WO1996031195A1

WO1996031195A1 - Package holding a procaterol hydrochloride aqueous solution formulation, and a procaterol hydrochloride aqueous solution formulation

Info

Publication number: WO1996031195A1
Application number: PCT/JP1996/000772
Authority: WO
Inventors: Yuzo Kimura; Shinichi Ishikawa; Masafumi Toda; Takakuni Matsuda
Original assignee: Otsuka Pharmaceutical Co Ltd
Current assignee: Otsuka Pharmaceutical Co Ltd
Priority date: 1995-04-04
Filing date: 1996-03-25
Publication date: 1996-10-10
Anticipated expiration: 1997-10-04
Also published as: KR19980703582A; AR002981A1; AU5015296A; CA2217360A1; MX9707695A; EP0820274A1

Abstract

An object of the present invention is to impart long-term storage stability to a pharmaceutical composition comprising an aqueous solution of procaterol hydrochloride. This invention is directed to an aqueous solution of procaterol hydrochloride which assures that the procaterol hydrochloride is kept from decomposing in the aqueous solution due to its oxidation reaction.

Description

DESCRIPTION

PACKAGE HOLDING A PROCATEROL HYDROCHLORIDE AQUEOUS SOLUTION FORMULATION, AND A PROCATEROL HYDROCHLORIDE AQUEOUS SOLUTION FORMULATION

Technical Field The present invention relates to a pharmaceutical composition comprising an aqueous solution of procaterol hydrochloride and a package which holds the pharmaceutical composition comprising an aqueous solution of procaterol hydrochloride. Bac ground Ajt;

Various procaterol preparations have been known. Procaterol hydrochloride in a low concentration has drawbacks of being unstable in an aqueous solution and low in long-term storage stability. The procaterol hydrochloride in a low concentration has a further disadvantage that it readily flows away by dint of our tear or snivel after administration.

Disclosure of the Invention An object of the present invention is to impart long-term storage stability to a pharmaceutical composition comprising an aqueous solution of procaterol hydrochloride (hereinafter referred to as "procaterol hydrochloride aqueous solution formulation") in a low concentration. Another object of the invention is to provide a procaterol hydrochloride aqueous solution capable of producing a prolonged effect after its application to the eye or the like.

The present inventors conducted extensive research to impart long-term storage stability to a procaterol hydrochloride aqueous solution formulation in a low concentration and found that the procaterol hydrochloride in a low concentration is decomposed in the aqueous solution by the oxidation reaction of the procaterol hydrochloride in the solution and that the oxidation reaction is not allowed to proceed in the absence of oxygen. The present invention has been completed based on these novel findings.

According to the present invention, there is provided a package holding a pharmaceutical composition comprising an aqueous solution of procaterol hydrochloride such that the procaterol hydrochloride is kept from decomposing in the aqueous solution due to its oxidation reaction. The decomposition of procaterol hydrochloride in an aqueous solution due to its oxidation can be prevented, for example, by maintaining the procaterol hydrochloride aqueous solution formulation under an oxygen-free atmosphere. The oxygen-free atmosphere can be produced by replacing the air in a glass container with nitrogen gas and sealing the container. Plastics containers most widely used for ophthalmic solutions have too high a gas permeability to retain the oxygen-free atmosphere even after replacement with nitrogen gas. Thus, according to the invention, the procaterol hydrochloride aqueous solution formulation is filled in a plastics container, and the container is packaged in a gas barrier packaging material. The present inventors' research found the following. When a plastics ophthalmic container full of an aqueous solution of procaterol hydrochloride is accommodated and sealed, together with an oxygen absorbent, in a bottle or a bag made of a gas-impermeable film, there is obtained a procaterol hydrochloride aqueous solution formulation which is excellent in the long-term storage stability.

Consequently a preferred embodiment of the package holding the procaterol hydrochloride aqueous solution formulation according to the invention is a package holding the procaterol hydrochloride aqueous solution formulation wherein the procaterol hydrochloride aqueous solution formulation is enclosed in a plastics container, and wherein the container is packaged, together with an oxygen absorbent, in a gas barrier packaging material .

Another preferred embodiment of the package holding the procaterol hydrochloride aqueous solution formulation according to the invention is a package holding the procaterol hydrochloride aqueous solution formulation wherein the procaterol hydrochloride aqueous solution formulation is enclosed in a plastics container; wherein the container is packaged in a gas barrier packaging material; and wherein a nitrogen gas and/or carbon dioxide gas is sealed in a space between the container and the gas barrier packaging material.

The present inventors further found that the effect of the procaterol hydrochloride solution formulation can be prolonged by incorporating into the formulation a water-soluble high-molecular-weight compound containing an anionic functional group and having a molecular weight of at least 10,000, preferably at least one water-soluble high-molecular-weight compound selected from the group consisting of acidic mucopolysaccharide and dextran sulfate containing a sulfuric acid group, and salts thereof.

Consequently, according to the present invention, there is also provided a procaterol hydrochloride aqueous solution formulation incorporating therein at least one high-molecular-weight compound containing an anionic functional group and having a molecular weight of at least 10,000.

Conventional plastics containers can be used as the container for accommodating the procaterol hydrochloride aqueous solution formulation according to the invention. The materials useful for the plastics containers are not specifically limited and can be known plastics such as polyethylene, polypropylene and like polyolefins, copolymers thereof, polyvinyl chloride, ethylene-vinyl acetate copolymers, polyester, nylon, polycarbonate, polyethylene terephthalate, etc. A combination of at least two of these same or different polymers having a complex multilayered structure may also be used. There is no specific limitation on the shape and size of the container insofar as the container can hold a usual procaterol hydrochloride aqueous solution formulation. Bag-like and bottle-like shapes are generally recommendable.

The procaterol hydrochloride aqueous solution formulations of the present invention include various formulations such as ophthalmic solutions, insufflation- type solutions, rhinal solutions, etc. Among them, ophthalmic solutions are preferred.

For example, procaterol hydrochloride ophthalmic solutions are described below in detail. The ophthalmic solution can be prepared in the conventional manner. Stated more specifically, procaterol hydrochloride as an active ingredient is mixed with a suitable carrier and the mixture is treated for sterilization. Suitable carriers include, for example, sterilized and purified water. When required, such ophthalmic solutions may contain any of various conventional additives such as solubilizing agents, buffers, antioxidants, stabilizers, antiseptics, isotonizing agents, pH adjusters, thickeners, etc. Examples of useful solubilizing agents are sodium carboxymethyl cellulose, polyoxyethylene glycol ethers such as polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, etc., polyethylene glycol higher fatty acid esters such as polyethylene glycol monolaurate, polyethylene glycol monooleate, etc., polyoxyethylene sorbitan monolaurate, polyoxyethylene fatty acid ester, etc. Examples of useful buffers are sodium phosphate, sodium hydrogenphosphate, potassium hydrogenphosphate, boric acid, sodium borate, citric acid, sodium citrate, tartaric acid, sodium tartrate, acetic acid, sodium acetate, ε-amino caproic acid, sodium gluta ate, etc. Useful antioxidants include, for example, sodium sulfite, sodium pyrosulfite, sodium bisulfite, sodium thiosulfite, ascorbic acid, etc. Useful stabilizers include, for example, ethylenediaminetetraacetic acid (EDTA), hydroxyquinolin sulfate, etc. Useful antiseptics are, for example, chlorobutanol, benzalkonium chloride, benzethonium chloride, mercuryphenyl salt, thi erosal, phenethyl alcohol, methylparaben, ethylparaben, propylparaben, butylparaben, etc. Useful isotonizing agents are sodium chloride, glucose, D-mannitol, glycerin, etc. Useful pH adjusters are sodium hydroxide, hydrochloric acid, etc. Useful thickeners are methyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and like cellulose derivatives, hydroxyethyl starch, methyl starch and like starch derivatives, polyvinyl alcohol, polyvinyl pyrrolidone, etc.

The insufflation-type solutions and rhinal solutions are formulated in the same manner as said procaterol hydrochloride ophthalmic solutions. In the case of the insufflation-type solutions, an isotonizing agent need not be incorporated.

A wide variety of conventional compounds are usable as at least one water-soluble high-molecular-weight compound containing an anionic functional group which is used in the invention to prolong the effect of the procaterol hydrochloride. Such compounds include, for example, hyaluronic acid, chondroitin sulfate, carrageenan, chitin sulfate, ^'chitosan sulfate, pullulan sulfate, alginic acid, carboxymethyl cellulose, carboxy- ethylcurdlan, carboxymethyldextran, carboxymethylpullu- lan, carboxymethylchitin, carboxymethylchitosan and like high-molecular-weight polysaccharides containing an anionic functional group and salts thereof, polystyrene- sulfonic acid, polyvinyl sulfate, polyacrylic acid, carboxyvinyl polymers, polymethacrylic acid and like synthetic high-molecular-weight compounds containing an anionic functional group and salts thereof. Among these water-soluble high-molecular-weight compounds, suitable compounds are those having a sulfuric acid group such as acidic mucopolysaccharide, dextran sulfate, polystyrenesulfonic acid and salts thereof. More specific examples are chondroitin sulfate, heparin, heparan sulfate, keratan sulfate, dextran sulfate, polystyrenesulfonic acid and salts thereof (e.g., sodium salt, potassium salt or calcium salt), etc. Among them, preferred are chondroitin sulfate, dextran sulfate, polystyrenesulfonic acid and salts thereof, and more preferred are sodium chondroitin sulfate, sodium dextran sulfate and sodium polystyrene sulfonate. Of them, most preferred is sodium chondroitin sulfate. In the practice of the invention, it is suitable to use said water-soluble high-molecular-weight compound having a molecular weight of at least 10,000, usually about 10,000 to about 3 millions. It is recommendable to use, in some cases, such compounds about 10,000 to about 100,000 in molecular weight and in other cases, those about 100,000 to about 1 million in molecular weight. The amount of such water-soluble high-molecular- weight compound to be used is at least 10 mg/ml, preferably 10 to 150 mg/ml, more preferably 15 to 100 mg/ml, most preferably 20 to 50 mg/ml, based on the amount of the procaterol hydrochloride aqueous solution formulation.

The amount of the procaterol hydrochloride to be incorporated in the formulation is not critical but usually 0.1 to 10,000 μg/ml, preferably 1 to 1,000 μg/ml, more preferably 5 to 500 μg/ml. For use as an ophthalmic solution, the amount is 10 to 300 μg/ml.

Oxygen absorbents useful in the invention include those heretofore known and comprising, e.g., iron hydroxide, iron oxide, iron carbide or like iron compounds as an active ingredient. Typical commercial products are, for example, those available under the tradenames

"AGELESS" (product of Mitsubishi Gas Chemical Co., Ltd.), "MODULAN" (product of Nippon Kayaku Co., Ltd.), "SEQUL" (product of Nippon Soda Co., Ltd.), "VITALON" (product of Toa Gosei Co., Ltd.), "TAMOTSU" (product of Oji Kako Co., Ltd.), etc. The form of the oxygen absorbent is not specifically limited insofar as the absorbent can be placed in the space between the plastics container holding the procaterol hydrochloride aqueous solution formulation and the gas barrier packaging material as its external cover. For example, if the oxygen absorbent is in a powder form, preferably the required quantity of the powder is placed into a small-size air-permeable bag or the like, and the bag is laid in said space.

Various materials can be used as the gas barrier packaging material which encloses therewith the plastics container holding the procaterol hydrochloride aqueous solution formulation. Examples of these materials include glass containers, films or sheets and bottles made of various materials widely used, etc. Specific examples are gas barrier materials containing at least one species selected from olefin resins such as polypropylene, high- density polyethylene or like polyethylenes, etc., polyethylene terephthalate, ethylene-vinyl alcohol copolymer resins, polyvinylidene chloride, polyacrylonitrile, polyvinyl alcohol, polycarbonate, polyamide resins such as nylon, etc., cellulose acetate, polyester, aluminum foil, glass and so on. Gas barrier materials for use herein include laminated films of the above-exemplified materials, for example, laminated films of nylon, ethylene-vinyl alcohol copolymer resin and polyethylene, etc. Gas barrier materials useful herein may be a laminate of aluminum foil and plastics such as polyethylene, a plastics film combined by vapor deposition with aluminum or silicic acid, etc. Preferred gas barrier materials have an oxygen permeability of not higher than 1.0 ml/m²'hr»atm at 25°C and 75% RH. The plastics container holding the procaterol hydrochloride aqueous solution formulation and the oxygen absorbent can be packaged (enclosed) in these packaging materials by conventional methods.

The package holding the procaterol hydrochloride aqueous solution formulation according to the present invention may be one produced without using an oxygen absorbent and by degassing the space between the plastics container and the gas barrier packaging material and sealing a nitrogen gas and/or carbon dioxide gas into said space. The space can be degassed in the conventional manner using, e.g. a vacuum packaging machine.

The procaterol hydrochloride aqueous solution formulation of the present invention can be used for the purposes which cover all known applications of procaterol hydrochloride. The formulation of the invention is suitable for use as a bronchodilator, peripheral vasodilators, antihypertensive, antiglaucoma, antiallergics, ophthalmic solutions for preventing and healing the inflammation and/or wound in eyes, etc.

Effects of the Invention The package holding the procaterol hydrochloride aqueous solution formulation according to the invention enhances the long-term storage stability of the formulation. Further the procaterol hydrochloride aqueous solution formulation containing the foregoing specific water-soluble high-molecular-weight compound can produce markedly prolonged effects. Examples

The following examples are given to illustrate the invention. However, the present invention is not limited to the examples. Formulation Example 1 Per milliliter,

Procaterol hydrochloride 0 . 003 mg Glycerin 24 . 8 mg

Anhydrous citric acid 0 . 422 mg Sodium citrate 0 . 824 mg Sodium ethylenediamine tetraacetate

0 . 1 mg

10% Benzalkonium chloride 1 μl Sodium hydroxide q . s Water for injection q . s In water for injection were dissolved the above- mentioned remaining ingredients. The solution was filtrated for sterilization using a proper filter paper, whereby an ophthalmic solution was produced. The pH of the ophthalmic solution was 5.0. Formulation Example 2

Per milliliter,

Procaterol hydrochloride 0.001 mg

Glycerin 24.8 mg

Anhydrous citric acid 0.422 mg Sodium citrate 0.824 mg

Sodium ethylenediamine tetraacetate

0.1 mg 10% Benzalkonium chloride 1 μl

Sodium hydroxide q.s. Water for injection q.s.

In water for injection were dissolved the above- mentioned remaining ingredients. The solution was filtrated for sterilization using a proper filter paper, whereby an ophthalmic solution was produced. The pH of the ophthalmic solution was 5.0. Formulation Example 3

An aqueous solution formulation was prepared in the same manner as in Formulation Example 1 with the exception of using procaterol hydrochloride in an amount of 0.01 mg. Formulation Example 4

Per milliliter,

Procaterol hydrochloride 0.01 mg

Glycerin 25 mg Sodium chondroitin sulfate 10 mg

Methylparaben 0.5 mg pH adjuster q.s.

Water for injection q.s.

In water for injection were dissolved the above- mentioned remaining ingredients. The solution was filtrated for sterilization using a proper filter paper, whereby an aqueous solution formulation was produced. The pH of the formulation was 5.0. Formulation Example 5 An aqueous solution formulation was prepared in the same manner as in Formulation Example 1 with the exception of altering the amount of procaterol hydrochloride to 0.01 mg and using 0.5 mg of methylparaben in place of benzalkonium chloride. Formulation Example 6

Per milliliter,

Procaterol hydrochloride 0.01 mg

Sodium chondroitin sulfate 10 mg

Sodium chloride 5.5 mg Chlorobutanol 3.5 mg Water for injection q.s.

In water for injection were dissolved the above- mentioned remaining ingredients. The solution was filtrated for sterilization using a proper filter paper, whereby an aqueous solution formulation was produced. Formulation Example 7

Per milliliter,

Procaterol hydrochloride 0.1 mg

Sodium chondroitin sulfate 10 mg Sodium chloride 5.5 mg

Chlorobutanol 3.5 mg

Water for injection q.s.

In water for injection were dissolved the above- mentioned remaining ingredients. The solution was filtrated for sterilization using a proper filter paper, whereby an aqueous solution formulation was produced. Formulation Example 8

Per milliliter,

Procaterol hydrochloride 0.1 mg Sodium dextran sulfate 50 mg

Glycerin 18 mg

Chlorobutanol 3 mg pH adjuster q.s.

Water for injection q.s. In water for injection were dissolved the above- mentioned remaining ingredients. The solution was filtrated for sterilization using a proper filter paper, whereby an aqueous solution formulation was produced. Formulation Example 9 Per milliliter,

Procaterol hydrochloride 0.001 mg

Sodium chondroitin sulfate 30 mg

Glycerin 18 mg

Chlorobutanol 3.5 mg pH adjuster q.s.

Water for injection q.s.

In water for injection were dissolved the above- mentioned remaining ingredients. The solution was filtrated for sterilization using a proper filter paper, whereby an aqueous solution formulation was produced. Formulation Example 10

Per milliliter,

Procaterol hydrochloride 0.01 mg

Sodium chondroitin sulfate 50 mg Glycerin 14 mg

Chlorobutanol 3.5 mg pH adjuster q.s.

Water for injection q.s.

In water for injection were dissolved the above- mentioned remaining ingredients. The solution was filtrated for sterilization using a proper filter paper, whereby an aqueous solution formulation was produced. Formulation Example 11

Per milliliter, Procaterol hydrochloride 0.1 mg

Sodium chondroitin sulfate 100 mg

Glycerin 4 mg

Chlorobutanol 3.5 mg pH adjuster q.s. Water for injection q.s.

In water for injection were dissolved the above- mentioned remaining ingredients. The solution was filtrated for sterilization using a proper filter paper, whereby an aqueous solution formulation was produced. Formulation Example 12

Per milliliter,

Procaterol hydrochloride 0.001 mg

Sodium dextran sulfate 30 mg

Glycerin 20 mg Citric acid 0.4 mg

Trisodium dihydrate citrate 0.26 mg

Chlorobutanol 3.5 mg pH adjuster q.s.

Water for injection q.s. In water for injection were dissolved the above- mentioned remaining ingredients. The solution was filtrated for sterilization using a proper filter paper, whereby an aqueous solution formulation was produced. Formulation Example 13 Per milliliter,

Procaterol hydrochloride 0.01 mg

Sodium dextran sulfate 50 mg

Glycerin 18 mg

Citric acid 0.4 mg Trisodium dihydrate citrate 0.26 mg

Chlorobutanol 3.5 mg pH adjuster q.s.

Water for injection q.s.

In water for injection were dissolved the above- mentioned remaining ingredients. The solution was filtrated for sterilization using a proper filter paper, whereby an aqueous solution formulation was produced. Formulation Example 14

Per milliliter, Procaterol hydrochloride 0.1 mg

Sodium dextran sulfate 100 mg

Glycerin 13 mg

Citric acid 0.4 mg

Trisodium dihydrate citrate 0.26 mg Chlorobutanol 3.5 mg pH adjuster q.s.

Water for injection q.s.

In water for injection were dissolved the above- mentioned remaining ingredients. The solution was filtrated for sterilization using a proper filter paper, whereby an aqueous solution formulation was produced. Formulation Example 15

Per milliliter,

Procaterol hydrochloride 0.01 mg Sodium chondroitin sulfate 30 mg

Chlorobutanol 2 mg

Benzalkonium chloride 0.023 mg

Sodium chloride 6 mg

Hydrochloric acid (pH adjuster) q.s. Water for injection q.s.

In water for injection were dissolved the above- mentioned remaining ingredients. The solution was filtrated for sterilization using a proper filter paper, whereby an aqueous solution formulation was produced. The formulation had a pH of 4.7-5.0 and an osmotic pressure ratio of 1.0. Formulation Example 16

Per milliliter,

Procaterol hydrochloride 0.03 mg Sodium chondroitin sulfate 30 mg Chlorobutanol 2 mg

Benzalkoniu chloride 0.023 mg

Sodium chloride 6 mg

Hydrochloric acid (pH adjuster) q.s. Water for injection q.s.

In water for injection were dissolved the above- mentioned remaining ingredients. The solution was filtrated for sterilization using a proper filter paper, whereby an aqueous solution formulation was produced. The formulation had a pH of 4.7-5.0 and an osmotic pressure ratio of 1.0. Formulation Example 17

Per milliliter,

Procaterol hydrochloride 0.1 mg Sodium chondroitin sulfate 30 mg

Chlorobutanol 2 mg

Benzalkonium chloride 0.023 mg

Sodium chloride 6 mg

Hydrochloric acid (pH adjuster) q.s. Water for injection q.s.

In water for injection were dissolved the above- mentioned remaining ingredients. The solution was filtrated for sterilization using a proper filter paper, whereby an aqueous solution formulation was produced. The formulation had a pH of 4.7-5.0 and an osmotic pressure ratio of 1.0. Formulation Example 18

Per milliliter,

Procaterol hydrochloride 0.3 mg Sodium chondroitin sulfate 30 mg

Chlorobutanol 2 mg

Benzalkonium chloride 0.023 mg

Sodium chloride 6 mg

Hydrochloric acid (pH adjuster) q.s. Water for injection q.s.

In water for injection were dissolved the above- mentioned remaining ingredients. The solution was filtrated for sterilization using a proper filter paper, whereby an aqueous solution formulation was produced. The formulation had a pH of 4.7-5.0 and an osmotic pressure ratio of 1.0. Formulation Example 19

An aqueous solution formulation was prepared in the same manner as in Formulation Example 15 with the exception of using sodium chondroitin sulfate in an amount of 10 mg. Formulation Example 20

An aqueous solution formulation was prepared in the same manner as in Formulation Example 16 with the exception of using sodium chondroitin sulfate in an amount of 10 mg.

Formulation Example 21

An aqueous solution formulation was prepared in the same manner as in Formulation Example 17 with the exception of using sodium chondroitin sulfate in an amount of 10 mg.

Formulation Example 22

An aqueous solution formulation was prepared in the same manner as in Formulation Example 18 with the exception of using sodium chondroitin sulfate in an amount of 10 mg.

Preparation Example 1

A 5 ml portion of each ophthalmic solution prepared in Formulation Example 1 or 2 was filled into an ophthalmic container (bottle made of colorless polyethylene; nozzle made of colorless polyethylene; cap made of colorless polypropylene, all manufactured by

Taisei Kako Co., Ltd.). The container, together with an oxygen absorbent (AGELESS) and an oxygen detecting composition (AGELESS EYE) was packaged in a gas barrier film to accomplish secondary packaging, whereby a package according to the present invention was obtained.

The following two types of gas barrier films were used. (i) An oxygen barrier laminated film comprising 15 μ-thick stretched nylon 66 film, 15 μ-thick nylon- ethylene vinyl alcohol copolymer film and 15 μ-thick polyethylene film, the film having an oxygen permeability of 0.8 ml/m²-24 hrs at 20^βC and 65% RH or 1.2 ml/m²»24 hrs at 25°C and 65% RH.

(ii) A vapor/oxygen barrier laminated film comprising 12 μ-thick polyethylene terephthalate film, 12 μ-thick film made of silicon oxide deposited on polyvinyl alcohol, and 50 μ-thick straight-chain low-density polyethylene film, the film having an oxygen permeability of 0.1 ml/m².24 hrs at 20^βC and 65% RH or 0.1 ml/m².24 hrs at 25°C and 65% RH.

The secondary package obtained by packaging the ophthalmic container filled with the ophthalmic solution of Formulation Example 1 using an oxygen barrier laminated film as a gas barrier film is hereinafter referred to as "present product A" . The secondary package obtained by packaging the ophthalmic container filled with the ophthalmic solution of Formulation Example 1 using the vapor/oxygen barrier laminated film as a gas barrier film is hereinafter referred to as "present product B" . The secondary package obtained by packaging the ophthalmic container filled with the ophthalmic solution of Formulation Example 2 using the oxygen barrier laminated film as a gas barrier film is hereinafter referred to as "present product C". The secondary package obtained by packaging the ophthalmic container filled with the ophthalmic solution of Formulation Example 2 using the vapor/oxygen barrier laminate film as a gas barrier film is hereinafter referred to as "present product D". The oxygen concentration in the secondary package was detected by AGELESS EYE. AGELESS EYE is adapted to turn pink in an oxygen concentration of up to 0.1% and adapted to turn blue in an oxygen concentration of not lower than 0.5%. All of "AGELESS EYE" compositions placed in the present products A to D became pink within 3 days. Preparation Example 2

A 5 ml portion of each ophthalmic solution prepared in Formulation Example 1 or 2 was filled into an ophthalmic container (bottle made of colorless polyethylene; nozzle made of colorless polyethylene; cap made of colorless polypropylene, all manufactured by Taisei Kako Co., Ltd.). The container was packaged in an aluminum foil or aluminum-deposited film. Then the space between the ophthalmic container and the secondary package was deaerated by a vacuum packaging machine and nitrogen gas was introduced into the space, whereby present product E (packaged in aluminum foil) and present product F (packaged in an aluminum-deposited film) were obtained Preparation Example 3

In the same manner as the production of present product B in Preparation Example 1, there were obtained present product G accommodating the aqueous solution formulation of Formulation Example 3, present product H accommodating the aqueous solution formulation of Formulation Example 4, and present product I accommodating the aqueous solution formulation of Formulation Example 5. Preparation Example 4 The aqueous solution formulations prepared in

Formulation Examples 6-8 were filled into polyvinyl chloride containers and the containers were packaged, together with an oxygen absorbent (MODULAN) , in a packaging material comprising a laminate of aluminum foil and polyethylene to accomplish secondary packaging, whereby the present product was obtained. Preparation Example 5

The aqueous solution formulations prepared in Formulation Examples 9-11 were filled into polyester containers and the containers were packaged, together with an oxygen absorbent (SEQUL), in a gas barrier film comprising an ethylene-vinyl alcohol copolymer resin to accomplish secondary packaging, whereby the present product was obtained. Preparation Example 6 The aqueous solution formulations prepared in Formulation Examples 12-14 were filled into containers of ethylene-vinyl acetate copolymer and secondary packaging was accomplished using a gas barrier film containing polyacrylonitrile. Thereafter carbon dioxide gas was sealed into the deaerated space, whereby the present product was obtained. Preparation Example 7

A 5 ml portion of each ophthalmic solution prepared in Formulation Examples 15, 16 and 17 was filled into an ophthalmic container (bottle made of colorless polyethylene; nozzle made of colorless polyethylene; cap made of colorless polypropylene, all manufactured by Taisei Kako Co., Ltd.). The container, together with an oxygen absorbent ("AGELESS"), was packaged in a packaging material comprising a laminate of aluminum foil and polyethylene to accomplish secondary packaging, whereby the present product was obtained.

The secondary package obtained by packaging the ophthalmic container filled with the ophthalmic solution of Formulation Example 15 is hereinafter referred to as "present product J". The secondary package obtained by packaging the ophthalmic container filled with the ophthalmic solution of Formulation Example 16 is hereinafter referred to as "present product K". The secondary package obtained by packaging the ophthalmic container filled with the ophthalmic solution of Formulation Example 17 is hereinafter referred to as "present product L". Test Example 1

Present products A to D were placed into a box of cardboard, and the box was left to stand in a chamber at 25°C and 75% RH or at 40°C, 75% RH. In 4 weeks, 7 weeks, 12 weeks, 18 weeks and 24 weeks, the amount of the procaterol hydrochloride in the ophthalmic solution was measured to calculate the ratio of remaining procaterol hydrochloride in the conventional manner. For comparison, a box of cardboard containing the ophthalmic containers filled with the ophthalmic solutions of Formulation Examples 1 and 2 (comparative products 1 and 2, respectively) were provided to calculate the ratio of remaining procaterol hydrochloride. The results are shown in Tables 1 and 2.

Table 1

Ratio of residual procaterol hydrochloride (%) |

4 weeks 7 weeks 12 weeks 18 weeks 24 weeks

Present product A 100.24 98.47 97.41 93.80 95.21

40°C, Present product B 99.11 98.17 98.55 94.89 96.29 75% RH Comparative product 1 98.65 96.82 95.95 91.11 90.20

Table 2

Tables 1 and 2 show the following. In Table 1, the comparative product 1 showed about 10% decrease in the ratio of residual procaterol hydrochloride after 24-week storage at 40°C and 75% RH, whereas the present products A and B showed less than 5% decrease in the ratio of residual procaterol hydrochloride. In Table 2, the comparative product 2 showed about 2% decrease in the ratio of residual procaterol hydrochloride after 12-week storage at 25°C and 75% RH, whereas the present products C and D had no decrease in the ratio of residual procaterol hydrochloride even after 24-week storage. Further, the comparative product 2 decreased by about 6% in the ratio of residual procaterol hydrochloride after 12-week storage at 40°C and 75% RH, whereas the present products C and D decreased by less than 5% in the ratio of residual procaterol hydrochloride even after 24-week storage. It has been be confirmed from these results that the removal of oxygen pronouncedly contributes to stabilization of procaterol hydrochloride. Test Example 2

Present products G to I were placed into a box of cardboard, and the box was left to stand in a chamber at 40°C and 75% RH. In 2 weeks, 4 weeks and 8 weeks, the amount of the procaterol hydrochloride in the aqueous solution formulation was measured to calculate the ratio of remaining procaterol hydrochloride in the conventional manner. For comparison, a box of cardboard containing the plastics containers filled with the aqueous solution formulations of Formulation Examples 3 to 5 was used to calculate the ratio of remaining procaterol hydrochloride in the same manner as above. The results are shown in Table 3.

Table 3

Ratio of residual procaterol hydrochloride (%)

2 weeks 4 weeks 8 weeks

Present product G 99.6 99.2 98.5

Present product H 98.5 98.8 97.3

Present product I 98.8 98.0

Formulation Ex. 3 98.7 98.4 97.5

Formulation Ex. 4 97.6 97.0 93.8

Formulation Ex. 5 96.1 97.3 94.7

Test Example 3

Test for effect on guinea pigs with histamine- induced conjunctivitis

Hartley-strain male guinea pigs (weight 440-570 g) were used as model animals. The test was carried out using the animal in a pentobarbital-anesthetized (30 mg/kg, i.p.) state. Test formulations (aqueous solution formulations of Formulation Examples 6-8) were applied by an eyedropper to the animal's right eye and 10 μl of ophthalmic buffer or physiological salt solution to the animal's left eye. One hour, 2 hours or 3 hours after application, 10 μl of 2 mg/ml histamine/physiological salt solution was applied to both eyes of the animals to induce conjunctivitis. To the non-treatment group was applied a physiological salt solution in place of histamine. Evans blue was intravenously administered at a dose of 10 mg/ml/kg immediately before application of histamine.

Blood was collected from vena cava inferior 30 minutes after application of histamine to determine the absorbance (A_g2n) of blood plasma at 620 nm. Animals' eyelids and conjunctiva were removed. Evans blue was extracted for 2 days using 1.5 ml of acetone-0.5% sodium sulfate (7 : 3, v/v) after which the absorbance of blood plasma at 620 nm was measured. The leakage of blood plasma was calculated by the following equation. Blood plasma leakage (μl/tissue)- A620 of tissue extract/A620 of blood plasma X 1500

The rise of vascular permeability due to histamine was expressed in terms of an increase with respect to the leakage of blood plasma of non-treatment group, i.e. 2.6 + 0.2 μl (mean ± S.E., n=7). The potency of the drug was expressed in terms of percent control of rise of vascular permeability of the right eye (drug- treated eye) against the left eye (control eye) . The percent control was calculated by the following equation.

% Control=₍l- ^Blood plasma leakage of right eye-2.6_{lχ 1Q Q} Blood plasma leakage of left eye-2.6 The results are shown in Table 4.

Table 4

Administra¬ % Control of blood tion time plasma leakage (mean ± S.E. )

1 hour

Formulation before 53.0 + 5.5 Example 6

2 hours before 27.3 ± 5.4

Formulation 2 hours Example 7 before 33.3 ± 5.2

Formulation 3 hours Example 8 before 35.3 ± 6.2 Test Example 4

Test for effect on guinea pigs with histamine- induced conjunctivitis Hartley-strain male guinea pigs (weight 440-570 g) were used as model animals. The test was carried out using the animal in a pentobarbital-anesthetized (30 mg/kg, i.p.) state. A test formulation (aqueous solution formulation of Formulation Example 17) was applied by an eyedropper to the animal's right eye and 10 μl of ophthalmic buffer or physiological salt solution to the animal's left eye. Five minutes or 3 hours after application, 10 μl of 2 mg/ml histamine/physiological salt solution was applied to both eyes of the animals to induce conjunctivitis. To the non-treatment group was applied a physiological salt solution in place of histamine. Evans blue was intravenously administered at a dose of 10 mg/ml/kg immediately before application of histamine. The leakage of blood plasma was calculated in the same manner as in Test Example 3 to determine the percent control of rise of vascular permeability. The results are shown in Table 5. For comparison. Table 5 also shows the results obtained when use was made of an aqueous solution formulation

(comparative product 4) prepared in the same manner as in Formulation Example 1 with the exception of using procaterol hydrochloride in an amount of 0.1 mg in Formulation Example 1 in place of the aqueous solution formulation of Formulation Example 17, and the results obtained when a physiological salt solution (control) was used.

Table 5

Test Example 5

Present products J to L were placed into a box of cardboard, and the box was left to stand in a chamber at 40°C and 75% RH. In 2 weeks, 4 weeks, 6 weeks, 8 weeks and 12 weeks, the amount of the procaterol hydrochloride in the ophthalmic solution was measured to calculate the ratio of remaining procaterol hydrochloride in the conventional manner. For comparison, a box of cardboard holding ophthalmic containers (bottle made of colorless polyethylene; nozzle made of colorless polyethylene; cap made of colorless polypropylene, all manufactured by Taisei Kako Co., Ltd.) full of ophthalmic solutions of Formulation Examples 15, 16 an 17. The results are shown in Table 6. In Table 6, comparative product 5 is one holding said ophthalmic container full of the ophthalmic solution of Formulation Example 15, comparative product 6 is one holding said ophthalmic container full of the ophthalmic solution of Formulation Example 16, and comparative product 7 is one holding said ophthalmic container full of the ophthalmic solution of Formulation Example 17.

Table 6

Ratio of residual procaterol hydrochloride (%) |

2 weeks 4 weeks 6 weeks 8 weeks 12 weeks

Present product J 98.3 98.3 98.4 98.3 98.1

Comparative product 5 94.7 90.4 86.8 83.4 75.0

Present product K 98.9 98.4 98.4 98.2 95.9

Comparative I product 6 96.9 93.5 91.0 88.2 80.9 ^■

I

Present product L 99.0 98.0 98.4 97.1 96.2

Comparative product 7 97.2 93.8 92.0 88.6 83.7 |

Claims

1. A package holding a pharmaceutical composition comprising an aqueous solution of procaterol hydrochloride such that the procaterol hydrochloride is kept from decomposing in the aqueous solution due to its oxidation reaction.

2. The package according to claim 1 wherein an oxygen-free atmosphere is retained.

3. The package according to claim 1 wherein the pharmaceutical composition is filled in the plastics container and the container is packaged in a gas barrier packaging material.

4. The package according to claim 3 wherein the pharmaceutical composition is filled in the plastics container and the container is packaged, together with an oxygen absorber, in a gas barrier packaging material.

5. The package according to claim 4 wherein the pharmaceutical composition is an ophthalmic solution.

6. The package according to claim 3 wherein the the pharmaceutical composition is filled in a plastics container; wherein the container is packaged in a gas barrier packaging material; and wherein a nitrogen gas and/or carbon dioxide gas is sealed in a space between the container and the gas barrier packaging material. 7 . The package according to claim 6 wherein the pharmaceutical composition is an ophthalmic solution.

8. The package according to claim 1 wherein the pharmaceutical composition contains a water-soluble high- molecular-weight compound containing an anionic functional group and having a molecular weight of at least 10,000. . The package according to claim 8 wherein the water-soluble high-molecular-weight compound is at least one species selected from the group consisting of acidic mucopolysaccharide, dextran sulfate and polystyrenesulfonic acid containing a sulfuric acid group, and salts thereof.

10. The package according to claim 8 wherein the water-soluble high-molecular-weight compound is at least one species selected from the group consisting of sodium chondroitin sulfate, sodium dextran sulfate and sodium polystyrene sulfonate.

11. The package according to claim 4 or 6 wherein the pharmaceutical composition contains a water- soluble high-molecular-weight compound containing an anionic functional group and having a molecular weight of at least 10,000.

12. The package according to claim 11 wherein the water-soluble high-molecular-weight compound is at least one species selected from the group consisting of acidic mucopolysaccharide, dextran sulfate and polystyrenesulfonic acid containing a sulfuric acid group, and salts thereof.

13. The package according to claim 11 wherein the water-soluble high-molecular-weight compound is at least one species selected from the group consisting of sodium chondroitin sulfate, sodium dextran sulfate and sodium polystyrene sulfonate.

14. The package according to claim 11 wherein the water-soluble high-molecular-weight compound is sodium chondroitin sulfate.

15. The package according to claim 14 wherein the pharmaceutical composition is an ophthalmic solution.

16. The package according to claim 15 wherein the pharmaceutical composition contains 1 to 1,000 μg/ml of procaterol hydrochloride and 10 to 150 mg/ml of sodium chondroitin sulfate.

17. A pharmaceutical composition comprising an aqueous solution of procaterol hydrochloride which contains a water-soluble high-molecular-weight compound containing an anionic functional group and having a molecular weight of at least 10,000.

18. The pharmaceutical composition according to claim 17 wherein the water-soluble high-molecular-weight compound is at least one species selected from the group consisting of acidic mucopolysaccharide, dextran sulfate and polystyrenesulfonic acid containing a sulfuric acid group, and salts thereof.

19. The pharmaceutical composition according to claim 17 wherein the water-soluble high-molecular-weight compound is at least one species selected from the group consisting of sodium chondroitin sulfate, sodium dextran sulfate and sodium polystyrene sulfonate.

20. The pharmaceutical composition according to claim 17 wherein the water-soluble high-molecular-weight compound is sodium chondroitin sulfate.

21. The pharmaceutical composition according to claim 20 which is an ophthalmic solution.

22. The pharmaceutical composition according to claim 21 which contains 1 to 1,000 μg/ml of procaterol hydrochloride and 10 to 150 mg/ml of sodium chontroitin sulfate.