate diluents, starch diluents, glyceryl diluents and vegetable oil based diluents. Examples of inert diluents include one or more sugars, including sugar alcohols (e.g., dextrose, lactose, sucrose, compressible sugar, mannitol and sorbitol), dextrates, dextrin, maltodextrin, calcium carbonate, calcium sulfate, calcium hydrogen phosphate, calcium phosphate, glyceryl palmitate hydrogenated vegetable oil (type I), kaolin, magnesium carbonate, magnesium oxide, microcrystalline cellulose, polymethacrylates, potassium chloride, powdered cellulose, hydroxypropylmethylcellulose, pregelatinized starch, sodium chloride, starches (e.g. wheat starch, corn, starch, potato starch, rice starch) , manioc starch) and modified starches. Preferred diluents have good cohesive properties. and used to join the substances together. Other preferred diluents are compressible substances and include a cellulosic component, a phosphate component, a starch component or a sugar component or mixtures thereof. Preferred examples of such diluents are microcrystalline cellulose, hydroxypropyl methylcellulose, dibasic calcium phosphate, calcium phosphate, maltodextrin, and soluble sugars such as lactose, sucrose and dextrin, especially microcrystalline cellulose, calcium phosphate and lactose. In a particularly preferred composition, the carrier comprises substantially one or more of the following diluents: microcrystalline cellulose, calcium phosphate and lactose. Most preferred diluents exhibit a combination of good cohesive properties (or binder properties) and good compressibility. More than one ingredient can provide these properties. These components may be used in the composition in an amount customary in the art. Usually, it will be in the range of 10 to 50% by weight of the composition, preferably 20 to 50% by weight of the composition, more preferably 20 to 45% by weight of the composition and most preferably 20 to 35% by weight of the composition.

Some inert diluents also have disintegrating properties, for example microcrystalline cellulose and / or hydroxypropyl methylcellulose, and therefore it is not always necessary to add an additional disintegrating agent. However, in conventional or rapid release tablets, it is preferable to use a disintegrant in addition to the diluent, although the diluent has or does not have disintegrating properties. Other diluents, for example some soluble diluents, have substantially no disintegrating properties. These facts. are known to those skilled in the art, and reference may be made in this connection to the Handbook of Pharmaceutical Excipients (Second Edition, Wade & Weller).

Examples of disintegrants include one or more selected from the group consisting of alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silica, croscarmellose sodium, guar gum, magnesium aluminum silicate, methylcellulose. microcrystalline cellulose, powdered cellulose, starch (e.g., wheat starch, corn starch, potato starch, rice starch, maniotic starch), pregelatinized starch, sodium alginate, sodium starch glycolate, low substituted hydroxypropylcellulose, or mixtures thereof. Preferably, the composition of the present invention comprises at least one disintegrant. Preferred disintegrants comprise one or more substances selected from the group consisting of croscarmellose sodium and sodium starch glycolate. These components are used in the composition in an amount known to those skilled in the art. This amount will generally be up to 15% by weight of the composition, for example 1 to 10% by weight, preferably 2 to 8% by weight of the dosage form.

Release modifying agents may also include agents that delay the release of any drug, such as polymers that swell in the presence of water (e.g., cellulose or gum ethers, such as xanthan gum and sodium alginate), or film-forming polymers (e.g., ethylcellulose or acrylic resin).

Preferred compositions comprise from about 20% to about 60% by weight of the carrier, including up to about 15% by weight of the disintegrating agent. Other preferred compositions comprise a carrier which is substantially a diluent without disintegrating properties (e.g., calcium phosphate), a diluent with disintegrating properties (e.g., microcrystalline cellulose). a separate disintegrant (e.g., croscarmellose sodium) and a lubricant (e.g., magnesium stearate or stearic acid).

The composition may also contain other ingredients. These components will be used in the composition in an amount known to those skilled in the art. They may be glidants such as talc or colloidal silicon dioxide, which may preferably be used in an amount of up to 4% by weight of the composition, for example 0.5 to 2.0% by weight of the composition. The composition may also contain lubricants such as stearic acid, sodium lauryl sulfate, polyethylene glycol, hydrogenated vegetable oil, hydrogenated cottonseed oil, calcium stearate, sodium stearyl fumarate, or sodium stearyl fumarate.

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Magnesium stearate or mixtures thereof. They may be used in an amount of up to 4% by weight of the dosage form, for example 0.5-2% by weight of the composition. In addition, anti-tack agents such as talc may be added in an amount of up to 4% by weight of the composition, for example 0.5 to 2% by weight of the composition.

Most often, in the solid composition of the present invention, the ingredients are compressed into tablets. Thus, the carrier can be compressed with the active ingredients to form a solid tablet with cohesive properties. The tabletting process may comprise a granulation step wherein at least one active ingredient and at least a portion of the diluent are mixed with a granulating liquid, either in the presence or absence of a granulating agent, and formed into a granular composition having sufficient fluidity and cohesive properties to be further processed. with other ingredients and compress into tablets. The granulation step can also be carried out dry, i.e. in the absence of a granulation liquid.

Thus, in a preferred aspect, the present invention provides a solid pharmaceutical composition comprising a compressed mixture of (i) granules comprising an ibuprofen medicament and optionally a domperidone medicament, a carrier comprising a release modifying additive; and (ii) a lubricant and optionally a glidant.

The composition can be made by compressing the granular composition with a lubricant and optionally a glidant with other optional ingredients and characterized in that the granular composition is prepared by a granulation process in the absence of a water-soluble polyvinylpyrrolidone.

The granulation step can be carried out in a dry manner by methods such as slugging or roller compaction; · *. . i i

-] (roller compaction) or by melt extrusion. It is preferable to add liquid in the granulation process. This process is called “wet granulation”. In a preferred wet granulation process, a granulation liquid in which ibuprofen is soluble is used. The dissolved ibuprofen after drying contributes to the adhesion of the granular composition without the need for a granulating agent such as water-soluble polyvinylpyrrolidone used in the granulation process. However, if necessary, a granulating agent may be used. The preferred granulating liquid is isopropyl alcohol. In another preferred method, a granulating liquid is selected in which ibuprofen may be substantially insoluble or only partially soluble (e.g. in water) and it may be advantageous to further add the granulating agent.

In another preferred aspect, the present invention provides a solid pharmaceutical composition comprising as components:

(a) an ibuprofen medicament; (b) a domperidone medicament;

(c) a carrier comprising a mixture of an inert diluent, a disintegrating component, at least one disintegrating agent and a granulating agent, said carrier being adapted to form a stable composition upon mixing the components.

Thus, the composition preferably further comprises a granulating agent. The terms "granulating agent and" binder are used interchangeably herein. Particularly preferred is a wet granulation process wherein the granulating agent imparts cohesive properties to the powders. This can be achieved in the presence of a suitable solvent (preferably water) which causes the granulating agent to adhere to the surface of the granular or powdered material and which, after drying, maintains the cohesion between the particles. Preferably, the solid compositions of the present invention are produced by a process comprising a wet granulation step in the process. · ·

4% of the granulating liquid and granulating agent. The granulating agent may be solid; it may be present as a solid powder material or may be dissolved in the granulating liquid. The granulating agent is preferably selected from polymeric substances, for example natural or synthetic gums or cellulosic materials, sugar granulating agents and starch granulating agents. Examples of granulating agents include, for polymeric substances, gum arabic, alginic acid, carbomer, sodium carboxymethylcellulose, alkylcellulose (such as methylcellulose and ethylcellulose), gelatin, guar gum, hydroxyalkylcellulose (such as hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose) ; in the case of sugar granulating agents (including sugar alcohols), liquid glucose, maltodextrin, sucrose and sorbitol; in the case of starch granulating agents, dextrin, pregelatinized starch, starch (e.g. wheat starch, corn starch, potato starch, rice starch, maniotic starch) and modified starch; as well as magnesium aluminum silicate and zein; or mixtures thereof. Preferred polymeric materials are hydroxypropylcellulose and hydroxypropylmethylcellulose. These additives are used in the composition in an amount known to those skilled in the art. It is usually in the range of up to 10% by weight (for example 0.1 to 10%), or preferably 0.5 to 5% by weight and most preferably 2 to 4% by weight.

In a particularly preferred aspect of the present invention is. a pharmaceutical composition in the form of a granulate, i. in granular form. In another preferred aspect, the pharmaceutical composition is a solid dosage form, preferably a tablet.

The composition of the present invention may be coated, for example, with a sugar or film having minimal effect on disintegration time. The preferred solid dosage form of the present invention is preferred. «» ···· · · aaaa aa «β» finding, i. the tablet may be film or sugar coated by conventional coating techniques.

The compositions of the present invention are prepared by admixing the ingredients, for example by mixing said lipuprofen medicament and said domperidone medicament with a carrier to form a homogeneous mixture and converting the mixture into a suitable dosage form, for example by compression, spraying or filling into capsules. Preferred dosage forms are prepared by compression, for example, into tablets (including tablets for oral administration, effervescent tablets and tablets adapted for dispersion in a liquid prior to ingestion), suppositories or tablets for insertion, and buccal or sublingual tablets. In the compression process, tablets are usually formed by wet granulation, dry granulation or direct compression. In these processes, the ingredients are mixed as desired either as a homogeneous mixture which is then compressed into tablets or various mixtures are prepared which are then compressed to give tablets with different layers. In the wet granulation process, one or both of the active ingredients are homogeneously mixed with at least a portion of the carrier and formed into granules by adding a granulating liquid, preferably in the presence of a granulating agent. Both the ibuprofen medicament and the domperidone medicament are preferably present in the granular product. The granulating agent may be added to the granulating liquid (preferably dissolved therein) before the mixture of the active ingredients and the carrier is added, or the granulating agent may be mixed with the active ingredient and the carrier prior to the addition of the granulating liquid. The granulating liquid may be water or an organic solvent, for example a C 1 -C 6 alkanol such as ethanol, propan-1-ol or propan-2-ol or mixtures thereof. The granular material is then dried, sieved, added as necessary. to the other ingredients and mixed to form a homogeneous mixture and then compressed into tablets. In the dry granulation process, the components are formed into granules in the absence of each of the wastes. · · «· # · · Φ · φ · · · · and in this case, roller compaction or slugging. The granules are then mixed with the remaining ingredients and compressed into a solid dosage form. The composition of the present invention may also be prepared by stitching the powder components into a container. then mixing to form a homogeneous mixture. The mixture may be directly compressed into tablets. The direct compression process does not include a pre-granulation step. The ingredients are mixed to form a homogeneous mixture and then filled into a tabletting machine and compressed into tablets.

In a preferred method, the composition is prepared by a process comprising the wet granulation step described above. Suitably both active ingredients are present in the granular product together with an inert diluent and disintegrant. In a composition prepared in a more preferred manner, a granulating agent or binder is present and comprises cellulosic substances (more preferably hydroxypropylmethylcellulose). The granulating liquid is preferably water. In another preferred method, the granulating agent or binder is mixed with the powdered ingredients and the granulating liquid (preferably water) is added. The granulation product is preferably mixed with a lubricant and compressed into tablets.

Thus, in another aspect, the present invention provides a method of preparing a compressed composition comprising (a) granulating said ibuprofen medicament, optionally with said domperidone medicament, with at least a first portion of said carrier and a granulating liquid; (b) drying said granules; (c) mixing with the lubricant and optionally a glidant to form a homogeneous mixture; and (d) compressing into tablets. In this method, the preferred granulating agent is a cellulosic material.

9 9 * 9 · 99 99 99 99 99 99 99 99

The dosage forms of the present invention may, if appropriate, contain other compatible pharmacologically active ingredients, for example codeine, caffeine or vitamin products.

Ibuprofen / domperidone combination therapy is primarily intended for the treatment of migraine and other diseases in which it is desirable to combine the properties of ibuprofen (particularly anti-inflammatory and antipyretic properties) with those of domperidone (especially for the treatment of nausea and dyspepsia).

According to the present invention there is also provided the use of a carrier substantially free of povidone and comprising at least one diluent combined with at least one release modifying agent in a stable pharmaceutical composition comprising ibuprofen and domperidone medicaments. The release modifying agent is preferably a disintegrating agent.

AND

Further general information regarding ingredients can be found in The Handbook of Pharmaceutical Excipients (Second Edition: Ed. Wade and Weller) and Remington: Science and Practice of Pharmacy (19 Ed.: Ed. Gennaro).

The invention will now be illustrated by the following non-limiting examples. In these examples, the ingredients are obtained from the sources listed below:

Both microcrystalline cellulose and colloidal cellulose are available under the trade names Avicel and are available from FMC Corporation; croscarmellose sodium is available from FMC Corporation under the tradename Ac-Di-Sol; hydrogenated cottonseed oil is available from Edward Mendeil under the trade name Lubritab; hydroxypropyl methylcellulose is available from Dow Corporation under the tradename Methocel E 50; hydroxypropyl cellulose is available from Dow Corporation under the tradename Klucel LF; colloidal silica is available from Degussa under the tradename Aerosil; xanthan gum is available from Monsanto under the tradename Keltrol; Polysorbate 80 is polyoxyethylene 20 oleate; Polysorbate 60 is polyoxyethylene 20 stearate.

DETAILED DESCRIPTION OF THE INVENTION

Examples 1 to 3

Component Example 1 Example 2 Example 3 Ibuprofen 60.5% 60.5% 60.3% Domperidone maleate 1.9% 1.9% 1.9% Microcrystalline cellulose 6,1% 6,1% - Croscarmellose sodium 9.7% 9.7% 3.0% Magnesium stearate 0.6% - 0.6% Hydrogenated seed oil - 0.6% - cotton Calcium phosphate 18.2% 18.2% - Oil Hydroxyp1cellulose 3.0% - - Hydroxypropylmethylcellulose - 3.0% - Sorbitol -. 34.2% The composition of Example 1 prepare help next

steps:

(a) ibuprofen, domperidone maleate, calcium phosphate, hydroxypropylcellulose, croscarmellose sodium and microcrystalline cellulose are sieved and mixed to form a homogeneous mixture;

(b) granulating the mixture with water and drying;

(c) mixing the dried granules with magnesium stearate;

(d) compressing the lubricated granules to form tablet cores each containing 200 mg ibuprofen and 5 mg domperidone or each containing 400 mg ibuprofen and 10 mg domperidone;

(e) the tablet cores are coated with a conventional coating film.

·

9 4 4 4 9 4 '9 4 9 4 «994 4444 4

4 '444' 44 -4

9 · f 9 9444 94 944

Example 2 is performed in a similar manner to that described in Example 1 except that in step (a), hydroxypropylmethylcellulose replaces hydroxypropylcellulose as a granulating agent and hydrogenated cottonseed oil replaces magnesium stearate as a lubricant in step (c).

Example 3 is carried out in a similar manner to that described in Example 1 except that sorbitol replaces microcrystalline cellulose and calcium phosphate and no granulating agent is present in step (a).

Examples 4 to 6

Component Example 4 Example 5 Example Ibuprofen 60.5% 62.4% 60.5% Domperidone maleate 1.9% 2.0% 1.9% Microcrystalline cellulose 6,1% 6.3% 6,1% Croscarmellose sodium 9.7% 10.0% 9.7% Stearic acid 0.6% 0.6% - Magnesium stearate - - 0.6% Calcium phosphate 18.2% 18.7% 18.2% Hydroxypropylmethylcellulose 3.0% - 3.0% Tablet cores contain 200 mg or 400 mg ibuprofen:

Example 4 is carried out in a similar manner to Example 1 except that hydroxypropylmethylcellulose replaces hydroxypropylcellulose as a granulating agent in step (a) and stearic acid replaces magnesium stearate as a lubricant in step (c).

Example 5 is performed in a similar manner to that described in Example 1 except that no granulating agent is present in step (a), isopropanol is used as the granulating liquid in step (b) and stearic acid replaces magnesium stearate as the lubricant in step (b). C).

Example 6 is carried out in a similar manner to that described in Example 1 except that hydroxypropylmethylcellulose replaces hydroxypropylcellulose as the granulating agent in step (a).

9% by weight 9% by weight 9% by weight

Example 7

Component

Ibuprofen

Domperidon

Colloidal silica Magnesium stearate Lactose

Microcrystalline cellulose

Sodium lauryl sulfate

Sodium starch glycolate

59 ', 8 % 1, 9 % 0, 2 % 0, 6 % 9, 2 % 22nd / 2 % 1, 9 % 3, 5 %

The composition of Example 7 is prepared by stitching and blending all of the above powdered ingredients to form a homogeneous mixture and compressing to form tablet cores containing 200 mg ibuprofen and 5 mg equivalent of domperidone or containing 400 mg ibuprofen and 10 mg equivalent of domperidone.

Tablets containing 200 mg ibuprofen 10 mg domperidone equivalent or 40 mg ibuprofen and 20 mg domperidone equivalent prepared according to the procedure may also be prepared. The racemic ibuprofen in the above examples may be replaced by a therapeutically equivalent weight of S (+) - ibuprofen or the sodium or lysine salt of racemic ibuprofen or S (+) - ibuprofen.

Examples 8 to 35

The following compositions (Examples 8 to 35) were prepared and tested as described below to determine their stability. The components for each example are shown in Tables 1, 2 and 3.

Examples 8 to 31 are carried out by mixing the powder components to form a homogeneous powder mixture.

Examples 32 to 35 are carried out by mixing the powder components to form a homogeneous powder mixture and then compressing them into tablets.

The compositions of the examples were tested for degradation of domperidone after storage for 1 week under controlled conditions at 50-60 ° C for detectable levels of cis-5-chloro-1- [1- [3- (2,3-dihydro-2-oxo-1H-pollutant)]. benzimidazol-1-yl) propyl] piperidin-4-yl] -2,3-dihydro-1H-benzimidazol-2-one-1-oxide (referred to herein as domperidone N-oxide). The measurement is performed by HPLC analysis. Examples where no detectable amount of domperidone N-oxide (<0.1%) was found to be satisfactory. ,

Table 1

Example Quantity s beds (mg) 8 9 10 11 12 13 Ibuprofen 200.0 200.0 200.0 200.0 200.0 2 00.0 Domperidon 2.5 2.5 2.5 2.5 2.5 2.5 Microcrystalline cellulose 100.0 100.0 100.0 100.0 100.0 100.0 Hydroxypropylmethylcellulose 10.0 Sodium lauryl sulfate - - 10.0 - - - Talc - - - 10.0 - - Magnesium stearate - - - - 10.0 - Stearic acid - - - - - 10.0

Table 1 (continued)

Example Component amount (mg) 14 15 Dec 16 17 Ibuprofen 200.0 200.0 200.0 200.0 Domperidon 2.5 2.5 2.5 2.5 Microcrystalline cellulose 100.0 100.0 100.0 100.0 Hydroxypropylmethylcellulose 10.0 - - - Sodium starch glycolate - 10.0 - - Hydroxypropylcellulose - - 10.0 - Hydrogenated vegetable oil - - - 10.0

• ·

Table 2

Example Component amount (mg) 18 19 Dec 20 May 21 22nd 23 Ibuprofen 200.0 200.0 200.0 200.0 200.0 200.0 Domperidon 2.5 2.5 2.5 2.5 2.5 2.5 Lactose 100.0 100.0 100.0 100.0 100.0 100.0 Hydroxypropylmethylcellulose 10.0 Sodium lauryl sulfate - - 10.0 - - - Talc - -  - 10.0 - - Magnesium stearate - - - - 10.0 - Stearic acid - - -. - - 10.0

Table 2 (continued)

Example Component amount (mg) 24 25 26 27 Mar: 28 29 30 31 Ibuprofen 200.0 200.0 200, 0 200.0 2 0 0.0 200.0 200.0 200.0 Domperidon 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 Colloidal oxide Silica 100.0 Phosphate Calcium 100.0 - • Cornstarch - - 100.0 - - - - -. Icing sugar - - - 100.0 - - - - Sorbitol - - - - 100.0 - - - Carboxymethylcellulose calcium 100.0 - Calcium hydrogen phosphate 100.0 Maltodextrin - -  - -. - - - 100.0

Table 3

Example Component amount (mg) 32 3 3 34 35 Ibuprofen 200.0 200.0 200.0 200.0 Domperidon 2.5 2.5 2.5 2.5 Microcrystalline cellulose 100.0 100.0 - - Lactose - - 100.0 100.0 Magnesium stearate 10.0 - 10.0 - Stearic acid - 10.0 - 10.0

φφφ φ ': · Φ ♦ · Φ Φ Φ Φ

ΦΦΦΦ ΦΦΦΦ Φφ ΦΦΦΦ 4

Analysis of the compositions of Examples 8 to 35 showed no detectable amount of domperidone N-oxide as an impurity (i.e., <0.1 wt%).

A disintegrant (e.g., croscarmellose sodium), a glidant (e.g., colloidal silica), as well as a lubricant (e.g., magnesium stearate) (as described above) may be added to the components of Examples 8 to 31, followed by compression into tablets.

Example 36

% Wt.

Ibuprofen 59.9 (200 mg)

Domperidone 0.6

Microcrystalline cellulose 18.0

Lactose 12.0

Magnesium stearate 0,5

Starch

A tablet formulation containing the ingredients mentioned above was prepared in a manner similar to that described in Example 3 or by direct compression in a manner similar to that described in Example 7.

The following may also be prepared. .resources:

Example 37

Prolonged-release tablets

% Wt.

Domperidone maleate 3.7

Ibuprofen 74.1

Xanthan gum 18.5

Hydroxypropylmethylcellulose 2,2

Stearic acid 1,1

Colloidal silica 0.4

The extended release tablet may be prepared by granulating hydroxypropyl methylcellulose and ibuprofen with about 20% of the total xanthan gum content using water as the granulating agent. The ibuprofen granules are mixed with the remainder of the xanthan gum. and • · · · 0 0.0 0 0 0 0 000 0 0

0 0 0 0 0 0 0 * 00 00 0000 00 000 of the other ingredients and compressed into tablets containing 400 mg ibuprofen and 20 mg domperidone.

Example 38

Capsules

Component% by weight

Ibuprofen 60.6

Domperidone 3.0

Lactose 30.3

Croscarmellose sodium 6.1

The ingredients are mixed to form a homogeneous mixture and filled into conventional hard gelatin capsules containing 200 mg ibuprofen and 10 mg domperidone.

Example 39

Liquid suspension Component. Domperidone Maleate Ibuprofen Colloidal Cellulose Glycerin Sorbitol. Kaolin Polysorbate 80 Purified water BP wt.

0.2

2,0

2.5

15.0

10.0

1.0

0,1 to 10 0

Polysorbate 80 can be added to water and then glycerine is added with stirring. Domperidone and ibuprofen, as well as colloidal cellulose, sorbitol and kaolin (as a thickener), can then be added under continuous stirring until a satisfactory suspension is obtained.

Example 40

Sparkling .granule

Slažka

Domperidone maleate Ibuprofen

Microcrystalline cellulose Powdered sugar%, wt.

0.3

10.2

2.5

51,2 • · Uůmatax component

Malic acid 25,5

Sodium bicarbonate 7.7

Anhydrous sodium carbonate 2.6

Sodium lauryl sulfate 0.1

Domperidone, ibuprofen, microcrystalline cellulose and sugar are granulated with water and then thoroughly dried. The remaining ingredients were added to form a powder mixture and filled into sachets each containing 400 mg ibuprofen and 20 mg domperidone maleate.

Example 41

Chewable tablets

% Wt.

Ibuprofen 17,6

Domperidone maleate 0.6

Sucrose 66.0

Sorbitol 13.2

Annealed silica 0,8

Stearic acid 1,8

The above ingredients are mixed to form a homogeneous mixture and then compressed directly to form a chewable tablet containing 200 mg ibuprofen and 7.5 mg domperidone maleate.

Example 42

Suppositories

Component, wt.

Domperidone maleate 0.9

Ibuprofen 23,6

Polysorbate 60 4.7

Witepsol H185 70.8

The polysorbate is dispersed in molten Witepsol and then ibuprofen and domperidone are added. The mixture is then injected into the molds to form a suppository shape and cooled to room temperature. Suppository contains 600 mg ibuprofen and 22.5 mg domperidone maleate.

• · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

2q ·· ············

Comparative Example 1

200 mg Ibuprofen and 2.5 mg domperidone maleate are formed into granules by standard granulation method using water and isopropyl alcohol as granulating liquid. After 1 week of storage at 50-60 ° C, no detectable level of domperidone N-oxide appears as an impurity (described in the test above) (i.e. <0.1%). Further, when 10 mg of povidone is added to the granules, an impurity level of greater than 1.5% (as defined above) is found after a week of storage at 50-60 ° C.

Comparative Example 2

Ibuprofen is mixed with domeperidone maleate in a conventional mixer to form a homogeneous powder mixture containing 200 mg ibuprofen and 2.5 mg domperidone maleate. The product is stored at 50-60 ° C for one week. No detectable amount of impurities (as defined above) was detected after analysis of the storage product.

In contrast, when 20 mg povidone is added to the powder mixture. the level of impurities after a week of storage at 50-60 ° C is found to be about 0.7% by weight. When crospovidone (Kollodon CL) is added to the tablets instead of povidone, the level of impurities (defined above) is determined after one week of storage at 50-60 ° C at about 7.9% by weight.

Comparative Examples 3 and 4

In a similar manner to that described in Example 2, 10 mg of povidone was added to the powder mixture of Example 8 (Comparative Example 3) as well as the powder mixture of Example 19 (Comparative Example 4) and after one week of storage at 50 to 60 ° C. a level of impurities (as defined above) of about 0.5% by weight is determined. Results with and without povidone (pvp) are shown in Table 4 below. ,

9 99 99 99 9 9 9 9

99 9 9

9 9 9 9 9

9 9 9 9 9 9 9 9 9 9 9 9 9 99 99 9999 99

Table 4

Comparative example % impurity (1 week) without pvp % impurity (1 week) with pvp 3 <0,1% ~ 0,5% 4 <0,1% - 0,5%

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Claims (24)

PATENT CLAIMS A stable pharmaceutical composition comprising a mixture of (i) an ibuprofen medicament; (ii) a domperide drug; and (iii) a carrier, wherein the carrier is substantially free of povidone and comprises at least one diluent combined with at least one release modifying agent. A stable pharmaceutical composition comprising a mixture of (i) an ibuprofen medicament (ii) a domperidone medicament; and (iii) a carrier; characterized in that the carrier is substantially free of povidone and comprises at least one diluent combined with at least one release modifying agent except (a) a compressed tablet comprising granular ibuprofen and a carrier comprising substantially either corn starch in an amount of 35 to 38% of the total tablet weight in combination with dried corn starch in an amount of 3 to 4% of the total weight of the tablet or microcrystalline cellulose in an amount of 10 to 11% of the total weight of the tablet in combination with croscarmellose sodium at 14 to 16% of the total weight of the tablet tablet weight; (b) a directly compressed tablet comprising a carrier consisting essentially of microcrystalline cellulose in an amount of 8 to 11% of the total weight of the tablet and a lactose in an amount of 5 to 6% of the total weight of the tablet; · · * * * * * · · • (C) hard gelatine capsules containing a carrier consisting essentially of maize starch in an amount of 15 to 20% of the total weight of the capsule content in combination with pregelatinized starch in 5 to 6% by weight of the total capsule content. 3. A compressed tablet composition comprising an ibuprofen medicament, a domperidone medicament, and a carrier consisting of a compressed mixture of (a) a granular component containing said. an ibuprofen medicament and at least a first portion of said carrier; and (b.) a powder component comprising a lubricant and optionally another portion of said carrier, said domperidone medicament may be present in each of components (a) and (b), wherein the carrier is substantially free of povidone and comprises at least one diluent combined with at least one disintegrant. , A composition according to any one of claims 1 to 3. comprising a granulating agent present in an amount up to 10% of the total weight of the tablet. Composition according to any one of claims 1 to 4, characterized in that it comprises a granulating agent consisting essentially of one or more of the following: polymeric granulating agents selected from natural gums, synthetic gums and cellulose-based substances; a sugar granulating agent; a starch granulating agent. A composition according to any one of claims 4 and 5, wherein the granulating agent is a cellulose derivative. J ť, 7 '· 7 -' '! <<' - 7-. -2- [.alpha.] - @ 22 I (12 @ 22 -1) @ -1. 7 I; · 'Λ-. d / th / oi?. 'ϊ' - ^'·?' -. z '' ·. . ? ' 7: ϊ '''' _/:: /, / ^-; /;/-7.?./- ^;; '<-''. // ^. / ^λ '.// ^: ''/ .. / f'. ·. 1 ' ^: '. / '/ -> / - ^; - / · 34 ········ ^β ** ·, 7. The tablet of claim 6, wherein the granulating agent is hydroxypropylcellulose or hydroxypropylmethylcellulose. 8. Directly (i) (ii) (iii) a compressed tablet composition comprising an ibuprofen medicament; domperidone drug; and a carrier, wherein the carrier is substantially free of povidone and comprises at least one diluent combined with at least one disintegrant and a lubricant. Composition according to any one of claims 1 to 8, characterized in that it contains 20 to 60% of the carrier, including up to 15% of the disintegrating agent alone. Composition according to any one of claims 1 to 9, characterized in that the carrier consists essentially of a diluent substantially free of disintegrating properties, a diluent. with disintegrating properties, separate disintegrating agent, and lubricating agent. •••and·..··.·. . . ,. Composition according to any one of claims 1 to 10, characterized in that the carrier comprises a cellulosic component, a phosphate component, a starch component or a sugar component or mixtures thereof. Composition according to any one of claims 1 to 11, characterized in that the carrier consists essentially of one or more of the following diluents: microcrystalline cellulose, calcium phosphate and lactose. Composition according to any one of claims 1 to 12, characterized in that it comprises one or more discrete disintegrants, including croscarmellose sodium and sodium starch glycolate. Composition according to any one of claims 1 to 13, characterized in that it is in unit dosage form containing 50 to 400 mg of ibuprofen drug and 5 to 20 mg of domperidone drug. A solid composition comprising an uncompressed mixture of (i) an ibuprofen medicament; (ii) a domperidone drug; and (iii) carriers; characterized in that the carrier is substantially free of povidone and comprises at least one diluent combined with at least one release modifying agent. A liquid or semisolid composition comprising three (i) an ibuprofen medicament; (ii.) a domperidone drug; and (iii). carrier; characterized in that the carrier is substantially free of povidone and comprises at least one diluent combined with at least one release modifying agent. Composition according to any one of claims 1 to 16, characterized in that it contains either racemic ibuprofen or S (+) -ibuprofen or its sodium or lysine salt, which are present in an amount of 50 to 65% by weight of the composition. A composition according to any one of claims 1 to 17, comprising either domperidone or its maleate salt, which are present in an amount of 1 to 5% by weight of the composition. 19. Use of a carrier substantially free of povidone and comprising at least one diluent combined with at least one release modifying agent in a stable pharmaceutical composition comprising an ibuprofen medicament and a domperidone medicament. The use of claim 19, wherein the release-modifying agent is a disintegrating agent. 21. A method of preparing a pharmaceutical composition according to claim 1, wherein said ibuprofen medicament and said domperidone medicament are combined with the carrier in a homogeneous mixture and formed into a unit dosage form. A method for preparing a compressed composition according to any one of claims 1 to 6, wherein (a) granulating said ibuprofen medicament, optionally with said domperidone medicament, with at least a first portion of said carrier and a granulating liquid; (b) drying said granules; (c) mixed with a lubricant and optionally a glidant to form a homogeneous mixture; and (d) compressed into tablets. 23. The method of claim 22, further comprising a cellulosic substance as a granulating agent. 24. A method of treating migraine comprising administering to a patient in need of such treatment a stable pharmaceutical composition according to any one of claims 1 to 18.