HK1051003B - Ciclesonide-containing aqueous pharmaceutical composition - Google Patents

Description

Ciclesonide-containing aqueous pharmaceutical composition

Technical Field

The invention relates to a ciclesonide-containing aqueous pharmaceutical composition for use in pharmacotherapy, which comprises ciclesonide and hydroxypropylmethylcellulose, wherein the ciclesonide is dispersed in an aqueous medium in the form of solid particles. More particularly, the present invention relates to a ciclesonide-containing aqueous pharmaceutical composition which has excellent ciclesonide dispersibility during production as compared to conventional aqueous pharmaceutical compositions.

Background

Ciclesonide aqueous pharmaceutical compositions containing ciclesonide dispersed in an aqueous medium in the form of solid particles are expected to represent a useful pharmaceutical form for reasons including 1) no need to completely dissolve ciclesonide, 2) direct administration to the affected site by spraying or the like for the treatment of local diseases such as those of the nasal mucosa, eye and epidermis, and 3) they are easier to swallow than tablets or granules or the like.

Ciclesonide is resistant to wetting and readily aggregates when present in an aqueous medium. In the prior art, in order to stably disperse a drug having such properties in an aqueous medium, a wetting agent such as polysorbate 80 is added during the production process, and stirred vigorously.

The improvement of drug dispersibility in aqueous pharmaceutical compositions containing a drug dispersed as solid particles in an aqueous medium by the addition of a cellulose-based polymer has been disclosed in the patent specification WO99-37286 to Morishima et al. However, this patent relates to the problem of redispersion of drug that settles during storage and is fundamentally different from the present invention, which relates to the need to overcome the problem of migration of ciclesonide to bubbles formed by vigorous stirring during production and the problem of adsorption of ciclesonide on the walls of the production apparatus. Furthermore, in the Morishima et al patent specification, the concentration of the cellulose-based polymer is 0.0001 to 0.003%, and methylcellulose may be used instead of hydroxypropylmethylcellulose for the cellulose-based polymer, while a nonionic surfactant is added. It is difficult to deduce the present invention from this patent, in which the optimum value of the concentration of hydroxypropylmethylcellulose is 0.01% w/w to 0.5% w/w, and a surfactant is not required.

Disclosure of Invention

During the production of ciclesonide aqueous pharmaceutical compositions, high shear force is required to disperse ciclesonide, and it is necessary to vigorously stir the ciclesonide-containing aqueous pharmaceutical compositions. Ciclesonide migrated into the bubbles formed at this time. Since this results in an increase in the ciclesonide concentration in the upper portion of the ciclesonide aqueous pharmaceutical composition and higher than that in the lower portion, and results in a change in the ciclesonide concentration of the produced ciclesonide aqueous pharmaceutical composition. In addition, the recovery rate is lowered due to adsorption of ciclesonide on the walls of the production apparatus and the like.

These changes in ciclesonide concentration and adsorption of ciclesonide on the production apparatus are hardly possible at all to be improved by the addition of wetting agents such as polysorbate 80, which have been used in the prior art. Conversely, the amount of bubbles formed also results in an increase that promotes further changes in ciclesonide concentration.

Therefore, there is a wide need to develop a ciclesonide aqueous pharmaceutical composition that can avoid changes in the ciclesonide concentration during production and a decrease in the ciclesonide recovery rate.

That is, an object of the present invention is to provide a ciclesonide aqueous pharmaceutical composition that can avoid changes in the ciclesonide concentration during production and a decrease in the ciclesonide recovery rate.

As a result of the earliest studies to solve the above problems, the present inventors have found that by using a ciclesonide aqueous pharmaceutical composition containing ciclesonide and hydroxypropylmethylcellulose, a ciclesonide aqueous pharmaceutical composition can be provided while avoiding changes in the ciclesonide concentration and decreases in the ciclesonide recovery rate during the production process, and have completed the present invention.

That is, the present invention relates to an aqueous pharmaceutical composition comprising ciclesonide and hydroxypropylmethylcellulose, wherein the ciclesonide is dispersed in an aqueous medium in the form of solid particles.

Detailed description of the invention

It is essential that the composition of the present invention contains ciclesonide, and a water-soluble, low water-soluble or water-insoluble drug may be added in addition to ciclesonide. Specific examples of these drugs include vasoconstrictors, bronchodilators, anti-allergic agents and expectorants.

Although the ciclesonide particles usable in the present invention may be of any size, they are preferably in the range of 10nm to 100 μm, particularly preferably 10nm to 10 μm.

Although any substance can be used for the water-insoluble or low water-soluble substance usable in the present invention, a preferred example is cellulose, and a particularly preferred example is crystalline cellulose.

In the present invention, the concentration of the water-insoluble substance and/or the low water-soluble substance present in the form of solid particles in the aqueous medium is preferably 0.3% w/w or more, particularly preferably 1% w/w to 10% w/w, relative to the total amount of the composition.

In addition, aqueous polymers may also be added to the pharmaceutical compositions of the present invention. Specific examples of such aqueous polymers include propylene glycol alginate, pectin, low methoxyl pectin, guar gum (gua gum), gum arabic, carrageenan (carrageenan), methylcellulose, sodium carboxymethylcellulose, xanthan gum (xanthan gum) and hydroxypropylcellulose, and particularly preferred examples include sodium carboxymethylcellulose, polyethylene glycol and hydroxypropylcellulose. In addition, crystalline cellulose sodium carboxymethyl cellulose is a combination of these water-soluble substances and water-insoluble substances which can be used in the present invention, and it consists of a mixture of sodium carboxymethyl cellulose and crystalline cellulose. In addition, in the case of adding these water-soluble polymers, the concentration of the polymers with respect to the water-insoluble substance and/or the low water-soluble substance is preferably 1% w/w to 30% w/w.

The ciclesonide-containing aqueous pharmaceutical composition of the present invention should further contain hydroxypropylmethylcellulose. Although it may be of any grade, a specific example is hydroxypropylmethylcellulose 2910.

Although the hydroxypropylmethylcellulose may be present at any concentration, its concentration relative to the total amount of the composition is preferably 0.01% w/w to 30% w/w, particularly preferably 0.01% w/w to 5% w/w, more particularly preferably 0.01% w/w to 1% w/w, most preferably 0.01% w/w to 0.5% w/w.

Although the present invention does not necessarily require the addition of a wetting agent, a wetting agent may be added, and specific examples thereof include polysorbate 80, glyceryl monostearate, stearate-polyoxyl ester, lauryl polyethylene glycol (lauromaprogol), sorbitan oleate, and sucrose fatty acid ester.

In the present invention, a substance for regulating osmotic pressure (osmotic pressure regulator) may also be added to regulate osmotic pressure, and specific examples thereof include salts such as sodium chloride and water-soluble sugars such as glucose, with glucose being particularly preferred.

The effective amount of ciclesonide used in the present invention can be determined depending on the type and degree of each disease, the age and weight of the patient, etc.

The concentration of ciclesonide of the present invention with respect to the total amount of the composition is preferably 0.01% w/w to 1% w/w, particularly preferably 0.05% w/w to 0.5% w/w.

Any method of dispersing a water-insoluble substance and/or a substance having low water solubility in an aqueous medium can be used for producing the ciclesonide-containing aqueous pharmaceutical composition of the present invention, and a specific example thereof is a method using a homomixer.

To improve physical properties, appearance, odor, or the like of the preparation, known antibacterial agents, pH adjusters, preservatives, buffers, colorants, flavors, and the like may be added to the composition of the present invention as necessary. Examples of antibacterial agents include benzalkonium chloride, examples of pH adjusters include hydrochloric acid and sodium hydroxide, examples of preservatives include ascorbic acid, examples of buffers include phosphoric acid and salts thereof, examples of colorants include red dye No. 2, and examples of flavoring agents include menthol.

As described above, the present invention provides a ciclesonide aqueous pharmaceutical composition that can more effectively avoid changes in the ciclesonide concentration during production and decreases in the ciclesonide recovery rate than the prior art aqueous pharmaceutical composition. These results also improve quality and reduce production costs due to higher recovery.

Therefore, the invention has extremely high significance in the aspects of quality and economic benefit of the production of the ciclesonide aqueous pharmaceutical composition.

Examples

The present invention is illustrated by the following examples.

Ciclesonide used in the present invention was produced by Byk Gulden Co., crystalline cellulose sodium carboxymethyl cellulose was produced by Asahi Chemical Industry Co., Ltd. (Avicel TMRC-A591NF), and hydroxypropyl methyl cellulose 2910 was produced by Shin-Etsu Chemical Co., Ltd. (TC-5RW^TMOr Metrose 60SH-4000^TM) Produced by Nippon Surfactant Co., Ltd, polysorbate 80 was produced by Nikko Chemical Co., Ltd, and sorbitan oleate triester was produced by Nikko Chemical Co., Ltd, using a homomixer ROBOMICS^TMProduced by Tokushu Kika Kogyo co., Ltd.

Example 1

Ciclesonide aqueous pharmaceutical compositions containing the following components were prepared on a 300ml scale by treatment using a homogeneous mixer. The homogeneous stirrer was treated at 6000rpm for 30 minutes.

Composition (1)

Ciclesonide: 0.1% w/w

Crystalline cellulose sodium carboxymethyl cellulose: 1.7% w/w

Hydroxypropyl methylcellulose 2910(TC-5 RW)^TM)：0.01％w/w

Composition (2)

Ciclesonide: 0.1% w/w

Crystalline cellulose sodium carboxymethyl cellulose: 1.7% w/w

Hydroxypropyl methylcellulose 2910(TC-5 RW)^TM)：0.1％w/w

Composition (3)

Ciclesonide: 0.1% w/w

Crystalline cellulose sodium carboxymethyl cellulose: 1.7% w/w

Hydroxypropyl methylcellulose 2910(TC-5 RW)^TM)：1％w/w

Composition (4)

Ciclesonide: 0.1% w/w

Crystalline cellulose sodium carboxymethyl cellulose: 1.7% w/w

Hydroxypropyl methylcellulose 2910(Metrose 60 SH-4000)^TM)：0.01％w/w

Composition (5)

Ciclesonide: 0.1% w/w

Crystalline cellulose sodium carboxymethyl cellulose: 1.7% w/w

Hydroxypropyl methylcellulose 2910(Metrose 60 SH-4000)^TM)：0.1％w/w

Immediately after the compositions 1 to 5 were treated with the homomixer, ciclesonide aqueous pharmaceutical compositions were collected from the upper and lower portions of the emulsification tank, followed by quantifying the concentration of ciclesonide by HPLC. The value of the upper part of the emulsification tank was calculated with the ciclesonide concentration in the lower part of the emulsification tank as 100%.

Next, the ciclesonide concentration in the ciclesonide aqueous pharmaceutical composition recovered from the emulsification tank was quantified by HPLC, and the ciclesonide recovery rate was determined based on the theoretical value of the ciclesonide concentration, which was calculated from the charged amount.

Those values are listed in table 1.

Comparative example 1

Ciclesonide aqueous pharmaceutical compositions containing the following components were prepared on a 300ml scale by treatment using a homogeneous mixer. The homogeneous stirrer was treated at 6000rpm for 30 minutes.

Composition (6)

Ciclesonide: 0.1% w/w

Crystalline cellulose sodium carboxymethyl cellulose: 1.7% w/w

Polysorbate 80: 0.1% w/w

Composition (7)

Ciclesonide: 0.1% w/w

Crystalline cellulose sodium carboxymethyl cellulose: 1.7% w/w

Sorbitan oleic acid triester: 0.1% w/w

Immediately after the compositions 6 to 7 were treated with the homomixer, ciclesonide aqueous pharmaceutical compositions were collected from the upper and lower portions of the emulsification tank, followed by quantifying the concentration of ciclesonide by HPLC. The value of the upper part of the emulsification tank was calculated with the ciclesonide concentration in the lower part of the emulsification tank as 100%.

Next, the ciclesonide concentration in the ciclesonide aqueous pharmaceutical composition recovered from the emulsification tank was quantified by HPLC, and the ciclesonide recovery rate was determined based on the theoretical value of the ciclesonide concentration, which was calculated from the charged amount.

Those values are listed in table 1.

TABLE 1

	Preparation	Ciclesonide concentration (%)		Recovery (%)
					The upper part of the emulsification tank	Lower part of the emulsification tank
		Embodiment 1	Composition 1				138.1	100.0	104.2
Composition 2	100.3			100.0	100.7
			Composition 3			99.6	100.0	101.5
Composition 4	147.9			100.0	98.4
			Composition 5			100.4	100.0	100.8
Comparative example 1	Composition 6			131.1	100.0				78.2
		Composition 7	438.7			100.0	43.0

In compositions 2, 3 and 5 containing 0.1-1% w/w hydroxypropylmethylcellulose 2910, the concentration of ciclesonide in the emulsification tank immediately after treatment with the homogeneous mixer was uniform and the recovery rate was almost 100%. In addition, in compositions 1 and 4 containing 0.01% w/w hydroxypropylmethylcellulose 2910, the concentration of ciclesonide in the emulsification tank immediately after treatment with the homogeneous mixer was not very uniform, but the recovery rate was almost 100%. In contrast, in composition 6 containing 0.1% w/w polysorbate 80, the concentration of ciclesonide in the upper portion of the emulsification tank immediately after treatment with the homomixer was 30% or more higher than the concentration in the lower portion of the emulsification tank. Furthermore, the recovery rate decreased by about 20%. In composition 7 containing 0.1% w/w sorbitan oleate triester, the concentration of ciclesonide in the upper part of the emulsification tank immediately after treatment with the homogeneous mixer was 40% or more higher than that in the lower part of the emulsification tank, and the recovery rate decreased by more than half.

From these results, it was found that the use of a composition containing hydroxypropylmethylcellulose can prevent the variation of ciclesonide concentration during the production process and the decrease of ciclesonide recovery rate.

Claims (14)

1. An aqueous pharmaceutical composition comprising ciclesonide and hydroxypropylmethylcellulose, wherein said ciclesonide is dispersed in an aqueous medium in the form of solid particles.

2. The aqueous pharmaceutical composition according to claim 1, wherein the concentration of the hydroxypropylmethylcellulose is 0.01% by weight to 30% by weight with respect to the total amount of the composition.

3. The aqueous pharmaceutical composition according to claim 1, wherein the concentration of the hydroxypropylmethylcellulose is 0.01% by weight to 5% by weight with respect to the total amount of the composition.

4. The aqueous pharmaceutical composition according to claim 1, wherein the concentration of the hydroxypropylmethylcellulose is 0.01 wt% to 1 wt% with respect to the total amount of the composition.

5. The aqueous pharmaceutical composition according to claim 1, wherein the concentration of the hydroxypropylmethylcellulose is 0.01 wt% to 0.5 wt% with respect to the total amount of the composition.

6. The aqueous pharmaceutical composition according to any one of claims 1 to 5, further comprising one or more types of water-insoluble substances and/or substances with low water solubility.

7. The aqueous pharmaceutical composition according to claim 6, wherein the water-insoluble substance and/or the substance having low water solubility is cellulose.

8. The aqueous pharmaceutical composition according to claim 7, wherein the cellulose is crystalline cellulose.

9. The aqueous pharmaceutical composition according to claim 1, further comprising a water-soluble polymer.

10. The aqueous pharmaceutical composition according to claim 9, wherein the water-soluble polymer is one or more types of substances selected from the group consisting of polyethylene glycol, propylene glycol alginate, pectin, low methoxyl pectin, guar gum, gum arabic, carrageenan, methylcellulose, sodium carboxymethylcellulose, xanthan gum and hydroxypropylcellulose.

11. The aqueous pharmaceutical composition of claim 9, wherein the water soluble polymer is sodium carboxymethyl cellulose.

12. The aqueous pharmaceutical composition of claim 9, wherein the water soluble polymer is polyethylene glycol.

13. An aqueous pharmaceutical composition according to claim 9, wherein the water soluble polymer is hydroxypropyl cellulose.

14. The aqueous pharmaceutical composition according to claim 1, wherein a combination of a water-insoluble substance and a water-soluble polymer is present, which is crystalline cellulose sodium carboxymethyl cellulose.