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WO1999026625A1 - Formulations contenant de la paroxetine dissoute - Google Patents

Formulations contenant de la paroxetine dissoute Download PDF

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Publication number
WO1999026625A1
WO1999026625A1 PCT/GB1998/003471 GB9803471W WO9926625A1 WO 1999026625 A1 WO1999026625 A1 WO 1999026625A1 GB 9803471 W GB9803471 W GB 9803471W WO 9926625 A1 WO9926625 A1 WO 9926625A1
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WO
WIPO (PCT)
Prior art keywords
paroxetine
solid
carrier
capsule
capsules
Prior art date
Application number
PCT/GB1998/003471
Other languages
English (en)
Inventor
Ahmad Ghazawi
Graham Stanley Leonard
Original Assignee
Smithkline Beecham Plc
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
Priority to KR1020007005532A priority Critical patent/KR20010032320A/ko
Priority to BR9814220-8A priority patent/BR9814220A/pt
Priority to HU0100580A priority patent/HUP0100580A3/hu
Priority to EP98954631A priority patent/EP1033986A1/fr
Priority to PL98340555A priority patent/PL340555A1/xx
Priority to APAP/P/2000/001821A priority patent/AP2000001821A0/en
Priority to CA002310407A priority patent/CA2310407A1/fr
Priority to IL13610698A priority patent/IL136106A0/xx
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to AU11680/99A priority patent/AU1168099A/en
Priority to JP2000521827A priority patent/JP2001523718A/ja
Priority to EA200000552A priority patent/EA200000552A1/ru
Priority to SK734-2000A priority patent/SK7342000A3/sk
Publication of WO1999026625A1 publication Critical patent/WO1999026625A1/fr
Priority to NO20002590A priority patent/NO20002590L/no
Priority to BG104527A priority patent/BG104527A/xx

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Classifications

    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • A61P25/24—Antidepressants

Definitions

  • the present invention relates to novel formulations of a pharmaceutically active compound, and to the use of the formulations in therapy.
  • this invention is concerned with new formulations of the anti-depressant paroxetine.
  • P.aroxetine hydrochloride hemihydrate is described in EP-A-0223403 of Beecham Group and paroxetine hydrochloride anhydrate Forms A, B, C and D are described in WO 96/24595 of SmithKline Beecham pic. All solid oral dosage forms of paroxetine hydrochloride sold to date have been in the form of oral swallow tablets, containing the hemihydrate.
  • WO 95/104448 discloses that paroxetine is likely to develop a pink colour unless it is formulated into tablets using a formulation process in which water is absent, such as dry direct compression of paroxetine or dry granulation of paroxetine followed by compression into tablets.
  • the present invention provides an oral swallow capsule containing paroxetine dissolved in a carrier.
  • the oral swallow capsule comprises a capsule shell containing paroxetine as the free base or a pharmaceutically acceptable salt or solvate thereof in solution in a carrier.
  • the carrier may be liquid or solid.
  • a liquid carrier may be a solvent present in the capsule as a flowable liquid, as a viscous liquid or semi-solid or as a gel.
  • the carrier may also be a solid or semi-solid solvent such as fats and waxes, or film-forming or thermoplastic polymers. Solvents in which supersaturated solutions can be formed are advantageous because of the possibility to increase the loading of active ingredient.
  • the paroxetine containing carrier may be self-supporting without encapsulation. Accordingly a self-supporting formulation may be encapsulated by other means than loading into a preformed capsule shell, for example by coating with an encapsulating material. Also the self-supporting formulation may be used as a dosage form without encapsulation.
  • the present invention provides an oral swallow solid dosage form containing paroxetine dissolved in a solid, semi-solid or gel carrier.
  • the solid dosage form comprises tablets, pellets, spheroids, gr.anules, lozenges or gels in which p.aroxetine is present as a solid solution in a polymeric carrier.
  • Capsules and solid dosage forms of this invention may be coated to assist in administration of the active ingredient, for example using an enteric coating material to prevent release of paroxetine in the stomach, coatings to delay or control release of paroxetine and coatings of taste-masking agents.
  • an enteric coating material to prevent release of paroxetine in the stomach
  • coatings to delay or control release of paroxetine and coatings of taste-masking agents Alternatively such materials can be incorporated in the carrier to achieve the same effect.
  • paroxetine is preferably used as the hydrochloride, -and .as such may be used as the hemihydrate, or as the anhydrate Form A, B, C or D, or as any other form of paroxetine hydrochloride or paroxetine, such as pharmaceutically acceptable salts other than the hydrochloride.
  • suitable paroxetine forms include paroxetine free base, and amorphous and non-crystalline forms of paroxetine and pharmaceutically acceptable derivatives of paroxetine.
  • the capsules or solid dosage forms of present invention use paroxetine hydrochloride in a form other than the hemihydrate, and are formulated under conditions such there is no detectable conversion to hemihydrate during the manufacturing process.
  • paroxetine hydrochloride anhydrate has a tendency to convert at least O 99/26625
  • the paroxetine hydrochloride may, for example, be present in .an .amorphous form or as a crystalline anhydrate. and dissolved in a carrier, or in the presence of excipients, which are essentially hydrophobic, or essentially anhydrous, typically containing less than 2%. more especially less than 1.5%, preferably less than 1% by wt., water.
  • the amount of paroxetine used in each capsule is preferably adjusted such that in a single unit dose there is a therapeutically effective amount of paroxetine.
  • the unit dose contains from 5 to 100 mg paroxetine (as measured in terms of the free base). More preferably the amount of paroxetine in a unit dose is lOmg, 20mg, 30mg, 40mg or 50mg. The most preferred amount of paroxetine in a unit dose is 20mg.
  • the paroxetine needs to be soluble in the carrier to an extent that allows a sufficient concentration so that the selected capsule volume can contain the desired unit dose.
  • the solvent In addition to being able to dissolve paroxetine, the solvent must be compatible with the capsule material and physiologically acceptable for adrninistration to a patient.
  • Solubilising agents such as the polysorbates, the poloxamers, cyclodextrins, ionic and non-ionic surface active agents, for example Pluronic F60 and Sorbitan esters may also be used to enhance the solubility of paroxetine hydrochloride in solvents acceptable for capsule use but in which paroxetine is poorly soluble.
  • oral swallow capsule most suitably denotes a capsule having a maximum volume of 0.86 ml .
  • Preferred capsules according to the present invention have a maximum volume of about 0.45 ml and more especially may lie in the range 0.2 to 0.4 ml , although capsules as small as 0.14 ml are also provided by the invention.
  • the capsule at the upper end of the size range acceptable for pharmaceutical use has a volume of 0.86 ml.
  • the solvent which is used has a solubility of at least 10 mg/ml for paroxetine hydrochloride and more preferably the solubility should be at least 25 mg/ml.
  • larger capsule sizes such as Hard Shell Size 00 (0.95 ml capacity), Supro A (0.68 ml) and Softgel Size 12 Oblong (1.01 ml) may be used when appropriate to provide higher drug dose with the same formulation.
  • solubility rules out many solvents conventionally used as liquid carriers for encapsulated drugs, such as the plant oils Sunflower, Saffiower, Peanut, Soybean, Cottonseed, Corn, Castor, Apricot seed, Olive, Wheat germ, Sesame, Evening Primrose and Canola (Rapeseed) oil, and also Mineral oil and liquid paraffin.
  • Other well known liquid carriers such as Miglyol (810 and 812), Oleic acid, Ethyl Oleate, Span 80 and 85, Labrafac lipophile, Plurol Oleique and Peceol (Glyceryl oleate) also show less than 1 Omg/ml solubility.
  • Solvents that show a useful solubility include Propylene Carbonate, Triacetin, Glycerol, Lauroglycol, Propylene glycol, PEG 300, Giycofurol, PEG 400, IP A, Span 20, Transcutol, Labrasol, Labrafil, Olepal, Glyceryl Linoleate (Maisine 35-1) and Pharmasolve.
  • a cosolvent such as ethanol.
  • the present invention makes use of these solvents and solvent systems as well as of functional equivalents thereof which can be identified using the techniques taught herein.
  • solubilising agent such as N-methyl-2-pyrrolidone (Pharmasolve, International Speciality Products, Texas, USA) as a cosolvent.
  • paroxetine optionally as the free base but more typically as a pharmaceutically acceptable salt such as the hydrochloride is dissolved in a solubilising agent and then blended with an oil or lipid carrier before filling capsules.
  • the invention also provides as a novel formulation a solution of paroxetine, optionally as the free b-ase but more typically as a pharmaceutically acceptable salt such as the hydrochloride in a blend of a solubilising agent and a lipid and or oil.
  • solubilising agent By use of a solubilising agent it is possible to solubilise paroxetine in oils and lipids previously regarded as unsuitable solvents, such as soybean oil, sunflower oil, and arachis oil.
  • paroxetine may dissolved in lipids, especially lipids derived from natural materials, such coconut oil-derived glycerides, Cithrol 4DL (PEG-8 dilaurate).
  • lipids derived from natural materials such as coconut oil-derived glycerides, Cithrol 4DL (PEG-8 dilaurate).
  • coconut oil-derived glycerides include Labrasol and Labrafac CM10(Gattefosse, France) which are C ⁇ /C ⁇ Q polyglycolised glycerides from coconut oil having a hydrophilic:lipophilic balance of 14 and 10 respectively.
  • Formulations based on a solubilising agent and oils/lipids are preferably formulated with at least one antioxidant to maintain stability of the solution on storage. If it desired to use the solutions for filling capsules then the compatibility of the solution with the capsule material must be investigated.
  • the present invention in a further aspect makes use of supersaturated solutions, for ex,ample in solid or semi-solid solvents such as fats and waxes. These may readily be prepared by heating and exhibit high stability because of inter alia their very high viscosity.
  • the solvents used in carrying out the invention contain less than 2%, more especially less than 1.5%, preferably less than 1%, water, or are essentially hydrophobic.
  • the solution may optionally contain one or more antioxidants such as the tocopherols, ascorbic acid, ascorbic palmitate, thiodipropionic acid, bis hydroxy toluene (BHT), bis hydroxy anisole (BHA), g lic acid, propyl octyl/dodecyl gallate, benzyl alcohol and nordihydroguaiaretic acid with or without the addition of pH modifiers and chelating agents such as citric acid and EDTA.
  • antioxidants such as the tocopherols, ascorbic acid, ascorbic palmitate, thiodipropionic acid, bis hydroxy toluene (BHT), bis hydroxy anisole (BHA), g lic acid, propyl octyl/dodecyl gallate, benzyl alcohol and nordihydroguaiaretic acid with or without the addition of pH modifiers and chelating agents such as citric acid and EDTA.
  • antioxidants such as the
  • the capsule shell may be of any conventional material that is stable to the liquid carrier and solute, for example hard and soft gelatin capsules and starch capsules.
  • the capsule shell In addition to resisting the solvent action of the liquid carrier attention must be paid to the pH of the liquid within the capsule.
  • soft gels have a pH limit of 2.5-7.5. Since the O 99/26625
  • paroxetine hydrochloride to a solvent system tends to lower the pH by at least 1 unit, then in general solvent systems with a pH of below 3.5 are not preferred.
  • the capsules have an enteric resistant coating or incorporate enteric resistant materials in the capsule shell, such that the paroxetine is not discharged in the acidic conditions of the stomach.
  • the object of this is to prevent any undesired uncontrolled precipitation of the paroxetine from solution, and to enable its absorption characteristics to be modified if desired by presenting it to the intestinal mucosa in non-aqueous solution.
  • the liquid carrier may be present in the capsule as a flowable liquid, as a viscous liquid or semi-solid or as a gel.
  • the viscosity characteristics may be varied by initial choice of solvent or by appropriate use of cosolvents or thickening agents.
  • a liquid carrier, or a solid or semi-solid carrier that has been softened or made flowable by heating, with dissolved paroxetine may be filled into capsules using conventional capsulation technology.
  • paroxetine hydrochloride in a form other tlran the hemihydrate, which is formulated into capsules or solid dosage forms under conditions such there is no detectable conversion to hemihydrate during the manufacturing process.
  • the paroxetine hydrochloride may, for example, be present in an amorphous form or as a crystalline anhydrate.
  • excipients or carriers which are essentially anhydrous (that is to say, they contain less than 2%, more especially less than 1.5%, preferably less than 1% water) or which are essentially hydrophobic.
  • the capsules and solid dosage forms are then preferably packaged with a desiccant in order to prevent conversion of anhydrate to hemihydrate on storage.
  • the present invention also provides a process for the preparation of paroxetine hydrochloride anhydrate capsules or solid dosage forms free of detectable hemihydrate which is characterised by the use of conditions such there is no detectable conversion of the anhydrate to hemihydrate during the manufacturing process.
  • Such conditions can be achieved by the use of essentially anhydrous,hydrophobic excipients a ⁇ nd/or carriers under conditions of low relative humidity
  • excipients with the necessary low moisture content include materials such as dibasic calcium phosphate anhydrous, anhydrous lactose, monosaccharide sugars eg mannitol, disaccharide sugars eg lactitol, powdered cellulose, pregelatinised starch and similar materials.
  • Dibasic calcium phosphate anhydrous is commercially available in a pharmaceutically acceptable grade, eg A-TAB (Rhone Poulenc).
  • liquid and semi-solid excipients with the necessary hydrophobicity include materials such as polyglycolised glycerides eg Gelucire 44/14; complex fatty materials of plant origin eg theobroma oil, carnauba wax; plant oils eg peanut, olive, palm kernels, cotton, corn, soya; hydrogenated plant oils eg peanut, palm kernels, cotton, soya, castor, coconut; natural fatty materials of animal origin eg beeswax, lanolin, fatty alcohols eg cetyl, stearyl, lauric, myristic, palmitic, stearic; esters eg glycerol stearate, glycol stearate, ethyl oleate, isopropyl myristate; solid interesterified semi-synthetic glycerides eg Suppocire, Witepsol; liquid interesterified semi-synthetic glycerides eg Mig
  • Liquids .and semi-solids having suitable solubility characteristics to act as carriers for dissolved paroxetine, and having similar hydrophobicity to the above liquid excipients, include Labraphil, a liquid interesterified semi-synthetic glyceride, and PEG 400, a polyoxyethylene glycol.
  • the above solid and liquid excipients may be blended with carriers of suitable solubility for paroxetine disclosed above and if necessary cosolvents to obtain solutions of paroxetine with anhydrous/hydrophobic properties.
  • Carriers already having suitable anhydrous/hydrophobic properties may be blended directly with paroxetine, again using cosolvents where neccessary to promote dissolution.
  • the formulations may be filled into capsules, such as gelatin capsule shells, or cellulose capsule shells of intrinsically low moisture content (eg Shionogi Qualicaps, ⁇ 3%).
  • Liquid interesterified semi-synthetic glycerides commercially available in a pharmaceutically acceptable grade include Labrafil M 2125CS (Gattfosse).
  • paroxetine hydrochloride anhydrate is mixed with Labrafil M 2125CS (Gatfosse) to produce a formulation for encapsulation in a hard or soft gelatin capsule.
  • Paroxetine in the form of the hydrochloride anhydrate may be prepared according to the procedures outlined in WO 96/24595. Suitable procedures for preparing paroxetine include those mentioned in US Patents 4,009,196, 4,902,801, 4,861,893 and 5,039,803 and PCT/GB 93/00721.
  • the present invention also provides solid dosage forms of paroxetine for oral swallow use in which paroxetine is dissolved in a polymeric carrier.
  • These forms include tablets, pellets, spheroids, granules, lozenges and gels containing paroxetine in solid solution.
  • the paroxetine needs to be soluble in the polymer carrier or a solvent/cosolvent that is soluble in the polymer carrier to an extent that allows a sufficient concentration so that the selected tablet size and volume can contain the desired unit dose.
  • the solvent/cosolvent must be compatible with the polymer carrier material and physiologically acceptable for administration to a patient.
  • the solid dosage form is granules or pellets then a plurality of granules or pellets may be collected in an aggregation that as a whole constitutes a unit dose.
  • the granules or pellets may be used as a fill for capsules or pressed, optionally with binders or excipients, into tablet form.
  • the solvents/co-solvents .and carriers which .are acceptable for use in the above dosage forms and for administration to patients need to be subjected to routine solubility testing to confirm that they can maintain an appropriate concentration of paroxetine.
  • higher loadings of a paroxetine form in a suitable solvent may be achieved by using conventional physical techniques such as heating, shaking and sonication.
  • good solvents for paroxetine may be used in small amounts as cosolvents to solubilize paroxetine in polymers that are acceptable for melt extrusion, melt granulation, gel formulation use but in which paroxetine is poorly soluble.
  • Solubilising agents such as the polysorbates, the poloxamers, cyclodextrins, ionic and non-ionic surface active agents, for example Pluronic F60 and Sorbitan esters may also be used to enhance the solubility of paroxetine hydrochloride in solvents acceptable for polymers used to produce solid solution systems in forms of tablet, pellet, granule, spheroid use but in which paroxetine is poorly soluble. It is preferred that the polymer and/or solvent which are used have a solubility of at least 10 mg/ml for paroxetine hydrochloride and more preferably the solubility should be at least 25 mg/ml.
  • melt extruded system such as tablets, pellets, spheroid and any other shape depending on the shape of the extruder die
  • melt extruded system such as tablets, pellets, spheroid and any other shape depending on the shape of the extruder die
  • melt extruded system such as tablets, pellets, spheroid and any other shape depending on the shape of the extruder die
  • melt extruded system such as tablets, pellets, spheroid and any other shape depending on the shape of the extruder die
  • melt granulated to produce pellets or granules can be injection moulded into different shapes and /or melt granulated to produce pellets or granules.
  • the granules can be milled and pressed into tablets and other shapes depending on the shape and design of the press die.
  • Examples of the pharmaceutical polymers used for the above applications are film forming and thermoplastic polymers that are generally approved substances listed in international Pharmacopoeias such as polyethylene oxide water soluble resins, ethoxylated glycerides and triglycerides, cetyl esters, cetyl p.almitate, glyceryl esters, polyvinyl acetate, cellulose, lanolin based product, vinyl resins, latex product, carbowax polyethylene glycols, gelatin (protein), ethylene oxide/glycol such as ethylene glycol, glycol ethers and ethanolamines, unipol polymers, polypropylene resins, silicone products, saturated polyglycolysed glycerides, glyceryl behenate, glyceryl palmitostearate, semisynthetic glycerides and vinyl acetate monomers.
  • the function(s) of these polymers will be as a drug carrier and/or solubiliser .and/or binder
  • Solvents that show a useful solubility for p.aroxetine such as Propylene Carbonate, Triacetin, Glycerol, Lauroglycol, Propylene glycol, PEG 300, Glycofurol, PEG 400, IPA, Span 20, Transcutol, Labrasol, Labrafil, Olepal, Glyceryl Linoleate (Maisine 35-1) and Pharmasolve mentioned previously, may be used as cosolvents to assist solubilisation of paroxetine in the soiide, semi-solid .and polymeric carriers mentioned above. For physiological suitability it may be desirable to use such solvents with another cosolvent such as ethanol.
  • the present invention makes use of these solvents and solvent systems as well as of functional equivalents thereof which can be identified using the techniques taught herein.
  • lanolin derivative e.g. ethoxy-75 lanolin is commercially available in a pharmaceutical grade e.g. Solan E (Croda).
  • Solan E Cosmetic grade
  • paroxetine hydrochloride hemihydrate is dissolved in Pharmasolve and mixed with O 99/26625
  • a polyglycolised glyceride is commercially available in a pharmaceutically acceptable grade .e.g. Gelucire 44/14 (Gattfosse).
  • Gelucire 44/14 Gelucire 44/14
  • paroxetine hydrochloride hemihydrate is dissolved in Pharmasolve and then mixed with molten Gelucire 44/14 to form a melt extrudate in forms of a tablet and/or pellet on cooling.
  • Polyethylene glycols of different molecular weights are commercially available in a pharmaceutically acceptable grade e.g. PEG 4000 (Union Carbide Corp & BASF).
  • PEG 4000 Union Carbide Corp & BASF
  • Paroxetine hydrochloride hemihydrate is dissolved in PEG 300 and then mixed with molten PEG 4000 to form melt extruded materials which on cooling as solid solution may be converted into forms of tablets and/or pellets.
  • the solid solution may optionally contain one or more antioxidants such as the tocopherols, .ascorbic acid, ascorbyl palmitate, thiodipropionic acid, bis hydroxy toluene (BHT), bis hydroxy anisole (BHA), gallic acid, propyl/octyl dodecyl gallate, benzyl alcohol and nordihydroguaiaretic acid with or without the addition of pH modifiers and chelating agents such as citric acid and EDTA.
  • antioxidants such as the tocopherols, .ascorbic acid, ascorbyl palmitate, thiodipropionic acid, bis hydroxy toluene (BHT), bis hydroxy anisole (BHA), gallic acid, propyl/octyl dodecyl gallate, benzyl alcohol and nordihydroguaiaretic acid with or without the addition of pH modifiers and chelating agents such as citric acid and EDTA.
  • antioxidants such as
  • the solid dosage form may have an enteric resistant coating such that paroxetine is not discharged in the acidic conditions of the stomach.
  • the object of this is to prevent .any undesired uncontrolled precipitation of the paroxetine from solution, and to enable its abso ⁇ tion characteristics to be modified if desired by presenting it to the intestinal mucosa in an aqueous solution.
  • the solid solution/semi-solid systems presented in this invention can be coated with suitable polymer that can be used with melt granulation or hot melt coating such as Precirol ATO 5 (Glyceryl palmito stearate) for taste-masking paroxetine and/or enterically coated with methacrylic acid copolymer C (e.g. Eudragit L 30 D-55).
  • suitable polymer that can be used with melt granulation or hot melt coating
  • Precirol ATO 5 Glyceryl palmito stearate
  • methacrylic acid copolymer C e.g. Eudragit L 30 D-55
  • the semi-solid or gel formulation can also be optionally capsulated.
  • the viscosity characteristics of the semi-solid or gel may be varied by initial choice and amount of solvent or by appropriate use of cosolvents or thickening agents.
  • the semi-solid or gel carrier with dissolved paroxetine may be filled into capsules using conventional capsulation technology.
  • Self-supporting solid of paroxetine solution can be successfully prepared in forms of tablet, pellets, spheroid, granules using Solan E, Gelucire, higher molecular weights of PEG's and gel based on gelatin with different cosolvents constituents.
  • the paroxetine is first dissolved in co-solvent constituents, such as PEG 300, Pharmasolve and water/ethanol (using sufficient mixing to assure complete wetting/solubilisation).
  • co-solvent constituents such as PEG 300, Pharmasolve and water/ethanol (using sufficient mixing to assure complete wetting/solubilisation).
  • the resultant mixture is then preheated and added to a suitable portions of a melted polymer such as Gelucire 44/14 (melting point 42-46 C), Solan E (melting point 45-50 C), PEG 6000 (melting point 55-63 C), PEG 4000 (melting point 50-58 C) or Gelatin (gelatin in liquid co-solvents melted between 50-55 C).
  • the samples may then be left at ambient condition for resolidification of the polymer to occur.
  • a shaping device may then be used to produce solid dosage forms as tablets, pellets, spheroids and gels.
  • the drug molecule dissolved in the polymer during the melting phase will remain dissolved in the finished product as a solid solution.
  • gelatin based formulations transparent solid solutions containing dissolved drug are produced.
  • paroxetine hydrochloride in a form other th.an the hemihydrate, which is formulated into self-supporting solid dosage forms under conditions such there is no detectable conversion to hemihydrate during the m-anufacturing process.
  • the paroxetine hydrochloride may, for example, be present in an amorphous form or as a crystalline anhydrate.
  • excipients or polymeric carriers which are essentially anhydrous (that is to say, they contain less than 2%, more especially less than 1.5%, preferably less than 1% water) or which are essentially hydrophobic.
  • paroxetine formulations of this invention include treatment of: alcoholism, anxiety, depression, obsessive compulsive disorder, panic disorder, chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, pre-menstrual syndrome (PMS), adolescent depression, trichotillomania, dysthymia. and substance abuse, referred to below as "the disorders”.
  • the present invention also provides: O 99/26625
  • paroxetine dissolved in a carrier to manufacture oral swallow capsules or solid dosage forms for the treatment or prophylaxis of one or more of the disorders
  • a method of treating the disorders which comprises administering an effective or prophylactic amount of paroxetine as a solution in a carrier in an oral swallow capsule or solid dosage form to a person suffering from one or more of the disorders; a method of treating the disorders which comprises administering an effective or prophylactic amount of paroxetine as a solution in a liquid formulation of the invention to a person suffering from one or more of the disorders.
  • formulations of this invention may also be used where appropriate for veterinary treatment of animals.
  • paroxetine is dissolved in a carrier, optionally assisted by a cosolvent, and filled into capsules.
  • Example 11 paroxetine is dissolved in a hydrophobic carrier.
  • paroxetine was dissolved in a cosolvent, and then blended with a molten polymer. Clear paroxetine solutions were obtained before solidification of the polymers.
  • PEG 4000 300.00 mg dl alfa tocopherol 0.1% w/w Tablet Ascorbyl Palmitate 0.1% w/w
  • PEG 1450 300.00 mg dl alfa tocopherol 0.1% w/w
  • Example 20 Paroxetine HCL 73.96 mg Gelatine 100.00 mg Purified water 350.00 mg Pharmasolve 150.00 mg Polysorbate 80 1 drop
  • Example 21 Paroxetine HCL 42.67 mg Gelatine 50.00 mg Purified water 200.00 mg Propylene Glycol 400.00 mg Propyl Gallate 0.1% w/w Ascorbic Acid 0.1% w/w
  • Example 22 Paroxetine HCL 113.79 mg Gelatine 50.00 mg Purified water 200.00 mg Pharmasolve 200.00 mg Propylene Glycol 200.00 mg Polysorbate 80 1 drop
  • Example 24 Paroxetine HCL 28.45 mg Gelatine 50.00 mg Purified water 200.00 mg Ethanol 200.00 mg
  • Example 25 Paroxetine HCL 45.52 mg Gelatine 50.00 mg Purified water 200.00 mg Propylene Glycol 400.00 mg PEG 300 50.00 mg
  • Example 27 Paroxetine HCL 28.45 mg Gelatine 50.00 mg Purified water 300.00 mg Propylene Glycol 300.00 mg
  • Example 28 Paroxetine HCL 68.28 mg Gelatine 50.00 mg Purified water 300.00 mg Pharmasolve 150.00 mg Propylene Glycol 150.00mg
  • Example 29 Paroxetine HCL 79.65 mg Gelatine 50.00 mg Purified water 300.00 mg Pharmasolve 150.00 mg Ethanol 150.00 mg Polysorbate 80 1 drop
  • Example 30 Paroxetine HCL 17.07 mg Gelatine 50.00 mg Purified water 300.00 mg Propylene Glycol 150.00 mg Ethanol 150.00 mg Gel Polysorbate 80 1 drop
  • paroxetine is initially dissolved in Pharmasolve and the resultant solution is blended with oil and lipid carriers, so that the paroxetine is dissolved in the carrier to give liquid formulations that may be capsulated (36 - 42) and also provided with an enteric coating (43 - 45)
  • Capsule Licaps size 1 (fill 20 capsules)
  • Capsule size 11 oblonge softgel (fill 15 softgel capsules)

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
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  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne des formulations pharmaceutiques de paroxétine dans lesquelles la paroxétine est en solution dans un véhicule solide, semi-solide ou liquide. On utilise ces solutions afin de remplir des gélules ou on prépare des formes galénique solides, telles que des comprimés ou des granules, à partir de solutions solides seules. Elle concerne également de nouvelles formulations liquides dans lesquelles on utilise un agent solubilisant afin solubiliser la paroxétine, soit dans des huiles, soit dans des lipides, ainsi que des procédés permettant d'éviter la conversion d'autres formes de paroxétine en son hémihydrate, par l'intermédiaire de véhicules anhydres ou hydrophobes.
PCT/GB1998/003471 1997-11-21 1998-11-18 Formulations contenant de la paroxetine dissoute WO1999026625A1 (fr)

Priority Applications (14)

Application Number Priority Date Filing Date Title
CA002310407A CA2310407A1 (fr) 1997-11-21 1998-11-18 Formulations contenant de la paroxetine dissoute
HU0100580A HUP0100580A3 (en) 1997-11-21 1998-11-18 Formulations comprising dissolved paroxetine
EP98954631A EP1033986A1 (fr) 1997-11-21 1998-11-18 Formulations contenant de la paroxetine dissoute
PL98340555A PL340555A1 (en) 1997-11-21 1998-11-18 Preparations containing dissolved paroxetin
APAP/P/2000/001821A AP2000001821A0 (en) 1997-11-21 1998-11-18 Formulations comprising dissolved paroxetine.
IL13610698A IL136106A0 (en) 1997-11-21 1998-11-18 Formulations comprising dissolved paroxetine
AU11680/99A AU1168099A (en) 1997-11-21 1998-11-18 Formulations comprising dissolved paroxetine
KR1020007005532A KR20010032320A (ko) 1997-11-21 1998-11-18 용해된 파록세틴을 포함하는 제형
BR9814220-8A BR9814220A (pt) 1997-11-21 1998-11-18 Formulações compreendendo paroxetinadissolvida
JP2000521827A JP2001523718A (ja) 1997-11-21 1998-11-18 溶存パロキセチンを含む処方
EA200000552A EA200000552A1 (ru) 1997-11-21 1998-11-18 Готовые препаративные формы, содержащие растворенный пароксетин
SK734-2000A SK7342000A3 (en) 1997-11-21 1998-11-18 Formulations comprising dissolved paroxetine
NO20002590A NO20002590L (no) 1997-11-21 2000-05-19 Formuleringer omfattende oppløst paroxetin
BG104527A BG104527A (en) 1997-11-21 2000-06-13 Formulations comprising dissolved paroxetine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9724544.3 1997-11-21
GBGB9724544.3A GB9724544D0 (en) 1997-11-21 1997-11-21 Novel Formulation

Publications (1)

Publication Number Publication Date
WO1999026625A1 true WO1999026625A1 (fr) 1999-06-03

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PCT/GB1998/003471 WO1999026625A1 (fr) 1997-11-21 1998-11-18 Formulations contenant de la paroxetine dissoute

Country Status (24)

Country Link
EP (1) EP1033986A1 (fr)
JP (1) JP2001523718A (fr)
KR (1) KR20010032320A (fr)
CN (1) CN1279608A (fr)
AP (1) AP2000001821A0 (fr)
AR (1) AR015485A1 (fr)
AU (1) AU1168099A (fr)
BG (1) BG104527A (fr)
BR (1) BR9814220A (fr)
CO (1) CO4970832A1 (fr)
DZ (1) DZ2658A1 (fr)
EA (1) EA200000552A1 (fr)
GB (1) GB9724544D0 (fr)
HU (1) HUP0100580A3 (fr)
IL (1) IL136106A0 (fr)
MA (1) MA24704A1 (fr)
NO (1) NO20002590L (fr)
OA (1) OA11385A (fr)
PE (1) PE20000381A1 (fr)
PL (1) PL340555A1 (fr)
SK (1) SK7342000A3 (fr)
TR (1) TR200001423T2 (fr)
WO (1) WO1999026625A1 (fr)
ZA (1) ZA9810637B (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999058116A2 (fr) * 1998-05-13 1999-11-18 Smithkline Beecham Plc Nouvelle formulation contenant de la paroxetine
WO2000054775A1 (fr) * 1999-03-12 2000-09-21 Basf Ag Forme galenique pharmaceutique stable pour anhydrate de paroxetine
WO2001001956A2 (fr) * 1999-07-02 2001-01-11 Knoll Aktiengesellschaft Preparations solides contenant de la paroxetine
US6720003B2 (en) 2001-02-16 2004-04-13 Andrx Corporation Serotonin reuptake inhibitor formulations
US6984632B1 (en) 1999-07-01 2006-01-10 Italfarmaco S.P.A. Complexes of paroxetine, with cyclodextrins or cyclodextrin derivatives
WO2006119779A2 (fr) * 2005-05-10 2006-11-16 Lifecycle Pharma A/S Composition pharmaceutique comprenant un antagoniste de l'aldosterone
AU2002364212B2 (en) * 2001-12-21 2007-09-20 Shire Laboratories Inc. Oral capsule formulation with increased physical stability

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE0200475D0 (sv) * 2002-02-15 2002-02-15 Ltp Lipid Technologies Provide Oral farmaceutisk beredning
WO2011071194A1 (fr) * 2009-12-08 2011-06-16 주식회사 일화 Dispersions solides contenant du 20-o-β-d-glucopyranosyl-20(s)-protopanaxadiol
GB201020032D0 (en) * 2010-11-25 2011-01-12 Sigmoid Pharma Ltd Composition
CN103961333B (zh) * 2014-05-07 2020-02-21 浙江华海药业股份有限公司 甲磺酸帕罗西汀胶囊及其制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996031197A1 (fr) * 1995-04-03 1996-10-10 Abbott Laboratories Melanges homogenes de medicaments fondant a basse temperature et d'additifs, destines a une liberation lente
WO1998031365A1 (fr) * 1997-01-15 1998-07-23 Smithkline Beecham Plc Compositions a base de paroxetine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996031197A1 (fr) * 1995-04-03 1996-10-10 Abbott Laboratories Melanges homogenes de medicaments fondant a basse temperature et d'additifs, destines a une liberation lente
WO1998031365A1 (fr) * 1997-01-15 1998-07-23 Smithkline Beecham Plc Compositions a base de paroxetine

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999058116A3 (fr) * 1998-05-13 2000-02-17 Smithkline Beecham Plc Nouvelle formulation contenant de la paroxetine
WO1999058116A2 (fr) * 1998-05-13 1999-11-18 Smithkline Beecham Plc Nouvelle formulation contenant de la paroxetine
JP4854115B2 (ja) * 1999-03-12 2012-01-18 エイシカ ファーマシューティカルス リミテッド 無水パロキセチン用安定製剤形
WO2000054775A1 (fr) * 1999-03-12 2000-09-21 Basf Ag Forme galenique pharmaceutique stable pour anhydrate de paroxetine
US6596309B2 (en) 1999-03-12 2003-07-22 Basf Aktiengesellschaft Stable pharmaceutical dosage form for paroxetin anhydrate
JP2004527447A (ja) * 1999-03-12 2004-09-09 バスフ アクチェンゲゼルシャフト 無水パロキセチン用安定製剤形
US6984632B1 (en) 1999-07-01 2006-01-10 Italfarmaco S.P.A. Complexes of paroxetine, with cyclodextrins or cyclodextrin derivatives
WO2001001956A2 (fr) * 1999-07-02 2001-01-11 Knoll Aktiengesellschaft Preparations solides contenant de la paroxetine
WO2001001956A3 (fr) * 1999-07-02 2001-07-12 Knoll Ag Preparations solides contenant de la paroxetine
US6720003B2 (en) 2001-02-16 2004-04-13 Andrx Corporation Serotonin reuptake inhibitor formulations
AU2002364212B2 (en) * 2001-12-21 2007-09-20 Shire Laboratories Inc. Oral capsule formulation with increased physical stability
WO2006119779A3 (fr) * 2005-05-10 2007-06-14 Lifecycle Pharma As Composition pharmaceutique comprenant un antagoniste de l'aldosterone
WO2006119779A2 (fr) * 2005-05-10 2006-11-16 Lifecycle Pharma A/S Composition pharmaceutique comprenant un antagoniste de l'aldosterone

Also Published As

Publication number Publication date
OA11385A (en) 2004-01-27
CO4970832A1 (es) 2000-11-07
NO20002590D0 (no) 2000-05-19
KR20010032320A (ko) 2001-04-16
JP2001523718A (ja) 2001-11-27
AR015485A1 (es) 2001-05-02
ZA9810637B (en) 2000-05-22
TR200001423T2 (tr) 2000-10-23
HUP0100580A2 (hu) 2002-04-29
CN1279608A (zh) 2001-01-10
AU1168099A (en) 1999-06-15
EA200000552A1 (ru) 2000-10-30
BG104527A (en) 2001-04-30
DZ2658A1 (fr) 2003-03-22
HUP0100580A3 (en) 2002-05-28
PL340555A1 (en) 2001-02-12
NO20002590L (no) 2000-07-19
EP1033986A1 (fr) 2000-09-13
GB9724544D0 (en) 1998-01-21
MA24704A1 (fr) 1999-07-01
BR9814220A (pt) 2001-12-26
SK7342000A3 (en) 2000-12-11
PE20000381A1 (es) 2000-05-07
IL136106A0 (en) 2001-05-20
AP2000001821A0 (en) 2000-06-30

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