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WO2011072839A1 - Comprimé orodispersible contenant de la dapoxétine - Google Patents

Comprimé orodispersible contenant de la dapoxétine Download PDF

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Publication number
WO2011072839A1
WO2011072839A1 PCT/EP2010/007619 EP2010007619W WO2011072839A1 WO 2011072839 A1 WO2011072839 A1 WO 2011072839A1 EP 2010007619 W EP2010007619 W EP 2010007619W WO 2011072839 A1 WO2011072839 A1 WO 2011072839A1
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WO
WIPO (PCT)
Prior art keywords
dapoxetine
orodispersible tablet
resinate
orodispersible
weight
Prior art date
Application number
PCT/EP2010/007619
Other languages
German (de)
English (en)
Inventor
Dominique Meergans
Sandra Brueck
Original Assignee
Ratiopharm Gmbh
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 Ratiopharm Gmbh filed Critical Ratiopharm Gmbh
Priority to EP10795618A priority Critical patent/EP2512440A1/fr
Publication of WO2011072839A1 publication Critical patent/WO2011072839A1/fr

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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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K9/2027—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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives

Definitions

  • the invention particularly relates to orodispersible tablets containing dapoxetine, preferably dapoxetine resinate. Furthermore, the invention relates to a process for the preparation of Dapoxetinresinat and a method for producing a orodispersible tablet containing Dapoxetinresinat.
  • Dapoxetine belongs broadly to the group of Selective Serotonin Reuptake Inhibitors (SSRIs), in particular it inhibits the transport molecule of serotonin.
  • SSRIs Selective Serotonin Reuptake Inhibitors
  • dapoxetine (S) - (+) - N, N-dimethyl-1-phenyl-3- (1-naphthalenyloxy) -propanamine.
  • the chemical structure of dapoxetine is shown in formula (1) below:
  • EP 1 225 881 B1 relates to the use of dapoxetine for the treatment or management of sexual dysfunction, in particular ejaculatio Praecox.
  • Capsule and tablet formulations with a dapoxetine content of about 2.5 to 10% by weight are proposed for this purpose.
  • the intake of hard gelatin capsules and tablets is usually done with liquid to facilitate the swallowing process.
  • this form of fluid intake requires a certain minimum of organization, which may be problematic given the range of indications of dapoxetine and the associated spontaneity of the patient.
  • Another disadvantage with regard to the intake of conventional capsule and tablet formulations with liquid is that taking in the lying down extremely difficult and that the patient may want to take the dosage form discretely, which would be much easier to do without liquid.
  • the preparation of suitable oral dosage forms of dapoxetine may prove problematic because dapoxetine has a bitter taste and a local anesthetic effect.
  • the abovementioned objects are to be achieved by means of a technically simple (and thus cost-effective) method in a high space-time yield.
  • the above objects could be achieved by providing dapoxetine resinate or orodispersible tablets containing dapoxetine.
  • the preparation of a orodispersible tablet containing dapoxetine resinate provides a formulation which unexpectedly solves the above objects.
  • the invention therefore relates to a fused tablet containing dapoxetine.
  • the invention further provides a process for the preparation of dapoxetine resinate, comprising the steps:
  • the subject matter of the invention is a process for the preparation of an orodispersible tablet containing dapoxetine resinate, comprising the steps:
  • the invention further relates to dapoxetinresinate for the treatment of sexual dysfunction wherein dapoxetine resinate is taken without liquid.
  • the subject of the invention is the use of a cation exchange resin for masking a local anesthetic effect and the bitter taste of a drug, preferably a drug for the treatment of sexual dysfunction, in the mouth.
  • the objects according to the invention are alternative solutions for the abovementioned objects.
  • an orodispersible tablet is understood to mean an orodispersible tablet as defined in the European Pharmacopoeia, 6th edition, Grundwerk 2008.
  • an orodispersible tablet is an oral tablet disintegrating in the oral cavity or a tablet-shaped oral dosage form.
  • the orodispersible tablet is an uncoated tablet, ie the tablet is uncoated or unfilmed.
  • Oral tablets are also referred to as oral dispersible tablets.
  • orodispersible tablets must disintegrate within 3 minutes.
  • the orodispersible tablets according to the invention have a disintegration time of less than 150 seconds, in particular of less than 50 seconds, in the mouth.
  • the disintegration time is determined in accordance with Ph. Eur. 6th edition of Chapter 2.9.1 Test A.
  • the test liquid used is water. If reference is made to the average disintegration time in the context of this application, this is to be understood as the mean value from the disintegration time determination of 10 tablets.
  • the orodispersible tablets according to the invention usually have a total weight of less than 1000 mg, more preferably less than 750 mg, in particular less than 500 mg. Usually, the orodispersible tablets according to the invention have a weight of more than 50 mg, preferably 100 mg or more, in particular more than 150 mg.
  • orodispersible tablets according to the invention are therefore clearly distinguishable from so-called “chewable tablets", since these usually have a higher weight (about 1.5 to 3 g) and a longer disintegration time.
  • the orodispersible tablets according to the invention usually have a breaking strength of from 25 to 80 N, preferably from 35 to 70 N, more preferably from 40 to 65 N, in particular from 45 to 60 N, on. Breaking strength is usually determined according to Ph. Eur. 6th edition, chapter 2.9.8. If reference is made in this application to the average breaking strength, this is to be understood as the mean value from the breaking strength determination of 10 tablets.
  • the resulting tablets preferably have a friability of less than 5%, particularly preferably less than 3%, in particular less than 1%.
  • the friability is calculated according to Ph.Eur. 6.0, Section 2.9.7.
  • the weight ratio of active ingredient (based on dapoxetine in the form of the free base) to excipients in the melt tablets according to the invention is usually 4: 1 to 1: 8, preferably from 2: 1 to 1: 6, in particular 1: 1 to 1: 5.
  • the orodispersible tablet according to the invention contains dapoxetine as component (a).
  • dapoxetine comprises (S) - (+) - N, N-dimethyl-1-phenyl-3- (1-naphthalenyloxy) -propanamine according to formula (1) above.
  • dapoxetine includes all pharmaceutically acceptable salts as well as hydrates and solvates thereof.
  • the salts may be acid addition salts.
  • suitable salts are hydrochlorides, carbonates, bicarbonates, acetates, lactates, butyrates, propionates, sulfates, methanesulfonates, citrates, tartrates, nitrates, sulfonates, oxalates and / or succinates.
  • Dapoxetine (a) is preferably used in the form of the hydrochloride in the context of this invention.
  • the dapoxetine (a) in the orodispersible tablet according to the invention in an amount of (a) from 1 to 25 wt .-%, preferably from 2 to 20 wt .-%, more preferably from 5 to 15 wt .-%, based on the Total weight of orodispersible tablet used. Unless otherwise indicated, all weights of component (a) refer to dapoxetine in the form of the (anhydrous) free base.
  • the orodispersible tablet according to the invention contains a polymeric adsorbent as component (b).
  • a polymeric adsorbent as component (b).
  • the polymeric adsorbent is a hydrophilic polymer.
  • polymers which have hydrophilic groups are polymers which have hydrophilic groups.
  • suitable hydrophilic groups are hydroxy, amino, carboxylic acid or carboxylate (hereinafter also referred to as carboxyl / carboxylate), sulfonic acid or sulfonate (hereinafter also referred to as sulfonic acid / sulfonate).
  • the polymeric adsorbent (b) is an ion exchange resin.
  • An ion exchange resin is a polymer with which dissolved ions can be replaced by other ions of the same charge type, but optionally with different charge.
  • a cation exchange resin is used as the component (b).
  • cation exchange resin is meant a polymer containing functional groups with a dissociable cation. Examples of these functional groups are sulfonic acid groups / sulfonate groups or carboxyl groups / carboxylate groups.
  • a polymer containing carboxyl groups / carboxylate groups and / or sulfonyl groups / sulfonate groups is preferably used as the component (b).
  • carboxylate or sulfonate groups are present, e.g. Ammonium, alkali and alkaline earth ions serve as counterions, preferred are sodium and potassium, in particular potassium.
  • Sodium starch glycolate is preferably not a polymeric adsorbent (b) for the purposes of this invention.
  • an anion exchange resin is used as the component (b).
  • anion exchange resin is meant a polymer containing functional groups with a dissociable anion. Examples of these functional groups are ammonium groups.
  • the polymeric adsorbent (b) is a copolyester obtainable by copolymerization of styrene and dinbenzene. Such copolymers are known under the name polystyrene sulfonate.
  • a preferred polystyrene sulfonate is monographed according to US Pharmacopeia and can be illustrated by the following structural formula.
  • the polymeric adsorbent (b) is a copolymer obtainable by copolymerization of methacrylic acid and divinylbenzene.
  • a copolymer is known as polacrilin.
  • polyacrilm in the form of the potassium salt (polacrilin potassium, in particular monographed according to US Pharmacopeia) is used.
  • Polacrilin potassium can be illustrated by the following structural formula.
  • x and y are natural numbers, for example from 10 'to 10 20 , preferably from 10 6 to 10 18 .
  • the ratio of x to y is usually 50: 1 to 1: 1, preferably 20: 1 to 2: 1, more preferably 10: 1 to 3: 1.
  • the polymeric adsorbent (b) in the orodispersible tablet according to the invention in an amount (B) from 1 to 60 wt .-%, preferably from 2 to 50 wt .-%, more preferably from 5 to 40 wt .-%, based on the total weight of the orodispersible tablet used.
  • the orodispersible tablets according to the invention usually have a weight ratio of dapoxetine (a) to polymeric adsorbent (b) of 1:10 to 10: 1, preferably 1: 5 to 5: 1, more preferably 1: 3 to 3: 1, in particular 1: 2 to 2: 1, up.
  • dapoxetine may form as a resinate.
  • dapoxetine resinate also referred to as component (a-b)
  • Dapoxetinresinate is explained in more detail following the comments on the orodispersible tablet according to the invention.
  • the orodispersible tablet according to the invention contains a breath freshening agent as component (c).
  • breath freshening agent one or more substances are commonly referred to, which usually generate fresh breath in the patient when ingested.
  • the 'breath freshening agent' preferably contains flavoring agents as defined in Council Directive 88/388 / EEC 'flavorings' of 22 June 1988.
  • Breath freshening agents (c) may be obtained as follows: i) by suitable physical processes (including distillation and solvent extraction) or by enzymatic or microbiological processes from substances of plant or animal origin used as such or by conventional food preparation processes (including drying, Roasting and fermentation) for human consumption; (ii) by chemical synthesis or by isolation by chemical processes, the chemical nature of which is identical to that of a substance naturally occurring in a substance of plant or animal origin referred to in (i); (iii) by chemical synthesis, but their chemical constitution is not identical to a substance naturally occurring in a substance of plant or animal origin as defined in (i).
  • a breath freshening agent may consist of one or, preferably, of several chemical compounds.
  • peppermint flavor may contain a collective of more than 10 chemical compounds.
  • the orodispersible tablet according to the invention contains several different breath freshening agents (i.e., several different aroma directions), more preferably, the orodispersible tablet according to the invention contains 2, 3 or 4 different breath freshening agents.
  • breath freshening agents are e.g. Aroma Peppermint with Aroma Menthol, Aroma Peppermint Aroma Lemon, Aroma Peppermint Aroma Menthol and Aroma Lemon, Aroma Garden Mint Aroma Lemon, Aroma Garden Mint Aroma Menthol, Aroma Garden Mint Aroma Lemon and Aroma Menthol, Aroma Grapefruit Aroma Peppermint, Aroma Grapefruit with aroma menthol and aroma peppermint, aroma grapefruit with aroma garden mint, aroma grapefruit with aroma garden mint and aroma menthol.
  • breath freshening agents examples include xylitol (example Xylisorb ®, available from Roquette), spray-dried sorbitol (such as Merisorb ®, available from Syral), L-menthol (eg available from Caelo).
  • the breath freshening agent (c) in the orodispersible tablet according to the invention in an amount (c) of 0, 1 to 7 wt .-%, preferably from 0.5 to 5 wt .-%, more preferably from 1 to 3 wt. %, based on the total weight of the orodispersible tablet.
  • the orodispersible tablet according to the invention contains a sweetener as component (d).
  • sweetener one or more substances are generally referred to, which usually cause a sweet taste sensation in the patient when ingested.
  • lactose (0.27-0.3), glycerol (0.5-0.8), D-glucose (0.5-0.6), maltose (0.6), galactose (0.6) , Invert sugar (0.8-0.9), cane sugar (1, 0), xylitol (1, 0), D-fructose (1, 0-1, 5), sodium cyclamate (30), D-tryptophan (35) , chloroform (40), glycyrrhizin (50), acesulfame (130), aspartame (180-200), dulcin (200), suosan ® (350), saccharin (sodium salt) (400-500), saccharin (ammonium salt) (600 ), 1-bromo-5-nitroaniline (700), naringin dihydrochalcone (1000-1500), thaumatin, monellin (peptides) (3000), P-4000, n-propoxy-2-amino-4-nitrobenzene (4000),
  • component (d) is usually added in an amount of from 0.01 to 10% by weight, more preferably from 0.1 to 5% by weight, in particular from 0.5 to 2.5% by weight. %, based on the total weight of the orodispersible tablet.
  • the orodispersible tablet according to the invention contains a plurality of different sweeteners, more preferably the tablet according to the invention contains 2, 3 or 4 different sweeteners.
  • component (d) contains
  • the components (d-1) and (d-2) can usually be used in a weight ratio of 5: 1 to 1: 5, preferably from 3: 1 to 1: 3.
  • Examples of an instant sweetener (d-1) are saccharin sodium salt, saccharin ammonium salt, sucralose, neotame, alitame, aspartame, cyclamate, thaumatin and / or acesulfame.
  • Examples of sweeteners with delayed sweetness (d-2) are glycyrrhizin or derivatives thereof, especially glycyrrhizin in the form of the mono-ammonium salt, thaumatin and neohesperidin DC.
  • the orodispersible tablet according to the invention contains a mucilage as component (e).
  • a mucilage is understood to mean one or more substances which reduce the contact of drugs with the papillae of the tongue by increasing the viscosity or by wrapping. This usually achieves a reduction in the intensity of the taste sensation.
  • component (e) substances are selected which lead as 2% strength by weight solution or mixture in distilled water to a viscosity of more than 2 mPas, preferably more than 4 mPas, in particular more than 6 mPas , measured at 25 ° C, according to Ph. Eur. 6th edition, Chapter 2.2.10.
  • the viscosity of the resulting solution or mixture can be up to 50,000, preferably up to 10,000, in particular up to 1,000 mPas.
  • gums (e) it is possible to use natural gums, cellulose derivatives, alginates and / or nonionic hydrocolloids.
  • mucilage examples are agar, alginic acid, alginate, chicle, carrageenan, dammar, marshmallow extracts, gellan (E 418), guar gum (E 412), gum arabic (E 414), maple gum gum, spruce juice gum, locust bean gum (E 410), Karaya (E 416), Konjac flour (E 425) extracted from the konjac root, Tarakernmehl (E 417), tragacanth (E 413), xanthan gum (E 415), preferably produced by bacterial fermentation, guar gum and / or lecithin.
  • mucilage examples are agar, alginic acid, alginate, chicle, carrageenan, dammar, marshmallow extracts, gellan (E 418), guar gum (E 412), gum arabic (E 414), maple gum gum, spruce juice gum, locust bean gum (E 410), Karaya (E 416), Konjac flour (E 42
  • mucilages based on cellulose derivatives e.g. Carboxymethylcellulose, hydroxyethylcellulose and / or methylcellulose.
  • component (e) is usually used in an amount of from 0 to 25% by weight, more preferably from 0.1 to 20% by weight, in particular from 0.5 to 20% by weight, based on the total weight of the orodispersible tablet used.
  • the orodispersible tablet according to the invention may contain further customary pharmaceutical auxiliaries.
  • fillers f
  • lubricants g
  • disintegrants h
  • acid agents e
  • Fillers (f) are generally to be understood as meaning substances which serve to form the tablet body in the case of tablets with small amounts of active ingredient. That is, fillers produce by "stretching" of the active ingredients sufficient Tablettiermasse. So fillers are usually used to obtain a suitable tablet size. Examples of preferred fillers are lactose, starch, starch derivatives, calcium phosphate, sucrose, calcium carbonate, calcium silicate,
  • suitable sugar alcohols are mannitol, sorbitol, xylitol, isomalt, glucose, fructose, maltose and mixtures thereof. Lactose is particularly preferably used as filler.
  • the orodispersible tablets according to the invention usually contain fillers in an amount of from 0 to 70% by weight, more preferably from 1 to 60% by weight, in particular from 2 to 55% by weight, based on the total weight of the orodispersible tablet.
  • Flow regulators have the task of reducing the interparticle friction (cohesion) between the individual particles as well as the adhesion of these to the wall surfaces of the mold (adhesion) in a tabletting mixture.
  • An example of an additive for improving powder flowability is disperse silica. Preference is given to using silica having a specific surface area of from 50 to 400 m 2 / g, determined by gas adsorption in accordance with Ph. Eur., 6th edition, Sept. 2, 1966. In this connection, it was unexpectedly found that by using silica having a specific surface area of 50 to 400 m 2 / g, the amount of filler can be advantageously reduced.
  • Lubricants can be used as the component (g 2 ).
  • Lubricants are generally used to reduce sliding friction.
  • the sliding friction is to be reduced, which consists during tabletting on the one hand between the up in the die bore and from moving punches and the die wall and on the other hand between the tablet web and die wall.
  • Suitable lubricants are for example stearic acid, adipic acid, sodium stearyl fumarate (such as Pruv ®), magnesium stearate and / or calcium tearat.
  • the component (g) is usually used in an amount of 0 to 10 wt .-%, more preferably from 0 , 1 to 5 wt .-%, in particular from 1, 0 to 3 wt .-%, based on the total weight of the tablet used.
  • disintegrants (h) are generally referred to substances that accelerate the disintegration of a dosage form, in particular a tablet, after being introduced into water.
  • Suitable disintegrants are, for example, organic disintegrants such as microcrystalline cellulose, starch, pregelatinized starch, sodium carboxymethyl starch, sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidones, sodium starch glycolate, and crospovidone.
  • Crosslinked polyvinylpyrrolidones and / or sodium starch glycolate are preferably used as disintegrating agents.
  • the orodispersible tablets according to the invention contain disintegrants (h) usually in an amount of from 0 to 35% by weight, more preferably from 1 to 30% by weight, in particular from 2 to 25% by weight, based on the total weight of the orodispersible tablet.
  • Acid (j) serve to obtain an acidic flavor component.
  • acidic agents are citric acid, tartaric acid and salts thereof.
  • the orodispersible tablets according to the invention usually comprise acidity agent (j) in an amount of from 0 to 15% by weight, more preferably from 1 to 10% by weight, in particular from 2 to 5% by weight, based on the total weight of the orodispersible tablet.
  • the invention also includes any combinations of the aforementioned preferred embodiments, i. preferred is a fused tablet containing
  • the unambiguous delimitation is therefore preferably the fiction that a Substance that is used as a particular adjuvant is not used at the same time as another pharmaceutical excipient.
  • polacrilin - if used as a polymeric adsorbent (b) - not additionally used as a disintegrant (although polacrilin also shows a certain explosive effect).
  • the orodispersible tablet according to the invention may contain components (a) to (h) and (J).
  • the combination of dapoxetine (a) with polymeric adsorbent (b) gives dapoxetine in the form of a resinate according to the invention.
  • the dapoxetine resinate (a-b) according to the invention is usually a combination of dapoxetine and a polymeric adsorbent (b).
  • component (b) The exact mechanism of this combination of dapoxetine and the polymeric adsorbent is not yet known. However, it is believed, without being bound by theory, that this combination is usually at least partially in the form of a salt.
  • the type and amount of dapoxetine (a) and polymeric adsorbent (b) are usually chosen so that the resulting combination (i.e., the resulting dapoxetine resetin) exhibits substantially no local anesthetic effect.
  • the type and amount of dapoxetine (a) and of polymeric adsorbent (b) are preferably chosen so that the resulting combination has substantially no bitter taste.
  • the water content of Dapoxetinresinat is usually 1 to 12 wt .-%, preferably 2 to 10 wt .-%, particularly preferably 3 to 7 wt .-%, based on the Dapoxetinresinat- total weight.
  • the water content is determined by coulometric Karl Fischer measurement with a Karl Fischer titrator AQUA 40.00 (Analytik Jena AG, Germany), wherein a sample of 20 mg is measured.
  • the invention is not only the Dapoxetinresinat invention but also a process for its preparation.
  • the invention therefore relates to a process for the preparation of dapoxetine resinate, comprising the steps:
  • step (iv) filtering the dispersion obtained from step (ii) or step (iii),
  • step (i) dapoxetine (a) is dissolved in a solvent.
  • the solvents of the invention used in step (i) are generally polar organic solvents.
  • Suitable solvents are e.g. Water, alcohol (e.g., methanol, ethanol, isopropanol), dimethyl sulfoxide (DMSO), acetone, butanol, ethyl acetate, heptane, pentanol, or mixtures thereof. Preferably, water is used.
  • dissolution is generally understood at least a partial dissolution, preferably the dissolution of a major part of dapoxetine, usually greater than 80 wt .-%, preferably greater than 90 wt .-%, particularly preferably greater than 95 wt .-%, in step ( ii) the polymeric adsorbent (b) is dispersed in the solution obtained in step (i), preferably suspended.
  • parts of the polymeric adsorbent (b) may also be dissolved.
  • greater than 10 wt .-%, preferably greater than 80 wt .-%, more preferably greater than 95 wt .-% of the polymeric adsorbent (b) in undissolved ( dispersed) form.
  • the pH of the resulting composition may change.
  • the dispersion obtained in step (ii) is stirred in optional step (iii) until a stable pH is reached.
  • a stable pH is usually a pH that does not change or only minimally changes. Minimal means a change of ⁇ 0.2 over a period of one minute.
  • step (iv) the dispersion obtained from step (ii) or step (iii) is filtered to obtain a filter cake.
  • filtration is understood to mean the separation of solid particles from liquids with suitable filters.
  • step (v) the drying of the filter cake obtained from step (iv) takes place.
  • drying is understood to mean the separation of solids adhering to solids.
  • the adhering liquids are preferably water in the form of adhesive water, capillary, hydration, adsorption, hydrate and constitutional water. Drying is generally carried out in conventional drying devices, such as cabinet or tray dryers, vacuum dryers, fluidized bed dryers, spray dryers or freeze dryers. Cabinet or tray dryers are preferably used according to the invention.
  • the drying time is usually 1 to 20 hours, preferably 2 to 17 hours, more preferably 5 to 15 hours.
  • the drying temperature is usually 40 to 120 ° C, preferably 50 to 100 ° C, especially 60 to 90 ° C.
  • the drying conditions are particularly preferably chosen so that the resulting dapoxetine resinate has the above-described water content.
  • step (i) a pharmaceutically acceptable salt of dapoxetine (a), preferably dapoxetine HCl, is dissolved in a solvent, preferably in water.
  • step (ii) a polymeric adsorbent, preferably a cation exchange resin, is dispersed with stirring in the solution obtained in step (i).
  • the quantities given above can be transferred to the process according to the invention.
  • step (i) dapoxetine HCl is used as component (a) and in step (ii) polacrilin potassium is used as component (b).
  • step (iii) is stirred to a pH of at least 7.0.
  • the mixture is then passed through a filter and the filter cake, e.g. dried at a temperature of 60 to 90 ° C.
  • the dapoxetine resinate obtainable by the process according to the invention is likewise the subject of this invention. It is preferably used for the preparation of the above-described orodispersible tablet.
  • the invention thus also provides a process for the preparation of an orodispersible tablet containing dapoxetine, in particular dapoxetine resinate, comprising the steps: (I) providing dapoxetine, preferably dapoxetine resinate, (II) mixing with other pharmaceutical excipients,
  • step (III) optionally granulating the mixture obtained from step (II),
  • step (II) of the process according to the invention dapoxetine, preferably dapoxetine resinate, is mixed with further pharmaceutical excipients.
  • the mixing can be done in conventional mixers.
  • the mixing in positive mixers or gravity mixers can be done, for example by Turbula ® T 10B (Bachofen AG, Switzerland).
  • the mixture obtained in step (II) of the process according to the invention in step (III) is granulated.
  • the granulation can be carried out by methods known in the art.
  • the granulation is preferably carried out as a dry granulation. Alternatively, a wet granulation can be done.
  • a melt granulation takes place.
  • the provided in step (I) dapoxetine, preferably Dapoxetinresinat be embedded in a melt.
  • matrix former is generally a pharmaceutical excipient which, when heated above the melting point, in particular in a melt granulation or melt extrusion process, is deformable and able to embed the dapoxetine resinate according to the invention, ie a matrix for to form particulate dapoxetine resinate.
  • the matrix former thus preferably has a thermoplastic behavior, ie it is a thermoplastic matrix former.
  • Polyvinylpyrrolidone preferably having a weight-average molecular weight of 10,000 to 40,000 g / mol, copolymer of vinylpyrrolidone and vinyl acetate, in particular having a weight-average molecular weight of 40,000 to 75,000 g / mol, polyethylene glycol, in particular having a weight-average molecular weight of 2,000 to 20,000, is preferably used as the matrix former g / mol, polyoxyethylene alkyl ethers and / or polyvinyl alcohol, preferably having a weight-average molecular weight of from 1,000 to 30,000 g / mol.
  • co-block polymers of polyethylene glycol and polypropylene glycol ie polyoxyethylene polyoxypropylene block polymers.
  • these have a weight-average molecular weight of from 1,000 to 20,000 g / mol, more preferably from 1,500 to 12,500 g / mol, in particular from 5,000 to 10,000 g / mol.
  • These block polymers are preferably obtainable by condensation of propylene oxide with propylene glycol and subsequent condensation of the resulting polymer with ethylene oxide. That is, preferably, the ethylene oxide portion is present as the "endblock".
  • the block polymers have a weight ratio of propylene oxide to ethylene oxide of from 50:50 to 95: 5, more preferably from 70:30 to 90:10.
  • the block polymers preferably have a viscosity at 25 ° C. of from 200 to 2000 mPas, more preferably from 500 to 1500 mPas, in particular from 800 to 1200 mPas, measured at 25 ° C. and according to Ph. Eur., 6th edition, Chapter 2.2.10 determined.
  • the weight-average molecular weight is preferably determined by means of gel permeation chromatography.
  • the compression of the mixture obtained from the step (II) or the granule obtained from the step (III) is made into a ore tablet, i. a compression to tablets.
  • the compression can be done with tableting machines known in the art.
  • the compression is preferably carried out in the absence of solvents.
  • Suitable tableting machines are eccentric presses or concentric presses.
  • a Korsch eccentric EK0 Korsch AG, Germany
  • Dapoxetinresinat is mixed with other pharmaceutical excipients, preferably with the proviso that no lubricant (g) is mixed.
  • the mixture is preferably carried out for 1 to 15 minutes, in particular for 3 to 7 minutes.
  • a Turbula ® T 10B can be used.
  • the mixture is then preferably sieved through a sieve, in particular with a mesh size of 500 to 1000 ⁇ , for example 800 ⁇ . Preference is mixed for another 1 to 15 minutes.
  • Lubricant (g) sieved through a sieve, eg via a sieve of mesh size 800 / im, and the mixture was added.
  • the mixture which is now obtained is preferably mixed again for, for example, 1 to 5 minutes.
  • the mixture obtained is then compressed, for example using a Korsch eccentric press EKO.
  • oral dosage forms are understood as meaning all pharmaceutical dosage forms which are taken orally
  • tablets according to the invention are tablets, capsules and granules
  • examples of tablets are orodispersible tablets, lozenges, uncoated tablets, coated tablets, effervescent tablets, enteric tablets, Modified release tablets, oral cavity tablets, tablets for the preparation of a suspension, preferred are orodispersible tablets.
  • Sexual dysfunction in the context of this invention is usually understood to mean a disorder of sexual functions or reactions, preferably an ejaculation of Praecox.
  • a cation exchange resin is useful in masking a local anesthetic effect of a drug, preferably a drug for the treatment of sexual dysfunction, in the mouth.
  • masking is understood as the weakening or obliterating of a sensation produced by one or more substances in the mouth of the patient.
  • the invention therefore further relates to the use of a cation exchange resin for masking a local anesthetic effect of a Drug, preferably a drug for the treatment of sexual dysfunction, in the mouth.
  • dapoxetine resinate according to the invention and orodispersible tablets containing dapoxetine resinate were prepared by the methods according to the invention.
  • the formulations used and the physical properties of the resulting orodispersible tablets are shown in the following table.
  • Example 1 Dapoxetine Resinate was prepared by the method according to the invention.
  • the dapoxetine resinate prepared in Example 1 was mixed with positions 2-7 for 5 minutes in the Turbula T 10B and then comminuted. The mixture was sieved through a sieve of mesh size 800 / ⁇ m and mixed for a further 10 minutes in Turbula T 10B. Subsequently, position 8 was screened through a sieve of size 300 ⁇ and added to the mixture. The mixture was then mixed for a further 5 minutes in the Turbula T 10B. The resulting mixture was pressed directly using a Korsch eccentric press EK0.
  • position 8 was sieved through a sieve of mesh size 300 ⁇ and added to the mixture. It was then mixed again for 3 minutes in the Turbula T10B. The resulting mixture was then compressed into tablets using the Korsch eccentric press EK0.
  • the disintegration time of the orodispersible tablets was determined in accordance with Pharm. Eur. 6.0, Chapter 2.9.1 Test A at a temperature of 37 ° C.
  • the local anesthetic effect was determined with the help of 10 test persons. On a scale of 1 to 4, the subjects were able to evaluate their perception of the local anesthetic effect in the mouth.
  • the individual stages 1 to 4 were defined as follows: (1) “strong local anesthetic effect", (2) “average local anesthetic effect”, (3) “slight local anesthetic effect (4)" no local anesthetic effect. "The evaluation points of the 10 test persons were added and the sum of all evaluation points classified accordingly: 10 to 15 points: “distinct local anesthetic effect", 16 to 30 points: “moderate local anesthetic effect", 31 to 40 points: "no local anesthetic effect".
  • the tasting took place 1 hour after the last meal.
  • the subjects were all male and non-smokers.
  • the test room was of a neutral odor, the temperature was 20 ° C.
  • the assessment of the stimulus sensations and the training of the test persons was carried out in accordance with DIN 10950.

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Abstract

La présente invention concerne en particulier des comprimés orodispersibles contenant de la dapoxétine, de préférence du résinate de dapoxétine. L'invention concerne également un procédé de production de résinate de dapoxétine ainsi qu'un procédé de production d'un comprimé orodispersible contenant du résinate de dapoxétine.
PCT/EP2010/007619 2009-12-15 2010-12-14 Comprimé orodispersible contenant de la dapoxétine WO2011072839A1 (fr)

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DE102009058321A DE102009058321A1 (de) 2009-12-15 2009-12-15 Schmelztablette, enthaltend Dapoxetin
DE102009058321.1 2009-12-15

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WO2013180675A1 (fr) * 2012-05-28 2013-12-05 Mahmut Bilgic Formulation en comprimés comprenant de la dapoxétine
CN109662950A (zh) * 2018-07-09 2019-04-23 华控创新（北京）药物研究院有限公司 一种含有盐酸达泊西汀的药物组合物
CN110833530A (zh) * 2019-12-12 2020-02-25 盖天力医药控股集团制药股份有限公司 一种盐酸达泊西汀口崩片及其制备方法和应用

Families Citing this family (3)

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US20150216798A1 (en) * 2012-08-17 2015-08-06 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Novel orally administered pharmaceutical formulations
US20150231092A1 (en) * 2012-08-17 2015-08-20 Sanovell IIac Sanayi Ve Ticaret Anonim Sirketi Novel effervescent sachet formulations of dapoxetine and a pde5 inhibitor
WO2014027981A2 (fr) * 2012-08-17 2014-02-20 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Formulations de comprimés effervescents de dapoxétine et d'un inhibiteur de pde5

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EP2233134A1 (fr) * 2009-03-27 2010-09-29 McNeil AB Dosage intra-buccal multi-portions avec des propriétés organoleptiques
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US20020004498A1 (en) * 1997-10-28 2002-01-10 Doherty Paul C. Transmucosal administration of phosphodiesterase inhibitors for the treatment of erectile dysfunction
WO2001017521A1 (fr) * 1999-09-03 2001-03-15 Eli Lilly And Company Techniques d'utilisation d'inhibiteurs selectifs de recaptage de serotonine a apparition rapide pour traiter un dysfonctionnement sexuel
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EP2233134A1 (fr) * 2009-03-27 2010-09-29 McNeil AB Dosage intra-buccal multi-portions avec des propriétés organoleptiques
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013180675A1 (fr) * 2012-05-28 2013-12-05 Mahmut Bilgic Formulation en comprimés comprenant de la dapoxétine
CN109662950A (zh) * 2018-07-09 2019-04-23 华控创新（北京）药物研究院有限公司 一种含有盐酸达泊西汀的药物组合物
CN109662950B (zh) * 2018-07-09 2021-07-16 华控创新（北京）药物研究院有限公司 一种含有盐酸达泊西汀的药物组合物
CN110833530A (zh) * 2019-12-12 2020-02-25 盖天力医药控股集团制药股份有限公司 一种盐酸达泊西汀口崩片及其制备方法和应用

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