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
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
  • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—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
• • 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
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• • 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
  • 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
• • 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
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/16—Otologicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• This invention relates to the use of desloratadine and/or other antihistamines for treating and/or preventing nasal congestion and/or nasal blockage as defined by symptomatic complaints of nasal airflow limitation associated with allergic and inflammatory conditions, such as seasonal allergic rhinitis.
• Desloratadine disclosed in U.S. Patent No. 4,659,716, is a non-sedating antihistamine useful for treating allergic reactions in animals including humans.
• U.S. Patent No. 5,695,997 discloses pharmaceutical compositions containing desloratadine and methods of using desloratadine for treating and preventing disease states, e.g., allergic rhinitis.
• Severe nasal congestion/stuffiness and/or blockage is a chronic symptom in patients with allergic disorders such as allergic rhinitis.
• allergic disorders such as allergic rhinitis.
• currently available antihistamines have not been effective in treating severe nasal blockage and congestion/stuffiness associated with allergic disorders.
• Congestion associated with allergic rhinitis has been treated by the administration of combination products containing an antihistamine and the decongestant pseudoephedrine.
• the Claritin D12 and D24 commercial products are combinations of loratadine and pseudoephedrine and the "Allegra-D" commercial product is a combination of fexofenadine and pseudoephedrine. See, Physicians Desk Reference 2000.
• pseudoephedrine may cause unwanted side effects.
• Side effects associated with pseudoephedrine include insomnia, dizziness, weakness, tremor or arrhythmia. These and other unwanted side effects may
• the present invention provides a method for treating and/or preventing nasal
• passages in a human in need thereof comprising administering to said human an amount of desloratadine effective for such treating and/or preventing.
• passages in a human in need thereof comprising administering to said human an
• a method for treating and/or preventing nasal congestion associated with allergic and inflammatory conditions of the airway passages in a human in need thereof comprising administering to said human an amount of antihistamine effective for such treating and/or preventing, wherein the antihistamine is selected from the group consisting of loratadine, cetirizine, fexofenadine, ebastine, astemizole, norastemizole, epinastine, efletirizine or a pharmaceutically acceptable salt thereof.
• antihistamine effective for such treating and/or preventing in combination with one or more additional decongestants, wherein the antihistamine is selected from the group consisting of loratadine, cetirizine, fexofenadine, ebastine, astemizole, norastemizole, epinastine, efletirizine or a pharmaceutically acceptable salt thereof.
• allergic and inflammatory conditions of the airway passages means those allergic and inflammatory conditions and symptoms found and in the upper and lower airway passages from the nose to the lungs.
• Typical allergic and inflammatory conditions or upper and lower airway passages include seasonal and perennial allergic rhinitis, non-allergic rhinitis, asthma including allergic and non- allergic asthma, sinusitis, and colds.
• the term “congestion” means an obstruction with a decreased diameter of the nasal cavity and an increased nasal airflow resistance, thus decreasing the obstruction, stuffiness or blockage of the upper airway passages and/or the constriction of the lower airway passages from the nose to the lungs, including severe nasal blockage and congestion.
• nasal blockage means a subject suffering from congestion such that the subject has complaints of moderate to severe nasal obstruction and blockage of nasal airflow, typically with less rhinorrhea.
• the subjects should demonstrate at the baseline visit, the 7 twice daily (in the AM and in the PM) run-in diary reflective scores that includes the three calendar days prior to baseline, as well as the AM of the baseline day.
• the scores may be as follows: the total rhinorrhea score should equal at least 14; the total nasal congestion score should exceed the total rhinorrhea score by at least two; the total nasal symptom score should equal at least 42; the total non-nasal symptom score should equal at least 28.
• the primary efficacy variable is the average AM-PM "reflective" nasal congestion symptom score, expressed as change from Baseline averaged over the treatment period (Days 1 through 8).
• the primary contrast for this variable will be for example, desloratadine versus placebo.
• Secondary efficacy parameters include the AM "instantaneous" nasal congestion score, as well as the average AM-PM “reflective" and “instantaneous" total symptom score minus nasal congestion (sum of six individual symptom scores); total symptom score (sum of the seven individual symptom scores including nasal congestion); nasal symptom score (sum of the four nasal symptom scores); total nasal symptom score minus nasal blockage/airflow; non-nasal symptom score (sum of the three individual non-nasal symptom scores); each of the seven individual symptom scores and subject and investigator/designee evaluation of therapeutic response to treatment.
• Assessment of safety will include routine subject- and investigator-evaluated adverse events; investigator-evaluated vital signs and EGG; laboratory evaluations of blood chemistry, hematology, and urinalysis.
• Subjects can be of either sex and any race at least 12 years of age; at least a 2 year history of moderate/severe spring seasonal allergic rhinitis, documented by positive skin prick test reactivity to the prevalent spring seasonal allergen(s) to which the patient is sensitive (history of allergy/skin test responsiveness to perennial allergens and molds will also be obtained for demographic purposes and for possible ad hoc sub-group analyses.
• a nasal rhinorrhea anterior or posterior score of at least moderate (score of at least 2)
• nasal congestion must be at least moderate (score of at least 2)
• total nasal symptom score must total at least 6, and total non-nasal score must equal at least 4.
• the seven twice-daily (AM and PM) run-in diary “reflective" scores which includes the three calendar days prior to Baseline, as well as the AM of the Baseline day, must be as follows: the symptom score for rhinorrhea must equal at least 14; the total nasal congestion
• Group will receive desloratadine 5.0 mg; Group II will receive placebo. Placebo
• the Ratio of subjects assigned to treatments will be 1 :1 ,
• Randomization will be performed in appropriately sized blocks using random numbers generated by SAS function UNIFORM with seed based on clock-time.
• Drop-outs will not be replaced at sites. This is a one-week, pilot Phase II study, composed of a total of 300 subjects to be enrolled. Each subject will be screened during the spring allergy season in the United States. Subjects must be sufficiently symptomatic with respect to nasal and non-nasal symptoms at both the Screening and Baseline visits. Subjects in the two treatment groups will be required to visit the office for a Baseline visit, usually 3 to 14 days after the screening visit, in order to qualify to receive the first dose of randomized treatment unit. In each treatment group, subjects will be required to revisit the office for one follow-up visit, on Day 8 (7 days after Baseline).
• the amount of desloratadine effective for treating or preventing congestion associated with allergic and inflammatory conditions of the airway passages will vary with the age, sex, body weight and severity of the allergic and inflammatory condition of the 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 to about 45 mg/day, preferably about 2.5 mg/day to about 20 mg/day, or about 5.0 mg/day to about 15 mg/day, or about 5.0 mg/day to about 10 mg/day, more preferably about 5.0 mg/day to about 7.5 mg/day, and most preferably about 5.0 mg/day in single or divided doses, or a single dose of 5.0 mg/day.
• 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 Schering Corporation, Kenilworth, N.J.
• the antihistamines that are also useful in the present invention include loratadine, cetirizine, levocetirizine, mizolastine for seasonal allergic rhinitis,
• fexofenadine and cetirizine is most preferred.
• Cetirizine reportedly is disclosed in U.S. Patent No. 4,525,358.
• Cetirizine reportedly is disclosed in U.S. Patent No. 4,525,358.
• the pharmaceutically acceptable salt is the hydrochloride, also known as
• cetirizine hydrochloride The amount of cetirizine which can be employed in a
• unit dosage form of the present composition can range from about 2.5 to 20 mg,
• Fexofenadine (MDL 16,455A) is reportedly disclosed in U.S. Patent No.
• the pharmaceutically acceptable salt is the hydrochloride
• fexofenadine hydrochloride also known as fexofenadine hydrochloride. The amount of fexofenadine which
• composition can range
• Ebastine reportedly is described in EP 134124. The amount of ebastine
• amount of astemizole which can be employed in a unit dosage form can range from about 5 to about 20 mg, preferably about 10 mg.
• Norastemizole reportedly is an antihistamine, whose technical name is 1- ((4-fluorophenyl)methyl)-N-4-piperidinyl-1 H-benzimidazol-2-amine.
• the compound is an active metabolite of astemizole.
• the amount of norastemizole which can be employed in a unit dosage form can range from about 5 to about 40 mg, also from about 10 to about 20 mg.
• Epinastine reportedly is described in DE 3008944 or Jpn.. J. Clin. Pharmocol. Ther.. 1991 , 22, page 617.
• the amount of epinastine which can be employed in a unit dosage form can range from about 1 to about 20 mg, preferably about 2 to about 18 mg.
• Efletirizine (UCB-28754) reportedly is an antihistamine, whose technical name is [2-[4-[Bis(p-fluorophenyl)methyl]-1-piperazinyl]ethoxy]acetic acid. CASReg. No. 140756-35-7.
• the amount of efletirizine which can be employed in a unit dosage form can range from about 4 to about 60 mg.
• U.S. Patent No. 4,282,233 discloses methods of making loratadine, pharmaceutical compositions containing it and methods of using loratadine and pharmaceutical compositions containing it to effect an anti-allergic response in mammals.
• Loratadine is available from Schering-Plough Corporation,
• compositions of desloratadine and/or other antihistamines can be adapted for any mode of administration e.g., for oral, parenteral, e.g., subcutaneous ('SC"), intramuscular (“IM”), intravenous (“IV)” and intraperitoneal (“IP”), topical or vaginal administration or by inhalation (orally or intranasally).
• 'SC subcutaneous
• IM intramuscular
• IV intravenous
• IP intraperitoneal
• desloratadine and/or other antihistamines is administered orally.
• compositions may be formulated by combining desloratadine and/or other antihistamines 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 acceptable acids include the mineral acids, e.g., HN0 3 , H 2 S0 , H 3 P0 4 , HCl, 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, suspensions and emulsions. 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, suspensions and emulsions.
• the compounds of the invention may also be deliverable transdermally.
• the transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
• the present invention includes combinations of desloratadine and/or other antihistamines and other decongestants. Due to the decongestant effect of desloratadine and/or other antihistamines, the other decongestants may be present in a reduced amount compared to other combinations of antihistamines and decongestants.
• Other decongestants which may be used in combination with desloratadine and/or other antihistamines include pseudoephedrine, phenylephrine and phenylpropanolamine.
• the pharmaceutical preparation is in a unit dosage 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.
• 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.
• Symptom Score 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.

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  • 2002-06-19 BR BR0210534-9A patent/BR0210534A/pt not_active IP Right Cessation
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