JPH1036253A - Aqueous suspended collyria - Google Patents

Abstract

PROBLEM TO BE SOLVED: To prepare an aqueous suspended collyria excellent in redispersion properties and hardly causing caking of a sedimented layer of the medicine even after a long period preservation. SOLUTION: This aqueous suspended collyria is the one containing slightly soluble medicine, e.g. fluorometholone, as an active ingredient and contains a suspending agent selected from the group of D-mannitol, D-sorbitol, xylitol, a propylene glycol, a citric acid salt and a mixture thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to an aqueous suspension ophthalmic solution excellent in redispersibility and storage stability.

[0002]

2. Description of the Related Art Steroidal anti-inflammatory drugs such as fluorometholone and dexamethasone have a strong anti-inflammatory action and are widely used as external or ophthalmic anti-inflammatory drugs, but have the disadvantage of low solubility in water. It is generally used for eye drops in the form of an aqueous suspension eye drop or an ointment. Aqueous suspension eye drops are aqueous preparations in which microcrystals or fine powders of such poorly soluble drugs are suspended in an aqueous medium.Easier eye drop method than ophthalmic ointment and less discomfort during eye drops It has the feature of.

[0003] However, the aqueous suspension ophthalmic solution has a problem that the suspended drug inevitably precipitates. For this reason, in the case of aqueous suspension eye drops, the sedimentation rate of the drug is reduced in order to increase the storage stability, and when a sedimentary layer is formed by the sedimentation of the drug, uniform shaking or agitation for a short period of time makes it uniform. There is a demand for characteristics (referred to as re-dispersibility or re-suspension) capable of regenerating a suspension.

In general, in the production of aqueous suspension eye drops, a suspending agent such as sodium carboxymethylcellulose, methylcellulose, and polysorbate 80 is used to efficiently suspend fine crystals and fine powder. Increasing the amount of the suspending agent to increase the viscosity of the suspension can slow down the sedimentation rate of fine crystals and fine powders. And the redispersibility deteriorates.

[0005] It is also known that the sedimentation speed can be reduced by reducing the particle size of the drug, but the redispersibility is deteriorated (for these, Junichi Miyazaki and Masahiko Takano co-authored, “Eye drops”・ How to make and apply ”, No. 1
11-113, published by Nanzando Co., Ltd., 1962). Thus, in aqueous suspension ophthalmic solutions, good storage stability [prevention of the formation of strong agglomerates in the drug deposition layer (such agglomerates are generally called "caking". It is not easy to achieve both redispersibility and “New Pharmaceutical Science”, page 76, published by Hirokawa Shoten Co., Ltd., 1993, etc.). In addition, the above-cited reference teaches that a surfactant can be used for improving redispersibility.

In aqueous suspension ophthalmic solutions containing deprodone propionate, concentrated glycerin, propylene glycol, polyethylene glycol, D-mannitol, a suspending aid such as sodium carboxymethylcellulose, are added to a suspending agent. It is known that when a polyhydric alcohol such as D-sorbitol or a saccharide such as glucose, lactose or maltose is used in combination, an eye drop having a low sedimentation rate of the drug and excellent in redispersibility can be produced ( JP
5-951).

The suspending agents specifically disclosed in this publication are cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose. When this cellulose derivative is used, the sedimentation rate of the drug is reduced. It is taught that this can be slowed down and that re-dispersion is also facilitated (Col. 2, line 36-38). above
Suspension aids such as D-mannitol and D-sorbitol are used in combination with the above suspending agents, but their effect is to reduce the fine particle size of the active ingredient deprodone propionate for a long time. It is taught to maintain the stability (column 2, lines 46 to 49 of the same publication).

[0008]

SUMMARY OF THE INVENTION An object of the present invention is to provide an aqueous suspension ophthalmic solution having excellent redispersibility, and an aqueous suspension having both storage stability (mainly reduced caking) and redispersibility. It is to provide a suspension ophthalmic solution. More specifically, an aqueous suspension ophthalmic solution containing as an active ingredient a sparingly soluble drug such as a steroidal anti-inflammatory drug or a non-steroidal anti-inflammatory drug, and when a sedimentary layer is formed by sedimentation of the drug during storage. It is an object of the present invention to provide an eye drop which can quickly regenerate a uniform suspension by a simple operation such as manual stirring. It is also an object of the present invention to provide an aqueous suspension ophthalmic solution having the above-mentioned characteristics, wherein the ophthalmic solution does not form an aggregate or a conjugate in the deposited layer of the active ingredient even when stored for a long period of time.

[0009]

Means for Solving the Problems The present inventors have made intensive efforts to solve the above-mentioned problems, and as a result, substances such as D-mannitol, D-sorbitol, and the like have been found to be capable of storing and suspending aqueous suspension eye drops by themselves. It has been found that the dispersibility can be significantly improved. Conventionally, in the technical field of formulation, D-mannitol has been used as an isotonic agent, tablet, excipient for capsules and excipients for lyophilized formulations, and D-sorbitol has been used as excipient for tablets and capsules. However, there is no known example of using the compound itself as a suspending agent for an aqueous suspension. An example has been reported in which an aqueous suspension ophthalmic solution was produced using propylene glycol, D-mannitol, D-sorbitol or the like as a suspending aid (JP-A-5-951). , But is merely used as a suspending aid in combination with a cellulosic suspending agent.

Therefore, D-mannitol, D-sorbitol, etc. act as an excellent suspending agent by themselves, improve the storage stability and redispersibility of the aqueous suspension, and prevent caking. It is surprising that it has the effect of regenerating a uniform suspension from the resulting deposited layer.
The present invention has been completed based on these findings.

That is, the present invention is an aqueous ophthalmic suspension of a poorly soluble drug, comprising D-mannitol, D-sorbitol, xylitol, propylene glycol, and citrate as a suspending agent, and a mixture thereof. An ophthalmic solution characterized by containing a suspending agent selected from the group. According to another aspect of the present invention, there is provided an aqueous ophthalmic suspension of a poorly soluble drug, wherein the suspending agent is D-mannitol, D-sorbitol, xylitol, propylene glycol, and citrate, and a mixture thereof. An ophthalmic solution comprising a suspending agent selected from the group consisting of and substantially free of a cellulosic suspending agent is also provided.

According to yet another embodiment of the present invention, there is provided an aqueous ophthalmic suspension of a poorly soluble drug, wherein the suspending agent is D-mannitol, D-sorbitol, xylitol, propylene glycol, and citrate; And an ophthalmic solution comprising a suspending agent selected from the group consisting of a mixture thereof and a polyvinyl alcohol-based suspending agent, and substantially not containing a cellulose-based suspending agent. You.
According to a preferred embodiment of each of the above inventions, there are provided the above-mentioned eye drops wherein the poorly soluble drug is a steroidal anti-inflammatory agent; and the above eye drops wherein the poorly soluble drug is fluorometholone. Further, according to the present invention, a suspending agent useful for the production of an aqueous suspension ophthalmic solution of a poorly soluble drug, comprising D-mannitol, D-sorbitol, xylitol, propylene glycol, and citrate, and a mixture thereof. A suspending agent selected from the group is provided.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION The active ingredient drug contained in the aqueous suspension ophthalmic solution of the present invention is a poorly soluble drug having low solubility in water, and is generally used as an aqueous suspension in eye drops. If it is not particularly limited, for example,
Drugs such as steroidal or non-steroidal anti-inflammatory agents are preferred. As steroidal anti-inflammatory drugs,
For example, hydrocortisone acetate, prednisolone acetate,
Mention may be made of prednisolone, dexamethasone, dexamethasone phosphate, dexamethasone metasulfobenzoate, fluorometholone, and physiologically acceptable salts thereof. As these salts, for example, sodium salts, potassium salts and the like can be used. As the nonsteroidal anti-inflammatory agent, for example, indomethacin, pirenoxine, pimaricin and the like can be used. Of these, fluorometholone (9-fluoro-11β, 17-dihydr
oxy-6 α-methyl-1,4-pregnadiene-3,20-dione, listed in the 13th Revised Japanese Pharmacopoeia).

The amounts of these active ingredients should be appropriately selected according to the kind of the active ingredients so that an effective concentration in the eye can be achieved when the eye drops are administered (one to several drops). Generally, it may be about 0.01 to 1.0% by weight, preferably about 0.05 to 0.5% by weight, based on the total weight of the eye drops.
When using fluorometholone, adjust the active ingredient concentration.
Preferably, it is about 0.1%.

The aqueous suspension ophthalmic solution of the present invention is a group consisting of an aqueous suspension of the above-mentioned drug, comprising D-mannitol, D-sorbitol, xylitol, propylene glycol, and citrate, and a mixture thereof. And a suspending agent selected from the group consisting of: As the citrate, for example, sodium citrate or the like can be used. When the above suspending agent is used, a conventional general-purpose suspending agent, for example, without mixing a cellulosic suspending agent, prevents caking of the drug deposition layer, and
An aqueous suspension eye drop having good redispersibility can be produced.
These substances may be used alone, but may be used in an appropriate combination as long as they are not contraindicated in combination. Of these, D-mannitol is preferred.
The compounding amount may be appropriately selected according to the type of the drug, and is, for example, about 0.1 to 5.0% by weight, preferably about 0.2 to 2.0% by weight, based on the total weight of the eye drops.

The aqueous suspension ophthalmic solution of a preferred embodiment of the present invention is characterized in that it does not substantially contain a cellulosic suspending agent conventionally used widely for the production of an aqueous suspension ophthalmic solution. As such a cellulosic suspending agent,
For example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose can be mentioned.
However, a suitable amount of a general-purpose suspending agent other than the cellulosic suspending agent may be added to the aqueous suspension ophthalmic solution of the present invention. As such a suspending agent, for example, polyvinyl alcohol, polysorbate 80 and the like can be mentioned, but it is preferable to use polyvinyl alcohol.

In the aqueous suspension ophthalmic solution of the present invention, in addition to the above components, a pH adjuster such as hydrochloric acid and sodium hydroxide; a tonicity agent such as sodium chloride and glycerin; benzethonium chloride and benzalkonium chloride And preservatives such as paraoxybenzoic acid ester; buffers such as phosphate buffer and borate buffer; surfactants such as polyoxyethylene hydrogenated castor oil; Additives may be added. The amounts of these components are not particularly limited, but can be usually used in the range of about 0.001 to 0.1%. The method for producing the aqueous suspension ophthalmic solution of the present invention is not particularly limited.For example, components other than the sparingly soluble drug which is an active ingredient are dissolved in distilled water for injection in an appropriate order, and sterilized by filtration if necessary. Then, a uniform suspension may be produced by adding a poorly soluble drug and homogenizer or ultrasonic irradiation.

[0018]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples, but the scope of the present invention is not limited to the following Examples. Example 1 Sodium dihydrogen phosphate dihydrate (0.5 g) and anhydrous disodium hydrogen phosphate (0.11 g) were added to distilled water for injection (80 ml).
To pH 7.5, and benzalkonium chloride (0.01 g)
Was added. To this solution was added D-mannitol (2 g) to dissolve, and then the pH was finely adjusted by adding an appropriate amount of hydrochloric acid. Further, sodium chloride was added to increase the osmotic pressure ratio with the physiological saline solution to 1.
After adjusting to 0, distilled water for injection was added to make the total volume 100 ml. To this solution, fluorometholone (0.1 g) was added, and then suspended using a homogenizer to produce an aqueous suspension ophthalmic solution of the present invention.

Example 2 An aqueous suspension of the present invention was prepared in the same manner as in Example 1 except that D-mannitol was 0.2%.

EXAMPLE 3 Sodium dihydrogen phosphate dihydrate (0.5 g) and anhydrous disodium hydrogen phosphate (0.11 g) were mixed with distilled water for injection (80 ml).
To pH 7.5, and benzalkonium chloride (0.01 g)
Was added. To this solution, D-sorbitol (0.86 g) was added to dissolve, and then the pH was finely adjusted by adding an appropriate amount of hydrochloric acid. Add sodium chloride to increase the osmotic pressure ratio with saline.
After adjusting to 1.0, add distilled water for injection to make the total volume 100 ml.
And Fluoromethorone (0.1 g) was added to this solution, and the mixture was suspended using a homogenizer to produce an aqueous suspension ophthalmic solution of the present invention.

EXAMPLE 4 Sodium dihydrogen phosphate dihydrate (0.5 g) and anhydrous disodium hydrogen phosphate (0.11 g) were mixed with distilled water for injection (80 ml).
To pH 7.5, and benzalkonium chloride (0.01 g)
Was added. Xylitol (0.05 g) was added to this solution to dissolve it, and then the pH was finely adjusted by adding an appropriate amount of hydrochloric acid. Further, sodium chloride was added to increase the osmotic pressure ratio with the physiological saline solution to 1.
After adjusting to 0, distilled water for injection was added to make the total volume 100 ml. Fluoromethorone (0.1 g) was added to this solution, and the mixture was suspended using a homogenizer to produce an aqueous suspension ophthalmic solution of the present invention.

EXAMPLE 5 Sodium dihydrogen phosphate dihydrate (0.5 g) and anhydrous disodium hydrogen phosphate (0.11 g) were mixed with distilled water for injection (80 ml).
To pH 7.5, and benzalkonium chloride (0.01 g)
Was added. Propylene glycol (1 g) was added to this solution to dissolve it, and then the pH was finely adjusted by adding an appropriate amount of hydrochloric acid. Further, sodium chloride was added to adjust the osmotic pressure ratio to physiological saline to 1.0, and then distilled water for injection was added to adjust the total amount.
The volume was 100 ml. Fluoromethorone (0.1 g) was added to this solution, and the mixture was suspended using a homogenizer to produce an aqueous suspension ophthalmic solution of the present invention.

EXAMPLE 6 Sodium dihydrogen phosphate dihydrate (0.5 g) and anhydrous disodium hydrogen phosphate (0.11 g) were mixed with distilled water for injection (80 ml).
To pH 7.5, and benzalkonium chloride (0.01 g)
Was added. Sodium citrate (0.85 g) was added to the solution to dissolve it, and then the pH was finely adjusted by adding an appropriate amount of hydrochloric acid. Further, sodium chloride was added to adjust the osmotic pressure ratio to physiological saline to 1.0, and then distilled water for injection was added to adjust the total amount.
The volume was 100 ml. Fluoromethorone (0.1 g) was added to this solution, and the mixture was suspended using a homogenizer to produce an aqueous suspension ophthalmic solution of the present invention.

EXAMPLE 7 Sodium dihydrogen phosphate dihydrate (0.5 g) and anhydrous disodium hydrogen phosphate (0.11 g) were mixed with distilled water for injection (80 ml).
To pH 7.5, and benzalkonium chloride (0.01 g)
Was added. To this solution, D-mannitol (2 g) and propylene glycol (1 g) were added to dissolve, and then the pH was finely adjusted by adding an appropriate amount of hydrochloric acid. Further, sodium chloride was added to adjust the osmotic pressure ratio to a physiological saline solution to 1.0, and then distilled water for injection was added to make a total volume of 100 ml. Fluoromethorone (0.1 g) was added to this solution, and the mixture was suspended using a homogenizer to produce an aqueous suspension ophthalmic solution of the present invention.

Example 8 Sodium dihydrogen phosphate dihydrate (0.5 g) and anhydrous disodium hydrogen phosphate (0.11 g) were added to distilled water for injection (80 ml).
To pH 7.5, and benzalkonium chloride (0.01 g)
Was added. To this solution, D-sorbitol (2 g) and sodium citrate (0.85 g) were added to dissolve, and then the pH was finely adjusted by adding an appropriate amount of hydrochloric acid. Further, sodium chloride was added to adjust the osmotic pressure ratio to a physiological saline solution to 1.0, and then distilled water for injection was added to make a total volume of 100 ml. Fluoromethorone (0.1 g) was added to this solution, and the mixture was suspended using a homogenizer to produce an aqueous suspension ophthalmic solution of the present invention.

Example 9 Sodium dihydrogen phosphate dihydrate (0.5 g) and anhydrous disodium hydrogen phosphate (0.11 g) were added to distilled water for injection (80 ml).
To pH 7.5, and benzalkonium chloride (0.01 g)
Was added. To this solution, D-mannitol (2 g) and polyvinyl alcohol (1.4 g) were added and dissolved, and then the pH was finely adjusted by adding an appropriate amount of hydrochloric acid. Further, sodium chloride was added to adjust the osmotic pressure ratio to a physiological saline solution to 1.0, and then distilled water for injection was added to make a total volume of 100 ml. Fluoromethorone (0.1 g) was added to this solution, and the mixture was suspended using a homogenizer to produce an aqueous suspension ophthalmic solution of the present invention.

Example 10 Sodium dihydrogen phosphate dihydrate (0.5 g) and anhydrous disodium hydrogen phosphate (0.11 g) were added to distilled water for injection (80 ml).
To pH 7.5, and benzalkonium chloride (0.01 g)
Was added. To this solution was added D-mannitol (2 g) to dissolve, and then the pH was finely adjusted by adding an appropriate amount of hydrochloric acid. Further, sodium chloride was added to increase the osmotic pressure ratio with the physiological saline solution to 1.
After adjusting to 0, distilled water for injection was added to make the total volume 100 ml. After adding indomethacin (0.5 g) to this solution,
An aqueous suspension of the present invention was prepared by suspending the suspension using a homogenizer.

Example 11 Sodium dihydrogen phosphate dihydrate (0.5 g) and anhydrous disodium hydrogen phosphate (0.11 g) were added to distilled water for injection (80 ml).
To pH 7.5, and benzalkonium chloride (0.01 g)
Was added. To this solution was added D-mannitol (2 g) to dissolve, and then the pH was finely adjusted by adding an appropriate amount of hydrochloric acid. Further, sodium chloride was added to increase the osmotic pressure ratio with the physiological saline solution to 1.
After adjusting to 0, distilled water for injection was added to make the total volume 100 ml. After adding dexamethasone (0.1 g) to this solution,
An aqueous suspension of the present invention was prepared by suspending the suspension using a homogenizer.

Comparative Example 1 Sodium dihydrogen phosphate dihydrate (0.5 g) and anhydrous disodium hydrogen phosphate (0.11 g) were mixed with distilled water for injection (80 ml).
To pH 7.5, and benzalkonium chloride (0.01 g)
Was added. Then, an appropriate amount of hydrochloric acid was added to finely adjust the pH, and sodium chloride was further added to adjust the osmotic pressure ratio to a physiological saline solution to 1.
After adjusting to 0, distilled water for injection was added to make the total volume 100 ml. Fluoromethorone (0.1 g) was added to the solution, and the mixture was suspended using a homogenizer to produce an aqueous suspension ophthalmic solution.

Comparative Example 2 Sodium dihydrogen phosphate dihydrate (0.5 g) and anhydrous disodium hydrogen phosphate (0.11 g) were mixed with distilled water for injection (80 ml).
To pH 7.5, and benzalkonium chloride (0.01 g)
Was added. Polyvinyl alcohol (1.4 g) was added to this solution to dissolve it, and then the pH was finely adjusted by adding an appropriate amount of hydrochloric acid. Further, sodium chloride was added to adjust the osmotic pressure ratio to physiological saline to 1.0, and then distilled water for injection was added to adjust the total amount.
The volume was 100 ml. Fluoromethorone (0.1 g) was added to the solution, and the mixture was suspended using a homogenizer to produce an aqueous suspension ophthalmic solution.

Comparative Example 3 Sodium dihydrogen phosphate dihydrate (0.5 g) and anhydrous disodium hydrogen phosphate (0.11 g) were mixed with distilled water for injection (80 ml).
To pH 7.5, and benzalkonium chloride (0.01 g)
Was added. To this solution was added methylcellulose (0.5 g) to dissolve, and then the pH was finely adjusted by adding an appropriate amount of hydrochloric acid. Add sodium chloride to increase the osmotic pressure ratio with saline.
After adjusting to 1.0, add distilled water for injection to make the total volume 100 ml.
And Fluoromethorone (0.1 g) was added to the solution, and the mixture was suspended using a homogenizer to produce an aqueous suspension ophthalmic solution.

Comparative Example 4 Sodium dihydrogen phosphate dihydrate (0.5 g) and anhydrous disodium hydrogen phosphate (0.11 g) were mixed with distilled water for injection (80 ml).
To pH 7.5, and benzalkonium chloride (0.01 g)
Was added. Polyvinyl alcohol (1.4 g) was added to this solution to dissolve it, and then the pH was finely adjusted by adding an appropriate amount of hydrochloric acid. Further, sodium chloride was added to adjust the osmotic pressure ratio to physiological saline to 1.0, and then distilled water for injection was added to adjust the total amount.
The volume was 100 ml. Fluoromethorone (0.1 g) was added to the solution, and the mixture was suspended using a homogenizer to produce an aqueous suspension ophthalmic solution.

Comparative Example 5 Sodium dihydrogen phosphate dihydrate (0.5 g) and anhydrous disodium hydrogen phosphate (0.11 g) were mixed with distilled water for injection (80 ml).
To pH 7.5, and benzalkonium chloride (0.01 g)
Was added. Polyvinyl alcohol (1.4 g) was added to this solution to dissolve it, and then the pH was finely adjusted by adding an appropriate amount of hydrochloric acid. Further, sodium chloride was added to adjust the osmotic pressure ratio to physiological saline to 1.0, and then distilled water for injection was added to adjust the total amount.
The volume was 100 ml. After dexamethasone (0.1 g) was added to this solution, it was suspended using a homogenizer to produce an aqueous suspension ophthalmic solution.

Test Example The redispersibility of a drug precipitated on the bottom of an eyedropper was evaluated by the following method. A 5 ml ophthalmic container was filled with the aqueous suspension ophthalmic solutions of Examples 1 to 9 and Comparative Examples 1 to 4 to sediment the drug, and the ophthalmic container was rotated at a speed of 100 rpm to uniformly precipitate the drug. The time to dispersion was determined. The redispersibility after storage at 40 ° C. for one month was examined in the same manner. The results are shown in the table below.

[0035]

[Table 1] 眼 One month after manufacture at 40 ° C ────────────────── Example 13 seconds 3 seconds Example 2 3 seconds 3 seconds Example 3 3 seconds 4 seconds Example 4 5 seconds 5 seconds Example 5 4 seconds 4 seconds Example 6 3 seconds 9 seconds Example 7 4 seconds 4 seconds Example 8 3 seconds 5 seconds Example 10 17 Seconds 18 seconds Example 11 4 seconds 3 seconds Comparative Example 1 10 minutes 30 seconds No redistribution ^* Comparative Example 2 10 minutes 43 seconds 12 minutes 20 seconds Comparative Example 3 2 minutes 00 seconds No redistribution ^* Comparative Example 4 Redistribute does ^* not redisperse ^* Comparative example 5 3 min 44 sec 5 min 00 sec ────────────────── ^* redispersion impossible due to aggregation of the drug deposited layer

[0036]

EFFECT OF THE INVENTION The aqueous suspension ophthalmic solution of the present invention is excellent in redispersibility and excellent in storage stability since there is no caking of the drug-deposited layer even after long-term storage.

 ──────────────────────────────────────────────────の Continuing on the front page (72) Inventor Takashi Nagata 2-17-11 Kyobashi, Chuo-ku, Tokyo Inside Showa Yakuhin Kako Co., Ltd.

Claims (5)

[Claims] 1. An aqueous ophthalmic suspension containing a poorly soluble drug as an active ingredient, wherein D-mannitol and D-mannitol are used as suspending agents.
Sorbitol, xylitol, propylene glycol,
And a citrate, and a suspending agent selected from the group consisting of a mixture thereof. 2. An aqueous ophthalmic suspension containing a poorly soluble drug as an active ingredient, wherein D-mannitol and D-mannitol are used as suspending agents.
Sorbitol, xylitol, propylene glycol,
An ophthalmic solution comprising a suspending agent selected from the group consisting of citrate, citrate, and a mixture thereof, and substantially free of a cellulosic suspending agent. 3. The ophthalmic solution according to claim 1, wherein the poorly soluble drug is a steroidal anti-inflammatory drug. 4. The ophthalmic solution according to claim 3, wherein the steroidal anti-inflammatory drug is fluorometholone. 5. A suspending agent for an aqueous suspension ophthalmic solution containing a poorly soluble drug as an active ingredient, comprising: D-mannitol, D-sorbitol, xylitol, propylene glycol, citrate, and a mixture thereof. A suspending agent selected from the group consisting of: