Orodispersible pharmaceutical compositions comprising an amino acid salt of ibuprofen

Abstract

A pharmaceutical orodispersible composition comprising: a) particles comprising a pharmaceutically acceptable ibuprofen amino acid salt, in which said ibuprofen salt is coated with a taste-masking coating comprising a polymer selected from the group consisting of: a polysaccharide, a polymer with pH-dependent solubility, a polymer with pH-independent solubility and mixtures thereof, b) a mix of extra-particulate excipients. A taste-masked particle as defined, comprising: (i) a pharmaceutically acceptable ibuprofen salt, in which said salt is an ibuprofen L-arginine salt; (ii) a taste-masking coating comprising a polymer selected from the group consisting of: a polysaccharide, a polymer with pH-dependent solubility, a polymer with pH-independent solubility and mixtures thereof.

Description

[0001] TITLE

[0002] ORODISPERSIBLE PHARMACEUTICAL COMPOSITIONS COMPRISING AN AMINO ACID SALT OF IBUPROFEN

[0003] FIELD OF INVENTION

[0004] The present invention relates to solid orodispersible pharmaceutical compositions containing coated ibuprofen salts, which do not cause sensory irritation to the oral cavity and which have optimal organoleptic characteristics and can therefore be taken even in the absence of water, while maintaining a rapid onset of the therapeutic action.

[0005] PRIOR ART

[0006] Ibuprofen (chemical name 2-(4-isobutylphenyl)propionic acid) is a well- known pharmaceutical active principle with analgesic, antiphlogistic and antipyretic properties.

[0007] Ibuprofen, and the pharmaceutically acceptable salts thereof, are used for the treatment of pain such as headache, toothache, menstrual pain, neuralgia, osteoarticular and muscular pain, episiotomy and postpartum pain, pain from dental avulsions, postoperative pain, and pain caused by minor injuries or trauma.

[0008] Ibuprofen is also used in various forms of rheumatism such as rheumatoid arthritis, ankylosing spondylitis, Still's disease, osteoarthritis (cervical, dorsal or lumbar arthrosis, gonarthrosis, coxarthrosis, polyarthrosis, etc.), tendinitis, fibrositis, bursitis, myalgia, lumbago, scapulohumeral periarthritis, sciatica and radiculitis-neuropathy.

[0009] Various oral pharmaceutical forms containing ibuprofen and pharmaceutically acceptable salts thereof are currently marketed in the dosage range from 100 to 800 mg.

[0010] In the landscape of oral pharmaceutical preparation containing ibuprofen and pharmaceutically acceptable salts thereof are available: film-coated swallowable tablets, effervescent tablets, chewable tablets, orodispersible tablets, hard gelatin capsules, soft gelatin capsules, granules to be dispersed in water, effervescent granules to be dispersed in water, orodispersible powders, syrups, and oral suspensions.

[0011] Said oral pharmaceutical forms are characterized by a release profile, absorption and therapeutic effect that may be more or less rapid depending on the chemical form in which ibuprofen is present; salified forms provide a much faster absorption profile due to the solubility of the salt, which allows rapid onset of the therapeutic effect.

[0012] Non-salified ibuprofen, which is sparingly soluble in gastrointestinal fluids, is instead characterized by a slower absorption profile, which results in a slower onset of the therapeutic effect. It follows that only salified forms of ibuprofen can guarantee a very rapid therapeutic effect, which is particularly important in the pain-relieving and antipyretic therapies for which the active principle is intended. In point of fact, for the same form and dosage, oral pharmaceutical forms containing non-salified ibuprofen display a later plasma peak than those containing pharmaceutically acceptable ibuprofen salts.

[0013] For example, the plasma peak of swallowable tablets containing 400 mg of non-salified ibuprofen is detected more than 60 minutes after taking the tablets, whereas in those at the same dosage containing ibuprofen arginine salt, the plasma peak is detected in about half the time compared to the former i.e. already within 30-35 minutes of taking. It should be noted that the plasma peak time of ibuprofen arginine salt in the form of granules to be dissolved in water at the dosage of 400 mg of ibuprofen is further reduced, thus allowing very rapid relief for the patient.

[0014] One problem to be taken into account during the development of ibuprofenbased products and pharmaceutically acceptable salts thereof is that this active principle is characterized by a very unfavourable oral sensory profile; intense bitterness and burning in the throat are typical of this molecule, especially at high dosages. This sensory profile becomes markedly more perceptible, and therefore negative, in salified ibuprofen. Specifically, due to its high solubility in water, the salified form can interact intensely with receptors present in the oral cavity, making the patient perceive the very negative sensory notes, and this can be detrimental to the taking of the preparation, leading to refusal of therapy.

[0015] For this reason, ibuprofen in salified form, used for the rapid therapeutic effect, is administered using pharmaceutical forms that do not envisage the possibility of contact between the molecule and the receptors in the oral cavity, for instance in the form of film-coated swallowable tablets. There are also pharmaceutical forms containing ibuprofen in a salified form that may envisage contact of the molecule with the receptors in the oral cavity, for instance effervescent tablets or granules to be dissolved in water; however, these pharmaceutical forms envisage dilution of the preparation in a suitable volume of water before they are taken, for the purpose of diluting the concentration of the active principle and thus the perception of its unpleasant sensory notes

[0016] Thus, ibuprofen in salified form provides a very rapid therapeutic effect that is particularly suitable in cases of onset of pain; the currently marketed fastacting pharmaceutical forms containing it, such as effervescent tablets or granules to be dissolved in water, however, require the use of water, which precludes their use in all circumstances where water is not available, for example during travel, while at work, while attending an event, during outdoor activities, and at any moment when it is important for the patient to have the medication and its therapeutic action available in the shortest possible time, even in the absence of water.

[0017] In addition, the pharmaceutical forms described above, for example film- coated swallowable tablets, effervescent tablets, effervescent or non- effervescent granules to be dissolved in water, are not suitable for patients with swallowing difficulties (children, elderly patients, or patients who cooperate poorly with paramedical staff, for example due to disabling conditions). The reason for this is that, in these clinical pictures, the patient may have difficulty in coordinating the movements necessary for swallowing, which involve closing the glottis and simultaneously contracting the muscles of the larynx that must push into the esophagus the tablet or the large volume of water required for dissolution of the active principle.

[0018] In these cases, it is appropriate to replace the pharmaceutical forms described above, which require the use of water and the swallowing of larger volumes needed for dissolution of the pharmaceutical form, with other oral formulations that are easy to swallow.

[0019] To date, to the best of the Applicant's knowledge, there does not appear to be a product on the market in which a pharmaceutically acceptable salt of ibuprofen, thus having a very rapid therapeutic effect, is formulated in an oral pharmaceutical form such that it can also be taken in the absence of water, in other words, a product that is easy to swallow, and in which the unfavourable organoleptic characteristics of ibuprofen in a pharmaceutically acceptable salt form are effectively masked.

[0020] Despite various attempts made in the known art to find effective means of eliminating the burning sensation in the mouth and throat after ingestion of ibuprofen in salified form, the need remains to develop solid preparations of ibuprofen salts, especially for high-dose ibuprofen, which are suitable for administration as oral solid formulations, which do not require the use of water, do not produce any sensory irritation, and nevertheless maintain a rapid onset of action.

[0021] Surprisingly, the inventors succeeded in creating the desired product by formulating ibuprofen salts in orodispersible granules that do not require the use of water for their intake, in which the flavour of the active agent is effectively masked, and in which the release profile is immediate in order to afford a very rapid therapeutic effect.

[0022] Specifically, ibuprofen arginine salt represents the preferred salt according to the invention. Although, in fact, the properties of ibuprofen arginine salt as a fast-acting pain-relieving and anti-inflammatory agent are well known, this salt has hitherto only been available in granule and tablet form. The granule form, which is highly soluble, guarantees a remarkable speed of action, but precisely because of its greater solubility, it unfortunately has a rather unpleasant taste.

[0023] In fact, among all the pharmaceutically acceptable salts of ibuprofen, salts of an amino acid, for instance the arginine salt, prove to be the most challenging to mask: as a result of its highly alkaline chemical nature, arginine has a very unpleasant taste characterized by intense amine notes reminiscent of rotten fish; for this reason, masking the taste of this salt is even more difficult. In patent EP 2 594 266 on behalf of the same Applicant, this problem was overcome by identifying a particular formulation of high-dose ibuprofen arginine granules, to be dissolved in water, in which the taste of the active principle was masked and the burning in the throat typical of ibuprofen effectively abated. Also in this, as in other studies, sucrose had to be used to create the sweetening base on which to build the masking of the taste of ibuprofen arginine salt.

[0024] It should be noted, however, that the high sucrose content of these products precludes their use in patients on a calorie-restricted diet or with diabetic conditions.

[0025] Chinese patent application CN 1528278, which uses ibuprofen arginine, describes the preparation of conventional (non-orodispersible) granules of the active ingredient prepared with one or more binders, covered with a coating consisting of sodium bicarbonate, ethylcellulose and silica, in which sodium bicarbonate constitutes the majority component.

[0026] In an attempt to construct efficient taste masking, the various chemical and physical processes that can be used must necessarily take into consideration the characteristics of the specific active principle as well as the particular features of the chosen pharmaceutical form. The limitations in the field of formulation dictated by the intrinsic organoleptic properties, size, shape, particle size distribution, and solubility of the active principle that goes into the chosen dosage form are, in fact, well known to those skilled in the art.

[0027] In fact, many of the approaches commonly used for taste masking involve more or less significant chemical and / or physical modifications of the pharmacologically active principle that affect its stability, dosage form and, first and foremost, the onset of action and also its bioavailability. Specifically, it is known that the most common taste-masking techniques (for example inclusion complexes, ion exchange resins, etc.) can negatively affect the speed of action of the active principle as they tend to make it insoluble in order to reduce contact with the receptors in the oral cavity.

[0028] All of the foregoing has been evaluated and effectively overcome in the present invention with the development of taste-masked particles, containing a salt of ibuprofen with a rapid therapeutic effect, which represent the most suitable intermediate for the development of pharmaceutical forms such as orodispersible tablets or orodispersible powders to be taken without the need for dissolution in water.

[0029] SUMMARY OF THE INVENTION

[0030] The invention relates to orodispersible compositions comprising particles comprising an ibuprofen salt of an amino acid, wherein said ibuprofen salt is coated with a taste-masking polymer coating. Such orodispersible compositions comprise, in addition to the particles, a mix of extra- particulate excipients.

[0031] The polymer coating comprises at least one polymer selected from the group consisting of: polysaccharides, gastrosoluble polymers with pH- dependent solubility and polymers with pH-independent solubility or mixtures thereof, in which said polysaccharides are chosen from water-soluble and water-insoluble celluloses, and mixtures thereof. Such a polymer coating may represent 5-50% of the total weight of the particle, more preferably 20%-50% w / w of each particle.

[0032] The ibuprofen salt is an amino acid salt and is chosen from the ibuprofen L- arginine salt or the L-lysine salt, where the arginine salt is preferred. In accordance with this aspect, each particle comprises at least 50% w / w of ibuprofen amino acid salt. The particular features of the orodispersible compositions (powders according to the preferred aspects) are: the low percentage of extra-particulate excipients required for the preparation of a final orosoluble palatable formulation, which may represent as little as 50% or even as little as 40% of the total composition, its pleasantness when it is taken and its speed of action. In fact, the ibuprofen arginine salt, the in vitro powder dissolution speed is more than 85% of the total active ingredient content in 15 minutes, with a speed of action typical of an ibuprofen salt.

[0033] Nevertheless, the taste of ibuprofen is completely masked for a time of at least 20 seconds, preferably at least 30 seconds after taking the formulation. This time is perfectly compatible with the swallowing time in the absence of water.

[0034] Such formulations allow the intake of an amount of ibuprofen corresponding to a dose of between 100 and 800 mg of acidic ibuprofen as equivalent amounts of the corresponding salt.

[0035] Even more preferably, the amount of acidic ibuprofen can be 200 mg or 400 mg, in equivalent amounts of the corresponding salt.

[0036] According to a further aspect, the invention relates to the taste-masked particles as defined above, in which the ibuprofen salt is preferably ibuprofen arginine salt in the form of essentially spheroidal aggregates with a regular surface and a non-polydisperse diameter, having a diameter in the range 150- 800 .m or more, preferably in the range 250-500 .m, in which such aggregates preferably consist of the arginine salt alone, and are covered with a taste-masking polymer coating, as defined above.

[0037] Such particles represent the most suitable intermediate for the development of pharmaceutical forms such as orodispersible tablets or orodispersible powders that can be taken even in the absence of water. Thus, a further subject of the invention is the use of particles according to the invention for the preparation of orodispersible pharmaceutical forms that are easy to swallow, such as for the elderly or children. DESCRIPTION OF THE FIGURES

[0038] Figure 1. Dissolution profile with pH change (at pH 1.2 for 30 minutes, then at pH 6.8) of: immediate-release tablets containing ibuprofen arginine salt (IBA-CPR) at the dosage corresponding to 400 mg of acidic ibuprofen, of the orodispersible powder 1 prepared according to Example 6 (I BA ODG) and of acidic ibuprofen contained in an orodispersible formulation (IBU ODG).

[0039] DETAILED DESCRIPTION OF THE INVENTION

[0040] The Authors of the present invention have found, unexpectedly, that an ibuprofen salt, preferably an ibuprofen amino acid salt, preferably ibuprofen arginine, can be formulated in an orodispersible form if such a salt, in an aggregate form, is suitably coated with a polymer composition (coating) that masks the unfavourable organoleptic characteristics of the active principle, overcoming the drawbacks presented in the known art with regard to ibuprofen salts, in particular ibuprofen organic salts.

[0041] Therefore, orodispersible pharmaceutical compositions containing salified ibuprofen in the form of taste-masked particles constitute the main subject of the present invention. They are capable of passing from the oral cavity to the stomach while avoiding the perception of the unfavourable organoleptic characteristics of ibuprofen salt and, by virtue of this important achievement, enable patients to take a fast-acting anti-inflammatory and pain-relieving pharmaceutical preparation in any situation, even without the availability of water.

[0042] Such a pharmaceutical preparation is thus also suitable for all patients who have difficulty in swallowing, such as the elderly or uncooperative patients, who take the drug and with a minimum amount of saliva can form a semisolid mass in the oral cavity that is easy to swallow and has a pleasant taste.

[0043] For the purpose of better understanding of the invention, the following technical definitions are herein provided:

[0044] - ibuprofen, acidic ibuprofen or IBU: 2-(4-isobutylphenyl)propionic acid, either in its racemic form, or in its enantiomeric forms and particularly in its S-(+) active enantiomeric form;

[0045] - I BA: ibuprofen arginine salt;

[0046] - aggregates (of I BA): ibuprofen arginine salt of essentially regular spheroidal shape, produced, for example, as described in US 5 463 117, by granulation. Aggregates are also referred to as pellets, pearls or beads,

[0047] - orodispersible preparation. Pharmaceutical preparation that disperses in the oral cavity in the presence of saliva alone and is rapidly swallowed;

[0048] - coating: coating having the function of masking taste and increasing the stability of the active principle;

[0049] - taste masking. The ability of a composition comprising at least one polymer chosen from: polysaccharides, pH-dependent gastrosoluble polymers, and pH-independent polymers or mixtures thereof, to mask the taste of an amino acid salt of ibuprofen, preferably ibuprofen arginine, for a time of at least 20 seconds at oral pH while avoiding the irritant effect;

[0050] - gastrosoluble polymers: polymers with pH-dependent solubility that dissolve rapidly at acidic pH, for example Eudragit® EPO;

[0051] - polymers with pH-independent solubility: polymers generally used for delayed drug release, for example cellulose or Eudragit® RS30D;

[0052] - Eudragit-based polymers®: optionally functionalized methacrylic acid copolymers (see, for example, Nikam A. et al. Pharmaceutics 2023, 15: 587. htps: / / doi.orq / 10.3390 / pharmaceutics15020587);

[0053] - extraparticulate: in the orodispersible granule preparation everything is not comprised in the particle structure.

[0054] Another object of the invention consists of taste-masked particles, each of which includes: a. a pharmaceutically acceptable aggregate (i.e. a particulate form) of an ibuprofen salt , optionally including one or more excipients, b. a polymer composition comprising at least one polymer coating said aggregate, able to mask (taste-masking) the organoleptic features (taste and irritation) of salified ibuprofen.

[0055] The pharmaceutically acceptable salt of ibuprofen, in the form of aggregates, optionally including one or more excipients, may also be referred to as the "core" in the following of the present patent application.

[0056] Also, in the following, aggregates of salified ibuprofen (or cores), coated with a taste-masking coating composition comprising at least one polymer as defined above, are referred to as "particles".

[0057] The polymer coating composition imparts to ibuprofen the taste-masking property, which consists of a minimum delay in the dissolution of the core and the salt therein included, upon contact with the oral mucosa.

[0058] Such taste-masking consists of a delay at least 20 seconds imparted by the coating to the perception of the irritant sensation of the ibuprofen salt, and of its unpleasant taste. The coating also imparts greater chemical stability of the active principle over time since it inhibits any chemical interactions between the active principle and extra-particulate excipients in the orodispersible formulation.

[0059] The polymer coating composition comprises at least one polymer chosen from: polysaccharides, gastro-soluble polymers, i.e. polymers with acid pH- dependent solubility, and polymers with pH-independent solubility, or mixtures thereof.

[0060] The polysaccharides are chosen from water-soluble or water-insoluble celluloses and mixtures thereof. The water-soluble celluloses are chosen from: hydroxyalkylcelluloses, particularly hydroxymethylcellulose and / or hydroxypropylmethylcellulose. The water-insoluble celluloses are chosen from alkylcelluloses, particularly ethylcellulose and propylcellulose.

[0061] Blends of water-insoluble and water-soluble celluloses are particularly preferred. According to a particularly preferred embodiment, the mixture of such celluloses comprises about 70-90% water-insoluble cellulose and 10- 30% soluble cellulose; even more preferably 75-85% and 15-25%, respectively (insoluble cellulose / soluble cellulose); even more preferably, the ratio of water-insoluble to water-soluble cellulose is about 85 to 15.

[0062] The preferred water-insoluble cellulose is ethylcellulose.

[0063] In contrast, the preferred water-soluble cellulose is hydroxypropylmethylcellulose.

[0064] Cellulose-based products that are suitable for use in the invention are commercially available, for instance: ethylcellulose, available under the brand name Surelease®, and hydroxypropylmethylcellulose, available under the brand name Methocel®.

[0065] According to a further embodiment, the polymer coating composition includes methacrylic acid copolymers that are either gastrosoluble and acidic pH-dependent or gastroresistant and pH-independent.

[0066] The polymer compositions coating the active ingredient aggregates can be directly used for coating as powders, as aqueous dispersions, or as solutions in suitable organic solvents.

[0067] Some compositions widely used for this purpose include methacrylic acid copolymers with different derivatizations, available under the brand name Eudragit®, for instance Eudragit® EPO (a cationic copolymer consisting of a polymer blend of dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate) which is soluble at acidic pH, Eudragit® RS30D, a gastroresistant cationic copolymer of ammonium methacrylate (copolymer of ethyl acrylate, methyl methacrylate and a methacrylic acid ester with quaternary ammonium groups) alone or in combination with Eudragit® RL. Some of these polymers are described, for example, in EP 1 368 007 B1.

[0068] A preferred coating composition comprises a polymer with pH-dependent solubility, soluble at acidic pH, such as Eudragit® EPO.

[0069] The polymer coating composition may include, in addition to the polymeric substance, one or more excipients, also called "coating functionals", chosen from plasticizers, salifiers, glidants, anti-aggregants, and / or release regulators (pore formers) that modulate its release activity. According to a preferred embodiment, the polymer functionals used together with Eudragit® EPO comprise stearic acid, sodium lauryl sulfate and silica as further excipients. These excipients can be replaced with excipients having a similar function. For example, stearic acid may be replaced with tartaric acid, silica may be replaced with talc or magnesium stearate or the like, as known in the art (Eudragit® Application Guidelines, 12thEdition, Chapter 7), as known by the skilled artisan.

[0070] In any case, the polymers that are suitable for the preparation of the coating according to the invention are not limited to the abovementioned preferred agents, but may also consist of possible combinations thereof, for instance basic derivatives of butylated polymethacrylates, ethylcellulose alone or in admixture with hydroxypropylmethylcellulose, and ethylcellulose in admixture with basic derivatives of butylated polymethacrylates.

[0071] The core of the particle according to the invention, as mentioned above, generally consists of aggregates of the ibuprofen salt with sizes in the range 150-800 .m, which are preferably not polydispersed, and which preferably have a particle diameter (particle size) in the range comprised from 250 to 500 .m.

[0072] It comprises the ibuprofen salt in a pharmaceutically acceptable form and is prepared by aggregation techniques to give spheroidal granules having an essentially regular surface that is easy to coat. Optionally, the aggregate includes a binder or other pharmaceutical excipient.

[0073] Such an excipient may be: a binder, for instance hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), methylcellulose (MC), microcrystalline cellulose, polyethylene glycol (PEG), povidone (PVP), polyethylene oxide (PEO), polyvinyl alcohol (PVA), modified starch (such as crosslinked or chemically modified pregelatinized starches) used as the sole excipient or as a combination thereof.

[0074] When present, the preferred binder according to the invention is chosen from: povidone (PVP), polyethylene glycol (PEG), pregelatinized starch, hydroxypropylmethylcellulose (HPMC), and microcrystalline cellulose (MCC). Other pharmaceutically acceptable excipients optionally present in the core may be glidants, for instance colloidal silica, talc, or other types of glidants.

[0075] Such excipients, i.e. binders and / or glidants, optionally present, are in a percentage in the range 0-10% by weight, or more preferably 0-5% relative to the total core weight.

[0076] As recalled above, the ibuprofen salt is chosen from an ibuprofen salt with a positively charged counterion organic in nature, such as an amino acid, i.e. L- arginine or L-lysine preferably, L-arginine.

[0077] Said salts may be formed beforehand or prepared directly in situ during mixing with suitable optional excipients and the selected counterion, according to techniques known to those skilled in the art.

[0078] Ibuprofen in pharmaceutically acceptable salt form, particularly ibuprofen arginine, is used in solid, amorphous, or crystalline form. It is preferably used in crystalline form and preferably prepared as described in US 5 463 117 by aggregation in the presence or absence of suitable excipients, for example using a wet rotary granulator.

[0079] The embodiment of aggregates of ibuprofen arginine salt prepared in the absence of excipients is particularly preferred.

[0080] The particle comprising the ibuprofen salt aggregate covered with a coating comprises an amount of taste-masking polymer of between 5% and 50 wt% depending on the polymer. When the polymer is cellulose, in various water- soluble and water-insoluble cellulose mixtures, the total amount is comprised from between 25% and 45% w / w, even more preferably between 30% and 40% w / w, whereas, when the polymer is a methacrylic acid copolymer with pH-dependent or pH-independent solubility, it is in an amount preferably between 5% and 25% w / w or even more preferably comprised between 10% and 20%.

[0081] Thus, in accordance with these preferred aspects, the particles according to the invention have the qualitative and quantitative compositions shown in the tables below.

[0082] Table 1. Weight percentage of particle components in which the coating polymer is a methacrylic acid copolymer of the Eudragit type®. The weight percentage of polymer relative to the total particle weight is given in parentheses.

[0083] *Polymer composition = Eudragit® + functional excipients of the coating if required

[0084] According to a further aspect of the invention, the coating of the particles consists of a polysaccharide polymer, which is soluble and / or insoluble in water or mixtures thereof, and which is cellulose-based, and the particles have the composition given below.

[0085] Table 2. Weight percentage of particle components where the coating polymer is cellulose.

[0086] Functional excipients of the coating are optionally present in wt% with respect to the total particle weight equal to 0-20%, or more preferably in weight percentages of between 0 and 18%, more preferably in the range 5- 16%, this percentage being close to the upper limit of the range in compositions containing pH-dependent solubility polymers .

[0087] The process for preparing aggregates preferably comprising or consisting of I BA is, according to a preferred embodiment, the one described in US 5,463,117 and is a wet aggregation process, performed, for example, with a rotary granulator; alternatively, it is possible to use wet extrusion followed, for example, by spheronization: Alternatively it is possible to use dry aggregation by, for example, rotary pelletization, preferably followed by vibro-sieving to recover the particle size fraction of interest,.

[0088] Aggregates of ibuprofen arginine salt can also be obtained in a fluidized- bed by a wet process, or by using different combinations of the processes described above.

[0089] The process for coating the particle can also be performed according to methods known in the art, depending on the polymer used. For example, the coating can be applied using fluidized bed technology according to the following configurations: bottom-spray, top-spray or tangential-spray, or by pan-coating and spray-coating.

[0090] To apply the coating polymers, the inventors have preferably used , the fluidized bed technology known to experts in the field.

[0091] In a preferred aspect of the invention, aggregation of the salt, optionally mixed with suitable excipients, and coating of said aggregates with the polymer, either alone or in admixture with other excipients (for example coating functional excipients) takes place in different devices. In this case, the active principle or mixture of active principle with suitable excipients are first aggregated using, for example, a high-shear granulator, extruder, roller compactor, or fluidized bed system; the resulting core is discharged, calibrated in terms of particle size, optionally milled, and again calibrated by sieving. These steps are optimized to ensure the least possible waste of active principle. The cores are then introduced into the fluidized bed, coated by spraying the polymer composition onto their surface and, finally, dried, to give the coated particles containing the taste-masked active principle.

[0092] Thus, in a particular aspect, the present invention also relates to a method for producing a solid orodispersible oral pharmaceutical composition, which comprises: a. aggregating the ibuprofen salt optionally in the presence of a binder to give a core; b. coating said core by applying the polymer composition to give the particle.

[0093] Such particles afford pharmaceutical formulations that are easy to swallow and that offer rapid release of the active principle.

[0094] Optimization of the procedure to prepare the coated particles according to the invention makes it possible to obtain aggregates comprising or consisting of ibuprofen arginine salt of spheroidal shape and regular size, which are not polydispersed.

[0095] Thus, according to a further aspect, the invention relates to particles obtained according to the process of the invention, that is, by aggregating crystals of ibuprofen arginine salt and coating these aggregates with a polymer composition as defined above, in a fluidized bed.

[0096] Such particles, prepared according to the present invention, can be used, after mixing with suitable extra- particulate excipients, in pharmaceutical dosages easy to swallow, for instance orodispersible powders or granules.

[0097] Alternatively, the particles according to the present invention can be incorporated into more complex dosages easy to swallow, for instance tablets that disintegrate rapidly in the oral cavity (ODT), chewable tablets, orodispersible microtablets, and orodispersible films. Indeed, the particles according to the invention have good mechanical strength and flowability properties and can be used directly in the preparation of oral dosage forms, only optionally after mixing with suitable pharmaceutical excipients.

[0098] Thus, a further object of the present invention is the use of a plurality of particles as described above in the preparation of fast-dissolving oral dosage forms that are easy to swallow.

[0099] Preferred dosage forms according to the present invention are orodispersible powders or granules, where the particles according to the invention are preferably mixed with extra-particulate excipients. Such excipients are, for example: diluents, preferably chosen from the group consisting of: mannitol, lactose, isomalt, sorbitol, xylitol, sodium bicarbonate, calcium carbonate and mixtures thereof; glidants such as silica, magnesium silicate, sodium stearate, L-leucine and mixtures thereof; sweeteners such as sodium saccharin, acesulfame potassium, aspartame, sucralose and mixtures thereof; and flavourings whose function is to make the powder palatable.

[0100] According to a preferred aspect of the invention, among the extraparticulate excipients, the diluents are chosen from mannitol, calcium carbonate, xylitol, sodium bicarbonate, or mixtures thereof; the glidants are selected from silica and L-leucine or mixtures thereof; and the sweeteners from sucralose and sodium saccharin, and mixtures thereof.

[0101] In a preferred aspect of the invention, the rapidly disintegrating pharmaceutical forms according to the invention have a qualitative-quantitative composition shown in Table 3:

[0102] Table 3. Orosoluble compositions: particle and extra-particulate component

[0103] The orodispersible compositions according to the invention are preferably in powder form conveniently contained in sachets or stickpacks. They provide a dose of salified ibuprofen corresponding to 100-800 mg of acidic ibuprofen, more preferably comprised from 200 to 600 mg. More preferably, ibuprofen is in a dose corresponding to 200 mg, 400 mg or 600 mg of acidic ibuprofen, in equivalent amounts of the corresponding salt.

[0104] It is clear then, that when the ibuprofen salt is ibuprofen arginine (or lysine), the weight amount of the salt required to achieve the therapeutically effective dosages (corresponding to the above amounts of acidic ibuprofen), may even double due to the contribution of the amino acid counterion. Thus, the amount of excipients that can be used to obtain an orodispersible dosage in a volume suitable for swallowing in one go is greatly reduced.

[0105] Specifically, ibuprofen arginine (or lysine) salt has almost twice the weight of the non-salified active principle alone, which considerably increases the amount of powder the patient has to swallow, especially for higher dosages such as the 400 mg or 600 mg dosage. In addition, the taste-masking coating of the particle can increase its unit weight by up to three times the weight of the active principle alone.

[0106] This is a technical problem not easy to overcome, moreover considering the fact that ibuprofen salt has unfavourable organoleptic qualities due to its high solubility in aqueous media, and therefore the orodispersible form must necessarily be taste-masked extremely efficiently.

[0107] Nevertheless, the Applicant has succeeded in developing, with the present invention, orodispersible powders comprising efficiently taste-masked particles in which the weight content of the particles represents at least 50%, more preferably at least 55% and even more preferably at least 60% or 65%, of the total weight of the orodispersible powder.

[0108] The particle-containing orosoluble powders according to the invention maintain the speed of action of the ibuprofen salt, preferably ibuprofen arginine salt, as confirmed by an in vitro dissolution time of more than 85% of the total active ingredient in 15 minutes, but have a very pleasant taste and texture. In these powders, therefore, the irritating and bitter taste of the active principle in salified form is perceived only after a time that is perfectly compatible with the swallowing time in the absence of water, while maintaining the speed of action typical of the ibuprofen salt.

[0109] In fact, according to the preferred embodiment of the invention, the perception of the bitter and irritating notes of the active ingredient as a salt is perceived not earlier than 20 seconds, preferably 30 seconds, after the composition (or powder) is taken.

[0110] This is an extremely satisfying result because, in order to obtain efficiently taste-masked orodispersible forms, the amount of excipients needed to cover the bad taste is generally much higher than the amount of at least 50% according to the invention. Indeed, in the known art, it is estimated that orodispersible powders cannot contain more than about 20% by weight of active ingredient relative to the final pharmaceutical form, so that about 80% by weight of extra-particulate excipient portion would be available for taste- maskiing the active principle and for the palatability of the product.

[0111] By appropriately calibrating the diluents, sweeteners and flavourings and nullifying the unfavourable organoleptic characteristics of ibuprofen arginine salt, the inventors were able to make the orodispersible powder pleasant and easy to swallow, using a proportion of extra- particulate excipients of less than 50%, more preferably less than 45%, more preferably less than 40% or even more preferably less than 35%.

[0112] According to a further aspect, the invention extends to the use of taste- masked particles prepared as described above for the preparation of pharmaceutical forms other than orodispersible powders, for instance orodispersible tablets.

[0113] The following Experimental Section gives a number of methods for preparing the particles and a number of embodiments of these particles or of the orosoluble powder obtained with such particles. However, these embodiments do not represent a limitation of the various embodiments possible according to the teachings of the present invention.

[0114] EXPERIMENTAL SECTION

[0115] Methods

[0116] The in vitro dissolution profile was measured in an aqueous medium at pH 7.2 for a comparison between immediate-release tablets containing ibuprofen arginine (I BA) salt at a dosage of 400 mg of acidic ibuprofen and the coated particles according to the invention, containing the same dosage of active principle, in the orodispersible formulation of the present invention. The dissolution profile at this pH measures the solubility of the active ingredient at the pH of the absorption site (the intestine), where ibuprofen is normally absorbed, and thus allows comparison with other oral pharmaceutical forms containing the same active principle. According to the international guidelines on the dissolution of solid pharmaceutical forms, a release of more than 85% of the total drug dose in 15 minutes is satisfactory as a particularly rapidrelease pharmaceutical form. Specifically, the powders prepared in the examples in accordance with the present invention have been shown to have a drug release of more than 85% in 15 minutes, despite the presence of the taste-masking polymer layer, which is known to slow down dissolution (see in this regard patent application WO 2008 / 119 033, page 2) and the other extraparticulate excipients in the orodispersible formulation.

[0117] At variance, the dissolution profile shown in Figure 1 was measured by introducing the orodispersible powder in vitro into a dissolution medium, first in an acidic environment (pH 1.2) (to simulate the gastric environment) for 30 minutes, and then at pH 6.8 (to simulate the intestinal environment).

[0118] Materials

[0119] All the materials used are approved for pharmaceutical use and meet the specifications of the European Pharmacopoeia and the USP.

[0120] Example 1. Preparation of the aggregate comprising the API (core 1 and core 2)

[0121] A. Agglomeration by wet rotary granulation

[0122] Aggregate - Core 1

[0123] Cores 1 and 2 of ibuprofen arginine salt were prepared according to the procedure described in patent US 5 463 117 by aggregation in a wet rotary granulator:

[0124] Briefly, ibuprofen, L-arginine and water were introduced into a Zanchetta RotoJIO rotary granulator and the mass was heated and allowed to react under intense and continuous agitation by the rotary granulator blade. When the reaction was complete, the vacuum was activated in order to dry the mass and the crusher was activated in order to obtain a more calibrated granulate. The granulate was transferred to a FitzM ill model WJVFS-DC-D6A paddle mill.

[0125] After the milling stage was complete, the product was sieved using a vibrating sieving machine equipped first with a 450-pm cut-off mesh and later equipped with a 250-pm cut-off mesh, recovering the particle size fraction between 250-450 m. The formation of the ibuprofen arginine salt contained in the particles produced according to the present example was confirmed by DSC analysis.

[0126] Aggregate - Core 2

[0127] Ibuprofen, L-arginine and water were introduced into a Zanchetta RotoP150 rotary granulator and the mass was heated and allowed to react under intense and continuous agitation by the rotary granulator blade. When the reaction was complete, the vacuum was activated in order to dry the mass and the crusher was activated in order to obtain a more calibrated granulate. The granulate was milled and once this stage was complete, the product was sieved in order to continuously extract the particle size fraction of interest comprised from 250 and 500 pm. The formation of ibuprofen arginine salt in the particles produced according to the present example was verified by DSC analysis.

[0128] B. Wet extrusion

[0129] Aggregate - Core 3

[0130] Core 3 was prepared by wet extrusion as follows: ibuprofen arginine salt prepared according to the procedure described in patent US 5,463,117 was fed into a Zanchetta model RotoJ 10 rotary granulator and subjected to kneading by spraying with demineralized water at room temperature with continuous agitation. The wet mass was fed into a Caleva model Extruder 20 and extruded using a 500-pm cut-off mesh. The filaments of extruded mass were loaded into a Caleva model MBS 250 Spheronizer and spheronized. At the end of the spheronization process, the particles were dried in a fluidized bed with top-spray configuration and sieved with a vibrating screen equipped with a 250 pm cut-off mesh.

[0131] Example 2. Preparation of aggregates by dry aggregation

[0132] Aggregate - Core 4

[0133] Core 4 was prepared by dry aggregation by rotary pelletization as follows: Ibuprofen arginine salt was prepared according to the procedure described in patent US 5,463,117. Particles with a diameter of less than 50 pm (84% w / w), silica (1% w / w) and PEG 4000 (15% w / w) were placed in a Zanchetta RotoJ 10 rotary granulator and brought to a temperature of 60°C with continuous stirring. When the temperature of 60°C was reached, the blade speed was increased to pelletize the powder. At the end of the pelletizing stage, the mass of particles was cooled to room temperature and transferred to a vibrating sieving machine with grading decks, equipped with 500 pm and 250 pm cut-off sieves for extraction of the particle size fraction of interest.

[0134] Example 3. Coating of cores with pH-dependent methacrylates

[0135] Ibuprofen arginine salt aggregates prepared according to the teachings of Examples 1 and 2 were introduced into a fluidized bed system (Glatt GPCG 1.1) and coated with an aqueous suspension of a mixture of Eudragit® EPO and functional excipients (stearic acid, sodium lauryl sulfate and silica). During the coating phase, the particle temperature was kept at about 30-35°C with a spray rate of 4-5 ml / min and an atomization pressure of 2.0 bar. At the end of the deposition phase, the aggregates were dried for about 1 hour in the fluidized bed at 40°C.

[0136] By means of the above procedure, particles according to the present invention having the following composition were prepared:

[0137] Particles 1

[0138] Core 2 63.4%

[0139] Eudragit EPO 20.9%

[0140] Sodium lauryl sulfate 2.1%

[0141] Stearic acid 3.1%

[0142] Silica 10.5%

[0143] Particles 2

[0144] Core 2 69.8%

[0145] Eudragit EPO 17.3%

[0146] Sodium lauryl sulfate 1.7%

[0147] Stearic acid 2.6% Silica 8.6%

[0148] Particles 3

[0149] Core 2 77.6%

[0150] Eudragit EPO 12.8%

[0151] Sodium lauryl sulfate 1.3%

[0152] Stearic acid 1.9%

[0153] Silica 6.4%

[0154] Particles 4

[0155] Core 1 63.4%

[0156] Eudragit EPO 20.9%

[0157] Sodium lauryl sulfate 2.1%

[0158] Stearic acid 3.1%

[0159] Silica 10.5%

[0160] Particles 5

[0161] Core 4 65.8%

[0162] Eudragit EPO 19.5%

[0163] Sodium lauryl sulfate 2.0%

[0164] Stearic acid 3.0%

[0165] Silica 9.7%

[0166] Example 4. Coating of cores with a methacrylate-based polymer composition with pH-independent solubility

[0167] Ibuprofen arginine salt particles prepared according to the teachings of Examples 1 and 2 were introduced into a fluidized bed system (Glatt GPCG 1) and coated with a suspension of Eudragit® RS30D (a water-insoluble, low- permeability polymer with pH-independent solubility) and the functional excipients given below. Using the procedure described above, particles according to the present invention were prepared, having the following composition:

[0168] Particles 6

[0169] Core 2 80.7% Eudragit RS30D 13.3%

[0170] Triethyl citrate 2.7%

[0171] Silica 3.3%

[0172] Example 5. Coating of cores with a cellulose-based polymer composition

[0173] Ibuprofen arginine salt particles prepared according to the teachings of Examples 1 and 2 were introduced into a fluidized bed system (Glatt GPCG 1.1) and coated with an ethylcellulose suspension (Surelease Clear / Methocel E5). During the coating phase, the temperature of the aggregates was kept at about 44-48°C with a spray rate of 5-7 ml / min and an atomization pressure of 2.0 bar. At the end of the deposition phase, the aggregates were dried for about 1 hour in the fluidized bed at 40°C.

[0174] By means of the above procedure, particles according to the present invention were prepared, having the following composition:

[0175] Particles 7

[0176] Core 1 68.0%

[0177] Surelease® 27.2%

[0178] Methocel® 4.8%

[0179] Particles 8

[0180] Core 2 63.8%

[0181] Surelease® 30.7%

[0182] Methocel® 5.5%

[0183] Example 6. Preparation of orodispersible powders comprising particles according to the invention

[0184] Particles prepared according to the procedure described in Example 3 were used to produce orodispersible powders obtaining oral pharmaceutical forms of ibuprofen arginine to be dispersed directly into the oral cavity without using water when they are taken. The powders were placed in an IMA model Cyclops Lab bin tumbler, mixed with the extra-particulate excipients given below, and then divided into single-dose sachets (stickpacks). llsing the procedure described above, powders having the following compositions were prepared:

[0185] Powder 1

[0186] Particles 1 63.9%

[0187] Xylitol 21.6%

[0188] Sucralose 0.8%

[0189] L-Leucine 1.6%

[0190] Sodium bicarbonate 10.5%

[0191] Flavouring 1.6%

[0192] Powder 2

[0193] Particles 1 64.6%

[0194] Mannitol 20.5%

[0195] Sodium saccharin 1.1%

[0196] L-Leucine 1.6%

[0197] Sodium bicarbonate 10.6%

[0198] Flavouring 1.6%

[0199] Powder 3

[0200] Particles 7 63.4%

[0201] Mannitol 22.0%

[0202] Sodium saccharin 1.0%

[0203] L-Leucine 1.6%

[0204] Sodium bicarbonate 10.5%

[0205] Flavouring 1.5%

[0206] Powder 4

[0207] Particles 6 65.7%

[0208] Isomalt 20.2%

[0209] Sucralose 1.3%

[0210] Silica 1.0%

[0211] Sodium bicarbonate 10.6%

[0212] Flavouring 1.2% Example 7. Dissolution test

[0213] To check the ability of the polymer to release the active principle from the particles that are the subject of the invention immediately after swallowing so as to ensure rapid plasma absorption, the in vitro dissolution profile was evaluated by introducing the powders into a dissolution medium whose pH was varied during the test to simulate transit through the entire gastrointestinal tract.

[0214] Figure 1 depicts the dissolution profiles in an acidic environment for up to 30 minutes (to simulate the gastric environment) then brought to pH 6.8 (to simulate the intestinal environment) of immediate-release tablets containing ibuprofen arginine salt at a dosage of 400 mg of ibuprofen, of the orodispersible formulation (powder 1) described in Example 6, and of a preparation containing non-salified ibuprofen at the same dosage in orodispersible powder form.

[0215] Figure 1 reveals that in the first 30 minutes at a pH that mimics gastric pH, there is partial dissolution of the ibuprofen arginine salt contained in both the immediate-release tablets and the orodispersible powder according to the invention, whereas there is only very little dissolution for the non-salified ibuprofen contained in the orodispersible powders. Partial dissolution of ibuprofen salts in an acidic environment is the key to rapid dissolution in the intestinal tract. After 30 minutes from the start of the dissolution test, the pH was raised to 6.8 to simulate intestinal transit, which is the site of ibuprofen absorption; as expected, dissolution of the ibuprofen arginine salt is noted for both the tablets of the known art and the orodispersible powder that is the subject of the invention, whereas for the orodispersible powders containing non-salified ibuprofen, the dissolution of the active principle is much slower and at 20 minutes after the pH change only 50% of the active principle appears to be dissolved. This test, which simulates the in vivo dissolution of ibuprofen, shows that the particles according to the invention consisting of ibuprofen arginine salt, despite being coated with a polymer system, are much more available for absorption than the same pharmaceutical form, i.e. an orodispersible powder but containing non-salified ibuprofen. This shows that the polymer film applied to the aggregates of ibuprofen arginine salt, while effective in taste- masking, does not compromise the rapid dissolution profile typical of ibuprofen salts.

[0216] Example 8. Sensory evaluation of ibuprofen salt particles coated with a pharmaceutically acceptable taste-masking polymer system

[0217] The taste-masking properties of the particles object of the present invention were analysed by in vivo testing by evaluating the time of onset of negative sensory notes such as bitterness and irritation. At the same time, the sensory profile of the orodispersible powders containing the particles that are the subject of the present application was evaluated by means of a suitably developed sensory evaluation protocol, which took into account all the critical aspects associated with the intake of pharmaceutical orodispersible powders; this protocol made it possible to define the most suitable excipient matrix for this type of preparation.

[0218] The in vivo test was performed using particles obtained by coating ibuprofen arginine cores with appropriate polymers or mixtures thereof prepared according to Examples 3-5.

[0219] Taste masking of at least 20 seconds was deemed satisfactory for the particles of the invention, which was considered optimal given that the product must be swallowed a few moments after introduction into the oral cavity and that the taste-masking effect is also supported by the extra-particulate excipients contained in the orodispersible powder.

[0220] Table 4: sensory evaluation for particles 1, Example 3

[0221] Table 5: sensory evaluation for particles 6, Example 4

[0222] Table 6: sensory evaluation for particles 7, Example 5 The sensory evaluation described above identified the amount of polymer needed to be applied to the cores to ensure taste-masking of the active ingredient. The sensory evaluation test confirms that the unfavourable organoleptic characteristics of the active principle were effectively masked by all the polymers used for particle preparation. The choice of the most suitable particle is then made taking into consideration additional characteristics, such as the rate of dissolution of the active principle comprised within the particles, the physical stability of the coating over time, and the simplicity of industrial application of the polymeric taste-masking system.

[0223] Example 9. Sensory evaluation of orodispersible powders comprising particles based on ibuprofen arginine

[0224] In order to check the overall sensory effect of the orodispersible powders containing the pharmaceutically active principle, ibuprofen arginine salt, an in vivo test was conducted using the orodispersible powders prepared as described in Example 6.

[0225] Sensory evaluation was performed by recruiting seven subjects who were asked to take the orodispersible powder by pouring the entire contents of the stickpack directly into the oral cavity and to swallow the powder, without the use of water, after a few moments. The subjects included were asked to rate the overall pleasantness of the product using a scale from 1 to 5, where 1 corresponds to good, 2 fair, 3 acceptable, 4 not good, and 5 very bad. The results all ranged from 1 to 3.

[0226] The sensory evaluation test confirms that the unfavourable organoleptic characteristics of the active principle were effectively masked, allowing administration of the pharmaceutically active principle contained in the particles formulated as orodispersible powders and that the powder can be easily swallowed .

[0227] Example 10. Homothetic compositions with IBA corresponding to IBU 200-600 mg

[0228] The compositions of the orodispersible powders containing ibuprofen arginine salt corresponding to the 200 mg or 600 mg dosage of acidic ibuprofen are homothetic to the 400 mg dosage formulation. Therefore, to obtain the powder composition at the 200 mg dosage of IBU, the content of each component of orodispersible powder 1 of Example 4 was halved, to obtain the 600 mg dosage, it was multiplied by 1.5, and so on.

Claims

CLAIMS1. A pharmaceutical orodispersible composition comprising: a) particles comprising a pharmaceutically acceptable ibuprofen amino acid salt, in which said ibuprofen salt is coated with a taste-masking coating comprising a polymer selected from the group consisting of: a polysaccharide, a polymer with pH-dependent solubility, a polymer with pH-independent solubility and mixtures thereof, b) a mix of extra-particulate excipients.

2. The pharmaceutical orodispersible composition according to Claim 1, in which each particle (a) comprises at least 50% w / w of ibuprofen amino acid salt.

3. The pharmaceutical orodispersible composition according to any one of claims 1 - 2, wherein said taste-masking coating amounts to 20%-50% w / w of each particle.

4. The pharmaceutical orodispersible composition according to any one of claims 1-3, wherein said polysaccharide is chosen from: a water-insoluble cellulose, a water-soluble cellulose and mixtures thereof.

5. The pharmaceutical orodispersible composition according to any one of claims 1-4, wherein the ibuprofen amino acid salt is: ibuprofen L-arginine or ibuprofen L-lysine.

6. The pharmaceutical orodispersible composition according to any one of claims 1-5, wherein said taste-masking coating comprises a polymer with pH- dependent solubility.

7. The pharmaceutical orodispersible composition according to claim 6, wherein said pH-dependent solubility polymer amounts to 5-20% w / w of the total weight of the particle.

8. The pharmaceutical orodispersible composition according to claim 1 , wherein the mix of extra-particulate excipients (b) amounts to less than 50% w / w of the total orodispersible composition, or preferably to less than 40% w / w and in which said excipients are preferably chosen among one or more of thefollowing: diluents, preferably selected from the group consisting of: mannitol, lactose, isomalt, sorbitol, xylitol, sodium bicarbonate, calcium carbonate or mixtures thereof; glidants, preferably selected from the group consisting of: silica, magnesium silicate, sodium stearate, L-leucine and mixtures thereof; sweeteners, preferably selected from the group consisting of: sodium saccharin, acesulfame-K, aspartame, sucralose and mixtures thereof, and flavourings.

9. The pharmaceutical orodispersible composition according to claim 1 , in which said particles (a) represent 50-80% w / w, more preferably at least 60%, of the total orodispersible composition.

10. The pharmaceutical orodispersible composition according to any one of claims 1-9, which is a powder.

11. The pharmaceutical orodispersible composition according to any one of claims 1-10, wherein said ibuprofen is in an amount of from 100-800 mg of acidic ibuprofen or in corresponding amounts of the amino acid salt.

12. The pharmaceutical orodispersible composition according to claim 11 , in which ibuprofen is in an amount of 200 mg or 400 mg of acidic ibuprofen or in corresponding amounts of the amino acid salt.

13. A taste-masked particle as defined in claim 1(a), comprising:(i) a pharmaceutically acceptable ibuprofen salt, in which said salt is an ibuprofen L-arginine salt;(ii) a taste-masking coating comprising a polymer selected from the group consisting of: a polysaccharide, a polymer with pH-dependent solubility, a polymer with pH-independent solubility and mixtures thereof.

14. Taste-masked particle according to claim 13, in which said ibuprofen L-arginine salt is present as an aggregate wherein said aggregate has a diameter size in the range 150-800 .m, preferably in the range 250-500 .m.

15. Use of a particle according to any one of claims 13 -14, for the preparation of an orodispersible dosage form.

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