JP4982643B2 - Ophthalmic pharmaceutical composition - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to the treatment of the ophthalmic field, and more particularly to an ophthalmic pharmaceutical composition for the treatment and / or prevention of ocular clinical symptoms in Sjogren's syndrome.
[0002]
[Prior art]
Sjögren's syndrome is a disease with a high frequency of occurrence, and since it is particularly frequent in elderly people, it is expected that the number will increase in the future with the aging society. Its characteristics are accompanied by infiltration of lymphocytes into the lacrimal gland and salivary gland and destruction of glandular cells. The cause is unknown, but the theory of autoimmune diseases is considered promising, and the diagnostic criteria are almost established. Clinical symptoms of the eye in Sjogren's syndrome include a foreign body sensation, a burning sensation, and an itching sensation. As the treatment method, symptomatic treatment such as instillation of artificial tears, wearing of goggles and protective glasses for dry eyes is mainly used. If there is no improvement in these treatments, symptomatic treatments such as surgery, steroids, and immunosuppressants are mainly used, but all require hospitalization or doctor guidance. Because of the necessity of equipment, there is a problem that normal social life is restricted for treatment. On the other hand, general eye drops commonly used in the ophthalmology field are easy to carry and use at the time of use. Recently, for the treatment of clinical symptoms of the eyes in Sjogren's syndrome, sodium hyaluronate is used. Although eye drops and the like are commercially available, an ophthalmic pharmaceutical composition for satisfactory treatment and / or prevention has not yet been obtained.
[0003]
[Problems to be solved by the invention]
An object of the present invention is to provide a useful and safe ophthalmic pharmaceutical composition, in particular an eye drop, an ointment and an eye cleanser, which is excellent in the therapeutic effect and / or preventive effect of clinical symptoms of eyes in Sjogren's syndrome. It is in.
[0004]
[Means to solve the problem]
In view of such circumstances, the present inventors have surprisingly found that as a result of searching for substances that are excellent in the treatment and / or prevention of clinical symptoms of eyes in Sjogren's syndrome and are safe for long-term use, It has been found that trehalose, which is widely used in cosmetics and cosmetics, exhibits a remarkable therapeutic effect and / or preventive effect on its clinical symptoms without any harmful effects caused by long-term administration. That is, this invention solves the said subject by the ophthalmic pharmaceutical composition which contains a trehalose as an active ingredient.
[0005]
Trehalose is a disaccharide in which two molecules of glucose are bonded together through reducing groups, and there are three types of optical isomers, α, α-trehalose, α, β-trehalose and β, β-trehalose. In the present invention, unless otherwise specified, these three types of trehalose are simply abbreviated as trehalose. Trehalose is widely distributed in bacteria, plants and animals in nature. In the food field, in addition to low sweetness, it has outstanding properties such as prevention of starch aging and prevention of protein denaturation during freezing and drying, and therefore, its demand is growing rapidly. In the cosmetic field, trehalose is excellent in moisture retention for the skin and its use is widespread. Furthermore, the safety of oral and dermal administration of trehalose has already been confirmed. However, with regard to the physiological functions of trehalose in the living body, only the improvement of osteoporosis and the function of regulating the metabolism of blood fatty acids are known. In particular, in the ophthalmic field, the cornea is easily damaged during ophthalmic surgery. There is only a report that it has an action of protecting endothelial cells and corneal epithelial cells (Japanese Patent Laid-Open No. 9-235233).
[0006]
Thus, although trehalose itself is a known substance, the knowledge that trehalose has therapeutic and / or preventive effects on clinical symptoms such as ocular foreign body sensation, burning sensation, pruritus sensation in Sjogren's syndrome is based on the present invention. Take it as a samurai.
[0007]
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an ophthalmic pharmaceutical composition for treating and / or preventing clinical ophthalmic symptoms in Sjogren's syndrome, comprising trehalose as an active ingredient. As described above, trehalose has three optical isomers (α, α-trehalose, α, β-trehalose and β, β-trehalose), all of which have therapeutic effects on clinical symptoms of the eye in Sjogren's syndrome. In the present invention, one or two or more kinds selected from α, α-trehalose, α, β-trehalose and β, β-trehalose are used in appropriate combination. Can do. In the ophthalmic pharmaceutical composition of the present invention, the above-mentioned three types of trehalose can be used alone or in combination of two or more, as long as they contain an effective content of trehalose. Absent.
[0008]
The trehalose used in the present invention is not limited as to its production method and origin unless it impairs the object of the present invention. As for α, α-trehalose, for example, JP-A-7-143766, JP-A-7-213283, JP-A-7-32283, JP-A-7-298880, JP-A-8-66187, A method of causing non-reducing saccharide-forming enzyme and trehalose-free enzyme to act on starch partial hydrolyzate disclosed in JP-A-8-66188, JP-A-8-336388 and JP-A-8-84586 is preferable. It is. Such trehalose is not only excellent in terms of economic efficiency, but also has a low possibility of contamination with toxic impurities, etc., compared to synthetic methods and the like, and is preferably used. Commercially-available products prepared by the enzyme method include food-grade trehalose (trehalose content 98% or more per solid weight, trade name “Treha (registered trademark)” sold by Hayashibara Corporation) and reagent-grade trehalose (solid content There is a trehalose content of 99% or more by weight, sold by Hayashibara Biochemical Laboratories, Inc.). The trehalose used in the present invention can be used without being limited to these commercially available trehalose as long as the object of the present invention is not impaired. Further, α, β-trehalose may be prepared by allowing an enzyme to act on a mixture of starch hydrolyzate and lactose, for example, by the method described in JP-A-4-179490. Furthermore, β, β-trehalose can be easily obtained by chemical synthesis. The trehalose used in the present invention does not have to be a pure product, and trehalose and the production thereof can be used as long as they do not detract from the therapeutic and / or preventive effects on clinical symptoms of eyes in Sjogren's syndrome, which is the object of the present invention. It may be a mixture with carbohydrates other than trehalose that are sometimes produced as by-products. Since eye drops directly come into contact with the mucous membrane of the eye, it is desirable to remove impurities such as pyrogen by a purification method including activated carbon, ion exchange chromatography, gel filtration chromatography, membrane filtration and the like.
[0009]
When the ophthalmic pharmaceutical composition containing the trehalose of the present invention is administered to a patient with clinical symptoms such as foreign body sensation, burning sensation, pruritus sensation in Sjogren's syndrome, not only the clinical symptoms are improved, but also irregular In patients with repeated occurrence and recovery of symptoms, administration can also be prevented during periods when there are no symptoms. The pharmaceutical composition of the present invention is used as an eye cleanser, eye drop or eye ointment.
[0010]
The ophthalmic pharmaceutical composition of the present invention can use a conventional base depending on its dosage form, and can be prepared by mixing an effective amount of trehalose. The base of the eye drop and the eye cleansing agent may be any as long as it is used for ordinary eye drops and eye cleansing agents, and purified water is usually used. The pharmaceutical composition may be preliminarily in a liquid form, or may be made into a solid agent by a method such as freeze-drying and dissolved before use. In the case of a solid preparation, it may be used by dissolving in purified water or physiological saline. Examples of the solid agent include tablets, granules, powders and the like. In the case of an ointment, ophthalmic petrolatum, plapeto and the like are used. These preparations can be prepared according to a known method, and in any case, it is desirable to sterilize by a known means using a membrane filter, an autoclave or the like.
[0011]
The trehalose content in the ophthalmic pharmaceutical composition of the present invention is usually 0.01% or more by weight, or in the range of about 0.01% to 30% as a final concentration. In view of the therapeutic effect and / or preventive effect of clinical symptoms of the eye in Sjogren's syndrome, 0.5 to 20% is desirable, and 2 to 10% is particularly desirable. The trehalose concentration means weight / volume (w / v) percent in the case of liquid eye cleansing agents and eye drops, and weight / weight (w / w) in the case of solid eye ointments. Percent means. In addition, since the ophthalmic pharmaceutical composition of the present invention directly contacts the ocular mucosa, the pH is preferably near neutral, particularly preferably 6.5 to 7.5 from the viewpoint of safety. The osmotic pressure is desirably adjusted to about 0.5 to 4.0 pressure ratio, and more preferably 1.0 to 1.5 pressure ratio. A known method is used for adjusting the pH and osmotic pressure.
[0012]
Trehalose has extremely stable properties in saccharides, and even if it coexists with vitamins, peptides, proteins, etc. having amino groups, it does not easily cause aminocarbonyl reaction and stabilizes those components. Have properties. Therefore, the ophthalmic pharmaceutical composition of the present invention appropriately contains one or more components selected from carbohydrates other than trehalose, electrolytes, amino acids, vitamins, lipids, pharmaceutical additives, pharmaceuticals, and the like as necessary. It can be prepared by adding. Specifically describing components other than trehalose used in the ophthalmic pharmaceutical composition of the present invention, for example, sugars such as glucose and maltose, various oligosaccharides, sugar alcohols such as mannitol and sorbitol, sodium chloride, and phosphoric acid Electrolytes such as sodium hydrogen, potassium chloride, magnesium sulfate, calcium chloride, various amino acids including glycine, alanine, thiamine hydrochloride, sodium riboflavin phosphate, pyridoxine hydrochloride, nicotinamide, folic acid, biotin, vitamin A, L-ascorbine Vitamins such as acids and α-glycosyl ascorbic acid and derivatives thereof may be mentioned, and these can be combined in combination as necessary. In particular, when the ophthalmic pharmaceutical composition of the present invention is an eye drop, other saccharides, particularly monosaccharides such as D-glucose and fructose, disaccharides such as maltose, and malt triose together with trehalose as an active ingredient. When one or two or more carbohydrates selected from the above oligosaccharides are used in combination, the therapeutic effect and / or the preventive effect on the clinical symptoms of the eye in Sjogren's syndrome due to trehalose tends to be more stable. At this time, the amount of carbohydrates other than trehalose to trehalose is usually 0.001 to 10 times, preferably 0.05 to 5 times, more preferably the amount of trehalose in terms of anhydride. , 0.05 to 2 times the range. In addition, unless the object of the present invention is impaired, additives used in ordinary ophthalmic preparations, for example, preservatives such as methyl parahydroxybenzoate, sodium dehydroacetate, benzalkonium chloride, borax, boric acid, carbonic acid Buffers such as sodium hydrogen, thickeners such as methylcellulose, carboxymethylcellulose, chondroitin sulfate, polyvinyl alcohol, pullulan, solubilizing agents such as polysorbate 80, stabilizers such as sodium edetate, sodium bisulfite, etc. One type or two or more types can be appropriately combined and blended. However, the use of preservatives such as methyl parahydroxybenzoate, sodium dehydroacetate, benzalkonium chloride, etc. may cause allergies in some patients and is therefore avoided in the present invention.
[0013]
When the ophthalmic pharmaceutical composition of the present invention is an ophthalmic ointment, a conventional ointment base can be used, and specific examples include ophthalmic white petrolatum, plastibase and the like. As the additive, liquid paraffin or the like is used. In addition, the ophthalmic pharmaceutical composition of the present invention is effective for treatment and / or prevention of clinical symptoms of the eye in Sjogren's syndrome, for example, steroid hormones such as methylprednisolone and anti-inflammatory agents such as tetracycline, if necessary, Antibiotics such as penicillin G, immunosuppressive agents such as cyclosporine, immunomodulators, analgesics, autologous serum, hyaluronic acid and other pharmaceuticals may be used in appropriate combination.
[0014]
The usage and dosage of the ophthalmic pharmaceutical composition of the present invention can be adjusted as appropriate according to the symptoms of the patient. In the case of eye drops, usually about 1 to 4 drops (about 0.025 ml to about 0.1 ml) are used once to about 10 times a day. In the case of an eye cleanser, usually put about 5 ml of the cleanser into a special container that can adhere to the face line around the eye, press it against the eye, turn the head backwards, face up, Blink your eyes several times and use once to 6 times a day, or use a washing bottle etc. once to 5 times a day to wash your eyes with 1 ml to 5 ml once . In the case of an eye ointment, an appropriate amount is usually applied to the conjunctival sac once to three times a day. Hereinafter, although an Example is given and this invention is used, this invention is not limited to this.
[0015]
[Example 1]
<Eye drops>
Α, α-trehalose 3.5g in 100ml
Sodium chloride 0.4g
Potassium chloride 0.15g
Sodium dihydrogen phosphate 0.2g
Borax 0.15g
Sterilized purified water Appropriate total volume 100ml
Using the above ingredients, a sterile preparation is prepared by a known method to give an eye drop. The pH is 7.3.
[0016]
[Example 2]
<Eye drops>
Α, α-trehalose in 100 ml 3.7 g
Sodium chloride 0.4g
D-glucose 0.04
Sterilized purified water Appropriate total volume 100 ml
Using the above ingredients, a sterile preparation is prepared by a known method to give an eye drop. The pH is 7.2.
[0017]
[Example 3]
<Eye drops>
7.0 g of α, α-trehalose in 100 ml
D-glucose 0.04
Sterilized purified water Appropriate total volume 100ml
Using the above ingredients, a sterile preparation is prepared by a known method to give an eye drop. The pH is 7.3.
[0018]
[Example 4]
<Eye drops>
Α, β-trehalose 0.5 g in 100 ml
Sodium chloride 0.6g
Potassium chloride 0.15g
Sodium dihydrogen phosphate 0.2g
Borax 0.15g
Benzalkonium chloride 0.005g
Sterilized purified water Appropriate total volume 100ml
Using the above ingredients, a sterile preparation is prepared by a known method to give an eye drop. The pH is 7.0.
[0019]
[Example 5]
<Eye cleaner>
0.1 g of α, α-trehalose in 100 ml
Sodium chloride 0.4g
Potassium chloride 0.05g
Calcium chloride 0.01g
Magnesium sulfate 0.01g
Sodium citrate 0.05g
Sodium bicarbonate 0.2g
Maltose 0.15g
1N hydrochloric acid appropriate amount sterilized purified water appropriate amount total amount 100ml
Using the above components, a sterile preparation is prepared by a known method to obtain an eye cleanser.
The pH is 7.2.
[0020]
[Example 6]
<Eye ointment>
Α, α-trehalose 3.5g in 100g
Liquid paraffin 5.0g
White vaseline for ophthalmology Appropriate amount 100g
Using the above components, a sterile preparation is prepared by a known method to obtain an eye ointment.
[0021]
[Test example]
<Test method>
In order to confirm the therapeutic effect of trehalose on clinical symptoms of eyes in Sjogren's syndrome, age 22 years old or older, diagnosed as Sjogren's syndrome and developing clinical symptoms of foreign body sensation, burning sensation, pruritus in both eyes A treatment test was conducted with 10 male and female patients 65 years old (average age 45 years). For the test, reagent grade α, α-trehalose (purity 99% or more, sold by Hayashibara Biochemical Laboratories Co., Ltd.), final concentrations of 3.5% (w / v) and 7.5 (w / v) % Was dissolved in physiological saline and sterilized with a membrane filter having a pore size of 0.22 μm, and then pyrogen was removed by a conventional method. As a control, a similar preparation was used except that α, α-trehalose was not dissolved. One eye for each of five male and female patients, 3.5 (w / v)% α, α-trehalose solution, and the other eye as a control, physiological saline for 1 day, when waking up, noon, evening 4 drops before going to bed, 2 drops to 3 drops (about 0.05 ml to about 0.075 ml) once a day for 4 weeks, before the start of the test and at the end of the test. The degree of pruritus was examined and examined. A similar test was carried out on the remaining 5 patients each, male and female, using 7.5 (w / v)% α, α-trehalose solution.
[0022]
<Result>
Eyes instilled with a solution of α, α-trehalose have a marked therapeutic effect on subjective symptoms. At any α, α-trehalose concentration, 9 out of 10 people feel eye irritation, burning, itching All of the feeling improved or disappeared. This therapeutic effect persisted for several days after the end of the study. On the other hand, as an objective finding, reduction of keratoconjunctival erosion stained with fluorescein and rose bengal was observed in all 10 people, and improvement in lacrimal gland layer destruction time was observed in 9 out of 10 people. It was. On the other hand, in the case of the control, the clinical symptoms tended to be temporarily reduced immediately after the instillation, but the symptoms reappeared before the next instillation, and no improvement in the symptoms was observed. After completion, the symptoms remained the same as those before the start of the study. In addition, no improvement in objective findings was observed. During and after the study, all 20 patients showed no exacerbation of clinical symptoms or other possible side effects in the eyes instilled with α, α-trehalose solution.
[0023]
【Effect of the invention】
Since the ophthalmic pharmaceutical composition of the present invention is highly effective in improving the clinical symptoms of the eye in Sjogren's syndrome, it can be advantageously used for its treatment and / or prevention. In addition, since trehalose itself is a safe and stable carbohydrate, it is a carbohydrate that can be used continuously for a long period of time without any problems of side effects.

Claims (1)

It contains trehalose obtained by a method in which a non-reducing saccharide-forming enzyme and trehalose-free enzyme are allowed to act on a partial starch hydrolyzate as an active ingredient, and does not contain pyrogen and benzalkonium chloride as a preservative. Liquid ophthalmic eye drops for the treatment and / or prevention of clinical symptoms of the eye in Sjogren's syndrome .