JP2008511609A - Controlled release dosage forms combining rapid and sustained release of low-solubility drugs - Google Patents

Abstract

  The controlled release dosage form includes an immediate release portion and an enteric coated sustained release core.

Description

  The present invention relates to a controlled release dosage form having an immediate release portion and an enteric coated sustained release core.

It is well known that for some background drugs, controlled release of a drug over time can provide many advantages over immediate release of the drug. The main purpose of controlled release dosage forms is to maintain the desired therapeutic effect over a long period of time. Accordingly, such dosage forms result in higher blood drug concentrations than effective or therapeutic concentrations for longer periods of time than corresponding immediate release dosage forms containing the same amount of drug. Controlled release dosage forms often result in a reduction or elimination of fluctuations in drug concentration in the blood, which improves the management of disease symptoms. In addition, controlled release formulations reduce the maximum drug concentration in the blood compared to the same dose immediate release formulation, so controlled release formulations minimize side effects and are routine With use, there may be little or no synergy or decreased drug activity. Finally, controlled release dosage forms improve patient compliance due to reduced dosing frequency, reduced side effects, or both.

  However, with low-solubility drugs, it is difficult to formulate the drug into a controlled release oral dosage form that maintains blood drug concentrations above effective concentrations for extended periods of time. In particular, such problems have a relatively short biological half-life and are hardly absorbed in any or all of the lower gastrointestinal tract (eg, terminal small intestine and colon), low-solubility Present in the drug. For these drugs, the combination of low-solubility, short absorption window and relatively fast clearance from the blood is quite detrimental to achieving high drug blood concentrations for long periods of time. The low-solubility of the drug limits absorption due to the low concentration of the drug within the lower gastrointestinal water-soluble environment. Since the drug is hardly absorbed over some or all of the lower gastrointestinal tract, the period of time during which the drug is absorbed may be relatively short. For drugs that are hardly absorbed over the length of the lower gastrointestinal tract (lower small intestine and colon), a good absorption period may be limited to the upper part of the small intestine. In such cases, the drug delivered from the controlled release dosage form may become poorly absorbed immediately (1-2 hours) after exiting the stomach. Finally, a relatively short biological half-life results in sustained absorption of the drug at a rate sufficient to eliminate clearance rates at therapeutic blood levels, even if relatively high blood drug concentrations are initially achieved. If no means to provide is found, it means that the blood drug concentration will decrease rapidly over a long period of time.

  Thus, controlled release provides a relatively long, effective blood drug concentration for a low-solubility drug that is hardly absorbed over at least a portion of the gastrointestinal tract and has a relatively short biological half-life There is still a need for oral dosage forms.

Summary of the Invention
In one aspect, the controlled release oral dosage form comprises an immediate release portion comprising a low-solubility drug and a sustained release core comprising a low-solubility drug. The low-solubility drug has a water solubility of at least about 100 ml. The sustained release core is surrounded by an enteric coating. The sustained release core is large enough to be retained in the stomach and provides a delayed release of the drug. The sustained release core alone releases at least 90% by weight of the drug within the core over a release period of about 1 hour to about 8 hours, and the drug in the sustained release core is a solubility-improved form.

  In another aspect of the invention, the controlled release oral dosage form comprises an immediate release portion comprising a low-solubility drug and a sustained release core comprising a low-solubility drug. The low-solubility drug has a dose-water solubility ratio of at least about 10 ml. The sustained release core is surrounded by an enteric coating. The sustained release core is large enough to be maintained in the stomach and provides a delayed release of the drug. The sustained release core releases at least 90% by weight of the drug in the core over a release period of about 1 hour to about 8 hours, and the drug has a clearance half-life of less than about 12 hours.

  In one embodiment, the sustained release core and coating comprehensively have a mass of at least 400 mg.

  In another embodiment, the sustained release core and enteric coating generally have a length of at least 5 mm.

  We have long effective blood for low-solubility drugs that are hardly absorbed in some or all of the lower gastrointestinal tract and have a relatively short biological half-life as follows: Solved the problem of providing medium drug concentration. First, the dosage form must have an immediate release portion for rapid drug release into the stomach. This provides an initial exposure of the drug resulting in an initial period of good absorption of the drug, resulting in a high blood drug concentration. Second, the dosage form should be kept in the stomach as much as possible. This can be achieved by having a relatively large core (eg, at least about 400 mg) that is not substantially destroyed during residence in the stomach. The sustained release core is also surrounded by an enteric coating that prevents the sustained release core from being degraded or destroyed in the stomach. In some cases, drugs that are to be administered in the fed state to maximize retention in the stomach are also preferred. Drugs present in the stomach are generally not well absorbed from the stomach, but drugs released from the dosage form while the dosage form is in the stomach can help deliver the drug to the upper small intestine over an extended period of time Results in good absorption of the drug for a long time.

  Third, the drug is delivered in the lower gastrointestinal tract (lower small intestine and possibly the colon) over some form and time that allows for good absorption. The drug needs to have at least partial absorption in the lower gastrointestinal tract. For drugs that are hardly absorbed in the terminal small intestine, it is necessary to formulate the drug in the sustained release core in a solubility-improved form so that absorption of the drug in the lower gastrointestinal tract is acceptable. These drugs tend to have a dose-solubility ratio of greater than about 100 ml. It is also preferred that the sustained release core releases the drug over a release period corresponding to the period when the dosage form is a releasable drug (which may be a soluble-improved form) at the site of the GI tract where the drug has good absorption . In general, the release period is about 1-8 hours after exiting the stomach for drugs that may have partial absorption in both the terminal small intestine and colon (because the drug is a soluble-improved form) For a drug that has good absorption in the small intestine but is hardly absorbed in the colon, it is about 1 to 4 hours.

  In one embodiment, the dosage form comprises an enteric coated sustained release core in the form of a matrix device. The intermediate release portion is in the form of an intermediate release coating.

  In another embodiment, the dosage form comprises an enteric coated sustained release core in the form of a permeable controlled-release device. The intermediate release portion is in the form of an intermediate release coating.

  In yet another embodiment, the dosage form comprises a capsule, the capsule comprising an enteric coated sustained release core and an immediate release portion.

  The above and other objects, features and advantages of the present invention will be more readily understood in view of the following detailed description of the invention.

Preferred controlled release dosage form of Detailed Description of the Invention The present embodiment increases the length of the blood (serum or plasma) higher period than the middle drug concentration effective concentration. Controlled release dosage forms accomplish this by providing a sustained release core and an immediate release portion. The sustained release core is surrounded by an enteric coating. Drug properties, sustained release cores, enteric coatings, and immediate release portions for which dosage forms are suitable are described in more detail below.

The term “drug” refers to a compound that is conventional and has beneficial prophylactic and / or therapeutic properties when administered to animals, particularly humans. The drug has a relatively fast clearance rate. “Clearing half-life” means the time required for the body to remove blood or drug so that the drug concentration in blood (serum or plasma) is reduced by a factor of two. Clearance half-life can be determined, for example, by measuring the blood drug concentration after administering the drug by intravenous infusion and fitting the data using a first order single segment pharmacokinetic model. See, for example, Pharmacokinetics and Metabolism in Drug Design, Smith et al. (Wiley-VCH 2001) pages 20-21. The clearance half-life is less than about 12 hours. In general, the invention has increased utility when the clearance half-life is reduced. The clearance half-life may be less than about 8 hours, less than about 6 hours, or even less than about 4 hours. Nevertheless, the clearance half-life must be large (eg, greater than about 1 hour) so that the drug can be absorbed and accumulated in the blood without being rapidly removed from the body.

  “Low-solubility drug” means drug solubility (mg / mL) in any physiologically relevant aqueous solution (eg, an aqueous solution having a pH value of 1-8), including USP simulated gastrointestinal buffer. It is the minimum observed and means that when the dose is mg, the drug has a dose-water solubility ratio higher than about 10 ml. Thus, the dose-water solubility ratio can be calculated by dividing the dose (mg) by the solubility (mg / mL). The present invention has high utility as the dose-water solubility ratio increases. Thus, the dose-water solubility may be greater than about 50 ml, greater than about 100 ml, even greater than about 500 ml, or even greater than about 1000 ml. “Dose” means the amount of drug present in a dosage form. Water solubility means minimal water solubility at physiologically relevant pH (eg, pH 1-8). In general, the minimum water solubility is usually less than 10 mg / mL. The present invention increases in usefulness as the minimum water solubility decreases. The minimum water solubility may be less than 1 mg / mL, less than 0.5 mg / mL, even less than 0.1 mg / mL, or even less than 0.01 mg / mL.

  The preferred types of drugs are not particularly limited, but antihypertensive drugs, anti-anxiety drugs, anticoagulants, anticonvulsants, blood sugar-lowering drugs, decongestants, antihistamines, antitussive drugs, anti-neoplastic drugs, beta Blockers, anti-inflammatory drugs, antipsychotic drugs, recognition enhancers, cholesterol-reducing drugs, anti-atherosclerotic drugs, obesity-suppressing drugs, autoimmune disease drugs, sexual dysfunction drugs, antibacterial and antifungal drugs, sleeping drugs, anti-Parkinson disease Includes drugs, anti-Alzheimer's disease drugs, antibiotics, antiepileptics, antiviral drugs, glycogen phosphorylase inhibitors, and cholesterol ester transfer proteins.

  The drug may be in any pharmaceutically acceptable form. “Pharmaceutically acceptable form” refers to stereoisomers, stereoisomer mixtures, enantiomers, solvates, hydrates, isomorphs, polymorphs, pseudomorphs, neutral forms, salt forms and prodrugs. Means any pharmaceutically acceptable derivative or variant, including.

  One type of drug that would benefit from the present invention is a drug that is relatively well absorbed in the upper small intestine but hardly absorbed in the terminal small intestine or colon. Such drugs generally have a dose-solubility ratio in the range of about 10 ml to 100 ml or more. Such drugs are often polar (eg, characterized by a dipole). Such drugs may have a logP of less than about 3.0, or even less than about 2.0. Specific types of such drugs include antiviral agents and antibiotics.

  Another class of drugs that would benefit from the present invention are drugs that have low-solubility and are poorly absorbed in the small and large intestines, but can be formulated to be better absorbed in the small intestine. Such drugs have a dose-solubility ratio higher than about 100 ml. For this type of drug, the drug is formulated in a solubility-improved form to improve absorption of the drug in the small intestine. The term “solubility-improved form” refers to delivery to an in vivo use environment (eg, mammalian gastrointestinal tract) or physiologically relevant in vitro solution (eg, phosphate buffered saline or Model Fasted Duodenal solution described below). When done, it means the form of the drug alone, which provides an increase in the concentration of the drug described in more detail below. In general, the solubility-improved form dissolves at a concentration where its equilibrium solubility is in excess, but precipitates or crystallizes so that the dissolved concentration approaches the equilibrium concentration. Examples of “solubility-improved forms” include but are not limited to: (1) crystalline highly soluble forms of drugs, such as salts; (2) high-energy crystalline forms of drugs; (3) Hydrate or solvate forms of drugs; (4) amorphous forms of drugs (for drugs that exist as either amorphous or crystalline); (5) drug particles with small or small particle size; (6) drugs (7) a combination of a drug and a cyclodextrin; (8) a combination of a drug and a solubilizer; (9) an amorphous form of the drug, eg a solid amorphous dispersion or an absorbent of an amorphous drug; and (10) a drug Semi-ordered forms. In one aspect of the invention, the solubility-improved form of the drug is a crystalline and highly soluble salt form of the drug. As used herein, “highly soluble salt form” means that the drug provides the highest concentration of the drug in at least one in vitro test medium that is higher than the equilibrium concentration provided by the lowest soluble form of the drug. Is in the form of a salt. The drug may be in the form of any basic, acidic or zwitterionic pharmaceutically acceptable salt that meets this criteria. Examples of such basic drug salt forms include chloride, bromide, acetate, iodide, mesylate, phosphate, maleate, citrate, sulfate, tartrate, lactate and the like. Examples of salt forms of acidic drugs include sodium, calcium, potassium, zinc, magnesium, lithium, aluminum, meglumine, diethanolamine, benzathine, choline and procaine salts. These salts are also used for zwitterionic drugs.

  An example of a drug having a crystalline, highly soluble salt form is ziprasidone. Ziprasidone hydrochloride monohydrate has a solubility (shown as the free base) of about 10 μgA / mL in phosphate buffered saline (pH 6.5), but the free base form is under the same conditions. Has a solubility of less than about 0.2 μgA / mL. Thus, crystalline ziprasidone hydrochloride is a solubility-improved form compared to the crystalline free base form of the drug.

  Alternatively, in another aspect of the invention, the drug exists as a high-energy crystalline form with improved solubility compared to the low-energy crystalline form. It is known that some drugs crystallize into one of several different crystal forms. Such crystal forms are commonly referred to as “polymorphs”. As used herein, “high-energy crystalline form” means that the drug is a crystalline form that provides the following increase in concentration. Such high-energy crystalline forms usually dissolve and precipitate or crystallize out of solution at lower energy states. The dissolved drug concentration will eventually approach its equilibrium concentration.

  In yet another aspect of the invention, in the composition, the drug can be present in either an amorphous or crystalline form, but the solubility-improved form is the amorphous form. Preferably, at least a majority of the drug is amorphous. “Amorphous” only means that the drug is in a non-crystalline state. As used herein, the term “major” means that at least 60% by weight of the drug in the composition is in an amorphous form rather than a crystalline form. Preferably, the drug is substantially amorphous. As used herein, “substantially amorphous” means that the amount of drug in the crystalline form does not exceed about 25% by weight. More preferably, the drug is “almost completely amorphous” which means that the amount of drug in the crystalline form does not exceed about 10% by weight. The amount of crystalline drug can be measured by powder X-ray diffraction (PXRD), scanning electron microscope (SEM) analysis, differential scanning calorimetry (DSC) or any other standard quantitative measurement.

  The amorphous form of the drug can be any form in which the drug is amorphous. An example of an amorphous form of a drug includes a solid amorphous dispersion of the drug in a polymer. For example, it is disclosed in commonly assigned US Patent Application Publication No. 2002 / 0009494A1, which is incorporated herein by reference. Alternatively, the drug can be absorbed in amorphous form on a solid substrate. For example, disclosed in commonly-assigned US Patent Application Publication 2003 / 0054037A1, which is incorporated herein by reference.

  As yet another option, the amorphous drug can be stabilized using a matrix material. For example, it is disclosed in commonly-assigned US Patent Application Publication 2003 / 0104063A1, which is incorporated herein by reference. In yet another embodiment, the solubility-improved form comprises sufficiently small drug particles that improve the rate of degradation of the drug relative to the bulk (large) crystalline form of the drug. “Small particle size” means that the drug particles have an average diameter of less than 50 microns, more preferably less than 20 microns, and even more preferably less than 10 microns. A particularly preferred and convenient method for forming small particles of drug involves grinding larger size particles into smaller size particles. The particle size can be achieved by any conventional method, for example by grinding or pulverizing. Specific milling devices include chaser milling, ball milling, vibrating ball milling, hammer milling, impact milling milling, fluid energy milling (jet milling) and a centrifugal-impact mill. Alternatively, small particles can be formed by micronization or precipitation. One way to reduce the drug particle size is jet milling. Small drug particles can also be formed by other means, for example by decomposition in a solvent such as alcohol or water, followed by precipitation with a non-solvent. Another method for reducing the particle size is to form a powder by dissolving or decomposing the drug in a solvent and micronizing the liquid obtained by spray coagulation or spray drying. Other methods for producing small crystalline drug particles include wet milling or processing in a homogenizer. The size of the drug particles required to increase drug degradation compared to the drug's bacul crystalline form will depend on the particular drug. In general, however, the degradation rate tends to increase as the drug particle size decreases. For example, in the case of the drug ziprasidone, the jet milled drug has an average particle size of less than about 10 microns, more preferably about 5 microns.

  In another embodiment, the drug may be in the form of microparticles. The term “microparticle” refers to a drug in the form of particles generally having an effective average particle size of less than about 500 nm, more preferably about 250 nm and even more preferably less than about 100 nm. Examples of such microparticles are further described in US Pat. No. 5,145,684.

  Drug microparticles can be prepared using any known method for producing microparticles. One method involves suspending the drug in a liquid dispersion medium and dropping mechanical means in the presence of a milling medium to reduce the particle size of the drug substance to an effective average particle size. The particles can be reduced in size in the presence of a surface modifier. Alternatively, the particles can be contacted with a surface modifier after being reduced. Other alternative methods for producing microparticles are described in US Pat. No. 5,560,932 and US Pat. No. 5,874,029, which are incorporated herein by reference.

  Another solubility-improved form of the drug includes the drug in combination with cyclodextrin. As used herein, the term “cyclodextrin” refers to all forms of cyclodextrin and derivatives thereof. Specific examples of cyclodextrins include α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin. Examples of cyclodextrin derivatives are mono- or polyalkylated β-cyclodextrin, mono- or polyhydroxyalkylated β-cyclodextrin, hydroxypropyl β-cyclodextrin (hydroxypropylcyclodextrin), mono, tetra or hepta- Substituted β-cyclodextrin, sulfoalkyl ether cyclodextrin (SAE-CD) and sulfobutyl ether cyclodextrin (SBECD).

  These solubility-improved forms, also known as cyclodextrin derivatives hereinafter referred to as “cyclodextrin / drug forms”, may be a single physical mixture. Such an example is found in US Pat. No. 5,134,127, which is incorporated herein by reference. Alternatively, the drug and cyclodextrin may be complexed together. For example, the active drug and sulfoalkyl ether cyclodextrin (SAE-CD) can be preformed into a complex prior to preparation of the final formulation. Alternatively, the drug can be formulated using a film coating surrounding a solid core comprising a release modifier and SAE-CD / drug mixture as disclosed in US Pat. No. 6,046,177, incorporated herein by reference. . Upon exposure in the environment of use, the SAE-CD / drug mixture is at least partially converted to a complex. Alternatively, a sustained release formulation comprising SAE-CD surrounds a physical mixture of one or more SAE-CD derivatives, optional release rate modifiers, therapeutic agents, most not complexed to SAE-CD, and the core It may consist of a core containing an optional release rate modifying coating. Other cyclodextrins / drug forms envisioned by the present invention are found in U.S. Pat.Nos. 5,134,127, 5,874,418 and 5,376,645, all of which are incorporated herein by reference. ing.

  Another drug solubility-improving form is a combination of a drug and a solubilizer. Such a solubilizer increases the water solubility of the drug. When a drug is administered to a water-soluble use environment in the presence of a solubilizer, it may exceed the equilibrium concentration of the dissolved drug at least temporarily. Examples of solubilizers include: pH adjusters such as buffers, organic acids and organic acid salts; partial glycerides; glyceride derivatives; polyoxyethylene and polyoxypropylene ethers and copolymers thereof; sorbitan esters; Sorbitan esters; carbonates; alkyl sulfonates; and phospholipids. In this aspect, both the drug and the solubilizer are preferably solid.

  Specific surfactants include fatty acids and alkyl sulfonates; commercial surfactants such as benzalkonium chloride (available from HYAMINE® 1622, Lonza, Inc., Fairlawn, New Jersey); sodium dioctyl sulfosuccinate (Docusate sodium, available from Mallinckrodt Spec. Chem., St. Louis, Missouri); polyoxyethylene sorbitan fatty acid ester (available from TWEEN®, ICI Americas Inc., Wilmington, Delaware; LIPOSORB®) ) O-20, available from Lipochem Inc., Patterson New Jersey; CAPMUL® POE-0, available from Abitec Corp., Janesville, Wisconsin); and natural surfactants such as sodium taurocholate, 1- Contains palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, lecithin and other phospholipids, and mono- and diglycerides.

  Another type of solubilizer consists of organic acids and organic acid salts. Examples of organic acids are acetic acid, aconitic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, choline acid, citric acid, decanoic acid, ersorbic acid, 1,2-ethanedisulfonic acid , Ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, glyoxylic acid, heptanoic acid, hippuric acid, hydroxyethanesulfonic acid, lactic acid, lactobionic acid, levulinic acid, lysine, maleic acid, malic acid , Malonic acid, mandelic acid, methanesulfonic acid, mucoic acid, 1- and 2-naphthalenesulfonic acid, nicotinic acid, pamonic acid, pantetonic acid, phenylalanine, 3-phenylpropionic acid, phthalic acid, salicylic acid, sugar acid, succinic acid , Tannic acid, tartaric acid, p-toluenesulfonic acid, tryptophan and urine Including the.

  Yet another type of solubilizer is a lipophilic-macrophage described in US Patent Application Publication No. 2003 / 0228358A1, published Dec. 11, 2003, which is incorporated herein by reference. -Made of forming material. The lipophilic-macrophage-forming material may comprise a surfactant and / or a lipophilic material. Thus, as used herein, “lipophilic macrophage-forming material” is intended to include a mixture of materials in addition to a single material. Examples of amphiphilic materials suitable for use as lipophilic macrophage-forming materials include: sulfonated hydrocarbons and salts thereof, such as docusate sodium (CROPOL) and sodium lauryl sulfate (SLS) Known sodium 1,4-bis (2-ethylhexyl) sulfosuccinate; Poloxamer, also called polyoxyethylene-polyoxypropylene block copolymer (PLURONIC, LUTROL); Polyoxyethylene alkyl ether (CREMOPHOR A, BRIJ) Polyoxyethylene sorbitan fatty acid esters (polysorbates, TWEEN); short-chain glyceryl mono-alkylates (HODAG, IMWITTOR, MYRJ); polyglycolized glycerides (GELUCIRE); polyol mono- and di-alkylates such as glycerol; Ionic surfactants such as polyoxyethylene monooleate 20 sorbitan (commercially available from ICI, polysorbate 80, trademark TWEEN 80); polyoxyethylene 20 sorbitan monolaurate (polysorbate 20, TWEEN 20); polyethylene (40 or 60) hydrogenated castor oil (CREMOPHOR (Registered trademark) RH40 and RH60 commercially available from BASF); polyoxyethylene (35) castor oil (CREMOPHOR (registered trademark) EL); polyoxyethylene (60) hydrogenated castor oil (Nikkol HCO-60); alpha tocopheryl Polyoxyethylene glycol 1000 succinic acid (Vitamin E TPGS); glyceryl PEG 8 caprylate / caprate (commercially available from Gattefosse with LABRASOL®); glyceryl PEG 32 laurate (Gattefosse by GELUCIRE 44/14 ), Polyoxyethylene fatty acid esters (commercially available from ICI under the registered trademark BRIJ). Depending on the number of alkylates per molecule and the number of carbons in the alkylate, the polyol alkylate ester may be considered amphiphilic or hydrophobic. When the polyol is glycerol, mono- and di-alkylates are generally considered amphiphilic, while glycerol trialkylates are generally considered hydrophobic. However, some scientists classify even medium chain mono- and di-glycerides as hydrophobic. See, for example, Patel et al. US Pat. No. 6,294,192 (B1), which is hereby incorporated by reference in its entirety. Disregarding the classification, compositions comprising mono- and di-glycerides are preferred compositions of the present invention. Other suitable amphiphilic materials are found in Patel, US Pat. No. 6,294,192 and are listed as “hydrophobic nonionic and hydrophilic ionic surfactants”.

  It should be noted that some amphiphilic materials are not themselves water immiscible, but instead are at least slightly water soluble. Nevertheless, such amphiphilic materials can form lipophilicity when used in a mixture, especially when used as a mixture with a hydrophobic material.

Examples of hydrophobic materials suitable for use as lipophilic macrophage-forming materials include: medium chain glyceryl mono-, di- and tri-alkylates (CAPMUL MCM, MIGLYOL 810, MYVEROL 18-92, ARLACEL 186 , Coconut oil, light vegetable oil); sorbitan esters (ARLACEL 20, ARLACEL 40); long-chain fatty alcohols (stearyl alcohol, cetyl alcohol, cetostearyl alcohol); long-chain fatty acids (stearic acid); and phospholipids (eg egg lecithin) Soybean, soybean lecithin, plant lecithin, sodium taurocholate, and 1,2-diacyl-sn-glycero-3-phosphocholine such as 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine, 1,2-di Palmitoyl-sn-glycero-3-phosphocholine, 1,2-distearoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-stearoyl-sn-glycero-3-phosphocholine, and other heavens Or synthetic phosphatidyl choline); mono and diglycerides of capric acid and caprylic acid: Capmul® MCM, MCM 8 and MCM 10, which are commercially available from Abitec, and Imwitor (registered) Trademarks) 988, 742 or 308, commercially available from Condea Vista; polyoxyethylene 6 apricot oil, commercially available from Gattefosse as Labrafil® M 1944 CS; polyoxyethylene corn oil, Labrafil Commercially available as M 212; Propylene glycol monolauric acid, commercially available from Gattefosse as Lauroglycol; Propylene glycol dicaprylic / capric acid; Captex® 200 from Abitec or Miglyol (registered) Trademark) 840 commercially available from Condea Vista; polyglyceryl oleate, commercial from Gattefosse as Plurol oleique Fatty acid sorbitan esters (eg, commercially available from Span® 20, Crill® 1, Crill® 4, ICI and Croda), and glyceryl monooleate (Maisine Peceol); Mixtures of medium chain triglycerides (MCT, C ₆ -C ₁₂ ) and long chain triglycerides (LCT, C14-C20) and mono- and triglycerides, or lipophilic derivatives of fatty acids, eg esters with alkyl alcohols Palm oil, eg, 56% caprylic acid (C ₈ ) triglyceride and 36% capric acid (C ₁₀ ) triglyceride Miglyol® 812, Miglyol® 810 (68% C ₈ and 28% C ₁₀ ), Neobee (R) M5, Captex (R) 300, Captex (R) 355, and Crodamol (R) GTCC; (Miglyols is supplied by Condea Vista Inc. (HuIs), Neobee (R) is By Stepan Europe, Voreppe, France Feed, Captex supplied by Abitec Corp, Crodamol supplied by Croda Corp); vegetable oils such as soybean, sunflower, corn, olive, cotton, peanut oil, sunflower seed, palm, rapeseed; fatty acid esters of alkyl alcohols such as ethyl oleate and Glyceryl monooleate. Other hydrophobic materials suitable for use as lipophilic macrophage-forming materials include those described in Patel US Pat. No. 6,294,192 as “hydrophobic surfactants”. Specific types of hydrophobic materials include: fatty alcohols; polyoxyethylene alkyl ethers; fatty acids; glycerol fatty acid monoesters; glycerol fatty acid diesters; acetylated glycerol fatty acid monoesters; acetylated glycerol fatty acid diesters; Polyester glycol fatty acid ester; Polyethylene glycol glycerol fatty acid ester; Polypropylene glycol fatty acid ester; Polyoxyethylene glyceride; Lactic acid derivative of monoglyceride; Lactic acid derivative of diglyceride; Propylene glycol diglyceride; Sorbitan fatty acid ester; Ethylene-polyoxypropylene block copolymer; transesterified vegetable oil; Sterols; sterol derivatives; sugar esters; sugar ethers; scroglycerides; polyoxyoxyethylene vegetable oils, polyoxyethylene hydrogenated vegetable oils; reaction products of polyols and at least of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils and sterols One; and combinations thereof. A mixture of a relatively hydrophilic material, such as a material referred to herein as "Amphiphilic" or a material referred to as Patel's "Hydrophilic Surfactant", and a hydrophobic material as described above, Particularly preferred. Specifically, the hydrophobic and hydrophilic surfactant mixtures disclosed by Patel are suitable and preferred for many compositions. However, unlike Patel, mixtures containing triglycerides as a hydrophobic component are also suitable.

In one embodiment, the lipophilic macrophage-forming material is a polyglycolized glyceride (GELUCIRE); polyethylene (40 or 60) hydrogenated castor oil (available from BASF as CREMOPHOR® RH40 and RH60); Oxyethylene (35) castor oil (CREMOPHOR® EL); polyethylene (60) hydrogenated castor oil (Nikkol HCO-60); α-tocopheryl polyethylene glycol 1000 succinic acid (Vitamin E TPGS); glyceryl PEG 8 capryl Acid ester / caprate (commercially available from Gattefosse as LABRASOL®); glyceryl PEG 32 laurate (commercially available from Gattefosse as GELUCIRE 44/14); polyoxyethylene fatty acid ester (registered trademark MYRJ from ICI) (Commercially available); polyoxyethylene fatty acid ether (commercially available from ICI under the registered trademark BRIJ); polyoxyethylene-polypropylene Pyrene block copolymer (PLURONIC, LUTROL); Polyoxyethylene alkyl ether (CREMOPHOR A, BRIJ); Long chain fatty alcohol (stearyl alcohol, cetyl alcohol, cetostearyl alcohol); Long chain fatty acid (stearic acid); Polyoxyethylene 6 anion Oil, available from Gattefosse as Labrafil® M 1944 CS; Polyoxyethylene corn oil, commercially available as Labrafil® M 2125; Propylene glycol monolaurate, commercially available from Gattefosse as Lauroglycol ; Polyglyceryl oleate, commercially available from Gattefosse as Plurol oleique; Triglycerides including medium chain triglycerides (MCT, C ₆ -C ₁₂ ) and long chain triglycerides (LCT, C ₁₄ -C ₂₀ ); , Miglyol (TM) 810 (68% C ₈ and 28% C _10), Neobee (R) M5, Captex (R 300, Captex® 355, and Crodamol® GTCC; (Miglyols supplied by Condea Vista Inc. (HuIs), Neobee® supplied by Stepan Europe, Voreppe, France, Captex supplied by Abitec Corp Supply, Crodamol is supplied by Croda Corp); vegetable oils such as soybean, sunflower, corn, olive, cotton, peanut oil, sunflower, palm, rapeseed; polyoxyethylene alkyl ether; fatty acid; lower alcohol fatty acid ester; polyethylene glycol fatty acid ester Polyethylene glycol glycerol fatty acid ester; polypropylene glycol fatty ester; polyoxyethylene glyceride; lactic acid derivative of monoglyceride; lactic acid derivative of diglyceride; propylene glycol diglyceride ;; transesterified vegetable oil; sterol; sterol derivative; Scroglycerides; polyoxyoxyethylene vegetable oils, polyoxyethylene hydrogenated vegetable oils; reaction products of polyols and at least one of the group consisting of fatty acids, glycerides, vegetable oils, hydrogenated vegetable oils and sterols; and combinations thereof Selected from the group of

  Particularly preferred lipophilic macrophage-forming materials are mixtures of polyethoxylated castor oil and medium chain glyceryl mono-, di- and / or tri-alkylates (eg, mixtures of CREMOPHOR RH40 and CAPMUL MCM), polyoxyethylene Mixtures of sorbitan fatty acid esters with medium chain glyceryl mono-, di- and / or tri-alkylates (e.g. mixtures of TWEEN 80 and CAPMUL MCM), polyethoxylated castor oil and medium chain glyceryl glyceryl mono-, di- and And / or a mixture with a tri-alkylate (eg, a mixture of CREMOPHOR RH40 and ARLACEL 20), a mixture of sodium taurocholate with palmitoyl-2-oleyl-sn-glycero-3-phosphocholine and other natural or synthetic phosphatidylcholines, And mixtures of polyglycolized glycerides with medium chain glyceryl mono-, di- and / or tri-alkylates (eg If, comprising a mixture) of Gelucire 44/14 and CAPMUL MCM.

  Another drug solubility-improved form is a semi-ordered drug, for example, US Provisional Application No. 60 / 403,087 by the same applicant filed on August 12, 2002, which is incorporated herein by reference. The drug disclosed in (1).

Several methods, such as in vitro dissolution tests or membrane permeability tests, can be used to determine whether a drug is in a solubility-improved form and the degree of solubility improvement. In vitro dissolution tests add drug solubility-improved forms to dissolution test media such as model fasted duodenum (MFD) solution, phosphate buffered saline (PBS) solution, simulated intestinal buffer solution, or distilled water, And it can be achieved by stirring to promote dissolution. A suitable PBS solution is an aqueous solution containing 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. A suitable MFD solution is the same PBS solution in which 7.3 mM sodium taurocholate and 1.4 mM 1-palmitryl-2-oleyl-sn-glycero-3-phosphocholine are also present. A suitable simulated intestinal buffer solution is 50 mM NaH ₂ PO ₄ and 2 wt% sodium lauryl sulfate. Distilled water is a preferred dissolution medium for some rapidly precipitated salts. In the case of drug solubility-improved forms, when a neutral buffer solution (pH 6-8) is used, the solubility-improved form is the lowest energy form of the drug, typically the neutral crystalline form, It is usually observed to convert rapidly. In such a case, it is preferable to use a non-buffered test medium such as distilled water as the dissolution medium.

  One method for assessing whether a form is a solubility-improved form is that the drug has a solubility-improved form of at least one, preferably two or less when tested in an in vitro dissolution test. Satisfy the condition of The first condition is that the solubility-improved form provides a higher drug maximum dissolved drug concentration (MDC) in an in vitro dissolution test compared to a control composition consisting of the lowest soluble crystalline form of the drug. It is. That is, as soon as the solubility-improved form is introduced into the use environment, the solubility-improved form provides a higher concentration of dissolved drug solution compared to the control composition. The control composition is the bulk crystalline form of the drug alone, with the least solubility. Preferably, the solubility-improved form provides drug MDC in solution at least 1.25-fold, more preferably at least 2-fold, and most preferably at least 3-fold that of the control composition. For example, if the MDC provided by the test composition is 22 μg / ml and the MDC provided by the control composition is 2 μg / ml, the solubility-improved form is that provided by the control composition Provides 11-times MDC.

  The second condition is that the solubility-improved form has a higher dissolution area under the dissolved drug concentration versus time curve (AUC) in the in vitro dissolution test compared to a control composition consisting only of an equivalent amount of drug. provide. More specifically, in an in vitro use environment, the solubility-improved form can be any 0 to about 270 minutes after introduction into the use environment of at least 1.25-fold the AUC of the control composition described above. Provides 90-minute AUC. Preferably, the AUC provided by the composition is at least 2-fold, more preferably at least 3-fold that of the control composition.

  In vitro tests to assess increased drug concentration in aqueous solution are: (1) While stirring a sufficient amount of the lowest soluble crystalline drug-only control composition, in vitro test media such as distilled water or MFD, Add to PBS or simulated intestinal buffer solution to achieve the equilibrium concentration of the drug; (2) If all the drug is dissolved, the theoretical concentration of the drug should be at least the equilibrium concentration provided by the control composition In a separate test, a sufficient amount of the test composition (eg, solubility-improved form) in the same test medium is added with stirring so that a factor of 2, preferably at least 10, is exceeded; and (3) Measurement of the test composition in the test medium can be carried out by comparing the MDC and / or water soluble AUC with the equilibrium concentration and / or the water soluble AUC of the control composition. To perform such a dissolution test, the amount of test or control composition used is such that if all of the drug is dissolved, the drug concentration is at least 2-fold, preferably at least 10- The amount is such that it is doubled, most preferably at least 100-fold.

  The dissolved drug concentration is typically measured as a function of time by taking a test medium and plotting the drug concentration in the test medium versus time to determine the MDC. MDC is the highest dissolved drug measured over the test period. Water-soluble AUC is between the time of introduction of the composition into the water-soluble use environment (when the time is zero) and 270 minutes after introduction into the water-soluble use environment (when the time is 270 minutes). Calculated by integrating any 90-minute concentration versus time curve. Typically, if the composition approaches MDC rapidly (within less than about 30 minutes), the time interval used to calculate AUC is from a time equal to zero to a time equal to 30 minutes. is there. However, a drug is considered to be a solubility-improved form if the AUC of the composition at any of the above 90-minutes meets the criteria of the present invention. To suppress large drug particles that would give false decisions, the test solution is filtered or separated. “Dissolved drug” is typically obtained either as material that passes through a 0.45 μm syringe filter or as material that remains in the supernatant after centrifugation. Filtration can be performed using a 13 mm, 0.45 μm polyvinylidene difluoro syringe filter marketed by Scientific Resources as TITAN®. Centrifugation is typically performed in polypropylene microcentrifuge tubes by centrifuging at 13,000 G for 60 seconds. Other similar filtration or centrifugation methods can be employed with useful results. For example, using other types of microfilters gives somewhat higher or lower values (± 10-40%) than those obtained with the specific filter above, but still allows the identification of preferred solubility-improved forms will do. This definition of “dissolved drug” is not only for monomeric solvated drug molecules but also for a wide range of species, for example, polymer / drug aggregates with submicron size, such as drug aggregates, polymers and drugs, micelles , Polymer micelles, aggregates of mixtures with colloidal particles or nanocrystals, polymer / drug complexes, and other such drug-containing species present in the filtrate or supernatant in certain degradation tests.

  Another method for assessing whether a drug form is a solubility-improved form is to measure the dissolution rate of the solubility-improved form and compare it with the dissolution rate of the lowest soluble bulk crystal form of the drug Is done. The dissolution rate can be tested in any suitable dissolution medium such as PBS solution, MFD solution, simulated intestinal buffer solution or distilled water. Distilled water is a preferred dissolution medium for salt forms that cause rapid precipitation. The dissolution rate of the solubility-improved form is higher than the dissolution rate of the lowest drug dissolved form in its bulk crystal form. Preferably, the dissolution rate is 1.25-fold the lowest dissolution form of the drug, more preferably at least 2-fold, and even more preferably at least 3-fold the lowest dissolution form of the drug.

  Alternatively, an in vitro membrane-permeability test can be used to determine whether a drug is a solubility-improved form. In this test, the solubility-improved form is placed in an aqueous solution, dissolved in the aqueous solution, suspended or delivered to the aqueous solution to form a feed solution. The aqueous solution may be any of the physiologically relevant solutions described above, such as MFD or PBS or simulated intestinal buffer solution. After forming the feed solution, the solution may be stirred to dissolve or disperse the solubility-improved form, or may be added immediately to the feed solution reservoir. Alternatively, the feed solution may be prepared immediately in the feed solution reservoir. After administration of the solubility-improved form prior to performing the membrane-permeability test, the feed solution is preferably not filtered or centrifuged.

  The feed solution is then placed in contact with the feed-side surface of the microporous membrane, the feed-side surface of the microporous membrane being hydrophilic. The portion of the membrane pore that is not hydrophilic is filled with an organic fluid, such as decanol and decane, and the permeable side of the membrane is in communication with a permeable solution containing the organic fluid. The feed solution and organic fluid are in contact with the microporous membrane during the test period. The length of the test may be from minutes to hours or days.

  The rate of drug transfer from the feed solution to the permeable solution is determined by measuring the drug concentration in the organic fluid in the permeable solution as a function of time, or by measuring the drug concentration in the feed solution as a function of time, or Determined by measuring both. This includes ultraviolet / visible (UV / Vis) spectroscopy, high performance liquid chromatography (HPLC), gas chromatography (GC), nuclear magnetic resonance (NMR), infrared (IR) spectroscopy, polarization, specific gravity and refractive index. Can be achieved by methods well known in the art, including the use of The drug concentration in the organic fluid can be determined by taking the organic fluid at different time points and analyzing the drug concentration or continuously analyzing the drug concentration in the organic fluid. For continuous analysis, UV / Vis probes are used as flow-through cells. In all cases, the drug concentration in the organic fluid is determined by comparing the results against a set of standards that are well known in the art.

  From these data, the maximum membrane permeation flux of the drug across the membrane is calculated by multiplying the maximum slope of the drug concentration in the permeation solution vs. time plot by the permeate volume and dividing by the membrane area. . This maximum slope is typically determined during the first 10-90 minutes of the test, and the drug concentration in the permeable solution usually increases at an almost constant rate after a short time lag of a few minutes. At longer times, the slope of the concentration vs. time plot decreases as more drug is removed from the feed solution. In general, as the driving force for drug transport across the membrane approaches zero, the slope becomes zero; that is, the drugs in the two phases approach equilibrium. Maximum membrane permeation flux is determined from the linear portion of the concentration versus time plot or estimated from the tangent of the concentration versus time plot at the point where the slope has the highest value when the curve is non-linear . Further details of this membrane-permeability test are pending in the name of “Method and Device for Evaluation of Pharmaceutical Compositions”, filed March 30, 2004 (Docket PC25968), incorporated by reference. U.S. Patent Application No. 60 / 557,897.

  A typical in vitro membrane-permeability test to assess solubility-improved drug forms is: (1) If all drugs are dissolved, the theoretical concentration of the drug is the equilibrium concentration, a factor of at least 2. Add a sufficient amount of test composition (ie, drug solubility-improved form) to exceed; (2) In a separate test, equal amount of control composition (ie, minimum drug solubility) (3) whether or not the maximum membrane permeation flux measured for the drug provided by the test composition is at least 1.25-fold that provided by the control composition Is performed by determining. When providing a maximum membrane permeation flux of the drug in the above test, which is at least about 1.25-times the maximum membrane permeation flux provided by the control composition when dosed in an aqueous use environment Things are a solubility-improved form. Preferably, the maximum membrane permeation flux provided by the composition is at least about 1.5-fold, more preferably at least about 2-fold, and even more preferably at least about 3-fold that provided by the control composition. It is.

The sustained release core dosage form comprises a sustained release core comprising a low-solubility drug. The core is large enough to be maintained in the stomach to delay the elimination of the dosage form from the stomach, thus providing a delayed release of the drug. Preferably, the dosage form is large enough to provide a delay of at least 1 hour, more preferably a delay of 2 to 6 hours or longer. When large, non-destructive or soluble dosage forms are administered in the fed state, gastric retention times range from about 2 to 8 hours. Stomach retention is related to the size and mass of the dosage form. In one embodiment, the dosage form has a longest length of at least 5 mm, more preferably at least 7 mm and even more preferably at least 10 mm. For example, a tablet having a height of 5 mm and a diameter of 10 mm will have a longest length of 10 mm. In another embodiment, the enteric coated sustained release core has a mass of at least about 400 mg. That is, comprehensively, the core and enteric coating have a total mass greater than 400 mg. As long as the resulting dosage form can be conveniently swallowed, the enteric coated sustained release core may be larger. Thus, the enteric coated sustained release core may be at least about 500 mg, or even at least about 600 mg. In addition, the dosage form swells by absorbing water during consumption, resulting in an increase in size and further promotion of retention in the stomach.

  The sustained release core releases the drug over a long period of time that coincides with the period of time that the drug is absorbed in the lower gastrointestinal tract. When the drug is well absorbed in the small intestine but rarely absorbed in the colon, the sustained release core delivers more than 90% by weight of the drug over a release period of about 1-6 hours and more preferably about 1-4 hours. discharge. For drugs that are well absorbed in the small intestine and colon when in solubility-improved form, the release period is about 1-8 hours. “Release period” means the time required for the drug to be released from the core within the intestinal use environment as soon as the enteric coating is dissolved.

In vitro testing can be used to determine whether a dosage form has a release period within the scope of the present invention. In vitro testing is well known in the art. An example is the “residual test” and is shown below for sertraline hydrochloride. The dosage form is 900 mL of a stirred USP type 2 Dissoette containing a buffer solution imitating the contents of the small intestine (6 mM KH ₂ PO ₄ , 64 mM KCl, 35 mM NaCl, pH 7.2, 210 mOsm / kg). Place in flask. The dosage form is placed in a wire support that keeps the dosage form close to the bottom of the flask so that all of the surface is exposed to the moving release solution and the solution is stirred using a paddle rotating at a speed of 50 rpm. Put in. At each time interval, the single dosage form is removed from the solution, the released material is removed from the surface, the dosage form is cut in half, and 100 mL of recovery solution ((1: 1 ethanol: water, 0.1 N HCl Adjust the pH to 3) and stir vigorously overnight at ambient temperature to dissolve any remaining drug in the dosage form.A sample of the recovered solution containing the dissolved drug can be added to the Gelman Nylon® ) Filter using Acrodisc® 13, 0.45 μm pore size filter, place in vial, cap, and analyze remaining drug by HPLC.Drug concentration determines sample UV absorption as absorption of drug standard The amount remaining in the tablet is subtracted from the total drug to obtain the amount released at each time interval.

  An alternative in vitro test is a direct test and is described below for sertraline hydrochloride. A sample of the dosage form is placed in a stirred USP Type 2 Dissoette flask containing 900 mL of a receiving solution such as USP sodium acetate buffer (27 mM acetic acid and 36 mM sodium acetate, pH 4.5) or 88 mM NaCl. Samples are taken at regular intervals using a VanKel VK8000 autosampling Dissoette with automatic solution exchange. The tablet is placed in the wire support described above, the paddle height is adjusted, and the Dissoette flask is stirred at 37 ° C., 50 rpm. An automatic sampler Dissoette machine is programmed to periodically remove the sample of the receiving solution and the drug concentration is analyzed by HPLC using the method described above.

  The sustained release core can be any solid dosage form core that can be administered as a large core and coated with an enteric coating. Specific cores are matrix devices, permeable cores and capsules.

Matrix equipment
In one embodiment, the sustained release core is a matrix device in which the drug is incorporated into a destructive or non-destructive polymeric matrix. By destructive matrix is meant purely destructive, swellable or soluble, meaning that it requires the presence of sufficient acid or base to ionize the polymeric matrix sufficient to cause destruction or dissolution. It means water-soluble-destructible or water-swellable or water-soluble. When contacted with a water-soluble use environment, the destructible polymeric matrix absorbs water and forms a water-soluble-swelling gel or “matrix” that encloses the drug. The water-soluble-swelling matrix gradually breaks, swells, disintegrates or dissolves in the environment of use. As a result, the release of the drug to the use environment can be controlled. Examples of such dosage forms are well known in the art. See, for example, Remington: The Science and Practice of Pharmacy, 20th edition, 2000. An example of such a dosage form is pending US patent application Ser. No. 09 / 495,059 filed Jan. 31, 2000, filed Jan. 31, 2000, claiming the benefit of provisional application No. 60 / 119,400 filed Feb. 10, 1999. It is also disclosed in the issue. The related disclosure is incorporated herein by reference. Other examples are disclosed in US Pat. No. 4,839,177 and US Pat. No. 5,484,608, which are incorporated herein by reference.

  The destructive polymeric matrix into which the drug is incorporated is generally mixed with the drug that absorbs water when in contact with a water-soluble use environment and forms a water-swellable gel or “matrix” that encloses the drug Can be described as a set of excipients. Drug release occurs by a variety of mechanisms: the matrix disintegrates or dissolves from the particles or granules of the drug; or the drug dissolves in the absorbed aqueous solution and diffuses from the tablet, beads or granules of the dosage form . An important component of this water-swelling matrix is a water-swellable, destructible or soluble polymer and can generally be described as a permeable polymer, a hydrogel or a water-swellable polymer. Such polymers may be linear, branched or cross-linked. They may be homopolymers or copolymers. They may be synthetic polymers obtained from vinyl, acrylate, methacrylate, urethane, ester and oxide monomers, but natural polymer derivatives such as polysaccharides or proteins are most preferred. Examples of materials include hydrophilic vinylic and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG). Examples of natural polymers are natural polysaccharides such as chitin, chitosan, dextran, and pullulan; agar gum, gum arabic, caraya gum, locust bean gum, tragacanth gum, carrageenan, gati gum, guar gum, xanthone and scleroglucan; starch such as dextrin and malto Dextrins; hydrophilic colloids such as pectin; phosphatides such as lecithin; alginates such as ammonium alginate, sodium, potassium or calcium alginate, propylene glycol alginate; gelatin; collagen; and cellulose derivatives. “Cellulose derivative” means a cellulosic polymer that is modified by reaction of at least a portion of the hydroxyl groups on the saccharide repeat unit with a compound to form an ester-linked or ether-linked substituent. For example, the cellulose derivative, ethylcellulose, has an ether-bonded ethyl substituent bonded to a saccharide repeat unit, while the cellulose derivative, cellulose acetate, has an ester-linked acetate ester substituent.

  Preferred types of cellulose derivatives for the destructible matrix are water-soluble and water-destructible cellulose derivatives such as ethyl cellulose (EC), methyl ethyl cellulose (MEC), carboxymethyl cellulose (CMC), carboxymethyl ethyl cellulose (CMEC), hydroxyethyl cellulose (HEC), hydroxypropylcellulose (HPC), cellulose acetate (CA), cellulose propionate (CPr), cellulose butyrate (CB), cellulose acetate butyrate (CAB), cellulose acetate phthalate (CAP), cellulose acetate trimellitic acid (CAT), hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylmethylcellulose acetate trimellitate (HPMCAT) Fine ethyl hydroxyethyl cellulose containing (EHEC). Particularly preferred types of such cellulose derivatives include various degrees of low viscosity (MW less than 50,000 daltons) and high viscosity (MW greater than 50,000 daltons MW) HPMC. Commercially available low viscosity HPMC polymers include Dow METHOCEL series E5, E15LV, E50LV and K100LY; whereas high viscosity HPMC polymers include E4MCR, E10MCR, K4M, K15M and K100M; particularly preferred in this group The thing is the METHOCEL® K series. Another commercially available HPMC type is the Shin Etsu METOLOSE 90SH series.

  Although the main role of the destructive matrix material is to control the rate of drug release to the environment of use, the inventors have determined that the choice of matrix material is the highest drug concentration and the high drug concentration that can be obtained by the dosage form. It can have a great effect on maintenance. In one embodiment, the matrix material is a precipitation-inhibiting polymer as defined herein.

  Other materials useful as the destructive matrix material include, but are not limited to, pullulan, polyvinylpyrrolidone polyvinyl alcohol, polyvinyl acetic acid, glycerol fatty acid esters, polyacrylamide, polyacrylic acid, ethacrylic acid or methacrylic acid copolymers (EUDRAGIT® ), Rohm America, Inc., Piscataway, New Jersey), and other acrylic acid derivatives such as butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate and (trimethylaminoethyl) methacrylate chloride Homopolymers and copolymers of

  Destructive matrix polymers are a wide range of additives and additives known in the pharmaceutical art, including permeable polymers, osmagen, solubility-increasing or inhibiting agents and excipients that facilitate dosage form stability or processing. A form may also be included.

  Alternatively, the matrix device may be a non-destructive matrix dosage form. In such dosage forms, the drug is distributed within an inert matrix. The drug is released by diffusion through an inert matrix. Examples of suitable materials for the inert matrix include insoluble plastics such as methyl acrylate-methyl methacrylate copolymers, polyvinyl chloride and polyethylene; hydrophilic polymers such as ethyl cellulose, cellulose acetate and crosslinked polyvinyl pyrrolidone (also known as crospovidone); and Including aliphatic compounds such as carnauba wax, microcrystalline wax and triglycerides. Such dosage forms are further described in Remington: The Science and Practice of Pharmacy, 20th Edition (2000).

  Matrix devices can be prepared by mixing drugs and other excipients together and then forming tablets, caplets, pills, or other dosage forms formed by compressive forces. Such compressed dosage forms can be formed using any of a wide variety of compressors used in the manufacture of pharmaceutical dosage forms. Examples include single-drillers, rotary tablet presses and multi-layer rotary tablet presses, all well known in the art. See, for example, Remington: The Science and Practice of Pharmacy, 20th edition, 2000. The compressed dosage form may be any shape including circular, oval, rectangular, cylindrical or triangular. The upper and lower surfaces of the compressed dosage form may be flat, circular, concave or convex.

When formed by compression, the matrix device preferably has a “strength” of at least 5 kilopounds (kp) / cm ² and more preferably at least 7 kp / cm ² . Here, “strength” is the faction force required to crush a tablet formed from a material, also known as tablet “hardness”, and is average to the crushing force. It is the value divided by the maximum tablet cross-sectional area. The crushing force can be measured using a Schleuniger Tablet Hardness Tester, Model 6D. The compression force required to achieve this strength will depend on the tablet size, but is generally greater than about 5 kp. Friability is a well-known indicator of dosage form resistance to surface wear, which measures the percentage weight loss after subjecting the dosage form to a standardized agitation method. A crush value of 0.8-1.0% is considered to constitute an acceptable upper limit. A dosage form having a strength greater than about 5 kp / cm ² is very robust and generally has a friability of less than about 0.5%.

  Other methods of forming matrix devices are well known in the pharmaceutical art. See, for example, Remington: The Science and Practice of Pharmacy, 20th edition, 2000.

The osmotic core or drug can be incorporated into the osmotic sustained release core. Such an osmotic sustained release core has at least two components: (a) an inner core comprising an osmotic agent and a drug; and (b)
The water-permeable, non-dissolvable and non-friable coating around the inner core, where the coating is such that drug release occurs by draining part or all of the inner core to the environment of use. Control water inflow from the water-soluble environment into the inner core. The osmotic agent contained within the osmotic sustained release core may be a water soluble-swellable hydrophilic polymer or an osmogen, also known as an osmagent. The coating is preferably polymeric, water-soluble and permeable and has at least one delivery port. Examples of such cores are well known in the art. See, for example, Remington: The Science and Practice of Pharmacy, 20th Edition, 2000. Examples of such osmotic sustained release cores are also disclosed in US Pat. No. 6,706,283, which is incorporated herein by reference.

  In addition to the drug, the interior of the osmotic sustained release core optionally includes an “osmotic agent”. By “osmotic agent” is meant any agent that creates a driving force for the transport of water from the environment of use to the inner core. A specific penetrant is a water-swellable hydrophilic polymer, which is osmogen (or osmogen). Thus, the inner core may include water-swellable hydrophilic polymers that are ionic and non-ionic, commonly referred to as “osmopolymers” and “hydrogels”. The amount of water-swellable hydrophilic polymer present in the inner core may range from about 5 to 80% by weight, preferably 10 to 50% by weight. Specific materials include hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly (2-hydroxyethyl ethacrylate), poly (acrylic) ) Acid, poly (methacrylic acid), polyvinylpyrrolidone (PVP) and cross-linked PVP, polyvinyl alcohol (PVA), PVA / PVP copolymer and PVA / PVP copolymer with hydrophobic monomers such as methyl methacrylate, vinyl acetate, large PEO block Hydrophilic polyurethane containing croscarmellose sodium, carrageenan, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC) and carboxyethylcellulose (CEC), sodium alginate Contains lithium, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate. Other materials include hydrogels that include an interpenetrating network of polymers that can be formed by addition or condensation polymerization, the components of which may include hydrophilic and hydrophobic monomers such as those described above. Preferred polymers for use as water-swellable hydrophilic polymers include PEO, PEG, PVP, croscarmellose sodium, HPMC, sodium starch glycolate, polyacrylic acid and cross-linked variants or combinations thereof.

  The inner core may include osmogen (or osmagent). The amount of osmogen present in the inner core may range from about 2 to about 70% by weight, preferably 10 to 50% by weight. Typical types of suitable osmogens are water-soluble organic acids, salts, and sugars that can absorb water, thus providing an osmotic gradient to the surrounding coating barrier. Typical useful osmogens are magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium carbonate, sodium sulfite, lithium sulfite, potassium chloride, sodium sulfate, mannitol, xylitol, urea, sorbitol, inositol , Raffinose, sucrose, glucose, fructose, lactose, citric acid, succinic acid, tartaric acid, and combinations thereof. Particularly preferred osmogens are glucose, lactose, sucrose, mannitol, xylitol and sodium chloride.

  The inner core may include a wide variety of additives and excipients that improve the performance of the inner core or promote stability, tableting or processing. Such additives and excipients include tableting aids, surfactants, water-soluble polymers, pH adjusters, fillers, binders, pigments, disintegrants, antioxidants, lubricants and fragrances. Examples of such ingredients are microcrystalline cellulose; metal salts of acids such as aluminum stearate, calcium stearate, magnesium stearate, sodium stearate and zinc stearate; pH adjusting agents such as buffers, organic acids and organic acid salts and organic Salts and inorganic salts; fatty acids, hydrocarbons and fatty alcohols such as stearic acid, palmitic acid, liquid paraffin, stearyl alcohol and palmitol; fatty acid esters such as glyceryl (mono- and di-) stearic acid, triglycerides, glyceryl (palmitistearic acid) ) Esters (glyceryl (palmiticstearic) ester), sorbitan esters such as sorbitan monostearic acid, saccharose monostearic acid, saccharose monopalmitic acid, and sodium stearyl fumarate; polyoxyethylene sol Surfactants such as alkyl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; polymers such as polyethylene glycol, polyoxyethylene glycol, polyoxyethylene and polyoxypropylene ethers and copolymers thereof, and polytetrafluoroethylene; and Inorganic materials such as talc and dicalcium phosphate; cyclodextrins; sugars such as lactose and xylitol; and sodium starch glycolate. Examples of disintegrants include sodium starch glycolate (eg Explotab ™), microcrystalline cellulose (eg Avicel ™), microcrystalline silica cellulose (eg ProSolv ™), croscarmellose sodium (eg Ac-Di-Sol (trademark)).

  One embodiment of an osmotic sustained release core consists of one or more drug layers comprising a drug, a swellable layer comprising a water-swellable polymer, and a coating surrounding the drug layer and the swellable layer. Each layer contains other excipients. For example, tableting aids, osmagents, surfactants, water-soluble polymers and water-swellable polymers may be included.

  Such osmotic sustained release cores can be made with a variety of geometries including two layers, the core including a drug layer and a swellable layer adjacent to each other; in three layers, the inner core is 2 Containing a swellable layer “sandwich” between two drug layers; concentrically, the inner core comprises a central swellable composition surrounded by a drug layer.

  Such tablet coatings include a water permeable membrane, but are substantially impermeable to the drug and include excipients therein. The coating includes one or more drainage passages or ports that communicate with the drug-containing layer (s) to deliver the composition. The inner drug-containing layer (s) comprise the drug composition (including any osmagent and hydrophilic water-soluble polymer), while the swellable layer consists of a swellable hydrogel and an additional penetrant Or not.

  When placed in an aqueous medium, the osmotic sustained release core absorbs water through a coating around the inner core. This causes the composition to form an unwanted aqueous composition and causes the hydrogel layer to expand and push the drug-containing composition, forcing the composition through the discharge passage. The composition can swell, which aids in extruding the drug from the passageway. The drug can be delivered from such type of delivery system dissolved or dispersed in the composition that is discharged from the discharge passage.

  The rate of drug delivery is controlled by factors such as the permeability and thickness of the coating, the osmotic pressure of the drug-containing layer, the degree of hydrophilicity of the hydrogel layer and the surface area of the inner core. One skilled in the art will see that increasing the coating thickness will decrease the release rate, while any of the following: increased coating permeability; increased hydrogel layer hydrophilicity; drug-containing layer osmotic pressure It will be appreciated that increasing; or increasing the surface area of the inner core will increase the rate of release.

  In addition to the drug, examples of materials effective to form a drug-containing composition include HPMC, PEO and PVP and other pharmaceutically acceptable carriers. In addition, osmagents such as sugars or salts, in particular sucrose, lactose, xylitol, mannitol or sodium chloride can also be added. Materials useful for forming hydrogel layers include sodium CMC, PEO, poly (acrylic acid), sodium (polyacrylic acid), croscarmellose sodium, sodium starch glycolate, PVP, cross-linked PVP, and other high It is a molecular weight hydrophilic material. PEO polymers having an average molecular weight of about 5,000,000 to about 7,500,000 daltons are particularly useful.

  In the case of a bilayer geometry, the delivery port (s) or drainage passage (s) may be located on the face of the tablet containing the drug composition, or on both sides of the sustained release core or even on the tablet. It may be on the edge. The discharge passage (s) can be produced by mechanical means or laser drilling, or by using a specific machine tool instrumentation equipment during tablet compression or by creating other areas that are difficult to coat on the tablets.

  Osmotic sustained release cores can also be made with a uniform inner core surrounded by a semipermeable membrane as described in US Pat. No. 3,845,770. The drug is incorporated into the inner core and the semipermeable membrane coating can be applied by conventional tablet-coating techniques, such as using a bread coater. Drug delivery passages can then be formed in this coating by drilling holes in the coating, either by laser or mechanical means. Alternatively, the passage can be formed by breaking apart a portion of the coating or by creating an area on the tablet that is difficult to coat.

  Particularly useful embodiments of the osmotic core include: (a) (i) a drug, (ii) hydroxyethylcellulose and (iii) osmagent, wherein hydroxyethylcellulose is about 2.0 wt% to about 35 wt% in the core. And a single layer-layer compressed inner core comprising: about 15% to about 70% by weight of the osmagent; At least one passage in the layer (b) for delivering the drug to the surrounding liquid environment. Such an inner core is disclosed in more detail in co-pending US patent application Ser. No. 10 / 352,283 entitled “Osmotic Delivery System”. This disclosure is incorporated herein by reference.

  Another example of an osmotic core is an osmotic capsule. The capsule shell or part of the capsule shell may be semi-permeable. Capsules can be filled with either powders or liquids consisting of drugs, water-absorbing excipients and / or water-swellable polymers, or optionally soluble excipients . Capsule cores can also be made to have a bilayer composition or a multi-layer composition similar to the bilayer, trilayer or concentric geometry described above.

  Another type of osmotic sustained release core useful in the present invention is described in EP 378 404, which is incorporated herein by reference. Coated swellable tablets comprise a tablet inner core comprising a solubility-improved form of the drug and a swellable material, preferably a hydrophilic polymer. This includes holes or holes that are coated with a membrane through which the hydrophilic polymer extrudes and carries the drug composition in a water-soluble use environment. Alternatively, the membrane may comprise a polymeric or low molecular weight water-soluble “porosigen”. Porosigen dissolves in a water-soluble environment of use and provides pores through which the hydrophilic polymer and drug are extruded. Examples of porosigens are water-soluble polymers such as HPMC, PEG and low molecular weight compounds such as glycerol, sucrose, glucose and sodium chloride. In addition, holes can be formed in the coating by drilling holes in the coating using laser, mechanical means, or other means. For this type of osmotic sustained release core, the coating material may comprise any film-forming polymer, including polymers that are water permeable or impermeable. As a result, the membrane placed on the tablet core is porous or contains water-soluble prosigen, or has macroscopic holes for water entry and drug release. Embodiments of this type of sustained release core may be multilayered as described in EP 378 404 A2.

  The osmotic sustained release core of the present invention also includes a coating. The inherent limitation with respect to coatings for osmotic sustained release cores that are water-permeable is that the drug is substantially delivered via the delivery port (s) Has at least one port for drug delivery to be delivered through the pores and is non-dissolvable and non-friable during release of the drug formulation. “Delivery port” means any passage, which is open or a hole, mechanically, by laser drilling, by hole formation either during the coating process or as it is in use, or Created by rupture in use. The coating should be present in an amount in the range of about 5-30% by weight, preferably 10-20% by weight, based on the core weight.

  A preferred form of coating is a semi-permeable polymeric membrane having ports (s) formed there either before or during use. The thickness of such polymeric membranes may vary in the range of about 20-800 μm, preferably 100-500 μm. The delivery port (s) generally have a diameter in the range of 0.1 to 3000 μm or more, preferably in the order of 50 to 3000 μm. Such ports are formed after coating by mechanical or laser drilling, or formed as is by rupture of the coating; such rupture is by deliberately placing a relatively small weak part in the coating. Can be controlled. The delivery port may be formed as such by erosion of the plug of water soluble material or by rupturing a thinner portion of the coating over the recess in the core. In addition, the delivery port can be used during coating as in the case of asymmetric membrane coatings of the type disclosed in U.S. Patent Nos. 5,612,059 and 5,698,220, which are incorporated herein by reference. It can also be formed.

  In the case where the delivery port is formed as is by rupture of the coating, a particularly preferred embodiment is an aggregate of beads that are essentially the same or variable composition. The drug is mainly released from such beads after the rupture of the coating, and after rupture, such release occurs gradually or relatively suddenly. If the bead population has a composition that is susceptible to change, the composition is selected such that the beads burst at various times after administration. The result is an overall release of drug that lasts for a desired period of time.

  The coating may be dense, microporous or “asymmetric” and has a dense pore region, eg, a dense region supported by the pore regions disclosed in US Pat. Nos. 5,612,059 and 5,698,220. If the coating is dense, the coating consists of a water-permeable material. If the coating is porous, it consists of either a water-permeable or water-impermeable material. If the coating consists of a porous water-impermeable material, the water penetrates the pores of the coating as either liquid or gas.

  Examples of permeable cores that utilize a dense coating include US Pat. Nos. 3,995,631 and 3,845,770. This disclosure relating to dense coatings is incorporated herein by reference. Such dense coatings are permeable to external liquids such as water and may be composed of any material described in these patents, and other water-permeable polymers known in the art.

  The membrane may be porous as disclosed in US Pat. Nos. 5,654,005 and 5,458,887, or may be formed from a water-resistant polymer. US Pat. No. 5,120,548 describes another suitable process for forming a coating from a mixture of a water-insoluble polymer and a leachable water-soluble additive. The related disclosure is incorporated herein by reference. The porous membrane can also be formed by the addition of a pore-forming agent as disclosed in US Pat. No. 4,612,008. The related disclosure is incorporated herein by reference.

  In addition, the gas-permeable coating can be formed from extremely hydrophobic materials such as polyethylene or polyvinylidene difluoride. Such hydrophobic materials, when dense, are essentially water-impermeable as long as such coatings are porous.

  Materials useful for forming coatings are a variety of materials that are water-permeable and water-insoluble at physiologically relevant pH, or are susceptible to water-insolubility due to chemical changes such as cross-linking. Grade acrylic, vinyl, ether, polyamide, polyester and cellulose derivatives.

  Specific examples of suitable polymers (or crosslinked variants) useful for forming coatings are plastic and non-plastic and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, propion CA, nitric acid CA, cellulose butyrate acetate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, succinic acid CA, trimellitic acid cellulose acetate (CAT), dimethylaminoacetic acid CA, CA ethyl carbonate, chloroacetic acid CA, ethyl oxalic acid CA, Methylsulfonic acid CA, butylsulfonic acid CA, p-toluenesulfonic acid CA, agar acetate, amylose triacetate, β-glucan acetate, β-glucan triacetate, acetaldehyde dimethylacetate, triacetic acid of locust bean gum, hydroxylated and ethylene-acetic acid Vinyl, EC, PEG, PPG, PEG / PPG copolymer, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPM CAT, poly (acrylic acid) and esters and poly- (methacrylic acid) and esters and copolymers thereof, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkene, polyether, polysulfone, polyethersulfone, polystyrene, polyvinyl halide, Polyvinyl esters and ethers, natural waxes and synthetic waxes.

  Preferred coating compositions comprise cellulosic polymers, in particular cellulose ethers, cellulose esters and cellulose ester-ethers, ie cellulose derivatives having a mixture of ester and ether substituents.

  Another preferred type of coating material is poly (acrylic acid) and esters, poly (methacrylic acid) and esters, and copolymers thereof.

  A more preferred coating composition comprises cellulose acetate. Even more preferred coatings comprise cellulosic polymers and PEG. The most preferred coating comprises cellulose acetate and PEG.

  Coating was done by a common method, typically by dissolving or suspending the coating material in a solvent and then coating by dipping, spray coating or preferably pan-coating. Preferred coating solutions contain 5-15% by weight polymer. Typical solvents useful for the above cellulosic polymers are acetone, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, Includes methylene dichloride, ethylene dichloride, propylene dichloride, nitroethane, nitropropane, tetrachloroethane, 1,4-dioxane, tetrahydrofuran, diglyme, water and combinations thereof. The pore-forming agent and non-solvent (eg, water, glycerol and ethanol) or plasticizer (eg, diethyl phthalate) may be added in any amount that allows the polymer to remain soluble at the spray temperature. Pore-forming agents and their use in forming coatings are described in US Pat. No. 5,612,059, the related disclosures of which are hereby incorporated by reference. The coating may be a hydrophilic microporous layer. Here, the pores are substantially filled with air and are not wet by the aqueous medium but are permeable to water vapor. This is disclosed in US Pat. No. 5,798,119, the disclosure of which is hereby incorporated by reference. Such hydrophobic but water vapor permeable coatings are typically hydrophobic polymers such as polyalkenes, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrene, polyvinyl halides, polyvinyl esters and ethers, natural It consists of wax and synthetic wax. Particularly preferred hydrophobic microporous coating materials include polystyrene, polysulfone, polyethersulfone, polyethylene, polypropylene, polyvinyl chloride, polyvinyl fluoride and polytetrafluoroethylene. Such hydrophobic coatings are made by air quenching, liquid quenching, heat treatment, known phase transformations using leaching of soluble material from the coating, or by sintering the coated particles. In heat treatment, the latent solvent polymer solution reaches the liquid-liquid phase during the cooling phase. If evaporation of the solvent is unavoidable, the resulting membrane is typically porous. Such a coating process can be carried out by the processes disclosed in US Pat. Nos. 4,247,498; 4,490,431 and 4,744,906, which are also incorporated herein by reference.

  The osmotic sustained release core can be prepared using methods known in the pharmaceutical field. See, for example, Remington: The Science and Practice of Pharmacy, 20th edition, 2000.

Capsules In yet another embodiment, the sustained release core may comprise a sustained release capsule, such as an osmotic capsule. Osmotic capsules are made for the osmotic core using the same or similar components as described above. The capsule shell or a portion of the capsule shell is semi-permeable and made from the materials described above and may be a hard gelatin capsule or a soft gelatin capsule well known in the art (eg, Remington: The Science and Practice of Pharmacy, ( 20th edition, 2000)). The encapsulant may consist of several layers, for example an outer enteric layer and an inner semipermeable layer. Capsules are filled with either a low-solubility drug, an excipient that absorbs water to provide osmotic power, and / or a powder or liquid consisting of a water-swellable polymer, or optionally a soluble excipient Is done. Capsules can also be made to have a bilayer or multilayer composition similar to the bilayer, trilayer or concentric geometry described above. Sustained release capsules are further described in US Pat. Nos. 4,627,850, 5,324,280, and 5,413,572, which are incorporated herein by reference.

Precipitation-inhibiting polymer
In one embodiment, the dosage form comprises a precipitation-inhibiting polymer. Precipitation-inhibiting polymers suitable for use in the present invention must be inert in the sense that they do not chemically react with the drug in the opposite manner, and are pharmaceutically acceptable and physiologically relevant pHs. Have at least some solubility in aqueous solutions (eg, 1-8). The polymer may be neutral or ionic and should have a water-solubility of at least 0.1 mg / mL in at least part of the pH range of 1-8.

  Suitable precipitation-inhibiting polymers for use in the present invention may be cellulosic or non-cellulosic. The polymer may be neutral or ionic in aqueous solution. Of these, ionic and cellulose polymers are preferred, and ionic cellulose polymers are more preferred. Preferred types of precipitation-inhibiting polymers include those that are “amphiphilic” in nature, meaning that the polymer has hydrophobic and hydrophilic moieties. The hydrophobic moiety may include groups such as aliphatic or aromatic hydrocarbon groups. The hydrophilic moiety may comprise any ionic or non-ionic group capable of hydrogen bonding, such as hydroxyl, carboxylic acid, ester, amine or amide.

  One type of precipitation-inhibiting polymer suitable for use in the present invention comprises neutral non-cellulosic polymers. Specific polymers include: vinyl polymers and copolymers having hydroxyl, alkylacyloxy or cyclic amide substituents; polyvinyl alcohol having at least a portion of repeating units in a non-hydroxylated (vinyl acetate) form; polyvinyl alcohol polyvinyl acetate copolymer Polyvinylpyrrolidone; polyoxyethylene-polyoxypropylene copolymer, also known as poloxamer; and polyethylene polyvinyl alcohol copolymer.

  Another type of precipitation-inhibiting polymer suitable for use in the present invention includes ionic non-cellulosic polymers. Specific polymers include: Carboxylic acid-functionalized vinyl polymers such as carboxylic acid functionalized polymethacrylates and carboxylic acid functionalized polyacrylates such as EUDRAGITS® from Rohm Tech Inc. of Maiden, Massachusetts. Amine-functionalized polyacrylates and polymethacrylates; proteins; and carboxylic acid functionalized starches such as starch glycolate.

  Non-cellulosic polymers that are amphiphilic are copolymers of relatively hydrophilic and relatively hydrophobic monomers. Examples include acrylate and methacrylate copolymers, and polyoxyethylene-polyoxypropylene copolymers. Specific brand names of kacal polymers include EUDRAGITS, which is a copolymer of methacrylate and acrylate, and PLURONICS or LUTROLS, which are polyoxyethylene-polyoxypropylene copolymers supplied by BASF.

  Preferred types of precipitation-inhibiting polymers include ionic and neutral cellulosic polymers. The polymer has at least one ester- and / or ether bond substituent, and the polymer has a degree of substitution of at least 0.1 for each substituent.

  Note that in the polymer nomenclature used herein, the ether-linked substituent is located before “cellulose” as the moiety attached to the ether group; for example, “cellulose ethyl benzoate” is ethoxy benzoic acid. Has an acid substituent. Similarly, an ester-linked substituent is located after “cellulose” as a carboxylate; for example, “cellulose phthalate” includes one carboxylic acid of each phthalate moiety ester-linked to the polymer, and unreacted Has other carboxylic acids.

  It is further noted that the polymer name, eg, “cellulose acetate phthalate” (CAP), is an optional name for any cellulosic polymer having acetate and phthalate groups attached by ester linkages to a significant portion of the hydroxyl groups of the cellulosic polymer. Refers to a group. In general, the degree of substitution of each substituent may range from about 0.1 to 2.9 as long as the other criteria of the polymer are met. “Degree of substitution” refers to the average number of three hydroxyls per saccharide repeat unit on a substituted sugar chain. For example, if all of the hydroxyls on the cellulose chain are substituted phthalates, the degree of substitution of phthalates is 3. Each polymer group type also includes cellulosic polymers with additional substituents added in relatively small amounts that do not substantially alter the performance of the polymer.

  Amphiphilic cellulose derivatives include polymers in which the parent cellulosic polymer is substituted with at least a portion of the hydroxy groups present on the saccharide repeat unit of the polymer having at least one relatively hydrophobic substituent. . The hydrophobic substituent can be essentially any substituent that can give the cellulosic polymer essentially water insolubility when substituted with a high substitution level or degree of substitution. Examples of hydrophobic substituents are ether-linked alkyl groups such as methyl, ethyl, propyl, butyl and the like; or ester-linked alkyl groups such as acetate, propionate, butyrate and the like; and ether-and / or ester-linked Contains aryl groups such as phenyl, benzoate or phthalate. The hydrophilic region of the polymer can be a relatively unsubstituted moiety because the unsubstituted hydroxyl is itself relatively hydrophilic, or can be a region substituted with a hydrophilic substituent. Hydrophilic substituents include ether- or ester-linked nonionic groups such as hydroxyalkyl substituents hydroxyethyl, hydroxypropyl, and alkyl ether groups such as ethoxyethoxy or methoxyethoxy. Particularly preferred hydrophilic substituents are ether- or ester-linked ionic groups such as carboxylic acids, thiocarboxylic acids, substituted phenoxy groups, amines, phosphates or sulfonates.

  One type of cellulosic polymer includes a neutral polymer. Neutral polymer means substantially non-ionic in aqueous solution. Such polymers contain nonionic substituents that can be either ether-linked or ester-linked. Specific ether-linked non-ionic substitution bases include: alkyl groups such as methyl, ethyl, propyl, butyl and the like; hydroxyalkyl groups such as hydroxymethyl, hydroxyethyl, hydroxypropyl and the like; and aryl groups For example phenyl. Specific ester-linked non-ionic substitution bases include: alkyl groups such as acetate, propionate, butyrate and the like; and aryl groups such as phenylate. However, when aryl groups are included, the polymer is required to contain a sufficient amount of hydrophilic groups so that the polymer has at least some water solubility at any physiologically relevant pH of 1-8. The

  Specific non-ionic polymers that can be used as the polymer include: hydroxypropyl methylcellulose acetate, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxyethylmethylcellulose, hydroxyethylcellulose acetate, and hydroxyethylethylcellulose.

  A preferred group of neutral cellulosic polymers are amphiphilic polymers. Specific polymers include hydroxymethylcellulose and hydroxypropylmethylcellulose acetate, where cellulose repeat units having a relatively large number of methyl or acetate substituents compared to unsubstituted hydroxy or hydroxypropyl substituents are present on the polymer. It constitutes a hydrophobic region compared to other repeating units. Suitable neutral polymers for use in the present invention are described in more detail in co-pending US patent application Ser. No. 10 / 175,132 filed Jun. 18, 2002, which is hereby incorporated by reference. It is described in.

  A preferred type of cellulosic polymer that is at least partially ionic at physiologically relevant pH and that contains at least one ionic substituent may be an ether-bonded or ester-bonded offset. Specific ether-linked ionic substituents include: various isomers of carboxylic acids such as acetic acid, propionic acid, benzoic acid, salicylic acid, alkoxybenzoic acids such as ethoxybenzoic acid or propoxybenzoic acid, alkoxyphthalic acid Various isomers of isomers such as ethoxyphthalic acid and ethoxyisophthalic acid, alkoxynicotinic acid such as ethoxynicotinic acid, and picolinic acid such as ethoxypicolinic acid; thiocarboxylic acids such as thioacetic acid; substituted phenoxy groups Amines such as aminoethoxy, diethylaminoethoxy, trimethylaminoethoxy, etc .; phosphates such as ethoxyphosphate; and sulfonates such as ethoxysulfonate. Specific ester-linked ionic substituents include: carboxylic acids such as succinate, citrate, phthalate, terephthalate, isophthalate, trimellitate, and various isomers of pyridinedicarboxylic acid; thiocarboxylic acids such as thiosuccinic acid esters; Substituted phenoxy groups such as aminosalicylic 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. In order for the aromatic-substituted polymer to also have the required water solubility, sufficient hydrophilic groups such as hydroxypropyl or carboxylic acid to provide water solubility at least at the pH value at which any ionic group is ionized. It is also desirable that the acid functionality be attached to the polymer. In some cases, the aromatic group may itself be an ionic, phthalate or trimellitate substituent.

  Specific cellulosic polymers that are at least partially ionized at physiologically relevant pH include: hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose succinate, hydroxypropyl cellulose acetate succinate, hydroxy Ethylmethylcellulose succinate, hydroxyethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxyethylmethylcellulose acetate succinate, hydroxymethylcellulose acetate phthalate, carboxyethylcellulose, carboxymethylcellulose, carboxymethylethylcellulose, cellulose acetate phthalate, methylcellulose acetate phthalate, ethyl Rulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate succinate, hydroxypropyl methylcellulose acetate succinate phthalate, hydroxypropyl methylcellulose succinate phthalate, cellulose propionate phthalate, hydroxypropyl Cellulose butyrate phthalate, cellulose acetate trimellitate, methyl cellulose acetate trimellitate, ethyl cellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate trimellitate, hydroxypropyl cell Loose acetate trimellitate succinate, cellulose propionate trimellitate, cellulose butyrate trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridinedicarboxylate, cellulose salicylate, cellulose acetate hydroxypropyl salicylate, ethyl Benzoic acid cellulose acetate, hydroxypropylethyl benzoic acid cellulose acetate, ethyl phthalic acid cellulose acetate, ethyl nicotinic acid cellulose acetate, and ethyl picolinic acid cellulose acetate.

  A specific cellulosic polymer satisfying the amphiphilic definition having hydrophilic and hydrophobic sites is that the cellulose repeating unit having one or more acetate substituents has no acetate substituent or one or more ionized phthalates Or polymers such as cellulose acetate phthalate and cellulose acetate trimellitate that are more hydrophobic than those having trimellitate substituents.

  A particularly desirable subgroup of cellulosic ionic polymers are those having carboxylic acid functional aromatic substituents and alkylate substituents, ie, amphiphilic. Specific polymers include cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate succinate, cellulose propionate phthalate, Hydroxypropylcellulose butyrate phthalate, cellulose acetate trimellitate, methylcellulose acetate trimellitate, ethylcellulose acetate trimellitate, hydroxycellulose acetate trimellitate, hydroxypropyl methylcellulose acetate trimellitate, hydroxypropyl Pyrcellulose acetate trimellitate succinate, cellulose propionate trimellitate, cellulose butyrate trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose acetate pyridine dicarboxylate, cellulose salicylate, cellulose acetate hydroxypropyl salicylate, Including ethyl benzoate cellulose acetate, hydroxypropylethyl benzoate cellulose acetate, ethyl phthalate cellulose acetate, ethyl nicotinate cellulose acetate, and ethyl picolinate cellulose acetate.

  Another particularly desirable subgroup of cellulosic ionic polymers are polymers having non-aromatic carboxylate substituents. Specific polymers are hydroxypropyl methylcellulose acetate succinate, hydroxypropylmethylcellulose succinate, hydroxypropylcellulose acetate succinate, hydroxyethylmethylcellulose acetate succinate, hydroxyethylmethylcellulose succinate, hydroxyethylcellulose acetate succinate And carboxyethyl ethyl cellulose.

  As noted above, although a wide range of polymers can be used, the inventors have found that relatively hydrophobic polymers have shown the best ability to demonstrate in vitro dissolution tests. In particular, cellulosic polymers that are water-insoluble in the non-ionized state but water-soluble in the ionized state perform particularly well. A particular subgroup of such polymers is referred to as so-called “enteric” polymers, for example, hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropylmethylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), cellulose acetate trioxide. Contains melitte (CAT) and carboxymethyl ethyl cellulose (CMEC). In addition, the non-enteric class of such polymers and closely related cellulosic polymers are expected to function well due to similarities in physical properties.

  Therefore, particularly preferred polymers are hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropylmethylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), methylcellulose acetate phthalate, hydroxypropyl methylcellulose acetate. Includes phthalate, cellulose acetate terephthalate, cellulose acetate isophthalate, and carboxymethyl ethyl cellulose (CMEC). The most preferred ionic cellulosic polymers include hydroxypropyl methylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate and carboxymethylethylcellulose.

  Although certain polymers have been discussed as suitable for use in the dosage forms of the present invention, blends of such polymers are also suitable. Thus, the term “polymer” is intended to include polymer blends in addition to one polymer.

  Another preferred type of polymer consists of neutralized acidic polymers. By “neutralized acidic polymer” is meant any acidic polymer in which a “acidic moiety” or a substantial portion of an “acidic substituent” is “neutralized”; that is, present as its deprotonated form. . “Acid polymer” means any polymer having a significant number of acidic moieties. In general, a significant number of acidic moieties are greater than or equal to about 0.1 milligram equivalents of acidic moieties per gram of polymer. An “acidic moiety” includes any functional group that is sufficiently acidic that it can contact or dissolve in water to at least partially give hydrogen cations to water and increase the concentration of hydrogen ions. This definition includes any functional group or “substituent” referred to when the functional group is covalently attached to a polymer having a pKa of less than about 10. Specific types of functional groups included above include carboxylic acids, thiocarboxylic acids, phosphates, phenol groups, and sulfonates. Such functional groups can create the primary structure of the polymer, eg, polyacrylic acid, but more commonly are covalently bonded to the backbone of the parent polymer and are referred to as “substituents”. Neutralized acidic polymers are described in more detail in co-pending US patent application Ser. No. 10 / 175,566, filed Jul. 17, 2002, under the name “Pharmaceutical Compositions of Drugs and Neutralized Acidic Polymers”. Are listed. Relevant disclosures are incorporated herein by reference.

  In addition, the preferred polymers described above are amphiphilic cellulosic polymers and tend to have higher precipitation-inhibiting properties than other polymers of the present invention. In general, precipitation-inhibiting polymers with ionic substituents tend to work well. In vitro testing of compositions with such polymers tends to have higher MDC and AUC values than compositions with other polymers of the invention.

  The precipitation-inhibiting polymer is present in an amount sufficient to improve the concentration of dissolved drug as compared to the low-dissolving drug alone (ie, it is a soluble-improved form of the drug and the precipitation-inhibiting polymer is not). Several methods, such as in vitro dissolution tests or membrane permeability tests, can be used to evaluate the precipitation-inhibiting polymer and the degree of concentration increase provided by the polymer. It has been determined that increased drug concentration in in vitro dissolution tests with MFD solution, PBS solution or simulated intestinal buffer solution is a good indicator of in vivo function and bioavailability. When tested using the above in vitro dissolution test, the composition of low-dissolving drug and precipitation-inhibiting polymer meets at least one of the following conditions, preferably both. The first condition is that the composition increases the maximum dissolved drug concentration (MDC) of the drug in an in vitro dissolution test compared to a control composition consisting of an equal volume of drug in solubility-improved form and no polymer Let it be. That is, once the composition is introduced to the use environment, the composition increases the water-soluble MDC of the drug compared to the control composition. The control composition consists only of the solubility-improved form of the drug (no precipitation-inhibiting polymer). Preferably, the composition of the invention provides drug MDC in aqueous solution that is at least 1.25-fold, more preferably at least 2-fold, and most preferably at least 3-fold that of the control composition. For example, if the MDC given by the test composition is 5 mg / ml and the MDC given by the control composition is 1 mg / ml, the test composition will be 5-fold given by the control composition Give MDC.

  The second condition is that the composition of the low-solubility drug and polymer consists of an equivalent amount of the drug in solubility-improved form but does not contain the polymer in an in vitro dissolution test. Increasing the dissolution area of the concentration versus time curve (AUC). (Calculation of AUC is a well-known method in the pharmaceutical field, and is described in, for example, Welling, “Pharmacokinetics Processes and Mathematics,” ACS Monograph 185 (1986).) More specifically, in a use environment, -The composition of soluble drug and polymer should have any 90-minute AUC within about 0 to about 270 minutes after introduction to the use environment that is at least 1.25-times the AUC of the control composition above. provide. Preferably, the AUC provided by the composition is at least 2-fold, preferably at least 3-fold that of the control composition.

  Typical in vitro tests to assess increased drug concentration in aqueous solution are: (1) In vitro test media such as MFD, PBS with stirring sufficient amount of control composition, i.e. drug solubility-improved form only Or added to a simulated intestinal buffer solution to achieve an equilibrium concentration of the drug; (2) In a separate test, when all of the drug is dissolved, the theoretical concentration of the drug is at least equal to the equilibrium drug concentration The same test medium while stirring a sufficient amount of the test composition (eg, a composition comprising a combination of a solubility-improved form of drug and a precipitation-inhibiting polymer) to exceed a factor, preferably a factor of at least And (3) comparing the measured water-soluble AUC of the test composition in the MDC and / or test medium with the equilibrium concentration and / or water-soluble AUC of the control composition. In performing such solubility tests, the amount of test or control composition used is such that when all of the drug is dissolved, the drug concentration is at least 2-fold, preferably at least 10-fold, most preferably the equilibrium concentration. The amount is preferably at least 100-fold.

  Alternatively, an in vitro membrane-permeability test can be used to determine whether a composition comprising a precipitation-inhibiting polymer increases the concentration relative to a control composition. In this test described above, the composition is placed in an aqueous solution, dissolved, suspended, or delivered to an aqueous solution to make a feed solution. A typical in vitro membrane permeability test for evaluating the compositions of the present invention is: (1) If all of the drug is dissolved, the theoretical concentration of the drug will be a factor of at least about 2 A sufficient amount of the test composition (ie solubility-improved drug form and precipitation-inhibiting polymer) is administered to the feed solution so that it will be exceeded in (2) an equal amount of control composition in a separate test (Ie, drug solubility-improved form only) is added to an equal volume of test medium; and (3) the measured maximum drug membrane permeation flux provided by the test composition is given by the control composition This can be done by determining if it is at least 1.25-times that of the thing. The solubility-improved form and the precipitation-inhibiting polymer provide the maximum drug membrane permeation flux in the above test when dosed in an aqueous use environment, which is the maximum membrane provided by the control composition. At least about 1.25-times the permeate flux. Preferably, the maximum membrane permeation flux provided by the test composition is at least about 1.5-fold, more preferably at least about 2-fold, and even more preferably at least about 3-fold that provided by the control composition.

  The sustained release core of this embodiment comprises a combination of drug solubility-improved form and precipitation-inhibiting polymer. As used herein, “combination” means that the solubility-improved form and the precipitation-inhibiting polymer are in physical contact with or in close proximity to each other without physical mixing. . For example, if the sustained release core includes multiple layers, one or more layers may include a solubility-improved form and one or more different layers may include a precipitation-inhibiting polymer. Yet another example is a coated core, wherein the drug solubility-improved form or precipitation-inhibiting polymer or both are present in the core and the coating is soluble-improved form or precipitation-inhibiting polymer or its You may comprise the said core containing both. Alternatively, the combination is in the form of a single dry physical mixture in which the solubility-improved form and the precipitation-inhibiting polymer are mixed in particle form, and regardless of size, each of the particles exhibits the same in bulk In this form, the physical properties of each of the above may be maintained. Any common method used to mix the polymer and drug together can be used, such as physical mixing and dry or wet granulation.

  A combination of a solubility-improved form and a precipitation-inhibiting polymer can be prepared by dry- or wet mixing a drug or drug mixture with a precipitation-inhibiting polymer to form a composition. Mixing processes include physical processes as well as wet-granulation and coating processes.

  For example, the mixing method includes convective mixing, shear mixing or diffusion mixing. Convective mixing involves the transfer of a relatively large amount of material from one part of the powder bed to another by means of feathers or paddles, rotating screws, or powder bed inversion. Shear mixing occurs when sliding surfaces are formed in the material being mixed. Diffusion mixing involves position exchange by a single particle. These mixing processes can be carried out using batch or continuous mode equipment. A rotary mixer (eg, a twin-shell) is commonly used in batch process equipment. Continuous mixing is used to improve the uniformity of the composition.

  Squeezing may be used to prepare the composition of the present invention. Squeezing is a mechanical method that reduces the particle size of solids (pulverization). In some cases, squeezing changes the crystalline structure and causes chemical changes in certain materials, so squeezing conditions that do not change the physical form of the drug are generally selected. The most common types of presses are rotary cutters, hammers, rollers and liquid energy presses. The choice of machine depends on the characteristics of the ingredients in the drug form (eg, soft, abrasive or friable). Wet- or dry-squeeze methods can be selected for some of these processes, depending on the characteristics of the ingredients (eg drug stability in solvent). The pressing process simultaneously serves as a mixing process if the feed is non-uniform. General mixing and pressing processes suitable for use in the present invention are discussed in more detail in Lachman et al., The Theory and Practice of Industrial Pharmacy (3d Ed. 1986). The components of the composition of the present invention may be mixed by a dry- or wet-granulation process.

  In one preferred embodiment, the combination comprises particles of drug solubility-improved form at least partially coated with a precipitation-inhibiting polymer. The particles may be drug crystals or some other solubility-improved form of particles, such as amorphous drugs or cyclodextrin complexes. This embodiment finds particular utility when it is desirable to provide drug absorption in the small intestine, particularly in the colon. Without being bound by a particular theory, when the polymer and drug are released into the enteric use environment, the polymer may begin to dissolve and become gel before the drug dissolves. Thus, as the drug dissolves in the enteric use environment, the dissolved drug encounters the dissolved polymer surrounding the dissolved drug. This has the advantage of suppressing drug nucleation and consequently reduces the rate of drug precipitation.

  The polymer may be coated around the drug crystals using any common method. A preferred method is the spray-drying method. The term spray-drying is commonly used and is widely used in containers where there is a strong driving force of crushing (micronizing) a liquid mixture or suspension into small droplets and evaporation of the solvent. Refers to a process that involves the rapid removal of solvent from a drop.

  To coat drug particles by spray drying, a suspension of drug particles and dissolved polymer is first formed in the solvent. The relative amounts of drug suspended in the solvent and polymer dissolved in the solvent are selected to provide the desired drug to polymer ratio within the resulting particles. For example, if particles with a drug to polymer ratio of 0.33 (25 wt% drug) are desired, the spray solution includes 1 part of drug particles and 3 parts of polymer dissolved in the solution. The total solids content of the spray solution is preferably high enough that the spray solution causes efficient generation of particles. Total solids refers to the amount of solid drug, dissolved polymer and other excipients dissolved in the solvent. For example, to form a spray solution having a dissolved solid content of 5% by weight, resulting in particles having a drug loading of 25% by weight, the spray solution is 1.25% drug, 3.75% polymer and 95% by weight. % Contains solvent. In order to achieve a good yield, the spray solution preferably has a solids content of at least 3% by weight, more preferably at least 5% by weight and even more preferably at least 10% by weight. However, the amount of solids dissolved need not be so high and if the spray solution is too viscous, it cannot be efficiently micronized into small droplets.

  The solvent is selected based on the following characteristics: (1) the drug is insoluble or slightly soluble in the solvent; (2) the polymer is soluble in the solvent; and (3) the solvent is It is relatively volatile. Preferably, the solvent solubility of the drug is less than 5% by weight of the amount of drug suspended in the spray solution, more preferably less than 1% by weight of the amount of drug suspended in the spray solution, even more preferably Less than 0.5% by weight of the amount of drug suspended in the solution. For example, if the spray solution contains 10 wt% drug, the drug has a solubility in the solvent of less than 0.5 wt%, more preferably less than 0.1 wt%, even more preferably less than 0.05 wt%. Preferred solvents are alcohols such as methanol, ethanol, n-propanol, iso-propanol and butanol; ketones such as acetone, ethyl ethyl ketone and methyl iso-butyl ketone; esters such as ethyl acetate and propyl acetate; Other solvents such as acetonitrile, methylene chloride, toluene, THF, cyclic ethers and 1,1,1-trichloroethane are included. Mixtures of solvents that can be mixed with water can also be used as long as the polymer is sufficiently soluble to perform the spray-drying process and the drug is sufficiently insoluble to maintain suspension and not dissolve. In some cases, it may be desirable to add a small amount of water to help the solubility of the polymer in the spray solution.

  Spray drying to form a polymer coating around drug particles is well known, e.g., U.S. Pat.Nos. 4,767,789, 5,013,537, and U.S. Patent Application Publication No. 2002, which are incorporated herein by reference. / 0064108A1.

  Alternatively, the polymer may be coated around the drug crystals using a rotary circular nebulizer, as described in US Pat. No. 4,675,140, incorporated herein by reference.

  Alternatively, the precipitation-inhibiting polymer may be sprayed onto drug particles in a high shear mixer or fluid bed.

  The amount of precipitation-inhibiting polymer can vary widely. In general, the amount of precipitation-inhibiting polymer should be sufficient to provide an increase in drug concentration as compared to the drug-only control composition described above. The weight ratio of solubility-improved form to precipitation-inhibiting polymer ranges from 0.01 to 100. Good when the polymer to drug weight ratio is at least 0.33 (at least 25 wt% polymer), more preferably at least 0.66 (at least 40 wt% polymer), even more preferably at least 1 (at least 50 wt% polymer) Results are generally obtained. However, since it is desirable to limit the size of the dosage form, the amount of precipitation-inhibiting polymer may be less than the amount that provides the highest degree of concentration increase.

The enteric coating sustained release core is coated with an enteric coating so that the sustained release core does not begin to release the drug or at least a substantial portion of the drug within the sustained release core is in the stomach. ing. By “enteric coating” is meant an acid resistant coating that remains intact and does not dissolve at a pH below about 4. The enteric coating surrounds the sustained release core so that the core does not dissolve or break in the stomach, and the sustained release core does not begin to release a substantial amount of drug. The enteric coating may include a coating polymer. The enteric coating polymer is generally a polyacid having a pKa of about 3-5. Examples of enteric coating polymers include: cellulose derivatives such as cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate succinate, carboxymethylethylcellulose, methylcellulose phthalate and ethylhydroxycellulose phthalate. Vinyl polymers such as polyvinyl acetate phthalate, vinyl acetate-maleic anhydride copolymers; polyacrylates; and polymethacrylates such as methyl acrylate-methacrylic acid copolymers, methacrylate-methacrylic acid-octyl acrylate copolymers; and styrene-maleic acid monoester copolymers . These may be used alone or in combination or together with other polymers other than those mentioned above.

  One preferred coating material is a pharmaceutically acceptable methacrylic acid copolymer. This is an inherently anionic copolymer based on methacrylic acid and methyl methacrylate, such as a ratio of free carboxyl groups: methyl-esterified carboxy groups of 1: 3, for example about 1: 1 or 1: 2. A copolymer having an average molecular weight of 135,000 daltons. Some of these polymers are known and are commercially available as enteric polymers. For example, commercially available EUDRAGIT enteric polymer, such as Eudragit L 30, which has solubility in aqueous media at pH 5.5 and above, which is synthesized from dimethylaminoethyl methacrylate, Eudragit S and Eudragit NE. A cationic polymer.

  Coatings include dibutyl phthalate; phthalic acid dibutyl phthalate; dimethyl phthalate; triethyl citrate; benzyl benzoate; butyl and glycol esters of fatty acids; mineral oil; oleic acid; stearic acid; cetyl alcohol; stearyl alcohol; castor oil; Common plasticizers may be included, including corn oil; coconut oil; and camphor oil; and other excipients such as anti-sticking agents, lubricants, and the like. As plasticizers, triethyl citrate, coconut oil and dibutyl sebacate are particularly preferred. Typically, the coating comprises from about 0.1 to about 25% by weight plasticizer and from about 0.1 to about 10% by weight anti-blocking agent.

  Enteric coatings are insoluble materials such as alkyl cellulose derivatives such as ethyl cellulose, cross-linked polymers such as styrene-divinylbenzene copolymers, polysaccharides having hydroxy groups such as dextran, bifunctional cross-linkers such as epichlorohydrin, dichlorohydrin, 1, Cellulose derivatives treated with 2-, 3,4-diepoxybutane or the like may be included. The enteric coating may include starch and / or dextran. The enteric coating can be dropped onto the sustained release core by dissolving or suspending the enteric coating material in a suitable solvent. Examples of suitable solvents for use in coating drops are alcohols such as methanol, ethanol, propanol isomers and butanol isomers; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; hydrocarbons, Eg pentane, hexane, heptane, cyclohexane, methylcyclohexane and octane; ethers such as methyl tert-butyl ether, ethyl ether and ethylene glycol monoethyl ether; chlorocarbons such as chloroform, methylene dichloride and ethylene dichloride; tetrahydrofuran; dimethyl sulfoxide N-methylpyrrolidone; acetonitrile; water; and combinations thereof.

  The coating can be done in a conventional manner such as pan coaters, rotary granulators and fluidized bed coaters such as top-spray, tangential-spray or bottom-spray (Wurster This can be done by coating.

  One preferred coating solution consists of about 40 wt% Eudragit L30-D55 and 2.5 wt% triethyl citrate, about 57.5 wt% water. The enteric coating solution can be coated on the core using a pan coater or other suitable method as described above.

The immediate release controlled release dosage form includes an immediate release portion comprising a low-solubility drug. “Rapid release portion” broadly means that a portion of the drug can be released within 2 hours after dosing. “Administration” to a use environment where the in vivo use environment is a GI tract means delivery by ingestion or swallowing or other such means to deliver the dosage form. When the environment of use is in vitro, “administration” refers to the replacement or delivery of the dosage form to the in vitro test medium. The dosage form releases at least 70% by weight of the drug originally present in the immediate release portion of the dosage form within 2 hours after introduction into the stomach use environment. Preferably, the dosage form is at least 80% by weight during the first 2 hours after the dosage form is administered to the use environment, most preferably the dosage form is within the first 2 hours after the dosage form is administered to the use environment. Release at least 90% by weight of the drug initially present in the immediate release part of The immediate release of the drug can be achieved by any method known in the pharmaceutical field, including immediate release coatings, layers, powders, multiparticulates or granules.

  Virtually any means providing immediate release of drugs known in the pharmaceutical arts can be used in the dosage forms of the present invention. In one embodiment, the drug in the immediate release portion is in the form of an immediate release coating that surrounds the enteric coated sustained release core. The drug in the immediate release portion can be combined with a water soluble or water dispersible polymer such as HPC, HPMC, HEC, PVP and the like. The coating can be formed using solvent-based coating processes, powder-coating processes and hot melt coating processes, all of which are well known in the art. In a solvent-based process, the coating is made by first forming a solution or suspension containing the solvent, drug, coating polymer and optional coating additives. Preferably, the drug is suspended in the coating solvent. The coating material may be completely dissolved in the coating solvent or may be dispersed in the solvent as an emulsion or suspension or anywhere in between. Latex dispersions, including aqueous latex dispersions, are specific examples of emulsions or suspensions that are useful as coating solutions. The solvent used in the solution must be inert in the sense that it does not react with or reduce the quality of the drug and is pharmaceutically acceptable. In one aspect, the solvent is a liquid at room temperature. Preferably the solvent is a volatile solvent. “Volatile solvent” means that the material has a boiling point of less than about 150 ° C. at ambient pressure, although small amounts of solvents with higher boiling points can be used and acceptable results are still obtained.

  Examples of suitable solvents for use in applying the coating to the enteric coated sustained release core include alcohols, methanol, ethanol, propanol isomers and butanol isomers; ketones such as acetone, methyl ethyl ketone and Methyl isobutyl ketone; hydrocarbons such as pentane, hexane, heptane, cyclohexane, methylcyclohexane, octane and mineral oil; ethers such as methyl tert-butyl ether, ethyl ether and ethylene glycol monoethyl ether; chlorocarbons such as chloroform , Methylene dichloride and ethylene dichloride; tetrahydrofuran; dimethyl sulfoxide; N-methylpyrrolidone; acetonitrile; water; and combinations thereof.

  The coating formulation may include additives to promote the desired immediate release, simplify application, or improve the durability or stability of the coating. Types of additives include plasticizers, pore formers and lubricants. Examples of suitable coating additives for use in the compositions of the present invention include plasticizers such as mineral oil, petrolatum, lanolin alcohol, polyethylene glycol, polypropylene glycol, triethyl citrate, sorbitol, triethanolamine, diethyl phthalate, Dibutyl phthalate, castor oil, triacetin and others known in the art; emulsifiers such as polysorbate-80; pore formers such as polyethylene glycol, polyvinyl pyrrolidone, polyethylene oxide, hydroxyethyl cellulose and hydroxypropyl methyl cellulose; and lubricants such as Contains colloidal silicon dioxide, talc and corn starch. In one embodiment, the drug is suspended in a commercially available coating formulation, such as Opadry® Clear (commercially available from Colorcon, Inc., WestPoint, PA). Coating is carried out in a conventional manner, typically dipping, fluid bed coating, spray-coating, or pan coating.

  The immediate release coating can also be applied using powder coating methods well known in the art. In these methods, the drug is mixed with optional coating excipients and additives to form an immediate release coating composition. The composition can be applied using a compression force, for example in a tablet press.

  The coating can also be applied using a hot melt coating method. In this method, a dissolved mixture containing the drug and optional excipients and additives is formed and sprayed onto an enteric coated sustained release core. Typically, hot melt coating is applied in a fluidized bed with a top-spray process.

  In another embodiment, the immediate release portion is first formed into an immediate release powder, multiparticulates or granules that are mixed with the enteric coated sustained release core. The immediate release powder, multiparticulates or granules are mixed with an enteric coated sustained release core in a capsule. In one aspect, the immediate release composition consists essentially of a drug. In another aspect, the immediate release composition includes optional excipients such as binders, stabilizers, diluents, disintegrants and surfactants. Such immediate release powders can be formed by any common method for mixing drugs and excipients. Specific methods include wet- and dry-granulation.

  In addition to the drug, the immediate release portion may include other excipients that help form the immediate release portion. See, for example, Remington: The Science and Practice of Pharmacy (20th edition. 2000). Examples of other excipients include disintegrants, porosigens, matrix materials, fillers, diluents, lubricants, lubricants etc. such as those mentioned above.

Specific embodiments
In one embodiment, the dosage form comprises an immediate release portion and an enteric coated sustained release core. The sustained release core is in the form of a matrix controlled release device and the immediate release portion is in the form of an immediate release coating. In one aspect, see FIG. 1, dosage form 10 is in the form of a matrix tablet 12 comprising a drug (optionally a solubility-improved form) coated with an enteric coating 14. An immediate release coating 16 containing the drug and any of the above excipients surrounds the enteric coating 14. The immediate release coating 16 may optionally be coated with a common coating (not shown in FIG. 1).

  Alternatively, as schematically shown in dosage form 20 of FIG. 2, the dosage form comprises an immediate release portion and an enteric coated sustained release core. The sustained release core 22 is in the form of a matrix controlled release device coated with an enteric coating 23 and the immediate release portion is in the form of an immediate release layer 24 associated with the matrix device. By association is meant that the immediate release layer comprising the drug 24 is adjacent to or substantially in contact with the enteric coated matrix controlled-release device 22. The immediate release layer 24 may be separated from the matrix-release device by an intermediate layer (not shown in FIG. 2) containing a binder or diluent known in the art. The dosage form 20 may optionally be in contact with a common coating 26.

  In another embodiment, the dosage form comprises an immediate release portion and an enteric coated sustained release core, as shown schematically as dosage form 30 in FIG. The sustained release core is in the form of an osmotic controlled-release device 32 having an enteric coating 34 and the immediate release portion is in the form of an immediate release coating 36. The osmotic controlled-release device 32 includes a core 33, a coating 35 and a delivery port 37. The core may be a single composition or may consist of several layers, including a solubility-improved form of the drug and a layer comprising a highly swellable layer for delivering the drug to the use environment. The immediate release coating 36 may optionally be coated with a common coating (not shown in FIG. 3).

  In another embodiment, the dosage form is in the form of a capsule, the form of a capsule schematically shown as dosage form 40 in FIG. The capsule comprises (1) at least one enteric coated sustained release device 42 containing a drug (optionally in solubility-improved form), such as a matrix controlled-release device or osmotic controlled-release device; and (2) An immediate release composition 44. In this embodiment, the sustained release device 42 comprising the drug and immediate release composition 44 is first made using methods known in the art and then, for example, suitable capsules, such as hard gelatin capsules well known in the art. Alternatively, they can be mixed by placing them in soft gelatin capsules (see, for example, Remington: The Science and Practice of Pharmacy, (20th edition. 2000)). In one embodiment, the sustained release core is in the form of a matrix controlled-release device as described above. In another embodiment, the sustained release core is in the form of the osmotic controlled-release device described above. The immediate release composition 44 may be the active drug particles alone or in combination with any excipients, such as in the powder, granule or multiparticulate form described above.

The amount of drug and the relative amount of drug in the immediate release and sustained release portions may be that required to obtain the desired blood drug level. In a specific embodiment, the immediate release layer comprises about 20-80% by weight of the active drug in the dosage form, while the sustained release core comprises about 80% to about 20% by weight of the active drug. Included in the dosage form.

  The dosage form is administered orally. The dosage form is preferably administered in the fed state to maximize gastric retention of the dosage form so that the time in which the blood (serum or plasma) drug concentration is higher than the therapeutically effective drug concentration is increased. The We generally have gastric residence times ranging from about 2 to about 8 hours when administered in the fed state for large cores; conversely, the stomach when administered in the fasted state It has been found that the internal residence time is in the range of about 0.5 to about 2 hours.

  Other features and embodiments of the invention are not intended to limit the intended scope, but will be apparent from the following examples, which are given as illustrations of the invention.

In order to evaluate the crystalline form of ziprasidone hydrochloride, which proves that the solubility- improved form of ziprasidone is the improved form of ziprasidone, a microcentrifuge dissolution test was performed. In this test, a sufficient amount of ziprasidone hydrochloride monohydrate was added to the microcentrifuge tube so that when all of ziprasidone was dissolved, the ziprasidone concentration was 200 μgA / mL. The test was conducted at two points. The tubes were placed in a temperature-controlled chamber at 37 ° C. and a 1.8 ml MFD solution at pH 6.5 and 290 mOsm / kg was added to each tube. The sample was quickly mixed using a vortex mixer for about 60 seconds. Prior to collecting the samples, the samples were centrifuged at 13,000 G for 1 minute at 37 ° C. The resulting supernatant solution was then collected and diluted 1: 5 (volume) with methanol. Samples were analyzed by high performance liquid chromatography (HPLC) with UV absorption at 315 nm using a Zorbax RxC8 Reliance column and a mobile phase consisting of 55% (50 mM potassium dihydrogen phosphate, pH 6.5) / 45% acetonitrile. . The drug concentration was calculated by comparing the UV absorption of the sample with the absorption of the drug standard. The contents of each test tube were mixed on a vortex mixer and allowed to stand at 37 ° C. until the next sample was taken. Samples were collected at 4, 10, 20, 40, 90 and 1200 minutes after administration to the MFD solution. The results are shown in Table 1.

  A similar test was performed using crystalline ziprasidone free base as a control, and a sufficient amount of material was added so that when all of ziprasidone was dissolved, the compound concentration was 200 μgA / mL.

The ziprasidone concentrations obtained in these tests were used to determine the maximum dissolved concentration of ziprasidone (“MDC ₉₀ ”) and the area of the first 90 minute concentration-versus-time curve (“AUC ₉₀ ”). The results are shown in Table 2.

These results indicate that ziprasidone hydrochloride monohydrate provided 11-fold MDC ₉₀ provided by the free base and AUC ₉₀ was 14-fold provided by the free base. Thus, the hydrochloride form is a solubility-improved form of ziprasidone.

Ziprasidone crystals coated with precipitation-inhibiting polymer.
Pracidon containing 35% active ziprasidone hydrochloride monohydrate coated with HPMCAS-H, a precipitation-inhibiting polymer, was prepared as follows. A spray suspension was first prepared by dissolving HPMCAS (AQOAT HG grade, Shin Etsu, Tokyo, Japan) in acetone in a container equipped with a mixer attached to the top. The crystalline particles of ziprasidone hydrochloride monohydrate had an average particle size of about 10 μm and were added to the polymer solution and kept stirring with a mixer attached to the top. The composition consisted of 3.97 wt% crystalline ziprasidone hydrochloride monohydrate particles suspended in 6.03 wt% HPMCAS and 90 wt% acetone. The suspension was then transferred to a high shear in-line mixer (Bematek model LZ-150-6-PB multi-shear in-line mixer) using a circulation pump (Yamada air operated diagram pump model NDP-5FST). In the mixer, a series of rotor / stator shearing heads crushed the remaining crystalline aggregates. The high shear mixer was operated at a setting of 3500 ± 500 rpm for a 45-60 min / 20 kg solution. The circulation pump pressure was 35 ± 10 psig.

  Next, the suspension is sucked using a high-pressure pump, and a spray dryer (Niro type XP Portable equipped with a Liquid-Feed Process Vessel) equipped with a pressure nozzle (Spraying Systems Pressure Nozzle and Body-SK 74-20) Moved to Spray-Dryer ("PSD-1"). PSD-1 was equipped with a 5-foot 9-inch chamber extension. A chamber extension was added to the spray dryer to increase the longitudinal length of the dryer. The added length increased the residence time in the dryer, which allowed the product to dry before approaching the angled portion of the spray dryer. The spray dryer was also equipped with a 316 stainless steel circulating diffusion plate. This had an inch-drilled hole and 1% open area. This small open portion directed the flow of dry air to minimize product circulation in the spray dryer. The nozzle was flushed with a diffusion plate during operation. The suspension was delivered to the nozzle at about 285 g / min at about 300 psign pressure. The pump device included a pulsation dampener to minimize vibration at the nozzle. Dry air (eg, nitrogen) was delivered to the diffusion plate at a flow rate of 1850 g / min and an inlet temperature of 140 ° C. The evaporated solvent and moist dry air were discharged from the spray dryer at a temperature of 40 ° C. The coated crystals formed by this process were recovered in a Cyclone® and post-dried using a Gruenberg single-pass convection tray dryer operation at 40 ° C. for 4 hours. The properties of the coated crystals after drying are as follows.

  Ziprasidone-coated crystals were evaluated in vitro using a membrane permeability test. Accurel® PP 1E microporous polypropylene membrane was obtained from Membrana GmbH (Wuppertal, Germany). The membrane was washed with isopropyl alcohol in an ultrasonic bath at ambient temperature for 1 minute, rinsed with methanol, and then air dried at ambient temperature. The supply side of the membrane was plasma treated and the membrane sample was placed in the plasma chamber to impart hydrophilicity. The atmosphere in the plasma chamber was saturated with water vapor at a pressure of 550 mtorr. The plasma was generated using a radio frequency (RF) power inductively coupled to the chamber by an annular electrode for 45 seconds at a set power of 50 watts. The contact angle of water drops placed on the surface of the plasma-treated submembrane was about 40 °. The contact angle of water drops placed on the permeable side of the same membrane was greater than about 110 °.

The osmotic reservoir uses an epoxy-based adhesive (LOCTITE® E-30CL HYSOL® from Henkel Loctite Corp, Rocky Hill, Connecticut) to sample a membrane of the plasma-treated about 1 It was formed by bonding to a glass tube having an inner diameter of 2.5 inches. The membrane supply surface was aligned to be on the outside of the osmotic reservoir and the membrane osmotic surface was aligned to be on the inside of the reservoir. The effective membrane area of the membrane on the permeable reservoir was about 4.9 cm ² . The permeable reservoir was placed in a glass supply reservoir. The feed reservoir was equipped with a magnetic stirrer, the reservoir was placed on a stir plate and the stirrer speed was set at 100 rpm during the test. During the test, the machine was placed in a chamber maintained at 37 ° C. Further details of the test machine and protocol are described in pending US Patent Application No. 60 / 557,897. This was filed on March 30, 2004 under the name “Method and Device for Evaluation of Pharmaceutical Compositions” (Docket No. PC25968) and is incorporated herein by reference.

  To form the feed solution, a 1.39 mg sample of coated crystals was weighed and placed in the feed reservoir. To this was added the above 5 ml MFD solution consisting of PBS solution containing 7.3 Mm sodium taurocholate and 1.4 mM 1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine (0.5% NaTC / POPC). It was. If all of ziprasidone was dissolved, the ziprasidone concentration in the feed solution would be 100 μgA / ml. The feed solution was mixed using a vortex mixer for 1 minute. Prior to contacting the membrane with the feed solution, 5 ml of decane containing 60 wt% decanol was placed in the osmotic reservoir. The time zone in the test is the time when the membrane is contacted with the feed solution. A 50 ml aliquot of the osmotic solution was collected at a given time. Samples were then diluted with 250 ml IPA and analyzed using HPLC. The results are shown in Table 3.

  As a control, the membrane test was repeated with a 0.5-mg sample of crystalline ziprasidone alone so that if all of the drug was dissolved, the drug concentration would be 100 μgA / ml. These results are also shown in Table 3.

The maximum drug membrane permeation flux (in mgA / cm-min) of the entire membrane is at least square fitted to the data in Table 3 for 0-60 minutes to obtain a slope and the slope to the osmotic volume (5 ml) Multiplied by and divided by the membrane area (4.9 cm ² ). The analysis results are summarized in Table 4. This result indicates that the ziprasidone-coated crystals gave 2 times the initial membrane permeation flux provided by crystalline ziprasidone alone.

Dosage form
Dosage form DF-1
Dosage form DF-1 was prepared as follows. First, an enteric coated sustained release core was prepared comprising a matrix sustained release core comprising polymer coated crystals of ziprasidone hydrochloride. Coated crystals were made using the above process and contained 35 wt% active ziprasidone coated with HPMCAS-HF. The matrix tablet consisted of 30 wt% coated crystals, 29 wt% spray-dried lactose, 40 wt% PEO WSRN-10 (100,000 daltons) and 1 wt% magnesium stearate. Tablets were prepared by first mixing the coated crystals, lactose and PEO for 20 minutes in a twin-shell blender, squeezed using a Fitzpatric M5A press and then mixed in a twin-shell blender for an additional 20 minutes. The magnesium stearate was then added and the mixture was mixed again for 5 minutes. Tablets were produced from 381 mg of mixture using a F-press using a caplet-type tooling having a diameter of 0.30 inches and a length of 0.60 inches. The tablet core was compressed to a hardness of about 9.5 kp. The resulting sustained release matrix tablet contained 40 mg of active ziprasidone in a total amount and had a total mass of about 380 mg.

  DF-1 was then coated with an enteric coating. The coating solution consisted of 41.7 wt% Eudragit L30-D55 and 2.5 wt% triethyl citrate 55.8 wt% water. The coating was applied to an LDCS-20 pan coater. The coating weight was 10% by weight of the uncoated core weight. The resulting enteric coated sustained release matrix tablet had a total mass of about 419 mg.

  The immediate release coating was then applied dropwise to the enteric sustained release core. A coating suspension containing jet-compressed ziprasidone and hydroxypropyl methylcellulose was formed. The drug and polymer were collectively 2-15% by weight of the suspension. The suspension was stirred for 1 hour and filtered through a 250 μm sieve before use to remove any particulate polymer that could plug the spray nozzle. The enteric coated sustained release core was coated with a bread coater. At the end of the spray, the coated dosage form was dried for 1 hour at 40 ° C. in a tray dryer.

In Vitro Release Test An in vitro release test of the sustained release core of DF-1 was performed using the following direct drug partial rate analysis method. Sustained release core is first stirred USP type containing dissolution medium of 900 mL of simulated intestinal buffer solution consisting of 50 mM NaH ₂ PO ₄ (pH 7.5 and 37 ° C.) containing 2 wt% sodium lauryl sulfate 2 Placed in Dissoette flask. In the flask, slowly expose the dosage form away from the flask bottom so that all surfaces are exposed to the moving buffer solution and the solution is stirred with a paddle at a speed of 75 rpm. A release core was placed. Samples of dissolution media were taken at regular intervals using a VanKel VK8000 auto-sampling Dissoette with automatic receiving solution displacement. The dissolved drug concentration in the dissolution medium was then measured using a Zorbax RxC8 Reliance column and a moving bed consisting of 55% (50 mM potassium dihydrogen phosphate, pH 6.5) / 45% acetonitrile with UV absorption at 315 nm. Determined by HPLC. The drug concentration was calculated by comparing the UV absorption of the sample with the absorption of the drug standard. The drug concentration dissolved in the dissolved solution medium was calculated from the drug concentration in the medium and the volume of the medium and was expressed as a percentage of the amount of drug originally present in the dosage form. The results are shown in Table 5.

  This result indicates that the sustained release core released 90% by weight of the drug in the first 5 hours after administration to the in vitro test medium.

  The terms and expressions used in the foregoing specification are used herein as descriptive terms and are not limiting terms. The use of such terms and expressions is not intended to exclude equivalents of the embodiments shown or described or portions thereof. It will be appreciated that the scope of the invention is defined and limited only by the preceding claims.

FIG. 1 is a schematic cut-away view of a specific dosage form of the present invention. FIG. 2 is a schematic cutaway view of another specific dosage form of the present invention. FIG. 3 is a schematic cutaway view of yet another specific dosage form of the present invention. FIG. 4 is a schematic cutaway view of yet another specific dosage form of the present invention.

Claims (15)

(a) an immediate release portion comprising a low-solubility drug, wherein the low-solubility drug has a dose-water solubility ratio of at least about 100 ml; and
(b) a sustained release core comprising the low-solubility drug, wherein the sustained release core is surrounded by an enteric coating;
Here, the sustained release core is large enough to be retained in the stomach over a period of time, and the sustained release core is capable of the drug in the core over a release period of about 1 hour to about 8 hours. Said dosage form that releases at least 90% by weight and wherein said drug in said sustained release core is a solubility-improved form. (a) an immediate release portion comprising a low-solubility drug, wherein the low-solubility drug has a dose-water solubility ratio of at least about 10 ml; and
(b) a sustained release core comprising the low-solubility drug, wherein the sustained release core is surrounded by an enteric coating;
Here, the sustained release core is large enough to be retained in the stomach over a period of time, and the sustained release core is capable of the drug in the core over a release period of about 1 hour to about 8 hours. The dosage form releases at least 90% by weight and the drug has a clearance half-life of less than about 12 hours.   The dosage form of claim 2, wherein the drug has a dose-solubility ratio of greater than about 100 ml.   The dosage form of claim 1 or 2, wherein the drug has a dose-water solubility ratio of greater than about 1000 ml.   The dosage form of claim 1, wherein the drug has a clearance half-life of less than about 12 hours.   6. A dosage form according to claim 2 or 5, wherein the drug has a clearance half-life of less than 8 hours.   7. The dosage form of claim 1 or 6, wherein the drug is in the form of particles having an average particle size of less than about 100 microns.   7. A dosage form according to claim 1 or 6, further comprising a precipitation-inhibiting polymer.   The dosage form of claim 1 or 2, wherein the sustained release core and the enteric coating have a mass of at least about 400 mg.   The dosage form of claim 1 or 2, wherein the dosage form has a longest length of at least about 5 mm.   The dosage form of claim 1 or 2, wherein the sustained release core has a release period of about 1 to about 6 hours.   The dosage form according to claim 1 or 2, wherein the sustained-release core is selected from the group consisting of a matrix sustained-release core, a permeable sustained-release core and a capsule.   3. A dosage form according to claim 1 or 2, wherein the immediate release part is selected from the group consisting of layers, coatings, multiparticulates and granules.   The dosage form of claim 13, wherein the immediate release portion comprises a coating surrounding the enteric coating.   The low-solubility drug is ziprasidone or a pharmaceutically acceptable salt thereof. The dosage form according to any one of claims 1 to 14.

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