KR20140009819A - Pharmaceutical composition for topical administration comprising vancomycin or its salt and dexamethasone phosphate or its salt - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for topical administration comprising vancomycin or a pharmaceutically acceptable salt thereof and dexamethasone phosphate or a pharmaceutically acceptable salt thereof, wherein vancomycin or a pharmaceutically acceptable salt thereof and dexamethasone phosphate or a pharmaceutically acceptable salt thereof. It provides a pharmaceutical composition for topical administration containing an acceptable salt in a specific weight ratio. The pharmaceutical composition according to the present invention may be formulated in the form of a reconstitutable formulation, and a rapid solution may be obtained to obtain a clear solution without precipitation or gelation through rapid reconstitution. In addition, the reconstituted solution has good physical and chemical stability by not causing precipitation or gelation for a long time (eg, about 1 month) even at room temperature, and minimizing the generation of the flexible material.

Description

Pharmaceutical composition for topical administration comprising vancomycin or its salt and dexamethasone phosphate or its salt}

The present invention relates to a pharmaceutical composition for topical administration comprising vancomycin or a salt thereof and dexamethasone phosphate or a salt thereof.

Vancomycin is an antibiotic that is useful for the treatment of methicillin-resistant strains, including methicillin-resistant Staphylococcus epidemidis . Currently, vancomycin is marketed as a lyophilized injection or frozen Ringer's solution to ensure stability. The lyophilized injection is used after being dissolved in water for injection, physiological saline, etc., and needs to be used within 96 hours under refrigerated conditions. The freezing ringer solution requires freezing storage at -20 ℃. Dexamethasone phosphate (dexamethasone phosphate) is a corticosteroid and has a strong anti-inflammatory action, and is particularly useful for the treatment of allergic diseases, skin diseases, inflammatory eye diseases, and ear / otitis media.

The combination therapy of antibiotics and steroids has been reported to cause therapeutic improvement in various studies (Baum JL, et al., Am J Ophthalmol 1974; 80: 513-7; Barza M. et al., Infect Dis Clin Merelith TA, et al., Ophthalmology 1990; 108: 857-60; Maxwell DP Jr, et al., ≪ RTI ID = 0.0 > Ophthalmology 1990; 98: 1370-5, etc.). In addition, Smith MA et al. Have disclosed that the combination treatment of vancomycin and dexamethasone can achieve better effects in the treatment of inflammation than vancomycin alone (Smith MA, et al., J Infect Dis. 1997 Feb; 175; (2): 462-6). Therefore, pharmaceutical preparations containing vancomycin and dexamethasone as active ingredients are expected to be usefully used as preparations for topical administration for application to the eyes, ears, nose and skin.

On the other hand, in order to design a pharmaceutical formulation for topical administration containing vancomycin and dexamethasone simultaneously, it is required to have physical stability without precipitation or formation of fine particles in an aqueous medium such as water for injection. However, when vancomycin and dexamethasone are mixed with each other in an aqueous medium, precipitates form and it is difficult to expect physical stability. In the paper by Smith MA et al., Vancomycin and dexamethasone were administered using separate syringes to avoid precipitation.

The present inventors have conducted various studies to develop a pharmaceutical formulation having topical administration as a pharmaceutical formulation containing vancomycin and dexamethasone, without precipitation or formation of fine particles. The inventors have found through the various studies that vancomycin and dexamethasone greatly affect the stability according to the weight ratio. In particular, the present inventors, when using vancomycin and dexamethasone in specific weight ratios, formulated in the form of a reconstitutable formulation consisting of two compartments (eg, vials or plastic containers), rapid reconstitution It was found that a clear solution can be obtained without achieving precipitation or gelation by achieving. It has also been found that the reconstituted solution has good physical and chemical stability by not causing precipitation or gelation for long periods of time even at room temperature (eg, about 1 month) and minimizing the generation of analogues. This provides particularly good convenience compared to vancomycin-containing frozen formulations that must be frozen at −20 ° C.

Accordingly, an object of the present invention is to provide a pharmaceutical composition for topical administration containing vancomycin and dexamethasone phosphate in a specific weight ratio.

According to one aspect of the invention, a pharmaceutical composition for topical administration comprising vancomycin or a pharmaceutically acceptable salt thereof and dexamethasone phosphate or a pharmaceutically acceptable salt thereof, comprising: (i) vancomycin or a pharmaceutically acceptable salt thereof When the concentration is at least 1.0% (w / v) relative to the total composition, the weight ratio of vancomycin or a pharmaceutically acceptable salt thereof and dexamethasone phosphate or a pharmaceutically acceptable salt thereof is 1: 0.02 to 0.1; (ii) when the concentration of vancomycin or its pharmaceutically acceptable salt is less than 1.0% (w / v) relative to the total composition, the weight ratio of vancomycin or its pharmaceutically acceptable salt and dexamethasone phosphate or its pharmaceutically acceptable salt is 1: The pharmaceutical composition for topical administration which is 0.05-0.4 is provided.

In one embodiment of the invention, the pharmaceutical composition comprises a first compartment comprising vancomycin or a pharmaceutically acceptable salt thereof and dexamethasone phosphate or a pharmaceutically acceptable salt thereof; And a second compartment containing water.

In another embodiment of the present invention, the second compartment may further comprise glycerin, the concentration of which may be 20.0% (w / v) or less based on the total composition. In addition, the second compartment may further comprise 0.001 to 0.1% (w / w) chelating agent and / or 0.001 to 0.18% (w / v) preservative relative to the total composition.

It has been found by the present invention that vancomycin and dexamethasone are significantly affected by stability by weight ratio. In particular, when using vancomycin and dexamethasone in specific weight ratios to formulate in the form of a reconstitutable formulation consisting of two compartments (e.g., vials or plastic containers), a rapid reconstitution is achieved. It has been found by the present invention that a clear solution can be obtained without precipitation or gelation occurring.

In addition, it has been found by the present invention that the reconstituted solution has excellent physical and chemical stability by not causing precipitation or gelation for a long time (eg, about 1 month) even at room temperature and minimizing the generation of soft substances. . Therefore, the pharmaceutical composition according to the present invention has the advantage that it can be usefully used in multiple times for a long time while storing at room temperature (about 25 ° C.) as well as single use.

The present invention provides a pharmaceutical composition for topical administration comprising vancomycin or a pharmaceutically acceptable salt thereof and dexamethasone phosphate or a pharmaceutically acceptable salt thereof, wherein (i) the concentration of vancomycin or a pharmaceutically acceptable salt thereof is added to the total composition. When the ratio is 1.0% (w / v) or more, the weight ratio of vancomycin or a pharmaceutically acceptable salt thereof and dexamethasone phosphate or a pharmaceutically acceptable salt thereof is 1: 0.02 to 0.1; (ii) when the concentration of vancomycin or its pharmaceutically acceptable salt is less than 1.0% (w / v) relative to the total composition, the weight ratio of vancomycin or its pharmaceutically acceptable salt and dexamethasone phosphate or its pharmaceutically acceptable salt is 1: The pharmaceutical composition for topical administration which is 0.05-0.4 is provided.

It has been found by the present invention that vancomycin and dexamethasone are significantly affected by stability by weight ratio. That is, when vancomycin and dexamethasone are contained in the specific weight ratios described above, precipitation or gelation does not occur in the aqueous medium. The pharmaceutical composition for topical administration according to the present invention may be applied to eyes, ears, nose, skin, and the like, preferably in the form of an otic formulation applied to the ear.

In the pharmaceutical composition for topical administration according to the present invention, the pharmaceutically acceptable salt of vancomycin may be a conventional acid addition salt including hydrochloride, sulfate, and the like, and preferably vancomycin hydrochloride. The concentration of vancomycin or a pharmaceutically acceptable salt thereof may be in a therapeutically effective content range, preferably 0.3 to 4.0% (w / v) relative to the total composition.

In addition, the pharmaceutically acceptable salt of dexamethasone phosphate may be a conventional metal salt such as dexamethasone monosodium phosphate, dexamethasone disodium phosphate and the like, preferably dexamethasone disodium phosphate. The dexamethasone phosphate or a pharmaceutically acceptable salt thereof may be used in a therapeutically effective amount within the above weight ratios. As an example, when the concentration of vancomycin or a salt thereof is at least 1% (w / v), dexamethasone phosphate or a pharmaceutically acceptable salt thereof may be used at a concentration of 0.02 to 0.4% (w / v); When the concentration of vancomycin or its salt is less than 1% (w / v), dexamethasone phosphate or its pharmaceutically acceptable salt may be used at a concentration of 0.025 to 0.2% (w / v). Of course, the concentration of dexamethasone phosphate or a pharmaceutically acceptable salt thereof should be determined within the weight ratio range with vancomycin or salt thereof.

When vancomycin and dexamethasone are formulated in the form of a two-compartment reconstitutable formulation using specific weight ratios as described above, a rapid reconstitution is achieved to achieve a clear solution without precipitation or gelation. It has been found by the present invention that it can be obtained. In addition, it has been found by the present invention that the reconstituted solution has excellent physical and chemical stability by not causing precipitation or gelation for a long time (eg, about 1 month) even at room temperature and minimizing the generation of soft substances. . Accordingly, in one embodiment of the present invention, the pharmaceutical composition comprises a first compartment comprising vancomycin or a pharmaceutically acceptable salt thereof and dexamethasone phosphate or a pharmaceutically acceptable salt thereof; And a second compartment comprising water (eg water for injection).

The first compartment and the second compartment may have the form of a vial or plastic container.

The first compartment may contain a simple mixture of vancomycin or a pharmaceutically acceptable salt thereof and dexamethasone phosphate or a pharmaceutically acceptable salt thereof. In addition, the first compartment may contain their lyophilized form so that the content of vancomycin or its pharmaceutically acceptable salts and dexamethasone phosphate or its pharmaceutically acceptable salts can be precisely controlled. That is, the first compartment may include a solid obtained by lyophilizing an aqueous solution including vancomycin or a pharmaceutically acceptable salt thereof and dexamethasone phosphate or a pharmaceutically acceptable salt thereof.

The second compartment may further comprise glycerin as a stabilizer in addition to water (eg water for injection). Glycerin is a non-aqueous solvent that can be used on the ear, eye or nasal mucosa. The second compartment may contain glycerin as a stabilizer, and in terms of chemical stability and irritation, the concentration of glycerin is 20% (w / v) or less, preferably 0.5 to 10%, based on the total composition. It can be used in the range of (w / v).

In addition, the second compartment may further comprise 0.001 to 0.1% (w / w) chelating agent and / or 0.001 to 0.18% (w / v) preservative relative to the total composition. The chelating agent may be an edetate salt [for example, edetate disodium (including hydrate), edetate trisodium (including hydrate), edetate tetrasodium (including hydrate), etc.] Or diethyleneamine pentaacetate, but is not limited thereto. In addition, the preservative may be selected from one or more from methyl paraben, ethyl paraben, propyl paraben (including isopropyl paraben), isobutyl paraben and the like.

In one embodiment of the invention, there is provided a pharmaceutical composition for topical administration consisting of the following contents relative to the total composition, preferably a vial comprising vancomycin hydrochloride and dexamethasone disodium phosphate; There is provided a pharmaceutical composition for topical administration consisting of a plastic container comprising glycerin, edetate disodium, methylparaben, propylparaben, and water for injection:

In another embodiment of the present invention, there is provided a pharmaceutical composition for topical administration consisting of the following contents relative to the total composition, preferably a vial comprising vancomycin hydrochloride and dexamethasone disodium phosphate; There is provided a pharmaceutical composition for topical administration consisting of a plastic container comprising glycerin, edetate disodium, methylparaben, propylparaben, and water for injection:

In another embodiment of the invention, there is provided a pharmaceutical composition for topical administration consisting of the following contents relative to the total composition, preferably a vial comprising vancomycin hydrochloride and dexamethasone disodium phosphate; There is provided a pharmaceutical composition for topical administration consisting of a plastic container comprising glycerin, edetate disodium, methylparaben, propylparaben, and water for injection:

In another embodiment of the invention, there is provided a pharmaceutical composition for topical administration consisting of the following contents relative to the total composition, preferably a vial comprising vancomycin hydrochloride and dexamethasone disodium phosphate; There is provided a pharmaceutical composition for topical administration consisting of a plastic container comprising glycerin, edetate disodium, methylparaben, propylparaben, and water for injection:

Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are for illustrating the present invention, and the present invention is not limited to these examples.

Example  1. Preparation of Pharmaceutical Composition

According to the ingredients and contents of Table 1, a formulation for topical administration containing vancomycin hydrochloride and dexamethasone disodium phosphate was prepared. The content in Table 1 below means the content [% (w / v)] based on the solution obtained by mixing the first compartment and the second compartment.

≪ Preparation of first compartment >

Vancomycin hydrochloride was completely dissolved in 900 mL of water for injection. While stirring the obtained solution, dexamethasone disodium phosphate was added and completely dissolved. The solution was adjusted to 1,000 mL with the injection water, and stirred for about 30 minutes. The resulting solution was aseptically filtered, dispensed into sterile vials, and lyophilized. Each vial was sealed with a rubber stopper.

<Production of Second Vial>

After 900 mL of water for injection was heated to about 90 캜, propylparaben and methylparaben were dissolved. After cooling the obtained solution to room temperature, sodium edetate hydrate and glycerin were dissolved. The solution was adjusted to 1,000 mL with the injection water, and stirred for about 30 minutes. The resulting solution was sterile filtered, then dispensed into sterilized vials, then dispensed into a plastic container and then closed with a sterile sealing cap.

Example  2. Physical stability assessment

Vancomycin hydrochloride was dissolved in water for injection at a predetermined concentration as shown in Table 2 below. While each solution obtained was stirred, dexamethasone disodium phosphate was added at various concentrations (see Table 2), and then the occurrence of precipitate was measured. The results are shown in Table 2 below. In Table 2 'vancomycin' refers to vancomycin hydrochloride and 'dexamethason' refers to dexamethasone disodium phosphate. In addition, '%' means% (w / v), O means a transparent solution, X means sediment generation.

From the results of Table 2, when the concentration of vancomycin hydrochloride is 0.5% (w / v) or more, it can be seen that the precipitate occurred according to the concentration of dexamethasone disodium phosphate. In addition, when the concentration of vancomycin hydrochloride is less than or equal to about 4.0% (w / v) in the therapeutically effective concentration range, for example 1.0 to 4.0% (w / v), the physical stability of vancomycin hydrochloride and dexamethasone disodium phosphate It can be seen that the weight ratio can be ensured in the range of 1: 0.02 to 0.1. In addition, when the concentration of vancomycin hydrochloride is less than 1.0% (w / v), it can be seen that the physical stability can be ensured in the weight ratio of vancomycin hydrochloride and dexamethasone disodium phosphate in the range of 1: 0.05 to 0.4.

Example  3. Chemical Stability Assessment

(1) Chemical stability evaluation [concentration of vancomycin hydrochloride: 1.0% (w / v)]

As shown in Table 3 below, the concentration of vancomycin hydrochloride was fixed at 1.0% (w / v), and the content of dexamethasone disodium phosphate was adjusted to prepare a first compartment in the same manner as in Example 1. Each of the obtained first compartments was dissolved by adding water for injection. Each concentration in Table 3 represents the concentration of the final formulation obtained when water for injection is added. The content of the initial flexible material of each solution was measured, and then stored for 1 month at room temperature (25 ° C.), and the content of the flexible material was measured again. The results are shown in Table 4 below.

(2) chemical stability evaluation [concentration of vancomycin hydrochloride: 2.5% (w / v)]

As shown in Table 5 below, the concentration of vancomycin hydrochloride was fixed at 2.5% (w / v), and the content of dexamethasone disodium phosphate was adjusted to prepare a first compartment in the same manner as in Example 1. Each concentration in Table 5 represents the concentration of the final formulation obtained when water for injection is added. For each solution, chemical stability was evaluated in the same manner as in (1) above. The results are shown in Table 6 below.

(3) Chemical stability evaluation [concentration of vancomycin hydrochloride: 4.0% (w / v)]

As shown in Table 7 below, the concentration of vancomycin hydrochloride was fixed at 4.0% (w / v), and the content of dexamethasone disodium phosphate was adjusted to prepare a first compartment in the same manner as in Example 1. Each concentration in Table 7 represents the concentration of the final formulation obtained when water for injection is added. For each solution, chemical stability was evaluated in the same manner as in (1) above. The results are shown in Table 8 below.

(4) Chemical stability evaluation [concentration of vancomycin hydrochloride: 0.3% (w / v)]

As shown in Table 9 below, the concentration of vancomycin hydrochloride was fixed at 4.0% (w / v), and the content of dexamethasone disodium phosphate was adjusted to prepare a first compartment in the same manner as in Example 1. Each concentration in Table 9 represents the concentration of the final formulation obtained when water for injection is added. For each solution, chemical stability was evaluated in the same manner as in (1) above. The results are shown in Table 10 below.

(5) Chemical stability evaluation [concentration of vancomycin hydrochloride: 0.5% (w / v)]

As shown in Table 11 below, the concentration of vancomycin hydrochloride was fixed at 0.5% (w / v), and the content of dexamethasone disodium phosphate was adjusted to prepare a first compartment in the same manner as in Example 1. Each concentration in Table 11 represents the concentration of the final formulation obtained when water for injection is added. For each solution, chemical stability was evaluated in the same manner as in (1) above. The results are shown in Table 12 below.

From the results of Tables 4, 6, and 8, when the concentration of vancomycin hydrochloride is 1.0% (w / v) or more, when the concentration of dexamethasone disodium phosphate is increased to 0.1% (w / v), vancomycin hydrochloride It can be seen that the occurrence of the flexible substance of. Particularly, when vancomycin hydrochloride alone was used, it was unsuitable to the acceptable softener standard. However, it is surprising that the addition of dexamethasone disodium phosphate reduces the formation of the softener of vancomycin hydrochloride. Acceptable baselines for vancomycin and dexamethasone are 20.0% and 2.0%, respectively. Therefore, as can be seen from the above results, when the concentration of vancomycin hydrochloride is 1.0% (w / v) or more, the weight ratio of vancomycin hydrochloride and dexamethasone disodium phosphate ranges from 1: 0.02 to 0.1 in terms of physical and chemical stability. Suitable.

In addition, it can be seen from the results of Tables 10 and 12 that when the concentration of dexamethasone disodium phosphate was increased to a specific range, the generation of analogues of vancomycin hydrochloride decreased. In addition, as can be seen from the above results, when the concentration of vancomycin hydrochloride is less than 1.0% (w / v), the weight ratio of vancomycin hydrochloride and dexamethasone disodium phosphate ranges from 1: 0.05 to 0.4 in terms of physical and chemical stability. Suitable.

Example  4. Evaluation of Stabilizers (Glycerin)

(1) Evaluation of efficacy and reconstituion of stabilizers

A first compartment and a second compartment were manufactured in the same manner as in Example 1, except that the concentration of glycerin was changed according to Table 13 below. The time taken to reconstitute each of the first and second compartments into a solution, ie, the reconstitution time, was measured, and the change in the soft matter of vancomycin was measured for each of the obtained solutions. . The results are shown in Table 13 below.

As can be seen from the results in Table 13, the higher the concentration of glycerin, the better the chemical stability (A to F). However, when the concentration of glycerin exceeded 20% (w / v), the reconstruction time increased markedly while not having a significant effect on chemical stability.

(2) stimulus evaluation

According to Table 14 below, the vancomycin hydrochloride and dexamethasone disodium phosphate concentrations were fixed at 1.0% (w / v) and 0.1% (w / v), respectively, and the stimulation according to the concentration of glycerin was evaluated. Each concentration represents a concentration in water for injection. However, G8 was dissolved in vancomycin hydrochloride and dexamethasone disodium phosphate at 1.0% (w / v) and 0.1% (w / v), respectively, using glycerin as a solvent without using water for injection. The irritation was evaluated using eye of Beagledog, and the number of animals per test group was used three. Administration was performed by 0.1 mL each of the left eye and the right eye. In the left eye, water for injection was added to the control group, and for the right eye, test substance was instilled. The number of eye blinks was scored according to the degree of eye irritation, and the higher the score, the higher the stimulus. The results are shown in Table 15.

As can be seen from the results of Table 15, the stimulation of glycerin was increased, and when the concentration of glycerin exceeds 20% (w / v), the irritation was rapidly increased.

Therefore, it can be seen from the above results that the concentration of glycerin is suitably 20% (w / v) or less.

Claims (21)

A pharmaceutical composition for topical administration comprising vancomycin or a pharmaceutically acceptable salt thereof and dexamethasone phosphate or a pharmaceutically acceptable salt thereof,
(i) when the concentration of vancomycin or its pharmaceutically acceptable salt is at least 1.0% (w / v) relative to the total composition, the weight ratio of vancomycin or its pharmaceutically acceptable salt and dexamethasone phosphate or its pharmaceutically acceptable salt is 1: 0.02 to 0.1;
(ii) when the concentration of vancomycin or its pharmaceutically acceptable salt is less than 1.0% (w / v) relative to the total composition, the weight ratio of vancomycin or its pharmaceutically acceptable salt and dexamethasone phosphate or its pharmaceutically acceptable salt is 1: 0.05 to 0.4
Pharmaceutical composition for topical administration. The pharmaceutical composition for topical administration according to claim 1, wherein the pharmaceutically acceptable salt of vancomycin is vancomycin hydrochloride or sulfate. The pharmaceutical composition for topical administration according to claim 1, wherein the concentration of vancomycin or a pharmaceutically acceptable salt thereof is 0.3 to 4.0% (w / v) based on the total composition. The pharmaceutical composition for topical administration according to claim 1, wherein the pharmaceutically acceptable salt of dexamethasone phosphate is dexamethasone disodium phosphate. The pharmaceutical composition for topical administration according to claim 1, further comprising glycerin. The pharmaceutical composition for topical administration according to claim 5, wherein the concentration of glycerin is 20.0% (w / v) or less based on the total composition. The pharmaceutical composition for topical administration according to claim 1, further comprising 0.001 to 0.1% (w / w) chelating agent relative to the total composition. The pharmaceutical composition for topical administration according to claim 7, wherein the chelating agent is an edetate salt or diethyleneamine pentaacetate. The pharmaceutical composition for topical administration according to claim 1, further comprising 0.001 to 0.18% (w / v) preservative relative to the total composition. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises a first compartment comprising vancomycin or a pharmaceutically acceptable salt thereof and dexamethasone phosphate or a pharmaceutically acceptable salt thereof; And a second compartment containing water. &Lt; RTI ID = 0.0 &gt; 11. &lt; / RTI &gt; The pharmaceutical composition for topical administration according to claim 10, wherein the first compartment and the second compartment have the form of a vial or a plastic container. The method according to claim 10, wherein the first compartment comprises a solid obtained by lyophilizing an aqueous solution comprising vancomycin or a pharmaceutically acceptable salt thereof and dexamethasone phosphate or a pharmaceutically acceptable salt thereof. Pharmaceutical composition for topical administration. The pharmaceutical composition for topical administration according to claim 10, wherein the second compartment further comprises glycerin. The pharmaceutical composition for topical administration according to claim 13, wherein the concentration of glycerin is 20.0% (w / v) or less based on the total composition. The pharmaceutical composition for topical administration according to claim 10, wherein the second compartment further comprises 0.001 to 0.1% (w / w) chelating agent relative to the total composition. The pharmaceutical composition for topical administration according to claim 10, wherein the chelating agent is an edetate salt or diethyleneamine pentaacetate. The pharmaceutical composition for topical administration according to claim 10, wherein the second compartment further comprises 0.001 to 0.18% (w / v) preservative relative to the total composition. A pharmaceutical composition for topical administration consisting of the following contents relative to the total composition:

A pharmaceutical composition for topical administration consisting of the following contents relative to the total composition:

A pharmaceutical composition for topical administration consisting of the following contents relative to the total composition:

A pharmaceutical composition for topical administration consisting of the following contents relative to the total composition: