WO2003070213A2

WO2003070213A2 - Liquid mucoadhesive pharmaceutical composition

Info

Publication number: WO2003070213A2
Application number: PCT/BG2003/000005
Authority: WO
Inventors: Christo Tzachev Tzachev; Todor Alexandrov Popov
Original assignee: Bio Therapeutics
Priority date: 2002-02-22
Filing date: 2003-02-18
Publication date: 2003-08-28
Also published as: AU2003205460A1; BG65734B1; WO2003070213A3; BG106430A

Abstract

The present invention relates to liquid mucoadhesive pharmaceutical composition to be applied to the mucosal epithelia with prolonged and improved coating and protection effect. The composition can be used in the medical practice as oral, ocular, nasal, rectal, vaginal and periodontal pharmaceutical preparations. The liquid pharmaceutical composition comprises xylomethazoline.HCl about 0.10 wt.% to 10.00 wt.%, hydroxypropyl methycellulose from 0.01 wt.% to 10 wt.%, disodium ethylenediamine tetraacetate from 0.01 wt.% to 10.00 wt.%, phosphate buffer to 100 wt. % with pH about 5 to 7, the relative viscosity of the solution is about 70.00 to 90.00, and the relative adhesive capacity is 105.0 % to 120.0 %. The composition according to the invention can be applied easilly and has a prolonged contact to the mucosal surface. In this way the composition provides a good therapeutic effect at lower does and has a good bioavailability.

Description

LIQUID MUCOADHESrVΕ PHARMACEUTICAL COMPOSITION

Technical field

The present invention relates to mucoadhesive pharmaceutical composition to be applied to the mucosal epithelia with prolonged and improved coating and protection effect. The composition can be used in the medical practice as oral, ocular, nasal, rectal, vaginal and periodontal pharmaceutical preparations.

Background of the invention

Mucoadhesion is of great interest to pharmaceutical formulators and drug delivery scientists in the last years. This technology relates to the controlled release of the active substance in the pharmaceutical composition and is in connection with its adhesive properties. The term adhesion refers to the relationship between two bodies, an adhesive and a substrate. An "adhesive" is a substance capable of holding materials together by surface attachment and can establish adhesive bond between the surfaces of the two materials. "Bioadhesion" implies that at least one of the two surfaces is of biological origin. When the surface is the adherent mucus layer covering the mucosal epithelia the term "mucoadhesion" is used. The mucoadhesion is specific type of bioadhesion and not a synonym thereof Mucoadhesive materials are useful to provide prolonged and improved efficacy of the mucoadhesive pharmaceutical compositions to the damaged mucosal tissue.

Different mucoadhesive systems that use various bioadhesive polymers are known from the prior art. For example US patent No. 5458879 teaches solid dissolvable oral pharmaceutical mucoadhesive compositions which comprise water soluble mucoadhesive polymer selected from the group consisting of oly(ethylene oxide), polyethylene glycol, poly (vinyl alcohol), polyvinyl pyrrolidine., poly(acrilic acid), polyhydroxyethyl methacrylates., hydroxyethyl cellulose and hitosan.

Patent No.US 5976573 discloses an aqueous pharmaceutical composition which is capable of being sprayed into the nasal cavity of an individual, which is odorless, propellant-free and has a pH about 4.5 to 7.5 and which comprises about 85 wt % of water, about 0.001 to 2 wt % solid particles of medicament, about 1 to 5 wt % suspending agent a mixture of microcrystaline cellulose and carboxymethyl cellulose, the viscosity of the composition in unsheared form is 400 to 800 cp, and 0.02 wt % of antimicrobial agent and 0.01 to 0.5 wt % chelating agent- disodium ethylenediamine tetraacetate.

Patent US 5472704 describes a controlled release mucoadhesive pharmaceutical composition containing core particles with at least one pharmaceutically active ingredient and mucoadhesive polymer as hydroxypropylmethylcelluloses, hydroxypropylcelluloses in weight ratio from about 5 ; 1 to 1 : 10.

US 6 319 513 discloses oral liquid mucoadhesive compositions comprising 2% to 50% by weight of colloidal partials of titanium dioxide, silica, clay and mixture thereof and effective amount of pharmaceutical active compound, wherein the composition has a sedimentation volume ratio of greater then about 0.90 when measured after about 48 hours an the triggered viscosity ratio of the composition is at least about 1.2. A mucoretentive intranasal spray decongestant is consisting of the following components in wt. % : magnesium aluminium silicate type D , colloidal fumed silica, (Carbosil M5), titanium dioxide, tyloxapol, dibasic sodium phosphate, monobasic potassium phosphate, xantan gum, benzalkonium chloride, chlorexidine gluconate, disodium EDTA. The liquid compositions of this document can be administered intranasaly, per oral as a liquid or sprayed into the oral cavity or sprayed on the back of the throat, or they can be filled in soft gelatine capsules. The intranasal composition is applied to the nasal mucosa via topical application .

Disclosure of the invention

The present invention relates to a liquid mucoadhesive pharmaceutical composition comprising a pharmaceutically active ingredient, mucoadhesive compound, preservative and chelating agent and buffer system. The pharmaceutical composition is capable of being sprayed into the nasal cavity and is providing a good contact of the active ingredient with the mucosa. This composition is ensuring an enhanced diffusion, absorption and a good retainability. It can be adapted to oral, ocular, rectal, vaginal, nasal or periodontal administrations.

The liquid pharmaceutical composition according to the invention is characterized in that it comprises xylomethazoline.HCl about 0.10 wt.% to 10.00 wt.%, hydroxypropyl methycellulose from 0.01 wt,% to 10 wt.%, disodium ethylenediamine tetraacetate from 0.01 wt.% to 10.00 wt.%, phosphate buffer to 100 wt. % with pH about 5 to 7, the relative viscosity of the solution is about 70.00 to 90.00, and the relative adhesive capacity is 105.0% to 120.0% The liquid φucoadhesive pharmaceutical, composition according to the invention is characterized in that as pharmaceutically active substance can be used xylometazoline hydrochloride or metoclopramide hydrochloride in amount of 0.01 wt.% up to 10.00 wt.%, preferably from 0.01 wt% to 5.00 wt.%.

Furthermore the composition contains effective amount of mucoadhesive compound selected from the group consisting of cellulose derivatives as hydroxypropyl methyl cellulose, sodium carboxy-methyl cellulose or polyoxyalkylene block copolymer from about 0.01 wt.% to 10.00 wt.%. As preservative and chelating agent in the composition is used ethylenediamine tetraacetic acid (EDTA) disodium salt from 0.01 wt.% to 5.00 wt.%, preferably from 0.01 wt.% to 1.00 wt.%.

The liquid pharmaceutical composition can contain xylometazoline hydrochloride from 0.01 w.% to 0.50 w.%, hydroxypropyl methyl cellulose from 0.01 w.% to 10.00 w.% and EDTA disodium salt from about 0.01 wt.% to 10.00 wt.%, phosphate buffer with pH 5-7 to 100 w.%, NaCl from 0.10 to 0.90 wt.%, the relative viscosity of the solution is from 50.00 to 500.00, and the relative adhesive capacity is from 105.0% to 120.0%.

The liquid pharmaceutical composition can contain metoclopramide hydrochloride from 0.01 wt.% to 0.50 wt.%, hydroxypropyl methyl cellulose from 0,01 w.% to 10.00 w.% and EDTA disodium salt from 0.01 wt.% to 10.00 wt.%, phosphate buffer with pH 5-7 to 100 wt.%, NaCl from 0.10 to 0.90 wt.%, the relative viscosity of the solution is from 50.00 to 500.00, and the relative adhesive capacity is from 105.0% to 120.0%.

The liquid mucoadhesive composition according to the invention contains effective amount of mucoadhesive substance selected from the group of : hitosan; anionic- active polymers from the groups of xantans, gelans, alginates, hialuronic acid, carboxymβthyl cellulose, block copolymers, from the group of copolymers of poloxamines, poloxameres and poly(lactide) polyoxyethylene; cellulose derivatives: methylcellulose, ethylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose; derivatives of polyethylene oxide with different molecular weight, natural resins: acacia, agar-agar, clay , tragacanth, guar.

The concentration of the mucoadhesive substance is from about 0.01 to about 20 %, preferably from about 0.1% to about 10.00%.

The liquid mucoadhesive composition can contain therapeutically effective amount of a pharmacological active from the groups consisting of analgesics, decongestants, expectorants, antitussive, antihistamine, bronchodilators, topical anesthetics, oral care agents, topical corticosteroids, substances acting on the central nervous system, substances acting on the vascular system^ hypothalamic hormones;, immune modulators, vaccines, antiemetics and sϊbεføwes th &of.

The composition according to the invention can be applied easily, properly and fast on the mucosa. because it has no irritating effect. The used mucoadhesive substance allows optimal contact with the mucus and provides easy diffusion of the active substance to the site of absorption. The composition provides an improved bioavailability and optimal rheological properties, fast diffusion on the treated layer and has excellent mucoadhesive qualities. This is demonstrated by the in vitro and in vivo studies.

The therapeutic advantages of the mucoadhesive system according to the invention are as

The liquid mucoadhesive pharmaceutical composition gives the opportunity for easy dosase. and imnroved bioavailabilitv (because of the nrolonsed time for absorotion on the treated mucous laver) and comfort- because of the decreasing of the number of aoolications.

The liquid mucoadhesive pharmaceutical composition assures long local effect of medicinal substances for local application, because of its prolonged stay on the nasal mucosa.

The liquid mucoadhesive pharmaceutical composition has low viscosity and high adhesivit .

The low viscositv allows snravine under nressure with dosins mechanical numn.

The liquid mucoadhesive pharmaceutical composition does not render the breathing difficult and it is well tolerated.

The liquid mucoadhesive pharmaceutical composition has a prolonged contact to a mucosal surface compared to the regular non mucoadhesive solutions and in this manner a better therapeutic effect is achieved at lower doses.

Abbreviations:

HPMC- hydroxy propyl methyl cellulose

NaCMC- carboxymethyl cellulose sodium salt

Poloxamer 407 - polyoxyethylene - polyoxypropylene block copolymer

EDTA disodium salt - ethylenediamine tetraacetic acid disodium salt

NaCl- sodium chloride

Ph. Eur. - European Pharmacopoeia

USP - United States PharmacoD _* oeia

TS - test solution RS -reference solution NAP* - nasal sir resistance NAR _TS - nasal-air resistance after application of the test solution NARog -nasal -air resistance after application of the reference solution T- time (min) SD - standard deviation

The invention was illustrated with the following examples: EXAMPLE 1. Mucoadhesive comoosition of solution A

Method of preparation of the solution

The solution of the invention was prepared by heating 98.75 weight parts (wt.p.) of nhosnhate buffer nH 6.6 at 50°C. Then 0.75 wt nart of hvdronroxvmethvl cellulose was added to 0.50 wt.parts EDTA disodium salt. The obtained mixture was added in small portions to the buffer with continuous stirring with electromagnetic stirrer at about 1000 r/min. The stirring continues for 10 min. Then the mixture was cooled to 20°C and the stirring continues for additional 3 h. The reaction mixture is allowed for 24 hours at temnerature 18-20°C. and then is stirred for another 2 hours at 1000 r/min. The bubbles are removed with stirring (500 r/min.) under lowered nressure.

The analysis of the prepared solution shows the following data:

Relative viscosity (η _rs! = 80.11 ± SD 0.61), internal viscosity (η ^ = 422.41 ± SD 0.98 ml/g), relative adhesive caoacitv 113.8 ±6.3%. measured at 20°C.

Mucoadhesive composition of solution B

Method of nrenaration

98.9 wt. parts of phosphate buffer pH 6.6 was heated to 40°C. Then 0.60 wt. parts of Na CMC was added to 0.50 wt.parts EDTA-disodium salt. The obtained mixture was added in small nortions to the buffer solution at stirring with an electromaenetic stirrer (1000 r/min.). The mixture was stirred for additional 3 h. Then the mixture was allowed to cool to room temperature 18-20°C over 24 h and then mixture was stirred at 1000 r/min. over additional 2 h at the same temperature. The bubbles were removed with stirring (500 r/min.) under lowered pressure (vacuum).

The solution has relative viscosity (η _∞ι= 53.71 ± SD 0.43). internal viscosity (η ₁^ = 3703.30 ± SD 9.11 ml/g), relative adhesive capacity 111.6 ± +2.2%, measured at 20°C.

Mucoadhesive composition - solution C.

Method of preparation

Solution of 98.5 wt. parts of phosphate buffer with pH 6.6 was heated at 40°C.

0.50 wt. narts of EDTA disodium salt was added at stirrine with an electromaenetic stirrer (1000 r/min.). The mixture was stirred for 1 h at 40°C. then cooled to 10°C. Poloxamer 407 (0.60 wt.narts) was added in small nortions at continuous stirring (1000 r/min.) . The mixture was stirred for additional 3 h. The obtained solution was allowed to cool to 18-20°C over 24h and after that was stirred again (1000 r/min.) at 20°C for additional 2 h . The bubbles were removed with stirring (500 r/min.) under lowered pressure (vacuum).

The solution has relative viscositv

12.49 ± SD 0.67 ml/s\ relative adhesive caoacitv 118.2 ± SD 3.1%. measured at 20°C.

EXAMPLE 2

Composition of mucoadhesive solution based on mucoadhesive carrier, described in examnle 1 which contains xylomethazoline hvdrochloride as an active substance.

Method of preparation

To 98.27 wt.parts of phosphate buffer with pH 6.6 and temperature 20°C was added 0.38 wt. parts NaCl and stirred with electromagnetic stirrer (1000 r/min.) over 10 min. Then the solution was heated to 50°C. A mixture of 0.75 wt. parts HPMC and 0.50 wt. parts EDTA- disodium salt was added to the buffer solution in portions and continuously was stirred at 1000 r/min. Then the stirring continued for 10 min. at 50°C and than at gradually cooling to 20°C for another 3 h. The obtained solution was allowed at temperature 18-20°C for 24 h and then was stirred at 1000 r/min. for 2 h. The bubbles are removed with mixing (500 r/min.) under lowered pressure.

EXAMPLE 3

Composition of mucoadhesive solution based on mucoadhesive carrier, described in examnle IB, which contains xvlomethazoline hvdrochloride as an active substance.

Method of preparation

To 98.45 wt. parts of phosphate buffer with pH 6.6 was added 0.38 wt. parts of NaCl at temperature 20°C and was stirred with electromagnetic stirrer (1000 r/min.) for 10 min. The obtained solution was heated to 40°C. Then 0.60 wt. narts NaCMC was mixed with 0.50 wt. parts EDTA disodium salt and was added in small portions to the buffer at continuous stirring with an electromagnetic stirrer (1000 r/min) for 3 h. Then the solution was allowed for 24 h. at temperature 18-20°C and then was stirred at 1000 r/min. for 2 h.

The bubbles were removed with stirring (500 r/min.) under lowered pressure.

EXAMPLE 4

Composition of mucoadhesive solution based on mucoadhesive carrier, described in examole lC. which contains xvlomethazoline hvdrochloride as an active substance.

Method of preparation

To 98.02 wt. parts of phosphate buffer with pH 6.6 was added 0.50 wt. parts of EDTA- disodium salt and the mixture was stirred (1000 r/min.) at temnerature 40°C. The mixture was stirred over 1 h. and then was allowed to cool to 10°C. To the obtained solution 0.38 wt. parts of NaCl was added and was stirred continuously (1000 r.p.m.) over 10 min. Poioxamer 407(0.60 wt. parts) was added in small portions. The mixing continues for 3 h. and then the obtained solution was allowed for 24 h. at temnerature 18-20°C. Then the mixture was stirred again (500 r/min.) under lowered nressure.

EXAMPLE 5

Composition of mucoadhesive medicinal solution based on mucoadhesive carrier, described in example 1 A. which contains metoclopramide hvdrochloride as an active substance.

Method of preparation. To 95.00 wt parts of the solution obtained according to example 1 A 5.00 wt. parts of metoclonramide hvdrochloride was added and the mixture was stirred with electromagnetic stirrer (1000 r/min for 2 h at temnerature 20°C.

EXAMPLE 6

Composition of mucoadhesive medicinal solution based on mucoadhesive carrier, described in examnle IB. which contains metoclopramide hydrochloride as an active substance.

Method of preparation

To 95.00 wt. parts of the solution obtained according to example IB 5.00 wt. parts of metoclonramide hydrochloride was added and the mixture was stirred with electromagnetic stirrer (1000 r/min) for 2 h at temperature 20°C.

EXAMPLE 7

Composition of mucoadhesive medicinal solution based on mucoadhesive carrier, described in example 1 C, which contains metoclonramide hydrochloride as an active substance.

Method of preparation

To 95.00 wt. parts of the solution obtained according to example 1C 5.00 wt. parts of metoclopramide hydrochloride was added and the mixture was stirred with electromagnetic stirrer (1000 r/min for 2 h at temnerature 20°C.

EXAMPLE 8. Method for examination of the relative adhesive capacity of noly er solutions The used method for the adhesive capacity studying was based on the tensional principle and is using a microbalance.

The use of microbalances for testing the adhesiveness of polymers is known (e.g. Smart and Kellaway method) but is based on another model, with which can be examined solid adhesives and els, excluding solutions.

1. Experimental set-up

The experimental set-up is shown on fig 1. The polymer solution, which is going to be tested, is placed into a glass vial of 15 ml. The glass plate is covered with gelatin film as a reference polymer, imitating the mucus. According to it the polymer solutions are tested for adhesion. The plate, (18x18 mm), is suspended from a microforce balance (WAGA T RS.T.TNA-WT, Techniport. Poland). Using screw 1, the plate is immersed in the 15 ml glass vial filled with the examined solution. After the defined time for contact (5 min), the late is raised gradually, using screw 1. The force required for detachment of the plate from the solution is registered. Tt is related to the adhesive force between the polymer and the mucus. As a standard the clean plate is tested before and after coating with the polymer. The force for detachment of the coated plate is expressed as a percentage of the clean plate detachment force, i.e. the results have relative values. (Fig.2).

2. Preparing the polymer film on the glass late

The film was prepared by dropping 0.5 ml 1% solution of gelatin and spreading it onto the whole plate surface. After a 24h period (at 20-22°C), necessary for a smooth film forming, on a leveled surface the film was oven-dried at 40°C to a constant weight. The films obtained were uniform and exhibited a good reproducibility in the weight (sd<5%).

3. Experimental conditions

The tests were carried out at 20°C. 25°C. 30°C and 37°C: contact time 5 min and means weight of the films 5.10 mg. SD ±0.04. All the test solutions are with pH 6.6 (phosphate buffer. USP).

All the mucoadhesive solutions were tested initially for adhesive capacity and viscosity at 20°C, 25°C, 30°C and 37°C. After that they were cooled from 37°C to 20°C. The values of the adhesion and the viscosity have to be similar to the results from the primary testing at 20°C. This gives the right to consider that the change of the adhesivity and of the viscosity of these solutions at higher temperatures is a result of the increased molecular flexibility ( i.e. the ability of the molecules to coil in the space and to place the most convenient position), and not a result of the molecule decomposition. This fact is imnortant. as in the nasal cavitv conditions - temperature from 32-36°C (especially 33-34°C), the polymer systems will obtain higher flexibility and thus increased Denetration trouεh the mucus resultine to better adhesivitv Fie. 3-6; table 1-6}.

EXAMPLE 9

Using of EDTA-disodium salt as single preservative for liquid medicinal forms for local

It is used a mucoadhesive solution, which contains 0.50 % (wt/wt) EDTA-disodium salt as a preservative.

1. Microbial strains

Fresh made suspensions of the strains Staphylococcus Aureus, Pseudomonas Aeru inosa, Escerichia Coli, Asper illus Niger and Candida Albicans (in accordance to the requirements of Ph.Eur. and USP for pharmaceutical formulations for topical application) were standardized as per 1 x 10⁸ cells/ml (100000000 in ml) using turbidimetric standard.

2. Dilutions

Specified quantities of the standardized suspensions are added to the original packages of model solutions in order to obtain the USP-specified dilution 200 times of the contaminating microorganisms.

The so obtained solutions are stored nrotected from lieht at 25°C.

The solutions are in accordance to the Pharmacopeial requirements for effective conservation. (Fig. 7)

EXAMPLE 10. Test assav in vivo

Study of the eye irritation effect of the mucoadhesive solution as per EU - EPA.The studv has been made on 8 "Chinchilla" rabbits weiehtine from 3.000 -to 3.500 ke. raised in standard conditions. In the conjunctival sac of the right eye is dropped dose of the mucoadhesive solution equal to 30 mg metoclopramide. After 24 h. both eyes were treated with fluorescin sodium solution. The rabbits were monitored every day for 7 days, and the results were recorded in a score scale in accordance to the EU - EPA rating system for observation of the eye irritating effect for single application of chemical agents and the eventual changes in the cornea, iris, and conjunctiva were also studied.

Based on the classification of the chemical aeents irritatine the eves as ner EU — EPA. metoclonramide nasal solution belones to 1 class, which includes insienificant or missine eve irritation effect. In the oresent studv there is no irritatine effect, no coloring of the cornea with fluorescine . The insignificant change in the conjunctiva (class 1) was eliminated within 24 h. The iris was normal and no change was observed.

EXAMPLE 11

Clinical test of mucoadhesive solution, containing xylomethazoiine hydrochloride 0.1% The solution described in Example 2 is used.

1. Subiects

Twenty subjects (7 men and 13 women aged between 18 and 69 years, 5 atonic, 3 current smokers) from among the outpatients of the Clinical Center of Allergology of the Medical University in Sofia diaenosed with allereic rhinitis eave informed consent to volunteer for the studv. Thev all indicated nasal coneestion to be their main svmntom. The obiective examination excluded the nresence of nasal nolvns. sentu deviations or anv other oreanic conditions, which could interfere with the results of the study.

2. Study design

Upon inclusion in the study each subject was randomly assigned to receive either TS or RS for a period of 5 davs. After a 7-davs wash-out period the alternative preparation was eiven. On the first and fifth days of each period we measured the nasal airflow resistance (NAR) before application (T₀) and at 15, 30 and 60 min. intervals until the 6^th hour (T₁₅, T₃₀, T₆₀, T₉₀, T₁₂₀, Tι»n. To,m and T-»«Λ. At all time noints the main svmntoms (coneestion. rhinorrhoea. itchine and sneezine were recorded usine a 6-erade scorine scale from 1 (no svmntom} to 6 (full-blown exnressionY Subiects were instructed to annlv both solutions on "as needed" basis, but no more than 6 times daily and to fill in the diaries the number of applications and drops, along with their daily symptom scores. Side effects were spontaneously reported by patients or specifically asked for by the investigators at day 5 of both treatment periods.

3. Equipment

A rhinomanometer Rhinoscreen /Jaeεer/ was used to measure nasal airflow resistance (NARY NAR was exnressed as Pa/l/s. TS and RS were kent in identically lookine coded bottles. The annlication ninettes were calibrated and marked to annlv identical volumes from the solutions. 4. Statistical analysis

Comparison between the continuous variables for each nrenaration nresented as mean +/- SEM were done using paired Student* s t-test and Manova. Wilcoxon's Signed Ranks Test was used to compare the incidence of side effects with both preparations. Correlation between objective and subjective measurements were performed using Pearson's correlation coefficient. A two-tailed level of significance of p < 0.05 was accepted.

5.1. Nasal rhinomanometry

The data obtained from TS and RS are compared in fie. 8 and fie. 9. The results are expressed as NARn-NAR; vs time and demonstrate sienificant decrease in resistance with peak between Tj* to TQΛ and slow return to base levels (NARn). However. TS provides stroneer and longer lasting effect: after a mean of 258 minutes NAR of RS reaches baseline (0) and further increases (NARn - AR^ = - 0.16 Pa/l/min}. while it still remains above 0 after 360 minutes (the end-point of the measurements) of TS. The area under the resistance/time curve (AUC) is 558.0 ± 89.7 sαuare units for TS and 156.9 ± 104.7 sαuare units for the RS ⁽n < 0.001}.

The values of NAR on both treatment arms were compared on days 0 and 5 of treatment (Fig. 10). The measurements were carried out in the morning prior to the application of any medication. On day 0 there was no significant difference between the solutions, while on day 5 on TS the initial mornine NAR was bv 34.2% than on dav 1 (n < 0.005}. while RS showed slisht increase.

3.2. Subjective measures

Discomfort due to nasal svmnto s and snecificallv the duration of the effect of the applied preparation appeared to be quite individual and did not correlate with the objective measurement of NAR. Still, patients gave definite preference to TS.

3.2.1. Nasal coneestion

Nasal coneestion was the main svmntom botherine patients in correspondence with their initial selection and was significantly reduced on day 5 of treatment with TS, compared to RS: the mean difference (TS-TR) between the treatment arms was (-1.12±0.59).

,3,2,2, Duration of effect

Desnite of the individual variations the subiects recorded in their diaries a sienificantlv longer effect of TS (4.88 + 0.12 h) versus RS (2.52 ± 0.08 h) solution.

3.2.3. Need for medication Patients applied less often TS (2 87 + 0.22 times per day) than RS (3.97 ± 0.25 times per day. p < 0.05.

3 24. Symptom scores for the other nasal symptoms

The effect of both solutions on rhinorrhoea. itchine and sneezine was similar and rather inconspicuous.

3 5. Side effects The main side effects snontaneouslv reported bv the subiects can be summarized in table 7. No changes in the pulse rate and blood pressure values were detected with any of the medications.

Claims

C ATMS

1. Liαuid mucoadhesive pharmaceutical composition, characterized in that it contains oharmaceuticallv active substance from 0.01 UP to 10.00 wt.%. mucoadhesive substance from 0.1 up to 10.0 wt.%. preservative from 0.01 up to 5.00 wt.%. sodium chloride from 0.1 up to 0.9 wt.%. and buffer system with pH 5-7 up to 100 wt.%, the relative viscosity of the solution is from 5.00 uo to 500.00 and relative adhesive canacitv is 105.0% UP to 120.0%

2. Liquid mucoadhesive composition according to claim 1. characterized in that the oharmaceuticallv active substance is xylomethazoiine hvdrochloride from 0.01 UP to 0.5 wt.%. the mucoadhesive substance is hvdroxvnropvl methvlcellulose from 0.01 un to 10.00 wt.%. the buffer svstem is nhosnhate buffer with nH about 5-7 and uo to 100.00 wt. %. the preservative is disodium salt of ethylenediamine tetraacetic acid from 0.01 uo to 5.00 wt.%. and contains also sodium chloride from 0.10 un to 0.90 wt.%. the relative viscositv is from 50.00 un to 500.00. and the relative adhesive canacitv is from 105.0% uo to 120.0%.

3. Liquid mucoadhesive composition, as per claim 1, characterized in that it contains xvlomethazoline hvdrochloride from 0.01 to 0.50 wt.%. mucoadhesive substance sodium carboxvmethvl cellulose from 0.01 to 10.00 wt.%. buffer svstem-ohosohate buffer UP to 100.00 wt.% with nH 5-7. nreservative a disodium salt of EDTA from 0 01 to 5.00 wt.%. sodium chloride from 0.10 to 0.90 wt.%: the solution relative viscositv is from 5.00 to 500.00 and relative adhesive canacitv 105.0% to 120.0%.

4. Liαuid mucoadhesive composition accordine to claim 1. characterized in that it contains xylomethazoiine hydrochloride from 0.01 to 0.50 wt.%, mucoadhesive substance polvoxvalkvlene block cooolvmer from 0.01 to 10.00 wt.%. buffer svstem ohosohate buffer UP to 100.00 wt.% with oH 5-7. preservative disodium salt of EDTA from 0.01 to 5.00 wt.%. sodium chloride from 0.10 to 0.90 wt.%: the solution relative viscosity is from 1.00 to 50.00 and relative adhesive capacity 105.0% to 120.0%.

5. Liquid mucoadhesive composition accordine to claim 1 , characterized in that it contains metoclopramide hydrochloride from 0.50 to 5.00 wt.%. mucoadhesive substance hydroxypropyl methylcellulose from 0.01 to 10.00 wt.%, the buffer system is phosphate buffer up to 100.00 wt.% with pH 5-7, preservative disodium salt of EDTA from 0.01 to 5.00 wt.%, sodium chloride from 0.10 to 0.90 wt.%; the solution relative viscosity is from 5.00 to 500.00 and relative adhesive canacitv 105.0% to 120.0%.

6. Liquid mucoadhesive composition, according to claim 1, characterized in that it contains metoclonramide hvdrochloride from 0.50 to 5.00 wt.%. mucoadhesive substance sodium carboxvmethvl cellulose from 0.01 to 10.00 wt.%. buffer svstem ohosnhate buffer un to 100.00 wt.% with pH 5-7, preservative disodium salt of EDTA from 0.01 to 5.00 wt.%, sodium chloride from 0.10 to 0.90 wt.%: the solution relative viscosity is from 5.00 to 500.00 and relative adhesive capacity about 105.0% to 120.0%.

7. Liαuid mucoadhesive composition accordine to claim 1. characterized in that it contains metoclopramide hydrochloride from 0.50 to 5.00 wt.%, mucoadhesive substance polvoxvalkvlene block conolvmer about 0.01 to 10.00 wt.%. buffer svstem - phosphate buffer UP to 100.00 wt.% with oH 5-7. preservative disodium salt of EDTA about 0.01 to 5.00 wt.%. sodium chloride from 0.10 to 0.90 wt.%: the solution relative viscosity is from 1.00 to 50.00 and relative adhesive canacitv 105.0% to 120.0%.