WO1995033451A1 - Medication pour traiter les allergies et les congestions des sinus sans effets sedatifs - Google Patents

Medication pour traiter les allergies et les congestions des sinus sans effets sedatifs Download PDF

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Publication number
WO1995033451A1
WO1995033451A1 PCT/US1995/003308 US9503308W WO9533451A1 WO 1995033451 A1 WO1995033451 A1 WO 1995033451A1 US 9503308 W US9503308 W US 9503308W WO 9533451 A1 WO9533451 A1 WO 9533451A1
Authority
WO
WIPO (PCT)
Prior art keywords
sinus
caffeine
cellulose
antihistamine
allergy medication
Prior art date
Application number
PCT/US1995/003308
Other languages
English (en)
Inventor
Frank Volpe
R. Michael Buch
Timothy H. Weng
Original Assignee
Warner-Lambert 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 Warner-Lambert Company filed Critical Warner-Lambert Company
Priority to AU21007/95A priority Critical patent/AU2100795A/en
Publication of WO1995033451A1 publication Critical patent/WO1995033451A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine

Definitions

  • the present invention relates generally to allergy and sinus medications that provide relief to sufferers with blocked sinuses, itchy, watery eyes, headache and other allergic symptoms.
  • Diphenhydramine hydrochloride (2-diphenylmethoxy-N ! N-dimethylethanamine hydrochloride) has been widely used over the years as an antihistamine which provides relief of these symptoms by blocking the action of histamines, the allergic response in the body.
  • the problem that arises however, is that many who take diphenhydramine for relief of the allergic symptoms report that the antihistamine also causes a drowsiness and lethargic effect. Obviously, this side effect of the drug is not desirable during daytime or waking hours.
  • An antihistamine such as diphenhydramine is combined with a stimulant such as theophylline or caffeine which counteracts the drugs' inherent lethargic effects.
  • the stimulant is formulated as a delayed, sustained release composition so that its effect will coincide with the onset of lethargy that accompanies the systemic relief afforded by the antihistamine.
  • United States Patent No. 4,466,960 to Silverman et. al. discloses a pharmaceutical composition designed for the relief of pre-menstrual syndrome (PMS) .
  • An antihistamine such as diphenhydramine is combined with an analgesic such as acetaminophen, caffeine and an ammonium salt diuretic such as pyrilamine maleate.
  • the antihistamine assertedly relieves cramping and backache while the acetaminophen relives headache and other assorted pains.
  • Caffeine a central nervous stimulant, is incorporated to relieve fatigue and lethargy that accompanies PMS and admittedly counteracts the sedative effect of the antihistamine.
  • the diuretic helps relieve bloating and water retention that also accompany PMS.
  • United States Patent No. 5,011,688 to Calam et. al. discloses and claims a liquid composition for the relief of premenstrual and menstrual discomfort comprising an effective amount of an analgesic such as aspirin or acetaminophen, an antihistamine such as pyrilamine maleate and a diuretic such as caffeine or ammonium chloride.
  • analgesic such as aspirin or acetaminophen
  • an antihistamine such as pyrilamine maleate
  • a diuretic such as caffeine or ammonium chloride
  • Caffeine and diphenhydramine have also been combined as an anti-travel sickness drug known as kaffinautin sold in Scandanavia. It is well documented that the composition is widely abused since it often produces a stimulating euphoria which unfortunately can result in transitory psychotic symptoms.
  • a non-sedating, non-drowsy sinus and allergy medication allows for the relief from cold, hay fever and other sinus congestion symptoms without the inherent side effects of lethargy and drowsiness that can affect ones functions when taking this drug.
  • An antihistamine such as diphenhydramine hydrochloride is combined with a sustained release, encapsulated caffeine composition that is released and absorbed by the body at the same time as the antihistamine. This results in simultaneous drug interaction whereby the central nervous system depression caused by the antihistamine is offset by the central nervous system stimulation caused by the caffeine. Hence, relief is afforded with minimal side effects.
  • Alcohol may comprise up to from about 25% to about 30% w/v of the composition and at the higher levels may certainly depress central nervous system function.
  • the caffeine then must be formulated in such a way that it's release is not only delayed and timed so as to provide stimulation upon onset of the antihistaminic effect but also in a sustained and delayed manner so as to offset and combat the more long term effects of the alcohol.
  • Caffeine, (1,3,7-trimethyll xanthine) is an odorless, bitter tasting compound that is a well known central nervous system stimulant that has been useful as both a cardiac and respiratory stimulant as well as a diuretic.
  • the t max for any given active compound is the time that the compound takes from administration or absorption to the time when its concentration in the blood plasma is at a maximum; i.e., the time at which the effect of the drug in the system is at its greatest. Whereas the t max for caffeine is 42 minutes, the tmax for diphenhydramine hydrochloride is 102 minutes. In order to reduce the lethargic effects of the diphenhydramine, these t max values must be equalized. Whereas the t ma ⁇ of diphenhydramine will not easily be lowered, it was surprisingly found that the t max value for caffeine can be increased so that the desired pharmacological effect would be obtained.
  • Delayed and sustained release of the caffeine was obtained through the encapsulation of the drug using natural and artificial gums such as xanthan and guar gum, water soluble polymers, acrylic resin, acrylic acid polymers such as Carbopol AP (B.F. Goodrich Co.) polysaccharides, polyesters, waxes such as carnauba wax and mixtures thereof. More specifically, these compounds include cellulose polymers such as hydroxypropyl cellulose (HPC), methyl cellulose (MC) hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose, hydroxy cellulose, ethyl cellulose, celulose acetate, sodium carboxymethyl cellulose, sodium cross carmellose, and the like.
  • HPC hydroxypropyl cellulose
  • MC methyl cellulose
  • HPMC hydroxypropyl methyl cellulose
  • HPMC hydroxyethyl cellulose
  • celulose acetate sodium carboxymethyl cellulose, sodium cross carmellose, and the like.
  • formulations of the present invention will comprise diphenhydramine hydrochloride in amounts of from about 25 mg. to about 75 mg. per dose, more preferably from about 40 mg. to about 60 mg. per dose and most preferably, about 50 mg./dose.
  • Caffeine is employed in the formulations in amounts of from about 100 mg. to about 300 mg./dose, preferably, from about 150 mg. to about 250 mg./dose and most preferably about 200 mg. per dose.
  • the preferred formulation of the present invention that insures that both the caffeine and the diphenhydramine hydrochloride possess the same or similar t max values comprises a sustained release core containing the caffeine and an immediate release coating thereon containing the diphenhydramine.
  • the core is comprised of caffeine in an amount of from approximately 100 mg./tablet to about 300 mg./tablet combined with a food grade polymer such as hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, cellulose acetate, cellulose ethers, microcrystalline cellulose and mixtures thereof.
  • Standard tabletting materials known in the art such as magnesium stearate, silicon dioxide and the like are added so that a defined core is made.
  • Diphenhydramine hydrochloride is then mixed in an aqueous solution of a film-forming agent such as Opadry®, a polyvinyl chloride polymer.
  • a film-forming agent such as Opadry®, a polyvinyl chloride polymer.
  • film-forming agents are polyvinyl pyrrolidone, polyvinyl acetate, polyethylene glycol, polypropylene, polyethylene, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and mixtures thereof.
  • the antihistamine and film forming agent are combined on a 1:1 weight ratio but
  • SUBSTITUTESHEET(RULE25) ratios outside this range are certainly possible, this is merely the preferred ratio.
  • Fifty mgs.. of antihistamine may be mixed with 50 mg. film forming agent in water and this may be applied as a coating to the caffeine core by any one of the many coating procedures known in the art including spray drying, pan coating, condensation and the like. The coating is dried about the core removing the water and solidifying the drug/film-former coating thereon.
  • Caffeine then, will comprise from about 3% to about 90% by weight of the entire formulation and preferably from approximately 20% to about 70%.
  • the sustained release agent core material such as hydroxypropyl methyl cellulose will comprise from about 10% to about 30% by weight of the formulation and preferably about 20% thereof.
  • the diphenhydramine hydrochloride will comprise from approximately 1% to about 40% by weight and preferably from about 3% to about 20% thereof.
  • the water soluble film forming polymer will comprise from about 3% to about 30% and preferably from about 10% to 20% by weight of the total weight of the formulation.
  • Bulking agents such as macrocrystalline cellulose, tableting agents such as colloidal silicon dioxide and lubricants such as magnesium stearate may be added in deminimus amounts of from about 0.1 to 2.0% by weight as is known in the art.
  • the non-drowsy, non-sedating sinus and allergy medications of the present invention can also be dosed in one of several possible embodiments.
  • the composition can be formulated as a two layer tablet with the caffeine encapsulated or uniformly distributed in the polymer matrix as one layer and the diphenhydramine in the other immediate release layer. The release of each active can be coordinated depending on the encapsulant and the amount thereof used.
  • the medication can also be dosed as a spanule capsule delivery system whereby the caffeine is granulated, coated and formed into spanules which are then mixed with uncoated spanules of diphenhydramine. The two are then maintained in a gelatin type capsule.
  • the caffeine, hydroxypropyl methylcellulose and microcrystalline cellulose were slowly mixed together as dry powders until completely blended. To this was added the tabletting agents colloidal silicon dioxide and magnesium stearate. The mixture was then tabletted into specific 500 mg. tablets.
  • the caffeine core was then coated with an aqueous solution of the diphenhydramine hydrochloride and the film forming agent using a spray drying chamber as is known in the art.
  • the finished tablets are then collected and bottled.
  • Example 1 Using the process and ingredients set forth in Example 1 the following dose formulations were prepared. Amounts shown are per tablet.
  • Seventy-eight ( 78 ) human subjects suffering from sinus and/or allergy symptoms were given one or several of the above dosage forms and observed for the onset of lethargy and/or drowsiness and for symptomatic relief afforded.
  • the 20 mg. diphenhydramine dose either with or without caffeine showed no significant difference in drowsiness effect and relief from the double placebo.
  • the fifty (50) mg. dose of DPH showed a considerable increase in lethargy or drowsiness over that of the placebo, however, when formulated with the 200 mg. caffeine encapsulated core, substantial sinus relief was afforded without lethargy or drowsiness. The reduction in drowsiness and relief afforded was found to occur at approximately 3.5 hours after drug administration.

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

Abstract

Traitement de la congestion des sinus et des allergies par une médication non sédative et sans effet de somnolence qui combat notamment les refroidissements, les rhumes des foins et autres congestions des sinus, sans provoquer d'états de léthargie ni de somnolence susceptibles d'affecter certaines fonctions du patient. Un antihistaminique tel que l'hydrochlorure de diphenhydramine est associé à une préparation de caféine encapsulée à libération prolongée qui est diffusée et absorbée en même temps que l'antihistaminique. Du fait de la simultanéité d'action des deux substances, la dépression du système nerveux central due à l'antihistaminique est compensée par sa stimulation par la caféine.
PCT/US1995/003308 1994-06-06 1995-03-16 Medication pour traiter les allergies et les congestions des sinus sans effets sedatifs WO1995033451A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU21007/95A AU2100795A (en) 1994-06-06 1995-03-16 Non-sedating allergy sinus medication

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US25433694A 1994-06-06 1994-06-06
US08/254,336 1994-06-06

Publications (1)

Publication Number Publication Date
WO1995033451A1 true WO1995033451A1 (fr) 1995-12-14

Family

ID=22963889

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1995/003308 WO1995033451A1 (fr) 1994-06-06 1995-03-16 Medication pour traiter les allergies et les congestions des sinus sans effets sedatifs

Country Status (3)

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AU (1) AU2100795A (fr)
WO (1) WO1995033451A1 (fr)
ZA (1) ZA954611B (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997032586A1 (fr) * 1996-03-05 1997-09-12 The Procter & Gamble Company Utilisation de la cafeine et de la clemastine pour le traitement de troubles respiratoires
WO2004112771A1 (fr) * 2003-06-17 2004-12-29 Pediamed Pharmaceuticals, Inc. Compositions pharmaceutiques comprenant un antihistaminique et un stimulant et leur utilisation
WO2019084621A1 (fr) * 2017-11-03 2019-05-09 Brien Holden Vision Institute Compositions pharmaceutiques pour lutter contre et/ou réduire la progression de la myopie
CN111281874A (zh) * 2020-02-26 2020-06-16 中国人民解放军第二军医大学 一种苯海拉明和咖啡因复方组合物及其药物组合物和应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0013131A2 (fr) * 1978-12-27 1980-07-09 Mundipharma A.G. Composition pharmaceutique sous forme de dosage solide et procédé pour sa fabrication

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0013131A2 (fr) * 1978-12-27 1980-07-09 Mundipharma A.G. Composition pharmaceutique sous forme de dosage solide et procédé pour sa fabrication

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ALFONSO R. GENNARO ET AL.: "Remington's Pharmaceutical Sciences", MACK PUBLISHING COMPANY, EASTON, PENNSYLVANIA, US *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997032586A1 (fr) * 1996-03-05 1997-09-12 The Procter & Gamble Company Utilisation de la cafeine et de la clemastine pour le traitement de troubles respiratoires
WO2004112771A1 (fr) * 2003-06-17 2004-12-29 Pediamed Pharmaceuticals, Inc. Compositions pharmaceutiques comprenant un antihistaminique et un stimulant et leur utilisation
WO2019084621A1 (fr) * 2017-11-03 2019-05-09 Brien Holden Vision Institute Compositions pharmaceutiques pour lutter contre et/ou réduire la progression de la myopie
US20200345633A1 (en) * 2017-11-03 2020-11-05 Brien Holden Vision Institute Limited Pharmaceutical Compositions for Controlling and/or Reducing the Progression of Myopia
CN111281874A (zh) * 2020-02-26 2020-06-16 中国人民解放军第二军医大学 一种苯海拉明和咖啡因复方组合物及其药物组合物和应用

Also Published As

Publication number Publication date
ZA954611B (en) 1996-01-26
AU2100795A (en) 1996-01-04

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