Stabilized and conserved eye compositions containing ketotifen

FIELD: ophthalmology.

SUBSTANCE: main composition contains: (a) ketotifen fumarate to the concentration in calculation to free ketotifen from approx. 0.01 mas. % to approx. 0.1 mas.%;(b) source of hydrogen peroxide ensuring presence of hydrogen peroxide with trace quantities amounting from approximately 0.001 to approximately 0.1% (mas./vol.); (c) one or several stabilizers of hydrogen peroxide compatible with eyes; (d) hypromellose to the concentration from approximately 0.005 mas% to approximately 0.5 mas.%; and (e) sodium carboxymethyl cellulose to the concentration from approx. 0.005 mas.% to approx 0.5 mas.%. At this the value of composition pH amounts to approximately from 4.0 to 5.3.

EFFECT: invention is a method of treatment and prevention of allergic conjunctivitis which is ensured with application locally in the effective quantity of the mentioned eye composition to person with allergic conjunctivitis or sensitive to it.

13 cl, 15 tbl, 4 ex

 

Background of invention

The present invention relates to ophthalmic compositions that contain ketotifen as a pharmaceutically active agent (pharmaceutical active substance), the source of hydrogen peroxide as preservative and agents that increase the specific viscosity, intended for use in the treatment of allergic conjunctivitis. In the U.S. 5725887 (hereinafter designated as patent '887) and 5607698, and in application serial number 11/078209, specifically fully incorporated into the present description by reference, are described and claimed methods of preservation of ophthalmic solutions using either a stabilizing hydrogen peroxide individually, or in combination with increasing viscosity agents, hypromellose (HPMC) and carboxymethylcellulose (CMC), and preserved in this way the composition. However, hydrogen peroxide is a strong oxidant. Many chemical and pharmaceutical substance not compatible with hydrogen peroxide, i.e. they are sensitive to chemical oxidation by hydrogen peroxide. Ketotifen is a pharmaceutically active agent sensitive to chemical oxidation. Stable compositions containing ketotifen, which include hydrogen peroxide as a preservative, can be obtained by preparation of compositions at acidic EIT is aniah pH, for example, at pH values from 3.5 to 6.0, as described in the application in the name of F. Tsao, M. Wong, and S. Yen, registered on the same day as the present application. However, the application of the eye above the stable compositions containing ketotifen, especially compositions with high concentrations of ketotifen, for example, containing 0.05% ketotifen, may cause a burning feeling in the eye. When creating the present invention, it was found that the comfort for the eyes when applying such stable compositions prepared using high concentrations of ketotifen and HPMC, can be improved by adding CMC. In addition, it was found that it is possible to improve the bioavailability of stable compositions containing ketotifen by adding HPMC individually or in combination with CMC, thus obtaining stable comfort compositions containing ketotifen, which have significant clinical efficacy can be maintained for at least 16 hours

Summary of the invention

One of the objects of the present invention is an ophthalmic composition, which contains:

(a) ketotifen salt;

(b) a source of hydrogen peroxide, the presence of hydrogen peroxide in trace quantities, comprising from about 0.001 to about 0.1% (wt./vol.);

(C) one or a few is to be compatible with the eye of the stabilizers of hydrogen peroxide;

(g) hypromellose; and

(d) carboxymethylcellulose sodium, where the composition has a pH value sufficient to stabilize the ketotifen salt from oxidation by hydrogen peroxide.

Another object of the invention is a method for the treatment and prevention of allergic conjunctivitis, which is that the individual suffering from allergic conjunctivitis or sensitive to it, introducing an effective amount of the ophthalmic composition, which contains:

(a) ketotifen salt;

(b) a source of hydrogen peroxide, the presence of hydrogen peroxide in trace quantities, comprising from about 0.001 to about 0.1% (wt./vol.);

(C) one or more compatible with the eye of the stabilizers of hydrogen peroxide;

(g) hypromellose; and

(d) carboxymethylcellulose, where the composition has a pH value sufficient to stabilize the ketotifen salt from oxidation by hydrogen peroxide.

Detailed description of the invention

The present invention relates to a stable ophthalmic compositions that contain ketotifen salt, a source of hydrogen peroxide, the presence of hydrogen peroxide in trace quantities, comprising from about 0.001 to about 0.1% (wt./vol.); one or more compatible with the eye of the stabilizers of hydrogen peroxide HPMC and CMC. The composition is prepared so that it had a pH value sufficient to stabilize the ketotifen salt from oxidation by hydrogen peroxide, for example, a pH value of about 3.5 to about 6,0. It is known that the acid form of ketotifen is more stable than the neutral form of ketotifen. The inclusion of CMC in containing HPMC ketotifeno compositions prepared in such a way that they have a pH stabilizing ketotifen from oxidation by hydrogen peroxide, increases a comfortable feeling in the eye after the introduction of the stabilized compositions. Stabilized compositions containing ketotifen, which include how HPMC and CMC, are also characterized by a distribution coefficient, which is approximately three times greater than the distribution coefficient of compositions containing ketotifen/hydrogen peroxide, which include glycerine (see examples 1 and 3), this suggests that adding HPMC and CMC in such compositions may also increase the penetrating ability of the medicine and biological availability of medicines. The fact that the inclusion of HPMC and CMC in the stabilized compositions containing ketotifen may increase the penetrating ability of the medicine and biological availability of medicines is also confirmed by R the results of clinical trials, presented in the present description, which demonstrate that such compositions are effective in the treatment and prevention of allergic conjunctivitis and have a long action, characterized by a clinically significant reduction in itching that persists for a period of time up to 16 h after the dose (see example 4). Considering the clinical effectiveness, persisting for at least 16 h, the ophthalmic composition proposed in the present invention, it is possible to enter once a day.

The ketotifen salt is, for example ketotifen hydrochloride, ketotifen hydrogen bromide, ketotifen, pamoate, ketotifen maleate, sulfate and ketotifen ketotifen fumarate. The preferred salt ketotifen is ketotifen fumarate. The salt concentration of ketotifen in terms of ketotifen, typically ranges from about 0.01 to about 0.1% (wt./about.) and preferably from about 0.02 to about 0.06 percent (wt./vol.).

As a preservative for ophthalmic compositions proposed in the invention can be applied to trace amounts of peroxide compounds, stabilized with a stabilizer of hydrogen peroxide, primarily diethylenetriaminepenta(methylenephosphonic acid) or 1-hydroxyethylidene-1,1-diphosphonic acid. The source of hydrogen peroxide can serve as l is the battle of peroxide compound, which hydrolyses in water to form hydrogen peroxide. Examples of sources of hydrogen peroxide, which provide efficient, the resulting amount of hydrogen peroxide, are perborate sodium tetrahydrate sodium perborate, sodium peroxide and urea peroxide. It was found that peracetic acid, an organic peroxide compound, cannot be stabilized using the proposed in the present invention system.

The source of hydrogen peroxide is present in a quantity sufficient for the formation of hydrogen peroxide in a concentration of from about 0.001 to about 0.1% (wt./vol.), preferably from about 0.001 to about 0.01 percent (wt./vol.). For example, such a source of hydrogen peroxide, as the tetrahydrate sodium perborate may be present in an amount of from about 0.005-about 0.5% (wt./vol.).

In the context of the present description, the term "stabilizer of hydrogen peroxide" refers to any known stabilizer, peroxide compounds, including phosphonates, phosphates, stannate, etc. Can be used as the physiologically compatible salts of phosphonic acids, such as diethylenetriaminepenta(methylenephosphonate acid) and its physiologically compatible salts and 1-hydroxyethylene-1,1-diphosphonic acid and its physiologically acceptable salts. Other stabilizers peroxy the data connection, you can apply for the implementation in practice of the present invention described in the patent '887, among other things, starting with column 5, line 55 to column 6, line 34.

The above stabilizers can be used in almost all previously mentioned the indications for which it is possible to apply the invention. However, in the case when the solution comes into contact with the soft hydrogel contact lenses, you should avoid stabilizers containing stannate, as they tend to "blur" the material of the lens.

When the peroxide stabilizer is diethylenetriaminepenta(methylenephosphonic acid), it may be present in the ophthalmic compositions in amounts of from approximately 0.001 to approximately 0.02% (wt./vol.), or in the amount of from about 0.002 to about 0,012% (wt./vol.).

When the peroxide stabilizer is a 1-hydroxyethylene-1,1-diphosphonic acid, it may be present in the ophthalmic compositions in amounts of from about 0.002 to about 0.2 percent (wt./about.) in terms of the volume of the composition.

Stabilizers other than diethylenetriaminepenta(methylenephosphonic acid) (available for sale from the company Monsanto Company, St. Louis, stricture, under the trademark DEQUEST 2060) and its physiologically compatible salts and 1-hydroxyethylene-1,1-diphosphonic acid and its physiologically the ski acceptable salts, used in physiologically-tolerated amounts.

Soluble salts of alkaline-earth metals can be used in the compositions in amounts from about 0.002 to 0.2 percent (wt./about.) in terms of the volume of the composition, or from about 0.01 and 0.1 wt.% in terms of the weight of the composition. Such salts of alkali metals can serve as water-soluble salts of magnesium and calcium. The addition of such soluble salts of alkaline-earth metals increases the antifungal efficacy of preservatives in ophthalmic compositions, canned using small amounts of hydrogen peroxide.

The pH value stable ophthalmic composition proposed in the present invention, is brought to a pH sufficient to stabilize the ketotifen salt from oxidation by hydrogen peroxide, for example, to a pH from about 3.5 to about 6,0. Preferably the pH value of the ophthalmic composition is from about 3.8 to about 5.5, and more preferably from about 4.0 to about 5,3. For example, the pH value of the ophthalmic composition may range from 3.5 to 6.0, preferably from 3.8 to 5.5, and more preferably from 4.0 to 5.3. If necessary, the pH value can be adjusted by inclusion in acceptable quantities of acids or bases, which are physiologically tolerated in the applicable amounts, for example, hydrochloric key is lots and sodium hydroxide.

In ophthalmic compositions proposed in the present invention may have one or more common practically inert physiologically acceptable agents that increase toychest. As such agents can be applied, for example, mannitol, sorbitol, glycerol, halides of alkali metals, phosphates, biphosphate and borates. Preferred are sodium chloride, monopotassium phosphate, sodium secondary acidic sodium phosphate. The function of such increase toychest agents is to provide approximately physiological level of toychest composition, which is instilled into the eye, or to facilitate such toychest after dilution, if before contact with the eye should be breeding because of the presence of the above peroxide.

Preferably in solution are present in sufficient quantities providing toychest agents, so that it is almost isotonic, this means that after the decomposition or dissolution of the presence of the hydrogen peroxide formed composition is almost isotonic, for example, almost equivalent toychest aqueous 0.9 wt.%-the resultant solution of sodium chloride. Preferably the amount of increase toychest agent that is present in the ophthalmic compositions is from the ome 0.01 to about 1% (wt./vol.).

In addition, the ophthalmic composition proposed in the present invention contain both increase the viscosity agent, HPMC and CMC. Suitable for quality (purity) types GPMC are products with factory mark Methocel a, E, F, J and K,manufactured by Dow Chemical, and suitable quality types of CMC are Akucell AF 2781, Aqualon 7H3SXF PH, 7L, 7M, manufactured by companies Akzo Nobel, Aqualon. Concentration GPMC in the compositions proposed in the invention is from about 0.005-about 1%(wt./about.) and preferably ranges from about 0.1 to about 0.5% (wt./vol.). In one of the embodiments of the invention, the concentration of HPMC is from 0.1 to 0.5% (wt./vol.). The CMC concentration in the compositions proposed in the invention is from about 0.005-about 0.5% (wt./about.) and preferably ranges from about 0.05 to about 0.4% (wt./vol.). In one of the preferred embodiments of the invention, the CMC concentration is from 0.05 to 0.4% (wt./vol.). In a particularly preferred variant of the invention, the concentration HPMC and CMC in the composition proposed in the present invention, at 0.3% and 0.10%, respectively.

In one variant of the invention, the ophthalmic composition proposed in the present invention contains:

(a) ketotifen fumarate in a concentration of from about 0,0138 to about was 0.138% (wt./vol.);

<> (b) perborate sodium in a concentration of from about 0.005-about 0.5% (wt./vol.);

(C) diethylenetriaminepenta(methylenephosphonic acid) and its physiological salt in a concentration of from about 0.001 to about 0.02 percent (wt./about.) or 1-hydroxyethylidene-1-diphosphonic acid or its physiological salt in a concentration of from about 0.002 to about 0.2 percent (wt./vol.);

(g) HPMC in a concentration of from about 0.005-about 1% (wt./vol.); and

(d) CMC at a concentration of from about 0.005-about 0.5% (wt./vol.), moreover, the composition has a pH value of about 3.5 to about 6,0.

In a particularly preferred variant of the invention, the ophthalmic composition proposed in the present invention contains:

(a) ketotifen fumarate in concentration 0,069% (wt./vol.);

(b) tetrahydrate sodium perborate concentration 0,028% (wt./vol.);

(C) diethylenetriaminepenta(methylenephosphonic acid) at a concentration of 0,006% (wt./vol.);

(g) HPMC at a concentration of 0.30% (wt./vol.);

(d) CMC at a concentration of 0.10% (wt./vol.); and

(e) NaCl at a concentration of 0.64% (wt./vol.), where the pH value of the composition is from about 4.0 to 5.3. Purified water is added to bring the total volume to 100%.

Eye of the composition proposed in the present invention, are also its very high stability, even under extreme conditions, for example, by heating plants the Directors to 100°C for 24 hours Thus, such compositions have an increased shelf life when stored. In addition, the composition proposed in the present invention, different physiological tolerance after decomposition of hydrogen peroxide.

Another advantage of using hydrogen peroxide in ophthalmic compositions is that the hydrogen peroxide used in trace quantities, primarily in concentrations less than 100 ppm million, split after bringing it in contact with the tissues of the eye. For example, catalase is present in ocular tissue, breaks down hydrogen peroxide to water and oxygen. As a result, the composition after administration becomes free from preservatives, which greatly minimizes adverse reactions. Thereby avoids the problems arising from the use of other preservatives, such as the inability to split harmless compounds.

The composition proposed in the invention can be prepared by any conventional method. For example, all the components other than hydrogen peroxide and water can be placed in a container and add while stirring the freshly prepared, preferably concentrated hydrogen peroxide. Alternatively, anhydrous components can grind with a small portion of liquid stabilizer, then add the OS is asuza part of the stabilizer, then the hydrogen peroxide and most of the water. You can then add other components, such as agents that regulate toychest, or the resulting composition can be added to such agents.

In one embodiment, preparation of the composition in a container containing water, add GPMC, heated and stirred at a temperature of from 80 to 90°C. to obtain a dispersion, and then add CMC and stirred until dissolution. Then a solution containing two polymer sterilized at a temperature of at least 121°C. the Final sterile solution is cooled to room temperature and stirred until dissolution. In a separate container make ketotifen fumarate and sodium chloride and stirred until dissolution. After this, the solution ketotifen fumarata and sodium chloride is sterilized by passing through the filter into the container containing the solution HPMC/CMC, and stirred until dissolution. The mixture is then brought to final volume with sterile water and adjust the pH by adding hydrochloric acid or sodium hydroxide. Specialist in this field should be apparent, numerous variations of the method of preparation of the compositions proposed in the present invention.

Another object of the present invention is a method for the treatment and prevention of allergic conjunctivitis. The way clochette is that the individual is suffering from allergic conjunctivitis or sensitive to it, enter the above ophthalmic composition in an effective amount.

In one embodiment, the implementation of this method, the ophthalmic composition can be injected directly into the eye, preferably in the form of eye drops to treat and reduce itching sensation in the eye, caused by allergic conjunctivitis, and to treat and reduce symptoms or any symptoms of seasonal (spring) allergic conjunctivitis. Dose ophthalmic compositions should depend on the severity of allergic conjunctivitis and the concentration of ketotifen salt in the composition, and it can be easily determined by the person skilled in the art. Typically, when using the compositions proposed in the present invention, once injected from one to ten or one to five or from one to three drops. For example, when applying a ketotifen salt in a high concentration, for example ketotifen fumarata concentration 0,069% (wt./vol.), carried out by the local application of one drop once a day.

In another embodiment, this method ophthalmic compositions can be prepared in a form suitable for use in the composition of the solutions for the care of contact lenses, for example, solutions for wetting, storage, mitigation, treatment, desinfecte the contact lenses and solutions for cosmetic care.

Eye of the composition proposed in the present invention can be packaged in any pharmaceutically acceptable packaging, but preferably, they are Packed into amenable to compression plastic containers containing multiple doses, such as drip dispensers. Such dispensers can be produced, for example, of polyethylene or polypropylene or mixtures thereof. Drip dispenser, as a rule, allows to produce a drop in volume from about 25 to about 50 ml. When it is necessary to "neutralize" peroxide activity, it is sufficient to use any known means, such as washing, bringing into contact with a solution containing platinum, catalase, or any other substance in respect of which it is known that she has the ability to break down hydrogen peroxide. Other physiologically compatible agents, which are able to neutralize the peroxide, are reducing agents such as pyruvic acid and its acceptable salts such as the sodium salt.

The examples below are for illustration purposes and are not intended to limit the scope of the present invention, they demonstrate the stability of ophthalmic compositions stabilized according to the present invention. Unless otherwise stated, all parts are % (wt./vol.).

Example 1

Prigoda ivali preparative forms 1-7 (table 1-7), containing specified in tables ingredients. Each preparative uniform was made in a drip dispenser disguised label and 6-7 patients were entered on two preparative forms by instillation of one drop in each eye. After putting in the human eye was assessed by the level of comfort when using the preparative form 1 (containing HPMC and CMC) and the preparative form 7 (containing only HPMC) using the following scale sensations:

a strong burning sensation, mild burning, uncomfortable, acceptable comfort, comfort. Measured distribution coefficient preparative forms 2-7 in the system n-octanol/water solution by adding in a glass vial with cap eyedropper-equal amounts of octanol and water solution. Then bottle and the solution was intensively shaken for 30 min, then allowed to stand until complete separation of the two layers. Then the pipette was collected aqueous layer and measured the concentration of ketotifen (A), which was compared with the concentration of ketotifen to shaking of the vial (B). The distribution coefficient (D) was calculated by the following formula: D=(B-A)/A.

Example 2

The results of the study described in example 1, to evaluate the level of comfort when using preparative forms 1 and 7 below in table 8.

Table 1
Preparative form 1
Ketotifen fumarate 0,069% (wt./about.)
GPMCof 0.3% (wt./about.)
Dequest 20600,006% (wt./about.)
Perborate sodium0,028% (wt./about.)
CMC (carboxymethylcellulose sodium)0,1% (wt./about.)
Added purified water to the desired volume
Adjusted pH value
4,147
Toychest225 mOsm/kg
Table 2
Preparative form 2
Ketotifen fumarate0,069%
Glycerin2%
Dequest 206060 part./million
Perborate sodium0,028% (wt./about.)
pH4,100
Toychest186 mOsm/kg
The distribution coefficient0,235
Table 3
Preparative form 3
Ketotifen fumarate0,069% (wt./about.)
GPMCof 0.2% (wt./about.)
Dequest 20600,006% (wt./about.)
Perborate sodium0,028% (wt./about.)
Sodium chlorideof 0.5% (wt./about.)
pH4,100
Toychest214 mOsm/kg
The distribution coefficient1,044
Table 4
Preparative form 4
Ketotifen fumarate0,069% (wt./about.)
GPMCof 0.2% (wt./about.)
CMC0,1% (wt./about.)
Dequest 20600,006% (wt./about.)
Perborate sodium0,028% (wt./about.)
Sodium chloride0,62% (wt./about.)
pH 4,042
Toychest
The distribution coefficient
223 mOsm/kg
1,019
Table 5
Preparative form 5
Ketotifen fumarate0,069% (wt./about.)
CMC0,1% (wt./about.)
Dequest 20600,006% (wt./about.)
Perborate sodium0,028% (wt./about.)
Sodium chlorideof 0.6% (wt./about.)
PH4,034
Toychest207 mOsm/kg
The distribution coefficient1,053
Table 6
Preparative form 6
Ketotifen fumarate0,069% (wt./about.)
CMC0,1% (wt./about.)
The dihydrate of calcium chlorideof 0.05% (wt./about.)
The uranyl chlorite is and magnesium of 0.05% (wt./about.)
Dequest 20600,006% (wt./about.)
Perborate sodium0,028% (wt./about.)
Sodium chlorideof 0.5% (wt./about.)
pH4,027
Toychest193 mOsm/kg
The distribution coefficient1,014 registered
Table 7
Preparative form 7
Ketotifen fumarate
GPMC
0,069% (wt./about.)
of 0.3% (wt./about.)
Boric acidof 0.5% (wt./about.)
Potassium chloride0,12% (wt./about.)
Dequest 20600,006% (wt./about.)
Perborate sodium0,028% (wt./about.)
Sodium chloride0,31% (wt./about.)
pH4,058
Toychest212 mOsm/kg
Table 8
The results of the research comfort
Preparative formThe feeling in the eye
7strong burning and uncomfortable feeling
1acceptable comfort

The results presented in table 8 demonstrate that the preparative form 1 containing as HPMC and CMC, after putting in the eye has a higher level of comfort than the preparative form 7, containing only HPMC.

Example 3

The results of the study described in example 1, by definition of the distribution coefficient preparative forms 2-6 are summarized in the following table 9.

Table 9
The results of the study of the distribution coefficient
Preparative formCoeff is consistent with a person's distribution in the system n-octanol/water solution
20,235
31,044
41,019
51,053
61,014 registered

The results presented in table 9, show that the distribution coefficient for preparative forms containing CMC and HPMC is significantly higher.

Example 4

Randomized conducted double-blind method using as a control placebo valuations beginning and duration of a modified formulation Zaditor (ketotifen fumarata 0.05%) compared with the filler on the model-based control infection conjunctival allergen (CAC).

This study compared the efficacy of a single dose of 0.05%ophthalmic solution ketotifen fumarata [formula: 0,069% (wt./about.) ketotifen fumarata, of 0.30% (wt./about.) GPMC, of 0.10% (wt./about.) CMC, 0,028% (wt./about.) tetrahydrate sodium perborate, 0,006% (wt./about.) phosphonic acid - Dequest 2060S, 0,64% (wt./about.) sodium chloride and water; the pH from 4.0 to 5.0] and the corresponding filler - placebo [formula: 0,30% (wt./about.) GPMC, of 0.10% (wt./about.) CMC, 0,028% (wt./about.) perborate tetrahydrate in the rija, 0,006% (wt./about.) phosphonic acid - Dequest 2060S, 0,64% (wt./about.) sodium chloride and water, a pH of from 4.0 to 5.0] in individuals with a history of disease, allergic conjunctivitis, caused by cat hair, cat dander, ragweed pollen and/or trees, using the CAC model after 15 min and 16 h after instillation. The aim was to determine whether ketotifen fumarate in concentration 0,069% (wt./about.) (equivalent to the concentration of free base 0,05%) 15-minute onset of action and a 16-hour duration of action.

A. Method

This study was conducted in a single center double-blind parallel group randomized experience with the use of a placebo control using the control contamination allergen, providing 4 research visits: visit 1 day 0, screening based conjunctival allergic provocative tests (Conjunctival Provocation Test (CPT)], visit 2 (day 7±2, CAC), visit 3 (day 21±3, randomization, after 16 h after control of infection allergen) and visit 4 (day 35±3, 15 min after control of infection the end of the experience). At visit 1 was carried out by the CPT to determine the response of the individual for 1 or more eye allergens. After determining the concentration of allergen that causes a pronounced response was evaluated vos is proizvoditeli response by confirming the control of infection allergen at visit 2. At this time suitable for the study individuals were randomly divided into 4 groups (in the ratio 1:2:2:1), which was treated: of 0.05%ketotifen-fumarate - each eye (OU); 0,05%ketotifen-fumarate - right eye (OD), placebo - left eye (OS); of 0.05%ketotifen-fumarate - OS, placebo - OD; or placebo - OU. At visits 3 and 4 each group were treated with dose, representing 1 eye drop solution, which was administered in each eye. Both visits 3 and 4 was performed after a 2-week period of "cleaning". Control contamination allergen was performed after 16 h after injection of the dose at visit 3 and 15 min after the dose at visit 4.

For selection of 60 of suitable individuals were planning to carry out screening approximately 100 individuals without any serious violations of the Protocol. In total randomization was subjected 54 of the individual and give them the investigational medicinal product at visits 3 and 4 (9, ketotifen OU; 9, placebo OU; 36, ketotifen/placebo). All individuals were evaluated from the standpoint of efficacy and safety.

B. evaluation Criteria

The main variable (criterion) in determining the efficiency was itching in the eye (scale from 0 to 4), which was evaluated at 3, 5 and 7 min after a 16-hour and 15-minute period of time after the control of infection allergen at visits 3 and 4, respectively. W the ranks variables effectiveness was mixed ocular hyperemia (conjunctival, ciliary and episcleral) (same scale from 0 to 4, each vascular bed); chemosis (scale from 0 to 4); mucous secretion (absence or presence); tearing (absence or presence); swelling of the century (scale from 0 to 3) and the total score nasal symptom. Secondary ocular variables was evaluated at 5, 7 and 15 min after a 16-hour and 15-minute period of time after the control of infection allergen.

Nasal symptoms were evaluated at 10, 20 and 30 min after control of infection. For each scale, lower scores corresponded to better condition (less intense).

C. Statistical methods

Analyses of efficacy were performed on prepared to handle" ("intent-to-treat") (ITT) population, which included all distributed randomly into groups of individuals who received at least 1 dose of investigational medicinal product and for which data were obtained about the effectiveness after the initial level. Did not use any methods for the introduction of missing data. When the safety analysis took into account all available data obtained for individuals who received at least 1 dose of investigational medicinal product and for which data were obtained about security after the initial level. Did not plan and did not conduct any interim analysis. Everything statisticheskie criteria were bilateral, and the results was recognized as statistically significant if the corresponding P value was ≤0,050.

In the primary analysis of itching in the eye ophthalmic solution containing 0.05% ketotifen fumarata, compared from the point of view of its superiority to placebo. To summarize the average values and the changes of the average values of points ocular itching compared to the baseline (which was determined on the basis of points after control of infection at visit 2) was used descriptive statistics. In the analysis included the results obtained in the groups in which both eyes of the individuals were treated as equal and different way. Average values by the method of least squares was calculated and analyzed using analysis of variance (ANOVA) using the model including the factor treatment. Got the mean differences between treatments and associated bilateral 95%confidence intervals (CI). Clinically significant differences between treatments were considered differences that constitute at least 1 unit. The percentage of individuals in different groups of processing for which the scores itching was equal to zero (analysis of responders), were compared using Fisher's exact test. For each time point after administration of the dose and after control of infection the implementation of the Lyali all analyses. Methods similar to the methods used for the primary variables of efficiency, was used for all other variables efficiency. For binary variables, such as tearing and mucous, received only percent and evaluation results using Fisher's exact test. The final results of the evaluation of nasal symptoms was obtained considering the fact that they are caused by processing in three variants - treatment active ingredient in both eyes, the processing of the active substance in one eye and placebo treatment in both eyes. A secondary analysis was performed using paired t-test, was an analysis of differences in levels of eye itching, redness, swelling of the century and chemosis in some individuals, which were administered 0.05%ketotifen fumarate in 1 eye and placebo in the second eye.

G. the results of the evaluation of effectiveness

At each assessment and each time the feeling of itching after control of infection allergen in the eyes treated with a 0.05%ketotifen, was statistically significantly (P<0,001) more weak than in eyes treated with placebo (table 10). After 16 h after dose (visit 3) average of the difference scores sensations of ocular itching between treatments were clinically significant (i.e. the difference was >1 unit) when assessed after 5 min after CAC (-1,05 is denizi) and was close to clinically significant after 7 min (-0,96 units). When the control contamination allergen, which was carried out 15 min after the dose (visit 4), clinically significant differences between treatments were detected in 3, 5 and 7 min after control of infection (-1,52, -1,65 and -1,51 units, respectively).

Table 10
Primary efficiency - ocular itching after dose (ITT)
Time estimates after controlling infectionProcessingThe average scoreThe difference between treatments and 95%CI (active substance - placebo)1P value2
after 15 after dose
3 minKetotifen0,40-1,52 (-1,87, -1,17)<0,001
0,05%
Placebo 1,93
5 minKetotifen0,40-1,65 (-1.98, -1,33)<0,001
0,05%
Placeboto 2.06
7 minKetotifen0,46-1,51 (-1,83, -1,19)<0,001
0,05%
Placebo1,97
after 16 h after injection dose
3 minKetotifen0,94-0,87 (-1,25, -0,49)<0,001
0,05%
Placebo1,81
5 minKetotifen0,96-1,05 (-1,41, -0,69)<0,001
0,05%
Placebo2,01
7 minKetotifen0,98-0,96 (-1.29, -0,64)<0,001
0,05%
Placebo1,94
1A negative difference indicates that the preparation containing the active is emesto, has a better effect compared with placebo.
2The results obtained using variance analysis.

Similar trends were identified in the analysis of sensations of ocular itching in the other eye (table 11). In the eyes treated with a 0.05%ketotifen, itchy sensation after control of infection allergen, was statistically significantly (P<0,001) more weak than in eyes treated with placebo. At each time point were clinically significant differences (more favorable effect of 0.05%ketotifen).

after 16 h after injection dose
Table 11
The primary efficacy analysis (other eye) - eye itching after dose (ITT)
Time estimates after controlling infectionProcessingPoint in the processing groupThe mean difference between treatments (active substance - placebo)P value1
after 15 after dose
3 minketotifen the 0,47-1,14<0,001
0,05%
placebo1,61
5 minketotifen0,42-1,38<0,001
0,05%
placebo1,79
7 minketotifen0,49-1,28<0,001
0,05%
placebo1,76
3 minketotifen0,72-1,04<0,001
0,05%
placebo1,76
5 minketotifen0,78-1,17<0,001
0,05%
placebo1,94
7 minketotifen0,79-1,03<0,001
0,05%/td>
placebo1,82
1The results obtained using paired t-test.

At each assessment and each time when processing the eyes of 0.05%ketotifen number of responders (i.e. individuals who were assessed score of 0 stinging sensation after CAC) was statistically significantly (P<0,001) higher compared with the corresponding quantity in the processing of eye placebo (table 12). Approximately 35-40% of individuals whose eyes were treated with ketotifen, did not feel itching in the eyes after control of infection allergen conducted after 16 h after dose (visit 3), compared to 4-7% of individuals whose eyes were treated with placebo. This difference was even more pronounced after controlling contamination allergen, which was carried out 15 min after the dose at visit 4.

Table 12
Analysis of responders - no scratchy feeling in the eye after dose (ITT)
Time estimates after controlling infectionProcessing% of responders
after 15 min after the injection doseafter 16 h after injection dose
no itching1P value2no itchinga value of P
3 minketotifen 0.05% of placebo63,5%
7,4%
<0,00140,7%
7,4%
<0,001
5 minketotifen 0.05% of placebo65,4%
3,7%
<0,00138,9%
5,6%
<0,001
7 minketotifen 0.05% of placebo63,5%
3,7%
<0,00135,2%
3,7%
<0,001
1in this case, the score itching sensation equal to 0.
2P value based on Fisher's exact test.

On the basis of the amounts of the situations score ocular hyperemia is possible to conclude that, when each assessment and each time the redness of the eyes treated with a 0.05%ketotifen, was smaller compared with eyes treated with placebo (table 13). Statistically significant differences between treatments were detected after 16 h after dose after 5 and 7 min after CAC and 15 min after a dose of 5, 7, and 15 min after CAC. Between treatments was not detected clinically significant differences (i.e. differences that make up ≥3 units). Similar trends were identified for each scoring redness included in the total score (conjunctival, ciliated and episcleral). The results of the analysis of ocular hyperemia other eye were comparable with the results presented in table 13.

Table 13
Secondary efficacy - total ocular hyperemia after dose (ITT)
Time estimates after controlling infectionProcessingThe average scoreThe difference between treatments and 95%CI (active substance - placebo)1P value2
After 15 min after the injection dose
5 minketotifen2,14-1,78 (-2,70,
-0,86)
<0,001
0,05%
placebo3,93
7 minketotifen2,81-1,68 (-2,62,
-0,75)
<0,001
0,05%
placebo4,49
15 minketotifen3,94-1,12 (-2,11,
-0,13)
<0,027
0,05%
placeboof 5.06
after 16 h after injection dose
5 minketotifen2,70-0,78 (-1,55,
-0,01)
<0,047
0,05%
placebo3,48
7 minketotifen3,42-0,78 (-1,50,
-0,05)
<being 0.036
0,05%
placebo4,19
15 minketotifen4,15-0,60 (-1,35,
0.14)
0,112
0,05%
placebo4,75
1A negative difference indicates that the product containing the active substance, has a better effect compared with placebo.
2The results obtained using.

For each evaluation and each time for eyes treated with a 0.05%ketotifen found less swelling of the eyelids and lower chemosis after the control of allergen contamination than eyes treated with placebo (table 14). About swelling of the eyelids, these differences were not statistically significant at visit 3 (after 16 h after control of infection dose), but they are accurate in every time after CAC at visit 4 (after 15 min after control of infection dose). When evaluating chemosis were statistically significant differences when the visit is 3 through 5 minutes after CAC and at visit 4 through 5, 7 and 15 min after CAC. For both parameters did not reveal clinically significant differences between treatments (i.e. differences average of≥1 unit). The results of the analysis of the century swelling and chemosis for the other eye were comparable with the results presented in table 14, although in the analysis of other eye statistically significant differences (more favorable effect of 0.05%ketotifen) were found for both parameters at each point in time.

Table 14
Secondary efficacy - swelling of the eyelids and chemosis after dose (ITT)
Time estimates after controlling infectionProcessingThe average scoreThe difference between treatments and 95%CI (active substance - placebo)1P value2
Swelling of the eyelids after 15 min after the injection dose
5 minketotifen 0.05% of placebo0,10
0,43
-0,33 (-054, -0,12)0,002
7 minketotifen 0.05% of placebo0,13
0,57
-0,44 (-0,67, -0,21)<0,001
15 minketotifen 0.05% of placebo0,13
0,52
-0,38 (-0,61,-0,16)0,001
after 16 h after injection dose
5 minketotifen 0.05% of placebo0,13
0,31
-0,19 (-0,38, 0,01)0,063
7 minketotifen 0.05% of placebo0,22
0,41
-0,19 (-0,40, 0,03)0,085
15 minketotifen 0.05% of placebo0,37
0,48
-0,11 (-0,36, 0,14)0,383
The chemosis after 15 min after the injection dose
5 minketotifen 0.05% of placebo0,23
0,41
-0,18 (-0,33, -0,03)0,021

Time estimates after controlling infectionProcessingThe average scoreThe difference between treatments and 95%CI (active substance - placebo)1P value2
7 minketotifen 0.05% of placebo0,32
0,55
-0,23 (-0,38, -0,08)0,003
15 minketotifen 0.05% of placebo0,41
0,59
-0,18 (-0,35, -0,01)0,037
after 16 h after injection dose
5 minketotifen 0.05% of placebo0,15
0,27
-0,12 (-0,23, -0,01)0,031
7 min ketotifen 0.05% of placebo0,31
0,39
-0,07 (-0,19, 0,04)0,189
15 minketotifen 0.05% of placebo0,43
0,54
-0,11 (-0,28, 0,05)0,183
1A negative difference indicates that the product containing the active substance, has a better effect compared with placebo.2The results obtained using variance analysis.

For each evaluation and each time the percentage of individuals experiencing tearing after control of infection allergen was higher in the groups in which eye was treated with placebo, compared with the group in which the eyes were treated with ketotifen (table 15). These differences were not statistically significant at any time after CAC at visit 3 (after 16 h after control of infection dose), but they were statistically significant at each time point at visit 4 (after 15 min after control of infection dose). None of the individuals were not identified mucous discharge at any time after control of infection at visits 3 and 4.

Table 15
Secondary analysis - tearing after dose (ITT)
Time estimates after controlling infectionProcessing% of individuals
After 15 min after the injection doseAfter 16 h after injection dose
Tearing1P value2TearingA value of P
5 minketotifen 0.05% of placebo11,5%
35,2%
0,00618,5%
27,8%
0,362
7 minketotifen 0.05% of placebo9,6%
37,8%
0,00120,4%
35,2%
0,132
15 minketotifen 0.05% of placebo7,7%
24,1%
0,03316,7%
22,2%
0,628
1Means the presence of slezootdelenia.
2P value based on Fisher's exact test.

For each evaluation, and in each moment of time for the individuals in the group, which is 0.05%ketotifen worked both eyes, total score nasal symptom was less than in the group in which individuals each eye (OU) was treated with placebo. However, due to the small number of individuals in each of these groups (N=9), caution must be exercised when interpreting these results.

D. Conclusions

As with the statistical and clinical perspectives the results of this study using control contamination allergen suggest that ophthalmic solution containing 0.05% ketotifen fumarata significantly superior to placebo in reducing the severity of the itching sensation in the eye in sensitive individuals after contact with the allergen. 0.05%ketotifen is characterized by rapid onset of action (15 min) and prolonged action, and clinically significant reduction burning sensation persists for a period of time up to 16 h after dose. 0.05%ketotifen also reduces other signs and symptoms associated with exposure to the allergen, namely ocular hyperemia, swelling of the eyelids, chemosis and tearing.

1. Ophthalmic composition, which contains:
(a) ketotifen fumarate concentration in the expectation of free ketotifen from about 0.01 wt.% to about 0.1 wt.%;
(b) a source of hydrogen peroxide, the presence of hydrogen peroxide in trace quantities, comprising from about 0.001 to about 0.1% (wt./vol.);
(C) one or more compatible with the eye of the stabilizers of hydrogen peroxide;
(g) hypromellose in a concentration of from about 0.005 wt.% up to about 0.5 wt.%; and
(d) carboxymethylcellulose sodium in a concentration of from about 0.005 wt.% up to about 0.5 wt.%, moreover, the pH value of the composition is from about 4.0 to about 5,3.

2. The composition according to claim 1, in which the source of hydrogen peroxide selected from the group comprising perborate sodium tetrahydrate sodium perborate, sodium peroxide and urea peroxide.

3. The composition according to claim 1, in which the source of hydrogen peroxide is present in a concentration of from about 0.001 to about 0.01 percent (wt./vol.).

4. The composition according to claim 1, in which one or more stabilizers of hydrogen peroxide selected(s) from the group consisting of diethylenetriaminepenta(methylenephosphonic acid), 1-hydroxyethylidene-1,1-diphosphonic acid and their physiologically acceptable salts.

5. The composition according to claim 4, where the stabilizer of hydrogen peroxide is diethylenetriaminepenta(METI apostolou acid).

6. The composition according to claim 4, where the stabilizer of hydrogen peroxide is a 1-hydroxyethylidene-1,1-diphosphonic acid.

7. The composition according to claim 4, where the composition comprises from about 0,001% by weight up to about 0.02 wt.% diethylenetriaminepenta(methylenephosphonic acid) or its physiologically acceptable salt.

8. The composition according to claim 4, where the composition comprises from about 0.002 wt.% to about 0.2 wt.% 1-hydroxyethylidene-1,1-diphosphonic acid and its physiologically acceptable salt.

9. The composition according to claim 4, where the composition further comprises increasing toychest agent.

10. The composition according to claim 1, in which the concentration of hydroxypropylmethylcellulose is from about 0.1 to about 0.5% (wt./about.) and where the concentration of carboxymethylcellulose sodium is from about 0.04 to about 0.4% (wt./vol.).

11. Ophthalmic composition, which contains:
(a) ketotifen fumarate in concentration 0,069% (wt./vol.);
(b) tetrahydrate sodium perborate concentration 0,028% (wt./vol.);
(C) diethylenetriaminepenta(methylenephosphonic acid) at a concentration of 0,006% (wt./vol.);
(g) HPMC at a concentration of 0.3% (wt./about.) and
(d) CMC at a concentration of 0.1% (wt./vol.), moreover, the pH value of the composition is from about 4.0 to about 5,3.

12. Method for the treatment or prevention of allergic conjunctivitis, which is that the individual suffering and the lergicheskie conjunctivitis or sensitive to it, applied topically effective amount of the ophthalmic composition according to any one of claims 1 to 11.

13. The method according to item 12, wherein the ophthalmic composition is applied once a day.



 

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2 ex

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28 cl, 4 tbl, 11 ex

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2 cl, 2 tbl, 4 ex

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8 cl, 4 ex, 4 tbl

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8 cl, 1 tbl, 4 ex

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5 ex

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7 cl, 1 tbl, 5 ex

FIELD: medicine, pharmaceutics.

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2 ex

7FIELD: medicine, pharmaceutics.

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77 cl, 2 dwg, 8 tbl, 257 ex

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