JPS62292719A - Clear water-soluble drug for external use and production thereof - Google Patents

Abstract

PURPOSE:To provide the titled drug containing 1,3-bis(2-carboxychromon-5-yl)-2- hydroxypropane and an anticlouding agent, capable of effectively giving a clear aqueous solution and useful for the remedy of bronchial asthma, etc. CONSTITUTION:The objective drug contains (A) 1,3-bis(2-carboxychromon-5-yl)-2- hydroxypropane or its pharmacologically permissible salt [preferably disodium salt (sodium cromoglycate)] and (B) an anticlouding agent as active components. The concentration of the component A in the drug is preferably 0.05-10.0%(W/V). The anticlouding agent is e.g. cyclodextrin or nonionic, anionic or ampholytic surfactant, e.g. alpha-cyclodextrin. The concentration of the anticlouding agent is preferably 0.001-10.0%, especially 0.1-5.0% for cyclodextrin and 0.01-3.0% for surfactant.

Description

Detailed Description of the Invention 3. Detailed Description of the Invention [Field of Industrial Application] The present invention provides 1,3-bis(2-carboxychromone-5
The present invention relates to a clear water-soluble preparation for external use containing as an active ingredient a -yloxy)-2-hydroxypropane or a pharmaceutically acceptable salt thereof, and a method for producing the same.

[Prior Art] Disodium salt of 1.3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane (hereinafter referred to as sodium cromoglycate) is effective for treating bronchial asthma, allergic conjunctivitis, or allergic rhinitis. It is used as a therapeutic agent.

For example, Japanese Patent Publication No. 54-25082 describes a water-soluble preparation containing sodium cromoglycate as an active ingredient, containing a therapeutically useful proportion of 1,3-bis(
2-Carboxychromon-5-yloxy)-propan-2-ol or a pharmaceutically acceptable salt thereof, if the concentration of metal ions in this aqueous solution exceeds 0.40 ppm, A method of making a substantially clear sterile aqueous pharmaceutical composition comprising the active ingredient described above is disclosed, which comprises adding an effective amount of a chelating or sequestering agent to obtain the active ingredient. Also, special public service 57-5644
No. 8 discloses that a therapeutically effective amount of 1,3-bis(2-carboxychromon-5-yloxy)-propan-2-ol or a pharmaceutically acceptable salt thereof is useful for the treatment of the eye. compounds and additives which have the effect of increasing the viscosity of the aqueous solution and prolonging the action of the said therapeutically active ingredient, and in this case the elements of the Periodic Table 1 in the aqueous solution are added.
A method for producing a substantially clear sterile aqueous solution for ophthalmic use is disclosed, characterized in that the concentration of metal ions of groups b, na, Ilb, ma, IVa and IVb is kept below 20 PPm.

[Problem that the invention seeks to solve]

As described in the above patent publication, 1,3-bis(2
-carboxychromon-5-yloxy)-2-hydroxypropane or a pharmaceutically acceptable salt thereof, such as its disodium salt, is known to be routinely formulated into a clear aqueous solution.

++ That is, metal ions (Pb.

10+ ++ 10 earth 10+ 10+
+ 10÷Ca, Cu, AI
, Fe, Fe, Zn
.

ff Mg) When the 3 degree exceeds 0.4 pptn, or when a small amount of other coexisting substances are contained, mutual reactions occur, resulting in turbidity and precipitation, resulting in the formation of a composition that is completely unacceptable as a pharmaceutical product. Therefore, it is difficult to formulate a formulation, and as a solution to this problem,
Although there are methods disclosed in the above-mentioned patent publications, none are yet satisfactory.

[Means for solving problems]

The present inventors have discovered a formulation and a method for producing the same that more effectively forms a clear sterile aqueous solution without using the chelating agent and sequestering agent described in the above patent publication.

Therefore, according to the present invention, the active ingredient 1,3-bis(
By incorporating a pharmaceutically acceptable anti-clouding agent into 2-carboxychromon-5-yloxy)-2-hydroxypropane or a pharmaceutically acceptable salt thereof, the active ingredient is stabilized in the form of a clear aqueous solution. is maintained.

Suitable anti-whitening agents include cyclodextrin or nonionic, anionic or amphoteric surfactants, preferably α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin or tri0-methyl-β-cyclodextrin or cyclodextrin. Oxyethylene castor oil (Dinocol Co-40TX, C○-60TX, etc.), polyoxyethylene monostearate (Dinocol MYS-40, etc.), polyoxyethylene lauryl ether (Dinocol BL-9EX, BL-25, etc.), Sodium lauryl sulfate, Sokol SLS, etc.), sodium lauroyl sarcosinate, Sokol sarcosinate L, etc.
N, etc.), lauryldimethylaminoacetic acid betaine (Ninocol 5WANOL AM301, etc.), or Yashiura fatty acid amidopropyl dimethylaminoacetic acid betaine (
Ninocol 5WANOL AM 3130 etc.), polyoxyethylene hydrogenated castor oil and Kkkol 1 (C○-40
゜HCO-60, etc.), polyoxyethylene sorbitan monooleate (Polysorbate 80), etc.

The concentration of the clouding preventive agent used in the present invention is usually 0°001
~]0.0 w/v%, preferably 0.1 to 5.0 w/v% in the case of cyclodextrin, and 0.01 to 3.0 w/v% in the case of surfactant. 1,3-
Bis(2-carboxychromon-5-yloxy)-2
- Pharmaceutically acceptable salts of hydroxypropane include, for example, disodium salts and dipotassium salts, but disodium salts (sodium cromoglycate) are preferred.6 Also, 1,3-bis(2-carboxychromone-
The concentration of 5-yloxy)-2-hydroxypropane or a pharmaceutically acceptable salt is 0.05-10,0 w/v%
It is.

It is preferable to keep the concentration of metal ions that can form metal salts with the active ingredient in the aqueous solution as low as possible, but the addition of the chelating agent and sequestering agent described in the above patent publication may cause the concentration to become cloudy. Even when metal ions are contained at a concentration of 90%, the formulation of the clouding preventive agent of the present invention does not cause clouding at all and is stably maintained in the state of a bright liquid. Furthermore, the clear water-soluble formulation for external use of the present invention is pharmaceutically acceptable11)
It can contain all preservatives, buffers, excipients, viscous agents and other pharmaceutically active ingredients, and can be used in various dosage forms, such as eye drops, nasal drops, inhalation solutions, infusions, and injection solutions. and other dosage forms.

Typically, the topical clear water-soluble formulations of the present invention are packaged in multi-dose containers containing 1 to 100 mQ.

If the product does not contain preservatives or preservatives, it can be packed into single-dose containers with a capacity of 0.05 mQ or more by aseptic processing in a conventional manner.

Examples of pharmaceutically acceptable preservatives and preservatives include:
Methyl, ethyl, propyl or butyl paraben, benzalkonium chloride, benzethyl chloride, chlorhexidine gluconate, cetylpyridinium chloride, chlorobutanol, phenylethyl alcohol, benzyl alcohol, sodium dehydroacetate, sorbic acid, sodium sorbate, parachlor Methoxyphenol, parachlormetacresol, thimerosal, phenylmercuric nitrate, phenylmercuric borate, nitromezole, polymyxin B sulfate, and the like can be used.

Combinations of the above preservatives and preservatives can also be used.

In addition, as a pharmaceutically active ingredient, for example, an antiviral agent (
idoxuridine, etc.), anti-inflammatory agents (flurbiprofen, ibuprofen, fluoromesolone, dexamethasone sodium metasulfobenzoate, naphazoline hydrochloride, etc.), antihistamines (such as d-glolpheniramine maleate), and antibiotics (colistin). 1-lium methanesulfonate, chloramphenicol, cefbuperazone sodium, cephalexin, cephaloridine, etc.)
can be given.

Hereinafter, sodium cromoglycate will be explained as Test Examples and Examples, but the present invention is not limited thereto.

[Test Example 1] The anti-white turbidity effect of a sodium cromoglycolate-containing aqueous solution obtained using the anti-white turbidity agent of the present invention was tested. As additives, after dissolving them in water using a clearing agent, a metal ion sequestering agent, and an anti-clouding agent of the present invention described in the above patent publication, chromoglycate containing metal ions is added. - Lium was added and dissolved. Table 1 shows the state of the prepared aqueous solution.

In the case of the chelating agent and sequestering agent described in the above-mentioned patent publications, clouding occurs, but in the case of the clouding preventive agent discovered in the present invention, a clear aqueous solution is formed.

[Test Example 2] A stability test was conducted on the external clear water-soluble formulation of the present invention. The various compositions shown in Table 2 were prepared, filled into 5rnQ airtight containers, and stored at 40°C for 3 months.The properties of each sample and other test items [] were compared with those at the start of the test. did. The results obtained are shown in Table 3.

As shown in Table 3, no change was observed in any of the test items in any of the samples, indicating that they were stable. In the method for preparing preparation samples with various compositions shown in Table 2, the patent publication discloses that when preparing the comparative samples in Table 2, one contains sodium cromoglycolate and disodium ethylenediaminetetraacetate, and the other contains benzalkonium chloride. Make twice the desired final concentration containing phenylethyl alcohol and phenylethyl alcohol, and mix the two equal volumes of aqueous solutions slowly over time, otherwise clouding will occur. This is because a mixed solution of an anionic active ingredient (sodium cromoglycate) and a cationic preservative (benzalkonium chloride) becomes cloudy. However, in the present invention, A- in Table 2
When preparing sample D, there is no need to prepare two different aqueous solutions, and a clear sterile aqueous solution can be prepared by simply adding a nonionic surfactant or cyclodextrin as an anti-whitening agent in sequence.

[Test Example 3] Experimental conjunctivitis was produced using rats, and pharmacological studies were conducted on specimens A to D and comparative samples in Table 2.

(Experimental Method) Rat anti-Egg antibodies were produced by sensitizing female Wistar rats with Bordetella pertussis and Egg-albumin (Seikagaku Corporation). The antibody titer was 128 times higher in the rat back P, C, A reaction. This antibody was diluted 8 times with physiological saline and used in female Wistar rats (body weight 150-160 g).
) was injected under the upper eyelid mucosa of 30 μQ, and used in the experiment 72 hours later. 0.5% Egg-albumin, 0.5% Ev
ans Blue mixture (dissolved in physiological saline)1. O
Thirty minutes and 15 minutes before mQ was injected into the femoral vein, 5 μQ of the eye drops of each specimen were instilled into both eyes. In the control group, the same amount of physiological saline was instilled into the eyes.

Thirty minutes after the injection of the egg-albumin and Evans Blue mixture, the rats were sacrificed and the amount of dye leaked into the inflamed area was measured. The results obtained are shown in Table 4.

Table 4 As shown in Table 4, both Specimens A to D and the comparative sample show significant inhibition of inflammation compared to the control group.

From the above, the anti-whitening agent discovered in the present invention has a 1.3-
Bis(2-carboxychromon-5-yloxy)-2
- It has been found that hydroxypropane or its pharmaceutically acceptable salts, such as disodium, can be effectively prepared into clear aqueous solutions, and can be used without any pharmaceutical or pharmacological problems. 6 (Example 1) Sodium cromoglycate 1.0 g γ-cyclodextrin 0.3 g Sodium chloride
0.8g total ff1(rn Q)
100γ-cyclodextrin,
Sodium cromolycate and 1 to 3 lithium chlorides were dissolved in distilled water for injection in this order, filtered aseptically, the resulting solution was filled into an ampoule, and incubated at a temperature of 115°C for 3 hours.
Autoclave for 0 minutes.

(Example 2) Sodium cromolycate 360g 60g Nilacol -400.2g (Nonionic surfactant) Thimerosal 0.003g Total amount (
mQ) 100 Nilacol MYS-40, chromoglycate, and thimerosal are dissolved in sterilized purified water in this order, and then filtered aseptically. Fill this into a polyethylene container.

(Example 3) Sodium cromolycate 2.0g Nikolt IC0-400, 1g (Nonionic surfactant) Boric acid
1.5 g porcelain sand
0.2g Sodium chloride 0
．． 25g Chlorobutanol 0.4g
Total amount (rr+Q) 100 Chlorobutanol, boric acid, borax, sodium chloride,
Nisocort Ic0-40 and sodium cromoglycate are dissolved in sterilized purified water in this order, and then filtered aseptically. This is filled into a polypropylene container.

(Example 4) Sodium cromoglycate 2.0g Idoxuridine 0.1g Polysorbate 80
0.05g (nonionic surfactant) Chlorobutanol 0.4g total amount (mQ)
+00 Chlorobutanol, polysorbet 1-80, idoxuridine and sodium cromoglycate are dissolved in sterile purified water in this order and then filtered aseptically. Fill this into a polypropylene container.

(Example 5) Sodium cromoglycate 2.0 g Flurbiprofen 0.1 g β-Cyclodex 1
-Rin O, Sg Nitsukor HC○-600,
05g (Nonionic surfactant) Disodium hydrogen phosphate 1.6g Sodium dihydrogen phosphate 0.6g Sodium chloride
0.2g polyvinyl alcohol
1.0g Chlorobutanol 0.4g
Total amount (mQ) 1o.

Polyvinyl alcohol, chlorobutanol, disodium hydrogen phosphate, sodium dihydrogen phosphate, Nilacol H
C○-60, β-cyclodextrin, sodium chloride, flurbiprofen, and sodium cromoglycate are dissolved in sterilized purified water in this order, and then filtered aseptically. This is filled into a polypropylene container.

Claims (1)

[Claims] 1. Contains 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane or a pharmaceutically acceptable salt thereof (A) and an anti-clouding agent (B). A clear water-soluble formulation for external use. 2. The clear water-soluble preparation for external use according to claim 1, wherein the clouding preventive agent is cyclodextrin or a surfactant. 3. The clear water-soluble preparation for external use according to claim 1, wherein the concentration of component A is 0.05 to 10.0 w/v%. 4. The clear water-soluble preparation for external use according to claim 1 or 2, wherein the concentration of component B is 0.001 to 10.0 w/v%. 5. Claim 1, which contains component A and component B, and can further contain pharmaceutically acceptable preservatives, buffers, excipients, viscosity agents, and pharmaceutically active ingredients. The clear water-soluble preparation for external use according to item 2, 3 or 4. 6. The clear water-soluble preparation for external use according to claim 1, 2, 3, 4, or 5, wherein the pH is adjusted to 4.0 to 8.0. 7 Adding and dissolving 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane or its pharmaceutically acceptable (A) and anti-whitening agent (B) in an aqueous medium. A method for producing a clear water-soluble preparation for external use. 8. The method for producing a clear water-soluble preparation for external use according to claim 7, wherein the clouding preventive agent is cyclodextrin or a surfactant. 9. The method for producing a clear water-soluble preparation for external use according to claim 7, wherein the component A is added at a concentration of 0.05 to 10.0 w/v%. 10. The method for producing a clear water-soluble preparation for external use according to claim 7 or 8, wherein the component B is added at a concentration of 0.001 to 10.0 w/v%. 11 Claim 7, which contains component A and component B, and can further include pharmaceutically acceptable preservatives, buffers, excipients, viscosity agents, and pharmaceutically active ingredients;
A method for producing a clear water-soluble preparation for external use according to item 8, 9 or 10. 12. Claims 7, 8, 9, 10, or 11, wherein the pH is adjusted to 4.0 to 8.0.
A method for producing a clear water-soluble preparation for external use as described in .