JPH07316038A - Medicine composition for mucosal administration - Google Patents

Abstract

PURPOSE:To prepare the sustained release medicine composition for mucosal administration, efficiently adhering to mucosal sites, after the administration, and releasing the medicine from the composition over a long period. CONSTITUTION:The medicine composition comprises (A) an acrylic acid-alkyl (meth)acrylate copolymer, preferably the copolymer in which the alkyl group has a carbon number of 10-30 and whose 0.2% aqueous solution has a pH of 2.0-4.5, (B) the water-soluble inorganic salt or organic salt of an alkali metal and/or an alkaline earth metal, (C) a medicine, and (D) water, and has a viscosity controlled in a range of 100-100000mPa.S. The concentration of the component A in the composition is 0.1-2.0wt.%, preferably 0.2-1.5wt.%, and the concentration of the component B is preferably 0.01-3.0wt.%, especially 0.05-1.5wt.%. The medicine includes a local angiotonic agent, an antiallergic agent, a mydriatic agent, an antibiotic, a synthetic antibacterial agent, a steroid agent, and an antiinflammatory agent, and the content of the medicine is preferably 0.01-10wt.%.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a sustained-release pharmaceutical composition for mucosal administration. Specifically, it is a sustained-release drug composition for mucosal administration that efficiently adheres to a mucosal site after administration and further releases the drug from the composition over a long period of time.

[0002]

2. Description of the Related Art Since drugs that undergo a first-pass effect and physiologically active substances such as prostaglandins and peptide hormones are decomposed or metabolized in the digestive tract or liver, their effects are weakened or disappeared by oral administration. Therefore, in recent years, transmucosal administration has been attracting attention as an administration method in which a drug directly enters the bloodstream without passing through the liver. Furthermore, due to the increase in the number of hay fever patients in recent years, the demand for eye drops and nasal drops containing antiallergic agents, antihistamines and steroids has been rapidly increasing. Transmucosal preparations including systemic and local effects The importance of about has received much attention.

However, many conventional eye drops / nasal drops are liquids, and they are eliminated from the administration site or cause a dripping phenomenon immediately after administration, so that sufficient effects cannot be obtained or discomfort occurs. There was a drawback. Therefore, some of them are required to be administered 4 to 6 times a day in the preparation of anti-allergic drug and anti-histamine drug. Therefore, development of a mucosal preparation having a long-lasting effect is required. Is desired.

[0004]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a pharmaceutical composition for mucosal administration, which is excellent in the adhesiveness at the mucosal site and the sustained effect.

[0005]

Means for Solving the Problems The present inventors have made various studies on a pharmaceutical composition for mucosal administration, which has adhesiveness at the administration site and further has sustained drug release. As a result, it was found that a drug composition prepared by using an alkyl acrylate (meth) acrylate copolymer or a salt thereof has adhesiveness at a mucous membrane site. And, surprisingly, it was found that the addition of an alkali metal salt and / or an alkaline earth metal salt to the product results in a sustained drug release remarkably as compared with the case of no addition, and the present invention was completed. It was That is, the present invention provides: a) an alkyl (meth) acrylate copolymer or a salt thereof, b) an alkali metal salt and / or an alkaline earth metal salt, c) a drug and d).
The present invention provides a pharmaceutical composition for mucosal administration containing water as an essential component.

[0006] A used in the pharmaceutical composition for mucosal administration of the present invention
Acrylic acid (meth) acrylate copolymer or its
Salts are hydrophilic acrylic acid and lipophilic (meth) acrylic
It is a copolymer of acid alkyl ester. (Meth) Acry
The number of carbon atoms of the alkyl group in the acid alkyl ester is 1
~ 35 is preferred, and more preferably 10-30.
The alkyl acrylate (meth) acrylate copolymer itself is
It is a white powder and has no odor or a slightly peculiar odor.
And its 0.2% aqueous solution has a pH of 2.0 to 4.5
Is preferred. In addition, the copolymer has an infrared absorption spectrum
Wavenumber when measured by the potassium bromide tablet method
2940 cm^-1, 1710 cm^-1, 1455cm ^-1And 12
40 cm^-1It is preferable to have a characteristic absorption in the vicinity. In the present invention
Acrylic acid (meth) acrylic acid alkyl copolymer used
Dispersing 0.5 g in 100 ml of water results in an acidic viscosity.
It becomes a neutral liquid and is neutralized by adding an aqueous solution of a water-soluble basic substance.
When it becomes a viscous gel. Acrylic acid (meth) ac
As a preferred example of the alkyl phosphate copolymer, PEMU
LEN TR-1, TR-2 (US BF Goodr
(commercially available from ich)) and the like. Composition in the present invention
Concentration of acrylic acid (meth) acrylate copolymer
The degree is generally 0.1 to 2.0% by weight, preferably 0.2 to
It is 1.5% by weight.

Examples of the salt of an alkyl acrylate (meth) acrylate copolymer include ammonium salts and sodium salts. All or part of the carboxyl group of the alkyl acrylate (meth) acrylate copolymer is a salt. It is in the form of. In the present invention, the alkyl acrylate (meth) acrylate copolymer can be used as it is in the form of an acid, but in this case, it is preferable to add a water-soluble basic substance and change the acid into a salt. Examples of such water-soluble base substances include inorganic bases such as sodium hydroxide, potassium hydroxide, and ammonia water; organic bases include alkylamines such as methylamine, ethylamine, and propylamine; dimethylamine, diethylamine, and diamine. Dialkylamines such as propylamine; trialkylamines such as trimethylamine, triethylamine, tripropylamine; methanolamine, ethanolamine,
Alkanolamines such as propanolamine; dialkanolamines such as dimethanolamine, diethanolamine, dipropanolamine; trimethanolamine,
Trialkanolamines such as triethanolamine and tripropanolamine; amino acids such as arginine, lysine, histidine, ornithine and the like can be mentioned. Further, instead of the water-soluble basic substance, neutral amino acids such as glycine and glycols such as glycerin, propylene glycol, 1,3-butylene glycol, polyethylene glycol and the like can be added.

The alkali metal salt and / or alkaline earth metal salt used in the present invention include sodium chloride, potassium chloride, magnesium chloride, calcium chloride, barium chloride, monosodium phosphate, disodium hydrogen phosphate,
Monopotassium phosphate, dipotassium hydrogen phosphate, sodium sulfate, magnesium sulfate, sodium acetate, potassium acetate, sodium carbonate, monosodium hydrogen carbonate, potassium carbonate, monopotassium hydrogen carbonate, sodium citrate, sodium oxalate, sodium tartrate, Examples thereof include water-soluble inorganic salts or water-soluble organic salts such as sodium potassium tartrate, sodium succinate, sodium lactate, and sodium glutamate. These salts may be used alone or in combination.

The alkali metal salt used in the present invention and /
Alternatively, the concentration of the alkaline earth metal salt is preferably 0.01 to 3.0% by weight, more preferably 0.05 to 1.5% by weight in consideration of the osmotic pressure for administration to the mucous membrane. %
Is. Examples of the drug in the pharmaceutical composition of the present invention include local vasoconstrictors such as naphazoline hydrochloride and tetrahydrozoline hydrochloride; antiallergic agents such as sodium cromoglycate, ketotifen fumarate, oxatomide, emedastine fumarate; and pilocarpine hydrochloride, physostigmine salicylate and the like. Ocular agents; Mydriatic agents such as atropine sulfate and tropicamide; Antibiotics and synthetic antibacterial agents such as cephalexin, ofloxacin, norfloxacin; Steroid agents such as beclomethasone propionate and prednisolone; Anti-inflammatory agents such as indomethacin, pranoprofen, diclofenac sodium Local anesthetics such as lidocaine and ethyl aminobenzoate; bioactive polypeptides such as insulin, calcitonin, TPA, interferon and influenza vaccine It can be. Although the content can be arbitrarily determined in relation to the drug effect, it is preferably 0.01 to 10% by weight.

The balance of the pharmaceutical composition for mucosal administration of the present invention is water. Furthermore, in the present invention, if desired, in addition to water, it is possible to add appropriate additives within a range that does not impair the effects of the present invention. Specific examples of such additives include various surfactants; polysorbate 80, polyoxyethylene hydrogenated castor oil, suspending agents such as glycerin monostearate; lower alcohols such as ethanol and isopropanol; glycerin, propylene glycol. , Glycols such as 1,3-butylene glycol and polyethylene glycol; preservatives such as methylparaben, propylpyraben and benzalkonium chloride; isotonic agents such as mannitol and sorbitol; stabilizers such as sodium ethylenediaminetetraacetate; Liquid paraffin, castor oil, soybean oil and other solubilizers, sodium hyaluronate, hydroxypropyl cellulose, carboxyvinyl polymers and other polymers and the like can be mentioned.

To prepare the composition of the present invention, for example,
A water-soluble basic substance or the like is added to an aqueous solution of an alkyl acrylate (meth) acrylate copolymer or a salt thereof and uniformly mixed to adjust to a desired pH, for example 4 to 9, and an alkali metal salt and / or an alkaline earth metal. It can be prepared by adding an aqueous solution of salt with stirring and finally adding a drug. The viscosity of the pharmaceutical composition of the present invention is preferably adjusted depending on the administration site, and is 100 to 100,000 mPa · S.
Within the range, a composition having good adhesion to the mucosal site can be obtained. The viscosity of this range is acrylic acid (meth)
It can be adjusted by the concentration of the alkyl acrylate copolymer or its salt and the alkali metal salt and / or the alkaline earth metal salt, and a more preferable viscosity range is 1,000 to 50,000.
It is mPa.S. However, the viscosity is DV manufactured by Tokyo Keiki Co., Ltd.
Using an ME rotational viscometer, using the following rotor,
It is a value when measured under the conditions of 25 ° C. and rotation speed of 5 rpm. (Because the composition of the present invention is a non-Newtonian fluid,
The viscosity varies depending on the rotor used and the rotation speed. )

Viscosity Rotor 2,000 to 20,000 mPa · S ST 20,000 to 100,000 mPa · S S4-1 The administration site of the pharmaceutical composition for mucosal administration provided by the present invention is ocular , Nasal cavity, oral cavity, rectum, urethra, vaginal mucosa. Furthermore, as a method of administering the pharmaceutical composition for mucosal administration of the present invention, a drop-type container, a spray container or a container suitable for applying such a pharmaceutical composition to each mucous membrane, for example, an inserter capable of quantitative administration. Etc., drop it,
There are methods such as spraying and inserting, or putting into a tube and applying it like an ointment.

[0013]

INDUSTRIAL APPLICABILITY According to the present invention, the components (a) and (b) are used in combination so that an appropriate viscosity can be obtained, the influence of salts and the like on the mucous membrane after mucosal administration is reduced, and liquefaction of the composition due to viscosity reduction is achieved. It is possible to prevent the drug from being released slowly. The medicinal composition for mucosal administration of the present invention has excellent adhesiveness at the mucosal site, and further, sustained release of the drug, resulting in excellent sustaining of the effect.
Furthermore, an O / W type emulsion preparation can be obtained by adding an oil phase and mixing them uniformly when preparing the pharmaceutical composition of the present invention. Emulsion preparations are extremely useful for sustained-release or targeting of drugs. Originally, emulsions are prepared by emulsifying water and oil with a surfactant. When applied to mucous membranes, there are major problems in terms of toxicity and safety, and there are only limited surfactants that have precedent use in mucosal administration. However, in the pharmaceutical composition of the present invention, it is possible to use no surfactant at all or to reduce the amount to a small amount even if it is used, and it is possible to reduce problems in terms of toxicity and safety.

[0014]

The present invention will be described in more detail below with reference to examples and test examples, but the present invention is not limited thereto. Example 1 Alkyl Methacrylate Acrylate Copolymer (PEMUL
After dissolving 0.5 g of EN TR-2) in 50 g of purified water, another solution of 0.15 g of sodium hydroxide dissolved in 10 g of purified water was added and stirred. To this, 0.5 g of sodium chloride and 0.05 g of benzalkonium chloride dissolved in 10 g of purified water were added and stirred, and then a solution of 0.05 g of naphazoline hydrochloride dissolved in 10 g of purified water was gradually added to the purified water. After adding to 100 g, the mixture was stirred uniformly to obtain a pharmaceutical composition (pH: 5.2, viscosity: 990 mP
aS).

Example 2 After dissolving 0.6 g of the same alkyl acrylate methacrylate copolymer as in Example 1 in 60 g of purified water, another 0.2 g of sodium hydroxide dissolved in 10 g of purified water was added and stirred. . Sodium chloride (1 g) and benzalkonium chloride (0.05 g) dissolved in purified water (10 g) were added and stirred, and naphazoline hydrochloride (0.05 g) was added to purified water (1).
The solution dissolved in 0 g was gradually added, and purified water was further added to 1
After being set to 00 g, the mixture was stirred uniformly to obtain a pharmaceutical composition (p
H: 5.3, viscosity: 1,060 mPa.S).

Example 3 After dissolving 0.6 g of the same alkyl acrylate copolymer as in Example 1 in 30 g of purified water, another 0.2 g of sodium hydroxide dissolved in 8 g of purified water was added and stirred. . 50 g of castor oil and 0.0 of prednisolone
A solution in which 2 g was dissolved was gradually added and stirred to prepare an O / W emulsion. To this, 1 g of sodium chloride and 0.05 g of benzalkonium chloride dissolved in 10 g of purified water were added, and further purified water was added to 100 g, followed by stirring to obtain a pharmaceutical composition (pH: 6.5, Viscosity: 10,0
40 mPa.S).

Comparative Example 1 After 0.2 g of the same alkyl acrylate copolymer as in Example 1 was dissolved in 50 g of purified water, another 0.15 g of sodium hydroxide dissolved in 10 g of purified water was added and stirred. did. 0.05g of benzalkonium chloride
Was dissolved in 10 g of purified water and stirred, 10 g of a solution of 0.05 g of naphazoline hydrochloride in purified water was gradually added, and 100 g of purified water was further added, followed by uniform stirring to obtain a pharmaceutical composition. Was obtained (pH: 5.2, viscosity:
970 mPa.S).

Comparative Example 2 0.2 g of the same acrylic acid (meth) acrylate copolymer as in Example 1 was dissolved in 50 g of purified water, and then 0.2 g of sodium hydroxide was dissolved in 10 g of purified water. Addition and stirring. A solution of 0.02 g of prezonisolone in 50 g of castor oil was gradually added to this and stirred,
Prepare W emulsion. To this, a solution prepared by dissolving 0.05 g of benzalkonium chloride in 10 g of purified water was added, and after further adding purified water to 100 g, the mixture was stirred to obtain a pharmaceutical composition (pH: 6.6, viscosity: 10, 090mPa.S
). The drug releasing properties of the drug compositions for mucosal administration obtained in Examples 1 to 3 and Comparative Examples 1 and 2 were evaluated by the following method.

Evaluation of release property Using a suppository release tester manufactured by Toyama Sangyo Co., Ltd., a membrane filter (Millipore filter SSWP 0470) was used.
0) as a diaphragm, 37 ° pH 7.4 phosphate buffered saline as a test solution, and a sample side rotation speed of 25 rpm,
The test solution was sampled over time under the condition that the test solution side rotation speed was 100 rpm, and the drug concentration was quantified by the absorbance measurement method for naphazoline hydrochloride and the liquid chromatography method for prednisolone. 1) FIG. 1 shows the relationship between the amount of the drug (naphazoline hydrochloride) composition prepared in Examples 1 and 2 and Comparative Example 1 and the square root of time, and Table 1 shows the apparent release rate constants obtained from the slopes. Indicated. In FIG. 1, ◯ represents Comparative Example 1 (sodium chloride concentration 0.0%), Δ represents Example 1 (sodium chloride concentration 0.5%), and □ represents Example (sodium chloride concentration 1.0%). The vertical axis represents the amount of drug released (ng / ml), and the horizontal axis represents the square root of time.

[0020]

[Table 1] Table-1 ─────────────────────────────────── Example: Sodium chloride concentration Apparent release rate Constant (ng / ml ・ hr ^-1/2 ) ─────────────────────────────────── Comparative Example 1 0.0% 4446.9 ± 325.2 Example 1 0.5% 3882.0 ± 45.4 ^* Example 2 1.0% 3057.1 ± 123.3 ^** ───────── ─────────────────────────── ^{* *} P <0.05 ^** P <0.01 (significant difference from Comparative Example 1)

As is clear from FIG. 1 and Table 1, the drug composition for mucosal administration prepared by the present invention has a drug release property which is sustained in proportion to the sodium chloride concentration as compared with the comparative example. You can see that

2) FIG. 2 shows the relationship between the dissolution amount of the drug (prednisolone) composition prepared in Example 3 and Comparative Example 2 and the square root of time. Table 2 shows the apparent release rate constants obtained from the slopes. Indicated. In FIG. 2, ◯ represents Comparative Example 2 (sodium chloride concentration 0.0%), and □ represents Example 3 (sodium chloride concentration 1.0%). Drug release amount (ng /
ml) and the square root of time was taken on the horizontal axis.

[0023]

[Table 2] Table-2 ─────────────────────────────────── Example Sodium chloride concentration Apparent release rate Constant (ng / ml ・ hr ^-1/2 ) ─────────────────────────────────── Comparative Example 2 0.0% 731.3 ± 49.3 Example 3 1.0% 338.4 ± 60.5 ^* ───────────────────────── ─────────── ^* P <0.01 (Significant difference from Comparative Example 1)

As is clear from FIG. 2 and Table 2, the drug composition for mucosal administration prepared according to the present invention has a sustained drug release property as compared with the comparative example.

[Brief description of drawings]

1 shows the amount of drug released over time for the compositions of Examples 1 and 2 and Comparative Example 1. FIG.

FIG. 2 shows the drug release amount over time of the compositions of Example 3 and Comparative Example 2.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical display location A61K 45/00 47/02 Z 47/32 B C C08L 33/02 LHR 33/08 LHU

Claims (3)

[Claims] 1. A pharmaceutical composition for mucosal administration containing the following a) to d) as essential components. a) alkyl acrylate (meth) acrylate copolymer or salt thereof b) alkali metal salt and / or alkaline earth metal salt c) drug d) water 2. An alkyl acrylate (meth) acrylate copolymer or a salt thereof is 0.1 to 2.0% by weight, and an alkali metal salt and / or an alkaline earth metal salt is 0.01 to 3.
0% by weight, viscosity 100-100,000 mPa · S
The composition of claim 1 which is 3. The composition according to claim 1, which is substantially free of a surfactant.