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US20030224043A1 - Immediate release dosage forms containing solid drug dispersions - Google Patents

Immediate release dosage forms containing solid drug dispersions Download PDF

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Publication number
US20030224043A1
US20030224043A1 US10/355,706 US35570603A US2003224043A1 US 20030224043 A1 US20030224043 A1 US 20030224043A1 US 35570603 A US35570603 A US 35570603A US 2003224043 A1 US2003224043 A1 US 2003224043A1
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Prior art keywords
drug
dosage form
dispersion
concentration
polymer
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Inventor
Leah Appel
John Byers
Marshall Crew
Dwayne Friesen
Bruno Hancock
Stephen Schadtle
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Lonza Bend Inc
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Pfizer Corp SRL
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Priority to US10/355,706 priority Critical patent/US20030224043A1/en
Publication of US20030224043A1 publication Critical patent/US20030224043A1/en
Priority to US11/928,426 priority patent/US9211261B2/en
Assigned to BEND RESEARCH, INC. reassignment BEND RESEARCH, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PFIZER PRODUCTS INC., PFIZER INC.
Assigned to LONZA BEND INC. reassignment LONZA BEND INC. CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: BEND RESEARCH, INC.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • solid amorphous dispersions undergo plastic deformation rather than fracture when compressed into a tablet. This can lead to unacceptably low tablet porosity.
  • solid amorphous dispersions adhere better than conventional crystalline bulk drug, due to their plastic flowabilty and strong surface interactions.
  • the low porosity obtained when solid amorphous dispersions are compressed into a tablet made using conventional tableting formulations leads to slow wicking of water into the tablet, also slowing tablet disintegration.
  • solid amorphous dispersions can form strong hydrogels, thereby inhibiting rapid tablet disintegration.
  • the invention provides an immediate release dosage form comprising at least 50 wt % of a solid amorphous drug dispersion, at least 5 wt % of a disintegrant and a porosigen where the dosage form has the same disintegration and drug release characteristics as described above.
  • the amount of a particular drug which is administered will necessarily be varied according to principles well known in the art, taking into account factors such as the particular drug of interest, the severity of the disease or condition being treated and the size and age of the patient.
  • the drug is to be administered so that an effective dose is received, with the effective dose being determined from safe and efficacious ranges of administration already known for the particular drug of interest.
  • FIG. 1 is a schematic of a dynamic mechanical analyzer (DMA) test apparatus used to evaluate excipients used in the dosage forms of the present invention.
  • DMA dynamic mechanical analyzer
  • FIG. 2 presents the results of DMA tests for various excipients evaluated for use in the dosage forms of the present invention.
  • a dosage form specifically designed to provide immediate release of low solubility drug in the form of a solid amorphous dispersion to a use environment.
  • immediate release is meant that the dosage form satisfies at least one of the following requirements.
  • the dosage form disintegrates in 10 minutes or less following introduction to a disintegration medium, the disintegration time being determined according to the USP XXIV disintegration test procedure, using, for example, a Erweka ZT-71 disintegration tester.
  • the dosage form releases at least 70 wt % of the drug within 15 minutes following introduction to a dissolution medium.
  • a dosage form is considered to be within the scope of this invention if it satisfies either one or both of these requirements.
  • Suitable low solubility drugs and concentration-enhancing polymers for use in the solid amorphous dispersion, as well as methods for forming the dispersion, and excipients and methods for making the immediate release dosage forms, are discussed in more detail below.
  • drug is conventional, denoting a compound having beneficial prophylactic and/or therapeutic properties when administered to an animal, especially humans.
  • the drug does not need to be a low-solubility drug in order to benefit from this invention, although low-solubility drugs represent a preferred class for use with the invention.
  • Even a drug that nonetheless exhibits appreciable solubility in the desired environment of use can benefit from the increased solubility/bioavailability made possible by this invention if the addition of the concentration-enhancing polymer can reduce the size of the dose needed for therapeutic efficacy or increase the rate of drug absorption in cases where a rapid onset of the drug's effectiveness is desired.
  • the present invention is particularly suitable for preparing immediate release dosage forms containing a solid dispersion that enhances the solubility of a “low-solubility drug,” meaning that the drug may be either “substantially water-insoluble,” which means that the drug has a minimum aqueous solubility at physiologically relevant pH (e.g., pH 1-8) of less than 0.01 mg/mL, “sparingly water-soluble,” that is, has an aqueous solubility up to about 1 to 2 mg/mL, or even low to moderate aqueous-solubility, having an aqueous-solubility from about 1 mg/mL to as high as about 20 to 40 mg/mL.
  • physiologically relevant pH e.g., pH 1-8
  • syntheticly water-soluble that is, has an aqueous solubility up to about 1 to 2 mg/mL, or even low to moderate aqueous-solubility, having an aqueous-solubility from about 1 mg/mL to as
  • the invention finds greater utility as the solubility of the drug decreases.
  • dosage forms of the present invention are preferred for low-solubility drugs having a solubility of less than 10 mg/mL, more preferred for low-solubility drugs having a solubility of less than 1 mg/mL, and even more preferred for low-solubility drugs having a solubility of less than 0.1 mg/mL.
  • the drug has a dose-to-aqueous solubility ratio greater than 10 mL, and more typically greater than 100 mL, where the drug solubility (mg/mL) is the minimum value observed in any physiologically relevant aqueous solution (e.g., those with pH values between 1 and 8) including USP simulated gastric and intestinal buffers, and the dose is in mg.
  • a dose-to-aqueous-solubility ratio may be calculated by dividing the dose (in mg) by the solubility (in mg/mL).
  • hydrophobic drugs drugs that are especially well-suited for use in the dosage forms of the present invention.
  • This subclass of drugs are essentially aqueous insoluble, highly hydrophobic, and are characterized by a set of physical properties.
  • the hydrophobicity of this subclass of drugs not only leads to extremely low aqueous solubility but also tends to make the drugs poorly wetting and slow to dissolve, further reducing their tendency to dissolve and be absorbed from the gastrointestinal tract.
  • Solid amorphous dispersions made using these drugs exhibit dramatic enhancements in aqueous concentration and bioavailability, but often have properties that are difficult to predict based on the nature of the drug. As a result, solid amorphous dispersions made using this subclass of drug often cannot be formulated into an immediate release dosage form using conventional technology known in the art.
  • the first property of this subclass of essentially aqueous insoluble, hydrophobic drugs is extremely low aqueous solubility.
  • Extremely low aqueous solubility is meant that the minimum aqueous solubility at physiologically relevant pH (pH of 1 to 8) is less than about 10 ⁇ g/mL and preferably less than about 1 ⁇ g/mL.
  • a third property of this subclass of essentially insoluble, hydrophobic drugs is that they are extremely hydrophobic.
  • extremely hydrophobic is meant that the Clog P value of the drug has a value of at least 3.0, preferably a value of at least 4.0, and more preferably a value of at least 5.0.
  • Clog P is a widely accepted measure of hydrophobicity, defined as the base 10 logarithm of the ratio of the drug solubility in octanol to the drug solubility in water.
  • drugs of this subclass typically have very low absolute bioavailabilities. Specifically, the absolute bioavailability of drugs in this subclass when dosed orally in their undispersed state is less than about 25% and more often less than about 10%.
  • Each named drug should be understood to include the neutral form of the drug, pharmaceutically acceptable salts, as well as prodrugs.
  • antihypertensives include prazosin, nifedipine, amlodipine besylate, trimazosin and doxazosin; specific examples of a blood glucose-lowering agent are glipizide and chlorpropamide; a specific example of an anti-impotence agent is sildenafil and sildenafil citrate; specific examples of antineoplastics include chlorambucil, lomustine and echinomycin; a specific example of an imidazole-type antineoplastic is tubulazole; a specific example of an anti-hypercholesterolemic is atorvastatin calcium; specific examples of anxiolytics include hydroxyzine hydrochloride and doxepin hydrochloride; specific examples of anti-inflammatory agents include betamethasone, prednisolone, aspirin, piroxicam, valdecoxi
  • Concentration-enhancing polymers suitable for use in the solid drug dispersions used in the dosage forms of the invention should be inert, in the sense that they do not chemically react with the drug in an adverse manner.
  • the polymer can be neutral or ionizable, and should have an aqueous solubility of at least 0.1 mg/mL over at least a portion of the pH range of 1-8.
  • concentration-enhancing polymer be “amphiphilic” in nature, meaning that the polymer has hydrophobic and hydrophilic portions. Amphiphilic polymers are preferred because it is believed that such polymers tend to have relatively strong interactions with the drug and may promote the formation of various types of polymer/drug assemblies in solution.
  • the hydrophilic, hydroxyl-containing repeat units A may simply be hydroxyl (—OH) or they may be any short chain alkyl (containing 1 to 6 carbons) with one or more hydroxyls attached thereto.
  • the hydroxyl-substituted alkyl may be attached to the vinyl backbone via carbon-carbon or ether linkages.
  • exemplary A structures include, in addition to hydroxyl itself, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxymethoxy, hydroxyethoxy and hydroxypropoxy.
  • the hydrophobic substituent B may simply be: hydrogen (—H), in which case the hydrophobic repeat unit is ethylene; an alkyl or aryl substituent with up to 12 carbons attached via a carbon-carbon bond such as methyl, ethyl or phenyl; an alkyl or aryl substituent with up to 12 carbons attached via an ether linkage such as methoxy, ethoxy or phenoxy; an alkyl or aryl substituent with up to 12 carbons attached via an ester linkage such as acetate, propionate, butyrate or benzoate.
  • the amphiphilic hydroxyl-functional vinyl copolymers of the present invention may be synthesized by any conventional method used to prepare substituted vinyl copolymers. Some substituted vinyl copolymers such as polyvinyl alcohol/polyvinyl acetate are well known and commercially available.
  • a particularly convenient subclass of amphiphilic hydroxyl-functional vinyl copolymers to synthesize are those where the hydrophobic substituent B comprises the hydrophilic substituent A to which an alkylate or arylate group is attached via an ester linkage to one or more of the hydroxyls of A.
  • Such copolymers may be synthesized by first forming the homopolymer of the hydrophobic vinyl repeat unit having the substituent B, followed by hydrolysis of a portion of the ester groups to convert a portion of the hydrophobic repeat units to hydrophilic, hydroxyl-containing repeat units having the substituent A.
  • partial hydrolysis of the homopolymer polyvinylbutyrate yields the vinylalcohol/vinylbutyrate copolymer for which A is hydroxyl (—OH) and B is butyrate (—OOC—CH 2— CH 2— CH 3 ).
  • n the value of n must be sufficiently large relative to the value of m that the resulting copolymer is at least partially water soluble.
  • the value of the ratio, n/m varies depending on the identity of A and B, it is generally at least about 1 and more commonly about 2 or more.
  • the ratio n/m can be as high as 200.
  • percent hydrolysis the fraction (expressed as a percent) of the total repeat units of the copolymer that are in the hydrolyzed or hydroxyl form.
  • vinylbutyrate/vinylalcohol copolymer formed by hydrolysis of a portion of the butyrate groups having a percent hydrolysis of 75% has an n/m ratio of 3.
  • a particularly preferred family of amphiphilic hydroxyl-functional vinyl copolymers are those where A is hydroxyl and B is acetate. Such copolymers are vinylacetate/vinylalcohol copolymers. Some commercial grades are also sometimes referred to simply as polyvinylalcohol. However, the true homopolymer polyvinylalcohol is not amphiphilic and is almost entirely water-insoluble.
  • Preferred vinylacetate/vinylalcohol copolymers are those where H is between about 67% and 99.5%, or n/m has a value between about 2 and 200. The preferred average molecular weight is between about 2500 and about 1,000,000 daltons and more preferably between about 3000 and about 100,000 daltons.
  • polymers suitable for use with the present invention comprises ionizable non-cellulosic polymers.
  • exemplary polymers include: carboxylic acid-functionalized vinyl polymers, such as the carboxylic acid-functionalized polymethacrylates and polyacrylates such as the EUDRAGIT® series manufactured by Rohm Tech Inc., of Maiden, Mass.; amine-functionalized polyacrylates and polymethacrylates; proteins, such as gelatin and albumin; and carboxylic acid-functionalized starches such as starch glycolate.
  • a preferred class of polymers comprises (i) ionizable and (ii) neutral or non-ionizable cellulosic polymers with at least one ester- and/or ether-linked substituent in which the polymer has a degree of substitution of at least 0.05 for each substituent.
  • “Degree of substitution” refers to the average number of the three hydroxyls per saccharide repeat unit on the cellulose chain that have been substituted. For example, if all of the hydroxyls on the cellulose chain have been phthalate-substituted, the phthalate degree of substitution is 3.
  • ether-linked substituents are recited prior to “cellulose” as the moiety attached to the ether group; for example, “ethylbenzoic acid cellulose” has ethoxybenzoic acid substituents.
  • ester-linked substituents are recited after “cellulose” as the carboxylate; for example, “cellulose phthalate” has one carboxylic acid of each phthalate moiety ester-linked to the polymer and the other carboxylic acid unreacted.
  • a polymer name such as “cellulose acetate phthalate” (CAP) refers to any of the family of cellulosic polymers that have acetate and phthalate groups attached via ester linkages to a significant fraction of the cellulosic polymer's hydroxyl groups.
  • CAP cellulose acetate phthalate
  • the degree of substitution of each substituent group can range from 0.05 to 2.9 as long as the other criteria of the polymer are met.
  • Also included within each polymer family type are cellulosic polymers that have additional substituents added in relatively small amounts that do not substantially alter the performance of the polymer.
  • Amphiphilic cellulosics comprise polymers in which the parent cellulosic polymer has been substituted at any or all of the 3 hydroxyl groups present on each saccharide repeat unit with at least one relatively hydrophobic substituent.
  • Hydrophobic substituents may be essentially any substituent that, if substituted to a high enough level or degree of substitution, can render the cellulosic polymer essentially aqueous-insoluble.
  • hydrophobic substitutents examples include ether-linked alkyl groups such as methyl, ethyl, propyl, butyl, etc.; or ester-linked alkyl groups such as acetate, propionate, butyrate, etc.; and ether- and/or ester-linked aryl groups such as phenyl, benzoate, or phenylate.
  • Hydrophilic regions of the polymer can be either those portions that are relatively unsubstituted, since the unsubstituted hydroxyls are themselves relatively hydrophilic, or those regions that are substituted with hydrophilic substituents.
  • Hydrophilic substituents include ether- or ester-linked nonionizable groups such as the hydroxy alkyl substituents hydroxyethyl, hydroxypropyl, and the alkyl ether groups such as ethoxyethoxy or methoxyethoxy.
  • Particularly preferred hydrophilic substituents are those that are ether- or ester-linked ionizable groups such as carboxylic acids, thiocarboxylic acids, substituted phenoxy groups, amines, phosphates or sulfonates.
  • One class of cellulosic polymers useful in the invention comprises neutral polymers, meaning that the polymers are substantially non-ionizable in aqueous solution.
  • Such polymers contain non-ionizable substituents, which may be either ether-linked or ester-linked.
  • exemplary ether-linked non-ionizable substituents include: alkyl groups, such as methyl, ethyl, propyl, butyl, etc.; hydroxy alkyl groups such as hydroxymethyl, hydroxyethyl, hydroxypropyl, etc.; and aryl groups such as phenyl.
  • Exemplary ester-linked non-ionizable substituents include: alkyl groups, such as acetate, propionate, butyrate, etc.; and aryl groups such as phenylate.
  • alkyl groups such as acetate, propionate, butyrate, etc.
  • aryl groups such as phenylate.
  • the polymer may need to include a sufficient amount of a hydrophilic substituent so that the polymer has at least some water solubility at a physiologically relevant pH of from 1 to 8.
  • Exemplary neutral cellulosic polymers that may be used as the polymer include: hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl methyl cellulose, hydroxyethyl cellulose acetate, and hydroxyethyl ethyl cellulose.
  • a preferred set of neutral cellulosic polymers are those that are amphiphilic.
  • Exemplary polymers include hydroxypropyl methyl cellulose and hydroxypropyl cellulose acetate, where cellulosic repeat units that have relatively high numbers of methyl or acetate substituents relative to the unsubstituted hydroxyl or hydroxypropyl substituents constitute hydrophobic regions relative to other repeat units on the polymer.
  • a preferred class of cellulosic polymers comprises polymers that are at least partially ionizable at a physiologically relevant pH and include at least one ionizable substituent, which may be either ether-linked or ester-linked.
  • exemplary ether-linked ionizable substituents include: carboxylic acids, such as acetic acid, propionic acid, benzoic acid, salicylic acid, alkoxybenzoic acids such as ethoxybenzoic acid or propoxybenzoic acid, the various isomers of alkoxyphthalic acid such as ethoxyphthalic acid and ethoxyisophthalic acid, the various isomers of alkoxynicotinic acid such as ethoxynicotinic acid, and the various isomers of picolinic acid such as ethoxypicolinic acid, etc.; thiocarboxylic acids, such as thioacetic acid; substituted phenoxy groups, such as hydroxyphenoxy, etc.; amines, such
  • ester-linked ionizable substituents include: carboxylic acids, such as succinate, citrate, phthalate, terephthalate, isophthalate, trimellitate, and the various isomers of pyridinedicarboxylic acid, etc.; thiocarboxylic acids, such as thiosuccinate; substituted phenoxy groups, such as amino salicylic acid; amines, such as natural or synthetic amino acids, such as alanine or phenylalanine; phosphates, such as acetyl phosphate; and sulfonates, such as acetyl sulfonate.
  • carboxylic acids such as succinate, citrate, phthalate, terephthalate, isophthalate, trimellitate, and the various isomers of pyridinedicarboxylic acid, etc.
  • thiocarboxylic acids such as thiosuccinate
  • substituted phenoxy groups such as amino salicylic acid
  • amines such
  • aromatic-substituted polymers to also have the requisite aqueous solubility, it is also desirable that sufficient hydrophilic groups such as hydroxypropyl or carboxylic acid functional groups be attached to the polymer to render the polymer aqueous soluble at least at pH values where any ionizable groups are ionized.
  • the aromatic substituent may itself be ionizable, such as phthalate or trimellitate substituents.
  • Exemplary ionizable cellulosic polymers that meet the definition of amphiphilic, having hydrophilic and hydrophobic regions include polymers such as cellulose acetate phthalate and cellulose acetate trimeilitate where the cellulosic repeat units that have one or more acetate substituents are hydrophobic relative to those that have no acetate substituents or have one or more ionized phthalate or trimellitate substituents.
  • a particularly desirable subset of cellulosic ionizable polymers are those that possess both a carboxylic acid functional aromatic substituent and an alkylate substituent and thus are amphiphilic.
  • Exemplary polymers include cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxylpropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate succinate, cellulose propionate phthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetate trimellitate, methyl cellulose acetate trimellitate, ethyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate, hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate succinate,
  • HPMCAS hydroxypropyl methyl cellulose acetate succinate
  • HPMCP hydroxypropyl methyl cellulose phthalate
  • CAP cellulose acetate phthalate
  • CAT cellulose acetate trimellitate
  • CMEC carboxymethyl ethyl cellulose
  • neutralized acidic polymer is meant any acidic polymer for which a significant fraction of the “acidic moieties” or “acidic substituents” have been “neutralized”; that is, exist in their deprotonated form.
  • neutralized acidic cellulosic polymers is meant any cellulosic “acidic polymer” for which a significant fraction of the “acidic moieties” or “acidic substituents” have been “neutralized.”
  • acidic polymer is meant any polymer that possesses a significant number of acidic moieties.
  • Exemplary classes of functional groups that are included in the above description include carboxylic acids, thiocarboxylic acids, phosphates, phenolic groups, and sulfonates. Such functional groups may make up the primary structure of the polymer such as for polyacrylic acid, but more generally are covalently attached to the backbone of the parent polymer and thus are termed “substituents.” Neutralized acidic polymers are described in more detail in commonly assigned U.S. Patent Application Serial No. 60/300,255 filed Jun. 22, 2001, the pertinent disclosure of which is incorporated by reference.
  • the amount of concentration-enhancing polymer relative to the amount of drug present in the solid drug dispersions depends on the drug and concentration-enhancing polymer and may vary widely from a drug-to-polymer weight ratio of 0.01 to 5, or from about 1 to about 80 wt % drug. However, in most cases, except when the drug dose is quite low, i.e., 25 mg or less, it is preferred that the drug-to-polymer ratio is greater than 0.05 and less than 2.5 (from about 5 to about 70 wt % drug) and often the enhancement in drug concentration or relative bioavailability is observed at drug-to-polymer ratios of 1 (about 50 wt % drug) or less or for some drugs even 0.2 (about 17 wt % drug) or less.
  • the drug in the dispersion is “amorphous,” meaning simply that the drug is in a non-crystalline state.
  • the term “a major portion” of the drug means that at least 60% of the drug in the dispersion is in the amorphous, as opposed to the crystalline form.
  • the drug in the dispersion is “substantially amorphous,” meaning that the amount of the drug in crystalline form does not exceed about 25%. More preferably, the drug in the dispersion is “almost completely amorphous,” meaning that the amount of drug in the crystalline form does not exceed about 10%.
  • Amounts of crystalline drug may be measured by Powder X-Ray Diffraction (PXRD), Scanning Electron Microscope (SEM) analysis, Differential Scanning Calorimetry (DSC), or any other standard quantitative measurement.
  • the solid dispersions may contain from about 1 to about 80 wt % drug, depending on the dose of the drug and the effectiveness of the concentration-enhancing polymer. Enhancement of aqueous drug concentrations and relative bioavailability are typically best at low drug levels, typically less than about 25 to about 40 wt %. However, due to the practical limit of the dosage form size, higher drug levels are often preferred and in many cases perform well.
  • the amorphous drug can exist within the solid amorphous dispersion as a pure phase, as a solid solution of drug homogeneously distributed throughout the polymer or any combination of these states or those states that lie intermediate between them.
  • the amorphous drug is preferably dispersed as homogeneously as possible throughout the polymer so that the dispersion is “substantially homogeneous,” meaning that the fraction of drug that is present in relatively pure amorphous domains within the solid dispersion is relatively small, on the order of less than 20%, and preferably less than 10% of the total amount of drug.
  • the solid drug dispersion may have some drug-rich domains, it is preferred that the dispersion itself have a single glass transition temperature (T g ), which confirms that the dispersion is substantially homogeneous. This is in contrast to a simple physical mixture of pure amorphous drug particles and pure amorphous polymer particles which generally display two distinct T g s, one being that of the drug and one that of the polymer.
  • T g as used herein is the characteristic temperature where a glassy material, upon gradual heating, undergoes a relatively rapid (i.e., in 10 to 100 seconds) physical change from a glassy state to a rubbery state.
  • the T g of an amorphous material such as a polymer, drug or dispersion can be measured by several techniques, including by a dynamic mechanical analyzer (DMA), a dilatometer, a dielectric analyzer, and by DSC.
  • DMA dynamic mechanical analyzer
  • the exact values measured by each technique can vary somewhat, but usually fall within 10° to 30° C. of each other.
  • amorphous dispersion exhibits a single T g , this indicates that the dispersion is substantially homogenous.
  • Dispersions that are substantially homogeneous generally are more physically stable and have improved concentration-enhancing properties and, in turn, improved bioavailability, relative to nonhomogeneous dispersions.
  • the polymer used in the dispersion is a “concentration-enhancing polymer,” meaning that it meets at least one, and preferably both, of the following conditions.
  • the first condition is that the concentration-enhancing polymer increases the maximum drug concentration (MDC) of the drug in the environment of use relative to a control composition consisting of an equivalent amount of the undispersed drug but no polymer. That is, once the composition is introduced into an environment of use, the polymer increases the aqueous concentration of drug relative to the control composition.
  • the control composition is free from solubilizers or other components that would materially affect the solubility of the drug, and that the drug is in solid form in the control composition.
  • the polymer increases the MDC of the drug in aqueous solution by at least 1.25-fold relative to a control composition, more preferably by at least 2-fold, and most preferably by at least 3-fold.
  • the second condition is that the concentration-enhancing polymer increases the area under the concentration versus time curve (AUC) of the drug in the environment of use relative to a control composition consisting of the undispersed drug but no polymer.
  • AUC concentration versus time curve
  • the composition comprising the drug and the concentration-enhancing polymer provides an AUC for any 90-minute period of from about 0 to about 270 minutes following introduction to the use environment that is at least 1.25-fold that of the control composition described above.
  • the AUC provided by the inventive composition is at least 2-fold, more preferably at least 3-fold that of the control composition.
  • the solid drug dispersions used in the inventive dosage forms provide enhanced concentration of the dissolved drug in in vitro dissolution tests. It has been determined that enhanced drug concentration in in vitro dissolution tests in MFD solution or in PBS solution is a good indicator of in vivo performance and bioavailability.
  • An appropriate PBS solution is an aqueous solution comprising 20 mM Na 2 HPO 4 , 47 mM KH 2 PO 4 , 87 mM NaCl, and 0.2 mM KCl, adjusted to pH 6.5 with NaOH.
  • the concentration of dissolved drug is typically measured as a function of time by sampling the test medium and plotting drug concentration in the test medium vs. time so that the MDC can be ascertained.
  • the MDC is taken to be the maximum value of dissolved drug measured over the duration of the test.
  • the aqueous AUC is calculated by integrating the concentration versus time curve over any 90-minute time period between the time of introduction of the composition into the aqueous use environment (when time equals zero) and 270 minutes following introduction to the use environment (when time equals 270 minutes).
  • the time interval used to calculate AUC is from time equals zero to time equals 90 minutes.
  • the composition formed is considered to be within the scope of this invention.
  • dissolved drug encompasses not only monomeric solvated drug molecules but also a wide range of species such as polymer/drug assemblies that have submicron dimensions such as drug aggregates, aggregates of mixtures of polymer and drug, micelles, polymeric micelles, colloidal particles or nanocrystals, polymer/drug complexes, and other such drug-containing species that are present in the filtrate or supernatant in the specified dissolution test.
  • the solid drug dispersions when dosed orally to a human or other animal, provide an AUC in drug concentration in the blood that is at least about 1.25-fold, preferably at least about 2-fold, and more preferably at least about 3-fold, than that observed when a control composition consisting of an equivalent quantity of undispersed drug is dosed. It is noted that such compositions can also be said to have a relative bioavailability of from about 1.25-fold to about 3-fold that of the control composition.
  • Relative bioavailability of drugs in the dispersions can be tested in vivo in animals or humans using conventional methods for making such a determination.
  • An in vivo test such as a crossover study, may be used to determine whether a composition of drug and concentration-enhancing polymer provides an enhanced relative bioavailability compared with a control composition as described above.
  • a test composition of drug and polymer is dosed to half a group of test subjects and, after an appropriate washout period (e.g., one week) the same subjects are dosed with a control composition that consists of an equivalent quantity of undispersed drug as the test composition (but with no polymer present). The other half of the group is dosed with the control composition first, followed by the test composition.
  • the relative bioavailability is measured as the concentration in the blood (serum or plasma) versus time area under the curve (AUC) determined for the test group divided by the AUC in the blood provided by the control composition.
  • AUC time area under the curve
  • this test/control ratio is determined for each subject, and then the ratios are averaged over all subjects in the study.
  • In vivo determinations of AUC can be made by plotting the serum or plasma concentration of drug along the ordinate (y-axis) against time along the abscissa x-axis).
  • a dosing vehicle may be used to administer the dose.
  • the dosing vehicle is preferably water, but may also contain materials for suspending the test or control composition, provided these materials do not dissolve the composition or change the drug solubility in vivo.
  • the drug may exist in the molten mixture as a pure phase, as a solution of drug homogeneously distributed throughout the molten mixture, or any combination of these states or those states that lie intermediate between them.
  • the molten mixture is preferably substantially homogeneous so that the drug is dispersed as homogeneously as possible throughout the molten mixture.
  • the temperature of the molten mixture is below the melting point of both the drug and the concentration-enhancing polymer, the molten excipients, concentration-enhancing polymer, and drug are preferably sufficiently soluble in each other that a substantial portion of the drug disperses in the concentration-enhancing polymer or excipients. It is often preferred that the mixture be heated above the lower of the melting points of the concentration-enhancing polymer and the drug.
  • the molten mixture may also include an excipient that will reduce the melting temperature of the molten mixture, thereby allowing processing at a lower temperature.
  • excipients When such excipients have low volatility and substantially remain in the mixture upon solidification, they generally can comprise up to 30 wt % of the molten mixture.
  • a plasticizer may be added to the mixture to reduce the melting temperature of the polymer.
  • plasticizers include water, triethylcitrate, triacetin, and dibutyl sebacate. Volatile agents that dissolve or swell the polymer, such as acetone, water, methanol and ethyl acetate, may also be added to reduce the melting point of the molten mixture.
  • the processing may be considered to be a combination of solvent processing and melt-congealing or melt-extrusion. Removal of such volatile excipients from the molten mixture can be accomplished by breaking up or atomizing the molten mixture into small droplets and contacting the droplets with a fluid so that the droplets both cool and lose all or part of the volatile excipient.
  • the molten mixture may be mixed to ensure the drug is homogeneously distributed throughout the molten mixture.
  • Such mixing may be done using mechanical means, such as overhead mixers, magnetically driven mixers and stir bars, planetary mixers, and homogenizers.
  • the contents of the vessel can be pumped out of the vessel and through an in-line or static mixer and then returned to the vessel.
  • the amount of shear used to mix the molten mixture should be sufficiently high to ensure uniform distribution of the drug in the molten mixture.
  • the molten mixture can be mixed from a few minutes to several hours, the mixing time depending on the viscosity of the mixture and the solubility of the drug and the presence of optional excipients in the concentration-enhancing polymer.
  • Yet another method of preparing the molten mixture is to use two vessels, melting the drug in the first vessel and the concentration-enhancing polymer in a second vessel. The two melts are then pumped through an in-line static mixer or extruder to produce the molten mixture that is then rapidly solidified.
  • Still another method of preparing the molten mixture is by the use of an extruder, such as a single-screw or twin-screw extruder, both well known in the art.
  • an extruder such as a single-screw or twin-screw extruder, both well known in the art.
  • a solid feed of the composition is fed to the extruder, whereby the combination of heat and shear forces produce a uniformly mixed molten mixture, which can then be rapidly solidified to form the solid amorphous dispersion.
  • the solid feed can be prepared using methods well known in the art for obtaining solid mixtures with high content uniformity.
  • the extruder may be equipped with two feeders, allowing the drug to be fed to the extruder through one feeder and the polymer through the other.
  • Other excipients to reduce the processing temperature as described above may be included in the solid feed, or in the case of liquid excipients, such as water, may be injected into the extruder using methods well known in the art
  • the processing temperature may be below the melting temperature of the undispersed drug but greater than the melting point of the polymer, since the drug will dissolve into the molten polymer.
  • the processing temperature may be above the melting point of the undispersed drug but below the melting point of the undispersed concentration-enhancing polymer since the molten drug will dissolve in or be absorbed into the polymer.
  • the mixture should be rapidly solidified to form the solid amorphous dispersion.
  • rapidly solidified is meant that the molten mixture is solidified sufficiently fast that substantial phase separation of the drug and polymer does not occur. Typically, this means that the mixture should be solidified in less than about 10 minutes, preferably less than about 5 minutes and more preferably less than about 1 minute. If the mixture is not rapidly solidified, phase separation can occur, resulting in the formation of drug-rich and polymer-rich phases.
  • Solidification often takes place primarily by cooling the molten mixture to at least about 10° C. and preferably at least about 30° C. below its melting point.
  • solidification can be additionally promoted by evaporation of all or part of one or more volatile excipients or solvents.
  • the molten mixture is often formed into a high surface area shape such as a rod or fiber or droplets.
  • the molten mixture can be forced through one or more small holes to form long thin fibers or rods or may be fed to a device, such as an atomizer such as a rotating disk, that breaks the molten mixture up into droplets from 1 ⁇ m to 1 cm in diameter.
  • the droplets are then contacted with a relatively cool fluid such as air or nitrogen to promote cooling and evaporation.
  • solvent processing which consists of dissolution of the drug and one or more polymers in a common solvent.
  • “Common” here means that the solvent, which can be a mixture of compounds, will dissolve both the drug and the polymer(s). After both the drug and the polymer have been dissolved, the solvent is rapidly removed by evaporation or by mixing with a non-solvent. Exemplary processes are spray-drying, spray-coating (pan-coating, fluidized bed coating, etc.), and precipitation by rapid mixing of the polymer and drug solution with CO 2 , water, or some other non-solvent.
  • the drug is dispersed as homogeneously as possible throughout the polymer and can be thought of as a solid solution of drug dispersed in the polymer(s), wherein the dispersion is thermodynamically stable, meaning that the concentration of drug in the polymer is at or below its equilibrium value, or it may be considered to be a supersaturated solid solution where the drug concentration in the dispersion polymer(s) is above its equilibrium value.
  • the solvent may be removed by spray-drying.
  • spray-drying is used conventionally and broadly refers to processes involving breaking up liquid mixtures into small droplets (atomization) and rapidly removing solvent from the mixture in a spray-drying apparatus where there is a strong driving force for evaporation of solvent from the droplets.
  • Spray-drying processes and spray-drying equipment are described generally in Perry's Chemical Engineers' Handbook , pages 20-54 to 20-57 (Sixth Edition 1984). More details on spray-drying processes and equipment are reviewed by Marshall, “Atomization and Spray-Drying,” 50 Chem. Eng. Prog. Monogr. Series 2 (1954), and Masters, Spray Drying Handbook (Fourth Edition 1985).
  • the strong driving force for solvent evaporation is generally provided by maintaining the partial pressure of solvent in the spray-drying apparatus well below the vapor pressure of the solvent at the temperature of the drying droplets. This is accomplished by (1) maintaining the pressure in the spray-drying apparatus at a partial vacuum (e.g., 0.01 to 0.50 atm); or (2) mixing the liquid droplets with a warm drying gas; or (3) both (1) and (2). In addition, at least a portion of the heat required for evaporation of solvent may be provided by heating the spray solution.
  • a partial vacuum e.g. 0.01 to 0.50 atm
  • at least a portion of the heat required for evaporation of solvent may be provided by heating the spray solution.
  • Solvents suitable for spray-drying can be any organic compound in which the drug and polymer are mutually soluble.
  • the solvent is also volatile with a boiling point of 150° C. or less.
  • the solvent should have relatively low toxicity and be removed from the dispersion to a level that is acceptable according to The International Committee on Harmonization (ICH) guidelines. Removal of solvent to this level may require a subsequent processing step such as tray-drying.
  • ICH International Committee on Harmonization
  • Preferred solvents include alcohols such as methanol, ethanol, n-propanol, iso-propanol, and butanol; ketones such as acetone, methyl ethyl ketone and methyl iso-butyl ketone; esters such as ethyl acetate and propylacetate; and various other solvents such as acetonitrile, methylene chloride, toluene, and 1,1,1-trichloroethane. Lower volatility solvents such as dimethyl acetamide or dimethylsulfoxide can also be used.
  • solvents such as 50% methanol and 50% acetone
  • water so long as the polymer and drug are sufficiently soluble to make the spray-drying process practicable.
  • non-aqueous solvents are preferred, meaning that the solvent comprises less than about 10 wt % water.
  • the solvent-bearing feed comprising the drug and the concentration-enhancing polymer
  • various types of nozzles can be used to atomize the spray solution, thereby introducing the spray solution into the spray-dry chamber as a collection of small droplets.
  • any type of nozzle may be used to spray the solution as long as the droplets that are formed are sufficiently small that they dry sufficiently (due to evaporation of solvent) that they do not stick to or coat the spray-drying chamber wall.
  • the maximum droplet size varies widely as a function of the size, shape and flow pattern within the spray-dryer, generally droplets should be less than about 500 ⁇ m in diameter when they exit the nozzle.
  • types of nozzles that may be used to form the dispersions include the two-fluid nozzle, the fountain-type nozzle, the flat fan-type nozzle, the pressure nozzle and the rotary atomizer.
  • a pressure nozzle is used, as disclosed in detail in commonly assigned copending U.S. Provisional Application No. 60/353,986 filed Feb. 1, 2002 (Attorney docket No. PC23203), the disclosure of which is incorporated herein by reference.
  • the large surface-to-volume ratio of the droplets and the large driving force for evaporation of solvent leads to rapid solidification times for the droplets. Solidification times should be less than about 20 seconds, preferably less than about 10 seconds, and more preferably less than 1 second. This rapid solidification is often critical to the particles maintaining a uniform, homogeneous dispersion instead of separating into drug-rich and polymer-rich phases.
  • the height and volume of the spray-dryer are adjusted to provide sufficient time for the droplets to dry prior to impinging on an internal surface of the spray-dryer, as described in detail in commonly assigned, copending U.S. Provisional Application No. 60/354,080 filed Feb. 1, 2002 (Attorney Docket No. PC23195), the disclosure of which is incorporated herein by reference. As noted above, to get large enhancements in concentration and bioavailability it is often necessary to obtain as homogeneous a dispersion as possible.
  • the dispersion is usually in the form of small particles.
  • the particles may be less than 500 ⁇ m in diameter, or less than 100 ⁇ m in diameter, less than 50 ⁇ m in diameter or less than 25 ⁇ m in diameter.
  • the resulting dispersion is in the form of such small particles.
  • the dispersion is formed by other methods such by melt-congeal or extrusion processes, the resulting dispersion may be sieved, ground, or otherwise processed to yield a plurality of small particles.
  • composition may then be milled to achieve the desired particle size.
  • suitable processes for milling the composition include hammer milling, ball milling, fluid-energy milling, roller milling, cutting milling, and other milling processes known in the art.
  • the dosage form of the present invention disintegrates in 10 minutes or less following introduction to a disintegration medium. More preferably, the dosage form disintegrates in 5 minutes or less, and most preferably in 2 minutes or less.
  • the disintegration time is determined according to the USP XXIV disintegration test procedure. In this procedure, a dosage form is placed inside a wire basket, the basket being made from a stainless steel wire cloth with 1.8 to 2.2-mm mesh apertures and a wire diameter of 0.60 to 0.655 mm.
  • the wire basket containing the dosage form is raised and lowered in a disintegration medium at a frequency between 29 and 32 cycles per minute.
  • the disintegration medium typically water is held at 37° C.
  • the “disintegration time” is the time required to render any residue of the dosage form remaining on the wire basket a soft mass having no palpably firm core, excluding fragments of insoluble coating.
  • an in vivo test may be used to determine whether a dosage form provides a drug release profile within the scope of the present invention, and even though the ultimate use environment is often the human GI tract, due to the inherent difficulties and complexity of in vivo tests, it is preferred that in vitro tests be used to evaluate dosage forms.
  • the dosage form of the present invention also comprises a disintegrant.
  • disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpolypyrrolidone, methyl cellulose, microcrystalline cellulose, powdered cellulose, lower alkyl-substituted hydroxypropyl cellulose, polacrilin potassium, starch, pregelatinized starch, sodium alginate, and mixtures thereof.
  • the tablet When introduced to an aqueous environment of use, the tablet rapidly takes up water, leading to swelling of the disintegrant and rapid disintegration of the tablet before the dispersion polymer can form a hydrogel.
  • the disintegrant should be chosen such that it (1) swells rapidly when introduced into the use environment and (2) has a low tendency to form or promote formation of a hydrogel.
  • the inventors have found that the rate of swelling of the disintegrant is directly correlated to tablet disintegration times—that is, tablets containing disintegrants that cause more rapid swelling have faster disintegration times at comparable disintegrant levels.
  • W is the work or swelling energy of the disintegrant
  • P is the pressure applied by the probe
  • ⁇ V is the volume change of the sample.
  • the swelling energy per mass of disintegrant is used.
  • the disintegrant generates a swelling energy of at least 0.05 J/g within about 10 minutes, more preferably within about 7 minutes, and most preferably within about 5 minutes following addition of water to the liquid reservoir.
  • the dosage form of the present invention also includes a porosigen.
  • a “porosigen” is a material that, when present in the formulation containing the solid amorphous dispersion, leads to a high porosity and high strength following compression of the blend into a tablet.
  • preferred porosigens are soluble in an acidic environment with aqueous solubilities typically greater than 1 mg/mL at a pH less than about 5. Generally, the predominant deformation mechanism for porosigens under compression is brittle fracture rather than plastic flow.
  • porosigens include acacia, calcium carbonate, calcium sulfate, calcium sulfate dihydrate, compressible sugar, dibasic calcium phosphate (anhydrous and dihydrate), tribasic calcium phosphate, monobasic sodium phosphate, dibasic sodium phosphate, lactose, magnesium oxide, magnesium carbonate, silicon dioxide, magnesium aluminum silicate, maltodextrin, mannitol, methyl cellulose, microcrystalline cellulose, sorbitol, sucrose, xylitol and mixtures thereof. Of these, microcrystalline cellulose, both forms of dibasic calcium phosphate (anhydrous and dihydrate), and mixtures thereof are preferred.
  • the amount of porosigen included in the dosage form will depend on the properties of the dispersion, the disintegrant and the porosigen selected. Generally, the porosigen will comprise from 5 to 70 wt %, and preferably from 10 to 50 wt % of the dosage form.
  • Tablets are generally formed by blending the dispersion, disintegrant, and porosigen, with optional excipients, and then compressing the powder to form tablets using any of a wide variety of presses used in the fabrication of pharmaceutical dosage forms. Often it is desirable to granulate the compositions themselves, with or without the addition of excipients prior to compression.
  • the dispersion, disintegrant, and porosigen may be granulated by mechanical means by, for example, roller compaction or “slugging,” followed by milling to form granules.
  • the granules typically have improved flow, handling, blending, and compression properties relative to the ungranulated materials.
  • wet granulation techniques may also be employed, provided the solvents and process selected do not alter the properties of the solid amorphous dispersion. Improved wetting, disintegrating, dispersing and dissolution properties may be obtained by the inclusion of other excipients, as described below.
  • the dispersion, disintegrant, and porosigen result in a tablet that has a “strength” of at least 5 Kiloponds (Kp)/cm 2 , preferably at least 10 Kp/cm 2 .
  • “strength” is the fracture force, also known as the tablet “hardness,” required to fracture a tablet formed from the materials, divided by the maximum cross-sectional area of the tablet normal to that force. The fracture force may be measured using a Schleuniger Tablet Hardness Tester, model 6D.
  • the mixture of dispersion, disintegrant, and porosigen should be compressed with sufficient force while forming the tablets.
  • Friability is a well-known measure of a tablet's resistance to surface abrasion that measures weight loss in percentage after subjecting the tablets to a standardized agitation procedure. Friability values of from 0.8 to 1.0% are regarded as constituting the upper limit of acceptability. Tablets having a strength of greater than 5 kP/cm 2 generally are very robust, having a friability of less than 0.5%, preferably less than 0.1%.
  • tablet porosity should be at least 0.15, more preferably at least 0.20, and most preferably at least 0.25. Accordingly, the disintegrant and porosigen should be selected so that the immediate release dosage form has high strength as well as the high porosity required to achieve rapid disintegration and/or release of drug when the dosage form is introduced to a use environment.
  • excipients may be employed in the dosage forms of the invention, including those excipients well known in the art, e.g., as described in Remington's Pharmaceutical Sciences (18th ed. 1990). Generally, excipients such as surfactants, pH modifiers, fillers, matrix materials, complexing agents, solubilizers, pigments, lubricants, glidants, flavorants, and so forth may be used for customary purposes and in typical amounts without adversely affecting the properties of the compositions.
  • excipients such as surfactants, pH modifiers, fillers, matrix materials, complexing agents, solubilizers, pigments, lubricants, glidants, flavorants, and so forth may be used for customary purposes and in typical amounts without adversely affecting the properties of the compositions.
  • surfactants preferably present from 0 to 10 wt %.
  • Suitable surfactants include fatty acid and alkyl sulfonates; commercial surfactants such as benzalkonium chloride (HYAMINE® 1622 from Lonza, Inc. of Fairlawn, N.J.); dioctyl sodium sulfosuccinate (DOCUSATE SODIUM from Mallinckrodt Specialty Chemicals of St. Louis, Mo.); polyoxyethylene sorbitan fatty acid esters (TWEEN® from ICI Americas Inc. of Wilmington, Del.; LIPOSORB® 0-20 from Lipochem Inc.
  • HYAMINE® 1622 from Lonza, Inc. of Fairlawn, N.J.
  • dioctyl sodium sulfosuccinate DOCUSATE SODIUM from Mallinckrodt Specialty Chemicals of St. Louis, Mo.
  • TWEEN® from ICI Americas Inc. of Wilmington, Del.
  • Such materials can advantageously be employed to increase the rate of dissolution by, for example, facilitating wetting, or otherwise increase the rate of drug release from the dosage form.
  • Examples of other matrix materials, fillers, or diluents include lactose, mannitol, xylitol, dextrose, sucrose, sorbitol, compressible sugar, microcrystalline cellulose, powdered cellulose, starch, pregelatinized starch, dextrates, dextran, dextrin, dextrose, maltodextrin, calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, magnesium carbonate, magnesium oxide, poloxamers, polyethylene oxide, hydroxypropyl methyl cellulose and mixtures thereof.
  • the tablets may also be coated with a film coating using procedures well known in the art. These coatings may be used to mask taste, improve appearance, or facilitate swallowing of the dosage form. Such coatings may be fabricated by any conventional means including fluidized bed coating, spray-coating, pan-coating and powder-coating using aqueous or organic solvents.
  • the dosage form may also be overcoated with one or more pH-sensitive coating compositions, commonly referred to in the pharmaceutical arts as “enteric” coatings, by conventional procedures in order to delay the release of drug until it reaches the duodenum or small intestine.
  • pH-sensitive polymers suitable as enteric coatings include those which are relatively insoluble and impermeable at the pH of the stomach, but which are more soluble or disintegrable or permeable at the pH of the duodenum and small intestine.
  • a preferred group of pH-sensitive polymers includes CAP, PVAcP, HPMCP, HPMCAS, anionic acrylic copolymers of methacrylic acid and methylmethacrylate, and copolymers of acrylic acid and at least one acrylic acid ester.
  • the pH-sensitive polymer may first be dissolved in a suitable solvent to form a coating solution.
  • suitable solvents include ketones, such as acetone; alcohols, such as methanol, ethanol, isopropyl alcohol, n-propyl alcohol, and the various isomers of butanol; chlorinated hydrocarbons, such as methylene chloride; water; and mixtures of these solvents.
  • the polymer may also be suspended in the solvent.
  • the coating solution may also comprise a latex of the pH-sensitive polymer suspended in an aqueous solution.
  • the coating solution may also, contain one or more plasticizers, such as polyethylene glycols, triethyl citrate, propylene glycols, diethyl phthalate, dibutyl phthalate, castor oil, triacetin and others known in the art.
  • the coating solution may also contain one or more emulsifiers, such as polysorbate-80. Coating is conducted in conventional fashion, typically by dipping, spray-coating, or pan-coating.
  • a feed solution was formed containing 2.5 wt % Drug 1 (250 g), 7.5 wt % HPMCAS-HG (750 g), and 90 wt % acetone (9000 g) as follows.
  • the HPMCAS and acetone were combined in a container and mixed for 2 hours, causing the HPMCAS to dissolve.
  • the resulting mixture had a slight haze after the entire amount of polymer had been added.
  • Drug 1 was added directly to this mixture, and the mixture stirred for an additional 2 hours. This mixture was then filtered by passing it through a filter with a screen size of 250 ⁇ m to remove any large insoluble material from the mixture, thus forming the feed solution.
  • the feed solution was pumped using a high pressure gear pump (Zenith Z-Drive 2000) to a Niro PSD-1 Portable Spray-Dryer equipped with a liquid feed process vessel and a pressure nozzle (Model SK 71-16 from Spraying Systems, Inc.).
  • the dryer was also equipped with a 9-inch drying chamber extension to increase the length and volume of the drying chamber, which increased the residence time within the dryer, which allowed the product to dry before reaching the collection chamber of the dryer.
  • the dryer was also equipped with a gas-dispersing means for introduction of the drying gas to the spray drying chamber.
  • the gas-dispersing means consisted of a plate coextensive with the interior of the drying chamber (about 0.8 m diameter) and bearing a multiplicity of 1.7 mm perforations occupying about 1% of the surface area of the plate.
  • the perforations were uniformly distributed across the plate, except that the density of perforations at the center 0.2 m of the diffuser plate was about 25% of the density of perforations in the outer part of the diffuser plate.
  • the use of the diffuser plate resulted in organized plug flow of drying gas through the drying chamber and dramatically decreased product recirculation within the dryer.
  • the nozzle was arranged flush with the gas-disperser plate during operation.
  • the dispersion formed using the above procedure was subjected to secondary drying in a Gruenberg single-pass convection tray dryer operating at 40° C. for about 3 hours. Following drying, the dispersion was then equilibrated with ambient temperature and humidity.
  • Immediate release tablets containing 30 mg and 120 mg of active Drug 1 were formed from the spray-dried dispersion of Example 1.
  • the tablets contained 60 wt % of the dispersion of Example 1, 14.75 wt % microcrystalline cellulose (AVICEL PH105), 10 wt % crospovidone (POLYPLASDONE), 0.5 wt % magnesium stearate, and 14.75 wt % anhydrous dibasic calcium phosphate (EMCOMPRESS, Penwest Pharmaceuticals Co., Patterson, N.J.).
  • the dispersion, the microcrystalline cellulose, and the crospovidone were mixed for 15 minutes in a twin shell blender. Half of the magnesium stearate was then added to the blender and mixed for an additional 5 minutes.
  • the resulting blend had a specific volume of 4.2 to 5.0 cc/g.
  • This blend was then compressed into ribbons using a TF-mini compactor using smooth rollers, a rotation speed of 4 rpm, a roller back pressure of 25 to 30 kg/cm 2 and an auger speed of 25 to 30 rpm.
  • the compressed material was de-dusted on a 12-mesh (1680 ⁇ m) screen, and then milled using a Fitzpatrick M5A mill fitted with a rasping bar and a 0.033-inch (20 mesh, 840 ⁇ m) Conidur rasping plate. Mill rotation was in the knife direction at 500 rpm.
  • the mean particle size by screen analysis of the granulated material was 223 ⁇ m and the specific volume was 2.2 cc/g.
  • a Kilian T-100 rotary tablet press was used to make tablets containing 30 mgA Drug 1 (“mgA” means the amount of active drug in milligrams), using ⁇ fraction (5/16) ⁇ ′′ standard round concave (SRC) tooling.
  • SRC standard round concave
  • 200 mg of the final granulated material was placed in the tablet press.
  • a pre-compression force of approximately 2 kN was used and the compression force was set to deliver tablets having a hardness of 7 kiloponds (kP), as measured on a Schleuniger tablet hardness tester, Model 6D.
  • the “strength” of a tablet was calculated by dividing the tablet's hardness by the maximum cross-sectional area of the tablet. For the ⁇ fraction (5/16) ⁇ -inch SRC tooling, the maximum cross-sectional area is 0.495 cm 2 .
  • the strength of the tablets was 7 kP ⁇ 0.495 cm 2 , or 14.1 kP/cm 2 .
  • Disintegration time of the tablets was measured according to the USP XXIV disintegration test procedure, using a Erweka ZT-71 disintegration tester, as follows. One tablet is placed in each of six tubes of the basket-rack assembly, and the tester is operated using deionized water as the disintegration medium maintained at a temperature of 37° C. Complete disintegration is defined as that state in which any residue of the tablet remaining on the screen of the test apparatus, except fragments of insoluble coating, is a soft mass having no palpable firm core.
  • a disintegration time limit is established empirically, and is defined as the minimum time for at least 16 of 18 tablets to disintegrate completely. At the end of the time limit, the basket is lifted from the water, and the degree of disintegration of the tablets is observed. The mean disintegration time for the tablets was established to be less than 10 seconds.
  • a Kilian T-100 rotary tablet press was used to make tablets containing 120 mgA Drug 1, using oval (0.3437 inch ⁇ 0.6875 inch) tooling having a maximum cross-sectional area of 1.197 cm 2 .
  • 800 mg of the final granulated material was placed in the tablet press.
  • a pre-compression force of approximately 2 kN was used and the compression force was set to deliver tablets having a hardness of 16 kP, resulting in a tablet strength of 13.4 kP/cm 2 .
  • the mean disintegration time for the tablets was established at less than 15 seconds.
  • Drug 1 dissolution from the tablets of Example 2 was measured using an in vitro test.
  • a dissolution medium consisting of a simulated intestinal buffer solution was made by dissolving 6.8 g of KH 2 PO 4 in 750 mL of deionized water with 85 mL 0.2M NaOH. Water was added for a final volume of 1 L. The pH was adjusted to 6.8 ⁇ 0.1 using 0.2M NaOH.
  • 0.5 wt % sodium lauryl sulfate was added to the buffer.
  • a 900 mL sample of this solution was added to each of two vessels in a VanKel dissolution testing apparatus with automatic sampling. The solution temperature was maintained at 37° C., and stirred with a paddle speed of 100 rpm.
  • This dissolution medium acted as a sink for the 120 mgA tablets.
  • a tablet of Example 2 was added to each vessel containing the buffer solution, resulting in a Drug 1 concentration of 130 ⁇ gA/mL, assuming all of the drug had dissolved.
  • Samples were collected at 5, 15, 20, 35, 45, 60, 75, 90, 120 and 180 minutes, and then analyzed by HPLC using a Waters Symmetry C 8 column.
  • the mobile phase consisted of 0.2 vol % H 3 PO 4 (in water)/methanol in the ratio of 15/85 (vol/vol).
  • Drug 1 concentration was calculated by comparing UV absorbance at 256 nm to the absorbance of Drug 1 standards. The results (average of two tests) are reported in Table 1.
  • Example 3 immediate release tablets were made containing 50 wt % of the dispersion of Example 1, 12.0 wt % microcrystalline cellulose (AVICEL PH200), 12.5 wt % crospovidone, 0.5 wt % magnesium stearate, and 25.0 wt % anhydrous dibasic calcium phosphate. All ingredients except the magnesium stearate were mixed for 20 minutes in a Turbula blender. Half of the magnesium stearate was then added to the blender and mixed for an additional 5 minutes. The resulting mixture was formed into compacts using an F-Press, and the compacts were ground with a mortar and pestle until all the granules passed a 20-mesh screen.
  • the second half of the magnesium stearate was added to the ground mixture and blended in the Turbula blender for 5 minutes.
  • a Kilian T-100 rotary tablet press with 3 ⁇ 8-inch flat-beveled (FB) tooling having a 0.713 cm 2 cross-sectional area was used to make 250 mg tablets.
  • Example 6 immediate release tablets were made as in Example 3 containing 75 wt % of the dispersion of Example 1, 7.5 wt % microcrystalline cellulose, 7.5 wt % crospovidone, 0.5 wt % magnesium stearate and 9.5 wt % anhydrous dibasic calcium phosphate.
  • Example 3 The tablets of Examples 3-6 were formed using three different compression forces, measured by the Kilian tablet press. Tablets made at each compression force were tested for hardness on a Schleuniger tablet hardness tester, Model6D. Disintegration times were measured as in Example 2. Results of compression, hardness, strength and disintegration measurements for the tablets of Examples 3-6 are reported in Table 2. TABLE 2 Mean Disintegration Example No.
  • Example 7 immediate release tablets were made containing 70 wt % of the dispersion of Example 1, 20.0 wt % microcrystalline cellulose and 10.0 wt % crospovidone disintegrant. To form the tablets, the dispersion of Example 1 and the crospovidone were mixed in the Turbula blender for 10 minutes. The mixture was then formed into compacts on the F-Press. The compacts were milled with a mortar and pestle. The microcrystalline cellulose was added to the granules and mixed for 10 minutes in the Turbula blender. The granulation was then divided into 250 mg samples and the samples were compressed with the Killian tablet press using 3 ⁇ 8-inch FB tooling.
  • Example 8 immediate release tablets were made as in Example 7 containing 70 wt % of the dispersion of Example 1, 20.0 wt % of the Prosolv 90 and 10.0 wt % crospovidone.
  • Example 9 immediate release tablets were made as in Example 7 containing 70 wt % of the dispersion of Example 1, 20.0 wt % anhydrous dibasic calcium phosphate and 10.0 wt % crospovidone.
  • Example 10-11 the effect of disintegrants on tablet properties was examined.
  • the dispersion of Example 1 was formulated with 10 wt % croscarmellose sodium (AcDiSol) or 10 wt % crospovidone (POLYPLASDONE) as dry granulated binary blends with no lubricant. Hardness and disintegration of the tablets were measured as in previous Examples.
  • Example 10 immediate release tablets were made containing 90 wt % of the dispersion of Example 1 and 10 wt % AcDiSol. To form the tablets, the dispersion of Example 1 and the AcDiSol disintegrant were mixed in the Turbula blender for 10 minutes. The mixture was then formed into compacts on the F-Press. The compacts were milled with a mortar and pestle. The milled granules were mixed for 4 minutes in the Turbula blender. The granulation was then divided into 250 mg samples and the samples were compressed with the Kilian tablet press using 3 ⁇ 8-inch FB tooling.
  • Example 11 immediate release tablets were made as in Example 10 containing 90 wt % of the dispersion of Example 1 and 10 wt % POLYPLASDONE.
  • Example 12 shows results of experiments to measure the swelling force generated by the disintegrant. Tablets containing disintegrants that cause more rapid swelling have faster disintegration times at comparable disintegrant levels.
  • a feed solution was formed containing 1.0 wt % Drug 2 (742 g), 9.0 wt % HPMCAS-HG (6519 g), 72 wt % acetone (52,150 g) and 18 wt % methanol (13,038 g).
  • the feed solution was spray-dried with a Niro two-fluid external mix spray nozzle with nitrogen drying gas flow set at 2.6 bar and a feed rate of 192 g/min into the drying chamber of a Niro PSD-1 spray-dryer.
  • the drying gas was maintained at a temperature of 140° C. at the inlet, while the drying gas and evaporated solvent exited the dryer at 51° C.
  • the resulting solid amorphous dispersion was collected via a cyclone and then dried further in a Gruenberg solvent tray dryer by spreading the dispersion onto polyethylene-lined trays to a depth of not more than 1 cm and then heating them at 40° C. for 16 hours. After such tray-drying, the solid dispersion contained 10 wt % Drug 2.
  • Example 14-17 the effect of disintegrants on tablet properties was examined for tablets containing a dispersion of Drug 2.
  • immediate release tablets were made containing 65 wt % of the dispersion of Example 13, 19.0 wt % AVICEL PH102, 15 wt % AcDiSol and 1.0 wt % magnesium stearate.
  • the dispersion, AVICEL and AcDiSol were mixed for 10 minutes in a Turbula blender.
  • Half of the magnesium stearate was then added to the blender and mixed for an additional 4 minutes.
  • the resulting mixture was formed into compacts using an F-Press, and the compacts were ground with a mortar and pestle until all the granules passed a 20-mesh screen.
  • Example 15 immediate release tablets were made as in Example 14 containing 65 wt % of the dispersion of Example 13, 19.0 wt % AVICEL PH102, 15 wt % POLYPLASDONE and 1.0 wt % magnesium stearate.
  • Example 16 immediate release tablets were made as in Example 14 containing 65 wt % of the dispersion of Example 13, 19.0 wt % AVICEL PH102, 15 wt % EXPLOTAB and 1.0 wt % magnesium stearate.
  • Control 1 tablets were formed using conventional immediate release dosage form tableting excipients. Tablets were made containing 62.5 wt % of the Drug 2 dispersion of Example 13, 20.0 wt % Fast Flow lactose (Foremost/Van Water and Rogers, Baraboo, Wis.), 13.5 wt % AVICEL PH102, 3.0 wt % AcDiSol, and 1.0 wt % magnesium stearate. The dispersion, lactose, AVICEL, AcDiSol, and half of the magnesium stearate were mixed for 10 minutes in a Turbula blender.

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