WO2011071877A2 - Revêtement par immersion partielle de formes pharmaceutiques pour libération modifiée - Google Patents

Revêtement par immersion partielle de formes pharmaceutiques pour libération modifiée Download PDF

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Publication number
WO2011071877A2
WO2011071877A2 PCT/US2010/059228 US2010059228W WO2011071877A2 WO 2011071877 A2 WO2011071877 A2 WO 2011071877A2 US 2010059228 W US2010059228 W US 2010059228W WO 2011071877 A2 WO2011071877 A2 WO 2011071877A2
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WO
WIPO (PCT)
Prior art keywords
coating
core
dosage form
active ingredient
release
Prior art date
Application number
PCT/US2010/059228
Other languages
English (en)
Other versions
WO2011071877A3 (fr
Inventor
Saumitra Bagchi
Murali Vuppala
Original Assignee
Mcneil-Ppc, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mcneil-Ppc, Inc. filed Critical Mcneil-Ppc, Inc.
Priority to BR112012013676A priority Critical patent/BR112012013676A2/pt
Priority to CN2010800551678A priority patent/CN102639122A/zh
Priority to AU2010328353A priority patent/AU2010328353B2/en
Priority to CA2780347A priority patent/CA2780347A1/fr
Priority to EP10799155A priority patent/EP2509587A2/fr
Publication of WO2011071877A2 publication Critical patent/WO2011071877A2/fr
Publication of WO2011071877A3 publication Critical patent/WO2011071877A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2893—Tablet coating processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin

Definitions

  • the present invention relates to a dosage form comprising a tablet core containing at least one active ingredient and having at least one modified release coating that partially surrounds the tablet core.
  • the tablet core is preferably in the form of a compressed core wherein at least one modified release coating is provided on a portion of the exterior surface of the compressed core using dipping technology.
  • the invention also relates to a method of manufacturing the dosage form and a method of treatment using the dosage form.
  • Modified release pharmaceutical dosage forms have long been used to optimize drug delivery and enhance patient compliance, especially by reducing the number of doses of medicine the patient must take in a day. In some instances, it is also desirable for a dosage form to deliver more than one drug at different rates or times. Modified release dosage forms should ideally be adaptable so that release rates and profiles can be matched to physiological requirements.
  • onset and duration of the therapeutic efficacy of drugs vary widely, as do their absorption, distribution, metabolism, and elimination, it is often desirable to modify the release of different drugs in different ways, or to have a first dose of drug immediately released from the dosage form, while a second dose of the same or a different drug is released in a modified, e.g., delayed, pulsatile, repeat action, controlled, pH dependent, sustained, prolonged, extended, or retarded manner.
  • modified release dosage forms provide a desired blood concentration versus time (pharmacokinetic, or PK) profile for the drug.
  • PK profile for a drug is dependent on the rate of absorption of the drug into the blood, and the rate of elimination of the drug from the blood. To be absorbed into the blood (circulatory system), the drug must first be dissolved in the gastrointestinal fluids.
  • controlling the rate of dissolution allows the formulator to control the rate of drug absorption into the circulatory system of a patient.
  • the type of PK profile, and correspondingly, the type of dissolution or release profile desired depends on, among other factors, the particular active ingredient and physiological condition being treated.
  • One particularly desirable PK profile is achieved by a dosage form that delivers a delayed release dissolution profile, in which the release of one or more doses of drug from the dosage form is delayed for a pre-determined time after contacting of the dosage form by a liquid medium, such as for example, by the gastro-intestinal fluid after ingestion by the patient.
  • the delay period (“lag time") can be followed either by prompt release of the active ingredient ("delayed burst"), or by sustained (prolonged, extended, or retarded) release of the active ingredient ("delayed then sustained”).
  • U.S. Patent No. 5,464,633 to Jagotec discloses delayed-release dosage forms consisting of a core containing an active and polymeric substances and an external layer completely coating the core in which the external coating layer is applied by a compression coating process.
  • One particularly desirable type of delayed release PK profile is obtained from a "pulsatile" release profile, in which for example, a first dose of a drug is delivered, followed by a delay period ("lag time") during which there is substantially no release of the drug from the dosage form, followed by either prompt or sustained release of a subsequent dose of the same drug.
  • a first dose of a drug is delivered, followed by a delay period ("lag time") during which there is substantially no release of the drug from the dosage form, followed by either prompt or sustained release of a subsequent dose of the same drug.
  • the first dose is released essentially immediately upon contacting of the dosage form with a liquid medium and the delay period corresponds approximately to the time during which a therapeutic concentration of the first dose is maintained in the blood.
  • Pulsatile delivery systems are particularly useful for applications where a continuous release of drug is not ideal.
  • Examples of this are drugs exhibiting first pass metabolism by the liver, drugs that induce biological tolerance, i.e., the therapeutic effect decreases with continuous presence of the drug at the site of action, and drugs whose efficacy is influenced by circadian rhythms of body functions or disease.
  • One typical pulsatile dosage form design contains the first dose of drug in an exterior coating, or shell, while subsequent doses of drug are contained in underlying layers of subcoatings, or a central core.
  • Pulsatile dosage forms may deliver an active ingredient in a pH dependent or pH independent manner. pH dependent types of dosage forms typically deliver the active ingredient through the addition of a pH dependent polymer, such as an enteric or reverse-enteric polymer.
  • PCT Publication No. W099/62496 to Alza discloses a dosage form comprising an immediate-release dose of drug contained within an overcoat applied onto a surface of a semi-permeable coating of an osmotic dosage form.
  • U.S. Patents Nos. 4,857,330 and 4,801,461 to Alza disclose dosage forms comprising an exterior drug coat that surrounds a semi-permeable wall, which in turn surrounds an internal compartment containing a second dose of drug, and comprises exit means for connecting the interior of the dosage form with the exterior environment of use. These dosage forms are designed to release drug immediately from the exterior coating, followed by a relatively short delay period, followed by a sustained release of drug from the internal compartment.
  • U.S. Patent No. 4,865,849 to Pharmidea discloses a tablet that releases active substances at successive times, comprising a first layer containing a portion of the active substance, a water soluble or water gellable barrier layer, and a third layer containing the remaining portion of active substance, wherein the barrier layer and the third layer are in an insoluble, low-permeable casing.
  • the casing can be applied by various methods such as spraying, compression, or immersion, or the tablet parts can be inserted into a pre-formed casing.
  • U.S. Patent No. 4,839,177 to Jagotec discloses a system for the controlled release of active substances, consisting of: (a) a deposit-core; and (b) a support-platform applied to the deposit-core.
  • the deposit-core contains active substance and a polymeric material having a high degree of swelling on contact with water or aqueous liquids, a gellable polymeric material, and other adjuvants able to provide the mixture with suitable characteristics for its compression and for its intake of water.
  • U.S. Patent No. 6,126,767 to Perrigo discloses a capsule medicament consisting of a solid core covered with two shrink-wrapped, hard-shell gelatin capsule halves.
  • the solid core is covered with the hard-shell gelatin capsule halves by individually shrink- wrapping onto first one end of the core a first hard-shell gelatin capsule half and then individually shrink-wrapping onto a second end of the core a second hard-shell gelatin capsule half.
  • the capsule medicament is designed for immediate release of the active ingredient.
  • U.S. Patent No. 6,113,945 to Perrigo discloses a caplet or tablet core with a clear or single color uniform covering that is applied either through an enrobing process, by spraying or by a single dip-coating step.
  • the core itself can have a first color or be colorless, and its clear or single color covering has the outer surface of one end or one side colored by a dye to provide a two-color appearance.
  • the dye can be applied by dipping or spray painting with a jet-spraying apparatus.
  • compositions for controlled delivery of at least one active substance comprising a first cellulose derivative which has thermoplastic properties and which is substantially insoluble in an aqueous medium in which the composition is to be used, and at least one of a second cellulose derivative which is soluble or dispersible in water, a plasticizer, and a filler.
  • U.S. Patent Publication No. 20030070584 to McNeil discloses a water soluble, gelatin-free dip coating for pharmaceutical solid dosage forms such as tablets comprising HPMC and xanthan gum, carrageenan, and mixtures thereof, or HPMC and castor oil or maltodextrin.
  • U.S. Patent No. 20080166407 to Shalaby et al. discloses multifunctional, single, bilayer, and trilayer coated tablets for combination therapy wherein the bioactive agents responsible for the therapeutic multifunctionality are present as a combination of a gastric acid-reducing agent, such as omeprazole and ranitidine, and at least one analgesic/anti-inflammatory agent, such as acetaminophen, naproxen sodium, ibuprofen, tolmetin, and aspirin.
  • a gastric acid-reducing agent such as omeprazole and ranitidine
  • analgesic/anti-inflammatory agent such as acetaminophen, naproxen sodium, ibuprofen, tolmetin, and aspirin.
  • Coating methods such as those described above have inherent disadvantages, including long processing times, limited ability to allow functional placement of coatings, or multiple coating steps in order to provide multiple release rates (as in spray coatings), thick coatings which can affect swallowability and limit types of release rates (such as compression coatings), or the use of laser drilling equipment (such as osmotic coatings).
  • a dosage form with immediate release and modified release portions in the tablet manufactured by application of release controlling coating on the modified release portion.
  • Such a core does not require multiple pieces (as in a muticore form) or multilayers (as in a bilayer or trilayer core).
  • Controlled release dosage forms provide many advantages over immediate release dosage forms.
  • the invention involves partially coating a tablet with a semipermeable or a low-permeable coating to a predetermined height using an aqueous or a nonaqueous solution of a polymer and air drying the tablet.
  • the uncoated portion of the tablet releases the drug immediately and the portion of the tablet that is coated releases the drug slowly as the tablet surface that is exposed to the medium is reduced to the cross sectional area of the tablet.
  • dissolution medium has to travel deep into the tablet coated with polymer shell to dissolve the drug and release it to the medium.
  • the modified release tablets of the invention which are simpler and potentially more cost effective than sustained release tablets that utilize multiple spray coating steps, or particulate coatings, provide users with convenience and lower doses. Convenience is provided during the manufacturing process as the dipped coatings of the present invention allow for a single application of coating.
  • the dip coatings of the invention also involve reduced cost as a great amount of cost lies in the processing time involved with applying multiple coatings to a tablet, as in spray coating or osmotic coating.
  • the dipped dosage forms of the invention exhibit modified release of one or more active ingredients contained therein. The active ingredient or ingredients may be found within the core.
  • modified release shall apply to dosage forms, coatings, shells, cores, portions thereof, or compositions that alter the release of an active ingredient in any manner.
  • the active ingredient or ingredients that are released in a modified manner may be contained within the coating, shell, core, composition, or portion thereof providing the modification.
  • the modified release active ingredient may be contained in a different portion of the dosage form from the coating, shell, core, composition, or portion thereof providing the modification; for example the modified release active ingredient may be contained in a core portion, and the modification may be provided by the overlaying shell portion.
  • Types of modified release include controlled, prolonged, sustained, extended, delayed, pulsatile, repeat action, and the like.
  • modified release properties of the dosage form may be achieved through design of the core or a portion thereof, or of the coating or portions of the coating, or a combination of these parts of the dosage form.
  • the dissolution profile of each active ingredient from the dosage form may be governed by a sum of contributions from the properties of the various portions. Additionally, a single portion, for example a core portion, may possess a combination of erosional and diffusional properties. In any case, the dissolution rate of a particular active ingredient from the dosage form will be the sum of the contributions from all the various mechanisms contributed by the various portions of the dosage form which effect the release of that particular active ingredient, as depicted by the following equation:
  • Rate total ... ...X l Rate l ... + X 2 Rate 2 ... + X 3 Rate 3 ... + X n Rate n
  • Xi, X 2 , X 3 , ... X n are the relative contribution fractions of the total release rate
  • Ratei, Rate 2 , Rate 3 , ... Raten are the various release rates contributed by effects of the various portions of the dosage form on a particular active ingredient.
  • Another particularly desirable PK profile is achieved by a dosage form that delivers a delayed release dissolution profile, in which the release of one or more doses of drug from the dosage form is delayed for a pre-determined time after contact with a liquid medium, e.g., upon ingestion by the patient.
  • the delay period (“lag time") can be followed either by prompt release of the active ingredient ("delayed burst”), or by sustained (prolonged, extended, or retarded) release of the active ingredient (“delayed then sustained”).
  • One particularly desirable type of delayed release PK profile is a "pulsatile" profile in which, for example, a first dose of a first drug is delivered, followed by a delay period during which there is substantially no release of the first drug from the dosage form, followed by either prompt or sustained release of a subsequent dose of the same drug.
  • the first dose is released essentially immediately upon contacting of the dosage form with a liquid medium.
  • the delay period corresponds approximately to the time during which a therapeutic concentration of the first dose is maintained in the blood.
  • Pulsatile delivery systems are particularly useful for applications where a continuous release of drug is not ideal. Examples of this are drugs exhibiting first pass metabolism by the liver, drugs that induce biological tolerance (i.e., the therapeutic effect decreases with continuous presence of the drug at the site of action), and drugs whose efficacy is influenced by circadian rhythms of body functions or diseases.
  • the dosage form is a tablet that is partially dip coated on both sides of the tablet leaving the central band uncoated.
  • the dosage form is a tablet having a portion that is partially dip coated with low-permeable coating and another portion of the tablet is dip coated with a semi-permeable coating.
  • the coating may contain coating polymers applied from a solvent based solution or from a latex based aqueous dispersion (typically with the addition of a plasticizer).
  • the dosage form which includes the modified release tablets of the invention provide the blood levels quickly with active in order to provide quick relief and with sustained levels of active over time to provide continued relief.
  • the dosage form which includes the modified release tablets of the invention may contain a single active or more than one active and/or may treat a single indication or multiple indications and/or a single symptom or multiple symptoms.
  • the dosage form which includes the modified release tablets of the invention can provide zero and/or first order release.
  • the invention also relates to a method of manufacturing the dosage form and a method of treatment using the dosage form.
  • dosage form applies to any solid object, semi-solid, or liquid- filled composition designed to contain a specific pre-determined amount (dose) of a certain ingredient, for example, an active ingredient as defined below.
  • Suitable dosage forms may be pharmaceutical drug delivery systems, including those for oral administration, buccal administration, rectal administration, topical or mucosal delivery, or subcutaneous implants, or other implanted drug delivery systems; or compositions for delivering minerals, vitamins and other nutraceuticals, oral care agents, flavorants, and the like.
  • the dosage forms of the present invention are considered to be solid, however they may contain liquid or semi-solid components.
  • the dosage form is an orally administered system for delivering a pharmaceutical active ingredient to the gastro-intestinal tract of a human.
  • Suitable "active ingredients" for use in this invention include for example pharmaceuticals, minerals, vitamins and other nutraceuticals, oral care agents, flavorants and mixtures thereof.
  • suitable pharmaceuticals include analgesics, anti-inflammatory agents, antiarthritics, anesthetics, antihistamines, antitussives, antibiotics, anti-infective agents, antivirals, anticoagulants, antidepressants, antidiabetic agents, antiemetics, antiflarulents, antifungals, antispasmodics, appetite suppressants, bronchodilators, cardiovascular agents, central nervous system agents, central nervous system stimulants, decongestants, oral contraceptives, diuretics, expectorants, gastrointestinal agents, migraine preparations, motion sickness products, mucolytics, muscle relaxants, osteoporosis preparations, polydimethylsiloxanes, respiratory agents, sleep-aids, urinary tract agents and mixtures thereof.
  • Suitable oral care agents include breath fresheners, tooth whiteners, antimicrobial agents, tooth mineralizers, tooth decay inhibitors, topical anesthetics, mucoprotectants, and the like.
  • Suitable flavorants include menthol, peppermint, mint flavors, fruit flavors, chocolate, vanilla, bubblegum flavors, coffee flavors, liqueur flavors and combinations and the like.
  • Suitable gastrointestinal agents include antacids such as calcium carbonate, magnesium hydroxide, magnesium oxide, magnesium carbonate, aluminum hydroxide, sodium bicarbonate, dihydroxyaluminum sodium carbonate; stimulant laxatives, such as bisacodyl, cascara sagrada, danthron, senna, phenolphthalein, aloe, castor oil, ricinoleic acid, and dehydrocholic acid, and mixtures thereof; H2 receptor antagonists, such as famotadine, ranitidine, cimetadine, nizatidine; proton pump inhibitors such as omeprazole or lansoprazole; gastrointestinal cytoprotectives, such as sucraflate and misoprostol; gastrointestinal prokinetics, such as prucalopride, antibiotics for H.
  • antacids such as calcium carbonate, magnesium hydroxide, magnesium oxide, magnesium carbonate, aluminum hydroxide, sodium bicarbonate, dihydroxyaluminum
  • pylori such as clarithromycin, amoxicillin, tetracycline, and metronidazole
  • antidiarrheals such as diphenoxylate and loperamide
  • glycopyrrolate such as glycopyrrolate
  • antiemetics such as ondansetron
  • analgesics such as mesalamine.
  • a preferred gastrointestinal agent is omeprazole.
  • the active ingredient may be selected from bisacodyl, famotadine, ranitidine, cimetidine, prucalopride, diphenoxylate, loperamide, lactase, mesalamine, bismuth, antacids, and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof.
  • the active ingredient is selected from analgesics, antiinflammatories, and antipyretics, e.g., non-steroidal anti-inflammatory drugs (NSAIDs), including propionic acid derivatives, e.g., ibuprofen, naproxen, ketoprofen and the like; acetic acid derivatives, e.g., indomethacin, diclofenac, sulindac, tolmetin, and the like; fenamic acid derivatives, e.g., mefanamic acid, meclofenamic acid, flufenamic acid, and the like; biphenylcarbodylic acid derivatives, e.g., diflunisal, flufenisal, and the like; and oxicams, e.g., piroxicam, sudoxicam, isoxicam, meloxicam, and the like.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • the active ingredient is selected from propionic acid derivative NSAID, e.g., ibuprofen, naproxen, flurbiprofen, fenbufen, fenoprofen, indoprofen, ketoprofen, fluprofen, pirprofen, carprofen, oxaprozin, pranoprofen, suprofen, and pharmaceutically acceptable salts, derivatives, and combinations thereof.
  • NSAID e.g., ibuprofen, naproxen, flurbiprofen, fenbufen, fenoprofen, indoprofen, ketoprofen, fluprofen, pirprofen, carprofen, oxaprozin, pranoprofen, suprofen, and pharmaceutically acceptable salts, derivatives, and combinations thereof.
  • the active ingredient may be selected from acetaminophen, acetyl salicylic acid, ibuprofen, naproxen, ketoprofen, flurbiprofen, diclofenac, cyclobenzaprine, meloxicam, rofecoxib, celecoxib, and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof.
  • a preferred (analgesic) is acetaminophen.
  • the active ingredient may be selected from upper respiratory agents, such as pseudoephedrine, phenylephrine, guaifensin, phenylpropanolamine, chlorpheniramine, dextromethorphan, diphenhydramine, astemizole, terfenadine, fexofenadine, loratadine, desloratadine, cetirizine, mixtures thereof and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof.
  • upper respiratory agents such as pseudoephedrine, phenylephrine, guaifensin, phenylpropanolamine, chlorpheniramine, dextromethorphan, diphenhydramine, astemizole, terfenadine, fexofenadine, loratadine, desloratadine, cetirizine, mixtures thereof and pharmaceutically acceptable salts, esters, isomers, and mixtures thereof.
  • the active ingredient or ingredients are present in the dosage form in a therapeutically effective amount, which is an amount that produces the desired therapeutic response upon oral administration and can be readily determined by one skilled in the art. In determining such amounts, the particular active ingredient being administered, the bioavailability characteristics of the active ingredient, the dosing regimen, the age and weight of the patient, and other factors must be considered, as known in the art.
  • the dosage form comprises at least about 1 weight percent, for example, the dosage form comprises at least about 5 weight percent, say at least about 20 weight percent, of a combination of one or more active ingredients.
  • a core comprises a total of at least about 25 weight percent (based on the weight of the core) of one or more active ingredients.
  • the active ingredient or ingredients may be present in the dosage form in any form.
  • the active ingredient may be dispersed at the molecular level, e.g., melted or dissolved, within the dosage form, or may be in the form of particles, which in turn may be coated or uncoated.
  • the particles typically have an average particle size of about 1-2000 microns.
  • such particles are crystals having an average particle size of about 1-300 microns.
  • the particles are granules or pellets having an average particle size of about 50-2000 microns, preferably about 50-1000 microns, most preferably about 100-800 microns.
  • Each core may be any solid form.
  • core refers to a material which is at least partially enveloped or surrounded by another material and has a thickness of at least about 2 mm to about 30 mm.
  • a core is a self-contained unitary object, such as a "tablet”, which is a compressed or molded solid dosage form of any size or shape.
  • Solid, generally oblong-shaped tablets may sometimes be referred to as "caplets”.
  • the cores may be prepared by any suitable method, including for example compression or molding, and depending on the method by which they are made, typically comprise active ingredient and a variety of excipients.
  • suitable excipients include fillers, binders, disintegrants, lubricants, glidants, and the like, as known in the art.
  • Suitable fillers for use in making a core or core portion by compression include water-soluble compressible carbohydrates such as sugars, which include dextrose, sucrose, maltose, and lactose, sugar-alcohols, which include mannitol, sorbitol, maltitol, xylitol, starch hydrolysates, which include dextrins, and maltodextrins, and the like, water insoluble plastically deforming materials such as microcrystalline cellulose or other cellulosic derivatives, water-insoluble brittle fracture materials such as dicalcium phosphate, tricalcium phosphate and the like and mixtures thereof.
  • water-soluble compressible carbohydrates such as sugars, which include dextrose, sucrose, maltose, and lactose
  • sugar-alcohols which include mannitol, sorbitol, maltitol, xylitol
  • starch hydrolysates which include dextrins, and maltod
  • Suitable binders for making a core or core portion by compression include dry binders such as polyvinyl pyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, and the like; wet binders such as water-soluble polymers, including hydrocolloids such as acacia, alginates, agar, guar gum, locust bean, carrageenan, carboxymethylcellulose, tara, gum arabic, tragacanth, pectin, xanthan, gellan, gelatin, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, inulin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan, polyvinyl pyrrolidone, cellulosics, sucrose, starches, and the like; and derivatives and mixtures thereof.
  • dry binders such as polyviny
  • Suitable disintegrants for making a core or core portion by compression include sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked carboxymethylcellulose, starches, microcrystalline cellulose, crospovidone and the like.
  • Suitable lubricants for making a core or core portion by compression include long chain fatty acids and their salts, such as magnesium stearate and stearic acid, talc, glycerides and waxes.
  • Suitable colorants include lakes, dyes, and opacifiers, including metal containing lakes such as aluminum, magnesium and calcium lakes.
  • Specific opacifiers include but are not lmited to titanium dioxide.
  • Suitable glidants for making a core or core portion by compression include colloidal silicon dioxide, and the like.
  • Suitable pH-dependent polymers for use as release-modifying excipients for making a core or core portion by compression include enteric cellulose derivatives, for example hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate; natural resins such as shellac and zein; enteric acetate derivatives such as for example polyvinylacetate phthalate, cellulose acetate phthalate, acetaldehyde dimethylcellulose acetate; and enteric acrylate derivatives such as for example polymethacrylate-based polymers such as poly(methacrylic acid, methyl methacrylate) 1 :2, which is commercially available from Rohm Pharma GmbH under the tradename EUDRAGIT S, and poly(methacrylic acid, methyl methacrylate) 1 : 1, which is commercially available from Rohm Pharma GmbH under the tradename EUDRAGIT L, and the like, and derivatives, salts, copolymers, and combinations thereof.
  • a pH dependent polymer is applied to the core containing the active ingredient in a first coating step.
  • this first coating step substantially surrounds the core.
  • substantially surrounds includes covering at least 95%, e.g., at least 99% of the surface area of the core.
  • This first coating step may be applied by any method; including spraying, compression coating, enrobing or dipping.
  • a subcoat is applied in the first coating step.
  • the subcoat may comprise a modified release coating, an immediate release coating, or a pH dependent coating.
  • Suitable materials for use as the immediate release coating include polyvinylalcohol (PVA); water soluble polycarbohydrates such as hydroxypropyl starch, hydroxyethyl starch, pullulan, methylethyl starch, carboxymethyl starch, pre-gelatinized starches, and film-forming modified starches; water swellable cellulose derivatives such as hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), methyl cellulose (MC), hydroxyethylmethylcellulose (HEMC), hydroxybutylmethylcellulose (HBMC), hydroxyethylethylcellulose (HEEC), and hydroxyethylhydroxypropylmethyl cellulose (HEMPMC); water soluble copolymers such as methacrylic acid and methacrylate ester copolymers, polyvinyl alcohol and polyethylene glycol copolymers, polyethylene oxide and polyvinylpyrrolidone copolymers; and derivatives and combinations thereof.
  • PVA polyvin
  • the degree to which the modified release dipped coating is applied to the core will regulate the rate and amount of active ingredient which is dispersed into the gastrointestinal media upon ingestion.
  • the amount of dipped portion will be dependent of the amount of active ingredient in the core, the amount of active ingredient which is desired for immediate release versus modified release, and the type of modified release.
  • the dipped portion is applied at about 10 percent, up to about 25 percent, up to about 50 percent, up to about 75 percent up to about 90 percent, up to about 95 percent of the surface area of the core portion.
  • the core is a caplet and the dipped portion circumscribes the longitudinal axis of the core such that the dipped portion can easily be modified to regulate release.
  • a top and bottom portion of a tablet are dipped with the modified release coating and the center portion is exposed for immediate release of the active ingredient.
  • the tablet is held or gripped in a holder which is designed to mask the portion of the tablet which is not coated upon dipping, in order to precisely apply the appropriate amount of the modified release coating,
  • the thickness of the dipped coating portion may be adjusted by adjusting the viscosity of the dipping solution, and by adjusting the level of solids in solution.
  • the solids of the coating solution may be from about 2 percent solids to about 50 percent solids, preferably from about 5 percent to about 25 percent solids.
  • the core is a multilayer tablet.
  • Multilayer tablets may be employed in order to separate incompatible active ingredients, or to further modify the release rate of the at least one active ingredient.
  • the multilayer tablet is a bilayer tablet, which comprises one active ingredient in the first layer and a second active ingredient or a second portion of the first active ingredient in the second layer.
  • the first layer portion may be coated with a dipped portion or uncoated (i.e., exposed) with the dipped portion and the second layer portion may be coated with the dipped portion.
  • the first layer portion is an immediate release portion.
  • the dipping coating solution may be applied via a solvent based or an aqueous based solution.
  • Suitable solvents may be employed in order to dissolve the modified release agents or polymers, and include but are not limited to ethanol, methanol, isopropanol, acetone, methylene chloride and hexane(s).
  • the dipped portion contains a pore forming agent in order to create a semi-permeable coating.
  • the term "semi-permeable” means permeable to the passage of water but not permeable to the passage of active ingredient therethrough.
  • the semi-permeable dipped portion allows water to be absorbed therethrough and into the core of the dosage form from the environment, such as the dissolution media or gastro-intestinal fluids.
  • the semi-permeable dipped portion functions as a barrier to the passage of active ingredient from the underlying core portion, forcing the active ingredient to be released from the dosage form via a different avenue, such as an orifice or passageway, or through a diffusible dipped coating portion.
  • the semi-permeable dipped coating portions are non-erodible, and they are insoluble in fluids.
  • Suitable pore forming agents include but are not limited to crystalline materials such as sugars and salts, or water soluble polymers such as but not limited to hypromellose, hydroxypropylcellulose, polyetheylene glycol, and methylcellulose.
  • Suitable pharmaceutically acceptable adjuvants for making a core or core portion by compression include, preservatives; high intensity sweeteners such as aspartame, acesulfame potassium, sucralose, and saccharin; flavorants; colorants; antioxidants; surfactants; wetting agents; and the like and mixtures thereof.
  • a dry blending i.e., direct compression
  • wet granulation process may be employed, as known in the art.
  • a dry blending (direct compression) method the active ingredient or ingredients, together with the excipients, are blended in a suitable blender, then transferred directly to a compression machine for pressing into tablets.
  • a wet granulation method the active ingredient or ingredients, appropriate excipients, and a solution or dispersion of a wet binder (e.g., an aqueous cooked starch paste, or solution of polyvinyl pyrrolidone) are mixed and granulated.
  • a wet binder e.g., an aqueous cooked starch paste, or solution of polyvinyl pyrrolidone
  • a dry binder may be included among the excipients, and the mixture may be granulated with water or other suitable solvent.
  • Suitable apparatuses for wet granulation are known in the art, including low shear, e.g., planetary mixers; high shear mixers; and fluid beds, including rotary fluid beds.
  • the resulting granulated material is dried, and optionally dry-blended with further ingredients, e.g., adjuvants and/or excipients such as for example lubricants, colorants, and the like.
  • the final dry blend is then suitable for compression.
  • Methods for direct compression and wet granulation processes are known in the art, and are described in detail in, for example, Lachman, et al, The Theory and Practice of Industrial Pharmacy, Chapter 11 (3rd ed. 1986).
  • the dry-blended, or wet granulated, powder mixture is typically compacted into tablets using a rotary compression machine as known in the art.
  • one or more core portions function as a diffusional matrix.
  • the core portion preferably comprises active ingredient, distributed throughout an insoluble porous matrix, which contains pores or channels through which fluids can enter the core portion, and the active ingredient must diffuse to be released from the dosage form.
  • the rate of active ingredient release from the core portion will depend upon the area (A) of the matrix, the diffusion coefficient (D), the porosity (E) and tortuosity (T) of the matrix, the drug solubility (Cs) in the dissolution medium, and the drug concentration (Cp) in the dosage form.
  • a core portion functions as a diffusional matrix
  • the release of the active ingredient from the core portion may be described as controlled, prolonged, sustained, or extended.
  • the contribution to active ingredient dissolution from the subject core portion may follow zero-order, first-order, or preferably square-root of time kinetics.
  • the diffusional matrix core portion preferably comprises a pore former.
  • the dipped coating portion comprises at least one water insoluble polymer.
  • suitable water-insoluble polymers include ethylcellulose, polyvinyl alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate and its derivatives, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate acrylates, methacrylates, acrylic acid copolymers; and the like and derivatives, copolymers, and combinations thereof.
  • the dipped coating portion comprises at least one aqueous polymer.
  • suitable aqueous polymers include hydroxypropylcellulose (HPC), hypromellose, methylcellulose, povidone, and polyvinylalcohol (PVA).
  • Aqueous polymers further include water soluble polycarbohydrates such as hydroxypropyl starch, hydroxyethyl starch, pullulan, methylethyl starch,carboxymethyl starch, dextrins, pre-gelatinized starches, and film-forming modified starches; water soluble copolymers such as methacrylic acid and methacrylate ester copolymers, polyvinyl alcohol and polyethylene glycol copolymers, polyethylene oxide and polyvinylpyrrolidone copolymers; and derivatives and combinations thereof.
  • the modified release coating is applied via an aqueous polymer it may be desirable to add a thickening agent to modify the viscosity during dipping.
  • Suitable thickening agents include but are not limited to gelatin, gellan gum, carageenan, iota carageenan, kappa carageenan, lambda carageenan, xanthan gum, guar gum, tara gum, maltodextrin, chitin, cyclodextrin, pectin, sodium carboxymethylcellulose, gelling starches, and microcrystalline cellulose.
  • the thickener may be added from about 0.1 percent to about 10 percent by weight of the dried dipped portion.
  • the dipped portion comprises gelatin for use as a thickener.
  • Gelatin is a natural, thermogelling polymer. It is a tasteless and colorless mixture of derived proteins of the albuminous class which is ordinarily soluble in warm water.
  • Two types of gelatin - Type A and Type B - are commonly used.
  • Type A gelatin is a derivative of acid-treated raw materials.
  • Type B gelatin is a derivative of alkali- treated raw materials.
  • Bloom is defined as the weight in grams required to move a half-inch diameter plastic plunger 4 mm into a 6.67% gelatin gel that has been held at 10°C for 17 hours.
  • the flowable material is an aqueous solution comprising 20% 275 Bloom pork skin gelatin, 20% 250 Bloom bone gelatin, and approximately 60% water.
  • the dipped coating portion comprises at least one pH dependent polymer.
  • Suitable pH dependent polymers for use in the dipped coating portion include but are not limited to include enteric cellulose derivatives, for example hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate phthalate; natural resins such as shellac and zein; enteric acetate derivatives such as for example polyvinylacetate phthalate, cellulose acetate phthalate, acetaldehyde dimethylcellulose acetate; and enteric acrylate derivatives such as for example polymethacrylate-based polymers such as poly(methacrylic acid, methyl methacrylate) 1:2, which is commercially available from Rohm Pharma GmbH under the tradename EUDRAGIT S, and poly(methacrylic acid, methyl methacrylate) 1 : 1, which is commercially available from Rohm Pharma GmbH under the tradename EUDRAGIT L, and the like, and derivatives, salts,
  • the dipped coated portion comprises at least one plasticizer.
  • plasticizers include but are not limited to polyethylene glycol; propylene glycol; glycerin; sorbitol; triethyl citrate; tribuyl citrate; dibutyl sebecate; vegetable oils such as castor oil, rape oil, olive oil, and sesame oil; surfactants such as polysorbates, sodium lauryl sulfates, and dioctyl-sodium sulfosuccinates; mono acetate of glycerol; diacetate of glycerol; triacetate of glycerol; natural gums; triacetin; acetyltributyl citrate; diethyloxalate; diethylmalate; diethyl fumarate; diethylmalonate; dioctylphthalate; dibutylsuccinate; glyceroltributyrate; hydrogenated castor oil;
  • the tablet core or a portion thereof comprises at least one osmagent, an osmotically effective solute or osmotically effective compound that can be blended homogeneously or heterogeneously with the core constituents to form a push member, acting as osmotically effective solutes that are soluble in liquid medium imbibed into the core, and exhibit an osmotic pressure gradient across the semi-permeable shell or shell portion against an exterior liquid medium.
  • Osmagents useful in the present invention include compounds disclosed at col. 8, lines 18-35, of U.S. Patent No. 5,830,501, which is incorporated herein by reference.
  • the core or a portion thereof comprises at least one osmopolymer.
  • the osmopolymer if employed, exhibits fluid absorbing and or fluid imbibing properties.
  • the osmopolymer comprises a hydrophilic polymer that can interact with water and aqueous biological fluids and then swell or expand to an equilibrium state. The osmopolymer exhibits the ability to retain a significant portion of the imbibed or absorbed fluid.
  • osmopolymers include poly(hydroxyalkyl methacrylate) having a molecular weight of 20,000 to 5,000,000; poly(vinylpyrrolidone) having a molecular weight of about 10,000 to 360,000; poly(vinylalcohol) having a low acetate content and lightly cross-linked with glyoxal, formaldehyde, or glutaraidehyde and having a degree of polymerization from 2,000 to 30,000; poly(ethylene oxide) having a molecular weight from 10,000 to 7,800,000; acidic carboxy polymers known as carboxypolymethylene or as carboxyvinyl polymers, a polymer consisting of acrylic acid lightly cross-linked with polyallylsucrose and sold under the trade name CARBOPOL; acidic carboxy polymer having a molecular weight of 200,000 to 6,000,000, including sodium acidic carboxyvinyl hydrogel and potassium acidic carboxyvinyl hydrogel; CYANAMER polyacrylamide; and the like.
  • At least about 30% of the cross-sectional area of the semipermeable dipped portion, or semi-permeable dipped portion used in dosage forms of this invention is non-striated. In other embodiments, at least about 50% of the cross-sectional area of the semi-permeable dipped portion or semi-permeable dipped portion is non-striated. In yet other embodiments, at least about 80% of the cross-sectional area of the semipermeable dipped portion or semi-permeable dipped portion is non-striated.
  • “non-striated” means homogeneous with respect to appearance, and with respect to the internal structure of the dipped portion when viewed under any magnification and lighting conditions. For example a cross-section of the dipped portion is free of striations, and uniform with respect to refractive properties when observed utilizing a light microscope at a magnification of about 50 to about 400 times.
  • the thickness of the dipped coating is at least 75 microns, e.g., at least 150 microns.
  • the dipped portion is substantially free of pores having a diameter of 0.5-5.0 microns.
  • substantially free means that the dipped portion has a pore volume of less than about 0.02 cc/g, preferably less than about 0.01 cc/g, more preferably less than about 0.005 cc/g, in the pore diameter range of 0.5 to 5.0 microns.
  • Typical compressed materials have pore volumes of more than about 0.02 cc/g in this pore diameter range.
  • Pore volume, pore diameter and density may be determined using a Quantachrome Instruments PoreMaster 60 mercury intrusion porosimeter and associated computer software program known as "Porowin.” The procedure is documented in the Quantachrome Instruments PoreMaster Operation Manual.
  • the PoreMaster determines both pore volume and pore diameter of a solid or powder by forced intrusion of a non-wetting liquid (mercury), which involves evacuation of the sample in a sample cell (penetrometer), filling the cell with mercury to surround the sample with mercury, applying pressure to the sample cell by: (i) compressed air (up to 50 psi maximum); and (ii) a hydraulic (oil) pressure generator (up to 60000 psi maximum).
  • Intruded volume is measured by a change in the capacitance as mercury moves from outside the sample into its pores under applied pressure.
  • High pressure fluid (Dila AX, available from Shell Chemical Co.).
  • the cell (filled with mercury) is then removed and weighed.
  • the cell is then emptied into the mercury reservoir, and two tablets from each sample are placed in the cell and the cell is reassembled.
  • the weight of the cell and sample are then recorded.
  • the cell is then installed in the low-pressure station, the low-pressure option is selected from the menu, and the following parameters are set:
  • a tablet dosage form according to the present invention providing immediate release and sustained release during dissolution was manufactured using acetaminophen as model drug as follows.
  • a granulation containing acetaminophen (see Table 1) was compressed into tablets using a Carver Press.
  • the core tablets were then partially coated with methacrylate copolymer solution (see Table 2) using partial dip coating technology to a predetermined length along the longitudinal axis to form a low-permeable coating. Approximately 60 percent of the tablet length (long axis of the tablet) was coated with the polymer coating.
  • the dip coated tablets were then air dried at room temperature for 6-8 hours.
  • a controlled release tablet dosage form containing phenylephrine hydrochloride was manufactured.
  • the core tablet was manufactured using the formula in Table 4 and a Carver Press. Core tablets were partially dip coated to cover 75% of the tablet using the partial dip coating technology as described in Example 1 (Table 2) and tested for drug release. As seen in Figure 3, approximately 35% of the drug was released immediately from the uncoated portion and the rest of the drug was released slowly (greater than 6 hours).
  • the core tablets from Example 3 were partially dip coated with low-permeable polymer (Table 2) on one side and a semi-permeable polymer (Table 5) on the other side using partial dip coating technology. Approximtely 25 percent of the tablet length (long axis of the tablet) was coated with the semi-permeable polymer coating, and approximately 75 percent of the tablet length was coated with the low permeable polymer coating.
  • Methacrylate copolymer* poly (ethyl 12.5 19.23 acrylate, methyl methacrylate, trimethylaminoethyl- methacrylate chloride)(l:2:02)
  • a dosage form according to the present invention providing controlled release of ibuprofen was manufactured.
  • the formula of the core with 400 mg of active is given in Table 6.
  • dip coating of the tablets was performed by following the general procedure described in Example 1 using the coating solution composition provided in Table 7. This coating solution is based on an aqueous based polymeric dispersion. Core tablets were dip coated up to 50-60% of the length of the tablet.
  • the release profile of the dosage form prepared according to this example was measured using a USP type II apparatus in 0.1M phosphate buffer at pH 6.8. As seen in Figure 5, there was an immediate release of active (50%) followed by sustained release of active over 7.5 hours (>75% in 7.5 hr).
  • Figures 6A to 6C are illustrations showing dosage forms of the invention.
  • Figure 6A shows one-sided partial coated tablet with very low-permeable coating.
  • Figure 6B shows two-sided partial coated tablet with very low-permeable coating.
  • Figure 6C shows partial coated tablet with one side semi-permeable coating and other side very low-permeable coating.

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Abstract

L'invention porte sur une forme pharmaceutique, qui comprend un cœur de cachet contenant au moins un ingrédient actif, et ayant au moins un revêtement de libération modifiée qui entoure partiellement le cœur de cachet. Le cœur de cachet se présente, de préférence, sous la forme d'un cœur comprimé dans lequel le ou les revêtements de libération modifiée sont disposés sur une position de la surface extérieure du cœur comprimé à l'aide d'une technologie d'immersion. L'invention porte également sur un procédé de fabrication de la forme pharmaceutique et sur un procédé de traitement utilisant la forme pharmaceutique.
PCT/US2010/059228 2009-12-07 2010-12-07 Revêtement par immersion partielle de formes pharmaceutiques pour libération modifiée WO2011071877A2 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
BR112012013676A BR112012013676A2 (pt) 2009-12-07 2010-12-07 revestimento por imersão parcial de formas de dosagem para liberação modificada
CN2010800551678A CN102639122A (zh) 2009-12-07 2010-12-07 调释剂型的部分浸渍包衣
AU2010328353A AU2010328353B2 (en) 2009-12-07 2010-12-07 Partial dip coating of dosage forms for modified release
CA2780347A CA2780347A1 (fr) 2009-12-07 2010-12-07 Revetement par immersion partielle de formes pharmaceutiques pour liberation modifiee
EP10799155A EP2509587A2 (fr) 2009-12-07 2010-12-07 Revêtement par immersion partielle de formes pharmaceutiques pour libération modifiée

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US61/267,137 2009-12-07

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US9389337B1 (en) 2012-10-24 2016-07-12 Chia-Jean Wang Selective coating of a component using a potting process
US9132117B2 (en) 2013-06-17 2015-09-15 Kgk Synergize, Inc Compositions and methods for glycemic control of subjects with impaired fasting glucose
CN117427043A (zh) * 2022-07-21 2024-01-23 越洋医药开发(广州)有限公司 一种双相控释制剂及其制备方法

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See also references of EP2509587A2

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US20110135694A1 (en) 2011-06-09
WO2011071877A3 (fr) 2011-08-04
EP2509587A2 (fr) 2012-10-17
US9259394B2 (en) 2016-02-16
BR112012013676A2 (pt) 2016-04-19
CA2780347A1 (fr) 2011-06-16
AU2010328353A1 (en) 2012-05-31
AU2010328353B2 (en) 2015-07-16
CN102639122A (zh) 2012-08-15

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