KR19980703582A - Package holding aqueous solution of procaterol hydrochloride and aqueous solution of procaterol hydrochloride - Google Patents

Abstract

It is an object of the present invention to impart long term storage stability to pharmaceutical compositions comprising aqueous procaterol hydrochloride solution. The present invention is directed to an aqueous solution of procaterol hydrochloride which ensures that procaterol hydrochloride is not decomposed by an oxidation reaction in an aqueous solution.

Description

Package Holding a Procaterol Hydrochloride Aqueous Solution Formulation, and a Procaterol Hydrochloride Aqueous Solution Formulation

Various procaterol preparations are known. Low concentrations of procaterol hydrochloride are unstable in aqueous solutions and have low stability for long-term storage. In addition, low concentrations of procaterol hydrochloride have the disadvantage of easily flowing by tears or runny nose after administration.

The present invention is directed to a package containing a pharmaceutical composition comprising an aqueous solution of procaterol hydrochloride and a pharmaceutical composition comprising an aqueous solution of procaterol hydrochloride.

It is an object of the present invention to impart long term storage stability to pharmaceutical compositions (hereinafter referred to as aqueous solution of procaterol hydrochloride) which comprise a low concentration of aqueous solution of procaterol hydrochloride.

It is another object of the present invention to provide an aqueous solution of procaterol hydrochloride that can produce prolonged efficacy after administration to an eye or the like.

The inventors have conducted extensive studies to give long-term storage stability to low concentrations of aqueous solution of procaterol hydrochloride, and the fact that low concentrations of procaterol hydrochloride are decomposed by the oxidation reaction of procaterol hydrochloride in solution in aqueous solution. Found. It was also found that this oxidation reaction did not proceed in the absence of oxygen. The present invention has been completed based on this novel finding.

According to the present invention, a package is provided which holds a pharmaceutical composition comprising an aqueous solution of procaterol hydrochloride that is not decomposed by an oxidation reaction in an aqueous solution.

For example, if the aqueous solution of procaterol hydrochloride is maintained in an oxygen-free atmosphere, decomposition of the procaterol hydrochloride by the oxidation reaction in the aqueous solution can be prevented.

An oxygen free atmosphere can be achieved by replacing the air in the glass container with nitrogen gas and sealing the container. The most widely used plastics for eye drops are too permeable to gas to maintain an oxygen-free atmosphere even after replacing them with nitrogen gas. Thus, according to the present invention, the aqueous solution of procaterol hydrochloride is filled into a plastic container and then the container is packed with the next packing material.

The researches of the present inventors revealed the following facts. When a plastic eye drop container filled with an aqueous solution of procate hydrochloric acid is sealed with an oxygen adsorbent in a bottle or a container made of a gas impermeable membrane, an aqueous solution of procaterol hydrochloride solution having excellent long-term storage stability can be obtained.

Therefore, a preferred embodiment of the package holding the aqueous solution of procaterol hydrochloride according to the present invention is a solution of procaterolic acid hydrochloride prepared in a plastic container, which is packaged with a next packing material together with an oxygen adsorbent. It is a package holding an aqueous solution formulation.

Another preferred embodiment of the package holding the aqueous solution of procaterol hydrochloride according to the present invention is a solution containing the aqueous solution of procaterol hydrochloride in a plastic container; The plastic container is packaged with a fillable packing material; And a package containing an aqueous solution of procaterol hydrochloride prepared by filling a space between the container and the next packing material with nitrogen gas and / or carbon dioxide gas.

The inventors have found that the efficacy of a procaterol hydrochloride solution formulation is at least one water soluble selected from the group consisting of an aqueous functional compound containing an anionic functional group and having at least a molecular weight of 10000, preferably dextran sulfur and an acidic mucopolysaccharide comprising a sulfate group. It has also been found that polymer compounds and their salts can be extended by incorporation into the formulations.

As a result, according to the present invention, there is also provided an aqueous solution of procaterol hydrochloride containing at least one polymer compound containing a functional group of an anion and having a molecular weight of at least 10000.

Conventional plastic containers can be used as containers containing the aqueous solution of procaterol hydrochloride according to the invention. Materials useful as plastic containers are not particularly limited and are known as polyolefins such as polyethylene, polypropylene, copolymers thereof, polyvinyl chloride, ethylene-vinyl acetate copolymers, polyesters, nylons, polycarbonates, polyethylene terephthalates and the like. Plastic is also possible. Combinations of at least two or more identical or different polymers having a composite multilayer structure may also be used. There is no particular limitation on the shape or size of the container as long as the container can accommodate a normal aqueous solution of procaterol hydrochloride. Generally, a shape such as a bag or bottle is recommended.

The aqueous solution of procaterol hydrochloride of the present invention includes various formulations such as eye drops, inhalation solutions, nasal solutions, and the like. Among them, eye drops are preferred.

For example, procaterol hydrochloride eye drops are described in detail below. Eye drops are prepared by conventional methods. In more detail, procaterol hydrochloride as an active ingredient is mixed with a suitable carrier and the mixture is sterilized. Suitable carriers include, for example, sterile, purified water. When necessary, such eye drops include various conventional additives such as solvents, buffers, antioxidants, stabilizers, preservatives, isotonic agents, pH adjusters, thickeners and the like. Examples of useful solvents include sodium carboxymethyl cellulose, polyoxyethylene glycol ethers such as polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, and the like, polyethylene glycol highland such as polyethylene glycol monolaurate, polyethylene glycol monooleate, and the like. Disperse ester, polyoxyethylene sorbitan monolaurate, polyoxyethylene fatty acid ester and the like. Examples of useful buffers include sodium phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, boric acid, sodium borate, citric acid, sodium citrate, tartaric acid, sodium tartrate, acetic acid, sodium acetate, δ-amino caproic acid, sodium glutamate, and the like. Useful antioxidants include, for example, sodium sulfate, sodium pyrosulfite sodium, bisulfite sodium, thiosulfite sodium, ascorbic acid and the like. Useful stabilizers include, for example, ethylenediaminetetraacetic acid (EDTA), hydroxyquinoline sulfate, and the like. Useful preservatives include, for example, chlorobutanol, benzalkonium chloride, benzethonium chloride, mercuryphenyl salt, thimerosal, phenethyl alcohol, methylparaben, ethylparaben, propylparaben, butylparaben and the like. Useful isotonic agents include sodium chloride, glucose, D-mannitol, glycerin and the like. Useful pH adjusting agents include sodium hydroxide, hydrochloric acid and the like. Useful thickeners include methyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and such cellulose derivatives, hydroxyethyl starch, methyl starch, and such starch derivatives, polyvinyl alcohol And polyvinyl pyrrolidone.

Inhalable solutions and nasal solutions are formulated in the same manner as the above hydrochloride procaterol eye drops. In the case of inhaled solutions, no isotonicity agent needs to be incorporated.

Various conventional compounds can be used as the at least one water soluble high molecular compound comprising the anionic functional groups used in the present invention to maintain the efficacy of procaterol hydrochloride. Such compounds are, for example, hyaluronic acid, chondroitin sulfate, carrageenan, chitin sulfate, chitosan sulfate, pullulan sulfate, alginic acid, carboxymethyl cellulose, carboxymethylkurdlan, carboxymethyldextran, carboxymethyl pullulan, carboxymethyl High molecular weight polysaccharides comprising chitin, carboxymethylchitosan and such anionic functional groups and salts thereof, polystyrene sulfonic acid, polyvinyl sulfate, polyacrylic acid, carboxyvinyl polymer, polymethacrylic acid and synthetic polymers comprising such anionic functional groups Compounds, salts thereof, and the like. Suitable compounds among these water-soluble high molecular compounds are those having sulfuric acid groups such as acidic mucopolysaccharides, dextran sulfates, polystyrenesulfonic acids and salts thereof. More specific examples include chondroitin sulfate, heparin, heparan sulfate, keratan sulfate, dextran sulfate, polystyrenesulfonic acid and salts thereof (eg, sodium salts, potassium salts, or calcium salts). Of these, chondroitin sulfate, dextran sulfate, polystyrene sulfonic acid and salts thereof are preferred, and sodium chondroitin sulfate, dextran sulfate and polystyrene sulfonate are more preferred. Most preferred of these is sodium chondroitin sulfate. In the practice of the present invention, it is suitable to use the above water-soluble high molecular compound having a molecular weight of at least 10000, usually about 10000 to about 3000000. In some cases it is advisable to use compounds having a molecular weight of about 10000 to about 100000 and in other cases compounds having a molecular weight of about 100000 to about 1000000.

The amount of such water soluble high molecular 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, based on the amount of the aqueous solution of procaterol hydrochloride. To 50 mg / ml.

The amount of procaterol hydrochloride to be incorporated into the formulation is not critical but is usually 0.1 to 10000 μg / ml, preferably 1 to 1000 μg / ml, more preferably 5 to 500 μg / ml. For use as eye drops, the amount is 10 to 300 μg / ml.

Oxygen adsorbents useful in the present invention include, for example, iron hydroxides, iron oxides, iron carbides or such iron compounds as active ingredients and include those known to date. Typical commercial products are, for example, AGELESS (product of Mitsubishi Gas Chemical Co., Ltd.), MODULAN (product of Nippon Kayaku Co., Ltd.), SEQUL (Nippon Soda Co., Ltd.) Product), VITALON (product of Toa Kosei Co., Ltd.), TAMOTSU (product of Oji Kako Co., Ltd.). The form of the oxygen adsorbent is not particularly limited as long as the adsorbent can be placed in the space between the plastic container holding the aqueous solution of prochlorate hydrochloric acid and the outer packing material as its outer cover. For example, if the oxygen adsorbent is in the form of a powder, it is preferable to put the necessary amount in a small air permeable bag or the like and put it in the above-mentioned space.

Various materials may be used as the next packing material that will surround the plastic container holding the aqueous solution of procaterol hydrochloride. Examples of such materials include glass containers, films or sheets, and bottles of various materials that are widely used. Specific examples include olefin resins such as polypropylene, high density polyethylene or polyethylene such as polyethylene terephthalate, ethylene-vinyl alcohol copolymer resin, polyvinylidene chloride, polyacrylonitrile, polyvinyl alcohol, polycarbonate, nylon, and the like. And at least one kind selected from polyamide resin, cellulose acetate, polyester, aluminum foil, glass, and the like. The secondary materials used herein include laminated films of the materials exemplified above, for example, laminated films such as nylon, ethylene-vinyl alcohol copolymer resins, polyethylene, and the like. The useful next material may be a laminate of plastics such as aluminum foil and polyethylene, and a plastic film combined with aluminum or silicic acid by evaporation. Preferred airborne materials have an oxygen permeability of 1.0 ml / m 2 · hr · atm or less at 25 ° C., 75% RH. The plastic container and oxygen adsorbent holding aqueous hydrochloric acid solution formulation may be packaged with such packing material by conventional methods.

A package holding the aqueous solution of procaterol hydrochloride according to the present invention is produced by removing gas from the space between the plastic container and the next packing material without using an oxygen adsorbent and sealing the space with nitrogen gas and / or carbon dioxide gas. do. The space is degassed in a conventional manner, for example using a vacuum packing machine.

The aqueous solution of procaterol hydrochloride of the present invention can be used for the purpose of covering all known uses of procaterol hydrochloride. The preparation of the present invention is suitable for use as an ophthalmic solution for the prevention or treatment of inflammation or wounds such as bronchodilators, peripheral vasodilators, antihypertensive agents, antiglaucoma agents, antiallergic agents, eyes, and the like.

Effects of the Invention

The package holding the aqueous solution of procaterol hydrochloride according to the present invention increases the long term storage stability of the preparation. In addition, the aqueous solution of procaterol hydrochloride containing the above-mentioned specific water-soluble high molecular compound can be remarkably effective for a long time.

The following examples are presented to illustrate the present invention. However, the present invention is not limited to this embodiment.

Formulation Example 1

per ml,

Procaterol hydrochloride 0.003 mg

Glycerin 24.8 mg

0.422 mg citric anhydride

Sodium Citrate 0.824 mg

0.1 mg of ethylenediamine tetraacetate

1 μl 10% benzalkonium chloride

Sodium hydroxide q.s.

Injection water q.s.

Infusion water contains the remaining components mentioned above. The solution was filtered using a suitable filter paper for sterilization, thus producing an eye drop. The pH of the eye drops is 5.0.

Formulation Example 2

per ml,

Procaterol hydrochloride 0.001 mg

Glycerin 24.8 mg

0.422 mg citric anhydride

Sodium Citrate 0.824 mg

0.1 mg of ethylenediamine tetraacetate

1 μl 10% benzalkonium chloride

Sodium hydroxide q.s.

Injection water q.s.

Infusion water contains the remaining components mentioned above. The solution was filtered using a suitable filter paper for sterilization, thus producing an eye drop. The pH of the eye drops is 5.0.

Formulation Example 3

An aqueous solution preparation was prepared in the same manner as in Preparation Example 1, except that the amount of procaterol hydrochloride was used as 0.01 mg.

Formulation Example 4

per ml,

Hydrochloric acid 0.01 mg

Glycerin 25 mg

Sodium chondroitin sulfate 10 mg

Methylparaben 0.5 mg

pH regulator q.s.

Injection water q.s.

Infusion water contains the remaining components mentioned above. The solution was filtered using a suitable filter paper for sterilization, thus producing an aqueous solution formulation. The pH of the formulation is 5.0.

Formulation Example 5

An aqueous solution preparation was prepared in the same manner as in Preparation Example 1 except that the amount of procaterol hydrochloride was changed to 0.01 mg and 0.5 mg of methylparaben was used instead of benzalkonium chloride.

Formulation Example 6

per ml,

Hydrochloric acid 0.01 mg

Sodium chondroitin sulfate 10 mg

Sodium chloride 5.5 mg

Chlorobutanol 3.5 mg

Injection water q.s.

Infusion water contains the remaining components mentioned above. The solution was filtered using a suitable filter paper for sterilization, thus producing an aqueous solution formulation.

Formulation Example 7

per ml,

Procaterol hydrochloride 0.1 mg

Sodium chondroitin sulfate 10 mg

Sodium chloride 5.5 mg

Chlorobutanol 3.5 mg

Injection water q.s.

Infusion water contains the remaining components mentioned above. The solution was filtered using a suitable filter paper for sterilization, thus producing an aqueous solution formulation.

Formulation Example 8

per ml,

Procaterol hydrochloride 0.1 mg

Dextran sodium sulfate 50 mg

Glycerin 18 mg

Chlorobutanol 3 mg

pH regulator q.s.

Injection water q.s.

Infusion water contains the remaining components mentioned above. The solution was filtered using a suitable filter paper for sterilization, thus producing an aqueous solution formulation.

Formulation Example 9

per ml,

Procaterol hydrochloride 0.001 mg

Sodium chondroitin sulfate 30 mg

Glycerin 18 mg

Chlorobutanol 3.5 mg

pH regulator q.s.

Injection water q.s.

Infusion water contains the remaining components mentioned above. The solution was filtered using a suitable filter paper for sterilization, thus producing an aqueous solution formulation.

Formulation Example 10

per ml,

Hydrochloric acid 0.01 mg

50 mg sodium chondroitin sulfate

Glycerin 14 mg

Chlorobutanol 3.5 mg

pH regulator q.s.

Injection water q.s.

Infusion water contains the remaining components mentioned above. The solution was filtered using a suitable filter paper for sterilization, thus producing an aqueous solution formulation.

Formulation Example 11

per ml,

Procaterol hydrochloride 0.1 mg

100 mg sodium chondroitin sulfate

Glycerin 4 mg

Chlorobutanol 3.5 mg

pH regulator q.s.

Injection water q.s.

Infusion water contains the remaining components mentioned above. The solution was filtered using a suitable filter paper for sterilization, thus producing an aqueous solution formulation.

Formulation Example 12

per ml,

Procaterol hydrochloride 0.001 mg

Dextran sodium sulfate 30 mg

Glycerin 20 mg

Citric acid 0.4 mg

0.26 mg trisodium dihydrate citrate

Chlorobutanol 3.5 mg

pH regulator q.s.

Injection water q.s.

Infusion water contains the remaining components mentioned above. The solution was filtered using a suitable filter paper for sterilization, thus producing an aqueous solution formulation.

Formulation Example 13

per ml,

Hydrochloric acid 0.01 mg

Dextran sodium sulfate 50 mg

Glycerin 18 mg

Citric acid 0.4 mg

0.26 mg trisodium dihydrate citrate

Chlorobutanol 3.5 mg

pH regulator q.s.

Injection water q.s.

Infusion water contains the remaining components mentioned above. The solution was filtered using a suitable filter paper for sterilization, thus producing an aqueous solution formulation.

Formulation Example 14

per ml,

Procaterol hydrochloride 0.1 mg

Dextran sodium sulfate 100 mg

Glycerin 13 mg

Citric acid 0.4 mg

0.26 mg trisodium dihydrate citrate

Chlorobutanol 3.5 mg

pH regulator q.s.

Injection water q.s.

Infusion water contains the remaining components mentioned above. The solution was filtered using a suitable filter paper for sterilization, thus producing an aqueous solution formulation.

Formulation Example 15

per ml,

Hydrochloric acid 0.01 mg

Sodium chondroitin sulfate 30 mg

Chlorobutanol 2 mg

Benzalkonium chloride 0.023 mg

Sodium chloride 6 mg

Hydrochloric acid (pH regulator) q.s.

Injection water q.s.

Infusion water contains the remaining components mentioned above. The solution was filtered using a suitable filter paper for sterilization, thus producing an aqueous solution formulation. The formulation has a pH of 4.7-5.0 and an osmotic ratio of 1.0.

Formulation Example 16

per ml,

Hydrochloric acid 0.03 mg

Sodium chondroitin sulfate 30 mg

Chlorobutanol 2 mg

Benzalkonium chloride 0.023 mg

Sodium chloride 6 mg

Hydrochloric acid (pH regulator) q.s.

Injection water q.s.

Infusion water contains the remaining components mentioned above. The solution was filtered using a suitable filter paper for sterilization, thus producing an aqueous solution formulation. The formulation has a pH of 4.7-5.0 and an osmotic ratio of 1.0.

Formulation Example 17

per ml,

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 regulator) q.s.

Injection water q.s.

Infusion water contains the remaining components mentioned above. The solution was filtered using a suitable filter paper for sterilization, thus producing an aqueous solution formulation. The formulation has a pH of 4.7-5.0 and an osmotic ratio of 1.0.

Formulation Example 18

per ml,

0.3 mg of procaterol hydrochloride

Sodium chondroitin sulfate 30 mg

Chlorobutanol 2 mg

Benzalkonium chloride 0.023 mg

Sodium chloride 6 mg

Hydrochloric acid (pH regulator) q.s.

Injection water q.s.

Infusion water contains the remaining components mentioned above. The solution was filtered using a suitable filter paper for sterilization, thus producing an aqueous solution formulation. The formulation has a pH of 4.7-5.0 and an osmotic ratio of 1.0.

Formulation Example 19

An aqueous solution formulation was prepared in the same manner as in Formulation Example 15, except that 10 mg of sodium chondroitin sulfate was used.

Formulation Example 20

An aqueous solution formulation was prepared in the same manner as in Formulation Example 16, except that 10 mg of sodium chondroitin sulfate was used.

Formulation Example 21

An aqueous solution formulation was prepared in the same manner as in Formulation Example 17, except that 10 mg of sodium chondroitin sulfate was used.

Formulation Example 22

An aqueous solution formulation was prepared in the same manner as in Formulation Example 18, except that 10 mg of sodium chondroitin sulfate was used.

Preparation Example 1

5 ml of each eye drop prepared in Formulation Example 1 or 2 was placed in an eye drop container (a bottle made of colorless polyethylene; a nozzle made of colorless polyethylene; a cap made of colorless polypropylene, all manufactured by Taisei Kako Corporation). Fill in. The vessel was packed with an air absorbent film to carry out a second packing with an oxygen adsorbent (Azeles) and an oxygen detection composition (Azeles Eye) to obtain a package according to the present invention.

Two types of air-permeable films were used:

(i) Oxygen barrier laminated film comprising nylon 66 film stretched to 15 μ thick, 15 μ thick nylon-ethylene vinyl alcohol copolymer film and 15 μ thick polyethylene film, 0.8 ml at 20 ° C., 65% RH A film having an oxygen permeability of 1.2 ml / m 2 · 24 hrs at / m 2 · 24 hrs or 25 ° C., 65% RH.

(ii) a vapor / oxygen barrier laminated film comprising a 12 μ thick polyethylene terephthalate film, a 12 μ thick film made of silicon oxide adsorbed on polyvinyl alcohol, and a 50 μ thick straight chain low density polyethylene film, A film having an oxygen permeability of 0.1 ml / m 2 · 24 hrs at 20 ° C., 65% RH or 0.1 ml / m 2 · 24 hrs at 25 ° C., 65% RH.

The second package obtained by packing the ophthalmic solution container filled with the ophthalmic solution of Formulation Example 1 using the oxygen barrier laminated film as the next film is referred to as the product A of the present invention. The second package obtained by packing the eye drop container filled with the eye drop solution of Formulation Example 1 using the vapor / oxygen barrier laminated film as the next film is referred to as the product B of the present invention. The second package obtained by packing the ophthalmic solution container filled with the ophthalmic solution of Formulation Example 2 using the oxygen barrier laminated film as the next film is referred to as the product C of the present invention. The second package obtained by packing the eye drop container filled with the eye drop solution of Formulation Example 2 using the vapor / oxygen barrier laminated film as the next film is referred to as the product D of the present invention.

Oxygen concentration in the second package is detected by AGELESS EYE. The Angeles eye was adjusted to turn pink at oxygen concentrations up to 0.1% and to blue at oxygen concentrations above 0.5%. In products A to D of the present invention, all the azeles' eyes became pink within 3 days.

Preparation Example 2

5 ml of each eye drop prepared in Formulation Example 1 or 2 was placed in an eye drop container (a bottle made of colorless polyethylene; a nozzle made of colorless polyethylene; a cap made of colorless polypropylene, all manufactured by Taisei Kako Corporation). Fill in. The container is packaged in aluminum foil or a film of aluminum adsorbed. The space between the eye drop container and the second package is then evacuated with a vacuum packing machine and nitrogen gas is injected into the space to produce the product E (packing with aluminum foil) and the product F (aluminum) of the invention. Packing with adsorbed film).

Preparation Example 3

In the same manner as in the production of the product B of the present invention in Production Example 1, the aqueous solution formulation according to Formulation Example 3 was adjusted to adjust the product G of the present invention, and the aqueous solution formulation according to Formulation Example 4 was adjusted to obtain the product H of the present invention. And the aqueous solution preparation by Formulation Example 5 was adjusted and the product I of this invention was obtained.

Preparation Example 4

The aqueous solution preparation prepared in Formulation Examples 6 to 8 was filled into a polyvinyl chloride container, and the container was packaged with a packing material containing a laminate of aluminum foil and polyethylene to carry out a second packing, together with an oxygen adsorbent (modulan). The product of the present invention was obtained.

Preparation Example 5

The aqueous solution preparation prepared in Formulation Examples 9 to 11 was filled into a polyester container, and the container was packed with an oxygen adsorbent (Sekul) with a packing material containing ethylene-vinyl alcohol copolymer resin for carrying out the second packing. The product of the present invention was obtained.

Preparation Example 6

The aqueous solution preparation prepared in Formulation Examples 12 to 14 was filled into a container of ethylene-vinyl acetate copolymer, and a second packing was carried out using an air-permeable film containing polyacrylonitrile. Then, the air-free space was sealed with carbon dioxide gas to obtain the product of the present invention.

Preparation Example 7

5 ml of each ophthalmic solution prepared in Formulation Examples 15, 16 and 17 was prepared from eye drop container (bottle made of colorless polyethylene; nozzle made of colorless polyethylene; cap made of colorless polypropylene, all manufactured by Taisei Kako Co., Ltd.). Filled in). The vessel was packaged with a packing material comprising a laminate of aluminum foil and polyethylene to carry out the second packing with an oxygen adsorbent (Azeles) to obtain the product of the present invention.

The second package obtained by packing the ophthalmic solution container filled with the ophthalmic solution of Formulation Example 15 is hereinafter referred to as product J of the present invention. The second package obtained by packing the ophthalmic solution container filled with the ophthalmic solution of Formulation Example 16 is hereinafter referred to as the product K of the present invention. The second package obtained by packing the ophthalmic solution container filled with the ophthalmic solution of Formulation Example 17 is hereinafter referred to as the product L of the present invention.

Test Example 1

Products A to D of the present invention were placed in cardboard boxes and placed in a room at 25 ° C. and 75% RH or 40 ° C. and 75% RH. At 4 weeks, 7 weeks, 12 weeks, 18 weeks and 24 weeks, the amount of procaterol hydrochloride contained in the eye drop solution was measured by calculating the ratio of remaining procaterol hydrochloride by the usual method. For comparison, cardboard boxes containing eye drops containers filled with the eye drops of Formulation Examples 1 and 2 (Comparative Products 1 and 2, respectively) were provided to calculate the percentage of procaterol hydrochloride remaining. The results are shown in Tables 1 and 2.

Proportion of remaining hydrochloric acid (%) 4 weeks 7 Weeks 12 Weeks 18 Weeks 24 Weeks 40 ℃, 75% RH Product A of the Invention Product B of the Invention B Comparative Product 1 100.24 98.47 97.41 93.80 95.21 99.11 98.17 98.55 94.89 96.29 98.65 96.82 95.95 91.11 90.20

Proportion of hydrochloric acid remaining (%) 4 weeks 7 Weeks 12 Weeks 18 Weeks 24 Weeks 25 ℃, 75% RH Product C of the Invention D Product of the Invention D Comparative Product 2 100.20 101.48 101.73 99.29 101.60 102.17 101.25 101.53 99.08 100.35 99.1 98.5 97.6 40 ℃, 75% RH Product C of the Invention D Product of the Invention D Comparative Product 2 101.47 100.15 98.20 95.93 95.68 101.15 99.93 99.03 95.56 96.17 97.6 97.7 93.8

Tables 1 and 2 show the following. In Table 1, Comparative Product 1 shows a reduction of about 10% in the proportion of procaterol hydrochloride remaining after 24 weeks storage at 40 ° C. and 75% RH, whereas products A and B of the present invention show remaining hydrochloric acid pro A decrease of up to 5% in the proportion of caterol. In Table 2, Comparative Product 2 shows about a 2% reduction in the proportion of procatrol remaining hydrochloride after 12 weeks storage at 25 ° C. and 75% RH, whereas products C and D of the present invention remain hydrochloric acid The proportion of procaterol shows little decrease even after 24 weeks. In addition, Comparative product 2 shows a decrease of about 6% in the proportion of remaining procaterol hydrochloride after 12 weeks storage at 40 ° C. and 75% RH, whereas products C and D of the present invention have remaining procate hydrochloride The percentage of rolls shows a drop below 5% even after 24 weeks. From these results, it can be seen that the removal of oxygen clearly contributes to the stabilization of procaterol hydrochloride.

Test Example 2

The products G-I of the invention were placed in cardboard boxes and placed in a room at 40 ° C. and 75% RH. At 2, 4 and 8 weeks, the amount of procaterol hydrochloride contained in the eye drop solution was measured by calculating the ratio of remaining procaterol hydrochloride by the usual method. For comparison, a cardboard box comprising a plastic container filled with the aqueous solution formulations of Formulation Examples 3 to 5 was used to calculate the proportion of procatrol hydrochloride remaining in the same manner as described above. The results are shown in Table 3.

Proportion of hydrochloric acid remaining (%) 2 weeks 4 weeks 8 Weeks Product G of the Invention 99.6 99.2 98.5 Product H of the Invention 98.5 98.8 97.3 Product I of the Invention 98.8 98.0 Formulation Example 3 98.7 98.4 97.5 Formulation Example 4 97.6 97.0 93.8 Formulation Example 5 98.1 97.3 94.7

Test Example 3

Efficacy test for guinea pigs with conjunctivitis induced by histamine

Hartley-strain guinea pigs (weight 440-570 g) were used as model animals. Testing was performed using animals in anesthesia with pentobarbital (30 mg / kg, i.p.). Test formulations (aqueous formulations of Formulation Examples 6-8) were administered to the animal's right eye using an eye drop, and 10 μl of eye buffer buffer or physiological saline was administered to the animal's left eye. One hour, two hours, or three hours after dosing, 10 μl of 2 mg / ml histamine / physiological saline was administered to both eyes of the animal to induce conjunctivitis. Untreated groups received physiological saline instead of histamine. Evans Blue was administered in an amount of 10 mg / ml / kg by intravenous injection immediately before administration of histamine.

Blood was collected from the vena cava 30 minutes after histamine administration to determine the absorbance (A ₆₂₀ ) of the plasma at 620 nm. Animal eyelids and conjunctiva were removed. Evans Blue was extracted using 1.5 ml of acetone-0.5% sodium sulfate (7: 3, v / v) for 2 days and the absorbance of the plasma was measured at 620 nm. The leakage of plasma is calculated by the equation

The increase in vascular permeability by histamine is expressed in terms of an increase in plasma leakage from the untreated group, ie 2.6 ± 0.2 μl (mean ± S.E., N = 7). Drug efficacy is expressed in terms of the percentage control of increased vascular permeability of the left eye (controlled eye) to the right eye (treated eye). Percent control is calculated by

The results are shown in Table 4.

Dosing time % Control of plasma leakage (mean ± S. E.) Formulation Example 6 1 hour before 53.0 ± 5.5 2 hours ago 27.3 ± 5.4 Formulation Example 7 2 hours ago 33.3 ± 5.2 Formulation Example 8 3 hours ago 35.3 ± 6.2

Test Example 4

Efficacy test for guinea pigs with conjunctivitis induced by histamine

Hartley-strain guinea pigs (weight 440-570) were used as model animals. Testing was performed using animals in anesthesia with pentobarbital (30 mg / kg, i.p.). The test formulation (the aqueous solution formulation of Formulation Example 17) was administered to the right eye of the animal using an eye drop, and 10 μl of eye drop buffer or physiological saline was administered to the left eye of the animal. Five minutes or three hours after administration, 10 μl of 2 mg / ml histamine / physiological saline was administered to both eyes of the animal to induce conjunctivitis. Untreated groups received physiological saline instead of histamine. Evans Blue was administered in an amount of 10 mg / ml / kg by intravenous injection immediately before administration of histamine.

Plasma leakage was calculated in the same manner as in Test Example 3 to determine the percentage control of vascular permeability increase.

The results are shown in Table 5. For comparison, Table 5 also shows an aqueous solution preparation prepared in the same manner as in Formulation Example 1 except that 0.1 mg of procaterol hydrochloride in Formulation Example 1 was used instead of the aqueous solution formulation of Formulation Example 17 (Comparative Product 4). The results obtained using and the results obtained using physiological saline (control) are also shown.

Dosing time Test medicine % Control of plasma leakage (mean ± S. E.) 5 minutes ago Control -3.3 ± 3.3 Comparative product 4 66.7 ± 4.2 Formulation Example 17 68.4 ± 9.4 3 hours ago contrast -3.3 ± 3.3 Comparative product 4 -7.0 ± 9.5 Formulation Example 17 40.6 ± 5.8

Test Example 5

The products J to L of the present invention were placed in a cardboard box and placed in a room at 40 ° C. and 75% RH. At 2 weeks, 4 weeks, 6 weeks, 8 weeks, and 12 weeks, the amount of procaterol hydrochloride in the eye drop solution was measured by calculating the ratio of remaining procaterol hydrochloride by the usual method. For comparison, eye drops containers filled with the eye drops of Formulation Examples 15, 16 and 17 (bottles made of colorless polyethylene; nozzles made of colorless polyethylene; caps made of colorless polypropylene, all manufactured by Taisei Kako Co., Ltd.) Use cardboard boxes containing the comparative products (5, 6, 7 respectively). The results are shown in Table 6. In Table 6, comparative product 5 is to hold the above-mentioned eye drop container filled with the ophthalmic solution of Formulation Example 15, and comparative product 6 is to hold the above eye drop container filled with the ophthalmic solution of Formulation Example 16, and comparative product 7 holds the above-mentioned eye drop container filled with the eye drop of Formulation Example 17.

Proportion of remaining hydrochloric acid (%) 2 weeks 4 weeks 6 Weeks 8 Weeks 12 Weeks Product J of the Invention 98.3 98.3 98.4 98.3 98.1 Comparative product 5 94.7 90.4 86.8 83.4 75.0 Product K of the Invention 98.9 98.4 98.4 98.2 95.9 Comparative product 6 96.9 93.5 91.0 88.2 80.9 Product L of the Invention 99.0 98.0 98.4 97.1 96.2 Comparative product 7 97.2 93.8 92.0 88.6 83.7

Claims (22)

A package for holding a pharmaceutical composition comprising an aqueous solution of procaterol hydrochloride that prevents procaterol hydrochloride from being decomposed by an oxidation reaction in an aqueous solution. The package of claim 1 wherein an oxygen free atmosphere is maintained. The package of claim 1, wherein the pharmaceutical composition is filled in a plastic container, the container being packaged with a next packing material. The package of claim 3, wherein the pharmaceutical composition is filled in a plastic container, the container being packaged with a next packing material with an oxygen adsorbent. The package of claim 4, wherein the pharmaceutical composition is an eye drop. 4. The pharmaceutical composition of claim 3, wherein the pharmaceutical composition is filled in a plastic container, the container is packaged with an airtight packing material, and the space between the container and the airtight packing material is sealed with nitrogen gas and / or carbon dioxide gas. package. The package of claim 6, wherein said pharmaceutical composition is an eye drop. The package of claim 1, wherein said pharmaceutical composition comprises a water soluble high molecular compound comprising an anionic functional group and having a molecular weight of at least 10000. The package according to claim 8, wherein the water-soluble high molecular compound is at least one kind selected from the group consisting of acidic mucopolysaccharides, dextran sulfates containing sulfuric acid groups and polystyrenesulfonic acids, and salts thereof. The package of claim 8, wherein the water soluble high molecular compound is at least one kind selected from the group consisting of sodium chondroitin sulfate, sodium dextran sulfate, and sodium polystyrene sulfonate. 7. A package according to claim 4 or 6, wherein the pharmaceutical composition comprises a water soluble high molecular compound comprising an anionic functional group and having a molecular weight of at least 10000. The package according to claim 11, wherein the water-soluble high molecular compound is at least one kind selected from the group consisting of acidic mucopolysaccharides, dextran sulfate and polystyrene sulfonic acid containing sulfuric acid groups, and salts thereof. 12. The package of claim 11, wherein said water soluble high molecular compound is at least one kind selected from the group consisting of sodium chondroitin sulfate, sodium dextran sulfate and sodium polystyrene sulfonate. The package of claim 11, wherein said water soluble high molecular compound is sodium chondroitin sulfate. The package of claim 14, wherein said pharmaceutical composition is an eye drop. The package of claim 15 wherein the pharmaceutical composition comprises 1 to 1000 μg / ml of procaterol hydrochloride and 10 to 150 mg / ml of chondroitin sodium sulfate. A pharmaceutical composition comprising an aqueous solution of procaterol hydrochloride containing an anionic functional group and containing a water soluble high molecular compound having a molecular weight of at least 10000. 18. The pharmaceutical composition according to claim 17, wherein the water-soluble high molecular compound is at least one kind selected from the group consisting of acidic mucopolysaccharides, dextran sulfates containing sulfuric acid groups and polystyrenesulfonic acids, and salts thereof. 18. The pharmaceutical composition of claim 17, wherein the water soluble high molecular compound is at least one kind selected from the group consisting of sodium chondroitin sulfate, sodium dextran sulfate, and sodium polystyrene sulfonate. 18. The pharmaceutical composition of claim 17, wherein the water soluble high molecular compound is sodium chondroitin sulfate. The pharmaceutical composition of claim 20 which is an eye drop. The pharmaceutical composition of claim 21 comprising 1 to 1000 μg / ml of procaterol hydrochloride and 10 to 150 mg / ml of sodium chondroitin sulfate.