JPH09157157A - Medicine composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicine composition containing a slightly water-soluble medicine, a polyhydric alcohol and a nonionic surfactant, and suitable for its administration into sites such as ear, nose and throat. SOLUTION: This solubilization type aqueous medicine composition contains 0.01-10wt.% of a slightly water-soluble medicine, 0.1-20% of a polyhydric alcohol (e.g. propylene glycol) and 0.01-10wt.% of a nonionic surfactant [e.g. polyoxyethylene (20) sorbitan oleate]. The medicine composition can be applied to allergic rhinitis, allergic pharyngits, ceruminosis, vasomotor rhinitis, infectious anemia, infectious pharygits, etc. The medicine composition can be administered in the form of collunarium, ear drop, directly mucous membrane-coating medicine, directly mucous membrane-spraying medicine. etc. The slightly water-soluble medicine includes an antiinflammatory medicine: amlexanox, a steroid hormone: beclomethasone propionate, and an earwax-removing agent: dioctyl disodium sulfosuccinate.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical composition suitable for administration to a site such as ear, nose or pharynx.

[0002]

2. Description of the Related Art In recent years, due to the epidemic of allergic rhinitis and the like, the number of people who have diseases such as inflammation in the nose and pharynx has increased dramatically. On the other hand, treatments such as administration of anti-inflammatory agents, steroid hormones and anti-allergic agents are being performed. However, since many of these drugs are poorly soluble in water, they are often dissolved in CFCs and used as an aerosol. Aerosol formulations have become difficult to use at present from the viewpoint of air pollution, and in addition, when solubilized in water with a surfactant, etc., there is a problem that irritation to these application sites by the solubilizer occurs. The development of an alternative prescription has been awaited.

On the other hand, with respect to the drug relating to the ears, there are many substances that are poorly soluble in water, such as an agent for removing earwax, and solubilization and suppression of the expression of irritation to the ears have been major problems.

Although such a drug can be administered by uniformly dispersing it in a vehicle, for example, a preparation such as an eye ointment can be considered.
Since the bioavailability of such a preparation is remarkably lowered, it is not preferable in terms of the preparation and setting of the dose, and it is difficult to say that it is suitable for practical use.

The present invention has been made under such circumstances, and it is an aqueous solution of a poorly water-soluble drug that exhibits low irritation to the ear, nose and / or pharynx. It is an object to provide a formulation.

[0005]

In view of such circumstances, the present inventors have earnestly sought an aqueous preparation of a poorly water-soluble drug with low irritation to the ear, nose and / or pharynx. As a result of repeated research, a solubilized aqueous pharmaceutical composition containing a poorly water-soluble drug, a polyhydric alcohol, and a nonionic surfactant is less irritating to the mucous membranes of the ear, nose, and pharynx, and is bioavailable. I found that it was also excellent and completed the invention. Hereinafter, the present invention will be described in detail.

(1) Pharmaceutical Composition of the Present Invention The pharmaceutical composition of the present invention is characterized by containing a poorly water-soluble drug, a polyhydric alcohol and a nonionic surfactant.
A pharmaceutical composition for the ear, nose and / or pharynx. Examples of diseases to which such a pharmaceutical composition is applied include allergic rhinitis, allergic pharyngitis, earwax plugging, vasomotor rhinitis, infectious rhinitis, infectious pharyngitis and the like. Examples of the administration form include nasal drops, ear drops, direct mucous membrane application, and mucous membrane direct spraying. As a suitable administration method, it may be dropped, sprayed or applied so that it can be uniformly administered to the affected area, and this work may be performed once or several times a day. The pharmaceutical composition of the present invention is
As will be described later, since there is little irritation to the mucous membrane, it is possible to safely administer an amount capable of suppressing symptoms such as inflammation.

(2) Water-insoluble drug used in the present invention The water-insoluble drug used in the present invention is hardly soluble in water, and
As long as the drug can be administered to the nose, throat, ears, etc., it can be used without particular limitation. Preferred examples of such drugs include anti-inflammatory agents amlexanox, flunisolide, steroid hormone beclomethasone propionate, and earwax remover dioctyldisodium sulfosuccinate. All of these are drugs that are poorly soluble in water and are often administered in a dosage form such as an aerosol. In the pharmaceutical composition of the present invention,
The preferable compounding amount of these drugs depends on the optimal application amount of each drug, but is generally 0.01-
10% by weight is preferable, 0.05 to 5% by weight is more preferable, and 0.1 to 1% by weight is further preferable. These may be used alone or in combination of two or more.

(3) Polyhydric Alcohol Used in the Present Invention The polyhydric alcohol used in the present invention is particularly limited as long as it is miscible with water at an arbitrary ratio and has two or more hydroxyl groups. Can be used without receiving. Suitable examples of such polyhydric alcohols include propylene glycol, polyethylene glycol, glycerin, 1,3-butanediol, sorbitol and maltitol. These polyhydric alcohols can help dissolve poorly water-soluble drugs and can reduce irritation of the drugs and surfactants to the nose, throat, and ears. In the present invention,
The preferable blending amount of these polyhydric alcohols is 0.1 to 2
0% by weight, more preferably 0.5 to 10% by weight,
1 to 8% by weight is more preferable. These polyhydric alcohols may be used alone or in combination of two or more.

(4) Nonionic Surfactant Used in the Present Invention The nonionic surfactant used in the present invention is not particularly limited as long as it has a solubilizing ability, that is, an HLB of 7 to 20. Can be used without receiving. Examples of such nonionic surfactants include polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester,
Preferable examples include polyoxyethylene glycerin fatty acid ester and polyoxyethylene alkyl ether.
Most preferred of these are polyoxyethylene sorbitan fatty acid esters. These are all commercially available. Further, the number of addition moles of these polyoxyethylenes is preferably 6 to 40, more preferably 10
It is -30, and more preferably 10-20.
The preferred carbon chain length of the fatty acid or alkyl group is
It is 8 to 22, more preferably 10 to 20, and still more preferably 12 to 18. These alkyl moieties may be linear or branched, but linear ones are preferred. The unsaturated bond may or may not be included, but it is preferable to include one. A concretely most preferable nonionic surfactant is polyoxyethylene (20) sorbitan oleate. The content of these nonionic surfactants in the present invention is preferably 0.01 to 10% by weight, more preferably 0.05 to 8% by weight, still more preferably 0.1 to 5% by weight. Is. These may be used alone or in combination of two or more.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below with reference to examples, but it goes without saying that the present invention is not limited to these examples. All numerical values represent parts by weight.

Example 1 A nasal drop was prepared according to the following prescription. That is, the prescription ingredients were dissolved by heating at 80 ° C., cooled to room temperature, and then packaged in a nasal drop bottle to prepare a nasal drop. still,
The solution was a colorless and transparent liquid. Amlexanox 1 POE (10) sorbitan monooleate 3 Propylene glycol 8 Methylparaben 0.2 Water 87.8

Example 2 A nasal drop was prepared in the same manner as in Example 1.
The solution was colorless and transparent. Flunisolide 1 POE (20) oleyl ether 0.1 1,3-butanediol 15 methylparaben 0.2 water 83.7

Example 3 A drug for spraying on the nose or throat was prepared according to the following formulation. That is, 80 prescription ingredients
It was melted by heating at ℃, filled in a spray bottle and used as a spray. The solution was colorless and transparent. Beclomethasone propionate 5 POE (30) sorbitan sesquioleate 3 glycerin 5 propylene glycol 5 methylparaben 0.2 water 81.8

Example 4 An earwax remover was prepared in the same manner as in Example 1. The liquid state was a slightly cloudy liquid. Dioctyl disodium sulfosuccinate 5 POE (45) stearate 2 Maltitol 5 Sorbitol 3 Methylparaben 0.2 Water 84.8

(Example 5) A spray for the throat or nose was prepared in the same manner as in Example 3. The solution was colorless and transparent. Beclomethasone propionate 3 Amlexanox 1 POE (6) sorbitan monooleate 2 POE (30) behenyl ether 2 propylene glycol 9 polyethylene glycol 6000 3 methylparaben 0.2 water 79.8

[0016]

EXAMPLES The action of the pharmaceutical composition of the present invention will be described in detail below with reference to examples.

Example 1 Ocular Mucosal Irritation Test Hartley white guinea pig (male, 300-350)
g) Examples 1 to 1 of the above-mentioned embodiment using 5 animals per group
5 and those in which those polyhydric alcohols were replaced with water (Comparative Examples 1 to 5) were examined for irritation to mucous membranes using the Draize method. That is. -: No reaction, +: clear hyperemia, ++: edema reaction. Table 1 shows the results. From this, it can be seen that all the pharmaceutical compositions of the present invention have low irritation to mucous membranes. In addition, Comparative Examples 1 to 5 were all cloudy, and Comparative Example 4 was more cloudy than Example 4.

[0018]

[Table 1]

Example 2 Skin Irritation Test Hartley white guinea pig (female, 350-400)
After shaving the back using g), the same sample as in Example 1 was closed-patched for 48 hours, and the skin reaction was evaluated 49 hours after administration by the Draize criterion. That is, −: no reaction, ±: false positive reaction, +: reaction with clear erythema, +
+: Reaction accompanied by edema. Table 2 shows the results. From this, it can be seen that the pharmaceutical composition of the present invention has improved safety.

[0019]

[Table 2]

Example 3 Persistence test The nasal drops of Example 1 of the embodiment of the invention and the propylene glycol replaced by water (Comparative Example 1), POE of Example 1
(10) With respect to the sorbitan monooleate replaced with water (Comparative Example 6), a sustainability test was conducted using 5 Hartley guinea pigs (male, 300 to 350 g) per group. That is, an endotoxin 0.5 mg / ml physiological saline solution was administered into the glass body of 5 μl at a certain time after drug administration, and 1 hour after that, it was observed on the basis of Draize. Table 3 shows the results. From this, it can be seen that the pharmaceutical composition of the present invention has excellent durability.

[0021]

[Table 3]

Example 4 Actual Use Test A comparative test was conducted on Example 1 and Comparative Example 2 using 20 patients with allergic rhinitis. That is, 20 people were divided into 2 groups of 10 people, each group used Example 1 for the first week, washed out for 1 week, and then used Comparative Example 1 for one week. The remaining group used Comparative Example 1 for the first week, 1
Example 1 was used for one week after weekly washout.
The result of the comparison was answered by a questionnaire. Table 4 shows the results
Shown in From this, it is confirmed that the present invention has durability and mildness.

[0023]

[Table 4]

[0024]

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a pharmaceutical composition for nose, throat, and / or ear containing a poorly water-soluble drug having low irritation and excellent durability.

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Claims (5)

[Claims] 1. A pharmaceutical composition for ear, nose and / or pharyngeal administration containing a poorly water-soluble drug, a polyhydric alcohol and a nonionic surfactant. 2. The content of poorly water-soluble drug is 0.01 to 10
The pharmaceutical composition according to claim 1, wherein the content of the polyhydric alcohol is 0.1 to 20% by weight, and the content of the nonionic surfactant is 0.01 to 10% by weight. 3. The poorly water-soluble drug is one or more selected from anti-inflammatory agents amlexanox, flunisolide, steroid hormone beclomethasone propionate, and earwax remover dioctyldisodium sulfosuccinate. Item 3. A pharmaceutical composition according to item 1 or 2. 4. The polyhydric alcohol is one or more selected from propylene glycol, polyethylene glycol, glycerin, 1,3-butanediol, sorbitol and maltitol, and the polyhydric alcohol is any one of claims 1 to 3. The pharmaceutical composition according to. 5. The nonionic surfactant is one or more selected from polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene glycerin fatty acid ester, and polyoxyethylene alkyl ether. The pharmaceutical composition according to any one of claims 1 to 4.