EP2032124A1 - Système de délivrance osmotique multiparticulaire - Google Patents

Système de délivrance osmotique multiparticulaire

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Publication number
EP2032124A1
EP2032124A1 EP07736118A EP07736118A EP2032124A1 EP 2032124 A1 EP2032124 A1 EP 2032124A1 EP 07736118 A EP07736118 A EP 07736118A EP 07736118 A EP07736118 A EP 07736118A EP 2032124 A1 EP2032124 A1 EP 2032124A1
Authority
EP
European Patent Office
Prior art keywords
drug
composition
weight
dissolution medium
osmotic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07736118A
Other languages
German (de)
English (en)
Inventor
Graham Jackson
Tien Nghiem
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Valeant International Bermuda
Original Assignee
Biovail Laboratories International SRL
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 claimed from US11/475,252 external-priority patent/US7241805B2/en
Application filed by Biovail Laboratories International SRL filed Critical Biovail Laboratories International SRL
Publication of EP2032124A1 publication Critical patent/EP2032124A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0002Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0004Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings

Definitions

  • the composition excludes a sealcoat.
  • the modified release coating includes at least one polymer.
  • the polymer is an acrylate dispersion.
  • the polymer in the modified release coating is EUDRAGIT® NE30D.
  • a modified release pharmaceutical composition for oral administration suitable for once daily dosing comprising (i) a core including at least one drug; (ii) an osmotic subcoat including at least one osmotic agent and at least one osmotic deposition vehicle, wherein the osmotic subcoat at least partially or fully surrounds the core; (iii) a modified release coating that at least partially or fully surrounds the osmotic subcoat; and (iv) an additional overcoat that includes at least one drug, wherein the additional overcoat at least partially or fully surrounds the modified release coating.
  • the modified release coat provides delayed release of the drug(s).
  • the modified release dosage form comprises at least one modified release coat, which comprises at least one aqueous dispersion of a neutral ester copolymer without any functional groups, a poly glycol having a melting point greater than about 55°C, and one or more pharmaceutically acceptable excipients and is cured at a temperature at least equal to or greater than the melting point of the poly glycol.
  • the modified release dosage form comprises at least one delayed release coat, which coat comprises at least one pH dependent polymer.
  • the modified release dosage form comprises two or more coats, ⁇ wherein one coat comprises a modified release coat.
  • the modified release dosage form comprises two or more coats, wherein one coat comprises a delayed-release coat. In at least one embodiment the modified release dosage form comprises at least one nonfunctional soluble coat.
  • the modified release dosage form is in the form of a plurality of microparticles, wherein each microparticle comprises an osmotic subcoat.
  • the modified release dosage form comprises at least one immediate release matrix core coated with at least one aqueous controlled-release coat.
  • FIG. 3 illustrates the effect of the osmotic subcoat on rate and extent of drug release from Diltiazem modified release microparticles.
  • FIG. 4 illustrates lagtimes achieved from Rivastigmine delayed release microparticles in
  • FIG.7 illustrates pulsatile drug release from Rivastigmine delayed release microparticles coated with an additional overcoat containing Rivastigmine.
  • a prodrug is a molecule or ion whose biological activity is altered and/or increased after being introduced into the body, for example, by alteration of the molecule or ion, for example by oxidation and/or amination and/or deamination and/or reduction and/or conjugation and/or acylation and/or alkylation and/or hydrolysis and/or dealkylation, and/or rearrangement of the molecule or ion, and/or or removal of some part of the molecule or ion.
  • the term "high-solubility drug" as used herein refers to drugs wherein about ten parts of
  • high-dose drug refers to drugs that are dosed at about 200mg or more per dosage form including about 200mg, about 300mg, about 400mg, about 500mg, about 600mg, about 700mg, about 800mg, about 900mg, about lOOOmg, and even higher doses, including all values, ranges and subranges between about 200 mg and about 1000 mg, and including all values, ranges and subranges between about 200 mg and about 10,000 mg.
  • modified release dosage forms of certain embodiments of the invention therefore, avoid large peak-to-trough fluctuations normally seen with conventional or immediate release dosage forms and can provide a substantially flat serum concentration curve throughout the therapeutic period.
  • Modified-release dosage forms of certain embodiments can be designed to provide a quick increase in the plasma concentration of the drug which remains substantially constant within the therapeutic range of the drug for a period of time ⁇ e.g. at least ⁇ a 24-hour period).
  • modified-release dosage forms of certain embodiments can be designed ⁇ to provide a quick increase in the plasma concentration of the drug, which although may not remain constant, declines at rate such that the plasma concentration remains within the therapeutic range for a period of time (e.g. at least a 24-hour period).
  • osmotic fluid imbibing agents as used herein are used interchangeably, and define any material that is soluble ⁇ i.e. can be partially or totally solubilized) or swellable in a solvent ⁇ e.g. water) that enters the composition, and which exhibits an osmotic pressure gradient across the selectively-permeable membrane ⁇ e.g. modified release overcoat), thus increasing the hydrostatic pressure inside the osmotic dosage form.
  • osmotic deposition vehicle as used herein is defined to mean a carrier for the osmotic agent in the osmotic subcoat.
  • the osmotic deposition vehicle can be any type of hydrophilic polymer.
  • the compression force used in the manufacture of the modified release matrix core can alter the porosity of the matrix core and hence the rate of release of the drug. It will be understood by one of ordinary skill in the art of drug delivery that a more rigid matrix will be less porous and hence release the drug more slowly compared to a less rigid modified release matrix core.
  • the modified release matrix core can comprise insoluble or inert matrix dosage forms, swellable matrix dosage forms, swellable and erodable matrix dosage form, hydrophobic matrix dosage forms, hydrophilic matrix dosage forms, erodable matrix dosage forms, reservoir dosage forms, or any combination thereof.
  • the modified release matrix core can comprise at least one insoluble matrix, at least one swellable matrix, at least one swellable and erodable matrix, at least one hydrophobic matrix, at least one hydrophilic matrix, at least one erodable matrix, or a combination thereof in which the rate of release is slower than that of uncoated immediate-release dosage forms.
  • Modified release matrix cores can be coated with at least one modified release coat to further slow the release of the drug from the modified release matrix core.
  • Such coated modified release matrix cores can exhibit modified-release, controlled-release, sustained- release, extended-release, prolonged-release, bi-phasic release, delayed-release or combinations thereof of the drug.
  • Modified release matrix cores can also be coated with a non-functional soluble coat.
  • plasticizer as used herein includes any compounds capable of plasticizing or softening a polymer or a binder used in the present invention.
  • the use of plasticizers is optional, and can be included in the dosage form to modify the properties and characteristics of the polymers used in the coat(s) or core of the dosage form for convenient processing during manufacture of the coat(s) and/or the core of the dosage form.
  • certain plasticizers can function to increase the hydrophilicity of the coat(s) and/or the core of the dosage form in the environment of use.
  • the plasticizer can lower the melting temperature or glass transition temperature (softening point temperature) of the polymer or binder.
  • are used interchangeably in this application, and are defined to mean an excipient that can be added to a coating ⁇ e.g. the modified release overcoat), wherein upon exposure to fluids in the environment of use, the pore former dissolves or leaches from the coating to form pores, channels or paths in the coating, 5 that can fill with the environmental fluid and allow the fluid to enter the core and dissolve the drug, and modify the release characteristics of the formulation.
  • the pore formers can be inorganic or organic, and include materials that can be dissolved, extracted or leached from the coating in the environment of use.
  • substantially full release refers to the extent of drug released into5 the dissolution medium whereby at least about 90% of the total amount of drug is released during the dissolution period, or at least about 91%, or at least about 92%, or at least about 93%, or at least about 94%, or at least about 95%, or at least about 96%, or at least about 97%, or at least about 98%, or at least about 99%, or at least about 100%, or at least about 90% to about 100% of the drug is released during the dissolution period.
  • dissolution profile or “release profile” as used herein are used interchangeably in this application, and means a quality control test conducted according to instructions found in the United States Pharmacopoeia ("USP"), i.e. using a USP apparatus design with a dissolution medium as found in the USP. Dissolution tests in-vitro measure the rate and extent of dissolution of the drug in an aqueous dissolution medium.
  • USP United States Pharmacopoeia
  • dose dumping as used herein in respect of "alcohol induced dose dumping” or
  • Alcohol induced dose dumping is the rapid release of a drug from the modified release dosage form over a period of about 2 hours when dissolution is tested in 900 ml of Alcohol USP comprising dissolution media using USP Apparatus 1 at 75 rpm at 37 0 C.
  • Alcohol USP comprising dissolution media means any dissolution media comprising from about 5 to about 40% (v/v) of Alcohol USP, or from5 about 10% to about 40%, or from about 15% to about 40%, or from about 20% to about 40%, or from about 25% to about 40%, or from about 30% to about 40%, or from about 35% to about 40% (v/v) of Alcohol USP, including all values, ranges, and subranges therebetween.
  • first administration refers to the first single dose of the composition administered to a patient, or patient in need thereof, or the first dose administered to a 5 patient, or patient in need thereof, after a suitable washout period.
  • the present invention is directed to a modified release osmotic dosage form that can provide modified release of at least one drug.
  • the present invention can be used with compositions having at least one drug, non-limiting examples of which include low-solubility drugs, low-dose drugs, high- solubility drugs, high-dose drugs, normal-solubility drugs, normal-dose drugs, and/or any mixtures thereof.
  • the osmotic dosage form comprises at least one means for providing increased release of the at0 least one drug, said means including at least one osmotic subcoat.
  • the osmotic dosage form comprises at least one means for providing full release of the at least one drug, said means including at least one osmotic subcoat.
  • the osmotic dosage form provides a sustained release of at least one drug. In at least one embodiment the osmotic dosage form provides an extended release of at least5 one drug. In at least one embodiment the osmotic dosage form provides a delayed release of at least one drug, wherein the release profile includes a predetermined lag time. In at least one embodiment the osmotic dosage form provides a delayed release of at least one drug, wherein the predetermined lag time ⁇ is substantially independent of the pH of the dissolution medium. In at least one embodiment the ⁇ * osmotic dosage form provides a release profile that does not include a lag time.
  • the osmotic dosage form provides the skilled artisan with the flexibility to control the release profile by manipulating the level of the osmotic agent and/or the level of the osmotic deposition vehicle in the formulation, without requiring the use of a sealcoat around the core.
  • the osmotic dosage form provides the skilled artisan with the flexibility to control the release profile without a sealcoat surrounding the core.
  • the osmotic delivery system is a multiparticulate system comprising a plurality of microparticle cores that are each surrounded by an osmotic subcoat, which in turn is surrounded by a functional coat ⁇ e.g. modified-release overcoat).
  • the microparticle cores include at least one drug. In at least one embodiment the microparticle cores can be further surrounded by at least one non-functional coat. In at least one embodiment an additional0 overcoat containing at least one drug can surround the modified-release overcoat of each microparticle. In at least one embodiment the coated microparticles ⁇ e.g. coated with at least one osmotic subcoat and at least one modified release overcoat) can be compressed into a tablet using suitable excipients. In at least one embodiment an additional overcoat containing at least one drug can surround the tablet. In at least one embodiment the coated microparticles ⁇ e.g. coated with at least one osmotic subcoat and at5 least one modified release overcoat) can be filled into a capsule. In at least one embodiment an additional overcoat containing at least one drug can surround the capsule.
  • the osmotic delivery system is a multiparticulate system comprising a plurality of microparticle cores that are each surrounded by an osmotic subcoat.
  • the microparticle cores include at least one drug.
  • the0 microparticle cores can be surrounded by at least one functional coat and/or non-functional coat.
  • an additional overcoat containing at least one drug can surround the osmotic subcoat of each microparticle.
  • the coated microparticles ⁇ e.g. coated with at least one osmotic subcoat) can be compressed into a tablet using suitable excipients; wherein such tablet can be surrounded by a modified release overcoat.
  • an additional overcoat5 containing at least one drug can surround the modified release overcoat of the tablet.
  • the coated microparticles ⁇ e.g. coated with at least an osmotic subcoat) can be filled into a capsule; wherein such capsule can be surrounded by a modified release overcoat, [e.g. LA. Felton and J. W. McGinity, Enteric Coating of Soft Gelatin Capsules, Drug Development and Technology, 3 (6), 34-39, _ 2003.]
  • an additional overcoat containing at least one drug can surround the ⁇ modified release overcoat of the capsule.
  • the osmotic delivery system is a tablet comprising a plurality of microparticle cores.
  • the microparticle cores are compressed into a tablet using 5 suitable excipients; wherein such tablet is surrounded by an osmotic subcoat, which in turn is surrounded by a modified release overcoat.
  • the microparticle cores can be surrounded by at least one functional coat and/or non-functional coat.
  • the microparticle cores include at least one drug.
  • an additional overcoat containing at least one drug can surround the modified release overcoat of the tablet.
  • the osmotic delivery system is a capsule comprising a plurality of microparticle cores.
  • the osmotic delivery system comprises a matrix core that is surrounded by an osmotic subcoat.
  • the matrix core is a modified release matrix core that includes at least one drug, which cores can be surrounded by an osmotic subcoat, which0 in turn can be surrounded by at least one functional coat and/or non-functional coat.
  • the matrix core is an immediate release matrix core that includes at least one drug, which cores can be surrounded by an osmotic subcoat, which in turn can be surrounded by at least one functional coat ⁇ e.g. modified release overcoat) and/or non-functional coat.
  • an additional overcoat containing at least one drug can surround the modified-release overcoat of the5 matrix core.
  • the present invention also encompasses other orally and non-orally administerable medicaments such as microparticles, suppositories, sachets, troches, and lozenges, as well as liquid suspensions and elixirs.
  • the present invention can be administered via any route known for administration.
  • Non-limiting routes ⁇ of administration include administering orally, intra-nasally, rectally, intra-muscularly, intra-venously, sub- ⁇ cutaneously, trans-dermally, intra-occularly, topically, via inhalation into the lungs, sub-lingually, intra- vaginally, or through the ear canal.
  • rivastigmine is released within about 24 hours0 without the use of pore forming additives.
  • increased release of a low-dose drug is achieved in about 24 hours or less without the use of a pore forming additive in a functional coat (e.g. the modified-release overcoat) or non-functional coat (e.g. taste-masking coat).
  • Another method of manufacturing drug-containing micropartides of certain embodiments of the present invention is the spheronization process.
  • a non-limiting example is the applicant's proprietary CEFORMTM (Centrifugally Extruded & Formed Microspheres) technology, which is the simultaneous use of 5 flash heat and centrifugal force, using proprietary designed equipment, to convert dry powder systems into micropartides of uniform size and shape.
  • CEFORMTM Chiptrifugally Extruded & Formed Microspheres
  • the production of micropartides containing a drug using the CEFORMTM technology is described for example in United States Patent No. 5,683,720. This reference gfe deals with the use of LIQUIFLASH® processing to spheronize compositions containing one or more drugs to form LIQUIFLASH® microparticles.
  • the microparticles include, in addition to the drug, at least one spheronization aid (also known as "spheronization agent").
  • Spheronization aids can assist the drug-containing mix to form robust durable spherical particles.
  • rivastigmine can be present in an amount of from about 0.1% to about 90%, in other embodiments from about 1% to about 40%, in still other embodiments from about 2% to about 20%, and in even still other embodiments from about 5% to about 15% by weight of the microparticle.
  • rivastigmine tartrate is present in an amount of about 10% by weight of the microparticle.
  • the microparticles include about 60 grams of rivastigmine tartrate and about 540 grams of the spheronization aid(s). For example, in certain embodiments that include dexmethylphenidate ⁇ e.g.
  • the spheronization aid(s) can be present in an amount of from about 5% to about 99%. In certain embodiments within this example, the spheronization aid(s) can be present in an amount from about 10% to about 99%, in still other embodiments from about 80% to about 95%, and in even still other embodiments from about 85% to about 95% by weight of the microparticle. In at least one embodiment the spheronization aid is present in an amount of about 90% by weight of the microparticle.
  • dexmethylphenidate can be present in an amount of from about 0.1% to about 90%, in other embodiments from about 1% to about 40%, in still other embodiments from about 2% to about 20%, and in even still other embodiments from about 5% to about 15% by weight of the microparticle. In at least one embodiment dexmethylphenidate is present in an amount of about 10% by weight of the microparticle. In at least one embodiment, the microparticles include about 60 grams of dexmethylphenidate and about 540 grams of the spheronization aid(s).
  • various other embodiments of the invention include a lipophilic component, which can be a lipophilic surfactant, including a mixture of lipophilic surfactants, a triglyceride, or a mixture thereof.
  • the lipophilic surfactant can provide any of the advantageous characteristics listed above for hydrophilic surfactants, as well as further enhancing the function of the surfactants.
  • Surfactants suitable for certain embodiments of the present invention can be anionic, cationic, zwitterionic or non-ionic. Examples of such surfactants can be grouped into the following general chemical classes detailed in Tables 1-18 herein.
  • the HLB values given in Tables 1-18 below generally represent the HLB value as reported by the manufacturer of the corresponding commercial product. In cases where more than one commercial product is listed, the HLB value in the noted Tables is the value as reported for one of the commercial products, a rough average of the reported values, or a value that, in the judgment of the present inventors, is more reliable.
  • mixtures of surfactants are also useful in certain embodiments of the present invention, including mixtures of two or more commercial surfactant products.
  • PEG-fatty acid esters are marketed commercially as mixtures or mono- and diesters.
  • Representative surfactant mixtures are shown in Table 3.
  • Polyglycerol esters of fatty acids are also suitable surfactants for certain embodiments of the present invention.
  • suitable polyglyceryl esters are shown in Table 6.
  • ICI ICI
  • PLURONIC® series BASF
  • EMKALYXTM EMKALYXTM
  • LUTROLTM BASF
  • SUPRONICTM MONOLANTM
  • Sorbitan esters of fatty acids are suitable surfactants for use in certain embodiments of the present invention. Examples of these surfactants are shown in Table 16.
  • Esters of lower alcohols (C 2 to C 4 , including C 3 ) and fatty acids (C 8 to C 18 , including C 9 , Ci 0 , Cn, c i2 / Ci3, c i4/ c i 5/ Ci 6 , and Ci 7 ) are suitable surfactants for use in certain embodiments of the present invention. Examples of these surfactants are shown in Table 17.
  • ⁇ fc Ionic surfactants, including cationic, anionic and zwitterionic surfactants are suitable hydrophilic surfactants for use in certain embodiments of the present invention.
  • the surfactant is an anionic surfactant such as a fatty acid salt, a bile salt, or a combination thereof.
  • Derivatives, analogs, homologs, esters, amides, inorganic and organic salts, etc., of oil- soluble vitamins, such as vitamins A, D, E, K, etc., are also useful surfactants for the compositions of certain embodiments of the present invention.
  • An example of such a derivative is tocopheryl PEG-1000 succinate (TPGS, available from Eastman).
  • Non-limiting examples of non-ionic hydrophilic surfactants include alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyethylene alkyl ethers; polyoxyethylene alkylphenols; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglycerol fatty acid esters; polyoxyethylene glycerides; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; reaction mixtures of polyols with fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols; sugar esters, sugar ethers; sucroglycerides; polyethoxylated fat-soluble vitamins or derivatives; and mixtures thereof.
  • the non-ionic hydrophilic surfactant is selected from the group consisting of polyoxyethylene alkylethers; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyglyceryl fatty acid esters; polyoxyethylene glycerides; polyoxyethylene vegetable oils; and polyoxyethylene hydrogenated vegetable oils.
  • the glyceride can be a monoglyceride, diglyceride, triglyceride, or a mixture thereof.
  • the surfactants used are non-ionic hydrophilic surfactants that are reaction mixtures of polyols and fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils or sterols. These reaction mixtures are largely composed of the transesterification products of the reaction, along with often complex mixtures of other reaction products.
  • the polyol can be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, a saccharide, or a mixture thereof.
  • the hydrophilic surfactant can also be, or include as a component, an ionic surfactant.
  • ionic surfactants include alkyl ammonium salts; bile acids and salts, analogues, and derivatives thereof; fusidic acid and derivatives thereof; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; acyl lactylates; mono-,diacetylated tartaric acid esters of mono-,diglycerides; succinylated monoglycerides; citric acid esters of mono-,diglycerides; alginate salts; propylene glycol alginate; lecithins and hydrogenated lecithins; lysolecithin and hydrogenated lysolecithins; lysophospholipids and derivatives thereof; phospholipids and derivatives thereof; salts of alkyls
  • the ionic surfactants include bile acids and salts, analogues, and derivatives thereof; lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; salts of alkylsulfates; salts of fatty acids; sodium docusate; acyl lactylates; mono-,diacetylated tartaric acid esters of mono-,diglycerides; succinylated monoglycerides; citric acid esters of mono-diglycerides; carnitines; and mixtures thereof.
  • Non-limiting examples of ionic surfactants include lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidyl lycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholate, taurocholate, glycocholate, deoxycholate, taurodeoxychol
  • ionic surfactants used include lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, lysophosphatidylcholine, PEG- phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholate, taurocholate, glycocholate, deoxycholate, taurodeoxycholate, glycodeoxycholate, cholylsarcosine, caproate, caprylate, caprate, laurate, oleate, lauryl sulfate, docusate, and salts and mixtures thereof.
  • Non-limiting examples of lipophilic surfactants include alcohols; polyoxyethylene alkylethers; fatty acids; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; polyethylene glycol fatty acids esters; polyethylene glycol glycerol fatty acid esters; polypropylene glycol fatty acid esters; polyoxyethylene glycerides; lactic acid derivatives of mono/diglycerides; propylene glycol diglycerides; sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; transesterified vegetable oils; sterols; sterol derivatives; sugar esters; sugar ethers; sucroglycerides; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; and mixtures thereof.
  • the lipophilic surfactants include one or more selected from the group consisting of fatty acids; lower alcohol fatty acid esters; polyethylene glycol glycerol fatty acid esters; polypropylene glycol fatty acid esters; polyoxyethylene glycerides; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lactic acid derivatives of mono/diglycerides; sorbitan fatty acid esters; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene-polyoxypropylene block copolymers; polyoxyethylene vegetable oils; polyoxyethylene hydrogenated vegetable oils; and reaction mixtures of polyols and fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, sterols, and mixtures thereof.
  • lipophilic surfactants which are the reaction mixture of polyols and fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils, and sterols.
  • polyols are polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, and mixtures thereof.
  • the surfactant used in the microparticle includes a polyethylene-polypropylene glycol that has an average molecular weight of from about 9,840 to about 14,600, fromabout 10,000 to about 14,600, from about 11,000 to about 14,600, from about 12,000 to about 14,600, from about 13,000 toabout 14,600, or fromabout 14,000 to about 14,600.
  • the surfactant used in the microparticle includes a polyethylene glycol that has an average molecular weight of from about 3,000 to about4,800, from about 3,200 to about 4,800, from about 3,400 to about 4,800, from about 3,600 to about 4,800, from about 3,800 to about 4,800, from about 3,900 to about 4,800, from about 4,000 to about 4,800, from about 4,100 to about 4,800, from about 4,200 to about 4,800, from about ⁇ 4,300 to about 4,800, from about 4,400 to about 4,800, from about 4,500 to about 4,800, from about 4,600 to about 4,800, or from about 4,700 to about 4,800.
  • a polyethylene glycol that has an average molecular weight of from about 3,000 to about4,800, from about 3,200 to about 4,800, from about 3,400 to about 4,800, from about 3,600 to about 4,800, from about 3,800 to about 4,800, from about 3,900 to about 4,800, from about 4,000 to about 4,800, from about 4,100 to about 4,800, from about 4,200 to about 4,800, from
  • solubility enhancers ⁇ i.e. surfactants
  • macrogol fatty acid esters useful as solubility enhancers in certain embodiments include GELUCIRE 50/13® and GELUCIRE 44/14®.
  • solubility enhancer is GELUCIRE
  • the solubility enhancer can be present in an amount of from about 0% to about 90% by weight of the microparticle.
  • the solubility enhancer is present in an amount of from about 0.1% to about 50%, or in an amount of about 5%, about 10%, or about 20%; in other embodiments from about 30% to about 40%; and in still other embodiments about 35% by weight of the microparticle.
  • one or more other pharmaceutically acceptable excipients consistent with the objects of the present invention can be used in the microparticles, non-limiting examples of which include a lubricant, a binder, a pH modifier, a filler and/or a glidant.
  • the microparticle core comprises at least one of the following excipients: glyceryl monostearate, glyceryl behenate, glyceryl palmitostearate, carnauba wax, microcrystalline cellulose, lactose, and mixtures thereof.
  • the process for manufacturing the drug-containing microparticles of certain embodiments of the present invention is not limited to the CEFORMTM technology, and any other technology resulting in the formation of the drug-containing microparticles consistent with the present invention can also be used.
  • microparticles of other embodiments of the present invention can also be manufactured by extrusion/spheronization, granulation or peptization.
  • Extrusion/spheronization is a multi-step process used to make uniformly sized spherical particles.
  • the technique offers the ability to incorporate high levels of ingredients (e.g., drugs) without producing excessively large particles.
  • the main steps in the process include: (i) Dry-mixing of ingredients to achieve a homogenous powder dispersion; (ii) Wet massing using for example a high-shear wet granulator to form rod shaped particles of uniform diameter; (iii) Extrusion to form rod-shaped particles of uniform diameter; (iv) Spheronization to round off the rods into spherical particles; and (v) Screening to achieve the desired narrow particle size distribution.
  • an extrusion/spheronization formulation of the present invention can be as follows:
  • the drug can be present in an amount of from about 1% to about 80% w/w.
  • the drug is present in an amount of from about 1% to about 50% w/w; in other embodiments from about 10% to about 30%; and in still other embodiments at about 10% w/w.
  • the filler can be present in an amount of from about 0% to about 80% w/w.
  • the filler is present in an amount of from about 10% to about 60%; and in other embodiments at about 40% w/w.
  • microcrystalline cellulose can be present in an amount of from about 10% to about 90% w/w.
  • Suitable fillers in this example include but are not limited to calcium phosphate dibasic, tricalcium phosphate, calcium carbonate, starch (such as corn, maize, potato and rice starches), modified starches (such as carboxymethyl starch, etc.), microcrystalline cellulose, sucrose, dextrose, maltodextrins, lactose, and fructose.
  • uniform mixture in this example means that the components of the mixture are uniformly dispersed in the formulation by a mixing process which provides the uniform distribution of each component.
  • a reasonable mixing time in this example can range from about 1 to about 60 minutes, for example about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, or about 50 minutes using one of the mixing equipments conventionally used for the dry mixing of the powders ⁇ e.g. "V", fixed body, rotating body, sigma mixers).
  • liquid in this example means any liquid substance or mix (solution or emulsion) of liquids of normal pharmaceutical use able to moisten the powder mix, as for example water, aqueous solutions having different pH, organic solvents of normal pharmaceutical use ⁇ e.g.
  • oils and surfactants which can be used in this example are: natural oils, either saturated or unsaturated (olive, peanut, soybean, corn, coconut, palm, sesame and similar oils); semisynthetic and synthetic mono-, di- and triglycerides containing saturated and/or unsaturated fatty acids and their polyhydroxyethylated derivatives (caprico-caprilic triglycerides
  • anionic surfactants for example sodium lauryl sulfate, sodium stearate, sodium oleate
  • cationic surfactants for example tricetol
  • lecithins for example phospholipids and their semisynthetic or synthetic derivatives.
  • certain drugs and/or excipients can be dissolved, dispersed and/or emulsified in such liquids.
  • inorganic additives can be added to accelerate the solidification of the drug, examples of which include: silicas, inorganic oxides such as titanium or iron oxide, phosphates, carbonates, clays, and talc.
  • a surface-active agent can be added to improve the dispersion of the drug in the crystallization additive, examples of which include: sorbitol esters, the polyoxyethylene polysorbates marketed under the mark TWEEN®, and glycols such as glycerine or propylene glycol.
  • Alternative procedures for manufacturing drug- containing microparticles of the present invention can include wet granulation, solvent granulation and melt granulation. All of these techniques involve the addition of an inactive binder to aggregate smaller particles into larger granules.
  • wet granulation and solvent granulation involve the addition of a liquid binder which aggregates the drug materials and excipients into granules. After granulation, the liquid can be removed by a separate drying step.
  • Melt granulation is similar to wet granulation, but uses a low melting point solid material as a binder.
  • one of the feed powders in order to serve as a binder, has a lower melting point than the other powder.
  • the feed powders are introduced into a vertical vessel with rotatable horizontal-disk located in the bottom of the vessel.
  • the powder is maintained in fluidized state by at least one stream of filtered air being circulated from the bottom of the vertical vessel through one or more inlets.
  • the rotatable horizontal disk is then rotated while the air supplied to fluidize the powder is maintained at a temperature sufficient to soften or melt the lower melting point powder.
  • the temperature to which the binder must be heated to soften can be empirically determined by observing the formation of granules at various temperatures for various binders.
  • Suitable powders for use in rotomelt granulation have a diameter size in the range of from about 5 micron to about 150 micron, for example about 10 micron, about 20 micron, about 30 micron, about 40 micron, about 50 micron, about 60 micron, about 70 micron, about 80 micron, about 90 micron, about 100 micron, about 110 micron, about 120 micron, about 130 micrion, or about 140 micron; and in certain embodiments have a diameter size in the range of from about 35 micron to about 80 micron.
  • the temperature which the components will be exposed to depends at least in part on the binder employed to aggregate the powders. Generally, the melting point of the binder is above about 30 0 C; and in certain embodiments is below about 100°C.
  • the powders used in these micropartides manufactured by rotomelt granulation can be formed into granules by at least two alternative granulation mechanisms.
  • the first mechanism for granule formation utilizes a larger particulate binder and a smaller particulate powder.
  • the temperature during the rotomelt granulation is then elevated only to the point where the external surface of the binder particles become tacky.
  • the second powdered material of a smaller size is contacted with the tacky surface it forms a microlayer on the surface of the binder particle.
  • This granulation mechanism results in granules which have size distribution similar to the original binder particles employed.
  • the rotomelt granulation can be conducted at a temperature at which the binder acts as a cement bridging the gaps between the unmelted particles (this is referred to as agglomeration).
  • This mechanism results in the formation of granules where the components are intermingled.
  • the mechanism can be controlled primarily by the temperature at which the rotomelt granulation is performed.
  • the granules formed can be observed by electron microscopy to determine the type of granulation process occurring. If one particular type of granule is desired, the process conditions or starting materials can be varied to produce the desired granules.
  • the drug is melted to act as a binding
  • suitable excipients include those selected from the following: fillers, lubricants and antiadherents.
  • suitable fillers include but are not limited to calcium phosphate dibasic, tricalcium phosphate, calcium carbonate, starch (such as corn, maize, potato and rice starches), modified starches (such as carboxymethyl starch, etc.), microcrystalline cellulose, sucrose, dextrose, maltodextrins, lactose, and fructose.
  • the binders can have a melting point of from about 30°C to about 100°C; and in certain embodiments from about 4O 0 C to about 85°C.
  • a rotomelt granulation process about 32Og of drug and about 8Og PEG 8000 is dry blended and poured into a Glatt 1.1 chamber set-up as a rotary granulator with a longitudinal plate.
  • Inlet air temperature is set to about 60 0 C and the product chamber heated to about 50 0 C.
  • the blend is fluidized at about 120m3/hr and the frictional plate set to about 900rpm.
  • the product chamber temperature is raised to about 60 0 C and then gradually reduced to about 2O 0 C over a period of about 20 minutes, during which spheronization is achieved.
  • the amount of sweetening compound used can depend on a number of factors including the size of the resulting microparticles, the size or volume of the resulting tablet, the sturdiness of the microparticle-coated microparticulant, the speed at which the tablet will disintegrate in the mouth, the degree of sweetness imparted by the particular sweetener used, either in the microparticle or in the tablet, or both, amount of drug used, "and the like.
  • particularly rugged microparticles can be less break during chewing and/or compression. Therefore, the amount of material provided to protect against the release of objectionably flavored material can be lessened. In other cases a greater relative amount of sweetening compound can be used.
  • the amount of sweetening material used can range from greater than zero to about 80%, for example about 10%, about 20%, about 30%, about 40%, about
  • the sweetener and drug can be combined in any number of known ways, such as for example by wet granulation, dry granulation, agglomeration, or spray coating.
  • the sweetener can be used as an adsorbent for the drug.
  • particles of each can also be simply mixed together.
  • One or more binders, or other adjuvants can also be used in the formulation of a tablet as well.
  • Binders in these embodiments include, for example: starch (for example, in an amount of from about 5% to about 10% as an aqueous paste); pregelatinized starch (for example, in an amount of from about 5% to about 10% added dry to powder); gelatin (for example, in an amount of from about 2% to about 10% as an aqueous solution, or about 2% in starch paste); polyvinylpyrrolidone (for example, in an amount of from about 2% to about 20% in an aqueous or alcoholic solution); methylcellulose (for example, in an amount of from about 2% to about 10% as an aqueous solution); sodium carboxy methylcellulose (for example, in an amount of from about 2% to about 10% as an aqueous solution); ethylcellulose (for example, in an amount of from about 5% to about 10% as an alcohol or hydroalcoholic solution); polyacrylamides (Polymer JR) (for example, in an amount of from about 2% to about 8% as an aqueous solution); polyviny
  • adjuvants can also be used in forming the core of the microparticles of the present embodiments of the invention, non-limiting examples of which include: calcium sulfate NF, Dibasic Calcium phosphate NF, Tribasic calcium sulfate NF, starch, calcium carbonate, microcrystalline cellulose, modified starches, lactose, sucrose and the like, STA-RXTM, AVICELTM, SOLKA-FLOCTM BW40, Alginic acid, EXPLOTABTM, AUTOTABTM, guar gum, kaolin, VECGUMTM, bentonite, and mixtures thereof.
  • the coating suspension of certain embodiments can also comprise a permeabilizer which, on account of its intrinsic solubility properties, can cause perforation of the membrane coating, thus allowing the drug to be released.
  • permeabilizers include povidone and its derivatives, polyethylene glycol, silica, polyols, low-viscosity cellulose polymers, and mixtures thereof. Polymers such as hypromellose, whose viscosity is equal to about 6 centipoises, can be used, for example, as a low- viscosity cellulose polymer.
  • the dry-mixing of initial powder and the granulation, coating and drying steps are performed in a fluidized bed.
  • the initial powder mixture is first fluidized before being granulated by spraying said powder with the excipient mixture comprising at least the binder; the grains obtained then being coated by spraying with the coating suspension; the coated granules formed finally being dried in the fluidized bed.
  • the mixture of excipients used during the granulation step and the coating suspension used during the coating step form a single mixture.
  • the granulation step can be distinguished from the spraying step by varying different parameters, such as the rate of spraying of the mixture and the atomization pressure of said mixture.
  • the rate of spraying of the coating suspension is higher during the granulation step ⁇ tian during the coating step, whereas the atomization pressure of the coating suspension is lower during
  • the rate of spraying of the coating suspension is between about 10 grams/minute and about 25 grams/minute, for example about 15 grams/minute or about 20 grams/minute, and the atomization pressure is between about 1 bar and about 1.8 bar, for example about 1.2 bar, about 1.4 bar, or about 1.6 bar.
  • a granulation solution is first prepared by dissolving about 48 g of ethylcellulose in about 273 g of ethyl alcohol.
  • a coating suspension is then prepared by mixing about 97 g of ethylcellulose, about 28.5 g of polyethylene glycol 6000, about 26 g of sodium croscarmellose, about 10 g of precipitated silica and about 27.5 g of aspartam in about 1900 g of ethyl alcohol, until a homogeneous suspension is obtained.
  • the powder mixture comprising about 700 grams of drug and about 35 grams of Acdisol is then fluidized.
  • microcrystals that can subsequently be incorporated into a tablet.
  • the microcrystals can possess diversified features such as gastroresistance and modified release due to the fact that the coated or non- coated microcrystals and microgranules preserve, after having been shaped in the form of a multiparticulate tablet, their initial properties amongst which are included masking of taste, gastroresistance and controlled release of the drug.
  • the micropartides are coated with the osmotic subcoating solution in a GLATT®-Powder-Coater-Granulator (GPCG 1.1) to about a 4.6% weight gain with the following parameters: An inlet temperature of from about 4O 0 C to about 45 0 C; an outlet temperature of from about 3O 0 C to about 35 0 C; a product temperature of from about 3O 0 C to about 35 0 C; an air flow of from about 60 c.m/h to about 80 c.m/h; an atomizing pressure of about 2 bar; a curing temperature of from about 3O 0 C to about 4O 0 C; and a curing time of about 30 minutes.
  • GPCG 1.1 GLATT®-Powder-Coater-Granulator
  • the modified release overcoat provides modified release of the drug from a microparticle core, and substantially full release of the drug being achieved in about 24 hours.
  • the modified release overcoat can provide substantially full release of the drug from the core without requiring the use of any pore formers. In at least one embodiment, the modified release overcoat does not include any pore formers.
  • the quaternary ammonium atom can also be part of a heterocycle, as in methacryloxyethylmethyl-morpholiniom chloride or the corresponding piperidinium salt, or it can be joined to an acrylic acid group or a methacrylic acid group by way of a group containing hetero atoms, such as a polyglycol ether group.
  • polymerizable quaternary ammonium compounds include quatemized vinyl-substituted nitrogen heterocycles such as methyl-vinyl pyridinium salts, vinyl esters of quatemized amino carboxylic acids, styryltrialkyl ammonium salts, and mixtures thereof.
  • the modified release polymer(s) of the modified release overcoat includes an acrylic polymer comprised of one or more ammonio methacrylate copolymers.
  • Ammonio methacrylate copolymers (such as those sold under the Trade Mark EUDRAGIT® RS and RL) are described in NF XVII as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups.
  • the modified release overcoat includes two or more ammonio methacrylate copolymers having differing physical properties.
  • the modified release polymer can be a polyvinyl acetate stabilized with polyvinylpyrrolidone and sodium lauryl sulfate such as KOLLICOAT® SR30D (BASF).
  • the dissolution profile of such embodiments can be altered by changing the relative amounts of different acrylic resin lacquers included in the coating. Also, by changing the molar ratio of polymerizable permeability- enhancing agent (e.g., the quaternary ammonium compounds) to the neutral (meth)acrylic esters, the permeability properties (and thus the dissolution profile) of the modified release overcoat of certain embodiments can be modified.
  • polymerizable permeability- enhancing agent e.g., the quaternary ammonium compounds
  • the modified release polymer is ethylcellulose, which can be used as a dry polmer (such as ETHOCEL®, Dow Corning) solubilised in organic solvent prior to use, or as an aqueous dispersion.
  • a dry polmer such as ETHOCEL®, Dow Corning
  • aqueous dispersion of ethylcellulose is
  • the polymer(s) used in the modified release overcoat include one or more acrylate dispersions such as EUDRAGIT® NE30D, EUDRAGIT® NE40D (Rohm America LLC), KOLLICOAT® SR 3OD, and SURELEASE®. Combinations of these polymers is permissible.
  • the modified release polymer(s) used in the modified release overcoat include EUDRAGIT® NE30D. In such embodiments the polymer(s) can be present in an amount of from about 5% to about 99% by weight of the modified release overcoat dry weight, depending on the drug used and the modified release profile desired.
  • the polymer(s) can be present in an amount of from about 20% to about 99%; in other embodiments from about 50% to about 95%, and in still other embodiments from about 60% to about 90% of the modified release overcoat dry weight. In at least one of such embodiments, the polymer(s) is present in an amount of about 75%, and in at least one other embodiment the polymer(s) is present in an amount of about 87.6% of the modified release overcoat dry weight.
  • the modified release overcoat comprises polymers that can faciliatate mucoadhsion within the gastrointestinal tract. Non-limiting examples of polymers that can be used for mucoadhesion include carboxymethylcellulose, polyacrylic acid, CARBOPOLTM,
  • the modified release overcoat comprises at least one of the following types of polymers: poly (meth)acrylates neutral copolymer aqueous dispersions, polyvinyl acetate aqueous dispersions, ethylcellulose from which a 5% solution in a blend of about 80% toluene/ about 25% ethanol has a viscosity of from about 5OcP to about 100 cP, dispersions of poly (ethylacrylate, methyl acrylate), and mixtures thereof.
  • polymers poly (meth)acrylates neutral copolymer aqueous dispersions, polyvinyl acetate aqueous dispersions, ethylcellulose from which a 5% solution in a blend of about 80% toluene/ about 25% ethanol has a viscosity of from about 5OcP to about 100 cP, dispersions of poly (ethylacrylate, methyl acrylate), and mixtures thereof.
  • one or more pharmaceutically acceptable excipients consistent with the objects of the present invention can be used in the modified release overcoat, such as a lubricant, an emulsifier, an anti-foaming agent, a plasticiser, and/or a solvent.
  • microparticles are coated with a modified release overcoat in a fluidized bead coater with the following coating solution:
  • the amount of pore-former that can be included in the modified release overcoats of certain embodiments can be from about 0.1% to about 80%, for example about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, or about 70%, by weight, relative to the combined weight of polymer and pore-former.
  • the percentage of pore former as it relates to the dry weight of the modified release polymer can have an influence on the drug release properties of the composition.
  • a modified release polymer pore former dry weight ratio of between about 10:1 and about 1:1 can be present.
  • the modified release polymer: pore former dry weight ratio is from about 8:1 to about 1.5:1; and in other embodiments from about 6:1 to about 2:1.
  • EUDRAGIT® NE30D as the modified release polymer and a Hydroxypropylmethylcellulose (about 5cps viscosity (in about a 2% aqueous solution)) such as METHOCEL® E5, PHARMACOAT® 606G as the water-soluble pore former
  • a modified release polymer: pore former dry weight ratio ratio of about 2:1 is present.
  • Non-limiting examples of swelling agents that can be used in the modified release overcoat of certain embodiments include crosslinked polyvinylpyrrolidones ⁇ e.g. polyplasdone, crospovidone and mixtures thereof), crosslinked carboxyalkylcelluloses, crosslinked carboxymethylcellulose ⁇ e.g.
  • the concentration of the swelling agent in the modified release overcoat of certain embodiments that comprise a microparticle core can be from about 3% to about 40% by weight of the microparticle.
  • the concentration of the swelling agent in the modified release overcoat is from about 4% to about 30%, and in other embodiments from about 5% to about 25% by weight of the microparticle.
  • Antiadherent(s) can be included in the modified release overcoat to reduce the adhesion between the powder or granules and the punch faces and thus prevent tablet sticking to the punches during manufacturing.
  • Non-limiting examples of antiadherents include adipic acid, magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oils, sterotex, glyceryl monostearate, talc, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and mixtures thereof.
  • the antiadherent is talc.
  • Talc can also function as a wetting agent, glidant and/or lubricant.
  • Emulsifying agent(s) can be included in the modified release overcoat to reduce or overcome surface tension effects, facilitate actual emulsification during manufacture of the overcoat, and/or to ensure emulsion stability during the shelf-life of the product.
  • the emulsifying agent(s) that can be used in the modified release overcoat of such embodiments can be anionic, cationic, nonionic, or amphoteric.
  • emulsifying agents include naturally occurring materials and their semi synthetic derivatives, such as the polysaccharides, as well as glycerol esters, cellulose ethers, sorbitan esters ⁇ e.g.
  • the emulsifying agent(s) can be present in an amount of from about 0.01% to about 5%, for example about 1%, about 2%, about 3% or about 4% by weight of the modified release overcoat dry weight.
  • the emulsifying agent is present in an amount of from about 0.05% to about 1.5%, in other embodiments from about 0.05% to about 0.5%, and in still other embodiments at about 0.11% by weight of the modified release overcoat dry weight.
  • Non-limiting examples of plasticisers0 that can be used in the modified release overcoat include acetylated monoglycerides, acetyltributyl citrate, butyl phthalyl butyl glycolate, dibutyl tartrate, diethyl phthalate, dimethyl phthalate, ethyl phthalyl ethyl glycolate, glycerin; propylene glycol, triacetin, tripropioin, diacetin, dibutyl phthalate, acetyl monoglyceride, acetyltriethyl citrate, polyethylene glycols, castor oil, rape seed oil, olive oil, sesame oil, triethyl citrate, polyhydric alcohols, glycerol, glycerin sorbitol, acetate esters, gylcerol triacetate, acetyl5 triethyl citrate, dibenzyl phthalate, dihexyl
  • the amount of modified release polymer coating required during manufacture is related to the total surface area of the batch of microparticle cores that requires a modified release overcoating.
  • the modified released polymer surface area coverage can range from about 0.5 mg/cm 2 to about 30mg/cm 2 , for example about 1 mg/cm 2 , about 5 mg/cm 2 , about 10 mg/cm 2 , or about 20 mg/cm 2 .
  • the surface area coverage of the modified0 release polymer is from about 0.6 mg/cm 2 to about 20mg/cm 2 , and in other embodiments from about 1 mg/cm 2 to about 5mg/cm 2 .
  • EUDRAG1T® NE30D is used as the modified release polymer at a surface area coverage of about lOmg/cm 2 .
  • One approach to estimate the total surface area of a multiparticulate batch is the permeability method according to Blaine (ASTM Des. C
  • the modified release polymer is ETHOCELTM, an ethyl cellulose grade PRlOO, PR45, PR20, PRlO, PR7 polymer, or a mixture thereof
  • the polymer is present in5 an amount of from about 5% to about 30% by weight of the overcoated microparticle; in other embodiments from about 10% to about 25%; and in still other embodiments at about 20% by weight of the modified release overcoated microparticle.
  • the modified release overcoat includes about 96% EUDRAGIT®
  • EUDRAGIT® NE30D about 5.84% Magnesium stearate, about 5.84% Talc, about 0.12% TWEEN® 80, and about 0.58% Simethicone C by weight of the modified release overcoat dry weight.
  • EUDRAGIT® NE30D about 5.84% Magnesium stearate, about 5.84% Talc, about 0.12% TWEEN® 80, and about 0.58% Simethicone C by weight of the modified release overcoat dry weight.
  • the modified release polymer is present in an amount of from about 20% to about 99%, preferably from about 50% to about 95%, and more preferably from about 60% to
  • the weight gain from the modified release overcoat over the microparticle core is from about 5% to about 90%, preferably from about 10% to about 55%, and more preferably from about 15% to about 45%. In at least one embodiment the weight gain from the modified release overcoat over the micropartide core is about 35%.
  • the amount of water-insoluble water-permeable film-forming polymer in certain embodiments can be from about 35% to about 60% by weight of the modified release overcoat dry weight, and in other embodiments from about 40% to about 50% by weight of the modified release overcoat dry weight. In certain other embodiments the amount of water-insoluble water-permeable film-forming polymer is from about 2% to about 5% by weight of the dosage form dry weight, and in other embodiments from about 3% to about 4% by weight of the dosage form dry weight. With respect to the modified release overcoat itself, the water-insoluble water-permeable film-forming polymer in certain embodiments can be present in an amount of about 40% by weight of the modified release overcoat dry weight.
  • the ratio of the water-insoluble water-impermeable film- forming polyme ⁇ plasticize ⁇ water-soluble polymer in the modified release overcoat is from about 7:2:6 to. about 19:5:18. In at least one embodiment the ratio of water-insoluble water-permeable film forming polymer:plasticizer:water-soluble polymer for the modified release overcoat is about 13:4:12.
  • the modified release overcoat can be a stable monolithic coating comprising an aqueous dispersion of a neutral ester copolymer without any functional groups, a poly glycol having a melting point greater than about 55°C, and one or more pharmaceutically acceptable excipients.
  • the coat composition is coated onto the dosage form and cured at a temperature at least equal to or greater than the melting point of the poly glycol.
  • the coating formulation of these embodiments is quite versatile in that it can be used to coat a variety of drug cores and can be easily manipulated to obtain the desired drug release profile.
  • neutral ester copolymers without any functional groups include EUDRAGIT® NE30D, EUDRAGIT® NE40D (Rohm America LLC), and mixtures thereof.
  • hydrophilic agents include hydrophilic water-soluble polymers such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC) and combinations thereof.
  • HPMC is the hydrophilic water-soluble polymer.
  • the agents can be present in an amount from about 0.1% to about 10% by weight of the coating composition.
  • the hydrophilic agents are present in an amount of from about 0.1% to about 5%, and in other embodiments from about 0.1% to about 3% by weight of the modified release overcoat composition.
  • Non-limiting examples of the poly gycol with a melting point of greater than about 55 0 C include polyethylene glycol 6000, polyethylene glycol 8000, polyethylene glycol 10000, polyethylene glycol 20000, and mixtures thereof.
  • the poly glycol is polyethylene glycol 8000.
  • the poly glycol can be present in an amount of from about 0.1% to about 5% by weight of the coat.
  • suitable polyglycol derivatives having a melting point of at least about 55°C include, but are not limited to, Poloxamer 188, Poloxamer 338, Poloxamer 407, Polyethylene Oxides, Polyoxyethylene Alkyl Ethers, Polyoxyethylene Stearates, and mixtures thereof.
  • the modified release overcoat of such embodiments can be quite versatile.
  • the length and time for a delay can be controlled by rate of hydration and the thickness of the coat.
  • the drug release rate subsequent to the delay can be determined by the thickness and permeability of the hydrated coat.
  • the coat thickness will depend on the controlled release profile desired. Other parameters in combination with the thickness of the coat include varying the concentrations of some of the ingredients of the overcoat composition described and/or varying the curing temperature and length of curing time.
  • the second lubricant is magnesium stearate.
  • an aqueous dispersion of a neutral ester copolymer is added and mixed for about 30 minutes at about 500 rpm.
  • the aqueous dispersion of a neutral ester copolymer is EUDRAGIT® NE30D. The resultant modified release overcoat solution can then be used to overcoat the osmotic subcoated microparticles to about a 35% weight gain
  • the resultant overcoated microparticles can then be discharged from the coating chamber and ovencured with the following parameters: A curing temperature of from about 2O 0 C to about 65 0 C, preferably from about 3O 0 C to about 55 0 C, and more preferably about 4O 0 C; and a curing time of from about 2 hours to about 120 hours, preferably from about 10 hours to about 40 hours, and more preferably about 24 hours. Any other technology resulting in the coating formulation of the modified release overcoat consistent with the objects of the invention can also be used.
  • the preparation and application of the modified release overcoat can be as follows:
  • the water-insoluble water-permeable film-forming polymer can be dissolved in the organic solvent without the plasticizer.
  • the water-soluble polymer ⁇ e.g.
  • the printed dosage forms are transferred through a drying element prior to discharging into bulk containers. Samples for final testing are taken throughout the printing process.
  • controlling the permeability can control the release of the drug and/or the amount of coating applied to the cores.
  • the permeability of the modified release overcoat can be altered by varying the ratio of the water-insoluble, water-permeable film- forming polymer:plasticizer:water-soluble polymer and/or the quantity of coating applied to the core. A more extended release can be obtained with a higher amount of water-insoluble, water-permeable film forming polymer.
  • the addition of other excipients can also alter the permeability of the modified release overcoat.
  • the preparation and application of the modified release overcoat can for example be as follows: the modified release overcoat can be applied onto a core comprising an effective amount of the drug by a process which involves the atomization (spraying) of the coating solution or suspension onto a bed of the tablet cores.
  • Some examples of equipment suitable for film coating include: Accela Cota (Manesty Machines, Liverpool, UK), Hi-Coater (Freund Company, Japan), Driacoater (Driam Metall Screen GmbH, Germany), HTF/150 (GS, Italy), and IDA (Dumoulin, France). Examples of units that function on a fluidized-bed principle include: Aeromatic (Fielder, Switzerland and UK) and Glatt AG (Switzerland).
  • the apparatus used for film coating is the Accela Cota.
  • the coating fluid can be delivered to the coating apparatus from a peristaltic pump at the desired rate and sprayed onto the rotating or fluidizing tablet cores.
  • the tablet cores are pre-warmed to about 30 0 C.
  • the product temperature range is maintained between about 25°C and about 35°C by adjusting the flow rate of the inlet and outlet air, temperature of the inlet air and spray rate.
  • a single layer of coat is applied and once spraying is complete, the coated tablet cores are dried between about 3O 0 C to about 40 0 C for from about 3 to about 5 minutes at a low pan speed and low air flow. The pan is readjusted to jog speed, and drying continues for from about 12 to about 15 minutes.
  • the coated tablet cores are placed onto a tray and cured (post coating thermal treatment) in an electrical or steam oven at a temperature above the temperature of the melting point of the polyethylene glycol or derivative thereof.
  • the curing temperature is preferably greater than the melting point of the polyethylene glycol or derivative thereof.
  • the curing time is preferably from about 2 to about 7 hours.
  • the cured coated tablets are subsequently cooled to room temperature.
  • the amount of the methacrylic acid copolymer is present at about 2.5% of the dosage form dry weight.
  • the amount of the methacrylic acid copolymer in certain embodiments can be present in an amount of from about 55% to about 70% by weight of the moisture barrier coat dry weight. In at least one embodiment the methacrylic acid copolymer is present in an amount of about 60% of the moisture barrier coat dry weight.
  • the plasticizer in the moisture barrier coat comprises a combination of triethyl citrate and polyethylene glycol 4000 ⁇ e.g. CARBOWAX® 4000). In certain of these embodiments, the ratio of triethyl citrate to polyethylene glycol 4000 is about 1:2.
  • the plasticizer in the moisture barrier coat of certain embodiments can be present in an amount from about 0.2% to about 0.5% of the dosage form ⁇ e.g. tablet) dry weight. With respect to the moisture barrier coat itself, the plasticizer, if present, can be present in an amount of from about 1% to about 30% by weight of the moisture barrier coat dry weight.
  • synthetic water-soluble polymers can be used as permeation enhancers in the moisture barrier coat, non-limiting examples of which include polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone, polyethylene oxide, water-soluble polydextrose, saccharides and polysaccharides, such as pullulan, dextran, sucrose, glucose, lactose, fructose, mannitol, mannose, galactose, sorbitol and mixtures thereof.
  • the permeation enhancer includes hydroxypropyl-methylcellulose.
  • permeation enhancers which can be useful in the formulations of the present invention include starch, modified starch, and starch derivatives, gums, including but not limited to xanthan gum, alginic acid, other alginates, benitonite, veegum, agar, guar, locust bean gum, gum arabic, quince psyllium, flax seed, okra gum, arabinoglactin, pectin, tragacanth, scleroglucan, dextran, amylose, amylopectin, dextrin, etc., cross-linked polyvinylpyrrolidone, ion-exchange resins, such as potassium polymethacrylate, carrageenan, kappa-carrageenan, lambda-carrageenan, gum karaya, biosynthetic gum, and mixtures thereof.
  • gums including but not limited to xanthan gum, alginic acid, other alginates, beni
  • the moisture barrier coat of certain embodiments does not meet this requirement for the following reasons even though the drug may not be negatively affected in acidic media nor irritate the gastric mucosa: (1) to obtain enteric integrity with a film containing EUDRAGIT® L 30 D-55, a weight gain of between 6% to 8% based on the dry polymer per dosage unit is recommended.
  • the amount of EUDRAGIT® L 30 D-55 solid applied onto the coated cores is not more than about 6%, and in at least one embodiment, is not more than about 3%, (2) if enteric integrity would be required, the dissolution test for the finished product ⁇ i.e., the moisture barrier coated tablet cores) at the 2 hour time point would not stipulate a limit of no more than 20%, and (3) analytical tests performed on these coatings indicate that the coatings do not meet all the test requirements as an enteric coated product as defined by USP test methods.
  • an enteric coat is included in the composition to surround the drug- containing core.
  • an enteric coat is applied directly onto the modified release overcoat, and in other embodiments directly onto the additional overcoat.
  • an enteric coat is not included in the dosage form.
  • the enteric coat of certain embodiments can control the location in the digestive system where the drug is absorbed.
  • the enteric coat can be used to: (i) protect the drug from the destructive action of the enzymes or low pH environment of the stomach; (ii) prevent nausea or bleeding associated with the irritation of the gastric mucosa by the drug; and/or (iii) deliver the drug in an undiluted form in the intestine.
  • the enteric coat comprises EUDRAGIT® L30D (methacrylic copolymer), talc and polyethyleneglycol.
  • the enteric coat includes an enteric polymer ⁇ e.g. methacrylic acid copolymer) in an amount of from about 5% to about 30%; a plasticizer in an amount of from about 1% to about 6%; and an anti-adherent in an amount of from about 0.1% to about 4% by weight of the enteric coat dry weight.
  • the low-visocity polymer used in the additional overcoat is PHARMACOAT® 606G.
  • the low viscosity polymer of the additional overcoat can be present in an amount of from about 1% to about 99% of the additional overcoat dry weight.
  • the low viscosity polymer is present in an amount of from about 15% to about 60%, in other embodiments from about 20% to about 40%, and in still other embodiments at about 30% of the additional overcoat dry weight.
  • the additional overcoat can also include a lubricant such as talc.
  • ⁇ P Talc can be present in an amount of from about 1% to about 80%, for example about 10%, about 20%, about 30%, about 40%, about 50%, about 60% or about 70% of the additional overcoat dry weight.
  • the lubricant is present in an amount of from about 5% to about 50%, and in still other embodiments at about 7.5% of the additional overcoat dry weight.
  • the drug in the additional overcoat can be present in an amount of from about 1% to about
  • the additional overcoat is designed to achieve a pulsatile release of at least one drug from the coated composition.
  • the drug(s) released from the additional overcoat in the first phase of drug release is different from the drug(s) that is released from the core in the second phase of drug release. In certain other embodiments the drug(s) released from the additional overcoat in the first phase of drug
  • 20 release is the same drug(s) that is released from the core in the second phase of drug release.
  • certain other embodiments of the present invention allow for combinations of different groups of micropartides into a single dosage form, wherein each group of micropartides has a different release profile and/or functional coating.
  • each group of micropartides has a different release profile and/or functional coating.
  • a first group of immediate release taste-masked or enteric coated micropartides with a second group of delayed release micropartides ⁇ e.g. having a modified release overcoat with a delayed release profile
  • a pulsatile drug release profile or chronotherapeutic profile can be achieved.
  • a dosage form in certain embodiments, includes one or more microparticle cores comprising a drug and a spheronization aid; an osmotic subcoat comprising an osmotic agent and an osmotic deposition vehicle that surrounds each microparticle core; a modified release overcoat that surrounds each osmotically subcoated microparticle; and at least one pharmaceutical excipient such as a binder ⁇ e.g. polyvinyl alcohol), a lubricant ⁇ e.g. glyceryl behenate), and/or filler, that is combined with the coated micropartides and compressed into a tablet.
  • a binder ⁇ e.g. polyvinyl alcohol
  • a lubricant ⁇ e.g. glyceryl behenate
  • the dissolution profile of the coated multiparticles and the effect of the osmotic agent are not affected by the compression of the micropartides into a tablet.
  • Tablets can be manufactured by compressing the coated micropartides with suitable inert excipients using known compression techniques.
  • the inert excipients can be added to facilitate the preparation and/or improve patient acceptability of the final modified release dosage form as described herein.
  • the additional inert excipients are well known to the skilled artisan and can be found in the relevant literature, for example in the Handbook of Pharmaceutical Excipients.
  • coated micropartides are filled into capsules.
  • the forms of administration suitable for the dosage forms of the present invention include oral administration.
  • Non-limiting examples of such dosage forms include tablets and capsules.
  • Other possible dosage forms include pellets, beads or microtablets, which can then be packaged into capsules or compressed into a unitary solid dosage form.
  • Other solid oral dosage forms can be prepared by the skilled artisan, even if such other solid oral dosage forms may be more difficult to commercially manufacture.
  • the present invention also contemplates combinations of differently coated microparticles into a dosage form to provide a variety of different release profiles. For example, in certain embodiments, microparticles with a delayed release profile can be combined with other microparticles having a sustained release profile to provide a multiple component modified release formulation. In addition, other embodiments can include one or more further components having an immediate release profile.
  • the immediate release component can take the form of uncoated microparticles or powders; microparticles coated with a highly soluble immediate release coating, such as an OPADRY® type coating, as are known to those skilled in the art, or a combination of any of the foregoing.
  • the multiple components can then be blended together in the desired ratio and placed in a capsule, or formed into a tablet. Examples of multiple component modified release formulations can be found in United States Patent No. 6,905,708.
  • an oral delivery system for delivering drug- containing microparticles in admixture with a fluid.
  • an oral delivery system which comprises a hollow drug formulation chamber.
  • the chamber has a first end and a second end, and contains a formulation in the form of osmotically subcoated microparticles.
  • the system further comprises a fluid passing drug formulation retainer in the first end of the chamber. The retainer prevents release of the microparticles from the first end while permitting fluid entry into the chamber.
  • the present invention further provides a method for orally delivering osmotically subcoated microparticles containing at least one drug in admixture with a fluid.
  • the method involves inserting osmotically subcoated microparticles into a hollow drug delivery chamber of a drug delivery device.
  • the chamber has a first end and a second end.
  • the first end of the chamber has a fluid passing drug formulation retainer.
  • the drug delivery device has a first and second end.
  • the first end of the drug delivering device is inserted into a fluid and the second end is inserted into the mouth of a patient.
  • the patient then applies suction to the second end of the device to cause delivery of the fluid and microparticles into the patient's mouth.
  • the dispensing device of this embodiment of the invention finds use where it is inconvenient or unsafe to use solid oral dosage forms such as capsules or tablets.
  • the devices can be particularly useful in geriatric or pediatric patient populations but they can also be useful for those who have difficulty swallowing capsules or tablets.
  • a single delivery device or several devices can be administered to a patient during a therapeutic program.
  • the fluid passing drug formulation retainer permits the free flow of liquid medium but prohibits passage of the drug formulation from the device prior to delivery.
  • the retainer comprises a one-way plug or valve
  • the plug or valve will seal the straw at atmospheric pressure. When suction is applied, fluid will be drawn around the plug and into the drug formulation chamber. Further, the plug has a density of less than one so that it will ascend to the top as the drug formulation is delivered into the
  • the plug can be prepared from closed cell polyethylene foam such as ETHAFOAM®.
  • Other forms of one way plugs can be a balloon of elastomeric material, a one-way mechanical ball valve and the like.
  • Examples of fluid that can be used for suspending the drug formulation by sipping through 30 the drug formulation chamber include any palatable liquid such as water, juice, milk, soda, coffee, tea etc. Care must be taken to ensure compatibility of the fluid with the drug formulation.
  • 20 agent include varying the concentrations of some of the ingredients of the overcoat composition of the invention described and/or varying the curing temperature and length of curing the coated microparticles.
  • concentrations of some of the ingredients of the overcoat composition of the invention described and/or varying the curing temperature and length of curing the coated microparticles.
  • the skilled artisan will know which parameters or combination of parameters to change for a desired modified release profile.
  • dissolution profiles of the present invention are from 25 quality control assays conducted according to instructions found in the United States Pharmacopoeia.
  • the osmotic subcoat and/or the outer coat contained substantially no water and/or no water.
  • Dissolution Method The dissolution tests were performed using a paddle apparatus (USP II, pH 6.8 Phosphate buffer) with a rotation of 50rpm.
  • the external environment of use includes: a dissolution medium, the temperature of the dissolution medium was 37 0 C +/- 0.5 0 C, the volume of the dissolution medium was 500 ml, the dissolution medium was a phosphate buffer having a pH of 6.8, and the pressure of the atmosphere on the dissolution medium was 1 atmosphere.
  • a dissolution medium Dissolution profiles of Pramipexole modified release microparticles with and without an osmotic agent (NaCI) in the subcoat.
  • Figure 1 illustrates the effect of the osmotic agent in the osmotic subcoat on the rate and extent of drug release from Pramipexole modified release microparticles. Higher rate and extent of drug release (increased release and substantially full release) were observed with the Pramipexole modified release microparticles that had an osmotic subcoat containing an osmotic agent (NaCI), when compared to those without an osmotic agent in the subcoat.
  • NaCI osmotic agent
  • the external environment of use includes: a dissolution medium, the temperature of the dissolution medium was 37 0 C +/- 0.5 0 C, the volume of the dissolution medium was 500 ml, the dissolution medium was a phosphate buffer having a pH of 6.8, or a phosphate buffer having a pH of 6.8 with 15.7g NaCI added per Litre of buffer, and the pressure of the atmosphere on the dissolution medium was 1 atmosphere.
  • Dissolution Method The dissolution tests were performed using a paddle apparatus (USP II, pH 6.8 Phosphate buffer with and without added NaCI with a rotation of 50rpm.
  • FIG. 2 compares release profiles of Pramipexole modified release microparticles in different dissolution media. The results showed a lower release (in terms of both rate and extent of drug release) of Pramipexole in the dissolution medium with added NaCI, as compared to the same Pramipexole modified release microparticles in dissolution medium without added NaCI. This demonstrates that drug release from coated microparticles is influenced by an osmotic gradient between the microparticle core and the external environment of use. The extra NaCI in the dissolution medium reduced the concentration differential between the outside medium and the osmotic subcoated microparticle, and thus reduced the osmotic pressure.
  • an amount of microspheres equivalent to 360mg Diltiazem was sprinkled onto the media surface.
  • the external environment of use includes: a dissolution medium, the temperature of the dissolution medium was 37 0 C +/- 0.5 °C, the volume of the dissolution medium was 900 ml, the dissolution medium was water, and the pressure of the atmosphere on the dissolution medium was 1 atmosphere. See Figure 3: Dissolution profiles of Diltiazem modified release microparticles with and without an osmotic subcoat.
  • FIG. 3 illustrates the effect of the osmotic subcoat on the rate and extent of drug release from Diltiazem modified release microparticles.
  • the results showed a higher rate and extent of drug release (increased release and substantially full release) of the Diltiazem modified release microparticles that had an osmotic subcoat containing an osmotic agent (NaCI), as compared to an otherwise similar composition without an osmotic subcoat.
  • NaCI osmotic agent
  • Rivastigmine Dissolution Data Dissolution method: The dissolution tests were performed using a paddle apparatus (USP II) with a rotation of 50 rpm. Dissolution media used were 0.1N HCI; pH 4.5 acetate buffer and pH 6.8 phosphate buffer.
  • an amount of microspheres equivalent to 19.2mg Rivastigmine Tartrate was sprinkled onto the media surface
  • the external environment of use includes: a dissolution medium, the temperature of the dissolution medium was 37 0 C +/- 0.5 0 C, the volume of the dissolution medium was 500 ml, the dissolution medium was a 0.1 N HCI solution, a pH 4.5 acetate buffer solution, or a pH 6.8 phosphate buffer solution, and the pressure of the atmosphere on the dissolution medium was 1 atmosphere. See Figure 4: Lagtime achieved from Rivastigmine delayed release microparticles in different dissolution media
  • FIG. 4 illustrates lagtimes achieved from Rivastigmine delayed release microparticles in different dissolution media. The results demonstrate that lagtimes of the delayed release microparticles are substantially independent of the pH of the dissolution media.
  • the dissolution tests were performed using a paddle apparatus (USP II, 0.1N HCI) with a rotation of 50rpm.
  • the amount of dissolution medium, in each case, was 500 ml and the temperature of the dissolution medium was, in each case, 37 0 C +/- 0.5 0 C.
  • the external environment of use includes: a dissolution medium, the temperature of the dissolution medium was 37 0 C +/- 0.5 0 C, the volume of the dissolution medium was 500 ml, the dissolution medium was a 0.1 N HCI solution, and the pressure of the atmosphere on the dissolution medium was 1 atmosphere.
  • Dissolution data :
  • FIG. 5 illustrates the effect of the level of osmotic agent (NaCI) on the release profiles of Rivastigmine modified release microparticles.
  • a faster release of Rivastigmine was seen in compositions that had a higher level of osmotic agent (NaCI) when compared to an otherwise similar composition that had a lower level of osmotic agent (regardless of weight gain).
  • FIG.7 illustrates a pulsatile release profile of Rivastigmine from Rivastigmine delayed release microparticles coated with an additional overcoat containing Rivastigmine.
  • the dissolution tests were performed using a paddle apparatus (USP II, 0.1N HCI with added Sodium Chloride - 14 g NaCl / Litre) with a rotation of 50rpm.
  • the external environment of use includes: a dissolution medium, the temperature of the dissolution medium was 37 0 C +/- 0.5 0 C, the volume of the dissolution medium was 500 ml, the dissolution medium was a 0.1 N HCI solution with sodium chloride added in an amount of 14 g NaCI per liter of solution, a pH 4.5 acetate buffer solution, or a pH 6.8 phosphate buffer solution, and the pressure of the atmosphere on the dissolution medium was 1 atmosphere.
  • FIG.8 illustrates the effect of the osmotic subcoat on the rate and extent of drug release from Rivastigmine modified release microparticles, wherein the modified release polymer is SURELEASE®.
  • FIG. 10 illustrates the stability of the Rivastigmine delayed release microparticles having an additional overcoat containing Rivastigmine. Pulsatile drug release is shown where approximately half of the drug was released immediately from an additional overcoat containing Rivastigmine, followed by a second phase of drug release from the microparticle core starting at approximately the 6 hour timepoint (lag time of 6 hours). The results demonstrate that there is no significant difference in the dissolution profiles at time zero and after 1 month storage at 25°C/60% RH.
  • FIG. 11 illustrates the stability of a dosage form containing a mixture of Rivastigmine immediate release microparticles and Rivastigmine delayed release microparticles. Pulsatile drug release is shown where approximately half of the drug was released immediately from the immediate release microparticles, followed by a second phase of drug release from the delayed release microparticles starting at approximately the 6 hour timepoint (lag time of 6 hours). The results demonstrate that there is no significant difference in the dissolution profiles at time zero and after 1 month storage at 25°C/60%RH.
  • the present invention relates to a multiparticulate osmotic delivery system.
  • the system is a modified release composition suitable for oral administration.
  • the composition includes a core that includes at least one drug in combination with at least one pharmaceutically acceptable excipient.
  • the composition further includes an osmotic subcoat surrounding the core, and a modified release overcoat surrounding the osmotic subcoated core.
  • PEG polyethylene glycol
  • Polyethylene glycol (PEG) fatty acid diesters are also suitable for use as surfactants in the compositions of the present invention.
  • Representative PEG-fatty acid diesters are shown here in Table 2.

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Abstract

La présente invention concerne une composition pharmaceutique qui comprend au moins une microparticule ayant au moins un noyau enrobé au moins partiellement par au moins une sous-couche osmotique et au moins une couche externe qui enrobe au moins partiellement la ou les sous-couches osmotiques. Le ou les noyaux comprennent au moins un médicament et au moins un excipient et ladite ou lesdites sous-couches osmotiques comprennent au moins un agent osmotique et au moins un véhicule/excipient de dépôt par osmose.
EP07736118A 2006-06-27 2007-06-26 Système de délivrance osmotique multiparticulaire Withdrawn EP2032124A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US11/475,252 US7241805B2 (en) 2005-06-27 2006-06-27 Modified release formulations of a bupropion salt
PCT/US2006/024832 WO2007002597A2 (fr) 2005-06-27 2006-06-27 Formulations a liberation modifiee d'un sel de bupropion
PCT/IE2007/000062 WO2008001341A1 (fr) 2006-06-27 2007-06-26 Système de délivrance osmotique multiparticulaire

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