JP2002068963A - Liquid agent and container - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a liquid agent which can prevent the decrease in the concentration of a lipo-soluble ingredient such as a functional ingredient over a long period. SOLUTION: A liquid agent 14 containing a lipo-soluble ingredient is received in a sealable container having a receiving portion 11 for receiving the liquid agent and a neck portion 12 which is extended from the receiving portion and whose tip is sealed. The inside of the container is formed from a rigid synthetic resin (a polyester-based resin, a polycarbonate-based resin, or the like). The lipo-soluble ingredient is, for example, a terpene-based compound (a menthol compound, a camphor compound, or the like), and the content of the terpene- based compound is about 0.0001 to 5 (W/V)%.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a solution containing a fat-soluble component, a container for containing the solution, and a method for suppressing the adsorption of a fat-soluble component using the container.

[0002]

2. Description of the Related Art Conventionally, a container for accommodating a liquid agent such as an eye drop is generally composed of a plurality of members such as a container body, a nozzle and a cap. The container body has a neck at the upper part of the liquid container formed in a hollow shape, and an opening is formed at the top of the neck. In addition, a nozzle is fitted into the opening of the container body in order to pour out an appropriate amount of the content liquid, and the entire opening is covered with a cap in order to suppress leakage of the content liquid from the nozzle outlet. In such a container, the container body is usually manufactured by blow molding, injection molding, injection blow molding or the like using a hard synthetic resin such as polyethylene terephthalate or a soft synthetic resin such as polyethylene as a raw material.
The nozzle is made of a soft synthetic resin such as polyethylene, and the cap is made of a hard synthetic resin such as polystyrene.

On the other hand, liquid preparations such as eye drops contained in containers contain terpene compounds such as menthols and camphors as functional components (perfume components, refreshing components) and the like. Many products have sensory characteristics such as refreshing sensation as product characteristics. And
For products that are applied to organs that are sensitive to irritation, such as mucous membranes, if the compounding concentration of the functional component is too high, burning or excessive irritation may occur, causing discomfort. is there. However, since the functional component is fat-soluble, it is easily adsorbed on a soft synthetic resin such as polyethylene or polypropylene which is a container material. For this reason, when the liquid agent is filled in a container made of a soft synthetic resin, these easily adsorbable components (functional components) having a low compounding concentration are further adsorbed to the container, so that the concentration of the functional components over time increases. It is further reduced and the sensory characteristics of the product are likely to be impaired.

In order to avoid such a problem, when an existing container having an opening in the container body is used, it is considered that the container body is made of a hard synthetic resin which does not adsorb functional components such as polyethylene terephthalate. However, it is necessary to use a soft synthetic resin such as a flexible polyethylene for the nozzle in order to facilitate the fitting with the container body.

[0005] Japanese Utility Model Publication No. 1-152929 discloses a chemical bottle made of a soft synthetic resin and a mouth portion (opening) of the chemical bottle.
There is disclosed a container comprising an inner plug attached to the inner plug, and the inner plug has a double structure formed by an inner cylinder made of a hard synthetic resin and an outer cylinder made of a soft synthetic resin. In this document,
When a soft synthetic resin is used for the inner plug, there is a risk that the chemical solution may be deteriorated because a part of the chemical solution is adsorbed. By forming the inner cylinder of the inner plug with a hard synthetic resin, the contact between the chemical solution and the soft synthetic resin may occur. It is described that deterioration of the contained chemical solution can be prevented by substantially eliminating the above. However, even if such an inner plug is used, it is difficult to sufficiently reduce the adsorption of the easily adsorbable component in the chemical solution, and there is a problem particularly when the concentration of the easily adsorbable component is low. In addition, although it is conceivable to use a hard synthetic resin for all the materials of the nozzle, not only is it restricted in molding, but even if it can be molded, the container body is made of the same hard synthetic resin as the nozzle, The sealing performance is poor only by fitting the container body to the nozzle. In order to solve this problem, it is conceivable that after the nozzle is fitted to the container body, the fitted portion is bonded by welding, welding, or the like, but there are many problems in the process control and the reality is poor.

In order to simplify the manufacturing process, a liquid container having no nozzle is also known. For example, JP-A-48-50880 and registered utility model No. 2560
No. 817 discloses a plastic container in which the top of a neck portion in a container body is closed until use. The container of the registered utility model No. 2560817, according to a known blow molding method, after the portion except the outlet end of the parison is hollow-formed, and after injecting a predetermined liquid,
It is manufactured by closing the outlet end of the molded body. By using such a container, the container body can be kept sealed until it is opened using a projection such as a pin. There is no fear. As a material for forming the container body, a soft synthetic resin such as polyethylene is mainly used.

[0007]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a liquid agent and a container which can prevent a decrease in the concentration of fat-soluble components such as a fragrance component and a refreshing component over a long period of time.

Another object of the present invention is to provide a liquid agent and a container which can maintain the concentration of fat-soluble components at a low concentration for a long period of time.

[0009]

Means for Solving the Problems The present inventors have conducted intensive studies to achieve the above object, and as a result, using a tightly sealed container made of a hard synthetic resin, a fat-soluble component (particularly, a fragrance component, The present inventors have found that a decrease in the concentration of a functional component such as a cooling component) can be suppressed and the liquid preparation can be stably stored for a long period of time, and thus the present invention has been completed.

That is, the liquid preparation (mucosal preparation, etc.) of the present invention contains a fat-soluble component, and contains a storage section for storing the liquid preparation, and a neck section extending from this storage section and having a closed end. In a hermetically sealed container having The inner surface of the container is formed of a hard synthetic resin (polyester resin, polycarbonate resin, etc.).
The fat-soluble component may be, for example, a terpene compound (menthols, camphors, etc.), and the content of the terpene compound may be about 0.0001 to 5 (W / V)%.

The present invention also includes a container having at least an inner surface formed of a hard synthetic resin and containing the liquid agent. The container has a storage section for storing the liquid agent,
And an openable closing portion for allowing the liquid agent to flow out of the storage portion.

[0012] The present invention also includes a method of containing a liquid preparation containing a fat-soluble component in the container to suppress the adsorption of the fat-soluble component to the container.

In this specification, "sealing" means that gas and liquid do not enter or leak. Further, the “sealing container” refers to a container in which an outlet for a liquid agent (such as the top of a neck portion) is physically and irreversibly closed by a closing portion, and is sealed. It means a container that is not closed by a detachable member such as a stopper but whose outlet is physically closed by fusion, welding, or the like until use, such as a blow-fill seal container.

[0014]

DESCRIPTION OF THE PREFERRED EMBODIMENTS [Solution] The solution (chemical solution) of the present invention contains a fat-soluble component. As fat-soluble components, components that are adsorbable to soft synthetic resins (such as polyethylene)
For example, terpene compounds, xanthine compounds (such as caffeine), fat-soluble vitamins (such as vitamin A, vitamin D, vitamin E, and vitamin K), and fat-soluble drugs can be exemplified. The fat-soluble components can be used alone or in combination of two or more. Usually, at least one component selected from terpene compounds, xanthine compounds, and fat-soluble vitamins is used.

The terpene compounds include terpene hydrocarbons (monoterpene hydrocarbons such as limonene, pinene and camphor, sesquiterpene hydrocarbons such as licitin) and terpene alcohols (citronellol, geraniol, linalool, menthol). , Terpineol,
Monoterpene alcohols such as borneol, sesquiterpene alcohols such as farnesol, diterpene alcohols, etc., terpene aldehydes (citronellal, citral (β-citral = neral),
Examples thereof include monoterpene aldehydes such as safranal, diterpene aldehydes such as retinal, and terpene ketones (monoterpene ketones such as mentone, carbomentone, and yonone). These terpene compounds may be d-, l-, or dl-forms. Further, the fat-soluble component includes oily components including terpene compounds, for example, essential oils such as eucalyptus oil, bergamot oil, fennel oil, peppermint oil, rose oil, peppermint oil, and cool mint.

Preferred fat-soluble components include terpene compounds, xanthine compounds, etc., more preferably terpene hydrocarbons (limonenes, pinenes, camphors, etc.), terpene alcohols (geraniols, menthols, borneols) (D-borneol, dragon brain, etc.), essential oils (eucalyptus oil, bergamot oil, cool mint, etc.), especially menthols (l-menthol, dl-menthol, etc.), camphors (dl-camphor, d-camphor) Etc.) are included. The terpene compound has aromaticity and coolness, and is generally used in a small amount in a liquid agent because a large amount of the terpene compound is too stimulating. In the present invention, even with such an aromatic component (perfume component) or a refreshing component, since the liquid agent is contained in a specific container, a decrease in concentration during storage can be suppressed, and the aromatic or refreshing property can be suppressed. Loss can be prevented.

The amount of the fat-soluble component is not particularly limited, but is relatively small when the fat-soluble component has an aromatic or refreshing property. The content of the fat-soluble component (especially, a functional component such as a terpene compound) in the solution is, for example, 0.00
About 01 to 5 (W / V)%, preferably 0.001 to 5 (W / V)
About 0.5 (W / V)%, more preferably 0.001%
About 0.1 (W / V)%. In the liquid preparation for mucous membrane application, the content of fat-soluble components (particularly, functional components such as terpene compounds) is usually 0.001 to 0.1 (W /
V)%, preferably 0.001 to 0.01 (W /
V)%.

The above-mentioned liquid preparations include solutions, suspensions, emulsions, extracts or tinctures, syrups, lotions and the like. Preferred preparations include liquids applied to mucous membranes (ocular mucosa, nasal mucosa, etc.) [topical treatments such as ophthalmic therapeutic agents (including ophthalmic liquids such as eye drops, eyewashes, intraocular perfusion fluids), nasal drops, etc. Liquids for oral administration], liquids for oral administration (aqueous liquids for internal use, for example, nourishing tonics, health drugs, cold medicines, etc.),
Examples thereof include liquids for contact lenses, preparations for injections, liquids for external use, and the like, and cosmetics and the like. In particular, the preparation of the present invention is useful as a preparation for mucosal application, for example, a preparation for ocular or nasal mucosa (for example, eye drops, eyewash, nasal drops, etc.).

The type of the active ingredient (pharmacologically active or physiologically active ingredient) in the liquid preparation is not particularly limited, and various active ingredients such as an anti-inflammatory drug component, an anti-allergic drug component, Antipyretic analgesic component, antipsychotic component, antihypertensive component, diuretic component, antitussive component, expectorant component, antiasthmatic component, stomachic component, digestive component,
Ulcer therapeutic components, anemia components, astringent components, antibacterial or bactericidal components, antitumor components, hormones, proteins or peptides, vitamins, amino acids and the like can be used. Examples of the components of the preparation for mucosal application (particularly, ophthalmic solutions and nasal drops) suitable in the present invention include the following components (particularly, components applied to the eye and nasal mucosa).

Decongestants (vasoconstrictors or sympathomimetics): α-adrenergic agonists, such as imidazoline derivatives (naphazoline, tetrahydrozoline, etc.), β
-Phenylethylamine derivatives (phenylephrine, epinephrine, ephedrine, methylephedrine and the like) and their salts (eg, naphazoline hydrochloride, naphazoline nitrate, phenylephrine hydrochloride, epinephrine hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, tetrahydrozoline hydrochloride, tetrahydrozoline nitrate, etc.) Antihypertensives: for example, pilocarpine or a salt thereof (such as pilocarpine hydrochloride), isopropyl unoprostone, distigmine bromide, carbacomal, carteolol hydrochloride,
Befnolol hydrochloride, Timolol maleate, Dipivefrin hydrochloride, Ecothiopart iodide, Diclofenamide, β
Ocular muscle modulator: Cholinesterase inhibitor having an active center similar to acetylcholine, for example, quaternary ammonium compounds such as neostigmine methylsulfate Myopia treatment / prevention agent: For example, tropicamide, cyclopentolate, endothelin Anti-inflammatory (or anti-inflammatory) or astringent: for example, epsilon-aminocaproic acid, berberine, azulene sulfonic acid, glycyrrhizic acid, anti-inflammatory enzyme agents (such as lysozyme chloride), methyl salicylate, allantoin, zinc and salts thereof (berberine chloride) , Berberine sulfate, sodium azulene sulfonate, dipotassium glycyrrhizinate,
In addition, as an anti-inflammatory (or anti-flame) agent, aromatic carboxylic acid derivatives, for example, aryl carboxylic acids (ibuprofen, ketoprofen, naproxen, suprofen,
Indomethacin, planoprofen, mefenamic acid, diclofenac, bromfenac, 2-naphthylacetic acid, 2-naphthoxyacetic acid, salicylic acid, etc., pyridonecarboxylic acids (romefloxane, norfloxacin, ofloxacin, enoxacin, ciprofloxacin, tosfloxacin, etc.) Can also be exemplified.

Antihistamines: for example, chlorpheniramine maleate, diphenhydramine, iproheptin, ketotifen fumarate, emedastine fumarate, clemastine fumarate, azelastine, levocabastine,
Olovatadine and salts thereof (diphenhydramine hydrochloride, iproheptin hydrochloride, azelastine hydrochloride, levocabastine hydrochloride, olobatadine hydrochloride, etc.) Antiallergic agents: for example, cromoglycic acid, amlexanox, ibudilast, suplatast tosilate, pemirolast, tranilast and their salts (chromoglyc) Antibacterial agents or sulfa drugs: for example, sulfonamides (sulfamethoxazole, sulfisoxazole or salts thereof (sulfamethoxazole sodium, sulfisomidine sodium, etc.)), acrinol, Quaternary ammonium salts (benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, etc.), alkyl polyaminoethyl glycine, ofloxacin, norfloxacin Vitamins: For example, vitamin B ₂ (or flavin adenine dinucleotide sodium), vitamin B ₆ (or pyridoxine hydrochloride), vitamin B ₁₂ (or cyanocobalamin), retinol acetate (vitamin A acetate), retinyl palmitate, tocopherol acetate (vitamin E-acetate), d-α-tocopherol acetate, panthenol, sodium pantothenate, calcium pantothenate, etc. Amino acids: For example, L-aspartic acid or a salt thereof (potassium L-aspartate, magnesium L-aspartate, L-asparagine) Saccharides: for example, monosaccharides (eg, glucose), disaccharides (eg, trehalose, lactose, fructose), cellulose or Derivatives (hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, etc.), high-molecular sugars (chondroitin sulfate sodium, sodium hyaluronate, etc.), sugar alcohols (mannitol, xylitol, sorbitol, etc.) Other components: polyvinyl alcohol, polyvinylpyrrolidone, etc. Furthermore, if necessary depending on the application, a local anesthetic (oxybuprocaine, lidocaine, lidocaine hydrochloride, etc.),
Various active ingredients such as soothing agents (such as procaine hydrochloride) may be used.

Usually, among these components, at least one component selected from the following group or a pharmaceutically acceptable salt thereof can be used.

Naphazoline, phenylephrine, epinephrine, ephedrine, methylephedrine, tetrahydrozoline, methylneostigmine sulfate, epsilon-aminocaproic acid, berberine chloride, azulenesulfonic acid, glycyrrhizic acid, lysozyme chloride, allantoin, zinc, chlorpheniramine maleate, diphenhydramine, Iproheptin, ketotifen fumarate, emedastine fumarate, clemastine fumarate, azelastine, levocabastine, olobatadine, cromoglycic acid, amlexanox, ibudilast, suplatast tosilate, pemirolast, tranilast, sulfamethoxazole, sulfisoxazole, sulfisoxazole, sulfisoxazole
Acrinol, benzethonium chloride, cetylpyridinium chloride, alkyl polyaminoethylglycine, ofloxacin, norfloxacin, flavin adenine dinucleotide, pyridoxine, cyanocobalamin, retinol, tocopherol, panthenol, pantothenic acid, aspartic acid, aminoethylsulfonic acid, glucose,
Chondroitin sulfate, hyaluronic acid, and polyvinyl alcohol These components can be used alone or in combination of two or more.

The content of these components can be selected according to the type (or use) of the liquid preparation, the type of the active ingredient, and the like. For example, 0.0001 to 30 (W / V) based on the whole liquid preparation.
%, Preferably from about 0.001 to 10 (W / V)%, more preferably from about 0.01 to 10 (W / V)%.

More specifically, in the aqueous solution (ophthalmic solution or nasal solution) suitable in the present invention, the content (unit: (W / V)%) of each component is, for example, as follows. is there.

Decongestant (vasoconstrictor or sympathomimetic): For example, an effective amount (eg, 0.0001) to 0.
5, preferably about 0.0005 to 0.3, more preferably about 0.001 to 0.1 Intraocular pressure lowering agent: for example, an effective amount (eg, 0.001) to 1
0, preferably 0.005 to 5, more preferably 0.
About 01 to 3 Ocular muscle adjusting component: For example, an effective amount (for example, 0.0001)
-0.01, preferably 0.0002-0.05, more preferably about 0.0003-0.005 Myopia treatment / prevention agent: for example, an effective amount (for example, 0.00
1) to 5, preferably 0.005 to 3, more preferably about 0.01 to 1 Anti-inflammatory (or anti-inflammatory) agent or astringent: for example, an effective amount (eg, 0.001) to 10, preferably 0.1 to 0.1. 005-5,
More preferably, about 0.01 to 3 antihistamines: for example, an effective amount (eg, 0.000
1) to 0.1, preferably about 0.0005 to 0.07, more preferably about 0.001 to 0.05 Antiallergic agent: for example, an effective amount (eg, 0.001)
Antibacterial agent or sulfa agent: for example, an effective amount (for example, 0.0
01) to 10, preferably about 0.003 to 10, more preferably about 0.01 to 10 vitamins: for example, an effective amount (for example, 0.0001) to
0.5, preferably 0.0005 to 0.3, more preferably about 0.001 to 0.1 amino acids: for example, an effective amount (for example, 0.0001) to
5, preferably about 0.0005 to 3, more preferably about 0.001 to 2.

[0027] The liquid preparation of the present invention may be of the type (or use) of the liquid preparation.
It can be prepared using various bases and additives according to the conditions. For example, aqueous liquid preparations (mucosal preparations such as eye drops and nasal drops)
Can be usually prepared using water (such as purified water) as a base. For the non-aqueous liquid, various oily bases such as vegetable oils (eg, olive oil, soybean oil, sesame oil, and cottonseed oil), propylene glycol, and liquid paraffin can be used.

Preparations such as aqueous liquid preparations may contain a surfactant in addition to the base. Surfactants can be used not only as solubilizers, solubilizers, and emulsifiers for poorly water-soluble components, but also to reduce the surface tension of liquids. When the surface tension of the liquid is reduced, it is possible to prevent the liquid from accumulating in the storage container of the liquid, particularly at the neck of the container. For this reason, there is no danger of the liquid pool being concentrated at the neck due to the permeation of water vapor.

As the surfactant, for example, polyoxyethylene (POE) -polyoxypropylene (POP)
A block copolymer (BASF Wyandotte Corporation, Pluronic), a POE-POP block-substituted alkylene diamine (BASF Wyandotte Corporation, Tetronic) in which a block chain composed of a POE block and a POP block is added to an alkylenediamine (such as ethylenediamine), polysorbate, Polyoxyethylene sorbitan fatty acid ester (polyoxyethylene sorbitan monooleate), polyoxyethylene oxystearic acid triglyceride, polyoxyethylene mono higher fatty acid ester (polyoxyethylene monostearate), polyethylene glycol, polyoxyethylene hydrogenated castor oil, etc. Nonionic surfactants; aliphatic amine salts such as _C10-20 alkyldimethylamine salts, and quaternary surfactants such as benzalkonium chloride and benzethonium chloride Cationic surfactants such as quaternary ammonium salts; anionic surfactants such as alkyl benzene sulfonate and alkyl sulfate; amphoteric surfactants such as alkyl polyaminoethyl glycine hydrochloride can be used.

The concentration of the surfactant is not particularly limited, but is, for example, about 0.001 to 1 (W / V)%, preferably about 0.01 to 0.8 (W / V)%, more preferably. Is about 0.01 to 0.5 (W / V)%. In addition,
The ratio between the fat-soluble component and the surfactant is, for example, 99/1.
About 1/99 (weight ratio), preferably 70/30 to 1
About 0/90 (weight ratio), more preferably 50/50
About 20/80 (weight ratio).

The above-mentioned liquid preparations include inorganic salts, buffers, isotonic agents, preservatives or preservatives, thickeners, chelating agents,
Various components such as a stabilizer, a pH adjuster, an antioxidant, a coloring agent, a flavoring agent or a fragrance may be contained.

Examples of the inorganic salts include sodium chloride, potassium chloride, sodium carbonate, dried sodium carbonate, sodium hydrogen carbonate, calcium chloride, magnesium sulfate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, Examples thereof include sodium thiosulfate, and these inorganic salts may be used as a buffer component or a tonicity component.

Examples of the buffer include a phosphate buffer,
Examples thereof include a borate buffer, a carbonate buffer, a citrate buffer, a tartrate buffer, an acetate buffer, and an amino acid (epsilon aminocaproic acid, aspartate and the like). Among them, a phosphate buffer, a borate buffer, and a carbonate buffer, which more effectively exhibit a stimulus-reducing effect, are preferable. Particularly, a borate buffer and a carbonate buffer are preferred.

Examples of the tonicity agent include sugars (sorbitol, glucose, mannitol, etc.), polyhydric alcohols (glycerin, polyethylene glycol, propylene glycol, etc.), and inorganic salts (sodium chloride, potassium chloride, etc.). it can.

As the preservative or preservative, for example,
Quaternary ammonium salts (benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, etc.), paraoxybenzoic acid esters (methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate), benzyl alcohol,
Phenethyl alcohol, phenoxyethanol, sorbic acid or a salt thereof (such as a potassium salt), alkyl polyaminoethyl glycine, thimerosal, chlorobutanol,
Examples thereof include sodium dehydroacetate, polymyxin B sulfate, polyquad, polyhexamethylene biguanide, and chlorhexidine.

Examples of the thickening agent include polyvinyl alcohol (completely or partially saponified), polyvinylpyrrolidone (K25, K30, K90, etc.), polysaccharides and derivatives thereof [cellulose derivatives (hydroxyethylcellulose,
Hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose (2208,290
6,2910), cellulose ethers such as carboxymethylcellulose or salts thereof), gum arabic powder, sodium chondroitin sulfate, powder of tragacanth, etc.), sugars (such as glucose, sorbitol, dextran 70), carboxyvinyl polymer, macrogol 4000 and the like. A block copolymer containing the polyoxyethylene block and the polyoxypropylene block (BASF Wyandotte Coproration, Pluronic, Tetronic, etc.) can also be used as a thickening agent. Among these thickeners, polyvinyl alcohol, polyvinylpyrrolidone, cellulose derivatives (hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose) and the like are usually used.

As the chelating agent, for example, ethylenediaminetetraacetic acid salt, edetic acid or a salt thereof (alkali metal salt such as disodium edetate, trisodium edetate, tetrasodium edetate, or alkaline earth such as calcium edetate) Metal salts), nitrilotriacetic acid or a salt thereof,
Examples include sodium hexametaphosphate and citric acid.

Examples of the stabilizer include edetates (such as sodium edetate) and ethylenediaminetetraacetate.

As the pH adjuster, bases (hydroxides of alkali metals such as sodium hydroxide and potassium hydroxide,
Examples thereof include alkali metal carbonates or bicarbonates such as sodium carbonate, acids (organic acids such as acetic acid and citric acid, and inorganic acids such as hydrochloric acid and phosphoric acid), and borax.

Aqueous solutions (particularly, solutions for mucosal application, for example,
The pH of ophthalmic solutions such as eye drops, nasal drops, etc.) is usually 4 to 9, preferably 5 to 8.5 (for example, 5.5 to 5.5).
8) about. The osmotic pressure is usually 150-500 mO
The osmotic pressure ratio with respect to physiological saline is usually 0.6 to 2.0, preferably 0.7 to 1.7, and particularly about 0.8 to 1.5.

The liquid preparation of the present invention can be produced by a conventional method using the fat-soluble component, the base, and if necessary, additives (such as a surfactant). For example, aqueous solutions such as eye drops are prepared by dissolving or suspending the fat-soluble component using water (purified water, distilled water, etc.) and additives, adjusting to a predetermined osmotic pressure, and sterilizing by filtration. Can be prepared.

The usage and dosage of the liquid preparation of the present invention can be selected according to the type (or use) of the liquid preparation, the condition and age of the patient. For example, the usage and dosage of an ophthalmic aqueous solution (such as eye drops) are usually about 1 to 6 times per day,
The number of drops at a time is about 1 to 3 drops.

[Container] FIG. 1 is a schematic sectional view showing an example of a synthetic resin container for containing the liquid agent. The resin container includes a storage section 11 for storing a liquid agent, and a storage section 1.
Hollow projecting portion (neck portion) 12 extending (projecting) from 1
And the accommodating portion 11 and the neck portion 12 are integrally formed of a hard synthetic resin. The top portion (tip portion) 13 of the neck portion 12 is sealed by a suitable closing means (such as heat fusion) after the contents (liquid) 14 are filled. Since a nozzle is not used in such a hermetically sealed container, even if a liquid agent is enclosed, it is possible to prevent the fat-soluble component from adsorbing to the nozzle or diffusing from the fitting portion. Further, since the container is made of a hard synthetic resin, even if the content of the fat-soluble component is low, the concentration can be reliably prevented from lowering.

FIGS. 2 and 3 are schematic sectional views for explaining the opening (or unsealing) of the neck portion. That is, a spiral groove is formed on the outer peripheral wall of the neck portion 12 of the container, and a cap (such as a hard synthetic resin cap) 16 is screwed to the neck portion 12. A needle portion 19 extending in the axial direction of the cap 16 is formed on the inner surface of the top of the cap 16. This cap 16
By inserting the needle portion 19 into the container body from the top portion 13 of the neck portion 12, the top portion 13 can be opened, and a discharge port (not shown) is formed.

The neck portion 12 can be formed by various methods, for example, by cutting a proper portion (for example, a closed portion such as a tip portion) of the neck portion 12 by a cutting means (cutter, scissors, etc.), or a thread cutting means (pliers, etc.). ) Can be opened (or unsealed) by, for example, threading with a piercing device or piercing with a piercing device.

In order to improve the sealing property after opening, the opening portion may be sealed by a sealing means. For example, in the examples of FIGS. 2 and 3, the cap 16 and the top 1
Even if a packing (especially a packing formed of a resin having low adsorption to fat-soluble components) (not shown) is interposed between the sealing member 3 and the cap 16, the opening portion is sealed. Good. The packing may be attached to the inner surface of the cap 16 in advance.

The opening portion of the container is not particularly limited, and may be openable in the longitudinal direction of the neck portion (such as the center in the longitudinal direction) in addition to the tip of the neck portion. FIG. 4 is a schematic perspective view for explaining a container that can be opened (or opened) halfway in the longitudinal direction of the neck portion. This container has a vertically long rectangular flat receiving portion (flat rectangular receiving portion) 11b for storing a liquid agent, and a neck portion (hollow extending portion) extending from one end of the receiving portion. ) 12b, and a knob (plate-shaped knob) 17 extending from the tip (top) 13b of the neck 12b. The neck portion 12b includes an inclined portion 12c that continuously narrows from the housing portion 11b toward the distal end portion 13b,
And a wide portion 12d extending in a substantially rectangular shape from the narrowest portion of the wide portion, and a distal end (top portion) 13b of the wide portion is closed. Then, in the longitudinal direction of the neck portion 12b (in this example, the narrowest portion of the neck portion 12b (the inclined portion 12c).
And a wide portion 12d), a thin portion 18 is formed. When such a container is used, the knob 17
The container can be opened by breaking the thin-walled portion 18 using the above.

The container shown in FIG. 4 can be suitably used as a container for unit dose. For example, in the example of FIG. 4, a holding unit 1 for holding a container is provided at the other end of the storage unit.
5 is attached. For this reason, even if the capacity of the storage section is small, there is no possibility that the handleability of the container is reduced.

In the unit dose container, a plurality of containers may be connected in the same axial direction so as to be breakable. For example, a plurality of containers may be connected adjacently in parallel. When such a container is used, it is convenient to carry the container, and at the time of use, the containers can be removed and used one by one.

The container of the present invention is not particularly limited as long as at least the inner surface is formed of a hard synthetic resin and the top of the neck is closed, and various containers can be used. As a method of closing the neck portion, for example, welding, fusion (thermal fusion of resin or the like), closure with a sealing agent, and the like can be mentioned.

In the present invention, the shape of the housing portion is not particularly limited. For example, the front shape is polygonal (triangular,
Square, pentagonal, hexagonal, octagonal, decagonal, etc.), circular, elliptical, semicircular, semielliptical, and heart-shaped. Further, the housing portion may be in a bag shape or a flat shape (a flat elongated shape or the like).

The neck portion may be formed at an appropriate position of the accommodation portion, for example, a surface facing the bottom surface of the accommodation portion.

The shape of the neck may be cylindrical (cylindrical), polygonal (quadrangular, etc.). Further, the neck portion may be formed to be narrowed continuously or stepwise toward the tip portion.

The container body (housing section, neck section, etc.)
The container may be formed of a plurality of resin layers, if necessary, as long as at least the inner surface is formed of a hard synthetic resin. For example, the inner layer may be formed of a hard synthetic resin, and the outer layer may be formed of a soft synthetic resin. Usually, the container is formed entirely of a hard synthetic resin.

As the hard synthetic resin, for example, polyester resin, polyphenylene ether resin, polycarbonate resin, polysulfone resin, polyamide resin, hard vinyl chloride resin, styrene resin (polystyrene, acrylonitrile-styrene copolymer ( AS resin)
And the like, and preferably, a resin (polyester-based resin, polycarbonate-based resin, or the like) having low adsorption to fat-soluble components (particularly, terpene-based compounds) such as cellulose acetates.

As the polyester resin, a resin composed of a dicarboxylic acid component (such as an aromatic dicarboxylic acid component such as phthalic acid, terephthalic acid, and naphthalenedicarboxylic acid) and a diol component can be used. The diol component includes aliphatic diols (e.g., _C2-6 alkylene glycols such as ethylene glycol, propylene glycol, and tetramethylene glycol, cycloalkanediols such as cyclohexanediol and cyclohexanedimethanol), and aromatic diols (such as bisphenol-A). Bisphenols, etc.). As the polyester resin, an aromatic polyester resin, for example, polyalkylene terephthalate (polyethylene terephthalate (PET), polybutylene terephthalate (PBT))
Such as poly C _2-4 alkylene terephthalate, polyalkylene naphthalate (polyethylene naphthalate (PEN), polybutylene naphthalate, etc.)
_2-4 alkylene naphthalate, etc.), polycycloalkyl terephthalate (poly 1,4-cyclohexyl dimethylene terephthalate (PCT), etc.), polyarylates (bisphenols (bisphenol-A, etc.) and phthalic acids (phthalic acid, terephthalic acid) And the like). Also,
Examples of the polyester-based resin include a copolyester containing the homopolyester unit as a main component (for example, 50% by weight or more) and a copolymer of the homopolyester (PET and P
Etc.) and the like.

The polycarbonate resin is, for example, an aromatic polycarbonate based on bisphenols (such as bisphenol-A).

The hard synthetic resin may be a polymer alloy (such as a polymer blend) as long as there is no harm in cost performance, strength, light transmittance, gas or water vapor barrier properties (moisture permeability), and the like. Preferred polymer alloys include polymer blends of multiple rigid synthetic resins (PE
Polymer blends of T and PEN).

The hard synthetic resin may be a resin having durability against repeated pressing, a transparent resin, or the like. Further, the hard synthetic resin may be colored as necessary.

Preferred rigid synthetic resins include polyethylene terephthalate, polyethylene naphthalate, polyarylate, polycarbonate and the like.

The method of enclosing the liquid agent in the hermetically sealed container is not particularly limited. For example, the hermetically sealed container is molded by a conventional molding method (blow molding, extrusion molding, etc.), and the liquid agent is injected into the container with an injection needle or the like. Then, the injection port formed by the injection needle may be closed by heat melting or the like. Preferably, the liquid agent is filled into the hermetically sealed container by a method of filling the liquid agent while forming the hermetically sealed container (such as a blow fill seal (BFS) method). By the blow-fill sealing method, the neck portion with the top opened and the storage portion are integrally formed, the liquid agent is sealed, and the top of the neck is closed. The liquid can be filled and the opening can be closed (such as heat fusion) without washing, drying, or sterilizing. Therefore, the manufacturing process can be simplified and the manufacturing cost can be reduced while maintaining the same quality as when using a preformed container.

The container may be for single use or disposable (unit dose) or for multiple use (multi dose).

The size of the container is, for example, 0.3 to 5 in capacity.
It can be appropriately selected from the range of about 00 mL according to the application. In the case of a unit dose, the capacity is about 0.3 to 50 mL, preferably about 0.3 to 5 mL, and in the case of a multi-dose,
About 1-500mL capacity, preferably 2-300m capacity
The volume may be about L, more preferably about 5 to 100 mL.

When the liquid is filled in the hermetic container, since the inner surface is formed of a hard synthetic resin, the adsorption of fat-soluble components can be suppressed for a long period of time. For this reason, even if components used at a relatively low concentration, such as a fat-soluble drug and a functional component, the concentration can be maintained and, for example, loss of the functionality can be prevented. Therefore, it can be advantageously used for a liquid agent that acts on a part that is sensitive to a stimulus (mucous membrane such as eyes or nose).

[0065]

According to the present invention, since the liquid is sealed in a hermetically sealed container whose inner surface is formed of a hard synthetic resin, the fat-soluble component in the liquid during transport or storage (particularly, before opening). Can be suppressed from decreasing.

[0066]

EXAMPLES The present invention will be described below in more detail with reference to Examples, but the present invention is not limited to these Examples.

Example 1 15 ml of a liquid preparation was sealed in a polyethylene terephthalate hermetic container (capacity: 15 ml) by blow-fill sealing. A test solution having the following composition was used for the liquid preparation.

Test solution: 1-menthol (0.03 g) and polyoxyethylene hydrogenated castor oil (0.10 g) were dissolved in a small amount of purified water, and the pH was adjusted to 5.5 with a pH adjuster (boric acid). And purified by filtration with a water-based membrane filter (0.22 μm) (1-menthol concentration: 0.03% (W / V)).

Comparative Example 1 A container (bottle) made of polyethylene terephthalate was filled with the same test solution as in Example 1, a polyethylene nozzle was attached to the container, and the container was covered with a polystyrene cap.

Comparative Example 2 The procedure of Comparative Example 1 was repeated except that a double nozzle having an inner layer made of polyethylene terephthalate and an outer layer made of polyethylene was used.

The test solutions contained in the hermetically sealed containers prepared in Examples and Comparative Examples were stored at a temperature of 25 ° C. and a humidity of 75% RH. The change with time in the concentration of l-menthol during storage was measured, and the residual ratio of l-menthol relative to the start of storage was determined. Table 1 shows the results.

[0072]

[Table 1]

As is apparent from Table 1, in the embodiment, l
-Menthol did not decrease at all and maintained the same concentration (0.003% (W / V)) as in the initial stage. In contrast, in Comparative Example 1, after 15 months, the initial concentration of 6
L-Menthol was reduced to 3% (about 0.002% (W / V)). In Comparative Example 2 (double nozzle), the amount of decrease in l-menthol in the initial stage of storage was smaller than that in Comparative Example 1 (polyethylene nozzle). 0.002% (W / V)
The l-menthol decreased to.

The concentration of l-menthol (0.003% (W
/ V), 0.002% (W / V)) is functional (cooling)
Was evaluated according to the following method.

The following two types of test solutions were prepared.

Test solution 1: 0.03 g of l-menthol, 0.2 g of chlorobutanol, 0.1 ml of ethanol, 1.7 g of boric acid, 0.01 g of borax, and 0.01 ml of benzalkonium chloride in sterilized purified water And the total amount is 10
After adjusting the volume to 0 ml, the aqueous membrane filter (0.
(L-menthol concentration 0.0).
03% (W / V), pH 5.8).

Test solution 2: The same as Test solution 1 except that 0.02 g of l-menthol was used (l-menthol concentration: 0.002% (W / V), pH: 5.8).

The refreshing sensation of Test Solution 1 and Test Solution 2 was evaluated by 12 dedicated panelists based on the following criteria.
The test was performed blind.

[Absolute evaluation] 1 ... weak 2 ... slightly weak 3 ... ordinary 4 ... slightly strong 5 ... strong [Relative evaluation] The cooling sensation of the test solution 2 is almost the same. C. The cooling sensation is stronger in the test solution 2 than in the test solution 1.

[0080]

[Table 2]

[0081]

[Table 3]

As is clear from Tables 2 and 3, the concentration of 1-menthol was 0.003% (W / V) to 0.001%.
When it is reduced to 2% (W / V), the refreshing feeling is also weakened.

[Brief description of the drawings]

FIG. 1 is a schematic sectional view showing an example of the container of the present invention.

FIG. 2 is a schematic sectional view for explaining an example of a state before opening the container of the present invention.

FIG. 3 is a schematic cross-sectional view for explaining an example of a state after opening the container of the present invention.

FIG. 4 is a schematic perspective view showing another example of the container of the present invention.

[Explanation of symbols]

 DESCRIPTION OF SYMBOLS 11 ... Housing part 12 ... Neck part 13 ... Outflow port 14 ... Liquid material

Claims (8)

[Claims] 1. A sealing container having a storage portion for storing a liquid agent, a neck portion extending from the storage portion and having a closed end portion, and at least an inner surface formed of a hard synthetic resin. A liquid preparation containing at least a fat-soluble component. 2. The liquid preparation according to claim 1, wherein the fat-soluble component is a terpene compound. 3. The liquid preparation according to claim 1, wherein the fat-soluble component is at least one selected from menthols and camphors. 4. The terpene compound content is 0.000.
The liquid preparation according to claim 2, wherein the amount of the liquid preparation is 1 to 5 (W / V)%. 5. The liquid preparation according to claim 1, wherein the container is formed of at least one hard synthetic resin selected from a polyester resin and a polycarbonate resin. 6. The liquid preparation according to claim 1, which is a preparation for mucosal application. 7. A container containing at least an inner surface made of a hard synthetic resin and containing the liquid agent according to any one of claims 1 to 6, wherein a container for accommodating the liquid agent is provided. A container having an openable closing portion for allowing the liquid agent to flow out of the storage portion. 8. A method for suppressing the adsorption of a fat-soluble component to a container by containing a liquid containing the fat-soluble component in the container according to claim 7.