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WO2025237808A1 - Compositions pharmaceutiques orodispersibles comprenant un sel d'acide aminé d'ibuprofène - Google Patents

Compositions pharmaceutiques orodispersibles comprenant un sel d'acide aminé d'ibuprofène

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Publication number
WO2025237808A1
WO2025237808A1 PCT/EP2025/062635 EP2025062635W WO2025237808A1 WO 2025237808 A1 WO2025237808 A1 WO 2025237808A1 EP 2025062635 W EP2025062635 W EP 2025062635W WO 2025237808 A1 WO2025237808 A1 WO 2025237808A1
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WO
WIPO (PCT)
Prior art keywords
ibuprofen
orodispersible
pharmaceutical
salt
polymer
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/EP2025/062635
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English (en)
Inventor
Alberto Moretto
Alessandra De Lazzari
Diego BENFENATI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zambon SpA
Original Assignee
Zambon SpA
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Filing date
Publication date
Application filed by Zambon SpA filed Critical Zambon SpA
Publication of WO2025237808A1 publication Critical patent/WO2025237808A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin

Definitions

  • 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.
  • Ibuprofen (chemical name 2-(4-isobutylphenyl)propionic acid) is a well- known pharmaceutical active principle with analgesic, antiphlogistic and antipyretic properties.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • the pharmaceutical forms described above 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).
  • swallowing difficulties children, elderly patients, or patients who cooperate poorly with paramedical staff, for example due to disabling conditions.
  • 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.
  • 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.
  • ibuprofen arginine salt represents the preferred salt according to the invention.
  • 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.
  • 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.
  • 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.
  • 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.
  • a polymer coating may represent 5-50% of the total weight of the particle, more preferably 20%-50% w/w of each particle.
  • 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.
  • each particle comprises at least 50% w/w of ibuprofen amino acid salt.
  • the particular features of the orodispersible compositions 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.
  • 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.
  • 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.
  • 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.
  • the amount of acidic ibuprofen can be 200 mg or 400 mg, in equivalent amounts of the corresponding salt.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • IBA-CPR immediate-release tablets containing ibuprofen arginine salt
  • IBU ODG acidic ibuprofen contained in an orodispersible formulation
  • an ibuprofen salt preferably an ibuprofen amino acid salt, preferably ibuprofen arginine
  • an ibuprofen salt preferably an ibuprofen amino acid salt, preferably ibuprofen arginine
  • a polymer composition coating
  • 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.
  • 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.
  • 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,
  • 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;
  • - gastrosoluble polymers polymers with pH-dependent solubility that dissolve rapidly at acidic pH, for example Eudragit® EPO;
  • polymers with pH-independent solubility polymers generally used for delayed drug release, for example cellulose or Eudragit® RS30D;
  • 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.
  • a pharmaceutically acceptable aggregate i.e. a particulate form
  • an ibuprofen salt optionally including one or more excipients
  • 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.
  • 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.
  • 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”.
  • 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.
  • 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.
  • 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.
  • 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.
  • Blends of water-insoluble and water-soluble celluloses are particularly preferred.
  • 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.
  • the preferred water-insoluble cellulose is ethylcellulose.
  • the preferred water-soluble cellulose is hydroxypropylmethylcellulose.
  • 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®.
  • the polymer coating composition includes methacrylic acid copolymers that are either gastrosoluble and acidic pH-dependent or gastroresistant and pH-independent.
  • 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.
  • 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.
  • Eudragit® EPO a cationic copolymer consisting of a polymer blend of dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate
  • Eudragit® RS30D a gastroresistant cationic copoly
  • a preferred coating composition comprises a polymer with pH-dependent solubility, soluble at acidic pH, such as Eudragit® EPO.
  • 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.
  • excipients also called “coating functionals”
  • 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.
  • 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, 12 th Edition, Chapter 7), as known by the skilled artisan.
  • 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.
  • the core of the particle according to the invention 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.
  • 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.
  • the aggregate includes a binder or other pharmaceutical excipient.
  • 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.
  • HPC hydroxypropylcellulose
  • HPMC hydroxypropylmethylcellulose
  • MC methylcellulose
  • 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.
  • PEG polyethylene glycol
  • PVP povidone
  • PEO polyethylene oxide
  • PVA polyvinyl alcohol
  • modified starch such as crosslinked or chemically modified pre
  • the preferred binder according to the invention is chosen from: povidone (PVP), polyethylene glycol (PEG), pregelatinized starch, hydroxypropylmethylcellulose (HPMC), and microcrystalline cellulose (MCC).
  • PVP povidone
  • PEG polyethylene glycol
  • HPMC hydroxypropylmethylcellulose
  • MMC microcrystalline cellulose
  • Other pharmaceutically acceptable excipients optionally present in the core may be glidants, for instance colloidal silica, talc, or other types of glidants.
  • 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.
  • 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.
  • 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.
  • Ibuprofen in pharmaceutically acceptable salt form 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.
  • 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.
  • 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%.
  • the particles according to the invention have the qualitative and quantitative compositions shown in the tables below.
  • 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.
  • 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.
  • Table 2 Weight percentage of particle components where the coating polymer is cellulose.
  • 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 .
  • 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,.
  • 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.
  • the process for coating the particle can also be performed according to methods known in the art, depending on the polymer used.
  • 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.
  • the inventors have preferably used , the fluidized bed technology known to experts in the field.
  • 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.
  • 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.
  • 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.
  • Such particles afford pharmaceutical formulations that are easy to swallow and that offer rapid release of the active principle.
  • 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.
  • Such particles can be used, after mixing with suitable extra- particulate excipients, in pharmaceutical dosages easy to swallow, for instance orodispersible powders or granules.
  • 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.
  • ODT oral cavity
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the rapidly disintegrating pharmaceutical forms according to the invention have a qualitative-quantitative composition shown in Table 3:
  • 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.
  • the ibuprofen salt is ibuprofen arginine (or lysine)
  • the weight amount of the salt required to achieve the therapeutically effective dosages may even double due to the contribution of the amino acid counterion.
  • 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.
  • 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.
  • the taste-masking coating of the particle can increase its unit weight by up to three times the weight of the active principle alone.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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%.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • pH 1.2 an acidic environment
  • pH 6.8 to simulate the intestinal environment
  • Example 1 Preparation of the aggregate comprising the API (core 1 and core 2)
  • 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:
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • the aggregates were dried for about 1 hour in the fluidized bed at 40°C.
  • particles according to the present invention having the following composition were prepared:
  • 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:
  • Example 5 Coating of cores with a cellulose-based polymer composition
  • 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.
  • particles according to the present invention were prepared, having the following composition:
  • 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:
  • 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.
  • 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.
  • 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.
  • Example 8 Sensory evaluation of ibuprofen salt particles coated with a pharmaceutically acceptable taste-masking polymer system
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Example 9 Sensory evaluation of orodispersible powders comprising particles based on ibuprofen arginine
  • 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.
  • 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 .
  • Example 10 Homothetic compositions with IBA corresponding to IBU 200-600 mg
  • 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.

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Abstract

L'invention concerne une composition pharmaceutique orodispersible comprenant : a) des particules comprenant un sel d'acide aminé d'ibuprofène pharmaceutiquement acceptable, ledit sel d'ibuprofène étant enrobé d'un enrobage de masquage de goût comprenant un polymère choisi dans le groupe constitué par : un polysaccharide, un polymère ayant une solubilité dépendante du pH, un polymère ayant une solubilité indépendante du pH et des mélanges de ceux-ci, b) un mélange d'excipients extra-particulaires. L'invention concerne une particule à goût masqué telle que définie, comprenant : (i) un sel d'ibuprofène pharmaceutiquement acceptable, ledit sel étant un sel de L-arginine d'ibuprofène; (ii) un enrobage de masquage de goût comprenant un polymère choisi dans le groupe constitué par : un polysaccharide, un polymère ayant une solubilité dépendante du pH, un polymère ayant une solubilité indépendante du pH et des mélanges de ceux-ci.
PCT/EP2025/062635 2024-05-14 2025-05-08 Compositions pharmaceutiques orodispersibles comprenant un sel d'acide aminé d'ibuprofène Pending WO2025237808A1 (fr)

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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5463117A (en) 1993-07-30 1995-10-31 Zambon Group S.P.A. Process for the preparation of salts of 2-(4-isobutylphenyl)propionic acid
CN1528278A (zh) 2003-10-15 2004-09-15 杭州容立医药科技有限公司 含有布洛芬精氨酸组合物的颗粒制备方法
US6951657B1 (en) * 1998-11-06 2005-10-04 Laboratoires Des Produits Ethiques Ethypharm Sa Particles coated with granulated crystalline ibuprofen
EP1368007B1 (fr) 2001-02-27 2005-10-05 Röhm GmbH & Co. KG Agent d'enrobage et liant pour compositions pharmaceutiques a stabilite amelioree en cas de stockage
WO2008119033A1 (fr) 2007-03-27 2008-10-02 Eurand, Inc. Compositions pharmaceutiques comprenant une substance active issue de la famille des benzyhydrylpipérazines substituées
CN101455653A (zh) * 2007-12-13 2009-06-17 天津医科大学 精氨酸布洛芬口腔崩解片及其制备方法
EP2594266A1 (fr) 2011-11-17 2013-05-22 Zambon S.p.A. Compositions solides pharmaceutiques contenant des sels ibuprofènes
WO2013183062A2 (fr) * 2012-06-05 2013-12-12 Rubicon Research Private Limited Formulations d'ibuprofène de goût agréable
US20190000765A1 (en) * 2015-12-28 2019-01-03 Nippon Shinyaku Co., Ltd. Compression-molded preparation

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5463117A (en) 1993-07-30 1995-10-31 Zambon Group S.P.A. Process for the preparation of salts of 2-(4-isobutylphenyl)propionic acid
US6951657B1 (en) * 1998-11-06 2005-10-04 Laboratoires Des Produits Ethiques Ethypharm Sa Particles coated with granulated crystalline ibuprofen
EP1368007B1 (fr) 2001-02-27 2005-10-05 Röhm GmbH & Co. KG Agent d'enrobage et liant pour compositions pharmaceutiques a stabilite amelioree en cas de stockage
CN1528278A (zh) 2003-10-15 2004-09-15 杭州容立医药科技有限公司 含有布洛芬精氨酸组合物的颗粒制备方法
WO2008119033A1 (fr) 2007-03-27 2008-10-02 Eurand, Inc. Compositions pharmaceutiques comprenant une substance active issue de la famille des benzyhydrylpipérazines substituées
CN101455653A (zh) * 2007-12-13 2009-06-17 天津医科大学 精氨酸布洛芬口腔崩解片及其制备方法
EP2594266A1 (fr) 2011-11-17 2013-05-22 Zambon S.p.A. Compositions solides pharmaceutiques contenant des sels ibuprofènes
WO2013183062A2 (fr) * 2012-06-05 2013-12-12 Rubicon Research Private Limited Formulations d'ibuprofène de goût agréable
US20190000765A1 (en) * 2015-12-28 2019-01-03 Nippon Shinyaku Co., Ltd. Compression-molded preparation

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* Cited by examiner, † Cited by third party
Title
NIKAM A. ET AL., PHARMACEUTICS, vol. 15, 2023, pages 587

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