EP1239859A2 - Traitement destines a des affections inflammatoires et allergiques - Google Patents

Traitement destines a des affections inflammatoires et allergiques

Info

Publication number
EP1239859A2
EP1239859A2 EP00986552A EP00986552A EP1239859A2 EP 1239859 A2 EP1239859 A2 EP 1239859A2 EP 00986552 A EP00986552 A EP 00986552A EP 00986552 A EP00986552 A EP 00986552A EP 1239859 A2 EP1239859 A2 EP 1239859A2
Authority
EP
European Patent Office
Prior art keywords
desloratadine
study
subjects
pediatric
allergic
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
EP00986552A
Other languages
German (de)
English (en)
Inventor
Molton B. Affrime
Christopher R. Banfield
Samir K. Gupta
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Sharp and Dohme LLC
Original Assignee
Schering Corp
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 Schering Corp filed Critical Schering Corp
Publication of EP1239859A2 publication Critical patent/EP1239859A2/fr
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • 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
    • A61P11/02—Nasal agents, e.g. decongestants
    • 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
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • This invention relates to the use of desloratadine for the preparation of a medicament for treating and/or preventing allergic and inflammatory conditions in a pediatric patient and a pediathc pharmaceutical composition comprising an amount of desloratadine effective for such treating and/or preventing.
  • Loratadine is disclosed in U.S. Patent No. 4, 282, 233 as a non- sedating antihistamine useful for treating allergic reactions in animals including humans.
  • the recommended daily dose of loratadine is 10 mg, once daily, for adults and children, 12 years of age and older as well as for children, ages 6 to 11 ( in the form of the syrup): .
  • the present invention provides the use of desloratadine for the preparation of a medicament for treating and/or preventing an allergic and inflammatory condition of the skin or airway passages in a pediatric patient wherein the medicament comprises an effective amount of desloratadine and a pharmaceutically acceptable carrier.
  • the present invention also provides a pharmaceutical composition for treating and/or preventing an allergic and inflammatory condition of the skin or airway passages in a pediatric patient which comprises an effective amount of desloratadine and a pharmaceutically acceptable carrier.
  • the present invention provides a method of treating and/or preventing an allergic and inflammatory condition of the skin or airway passages in a pediatric patient in need of such treating and /or preventing which comprises administering an amount of desloratadine to the pediatric patient effective for such treating and/or preventing
  • the present invention also provides a method of treating and/or preventing seasonal or perennial allergic rhinitis in a pediatric patient which comprises administering an amount of desloratadine to the pediatric patient effective for such treating and/or preventing.
  • the present invention provides a method of treating and/or preventing atopic dermatitis or urticaria in a pediatric patient in need of such which comprises administering an amount of desloratadine to the pediatric patient effective for such treating and/or preventing.
  • Figure 1 graphically displays the variation over time (time zero to 96 hrs) of the mean plasma concentrations of desloratadine (ng/mL of plasma) following (I) a single 5 mL (2.5 mg) dose of desloratadine syrup (0.5 mg/mL) to pediatric volunteers ages 2-5 years and (ii) a single 10 mL (5.0 mg) dose of desloratadine syrup (0.5 mg/mL) to healthy adult volunteers ages 18 to 45 years.
  • Figure 2 graphically displays the variation over time (time zero to 96 hrs) of the mean plasma concentrations of desloratadine (ng/mL of plasma) following (I) a single 10 mL (5 mg) dose of desloratadine syrup (0.5 mg/mL) to pediatric volunteers ages 6-1 1 years and (ii) a single 10 mL (5.0 mg) dose of desloratadine syrup (0.5 mg/mL) to healthy adult volunteers ages 18 to 45 years.
  • allergic and inflammatory condition of the skin or airway passages means those allergic and inflammatory conditions and symptoms found on the skin and in the upper and lower airway passages from the nose to the lungs.
  • Typical allergic and inflammatory conditions of the skin or upper and lower airway passages include seasonal and perennial allergic rhinitis, non-allergic rhinitis, asthma including allergic and non-allergic asthma, sinusitis, colds (in comoination with a NSAID, e.g., aspirin, ibuprofen
  • SUBSTTTUTE SHEET (RULE 26) or APAP) and/or a decongestant e.g. pseudoephedrine
  • dermatitis especially allergic and atopic dermatitis, and urticaria and symptomatic dermographism as well as retinophathy, and small vessel diseases, associated with diabetes mellitus.
  • the amount of desloratadine effective for treating or preventing allergic and inflammatory conditions of the skin or airway passages will vary with the age, sex, body weight, growth and developmental changes as well as the severity of the allergic and inflammatory condition of the pediatric patient.
  • the amount of desloratadine effective for treating or preventing such allergic and inflammatory conditions is in the range of about 2.5 mg/day for pediatric patients, ages 6 to less than 12 years, about 1.25 mg/day for pediatric patients, ages 2 to less than 6 years, and about 0.60 to about 0.70 mg/day, preferably about 0.63 mg/day, more preferably about 0.625 mg/day for pediatric patients, ages 6 months to less than 2 years, in single or divided doses, preferably a single daily dose in the form of a syrup.
  • Desloratadine is a non-sedating long acting histamine antagonist with potent selective peripheral H1 -receptor antagonist activity. Following oral administration, loratadine is rapidiy metabolized to descarboethoxyloratadine or desloratadine, a pharmacologically active metabolite. In vitro and in vivo animal pharmacology studies have been conducted to assess various pharmacodynamic effects of desloratadine and loratadine. In assessing antihistamine activity in mice (comparison of ED 50 value), desloratadine was relatively free of producing alterations in behavior alterations in behavior, neurologic or autonomic function. The potential for desloratadine or
  • Efficacy endpoints in all the studies were Total Symptom Score, Total Nasal Symptom Score, Total Non-nasal Symptom Score, and Health Quality of Life (HQOL) analysis in efficacy trials.
  • Desloratadine (5 mg once daily) significantly reduced the total symptom scores (the sum of individual scores for rhinorrhea, sneezing, congestion/stuffiness, nasal itching, itchy/burning eyes, tearing, ocular redness, and itchy ears/palate).
  • Desloratadine (5 mg) was significantly (p ⁇ 0.01 ) more effective than placebo in reducing nasal symptoms.
  • An important efficacy endpoint analyzed in the desloratadine studies is the AM NOW total symptom score. This parameter measures the total symptom relief by the patient after 24 hours before taking the next day dose. Statistically significant (p ⁇ 0.05) reductions were maintained for the full 24 hour dosing interval over the entire dosage range
  • SUBSTTTUTE SHEET (RULE 25) defined by gender, age, or race. Desloratadine is particularly useful for the treatment and prevention of the nasal (stuffiness/congestion, rhinorrhea, nasal itching, sneezing) and non-nasal (itchy/burning eyes, tearing/watery eyes, redness of the eyes, itching of the ears/palate) symptoms of seasonal allergic rhinitis, including nasal congestion, in patients in need of such treating and/ or preventing.
  • Study Treatments Subjects were confined to the study site at least 12 hours prior to each treatment administration. In the morning of Day 1 following a 10 hour overnight fast, each subject received one of the following treatments based on his/her subject number and the study period: fasting (Treatment A) or did not eat again (Treatment B) until the 4-hour study procedures were completed, at which time lunch was served. Water was permitted throughout the fasting period except for 2 hours following treatment administration. The subjects remained awake and seated upright/ambulatory for 4 hours post-dose. A physician was present at the time of dosing and remained on site until at least 4 hours post-dose. Subjects were under medical supervision throughout their confinement at the study site. Each treatment administration was separated by at least a 7 day washout period. Pharmacokinetics
  • the plasma concentration data for desloratadine were used to estimate the following pharmacokinetic parameters using standard methodologies well known to those skilled in the art.
  • the major pharmacokinetic variables of interest were the plasma AUC and Cmax. All plasma samples were assayed for desloratadine concentrations using a validated method such as gas/liquid chromatography with a NP detector(GLCVNPD). The validation of the assay methods included documentation of its selectivity, limit of quantitation, linearity, precision and accuracy. The lower limit of quantitation (LOQ) of the assay was established at 0.1 ng/mL for desloratadine.
  • Subjects were confined at the study site at least 12 hours prior to each treatment (Day -1 ). In the morning of Day 1 following a 10 hour overnight fast, each subject received one of the following treatments based on his/her subject number and the study period:
  • Treatment A One desloratadine (DL) 5 mg tablet administered after a 10 hour fast.
  • Treatment B Ten (10) mL of DL syrup (0.5 mg/mL) following a 10 hour fast
  • Treatment C Ten (10) mL DL syrup (0.5 mg/mL) administered immediately following a standardized high-fat, high caloric breakfast.
  • SUBSTTTUTE SHEET Subjects randomized to receive the standardized high-fat, high caloric breakfast (Treatment C) consumed the prescribed meal in a 20-minute period prior to drug administration and received the appropriate dose of desloratadine within 5 minutes after completing the breakfast.
  • Subjects were males or females between the ages of 18 and 45 years inclusive, and had a Body Mass Index (BMI) between 19-27.
  • BMI Body Mass Index
  • Subjects were free of any clinically significant disease that required a physician's care and/or may have interfered with study evaluations, procedures or participation.
  • SUBSTITUTE SHEET (RULE 25) • Females who had a positive urine pregnancy test at screening or on admission to the study site.
  • Each dose was administered with 180 mL (6 fl oz) of non-carbonated room temperature water.
  • the tablet was swallowed whole, not chewed or crushed. After dosing, the oral cavity will be inspected to assure that the subject had swallowed the tablet/syrup.
  • the study medication was administered by having the volunteer drink the entire 10 mL of desloratadine syrup, followed by two 10 mL tap water rinses of the dose container (i.e., oral syringe, etc.) to ensure complete dose intake. Subjects continued fasting (Treatment A and B) or did not eat again (Treatment C) until the 4-hour study procedures were completed, at which time lunch was served.
  • the objective of this open label study was to characterize the pharmacokinetic profile of desloratadine and 3-OH desloratadine following a single dose of 5 mL (2.5 mg) desloratadine syrup (0.5 mg/mL) administered
  • each subject received a single 5 mL (2.5 mg) dose of desloratadine syrup (0.5 mg/mL) administered orally
  • Subjects were screened within 3 weeks of dosing, and those who met the entry criteria were confined to the study center within 24 hours prior to dosing. Upon confinement, the clinical laboratory safety tests performed at Screening were repeated for each subject The next morning all subjects received the study medication Vital signs were obtained daily. Blood samples were collected at pre-specified times before and after dosing for
  • SUBSTTTUTE SHEET (RULE 26) safety and pharmacokinetic evaluations. Subjects were continually observed and questioned throughout the study for the possible occurrence of adverse events. Subjects were also instructed to report any unusual experiences or discomfort. No strenuous physical activity was permitted, and the subjects were not allowed visitors (besides the parents or legal guardians) while they were confined to the study site. Following the 24-hour study-related procedures for safety and pharmacokinetic evaluations, subjects were dismissed from the study site. They returned to the study site on Days 3, 4 and 5 for the 48-hour, 72-hour and 96-hour study-related procedures. Following completion of all study-related procedures on Day 5, subjects were discharged from the study.
  • %CV percent coefficient of variation, which is a relative measure of variability. See Steele and Torrie, “Principles and Procedures of Statistics", (1980) 2 nd Edition, McGraw-Hill, NY, at page 27.
  • the objective of this study was to characterize the pharmacokinetic profile of desloratadine following a single dose of 10 mL (5 mg) desloratadine syrup (0.5 mg/mL) administered orally to healthy pediatric subjects ranging in
  • each subject received a single 10 mL (5 mg) dose of desloratadine syrup (0.5 mg/mL) administered orally.
  • Subjects were screened within 3 weeks of dosing, and those who met the entry criteria were confined to the study center within 24 hours prior to dosing. Upon confinement, the clinical laboratory safety tests performed at Screening were repeated for each subject. The next morning all subjects received the study medication. Vital signs were obtained daily. Blood samples were collected at pre-specified times before and after dosing for safety and pharmacokinetic evaluations. Subjects were continually observed and questioned throughout the study for the possible occurrence of adverse events. Subjects were also instructed to report any unusual experiences or discomfort. No strenuous physical activity was permitted, and the subjects were not allowed visitors (besides the parents or legal guardians) while they were confined to the study site. Following the 24-hour study-related procedures for safety and pharmacokinetic evaluations, subjects were dismissed from the study site. They returned to the study site on Days 3, 4 and 5 for the 48-hour, 72-hour and 96-hour study-related procedures. Following completion of all study-related procedures on Day 5, subjects were discharged from the study.
  • SUBSTTTUTE SHEET (RULE 26) (5.0mg) dose of desloratadine syrup (0.5mg/mL) to adult subjects (ages 18 to 45).
  • %CV percent coefficient of variation, which is a relative measure of variability. See Steele and Torrie, “Principles and Procedures of Statistics", (1980) 2 nd Edition, McGraw-Hill, NY, at page 27.
  • the dose should be reduced by 50% to 2.5mg
  • the objective of this open label study will be to characterize the pharmacokinetic profile of desloratadine following a single dose of 2.5 mL (1.25 mg) desloratadine syrup (0.5 mg/mL) administered orally to healthy
  • the protocol of Study No. 2 will be followed
  • U.S. Patent No. 4,659,716 discloses methods of making desloratadine, pharmaceutical compositions containing it and methods of using desloratadine and pharmaceutical compositions containing it to treat allergic reaction in mammals.
  • U.S. Patent No. 5,595,997 discloses pharmaceutical compositions containing desloratadine and methods of using desloratadine for treating and preventing various disease states, e.g., allergic rhinitis.
  • Desloratadine is available from Schehng Corporation, Kenilworth, N.J.
  • the desloratadine syrup (0.5mg/mi) is disclosed in International Patent Application PCT/US99/10469 having an international application date of 27/01/99
  • compositions of desloratadine can be adapted for any mode of administration e.g., for oral, parenteral, e.g., subcutaneous ('SC"), intramuscular (“IM”), and intraperitoneal (“IP”), topical or vaginal administration or by inhalation (orally or intranasally).
  • 'SC subcutaneous
  • IM intramuscular
  • IP intraperitoneal
  • desloratadine is administered orally.
  • compositions may be formulated by combining desloratadine or an equivalent amount of a pharmaceutically acceptable salt thereof with a suitable, inert, pharmaceutically acceptable carrier or diluent that may be either solid or liquid.
  • Desloratadine may be converted into the pharmaceutically acceptable acid addition salts by admixing it with an equivalent amount of a pharmaceutically acceptable acid.
  • suitable pharmaceutically aceptable acids include the mineral acids, e.g., HNO 3 , H 2 SO 4 , H 3 PO , HCI, HBr, organic acids, including, but not limited to, acetic, trifluoroacetic, propionic, lactic, maleic, succinic, tartaric, glucuronic and citric acids as well as alkyl or arylsulfonic acids, such as p-toluenesulfonic acid, 2- naphthalenesulfonic acid, or methanesulfonic acid.
  • the preferred pharmaceutically acceptable salts are trifluoroacetate, tosylate, mesylate, and chloride. Desloratadine is more stable as the free base than as an acid addition salt and the use of the desloratadine free base in pharmaceutical compositions of the present invention is more preferred.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories.
  • the powders and tablets may be comprised of from about 5 to about 95 percent active ingredient.
  • Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania.
  • Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection. Solid form preparations may be converted into liquid preparations shortly before use for either oral or administration. Parenteral forms to be injected intravenously, intramuscularly or subcutaneously are usually in the form of sterile solutions and may contain tonicity agents (salts or glucose), and buffers. Opacifiers may be included in oral solutions,
  • Liquid form preparations may also include solutions for intranasal administration.
  • Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g., nitrogen.
  • a pharmaceutically acceptable carrier such as an inert compressed gas, e.g., nitrogen.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
  • liquid forms include solutions, syrups suspensions and emulsions.
  • the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.

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

Abstract

L'invention concerne l'utilisation de la desloratadine pour la préparation d'un médicament permettant de traiter et/ou d'empêcher une affection inflammatoire et allergique de la peau des voies respiratoires supérieures et inférieures chez un enfant, et une composition pharmaceutique pour enfant, permettant d'y parvenir. Cette composition pharmaceutique comprend une quantité efficace de desloratadine et un excipient pharmaceutiquement acceptable.
EP00986552A 1999-12-21 2000-12-19 Traitement destines a des affections inflammatoires et allergiques Ceased EP1239859A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US17291199P 1999-12-21 1999-12-21
US172911P 1999-12-21
PCT/US2000/034418 WO2001045688A2 (fr) 1999-12-21 2000-12-19 Traitement destines a des affections inflammatoires et allergiques

Publications (1)

Publication Number Publication Date
EP1239859A2 true EP1239859A2 (fr) 2002-09-18

Family

ID=22629711

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00986552A Ceased EP1239859A2 (fr) 1999-12-21 2000-12-19 Traitement destines a des affections inflammatoires et allergiques

Country Status (6)

Country Link
EP (1) EP1239859A2 (fr)
JP (1) JP2003518045A (fr)
AU (1) AU2277301A (fr)
CA (1) CA2393837A1 (fr)
MX (1) MXPA02006347A (fr)
WO (1) WO2001045688A2 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7405223B2 (en) 2000-02-03 2008-07-29 Schering Corporation Treating allergic and inflammatory conditions
US6863901B2 (en) 2001-11-30 2005-03-08 Collegium Pharmaceutical, Inc. Pharmaceutical composition for compressed annular tablet with molded triturate tablet for both intraoral and oral administration
US6827946B2 (en) * 2001-12-05 2004-12-07 Collegium Pharmaceutical, Inc. Compositions containing both sedative and non-sedative antihistamines

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5595997A (en) * 1994-12-30 1997-01-21 Sepracor Inc. Methods and compositions for treating allergic rhinitis and other disorders using descarboethoxyloratadine
US5900421A (en) * 1997-02-11 1999-05-04 Sepracor Inc. Methods and compositions for treating allergic asthma and dermatitis using descarboethoxyloratadine
US6132758A (en) * 1998-06-01 2000-10-17 Schering Corporation Stabilized antihistamine syrup

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0145688A2 *

Also Published As

Publication number Publication date
CA2393837A1 (fr) 2001-06-28
WO2001045688A3 (fr) 2002-05-02
WO2001045688A2 (fr) 2001-06-28
AU2277301A (en) 2001-07-03
MXPA02006347A (es) 2002-12-13
JP2003518045A (ja) 2003-06-03

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