JP2003128588A - Polysaccharide-containing composition and application thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a low-viscosity liquid composition containing polysaccharides in high concentration for pharmaceutical preparations, instillations, cosmetics, or toiletries having unique functions and foods having excellent taste. SOLUTION: This composition in a low-viscosity liquid state is obtained by heating an aqueous medium containing polysaccharides such as agar-agar at high concentrations followed by cooling the medium under shearing force; thus offering pharmaceutical preparations, instillations, foods, cosmetics, toiletries, etc., having new palate feeling and/or functions. This composition is usable as a water-based pharmaceutical composition base easy to apply and hard to drip off. The instillation compounded with agar-agar as one of the polysaccharides has the effect of improving the ocular migration of a medicament therein. Further, another version of the instillation compounded with agar-agar in the form of microparticles is good at crispness because of keeping the viscosity low, also affording good feeling when applied.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a polysaccharide-containing composition which exhibits a characteristic of low viscosity while containing a high concentration of polysaccharide. The present invention also relates to a composition which can prolong the holding time of the contained drug, pigment, paint, etc. by using the composition of the present invention. In addition, the present invention relates to an ophthalmic solution in which agar is incorporated to improve the intraocular transfer of the drug. In particular, when fine particle agar is used as a base for eye drops, an eye drop having excellent properties can be obtained.

[0002]

Various gelling agents and thickeners are used in the fields of pharmaceuticals, foods, cosmetics, toiletries and the like, and many gel and sol products are on the market. Although natural polysaccharides and proteins that are safe and have a good image are used in these fields, the diversity and stability of the texture of sol and gel, or the reversible control of gelation temperature and sol / gel state Is required.

As a document showing that a polysaccharide is first made into a hydrogel and then it is pulverized by using a shearing force so as to have fluidity, Japanese Patent Publication No. 2002-514395, JP-A-20-200945.
No. 00-239147, etc., but the resulting composition had a high viscosity and lacked uniformity of fluid.

Other known literatures relating to polysaccharide-containing compositions having low viscosity and fluidity include, for example, European Patent No.432.
In No. 835, by performing a shearing step when cooling from a temperature higher than the gelling temperature of the polysaccharide to a temperature below the gelling temperature,
Fluid compositions containing polysaccharide microgels and methods of making the same are described.

Further, as an example of a polysaccharide-containing composition having low viscosity and fluidity produced by the same production method,
Japanese Patent No. 2513506, Japanese Patent Laid-Open No. 2000-119116
Japanese publications are known. These series of fluid compositions,
And the manufacturing method is International Jornal of Biologi
As summarized in cal Macromolecules, 26 (1999), p255-261, Fig 8, the higher the shear force (shear rate), the lower the viscosity of the fluid.

[0006] In addition, as an aqueous pharmaceutical composition for efficiently releasing a medicinal component to a mammal in need of treatment, there are several aqueous pharmaceutical compositions which are liquid at room temperature or lower and which are semi-solid or gel at the body temperature of mammals. Is also disclosed,
There is a problem that the gelation of the solution occurs due to the increase of the environmental temperature during storage.

For example, US Pat. No. 4,188,373 discloses a thermogelling aqueous pharmaceutical composition using Pluronic (trade name: PLURONIC), and US Pat. No. 4,478,822 discloses a heat-resistant gelled aqueous pharmaceutical composition. Drug release systems using gelled aqueous pharmaceutical compositions have been described.

[0008] However, skin creams for the purpose of sunscreen and the like have lotion-like (liquid), gel-like, and ointment-like forms, but the more liquid-like ones, the easier the uniform application. On the other hand, there is a drawback in that the liquid type is more likely to flow down.

Since agar contains dietary fiber, a bowel movement improving effect is expected. However, when the concentration is 0.1% by weight or more, it gels, and it has been desired to develop it as a drinkable food that is easy to ingest.

On the other hand, a general method for treating eye diseases is to administer a drug to the eye drop. Needless to say, the therapeutic effect on eye diseases by this eye drop administration depends on the efficacy of the drug itself, but in order to fully exert its efficacy, it is important how effectively the drug is transferred into the eye. It becomes a problem.

Various studies have been conducted in order to improve the drug transfer into the eye. For example, by using a carboxyl vinyl polymer (CVP) as a base, the viscosity of the eye drop is increased and the retention of the drug on the ocular surface. There is a technique (Japanese Patent Publication No. 60-56684) for prolonging the time and measuring the sustained release effect of the drug, thereby improving the intraocular migration. This technique utilizes the characteristics of CVP, that is, the property of dramatically increasing the viscosity of eye drops even with a small amount of addition.

In the case of an ophthalmic ointment, the above technique can be preferably used, but in the case of an eye drop, it is necessary to instill in the form of a liquid drop, so that it can be instilled as a liquid drop, There has been a demand for the development of eye drops capable of achieving intraocular migration. For example, a study on CVP showing Newtonian viscosity capable of being instilled in a droplet state (Japanese Patent No. 2873530).
No.), a polymer that rapidly gels when it comes into contact with tear fluid after being instilled in the form of droplets (Japanese Patent No. 2814637).
No.), a polysaccharide that causes a liquid-gel phase transition (Japanese Patent Publication No. 6-6
7853) and the like have been reported.

[0013]

Generally, polysaccharides typified by agar contain 0.1% by weight or more, and gelate when cooled from a temperature higher than the gel transition temperature, which is room temperature or higher. It could not be used as a liquid composition. Therefore, a composition having a low viscosity liquid state even at room temperature while containing a polysaccharide represented by agar at a high concentration is prepared, and a drug, a food, a cosmetic, a toiletry having a texture and / or function which has never been obtained. The challenge is to provide products. Another object of the present invention is to provide a liquid food that is easier to take than jelly when used as a bowel movement-improving food.

Further, regarding pharmaceuticals for ophthalmic use, it is difficult to obtain a base for eye drops that can be satisfied by the conventional techniques, and it is possible to improve the transferability of the drug into the eye, and a new base that can be instilled in the form of droplets Development is desired.

The important problems in the development of this new base are 1) there is no problem in safety, 2) raw materials can be easily obtained, 3) processing and handling are easy, and 4) liquid. It is to be easily instilled in the form of drops, 5) to have an excellent feeling of use (feeling of tightness when instilled), and 6) to have an excellent drug transfer into the eye.

[0016]

Means for Solving the Problems As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that after heating a polysaccharide such as agar in a water-containing liquid, a stress such as shearing force is applied. It was found that by cooling while cooling, it is possible to prepare a water-containing composition which is a liquid having a low viscosity while surprisingly containing a polysaccharide represented by agar in a concentration of 0.1% by weight or more. Invented.

That is, the first invention is "0.1-30
It contains polysaccharides in a weight percentage, and is a B-type viscometer (rotor No.
The viscosity measured in 2) under the conditions of 20 ° C. and 60 rpm is 7
A polysaccharide-containing composition, characterized in that it is at most 00 mPa · s. And "heating the polysaccharide in a water-containing liquid,
A method for producing the composition, which comprises cooling while applying a shearing force. Regarding As a result of further intensive studies, the greater the shearing force (shear rate), the higher the viscosity of the obtained polysaccharide-containing composition, and the polysaccharide-containing composition and the production method according to claim 1. . By using these “polysaccharide-containing composition” and “thickening composition”, it is possible to provide a completely new “medicine”, “intraocular migration enhancer”, “food”, and “cosmetics”. became.

Further, as a result of intensive studies to solve the above problems in ophthalmic applications, the present inventors focused on agar which is widely used in foods, etc., and as a result, after heating and dissolving the agar in an aqueous solution, It has been found that by cooling while applying stress, it is possible to prepare a liquid agar in the form of fine particles having a desired viscosity while containing a high concentration of agar. In general,
If 0.1% by weight or more of agar is contained, it will gel at room temperature, but this fine particle agar has the characteristics that it retains its liquidity even when it contains a high concentration of agar and its viscosity does not increase so much. And, it was found that if this fine particle agar is used as a base for eye drops, excellent intraocular migration of the drug is exhibited, and a new "eye drop" and "intraocular migration improver" can be provided. .

That is, the second aspect of the present invention is "an eye drop having an improved drug transfer into the eye by incorporating agar".
Is. In particular, when fine particle agar is used as a base for eye drops, an eye drop having excellent properties can be obtained. The present invention is also “a drug for improving intraocular migration of a drug characterized by using agar as a base”.

[0020]

BEST MODE FOR CARRYING OUT THE INVENTION The first aspect of the present invention is a "B-type viscometer (rotor No.
The viscosity measured in 2) under the conditions of 20 ° C. and 60 rpm is 7
And an agar-containing composition characterized in that the composition is 00 mPa · s or less. Traditionally, agar was used as a food, but it is usually used in a gel state,
The performance was also expressed by gel strength (an index showing the hardness of the gel) and the like, and was evaluated as a solid. It is the essence of the present invention that the agar can be obtained in a liquid state without gelation by heating the agar in a water-containing liquid and then cooling while applying a shearing force. The details will be described below.

The polysaccharides used in the present invention include, in a broad sense, all carbohydrates including oligosaccharides such as disaccharides, trisaccharides and tetrasaccharides, which produce two or more molecules of monosaccharides by hydrolysis. The naturally-occurring ones, processed naturally-occurring polysaccharides, artificially-synthesized ones and the like can be mentioned, but the polysaccharides derived from plants, especially seaweeds are preferable. Polysaccharides obtained from such plants include, for example, any of the general polysaccharides described in "Basics of Sugar Chemistry" (Kimiko Abu, Nobuko Seno; Kodansha, 1984). However, multiple polysaccharides may be used in combination. Specific examples include agar, agarose, agaropectin, starch, amylose, amylopectin, isolikenan, laminaran, lichenan, glucan, inulin, levan, fructan, galactan,
Mannan, xylan, arabinan, pentosan, alginic acid, pectic acid, protuberic acid, chitin, colominic acid, porphyran, fucoidan, ascofiran, carrageenan, pectin, locust bean gum, guar gum, tamarind gum, tara gum, gum arabic, gellan gum, etc. Among them, polysaccharides obtained from seaweed, agar, agarose, agaropectin, laminaran,
Fructans, galactans, pentosans, alginates, chitins, porphyrans, fucoidans, ascofilans, carrageenans and the like are preferable, and agar, agarose and agaropectin are more preferable.

Agar is a polysaccharide contained in the cell wall matrix of various red algae such as agar beetle and hornwort, and can be obtained by extraction with hot water. Agar is already used in foods and the like, and is highly safe because it is listed in the Japanese Pharmacopoeia and is widely used in foods and the like. In addition, agar is not a uniform substance, and agarose (a
Garose) and agaropectin containing a sulfate group (a
Garopectin). The proportion of agarose varies depending on the type of red alga, and agarose accounts for about 70% in Agarose agar.

Agarose is, as shown in chemical formula 1, D-galactose and 3,6-anhydro-L-galactose residues are alternately and repeatedly bonded by β- (1 → 4) bond and α- (1 → 3) bond. Is a polysaccharide having a straight chain structure, and agaropectin contains a sulfate group (formula 2), a methoxyl group (formula 3), a pyruvate residue (formula 4) and D-glucuronic acid (formula 5) in the basic skeleton of agarose. , A mixture of acidic polysaccharides in various proportions.

[0024]

[Chemical 1]

When agar is used, it may be produced by any method, but from the viewpoint of stable supply, it is preferable to use agar produced by an industrial method. The weight average molecular weight of the agar used is preferably from 5,000 to 1,200,000, more preferably from 30,000 to 800,000, further preferably from 5 to 50.
It's a million. By using a resin having such a range, a resin having good fluidity and excellent handling can be obtained. In particular, when it is used as a base for pharmaceuticals and the like, the formulation can take various forms such as dripping and spraying, and more excellent one can be obtained due to the retention of the drug and the like which is one of the objects of the present invention.

The polysaccharide-containing composition as referred to in the present invention includes embodiments such as a mixture of a polysaccharide and a solvent such as water, a mixture of a polysaccharide such as water and a solvent, and a component other than the solvent. .

The concentration of the polysaccharide used in the present invention is 0.1-0.1%.
It is 30% by weight. When used for food, the higher the concentration of agar, the higher the effect of improving bowel movements. Further, when a polysaccharide is used as a base other than food, retention of a functional agent such as a drug is obtained, and the effect tends to increase as the content increases. The lower limit of the content of the polysaccharide is preferably 0.2% by weight or more, more preferably 0.3% by weight or more, and further preferably 0.5% by weight or more. The upper limit is not particularly limited as long as the handleability of the final product is not impaired, but is preferably 30% by weight or less, more preferably 10% by weight or less, further preferably 5% by weight or less, and most preferably 1.5% by weight or less. It is less than or equal to weight%. When agar is used as the polysaccharide, it varies depending on the agar used, but if the concentration is too high, gelation occurs and the viscosity measured by a B type viscometer at 20 ° C. and 60 rpm is 700 m.
Since it may exceed Pa · s, it is preferably 5% by weight.
It is the following.

Examples of agar preferably used in the present invention include UP-6, UP-16 manufactured by Ina Food Industry Co., Ltd.
UP-37, M-7, M-9, AX-30, AX-10
0, AX-200, BX-30, BX-100, BX-
200, PS-5, PS-6, PS-7, PS-8 and the like. Such agar may be used alone or 2
You may mix and use agar of 2 or more types.

The viscosity of the polysaccharide-containing composition according to the present invention measured by a B-type viscometer at 20 ° C. and 60 rpm is
It is 700 mPa · s or less, preferably 500 mPa · s or less, more preferably 150 mPa · s or less, and most preferably 100 mPa · s or less. Although the lower limit of the viscosity is not particularly limited, it is about 1 mPa · s in consideration of practicality.

Ordinary polysaccharides such as agar are used in an amount of 0.1% by weight or more, as is clear from the fact that they have been used to utilize the gel property, and after being heated in an aqueous medium, cooled to room temperature. Then, it gels and naturally develops a very high viscosity. Especially, if 0.1% by weight or more, gelation occurs in most cases, and if 0.3% by weight or more, complete gelation occurs.
It is impossible to obtain those of mPa · s or less. The polysaccharide-containing composition of the present invention has such unique properties, and can be obtained, for example, by the method described below.

On the other hand, the optimum viscosity range from the viewpoint of application varies depending on the application, but the viscosity during storage is 20.
It is preferably 0 mPa · s or less, more preferably 150 mPa · s or less, and further preferably 100 m
It is desirable to adjust it so that it is not more than Pa · s (the viscosity value shown here is the value measured with a B-type viscometer at 20 ° C. and a rotation speed of 60 rpm). When it is used as an ointment or the like, it can be used even if it is larger than 700 mPa · s, but it is not preferable because it is poor in hygiene.

The polysaccharide-containing composition of the present invention preferably contains an aqueous medium as one component thereof. The aqueous medium is a liquid substance containing water as a main component, and the components other than water are not particularly limited, but the content of water is preferably more than 80% by weight, more preferably more than 90% by weight.

The aqueous medium preferably contains a water-soluble compound. The water-soluble compound is not particularly limited as long as it dissolves in water to give a stable composition. Examples thereof include alcohols such as methanol, ethanol, ethylene glycol, propylene glycol, and glycerin, various surfactants, emulsifiers, dispersants, and tonicity agents. In addition to the above low molecular weight compounds, water soluble polymer compounds such as polyethylene glycol and polyvinyl alcohol can also be used. Such water-soluble compounds may be used alone or in combination of two or more.

In the polysaccharide-containing composition of the present invention, the presence state of the polysaccharide may be partly or wholly forming a fine particle gel. An embodiment in which a part of the polysaccharide forms a particulate gel is preferable. Further, it is preferable that the fine particle gel is uniformly dispersed.

When a fine particle gel is formed,
The shape of the gel is not particularly limited, and examples thereof include a spherical shape, an elliptic shape, and an amorphous shape. It is preferably spherical because it does not give a foreign body sensation, and the particle size is preferably 100 μm or less, more preferably 50 μm or less.
It is less than or equal to μm, more preferably less than or equal to 20 μm, and most preferably less than or equal to 10 μm. When the particle size is too large, it adversely affects the storage stability of the composition, or when used for eye drop applications, for example, a feeling of foreign matter after eye drops is felt,
Functional inconvenience may occur.

Next, a method for obtaining the polysaccharide-containing composition of the present invention will be described with reference to specific examples.

First, a predetermined amount of a polysaccharide, an aqueous medium and, if necessary, other components are mixed, and the resulting mixture is heated to dissolve the polysaccharide. A conventionally known method can be adopted as the heating means. The heating is performed at a temperature not lower than the gel transition temperature, preferably not lower than the gel transition temperature + 20 ° C. It may also be necessary to bring the mixture to a boil. The liquid is preferably made transparent and uniform. Then, it is cooled while applying stress.

As a method of applying this stress, there is no particular method such as vibration, stirring, compression, crushing, etc., but since shearing force is applied to the liquid, stirring is most preferable. Specifically, a stirring device such as a magnetic stirrer, a mechanical stirrer, a mixer, a shaker, a rotor or a homogenizer may be used, or the stirring may be performed manually.

The cooling means may be air cooling, water cooling, ice cooling, solvent cooling, air cooling or the like, and conventionally known means can be adopted. The cooling rate may be appropriately selected depending on the properties of the polysaccharide used or the properties of the polysaccharide-containing composition to be obtained, but usually air cooling, water cooling, or ice cooling is performed. When cooling rapidly with water or ice, it is necessary to increase the stirring force so that gelation does not occur. In principle, it is sufficient to cool the gel to a temperature not higher than the gel transition temperature, but practically, the gel transition temperature is -20 ° C or lower, or the polysaccharide-containing composition of the present invention is usually used at room temperature. Since it is often seen, it is cooled to about 20 ° C. Further, even after the temperature of the composition reaches the target temperature, it is preferable to continue stirring for 10 minutes or more so that gelation does not occur.

When stirring is carried out, the viscosity of the polysaccharide-containing composition increases as the temperature decreases, but it is necessary to stir to resist this viscosity. It is preferable to use a strong means as the stirring means. Specifically, it is preferable to stir while adjusting the Reynolds number for stirring to be 100 or more even at room temperature.

When a stirring method having a relatively small shearing force such as a magnetic stirrer or a mechanical stirrer is used as the stirring means, the above-mentioned known document, Journal
f Biological Macromolecules, 26 (1999), p255-261, F
As shown in ig 8, the higher the shearing force (shearing speed), the lower the viscosity of the composition is obtained. It is preferable to perform the shearing using a means for applying a stress having a large shearing force (shearing rate) and a shearing force belonging to a shearing force region in which the viscosity of the product becomes higher when a higher shearing force is applied. By adopting such a method, the number of gel particles is reduced,
Alternatively, the particle size can be reduced, and it is excellent in comfort when used as a component of an eye drop, or can exhibit its effect more effectively when used together with a functional agent.

In the present invention, the polysaccharide-containing composition is B
Type viscometer (rotor No. 2) at 20 ℃, 60rp
It is prepared so that the viscosity measured under the condition of m is 700 mPa · s or less. The adjustment of the viscosity is performed by combining stress applying means, stress applying conditions and the like according to the type and concentration of the polysaccharide used. These are specifically illustrated in Examples and the like.

A low-viscosity and high-concentration agar-containing composition can be prepared by the above-mentioned method, but the principle is not clear, but it is considered as follows. It is considered that the gelation of agar is because the chains of agar molecules form hydrogen bonds between the molecular chains, and take a helical structure while taking in water molecules, and have a higher and stronger structure. When heated to high temperature to become uniform, the agar molecule, which had a random coil-shaped molecular structure, tries to assume a helical structure as it cools.
It is considered that by applying a strong shearing force to this, it is possible to prevent the formation of a helical structure, and to obtain a liquid composition having a low viscosity without gelation.

The isotonic agent preferably used in the present invention is a solute generally contained in an isotonic solution. An isotonic solution is a solution in which, when there are two or more kinds of solutions having different osmotic pressures, an isotonic agent is added to one solution so that the osmotic pressure becomes the same. A tonicity agent can be used when the composition of the present invention is used alone or in combination with a plurality of compositions. The amount of the tonicity agent added is not particularly limited as long as it is adjusted to an arbitrary osmotic pressure. Examples of such a tonicity agent include glycerin, propylene glycol, sorbitol, mannitol, sodium chloride, sodium phosphate, boric acid, borax, and the like.

Further, the composition of the present invention contains at least a polysaccharide and a water-soluble compound, and has preferable viscosity characteristics as a thickening ratio represented by the following formula, which is preferable for use in pharmaceuticals and in combination with other functional agents. Exert function. This thickening rate X is defined by the following formula.

X = Z / Y where Y is B of the polysaccharide-containing composition containing a water-soluble compound.
Is a viscosity measured by a viscometer (rotor No. 2) at 20 ° C. and 60 rpm, and Z is 0.9% by weight of Na in a polysaccharide-containing composition containing the above isotonicity agent and a water-soluble compound.
It is the viscosity measured with a B-type viscometer (rotor No. 2) at 20 ° C. and 60 rpm after addition of Cl.

When the thickening rate X is 1.005 or more, when the composition of the present invention is brought into contact with physiological fluid containing salt such as sweat or tears, it is difficult to flow down due to thickening, or the composition is long It exhibits characteristics such as staying for a period. In order to exert such characteristics more, the viscosity increase rate X is preferably 1.008 or more, more preferably 1.010 or more. However, when the thickening rate X exceeds 3.000, the viscosity increase after application is too rapid, which may cause discomfort when applied to cosmetics and the like.

Applications of the composition of the present invention include, but are not limited to, pharmaceuticals used for humans or animals, bases for pharmaceuticals, foods, cosmetics and toiletry products. Specifically, foods with a taste that remains in the mouth, sunscreen cream that does not run off with seawater, cosmetics that do not run off with sweat, pharmaceutical ointments that do not run off with sweat, eye drops that suppress the outflow of medicinal components due to tears,
And so on.

For example, when the composition of the present invention is used as a component of an ear drop, the active drug in the ear drop may be either water-soluble or insoluble. When a water-insoluble drug is used, a water-soluble compound such as ethanol, isopropanol, propylene glycol, glycerin, or a surfactant can be appropriately used as another component.

Examples of the active drug applicable to the present invention include hypnotic sedatives such as glutethimide, chloral hydrate, nitrazebam, amobarpital, phenobarpital: aspirin, acetaminophen, ibuprofen, flurpiprofen, indomethacin. , Ketoprofen, diclofenac sodium, theearamide hydrochloride,
Antipyretic and analgesic anti-inflammatory agents such as piroxicam, flufenamic acid, mefenamic acid, and ventazosin: local anesthetics such as methyl aminobenzoate and lidocaine: local vasoconstrictors such as naphazoline nitrate, tetrizoline nitrate, oxymetasone hydrochloride, tramazoline hydrochloride: chlorpheni maleate Antiallergic agents such as lamins, sodium cromoglycate, oxatomide, azelastine hydrochloride, ketotifen fumarate, traxanox sodium, and amlexanox: bactericidal agents such as benzethonium chloride, dopamine hydrochloride, nihidecarenone and other cardiotonics: propranolol hydrochloride, pindolol, phenytoin, disopyramide. Antiarrhythmic agents such as: Coronary vasodilators such as isosorbide nitrate, nifedipine, diltiazem hydrochloride, dipyridamole: Digestive agents such as domperidone:
Corticosteroids such as triamcinolone acetonide, dexamethasone, betamethasone sodium phosphate, prednisolone acetate, fluocinonide, peclomethasone propionate, and flunisolide: antiplasmin agents such as tranexamic acid: clotrimazole, miconazole nitrate, antifungal agents such as ketoconazole: tefugafu , Fluorouracil, mercaptopurine and other antineoplastic agents: Amoxicillin, ampicillin, cephalexin, cephalothin sodium, ceftizoxime sodium, nilithromycin, oxytetracycline hydrochloride, etc. antibiotics: calcitonin, insulin calcitonin, chicken calcitonin, nilcatonin, etc. , Urokinase, TPA,
Examples include bioactive peptides such as interferon; vaccines such as influenza vaccine, swine Pordetella infection preventive vaccine, hepatitis B vaccine, and the like.
The compounding amount of the active drug varies depending on the kind of the drug, but it is generally compounded in an amount sufficient to exert a desired drug.

The following are examples of agents that can be applied to the skin of mammals and are applicable to the present invention. Examples of the agent for parasitic skin disease include bifonazole, siccanin, bisdecalinium acetate, clotrimazole and salicylic acid, and examples of the agent for suppurative disease include sulfamethoxazole sodium, erythromycin and gentamicin sulfate, and anti-inflammatory. Analgesics include indomethacin, ketoprofen, benmethasone valerate and fluocinolone acetonide, antipruritics include diphenhydramine, and local anesthetics include procaine hydrochloride and lidocaine hydrochloride. Examples of the disinfectant include iodine, povidone iodine, benzalkonium chloride, chlorhexidine gluconate and the like.

The following is an example of a drug which can be applied to the body cavity of the mammal, namely, rectum, urethra, nasal cavity, vagina, ear canal, oral cavity or oral cavity, which is applied to the present invention. Examples of the antihistamine include diphenhydramine hydrochloride and chlorpheniramine maleate, and examples of the reproductive organ agents include clotrimazole, nafazolyl nitrate, ketotifen fumarate, miconazole nitrate, and the like. Examples include bronchodilators such as aminophylline, antimetabolites such as fluorouracin, examples of hypnotics include diazepam, and examples of antipyretic analgesics include aspirin, indomethacin, sulindac,
Examples include phenylbutazone and ibuprofen, adrenal hormones such as dexamethasone, triamcinolone and hydrocortisone, local anesthetics such as lidocaine hydrochloride, and agents for purulent disease such as sulfisoxazole and kanamycin. ,
Examples include tobramycin and erythromycin, and examples of synthetic antibacterial agents include norfloxacin and nalidixic acid.

The content of the effective drug varies depending on the kind of the drug, but it is generally preferable to be in the range of about 0.001 to 10% by weight.

Examples of the pH adjuster used in the composition of the present invention include acids such as hydrochloric acid, sulfuric acid, boric acid, phosphoric acid and acetic acid, and bases such as sodium hydroxide, monoethanolamine, diethanolamine and triethanolamine. To be

The composition of the present invention may optionally contain pharmaceutically acceptable buffers, salts, preservatives, solubilizers and the like. As a preservative, benzalkonium chloride,
Inverse soaps such as benzethonium chloride and chlorhexidine gluconate, methylparaben, ethylparaben,
Parabens such as propylparaben and butylparaben, alcohols such as chlorobutanol, phenylethyl alcohol and benzyl alcohol, organic acids such as sodium dehydroacetate, sorbic acid and sodium sorbate, and salts thereof can be used. Also,
A surfactant or chelating agent can be added as appropriate. These ingredients are generally about 0.001-2% by weight, preferably about
It is used in the range of 0.002 to 1% by weight. As the buffer, alkali metal salts of acids such as phosphoric acid, boric acid, acetic acid, tartaric acid, lactic acid and carbonic acid, glutamic acid, epsilon aminocaproic acid, amino acids such as aspartic acid, glycyl, arginine and lysine, taurine, trisaminomethane, etc. Can be given. Preferably, these buffers are added to the composition in the amounts necessary to maintain the pH of the composition at 3-10.

Examples of the solubilizing agent include polysorbate 80, polyoxyethylene hydrogenated castor oil, cyclodextrin, and the like. When these are used, 0.001 is used.
It is preferably used in the range of ˜15% by weight.

The second aspect of the present invention is "an eye drop in which agar is incorporated to improve the drug transfer into the eye". In particular, when fine particle agar is used as a base for eye drops, an eye drop having excellent properties can be obtained. The present invention is also “a drug for improving intraocular migration of a drug characterized by using agar as a base”.

Agar has already been used for foods and the like, and can be easily obtained from seaweeds such as Amakusa. The main component of agar is a polysaccharide composed of agarose and agaropectin, which is highly safe because it is listed in the Japanese Pharmacopoeia and is widely used in foods and the like. Also, agar is
It can be processed to have the desired properties and is relatively easy to modify physically or chemically. Commercially available agar usually contains 10 to 30% of water, but the eye drops of the present invention may use commercially available agar as it is, or may be agar that is physically or chemically modified. It can also be used.

The agar used in the eye drop of the present invention may be produced by any method, but it is preferable to use an agar produced by an industrial method from the viewpoint of stable supply. Examples of such agar include UP-6 and U manufactured by Ina Food Industry Co., Ltd.
P-16, UP-37, M-7, M-9, AX-30,
AX-100, AX-200, BX-30, BX-10
0, BX-200, PS-5, PS-6, PS-7, P
S-8 etc. are mentioned. The agar used in the present invention may be used alone or in combination of two or more.

The molecular weight of the agar contained in the eye drop of the present invention is not particularly limited, but the weight average molecular weight is preferably 5,000 to 1,200,000. A more preferable weight average molecular weight is 30,000 to 800,000. If the weight average molecular weight of the agar is less than 5,000, the intraocular transfer of the drug is not so improved, while if the weight average molecular weight exceeds 1.2 million, it is difficult to keep the viscosity of the eye drop below 150 mPa · s. Because it will be. The weight average molecular weight of agar can be measured using a gel permeation chromatograph.

The content of agar in the eye drop of the present invention is not particularly limited, but it is preferably 0.1 to 10% by weight. A more preferable agar content is 0.2 to 5% by weight. This is because if the content of agar is less than 0.1% by weight, the drug transfer into the eye will not be improved so much, and if it exceeds 10% by weight, the eye drops may become highly viscous and gel. .

From the viewpoint of ease of instillation, the viscosity of the eye drop of the present invention is E type viscometer (25 ° C., shear rate: 100 s).
^-1 ) is preferably adjusted to 150 mPa · s (= 150 centipoise) or less. A more preferable viscosity of the eye drop is 100 mPa · s or less. If the viscosity at the time of instillation exceeds 150 mPa · s, it becomes difficult to instill as a droplet. Even if a high-viscosity eye drop is applied, it cannot be instilled if force is applied, but the liquid is poorly drained, and the amount of one drop is not constant, which causes inconvenience that the eye feels a foreign substance. Further, although filtration sterilization is generally used as a method for sterilizing eye drops, if the viscosity becomes high, it becomes difficult to filter. By setting the viscosity as described above, it is possible to instill a stable amount of one drop, and the user feels a squeaky feeling when instilling. The viscosity of the eye drop of the present invention is a value measured with an E-type viscometer at a measurement temperature of 25 ° C. and a shear rate of 100 s ⁻¹ hour. When the eye drop of the present invention is used as an eye ointment, the eye ointment has a viscosity of 150.
There is no problem even if the pressure exceeds mPa · s.

The agar contained in the eye drop of the present invention includes:
The liquid whose main component is water may contain agar in any state, for example, in a state in which agar is completely dissolved, in a state in which agar is partially dissolved, or
It may be in a state in which agar particles are dispersed. The agar particles in a dispersed state are specifically those in which particulate agar is dispersed in water, and the particle size of the particulate agar is 10
It is preferably 0 μm or less. More preferably 20 μm
It is as follows, and more preferably 10 μm or less. If the particle size of the agar exceeds 100 μm, the storage stability of the eye drop is adversely affected, and inconvenience such as feeling a foreign substance after the eye drop may occur. The form of the agar in the form of fine particles is not particularly limited, and examples thereof include an irregular shape in addition to a spherical shape and an elliptical shape.

The eye drop of the present invention can be prepared by, for example, dissolving agar in an aqueous solution by heating and then cooling it while applying stress, and mixing a solution containing fine particle agar.

The method for preparing the solution containing agar (that is, the agar-containing composition) is not particularly limited, but after heating the agar-containing aqueous solution until it becomes uniform, stirring vigorously to prevent gelation, It is preferable to gradually cool to room temperature, but a liquid agar-containing solution can also be obtained by crushing the gelled product with a stress such as a strong shearing force.

The method of applying stress to the agar solution is not particularly limited, but examples thereof include vibration, shearing, stirring, compression, pulverization and the like, and stirring is the most preferable method for applying stress to the agar solution. As the stirring device, for example, a magnetic stirrer, a mechanical stirrer, a mixer,
Any stirring device such as a shaker, a rotor, a homogenizer (for example, TKHOMO MIXER manufactured by Tokushu Kiki Co., Ltd.) may be used, or the stirring may be performed manually. When preparing the agar-containing solution, it is preferable to use an apparatus having a strong stirring ability, and it is more preferable to stir while adjusting the Reynolds number of stirring to 100 or more even at room temperature.

The heating temperature of the agar-containing aqueous solution may be any temperature at which the agar-containing solution becomes uniform in appearance, and is preferably 80 ° C. or higher, more preferably 95 ° C. or higher. Further, it may be boiled if necessary.

The agar-containing solution can be cooled by air cooling, water cooling,
Any method such as ice cooling, solvent cooling, air cooling, refrigeration, and freezing may be used, but when rapidly cooling by water cooling, ice cooling, refrigeration, freezing, etc., it is necessary to increase the stirring power so as not to gel.

By the above method, a low-viscosity and high-concentration agar-containing solution can be prepared. The principle is not clear, but it is assumed as follows. It is thought that the agar gels because the chains of the agar molecules form hydrogen bonds between the molecular chains, and take a helical structure while taking in water molecules, resulting in a higher and stronger structure. The agar molecule, which had a random coil-shaped molecular structure when heated to a high temperature, tries to assume a helical structure as it cools, but when a strong stress is applied to it, it takes on a helical structure. It is speculated that as a result of hindering the reaction, the agar solution having a low viscosity without gelation is obtained.

Preferred embodiments of the eye drops of the present invention include:
For example, the weight average molecular weight is 5,000 to 1,200,000 and the particle size is 10
An eye drop having a viscosity of 150 mPa · s or less in which 0.1 to 10% by weight of agar having a particle size of 0 μm or less is mixed can be mentioned, and a more preferable embodiment has a weight average molecular weight of 30,000 to 80.
0.2 to 5% by weight of agar with a particle size of 20 μm or less
Is an eye drop having a viscosity of 100 mPa · s or less. Furthermore, the agar having a weight average molecular weight of 5,000 to 1,200,000 is dissolved by heating in an aqueous solution, and then cooled by applying a stress to obtain fine particles of agar having a particle size of 100 μm or less. Eyedrops with improved internal transferability, in particular, fine particles having a particle size of 20 μm or less obtained by heating and dissolving agar having a weight average molecular weight of 30,000 to 800,000 in an aqueous solution and then cooling while applying stress. An eye drop in which agar is incorporated to improve the drug transfer into the eye is preferable.

As a preferred embodiment of the drug intraocular migration improving agent of the present invention, for example, finely divided agar obtained by heating and dissolving agar in an aqueous solution and then cooling while applying stress is used as a base. An agent for improving intraocular migration of a drug, which is characterized in that, more preferably, agar having a weight average molecular weight of 5,000 to 1,200,000 is dissolved by heating in an aqueous solution, and then obtained by cooling while applying stress. Particle size is 100
It is an agent for improving intraocular migration of a drug that uses a particulate agar having a particle size of μm or less as a base, and more preferably, agar having a weight average molecular weight of 30,000 to 800,000 is heated and dissolved in an aqueous solution and then stressed. The particle size obtained by cooling while adding
It is an agent for improving intraocular migration of a drug, which uses fine particle agar having a size of 0 μm or less as a base.

The eye drop of the present invention is not limited with respect to the target disease, and is effective against each disease by containing a drug suitable for treating dry eye syndrome, glaucoma, cataract, inflammation, hay fever, etc. Act on.

The type of drug that can be incorporated in the eye drop of the present invention is not particularly limited, and examples thereof include antibacterial agents (quinolone antibacterial agents, cephalosporins, sodium sulfacetamide, sulfamethoxazole, etc.), anti-inflammatory agents. Agents (hydrocortisone, dexamethasone, prezonisolone, betamethasone, diclofenac, indomethacin, fluorometholone, planoprofen, dipotassium glycyrrhizinate, epsilon-aminocaproic acid, etc.), antihistamines (chlorpheniramine maleate, diphenhydramine hydrochloride, etc.), antiglaucoma agents ( Prostaglandin derivative,
Carbonic anhydrase inhibitors, etc.), antiallergic agents (sodium cromoglycate, etc.) and the like.

Examples of the immunosuppressant and antimetabolite include methotrexate, cyclophosphamide, cyclosporine, 6-mercaptopurine, azathioprine, fluorouracil, tegafur, and the like. Further, a mixture of the above compounds, for example, neomycin sulfate and phosphoric acid. Mixtures such as antibiotic / anti-inflammatory mixture, such as dexamethasone sodium combination, etc. may be mentioned, although other agents may be used to treat eye conditions and lesions.

The amount of drug added is 0.001 to 10% by weight.
However, the concentration is not particularly limited as long as the therapeutic effect is exhibited.

In addition to the above components, the eye drop of the present invention may appropriately contain other additives such as an isotonicity agent, a buffering agent, a pH adjusting agent, a solubilizing agent, a stabilizing agent and a preservative. You can

Examples of the tonicity agent include glycerin, propylene glycol, sodium chloride, potassium chloride,
Examples thereof include sorbitol and mannitol.

Examples of the buffer include phosphoric acid, phosphate, citric acid, acetic acid, ε-aminocaproic acid, trometamol and the like.

Examples of the pH adjusting agent include hydrochloric acid, citric acid, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide, boric acid, borax, sodium carbonate, sodium hydrogen carbonate and the like.

Examples of the solubilizing agent added when the drug or other additives are poorly water-soluble, for example, polysorbate 8
0, polyoxyethylene hydrogenated castor oil 60, Macrogol 4000 and the like.

Examples of the stabilizer include edetic acid and sodium edetate.

Examples of preservatives include sorbic acid, potassium sorbate, benzalkonium chloride, benzethonium chloride, methyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol, and the like, and these preservatives should be used in combination. You can also

The eye drop of the present invention can be prepared by adding agar and a drug to sterilized purified water, and if necessary, it may be subjected to treatments such as high speed stirring and ultrasonic irradiation to adjust it to a desired viscosity. it can.

In the test examples described later, fluorescein and pilocarpine were used as indicators for measuring the amount of intraocular transfer, and the fluorescence of fluorescein transferred into the cornea or aqueous humor or the pupil diameter due to pilocarpine was measured. Detailed results are shown in the section of Examples, but when the fine particle agar of the present invention was used as a base, markedly superior intraocular migration was recognized as compared with the control. As is clear from these test examples, by using fine particle agar as a base for an eye drop, the intraocular transfer of the drug can be improved.

The pH of the eye drop of the present invention is desirably set to 4.0 to 8.0, and the osmotic pressure ratio is desirably set to about 1.0.

The number of eye drops of the eye drop of the present invention depends on symptoms, age,
It can be appropriately selected depending on the dosage form and the like, but may be applied once to several times a day.

[0087]

The present invention will be described below with reference to examples.
These examples are for the purpose of better understanding the present invention and are not intended to limit the scope of the present invention.

(1) Preparation and evaluation test of composition containing agar (agar solution) Weight average molecular weight measurement The weight average molecular weight of agar was measured according to the following measurement conditions.

Measurement Conditions A. Equipment: Gel Permeation Chromatograph, (Waters) (M510 type high pressure pump, U6 universal injector) B. Data processing: TRC (Toray Research Center) GPC data processing system C.I. Column: TSK-gel-GMPWXL, (inner diameter 7.8 mm / length 30 cm) (2) (manufactured by Tosoh Corporation) D. Solvent: 0.1M-NaNO ₃ / distilled water E. Flow rate: 1.0 ml / min F. Column temperature: 50 ° C (column constant temperature bath: manufactured by Tosoh Corporation) G. Sample: Concentration: 0.1% (wt / vol) Solubility: Visually dissolved in the measurement solvent Filter: 0.45 μm-Mysholydisk W-13-5 (manufactured by Tosoh Corporation) Injection volume: 200 μl I.V. Detector: differential refractive index detector, R-401 (manufactured by Tosoh Corporation) J. Molecular weight calibration: 14 types of pullulan (Showa Denko)

Table 1 shows the weight average molecular weight of the agar measured under the above conditions. All the agars shown in Table 1 are manufactured by Ina Food Industry Co., Ltd.

[0091]

[Table 1]

Particle diameter measuring method After preparing the agar-containing composition, the particle diameter of each composition was measured by an optical microscope (OPTIPHOTO-2 manufactured by Nikon Corporation) to determine the maximum particle diameter of the particles.

Viscosity measuring method After preparing the agar-containing composition, a B-type viscometer (rotor N
o. In 2), the viscosity of each composition was measured under the conditions of 20 ° C. and 60 rpm.

Manufacturing Method Manufacturing Method A Agar was placed in a 500 ml flask, and distilled water was added to the solution to 50 ml.
It shall be 0 g. The mixture is heated, melted at about 100 ° C., and then cooled to 20 ° C. with stirring with a magnetic stirrer at 1500 rpm.

Preparation Method B Agar was placed in a 500 ml flask, and distilled water was added to the agar to give 50.
It shall be 0 g. This mixture is heated in a microwave oven, melted at a high temperature, and then cooled to 20 ° C. with stirring with a magnetic stirrer at 1500 rpm. Then 1 glycerin
Add 3g, and at 20 ℃, magnetic stirrer 15
Stir for 30 minutes at 00 rpm.

Manufacturing Method C Agar was attached to a Teflon (registered trademark) stirring blade 50.
Transfer to a 0 ml four-necked flask and add distilled water to 500 g.
And This mixture is heated in an oil bath to about 100
After melting at ℃, it is cooled to 20 ℃ while stirring at 700 rpm.

Production Method D 50 agar was attached to a Teflon (registered trademark) stirring blade.
Transfer to a 0 ml four-necked flask and add distilled water to 500 g.
And This mixture is heated in an oil bath to about 100
After melting at ℃, it is cooled to 80 ℃ while stirring at 700 rpm using a stirring blade. After transferring the solution to a stainless steel container, use a homomixer (TK HOMO manufactured by Tokushu Kiki Co., Ltd.
Mixer) and cool to 20 ° C. with stirring.

Production Example The production example of the agar-containing composition (agar solution) of the present invention is shown below. The agar solutions obtained in Production Examples 1 to 25 each had a viscosity of 700 mPa · s or less, and as a result of observation under an optical microscope, fine particle agar was present. In addition, Production Example 18
FIG. 1 shows an optical micrograph of the above agar solution.

Production Example 1 Agar-containing composition (agar solution) was prepared in Production Method A using 2.5 g (0.5% by weight) of agar (UP-6). The agar solution was cloudy, the viscosity was 93 mPa · s, and the particle size was less than 10 μm.

Production Example 2 2.5 g (0.5% by weight) of agar (AX-30) was used,
An agar solution was prepared in the production method A. The agar solution was cloudy, the viscosity was 40 mPa · s, and the particle size was less than 10 μm.

Production Example 3 Using 2.5 g (0.5% by weight) of agar (AX-30),
An agar solution was prepared in the production method B. This agar solution was cloudy and had a viscosity of 31 mPa · s.

Production Example 4 Using agar (AX-30), the homomixer was rotated at 30 rpm.
The agar solution was prepared according to the manufacturing method D by setting it to 00 rpm. This agar solution is pale yellow and cloudy and has a viscosity of 32 mPa · s.
The particle size was less than 10 μm.

Production Example 5 Using agar (AX-30), the homomixer was rotated at 40 rpm.
The agar solution was prepared according to the manufacturing method D by setting it to 00 rpm. This agar solution is pale yellow and cloudy with a viscosity of 51 mPa · s.
The particle size was less than 10 μm.

Production Example 6 Using agar (AX-30), the homomixer was rotated at 50 rpm.
The agar solution was prepared according to the manufacturing method D by setting it to 00 rpm. This agar solution is pale yellow and cloudy and its viscosity is 67 mPa.
· S, the particle size was less than 10 μm.

Production Example 7 Using agar (AX-30), the homomixer was rotated at 60 rpm.
The agar solution was prepared according to the manufacturing method D by setting it to 00 rpm. This agar solution is pale yellow and cloudy and its viscosity is 81 mPas.
· S, the particle size was less than 10 μm.

Production Example 8 Using agar (AX-30), the homomixer was rotated at 80 rpm.
The agar solution was prepared according to the manufacturing method D by setting it to 00 rpm. This agar solution is pale yellow and cloudy and its viscosity is 94 mPa.
· S, the particle size was less than 10 μm.

Production Example 9 Agar (AX-30) was used, and the rotation speed of the homomixer was 10 times.
The agar solution was prepared in the method D by setting it to 000 rpm. This agar solution is pale yellow and cloudy with a viscosity of 144 mPa.
In s, the particle size was less than 10 μm.

Production Example 10 2.5 g (0.5% by weight) of agar (UP-6) was used, the rotation speed of the homomixer was set to 6000 rpm, and an agar solution was prepared according to the production method D. This agar solution was cloudy and had a viscosity of 403 mPa · s. The particle size was less than 10 μm.

Production Example 11 2.5 g (0.5% by weight) of agar (M-9) was used, the rotation number of the homomixer was set to 6000 rpm, and an agar solution was prepared in the production method D. This agar solution is cloudy and has a viscosity of 2
It was 00 mPa · s. The particle size was less than 10 μm.

Production Example 12 2.5 g (0.5% by weight) of agar (AX-30) was used,
The rotation speed of the homomixer was set to 6000 rpm, and the agar solution was prepared in the production method D. The agar solution was pale yellow and opaque and had a viscosity of 20 mPa · s. The particle size is 1
It was less than 0 μm.

Production Example 13 2.5 g (0.5% by weight) of agar (AX-100) was used, the rotation speed of the homomixer was set to 6000 rpm, and the production method D was used.
An agar solution was prepared. This agar solution was pale yellow and opaque and had a viscosity of 62 mPa · s. The particle size was less than 10 μm.

Production Example 14 2.5 g (0.5% by weight) of agar (AX-200) was used, the rotation speed of the homomixer was set to 6000 rpm, and the production method D was used.
An agar solution was prepared. This agar solution was pale yellow and opaque and had a viscosity of 62 mPa · s. The particle size was less than 10 μm.

Production Example 15 2.5 g (0.5% by weight) of agar (BX-30) was used,
The rotation speed of the homomixer was set to 6000 rpm, and the agar solution was prepared in the production method D. The agar solution was pale yellow and opaque, and the viscosity was 96 mPa · s. The particle size is 1
It was less than 0 μm.

Production Example 16 2.5 g of agar (agarose DNA grade)
(0.5% by weight), the homomixer rotation speed is 6000
The agar solution was prepared according to the manufacturing method D by setting the rpm to rpm. This agar solution was cloudy and had a viscosity of 158 mPa · s. The particle size was less than 10 μm.

Production Example 17 2.5 g (0.5% by weight) of agar (PS-7) was used, the rotation speed of the homomixer was set to 6000 rpm, and an agar solution was prepared according to the production method D. This agar solution was cloudy and had a viscosity of 190 mPa · s. The particle size was less than 10 μm.

Production Example 18 An agar solution was prepared according to the production method A by using 5.0 g (1.0% by weight) of agar (UP-6). This agar solution was cloudy, had a viscosity of 384 mPa · s and a particle size of less than 20 μm.

Production Example 19 5.0 g of agar manufactured by Funakoshi [Product name BA-10]
(1.0% by weight) was used to prepare an agar solution in the production method A. This agar solution is cloudy and has a viscosity of 297 mPas.
-S, the particle size was less than 20 μm.

Production Example 20 An agar solution was prepared in Production Method A using 2.5 g (0.5% by weight) of agar (AX-100). This agar solution is cloudy, has a viscosity of 133 mPa · s and a particle size of 10 μm.
It was less than m.

Production Example 21 An agar solution was prepared in Production Method A using 2.5 g (0.5% by weight) of agar (AX-200). This agar solution is cloudy, has a viscosity of 133 mPa · s and a particle size of 10 μm.
It was less than m.

Production Example 22 2.5 g (0.5% by weight) of agar (BX-30) was used,
An agar solution was prepared in the production method A. The agar solution was cloudy, the viscosity was 41 mPa · s, and the particle size was less than 10 μm.

Production Example 23 2.5 g (0.5% by weight) of agar (BX-30) was used,
An agar solution was prepared in the manufacturing method C. The agar solution was clouded, the viscosity was 142 mPa · s, and the particle size was less than 10 μm.

Production Example 24 An agar solution was prepared according to the production method A using 2.5 g (0.5% by weight) of agar (PS-7). This agar solution is cloudy and has a viscosity of 87 mPa · s and a particle size of 10 μm.
Was less than.

Production Example 25 An agar solution was prepared in Production Method A using 2.5 g (0.5% by weight) of agar (M-9). This agar solution was cloudy, had a viscosity of 106 mPa · s and a particle size of less than 10 μm.

Production Example 26 Gellan gum (GP manufactured by Ina Food Industry Co., Ltd. was used instead of agar.
A gellan gum aqueous solution was prepared in the same manner as in Production Example 4 except that -10) was used. The solution is clear and has a viscosity of 1
At 37 mPa · s, the particle size was less than 10 μm.

Production Example 27 Gellan gum (GP manufactured by Ina Food Industry Co., Ltd.) was used instead of agar.
A gellan gum aqueous solution was prepared in the same manner as in Production Example 6 except that -10) was used. The solution is clear and has a viscosity of 1
At 60 mPa · s, the particle size was less than 10 μm.

Production Example 28 Gellan gum (GP manufactured by Ina Food Industry Co., Ltd. was used instead of agar.
A gellan gum aqueous solution was prepared in the same manner as in Production Example 7 except that -10) was used. The solution is clear and has a viscosity of 1
At 50 mPa · s, the particle size was less than 10 μm.

Production Example 29 Gellan gum (GP manufactured by Ina Food Industry Co., Ltd. was used instead of agar.
An aqueous gellan gum solution was prepared in the same manner as in Production Example 8 except that -10) was used. The solution is clear and has a viscosity of 1
At 48 mPa · s, the particle size was less than 10 μm.

Production Example 30 Gellan gum (GP manufactured by Ina Food Industry Co., Ltd. was used instead of agar.
A gellan gum aqueous solution was prepared in the same manner as in Production Example 9 except that -10) was used. The solution is clear and has a viscosity of 1
At 58 mPa · s, the particle size was less than 10 μm.

Production Example 31 Gellan gum (GP manufactured by Ina Food Industry Co., Ltd. was used instead of agar.
-10) was used, the rotation speed of the homomixer was set to 6000 rpm, and a gellan gum aqueous solution was prepared according to the production method D. The solution was transparent and had a viscosity of 103 mPa · s. The particle size was less than 10 μm.

Comparative Production Example 1 2.5 g of agar (UP-6) was added to a 500 ml flask.
(0.5% by weight) was taken, 500 g of distilled water was added to disperse the solution, and once dissolved at a high temperature, the solution was cooled to 20 ° C. without stirring. The prepared 0.5 wt% agar gel was filtered through a sieve with a pore size of 1 mm. The viscosity of the finely crushed gel is 900m
It was Pa · s.

Comparative Production Example 2 An agar solution was prepared in Production Method A using 0.25 g (0.05% by weight) of agar (AX-30). The viscosity of this agar solution was 14 mPa · s.

Comparative Production Example 3 2.5 g (0.5% by weight) of agar (AX-30) was used,
An agar solution was prepared in the production method A except that the rotation speed of the magnetic stirrer was changed to 500 rpm. This agar solution became a mixture of gel and solution, and the viscosity could not be measured.

Evaluation of Applicability The ease of application and the state after application were evaluated when the solutions of Production Examples 1 to 3 and Comparative Production Examples 1 to 3 were applied to the skin. The results are shown in Table 2.

[0134]

[Table 2]

As shown in Table 2, the solutions of Production Examples 1 to 3 have the characteristics that they are easy to apply and do not easily flow down. On the other hand, although the solutions of Comparative Production Examples 1 and 3 are hard to flow down,
Although it is difficult to apply and the solution of Comparative Production Example 2 is easy to apply, it has a drawback that it runs off immediately.

Relationship between Viscosity and Agitation Speed FIG. 2 shows the relationship between the viscosity and the agitation speed (corresponding to the shear rate) in Production Examples 4 to 9 and Production Examples 26 to 30. As is clear from FIG. 2, in Production Examples 4 to 9, the higher the stirring speed is, the higher the viscosity is, whereas in Production Examples 26 to 30, the viscosity is almost the same even if the stirring speed is increased. It is constant.

Thickening Rate Evaluation Test To 50 g of the agar solutions prepared in Production Examples 10 to 17 and Production Example 31, 0.025 g of fluorescein sodium, which is a water-soluble compound, and 1.3 g of glycerin were added, and after sufficiently mixing, the pH was adjusted. Was adjusted to 7. The viscosity of these agar solutions was measured with a B-type viscometer (rotor No. 2) at 20 ° C.
It was measured under the condition of 60 rpm. Let this viscosity value be Y.

Next, NaCl was added to the above agar solution to a concentration of 0.9% by weight, and they were mixed sufficiently. The viscosity of this agar solution was measured with a B-type viscometer (rotor No. 2) at 20 ° C. and 60 rpm. Let this viscosity value be Z.

The thickening rate X was calculated based on the following formula.

X = Z / Y Each solution was applied to human forearm skin and the ease of application and the state after application were compared. These results are shown in Table 3.
Shown in.

[0141]

[Table 3]

Table 3 shows that Test Examples 1 to 8 have the characteristics that they are easy to apply, have an appropriate viscosity on the skin surface, and are hard to run off. On the other hand, in Test Example 9 and Comparative Example Test Example 1, application was easy, but in Test Example 9, after application, the thickening was too rapid, resulting in gelation on the skin surface, causing discomfort, and in Comparative Test Example 1. It has the drawback that it runs off immediately after application.

(2) Intraocular migration test A. Intraocular Transfer Test by Fluorophotometry (i) Method for Preparing Test Eye Drops Agar solutions (100 g each) prepared in Production Examples 1, 2 and 18 to 25 were added with 0.05 g of fluorescein sodium and 0.05 g of concentrated glycerin, respectively. .6g was added. Next,
This was stirred for 2 minutes with a hybrid mixer (HM-500, manufactured by Keyence Corporation) to obtain each test eye drop. Also,
Add sodium hydroxide or dilute hydrochloric acid to each test eye drop and add p
Adjust H to 7.0 (± 0.5), E-type viscometer Rotovisc
Using CV20 (HAAKE Co.), the value at a shear rate of 100 s ⁻¹ hour was measured at a measurement temperature of 25 ° C. to obtain the viscosity. In addition, the particle size of the agar is determined by an optical microscope (OPTIPHOT manufactured by Nikon Corporation).
The maximum particle size of the particles was measured using O-2). In addition,
As a control, sterile purified water was used instead of the agar solution, and the same operation was performed to obtain a comparative eye drop (Comparative Test Example 2).

(Ii) Administration method and measurement method Each test eye drop obtained by the above-mentioned preparation method was applied to the eyes of a male Japanese white rabbit, and 1, 2, 3, 4, 6 and 8 hours later, and the cornea and The concentration of fluorescein in the aqueous humor was measured using a fluorescence spectrophotometer (each test eye drop and comparative eye drop was measured in 4 cases, and the average value was calculated). AUC from measured values of fluorescein concentration
(Area under the concentration curve) was calculated, and the AUC ratio of each test eye drop to the comparative eye drop was determined by the following formula. These results are shown in Table 4.
Shown in. Further, changes in fluorescein concentration in the cornea and the aqueous humor are shown in FIGS. 3 and 4.

[0145]

[Equation 1]

An eye drop was prepared in the same manner as the above-mentioned preparation method except that the CVP solution (1.0%) was used in place of the agar solution. However, the eye drop containing CVP had a very high viscosity ( Since it was 1139 mPa · s), it was not possible to instill it.

[0147]

[Table 4]

B. Intraocular transfer test using pilocarpine (i) Method for preparing test eye drop To the agar solution (100 g) prepared in Production Example 1, pilocarpine hydrochloride and concentrated glycerin were added at 1.0 g and 2.6 g, respectively. Next, this solution was stirred with a magnetic stirrer to prepare a test eye drop. In addition, the pH was adjusted to 7.0 by adding sodium hydroxide or dilute hydrochloric acid to the test eye drops. The viscosity (25 ° C.) was measured with an E-type viscometer. As a control, sterile purified water was used instead of the agar solution (Production Example 1), and the same operation was performed to obtain a comparative eye drop (Comparative Test Example 3).

(Ii) Administration method and measurement method Each test eye drop obtained by the above-mentioned preparation method was applied to the eyes of a male Japanese white rabbit, and then 0.25, 0.5, 0.75, 1, 1.
The pupil diameter was measured after 5, 2, 2.5 and 3 hours. A value obtained by subtracting the pupil diameter at each measurement from the pupil diameter before instillation was defined as a miosis value (6 test cases and comparative eye drops were each measured and an average value was calculated). Further, AUC (pharmacological effect-area under the time curve) was calculated from the obtained miosis value. The results are shown in Table 5 and FIG.

[0150]

[Table 5]

(3) Formulation Examples Formulation examples of typical eye drops and ear drops used in the present invention are shown below.

Formulation Example 1 Pilocarpine hydrochloride and concentrated glycerin were added to the agar solution (100 g) prepared in Production Example 18, and the mixture was stirred for 2 minutes with a hybrid mixer (HM-500, manufactured by Keyence Corporation), and then 0.1N. The pH was adjusted to 7.0 by adding sodium hydroxide or 0.1N dilute hydrochloric acid to prepare an eye drop.

[0153]     In 100g       Agar (UP-6) 1.0 g       Pilocarpine hydrochloride 1.0 g       Concentrated glycerin 2.6g       Sodium hydroxide suitable amount       Hydrochloric acid       Sterile purified water

Formulation Example 2 Planoprofen and concentrated glycerin were added to the agar solution (100 g) prepared in Production Example 1, and the mixture was stirred for 2 minutes with a hybrid mixer (HM-500, manufactured by KEYENCE CORPORATION), and then stirred at 0. The pH was adjusted to 7.0 by adding 1N sodium hydroxide or 0.1N dilute hydrochloric acid to prepare an eye drop.

[0155]     In 100g       Agar (UP-6) 0.5g       Planoprofen 0.1g       Concentrated glycerin 2.6g       Sodium hydroxide suitable amount       Hydrochloric acid       Sterile purified water

By preparing agar solutions of various concentrations and carrying out the same operations as in Formulation Examples 1 and 2, eye drops containing agar of a desired concentration can be prepared.

Prescription example 3 An ear drop solution was prepared according to the following formulation.

[0158] Gatifloxacin 0.5g Sodium edetate 0.1g Sodium chloride 0.9g Agar solution of Production Example 12 70.0 g Purified water 28.5g

These components were stirred and mixed until uniform, and the prepared solution was adjusted to pH 7.0 with an appropriate amount of hydrochloric acid or sodium hydroxide. The obtained ear drop solution had a low viscosity but was very excellent in spreading, and did not cause dripping after ear drop.

[0160]

INDUSTRIAL APPLICABILITY According to the present invention, a composition in a liquid state having a low viscosity while containing a high concentration of polysaccharide is prepared by heating a polysaccharide in a water-containing liquid and then cooling it while applying a shearing force. Thus, it becomes possible to provide pharmaceuticals, foods, cosmetics, toiletry products, etc. having an unprecedented texture and / or function. In addition, when the polysaccharide is used as a bowel movement-improving food, it has become possible to provide a liquid food that is easier to take than jelly.

From the results of the intraocular migration test by the fluorophotometry method (Table 4, FIG. 3 and FIG. 4), the eye drop of the present invention has a viscosity suitable for the eye drop, and if this is applied, fluorescein Is transferred to the cornea and aqueous humor and remains at a high concentration (3 to 6 times that of the control) for a long time. Further, from the results of the intraocular migration test using pilocarpine, which is an ophthalmic drug (Table 5 and FIG. 5), when the eye drop of the present invention was instilled, the AUC (pharmacological effect-area under the time curve) of pilocarpine was controlled. More than double. Thus, the eye drop containing the agar of the present invention exerts the effect of improving the intraocular migration of the drug, and since it can be kept at a low viscosity, the eye drop is well drained, and one drop thereof The amount is constant, and it feels good when you apply it.

[Brief description of drawings]

FIG. 1 shows an optical micrograph of an agar solution prepared in Production Example 1.

[Fig. 2] Fig. 2 shows Production Examples 4 to 9 and Production Examples 26 to 30.
The relationship between the viscosity and the stirring speed (corresponding to the shearing speed) in Example 1 is shown.

FIG. 3 shows that each of the eye drops of Test Example 10, Test Example 12 and Comparative Test Example 2 (control) was applied to a rabbit,
It is a graph which shows the result of having measured the fluorescein concentration in the cornea in each time. The vertical axis represents the concentration of fluorescein in the cornea (ng / mL), and the horizontal axis represents time (hr).

[Fig. 4] Fig. 4 is a drawing showing the eye drops of each of Test Example 10, Test Example 12 and Comparative Test Example 2 (control) after being applied to a rabbit.
It is a graph which shows the result of having measured the fluorescein concentration in the aqueous humor in each time. The vertical axis represents the fluorescein concentration (ng / mL) in the aqueous humor, and the horizontal axis represents the time (hr).

FIG. 5 is a graph showing the results of measuring the miosis value by pilocarpine at each time after instilling each eye drop of Test Example 20 and Comparative Test Example 3 (control) on a rabbit. The vertical axis is the miosis value (mm) due to pilocarpine,
The horizontal axis represents time (hr).

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 27/04 A61P 27/04 27/16 27/16 C08K 5/053 C08K 5/053 C08L 5/00 C08L 5/00 (72) Masato Yoshikawa Inventor Masato Yoshikawa 2-1201, Aiharago, Midori-ku, Nagoya, Aichi 1101 Sun Mansion Atre Narumi Aihara (72) Inventor Takashi Taniguchi 5-12-29 Omi Fuji, Yasu-cho, Yasu-gun, Shiga Prefecture (72) Inventor Mitsuru Yokota 1-24-20-402 Asahigaoka, Otsu City, Shiga Prefecture (72) Inventor Naoki Shimoyama 29-34 Wakabadai, Otsu City, Shiga Prefecture (72) Masaki Ue 16-minamicho, Takehana Jizoji Temple, Yamashina District, Kyoto City, Kyoto Prefecture B 27 (72) Inventor Miho Araki 1-1-12 Oe, Otsu City, Shiga Prefecture (72) Inventor Yukiko Sugihara 8916-16 Takayamacho, Ikoma City, Nara Santen Pharmaceutical Co., Ltd. (72) Inventor Horibe Yoshii 8916-16 Takayama-cho, Ikoma-shi, Nara Santen Pharmaceutical Co., Ltd. (72) Inventor Mitsuaki Kuwano 8916-16 Takayama-cho, Ikoma-shi, Nara Santen Pharmaceutical Co., Ltd. F-term (reference) 4B018 LB10 ME14 MF02 4C076 AA12 BB24 BB26 DD38E EE30G EE30N FF34 4C083 AC111 AD211 CC01 DD23 EE05 4J002 AB051 EC036 EC046 EC056 GB00

Claims (41)

[Claims] 1. Containing 0.1 to 30% by weight of a polysaccharide,
20 ° C, 60 rpm with B-type viscometer (rotor No. 2)
The polysaccharide-containing composition having a viscosity of 700 mPa · s or less measured under the conditions of. 2. A B type viscometer (rotor No. 2) having a viscosity of 20
Viscosity measured under conditions of ℃ and 60 rpm is 500 mPa
The polysaccharide-containing composition according to claim 1, wherein the composition is s or less. 3. The content of polysaccharide is 0.2 to 10% by weight.
The polysaccharide-containing composition according to claim 1 or 2, wherein 4. The polysaccharide-containing composition according to any one of claims 1 to 3, comprising a polysaccharide and an aqueous medium, the aqueous medium comprising water and a water-soluble compound. 5. The polysaccharide-containing composition according to claim 4, wherein the water-soluble compound is a polyhydric alcohol. 6. A polysaccharide-containing composition, which contains at least a polysaccharide and a water-soluble compound, and has a thickening rate X represented by the following formula of 1.005 or more. X = Z / Y (where Y is a B-type viscometer (rotor No. 2) of the polysaccharide-containing composition containing a water-soluble compound, 20 ° C., 60 rpm
Is a viscosity measured under the conditions of, and Z is added with 0.9% by weight of NaCl to the polysaccharide-containing composition, and thereafter is measured with a B-type viscometer (rotor No. 2) at 20 ° C. and 60 rpm. The measured viscosity. ) 7. The polysaccharide-containing composition according to claim 6, wherein the viscosity increase rate X is 1.008 or more. 8. The polysaccharide-containing composition according to claim 6, wherein the thickening factor X is 1.010 or more. 9. The polysaccharide according to claim 1, wherein the polysaccharide is in the form of fine particles, and the whole or a part of the fine particle polysaccharide is dispersed in an aqueous solution. Containing composition. 10. The particle size of the fine particle polysaccharide is 100 μm.
The polysaccharide-containing composition according to claim 9, wherein: 11. The polysaccharide-containing composition according to claim 9, wherein the particle size of the fine particle polysaccharide is 20 μm or less. 12. The polysaccharide-containing composition according to any one of claims 1 to 11, which contains a polysaccharide obtained from a plant. 13. The polysaccharide-containing composition according to claim 12, wherein the polysaccharide obtained from the plant is agar. 14. The weight average molecular weight of agar is 5,000 to 120.
14. The polysaccharide-containing composition according to claim 13, which is 100,000. 15. The polysaccharide-containing composition according to claim 13, wherein the agar has a weight average molecular weight of 30,000 to 800,000. 16. The polysaccharide-containing composition according to claim 1, further comprising an isotonicity agent. 17. A pharmaceutical base using the polysaccharide-containing composition according to any one of claims 1 to 16. 18. A medicine comprising the polysaccharide-containing composition according to any one of claims 1 to 16. 19. An intraocular migration improving agent comprising the polysaccharide-containing composition according to any one of claims 1 to 16. 20. A food containing the polysaccharide-containing composition according to any one of claims 1 to 16. 21. A cosmetic containing the polysaccharide-containing composition according to any one of claims 1 to 16. 22. A composition containing 0.1 to 30% by weight of a polysaccharide and an aqueous medium is heated to a temperature not lower than the gel transition temperature of the polysaccharide to be dissolved, and the composition is subjected to a shearing force. A method for producing a polysaccharide-containing composition obtained by cooling to a gel transition temperature or lower, wherein the composition obtained was measured using a B-type viscometer (rotor No. 2) under conditions of 20 ° C and 60 rpm. A method for producing a polysaccharide-containing composition, which has a viscosity of 700 mPa · s or less. 23. The shearing force according to claim 22 is selected from a shearing force region in which the viscosity of the product becomes higher when a higher shearing force is applied.
A method for producing the described polysaccharide-containing composition. 24. An ophthalmic solution containing agar which improves the drug transfer into the eye. 25. The weight average molecular weight of agar is 5,000 to 120.
25. The eye drop according to claim 24 26. The eye drop preparation according to claim 24, wherein the agar has a weight average molecular weight of 30,000 to 800,000. 27. The eye drop preparation according to claim 24, wherein the content of agar is 0.1 to 10% by weight. 28. The eye drop preparation according to claim 24, wherein the content of agar is 0.2 to 5% by weight. 29. The viscosity of the eye drop is an E-type viscometer (25 ° C.,
The eye drop according to claim 24, which has a shear rate of 100 s-1) and is 150 mPa · s or less. 30. An E-type viscometer (25 ° C.,
The eye drop according to claim 24, having a shear rate of 100 m-1 · s or less at 100 s-1). 31. The eye drop preparation according to claim 24, wherein the agar is in the form of fine particles having a particle size of 100 μm or less. 32. The eye drop preparation according to claim 24, wherein the agar is in the form of fine particles having a particle size of 20 μm or less. 33. A weight average molecular weight of 5,000 to 1,200,000,
0.1 to 10% by weight of agar having a particle size of 100 μm or less
Blended with E-type viscometer (25 ℃, shear rate: 100s-1)
An eye drop having a viscosity of 150 mPa · s or less as measured by. In 34. The weight average molecular weight of 30,000 to 800,000, blended with 0.2 to 5 wt% agar is a particle size 20μm or less, E-type viscometer (25 ° C., shear rate: 100s ^{- 1)} An eye drop having a viscosity of 100 mPa · s or less as measured by. 35. An ophthalmic solution comprising a fine agar obtained by heating and dissolving agar in an aqueous solution and then cooling while applying stress, thereby improving the drug transfer into the eye. 36. The weight average molecular weight of agar is 5,000 to 120.
36. The eye drop according to claim 35, wherein the particle size of the fine agar is 100 μm or less. 37. The eye drop preparation according to claim 35, wherein the agar has a weight average molecular weight of 30,000 to 800,000, and the fine agar has a particle size of 20 μm or less. 38. An agent for improving intraocular migration of a drug, which comprises using agar as a base. 39. An agent for improving intraocular migration of a drug, which comprises using finely divided agar obtained by heating and dissolving agar in an aqueous solution and then cooling while applying stress as a base. 40. The weight average molecular weight of agar is 5,000 to 120.
40. The agent for improving intraocular migration of a drug according to claim 39, wherein the particle diameter of the fine agar is 100 μm or less. 41. The agent for improving intraocular migration of a drug according to claim 39, wherein the agar has a weight average molecular weight of 30,000 to 800,000, and the fine agar has a particle size of 20 μm or less.