US20080226717A1 - Sublingual Coated Tablet - Google Patents

Sublingual Coated Tablet Download PDF

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Publication number
US20080226717A1
US20080226717A1 US11/909,057 US90905706A US2008226717A1 US 20080226717 A1 US20080226717 A1 US 20080226717A1 US 90905706 A US90905706 A US 90905706A US 2008226717 A1 US2008226717 A1 US 2008226717A1
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United States
Prior art keywords
active substance
coated tablet
fentanyl
sublingual
tablet according
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Abandoned
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US11/909,057
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English (en)
Inventor
Pascal Oury
Guillaume Benoist
Catherine Herry
Joseph Duvochel
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Ethypharm SAS
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Ethypharm SAS
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Assigned to ETHYPHARM reassignment ETHYPHARM ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BENOIST, GUILLAUME, DUVOCHEL, JOSEPH, HERRY, CATHERINE, OURY, PASCAL
Publication of US20080226717A1 publication Critical patent/US20080226717A1/en
Abandoned legal-status Critical Current

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    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • 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
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat

Definitions

  • the subject of the present invention relates to a sublingual coated tablet consisting of a compressed core devoid of pharmaceutically active substance and comprising one or more diluting agents, and a coating comprising an active substance, and also to a method for preparing such a coated tablet.
  • sublingual administration makes it possible to rapidly relieve a patient suffering from an acute attack of angina pectoris.
  • Fentanyl is one of these substances.
  • Fentanyl citrate is presently available in the form of a candy-on-a-handle (lollipop) for transmucosal administration which is marketed under the trade name Actiq®.
  • the problem linked to this specific form is that the patient must keep the lollipop in the mouth for at least 15 minutes in order to obtain the desired amount of fentanyl.
  • the amount of absorbed fentanyl is dependent of the frequency of saliva swallowing and thus very dependent of the patient. It is thus difficult to precisely check the absorbed amount of fentanyl.
  • the sublingual tablets known from the prior art are usually prepared by direct compression of a mixture of powders comprising the active substance and compression excipients, such as diluents, binders, disintegrating agents and adjuvants.
  • the active substance and the compression excipients can be dry- or wet-granulated beforehand.
  • the active substance is distributed throughout the mass of the tablet.
  • WO 00/16750 describes a tablet for sublingual use that disintegrates rapidly and comprises an ordered mixture in which the active substance is in the form of microparticles which adhere to the surface of water-soluble particles that are substantially greater in size, constituting a support for the active microparticles, the composition also comprising a mucoadhesive.
  • WO 00/57858 describes a tablet for sublingual use, comprising an active substance combined with an effervescent system intended to promote absorption, and also a pH modifier.
  • Sublingual administration is an administration route which has certain limits due to the size of the sublingual cavity in which the tablet is placed, to the limited volume of saliva for solubilizing the active substance or else to the limited amount of active substance that can cross the buccal mucosa.
  • the size of the tablet containing the highest dose, in particular its diameter, is no longer suitable for sublingual administration.
  • the use of particles of this size in tablets means that it is also necessary to adapt the particle size of the excipients constituting the mass of the tablet and to very precisely define the mixing parameters for the pulverulent mass, in order to obtain an ordered mixture in which the active substance is uniformly distributed, without witnessing the appearance of a segregation phenomenon in the feed hopper of the tablet press, which would be liable to compromise the uniformity of content of the tablets during the compression.
  • the risk of appearance of a segregation phenomenon is further increased when the unit dose of active substance in each tablet is low. This is, for example, the case with fentanyl, for which the unit dose is less than a milligram to a few milligrams.
  • the prior art describes tablets that disintegrate rapidly, suitable for sublingual administration, in which the active substance is distributed within the mass of the tablet.
  • the disintegration is less rapid, such that the tablet erodes gradually while releasing the active substance from the surface of the tablet to its centre.
  • This form is particularly suitable for sublingual administration, since it contains the active substance, not in the mass of the tablet as in the prior art, but at the surface of the compressed core.
  • the release of the pharmaceutically active substance is thus rendered completely independent of the rate of disintegration or of the hardness of the tablet, if the compressed core is formulated such that it only disintegrates after the complete release of the pharmaceutically active substance.
  • the compressed core can be swallowed or else can be kept under the tongue until complete disintegration thereof, the resulting suspension being formed and swallowed only after absorption of the active substance.
  • composition of the invention is perfectly suitable for the preparation of low-dose tablets, since the application of the coating by spraying has the advantage of a uniform distribution around the compressed core, and thus limits any risk of heterogeneity of content in the same batch of tablets, avoiding any possible demixing linked to the preparation of a mixture of powders in which the pharmaceutically active substance is diluted.
  • the present invention also solves the problem of the size of the tablet when the dosage range is spread by a considerable factor between the lowest unit dosage and the highest.
  • This characteristic is particularly advantageous in the case of buccal or sublingual administration, for which the size of the tablet is adjusted so as to be readily placed in the buccal cavity, whatever its dosage of pharmaceutically active substance.
  • the diluting agent can advantageously be chosen from sucrose, lactose, fructose, dextrose, mannitol, sorbitol, lactitol, erythritol, xylitol, dicalcium phosphate, tricalcium phosphate or a microcrystalline cellulose, alone or as a mixture.
  • the diluting agents preferably used are those that exist in a directly compressible form, the particle size of which is greater than 100 ⁇ m.
  • the compressed core comprises a mixture of diluting agent formed from mannitol and microcrystalline cellulose.
  • the diluting agent can consist of an inert support, also called “neutral microgranule”, “neutral substance” or “sugar sphere”, the shape of which is substantially spherical and the particle size distribution of which, measured by known methods such as laser diffraction, shows a monomodal profile such that the variation relative to the ranges indicated in the Pharmacopoeiae, for example the American Pharmacopoeia (USP XVII, 1990), is low, such that the diameter of the neutral microgranules is substantially uniform.
  • an inert support also called “neutral microgranule”, “neutral substance” or “sugar sphere”
  • the inert supports are usually prepared by coating of crystalline sucrose with a suspension of starch in sugar syrup, such as those sold by the company NP Pharm under the trademark Suglets® or NPTAB®.
  • the inert supports that are preferred in the context of the present invention have a diameter of between 180 ⁇ m and 500 ⁇ m, and even more preferably of between 180 and 250 ⁇ m.
  • the diluting agent is present in proportions that can range up to 100% by mass of the compressed core, preferably of between 50% and 95% by mass relative to the mass of the excipient core.
  • the binder is used in dry form and can be a starch, a sugar, polyvinylpyrrolidone or carboxymethylcellulose, alone or as a mixture.
  • the binder is used in a proportion that can range up to 15% by mass, preferably less than 10% by mass, calculated relative to the mass of the compressed core.
  • the swelling agent is chosen from the group comprising microcrystalline cellulose, starches, modified starches, such as carboxymethyl starch or sodium starch glycolate, alginic acid or sodium alginate, and mixtures thereof.
  • the swelling agent is used in a proportion that can range up to 20%, preferably of between 1 and 15% by mass, calculated relative to the mass of the compressed core.
  • the lubricant is chosen from the group comprising magnesium stearate, stearic acid, sodium stearyl fumarate, polyoxyethylene glycols, sodium benzoate, a pharmaceutically acceptable oil, preferably dimethicone or liquid paraffin, or mixtures thereof.
  • the antistatic agent can be chosen from the group comprising micronized or nonmicronized talc, colloidal silica (Aerosil® 200), treated silica (Aerosil® R972) or precipitated silica (Syloid® FP244), and mixtures thereof
  • the antistatic agent is used in a proportion that can range up to 5% by mass, calculated relative to the mass of the compressed core.
  • the active substance(s) can be chosen from any family of compounds, for example from gastrointestinal sedatives, antacids, opioid or non-opioid analgesics, anti-inflammatories, coronary vasodilators, peripheral and cerebral vasodilators, anti-infectious agents, antibiotics, antivirals, antiparasitic agents, anticancer agents, anxiolytics, neuroleptics, central nervous system stimulants, antidepressants, antihistamines, anti-diarrhoea agents, laxatives, nutritional supplements, immunosuppressants, blood cholesterol-lowering agents, hormones, enzymes, antispasmodics, anti-angina agents, medicinal products with an effect on heart rate, medicinal products used in the treatment of arterial hypertension, antimigraine agents, anti-emetics, medicinal products that have an effect on blood clotting ability, antiepileptics, muscle relaxants, medicinal products used in the treatment of diabetes, medicinal products used in the treatment of thyroid dysfunctions, di
  • Examples of active substances suitable for sublingual administration comprise opioid analgesics such as buprenorphine, nor-buprenorphine, fentanyl, methadone, levorphanol, morphine, hydromorphone, oxymorphone codeine, oxycodone, hydrocodone and their pharmaceutically acceptable salts.
  • opioid analgesics such as buprenorphine, nor-buprenorphine, fentanyl, methadone, levorphanol, morphine, hydromorphone, oxymorphone codeine, oxycodone, hydrocodone and their pharmaceutically acceptable salts.
  • fentanyl as active substance, is intended to mean, fentanyl and derivatives thereof, in the form of their pharmaceutically acceptable salts, in any polymorphic form, in racemic or enantiomeric form.
  • Derivatives of fentanyl comprise alfentanil, sufentanil and remifentanil.
  • Preferred active substances are fentanyl base, fentanyl citrate, alfentanil, alfentanil hydrochloride, sufentanil, sufentanil citrate, remifentanil, remifentanil hydrochloride.
  • Active substances may be used in any polymorphic form, in racemic or enantiomeric form.
  • the active substance can be in the form of a powder or of microcrystals.
  • Sublingual coated tablets according to the invention comprising an opioid analgesic as active substance are useful in the management of breakthrough pain, in particular breakthrough cancer pain, by sublingual administration in patients who are tolerant to opioid therapy.
  • Breakthrough pain means a transitory flare of pain of moderate to severe intensity occurring on a background of otherwise controlled pain.
  • Patients considered opioid tolerant are those who are taking at least 60 mg morphine/day, at least 25 ⁇ g transdermal fentanyl/hour, at least 30 mg of oxycodone daily, at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid for a week or longer.
  • the powder or the microcrystals have a size of between 0.5 ⁇ m and 10 ⁇ m, preferably of between 4 ⁇ m and 6 ⁇ m.
  • the compressed core can optionally comprise means for limiting or preventing such abuse.
  • Such active substances are opiate substances such as morphine or derivatives thereof, or alternatively partial opiate agonists such as buprenorphine, indicated in the treatment of opiate dependency, the tablets of which can be inappropriately used by drug addicts for the purpose of intravenous or nasal administration.
  • the compressed core can comprise a morphine receptor antagonist which is not absorbed sublingually and which is rapidly inactivated after oral administration, for example naloxone in the form of its hydrochloride, or which is made orally nonabsorbable by the method of preparation.
  • a morphine receptor antagonist which is not absorbed sublingually and which is rapidly inactivated after oral administration, for example naloxone in the form of its hydrochloride, or which is made orally nonabsorbable by the method of preparation.
  • the antagonist binds to the morphine receptors and thus prevents the active substance from acting.
  • such an antagonist is not considered to be a pharmaceutically active substance insofar as it exerts its effect only when the coated tablet of the invention is not directly administered sublingually or orally.
  • the binder which is optionally present in the coating, is used in proportions that can range up to 95% by mass relative to the dry mass of the coating, preferably up to 30% by mass relative to the dry mass of the active layer.
  • the binder is preferably chosen from polymers that are hydrophilic and/or soluble at the pH of saliva, so as to allow a more rapid release of the active substance, such as polyvinylpyrrolidones and cellulose-based polymers, acrylic polymers and polyethylene glycols.
  • the polyvinylpyrrolidone can be chosen from polymers having a molecular mass of between 10 000 and 50 000.
  • the cellulose-based polymer is chosen from hydroxylated derivatives, for example hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose phthalate and hydroxypropylmethylcellulose acetosuccinate.
  • the preferred polyethylene glycol is chosen from those for which the nominal molecular mass is 4000 or 6000 g/mol.
  • the soluble agent which may be optionally present in the coating, is used in a proportion that can range up to 90% by mass, preferably of between 1% and 60%, and even more preferably of between 30 and 60% by mass, calculated relative to the dry mass of the coating applied around the compressed core.
  • This soluble agent is used in particular for improving the solubilization of the active substance by accelerating the solubilization of the coating comprising the active substance.
  • the surfactant which is optionally present in the coating, can be chosen from cationic, anionic, nonionic or amphoteric agents, alone or as a mixture.
  • the antistatic agent which is optionally present in the coating, can be chosen from the same group of compounds as the antistatic agent of the compressed core. It can be identical to or different from the latter.
  • the pH-modifier is chosen from the group comprising citric acid and sodium citrate or potassium citrate, sodium hydroxide, monoethanolamine, diethanolamine, sodium bicarbonate or potassium bicarbonate, sodium phosphate, tartaric acid, propionic acid, lactic acid, malic acid and monosodium glutamate.
  • the acidic agent can consist of any inorganic or organic acid, in the form of a free acid, an acid anhydride or an acid salt.
  • the alkaline agent consists of a compound capable of generating a gas by reaction with a proton-donating compound.
  • the gas formed is carbon dioxide, oxygen or any other type of biocompatible gas.
  • the alkaline agent is chosen from the group comprising potassium carbonate, lithium carbonate, sodium carbonate, calcium carbonate, ammonium carbonate, L-lysine carbonate, arginine carbonate, sodium glycine carbonate, sodium carbonates of amino acids, anhydrous sodium perborate, effervescent perborate, sodium perborate monohydrate, sodium percarbonate, sodium dichloroisocyanurate, sodium hypochlorite, calcium hypochlorite, and mixtures thereof.
  • carbonate is intended to mean, without distinction, carbonates, sesquicarbonates and hydrogen carbonates.
  • a fraction of the pH modifier or of the effervescent pair can be included in the compressed core itself.
  • Suitable sweeteners may be selected from the group comprising in particular aspartame, acesulfam potassium, sodium saccharinate, neohesperidine dihydrochalcone, sucralose, monoammonium glycyrrhizinate, and mixtures thereof.
  • sweeteners and the flavourings of the coating may be chosen from the same group as those used in the compressed core, but it is possible for them not to be the same compound.
  • sweetener(s) and/or flavourings are particularly advantageous in order to mask the bitterness of certain active substance, such as fentanyl.
  • the colorants are those normally used in pharmacy.
  • the colorant is used in a proportion that can range up to 1% by mass, calculated relative to the dry mass of the layer applied around the compressed core.
  • the sublingual coated tablet according to the invention comprises another coating layer comprising a pH-modifying compound, said layer being named pH-modifying layer.
  • the pH-modifying layer allows the provision of a local alkaline or acid pH when the tablet is placed in the buccal cavity which enhances the absorption of active substance by the mucosa.
  • the choice of the pH-modifying compound depends on the nature of the active substance used. In the case, where absorption of the active substance by the buccal mucosa is enhanced under alkaline conditions, an alkaline compound will be used as pH-modifying compound. In the case, where absorption of the active substance by the buccal mucosa is enhanced under acid conditions, an acidic compound will be used as pH-modifying compound.
  • Alkaline compounds for use in the pH-modifying layer may be selected from the group comprising tris, tartrate, acetate, phosphate, and preferably anhydrous disodium phosphate and mixtures thereof.
  • the pH-modifying layer may optionally comprise excipients identical to those present in the active substance layer.
  • Said layer can be present above or under the active substance layer.
  • the pH-modifying compound can be present within the active substance containing layer.
  • colouring of the coating and/or the optional pH-modifying layer as a code to indicate the type and dosage of active substance.
  • the size of the tablets can be the same.
  • a specific colour can be associated to a specific dosage.
  • An advantage of the tablet according to the invention is the rapid dissolution of the coating, and thus the rapid release of the active substance, before the disintegration of the core.
  • the coated tablet of the invention has an disintegration time of less than 15 min, preferably of 5 to 15 min.
  • the disintegration time is measured in vivo by placing the coated tablet in the sublingual cavity, and measuring, using a stopwatch, the time that elapses between the beginning of the measurement and the moment when the coated tablet has completely disintegrated under the action of saliva and without chewing, so as to form only a viscous pulp, the patient not having to use, during all this time, any action of the jaws.
  • the tablet consists of a compressed core devoid of pharmaceutically active substance and comprising one or more diluting agents, and a coating comprising at least fentanyl as active substance.
  • fentanyl as active substance, is intended to mean, fentanyl and derivatives thereof, in the base form as well as in the form of their pharmaceutically acceptable salts, in any polymorphic form, in racemic or enantiomeric form.
  • Derivatives of fentanyl comprise alfentanil, sufentanil and remifentanil.
  • pharmaceutically acceptable salts is intended to mean the derivatives of the compounds described in which the pharmaceutically active base compound is converted to its salt with a base or acid, examples of pharmaceutically active salts comprising in particular organic and inorganic acid salts of basic residues, such as amines, alkali metal derivatives or organic salts of acidic residues, such as carboxylic acids, and the like.
  • Examples of pharmaceutically acceptable salts of fentanyl comprise fentanyl citrate and fentanyl hydrochloride.
  • Examples of derivatives of fentanyl and their pharmaceutically acceptable salts comprise alfentanil, alfentanil hydrochloride, sufentanil, sufentanil citrate, remifentanil, remifentanil hydrochloride.
  • the alkaline coating layer may optionally comprise excipients identical to those present in the fentanyl layer.
  • the alkaline coating layer may be present above or under the fentanyl layer.
  • the alkaline compound can be present within the fentanyl layer.
  • the alkaline compound is advantageously selected from the group comprising tris, tartrate, acetate, phosphate, and preferably anhydrous disodium phosphate and mixtures thereof.
  • the fentanyl tablets according to the invention comprise a sweetener and/or flavouring in order to mask the bitterness of fentanyl.
  • Suitable sweeteners may be selected from the group comprising in particular aspartame, acesulfam potassium, sodium saccharinate, neohesperidine dihydrochalcone, sucralose, monoammonium glycyrrhizinate, and mixtures thereof.
  • Suitable flavorings and colorants are those commonly used in pharmacy for the preparation of tablets.
  • colouring of the coating and/or the optional alkaline layer as a code to indicate dosage of fentanyl.
  • the size of the tablets can be the same.
  • a specific colour can be associated to a specific dosage.
  • An advantage of fentanyl tablets according to the invention is the rapid dissolution of the coating, and thus the rapid release of fentanyl, before the disintegration of the core.
  • the coated tablet of the invention has an disintegration time of less than 15 min, preferably of 5 to 15 min.
  • the disintegration time is measured in vivo by placing the coated tablet in the sublingual cavity, and measuring, using a stopwatch, the time that elapses between the beginning of the measurement and the moment when the coated tablet has completely disintegrated under the action of saliva and without chewing, so as to form only a viscous pulp, the patient not having to use, during all this time, any action of the jaws.
  • Fentanyl tablets according to the invention are useful in the management of breakthrough pain, in particular breakthrough cancer pain, by sublingual administration in patients who are tolerant to opioid therapy.
  • Breakthrough pain means a transitory flare of pain of moderate to severe intensity occurring on a background of otherwise controlled pain.
  • Patients considered opioid tolerant are those who are taking at least 60 mg morphine/day, at least 25 ⁇ g transdermal fentanyl/hour, at least 30 mg of oxycodone daily, at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid for a week or longer.
  • the compression of the excipient or the mixture of excipients so as to obtain the compressed core can be carried out on an alternating or rotary tablet press.
  • the compressing step can optionally be preceded by a step consisting in mixing the excipients intended to be compressed, in particular so as to allow the addition of a lubricant.
  • the compression is carried out directly without any prior mixing step other than the addition of a lubricant.
  • the stresses exerted during the compressing step can range from 5 kN to 50 kN, and are adjusted so as to obtain a tablet the hardness of which is preferably between 10 and 180 N, more preferably between 15 and 100 N, measured according to the method of the European Pharmacopoeia (2.9.8).
  • the hardness of the tablet is adjusted so as to obtain a friability, measured according to the method of the European Pharmacopoeia, of less than 1%.
  • the coated tablets can have a diameter of between 2 and 14 mm and a round, oval, oblong or other shape, can have a flat, convex, or other surface, and can optionally have engraving.
  • the coated tablets have a round biconvex shape, which is an advantageous shape for both the coating process and the contact of the coated tablet with saliva when said tablet is placed in the buccal cavity.
  • the size of the compressed cores can be readily adjusted so as to obtain the best compromise according to the various criteria, namely the unit dosage of the active substance, the solubility of the active substance, the ratio of the lowest dosage to the highest dosage and the final size of the tablet.
  • the disintegration time of the tablet does not influence the rate of release of the active substance, it is preferable, for the patient's comfort, for the disintegration time to be less than 15 minutes, preferably less than 10 minutes, and even more preferably less than 5 minutes.
  • the disintegration time is preferable for the disintegration time to be greater than 1 minute, preferably greater than 2 minutes.
  • the disintegration time is measured in vivo by placing the coated tablet in the sublingual cavity, and measuring, using a stopwatch, the time that elapses between the beginning of the measurement and the moment when the coated tablet has completely disintegrated under the action of saliva and without chewing, so as to form only a viscous pulp, the patient not having to use, during all this time, any action of the jaws.
  • the layer comprising the active substance forming the coating is distributed uniformly over the surface of the compressed core.
  • composition of the coating layer is adjusted such that the latter is completely solubilized when the tablet disintegrates.
  • the spraying of the coating onto the compressed cores is carried out in a perforated drum, in particular in a perforated drum having sections with triangular profiles, parallel to one another and defining the apertures between them, such as that described in patent application EP 1044064.
  • the spraying of the optional layer containing a pH modifying compound is usually carried out in a sugar-coating pan, a perforated drum or in a fluidized bed.
  • Said step can be carried out directly onto the compressed cores, or simultaneously with the spraying step of the coating containing the active substance, or onto the coating layer containing the active substance.
  • the choice of the equipment makes it possible to control the application of the pH modifying coating of the compressed cores and to prevent any sticking phenomena, linked to the nature of the active substance and of the excipients of the pH modifying coating composition, and to the various parameters of the method (temperature, air pressure, for example, solution flow rate).
  • the pH modifying compound is distributed uniformly over the surface of the compressed core or over the coating layer containing the active substance.
  • the alkaline or acidic character of the pH-modifying compound is determined according to pH value obtained according to usual potentiometric determination, for example described in European Pharmacopeia 5.0, 2.2.3.
  • pH measurement is performed onto an aqueous solution of the pH modifying compound, wherein the volume of solution is chosen as substantially equivalent to the volume of saliva in buccal cavity ( ⁇ 5 ml).
  • composition of the pH modifying coating layer including the amount of pH-modifying agent in said layer, is adjusted such that the latter is completely solubilized when the tablet comes into contact with the saliva in order to provide for a local alkaline pH (pH ⁇ 7) or acid pH (pH ⁇ 7) around the buccal area where the tablet is placed.
  • the same device as the one used for applying the active substance containing coating can be used to apply out the pH modifying coating.
  • the pH modifying coating composition is applied by spraying a solution, a suspension or a colloidal dispersion in an organic or aqueous solvent, or mixtures thereof, containing the pH-modifying compound and is then dried.
  • the organic solvent can be chosen from ethanol, isopropanol, tetrahydrofuran, isopropyl ether, acetone, methyl ethyl ketone, methylene chloride or a mixture of these solvents.
  • Purified water is the preferred solvent if the coating is devoid of effervescent agents; on the other hand, an organic solvent must be used when the sprayed composition contains an effervescent acid/base pair.
  • the method of the invention is also advantageous in terms of safety since it avoids the handling of active substances in the form of pulverulent mixtures, as is the case in the granulation and/or compression steps, and allows the product to be contained by using the active substance in the form of a sprayed solution or suspension.
  • the method of the invention avoids the handling of these substances in the form of pulverulent mixtures, as is the case in the traditional granulation and/or compression steps, and allows the highly toxic active substance to be contained by using the active substance in the form of a sprayed solution or suspension.
  • the method for preparing a coated sublingual tablet according to the invention comprises at least the following steps:
  • steps 1 and 2 of this embodiment are as described above in respect of the general method for preparing sublingual coated tablets according to the invention.
  • the spraying of the layer containing an alkaline substance is usually carried out in a sugar-coating pan, a perforated drum or in a fluidized bed.
  • Said step can be carried out directly onto the compressed cores, or simultaneously with the spraying step of the coating containing fentanyl, or onto the coating layer containing fentanyl.
  • step it is preferred to carry out said step as an over-coating, i.e. onto the coating layer containing fentanyl.
  • the choice of the equipment makes it possible to control the application of the alkaline coating of the compressed cores and to prevent any sticking phenomena, linked to the nature of the active substance and of the excipients of the alkaline coating composition, and to the various parameters of the method (temperature, air pressure, for example, solution flow rate).
  • the alkaline is distributed uniformly over the surface of the compressed core or over the coating layer containing fentanyl.
  • composition of the alkaline coating layer is adjusted such that the latter is completely solubilized when the tablet comes into contact with the saliva in order to provide for a local alkaline pH around the buccal area where the tablet is placed.
  • the same device as the one used for carrying the coating of fentanyl can be used to carry out the alkaline coating.
  • the alkaline coating composition is sprayed in the form of a solution, a suspension or a colloidal dispersion in an organic or aqueous solvent, or mixtures thereof, and is then dried.
  • the organic solvent can be chosen from ethanol, isopropanol, tetrahydrofuran, isopropyl ether, acetone, methyl ethyl ketone, methylene chloride or a mixture of these solvents.
  • Purified water is the solvent preferably used if the coating is devoid of effervescent agents; on the other hand, an organic solvent has to be used when the sprayed composition contains an effervescent acid/base pair.
  • An important advantage of the above particularly advantageous embodiment of the method of the invention is that it is very safe since it avoids the handling of fentanyl in the form of pulverulent mixtures, as is the case in the granulation and/or compression steps, and allows fentanyl to be contained by using the active substance in the form of a sprayed solution or suspension.
  • the present invention also relates to a method of treating pain which comprises introducing into the buccal cavity of a patient a therapeutically effective amount of a sublingual coated tablet of the invention wherein the active substance is selected from the group comprising opioid analgesics suitable for sublingual administration, such as buprenorphine, nor-buprenorphine, fentanyl, alfentanil, sufentanil, remifentanil, methadone, levorphanol, morphine, hydromorphone, oxymorphone codeine, oxycodone, hydrocodone and their pharmaceutically acceptable salts.
  • opioid analgesics suitable for sublingual administration such as buprenorphine, nor-buprenorphine, fentanyl, alfentanil, sufentanil, remifentanil, methadone, levorphanol, morphine, hydromorphone, oxymorphone codeine, oxycodone, hydrocodone and their pharmaceutically acceptable salts.
  • Fentanyl and its derivatives in any polymorphic form, in racemic or enantiomeric form, in the base form or in the form of a pharmaceutically acceptable salt are preferred active substances for use in the method of treating pain according to the invention.
  • Particularly preferred active substances are fentanyl, fentanyl citrate, alfentanil, alfentanil hydrochloride, sufentanil, sufentanil citrate, remifentanil, remifentanil hydrochloride.
  • Active substances may be used in any polymorphic form, in racemic or enantiomeric form.
  • Patients considered opioid tolerant are those who are taking at least 60 mg morphine/day, at least 25 ⁇ g transdermal fentanyl/hour, at least 30 mg of oxycodone daily, at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid for a week or longer.
  • This embodiment is particularly useful in the management of breakthrough cancer pain, more particularly for patients with malignancies who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain.
  • the invention also relates to the use of an opioid analgesic suitable for sublingual administration, such as buprenorphine, nor-buprenorphine, fentanyl, alfentanil, sufentanil, remifentanil, methadone, levorphanol, morphine, hydromorphone, oxymorphone codeine, oxycodone, hydrocodone and their pharmaceutically acceptable salts, for the manufacture of a sublingual coated tablet according to the invention.
  • an opioid analgesic suitable for sublingual administration such as buprenorphine, nor-buprenorphine, fentanyl, alfentanil, sufentanil, remifentanil, methadone, levorphanol, morphine, hydromorphone, oxymorphone codeine, oxycodone, hydrocodone and their pharmaceutically acceptable salts
  • the coating solution is sprayed, in a perforated drum, onto 700 g of compressed cores, this mass corresponding to approximately 10 000 tablets.
  • the coated tablets obtained have a unit dosage of 0.63 mg of fentanyl citrate, i.e. 0.4 mg of fentanyl base.
  • a pre-mix of Emcompress and Avicel was prepared by mixing in a cube mixer during 10 min at 40 rpm. Said pre-mix was lubricated by mixing with magnesium stearate in a cubic mixer during 1 min at 40 rpm.
  • Compression is performed using a tabletting machine PR12 equipped punches of diameter 5.5 mm.
  • the compressed cores have a round biconvex shape
  • the reference product is a fentanyl citrate formulation (solid drug matrix on a handle) designed to facilitate transmucosal absorption and marketed worldwide under trademark Actiq®.
  • Both the invention and the reference product contain fentanyl citrate in an amount equivalent to 0.4 mg of fentanyl base.
  • the fentanyl formulation according to invention displays improved pharmacokinetics with an earlier tmax and highly enhances bioavailability in comparison to the reference product (Actiq®).

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US8709479B2 (en) 2014-04-29
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US20060210632A1 (en) 2006-09-21
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IL185626A0 (en) 2008-01-06
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UA88509C2 (ru) 2009-10-26
NO20075345L (no) 2007-12-17
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ZA200707900B (en) 2009-01-28
RU2403043C2 (ru) 2010-11-10
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MX2007011440A (es) 2007-11-14
HK1109730A1 (en) 2008-06-20
PL1858491T3 (pl) 2012-03-30
DE602006021713D1 (de) 2011-06-16
CA2599502C (en) 2013-05-14
CN101141951B (zh) 2011-02-09
PT1858491E (pt) 2011-08-18
NZ561154A (en) 2010-12-24
KR20070114756A (ko) 2007-12-04
EP1858491B1 (en) 2011-05-04
FR2883179A1 (fr) 2006-09-22
CY1111729T1 (el) 2015-10-07
NO338771B1 (no) 2016-10-17
ES2365984T3 (es) 2011-10-14
ATE507824T1 (de) 2011-05-15
RU2007138647A (ru) 2009-04-27
CN101141951A (zh) 2008-03-12
SI1858491T1 (sl) 2011-09-30
CA2599502A1 (en) 2006-09-21

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Owner name: ETHYPHARM, FRANCE

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:OURY, PASCAL;BENOIST, GUILLAUME;HERRY, CATHERINE;AND OTHERS;REEL/FRAME:019961/0277

Effective date: 20070921

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION