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WO1996029986A1 - Microcapsules antitussives - Google Patents

Microcapsules antitussives Download PDF

Info

Publication number
WO1996029986A1
WO1996029986A1 PCT/US1996/002238 US9602238W WO9629986A1 WO 1996029986 A1 WO1996029986 A1 WO 1996029986A1 US 9602238 W US9602238 W US 9602238W WO 9629986 A1 WO9629986 A1 WO 9629986A1
Authority
WO
WIPO (PCT)
Prior art keywords
shell
microcapsule
microcapsule according
mixtures
microcapsules
Prior art date
Application number
PCT/US1996/002238
Other languages
English (en)
Inventor
Lowell Alan Sanker
Liezl Gonzales Peterson
James Grigg Upson
Carmelita Macklin Russell
Original Assignee
The Procter & Gamble Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Procter & Gamble Company filed Critical The Procter & Gamble Company
Priority to JP8529367A priority Critical patent/JPH11502839A/ja
Priority to AU49886/96A priority patent/AU4988696A/en
Publication of WO1996029986A1 publication Critical patent/WO1996029986A1/fr

Links

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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5052—Proteins, e.g. albumin
    • A61K9/5057—Gelatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents

Definitions

  • the present invention relates to compositions for use in the treatment of cough and/or sore throat in the form of microcapsules.
  • the cough reflex is an important mechanism whereby secretions from the lungs and airways are removed. Generally, such secretions are removed by the mucociliary escalator. However, when this mechanism is defective, or becomes overwhelmed by, for example, excessive secretions, cough then becomes a principal means of secretion removal.
  • the cough reflex is initiated by stimulation of mechanical receptors and is controlled by afferent pathways within the vagus (X), glossopharyngeal (IX), and superior laryngeal nerves to the cough center in the brainstem.
  • Cough can be caused by, for example, foreign bodies, dust, mucus, debris, gases and smoke in the lower respiratory tract. Irritation of various sensory nerves in the nose, sinuses, pharynx, ears, stomach, pericardium or diaphragm can also produce coughing. In many of these conditions, chronic or paroxysmal cough, however, can be exhausting and debilitating, particularly when it interferes with sleep.
  • Oral cough preparations such as tablets, lozenges, syrups, solutions, suspensions and the like, containing an effective antitussive agent have long been used for the symptomatic relief of coughs.
  • the most popular of such preparations contain either dextromethorphan (or its hydrobromide salt) or codeine (or its sulfate salt) as the active antitussive agent.
  • cough syrups and sore throat medications have been available as pourable liquids or thixotropic gels.
  • Exemplary prior art gel formulations for treatment of cough including those disclosed in U.S. Patent 4,427,681 , incorporated herein by reference which use a suspending agent (Avicel/R R-591 from FMC Corporation) that give a thixotropic character to the formulation that is very viscous and needs a special device or an appropriate amount of shear forces through a dispensing nozzle to pour.
  • Other formulations include liquid gelatin capsules which are well-known; however, they are intended to be swallowed and thereby do not provide any coating of the oral mucosa.
  • microcapsule compositions which contain an antitussive and/or anesthetic active which are portable and easy to use and which rupture rapidly upon biting or sucking and wherein the outer shell dissolves quickly (avoiding further irritation) thereby providing the user a quick delivery of an active ingredient to the irritated area.
  • microcapsules It is, therefore, an object of the present invention to provide improved microcapsules. It is still a further object of the present invention to provide such compositions which can treat the irritation, pain and discomfort associated with laryngopharyngitis and esophagitis. A further object of the present invention is to provide such microcapsule compositions containing a pharmaceutical active which is delivered quickly to the oral mucosa.
  • the present invention in one of its aspects relates to improved microcapsules which contain an antitussive and/or anesthetic active.
  • the shell material of the microcapsules of the present invention can be any materials which are suitable for ingestion as well as retention in the oral cavity.
  • Materials which are suitable include gelatin, polyvinyl alcohols, waxes, gums, sucrose esters and sugar candy type materials used in cough drops and mints, for example.
  • the shell material is used to form any of a wide variety of shapes such as spheres, oblong shapes, disks, puffed squares and cylinders.
  • the shell thickness is in the range of about 30 ⁇ m to about 0.5mm, preferably from about 30 ⁇ m to about 0.3mm. If the microcapsules are spherical, the particle diameter is generally in the range of from about 2mm to about 9mm, preferably from about 3mm to about 7mm.
  • the shells also have a water content of about 10% or greater, preferably 12% or greater and most preferably 15% or greater.
  • microcapsules made according to the present invention ruptures within about 45 seconds, preferably within about 35 seconds, more preferably within about 30 seconds and most preferably within about 25 seconds and dissolves within about 5 minutes, preferably within about 4 minutes and most preferably within about 3.5 minutes (USP Methodology XXII Method 701 "Disintegration").
  • Antitussive/Anesthetic Active preferably within about 45 seconds, preferably within about 35 seconds, more preferably within about 30 seconds and most preferably within about 25 seconds and dissolves within about 5 minutes, preferably within about 4 minutes and most preferably within about 3.5 minutes.
  • the antitussives preferred for use in the present invention include those such as dextromethorphan, chiophedianol, carbetapentane, caramiphen, noscapine, diphenhydramine, codeine, hydrocodone, hydro- morphone, fominoben, benzonatate, their pharmaceutically-acceptable salts, and mixtures thereof.
  • the oral anesthetics preferred for use include phenol, lidocaine, dyclonine, benzocaine, menthol, benzyl alcohol, salicyl alcohol, and hexylresorcinol, their pharmaceutically-acceptable salts, and mixtures thereof.
  • compositions of the present invention can also include at least one additional oral pharmacological active preferably selected from the following classes: (a) analgesic agents, (b) decongestants, (c) expectorants and (d) antihistamines.
  • the analgesics useful for this invention include acetaminophen, acetyl salicylic acid, indomethacin and optically active isomers or racemates of ibuprofen, naproxen, flurbiprofen, carprofen, tiaprofenic acid, cicloprofen, ketoprofen, ketorolac, etodolac, indomethacin, sulindac, fenoprofen, diclofenac, piroxicam, benzydomine, nabumetone, their pharmaceutically acceptable salts and mixtures thereof.
  • the decongestants prepared for use in the compositions of the present invention include pseudoephedrine, phenylpropanolamine, phenylephrine and ephedrine, their pharmaceutically acceptable salts, and mixtures thereof.
  • the preferred anesthetics include glyceryl guaiacolate, te ⁇ in hydrate, ammonium chloride, N acetylcysteine and bromhexine, ambroxol, their pharmaceutically acceptable salts, and mixtures thereof. All of these components, as well as their acceptable dosage ranges are described in the following: U.S. Patent 4,783,465 to Sunshine et al., issued November 8, 1988, U.S. Patent 4,619,934 to Sunshine et al., issued October 28, 1986, which are incorporated by reference herein.
  • bronchodilators such as terbutaline, aminophylline, epinephrine, isoprenaline, metaproterenol, bitoterol, theophylline and albuterol.
  • a highly preferred optional component is caffeine.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from nonorganic bases include sodium, potassium, lithium, ammonia, calcium, magnesium, ferrous, zinc, manganous, aluminum, ferric, manganic salts and the like.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, tertiary and quaternary amines, substi ⁇ tuted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as triethylamine, tripropylamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, lysine, arginine, histidine, caffeine, procaine, N-ethylpiperidine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglycamine, theo- bromine, purines, piperazine, piperidine, poiyamine resins and the like.
  • basic ion exchange resins such as triethylamine, tripropylamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, lysine, arginine, histidine, caffeine, procaine, N-
  • the amount of the pharmaceutical composition administered depends upon the percent of active ingredients within its formula, such as an analgesic, decongestant, cough suppressant, expectorant, antihistamine and/or gastrointestinal active required per dose, stability, release characteristics and other pharmaceutical parameters.
  • each individual dosage of the pharmaceutical compositions of the present invention range from about 1 mg/kg to about 25 mg/kg, preferably from about 2 mg kg to about 15 mg/kg and most preferably from about 3 mg kg to about 10 mg/kg. While dosages higher than the foregoing may be effective, care must be taken, as with any drug, in some individuals to prevent adverse side effects.
  • These pharmaceutical agents are used in an amount of from about 0.1% to about 50%.
  • Dispersed within the shell material may be the same agents at the same concentrations.
  • the solubilizing agent for the antitussive and/or anesthetic agents used in the cores of the present microcapsules can be any of a number of materials.
  • typical liquid formulations preferably contain a co-solvent, for example, propylene glycol, corn syrup, glycerin, sorbitol solution and the like, to assist solubilization and inco ⁇ oration of water-insoluble ingredients, such as flavoring oils and the like into the composition.
  • a co-solvent for example, propylene glycol, corn syrup, glycerin, sorbitol solution and the like, to assist solubilization and inco ⁇ oration of water-insoluble ingredients, such as flavoring oils and the like into the composition.
  • the compositions of this invention preferably contain from about 1 to about 70%v/v and, most preferably, from about 5 to about 50% v/v, of the co-solvent.
  • oils such as com, olive, rapeseed, sesame, peanut or sunflower.
  • Other preferred materials are triglycerides such as Captex 300 and polyethylene glycols such as PEG 400. These are used in an amount of from about 20% to about 80%, preferably
  • the present invention may optionally inco ⁇ orate a cool ⁇ ing agent or a combination of cooling agents.
  • Suitable cooling agents include, for example, menthol as well as those described in U.S. Patent 4.136.163. January 23, 1979, to Watson et al., U.S. Patent 4.230.668. October 28, 1980, to Rowsell et al. and U.S. Patent 4.032.661. to Rowsell et al., all of which are herein inco ⁇ orated by reference.
  • a particularly pre ⁇ ferred cooling agent is N-ethyl-p-menthane-3-carboxamide (WS-3 supplied by Sterling Organics), taught by the above inco ⁇ orated U.S. Patent 4.136.163.
  • TK-10 3-1- menthoxypropane 1,2-diol supplied by Takasago Perfumery Co., Ltd., Tokyo, Japan. This material is described in detail in U.S. Patent 4.459.425. July 10, 1984 to Amano et al. and inco ⁇ orated herein by reference.
  • the core of the microcapsules of this invention may contain any number of additional materials to provide additional efficacy and/or sensory perceptions.
  • agents may include flavoring agents such as thymol, eucalyptol, menthol, methyl salicylate or witch hazel. These agents are used in an amount of from about .1% to about 25%, preferably from about 5% to about 15% of the total capsule weight.
  • sweetening agents such as sugars, corn syrups, saccharin or aspartame may also be included in the core. These agents are used in an amount of from about .1% to about 5%, preferably from about .35% to about 1.5% of the total capsule weight.
  • the capsules of the present invention can be made using a variety of techniques. One method is described after the following examples. Industrial Applicability:
  • the capsules of the present invention are used by placing the capsules into the mouth which then rupture rapidly upon biting or sucking and wherein the outer shell dissolves quickly (avoiding further irritation) thereby providing the user a quick delivery of an active ingredient to the irritated area.
  • Captex 300 is a triglyceride supplied by Capitol City Product, Columbus, Ohio. 2)
  • This amount includes that in the gelatin shell as well as in the core.
  • compositions are prepared by mixing the components of the core in one container and the components of the shell(s) in another container.
  • the shell(s) materials are heated to provide a fluid medium.
  • the core and shell(s) materials are then pumped separately to a two or three fluid nozzle submerged in an organic carrier medium.
  • the capsules formed are allowed to cool and stiffen. They are then dried and separated for further handling.
  • any of a wide variety of other shell materials, optional pharmaceutical active agents, sweeteners as well as other compo ⁇ nents may be used in place of or in combination with the components listed above.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pulmonology (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention se rapporte à des compositions utilisées dans le traitement de la toux et/ou du mal de gorge, sous forme de microcapsules.
PCT/US1996/002238 1995-03-29 1996-02-20 Microcapsules antitussives WO1996029986A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP8529367A JPH11502839A (ja) 1995-03-29 1996-02-20 鎮咳剤マイクロカプセル
AU49886/96A AU4988696A (en) 1995-03-29 1996-02-20 Antitussive microcapsules

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US41304895A 1995-03-29 1995-03-29
US08/413,048 1995-03-29

Publications (1)

Publication Number Publication Date
WO1996029986A1 true WO1996029986A1 (fr) 1996-10-03

Family

ID=23635602

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1996/002238 WO1996029986A1 (fr) 1995-03-29 1996-02-20 Microcapsules antitussives

Country Status (3)

Country Link
JP (1) JPH11502839A (fr)
AU (1) AU4988696A (fr)
WO (1) WO1996029986A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998046235A1 (fr) * 1997-04-15 1998-10-22 Bayer Aktiengesellschaft Association d'analgesiques
EP1426045A1 (fr) * 2002-12-05 2004-06-09 Symrise GmbH & Co. KG Gélules remplies sans soudure
EP1559418A1 (fr) * 2000-06-26 2005-08-03 EpiCept Corporation Compositions pour le traitement analgesique de la muqueuse
US7138133B2 (en) 2001-10-10 2006-11-21 The Procter & Gamble Company Orally administered liquid compositions
US20110201685A1 (en) * 2008-08-22 2011-08-18 Reckitt Benckiser Healthcare (Uk) Limited Compositions

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4695326B2 (ja) * 2001-12-21 2011-06-08 第一三共ヘルスケア株式会社 鼻炎用医薬組成物
WO2006136197A1 (fr) * 2005-06-21 2006-12-28 V. Mane Fils Produit a fumer comprenant une capsule cassante, capsule cassante et procede de fabrication de cette capsule

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1060258A (en) * 1964-12-05 1967-03-01 Sandoz Products Ltd Improvements in or relating to pharmaceutical pastilles
US4656027A (en) * 1981-06-18 1987-04-07 Astra Lakemedel Aktiebolag Pharmaceutical mixture
US4935243A (en) * 1988-12-19 1990-06-19 Pharmacaps, Inc. Chewable, edible soft gelatin capsule
WO1991003236A1 (fr) * 1989-09-05 1991-03-21 University Of Utah Research Foundation Forme de dosage transmucosique
US5084278A (en) * 1989-06-02 1992-01-28 Nortec Development Associates, Inc. Taste-masked pharmaceutical compositions
WO1993011754A1 (fr) * 1991-12-11 1993-06-24 The Procter & Gamble Company Chlorure de cetylpyridinium et bromure de domiphene incorpores dans un solvant organique

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1060258A (en) * 1964-12-05 1967-03-01 Sandoz Products Ltd Improvements in or relating to pharmaceutical pastilles
US4656027A (en) * 1981-06-18 1987-04-07 Astra Lakemedel Aktiebolag Pharmaceutical mixture
US4935243A (en) * 1988-12-19 1990-06-19 Pharmacaps, Inc. Chewable, edible soft gelatin capsule
US5084278A (en) * 1989-06-02 1992-01-28 Nortec Development Associates, Inc. Taste-masked pharmaceutical compositions
WO1991003236A1 (fr) * 1989-09-05 1991-03-21 University Of Utah Research Foundation Forme de dosage transmucosique
WO1993011754A1 (fr) * 1991-12-11 1993-06-24 The Procter & Gamble Company Chlorure de cetylpyridinium et bromure de domiphene incorpores dans un solvant organique

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998046235A1 (fr) * 1997-04-15 1998-10-22 Bayer Aktiengesellschaft Association d'analgesiques
RU2218180C2 (ru) * 1997-04-15 2003-12-10 Байер Акциенгезельшафт Комбинация анальгетиков
US6929805B2 (en) 1997-04-15 2005-08-16 Bayer Aktiengesellschaft Analgesic combination
EP1559418A1 (fr) * 2000-06-26 2005-08-03 EpiCept Corporation Compositions pour le traitement analgesique de la muqueuse
US7138133B2 (en) 2001-10-10 2006-11-21 The Procter & Gamble Company Orally administered liquid compositions
EP1426045A1 (fr) * 2002-12-05 2004-06-09 Symrise GmbH & Co. KG Gélules remplies sans soudure
WO2004050069A1 (fr) * 2002-12-05 2004-06-17 Symrise Gmbh & Co. Kg Capsules fourrees sans soudures
EP1709958A1 (fr) * 2002-12-05 2006-10-11 Symrise GmbH & Co. KG Gélules remplies sans soudure
US7226613B2 (en) 2002-12-05 2007-06-05 Symrise Gmbh & Co. Kg Seamless filled capsules
US20110201685A1 (en) * 2008-08-22 2011-08-18 Reckitt Benckiser Healthcare (Uk) Limited Compositions
US8569375B2 (en) * 2008-08-22 2013-10-29 Reckitt Benckiser Healthcare (Uk) Limited Compositions
US20140039057A1 (en) * 2008-08-22 2014-02-06 Reckitt Benckiser Healthcare (Uk) Limited Compositions

Also Published As

Publication number Publication date
JPH11502839A (ja) 1999-03-09
AU4988696A (en) 1996-10-16

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