TWI756547B - 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-β-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-β-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 manufacturing method thereof

The present invention relates to a kind of nanometer eye drops and its manufacture method, especially refers to the invention that the sodium glucose cotransporter inhibitor (such as dapagliflozin, Dapagliflozin) used for treating diabetes is made into nanometer eye drops. Treatment of ocular cataracts caused by diabetes.

The twenty-first century has seen several new antidiabetic drugs, one being a sodium-glucose cotransporter (SGLT)-2 inhibitor, of which Dapagliflozin is the first of this new class of treatments for Treatment of patients with type 2 diabetes. Dapagliflozin has the effect of treating type 2 diabetes by inhibiting the transporter SGLT2 in the kidney, reducing the reabsorption of glucose in the kidney, and reducing the excretion of urine and blood sugar.

In addition, it has been confirmed that metabolic diseases such as diabetes can cause cataracts, and 50% of the global blind population is caused by cataracts. In recent years, related studies have found that the age group of patients with metabolic diseases has a downward trend in developing cataracts.

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

Therefore, the present invention proposes a method for manufacturing nanometer eye drops, comprising 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 part by weight between 16 and 24 A polyvinyl pyrrolidone is placed in between, and the three are mixed into a mixture, wherein the powder particle size of the above-mentioned components is between 100 nanometers and 1000 nanometers. The mixture was dissolved in an ethanol, stirred to dissolve uniformly, and then the ethanol was removed to obtain a uniformly mixed powder. The uniformly mixed powder was dissolved in an eye drop excipient to obtain 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.

Further, the powder particle size of the Dapagliflozin, the hydroxypropyl-β-cyclodextrin and the polyvinylpyrrolidone is less than 200 nm.

Further, while the mixture was dissolved in the ethanol, it was stirred with a magnet.

Further, the eye drop vehicle comprises a hydrophilic carrier.

The present invention further provides a nano eye drop, which is prepared by using the above-mentioned manufacturing method of the nano eye drop.

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 in the eyes, and can reduce the glycosylated hemoglobin, so as to treat the effect of cataract caused by diabetes.

2. Mix and dissolve sodium glucose cotransporter inhibitor, hydroxypropyl-β-cyclodextrin and polyvinylpyrrolidone in ethanol and stir with a magnet to obtain a uniform 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, so as to obtain a better therapeutic effect.

[Figure 1] is a flow chart of the manufacturing method of the present invention.

[Fig. 2] is a bar graph showing the changes of the glycated hemoglobin value in the eyes of the untreated cataract mice and the cataract mice treated with the eye drops of the present invention with time in the example of the present invention.

[Figure 3] is a bar graph of changes in body weight over time of untreated cataract mice and cataract mice treated with the eye drops of the present invention in the example of the present invention.

[FIG. 4] is a bar graph showing the changes of cataract index over time in the untreated cataract mice and the cataract mice treated with the eye drops of the present invention in the example of the present invention.

In view of the above technical features, the main effects of the nano eye drops of the present invention and the manufacturing method thereof will be clearly presented in the following examples.

Referring to the first figure, the manufacturing method of the nano eye drops of the present embodiment includes: taking the monosodium glucose cotransporter inhibitor between 0.8 and 1.2 parts by weight, and taking a part by weight between 16 and 24 parts Hydroxypropyl-β-cyclodextrin, and a polyvinyl pyrrolidone between 16 and 24 parts by weight, the three are mixed into a mixture, wherein the powder particle size of the above components is between 100 between nanometers and 1000 nanometers. In this embodiment, the sodium glucose cotransporter inhibitor uses Dapagliflozin, and the dapagliflozin, the hydroxypropyl-β-cyclodextrin and the polyvinylpyrrolidone are The mixing weight ratio is 1:20:20, and the powder particle size of each of the above components in this embodiment is less than 200 nanometers.

The mixture was dissolved in an ethanol, stirred to dissolve uniformly, and then the ethanol was removed to obtain a uniformly mixed powder. Specifically, when the mixture is dissolved in the ethanol, a magnet is placed, and the mixture is stirred at a rotational speed of 1200 rpm for 1 hour, and then the above-mentioned liquid is dried by a vacuum concentrator into powder. Dissolving in ethanol and stirring with the magnet will help the powder of each component to be uniformly mixed.

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

The experiments were performed with 6-week-old male Sprague-Dawley (SD) rats (300±15 g), which were purchased from the National Laboratory Animal Center and housed in the animal room of Kaohsiung Veterans General Hospital. In addition, rats housed in the animal room of Kaohsiung Veterans General Hospital were fed in a specific pathogen-free (SPF) room. SPF facilities are designed to keep rodents in an environment free of disease-causing and/or certain infectious organisms capable of interfering with research objectives. Rats were kept in individual cages in a light-controlled room (12 hr light/12 hr dark cycle) maintained at a temperature between 23°C and 24°C. Rats were fed normal rat chow (Purina; St. Louis, MO) and water ad libitum.

200mg/dl則屬於誘導糖尿病成功的動物模式。為了提申動物福祉，每周一次腹腔注射胰島素(1IU/kg)，使動物維持舒適的生活狀態。每兩周檢測一次糖化血色數(HBA1c)與使用裂隙燈檢測大鼠眼睛白內障程度。待大鼠白內障程度經眼科醫師評估達到1級霧化程度，給予前述奈米眼藥水(Dapagliflozin)治療。 Streptozotocin (STZ) is a glucosamine derivative, a toxin isolated from Streptomyces acromogenes, which has the effect of destroying pancreatic islet β-cell, and can be used as one of the drugs for inducing diabetes. The animal model was proposed by Ohno et al. (1998). The advantages of this animal model are that the animal retains the characteristics of the primate evolution process, so its characteristics are less different from those of humans, and the induction method is simple, and the induction rate is lower in males. Animals can be as high as 100%. This animal model facilitates the study of diabetes type 2-insulin-dependent (IDDM) and other types of diabetes. Therefore, in this experiment, the animal model of STZ induced rats (SD rats) was injected intraperitoneally (ip) with a single dose of 65 mg/kg. After 2 days, the blood glucose concentration of non-fasted was detected.

200mg/dl is a successful animal model for inducing diabetes. In order to improve the animal's well-being, insulin (1IU/kg) was injected intraperitoneally once a week to keep the animals in a comfortable living state. The glycated hemoglobin (HBA1c) was detected every two weeks and the cataract degree of the rat eyes was detected by slit lamp. When the cataract degree of the rats reached the first-level atomization degree as assessed by an ophthalmologist, the aforementioned nano eye drops (Dapagliflozin) were given for treatment.

Referring to Figures 2 and 3, the detection of glycated hemoglobin (HbA1c) is a simple and practical method for clinicians to assess blood sugar control in diabetic patients, and to adjust drugs or change the direction of treatment. Normal non-diabetic HbA1c is 3.5-5.5%. For those with well-controlled diabetes, the value is about 6.5%. Now, it is generally hoped that it can be controlled below 7%. If it exceeds 8%, it is a warning value. The second figure shows that the glycated hemoglobin (HbA1c) of the cataract rats treated with the nano eye drops of the present invention is significantly lower than that of the untreated cataract rats, and the longer the treatment time, the lower the glycated hemoglobin (HbA1c) the more obvious the degree. In the third figure, it is shown that there was no significant difference in body weight between treated and untreated cataract rats, indicating that the treatment did not produce major side effects.

Referring to Figure 4, during the 10-week period from the beginning to the end of the experiment, we used a slit lamp every two weeks to examine the development of cataracts after STZ injection, and gave drug treatment when the cataract degree was first-degree opacity. It was observed that the cataract degree of the untreated cataract rats reached the first grade at the fourth week, and the cataract index of the cataract rats treated with administration was expected to reach the first grade at the fifth week, so eye drops were started at the fifth week. do treatment. It was found that there was no significant difference in the cataract index between cataract rats treated for one week and untreated cataract rats. But over time, untreated The cataract rats of 8 to 10 weeks had a cataract index of grade 2 to 3, while the cataract rats treated with drug treatment had a cataract index of grade 1 to 2. Therefore, it can be known that using the nano eye drops of the present invention to treat cataract caused by diabetes can significantly slow down the deterioration of cataract.

Based on the descriptions of the above embodiments, one can fully understand the operation, use and effects of the present invention, but the above-mentioned embodiments are only preferred embodiments of the present invention, which should not limit the implementation of the present invention. Scope, that is, simple equivalent changes and modifications made according to the scope of the patent application of the present invention and the contents of the description of the invention, all fall within the scope of the present invention.

Claims (6)

A method for producing nano eye drops, comprising the steps of: taking the monosodium glucose cotransporter inhibitor in parts by weight between 0.8 and 1.2, and the monohydroxypropyl-β- Cyclodextrin and 16 to 24 parts by weight of a polyvinyl pyrrolidone, the three are mixed into a mixture, wherein the powder particle size of the above components is between 100 nanometers to 1000 nanometers, wherein, The sodium-glucose cotransporter inhibitor is dapagliflozin; the mixture is dissolved in ethanol, stirred to dissolve uniformly, and then the ethanol is removed to obtain a uniformly mixed powder; the uniformly mixed powder is dissolved in an eyedrop Formed into a nano eye drop. The method for producing nano eye drops according to claim 1, wherein the mixing weight ratio of the dapagliflozin, the hydroxypropyl-β-cyclodextrin and the polyvinylpyrrolidone is 1:20:20. The method for producing nano eye drops as claimed in claim 1, wherein the powder particle size of the dapagliflozin, the hydroxypropyl-β-cyclodextrin and the polyvinylpyrrolidone is less than 200 nanometers. The method for producing nano eye drops according to claim 1, wherein when the mixture is dissolved in the ethanol, it is stirred with a magnet. The method for producing nano eye drops as claimed in claim 1, wherein the eye drops excipient comprises a hydrophilic carrier. A nano-eye drop is prepared by using the manufacturing method of the nano-eye drop described in any one of claims 1 to 5.

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