EP2185137A1 - Trägerfreie im mund dispergierbare und/oder dispergierbare feste zusammensetzung mit bemerkbarer wirkung und herstellungsverfahren dafür - Google Patents

Trägerfreie im mund dispergierbare und/oder dispergierbare feste zusammensetzung mit bemerkbarer wirkung und herstellungsverfahren dafür

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Publication number
EP2185137A1
EP2185137A1 EP08787573A EP08787573A EP2185137A1 EP 2185137 A1 EP2185137 A1 EP 2185137A1 EP 08787573 A EP08787573 A EP 08787573A EP 08787573 A EP08787573 A EP 08787573A EP 2185137 A1 EP2185137 A1 EP 2185137A1
Authority
EP
European Patent Office
Prior art keywords
agent
composition
mixture
weight
composition according
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.)
Withdrawn
Application number
EP08787573A
Other languages
English (en)
French (fr)
Inventor
Jérôme BESSE
Laurence Besse
Julien Pournin
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.)
Galenix Innovations Sas
Original Assignee
Galenix Innovations Sas
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Galenix Innovations Sas filed Critical Galenix Innovations Sas
Publication of EP2185137A1 publication Critical patent/EP2185137A1/de
Withdrawn legal-status Critical Current

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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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to the field of pharmaceutical, cosmetic, parapharmaceutical, nutraceutical, food and agri-food compositions, as well as to their methods of preparation. More particularly, the present invention relates to a solid composition, without excipient with known effect, disintegrating in the oral cavity or under the tongue in less than 20s, or dispersing in water without prior stirring in less than 3 min, obtained according to a simple method of preparation that does not alter the physicochemical and pharmacokinetic properties of the active substance (s) present in the composition.
  • the active substance (s) present in the composition may (wind) be hydrophilic, hydrophobic or amphiphilic in nature, their average particle size distribution does not advantageously exceed 50 .mu.m.
  • the composition free of excipient with known effect, object of the present invention requires no coating or filming to mask the bad taste or bitterness of certain active substances.
  • the simple method of preparation guarantees the industrial feasibility of a homogeneous, stable and non-friable composition.
  • compositions disintegrating in the oral cavity have been placed on the market.
  • preparations in the form of oral lyophilisate have the advantage of being disintegrated rapidly despite the poor solubility of the active substance, but the process for producing such a form requiring a freeze-drying step is complex and expensive.
  • the compositions obtained are, in general, friable and require moisture-protective packaging to guarantee their integrity.
  • grains dispersed in the oral cavity confer a particularly uncomfortable granular and floury sensation
  • FlashTab® technology described by Ethypharm in patent application EP 1441704 relates to orodispersible tablets based on microcrystals or microgranules of coated active ingredient.
  • the international application WO 2005/034921 teaches an orodispersible composition based on a sparingly soluble or insoluble neurological agent preferably using, as a diluent for sugars, but which may optionally comprise as diluting agent microcrystalline cellulose or dextrate, excipients without known effect.
  • a stabilizing agent is needed.
  • the preferred embodiment incorporates a wet granulation step.
  • this composition can be a pharmaceutical composition, cosmetic, parapharmaceutical, nutraceutical, food or agri-food.
  • the solid composition object of the present invention is also remarkable in that it has the appropriate characteristics not only for an orodispersible composition but also for a dispersible composition.
  • the composition which is the subject of the present invention therefore constitutes an orodispersible and / or dispersible composition.
  • the solid, orodispersible and / or dispersible composition that is the subject of the present invention is in the form of an uncoated tablet, which disintegrates rapidly in the oral cavity or under the tongue, or disintegrates rapidly in a glass of water without alteration.
  • pharmacokinetic properties of the active substance (s) present in the composition said tablet being obtained according to a simple method of preparation.
  • the active substance (s) present in the composition may be of hydrophilic, hydrophobic or amphiphilic nature, their average particle size not exceeding, advantageously, 50 .mu.m.
  • the active substance (s) is (are) in a micronized form.
  • any active substance present in the composition according to the invention may have been subjected to a prior micronization process, no other prior treatment step such as an inert support deposit or granulation having been used.
  • the active substance (s) present (s) in the composition does not occur in multiparticulate form.
  • the characteristics of the solid, orodispersible and / or dispersible composition according to the invention have been achieved thanks to the development of a particular combination of a substance (s) active with excipients having particular features and the use of a manufacturing process comprising successive dilution steps and then a direct compression step.
  • composition object of the present invention is free of excipient with known effect and inexpensive.
  • the particles of active substance (s) do not require coating or filming to mask their unpleasant flavors.
  • the composition which is the subject of the present invention advantageously does not comprise a stabilizing agent.
  • the simple preparation method, object of the present invention guarantees the industrial feasibility of a homogeneous, stable and non-friable composition by a process comprising several dilution steps, then a direct compression step.
  • the term “homogeneous composition” means any composition which satisfies the uniformity test for the content of single-dose preparations as described in the current European Pharmacopoeia, namely an individual content of each unit. between 85 and 115% of the average content.
  • the term “stable composition” means any composition retaining these initial characteristics after having been subjected to an ICH stability study.
  • non-friable composition any composition that meets the friability test described in the European Pharmacopoeia in effect, namely a maximum mass loss of 1%.
  • the present invention relates, more particularly, to a solid, orodispersible and / or dispersible composition, without excipient with known effect, comprising: a) from 0.1 to 59% by weight of at least one active substance having a particle size not exceeding 50 ⁇ m; b) from 40 to 99% by weight of at least one diluent, with no notorious effect, not soluble in water; c) from 0.1 to 15% by weight of at least one disintegrating agent; and d) from 0.05 to 10% by weight of at least one sweetening agent with a particle size of less than 50 ⁇ m, the percentages by weight being expressed relative to the total weight of said composition.
  • orodispersible composition an uncoated tablet, intended to be placed in the mouth or under the tongue where it disperses quickly before being swallowed (European Pharmacopoeia 5.8).
  • An orodispersible tablet disintegrates or disintegrates in water at 37 ° C in less than 3 minutes. Better still, thanks to the invention, it disintegrates in less than 2 minutes, especially in less than 1 minute, in particular, in less than 30 seconds and, more particularly, in less than 20 seconds.
  • the term "dispersible composition” is intended to mean an uncoated tablet intended to be dispersed in water before administration to form a homogeneous dispersion (European Pharmacopoeia 5.8).
  • a dispersible tablet disintegrates in water at 15-25 ° C in less than 3 minutes without prior agitation. Better still, thanks to the invention, it disintegrates in less than 2 minutes, especially in less than 1 minute, in particular, in less than 30 seconds and, more particularly, in less than 20 seconds.
  • the homogeneous dispersion obtained must be able to pass through a sieve with a nominal mesh size of 710 ⁇ m.
  • any composition does not require any precaution for use for certain particular categories of patients.
  • polyols such as mannitol, xylitol, sorbitol, maltitol, maltitol syrup, isomalt, aspartame, etc. and any other excipient mentioned in the list of excipients will be excluded from the composition according to the invention. noticeable effect and likely to cause intolerance.
  • the acid boric acid and its salts at a dose greater than 3 mg / kg / day; wheat starch; bronopol at a dose greater than 0.05% (percentage by weight expressed relative to the total weight of the composition); benzalkonium chloride; organomercury compounds; ethanol at a dose greater than 0.05 g / day; formaldehyde at a dose greater than 0.05% (percentage by weight expressed relative to the total weight of the composition); fructose; galactose; glucose; glycerol at a dose greater than 1 g / dose or greater than 3 g / 24 hours; peanut oil; castor oil and its derivatives; soybean oil and its derivatives; sesame oil; lactose; paraformaldehyde at a dose greater than 0.5% (percentage by weight expressed relative to the total weight of the composition); polyethylene glycol at a dose greater than 2 g / dose or greater than 6 g / day
  • Any numerical value "X" provided in the context of the present invention means, taking into account the experimental errors, as X ⁇ Y with Y between X / 100 and X / 10.
  • said composition comprises a mixture of two, three, four or more different active substances.
  • the substance (s) active (s) included (s) in the composition according to the invention can (wind) be any active ingredient having an activity in the fields of pharmaceutical, parapharmaceutical, cosmetic, nutraceutical, food supplements or agri-food.
  • These active substances may be hydrophilic, lipophilic or amphiphilic.
  • their mean particle size distribution does not exceed 50 .mu.m, in particular 30 .mu.m and, more particularly, 20 .mu.m.
  • particle size of a powder according to the invention, the average size of the particles that constitute it.
  • the average particle size can be measured by any conventional technique known per se. In particular, those skilled in the art may use a laser particle size measurement of the Beckman Coulter® or Malvern® type.
  • the substance (s) active (s) capable (s) to be implemented in the composition according to the invention can (wind) be selected (s) among the active ingredients conventionally used in pharmacotherapy and especially in families pharmacotherapeutic: allergology, anesthesia / resuscitation, oncology and hematology, cardiology and angiology, contraception and termination of pregnancy, dermatology, endocrinology, gastroenteroheopathology, gynecology and obstetrics, immunology and drugs for transplantation, infectiology and parasitology, metabolism, diabetes and nutrition, neurology / psychiatry, ophthalmology, otolaryngology, pneumology, rheumatology, stomatology, toxicology, urology / nephrology, as well as analgesics. anti-pyretic and antispasmodic, anti-inflammatory, diagnostic products, hemostatics and blood treatment products and derivatives.
  • the active substance (s) may be selected from the group consisting of the active ingredients that are useful or used in the treatment, prevention and / or prophylaxis of a pathology or a disease.
  • the substance (s) active (s) can (wind) be selected (s) from the group consisting of anti-inflammatory and including nonsteroidal anti-inflammatory drugs, anti-epileptics, antiparkinsonians, antimyasthenics antispastics, antimigraine agents, antiepileptics, neuroleptics, antidepressants, psychotropic drugs, anticholinesterase agents, NMDA receptor antagonists, antacids, gastric antisecretory agents, dopamine antagonists, antispasmodics, antimigraine agents, choleretic agents, hepatotropic agents, laxatives, vitamin A derivatives, antivirals, anticancer drugs, analgesics, antiulcerics, antipsoriatic agents, antibiotics, cyclooxygenase inhibitors (COX inhibitors), sex hormones (for example, antiestrogens, estrogens, progestins, androgens and antiandrogens.
  • nonsteroidal anti-inflammatory drugs for example
  • the active substance (s) may be selected from the group consisting of acetazolamide, alclometasone dipropionate and acyclovir. , adapalene, ⁇ -3 adrenergic agonist, alclomethasone dipropionate, alosetron, alprostadil, alprozolam, benzodiazepine alprozolam, amcinonide, amelene, 5-aminolevulinic acid, amoxicillin, androstanolone, ⁇ -4-androstenedione, aripipazole, bamethan sulfate + escin, betamethasone valerate, betamethasone dipropionate, bufexamac, buprenorphine, buspirone, caffeine, calcipotriol monohydrate , capravirine, caspofungin acetate, cefaclor, cetrimonium bromide, cilomilast, clobeta
  • the active substance (s) used in the context of the present invention may also be chosen from the active agents conventionally used in cosmetics, parapharmacy and food supplements.
  • the contents of these assets are those conventionally used in the fields considered.
  • cosmetic and parapharmaceutical active ingredients are emollients, humectants, pigments and dyes, anti-wrinkle agents (such as retinol), antifungal agents, anti-acne agents, fabric softeners, perfumes, vitamins and the like. their mixtures.
  • vitamins such as vitamins A, B, E, C, B1, B2, B3, B6, B9, B12, B8H, B5, ...; minerals such as calcium, phosphorus, iron, magnesium, zinc, iodine, ...; carotenoids such as alpha-carotene, beta-carotene, gamma cartene, lutein, zeaxanthin, cryptoxanthin, lycopene, ...; phytoestrogens such as isoflavones (e.g., genistein, diadzein, biochanin A, formononetin); lignans (for example, enterolactone, enterodiol); coumestanes (eg, coumestrol); plant extracts and especially extracts of fennel, heather, blackcurrant, grape seeds, fucus, ginseng, green coffee, ginger, apple pectin, ...; oils such as evening primrose oil,
  • a mixture of active substances covers both a mixture of active substances of the same group (ie pharmaceutical active ingredients, cosmetic active ingredients, active ingredients for food supplements) than a mixture of substances. taken in at least two of the groups listed above.
  • the substance (s) active (s) implemented in the composition according to the invention can (wind) be of natural, chemical, synthetic or biological origin. Indeed, the substance (s) active (s) implemented in the composition according to the invention can (wind) be obtained (s) by chemical synthesis methods or genetic engineering well known to the skilled person.
  • the substance (s) active (s) put (s) in The composition of the invention may be used in the state after recovery of the medium in which it (s) is (s) in the natural state or not, including via extraction.
  • the active substance (s) used in the composition according to the invention may also be used after a prior transformation such as purification, dilution, filtration and concentration, drying, lyophilization or a process as described in the patent application FR 03 02802.
  • the amount of active substance (s) is comprised in the composition according to the invention between 0.1 and 60% by weight, between 0.1 and 59%, especially between 0.5 and 30% by weight. in particular between 0.75 and 10% by weight and, more particularly, between 1 and 5% by weight relative to the total weight of the composition.
  • a diluent with no known effect is used to complete the solid, orodispersible and / or dispersible pharmaceutical composition object of the present invention until a predetermined total volume containing the selected amount of active substance (s) is obtained.
  • the diluting agent without known effect in the composition according to the invention has sufficient binding properties dispensing the use of binding agent such as povidone, starch derivatives, polyvinyl alcohol or any other binding agent known by the art. skilled person.
  • binding agent such as povidone, starch derivatives, polyvinyl alcohol or any other binding agent known by the art. skilled person.
  • the solid, orodispersible and / or dispersible composition according to the invention does not comprise a binding agent.
  • the diluting agent without known effect implemented in the context of the present invention has good flow properties and compaction.
  • this diluting agent has a flow of less than 10 seconds and an apparent volume of less than 20 ml.
  • the diluting agent without known effect used in the context of the present invention represents from 40 to 99% by weight, in particular from 50 to 95% by weight and, in particular, from 60 to 90% by weight relative to the weight. total of the composition according to the invention.
  • the diluting agent without known effect implemented in the context of the present invention is a diluting agent, with no notorious effect, not soluble in water, chosen from cellulose powder, non-silicified microcrystalline cellulose, microcrystalline cellulose with a low water content (ie microcrystalline cellulose having a water content of less than 1.5% by weight relative to the total weight of the microcrystalline cellulose), cellulose acetate, di or tribasic calcium phosphate, calcium, dextrates, dextrins, hydrogenated vegetable oils, glyceryl palmitostearate, polymethacrylate. These agents may be used alone or as a mixture and in particular in a mixture of two, three, four or more. Microcrystalline cellulose is preferentially chosen.
  • disintegrating agent is intended to mean any substance or mixture of these which essentially contributes to the mechanical characteristics of disintegration in aqueous medium of the tablets made from the solid composition which is the subject of the present invention.
  • the disintegrating agent represents from 0.1 to 15% by weight, especially from 1 to 10% by weight and, in particular, from 2 to 6% by weight relative to the total weight of the composition.
  • the disintegrating agent used in the context of the composition according to the invention is chosen from crospovidone (or crosslinked polyvinylpyrrolidone), croscarmellose (or sodium crosslinked carboxymethylcellulose), sodium starch glycolate, sodium alginate, and hydroxypropyl cellulose, starch, pregelatinized starch, their derivatives and mixtures thereof. These agents may be used alone or as a mixture and in particular in a mixture of two, three, four or more. Crospovidone and croscarmellose are preferred disintegrants in the context of the present invention.
  • “Sweetening agent” means any substance or mixture of substances which considerably improves the compliance of this substance. composition, and more particularly any substance or mixture of substances with no notorious effect capable of masking the unpleasant taste and bitterness of certain active substances.
  • the sweetening agent (s) present (s) a particle size less than 50 microns. , better less than 30 microns, more preferably less than 10 microns. Thanks to the use of a sweetening agent with a particle size of less than 50 ⁇ m homogeneously distributed, the use of a coating agent or a film-coating agent is not necessary to mask the unpleasant flavors of certain active substances.
  • composition according to the invention may comprise a sweetening agent or a mixture of sweetening agents and in particular a mixture of two, three, four or more sweetening agent (s), provided that the percentage by weight of the agent sweetener or mixture of sweetening agents ranges from 0.05 to 10% by weight, in particular from 0.1 to 5% by weight and, in particular, from 0.5 to 2.5% by weight relative to the total weight of the composition.
  • the sweetening agent (s) is (are) advantageously chosen from synthetic sweeteners and, more particularly, from gluconate, potassium acesulfame, sodium saccharin, lithium saccharinate, cyclamate, or mixtures thereof. Indeed, in the context of the present invention, synthetic sweeteners that are not metabolized in the body with natural sweeteners are preferred. and this, to avoid adding an excipient with a known effect in the composition according to the invention.
  • the composition according to the invention may also comprise a flavoring agent or a mixture of flavoring agents.
  • a flavoring agent or a mixture of flavoring agents.
  • the organoleptic characteristics are further improved by the addition of this (or these) flavoring agent (s).
  • composition according to the invention may also comprise from 0.005 to 10% by weight, in particular from 0.05 to 8% by weight, in particular from 0.5 to 6% by weight and, more particularly from 0.75 to 4% by weight of a flavoring agent or a mixture of flavoring agents, relative to the total weight of the composition.
  • the flavoring agent (s) is (are) chosen from natural flavors, natural identical flavors or artificial flavors.
  • the flavoring agent (s) are chosen from a fruit aroma, a mint aroma, an anise aroma, a honey aroma, a vanilla aroma, a tea aroma and a verbena aroma.
  • flavoring agent apricot, apricot-orange, citrus, pineapple-coconut, anise, banana, cocoa, caramel, caramel-fruit, currant, cherry, cherry cherry, raspberry-cherry, lemon, lime-green, orange essence, orange blossom, strawberry, raspberry, passion fruit, forest fruits, orchard fruits, red fruits, red fruits / caramel, grenadine, gooseberry, orange juice, tangerine, mango, mint, peppermint, eucalyptus mint, honey, mirabelle plum, blackberry, blueberry, grapefruit, peach, pear, apple, plum, orange pulp, grape, licorice, rosemary-orange, tea, vanilla, verbena or violet.
  • the flavoring agent (or the mixture of flavoring agents) is adsorbed on a suitable support before being incorporated in the pharmaceutical composition according to the invention, in the form of a powder of the previously impregnated support.
  • a suitable support Any type of conventional pharmacy support may be used for the flavoring agent, such as, for example, silica, starch or cellulose powder.
  • composition according to the invention may comprise one or more flow agent (s) ensuring a homogeneous distribution of the active substance or mixture of active substances in the composition and a good flow of the final mixture.
  • the flow agent or the mixture of flow agents represents from 0.001 to 1% by weight, in particular from 0.005% to 0.8% by weight and, in particular, from 0.01% to 0.5% by weight. by weight relative to the total weight of the composition.
  • colloidal silica silica dioxide, magnesium or calcium silicate and talc.
  • colloidal silica is preferably chosen.
  • composition according to the invention may further comprise a lubricating agent or a mixture thereof.
  • a suitable amount of a lubricating agent or a mixture of lubricating agents is added to the outer layer of the latter and in particular to the final mixture of the composition according to the invention just before the submit to direct compression.
  • the appropriate amount of the lubricating agent is from 0.01 to 2% by weight, in particular from 0.05 to 1.5% by weight and, in particular, from 0.1 to 1% by weight relative to in total of the composition.
  • the lubricating agent (s) is (are) advantageously chosen from magnesium stearate, stearic acid and its derivatives, calcium stearate, sodium stearate, sodium stearyl fumarate, and the like.
  • Sodium benzoate can also be used as a preservative and anti-bacterial agent.
  • Magnesium stearate is one of the lubricating agents more preferably used in the composition according to the invention.
  • the composition may comprise a humectant or a mixture of humectants.
  • Humectant means any substance, in solid form, modifying the surface tension of water on the active substance in order to increase the wettability of the said active substance in an aqueous medium.
  • the humectant or the mixture of humectants represents from 0.01 to 5% by weight, especially from 0.05 to 2% by weight and, in particular, from 0.1 to 1% by weight relative to the weight. total of the composition.
  • the humectant is chosen from dodecyl sulphate, sodium lauryl sulphate (SLS), a polyoxyethylenated polysorbitan ester, such as monooleate, monolaurate, monopalmitate, monostearate, sorbitan esters, polyoxyethylenated ethers, sodium dioctylsulphosuccinate ( DOSS), lecithin, sodium docusate, and mixtures thereof.
  • SLS sodium lauryl sulphate
  • DOSS sodium dioctylsulphosuccinate
  • lecithin sodium docusate
  • composition according to the invention may also comprise other excipients of the adjuvant type such as dyes, salivation agents, preservatives, pH regulators, antioxidants, etc.
  • excipients of the adjuvant type such as dyes, salivation agents, preservatives, pH regulators, antioxidants, etc.
  • the person skilled in the art knows which type of compounds to use for each of the above classes of excipients and in what proportion, the only constraint is to choose excipients without known effect.
  • the constituents of the composition according to the present invention with the exception of the active substance (s), at most 10%, in particular at most 6% and, in particular, at most 4% of these constituents are soluble in water.
  • insoluble constituents of the composition according to the present invention with the exception of the active substance (s), at most 30%, at most 20%, in particular at most 10%, in particular at most 5% and, more particularly, at most 2% of these constituents are inorganic.
  • the pharmaceutical composition according to the invention is particularly suitable for oral administration and, more particularly, adapted for ambulatory oral and sublingual use and / or for use after dispersion.
  • the orodispersible and / or dispersible solid composition according to the invention is advantageously in unit dosage forms containing appropriate amounts of active substances, in particular pharmaceutically acceptable ones. Such amounts range from 0.05 to 2000 mg, especially from 0.1 to 1000 mg, in particular from 1 to 500 mg, and most particularly from 1 to 200 mg of active substance per unit dose.
  • the unit dosage form preferred in the context of the present invention is a preparation packaged in tablet form and, more particularly, orodispersible and / or dispersible tablets.
  • This tablet may be monolayer from a single homogeneous or multi-layer mixture from several mixtures.
  • each The mixture which meets the characteristics of the invention will constitute one of the layers of the tablet.
  • the present invention may relate in particular to two-layer or three-layer tablets.
  • the unit dosage form can be either such a tablet per se, or an appropriate number of such tablets.
  • Such unit dosage forms are particularly suitable for one (or more) daily intake (s) depending on the application and in particular depending on the therapy, the phase of therapy or other.
  • the present invention also relates to the use of the solid, orodispersible and / or dispersible composition according to the present invention as previously defined as a medicament, as a food or cosmetic supplement and therefore a solid, orodispersible and / or dispersible composition according to the present invention.
  • the present invention as defined above, for its use as a medicament, that dietary supplement or in cosmetics.
  • a final formulation in the form of tablets can be easily prepared by a simple process of successive dilutions and then direct compression of the mixture of the active ingredient and the excipients, of which the pharmacotechnical characteristics are optimal.
  • a tablet according to the invention has a breaking strength of between 10 and 150 N, in particular between 20 and 100 N and, in particular, between 30 and 60 N and disperses in distilled water at 20 0 C and / or disintegrates in the oral cavity in less than 3 minutes, especially in less than 2 minutes, especially in less than 1 minute and even better in less than 20 seconds.
  • the subject of the present invention is a process for preparing an orodispersible and / or dispersible tablet comprising the steps of:
  • “Homogeneous mixing” means, according to the European and American Pharmacopoeia, mixing in order to obtain a distribution of the active substance within the mixture which makes it possible to guarantee a coefficient of variation of the dosage of the said substance, by way of a Content uniformity measurement, not exceeding 6%.
  • excipients added to the mixture of the process of the invention comprise, in particular, the excipients previously described and, in particular, the flow, flavoring, coloring and humectant agents as previously defined and in the proportions previously defined.
  • the mixture of ingredients can be achieved by adding these ingredients either simultaneously or sequentially.
  • the sequential addition of the ingredients makes it possible to introduce one or more sieving and / or lubrication steps during the mixing step.
  • step (1) of the latter may comprise the steps of: a) mixing at least one active substance with a particle size not exceeding 50 ⁇ m as previously defined and in the proportions previously defined with at least one agent flow, without known effect and non-soluble in water as previously defined and in the proportions previously defined, b) optionally, sieving the mixture of step (a), c) adding at least one diluent agent such as than previously defined and then mix, d) optionally, sieving the mixture of step (c), e) adding to the optionally sieved mixture of step (d), at least one diluent agent as defined above, at least one agent disintegrating as defined above and in the proportions previously defined, at least one sweetening agent of particle size less than 50 microns as defined above and in the proportions previously defined and, optionally, at least one coloring agent as previously defined and in the proportions defined and then mix and at least one flavoring agent as previously defined and in the proportions previously defined, the diluents of
  • the step (1) of the latter may comprise the steps of: a ') mixing at least one active substance as defined above and in the proportions previously defined with at least one flow agent as defined above and in the proportions previously defined, b ') optionally, sieving the mixture of step (a'), c ') adding at least one diluent agent such as previously defined and then mix, optionally) sieving the mixture of step (c), e ') add at least one diluent as previously defined then mix, f') optionally, sieving the mixture of step (e) '), g') adding to the optionally sieved mixture of step (f '), at least one diluent agent as defined above, at least one disintegrating agent as previously defined and in the previously defined proportions, at least one sweetening agent having a particle size of less than 50 ⁇ m as defined above and in the previously defined proportions and, optional
  • steps (g ') is subjected to steps 2, 3 and 4 of the method as previously defined.
  • the various ingredients added in steps (c), (e), (c '), (e') and (g ') of the processes can be sieved before they are added.
  • a first variant (i) relates to step (a) and step (a ').
  • said at least one active substance as defined previously and in the proportions previously defined is mixed with a given amount of diluent before mixing with at least one flow agent as previously defined and in the proportions previously defined.
  • the only condition for this variant is: in the context of the first form of implementation previously defined, that the diluent used in this variant and the diluting agents of steps (c) and (e), which are identical or different, are such that the final proportion of agent (s) diluent (s) in the final tablet is 40 to 99% by weight relative to the total weight of the tablet; in the context of the second form of implementation previously defined, that the diluent used in this variant and the diluting agents of steps (c '), (e') and (g '), which are identical or different, are such that the final proportion of agent (s) diluent (s) in the final tablet is 40 to 99% by weight relative to the total weight of the tablet.
  • a second variant relates to step (e) and step (g '). Indeed, it is conceivable that the ingredients added, during these steps, respectively to the mixtures of steps (d) and (f ') are added
  • FIG. 1 illustrates a preparation process having variant (iii) for step
  • FIG. 6 illustrates a preparation process with both the variant (i) for step (a) and variant (iii) for step (e).
  • orodispersible and / or dispersible tablets can be prepared which have an in vitro dissolution profile in a pH 1.2 buffer solution with more than 75 % of active substance released in less than 5 min and in particular more than 90% of active substance released in less than 5 min.
  • FIG. 1 shows the manufacturing scheme used for the formulations containing risperidone (D 2 dopaminergic antagonist with a preferential action at the level of the limbic system) as an active principle and in accordance with a first variant of the preparation method as above defined.
  • FIG. 2 shows the dissolution profiles obtained in vitro for formulations according to the invention and for commercial oral lyophilizates containing as active principle either 0.5 mg or 2 mg of risperidone.
  • Figure 3 shows the manufacturing scheme used for the formulations containing donepezil (a cholinesterase inhibitor which, by centrally increasing the acetylcholine concentrations in the synaptic cleft, would improve cognitive function during the course of the disease. Alzheimer) as an active ingredient and according to a second variant of the preparation method as defined above.
  • donepezil a cholinesterase inhibitor which, by centrally increasing the acetylcholine concentrations in the synaptic cleft, would improve cognitive function during the course of the disease. Alzheimer
  • FIG. 4 shows the manufacturing scheme used for formulations containing donepezil as active principle and according to a third variant of the preparation method as defined above.
  • FIG. 5 shows the dissolution profiles obtained in vitro for formulations according to the invention containing as active principle either
  • FIG. 6 shows the manufacturing scheme used for the formulations containing nebivolol (cardioselective beta-blocker indicated in the treatment of hypertension) as an active principle and in accordance with a fourth variant of the preparation method as defined above. .
  • Example 1 Orodispersible / dispersible compositions of risperidone obtained by a dilution process / direct compression.
  • Microcrystalline Cellulose This excipient is a diluent commonly used in the manufacture of tablets.
  • Several types of microcrystalline cellulose are available. They differ in their method of manufacture, particle size, residual moisture, flow or other physical properties.
  • Vivapur® 12 marketed by the company JRS. Indeed, it has a residual moisture of less than 5%, a good flow, a particle size distribution adapted to other components (average particle size of 180 microns) and good ability to direct compression. Any supply of equivalent quality may be substituted for this one.
  • Croscarmellose Sodium (or Carboxymethylcellulose Crosslinked): This excipient is a disintegrating agent generally used in dry mix at 2 to 5% in the formula.
  • the croscarmellose sodium used during development is AcDiSol ® marketed by the company FMC Biopolymer. Any supply of equivalent quality may be substituted for this one.
  • Acesulfame Potassium This intense sweetener is frequently used in pharmaceutical specialties. Acesulfame potassium improves the flavor and enhances the effect of (or) flavor (s) used to mask the bad taste of the active substance.
  • the acesulfame potassium used during development is provided by ACT. Any supply of equivalent quality may be substituted for this one.
  • Mint-peppery aroma A mint flavoring has been selected to mask the unpleasant taste of the active substance.
  • the peppermint flavor used during development is provided by IFF. Any supply of equivalent quality may be substituted for this one.
  • Hydrophilic Colloidal Silica This excipient is used in the formula as a flow agent to allow a good distribution of the active substance.
  • colloidal silica makes it possible to correctly distribute the active substance in the mixture.
  • the used colloidal silica is supplied by Degussa under the name Aerosil ® 200. Any equivalent quality supplies can replace it.
  • Magnesium Stearate This excipient is commonly used in pharmaceutical specialties for its lubricating properties.
  • the magnesium stearate of plant origin used during development is provided by the company PETER GREVEN under the name Liga® MF2V. Any supply of equivalent quality may be substituted for this one.
  • Colorant E172 This natural iron oxide type pigment makes it possible to obtain a composition with a pink coloring.
  • the dye E172 used during development is supplied by BASF under the name Sicovit® Rouge 30.
  • Table 1 below shows, for each formulation made in the context of the present invention, its composition and its characteristics.
  • Figure 1 shows the manufacturing scheme used for risperidone formulations.
  • mixture 2 Add to mixture 2, the dye premixed with thinner and sieved on a mesh opening grid between 0.250 and 0.500 mm, the flavor premixed with diluent and sieved on a mesh opening grid of 0.800 mm, the sweetener premixed with diluent and sieved on a mesh gate of between 0.500 and 0.800 mesh mm, the disintegrating agent premixed with diluent and then the balance of thinner.
  • Example 2 orodispersible / dispersible compositions of Donepezil obtained by a dilution process / direct compression A. Choice of excipients
  • Microcrystalline Cellulose This excipient is a diluent commonly used in the manufacture of tablets. Several grades are available, the choice fell on Vivapur® 14 marketed by the company JRS. Vivapur® 14 is equivalent to Grade 12 but with a very low moisture content of less than 1.5%. This excipient is particularly suitable for active ingredients or compositions sensitive to moisture. Any supply of equivalent quality may be substituted for this one.
  • Croscarmellose sodium cf. example 1.
  • Pregelatinized Corn Starch This excipient is a disintegrating agent used for making tablets.
  • the choice fell on the Starch 1500 marketed by the company COLORCON. Thanks to its rheological properties (flow, granulometry %), this excipient is particularly suitable for direct compression. Any supply of equivalent quality may be substituted for this one.
  • Sodium Starch Glycolate This effective and inexpensive disintegrating agent is particularly suitable for direct compression.
  • the sodium starch glycolate used during the development of the composition is supplied by JRS Pharma under the trade name Explotab®. Any supply of equivalent quality may be substituted for this one.
  • Acesulfame potassium cf. example 1.
  • Saccharin Sodium Sodium saccharin is an intense sweetener used in beverages, food products, table top sweeteners and pharmaceutical formulations. Sodium saccharin is considerably more soluble in water than saccharin and also more frequently used in pharmaceutical formulations. Its sweetening power is approximately 300 times more potent than sugar. Sodium saccharin enhances the flavors and can be used to mask some unpleasant taste characteristics. All these characteristics are in line with the objective of developing an orodispersible and / or dispersible tablet. The COOPER laboratory supplies sodium saccharin used during development. Any supply of equivalent quality may be substituted for this one.
  • Mint-pepper aroma cf. example 1.
  • Hydrophobic anhydrous colloidal silica This excipient is used in the formula as a flow agent to allow a good distribution of the active substance.
  • the colloidal silica used is provided by Degussa under the name Aerosil® R972. This quality has hydrophobic properties and allows the orodispersible and / or dispersible tablet to be less sensitive to the phenomenon of moisture absorption. Any supply of equivalent quality may be substituted for this one.
  • Magnesium stearate cf. example 1.
  • Colorant E172 cf. example 1.
  • Figures 3 and 4 show two manufacturing schemes implemented for the formulations based on donepezil.
  • the preparation method which is the subject of FIG. 4 differs from the above method in that steps 1 and 2 are carried out simultaneously by mixing the flow agent and the total of donepezil with 50% of diluent.
  • Table 3 shows, for the formulation made in the context of the present invention, its composition and its characteristics. This composition is applicable whatever the desired dosage (1.25; 2.5; 5; 10 mg ).
  • Figure 6 shows a manufacturing scheme implemented for formulations based on nebivolol. The preparation process which is the subject of FIG. 6 is described in more detail below.
  • STEP 1 PREMIX Mix all of the Nebivolol (API) with an equivalent volume of diluent in a Rhede Wheel type mixer.
  • mixture 2 Add to mixture 2, the aroma pre-mixed with an equivalent volume of diluent and sieved on a grid of opening of mesh of 0,500 mm, the sweetener also premixed and sieved on a grid of opening of mesh of 0,500 mm with an equivalent volume of diluent then the diluent balance and the disintegrating agent. Mix together for 15 min at about 10 rpm.
  • STEP 5 FINAL MIXTURE Add to the mixture 3 the lubricant previously sieved on a grid of opening of mesh of 0,500 mm. Mix for 5 minutes at about 10 rpm.
  • STEP 6 COMPRESSION

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EP08787573A 2007-08-31 2008-08-29 Trägerfreie im mund dispergierbare und/oder dispergierbare feste zusammensetzung mit bemerkbarer wirkung und herstellungsverfahren dafür Withdrawn EP2185137A1 (de)

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FR0757295A FR2920311B1 (fr) 2007-08-31 2007-08-31 Composition solide, orodispersible et/ou dispersible, sans excipient a effet notoire et son procede de preparation
US97321607P 2007-09-18 2007-09-18
PCT/EP2008/061420 WO2009027521A1 (fr) 2007-08-31 2008-08-29 Composition solide, orodispersible et/ou dispersible, sans excipient a effet notoire et son procede de preparation

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EP2468254A1 (de) * 2010-12-15 2012-06-27 Hexal AG Oral zerfallende Tablette mit Geschmacksunterdrückungseffekt
CN103284969B (zh) * 2013-07-01 2015-05-27 南京正宽医药科技有限公司 一种利培酮分散片及其制备方法
SI3310333T1 (sl) 2015-06-18 2020-08-31 Estetra Sprl Orodisperzibilna enota odmerka, ki vsebuje komponento estetrola
KR102664563B1 (ko) 2015-06-18 2024-05-09 에스테트라, 소시에떼 아 레스폰서빌리떼 리미떼 에스테트롤 성분을 함유하는 구강분해성 투여 단위
KR102203229B1 (ko) * 2016-01-08 2021-01-14 에리슨제약(주) 용출률이 개선된 네비보롤을 포함하는 약학적 조성물
EP3458060B1 (de) * 2016-05-16 2024-06-26 Foster, Howell Kombinationstherapie bei männlicher sexueller dysfunktion
JOP20200260A1 (ar) 2018-04-19 2019-10-19 Estetra Sprl مركبات واستخداماتها للتخفيف من الأعراض المصاحبة لانقطاع الطمث
TWI801561B (zh) 2018-04-19 2023-05-11 比利時商依思特拉私人有限責任公司 化合物及其用於緩解絕經相關症狀的用途

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US5298261A (en) * 1992-04-20 1994-03-29 Oregon Freeze Dry, Inc. Rapidly distintegrating tablet
US6024981A (en) * 1997-04-16 2000-02-15 Cima Labs Inc. Rapidly dissolving robust dosage form
FR2785538B1 (fr) * 1998-11-06 2004-04-09 Prographarm Laboratoires Comprime a delitement rapide perfectionne
US6296868B1 (en) * 1998-11-19 2001-10-02 Advanced Technology Pharmaceuticals Corporation Chewable tablets containing mannitol and aspartame
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AU2008292085A2 (en) 2010-07-29
CA2697893A1 (fr) 2009-03-05
US20110250272A1 (en) 2011-10-13
WO2009027521A1 (fr) 2009-03-05

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