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WO2006022996A2 - Forme posologique contenant des medicaments multiples - Google Patents

Forme posologique contenant des medicaments multiples Download PDF

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Publication number
WO2006022996A2
WO2006022996A2 PCT/US2005/020499 US2005020499W WO2006022996A2 WO 2006022996 A2 WO2006022996 A2 WO 2006022996A2 US 2005020499 W US2005020499 W US 2005020499W WO 2006022996 A2 WO2006022996 A2 WO 2006022996A2
Authority
WO
WIPO (PCT)
Prior art keywords
dosage form
drug
pharmaceutically acceptable
layer
layered tablet
Prior art date
Application number
PCT/US2005/020499
Other languages
English (en)
Other versions
WO2006022996A3 (fr
Inventor
Viswanathan Srinivasan
Ralph Brown
David Brown
Himanshu Patel
Juan Carlos Menendez
Venkatesh Balasubramanian
Somphet Peter Suphasawud
Original Assignee
Sovereign Pharmaceuticals, Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US10/910,806 external-priority patent/US20060029664A1/en
Priority claimed from US10/939,351 external-priority patent/US9492541B2/en
Priority claimed from US11/012,267 external-priority patent/US9592197B2/en
Priority claimed from US11/102,725 external-priority patent/US20050281875A1/en
Priority claimed from US11/102,726 external-priority patent/US20070003622A1/en
Priority claimed from US11/115,293 external-priority patent/US20050232993A1/en
Priority claimed from US11/115,321 external-priority patent/US20050266032A1/en
Application filed by Sovereign Pharmaceuticals, Ltd. filed Critical Sovereign Pharmaceuticals, Ltd.
Publication of WO2006022996A2 publication Critical patent/WO2006022996A2/fr
Publication of WO2006022996A3 publication Critical patent/WO2006022996A3/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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to a pharmaceutical dosage form which comprises a first drug and a second drug, both of which are selected from decongestants, antitussives, expectorants, analgesics and antihistamines.
  • the dosage form releases the first drug and the second drug so as to provide pharmaceutically effective plasma concentrations of these drugs over similar periods of time.
  • the present invention also relates to a process for manufacturing the dosage form and to methods for alleviating conditions which can be alleviated by a combination of these drugs.
  • Conditions such as colds and allergies are accompanied by a variety of symptoms which frequently can not satisfactorily be ameliorated or treated with a single drug but require the administration of two or more drugs.
  • Drugs which are indicated for the amelioration of cold and allergy related symptoms often belong to at least one of the following classes: antihistamines, decongestants, antitussives, expectorants and analgesics.
  • antihistamines drugs which are indicated for the amelioration of cold and allergy related symptoms
  • decongestants drugs which are required for the amelioration of the various symptoms that a patient is experiencing it would be expedient to administer all of these drugs in a single dosage form, or at least in as few dosage forms as possible.
  • these different drags have significantly different pharmacokinetic properties.
  • a single dose of a first indicated drug may provide a therapeutically effective plasma concentration for a period of time which is significantly longer than the therapeutically effective plasma concentration that is provided by a single dose of a second indicated drug.
  • a dosage form such as, e.g., a tablet, liquid, syrup, suspension, gel, capsule, suppository and the like.
  • a dosage form such as, e.g., a tablet, liquid, syrup, suspension, gel, capsule, suppository and the like.
  • the present invention provides a pharmaceutical dosage form which comprises a first drug and a second drug, both of which are selected from decongestants, antitussives, expectorants, analgesics and antihistamines and preferably belong to different classes of drugs.
  • the dosage form provides a plasma concentration within the therapeutic range of the second drug over a period which is coextensive with at least about 70 % of the period over which the dosage form provides a plasma concentration within the therapeutic range of the first drug.
  • the first drug may comprise a decongestant.
  • the decongestant may comprise phenylephrine and/or pseudoephedrine and/or one or more pharmaceutically acceptable salts of one or both of two decongestants.
  • the first drug may comprise an antitussive.
  • the antitussive may comprise one or more of a morphine derivative such as, e.g., codeine, dihydrocodeine, hydrocodone and hydromorphone, dextromethorphan, carbetapentane, chlophedianol, benzonatate, caramiphen, noscapine and/or one or more pharmaceutically acceptable salts of one or more of these antitussive drugs.
  • the first drug may comprise an antihistamine.
  • Non-limiting examples of antihistamines for use in the present invention include acrivastine, astemizole, azatadine, azelastine, bromodiphenhydramine, brompheniramine, carbinoxamine, carebastine, cetirizine, chlophedianol, chlorcyclizine, clemastine, chlorothen, chlorpheniramine, cyclizine, cyproheptadine, descarboethoxyloratadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, dimethindene, diphenhydramine, diphenylpyraline, doxylamine, ebastine, epanastine, efletirizine, fexofenadine, hydroxyzine, isothipendyl, ketotifen, loratadine, meclizine, methapyrilene, mizolastine, mequitazin
  • the antihistamine may comprise at least one of promethazine, diphenhydramine, chlorpheniramine, carbinoxamine and pharmaceutically acceptable salts thereof.
  • the first drug may comprise an analgesic.
  • the analgesic may comprise one or more of aspirin, acetaminophen, ibuprofen, ketoprofen, naproxen, sodium naproxen, meloxicam, hydrocodone, oxycodone, morphine, meperidine and fentanyl.
  • the first drug may comprise an expectorant such as, e.g., guaifenesin and/or a pharmaceutically acceptable salt thereof.
  • the second drug may comprise a decongestant and/or an antitussive and/or an antihistamine and/or an analgesic and/or an expectorant.
  • a decongestant and/or an antitussive and/or an antihistamine and/or an analgesic and/or an expectorant include those which are given above as non-limiting examples of the first drug.
  • the plasma half-life of the second drug may differ from the plasma half-life of the first drug by at least about 2 hours, e.g., by at least about 3 hours, or by at least about 4 hours.
  • the plasma concentration within the therapeutic range of the second drug may be coextensive with at least about 80 %, e.g., at least about 90 %, or at least about 95 %, of the period of a plasma concentration within the therapeutic range of the first drug.
  • the dosage form may comprise a tablet such as, e.g., a bi-layered tablet.
  • the tablet may comprise a matrix which comprises the first drag or the second drug and has dispersed therein particles which comprise the other one of the first drug and the second drug.
  • the dosage form may comprise a solution or a suspension.
  • the present invention also provides a bi-layered tablet which comprises a first layer and a second layer.
  • the first layer comprises a first drug which is selected from decongestants, antitussives, expectorants, analgesics and antihistamines
  • the second layer comprising a second drug which is also selected from decongestants, antitussives, expectorants, analgesics and antihistamines but is different from the first drug and preferably belongs to a different class than the first drug.
  • the bi-layered tablet provides a plasma concentration within the therapeutic range of the second drug over a period which is coextensive with at least about 70 % of the period over which the bi-layered tablet provides a plasma concentration within the therapeutic range of the first drug.
  • the first layer and/or the second layer may comprise at least one drug that is selected from phenylephrine, pseudoephedrine, codeine, dihydrocodeine, hydrocodone, dextromethorphan, carbetapentane, chlophedianol, benzonatate, caramiphen, noscapine, guaifenesin, acrivastine, astemizole, azatadine, azelastine, bromodiphenhydramine, brompheniramine, carbinoxamine, carebastine, cetirizine, chlophedianol, chlorcyclizine, clemastine, chlorothen, chlorpheniramine, cyclizine, cyproheptadine, descarboethoxyloratadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, dimethindene, di
  • the period of a plasma concentration within the therapeutic range of the second drug may be coextensive with at least about 80 %, e.g., at least about 90 %, or at least about 95 %, of the period of a plasma concentration within the therapeutic range of the first drug.
  • the plasma half-life of the second drug may differ from the plasma half-life of the first drug by at least about 2 hours, for example, by at least about 3 hours.
  • the first or the second layer may be an immediate release layer, or the first and the second layers may both be controlled release layers.
  • the present invention also provides a multi-layered tablet which comprises at least a first layer and a second layer.
  • the first layer comprises a first drug which is selected from decongestants, antitussives, expectorants, analgesics and antihistamines and the second layer is a controlled release layer and comprises a second drug which is selected from decongestants, antitussives, expectorants, analgesics and antihistamines and is different from the first drug and preferably belongs to a different class than the first drug.
  • the first layer may be an immediate release layer and/or the second layer may be a controlled release layer.
  • the second drug may have a plasma half-life which differs from the plasma half-life of the first drug by at least about 2 hours, for example, by at least about 3 hours.
  • the tablet may provide a plasma concentration within the therapeutic range of the second drug over a period which is coextensive with at least about 90 % of the period over which the tablet provides a plasma concentration within the therapeutic range of the first drug.
  • the layers thereof may be discrete zones which are arranged adjacent to each other, or one of the first and second layers may be partially or completely surrounded by the other one of the first and second layers.
  • the present invention also provides a pharmaceutical dosage form which comprises a first drug which is selected from antihistamines and has a first plasma half-life, and a second drug which is selected from decongestants, antitussives, analgesics and expectorants and has a second plasma half-life that differs from the first plasma half-life by at least about 3 hours.
  • the dosage form provides a plasma concentration within the therapeutic range of the second drug over a period which is coextensive with at least about 80 % of the period over which the dosage form provides a plasma concentration within the therapeutic range of the first drug.
  • the first plasma half-life may be longer by at least about 4 hours, e.g., longer by at least about 6 hours, than the second plasma half-life. In another aspect, the first plasma half-life may be at least about 8 hours.
  • the period of a plasma concentration within the therapeutic range of the at least one second drug may be coextensive with at least about 90 %, e.g., at least about 95 %, or about 100 % of the period of a plasma concentration within the therapeutic range of the first drug.
  • the dosage form may be associated with instructions to administer the dosage form three or fewer times per day, e.g., once or twice per day.
  • the dosage form may comprise a tablet.
  • the second drug may comprise a decongestant.
  • the antihistamine may be selected from acrivastine, astemizole, azatadine, azelastine, bromodiphenhydramine, brompheniramine, carbinoxamine, carebastine, cetirizine, chlorcyclizine, clemastine, chlorothen, chlorpheniramine, cyclizine, cyproheptadine, descarboethoxyloratadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, dimethindene, diphenhydramine, diphenylpyraline, doxylamine, ebastine, epanastine, efletirizine, fexofenadine, hydroxyzine, isothipendyl, ketotifen, loratadine, meclizine, methapyrilene, mizolastine, mequitazine, mianserin, montel
  • the present invention also provides dosage forms as set forth above, including the various aspects thereof, which dosage forms are substantially free of antihistamines.
  • the present invention also provides a method of alleviating a condition which can be alleviated by administration of an antihistamine and at least one other condition which can be alleviated by administration of a drug which is at least one of a decongestant, an antitussive, an expectorant and an analgesic, wherein the method comprises administering a dosage form of the present invention, including the various aspects thereof, to a subject in need thereof.
  • the present invention also provides a process of making a pharmaceutical dosage form of the present invention, wherein the method comprises preparing a first composition which comprises the first drug and a second composition which comprises the second drug, and combining the first and the second compositions, for example, by using a tablet press.
  • the pharmaceutical dosage forms of the present invention comprise at least two drugs, i.e., a first drug and a second drug. It is noted that the terms "a first drug” and "a second drug” do not exclude, but rather include the presence of more than one first or second drug.
  • the dosage form may comprise one first drug and two or more (e.g., three, four, five, etc.) second drugs.
  • the dosage form desirably provides plasma concentrations within the therapeutic ranges of all of the second drugs over periods of time which individually are coextensive with at least about 70 % (e.g., at least about 80 %, at least about 90 %, at least about 95 %, or at least about 100 %) of the period of time over which the dosage form provides a plasma concentration within the therapeutic range of the first drug.
  • the first drug with the longest period of a plasma concentration with the therapeutic range is the standard, i.e., preferably all other drugs that are present in the dosage form show plasma concentrations within the therapeutic ranges thereof over periods of time which are coextensive with at least about 70 % (e.g., at least about 80 %, at least about 90 %, at least about 95 %, or at least about 100 %) of the period for the first drug with the longest period of a plasma concentration with the therapeutic range.
  • the pharmaceutical dosage form which constitutes one aspect of the present invention comprises first and second drugs which may be present in the form of a pharmaceutically acceptable salt thereof.
  • pharmaceutically acceptable salt refers to those salts of a particular drug that are not substantially toxic at the dosage administered to achieve the desired effect and do not independently possess significant pharmacological activity.
  • the salts included within the scope of this term are pharmaceutically acceptable acid addition salts of a suitable inorganic or organic acid.
  • suitable inorganic acids are, for example hydrochloric, hydrobromic, sulfuric and phosphoric acids.
  • Non-limiting examples of suitable organic acids include carboxylic acids, such as acetic, propionic, tannic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, cyclamic, ascorbic, maleic, hydroxymaleic, benzoic, phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic, anthranillic, cinnamic, salicylic, 4-aminosalicyclic, 2-phenoxybenzoic, 2-acetoxybenzoic and mandelic acids, as well as sulfonic acids, such as methanesulfonic, ethanesulfonic, and ⁇ - hydroxyethanesulfonic acids.
  • carboxylic acids such as acetic, propionic, tannic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, cyclamic, ascorbic, maleic
  • Non-limiting examples of drugs for use in the present invention in the form of their pharmaceutically acceptable salts include codeine phosphate, codeine sulfate, hydrocodone bitartrate, dihydrocodeine bitartrate, carbetapentane citrate, pseudoephedrine hydrochloride, phenephrine hydrochloride, azatadine maleate, bromodiphenhydramine HCl, brompheniramine maleate, carbinoxamine maleate, cetirizine HCl, chlorcyclizine HCl, clemastine fumarate, chlorothen citrate, chlorpheniramine maleate, dimethindene maleate, diphenhydramine HCl, fexofenadine HCl, hydroxyine HCl, isothipendyl HCl (theruhistin), methapyrilene fumarate, methapyrilene HCl, montelukast sodium, phenindamine tartrate, phen
  • the dosage form of the present invention will usually provide a plasma concentration within the therapeutic range of the second drug over a period which is coextensive with (overlaps) at least about 70 %, more preferred at least about 80 %, e.g., at least about 90 %, at least about 95 %, or about 100 %, of the period over which the dosage form provides a plasma concentration within the therapeutic range of the first drug.
  • therapeutic range refers to the range of drug levels (including active metabolite levels) within which most patients will experience a significant therapeutic effect (including alleviation of symptoms) without an undesirable degree of adverse reactions.
  • the term “coextensive with” does not exclude, but rather includes, cases where a part of the period over which the plasma concentration of the second drug (and/or active metabolites thereof) is within the therapeutic range is outside the period over which the plasma concentration of the first drug is within the therapeutic range.
  • a certain percentage preferably not more than about 30 %, e.g., not more than about 20 %, not more than about 10 % or even not more than about 5 %) of the total period over which the plasma concentration of the second drug is within the therapeutic range may be outside the period over which the plasma concentration of the first drug is within the therapeutic range.
  • the period over which the therapeutic range of a particular drug may be provided in a given case depends, at least in part, on the plasma half-life of the drug and/or active metabolites thereof.
  • plasma half-life refers to the time required for the plasma drug concentration to decline by 50 %. The shorter the plasma half-life of a particular drug, the shorter will be the period within the therapeutic range of the drug which is provided by a single administered dose of the drug.
  • the plasma half-life of the second drug will be shorter than the plasma half-life of the first drug by at least about 2 hours, e.g., by at least about 3 hours, by at least about 4 hours, by at least about 5 hours, by at least about 6 hours, by at least about 8 hours, or even by at least about 10 hours.
  • a preferred, although non-limiting, embodiment of the dosage form of the present invention is a tablet, in particular, a bi-layered tablet.
  • Non-limiting examples of other embodiments of the dosage form of the invention are capsules, pills, chewable tablets, suspensions, solutions, syrups, and suppositories.
  • the bi-layered tablet which forms one of the aspects of the present invention comprises two layers.
  • the first layer comprises a first drug which is selected from decongestants, antitussives, expectorants, analgesics and antihistamines.
  • the second layer comprises a second drug which is different from the first drug and is selected from decongestants, antitussives, expectorants, analgesics and antihistamines. Specific and non- limiting examples of such drugs are given above.
  • the bi-layered tablet or any other dosage form of the present invention is preferred for the bi-layered tablet or any other dosage form of the present invention to be substantially antihistamine-free, i.e., neither the first nor the second drug comprise more than insignificant amounts of antihistamines or any other drugs which have a substantial drying action.
  • the layers of the bi-layered tablet of the present invention may individually be immediate release layers or controlled release layers.
  • controlled release layer refers to any layer that is not an immediate release layer, i.e., does not release all of the active ingredients contained therein within a relatively short time (for example, within less than 1 hour, e.g., less than 0.5 hours, following ingestion of the dosage form). Accordingly, this term is a generic term which encompasses, e.g., sustained (extended) release layers, pulsed release layers, delayed release layers, and the like.
  • the controlled release layer releases the one or more drugs contained therein continuously or intermittently and, preferably, in approximately equal amounts per time unit (e.g., zero order release rate), over an extended period of time such as, e.g., at least about 2 hours, at least about 3 hours, at least about 4 hours, or at least about 6 hours.
  • time unit e.g., zero order release rate
  • the desirable length of the time period of continuous or intermittent (e.g., pulsed) release depends, inter alia, on the plasma half-life of the drug and/or an active metabolite thereof.
  • the first and second layers of the bi-layered tablet of the present invention will usually contain the first and second drugs in amounts which are commensurate with the intended duration of action but will not give rise to overdosing when present in the intended form (e.g., a particular pharmaceutically acceptable salt) and the intended release matrix (e.g., immediate release, controlled release, etc.).
  • the intended form e.g., a particular pharmaceutically acceptable salt
  • the intended release matrix e.g., immediate release, controlled release, etc.
  • a drug may be present in both the first layer and the second layer (and any additional layer, if present), for example, in order to obtain an as fast as possible release and, thus action of the drug (e.g., by using an immediate release matrix) and to at the same time extend the duration of the action of the drug (e.g., by using a controlled release matrix that releases the drug at a lower rate and/or at a later time than the immediate release layer).
  • action of the drug e.g., by using an immediate release matrix
  • a controlled release matrix that releases the drug at a lower rate and/or at a later time than the immediate release layer.
  • Promethazine at least about 0.1 mg, e.g., at least about 5 mg, at least about 6 mg, at least about 8 mg, at least about 12 mg, or at least about 25 mg, but not more than about 90 mg, e.g., not more than about 75 mg, not more than about 70 mg, not more than about 60 mg, or not more than about 50 mg of promethazine hydrochloride, or an equivalent amount (on a molar basis) of promethazine and/or any other pharmaceutically acceptable salt thereof.
  • Chlorpheniramine at least about 0.1 mg, e.g., at least about 2 mg, or at least about 4 mg, but not more than about 16 mg, e.g., not more than about 12 mg of chlorpheniramine maleate, or an equivalent amount of chlorpheniramine and/or any other pharmaceutically acceptable salt thereof.
  • Carbinoxamine at least about 0.1 mg, e.g., at least about 6 mg, but not more than about 32 mg, e.g., not more than about 24 mg of carbinoxamine maleate, or an equivalent amount of carbinoxamine and/or any other pharmaceutically acceptable salt thereof.
  • Diphenhydramine at least about 10 mg, e.g., at least about 15 mg, at least about 20 mg, at least about 40 mg, at least about 70 mg, or at least about 90 mg, but not more than about 200 mg, e.g., not more than about 150 mg, not more than about 120 mg, or not more than about 100 mg of diphenhydramine hydrochloride, or an equivalent amount of diphenhydramine and/or any other pharmaceutically acceptable salt thereof.
  • Carbetapentane at least about 1 mg, e.g., at least about 5 mg, at least about 10 mg, at least about 25 mg, or at least about 50 mg, but not more than about 120 mg, e.g., not more than about 100 mg, not more than about 70 mg, or not more than about 60 mg, of carbetapentane citrate, or an equivalent amount of carbetapentane and/or any other pharmaceutically acceptable salt thereof.
  • Codeine at least about 1 mg, e.g., at least about 10 mg, at least about 25 mg, or at least about 30 mg, but not more than about 120 mg, e.g., not more than about 80 mg, not more than about 60 mg, or not more than about 45 mg, of codeine phosphate, or an equivalent amount of codeine and/or any other pharmaceutically acceptable salt thereof.
  • Dihydrocodeine at least about 1 mg, e.g., at least about 5 mg, but not more than about 30 mg, e.g., not more than about 20 mg, of dihydrocodeine bitartrate, or an equivalent amount of dihydrocodeine and/or any other pharmaceutically acceptable salt thereof.
  • Hydrocodone at least about 1 mg, e.g., at least about 5 mg, but not more than about
  • hydrocodone bitartrate 20 mg, e.g., not more than about 15 mg, of hydrocodone bitartrate, or an equivalent amount of hydrocodone and/or any other pharmaceutically acceptable salt thereof.
  • Phenylepherine at least about 1 mg, e.g., at least about 10 mg, or at least about 15 mg, but not more than about 125 mg, e.g., not more than about 100 mg, not more than about
  • phenylephrine hydrochloride 90 mg, not more than about 75 mg, not more than about 50 mg, or not more than about 25 mg of phenylephrine hydrochloride, or an equivalent amount of phenylephrine and/or any other pharmaceutically acceptable salt thereof.
  • Pseudoephedrine at least about 1 mg, e.g., at least about 10 mg, at least about 25 mg, or at least about 50 mg, but not more than about 240 mg, e.g., not more than about 150 mg, not more than about 100 mg, or not more than about 70 mg of pseudoephedrine hydrochloride, or an equivalent amount of pseudoephedrine and/or any other pharmaceutically acceptable salt thereof.
  • Guaifenesin at least about 1 mg, e.g., at least about 10 mg, at least about 25 mg, at least about 50 mg, or at least about 100 mg, but not more than about 2400 mg, e.g., not more than about 1600 mg, not more than about 1500 mg, not more than about 1200 mg, not more than about 1000 mg, not more than about 600 mg, or not more than about 500 mg of guaifenesin, or an equivalent amount of a pharmaceutically acceptable salt thereof.
  • Acetaminophen at least about 10 mg, e.g., at least about 50 mg, or at least about 100 mg, but not more than about 1000 mg, e.g., not more than about 500 mg, or not more than about 250 mg of acetaminophen.
  • Another aspect of the present invention is a multi-layered tablet which comprises at least a first layer and a second layer, but may optionally comprise a third, fourth, fifth, etc. layer.
  • the first layer may be an immediate release layer or a controlled release layer, depending on the drug(s) contained therein and the desired release characteristics thereof, and comprises at least one first drug which is selected from decongestants, antitussives, expectorants, analgesics and antihistamines.
  • the mandatory second layer may also be an immediate release layer or a controlled release layer, depending on the drug(s) contained therein and the desired release characteristics thereof, and comprises at least one second drug which is different from the first drug and is selected from decongestants, antitussives, expectorants, analgesics and antihistamines. If more than two drugs are to be incorporated in the tablet, the first and/or the second layer may contain all of the additional drugs. Alternatively, separate additional layers may be provided for the additional drugs, for example, in cases where it would be difficult to design a controlled release layer which provides a desired release rate for both the first or second drug and/or the additional drug(s). Of course, a fourth, fifth, etc.
  • the second and a third layer may contain the same drug or drugs, but in different (relative) concentrations and/or incorporated in a different controlled release formulation.
  • the multi-layered tablet of the present invention will usually be made up of two or more distinct layers or discrete zones of granulation compressed together with the individual layers lying on top of one another. Layered tablets have the appearance of a sandwich because the edges of each layer or zone are exposed. Such conventional layered tablets are generally prepared by compressing a granulation onto a previously compressed granulation. The operation may be repeated to produce multi-layered tablets of more than two layers. In a preferred embodiment of the multi-layered tablet of the present invention, the tablet consists of two layers. [0058] It is to be noted that it is not necessary for the two or more individual layers of the multi-layered tablet of the present invention to lie on top of one another.
  • a second layer e.g., sustained release layer
  • a first layer e.g., an immediate release layer
  • the second layer may be coated with the first layer.
  • the third layer may be partially or completely coated with the second layer, which in turn may be partially or completely coated with the first layer.
  • the tablet may comprise an immediate release matrix which comprises one or more first drugs, which matrix has dispersed therein particles of one or more sustained release formulations which have the one or more second drugs and any of the additional desired drug(s) incorporated therein.
  • the at least one drug in the second layer may have a plasma half-life which is shorter by at least about 3 hours, e.g., shorter by at least about 4 hours, or shorter by at least about 6 hours, than the plasma half-life of the first drug or the first drug with the longest plasma half-life, respectively.
  • the tablet may provide a plasma concentration within a therapeutic range of the drug(s) in the second layer over a period which is coextensive with at least about 80 %, e.g., at least about 90 %, of the period over which the multi-layered tablet provides a plasma concentration within the therapeutic range of the drug(s) in the first layer.
  • a liquid dosage form preferably a suspension, which comprises (a) a first drug which is selected from decongestants, expectorants, antitussives, analgesics and antihistamines and (b) a second drug which is selected from decongestants, expectorants, antitussives, analgesics and antihistamines and is different from the first drug.
  • This liquid dosage form provides a plasma concentration within the therapeutic range of component (b) over a period which is coextensive with at least about 70 %, preferably at least 80 %, e.g., at least 90 %, of the period over which the liquid dosage form provides a plasma concentration within the therapeutic range of component (a).
  • component (b) may be incorporated into a solid controlled release formulation.
  • particles of component (b) may be provided with a controlled release coating (e.g. a controlled release coating comprising an organic polymer such as, e.g., a polyacrylate).
  • This formulation may then be comminuted, if necessary, in an appropriate manner (e.g., by milling) to form particles of a size which is small enough to be suitable for being suspended in a pharmaceutically acceptable liquid carrier.
  • Component (a) on the other hand, may be used as such or incorporated in a solid immediate release formulation, comminuted and incorporated into the liquid carrier as well.
  • a non-limiting example of a corresponding procedure is described in the Examples below.
  • component (a) and (b) Prior to incorporating components (a) and (b) into a pharmaceutically acceptable liquid carrier to form a liquid dosage form according to the present invention, at least a part of component (a) and/or at least a part of component (b) may be converted into a complex with a complexing agent.
  • suitable complexing agents comprise ion- exchange resins such as, e.g., (sodium) polystyrene sulfonate.
  • the dosage forms of the present invention can be manufactured by processes which are well known to those of skill in the art.
  • the active ingredients may be dispersed uniformly into a mixture of excipients, for example, by high shear granulation, low shear granulation, fluid bed granulation, or by blending for direct compression.
  • Excipients may include diluents, binders, disintegrants, dispersants, lubricants, glidants, stabilizers, surfactants and colorants.
  • Diluents, also termed "fillers” are typically used to increase the bulk of a tablet so that a practical size is provided for compression.
  • Non-limiting examples of diluents include lactose, cellulose, microcrystalline cellulose, mannitol, dry starch, hydrolyzed starches, powdered sugar, talc, sodium chloride, silicon dioxide, titanium oxide, dicalcium phosphate dihydrate, calcium sulfate, calcium carbonate, alumina and kaolin. Binders impart cohesive qualities to a tablet formulation and are used to ensure that a tablet remains intact after compression.
  • Non-limiting examples of suitable binders include starch (including corn starch and pregelatinized starch), gelatin, sugars (e.g., glucose, dextrose, sucrose, lactose and sorbitol), celluloses, polyethylene glycol, waxes, natural and synthetic gums, e.g., acacia, tragacanth, sodium alginate, and synthetic polymers such as polymethacrylates and polyvinylpyrrolidone.
  • Lubricants facilitate tablet manufacture; non-limiting examples thereof include magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, and polyethylene glycol.
  • Disintegrants facilitate tablet disintegration after administration, and non-limiting examples thereof include starches, alginic acid, crosslinked polymers such as, e.g., crosslinked polyvinylpyrrolidone, croscarmellose sodium, potassium or sodium starch glycolate, clays, celluloses, starches, gums and the like.
  • suitable glidants include silicon dioxide, talc and the like.
  • Stabilizers inhibit or retard drug decomposition reactions, including oxidative reactions.
  • Surfactants may be anionic, cationic, amphoteric or nonionic.
  • the tablets may also contain minor amounts of nontoxic auxiliary substances such as pH buffering agents, preservatives, e.g., antioxidants, wetting or emulsifying agents, solubilizing agents, coating agents, flavoring agents, and the like.
  • auxiliary substances such as pH buffering agents, preservatives, e.g., antioxidants, wetting or emulsifying agents, solubilizing agents, coating agents, flavoring agents, and the like.
  • Extended/sustained release formulations may be made by choosing the right combination of excipients that slow the release of the active ingredients by coating or temporarily bonding or decreasing the solubility of the active ingredients.
  • excipients include cellulose ethers such as hydroxypropylmethylcellulose (e.g., Methocel K4M), polyvinylacetate-based excipients such as, e.g., Kollidon SR, and polymers and copolymers based on methacrylates and methacrylic acid such as, e.g., Eudragit NE 3OD.
  • cellulose ethers such as hydroxypropylmethylcellulose (e.g., Methocel K4M)
  • polyvinylacetate-based excipients such as, e.g., Kollidon SR
  • polymers and copolymers based on methacrylates and methacrylic acid such as, e.g., Eudragit NE 3OD.
  • Manesty RotaPress Diamond a 45 station D tooling press
  • a 45 station D tooling press is capable of making bi-layered tablets described in this application.
  • Non-limiting examples of presses for the manufacture of bi-layered tablets include Fette America Model No. PT 3090; Maneklal Global Exports (Mumbai, India) Models JD and DH series; Niro Pharma Systems, Model R292F; and Korsch AG Models XL 800 and XL 400.
  • a liquid dosage form in accordance with the present invention which comprises promethazine hydrochloride, dihydrocodeine bitartrate and phenylephrine hydrochloride is illustrated as follows: Ingredients . Per 5 mL Per 425 L
  • Manufacturing process for 425 L batch size In a suitably sized stainless steel vessel, dissolve methyl paraben and propyl paraben in approximately 50L of warm (about 45 0 C), purified water. Add about half of the propylene glycol and mix for about 1 hr. In a separate 1000 L stainless steel tank equipped with a suitably sized agitator, add about 50 L of purified water. With the agitator on, add phenylephrine hydrochloride, promethazine hydrochloride, saccharin sodium and citric acid and dissolve.Add the previously prepared paraben/propylene glycol solution to the 1000 L tank. Rinse the first vessel with about 2 L of water and transfer the rinsate to the 1000 L tank.
  • a suspension formula in accordance with the present invention which comprises promethazine hydrochloride and phenylephrine tannate is illustrated as follows:
  • Citric Acid Monohydrate USP 0.16 1.333
  • Manufacturing process for 1000 kg batch In a suitably sized stainless steel vessel, dissolve saccharin sodium, sodium benzoate, citric acid, and sodium citrate in approximately 50L of warm (about 45 deg C), purified water. In another large stainless steel drum mix the silica, promethazine hydrochloride and micronized phenylephrine tannate until a uniform and consistent mixture is obtained. In a separate 1000 L stainless steel tank equipped with a suitably sized homogenizer/disperser add about 100 L of purified water. With the homogenizer on, add the silica mixture containing phenylephrine tannate and promethazine hydrochloride.
  • a bi-layered tablet in accordance with the present invention which comprises promethazine hydrochloride in one layer and phenylephrine hydrochloride and chlorpheniramine maleate in the other layer is illustrated as follows:
  • a bi-layered tablet of the following composition may be manufactured by using direct compression:
  • a bi-layered tablet in accordance with the present invention which comprises promethazine hydrochloride in one layer and pseudoephedrine hydrochloride and chlorpheniramine maleate in the other layer is illustrated as follows:
  • (a) Immediate release layer Screen all ingredients through a USP sieve size # 30. Blend promethazine hydrochloride (35.7 gms), silicified microcrystalline cellulose (158.6 gms) and croscarmellose sodium (14.3 gms) in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (4.3 gms povidone in 14.3 gms purified water). Dry the granulation until the loss on drying (LOD) is less than 2.0 %. Screen the dried granulation through a USP sieve size # 14.
  • LOD loss on drying
  • (b) Sustained release layer Screen all ingredients through a USP sieve size # 30. Blend the pseudoephedrine hydrochloride (87.5 gms), chlorpheniramine maleate (11.4 gms), microcrystalline cellulose PH 102 (42.9 gms), lactose monohydrate (142.9 gms), dicalcium phosphate (142.9gms), Methocel K4M Premium (302.9 gms) and stearic acid (28.6 gms) in a high shear mixer/granulator for 10 minutes.Granulate the above blend using a 30 % povidone solution (21.4 gms povidone in 71.3 gms purified water).
  • the above examples illustrate how to manufacture a bi-layered tablet containing an antihistamine, i.e., promethazine hydrochloride, in one layer and an antihistamine and/or a decongestant and/or an antitussive and/or an expectorant in the other layer.
  • an antihistamine i.e., promethazine hydrochloride
  • an antihistamine and/or a decongestant and/or an antitussive and/or an expectorant in the other layer.
  • combinations of one or more of each of the non-limiting examples of possible ingredients in an exemplary range as described in the following Table 1 can be made depending on the specific therapeutic effect desired.
  • Any active drug which is in the form of a salt such as promethazine hydrochloride, codeine phosphate, pseudoephedrine hydrochloride, morphine sulfate, or meperidine hydrochloride can be incorporated as an ion-exchange resin complex.
  • Granulate the drug/resin complex with a delayed release/enteric polymer e.g. Eugragit® L 100, Kollidon® MAE, Aquacoa®t cPD
  • a delayed release/enteric polymer e.g. Eugragit® L 100, Kollidon® MAE, Aquacoa®t cPD
  • Carbomer e.g., Carbopol® 974
  • glycerin glycerin
  • polysorbate 80 methyl paraben, propyl paraben, artificial grape flavor, FD&C red # 40 dye.
  • a bi-layered tablet in accordance with the present invention which comprises guaifenesin in a first sustained release layer and codeine phosphate and pseudoephedrine hydrochloride in a second sustained release layer is illustrated as follows:
  • Sustained release layer #1 Mix the guaifenesin, Methocel®K15M and silicified microcrystalline cellulose in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Dry the granulation until the LOD (weight loss on drying) is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes. [0088] (b) Sustained release layer #2: Screen all ingredients through a USP sieve size # 30.
  • a bi-layered tablet in accordance with the present invention which comprises promethazine hydrochloride in an immediate release layer and codeine phosphate and pseudoephedrine hydrochloride in a sustained release layer is illustrated as follows:
  • Immediate release layer #1 Mix the promethazine HCl, silicified microcrystalline cellulose and croscarmellose sodium, in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (3.0 gms povidone in 10.0 gms purified water). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.
  • Sustained release layer #2 Mix the codeine phosphate, pseudoephedrine HCl, microcrystalline cellulose PH 102, dicalcium phosphate, Methocel K4M Premium and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (15.0 gms povidone in 50.0 gms purified water). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.
  • a bi-layered tablet in accordance with the present invention which comprises phenylephrine hydrochloride and carbinoxamine maleate in a first sustained release layer and codeine phosphate in a second sustained release layer is illustrated as follows:
  • Sustained release layer #1 Mix the phenylephrine HCl, carbinoxamine maleate, Methocel®K4M and silicified microcrystalline cellulose in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.
  • (b) Sustained release layer #2 Screen all ingredients through a USP sieve size # 30. Mix the codeine phosphate, microcrystalline cellulose PH 102, and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Add the Methocel®K4M to the granulator and post mix for 5 minutes. Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.
  • a bi-layered tablet in accordance with the present invention which comprises pseudoephedrine hydrochloride and chlorpheniramine maleate in a first sustained release layer and codeine phosphate in a second sustained release layer is illustrated as follows:
  • Sustained release layer #1 Mix the pseudoephedrine HCl, chlorpheniramine maleate, Methocel®K4M and silicified microcrystalline cellulose in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.
  • Sustained release layer #2 Screen all ingredients through a USP sieve size # 30. Mix the codeine phosphate, microcrystalline cellulose PH 102, and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Add the Methocel®K4M to the granulator and post mix for 5 minutes. Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.
  • a bi-layered tablet in accordance with the present invention which comprises carbinoxamine maleate in a first sustained release layer and codeine phosphate in a second sustained release layer is illustrated as follows:
  • Sustained release layer #1 Mix the carbinoxamine maleate, Methocel®K4M, lactose monohydrate and silicified microcrystalline cellulose in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes. [0104] (b) Sustained release layer #2: Screen all ingredients through a USP sieve size # 30.
  • a bi-layered tablet in accordance with the present invention which comprises promethazine hydrochloride (longer half-life drug) in an immediate release layer and codeine phosphate (shorter half-life drug) in a sustained release layer is illustrated as follows:
  • Sustained release layer #2 Blend the codeine phosphate, lactose monohydrate, dicalcium phosphate and Kollidon® SR for 20 minutes. Add stearic acid and magnesium stearate to the above blend and mix for an additional time of three minutes.
  • Capsules may be manufactured by filling the same proportions into capsules.
  • a bi-layered tablet in accordance with the present invention which comprises pseudoephedrine tannate and chlorpheniramine tannate in an immediate release layer and codeine phosphate in a sustained release layer is illustrated as follows:
  • Immediate release layer #1 Mix the pseudoephedrine tannate, chlorpheniramine tannate, silicified microcrystalline cellulose and croscarmellose sodium, in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution
  • Sustained release layer #2 Mix the codeine phosphate, microcrystalline cellulose
  • PH 102 lactose monohydrate, dicalcium phosphate, Methocel K4M Premium and stearic acid in a high shear mixer/granulator for 10 minutes.
  • a bi-layered tablet in accordance with the present invention which comprises promethazine hydrochloride in an immediate release layer and codeine phosphate and phenylephrine hydrochloride in a sustained release layer is illustrated as follows:
  • Immediate release layer #1 Mix the promethazine hydrochloride, silicified microcrystalline cellulose and croscarmellose sodium, in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (3.0 gms povidone in
  • a bi-layered tablet in accordance with the present invention which comprises guaifenesin in a first sustained release layer and codeine phosphate in a second sustained release layer is illustrated as follows:
  • Sustained release layer #1 Screen all ingredients through a USP sieve size # 30.
  • Sustained release layer #2 Blend the codeine phosphate, lactose monohydrate, dicalcium phosphate and Kollidon® SR for 20 minutes. Add stearic acid and magnesium stearate to the above blend and mix for an additional time of three minutes.
  • a bi-layered tablet in accordance with the present invention which comprises guaifenesin in a first sustained release layer and codeine phosphate and phenylephrine hydrochloride in a second sustained release layer is illustrated as follows:
  • Sustained release layer #1 Mix the guaifenesin, Methocel®K15M and silicified microcrystalline cellulose in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.
  • (b) Sustained release layer #2 Screen all ingredients through a USP sieve size # 30. Mix the codeine phosphate, phenylephrine HCl, microcrystalline cellulose PH 102, dicalcium phosphate and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Add the Methocel® K4M to the granulator and post mix for 5 minutes. Dry the granulation until the LOD is less than 2.0%. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.
  • a bi-layered tablet in accordance with the present invention which comprises guaifenesin in a first sustained release layer and codeine phosphate and phenylephrine hydrochloride in a second sustained release layer is illustrated as follows:
  • Sustained release layer #1 Mix the guaifenesin, Methocel®K15M and silicified microcrystalline cellulose in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.
  • (b) Sustained release layer #2 Screen all ingredients through a USP sieve size # 30. Mix the codeine phosphate, phenylephrine HCl, microcrystalline cellulose PH 102, dicalcium phosphate and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Add the Methocel®K4M to the granulator and post mix for 5 minutes. Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes. [0128] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 1300 mgs and layer #2 is 275 mgs. Capsules may be manufactured by filling the same proportions into capsules.
  • a bi-layered tablet in accordance with the present invention which comprises codeine phosphate in a first sustained release layer and phenylephrine hydrochloride and chlorpheniramine maleate in a second sustained release layer is illustrated as follows:
  • Sustained release Layer #1 Screen all ingredients through a USP sieve size # 30.
  • a bi-layered tablet which contains codeine phosphate in an immediate release layer and codeine phosphate, phenylephrine hydrochloride and chlorpheniramine maleate in a sustained release layer may be manufactured by using direct compression:
  • a bi-layered tablet in accordance with the present invention which comprises codeine phosphate in an immediate release layer and codeine phosphate, pseudoephedrine hydrochloride and chlorpheniramine maleate in a sustained release layer is illustrated as follows:
  • Immediate release layer #1 Screen all ingredients through a USP sieve size # 30. Blend the codeine phosphate (11.9 grams), silicified microcrystalline cellulose (158.6 grams), and croscarmellose sodium in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (4.3 gms povidone in 14.3 gms purified water). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add granules and the prescreened magnesium stearate (1.4 gms) to the above blend and mix for 3 minutes.
  • Sustained release layer #2 Screen all ingredients through a USP sieve size # 30. Blend the pseudoephedrine hydrochloride (87.5 gms), chlorpheniramine maleate (11.4 gms), codeine phosphate (37.5 gms), microcrystalline cellulose PH 102 (42.9 gms), lactose monohydrate (142.9 gms), dicalcium phosphate (142.9gms), Methocel K4M Premium (302.9 gms) and stearic acid (28.6 gms) in a high shear mixer/granulator for 10 minutes.
  • a bi-layered tablet containing codeine phosphate in an immediate release layer and pseudoephedrine hydrochloride and chlorpheniramine maleate in a sustained release layer may be manufactured by using wet granulation:
  • the above examples 6-20 illustrate how to manufacture a bi-layered tablet containing an antitussive, i.e., codeine phosphate in (at least) a first layer and an antihistamine and/or a decongestant and/or an expectorant in (at least) a second layer.
  • an antitussive i.e., codeine phosphate in (at least) a first layer and an antihistamine and/or a decongestant and/or an expectorant in (at least) a second layer.
  • active ingredients in addition to the antitussive morphine derivative
  • Example 21 Extended Release Suspension (Gel)
  • An extended release suspension in the form of a gel
  • a codeine phosphate ion-exchange complex and promethazine hydrochloride is illustrated as follows (note that the codeine phosphate is used in a controlled release form since it has a shorter half-life than the promethazine hydrochloride):
  • promethazine hydrochloride e.g., Carbopol® 974
  • glycerin e.g., Carbopol® 974
  • polysorbate 80 e.g., methyl paraben, propyl paraben, artificial grape flavor, FD&C red # 40 dye.
  • An extended release suspension in the form of a liquid
  • a codeine phosphate ion-exchange complex pseudoephedrine tannate and chlorpheniramine tannate is illustrated as follows:
  • the homogenizer With the homogenizer on, add the silica mixture containing codeine phosphate ion-exchange complex, pseudoephedrine tannate, and the chlorpheniramine tannate. Add the previously prepared solution of saccharin sodium, sodium benzoate, citric acid, and sodium citrate to the 1000 L tank. Rinse the first vessel with about 2 L of water and transfer the rinsate to the 1000 L tank. Add the remaining ingredients and homogenize for 15 minutes.
  • An extended release suspension which contains a hydrocodone bitartrate ion- exchange complex, a dexchlorpheniramine maleate ion-exchange complex and a phenylephrine hydrochloride ion-exchange complex is illustrated as follows:
  • Granulate the drug/resin complex with a delayed release/enteric polymer e.g. Eugragit® L 100, Kollidon® MAE, Aquacoa®t cPD
  • a delayed release/enteric polymer e.g. Eugragit® L 100, Kollidon® MAE, Aquacoa®t cPD
  • Carbomer e.g., Carbopol® 974
  • glycerin glycerin
  • polysorbate 80 methyl paraben, propyl paraben, artificial grape flavor, FD&C red # 40 dye.
  • a suspension formula which comprises codeine phosphate and phenylephrine tannate is illustrated as follows:
  • Citric Acid Monohydrate USP 0.16 1.333
  • a liquid dosage form which comprises codeine phosphate and phenylephrine hydrochloride is illustrated as follows:
  • a bi-layered tablet in accordance with the present invention which comprises guaifenesin in a first sustained release layer and carbetapentane citrate and pseudoephedrine hydrochloride in a second sustained release layer is illustrated as follows:
  • Sustained release layer #1 Mix the guaifenesin, Methocel®K15M and silicified microcrystalline cellulose in a high shear mixer/granulator for 10 minutes. Granulate the above blend using the Eudragit® NE (30 %). Dry the granulation until the LOD (weight loss on drying) is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.
  • a bi-layered tablet in accordance with the present invention which comprises promethazine hydrochloride in an immediate release layer and carbetapentane citrate and pseudoephedrine hydrochloride in a sustained release layer is illustrated as follows:
  • Immediate release layer #1 Mix the promethazine HCl, silicified microcrystalline cellulose and croscarmellose sodium, in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (3.0 gms povidone in 10.0 gms purified water). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.
  • (b) Sustained release layer #2 Mix the carbetapentane citrate, pseudoephedrine HCl, microcrystalline cellulose PH 102, dicalcium phosphate, Methocel K4M Premium and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (15.0 gms povidone in 50.0 gms purified water). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes. [0164] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 150 mgs and layer #2 is 525 mgs. Capsules may be manufactured by filling the same proportions into capsules.
  • a bi-layered tablet in accordance with the present invention which comprises phenylephrine hydrochloride and carbinoxamine maleate in a first sustained release layer and carbetapentane citrate in a second sustained release layer is illustrated as follows:
  • Sustained release layer #1 Mix the phenylephrine HCl, carbinoxamine maleate,
  • a bi-layered tablet in accordance with the present invention which comprises pseudoephedrine hydrochloride and chlorpheniramine maleate in a first sustained release layer and carbetapentane citrate in a second sustained release layer is illustrated as follows:
  • Sustained release layer #1 Mix the pseudoephedrine HCl, chlorpheniramine maleate, Methocel®K4M and silicified microcrystalline cellulose in a high shear mixer/granulator for 10 minutes. Granulate the above blend using the Eudragit® NE (30 %). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.
  • (b) Sustained release layer #2 Screen all ingredients through a USP sieve size # 30. Mix the carbetapentane citrate, microcrystalline cellulose PH 102, and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using the Eudragit® NE (30 %). Add the Methocel®K4M to the granulator and post mix for 5 minutes. Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes. [0172] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 260 mgs and layer #2 is 215 mgs. Capsules may be manufactured by filling the same proportions into capsules.
  • a bi-layered tablet in accordance with the present invention which comprises carbinoxamine maleate in a first sustained release layer and carbetapentane citrate in a second sustained release layer is illustrated as follows:
  • Sustained release layer #1 Mix the carbinoxamine maleate, Methocel®K4M, lactose monohydrate and silicified microcrystalline cellulose in a high shear mixer/granulator for 10 minutes. Granulate the above blend using the Eudragit® NE (30 %). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.
  • Sustained release layer #2 Screen all ingredients through a USP sieve size # 30. Mix the carbetapentane citrate, microcrystalline cellulose PH 102, and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using the Eudragit® NE (30 %). Add the Methocel®K4M to the granulator and post mix for 5 minutes. Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.
  • a bi-layered tablet in accordance with the present invention which comprises promethazine hydrochloride (longer half-life drug) in an immediate release layer and carbetapentane citrate (shorter half-life drug) in a sustained release layer is illustrated as follows:
  • Sustained release layer #2 Blend the carbetapentane citrate, lactose monohydrate, dicalcium citrate and Kollidon® SR for 20 minutes. Add stearic acid and magnesium stearate to the above blend and mix for an additional time of three minutes.
  • Capsules may be manufactured by filling the same proportions into capsules.
  • a bi-layered tablet in accordance with the present invention which comprises pseudoephedrine tannate and chlorpheniramine tannate in an immediate release layer and carbetapentane tannate in a sustained release layer is illustrated as follows:
  • Immediate release layer #1 Mix the pseudoephedrine tannate, chlorpheniramine tannate, silicified microcrystalline cellulose and croscarmellose sodium, in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (3.0 gms povidone in 10.0 gms purified water). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.
  • (b) Sustained release layer #2 Mix the carbetapentane tannate, microcrystalline cellulose PH 102, lactose monohydrate, dicalcium phosphate, Methocel K4M Premium and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (15.0 gms povidone in 50.0 gms purified water). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes. [0184] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 190 mgs and layer #2 is 510 mgs. Capsules may be manufactured by filling the same proportions into capsules.
  • a bi-layered tablet in accordance with the present invention which comprises diphenhydramine hydrochloride in an immediate release layer and carbetapentane citrate and phenylephrine hydrochloride in a sustained release layer is illustrated as follows:
  • Immediate release layer #1 Mix the diphenhydramine hydrochloride, silicified microcrystalline cellulose and croscarmellose sodium in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (3.0 gms povidone in 10.0 gms purified water). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.
  • a bi-layered tablet in accordance with the present invention which comprises guaifenesin in a first sustained release layer and carbetapentane citrate in a second sustained release layer is illustrated as follows:
  • Sustained release layer #1 Screen all ingredients through a USP sieve size # 30.
  • Sustained release layer #2 Blend the carbetapentane citrate, lactose monohydrate, dicalcium citrate and Kollidon® SR for 20 minutes. Add stearic acid and magnesium stearate to the above blend and mix for an additional time of three minutes.
  • a bi-layered tablet in accordance with the present invention which comprises guaifenesin in a first sustained release layer and carbetapentane citrate and phenylephrine hydrochloride in a second sustained release layer is illustrated as follows:
  • Sustained release layer #1 Mix the guaifenesin, Methocel®K15M and silicified microcrystalline cellulose in a high shear mixer/granulator for 10 minutes. Granulate the above blend using the Eudragit® NE (30 %). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.
  • (b) Sustained release layer #2 Screen all ingredients through a USP sieve size # 30. Mix the carbetapentane citrate, phenylephrine HCl, microcrystalline cellulose PH 102, dicalcium phosphate and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using the Eudragit® NE (30 %). Add the Methocel®K4M to the granulator and post mix for 5 minutes. Dry the granulation until the LOD is less than 2.0%. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.
  • a bi-layered tablet in accordance with the present invention which comprises guaifenesin in a first sustained release layer and carbetapentane citrate and phenylephrine hydrochloride in a second sustained release layer is illustrated as follows:
  • Sustained release layer #1 Mix the guaifenesin, Methocel®K15M and silicified microcrystalline cellulose in a high shear mixer/granulator for 10 minutes. Granulate the above blend using the Eudragit® NE (30 %). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.
  • (b) Sustained release layer #2 Screen all ingredients through a USP sieve size # 30. Mix the carbetapentane citrate, phenylephrine HCl, macrocrystalline cellulose PH 102, dicalcium phospate and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using the Eudragit® NE (30 %). Add the Methocel®K4M to the granulator and post mix for 5 minutes. Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.
  • a bi-layered tablet which contains carbetapentane citrate in an immediate release layer and carbetapentane citrate, phenylephrine hydrochloride and chlorpheniramine maleate in a sustained release layer may be manufactured by using direct compression:
  • a bi-layered tablet in accordance with the present invention which comprises carbetapentane citrate in an immediate release layer and carbetapentane citrate, pseudoephedrine hydrochloride and chlorpheniramine maleate in a sustained release layer is illustrated as follows:
  • Immediate release layer #1 Screen all ingredients through a USP sieve size # 30. Blend the carbetapentane citrate, silicified microcrystalline cellulose, and croscarmellose sodium in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (4.1 gms povidone in 13.7 gms of solution). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add granules and the prescreened magnesium stearate (1.4 gms) to the above blend and mix for 3 minutes.
  • (b) Sustained release layer #2 Screen all ingredients through a USP sieve size # 30. Blend the pseudoephedrine hydrochloride (87.5 gms), chlorpheniramine maleate, carbetapentane citrate, microcrystalline cellulose PH 102, lactose monohydrate, dicalcium citrate, Methocel K4M Premium and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (20.7 gms povidone in 69 gms of solution). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add granules and the prescreened magnesium stearate (6.9 gms) to the above blend and mix for 3 minutes.
  • pseudoephedrine hydrochloride 87.5 gms
  • chlorpheniramine maleate carbetapentane citrate
  • microcrystalline cellulose PH 102
  • a bi-layered tablet containing carbetapentane citrate in an immediate release layer and carbetapentane citrate, pseudoephedrine hydrochloride and chlorpheniramine maleate in a sustained release layer may be manufactured by using wet granulation:
  • the above examples 21-40 illustrate how to manufacture a bi-layered tablet containing an antitussive, i.e., carbetapentane citrate, in (at least) a first layer and an antihistamine and/or a decongestant and/or an expectorant in (at least) a second layer.
  • an antitussive i.e., carbetapentane citrate
  • an antihistamine and/or a decongestant and/or an expectorant in (at least) a second layer.
  • Non- limiting examples of possible active ingredients (in addition to carbetapentane) in an exemplary range as described in the above Table 1 can be employed depending on the specific therapeutic effect desired.
  • An extended release suspension in the form of a gel
  • a carbetapentane citrate ion-exchange complex and promethazine hydrochloride is illustrated as follows (note that the carbetapentane citrate is used in a controlled release form since it has a shorter half-life than the promethazine hydrochloride):
  • promethazine hydrochloride e.g., Carbopol® 974
  • glycerin e.g., Carbopol® 974
  • polysorbate 80 methyl paraben, propyl paraben, artificial grape flavor, FD&C red # 40 dye.
  • Amberlite® IRP 69or Amberlite® 188N to a carbetapentane citrate solution. Stir the mix for 12 hrs to allow complete drug/resin complex formation. Separate and dry the insoluble drug/resin complex. Granulate the drug/resin complex with a delayed release/enteric polymer (e.g. Eudragit® L 100, Kollidon® MAE, Aquacoat® CPD) and dry the granules. Mill the granules, if needed.
  • a delayed release/enteric polymer e.g. Eudragit® L 100, Kollidon® MAE, Aquacoat® CPD
  • the homogenizer With the homogenizer on, add the silica mixture containing carbetapentane citrate ion-exchange complex, pseudoephedrine tannate, and the chlorpheniramine tannate. Add the previously prepared solution of saccharin sodium, sodium benzoate, citric acid, and sodium citrate to the 1000 L tank. Rinse the first vessel with about 2 L of water and transfer the rinsate to the 1000 L tank. Add the remaining ingredients and homogenize for 15 minutes.
  • An extended release suspension which contains a carbetapentane citrate ion- exchange complex, a dexchlorpheniramine maleate ion-exchange complex and a phenylephrine hydrochloride ion-exchange complex is illustrated as follows:
  • Granulate the drug/resin complex with a delayed release/enteric polymer e.g. Eugragit® L 100, Kollidon® MAE, Aquacoa®t cPD
  • a delayed release/enteric polymer e.g. Eugragit® L 100, Kollidon® MAE, Aquacoa®t cPD
  • Carbomer e.g., Carbopol® 974
  • glycerin glycerin
  • polysorbate 80 methyl paraben, propyl paraben, artificial grape flavor, FD&C red # 40 dye.
  • Example 45 Suspension Formula [0219] A suspension formula which comprises carbetapentane citrate and phenylephrine tannate is illustrated as follows:
  • Citric Acid Monohydrate USP 0.16 1.333
  • a liquid dosage form which comprises carbetapentane citrate and phenylephrine hydrochloride is illustrated as follows:
  • a bi-layered tablet in accordance with the present invention which comprises phenylephrine hydrochloride in a first sustained release layer and guaifenesin in a second sustained release layer is illustrated as follows:
  • Sustained release layer #1 Mix phenylephrine hydrochloride in Methocel®K15M and silicified microcrystalline cellulose in a high shear mixer/granulator for 10 minutes.
  • a bi-layered tablet in accordance with the present invention which comprises promethazine hydrochloride in an immediate release layer and phenylephrine hydrochloride in a sustained release layer is illustrated as follows:
  • Immediate release layer #1 Mix the promethazine HCl, silicified microcrystalline cellulose and croscarmellose sodium, in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (3.0 g povidone in 10.0 g purified water). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a US sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.
  • (b) Sustained release layer #2 Mix the phenylephrine hydrochloride, microcrystalline cellulose PH 102, dicalcium phosphate, Methocel K4M Premium and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (15.0 g povidone in 50.0 g purified water). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a US sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes. [0232] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 200 mg and layer #2 is 350 mg. Capsules may be manufactured by filling the same proportions into capsules.
  • a bi-layered tablet in accordance with the present invention which comprises phenylephrine hydrochloride and carbinoxamine maleate in a first sustained release layer and phenylephrine hydrochloride in a second sustained release layer is illustrated as follows:
  • Sustained release layer #1 Mix the phenylephrine HCl, carbinoxamine maleate, Methocel®K4M and silicified microcrystalline cellulose in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a US sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.
  • (b) Sustained release layer #2 Screen all ingredients through a US sieve size # 30. Mix the phenylephrine hydrochloride, microcrystalline cellulose PH 102, and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Add the Methocel®K4M to the granulator and post mix for 5 minutes. Dry the granulation until the LOD is less than 2.0 %. Screen granules through a US sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.
  • a bi-layered tablet in accordance with the present invention which comprises phenylephrine hydrochloride and diphenhydramine hydrochloride in a first sustained release layer and codeine phosphate in a second sustained release layer is illustrated as follows:
  • Sustained release layer #1 Mix the phenylephrine HCl, diphenhydramine hydrochloride, Methocel®K4M and silicified microcrystalline cellulose in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a US sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.
  • (b) Sustained release layer #2 Screen all ingredients through a US sieve size # 30. Mix the codeine phosphate, microcrystalline cellulose PH 102, and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Add the Methocel®K4M to the granulator and post mix for 5 minutes. Dry the granulation until the LOD is less than 2.0 %. Screen granules through a US sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.
  • a bi-layered tablet in accordance with the present invention which comprises carbinoxamine maleate in a first sustained release layer and phenylephrine hydrochloride in a second sustained release layer is illustrated as follows:
  • Sustained release layer #1 Mix the carbinoxamine maleate, Methocel®K4M, lactose monohydrate and silicified microcrystalline cellulose in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a US sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.
  • a bi-layered tablet in accordance with the present invention which comprises promethazine hydrochloride (longer half-life drug) in an immediate release layer and phenylephrine hydrochloride (shorter half-life drug) in a sustained release layer is illustrated as follows:
  • Immediate release layer #1 Screen all ingredients through a US sieve size # 30. Blend the promethazine hydrochloride, microcrystalline cellulose and sodium starch glycolate for 20 minutes. Add magnesium stearate to the above blend and mix for an additional time of three minutes.
  • Sustained release layer #2 Blend the phenylephrine hydrochloride, lactose monohydrate, dicalcium phosphate and Kollidon® SR for 20 minutes. Add stearic acid and magnesium stearate to the above blend and mix for an additional time of three minutes.
  • Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet the immediate release layer #1 is 150 mg and the sustained release layer #2 is 400 mg. Capsules may be manufactured by filling the same proportions into capsules.
  • a bi-layered tablet in accordance with the present invention which comprises phenylephrine tannate and chlorpheniramine tannate in an immediate release layer and phenylephrine tannate in a sustained release layer is illustrated as follows:
  • Immediate release layer #1 Mix the phenylephrine tannate, chlorpheniramine tannate, silicified microcrystalline cellulose and croscarmellose sodium, in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (3.0 Kg povidone in 7.0 Kg purified water). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a US sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.
  • (b) Sustained release layer #2 Mix the Phenylepherine tannate, microcrystalline cellulose PH 102, dicalcium phosphate, Methocel K4M Premium and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (15.0 Kg povidone in 35.0 Kg purified water). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a US sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes. [0252] Manufacture bi-layered tablets using a rotary bi-layer tablet press where in each tablet layer #1 is 290 mg and layer #2 is 410 mg. Capsules may be manufactured by filling the same proportions into capsules.
  • a bi-layered tablet in accordance with the present invention which comprises diphenhydramine hydrochloride in an immediate release layer and phenylephrine hydrochloride in a sustained release layer is illustrated as follows:
  • Immediate release layer #1 Mix the diphenydramine hydrochloride, silicified microcrystalline cellulose and croscarmellose sodium, in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (3.O g povidone in 10.0 g purified water). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a US sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes.
  • a bi-layered tablet in accordance with the present invention which comprises guaifenesin in a first sustained release layer and phenylephrine hydrochloride in a second sustained release layer is illustrated as follows:
  • Sustained release layer #1 Screen all ingredients through a US sieve size # 30.
  • a bi-layered tablet in accordance with the present invention which comprises brompheniramine maleate in a first sustained release layer and phenylephrine hydrochloride in a second sustained release layer is illustrated as follows:
  • Sustained release layer #1 Mix the brompheniramine maleate, MethoceI®K15M and silicified microcrystalline cellulose in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a US sieve size # 14. Add the granules and the prescreened magnesium stearate in a V shaped blender and mix for 3 minutes. [0263] (b) Sustained release layer #2: Screen all ingredients through a US sieve size # 30.
  • a bi-layered tablet in accordance with the present invention which comprises guaifenesin in a first sustained release layer and phenylephrine hydrochloride in a second sustained release layer is illustrated as follows:
  • Sustained release layer #1 Mix the guaifenesin, Methocel®K15M and silicified microcrystalline cellulose in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a Eudragit® NE (30 %). Dry the granulation until the LOD is less than 2.0
  • a bi-layered tablet in accordance with the present invention which comprises phenylephrine hydrochloride in a first immediate release layer and phenylephrine hydrochloride and diphenhydramine hydrochloride in a second sustained release layer is illustrated as follows:
  • a bi-layered tablet which contains phenylephrine hydrochloride in an immediate release layer and phenylephrine hydrochloride and dexbrompheniramine maleate in a sustained release layer (see the formula below) may be manufactured by using direct compression:
  • Example 60 Bi-layered Tablet (Wet Granulation) [0273]
  • a bi-layered tablet in accordance with the present invention which comprises phenylephrine hydrochloride in an immediate release layer and phenylephrine hydrochloride and chlorpheniramine maleate in a sustained release layer is illustrated as follows:
  • Immediate release layer #1 Screen all ingredients through a US sieve size # 30. Blend the phenylephrine hydrochloride, silicified microcrystalline cellulose, and croscarmellose sodium in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (4.3 Kg povidone in 10.0 Kg purified water). Dry the granulation until the LOD is less than 2.0 %. Screen granules through a US sieve size # 14. Add granules and the prescreened magnesium stearate to the above blend and mix for 3 minutes.
  • a bi-layered tablet containing phenylephrine hydrochloride in an immediate release layer and phenylephrine hydrochloride and chlorpheniramine maleate in a sustained release layer may be manufactured by using wet granulation:
  • a bi-layered tablet in accordance with the present invention which comprises phenylephrine hydrochloride in a sustained release layer and carbetapentane citrate in a immediate release layer is illustrated as follows:
  • the above examples 41-62 illustrate how to manufacture a bi-layered tablet containing a decongestant, i.e., phenylephrine hydrochloride, in (at least) a first layer and an antihistamine and/or a decongestant and/or an expectorant in (at least) a second layer.
  • a decongestant i.e., phenylephrine hydrochloride
  • Non- limiting examples of other possible active ingredients in an exemplary range as described in the above Table 1 can be employed depending on the specific therapeutic effect desired.
  • a bi-layered tablet in accordance with the present invention which contains phenylephrine hydrochloride in both an immediate release layer and a sustained release layer and carbetapentane citrate in both an immediate release layer and a sustained release layer is illustrated as follows:
  • (a) Immediate release layer #1 Mix the prescreened (# 30 mesh) phenylephrine hydrochloride,carbetapentane citrate, silicified microcrystalline cellulose and croscarmellose sodium, in a V shaped blender for 20 minutes. Add prescreened (# 40 mesh) magnesium stearate in a V shaped blender and mix for 3 minutes.
  • a bi-layered tablet in accordance with the present invention which comprises phenylephrine hydrochloride and guaifenesin in two different sustained release layers is illustrated as follows:
  • step 11 Charge the screened material from step 10 to the V-blender and blend for 2 minutes.
  • An extended release suspension in the form of a gel
  • a phenylephrine hydrochloride ion-exchange complex and promethazine hydrochloride is illustrated as follows (the phenylephrine hydrochloride is used in a controlled release form since it has a shorter half-life than the promethazine hydrochloride):
  • promethazine hydrochloride e.g., Carbopol® 974
  • glycerin e.g., Carbopol® 974
  • polysorbate 80 methyl paraben, propyl paraben, artificial grape flavor, FD&C red # 40 dye.
  • An extended release suspension in the form of a liquid
  • a codeine phosphate ion-exchange complex phenylephrine tannate and chlorpheniramine tannate is illustrated as follows:
  • the homogenizer With the homogenizer on, add the silica mixture containing the codeine phosphate ion-exchange complex, the phenylephrine tannate, and the chlorpheniramine tannate. Add the previously prepared solution of saccharin sodium, sodium benzoate, citric acid, and sodium citrate to the 1000 L tank. Rinse the first vessel with about 2 L of water and transfer the rinse to the 1000 L tank. Add the remaining ingredients and homogenize for 15 minutes.
  • An extended release suspension which contains a hydrocodone bitartrate ion- exchange complex, a dexchlorpheniramine maleate ion-exchange complex and a phenylephrine hydrochloride ion-exchange complex is illustrated as follows:
  • Granulate the drug/resin complex with a delayed release/enteric polymer e.g. Eugragit® L 100, Kollidon® MAE, Aquacoa®t cPD
  • a delayed release/enteric polymer e.g. Eugragit® L 100, Kollidon® MAE, Aquacoa®t cPD
  • Carbomer e.g., Carbopol® 974
  • glycerin glycerin
  • polysorbate 80 methyl paraben, propyl paraben, artificial grape flavor, FD&C red # 40 dye.
  • a suspension formula which comprises codeine phosphate and phenylephrine tannate is illustrated as follows:
  • Citric Acid Monohydrate USP 0.16 1.333
  • a liquid dosage form which comprises phenylephrine hydrochloride is illustrated as follows:
  • a liquid dosage form in accordance with the present invention which comprises diphenhydramine hydrochloride, dihydrocodeine bitartrate and phenylephrine hydrochloride is illustrated as follows:
  • Manufacturing process for 425 L batch size In a suitably sized stainless steel vessel, dissolve methyl paraben and propyl paraben in approximately 50L of warm (about 45 0 C), purified water. Add about half of the propylene glycol and mix for about 1 hr. In a separate 1000 L stainless steel tank equipped with a suitably sized agitator, add about 50 L of purified water. With the agitator on, add phenylephrine hydrochloride, diphenhydramine hydrochloride, saccharin sodium and citric acid and dissolve. Add the previously prepared paraben/propylene glycol solution to the 1000 L tank. Rinse the first vessel with about 2 L of water and transfer the rinsate to the 1000 L tank.
  • a suspension formula in accordance with the present invention which comprises diphenhydramine hydrochloride and phenylephrine tannate is illustrated as follows:
  • Citric Acid Monohydrate USP 0.16 1.333
  • Manufacturing process for 833.33 L batch In a suitably sized stainless steel vessel, dissolve saccharin sodium, sodium benzoate, citric acid, and sodium citrate in approximately 50 L of warm (about 45 0 C), purified water. In another large stainless steel drum mix the silica, diphenhydramine hydrochloride and micronized phenylephrine tannate until a uniform and consistent mixture is obtained. In a separate 1000 L stainless steel tank equipped with a suitably sized homogenizer/disperser add about 100 L of purified water. With the homogenizer on, add the silica mixture containing phenylephrine tannate and diphenhydramine hydrochloride.
  • a bi-layered tablet in accordance with the present invention which comprises diphenhydramine hydrochloride in one layer and phenylephrine hydrochloride and diphenhydramine hydrochloride in the other layer is illustrated as follows:
  • a bi-layered tablet of the following composition may be manufactured through direct compression:
  • a bi-layered tablet in accordance with the present invention which comprises diphenhydramine hydrochloride in one layer and pseudoephedrine hydrochloride and diphenhydramine hydrochloride in the other layer is illustrated as follows:
  • (a) Immediate release layer Screen all ingredients through a USP sieve size # 30. Blend diphenhydramine hydrochloride, silicified microcrystalline cellulose and croscarmellose sodium in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution (4.3 gms povidone in 14.3 gms purified water). Dry the granulation until the loss on drying (LOD) is less than 2.0 %. Screen the dried granulation through a USP sieve size # 14. Add the screened granulation and the prescreened magnesium stearate to the above blend and mix for 3 minutes.
  • LOD loss on drying
  • (b) Sustained release layer Screen all ingredients through a USP sieve size # 30. Blend the pseudoephedrine hydrochloride , diphenhydramine hydrochloride, Prosolv® (silicified microcrystalline cellulose), lactose monohydrate, dicalcium phosphate, Methocel K4M Premium and stearic acid in a high shear mixer/granulator for 10 minutes. Granulate the above blend using a 30 % povidone solution. Dry the granulation until the LOD is less than 2.0 %. Screen granules through a USP sieve size # 14. Add granules and the prescreened magnesium stearate to the above blend and mix for 3 minutes.
  • the above examples 63-74 illustrate how to manufacture a bi-layered tablet containing an antihistamine, i.e., diphenhydramine hydrochloride in one layer and a decongestant and/or an antitussive and/or an expectorant and/or an analgesic in the other layer (optionally in combination with diphenhydramine hydrochloride).
  • an antihistamine i.e., diphenhydramine hydrochloride
  • a decongestant and/or an antitussive and/or an expectorant and/or an analgesic in the other layer (optionally in combination with diphenhydramine hydrochloride).
  • active ingredients which may be used in combination with diphenhydramine hydrochloride depending on the specific therapeutic effect desired are listed in the above Table 1 together with exemplary ranges thereof.
  • Granulate the drug/resin complex with a delayed release/enteric polymer e.g. Eugragit® L 100, Kollidon® MAE, Aquacoat® PD
  • a delayed release/enteric polymer e.g. Eugragit® L 100, Kollidon® MAE, Aquacoat® PD
  • Carbomer e.g., Carbopol® 974
  • glycerin glycerin
  • polysorbate 80 methyl paraben, propyl paraben, artificial grape flavor, FD&C red # 40 dye.
  • Example 76 Bi-layered Tablet (Wet granulation)
  • a bilayered tablet in accordance with the present invention which comprises diphenhydramine hydrochloride and guaifenesin in both layers as sustained release layers is illustrated as follows.
  • step 11 Charge the screened material from step 10 to the V-blender and blend for 2 minutes.
  • Example 77 Bi-layered Tablet (Wet granulation)
  • a bilayered tablet in accordance with the present invention which comprises diphenhydramine hydrochloride in a sustained release layer and carbetapentane in an immediate release layer is illustrated as follows.
  • a bi-layered tablet for administration every 24 hours which comprises 100 mg of promethazine hydrochloride is illustrated as follows:
  • a bi-layered tablet for once-a-day administration which comprises 100 mg of promethazine hydrochloride in an immediate release layer and 240 mg of pseudoephedrine hydrochloride in a sustained release layer is illustrated as follows:
  • a bi-layered tablet for once-a-day administration which comprises 200 mg of diphenhydramine hydrochloride in a first layer and 240 mg of pseudoephedrine hydrochloride in a second layer is illustrated as follows: Diphenhydramine Layer
  • Aqueous suspension (30 % b. w.); water is removed during ry ng stage
  • Manufacturing Process Each layer is processed separately until the final compression.
  • the dry mix components are blended in a Lodige mixer for ten minutes (mixer blades on).
  • the sustained release agent (Eudragit dispersion) is then pumped into the dry mix (the suspension is stirred all times before and during pumping to avoid solids settlement).
  • the postmix component (Methocel K4M Premium) is added into the Lodige mixer, the choppers are turned on and the blend is kept for another minute.
  • the product is discharged and poured onto trays for drying in an oven for 18 hours at 45 0 C.
  • the granules as well as the final blend components are milled at high speed in a Fitzmill (knives forward) through a US # 14 screen and loaded into a "V"-blender.
  • the product is blended for 15 minutes; the lube blend component (Magnesium stearate) is passed through an oscillating granulator (US # 30 screen) and is then added to the "V"-blender for a final blend of 3 minutes.
  • the layer formulations are poured into different hoppers of the tableting machine to compress bi-layered tablets at 700 mg of tablet weight.

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

Cette invention concerne une forme posologique comprenant un premier médicament et un second médicament sélectionnés tous deux parmi des décongestionnants, des antitussifs, des expectorants, des analgésiques et des antihistaminiques. Ladite forme posologique permet d'obtenir une concentration de plasma dans la plage thérapeutique du second médicament pendant une période qui coïncide à au moins 70 % avec la période au cours de laquelle cette même forme posologique fournit une concentration de plasma dans la plage thérapeutique du premier médicament.
PCT/US2005/020499 2004-08-04 2005-06-13 Forme posologique contenant des medicaments multiples WO2006022996A2 (fr)

Applications Claiming Priority (14)

Application Number Priority Date Filing Date Title
US10/910,806 2004-08-04
US10/910,806 US20060029664A1 (en) 2004-08-04 2004-08-04 Dosage form containing carbetapentane and another drug
US10/939,351 2004-09-14
US10/939,351 US9492541B2 (en) 2004-09-14 2004-09-14 Phenylepherine containing dosage form
US11/012,267 US9592197B2 (en) 2004-12-16 2004-12-16 Dosage form containing diphenhydramine and another drug
US11/012,267 2004-12-16
US11/102,725 2005-04-11
US11/102,725 US20050281875A1 (en) 2003-12-17 2005-04-11 Promethazine containing dosage form
US11/102,726 US20070003622A1 (en) 2004-12-16 2005-04-11 Diphenhydramine containing dosage form
US11/102,726 2005-04-11
US11/115,293 2005-04-27
US11/115,293 US20050232993A1 (en) 2003-12-17 2005-04-27 Dosage form containing promethazine and another drug
US11/115,321 US20050266032A1 (en) 2003-12-17 2005-04-27 Dosage form containing multiple drugs
US11/115,321 2005-04-27

Publications (2)

Publication Number Publication Date
WO2006022996A2 true WO2006022996A2 (fr) 2006-03-02
WO2006022996A3 WO2006022996A3 (fr) 2006-12-21

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WO2009040750A1 (fr) * 2007-09-24 2009-04-02 The Procter & Gamble Company Composition et procédé destinés à stabiliser un ingrédient sensible stabilisé
WO2009089494A2 (fr) 2008-01-09 2009-07-16 Charleston Laboratories, Inc. Compositions pharmaceutiques
US8062667B2 (en) 2006-03-16 2011-11-22 Tris Pharma, Inc. Modified release formulations containing drug-ion exchange resin complexes
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US8653066B2 (en) 2006-10-09 2014-02-18 Charleston Laboratories, Inc. Pharmaceutical compositions
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US6797283B1 (en) * 1998-12-23 2004-09-28 Alza Corporation Gastric retention dosage form having multiple layers

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