JP4278473B2 - Novel pharmaceutical composition for treating or preventing dry eye - Google Patents

Description

The present invention relates to treatment / prevention of intractable eye diseases such as eye damage caused by dry eye and contact lenses.

In recent years, there are many opportunities to overuse the eyes surrounded by televisions, personal computers, etc., and the number of people who tend to get tired easily or feel some discomfort in the eyes is increasing. Discomfort in the eyes, such as tired eyes, is often very inconvenient not only in work but also in daily life. Recently, dry eyes have been attracting attention as a cause of such fatigue eyes. Although dry eye is estimated to affect more than 8 million patients in Japan, it is a disease with low recognition as a disease.

Dry eye, in which unpleasant symptoms appear due to dryness of the eyes, is a disease that causes damage to the surface of the eye due to decreased tears or qualitative changes. When tears are deficient, the eyes become dry and vulnerable. In severe cases, the surface of the eye may have countless scratches. Mild symptoms may heal over time, but if the symptoms are severe or persist forever, the surface of the eye may be damaged. In such a case, since pathogens are infected from the wound, or the wound becomes deep and there is a concern about a decrease in visual acuity, it is necessary to consult a medical institution.

The eye is an important organ that is necessary to obtain a lot of information by “seeing” it. When tears decrease and dry eyes occur, various symptoms appear, making it difficult to see things comfortably. When it gets worse, an eye disease called addictive corneal epithelial detachment occurs. In particular, seasonal “drying + drying by heating in the office”, “accumulation of stress due to computer work”, “reduction of“ Mabataki ”by staring at the display with heat,” “for eye strain” If there is no rest, even if the eyes are overworked and tears decrease and “mabataki” occurs, the eyes cannot be moistened with tears. It is not uncommon for dry eyes to cause blindness, but if it becomes severe, countless wounds may occur on the surface of the eye, causing damage to the cornea and conjunctiva, resulting in a situation where vision is reduced and the eye cannot be opened. Even when contact lenses are used, dry eye may occur frequently and eventually cannot be worn.

Also, dry eye may occur as a symptom of systemic illness. A typical example is Sjogren's syndrome. This is a disease in which the lacrimal glands that secrete tears are gradually destroyed by autoimmunity, resulting in a decrease in tear production. Not only the lacrimal glands but also the salivary glands are destroyed. When you eat, you need water. In addition, dry eye may be associated with rheumatoid arthritis, collagen disease and diabetes. On the other hand, side effects of tranquilizers and various other drugs can reduce tear volume. Also, since dry eye may occur depending on the type of eye drops and the number of eye drops, consult with a doctor if symptoms such as dry eyes or tired eyes appear after starting new drugs or starting new eye drops. There is a need.

In general, in the case of light dry eyes, eye drops having a component similar to tears, which is called artificial tears, are used as needed for the purpose of replenishing less tears. Again, there are various types of artificial tears, and it is necessary to look for artificial tears that are most suitable for the patient. In addition, when the feeling of dryness is strong and the number of eye drops increases, it is also necessary to consider eye drops that do not contain preservatives. Furthermore, when there are scratches on the surface of the black eye (cornea) or white eye (conjunctiva), and there is a feeling of strangeness or pain when blinking, an eye ointment may be used as a lubricant together with eye drops. In the case of severe dry eye that is not effective even after such treatment, the tears are closed because the remaining tears remain on the surface of the eyes for as long as possible. Give treatment. Another treatment is to wear glasses specially developed to prevent dry tears.

Cevimeline hydrochloride was approved in 2002 as an internal medicine for dry mice with Sjögren's syndrome, and began to be used in medical institutions, but its application to dry eyes has not been successful. Anethole trithione, which is an oral preparation that promotes bile secretion, also has a salivary secretion promoting action, so it is also used to improve the decrease in salivary secretion associated with Sjogren's syndrome. However, these drugs do not act to improve autoimmunity against salivary glands and lacrimal glands, which are common etiologies in dry mice and dry eyes. In other words, at present, there is no drug that can be safely improved to dry eye by internal use or injection. Therefore, pharmaceuticals or processed foods that are highly safe and can improve dry eye have been sought for many years.

It is a problem to be solved by the present invention to find a substance that can improve dry eye safely and without reducing the quality of life. As described above, dry eye occurs for various reasons. Sjogren's syndrome, which develops autoimmunity that destroys the lacrimal glands that produce tears, is known to cause dry eye, but rheumatoid arthritis, collagen disease, and type II diabetes often accompany dry eye. In addition, it is said that the attachment and detachment of computer and television displays and contact lenses also induce dry eyes, but the causal relationship is not clear. In any case, since dry eye is not a life-threatening disease, it is necessary that the therapeutic or food for dry eye be a substance that can improve the pathology without degrading the quality of life at all. This is a very difficult task.

The present inventors have repeated trial and error in order to solve the problem, and have found that lactoferrin clinically improves dry eye and have completed the present invention. The lactoferrin used in the present invention includes lactoferrin extracted from milk and recombinant human lactoferrin prepared by genetic engineering. The hint of the present invention is an experiment having an effect of significantly increasing the pH of saliva when 300 mg of milk lactoferrin is orally administered to a healthy person once a day for one week. Since saliva pH is proportional to the amount of saliva produced, this fact means that lactoferrin increased saliva production in healthy individuals. Since the test subjects in this study are healthy, it does not mean that milk lactoferrin increases saliva production in sick people suffering from dry mice. However, oral administration of milk lactoferrin improves allergic rhinitis, chronic bronchial asthma, rheumatoid arthritis, urticaria, etc., which are considered to be autoimmune, so milk lactoferrin administered orally introduces immune tolerance against autoimmunity, It is thought to have an effect of improving chronic inflammation. In other words, it was estimated that lactoferrin would also increase the production of tears by acting on the lacrimal gland from the effect of increasing saliva production and the introduction of immune tolerance for healthy individuals.

There is no suitable experimental animal pathology model for dry eye. Therefore, it is necessary to rely on human experiments to determine the usefulness by directly administering to humans. Therefore, 5 volunteers suffering from moderate to severe dry eye were orally administered with 2-6 tablets of milk lactoferrin per day, 2-3 times daily for 1 month, and the effect on dry eye was examined. An enteric preparation containing 100 mg of milk lactoferrin in one tablet was used. As a result, as shown in the examples, dry eye was remarkably improved 3 days after the start of oral administration and 7 days at the latest. In addition, there were three volunteers who recovered their vision, but it seems that this is because it became possible to stare at one place for a long time because dry eye was improved and it was no longer necessary to do the mabataki frequently.

The embodiments of the present invention are mainly oral preparations and injections, but can also be put to practical use in dosage forms such as suppositories, patches, drops, gargles, eye drops, and troches. Lactoferrin is a polymer having a molecular weight of around 80,000 daltons, and is relatively unstable. In the stomach, lactoferrin is easily degraded by pepsin under acidic conditions. For example, an oral preparation is preferably a preparation in which the surface of a lactoferrin granule or tablet is coated with an enteric film that does not dissolve in the stomach but flows into the intestine and dissolves. More specifically, it is as follows. Milk-derived lactoferrin lyophilized powder has a very low bulk specific gravity and is difficult to be directly compressed into tablets. Moreover, since it is unstable at moisture and high temperature, it is desirable to formulate it in a dry state. Therefore, lactoferrin is mixed with excipients, binders and disintegrants, and the mixture is pressure-molded with a slag machine to form a thin large flat disk, which is crushed and filtered to prepare grains of a certain size. The granules can be covered with an enteric coating, and a certain amount can be filled into a hard capsule to produce a product. In the case of commercialization as a tablet, a lubricant can be added to the granule for tableting, and the tablet can be covered with an enteric coating for commercialization.

Examples of excipients used in producing the enteric preparation of the present invention include lactose, sucrose, maltitol, glucose and other monosaccharides or disaccharides, corn starch, starches such as potato starch, crystalline cellulose, and inorganic substances. Examples include light silica gel, synthetic aluminum silicate, magnesium aluminate metasilicate, and calcium hydrogen phosphate. Examples of the binder include starches, carboxymethyl cellulose (CMC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose-sodium salt, and polyvinylpyrrolidone. Examples of disintegrating agents used for the purpose of disintegrating them into primary particles in the lower gastrointestinal tract include starch, carboxymethylcellulose-sodium salt, carboxymethylcellulose-calcium salt, croscarmellose sodium, and carboxymethyl starch sodium. . As a film agent for enteric coating of tablets and grains, hydroxypropyl methylcellulose phthalate, carboxymethylethylcellulose, cellulose acetate phthalate, methacrylic acid copolymer, zein contained in corn kernel And shellac that dissolves in the alkaline 'region.

The preparation of the present invention generally contains about 0.1 mg to about 100,000 mg, preferably about 1 mg to about 50,000 mg, more preferably about 10 mg to about 10,000 mg once a day as an active ingredient. Or in divided portions can be administered to patients in need of treatment or improvement of condition with the formulations of the invention. The dosage and dosage form can be individually determined according to the age, weight, pathological condition and purpose of administration of the patient to be administered.

Example 1: Lactoferrin bulk powder extracted from milk (purity 97% as protein, lactoferrin content 93% in protein) 30 kg microcrystalline cellulose (trade name; Avicel) 57.5 kg, dextrin 2.4 kg, magnesium stearate 0 .1 kg was pulverized with a mixer to obtain a powder passing through 100 mesh. This mixed powder was compressed into tablets with a diameter of 9 mm and a weight by a tableting machine. Next, the tablet is put into a coating machine, and an enteric coating solution consisting of 9% zein, 1% palmitic acid monoglyceride, 75% ethanol and 15% pure water is sprayed to give an enteric coating of 10% by weight of the tablet. Product.

Example 2: 48-year-old female: Wearing contact lenses since teenage for myopia. However, when I was 35 years old, my eyes hurt, so I was diagnosed with addictive corneal epithelial detachment due to dry eye. Since then, eye drops cannot be released due to eye pain. When the oral enteric preparation containing 100 mg of milk lactoferrin prepared in Example 1 from March 19, 2003 was divided into two morning and evening doses, the eye pain disappeared on the third day, and instillation was accompanied accordingly. The drug is no longer needed. Furthermore, the oral administration of the lactoferrin enteric preparation was continued, and an ophthalmologist was diagnosed in the second week. In addition, contact lenses that could not be worn for more than 30 years can be used again.

Example 3: A 55-year-old woman diagnosed with dry eye and having a visual acuity of 0.6 left and 0.5 right took 2 tablets of Example 1 every day for 2 months. After 1 week, dry eye was remarkably improved and visual acuity recovered to 1.0 on both the left and right sides. The headache that had been plagued for 20 years from around 3 days has disappeared. The headache had a meds that worked well, but switched to a less meds with side effects, but had little effect. However, since headache disappeared when two enteric lactoferrin enteric tablets were taken a day, no headache medicine is currently available. He also has a history of being depressed and having been taken to a hospital by calling an ambulance twice for hyperventilation syndrome. There was a social dance meeting on July 3rd, but it wasn't as intense as before. One month after oral administration of lactoferrin, serum triglyceride decreased greatly from 316 mg / dl to 85 mg / dl.

Example 4: The dry eye of a 45-year-old woman improved markedly by taking the tablet of Example 1 6 tablets 7 days a day. When she was 18 years old, she was pointed to myopia (left 0.5, right 0.3) by optometry and began to wear contact lenses. However, when I was 30 years old, I had a terrible dry eye, and my pain started running when the contact lenses were worn. Dry eyes gradually deteriorated, and at the age of 40, contact lenses could not be worn due to habitual corneal epithelial detachment. Eyeballs were dry and painful, so they had to blink frequently, and it was necessary to carry eye drops. However, when three tablets of Example 1 were taken immediately before breakfast and dinner, dry eye improved after one week, and eye drops were no longer required.

Example 5: The visual acuity of a man (46 years old) whose golf score had decreased due to dry eye was greatly improved by taking 3 tablets of Example 1 a day. At the age of thirty, he played golf links with a score of 70, but when he was forty, his eyesight decreased due to dry eyes and the undulation of the lawn could not be seen. There were many failures when I hit the heart. From May 1, 2003, 3 tablets per day of Example 1 were taken before each meal. The biggest change I noticed in the first week of internal use is that my eyesight has recovered and I can see the green undulation again. It became visible and the score of golf was greatly improved, and the score of 80 cars came out from the latter half of 70 cars again. Also, when putting a putter, it was a big change that happened when I started taking lactoferrin enteric preparations.

Example 6: The visual acuity of a 53-year-old woman who had been diagnosed with dry eye dramatically improved the tablet of Example 1 six months a day after one month. The visual acuity just before taking the lactoferrin tablet on April 19, 2003 was 0.6 on the left and 0.8 on the right. Two tablets of enteric lactoferrin tablets (containing 100 mg of lactoferrin extracted from milk in one tablet) were taken at 10:00, 15:00, and 20:00 three times a day without chewing. In the visual acuity measurement, the visual acuity improved to 1.2 on both the left and right sides. This improvement in visual acuity seems to be the result of the frequent loss of mabataki due to the improvement of dry eye.

Claims (3)

Characterized in that it contains lactoferrin as an active ingredient, dosage forms other than eye drops, dry eye, addictive corneal abrasion, or pharmaceutical composition for treating or preventing eye disorders by contact lenses.   The pharmaceutical composition according to claim 1, which is an oral preparation or an injection.   The pharmaceutical composition according to claim 2, which is an oral preparation.