TW202103684A - Nano eye drops and manufacturing method thereof - Google Patents

Abstract

The present invention relates to nano eye drops and manufacturing method thereof. The method includes the steps of: mixing monosodium glucose co-transporter inhibitor (e.g., dapagliflozin) with hydroxypropyl-[beta]-cyclodextrin and polyvinylpyrrolidone to form a mixture, wherein a weight ratio of the monosodium glucose is between 0.8 and 1.2, a weight ratio of the hydroxypropyl-[beta]-cyclodextrin is between 16 and 24, and a weight ratio of the polyvinylpyrrolidone is between 16 and 24, and wherein the powder of the above three components has a particle diameter of between 100 nm and 1000 nm; adding the mixture in ethanol and stirring to evenly dissolve the mixture in ethanol, and then removing the ethanol to obtain a uniformly-mixed powder; and dissolving the uniformly-mixed powder in eye drop excipient to form the nano eye drops. The nano eye drops of the present invention are effective for treating ocular cataract diseases caused by diabetes.

Description

Nano eye drops and its manufacturing method

The present invention relates to a nano-eye drops and a manufacturing method thereof, and particularly refers to the invention of preparing sodium-glucose cotransporter inhibitors (such as dapagliflozin, Dapagliflozin) for the treatment of diabetes into nano-eye drops, with Treatment of ocular cataracts caused by diabetes.

Several new anti-diabetic drugs have appeared in the 21st century. One is sodium-glucose cotransporter (SGLT)-2 inhibitors, among which dapagliflozin (Dapagliflozin) is the first of these new therapies. Treat patients with type 2 diabetes. Dapagliflozin (Dapagliflozin) inhibits the transporter SGLT2 in the kidney, reduces kidney glucose reabsorption, reduces urine sugar excretion and blood sugar levels, and achieves the effect of treating type 2 diabetes.

In addition, it has been proven that diabetes and other metabolic diseases can cause cataracts, and 50% of the global blind population is caused by cataracts. In recent years, relevant studies have found that the age group of metabolic disease patients with cataracts has a downward trend.

Based on the above problems, the present invention intends to make sodium-glucose cotransporter inhibitor into eye drops, so that the sodium-glucose cotransporter inhibitor can directly act on the eyes to reduce the absorption of sugar by the eye, and can reduce glycosylated hemoglobin to treat diabetes. Of cataracts.

In this regard, the present invention proposes a method for manufacturing nano-eye drops, which includes the following steps:

Take the monosodium glucose cotransporter inhibitor between 0.8 and 1.2 parts by weight, the monohydroxypropyl-β-cyclodextrin between 16 and 24 parts by weight, and the weight between 16 and 24 parts A polyvinyl pyrrolidone between the three, the three are mixed into a mixture, wherein the powder particle size of the above-mentioned components is between 100 nanometers and 1,000 nanometers. The mixture is dissolved in ethanol, stirred to make it uniformly dissolved, and then the ethanol is removed to obtain a uniformly mixed powder. The uniformly mixed powder is dissolved in an eye drop excipient to become a nano eye drop.

Further, the sodium-glucose cotransporter inhibitor is dapagliflozin.

Further, the mixing weight ratio of the dapagliflozin, the hydroxypropyl-β-cyclodextrin and the polyvinylpyrrolidone is 1:20:20.

Furthermore, the powder particle size of the dapagliflozin, the hydroxypropyl-β-cyclodextrin and the polyvinylpyrrolidone is less than 200 nanometers.

Furthermore, when the mixture is dissolved in the ethanol, it is stirred with a magnet.

Furthermore, the eye drops excipient contains a hydrophilic carrier.

The present invention further proposes a nano eye drop, which is made by using the aforementioned nano eye drop manufacturing method.

According to the above technical features, the following effects can be achieved:

1. The nano-eye drops of the present invention can directly act on the eyes of the sodium glucose cotransporter inhibitor to reduce the absorption of sugar by the eyes, and can reduce glycosylated hemoglobin to treat cataracts caused by diabetes.

2. The sodium glucose cotransporter inhibitor, hydroxypropyl-β-cyclodextrin and polyvinylpyrrolidone are mixed and dissolved in ethanol and stirred with a magnet to obtain a uniformly mixed powder, which can be uniformly dispersed in eye drops .

3. Mixing sodium-glucose cotransporter inhibitor, hydroxypropyl-β-cyclodextrin and polyvinylpyrrolidone with nano-powder can increase the absorption effect of the eye to obtain better therapeutic effect.

Based on the above technical features, the main effects of the nano-eye drops and the manufacturing method of the present invention will be clearly demonstrated in the following examples.

Referring to the first figure, the manufacturing method of nano eye drops in this embodiment includes:

Take the monosodium glucose cotransporter inhibitor between 0.8 and 1.2 parts by weight, the monohydroxypropyl-β-cyclodextrin between 16 and 24 parts by weight, and the weight between 16 and 24 parts A polyvinylpyrrolidone between the three, the three are mixed into a mixture, wherein the powder particle size of the above-mentioned components is between 100 nanometers and 1000 nanometers. In this embodiment, the sodium glucose cotransporter inhibitor uses dapagliflozin, and the dapagliflozin, the hydroxypropyl-β-cyclodextrin and the polyvinylpyrrolidone The mixing weight ratio is 1:20:20, and the powder particle size of the above-mentioned components in this embodiment is less than 200 nanometers.

The mixture is dissolved in ethanol, stirred to make it uniformly dissolved, and then the ethanol is removed to obtain a uniformly mixed powder. Specifically, when the mixture is dissolved in the ethanol, a magnet is placed, and after stirring at a rotation speed of 1200 rpm for 1 hour, the above-mentioned liquid is drained by a vacuum concentrator into a powder form. The dissolving in ethanol and stirring with the magnet help to mix the powders of the ingredients uniformly.

The uniformly mixed powder is dissolved in an eye drop excipient to form a nano eye drop, and the eye drop excipient includes the components of the conventional eye drop. Wherein, the eye drops excipient further includes a hydrophilic carrier to facilitate eye absorption.

The experiment was performed with 6-week-old male Sprague-Dawley (SD) rats (300±15 g), which were purchased from the National Laboratory Animal Center and placed in the animal room of the Kaohsiung Veterans General Hospital. In addition, rats raised in the animal room of Kaohsiung Veterans General Hospital ate in the SPF room. SPF facilities are designed to keep rodents in an environment free of certain infectious organisms that are disease-causing and/or capable of interfering with research targets. The rats are kept in individual cages in a light control room (12 hours light/12 hours dark cycle), and the temperature is maintained between 23°C and 24°C. The rats were fed normal rat feed (Purina; St. Louis, MO) and free drinking water.

Streptozotocin (STZ) is a glucosamine derivative, a toxin isolated from Streptomyces acromogenes. It has the effect of destroying the β-cell of the islets of the pancreas. It can be used as one of the drugs for inducing diabetes. This animal model was proposed by Ohno et al. (1998). The advantage of this animal model is that this animal retains the characteristics of the evolutionary process of primates, so its characteristics are smaller than that of humans, and the induction method is simple. The induction rate is lower in males. Animals can be as high as 100%. This animal model is helpful for the study of diabetes type II-insulin-dependent (IDDM) and other types of diabetes. Therefore, this experiment used the animal model of STZ-induced rats (SD rats), with a single dose of 65 mg/kg intraperitoneally (ip) rats, after 2 days, the fasting (non fasted) blood glucose concentration ≥ 200 mg/ dl is an animal model that successfully induces diabetes. In order to improve the welfare of animals, insulin (1 IU/kg) is injected into the intraperitoneal cavity once a week to keep the animals in a comfortable living condition. The glycated blood color number (HBA1c) and the slit lamp were used to detect the degree of cataract in the rat eyes every two weeks. When the degree of cataract in the rat reached the level of aerosolization as assessed by the ophthalmologist, the aforementioned nano-eye drops (Dapagliflozin) were given treatment.

As shown in the second and third figures, the detection of glycosylated hemoglobin (HbA1c) is a simple and practical method for clinicians to evaluate the blood sugar control of diabetic patients, and to adjust drugs or change the direction of treatment. Normal non-diabetic HbA1c is 3.5-5.5%, and those with well-controlled diabetes have a value of about 6.5%. Now it is generally hoped to be controlled below 7%, and if it exceeds 8%, it is a warning value. In the second figure, it is shown that the glycated hemoglobin (HbA1c) of cataract rats treated with the nano-eye drops of the present invention is significantly lower than that of untreated cataract rats, and the longer the treatment time, the lower the glycated hemoglobin (HbA1c) The more obvious the degree. The third figure shows that there is no significant difference in body weight between treated and untreated cataract rats, which means that the treatment did not produce significant side effects.

As shown in the fourth figure, during the 10 weeks from the beginning of the experiment to the end, we used a slit lamp to check the development of cataract after STZ injection every two weeks, and gave medication when the degree of cataract was the first degree of turbidity. Observation found that untreated cataract rats reached the first level in the fourth week, and the cataract rats that were expected to be treated would reach the first level in the fifth week, so the eye drops were started at the fifth week. Do treatment. The results showed that there was no significant difference in the cataract index between the cataract rats treated for one week and the untreated cataract rats. However, as time goes by, the cataract index of untreated cataract rats is 2 to 3 at 8 to 10 weeks, while the cataract index of cataract rats treated with administration is 1 to 2. Therefore, it can be seen that the use of the nano-eye drops of the present invention to treat cataracts caused by diabetes can significantly slow down the deterioration of cataracts.

Based on the description of the above embodiments, when one can fully understand the operation and use of the present invention and the effects of the present invention, but the above embodiments are only the preferred embodiments of the present invention, and the implementation of the present invention cannot be limited by this. The scope, that is, simple equivalent changes and modifications made according to the scope of the patent application of the present invention and the description of the invention, are all within the scope of the present invention.

no

[The first figure] is a flowchart of the manufacturing method of the present invention.

[The second graph] is a bar graph showing changes in the value of glycated hemoglobin in the eyes of untreated cataract mice and cataract mice treated with the eye drops of the present invention in the examples of the present invention.

[The third figure] is a bar graph showing the weight changes of untreated cataract mice and cataract mice treated with the eye drops of the present invention in the examples of the present invention.

[Fourth graph] is a bar graph showing changes in cataract index of untreated cataract mice and cataract mice treated with the eye drops of the present invention in the examples of the present invention.

Claims (7)

A method for manufacturing nano eye drops, including the following steps: Take the monosodium glucose cotransporter inhibitor between 0.8 and 1.2 parts by weight, the monohydroxypropyl-β-cyclodextrin between 16 and 24 parts by weight, and the weight between 16 and 24 parts A polyvinylpyrrolidone between the three, the three are mixed into a mixture, wherein the powder particle size of the above-mentioned ingredients is between 100 nm and 1000 nm; the mixture is dissolved in ethanol and stirred to make it uniformly dissolved. Then remove the ethanol to obtain a uniformly mixed powder; The uniformly mixed powder is dissolved in an eye drop excipient to become a nano eye drop. According to the method for manufacturing nano-eye drops described in item 1 of the scope of patent application, the sodium-glucose cotransporter inhibitor is dapagliflozin. The method for manufacturing nano-eye drops as described in item 2 of the scope of patent application, wherein the mixing weight ratio of the dapagliflozin, the hydroxypropyl-β-cyclodextrin and the polyvinylpyrrolidone is 1:20 :20. The method for manufacturing nano-eye drops as described in item 2 of the scope of patent application, wherein the powder particle size of the dapagliflozin, the hydroxypropyl-β-cyclodextrin and the polyvinylpyrrolidone is less than 200 nanometers Meter. According to the method for producing nano-eye drops described in item 1 of the scope of patent application, when the mixture is dissolved in the ethanol, the mixture is stirred with a magnet. According to the method for manufacturing nano-eye drops described in item 1 of the scope of patent application, the eye drops excipient includes a hydrophilic carrier. A nano eye drop is made by using the method for manufacturing nano eye drop as described in any one of items 1 to 6 of the scope of patent application.

Images