HK1056324A - Compositions and methods for treating allergic and inflammatory conditions with cough - Google Patents

Description

Compositions and methods for treating allergic and inflammatory conditions with cough

Background of the invention

The present invention relates to the treatment and/or prevention of allergic and inflammatory conditions associated with productive and non-productive cough in humans by administration of a combination of an antihistamine and an expectorant without sedative effect.

Antihistamines without sedative effect are known, see for example loratadine disclosed in U.S. Pat. No. 4,282,233; des1oratadine disclosed in U.S. Pat. No. 4,659,716. See also loratadine by the Claritin brand, product information table, date 1/99. Similarly, mucolytic expectorants have been known in the art for some time. See ambroxol disclosed in U.S. patent No. 3,536,712. Although useful, neither antihistamines nor expectorants, by themselves, are effective in treating the various symptoms associated with respiratory tract disorders, such as bronchitis and bronchospasm, seasonal allergic rhinitis, perennial allergic rhinitis, the common cold, sinusitis and complications associated with allergic asthma. Symptoms of such diseases may include sneezing, runny nose, nasal congestion, redness of the eye, tearing, itching of the ears or palate, and productive and non-productive coughs. It would be highly desirable to be able to provide a formulation of these known individual drugs which enhances their individual efficacy and which enhances their overall efficacy.

Summary of The Invention

The present invention provides a method of treating and/or preventing allergic and inflammatory conditions with cough in a person in need of such treatment and/or prevention, which comprises administering an effective amount of an antihistamine and an expectorant that are non-sedative. In a particular embodiment, the non-sedating antihistamine is loratadine and the expectorant is ambroxol. Treatment according to the claimed method is more effective than treatment with either an antihistamine or an expectorant alone without sedation and takes effect more rapidly than with the inclusion of an antihistamine without sedation.

The present invention provides a method of treating and/or preventing allergic or inflammatory conditions with cough in a person aged 6 or older in need of such treatment and/or prevention, which comprises administering an effective amount of an antihistamine without sedative effect in combination with an expectorant. In a preferred embodiment, the antihistamine is loratadine and the expectorant is ambroxol. In a particularly preferred embodiment, the amount of loratadine is from about 5.0 mg/day to about 15.0 mg/day in single or divided doses, more preferably about 10 mg/day, in single or divided doses, most preferably about 5 mg/day twice. In another embodiment, the amount of ambroxol is from about 30 mg/day to about 180 mg/day in single or divided doses, more preferably from about 30 mg/day to about 90 mg/day or about 60 mg/day in single or divided doses, most preferably about 30 mg/day twice.

The present invention also provides a method of treating and/or preventing allergic or inflammatory conditions with cough in a human 6 to 12 years of age in need of such treatment and/or prevention, which comprises administering an effective amount of an antihistamine without sedative effect in combination with an expectorant. In a preferred embodiment, the antihistamine is loratadine and the expectorant is ambroxol. In a particularly preferred embodiment, the amount of loratadine is about 0.5mg to about 15.0mg, in single or divided doses. The concentration of loratadine in the liquid dosage form is preferably from about 0.5mg/ml to about 3.0mg/ml, and can be administered in single or divided doses; more preferably about 2.0mg/ml per day in single or divided doses, most preferably about 1.0mg/ml twice per day, depending on body weight. The dose of loratadine is preferably from about 0.1mg/kg to about 0.3mg/kg per day, more preferably from about 0.2mg/kg to about 0.3mg/kg per day. In further embodiments, the ambroxol is about 0.6mg to about 180.0mg per day, in single or divided doses. The concentration of ambroxol is preferably from about 3.0mg/ml to 18.0mg/ml per day, administered in single or divided doses, depending on body weight; more preferably about 12.0mg/ml, in single or divided doses, most preferably about 6mg/ml, administered twice daily, depending on body weight. The dose of ambroxol is preferably from about 0.5mg/kg per day to about 2.0mg/kg per day, more preferably from about 1.0mg/kg per day to about 2.0mg/kg per day, and most preferably from about 1.0mg/kg to about 1.5mg/kg per day.

The present invention also provides a novel pharmaceutical formulation for the treatment and/or prevention of allergic and inflammatory conditions with cough in a human comprising effective amounts of an antihistamine and an expectorant without sedative effect, and a pharmaceutically acceptable carrier.

Detailed Description

The present invention provides novel pharmaceutical formulations consisting essentially of an antihistamine and an expectorant that are devoid of sedative effects. The formulations of the present invention are useful for the prevention and/or treatment of allergic and inflammatory conditions of the skin or respiratory tract associated with cough. The preparation is widely suitable for patients of various ages; particular embodiments provided herein include tablets for administration to persons 12 years or older and pediatric solutions for administration to persons 6-12 years of age.

The present invention also provides a method of treating and/or preventing allergic and inflammatory conditions with cough in a human in need of such treatment and/or prevention comprising administering an effective amount of an antihistamine that is non-sedative in combination with an expectorant.

The phrase "allergic and inflammatory conditions of the skin or respiratory tract" as used herein refers to the allergic and inflammatory conditions and symptoms found on the skin and in the upper and lower respiratory tracts from the nose to the lungs. Common allergic and inflammatory conditions of the skin or upper and lower respiratory tract include seasonal and perennial allergic rhinitis, non-allergic rhinitis, asthma including allergic and non-allergic asthma, sinusitis, cold, dermatitis, especially allergic and atopic dermatitis, as well as nettle and symptomatic skin scarification and retinopathy, and capillary disease associated with diabetes.

The definition of "6-12 year old human" as used herein refers to a pediatric patient, male or female, 6 to 12 years old. The definition of "12 or older" as used herein refers to male and or female pediatric patients older than 12 years to 18 years and adults older than 18 years.

Although in the preferred embodiment of the invention, loratadine and ambroxol are used for treatment (see examples 1 and 2), other antihistamines and expectorants are equally useful in the compositions and methods described herein. The following non-limiting list of representative antihistamines and expectorants that can be used in the present invention. I. Antihistaminic agents

Loratadine is an antihistamine with no sedative effect and has the chemical name 11- (4-piperidylidene) -5H-benzo- [5, 6]]-cyclohepta- [1, 2-b]-pyridine. This compound is described in U.S. Pat. No. 4,282,233. Loratadine is a potent tricyclic antihistamine with effects on peripheral nervous system H₁Selective antagonism of receptor activity. Loratadine may be used in unit dosage forms (i.e., single doses) of the compositions of the present invention in amounts of about 1.0mg to about 15.0mg, and also in amounts of about 2.5mg to about 10.0mg, preferably about 5.0mg to about 10.0 mg.

Desloratadine is a long-acting histamine antagonist with no sedative effect and has a strong selective antagonist of peripheral nervous system H1 receptor activity. In oral administration, loratadine is rapidly metabolized to a pharmacologically active metabolite, descarboethoxyloratadine or desloretadine. US4,659,716, 5,595,997 and 4,804,666 disclose methods of preparing desloratadine and pharmaceutical compositions comprising desloratadine, and methods of treating various disease conditions in mammals using the same. Desloratadine may be used in unit dosage forms (i.e., single doses) of the compositions of the present invention in amounts of from about 0.75mg to about 7.5mg, and also from about 1.25mg to about 5.0mg, preferably from about 2.5mg to about 5.0 mg.

Descarboethoxyloratadine (DCL) is an antihistamine with no sedative effect and has the chemical name 8-chloro-6, 11-dihydro-11- (4-piperidylidene) -5H-benzo [5, 6] cyclohepta [1, 2] pyridine. Quercia, et al, hosp. formula, 28: 137-53(1993), U.S. Pat. No. 4,659,716 and WO96/20708 describe this compound. DCL is an antagonist of the H-1 histamine receptor protein. The H-1 receptor is a receptor that mediates a response that can be antagonized by conventional antihistamines. H-1 receptors are present, for example, in the ileum, skin, and bronchial smooth muscle in humans and other mammals. Carboethoxyloratadine may be employed in unit dosage forms (i.e., single doses) of the present compositions in amounts ranging from about 2.5 to about 20mg, also from about 5 to 10mg, preferably about 5 or 7.5 mg.

Fexofenadine (MDL 16, 455A) is an antihistamine with no sedative effect and has the chemical name 4- [ 1-hydroxy-4- (4-hydroxy-diphenylmethyl) -1-piperidinyl) butyl ] - α, α -dimethyl-phenylacetic acid. A preferred pharmaceutically acceptable salt is the hydrochloride salt, known as fexofenadine hydrochloride. The amount of fexofenadine that can be employed in a unit dosage form of the present composition is from about 40 to 200mg, alternatively from about 60 to about 180mg, alternatively about 120 mg. Expectorant

Ambroxol is a metabolite of bromhexine, chemically known as trans-4 (2-amino-3, 5-dibromobenzil, amine) cyclohexane hydrochloride, which has been widely used as an expectorant or as a lung-stimulating surfactant over the past two decades. US 3,536,712 describes this compound. Ambroxol may be employed in an amount of about 30.0 to about 60.0mg, preferably about 60.0mg, in a unit dosage form.

Guaiafenesin is an expectorant and is chemically 3- (2-methoxyphenoxy) -1, 2-propanediol. US4,390,372 describes this compound. The amount of guaiafenesin that may be used in a unit dosage form is from about 300.0 to about 1200.0mg, preferably about 1200.0 mg.

Terpene glycol hydrate is an expectorant and has the chemical name 4-hydroxy-alpha, 4-trimethylcyclohexane-methanol. The amount of terpene glycol hydrate which may be used in the unit dosage form of the present composition is from 85.0 to 680.0 mg.

For the preparation of pharmaceutical compositions using the compounds described herein, inert, pharmaceutically acceptable diluents, excipients and carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules (solid, semi-solid or liquid filled), sachets and suppositories. The powders and tablets may contain from about 5 to about 95% of the active ingredient. Suitable solid carriers are known in the art, for example magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, sachets and capsules may be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods for preparing the various compositions are set forth in a.gennaro (ed.), Remington's Pharmaceutical Sciences, 18th edition, (1990), Mack Publishing co. In addition, suitable binders, lubricants, disintegrating agents and coloring agents may also be added to the mixture, as desired or needed. Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes. Among the lubricants that may be used in these dosage forms are metal stearates, talc, starch powder, stearic acid, different grades of polyethylene glycol, and the like. Disintegrants include starch, methylcellulose, guar gum, and the like. Sweetening and flavoring agents, and preservatives may also be included where appropriate.

In addition, the compositions of the present invention may also be formulated in sustained release formulations to provide a controlled release rate of any one or more of the components or active ingredients to optimize the therapeutic effect. Suitable sustained release dosage forms include multilayer tablets comprising various disintegration rate layers or controlled release polymeric matrices comprising the active ingredient as well as tablet forms or capsules comprising such impregnated or encapsulated porous polymeric matrices.

Liquid form preparations include solutions, suspensions and emulsions. As examples are mentioned water or water-polyethylene glycol solutions for parenteral injection, or solutions, suspensions and emulsions for oral administration with the addition of sweeteners and sedatives. Liquid formulations may also include solutions for intranasal administration.

Aerosol formulations suitable for inhalation may include solutions and powdered solids, and may contain a pharmaceutically acceptable carrier, such as an inert compressed gas, for example nitrogen.

Also included are solid dosage forms which are rapidly convertible, prior to use, into liquid dosage forms suitable for oral or parenteral administration. Such liquid formulation forms include solutions, suspensions and emulsions.

The compounds of the invention may also be administered transdermally. The transdermal compositions may be in the form of creams, lotions, aerosols and/or emulsions and may be contained in transdermal patches such as scaffolds or reservoirs commonly used in the art for this purpose.

Preferably, the compound is administered orally.

Preferably, the pharmaceutical formulation is in unit dosage form. In this form, the formulation is divided into suitably sized unit doses containing appropriate quantities of the active ingredient, e.g., an effective amount to achieve the desired purpose.

The amount of active compound in a unit dosage formulation may be varied or adjusted from about 0.01mg to about 1000mg, preferably from about 0.01mg to about 750mg, more preferably from about 0.01mg to about 750mg, and most preferably from about 0.01mg to about 250mg, depending on the particular application.

The actual dosage employed may be adjusted depending upon the needs of the patient and the severity of the condition being treated. The skilled person will be able to determine the appropriate dosage regimen according to the particular circumstances. For convenience, the total daily dose may be divided into several portions for administration as required throughout the day.

The amount and frequency of administration of the compounds of the invention are controlled by the diagnosis of the clinician, who will take into account such factors as age, condition and size of the patient and the severity of the condition being treated. The recommended daily dosage regimen for oral administration is about 5.0 to 10.0 mg/day for loratadine and 30 to 60.0 mg/day for ambroxol, divided into two to four doses.

Dosage forms-antihistamines and expectorants without sedative effect are prepared as delivery systems, i.e. tablets, capsules, oral gels, component powders or suspensions associated with the active ingredient.

Capsule-refers to a special container or shell made of methylcellulose, polyvinyl alcohol or modified gelatin or starch for supporting or containing the components comprising the non-sedating antihistamine and expectorant. Hard shell capsules are typically made by mixing bone and pigskin gelatin which have relatively high gel strength. The capsule itself may contain small amounts of dyes, opacifying substances, plasticizers and preservatives.

Tablet-refers to a compressed or shaped solid dosage form comprising an active ingredient and a suitable diluent. The tablet can be prepared by compressing a mixture or granules obtained by wet granulation, dry granulation or compression.

Oral gel-refers to antihistamines and expectorants without sedative effect dispersed or dissolved in a hydrophilic semi-solid matrix.

Component powders-refer to powder mixtures containing the active ingredient and a suitable diluent, which can be suspended in water or body fluids.

Diluent-refers to a substance that generally makes up the major portion of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol and sorbitol; starches derived from wheat, corn, rice and potato; and cellulose, such as microcrystalline cellulose. The amount of diluent in the composition may be from about 10 to about 90% by weight, preferably from about 25 to about 75% by weight, more preferably from about 30 to about 60% by weight, especially preferably from about 12 to about 60% by weight, based on the total weight of the composition.

Disintegrant-refers to a substance added to a composition to aid in the breaking (disintegration) of the composition and release of the drug. Suitable disintegrants include starch; modified starches that are "cold water soluble" such as sodium carboxymethyl starch; natural and synthetic gums such as locust bean gum, karaya gum, guar gum, tragacanth gum and agar; cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose; microcrystalline cellulose and cross-linked microcrystalline cellulose, such as croscarmellose sodium; alginates such as alginic acid and sodium alginate; clays, such as bentonite; and effervescent mixture, crospovidone. The amount of disintegrant in the composition is from about 2 to about 15% by weight, more preferably from about 4 to about 10% by weight of the composition.

Binders-refer to substances that bind or "cement" powders together, as well as agglomerate them by granulation, and are therefore referred to as "binders" in formulations. The binder increases the viscosity at which the diluent or filler is already available. Suitable binders include sugars, such as sucrose; starches derived from wheat, corn, rice and potato; natural gums such as acacia, gelatin and tragacanth; seaweed derivatives such as alginic acid, sodium alginate and calcium ammonium alginate; cellulosic materials such as methylcellulose and sodium carboxymethylcellulose and hydroxypropylmethylcellulose; polyvinylpyrrolidone; and inorganic substances such as magnesium aluminum silicate. The amount of binder in the composition is from about 2 to about 20% by weight of the composition, more preferably from about 3 to about 10% by weight, and especially preferably from about 3 to about 6% by weight.

Lubricant-refers to a substance added to a dosage form to ensure that a tablet, capsule, etc. is ejected from a die or die after it has been compressed by reducing friction or abrasion. Suitable lubricants include metal stearates, such as magnesium, calcium or potassium stearate; stearic acid; a high melting point wax; and water-soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycol and d' 1-leucine. Lubricants are usually added in the last step before compression because they must be present on the surface of the granules and between the granules and the tablet press. The amount of lubricant in the composition is from about 0.2 to about 5% by weight of the composition, preferably from 0.5 to about 2% by weight, more preferably from about 0.3 to about 1.5% by weight.

Glidants-this substance prevents caking and improves the flowability of the granules so that they flow more smoothly and uniformly. Suitable glidants include silicon dioxide and talc. The amount of glidant in the composition is from about 0.1 to about 5 weight percent, preferably from about 0.5 to 2 weight percent, based on the weight of the composition.

Colorant-is an excipient that provides coloration to the composition or dosage form. Such excipients include food grade dyes and food grade dyes adsorbed onto a suitable absorbent such as clay or alumina. The amount of colorant is from about 0.1 to about 5% by weight, preferably from about 0.1 to about 1% by weight of the composition.

Bioavailability-refers to the rate and extent to which an active pharmaceutical ingredient or therapeutic moiety is absorbed from an administered dosage form into the systemic circulation, as compared to a standard or control.

General methods for preparing tablets are known. Such methods include dry processes, such as direct compression and compression with the resulting granules, or wet processes or other specialized procedures.

The broad scope of the invention is best illustrated by the following examples, which are not intended to limit the invention to the particular embodiments.

Example I

Novel pharmaceutical composition

The present invention provides a novel combination in a novel pharmaceutical formulation which provides slow release of non-sedating antihistamines such as loratadine, and expectorants and mucolytics such as ambroxol. The composition is primarily used for treating patients exhibiting cough-related bronchopulmonary hypersensitivity conditions in which the viscous and mucoid attachments are increased, impeding the permeability of the respiratory tract. Its primary indications include, but are not limited to, allergic rhinitis with cough; acute, chronic, spastic and asthmatic bronchitis; bronchial asthma; bronchiectasis; sinusitis; otitis media; pneumonia; bronchopneumonia; atelectasis due to mucus plugging; tracheotomy and as an anterior and posterior prophylactic.

The formulation of each pharmaceutical form is illustrated in the following examplesThe method comprises the following steps: tablet formulationComponent name Concentration ofDeviation of% action

(mg/tablet) loratadine 5.00 active substance ambroxol hydrochloride 30.00 active substance anhydrous lactose 84.75 filler ± 20 corn starch 12.00 disintegrant ± 20 microcrystalline cellulose 16.75 disintegrant ± 10 colloidal (Colloidall) 0.75 glidant ± 10 magnesium stearate 0.75 lubricant ± 10 tablets weight 150.00mg manufacturing method:

the tablets are prepared by a direct compression method, the powder components are mixed in a mixer for a certain time to ensure uniform content, and then the mixture is compressed into tablets. Solutions ofComponent name Concentration ofDeviation of% action

mg/ml loratadine 1.00 active substance ambroxol hydrochloride 6.00 active substance citric acid 0.40 buffer ± 10 glycerol 150.00 solvent ± 20 propylene glycol 200.00 solvent ± 20 saccharin sodium 0.40 sweetener ± 10 sorbitol solution 70% 315.00 solvent ± 20Peach flavor corrigent No. 6092.50 flavor agent ± 10 purified water right amount solvent ± 20 preparation method:

the solution is prepared by adding loratadine and saccharin to propylene glycol and adding citric acid dissolved in water to the previous solution. Ambroxol is dissolved in the ambroxol solution and then dissolved. Glycerin, sorbitol and flavor are then added thereto and mixed until homogeneous.

Example 2

Clinical research

The safety and efficacy of the individual components of the loratadine/ambroxol composition are well established. Acute toxicity studies with loratadine (in a wide range of clinical and preclinical regimens) and ambroxol components have demonstrated low potential systemic toxicity, which is desirable for the composition.

Loratadine is a potent tricyclic antihistamine with slow release and selective antagonism against peripheral nervous system H₁The effect of receptor activity. Can be completely absorbed after oral administration. Its plasma elimination half-life was 9 hours. However, its antihistaminic effect may last for 24 hours. Its onset is rapid, estimated to be about 30 minutes. Loratadine is then metabolized primarily in the liver and excreted via urine and feces.

Ambroxol, a metabolite of bromhexine, is chemically known as trans-4 (2-amino-3, 5-dibromobenzil, amine) cyclohexane hydrochloride and has been widely used as an expectorant or as a stimulatory lung surfactant for more than twenty years. After oral administration, the absorption rate is rapid and complete. The estimated elimination half-life of humans is 20-25 hours, almost completely excreted through the urine. It has been found that the biotransformation pathways are similar in all species studies. Ambroxol is metabolized primarily by binding to glucuronic acid, and is carried by dibromoanthranilic acid in a small amount by reaction. Ambroxol is widely distributed and can pass through the placental barrier, and the fetal concentration can be measured 15 minutes after administration, which is 3 times higher than the maternal plasma concentration. It accumulates in the liver and lungs, and its maximum value can be measured 90 minutes after administration.

The clinical efficacy and safety of the novel composition of the invention was demonstrated by 3 groups of clinical trials: study one was a six month, control, prospective, longitudinal study that included 120 adult patients presenting with bronchial constriction of bronchitis symptoms; second, a six month prospective, double blind, control, randomized and comparative study involving 120 patients to evaluate the efficacy and safety of loratadine/ambroxol solutions versus the individual active ingredients, namely loratadine and ambroxol, used in children 6 to 12 years of age with allergic rhinitis and cough; study three was conducted with 30 healthy volunteers and is a single-center, randomized, open-label, three-way crossover single dose bioavailability study of loratadine-ambroxol tablets of the invention versus 30-mg ambroxol tablets and 10-mg loratadine tablets. The results of these clinical studies will demonstrate that loratadine and ambroxol in combination are safer and more effective than the individual components in treating and/or preventing allergic and inflammatory conditions of the skin or respiratory tract with associated cough than either component alone.

Clinical study protocol

The following three sets of clinical protocols were designed to (a) compare the safety and efficacy of loratadine/ambroxol combinations in adult patients with bronchitis with bronchoconstriction (study 1); (b) evaluation of the safety and efficacy of the loratadine/ambroxol combination on pediatric patients with allergic rhinitis and cough (study 2); and (c) comparing the relative bioavailability of the loratadine/ambroxol combination administered to healthy volunteers relative to each component individually (study 3).

Study 1

The study was a six month double-blind, control, prospective longitudinal study including 120 adult patients who showed symptoms of bronchitis with bronchoconstriction.

Purpose of study

The purpose of this study was to evaluate the efficacy and safety of the loratadine/ambroxol combination after administration to adult patients with bronchial constriction symptoms.

Study plan

General study protocol and plan: description of the invention

A total of 120 adult patients with bronchitis with bronchoconstriction were required for this study. The loratadine/ambroxol combination was administered orally in the form of tablets twice a day (12 hours apart) for 14 consecutive days.

During clinical assessment of the condition, the time of assessment of the symptoms is determined and symptoms and clinical signs are recorded. At the beginning of the study (day 1-basic test), the patients were diagnosed by the specialist and 3 follow-ups were performed on 7 days (visit 2), 14 days (last visit). At each visit, a comprehensive assessment of the disease changes must be made, comparing all results with those observed in the first and subsequent visits. The patient was observed at each visit and asked for adverse effects that may occur during the study. The type of response, severity, time and cause associated with the treatment were recorded. In the final visit, the patient is asked to assess the efficacy of the drug used. Each patient was randomized to receive one of three treatments:

treatment 1: a tablet of loratadine 5 mg/ambroxol 30mg combined tablet is orally taken every 12 hours for 14 days.

Treatment 2: one placebo tablet was administered orally every 12 hours for 14 days.Study population/inclusion/exclusion criteria

And (3) inclusion standard:

selecting adult males or females between the ages of 18 and 70.

Patients with bronchitis with bronchoconstriction.

In other aspects clinical health.

Patients understand the requirements and limitations of the study and agree to participate in the assessment visit.

Patients gave informed consent prior to conducting the relevant study.

Exclusion criteria:

pregnant or lactating patients.

Patients with allergic or hypersensitivity to the drugs used in the study.

Patients treated with antihistamines, expectorants or mucolytics 8 days prior to study.

Patients with heart, liver or kidney disease.

Patients receiving immunotherapy.

Patients who were unable to comply with his or her requirements during the study that did not use any prescription and non-prescription drugs other than study protocol drugs. Early termination and exclusion of treatment

For those patients whose continued research would compromise their well-being and physical health, the investigator has rights and obligations to discontinue the treatment. This class of patients must quit the study and they cannot continue to participate after the protocol is modified.

If the treatment ends prematurely for reasons other than the foregoing, the patient must be treated as a "fall back" and must replace his or her position with another patient. A case report form must be filled out for the straggler. Study of treatment

At visit 1 of the study, each patient must obtain a vial containing enough tablets for one of the three treatments (1 or 2) listed above. The patient must return the vial (empty or partially used) at the last visit.

After a preliminary assessment of the disease, the first dose is administered in the doctor's office. In the latter visit, the patient must be carefully interrogated to ensure that the treatment meets the protocol requirements. Variables such as forgetting to take or overdose must be recorded in the case report form.

Any adverse effects that compromise patient safety require the termination of treatment and withdrawal of the patient from the study. The patient must return to additional clinical assessments until the adverse effect disappears. Efficacy parameters

The following parameters were monitored:

loratadine:

bronchial stenosis relief

Inflammation of the skin

Ambroxol:

qualitative determination of cough

Fluidity of secretion

These parameters were ranked on similar 3-score scales and evaluated by a statistical method without parameters. Safety parameter

All adverse effects were recorded in the adverse effect table. Some adverse effects must be treated prematurely. If the occurrence of an adverse effect requires additional treatment administration, it must be recorded in the area of the case report entitled "concomitant treatment". The progress of the patient must also be recorded during subsequent visits.

The file of each adverse effect should include the time, location and duration of occurrence of the adverse effect; and the determination of the relationship to the drug under study.

Any patient experiencing severe adverse effects should be immediately withdrawn from the study. Whether or not associated with the test drug, all serious adverse effects must be telephonically notified to the Schering Plough monitor within the next 48 hours. Within the next 5 days a written report must be submitted.

Serious adverse effects are those that present significant risk or danger, contraindications, collateral effects, or forewarning. For clinical trials in humans, this includes any of the following effects: leading to patient death, immediate health risk, hospitalization or prolonged hospitalization, permanent, persistent or severe disability, leading to organ toxicity, including hematologic, hepatic, gastrointestinal and central nervous system toxicity. Furthermore, abnormalities that are 3 times higher than normal in laboratory tests are also considered organ toxicity. If the initially taken test value is outside the normal limits, any change of > 25% over the relevant base value must be reported

Carcinogenesis

Accidental or unintentional overdose

Deviation from teratogenic protocol

The protocol must be strictly executed following written instructions. Any change to this protocol must have an informed consent between the investigator and Schering Plough. The revision of the protocol must be signed by the investigator and Schering Plough before any changes are implemented.

The following are examples of protocol deviations for which the patient does not meet the subsequent visit requirements:

drugs or treatments that were contraindicated were applied.

Change in dose: failed to take one or several times or overdose during the treatment. Statistical analysis:

comparison of the signs and symptoms specifications to the base assessment, including assessment of their sum (sum of symptoms and signs) and the percentage improvement in the total signs and symptoms specifications; likewise, the general response to treatment obtained by the physician and the assessment made by the patient himself/herself (mother/father/guardian) are compared and used as efficacy criteria.

Study 2

The study is a 6 month prospective, double blind, control, randomized and comparative study to evaluate the efficacy and safety of a loratadine/ambroxol solution for individual active ingredients of loratadine and ambroxol for children 6 to 12 years of age with allergic rhinitis and cough.

Purpose of study

The objective of this study was to evaluate the efficacy and safety of the loratadine/ambroxol combination for administration to children 6 to 12 years old with allergic rhinitis and cough.

Study plan

Comprehensive study protocol and plan: description of the invention

A total of 120 children patients between 6 and 12 years of age who exhibited symptoms of allergic rhinitis and cough were required for this study. A pediatric solution comprising a loratadine/ambroxol combination is administered twice a day (12 hours apart) for 10 consecutive days, as compared to separate administration of each of the components loratadine and ambroxol.

The diagnosis of allergic rhinitis is based on nasal obstruction, clear nasal discharge, sneezing, lacrimation, itching of the conjunctiva, and must also be accompanied by coughing.

During clinical assessment of the condition, the time of assessment of the symptoms is determined and symptoms and clinical signs are recorded. At the beginning of the study (day 1-basic test), the patients were diagnosed by the specialist and 3 follow-ups were performed on 5 days (visit 2), 10 days (last visit). At each visit, a comprehensive assessment of the disease changes must be made, comparing all results with those observed in the first and subsequent visits. The patient was visited at each visit and asked for adverse effects that may occur during the study. The type of response, severity, time and cause associated with the treatment were recorded. In the final visit, a parent or patient's guardian is queried to assess the efficacy of the medication being used. Each patient was randomized to receive one of three treatments:

treatment 1: an oral dose of a pediatric solution of a combination of 1.0mg/ml loratadine and 6.0mg/ml ambroxol was administered every 12 hours for 10 days.

Treatment 2: an oral dose of loratadine 1.0mg/ml pediatric solution is administered every 12 hours for 10 days.

Treatment 3: an oral dose of 6.0mg/ml of a pediatric solution of ambroxol was administered every 12 hours for 10 days.

The dosage was determined according to age and body weight as shown in the following table:

age (age)	Body weight (kg)	Volume every 12 hours (ml)	12 h Loratadine (mg)	24 hours Loratadine (mg)	12 h ambroxol (mg)	24 h ambroxol (mg)
							6 to 9	20.3 to 29.9	2.5	2.5	5.0	15	30
10 to 12	30.0 to 44.0	5	5.0	10.0	30	60

The recommended dose per kg body weight is as follows:

loratadine:

6 to 9 years old: average body weight: 25.1 kg. Dosage: 0.199 mg/kg.

10 to 12 years old: average body weight: 37 kg. Dosage: 0.27 mg/kg.

Ambroxol:

6 to 9 years old: average body weight: 25.1 kg. Dosage: 1.19 mg/kg.

10 to 12 years old: average body weight: 37 kg. Dosage: 1.62 mg/kg.

For the present study, patients weighing less than 30kg were dosed with 2.5ml of solution every 12 hours, whereas patients weighing 30kg and above were dosed with 5ml of solution every 12 hours.Study population/inclusion/exclusion criteria

And (3) inclusion standard:

selecting a male or female between the ages of 6 and 12.

Patients with allergic rhinitis and cough.

In other aspects clinical health.

The parent or supervising person must understand the requirements and limitations of the study and agree to participate in the assessment visit.

Patients must give written warranty (before any relevant studies are performed).

Exclusion criteria:

patients with allergic or hypersensitivity to the drugs used in the study.

There was clinical evidence of nasopharyngeal bacterial infection.

Patients treated with antihistamines, expectorants or mucolytics 8 days prior to study.

Patients with heart, liver or kidney disease.

Patients with clinically abnormal vital signs, weight or height relative to their age, as observed by the investigator.

Patients receiving immunotherapy.

Patients who were unable to comply with his or her requirements during the study that did not use any prescription and non-prescription drugs other than the drugs used in the study protocol. Early termination and exclusion of treatment

For those patients whose continued research would compromise their well-being and physical health, the investigator has rights and obligations to discontinue the treatment. The patient must quit the study and they cannot continue to participate after the protocol is modified.

If treatment ends prematurely for reasons other than those previously described (e.g., no control can be performed), the patient must be considered "straggling" and must replace his or her position with another patient. A case report form must be filled out for the straggler. Study of treatment

At visit 1 of the study, each patient had to obtain a 14 day treatment vial containing one of the three treatments listed above. The patient must return the vial (empty or partially used) at the last visit. After a preliminary assessment of the disease, the first dose is administered in the doctor's office.

After a preliminary assessment of the disease, the first dose is administered in the doctor's office. In the latter visit, the patient (parent or guardian) must be carefully interrogated to ensure that the treatment meets the protocol requirements. Variables such as forgetting to take or overdose must be recorded in the case report form.

Any adverse effects that compromise patient safety require the termination of treatment and withdrawal of the patient from the study. The patient must return to additional clinical assessments until the adverse effect disappears. Efficacy parameters

The following parameters were monitored:

loratadine:

sneezing

Watery nasal discharge

Tear flow

Itching of the conjunctiva

Ambroxol:

decrease in cough frequency and intensity

Fluidity of secretion

These parameters were ranked on similar 3-score scales and evaluated by a statistical method without parameters. Safety parameter

All adverse effects were recorded in the adverse effect table. Some adverse effects must be treated prematurely. If the occurrence of an adverse effect requires additional treatment administration, it must be recorded in the area of the case report entitled "concomitant treatment". The progress of the patient must also be recorded during subsequent visits.

Each adverse effect file should include the time, location, and duration of the adverse effect; determination of the relationship to the drug under study. Serious adverse effects are those that present significant risk or danger, contraindications, collateral effects, or forewarning. For clinical trials in humans, this includes any of the following effects:

cause death of the patient

Immediate health risk

Resulting in or extending hospitalization

Cause permanent, persistent or severe disability

Causing organ toxicity, including hematologic toxicity, hepatotoxicity, gastrointestinal toxicity, and central nervous system toxicity. Furthermore, abnormalities that are 3 times higher than normal in laboratory tests are also considered organ toxicity. If the initially taken test value is outside the normal limits, any > 25% change in the relevant base value must be reported

Carcinogenesis

Accidental or unintentional overdose

Teratogenic form

Any patient experiencing severe adverse effects must be immediately withdrawn from the study. Whether or not associated with the test drug, in the following24 hoursAll serious adverse effects must be telephonically notified to the monitoring person of Schering Plough. At the following5 daysWithin which a written report must be submitted. Deviation of the scheme

The protocol must be strictly executed following written instructions. Any change to this protocol must have an informed consent between the investigator and Schering Plough. The revision of the protocol must be signed by the investigator and Schering Plough before any changes are implemented.

The following are examples of protocol deviations for which the patient does not meet the subsequent visit requirements:

drugs or treatments that were contraindicated were applied.

Change in dose: failed to take one or several times or overdose during the treatment. Statistical analysis:

comparison of the signs and symptoms specifications to the base assessment, including assessment of their sum (sum of symptoms and signs) and the percentage improvement in the total signs and symptoms specifications; likewise, the general response to treatment obtained by the physician and the assessment made by the patient himself/herself (mother/father/guardian) are compared and used as efficacy criteria.

Study 3

The study was conducted with 24 healthy volunteers and was a single-center, randomized, open-label (open-label), three-way crossover single dose bioavailability study of the tablets versus 30-mg ambroxol tablets and 10-mg loratadine tablets.

Purpose of study

The objective of this study was to compare the relative bioavailability of loratadine/ambroxol tablets administered to healthy volunteers and of the two administered separately.

Study plan

Comprehensive study protocol and plan: description of the invention

According to a randomized crossover protocol and subject selection principles, 30 healthy male volunteers aged between 18 and 50 years were picked and recruited in a single center into a three-way crossover study. All subjects were determined to have good health by medical history, physical examination, electrocardiogram and laboratory tests. The subject must comply with the following rules of neutralization and exclusion.

This study takes about 36 days to complete clinically. Subjects were screened within two days of treatment. Each course of treatment takes 2 days to complete and each treatment must be separated by an elution period of at least 2 weeks. Prior to administration of the initial dose, the study examiner or his/her designee must review all screening data to ensure that all subjects are eligible. Treatment of

In the morning (approximately 8 am), after a night of fasting, each subject received one of the following treatment regimens according to computer generated codes:

treatment A: two tablets of loratadine-ambroxol at 8:00 am.

Treatment B: two tablets of 30-mg ambroxol at 8:00 a.m.

Treatment C: 8:00 in the morning, one tablet of 10-mg loratadine.

TABLE 1

Period I	Period II	Period III
			Treatment A	Treatment B	Treatment C
Treatment B	Treatment C	Treatment A
			Treatment C	Treatment A	Treatment B

All treatments were administered with 240ml water. There was a 15 day elution period between treatments.Dosage forms and protocols

The following drugs were used:

loratadine-ambroxol (30-mg ambroxol and 5-mg loratadine) tablets.

Mucosolvan  (30-mg ambroxol) tablet

Clarityne  (10-mg loratadine) tablet

All supplies are stored in a secure location under the storage conditions specified on the label.Study population/inclusion/exclusion criteria

And (3) inclusion standard:

males between 18 and 50 years of age and having weights in accordance with Metropolitan Life insurance 1983 height and weight schedule (+ -10%) were selected for this study. Each patient received a physical examination within two weeks prior to the study. In addition, a complete medical history is taken, an electrocardiogram is obtained, and the following laboratory tests are performed:

1) whole blood cell count (including differential)

2) Hepatitis B surface antigen assay

3) HIV antibody assay

4) Blood chemistry

5) Total protein

6) Albumin

7) Calcium carbonate

8) Inorganic phosphorus

9) Cholesterol

10) Triglycerides

11) Fasting blood sugar

12) Urea nitrogen of blood

13) Uric acid

14) Total bilirubin

15) Alkaline phosphate

16) Lactate dehydrogenase

17) Serum glutamic acid pyruvic transaminase

18) Serum glutamic acid oxalacetic acid transaminase

19) Gamma-glutamic acid transpeptidase

20) Serum creatinine

21) Electrolytes (Na, K, Cl, bicarbonates such as CO)₂)

22) Urine analysis

Prior to initial dosing, the study monitor and his/her guardian must read the results of clinical laboratory tests and physical examinations performed for screening purposes. The subjects must understand the requirements of the study, be willing to comply with the protocol, and be able to perform the required examinations and treatments.

Each patient must be assigned a randomized code and informed consent agreed upon when participating in the study. This information should be tagged on the patient's case report form.

No other medications (prescription, study or OTC) could be taken two weeks before or during the study.

A patient's smoking history is obtained and recorded on a case report form.

Exclusion criteria

1) A subject having a history of cardiovascular, neurological, hematological, gastrointestinal, cerebrovascular, respiratory, hepatic or renal disease or any other condition requiring treatment by a physician.

2) Individuals whose laboratory test results are outside normal values (for the laboratory), the range is:

2.1) cannot be expected as a response to a known underlying disease and are studied and studied

Schering protocol supervisor/protocol physician deems it impossible to participate in the study

2.2) clinical evaluation and other testing based on the judgment of the investigator

Bed significance was clinically relevant to abnormal experimental tests.

3) Patients with a history of any local and systemic infectious disease and individuals who developed urinary tract infections within four weeks prior to administration.

4) Any individual who does not meet the requirement of not using any drug for at least two weeks prior to administration or alcohol for 24 hours prior to therapeutic administration or caffeine or cannabis for 24 hours prior to therapeutic administration.

5) Clinical trials were enrolled within the first two months of study initiation and individuals who had received the trial drug.

6) Individuals who have previously taken drug or alcoholism are known.

7) Individuals with an allergy to ambroxol or loratadine or a history of severe food or drug allergy are known.

8) Individuals who are positive for HIV antibodies.

9) Hepatitis B surface antibody or hepatitis C antibody positive individuals. Randomized selection

Investigators randomized subjects to A, B or C treatment in one of three possible sequences (ABC, BCA and CAB) according to computer generated codes by Schering Plough M-PDL. Subject replacement

All subjects who could not continue the study at an early stage and met the following criteria could be replaced:

10) any difficulty in proceeding for administrative reasons (e.g. preference of subject)

11) Patients who do not meet admission criteria

12) Subjects who failed to comply with the protocol requirements

Alternate subjects are numbered with the original subject number plus an "R" (e.g., 1 is substituted with 1R). The dosage regimen of the new subject is based on the dosage regimen of the original subject. Therapeutic study a. dosingCross dosing cycle

After signing the informed consent, subjects received treatment a, or treatment B, or treatment C, up to thirty-sixth day after study initiation (day 1, cycle I). After a 15 day elution period, subjects received additional (complementary) treatment of a or B or C according to the sequence described previously on day 18 (cycle II). After a 15 day elution period, on day 35 (cycle III), subjects received additional treatment with a or B or C according to the sequence described previously.

All treatments were administered at approximately 8 am. On days 1, 18 and 35, volunteers were dosed after overnight fasting and were unable to eat food or fluid 4 hours after dosing.

After each study session, the volunteers were examined and allowed to leave the study site. When the report returns to the phase II and III study, advices should be made to the volunteers. The doses must be separated by at least 15 days of elution.

After the study was completed (after the last blood sample was taken on day 36), the physical examination, blood chemistry, and blood chemistry performed during the screening were repeated for each volunteer,Urinalysis and electrocardiogram. If any laboratory test result is outside the reference range (except for the test expected to be outside the reference range) and is deemed clinically significant by the investigator, the test should be repeated at appropriate intervals until it returns to baseline or becomes a significant clinical finding.Dining food

On the day of dosing, breakfast was not consumed. Food and fluids (including water) were not consumed within 4 hours after treatment administration.

Breakfast is a standardized breakfast, all volunteers eat the same meal on the same day of each treatment cycle. Since grapefruit juice has been reported to inhibit the first-pass metabolism of certain drugs, grapefruit juice, grapefruit, or grapefruit-containing products cannot be consumed within the limits of the various treatment phases of the study.Blood sample

Blood samples were collected at specific times after each treatment on days 1 to 2, 18 to 19, and 35 to 36, followed by analysis of ambroxol and loratadine in human plasma. Laboratory tests, physical examinations and EKGs were performed prior to this study. In addition, important signs were recorded at 8:00 doses per treatment day, and subjects were continuously observed for possible adverse symptoms during the study. Any adverse symptoms should be recorded on the case report sheet.Clinical observations

At the sampling time of each cycle of the study, prior to administration, vital signs (BP, HR, respiratory rate, and oral body temperature) were obtained and recorded on a case report form.

The severity of adverse symptoms should be assessed by the following definitions:

mild: for volunteers, the symptoms were negligible and did not cause any substantial problems.

Medium: symptoms cause certain problems for the volunteers, but do not significantly affect the daily activities and clinical status of the volunteers.

And (3) severe degree: symptoms can severely affect normal daily activities and clinical status of volunteers. Clinical testing

The test results before and after the study were evaluated. Pharmacokinetics and bioequivalence

Pharmacokinetic analysis of plasma concentrations of loratadine and ambroxol was performed using a non-compartmental model using the WinNonlin Professional program. From this data, the maximum plasma concentration (Cmax) and the time required to reach the maximum plasma concentration (Tmax) can be directly obtained. The terminal phase rate constant (λ Z) is the negative of the terminal slope of the log-linear (log-linear) portion of the plasma concentration-time curve calculated using linear regression. The end phase half-life (T1/2) can be calculated using 0.693/λ Z.

The area under the plasma concentration curve of ambroxol from time 0 to infinity (AUC. about. ng. Hr/ml) can be calculated using the linear trapezoidal rule followed by the logarithmic trapezoidal rule. All pharmacokinetic parameters were calculated from the model 200 of WinNonlin Library.

Cmax: for single dose data: the maximum plasma concentration is between 0 and the last measurable amount.

Tmax: the time at which the maximum concentration was observed.

AUC _ 0-tmax: area under the curve from dose (dose _ time) to Tmax hour.

AUC _ 0-48: area under the curve from 0 (dose _ time) to 48 hours.

AUC _0- ∞: area under the curve from dose (dose _ time) to infinity.

T1/2_ λ z (hours): terminal half-life-length Ln (2)/λ z, wherein λ z (hr)^-1) Is the first order rate constant associated with the end (log linear) portion of the curve. This was estimated by linear regression with time on log concentration.

The results of this test are data obtained from loratadine-ambroxol.

The ratio of the mean values of the parameters (test piece/pair of photographs) and the confidence interval calculated by ANONA analysis for testing the bioequivalence of the product are described.

For loratadine, the area under the plasma-concentration curve from 0 to 48 hours (AUC _0-48 ng Hr/ml), and the area under the plasma-concentration curve from 0 to ∞ time (AUC ∞ ng Hr/ml) can be calculated and adjusted for dosing by using the linear trapezoidal rule followed by the logarithmic trapezoidal rule. All pharmacokinetic parameters were calculated according to the WinNonlin Library model 200 and analyzed in the same manner as described above. Statistical analysis

The pharmacokinetic data were statistically analyzed using an analysis of variance (ANOVA) model extracted from sequence, subjects, period, formulation, i.e.:

sequence + subject (Seq) + cycle + dosage form

The definition of subject (Seq) in this model is equivalent to the nested effect (nestefect) subject in Seq.

The effect of the sequence was examined as the square of the mean of the subjects (Seq) obtained as error from ANOVA. All other major effects will be examined with the residual error (residual mean square) from ANOVA.

Tmax, Cmax, and AUC _0- ∞weretested with a two-sided hypothesis at significance at the α ═ 0.05 level by constructing a 90% confidence interval between the test (loratadine-ambroxol) and control (loratadine tablets and ambroxol tablets) mean ratios.

Each activity relationship was analyzed according to FDA guidelines ("statistical methods of bioequivalence studies conducted with standard two-therapy cross-protocol involvement, month 7 1992) and taking into account four cycles.Theoretical research

The treatment claimed by the method of the invention is believed to be more effective than the use of antihistamines or expectorants alone without sedative effect and to take effect more rapidly than the inclusion of antihistamines without sedative effect.

All references cited herein are incorporated by reference to the same extent as if each publication or patent application was specifically and individually indicated to be incorporated by reference.

Many modifications and variations of this invention can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. The particular embodiments described herein are illustrative only, and the invention is to be limited only by the following claims, along with the full scope of equivalents to which such claims are entitled.

Claims (15)

1. Use of an antihistamine without sedative effect in combination with an expectorant for the preparation of a medicament for the treatment and/or prevention of allergic and inflammatory conditions with cough in a person in need of such treatment and/or prevention, comprising an effective amount of an antihistamine without sedative effect in combination with an effective amount of an expectorant.

2. A pharmaceutical composition for the treatment and/or prevention of allergic and inflammatory conditions with cough in a human, which composition comprises an effective amount of a combination of an antihistamine and an expectorant without sedative effect, together with a pharmaceutically acceptable carrier.

3. The use according to claim 1or a pharmaceutical composition according to claim 2, wherein the non-sedating antihistamine is loratadine.

4. The use or pharmaceutical composition according to claim 3, wherein the human is a human aged 12 and older than 12 years and the amount of loratadine is 5.0 mg/day to 15 mg/day, preferably 10 mg/day, in single or divided doses.

5. The use or pharmaceutical composition of claim 3, wherein the human is a 12 year old or older human and the amount of loratadine is 5.0mg twice a day.

6. The use as claimed in claim 1or a pharmaceutical composition as claimed in claim 2, wherein the expectorant is ambroxol.

7. The use or pharmaceutical composition as claimed in claim 6, wherein the human is a human being aged 12 years and older than 12 years, and the amount of ambroxol is 30 mg/day to 90 mg/day, preferably 60 mg/day, in single or divided doses.

8. The use or pharmaceutical composition as claimed in claim 6, wherein the human is a 12 year old or older human and the amount of ambroxol is 30mg twice a day.

9. The use as claimed in claim 1or a pharmaceutical composition as claimed in claim 2, wherein

a) The antihistamine without sedative effect is loratadine; and

b) the expectorant is ambroxol.

10. The use as claimed in claim 1or a pharmaceutical composition as claimed in claim 2, wherein the allergic or inflammatory condition is allergic rhinitis with cough, bronchial asthma, bronchitis, bronchiectasis, sinusitis, otitis media, pneumonia, bronchopneumonia, atelectasis due to mucus plugging, or bronchoconstriction.

11. The use as claimed in claim 1or a pharmaceutical composition as claimed in claim 2, wherein the human is a human 6 to less than 12 years old and the amount of loratadine is 0.1mg/kg to 0.3mg/kg per day, preferably 0.2mg/kg to 0.3mg/kg per day, in single or divided doses.

12. The use as claimed in claim 1or a pharmaceutical composition as claimed in claim 2, wherein the human is a 6 to less than 12 year old human and the amount of loratadine is 0.1mg/kg twice daily.

13. The use as claimed in claim 1or the pharmaceutical composition as claimed in claim 2, wherein the human is a human 6 to less than 12 years old and the amount of ambroxol is 0.5mg/kg to 2.0mg/kg per day, preferably 1.0mg/kg to 2.0mg/kg per day, in single or divided doses.

14. The use as claimed in claim 1or a pharmaceutical composition as claimed in claim 2, wherein the human is a human between 6 and less than 12 years of age and the amount of ambroxol is 0.7mg/kg twice daily.

15. The use according to claim 1or the pharmaceutical composition according to claim 2, wherein the human is a human between 6 and less than 12 years of age and wherein an oral dose of the combination of loratadine 1.0 mg/ml-ambroxol 6.0mg/ml solution is administered every 12 hours for 14 days.