JP3269770B2 - Aqueous suspension eye drops containing ionic polymer with excellent redispersibility - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an aqueous suspension type ophthalmic solution containing a poorly soluble drug having a viscosity of 100 cP or less containing an ionic polymer and a metal cation, and an aqueous suspension thereof. Type eye drops are characterized by exhibiting excellent drug redispersibility.

[0002]

2. Description of the Related Art When a drug having low solubility in water is formulated for ophthalmic use, an aqueous suspension type ophthalmic solution in which the drug is suspended may be considered. Commercially available aqueous suspension type eye drops include, for example, fluorometholone eye drops.

On the other hand, a preparation having a specific viscosity using a carboxyvinyl polymer (hereinafter, referred to as CVP), mainly for retaining a drug in eye drops in an eyelid,
It has been reported that it is a so-called gel-like preparation (JP-A-54-67021, JP-A-54-110312,
JP-A-2-503201).

When CVP is converted to an aqueous solution, it becomes a gel and exhibits a high viscosity. It is believed that due to this high viscosity property, the gel can stay on the cornea for a long time, and the gel gradually disintegrates to release the drug slowly and increase the absorption. Therefore, the technology described above is required to have a viscosity of at least 1000 cP, and it has been considered that this high viscosity is necessary for a sustained release action.

Further, it is known that the use of a CVP exhibiting Newtonian viscosity sheared by an ultrasonic irradiation device or the like can prepare an ophthalmic solution having a viscosity of 100 cP or less, which has an absorption promoting action (Japanese Patent Laid-Open No. 5-247308). No.).

[0006] However, none of the publications specifically describes an aqueous preparation in which the main drug is suspended. Furthermore, there is no description about the redispersibility of the suspended drug.

[0007]

When the aqueous suspension type ophthalmic solution is left for a long period of time, the drug sediments, and the container must be shaken and redispersed when instilling. However, when the precipitated drug causes secondary aggregation such as caking, it does not easily redisperse and must be shaken for a long time during instillation. One of the methods for improving redispersibility is to increase the particle size of the drug. However, in the case of eye drops, there is a disadvantage that large particles cause a foreign-body sensation to the eyes.

[0008] When CVP is blended with eye drops so as to have a viscosity of 10,000 cP or more, it becomes an ointment.
It is difficult to instill a certain amount from the instillation bottle, of course, and it is difficult for the patient to instill it, and it is necessary for the doctor to apply it to the conjunctival sac by hand. Furthermore, when preparing eye drops,
There are some difficult points such as difficulty in degassing due to bubbles in the solution and inability to sterilize by filtration.

For this reason, it was necessary to study an aqueous suspension type ophthalmic solution having low viscosity and excellent redispersibility.

[0010]

Means for Solving the Problems The present inventors have searched for an aqueous suspension type ophthalmic solution of a poorly soluble drug having a low viscosity and excellent redispersibility. Aqueous suspension type which is excellent in re-dispersibility of poorly soluble drugs by blending an ionic polymer such as CMC.Na) and a metal cation such as sodium ion or potassium ion to make the viscosity 100 cP or less. It has been found that an eye drop (hereinafter referred to as the eye drop of the present invention) can be obtained.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The ionic polymer used in the eye drops of the present invention includes CVP, CMC. Na, chondroitin sulfate, anionic polymers such as heparin sulfate are preferred,
In particular, synthetic polymers such as CVP and CMC. Na is more preferred.

The use concentration of the ionic polymer can be appropriately selected, but in the case of CVP, it is 0.001 to 0.2% (w /
v), particularly preferably 0.005 to 0.1% (w / v), and CMC. If it is Na, 0.01 to 0.1% (w /
v) is preferred.

The metal cation used in the ophthalmic solution of the present invention is a monovalent or divalent metal cation, preferably a monovalent metal ion such as a sodium ion or a potassium ion. If the concentration of the metal cation is too high, the redispersibility of the drug will be poor, and if the concentration is too low, the viscosity of the eye drop will be high and the desired eye drop cannot be obtained. The working concentration range is from 20 to 200 mM, especially from 100 to 150 mM.
mM is preferred. Metal cations include, for example, sodium chloride, potassium chloride, calcium chloride, sodium sulfate,
It can be supplied by using potassium sulfate, calcium sulfate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium carbonate, potassium carbonate, calcium carbonate, sodium acetate, sodium edetate, sodium citrate and the like.

Further, the pH affects the viscosity of the eye drops. That is, the viscosity increases as the pH increases,
As the pH decreases, so does the viscosity. Furthermore, pH also affects eye irritation, and it is not preferable that the pH is too high or too low. The pH range suitably used for the eye drops of the present invention is 4.0 to 8.0, more preferably 4.5 to 7.5.

The poorly soluble drug used in the ophthalmic solution of the present invention is one having low solubility in water such as clobetasone butyrate, fluorometholone, hydrocortisone acetate, dexamethasone, indomethacin and the like. In particular, the technique of the present invention can be suitably applied to fluorometholone eye drops.

The concentration of the sparingly soluble drug used can be appropriately selected.
(W / v), particularly preferably 0.02 to 0.1% (w / v).

The viscosity of the ophthalmic solution of the present invention is 100 cP or less in the concentration of ionic polymer or metal cation used.
Those having a viscosity of cP or less are more preferred.

In order to examine the usefulness of the eye drops of the present invention, the redispersibility of the eye drops of the present invention was examined. As a result, detailed data will be described in the section of redispersibility test described below. However, the ophthalmic solution of the present invention has a viscosity of 100 cP or less, has excellent redispersibility, and contains a poorly soluble drug, particularly flumeolotron as an active ingredient. It was confirmed that the composition was useful as an aqueous suspension type eye drop. It is considered that the effects of the present invention are achieved by the steric protection effect and the electrostatic protection effect by the polymer.

The general methods for preparing the eye drops of the present invention include the following. An ionic polymer is added to sterile purified water, and an isotonic agent, a buffering agent, and the like are added with stirring. Thereto, a sterile purified water suspension of the drug and the surfactant is added, and the mixture is further vigorously stirred and dispersed to obtain the eye drop of the present invention.

The above-mentioned tonicity agent is sodium chloride, concentrated glycerin, etc., the buffering agent is sodium phosphate, sodium acetate, etc., and the surfactant is polyoxyethylene sorbitan monooleate (hereinafter referred to as polysorbate 80). Do)
And stabilizers such as sodium edetate and sodium citrate, and preservatives such as benzalkonium chloride and paraben can be added in necessary amounts.

The formulation examples of the eye drops of the present invention and the results of redispersibility tests are shown below. These examples are for better understanding of the present invention, and limit the scope of the present invention. is not.

[0022]

[Examples of Formulation] Example 1 (Formulation 1) CVP (5 mg) was added to sterilized purified water (40 ml), and sodium chloride (800 mg) and sodium dihydrogen phosphate dihydrate (20 mg) were added with stirring. , Disodium hydrogen phosphate dodecahydrate (200 mg). There, fluorometholone (100mg) and polysorbate 80
(30 mg) of sterilized purified water (40 ml) was added thereto, and the mixture was further stirred vigorously. Then, sterilized purified water was added to make a total volume of 100 ml, pH 5.0, viscosity 0.93 cP,
A 0.1% (w / v) fluorometholone eye drop having a metal cation concentration of 140 mM is prepared.

Example 2 In the same manner as in Example 1, the concentrations of fluorometholone, polysorbate 80, sodium chloride, sodium dihydrogen phosphate dihydrate and disodium hydrogen phosphate dodecahydrate were measured in the same manner as in Example 1. 1 and 0.1% (w /
v) Prepare fluorometholone eye drops. A formulation containing no ionic polymer (Reference formulation 1) and a non-ionic polymer polyvinyl alcohol (hereinafter referred to as PVA)
) (Reference formulation 2). The pH of each formulation was 5.0 and the metal cation concentration was 140
mM. The number of each component in the table indicates% by weight (w / v).

[0024]

[Table 1]

Example 3 (Formulation 7) CVP (5 mg) was added to sterile purified water (40 ml), and sodium chloride (800 mg), sodium dihydrogen phosphate dihydrate (20 mg), and hydrogen hydrogen phosphate were added with stirring. Sodium dodecahydrate (200 mg), sodium edetate (10 mg) and benzalkonium chloride (5 mg) are added. To this was added a suspension of fluorometholone (20 mg) and polysorbate 80 (30 mg) in sterile purified water (40 ml), and the mixture was stirred vigorously. Then, sterile purified water was added to make a total volume of 100 ml, pH 7.3 and viscosity 10
0 cP or less, 0.02% of a metal cation concentration of 140 mM
(W / v) Prepare a fluorometholone eye drop.

Example 4 The concentrations of fluorometholone, polysorbate 80, sodium chloride, sodium dihydrogen phosphate dihydrate, disodium hydrogen phosphate dodecahydrate, sodium edetate and benzalkonium chloride were compared with those in Example 3. Similarly, fluorometholone and an ionic polymer are set as shown in Table 2, and a fluorometholone eye drop is prepared. The pH of each formulation
Is 7.3, the viscosity is 100 cP or less, and the metal cation concentration is 140 mM. The number of each component in the table is% by weight (w /
v).

[0027]

[Table 2]

[Redispersibility Test] A method by Matthews et al. For evaluating the redispersibility of a suspension by the number of rotations until it is uniformly dispersed is known (J. Pharm. Sci, 57 , 569-57).
3 (1968)). Therefore, the redispersibility of the eye drops of the present invention was examined according to the method described in this document.

(Experimental Method) After placing 50 ml of the suspension in a test tube and allowing it to stand at room temperature for 2 weeks, a constant speed (2 cycles / s) was obtained until the suspension was uniformly dispersed.
At ec), the film was inverted by 180 ° and redispersibility was observed.

(Results) As an example of the experimental results in Table 3, among the preparations containing fluorometholone as the main component, the preparations containing CVP (preparation 1, preparation 2, preparation 3) and CMC. The figure shows the number of inversions required for uniform re-dispersion in formulations containing Na (formulation 4, formulation 5, and formulation 6). In addition, a formulation containing a fluorometholone as a main component and containing no polymer (Reference Formulation 1) and a nonionic polymer PVA
The formula (Reference Formulation 2) containing the same was similarly shown.

[0031]

[Table 3]

As shown in Table 3, when the ionic polymer and the metal cation were blended, excellent redispersibility was recognized, and the degree depended on the blending concentration of the ionic polymer. In addition, the viscosity of each of these preparations was as very low as 20 cP or less.

[0033]

From the results of the redispersibility test described above, the ophthalmic solution of the present invention has excellent redispersibility, and is useful as an ophthalmic solution containing a poorly soluble drug, particularly fluorometholone as an active ingredient. Was found.

Continuation of the front page (58) Field surveyed (Int.Cl. ⁷ , DB name) A61K 9/10 A61K 47/30

Claims (2)

(57) [Claims] 1. A carboxyvinyl polymer, which is an ionic polymer, is compounded in an amount of 0.005 to 0.1% (w / v) and a metal cation in an amount of 100 to 150 mM.
An aqueous suspension type ophthalmic solution of a poorly soluble drug, wherein the redispersibility of the poorly soluble drug is enhanced by adjusting the viscosity to 7.5 cP or less. 2. A carboxyvinyl polymer, which is an ionic polymer, is compounded in an amount of 0.005 to 0.1% (w / v) and a metal cation in an amount of 100 to 150 mM.
An aqueous suspension of fluorometholone having 7.5 and a viscosity of 20 cP or less to enhance redispersibility.