JP2003509459A - Treatment of allergic and inflammatory conditions - Google Patents

Abstract

  (57) [Summary] The present invention relates to the use of desloratadine for the preparation of a medicament, which comprises allergic and / or inflammatory conditions of the skin or airway passages (eg seasonal allergic rhinitis, perennial allergies). A person suffering from rhinitis, atopic dermatitis, urticaria or allergic asthma) is substantially linked to the person's underlying work ability and labor productivity. It relates to use, which is a medicine for recovery.

Description

Detailed Description of the Invention

BACKGROUND OF THE INVENTION The present invention relates to desloratadine for the preparation of a medicament.
) Is used to determine the work capacity and / or labor productivity of a patient suffering from an allergic condition and / or an inflammatory condition, and It is a medicine for the physical recovery.

Symptoms and side effects of an allergic and / or inflammatory condition of the skin or upper and lower respiratory tracts (eg, seasonal allergic rhinitis (“SAR”)) include itching, dry eyes, sneezing, runny nose, Nasal congestion
ion), urticaria, somnolence and general malaise. Pharmacological effects of treatment of allergic and / or inflammatory conditions (eg, SAR) with sedative antihistamines include somnolence, blurred vision, dry mouth, and reduced individual ability at home, school and work. And labor productivity decline. SAR is 4 in the United States
It affects 5 million people and affects more people worldwide.

Cockburn, Rain M et al., Businesses & Health, 1
March 1999, pp. 49-50 and J. Occup Environ Med.
, November 1999, Vol. 41 (11), pp. 948-953, treatment of allergic reactions with sedative antihistamines alone or in combination with decongestants, but without sedative antihistamines. It is disclosed that it leads to a decline in individual abilities of workers and a decrease in labor productivity in comparison with.

Given the high prevalence of SAR, even relatively small effects on individual performance have significant effects on work performance and labor productivity in populations around the world. Therefore, the worker's skin and upper or lower respiratory allergic conditions and / or
Alternatively, there is a need for more clinically effective treatments that treat / prevent inflammatory conditions and substantially enhance the work capacity and labor productivity of workers.

SUMMARY OF THE INVENTION The present invention provides a method of substantially restoring the work performance of a person suffering from an allergic and / or inflammatory condition of the skin or respiratory tract to that person's underlying work performance. However, the method involves administering to this person an amount of desloratadine effective for such recovery.

The present invention provides a method of restoring the labor productivity of a person suffering from an allergic and / or inflammatory condition of the skin or respiratory tract to that person's basal labor productivity. , Administering to this person an amount of desloratadine effective for such recovery.

In a preferred embodiment, the present invention provides a method of substantially restoring the work performance of a person suffering from seasonal allergic rhinitis to that person's underlying work performance. , Administering to such a person an amount of desloratadine effective for such recovery.

In a preferred embodiment, the present invention provides a method of substantially restoring the labor productivity of a person suffering from seasonal allergic rhinitis to that person's basal labor productivity. The method comprises administering to such a person an amount of desloratadine effective for such recovery.

In another preferred embodiment, the present invention provides a method of enhancing the work capacity of a person suffering from atopic dermatitis or urticaria, which method is effective in such enhancement. Comprising administering an amount of desloratadine.

In another preferred embodiment, the present invention provides a method of substantially restoring the work performance of a person suffering from atopic dermatitis or urticaria to that person's underlying work performance. The method includes administering an amount of desloratadine effective for such recovery.

In another preferred embodiment, the present invention provides a method of substantially restoring the labor productivity of a person suffering from atopic dermatitis or urticaria to that person's basal labor productivity. Provided, the method comprises administering an amount of desloratadine effective for such recovery.

[0012] In another preferred embodiment, the present invention substantially restores the labor productivity of a person suffering from an allergic and / or inflammatory condition of the skin or respiratory tract to that person's basal labor productivity. The method is by administering to this person an initial dose of desloratadine effective for such recovery.

In another preferred embodiment, the present invention provides a method of substantially restoring the ability of a person suffering from an allergic and / or inflammatory condition of the skin or respiratory tract to his or her basal labor productivity. The method is by administering to this person an initial dose of desloratadine effective for such recovery.

The present invention also relates to the work ability and / or labor productivity of a person suffering from an allergic and / or inflammatory condition of the skin or respiratory tract, to the person's underlying work ability and / or work productivity. Contemplated is a pharmaceutical composition for substantial recovery, which composition comprises an amount of desloratadine effective for such recovery.

DETAILED DESCRIPTION OF THE INVENTION Allergic and / or inflammatory conditions of the skin and upper or lower respiratory tract (eg, seasonal allergic rhinitis) treated with an initial effective amount of desloratadine.
Those who suffer from the symptoms and side effects of are significantly more competent and significantly more likely to be in a controlled clinical setting compared to those who were untreated and those who were treated with the first standard dose of the sedative antihistamine, diphenhydramine. Shows high labor productivity.

As used herein, the phrase “human underlying work capacity” refers to the skin or respiratory tract, as measured by the art-recognized methods described herein below. Means the ability of a person to work before the signs and / or symptoms of an allergic and / or inflammatory condition of.

As used herein, the phrase “human basal labor productivity” refers to skin or as measured by art-recognized methods described herein below. It means the labor productivity of a person at a time before showing the signs and / or symptoms of an allergic and / or inflammatory condition of the respiratory tract.

As used herein with respect to a person's basal work capacity or basal labor productivity, the phrase “substantially recovers” means within about 5-10% of its basal value, preferably. , Within about 5%, and more preferably within about 1-2%.

As used herein, the phrase “skin or airway allergic and / or inflammatory condition” refers to an allergic and / or inflammatory condition found in the skin and airways from the nose to the lungs. And means a symptom. Typical allergic and / or inflammatory conditions of the skin and upper and lower respiratory tract include seasonal and perennial allergic rhinitis, non-allergic rhinitis, asthma (including allergic and non-allergic asthma) , Sinusitis, colds (in combination with NSAIDs (eg aspirin ibuprofen or APAP) and / or decongestants (eg pseudoephedrine)), dermatitis (especially,
Allergic dermatitis and atopic dermatitis), as well as urticaria and symptomatic cutaneous delineation, as well as retinopathy and small vessel disease (related to diabetes).

The amount of desloratadine effective to treat or prevent allergic and / or inflammatory conditions of the skin and upper and lower respiratory tracts depends on the age, sex, weight of the patient and the severity of allergic and inflammatory conditions. It depends on the severity. Typically, an effective amount of desloratadine for treating or preventing such allergic and inflammatory conditions is from about 2.5 mg / day to about 45 mg / day, preferably about 2.5 mg / day. Day to about 20 mg / day, or about 4.0 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 (eg,
Approximately 5. in a single dose or in divided doses (two 2.5 mg doses), or in a single dose.
0 mg / day).

Desloratadine is a non-sedating, long-acting histamine antagonist with potent selective peripheral H1 receptor antagonist activity. After oral administration, loratadine is rapidly metabolized to the pharmacologically active metabolite descarboethoxyloratadine or desloratadine. In vitro and in vivo veterinary pharmacological studies have been performed to evaluate the various pharmacodynamic effects of desloratadine and loratadine. In assessing antihistamine activity in mice (comparison of ED ₅₀ values), desloratadine produced less changes in behavioral, neural or autonomic function. The potential of desloratadine or loratadine to occupy the brain H1 receptor is i. p. Evaluated in guinea pigs after (intraperitoneal) administration, the results suggest that desloratadine or loratadine have poor accessibility to central histamine receptors.

In vivo studies also suggest that the inhibitory effect of desloratadine on allergic bronchospasm and cough may also be predicted.

The clinical efficacy and safety of desloratadine was demonstrated in more than 3,200 seasonal allergic rhinitis patients in four double-blind, randomized clinical trials. The results of these clinical studies demonstrated the efficacy of desloratadine in treating adult and adolescent patients with seasonal rhinitis.

Desloratadine is especially suitable for nasal symptoms (stiffnesses / stasis, rhinorrhea, nasal itchiness, sneezing) and non-nasal symptoms of seasonal allergic rhinitis (including nasal congestion). Useful in the treatment and / or prophylaxis of patients in need of treatment and / or prophylaxis of itching / burning of the eye, lacrimation / blunted eye, redness of the eye, itching of the ear / pallate) . Desloratadine can be used alone or as a decongestant (eg, pseudoephedrine (pseudeeoph).
)) and / or sedatives (eg NSAIDs such as acetaminophen or ibuprofen).

Study Design and Concepts A series of randomized, double-blind (treatment), placebo-controlled studies were tested as measured by work competence and labor productivity in selected areas recognized in the art. Designed to quantify the effects of seasonal allergic rhinitis (“SAR”) and SAR treatment on the body's work performance and labor productivity. In a series of studies, the effect of a subject's SAR (disease burden) is quantified by comparing the workability level of asymptomatic SAR subjects to their workability in symptomatic SAR subjects. In another series of studies, the differential effects of SAR on the subject's work performance after two different treatments are quantified: subjects with symptomatic SAR during exposure of the subject to ragweed pollen. Across the body, the effect of a 5 mg tablet of desloratadine is compared to 50 mg of diphenhydramine (and placebo for each drug). Consistent levels of ragweed pollen exposure were assessed by conducting these studies in the Environmental Exposure Unit (EEU). Basal work capacity and basal labor productivity of each subject are measured on Day 0 prior to exposure to ragweed pollen in the EEU.

Work Performance Tests The work performance of subjects tested in a series of studies was selected based on the consensus of a professional group of neuropsychologists, industrial psychologists and allergists. These work performances cover the areas that are most likely to be affected by the symptoms of SAR and / or the sedation caused by SAR treatment. In addition, the expert group ordered the competence areas most closely related to safety and productivity related abilities. These work abilities were then mapped by their specialized population to neuropsychological competence tests.

(First index) The effect of SAR (also called disease burden) was evaluated by asymptomatic subjects versus symptomatic subjects and symptomatic subjects treated with desloratadine 5 mg tablets versus symptomatic subjects treated with diphenhydramine 50 mg. Selective attention (selec) in a subject
It is measured by measuring the live attention.

[0028]

[Table 1] (Second index) 1. The effect of treatment (desloratadine vs. diphenhydramine) was determined by the perceptual speed in asymptomatic subjects versus symptomatic subjects treated with desloratadine 5 mg tablets versus symptomatic subjects treated with 50 mg diphenhydramine. ) Is determined.

[0029]

[Table 2] 2. Disease burden was measured in asymptomatic vs. symptomatic subjects; and in symptomatic vs. desloratadine-treated symptomatic subjects by measuring the information ordering as follows: It was measured:

[0030]

[Table 3] (Other indicators) Further measurement of some performance domains is also mentioned as the second indicator. These include problem susceptibility (pr
obesity sensitivity, memory (memory),
Number facility (number facility), time sharing (time sharing)
g), and response orientation, as well as rate control.

Inclusion and Exclusion Criteria Finally, using standard inclusion and exclusion criteria, other factors (eg,
Nicotine and / or alcohol use, or sleep deprivation) do not contribute to the observed effects.

Environmental Exposure Unit (EEU) EEU is a scientifically recognized pollen exposure system. This system was used to evaluate the effects of anti-allergic drugs, including demonstrating the "onset of action" of these drugs on the signs and symptoms of pollen-induced allergic rhinitis. Controlled exposure to air allergens (usually short ragweed pollen) ruled out changes associated with other methods of clinical evaluation of these drugs. The clinical relevance of the results of this test system is that clinical trials in this unit using other modalities of allergen challenge, specifically exposure of allergic subjects to increased natural environmental pollen levels. It is verified by comparing the results of.

On these study days (subject is symptomatic and work-related (work-rel)
aged performance and work-place
subject) for 3 hours prior to taking the test (productivity)).
Controlled pollen levels in the EEU (3500 ± 500 grains / m ³ respectively) during ~ 6 priming sessions.
) Is exposed to. Subjects should meet the criteria for symptom severity for the records in this study after they have been transferred to a pollen-free room for up to 1 hour of observation, or until 3 hours have elapsed. Record the severity of symptoms every 30 minutes. Subjects whose symptoms are too severe to remain in the EEU for at least 3 hours are transferred to a pollen-free room and excluded from the study. To qualify for enrollment, subjects must reach a total SAR symptom severity score of 10 or higher, consisting of a nasal symptom score of 6 or higher and a score of 4 or higher for non-nasal conditions. . Inclusion criteria will be assigned to computer randomization in leaving subjects in the EEU that meet a severity score.

On basal (symptomatic) and treatment study days, subjects enrolled at 7:30 am
Go to EEU. These subjects completed a one-day basal pre-exposure assessment of the subject's SAR symptom severity at 8:00 am, and then the subjects were given eight hours (ie, 8:00 am to pm Exposure (3500 ± 500 grains / m ³ ) to ragweed pollen at 4:00). Immediately following symptom severity assessment at 9:30 am, medication eligibility and study continuity will be assessed. Diary card (da at 10:00 am
Immediately after completion of the entry of the iry card, all subjects received a glass of water (18
0 mL) of the subject's drug.

Workability and labor productivity testing begins about one and a half hours after the first dose and continues until about two hours after the first dose. This timing allows the test to be completed during the time the two drugs are expected to show efficacy.

Labor Productivity Tests The selected labor productivity tests consist of the effects of sedation and the subject's susceptibility to seasonal allergic rhinitis conditions, and their suitability for the skills required for the documentation process. Based on relevancy. Use the same inclusion / exclusion criteria used for workability studies. Consistent levels of ragweed pollen exposure are assured by conducting these studies in the Environmental Exposure Unit (EEU) described above.

Objectives of the Initial Study: Subjects with symptomatic SAR were sedated after exposure of both sets of subjects to ragweed pollen in the EEU described above.
) To show greater labor productivity when treated with desloratadine (5 mg tablet antihistamine) than when treated with the antihistamine, diphenhydramine 50 mg.

(Purpose of Second Research) 1. 1. show that subjects with symptomatic SAR are more workable and productive when treated with desloratadine than when the subject is not treated; and To show that SAR negatively affects labor productivity.

Background of the study for this study The hypothesis regarding the purpose of these studies is that medication with diphenhydramine indicates that somnolence, as well as cognitive and psychomotor function and vigilan.
ce) and intuition projection dysfunction, as well as evidence that the signs and symptoms of SAR adversely affect the same functions as described above. SAR can exert its dysfunctional effects not only by affecting visual and auditory responses and upper respiratory tract breathing capacity, but also by feeling of general fatigue and discomfort. These impairments of work-related capacity result in reduced labor productivity.

Subjects of this study (History of ragweed pollen-related SAR and short ragweed (sho
rt ragweed) with a positive skin test demonstrated for pollen),
Simultaneous asymptomatic and symptomatic assessments are established to establish underlying work-related function and labor productivity data that meet the study objectives. These subjects are the subject's SAR
Subjects are required to meet at least the minimum requirements for typing / writing skills as they are evaluated for the effects of signs and symptoms, as well as the effects of the two drugs on individual performance and labor productivity.

Both drugs (desloratadine and diphenhydramine) were administered during the course of the treatment study day (starting immediately 1 and a half hours after dosing and continuing for the duration of the study).
It is expected to reduce the signs and symptoms of SAR.

General Experiments US Pat. No. 4,659,716 discloses methods for making desloratadine and desloratadine as non-sedating antihistamines, pharmaceutical compositions containing desloratadine, and desloratadine and desalatadine. Disclosed is a method of using a pharmaceutical composition comprising loratadine to treat an allergic reaction in a mammal.

US Pat. No. 5,595,997 discloses pharmaceutical compositions containing desloratadine and methods of using desloratadine to treat allergic rhinitis.

Desloratadine is commercially available from Schering Corporation, Kenil
north, N. J. Available from. Diphenhydramine is BENAD
It is available under the RYL trademark, which can be purchased without a prescription.

The pharmaceutical composition of desloratadine may be administered in any mode of administration (eg, oral, parenteral (eg, subcutaneous (“SC”)), intramuscular (“IM”), intravenous (“IV”).
) Administration, and intraperitoneal (“IP”) administration, topical or vaginal administration or inhalation (
Oral or intranasal)))). Preferably, desloratadine is administered orally.

Such a composition comprises desloratadine, or an equivalent amount of a pharmaceutically acceptable salt thereof and a suitable inert pharmaceutically acceptable carrier or diluent, which may be either solid or liquid. It can be prescribed by combining with. Desloratadine can be converted to a pharmaceutically acceptable acid addition salt by mixing desloratadine with an equal amount of a pharmaceutically acceptable acid. Representative suitable pharmaceutically acceptable acids include inorganic acids (eg HNO ₃ , H ₂ SO ₄ , H ₃ PO ₄ , HCl, HBr),
Organic acids (acetic acid, trifluoroacetic acid, propionic acid, lactic acid, maleic acid, succinic acid, tartaric acid, glucuronic acid, and citric acid, and alkyl or aryl sulfonic acids (eg, p-toluene sulfonic acid, 2-naphthalene sulfonic acid). , Or methanesulfonic acid), but is not limited thereto. Preferred pharmaceutically acceptable salts are trifluoroacetates, tosylates, mesylates, and hydrochlorides. Desloratadine is more stable as the free base than as the acid addition salt, and the use of desloratadine free base in the pharmaceutical compositions of the present invention is more preferred.

Solid form compositions include powders, tablets, dispersible granules, capsules, cachets,
And suppositories. Powders and tablets can contain from about 5 to about 95% active ingredient. Suitable solid carriers are known in the art, eg 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 making various compositions are:
A. Gennaro (ed.), Remington's Pharmaceuti
cal Sciences, 18th Edition, (1990), Mack Publics.
ing Co. , Easton, Pennsylvania.

Liquid form preparations include solutions, suspensions and emulsions. Examples include 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 parenteral administration. Parenteral forms that are injected intravenously, intramuscularly, or subcutaneously are usually in the form of a sterile solution and will contain a tonicity agent.
gent) (salt or glucose) and buffer. Opacifiers can 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. It can be in combination with a pharmaceutically acceptable carrier, such as a pressurized inert gas, such as nitrogen.

Also included are solid form preparations. This preparation is intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

Desloratadine may also be deliverable transdermally. Transdermal compositions can take the form of ointments, lotions, aerosols and / or emulsions, and can be included in matrix or reservoir type transdermal patches, which are conventional in the art for this purpose.

Preferably the pharmaceutical composition is in unit dosage form. In such form, the preparation will contain a suitable amount of desloratadine in a single amount and the other, of any suitable size, containing the active ingredient, eg, an effective amount to achieve the desired purpose. Divided into doses.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 29/00 A61P 29/00 37/08 37/08 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY) , KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CR, CR, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, HR, HU, ID, IL, IN, IS, JP, KG, KR, KZ, LC, LK, LR, LT , LU, LV, MA, MD, MG, MK, MN, MX, MZ, NO, NZ, PL, PT, RO, RU, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, US, UZ, VN, YU, ZA (72) Inventor Heath Off, Kim Allen United States New Jersey 08858-0423, Old Wik, P. Oh. Box 423, Williams Street 22F Term (Reference) 4C086 AA01 AA02 BC27 MA01 MA04 NA14 ZA34 ZA59 ZA89 ZB11 ZB13

Claims (8)

[Claims] 1. The use of desloratadine for the preparation of a medicament, said medicament comprising the ability of a person suffering from an allergic and / or inflammatory condition of the skin or respiratory tract to affect the basal capacity of the person. Use, which is a drug to substantially restore work ability. 2. Use of desloratadine for the preparation of a medicament, said medicament being capable of improving the labor productivity of a person suffering from an allergic and / or inflammatory condition of the skin or respiratory tract. Use, which is a drug to substantially restore the labor productivity of. 3. The use of desloratadine for the preparation of a medicament, which medicament makes the work ability of a person suffering from seasonal or perennial allergic rhinitis into a person's basal work ability. Use, which is a medicament for substantially recovering. 4. The amount of desloratadine is about 2.5 mg / day to about 45 mg.
Use according to any one of claims 1 to 3, which is / day. 5. The use according to any one of claims 1 to 4, wherein the amount of desloratadine is about 5 mg / day to about 15 mg / day. 6. The use according to any one of claims 1-5, wherein the amount of desloratadine is about 5 mg / day to about 10 mg / day. 7. The amount of desloratadine is about 5 mg / day.
Use according to any one of 6 to 6. 8. The allergic and / or inflammatory condition of the skin or respiratory tract is seasonal allergic rhinitis, perennial allergic rhinitis, atopic dermatitis, urticaria or allergic asthma. The use according to any one of 1 to 7.