WO2025014253A1 - Pharmaceutical composition comprising diquafosol exhibiting improved stability - Google Patents

Abstract

The present invention relates to a pharmaceutical composition comprising diquafosol or a pharmaceutically acceptable salt thereof as an active ingredient and comprising polycarbophil as a viscosity modifier. More specifically, the present invention relates to an ophthalmic composition comprising diquafosol or a pharmaceutically acceptable salt thereof and polycarbophil, the composition improving the amount of tear secretion and exhibiting excellent stability.

Description

Pharmaceutical composition comprising diquafosol having improved stability

The present invention relates to a pharmaceutical composition comprising diquafosol or a pharmaceutically acceptable salt thereof as an active ingredient and polycarbophil as a viscosity-controlling agent. More specifically, the present invention relates to an ophthalmic composition comprising diquafosol or a pharmaceutically acceptable salt thereof and polycarbophil having improved tear secretion amount and excellent stability.

Diquafosol has the chemical structure of the following [chemical formula 1] and is a _P2Y2 purine receptor agonist. It is generally used for the treatment of dry eye, and an eye drop containing this diquafosol as an active ingredient is commercially available as “Diquas Eye Drops 3%.”

[Chemical Formula 1]

The above Diquas eye drops are eye drops containing diquafosol sodium at a concentration of 3 w/v% and are administered six times a day. However, they have the disadvantage of requiring many administrations, which requires patients to administer the drug multiple times. In addition, for effective treatment, the drug must be administered in an appropriate dosage form, but the above Diquas eye drops require many daily administrations, making it difficult for patients to adhere to these administration regimens.

Accordingly, in order to solve the above-mentioned problem, the inventors of the present invention developed an ophthalmic composition that can reduce the discomfort of eye drop users by reducing the number of administrations while increasing the amount of tear secretion, thereby completing the present invention.

(Prior art literature)

(Patent Document)

(Patent Document 0001) Republic of Korea Patent Publication No. 10-2607126

The purpose of the present invention is to provide a pharmaceutical composition comprising diquafosol or a pharmaceutically acceptable salt thereof and polycarbophil, which has an improved tear secretion amount with an improved dosage form by significantly increasing the duration of effect of diquafosol by using polycarbophil as a viscosity modifier.

Another object of the present invention is to provide a pharmaceutical composition comprising diquafosol or a pharmaceutically acceptable salt thereof as an active ingredient; polycarbophil and hydroxyethyl cellulose as viscosity modifiers; and polysorbate and tyloxapol as surfactants.

The present invention relates to a pharmaceutical composition comprising diquafosol or a pharmaceutically acceptable salt thereof, and polycarbophil as a viscosity modifier.

The composition of the present invention may include hydroxyethyl cellulose.

The composition of the present invention may contain polysorbate.

Additionally, the composition of the present invention may contain tyloxapol.

The composition of the present invention may contain diquafosol or a pharmaceutically acceptable salt thereof at a concentration of 0.1 to 10 w/v%, preferably at a concentration of 1 to 5 w/v%, and more preferably at a concentration of 2 to 4 w/v%.

The composition of the present invention may contain polycarbophil at a concentration of 0.01 to 1.0 w/v%, preferably 0.1 to 0.6 w/v%.

The composition of the present invention may contain hydroxyethyl cellulose at a concentration of 0.1 to 2.0 w/v%, preferably at a concentration of 0.3 to 0.9 w/v%.

The composition of the present invention may contain polysorbate at a concentration of 0.1 to 2.0 w/v%, preferably at a concentration of 0.5 to 1.0 w/v%.

The composition of the present invention may contain tyloxapol at a concentration of 0.1 to 0.5 w/v%, preferably at a concentration of 0.2 to 0.3 w/v%.

The composition of the present invention may contain 1 or more, and preferably 1.5 or more, of polysorbate relative to the weight of hydroxyethyl cellulose.

The above polysorbate may be at least one selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80.

The composition of the present invention may additionally contain an osmotic pressure regulator, a pH regulator, or a stabilizer.

The composition of the present invention may be for ophthalmic use.

The composition of the present invention may have an osmotic pressure of 230 to 350 mOsmol/kg and a pH of 6.0 to 7.5, but is not limited thereto.

The composition of the present invention can be maintained as a transparent solution after storage for 3 months in an accelerated stability chamber at 40 degrees and 75%RH.

The present invention relates to a method for producing an ophthalmic composition, comprising: a first step of adding diquafosol or a pharmaceutically acceptable salt thereof, hydroxyethyl cellulose, polysorbate, and tyloxapol to purified water and dissolving them; a second step of adding polycarbophil to purified water and dispersing them; and a step of mixing the solution obtained in the first step with the solution obtained in the second step.

The ophthalmic composition comprising diquafosol or a pharmaceutically acceptable salt thereof according to the present invention and polycarbophil can exhibit an improved tear secretion effect with an improved dosage by significantly increasing the duration of diquafosol by applying polycarbophil as a viscosity-controlling agent.

In addition, the present invention can provide a composition that can be stored for a long period of time without phase separation and has excellent stability by combining hydroxyethyl cellulose, polysorbate, and tyloxapol.

Figure 1 shows the results of evaluating tear secretion amount in normal rabbits according to Experimental Example 1.

Figure 2 is an image evaluating the stability of an ophthalmic composition manufactured according to Example 1.

Hereinafter, with reference to the attached drawings, embodiments and examples of the present invention will be described in detail so that those skilled in the art can easily implement the present invention. However, the present invention may be implemented in various forms and is not limited to the embodiments and examples described herein.

Throughout this specification, whenever a part is said to "include" a component, this does not mean that it excludes other components, but rather that it may include other components, unless otherwise specifically stated.

The present invention provides a pharmaceutical composition comprising diquafosol or a pharmaceutically acceptable salt thereof; and polycarbophil as a viscosity modifier.

In addition, the present invention provides a pharmaceutical composition further comprising hydroxyethylcellulose, polysorbate and tyloxapol.

The "diquafosol" of the present invention can be applied to conjunctival epithelial disorders as a moisture secretion accelerator to promote mucin secretion.

In the present invention, the “pharmaceutically acceptable salt” may be, but is not limited to, a metal salt such as a sodium salt or a potassium salt; an alkaline earth metal salt such as a calcium salt or a magnesium salt; an organic amine salt such as a phenethylamine salt or an ammonium salt. In a preferred embodiment of the present invention, the pharmaceutically acceptable salt may include diquafosol sodium salt.

The above ophthalmic composition may contain diquafosol or a pharmaceutically acceptable salt thereof in a concentration of 0.1 to 10 w/v%, preferably in a concentration of 1 to 5 w/v%, and most preferably in a concentration of 2 to 4 w/v%.

In the present invention, the ophthalmic composition may use polycarbophil as a viscosity modifier. More specifically, the polycarbophil may be included in a concentration of 0.01 to 1 w/v%, preferably in a concentration of 0.1 to 0.6 w/v%, so that the diquafosol may act as a viscosity sufficient to sufficiently act on the eye.

By including the polycarbophil in an appropriate concentration in the ophthalmic composition according to the present invention, the duration of tear secretion can be significantly increased.

In the present invention, the ophthalmic composition may contain hydroxyethyl cellulose as a viscosity modifier at a concentration of 0.1 to 2 w/v%, preferably 0.3 to 0.9 w/v%.

In the present invention, the ophthalmic composition may contain polysorbate as a surfactant at a concentration of 0.1 to 2 w/v%, preferably 0.5 to 1.0 w/v%.

In the present invention, the ophthalmic composition may contain tyloxapol as a surfactant at a concentration of 0.1 to 0.5 w/v%, preferably 0.2 to 0.3 w/v%.

The ophthalmic composition according to the present invention can significantly improve the properties and phase stability of the ophthalmic composition by containing the hydroxyethyl cellulose, polysorbate, and tyloxapol in an appropriate ratio.

In addition, the ophthalmic composition of the present invention may additionally include at least one additive selected from the group consisting of an osmotic pressure regulator, a pH regulator, and a stabilizer.

More specifically, the osmotic pressure regulator can be easily adjusted to be applied to the body environment by maintaining the osmotic pressure of the cell constant. In one embodiment of the present invention, the osmotic pressure regulator can be mannitol.

The above pH regulator is a composition for controlling pH in order to ensure stable absorption in the body and exhibit appropriate efficacy. In one embodiment of the present invention, the pH regulator may be tromethamine.

The above stabilizer is a component added to prevent a change in state or chemical change during preservation of a material, and in one embodiment of the present invention, the stabilizer may be an edetate. The edetate may be a metal salt such as sodium, potassium, calcium, magnesium, zinc, or lithium, or an ammonium salt, but is not limited thereto, and preferably may be sodium edetate.

In the present invention, the ophthalmic composition may have an osmotic pressure of 230 to 350 mOsmol/kg.

In the present invention, the ophthalmic composition according to the present invention may have a pH of 6.0 to 7.5, although it is not limited to a specific value as long as it is within a range acceptable as a medicine.

The ophthalmic composition of the present invention may be a liquid eye drop composition having a transparent appearance. In one embodiment of the present invention, the ophthalmic composition of the present invention may contain water as an aqueous medium, and specifically, it may be sterile purified water, water for injection, etc. suitable for the manufacture of ophthalmic preparations.

In one embodiment of the present invention, the ophthalmic composition of the present invention can be used for the prevention or treatment of a conjunctival epithelial disorder. The conjunctival epithelial disorder can be at least one selected from the group consisting of dry eye, Sjogren's syndrome, Stevens-Johnson syndrome, postoperative drug-induced eye disease, trauma-induced eye disease, and contact lens-induced eye disease.

The term "treatment" as used in the present invention may mean any action whereby the symptoms of a suspected or affected individual are improved or beneficially changed by administration of a pharmaceutical composition.

Hereinafter, the present invention will be described in more detail through experimental examples and examples. However, the following examples are for the purpose of explanation only and are not intended to limit the scope of the present invention.

[Manufacturing Example 1]

Preparation of ophthalmic composition containing diquafosol (Example 1)

An ophthalmic composition (Example 1) containing diquafosol was prepared by the following method with the composition and content shown in Table 1 below.

In the first preparation tank, the main ingredients except polycarbophil, isotonic agent, stabilizer, preservative, pH regulator, surfactant, and viscosity regulator were added to purified water, stirred with a stirrer at room temperature for 30 minutes to dissolve, and then filtered through a 0.22 um filter.

After adding polycarbophil to purified water in the second preparation tank, it was stirred with a stirrer at room temperature for 1 to 4 hours. After confirming that polycarbophil was homogeneously dispersed in the second preparation tank, it was autoclaved at 120 degrees for 10 to 20 minutes.

After autoclaving and cooling sufficiently at room temperature, the liquid passed through the 0.22um filter of the first preparation tank was injected and stirred. Afterwards, it was filled into an eye drop container (disposable or reusable). All of the above were performed in sterile Grade B.

[Table 1]

[Manufacturing Example 2]

Preparation of ophthalmic compositions containing diquafosol (Examples 2 to 11)

The viscosity modifier of Manufacturing Example 1 was changed to the components and contents of Table 2 below, and compositions of Examples 2 to 11 were manufactured using the same method as Manufacturing Example 1.

[Table 2]

[Manufacturing Example 3]

Preparation of ophthalmic compositions containing diquafosol (Comparative Examples 1 to 4)

As a control group for the above Examples 1 to 11, Comparative Example 1 was an untreated group, and Comparative Example 2 was a group treated with 3% Diquas eye drop solution. In addition, Comparative Examples 3 and 4 were manufactured in the same manner as Manufacturing Example 1, but did not include Diquafosol and had the following ingredients and compositions.

[Table 3]

[Experimental Example 1]

Evaluation of tear secretion according to viscosity

Using the following method, the tear secretion amount was evaluated using the compositions of Examples 1 to 11 and Comparative Examples 1 to 4.

1.1. Test animals

(1) Species/lineage: NZW male rabbit

(2) Production and purchase location: Dongfang (CN)/ Peerbio

(3) Gender, number of animals, and weight range at time of acquisition: Male, 33 animals, 2.5 to 3.0 kg

(4) Reason for selection of test system: The NZW rabbit used in this test is an animal species commonly used in dry eye tests, and was selected because it is easy to interpret and evaluate the test results.

(5) Quarantine and acclimatization: Upon receiving the animals, their appearance was observed and a veterinary quarantine was conducted for their general health. In order to confirm that they were fit for testing and healthy animals, they were placed in an animal shelter for an acclimatization period of 14 days, and each animal was housed in a stainless steel box during the acclimatization period.

(6) Individual identification and husbandry management: The test name, test group, individual number, sex, administration date, and body weight were recorded on the breeding cage.

(7) Group separation: During the quarantine and acclimatization period, preliminary screening for tear secretion was conducted only on animals without any abnormalities, and only animals without any problems were separated into test groups according to body weight.

1.2. Administration and Observation

(1) Route of administration: Eye drops

(2) Number of administrations: Single dose, both eyes

(3) Dosage: 50 ㎕/eye (total 100 ㎕, both eyes)

(4) Administration method: After the rabbit was placed outside the cage, the upper and lower eyelids were opened and 50 ㎕ of the test substance was instilled into each eye using a pipette. After instillation, the eye was held in place for a certain period of time to prevent leakage.

(5) Measurement of tear secretion (Schirmer's test): Schirmer's test was performed before administration of the test substance, and Schirmer's test was performed again 60 minutes after administration of the test substance to evaluate the degree of increase in tear secretion caused by the test substance. In addition, Schirmer's test was performed by hanging a test paper between the lower eyelid and the eyeball at the edge of the eyeball and measuring tear secretion for 5 minutes with the eyes closed.

(6) Calculation of increased tear volume (%): Secretion volume after test substance administration (mm) / Secretion volume before test substance administration (mm) * 100 (%)

1.3. Test Results

The tear secretion amount in normal rabbits was evaluated using the test conditions and methods of 1.1 and 1.2 above, and the results are shown in Table 4 and Figure 1 below.

[Table 4]

As shown in Table 4 above, it was confirmed that the average tear secretion increase rate (%) differed depending on the viscosity regulator. In particular, it was confirmed that the composition of Example 1 containing polycarbophil as a viscosity regulator showed a significantly superior tear secretion increase rate compared to Comparative Example 2 (Diquas treatment group).

[Experimental Example 2] Stability Evaluation

A stability evaluation experiment was performed using the composition of Example 1 manufactured in the above Manufacturing Example 1 using the following method.

The composition of Example 1 was stored in a long-term/accelerated chamber for one month, and then the properties and phase stability were evaluated. The properties were evaluated to see if there was a difference in the properties from the initial point when the formulation was visually evaluated, and for phase stability, it was visually evaluated to see if the dispersed polycarbophil remained homogeneously dispersed as at the initial point. As shown in Fig. 2, it was confirmed that phase separation occurred.

[Manufacturing Example 4]

Preparation of ophthalmic compositions containing diquafosol (Examples 12 to 14)

In order to determine the reason for phase separation in a composition containing diquafosol as an active ingredient and polycarpophyllin as a viscosity modifier, a composition containing an ionic substance (Example 12), a composition containing a nonionic substance (Example 13), and a composition containing a nonionic substance but not containing an active ingredient (Example 14) were prepared using the following components and contents and by the same method as in Manufacturing Example 1.

[Table 5]

[Experimental Example 3] Stability Evaluation

A stability evaluation experiment was performed using the compositions of Examples 12 to 14 manufactured in Manufacturing Example 4 as the target using the following method.

The compositions of Examples 12 to 14 were stored in a long-term/acceleration chamber for one month, and then the properties and phase stability were evaluated in the same manner as in Experimental Example 2.

It was confirmed that phase separation occurred in both the compositions of Examples 12 and 13. In addition, it was confirmed that the composition of Example 14, which did not contain diquafosol, had a transparent phase and that phase separation did not occur. Therefore, it can be seen that diquafosol exists in the form of a sodium salt, and that phase separation occurs when a certain amount or more of an ionic substance is mixed with polycarbophil.

[Manufacturing Example 5]

Preparation of ophthalmic compositions containing diquafosol (Examples 15 to 23)

In the composition of Example 13 manufactured in Manufacturing Example 4, a viscosity modifier was added as shown in Table 6 below, and the compositions of Examples 15 to 23 were manufactured in the same manner as Manufacturing Example 1.

[Table 6]

[Experimental Example 4] Stability Evaluation

A stability evaluation experiment was performed using the compositions of Examples 14 to 23 manufactured in Manufacturing Examples 4 and 5 above, using the following method.

The compositions of Examples 14 to 23 were stored in a long-term/acceleration chamber for one month, and the properties and phase stability were evaluated in the same manner as in Experimental Example 2, and the results are shown in Table 7 below.

[Table 7]

Phase separation occurred in the compositions of all Examples 14 to 23, but it was confirmed that the compositions of Examples 18 and 23, which used hydroxyethyl cellulose and polysorbate, became most transparent, and it was also confirmed that the compositions of Example 19, which used tyloxapol, improved.

[Manufacturing Example 6]

Preparation of ophthalmic compositions containing diquafosol (Examples 24 to 32)

In the composition of Example 13 manufactured in Manufacturing Example 4, compositions of Examples 24 to 32 containing hydroxyethyl cellulose, polysorbate, and tyloxapol in the components and contents of Table 8 below were manufactured in the same manner as in Manufacturing Example 1.

[Table 8]

[Experimental Example 5] Stability Evaluation

A stability evaluation experiment was performed using the compositions of Examples 24 to 32 manufactured in Manufacturing Example 6 above, using the following method.

The compositions of Examples 24 to 32 were stored in a long-term/acceleration chamber for one month, and the properties and phase stability were evaluated in the same manner as in Experimental Example 2, and the results are shown in Table 9 below.

[Table 9]

As shown in Table 9 above, in the case of the composition of Example 32 using 0.6% hydroxyethyl cellulose, 1.0% polysorbate 80, and 0.3% tyloxapol, it was confirmed that a completely transparent phase was exhibited and no phase separation occurred.

[Experimental Example 6] Stability Evaluation

A stability evaluation experiment was performed using the composition of Example 32 manufactured in Manufacturing Example 6 as the target using the following method.

After storing the composition of Example 32 in an accelerated stability chamber at 40 degrees and 75% RH for 3 months, the properties were confirmed in the same manner as in Experimental Example 2, and the content and flexible substances were evaluated through liquid chromatography, and the results are shown in Table 10 below.

[Table 10]

As shown in Table 10 above, the compound of Example 32 was confirmed to be stable in the stability evaluation.

Claims (23)

A pharmaceutical composition comprising diquafosol or a pharmaceutically acceptable salt thereof, and polycarbophil as a viscosity modifier. A pharmaceutical composition according to claim 1, further comprising hydroxyethyl cellulose. A pharmaceutical composition further comprising polysorbate in claim 2. A pharmaceutical composition further comprising tyloxapol in claim 3. A pharmaceutical composition comprising diquafosol or a pharmaceutically acceptable salt thereof at a concentration of 0.1 to 10 w/v% in claim 1. A pharmaceutical composition comprising diquafosol or a pharmaceutically acceptable salt thereof at a concentration of 1 to 5 w/v% in claim 1. A pharmaceutical composition comprising diquafosol or a pharmaceutically acceptable salt thereof at a concentration of 2 to 4 w/v% in claim 1. A pharmaceutical composition comprising polycarbophil at a concentration of 0.01 to 1.0 w/v% in claim 1. A pharmaceutical composition comprising polycarbophil at a concentration of 0.1 to 0.6 w/v% in claim 1. A pharmaceutical composition comprising hydroxyethyl cellulose in a concentration of 0.1 to 2.0 w/v% in the second paragraph. A pharmaceutical composition comprising hydroxyethyl cellulose in a concentration of 0.3 to 0.9 w/v% in claim 2. An ophthalmic composition comprising polysorbate at a concentration of 0.1 to 2.0 w/v% in claim 3. An ophthalmic composition comprising polysorbate at a concentration of 0.5 to 1.0 w/v% in claim 3. An ophthalmic composition comprising tyloxapol at a concentration of 0.1 to 0.5 w/v% in claim 4. An ophthalmic composition comprising tyloxapol at a concentration of 0.2 to 0.3 w/v% in claim 4. A pharmaceutical composition comprising, in claim 3, polysorbate in an amount of 1 or more based on the weight of hydroxyethyl cellulose. A pharmaceutical composition comprising polysorbate in an amount of 1.5 or more based on the weight of hydroxyethyl cellulose in claim 3. A pharmaceutical composition in claim 3, wherein the polysorbate is at least one selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, and polysorbate 80. A pharmaceutical composition according to claim 1, further comprising an osmotic pressure regulator, a pH regulator or a stabilizer. A pharmaceutical composition in claim 1, wherein the composition is for ophthalmic use. A pharmaceutical composition in claim 20, wherein the composition has an osmotic pressure of 230 to 350 mOsmol/kg and a pH of 6.0 to 7.5. A pharmaceutical composition according to claim 1, wherein the composition remains a transparent solution after storage for 3 months in an accelerated stability chamber at 40 degrees and 75%RH. A first step of adding diquafosol or a pharmaceutically acceptable salt thereof, hydroxyethyl cellulose, polysorbate and tyloxapol to purified water and dissolving them; A second step of adding and dispersing polycarbophil into purified water; and A step of mixing the solution obtained in the first step and the solution obtained in the second step. A method for producing an ophthalmic composition comprising:

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