CN1422162A

CN1422162A - Composition and method for treating allergic and inflammatory conditions with cough containing a non-sedating histamine and an expectorant

Info

Publication number: CN1422162A
Application number: CN01807679A
Authority: CN
Inventors: S·R·乌洛尔卢戈; J·D·J·维拉坎帕拉莫斯
Original assignee: Schering Corp
Current assignee: Merck Sharp and Dohme Corp
Priority date: 2000-03-30
Filing date: 2001-03-28
Publication date: 2003-06-04
Also published as: AR025308A1; TWI243671B; WO2001074341A2; BR0003648A; AU4786701A; CR6232A; PA8500101A1; ZA200102605B; WO2001074341A3; PE20010576A1; AU2001247867B2; NZ520826A; CO5200779A1; SG96611A1

Abstract

The use of a non-sedating antihistamine in combination with an expectorant for the preparation of a medicament for treatment and/or prevention allergic and inflammatory conditions with cough in humans in need of such treating and/or preventing which comprise an effective amount of a non-sedating antihistamine, preferably loratadine, in combination with an expectorant, preferably ambroxol are disclosed. Pharmaceutical compositions for treating and/or preventing allergic and inflammatory conditions with cough in humans comprising an effective amount of a non-sedating antihistamine in combination with an expectorant and a pharmaceutically acceptable carrier are also disclosed.

Description

Be used for the treatment of with the allergy of cough and the compositions and the method for inflammatory conditions

Background technology of the present invention

The present invention relates to treat and/or prevent people's the allergy and the inflammatory conditions of coughing with relevant expectoration and nonproductive cough, this method is to take the antihistaminic that do not have sedation and the combination medicine form of expectorant.

The antihistaminic that does not have sedation is known, for example referring in the patent No. being disclosed loratadine in 4,282,233 the United States Patent (USP); In the patent No. disclosed Des1oratadine in 4,659,716 the United States Patent (USP).Also can be referring to the loratadine of Claritin label, product information table, the date is 1/99.Equally, mucolytics expectorant also be in the art known for some time.Referring in the patent No. being disclosed ambroxol in 3,536,712 the United States Patent (USP).Though it is useful, but no matter be the antihistaminic that does not have sedation, or expectorant, itself all can not treat the multiple symptom relevant with respiratory tract disease effectively, for example bronchitis and bronchospasm, seasonal allergic rhinitis, long-term allergic rhinitis, flu, sinusitis and with allergic asthma complications associated with arterial system shape.The symptom of such disease may comprise sneeze, rhinorrhea, nasal obstruction, sees red, sheds tears, ear or palate pruritus and expectoration and nonproductive cough are coughed.People extremely wish to provide a kind of preparation of these known single medicines, and said preparation can strengthen their individual effect, and can improve their overall efficacy.

Summary of the invention

The invention provides treat and/or prevent need such people who treats and/or prevents with the cough allergy and the method for inflammatory conditions, this method comprises antihistaminic that does not have sedation and the expectorant of taking effective dose.In specific embodiment, the antihistaminic that does not have sedation is a loratadine, and expectorant is an ambroxol.The treatment of carrying out according to method of the presently claimed invention does not have the treatment that antihistaminic or expectorant carried out of sedation more effective than using separately, and does not have the antihistaminic inclusions onset of sedation faster than use.

The invention provides treat and/or prevent need bigger people of such 6 years old for the treatment of and/or preventing or age with the allergy of cough or the method for inflammatory conditions, this method comprises the antihistaminic that does not have sedation of effective dose and expectorant administering drug combinations.In preferred embodiments, antihistaminic is a loratadine, and expectorant is an ambroxol.In especially preferred embodiment, the amount of loratadine is about 5.0mg/ days to about 15.0mg/ days, single dose or divided dose, and more preferably from about 10mg/ days, single dose or divided dose, most preferably from about 5mg/ is one day twice.In another embodiment, the amount of ambroxol is about 30mg/ days to about 180mg/ days, single dose or divided dose, and more preferably from about 30mg/ days to about 90mg/ days or about 60mg/ days, single dose or divided dose, most preferably from about 30mg/ is one day twice.

The present invention also provide treat and/or prevent need such people of 6 to 12 years old who treats and/or prevents with the cough allergy or the method for inflammatory conditions, this method comprises the antihistaminic that does not have sedation of effective dose and expectorant administering drug combinations.In preferred embodiments, antihistaminic is a loratadine, and expectorant is an ambroxol.In especially preferred embodiment, the amount of loratadine is that about 0.5mg is to about 15.0mg, single dose or divided dose.The concentration of loratadine is preferably about 0.5mg/ml to about 3.0mg/ml in liquid dosage form, can be by single dose or divided dose administration; More preferably from about every day 2.0mg/ml single dose or divided dose administration, according to body weight, twice of 1.0mg/ml every day most preferably from about.The dosage of loratadine is preferably every day about 0.1mg/kg to about 0.3mg/kg, more preferably about 0.2mg/kg every day about 0.3mg/kg extremely.In other embodiments, ambroxol be every day about 0.6mg to about 180.0mg, single dose or divided dose.According to body weight, the concentration of ambroxol is preferably about 3.0mg/ml to 18.0mg/ml every day, single dose or divided dose administration; 12.0mg/ml more preferably from about, single dose or divided dose are most preferably according to body weight twice administration every day, about 6mg/ml.The dosage of ambroxol is preferably about every day 0.5mg/kg to about every day of 2.0mg/kg, and more preferably every day, about 1.0mg/kg was to 2.0mg/kg every day approximately, most preferably about 1.0mg/kg every day about 1.5mg/kg extremely.

The present invention also provide be used for the treatment of and/or prevent the people with the cough allergy and the new medicinal preparation of inflammatory conditions, said preparation comprises the antihistaminic that does not have sedation and the expectorant of effective dose, and pharmaceutically useful carrier.

Detailed Description Of The Invention

The invention provides the novel medicament preparation, said preparation is made up of antihistaminic that does not have sedation and expectorant basically.Preparation of the present invention can be used for preventing and/or treating with the skin of cough or the allergy and the inflammatory conditions of respiratory tract.Said preparation is widely used in the patient at various ages; Particular provided here comprises to 12 years old or bigger people of age takes tablet, takes department of pediatrics solution for the people in 6-12 year.

The present invention also provide treat and/or prevent need carry out such people who treats and/or prevents with the cough allergy and the method for inflammatory conditions, this method comprises the antihistaminic that does not have sedation of effective dose and expectorant administering drug combinations.

Here employed phrase " allergy of skin or respiratory tract and inflammatory conditions " refers to allergy and inflammatory conditions and the symptom of being found in upper respiratory tract on skin and from the nose to the lung and the lower respiratory tract.The common allergy of skin or last lower respiratory tract and inflammatory conditions comprise allergic rhinitis, non-allergic rhinitis, the asthma that comprises anaphylaxis and non-allergic asthma, sinusitis, flu, dermatitis, especially anaphylaxis and atopic dermatitis and nettle disease and symptomatic dermatographism and retinopathy and the capillary disease relevant with diabetes seasonal and property throughout the year.

The definition of employed here " people in 6-12 year " refers to 6 years old to 12 years old sex pediatric patients.The definition of employed here " 12 years old or bigger people of age " refers to greater than 12 years old to male and or women's pediatric patients and 18 years old and bigger adult of age less than 18 years old.

Though be (the seeing embodiment 1 and 2) for the treatment of with loratadine and ambroxol in the preferred embodiment of the invention, other antihistaminic and expectorant can be used for compositions described here and method equally.Below nonrestrictive listing can be used to representational antihistaminic of the present invention and expectorant.I. antihistaminic

Loratadine is a kind of antihistaminic that does not have sedation, and its chemical name is 11-(4-piperidylidene)-5H-benzo-[5,6]-ring heptan-[1,2-b]-pyridine.It is in 4,282,233 the United States Patent (USP) that this chemical compound is described in the patent No..Loratadine is a kind of three potent ring antihistaminics, has peripheral nervous system H ₁The selection antagonism of receptor active.The amount of the loratadine that can be used in the unit dosage forms (being single dose) of the present composition is extremely about 15.0mg of about 1.0mg, also can be extremely about 10.0mg of about 2.5mg, and preferably about 5.0mg is to about 10.0mg.

Desloratadine is a kind of long-acting histamine antagonist that does not have sedation, has intensive selection antagonism to peripheral nervous system H1 receptor active.In oral administration, loratadine is rapidly metabolized to a kind of pharmacologically active metabolite, decarbonylation ethyoxyl loratadine or desloratadine.US4,659,716,5,595,997 and 4,804,666 disclose preparation desloratadine and the method that comprises the pharmaceutical composition of desloratadine, and treat the method for mammal various diseases situation with it.The amount of the desloratadine that can be used in the unit dosage forms (being single dose) of the present composition is extremely about 7.5mg of about 0.75mg, also can be extremely about 5.0mg of about 1.25mg, and preferably about 2.5mg is to about 5.0mg.

Decarbonylation ethyoxyl loratadine (DCL) is the antihistaminic that does not have sedation, and its chemical name is a 8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo [5,6] ring [1,2] pyridine in heptan.Quercia, etc., Hosp.Formul., 28:137-53 (1993), US4,659,716 and WO96/20708 this chemical compound is described.DCL is a kind of H-1 histamine receptor protein antagonist.The H-1 receptor is that mediation can be by the receptor of the reaction of the antihistaminic of routine institute antagonism.The H-1 receptor for example is present on ileum, skin and the people and other mammiferous bronchial smooth muscle.The carbonyl ethyoxyl loratadine amount that can be employed in the unit dosage forms (being single dose) of this compositions is about 2.5 to about 20mg, also can be about 5 to 10mg, preferred about 5 or 7.5mg.

Fexofenadine (MDL 16,455A) are a kind of antihistaminics that does not have sedation, and its chemical name is 4-[1-hydroxyl-4-(4-hydroxyl-diphenyl methyl)-piperidino) butyl]-α, alpha-alpha-dimethyl-phenylacetic acid.Preferred pharmaceutically useful salt is hydrochlorate, is called as the fexofenadine hydrochlorate.The amount of the fexofenadine that can be employed in the unit dosage forms of this compositions is about 40 to 200mg, also can be about 60 to about 180 milligrams, also can be about 120 milligrams.II. expectorant

Ambroxol is the bromhexine metabolite, and chemical name is anti--4 (2-amino-3,5-dibromo benzil, amine) cyclohexane monohydrochloride hydrochlorate, and between two more than ten years in the past, it has been used as expectorant widely or has stimulated the surface activity factor of lung.US 3,536, and 712 pairs of these chemical compounds are described.The amount of the ambroxol that can be employed in unit dosage forms is about 30.0 to about 60.0mg, preferably about 60.0mg.

Guaiafenesin is a kind of expectorant, and its chemical name is 3-(2-methoxyl group phenoxy group)-1, the 2-propylene glycol.US 4,390, and 372 pairs of these chemical compounds are described.The amount of the guaiafenesin that can be employed in unit dosage forms is about 300.0 to about 1200.0mg, preferably about 1200.0mg.

The terpinum hydrate is a kind of expectorant, and its chemical name is 4-hydroxyl-α, α, 4-trimethyl-cyclohexane-methanol.The amount of the terpinum hydrate that can be employed in the unit dosage forms of this compositions is 85.0 to 680.0 milligrams.

For with compound pharmaceutical composition described in the invention, inertia, acceptable diluents, excipient and carrier can be solid or liquid.The preparation of solid form comprises powder agent, tablet, dispersible granules agent, capsule (can fill solid, semisolid or liquid), sachet and suppository.This powder agent and tablet can comprise about 5 to about 95% active component.Suitable solid carrier is well known in the art, for example magnesium carbonate, magnesium stearate, Pulvis Talci, sugar or lactose.Tablet, powder agent, sachet and capsule can be used as the solid dosage forms of suitable for oral administration administration.The example of pharmaceutically suitable carrier and various preparation of compositions methods is seen A.Gennaro (ed.), Remington ' s Pharmaceutical Sciences, 18thEdition, (1990), Mack Publishing Co., Easton, Pennsylvania.In addition, when wanting or need, also can in this mixture, add the binding agent, lubricant, disintegrating agent and the coloring agent that are fit to.The binding agent that is fit to comprises starch, gelatin, natural sugar, corn sweetener, natural and paragutta for example arabic gum, sodium alginate, carboxymethyl cellulose, Polyethylene Glycol and wax.The lubricant that can be used in these dosage forms has Polyethylene Glycol of Metallic stearates, Pulvis Talci, starch powder, stearic acid, different brackets or the like.Disintegrating agent comprises starch, methylcellulose, guar gum or the like.Under suitable situation, also can comprise sweeting agent and correctives and antiseptic.

In addition, compositions of the present invention also can be prepared to the form of slow releasing preparation, so that the controllable rate of release of any or various ingredients or active component to be provided, thereby optimizes therapeutic effect.Suitable slow release formulation comprise the multilayer tablet that comprises various disintegration rate layers or comprise active component sustained release polymeric skeleton and comprise such dipping or seal the tablet form or the capsule of porous polymeric skeleton.

Liquid absorption member comprises solution, suspension and Emulsion.As the example of mentioning, be useful on the water or the water-polyglycol solution of parenteral route injection, or be added with sweeting agent and ataractic oral solution, suspension and the Emulsion of being used for.Liquid preparation also can comprise the solution that is used for intranasal administration.

The aerosol formulation that is suitable for sucking can comprise solution and pulverous solid, and said preparation can comprise pharmaceutically useful carrier, as inertia Compressed Gas, for example nitrogen.

Be also included within the solid preparation that can convert the liquid preparation form that is suitable for oral or parenteral administration before using fast to.Said such liquid preparation form comprises solution, suspension and Emulsion.

Chemical compound of the present invention also can percutaneous dosing.This transdermal administration composite can be the form of cream, lotion, aerosol and/or Emulsion, and can be contained in the transdermal patch such as skeleton that is usually used in this purpose in this area or bank class.

Preferably, this chemical compound passes through oral administration.

Preferably, this pharmaceutical preparation is unit dosage forms.In this form, said preparation is divided into the unit dose of the suitable specification that comprises the suitable active group component, and wherein said suitable active becomes component for example to reach the effective dose of desired purpose.

The amount of reactive compound can change or adjustment to the scope of about 1000mg at about 0.01mg according to specific application in unit dose formulations, and preferably about 0.01mg is to about 750mg, and more preferably from about 0.01mg is to about 750mg, and most preferably from about 0.01mg is to about 250mg.

Employed actual dose can be adjusted according to patient's needs and by the order of severity of treatment symptom.Those skilled in the art can determine the appropriate dosage scheme according to specific situation.For convenience, in one day, accumulated dose every day can be divided into several parts of administrations as required.

Diagnose administration quantity and the administration frequency of controlling The compounds of this invention according to the clinician, the clinician will consider the factor such as the order of severity of age, patient's situation and build size and quilt treatment symptom.Recommend the oral administration civil day dosage uses to be about 5.0 to 10.0mg/ days of loratadine and ambroxol 30 to 60.0mg/ days, divide two to four dosage uses.

Dosage form-do not have the antihistaminic of sedation and expectorant to be prepared to transmission system, i.e. tablet, capsule, oral gel, component powders agent or the suspension relevant with active component.

Capsule-refer to supports or holds the special container or the shell of the component that comprises the antihistaminic that do not have sedation and expectorant with the gelatin of methylcellulose, polyvinyl alcohol or modification or starch being used to of making.Hard-shell capsule higher relatively bone and the pigskin gelatin of gel strength generally commonly used is mixed with.Capsule itself can comprise a spot of dyestuff, opaque material, plasticizer and antiseptic.

Tablet-refer to compression that comprises active component and suitable diluents or the solid dosage forms of moulding.This tablet can compress by the mixture that will be got by wet granulation, dry granulation or compression or granule and be prepared.

Oral gel-refer to the antihistaminic and the expectorant that do not have sedation to be dispersed or dissolved in the hydrophilic semi-solid backbone.

Component powders agent-refer to comprise active component and suitable diluents, can be suspended in the mixture of powders in water or the body fluid.

Diluent-the refer to material of common composition compositions or dosage form major part.Suitable diluent comprises sugar, for example lactose, sucrose, mannitol and sorbitol; Derive from the starch of Semen Tritici aestivi, corn, Oryza glutinosa and Rhizoma Solani tuber osi; And cellulose, for example microcrystalline Cellulose.In the compositions amount of diluent can be composition total weight about 10 to about 90% weight, preferred about 25 to about 75% weight, more preferably from about 30 to about 60% weight, especially preferred about 12 to about 60% weight.

Disintegrating agent-refer to and add the material that helps compositions fragmentation (disintegrate) in the compositions and discharge medicine to.Suitable disintegrating agent comprises starch; The modified starch of " cold water solubles is separated ", for example carboxymethyl starch sodium; Natural and paragutta, for example locust bean gum, POLY-karaya, guar gum, Tragacanth and agar; Cellulose derivative, for example methylcellulose and sodium carboxymethyl cellulose; Microcrystalline Cellulose and crosslinked microcrystalline Cellulose, for example cross-linking sodium carboxymethyl cellulose; Alginate, for example alginic acid and sodium alginate; Clay, for example Bentonite; And effervescent agent mixture, polyvinylpolypyrrolidone.In the compositions amount of disintegrating agent be composition weight about 2 to about 15% weight, more preferably from about 4 to about 10% weight.

Binding agent-refer to powder-stuck or " gluing ", and by the material that granulation makes it to condense, therefore in preparation, be called as by " adhesive ".Binding agent has increased diluent or the available viscosity of filler.Suitable binding agent comprises sugar, for example sucrose; Derive from the starch of Semen Tritici aestivi, corn, Oryza glutinosa and Rhizoma Solani tuber osi; Natural gum, for example arabic gum, gelatin and Tragacanth; Sargassum derivant, for example alginic acid, sodium alginate and calcium ammonium alginate; Cellulosic material, for example methylcellulose and sodium carboxymethyl cellulose and hydroxypropyl emthylcellulose; Polyvinylpyrrolidone; And inorganic matter, for example aluminium-magnesium silicate.In the compositions amount of binding agent be composition weight about 2 to about 20% weight, more preferably from about 3 to about 10% weight, especially preferred about 3 to about 6% weight.

Lubricant-refer to joins in the dosage form, guarantees the material that materials such as tablet, capsule can be deviate from from mould or punch die by power of reducing friction or wearing and tearing after it is pressed molding.Suitable lubricant comprises Metallic stearates, for example magnesium stearate, calcium stearate or potassium stearate; Stearic acid; High melting-point wax; And soluble oil, for example sodium chloride, sodium benzoate, sodium acetate, enuatrol, Polyethylene Glycol and d ' 1-leucine.The lubricant normally final step before compression adds, and this is because they must be present between particulate surface and granule and the tablet machine.In the compositions amount of lubricant be composition weight about 0.2 to about 5% weight, preferred 0.5 to about 2% weight, more preferably from about 0.3 to about 1.5% weight.

Fluidizer-this material can prevent caking, and can improve particulate flowability, so that its mobile more smooth and easy and homogeneous.Suitable fluidizer comprises silicon dioxide and Pulvis Talci.In the compositions amount of fluidizer be composition weight about 0.1% to about 5% weight, preferred about 0.5 to 2% weight.

Coloring agent-be provides painted excipient for compositions or dosage form.Such excipient comprises food grade dyestuff and the food grade dyestuff that is adsorbed on suitable absorbent such as clay or the aluminium oxide.The amount of coloring agent be composition weight about 0.1 to about 5% weight, preferred about 0.1 to about 1% weight.

Bioavailability-refer to standard or contrast and compare, active medicine component or treatment part are absorbed body circulation speed and the degree of entering from form of administration.

The conventional method of preparation tablet is known.This kind method comprises dry method, for example direct compression and with the granule tabletting of compression gained, or wet method or other special operation.

Vast scope of the present invention will well describe with the following examples, but these examples are not the present invention will be limited on the specific embodiment.

Example I

New pharmaceutical composition

The present invention provides a kind of novel compositions in a kind of new pharmaceutical preparation, said composition can slowly discharge antihistaminic loratadine and expectorant and the mucolytic agent ambroxol for example for example that does not have sedation.Said composition is mainly used in treatment, and these show and the patient who coughs the irritated situation of broncho-pulmonary relevant, and in this situation, viscosity and mucus attachment increase, and have hindered the permeability of respiratory tract.Its principal indication includes but not limited to the allergic rhinitis with cough; Acute, chronic, spastic and asthmatic bronchitis; Bronchial asthma; Bronchiectasis; Sinusitis; Otitis media; Pneumonia; Bronchopneumonia; Block the pulmonary atelectasis that causes owing to mucus; Tracheotomy and as preceding and back preventive.

List the prescription of each medicament forms at following embodiment: tablet The component title ConcentrationEffect % deviation

(mg/ sheet) Loratadine 5.00 active material ambroxol salt hydrochlorates 30.00 active material Lactis Anhydrouses 84.75 fillers ± 20 cornstarch, 12.00 disintegrants ± 20 microcrystalline celluloses, 16.75 disintegrants ± 10 colloidal state (Colloidall), 0.75 glidant ± 10 silica dolomols, 0.75 lubricant ± 10 heavy 150.00mg manufacture methods:

Prepare this tablet with direct compression process, powdery components is mixed special time in blender,, then this mixture is pressed into tablet to guarantee uniform content.Solution The component title ConcentrationEffect % deviation

The 1.00ml preparation method is made in an amount of solvent ± 20 of purifying waste water, mg/ml Loratadine 1.00 active material ambroxol salt hydrochlorates 6.00 active material citric acids 0.40 cushion ± 10 glycerine, 150.00 solvents ± 20 propane diols, 200.00 solvents ± 20 saccharin sodiums, 0.40 sweetener ± 10 sorbitol solutions, 70% 315.00 solvents ± 20Peach flavouring No.609 2.50 flavourings ± 10:

This solution is by loratadine and glucide are added in the propylene glycol, and citric acid is dissolved in the water to be prepared in the solution that adds the front.Ambroxol is dissolved in wherein, makes it dissolving.Then glycerol, sorbitol and correctives are added wherein, mix until evenly.

Embodiment 2

Clinical research

The safety of each independent component and effect all are to determine very much in loratadine/ambroxol compositions.The studies on acute toxicity of carrying out with loratadine (before clinical and clinical widely in the scheme) and ambroxol component is verified, and potential general toxicity is low, and said composition is desired just for this.

Loratadine is a kind of potent three ring antihistaminics of slow release, has the antagonism of selection peripheral nervous system H ₁The effect of receptor active.Behind oral administration, can be absorbed fully.It is 9 hours that its blood plasma is eliminated the half-life.Yet its antihistamine effect can continue 24 hours.Its onset is very fast, estimates to be about 30 minutes.Then, mainly metabolism in liver of loratadine, and by urine and defecate.

Ambroxol is a kind of bromhexine metabolite, chemically is being called as anti--4 (2-amino-3,5-dibromo benzil, amine) cyclohexane monohydrochloride hydrochlorate, is used as the expectorant or the zest lung surface active factor widely in two more than ten years in the past.Behind oral administration, its absorption rate fast and fully.The people's of estimation the elimination half-life is 20-25 hour, almost completely passes through homaluria.Have been found that its biotransformation approach is similar in all species research.Ambroxol mainly carries out metabolism by combining with glucuronic acid, and a spot of is entrained by dibromoanthranilic acid by reaction.Ambroxol is widely distributed, can pass through placental barrier, just can record its fetus concentration in 15 minutes after administration, and this concentration is 3 times of parent plasma concentration.It is accumulated in liver and lung, can record its maximum in 90 minutes after administration.

The clinical efficacy of new compositions of the present invention and safety prove by 3 groups of clinical trials: research one is six months, the research of contrast, prospective, vertical (longitudinal), this research comprises 120 adult patients, and these patient table reveal the bronchitis symptom with bronchial stenosis; Research two is perspective, double blinding in six months, contrast, reaches comparative study at random, this research comprises 120 patients, be used to estimate of effect and the safety of loratadine/ambroxol solution with respect to single active component, wherein said single active component refers to loratadine and ambroxol, and employed patient is 6 to 12 years old the child who suffers from allergic rhinitis and cough; Research three usefulness 30 healthy volunteers carry out, be loratadine of the present invention-ambroxol tablet with respect to single center of 30-mg ambroxol tablet and 10-mg loratadine tablet, at random, open label, three-dimensional intersection single dose bioavailability study.These clinical researches result can prove that loratadine and ambroxol are united and use safer more effective respectively than its single component aspect the allergy of the skin of corresponding cough or respiratory tract and inflammatory conditions treating and/or preventing.

The clinical research scheme

Below the design three groups of clinical protocol be used for (a) relatively loratadine/ambroxol unite suffering from safety and effect (research 1) with the bronchitic adult patients of bronchial stenosis; (b) evaluation loratadine/ambroxol is united safety and the effect (research 2) to the pediatric patients of suffering from allergic rhinitis and cough; (c) relatively loratadine/ambroxol is united the relative bioavailability (research 3) that gives the healthy volunteer with respect to each component respectively.

Research 1

This research is double blinding in six months, contrast, perspective longitudinal study, comprises 120 adult patients that show with the bronchitis symptom of bronchial stenosis.

Research purpose

The purpose of this research is will estimate loratadine/ambroxol to unite suffering from effect and safety after the adult patients administration of the bronchitis symptom of bronchial stenosis.

Project

Overall study scheme and plan: explanation

This research needs the adult patient of 120 trouble with the bronchitis symptom of bronchial stenosis altogether.Loratadine/ambroxol is united form oral administration with tablet, one day twice (12 hours at interval), successive administration 14 days.

During the clinical assessment of disease, the evaluation time of decision symptom, and record symptom and clinical sign.In the incipient stage (the 1st day-basic test) of research, come patient is diagnosed by the expert, carry out 3 times and follow up a case by regular visits to 7 days (visiting 2), 14 days (visiting at last).When each the visiting, must comprehensively assess the variation of disease, all results and viewed result in the first time and visiting are afterwards compared.During each the visiting patient is observed, and the patient is inquired with regard to the ill effect that may occur during the research.Record response type, the order of severity, with treat relevant time and cause.In in the end visiting, inquire with effect to the patient and to assess used medicine.Each patient accepts one of following three kinds of treatments at random:

Treatment 1: a slice loratadine 5mg/ ambroxol 30mg unites tablet, every 12 hours oral administrations, and administration 14 days.

Treatment 2: a slice placebo tablet, every 12 hours oral administrations, administration 14 days. Study population/inclusion criteria/exclusion standard

Inclusion criteria:

Select adult male or the women of age between 18 to 70 years old.

The patient suffers from the bronchitis with bronchial stenosis.

At clinical health aspect other.

The patient understands the requirement and the restriction of this research, and agrees to participate in assessment and visit.

The patient provides Informed Consent Form before the research of being correlated with.

Exclusion standard:

The patient of pregnancy or age of sucking.

The medicine that institute is used has the patient of allergy or hypersensitivity.

Studying the patient who carried out treatment in preceding 8 days with antihistaminic, expectorant or mucolytic agent.

Have a heart disease, the patient of hepatopathy or nephropathy.

Accept the patient of immunization therapy.

Can not observe him or she and during studying, except using the research approach medicine, not use the patient of the requirement of any prescribed and non prescribed medicine.Finishing in advance and eliminating of treatment

Continue research association for those and endanger its happiness and healthy patient, researcher is had the right and obligation is interrupted this treatment.Such patient must withdraw from this research, and they can not continue to participate in behind modification.

If treatment is because former except that previous reasons thereby finish in advance, then this patient must be counted as " (dropout) falls behind ", and must replace his or her position with other patient.Must fill in a case report form for the person of falling behind.Treatment research

When visiting, each patient must obtain containing the treatment bottle of the tablet of one of enough three kinds of treatments as listed above (1 or 2) the 1st time of this research.The patient must return this medicine bottle (empty or used a part) when visiting the last time.

After disease is carried out entry evaluation, in doctor's office, take primary dosage.In the visiting of back, must carry out careful inquiry to the patient, meet the scheme requirement to guarantee treatment.The various parameters of necessary record in case report form for example once or have several times been forgotten to take medicine or overdose is taken medicine.

The ill effect of any harm patient safety all needs to finish treatment, and this patient is withdrawn from from this research.This patient must return in the other clinical assessment and disappear until this ill effect.Efficacy parameter

Following parameter is monitored:

Loratadine:

Bronchial stenosis is alleviated

Inflammation

Ambroxol:

The cough qualitative determination

The secretions flowability

These parameters are carried out classification with 3 similar grading systems, assess with the statistical method of no parameter.Security parameters

The all ill effects of record in the ill effect table.Some ill effects must finish treatment in advance.If the appearance of ill effect need be carried out other treatment administration, then it must be recorded in this case report and be entitled as in the zone of " following treatment ".In visiting subsequently, also must carry out record to this patient's progress.

The file of each ill effect should comprise time of origin, position and the persistent period of ill effect; And with the determining of the relation of research medicine.

Any patient who stands serious ill effect should withdraw from this research immediately.No matter whether relevant with trial drug, in subsequently 48 hours, must be with the supervisor of all serious ill effect phone Schering Plough.In subsequently 5 days, must submit reading report to.

Serious ill effect is to show significant risk or danger, contraindication, indirect action or early warning.The clinical trial of carrying out for personnel selection, it comprises following any effect: cause patient death at once the unsoundness risk cause being in hospital or prolong the hospital stays cause permanent, continue or serious deformity cause the organ toxicity, comprise hematotoxicity, liver toxicity, gastrointestinal toxicity and central nervous system's toxicity.In addition, in laboratory detects than normal limit exceed 3 times unusually also be considered to the organ toxicity.If the test value that begins to obtain is outside normal limit, then the change of any 〉=25% all must be reported on relevant rudimentary value basis

Carcinogenic

Have a mind to or overdose medication unintentionally

Teratogenesis scheme deviation

Must follow written explanation, strict this scheme of carrying out.Any change to this scheme all must be reached Informed Consent Form between researcher and Schering Plough.Before implementing any change, the revision of this scheme must be by researcher and Schering Plough signature.

Be that patient does not meet the example of visiting the scheme deviation that requires subsequently below:

The medicine or the treatment of forbidding have been used.

The change of dosage: once or several times fail to take medicine or during treating overdose take medicine.Statistical analysis:

The comparison of S﹠S specification and basis assessment comprises that assessment its summation (summation of sings and symptoms) and the total specification of sings and symptoms improve percentage ratio; Equally, will be by the doctor obtains the generally reflection of treatment and the assessment that he (mother/father/guardian) is carried out oneself by patient be compared, as the effect standard.

Research 2

This research is perspective, double blinding in 6 months, contrast, at random and comparative study, is used to assess at effect and the safety to 6 to 12 years old child suffering from allergic rhinitis and cough of the loratadine of single active component and the loratadine of ambroxol/ambroxol solution.

Research purpose

The purpose of this research is that assessment loratadine/ambroxol is united effect and the safety to child's administration of 6 to 12 years old suffering from allergic rhinitis and cough.

Project

Comprehensive study scheme and plan: explanation

This research needs 120 ages altogether between 6 to 12 years old, shows the child patient of allergic rhinitis and cough symptom.To comprise the department of pediatrics solution administration of loratadine/ambroxol associating, one day twice (12 hours at interval), successive administration 10 days, with wherein each component respectively administration compare, wherein said each component is meant loratadine and ambroxol.

The diagnosis of allergic rhinitis is based on nasal obstruction, transparent nasal mucus, sneeze, sheds tears, the conjunctiva pruritus is made, and must be with cough.

During the clinical assessment of disease, the evaluation time of decision symptom, and record symptom and clinical sign.In the incipient stage (the 1st day-basic test) of research, come patient is diagnosed by the expert, carry out 3 times and follow up a case by regular visits to 5 days (visiting 2), 10 days (visiting at last).When each the visiting, must comprehensively assess the variation of disease, all results and viewed result in the first time and visiting are afterwards compared.During each the visiting patient is visited, and the patient is inquired with regard to the ill effect that may occur during the research.Record response type, the order of severity, with treat relevant time and cause.In in the end visiting, inquire with effect to father and mother or patient's guardian and to assess used medicine.Each patient accepts one of following three kinds of treatments at random:

Treat the loratadine 1.0mg/ml of 1: one oral dosage and the department of pediatrics solution of ambroxol 6.0mg/ml associating, every administration in 12 hours, administration 10 days.

Treat the loratadine 1.0mg/ml department of pediatrics solution of 2: one oral dosage, every administration in 12 hours, administration 10 days.

Treat the ambroxol 6.0mg/ml department of pediatrics solution of 3: one oral dosage, every administration in 12 hours, administration 10 days.

As shown in the table, according to age and body weight decision dosage:

Age	Body weight (kg)	Every 12 hours volumes (ml)	12 hours loratadines (mg)	24 hours loratadines (mg)	12 hours ambroxols (mg)	24 hours ambroxols (mg)
Age	Body weight (kg)	Every 12 hours volumes (ml)	12 hours loratadines (mg)	24 hours loratadines (mg)	12 hours ambroxols (mg)	24 hours ambroxols (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	6 to 9	20.3 to 29.9	??2.5	??2.5	????5.0	????15	??30

The recommended dose of per kilogram of body weight is as follows:

Loratadine:

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

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

Ambroxol:

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

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

For this research, body weight is lower than the patient of 30kg every 12 hours administration 2.5ml solution, and body weight is 30kg and above patient, every 12 hours administration 5ml solution. Study population/inclusion criteria/exclusion standard

Inclusion criteria:

Select the sex of age between 6 to 12 years old.

The patient who suffers from allergic rhinitis and cough.

At clinical health aspect other.

Father and mother or prison expand requirement and the restriction that the people must understand this research, and agree to participate in assessment and visit.

The patient must provide sign a written pledge (before carrying out any relevant research).

Exclusion standard:

The clinical indication that the nasopharynx bacterial infection is arranged.

Have a heart disease, the patient of hepatopathy or nephropathy.

The person observes according to the study, has the patient of unusual clinically vital sign, body weight or height for its age.

Accept the patient of immunization therapy.

Can not observe him or she and during studying, except the medicine that uses research approach, not use the patient of the requirement of any prescribed and non prescribed medicine.Finishing in advance and eliminating of treatment

Continue research association for those and endanger its happiness and healthy patient, researcher is had the right and obligation is interrupted this treatment.This kind patient must withdraw from this research, and they can not continue to participate in behind modification.

If treatment is because former except that previous reasons thereby finish (for example can not contrast) in advance, then this patient must be counted as " falling behind ", and must replace his or her position with other patient.Must fill in a case report form for the person of falling behind.Treatment research

When visiting, each patient must obtain containing the office preparation bottle of 14 days therapeutic doses of one of three kinds of treatments as listed above the 1st time of this research.The patient must return this medicine bottle (empty or used a part) when visiting the last time.After disease is carried out entry evaluation, in doctor's office, take primary dosage.

After disease is carried out entry evaluation, in doctor's office, take primary dosage.In the visiting of back, must carry out careful inquiry to patient (father and mother or guardian), meet the scheme requirement to guarantee treatment.The various parameters of necessary record in case report form for example once or have several times been forgotten to take medicine or overdose is taken medicine.

Following parameter is monitored:

Loratadine:

Sneeze

Watery nasal mucus

Shed tears

The conjunctiva pruritus

Ambroxol:

Cough frequency and intensity reduce

The secretions flowability

The file of each ill effect should comprise time of origin, position and the persistent period of ill effect; With determining of the relation of research medicine.Serious ill effect is to show significant risk or danger, contraindication, indirect action or early warning.For the clinical trial that personnel selection is carried out, it comprises following any effect:

Cause patient death

Unsoundness risk at once

Cause being in hospital or prolonging the hospital stays

Cause permanent, that continue or serious deformity

Cause the organ toxicity, comprise hematotoxicity, liver toxicity, gastrointestinal toxicity and central nervous system's toxicity.In addition, in laboratory test than normal limit exceed 3 times unusually also be considered to the organ toxicity.If the test value that begins to obtain is outside normal limit, then the change of any＞25% all must be reported on relevant rudimentary value basis

Carcinogenic

Have a mind to or overdose medication unintentionally

Teratogenesis

Any patient who stands serious ill effect must withdraw from from this research immediately.No matter whether relevant with trial drug, subsequently 24 hoursIn, must be with the supervisor of all serious ill effect phone Schering Plough.Subsequently 5 daysThe interior necessary reading report of submitting to.The scheme deviation

The medicine or the treatment of forbidding have been used.

The comparison of S﹠S specification and basis assessment comprises that assessment its summation (summation of sings and symptoms) and the total specification of sings and symptoms improve percentage ratio; Equally, will be by the doctor obtains the generally reaction of treatment and the assessment that he (mother/father/guardian) is carried out oneself by patient be compared, as the effect standard.

Research 3

This research is carried out with 24 healthy volunteers, be this tablet with respect to single center of 30-mg ambroxol tablet and 10-mg loratadine tablet, at random, open label (open-label), three-dimensional intersect the single dose bioavailability study.

Research purpose

The purpose of this research is the healthy volunteer to be given relatively its relative bioavailability of loratadine/ambroxol tablet administration and the two individually dosed respectively back.

Project

Comprehensive study scheme and plan: explanation

Choose principle according to interleaved scheme and experimenter at random, in list, select and recruit 30 healthy male volunteers of age between 18 to 50 years old in the heart and enter in the three-dimensional crossing research.Determine that by medical history, physical examination, electrocardiogram and laboratory tests all experimenters have good condition of health.This experimenter must meet and followingly chooses and get rid of principle.

This research needs about 36 days ability to carry out clinically fully.In two days for the treatment of, the experimenter is screened.Needed just can finish each course of treatment in 2 days, and the necessary eluting phase at least 2 week at interval of treatment each time.Before giving predose, research tester or she/his des must inspect all garbled datas, and is all qualified to guarantee all experimenters.Treatment

In morning (approximately mornings 8 point), after one night of fasting, according to the code that computer produces, each experimenter accepts in the following therapeutic scheme:

The treatment A: morning 8:00, two tablets of loratadine-ambroxol tablets.

The treatment B: morning 8:00, two tablets of 30-mg ambroxol tablets.

The treatment C: morning 8:00, a slice 10-mg loratadine tablet.

Table 1

Cycle I	Cycle II	Cycle III
Cycle I	Cycle II	Cycle III	Treatment A	Treatment B	Treatment C
Treatment B	Treatment C	Treatment A	Treatment A	Treatment B	Treatment C
Treatment B	Treatment C	Treatment A	Treatment C	Treatment A	Treatment B

* all treatments all are with the administration of 240ml water.Between each treatment, all there is 15 days eluting phase. Dosage form and research approach

Medicine below using:

Loratadine-ambroxol (30-mg ambroxol and 5-mg loratadine) tablet.

Mucosolvan  (30-mg ambroxol) tablet

Clarityne  (10-mg loratadine) tablet

All supply medicines all are stored in safe place by condition of storage specified on the label. Study population/inclusion criteria/exclusion standard

Inclusion criteria:

This research selects for use the age between 18 to 50 years old, and body weight meets the male of Metropolitan Life insurance company 1983 heights and body weight table (± 10%) regulation.Each patient will accept physical examination in two weeks before carry out this research.In addition, take its complete medical history, obtain its electrocardiogram, and carry out following laboratory and detect:

1) complete blood count (comprising difference (differential))

2) hepatitis B surface antigen test

3) HIV antibody test

4) hematochemistry

5) total protein

6) albumin

7) calcium

8) Phos

9) cholesterol

10) triglyceride

11) fasting glucose

12) blood urea nitrogen

13) uric acid

14) total bilirubin

15) alkaline phosphate

16) lactic acid dehydrogenase

17) serum glutamic pyruvic transaminase

18) serum glutaminic acid oxalacetic acid transaminase

19) gamma-glutamyltranspeptidase

20) serum creatinine

21) electrolyte (Na, K, Cl, bicarbonate such as CO ₂)

22) urinalysis

Before initial administration, research human observer and he/her guardian must read the clinical laboratory that carries out in order to screen purpose and detect and the physical examination result.The experimenter must be able to understand the requirement of this research, is willing to keep appointments, and can carries out required inspection and treatment.

When participating in research, every necessary designated code at random of patient, and reach Informed Consent Form.This information should be labeled on patient's the case report form.

Before studying, can not take any other medicine (prescription drugs, research medicine or OTC) during fortnight or the research.

Obtain patient's smoking history and it is recorded on the case report form.

Exclusion standard

1) cardiovascular disease, sacred disease, hematologic disease, gastrointestinal disease, cerebrovascular disease, respiratory disorder, hepatopathy or nephropathy medical history or suffer from any other and need the individuality of the disease that the doctor treats are arranged.

2) individuality of laboratory detection result outside normal value (for this laboratory), this scope is:

2.1) can not be by reaction and be studied person and the quilt of expection as known underlying diseases

The Schering scheme person in charge/scheme doctor thinks can not participate in research

2.2) according to the judgement of researcher, detect facing on the basis at clinical assessment and other

The bed significance is clinical relevant with unusual test detection.

3) have the patient of any part and systemic infection history of disease and before administration around in the generation urinary tract infection individuality.

4) can not satisfy and do not using any medicine or do not use ethanol in preceding 24 hours or do not use any individuality of the requirement of caffeine or Fructus Cannabis in preceding 24 hours at administration the last fortnight at least in the treatment administration in the treatment administration.

5) in research beginning the first two months, participate in clinical trial, and accepted the individuality of trial drug.

6) the known individuality of taking drugs or indulging in excessive drinking in the past.

7) known irritated or the individuality of serious food or drug allergy history arranged to ambroxol or loratadine.

8) individuality that is positive of HIV antibody.

9) individuality that is positive of hepatitis B surface antibody or C type hepatitis antibody.Randomization is selected

Researcher is by Schering Plough M-PDL, and the code that produces according to computer makes the experimenter accept A, B or C treatment at random with three kinds of a kind of in may order (ABC, BCA and CAB).Experimenter's replacement

All can not continue this research in early days and meet the experimenter of following standard just can be replaced:

10) because administrative reason any is difficult to continue (for example experimenter's preference)

11) do not meet the patient of admission criteria

12) can not observe the experimenter that scheme subsequently requires

The experimenter of substitute adds that with former experimenter's numbering one " R " is numbered (for example 1 replaced by 1R).New experimenter's dosage is according to original experimenter's dosage and fixed.Treatment research A. administration Intersect the administration cycle

At signature informed consent postscript, at research beginning back (the 1st day, cycle I) experimenter receive treatment A or treatment B or treatment C, until the 36 day.At 15 days eluting after dates, accept additional (complimentary) treatment of A or B or C according to order described above the 18th day (cycle II) experimenter.At 15 days eluting after dates, at the 35th day (cycle III), the experimenter accepted the additional treatment of A or B or C according to order described above.

Administration when all treatments all are at about in the morning 8.At 1,18 and 35 day, the volunteer after one night of fasting by administration, and after administration 4 hours can not take food food or fluids.

After each conceptual phase finishes, the volunteer is checked, and can allow it leave the research place.When the II and the research in III stage are returned in report, should offer counsel to the volunteer.This dosage must be spaced apart by at least 15 days eluting phase institute.

Finish back (after getting last blood sample on the 36th day), the physical examination, hematochemistry, urinalysis and the electrocardiogram that are carried out when each volunteer is repeated to screen in research.If any experimental determination result thinks that (except the just mensuration outside term of reference of expection) and the person of being studied outside the term of reference important clinical meaning is arranged, then should repeat at interval to measure until it and return back to baseline or become great clinical discovery with reasonable time. Have meal

On administration same day, do not have breakfast.After the treatment administration, do not consume food and fluid (comprising water) in 4 hours.

Breakfast is standardization breakfast, and all volunteers eat identical meals on the same day separately each treatment cycle.Can suppress (first-pass) first metabolism of some drugs because reported Succus Citri grandis, so in the restricted period of phase is respectively treated in this research, can not consume Succus Citri grandis, Fructus Citri grandis or comprise the product of Fructus Citri grandis. Blood sample

At the 1st to 2,18 to 19 and 35 to 36 days, the special time after carrying out each treatment was collected blood sample, carries out ambroxol and loratadine analysis in the human plasma subsequently.Before this research, carry out laboratory detection, physical examination and EKGs.In addition, before every treatment day 8:00 administration, write down vital sign, during studying, observe the ill symptoms that the experimenter may occur continuously.Any ill symptoms all should be recorded on the case report form. Clinic observation

Study the sample time in each cycle at this, before the administration, (BP, HR, breathing rate and oral cavity body temperature (oral body temperature) also are recorded in it on case report form to obtain vital sign.Also obtain the vital sign line item of going forward side by side.During studying, the experimenter is observed and inquire with regard to contingent side effect.When any symptom of record, all should use medical term.

Should estimate the order of severity of ill symptoms with following definition:

Slightly: for the volunteer, symptom is insignificant, can not cause any question of substance.

Moderate: symptom can produce certain problem to the volunteer, but daily routines and clinical state that can not the appreciable impact volunteer.

Severe: symptom can have a strong impact on volunteer's normal daily routines and clinical state.Clinical detection

Before studying and research back test result is estimated.Pharmacokinetics and bioequivalence

With WinNonlin Professional program, the plasma concentration of loratadine and ambroxol is carried out pharmacokinetic analysis with non-compartment model method.Can directly obtain maximal plasma concentration (Cmax) and reach the required time of maximal plasma concentration (Tmax) by these data.End phase (terminal phase) speed constant (λ Z) is the negative value of the plasma concentration calculated with linear regression method-time graph log-linear (log-linear) terminal slope partly.Can calculate the last phase half-life (T1/2) with 0.693/ λ Z.

The plasma concentration area under curve (AUC_ ∞ ng*Hr/ml) of ambroxol in the time of then can calculating from the time 0 to infinity with the logarithm trapezoidal rule then with linear trapezoid method.Model 200 according to WinNonlin Library can calculate all pharmacokinetic parameters.

Cmax: for the single dose data: maximal plasma concentration 0 and the amount that can survey for the last time between.

Tmax: the time that observes Cmax.

AUC_0-tmax: area under curve from administration (administration _ time) to Tmax hour.

AUC_0-48: area under curve from 0 (administration _ time) to 48 hours.

AUC_0-∞: area under curve from administration (administration _ time) to infinite general goal.

T1/2_ λ z (hour): terminal half-life=Ln (2)/λ z, wherein λ z (hr ^-1) be and the relevant first order rate constant of curve end (log-linear) part.This makes linear regression with the time to logarithm concentration and estimates.

This result of the test is the data that obtained by loratadine-ambroxol.

Be described to the mean parameter ratio (detection lug/comparison film) that is used to check the product bioequivalence with by the confidence interval of ANONA analytical calculation.

For loratadine, area under blood plasma-concentration curve of from 0 to 48 hour (AUC_0-48 ng*Hr/ml), area (AUC_ ∞ ng*Hr/ml) can be with administration by then calculating and adjust with the logarithm trapezoidal rule with linear trapezoid method then under blood plasma-concentration curve of 0 to ∞ time.All pharmacokinetic parameters all are that the model 200 according to WinNonlin Library calculates, and analyze with the method identical with method described above.Statistical analysis

Use variance (ANOVA) model analysis of extracting to come pharmacokinetic data is carried out statistical analysis, that is: by order, experimenter, cycle, preparation

In proper order+experimenter (Seq)+cycle+agent shape

Experimenter's in this model (Seq) definition is equal to and nested effect (nestedeffect) experimenter in Seq..

The influence of sequence is with square the checking with experimenter (Seq) meansigma methods as error that derives from ANOVA.All other main influence will be checked with the residual error that derives from ANOVA (residualerror) (error mean square).

By the confidence interval of structure 90% between test (loratadine-ambroxol) and contrast (loratadine tablet and ambroxol tablet) average ratio, be used in two one-sided hypothesis test Tmax, Cmax and the AUC_0-∞ at the significance place of α=0.05 level.

To each activity relationship according to FDA guide (" relate to the bioequivalence Journal of Sex Research statistical method of carrying out, in July, 1992) and consider that four cycles analyze with two kinds of standards-treatment interleaved scheme. Theoretical research

Thinking treatment that the inventive method advocates does not have the antihistaminic of sedation or expectorant more effective than using separately, and than with there not being the antihistaminic inclusions onset of sedation faster.

Even each publication or patent application are all spelt out and show respectively and be introduced into as a reference, all reference materials of here being quoted also all are to be introduced into as a reference with identical degree.

Can carry out many modifications and changes to the present invention, this it will be apparent to those skilled in the art that, does not break away from the spirit and scope of the invention yet.Particular as described herein only is as an example, and the present invention only is subjected to the restriction of back claims, is consistent with the four corner of delegatable such claim equivalence.

Claims

1. do not have the antihistaminic of sedation and expectorant to unite to be used to prepare to treat and/or prevent the application with the medicine of the allergy of cough and inflammatory conditions that need carry out such people who treats and/or prevents, its antihistaminic that does not have sedation that comprises effective dose is united with the expectorant of effective dose.

2. be used for the treatment of and/or prevent the people with the cough allergy and the pharmaceutical composition of inflammatory conditions, said composition comprises the antihistaminic that does not have sedation of effective dose and the associating of expectorant, and pharmaceutically useful carrier.

3. application as claimed in claim 1 or pharmaceutical composition as claimed in claim 2, the antihistaminic that does not wherein have sedation is a loratadine.

4. application as claimed in claim 3 or pharmaceutical composition, wherein the people is the people more than 12 years old and 12 years old, the amount of loratadine is 5.0mg/ days to 15mg/ days, preferred 10mg/ days, with single dose or divided dose.

5. application as claimed in claim 3 or pharmaceutical composition, wherein the people is the people more than 12 years old and 12 years old, the amount of loratadine is a day twice of 5.0mg/.

6. application as claimed in claim 1 or pharmaceutical composition as claimed in claim 2, wherein expectorant is an ambroxol.

7. application as claimed in claim 6 or pharmaceutical composition, wherein the people is the people more than 12 years old and 12 years old, the amount of ambroxol is 30mg/ days to 90mg/ days, preferred 60mg/ days, with single dose or divided dose.

8. application as claimed in claim 6 or pharmaceutical composition, wherein the people is the people more than 12 years old and 12 years old, the amount of ambroxol is 30mg, one day twice.

9. application as claimed in claim 1 or pharmaceutical composition as claimed in claim 2, wherein

A) not having the antihistaminic of sedation is loratadine; With

B) expectorant is an ambroxol.

10. application as claimed in claim 1 or pharmaceutical composition as claimed in claim 2, wherein allergy or inflammatory conditions be with cough allergic rhinitis, bronchial asthma, bronchitis, bronchiectasis, sinusitis, otitis media, pneumonia, bronchopneumonia, because pulmonary atelectasis or the bronchial stenosis that the mucus obstruction causes.

11. application as claimed in claim 1 or pharmaceutical composition as claimed in claim 2, wherein the people is 6 to the people less than 12 years old, and the amount of loratadine is 0.1mg/kg to 0.3mg/kg every day, preferred every day 0.2mg/kg to 0.3mg/kg, with single dose or divided dose.

12. application as claimed in claim 1 or pharmaceutical composition as claimed in claim 2, wherein the people is 6 to less than 12 years old people, and the amount of loratadine is 0.1mg/kg, twice of every day.

13. application as claimed in claim 1 or pharmaceutical composition as claimed in claim 2, wherein the people is 6 to the people less than 12 years old, and the amount of ambroxol is 0.5mg/kg to 2.0mg/kg every day, preferred every day 1.0mg/kg to 2.0mg/kg, with single dose or divided dose.

14. application as claimed in claim 1 or pharmaceutical composition as claimed in claim 2, wherein the people is 6 to less than 12 years old people, and the amount of ambroxol is 0.7mg/kg, twice of every day.

15. application as claimed in claim 1 or pharmaceutical composition as claimed in claim 2, wherein said people is 6 to the people less than 12 years old, wherein every the loratadine 1.0mg/ml-ambroxol 6.0mg/ml combined soln of 12 hours administration one oral dosage, administration 14 days.