Ophthalmic preparation composition and preparation method thereof

Abstract

The invention relates to an ophthalmic composition in an aqueous solution form. The ophthalmic composition consists of cyclosporine, medium chain triglyceride, polyoxyethylene (40) hydrogenated castor oil, polyethylene glycol 400, glycerol, sodium acetate and water. The pH value of the ophthalmic composition is close to that of tears, and the ophthalmic composition is good in medication comfort and good in stability during storage.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations and relates to an ophthalmic preparation composition containing cyclosporine and a preparation method thereof. Background Art

[0002] Eye drops are sterile liquid preparations made of raw materials and suitable excipients for instillation into the eye. Because some raw materials, such as cyclosporine (CAS No. 59865-13-3), are extremely hydrophobic and cannot be dissolved in water to form a true solution, they are developed into emulsion eye drops or suspension eye drops to solve the problem of such raw materials being difficult to dissolve in water.

[0003] Currently, the cyclosporine eye drops available on the market include: The specification is 0.05%, and the indication is dry eye syndrome; developed by Santen Pharmaceutical and The specification is 0.1%, and the indication is conjunctivitis; it was developed by Sun Pharmaceuticals The specification is 0.09%, and the indication is dry eye syndrome, including and It is an emulsion eye drop. It is a micellar eye drop.

[0004] However, the production of emulsion eye drops requires the use of expensive high-speed homogenizers, and the production of suspension eye drops requires the use of colloid mills. In addition, due to their large particle size, both emulsion eye drops and suspension eye drops cannot be filtered and sterilized using a 0.22 μm pore size filter, and need to be sterilized at high temperatures in the liquid preparation tank. Special production equipment and production lines greatly limit the industrial production of such products. Moreover, high-temperature sterilization may accelerate the degradation of certain products.

[0005] Microemulsion is a nanoemulsion with a particle size between 10nm and 100nm, composed of an oil phase solvent, an emulsifier, and an emulsifier co-emulsifier. It is almost transparent to slightly transparent in appearance, and is very stable in both thermodynamics and kinetics. It can be prepared by simple stirring. Making cyclosporine into a microemulsion preparation can increase the solubility of cyclosporine, prolong the duration of action, and improve bioavailability.

[0006] CN110237233A discloses a cyclosporine ophthalmic preparation composition and a preparation method thereof. The preparation is a microemulsion preparation. However, the pH value of the preparation is between 5.53 and 5.68, which is different from the neutral pH value of tears.

[0007] There is still a need to develop ophthalmic preparations with better medication comfort and stability. Summary of the invention

[0008] After in-depth research, the inventors have prepared an ophthalmic composition in the form of an almost transparent to slightly transparent aqueous solution that can be filtered and sterilized with a 0.22 μm pore filter by using microemulsification technology. The ophthalmic composition is added with sodium acetate as a buffer, has a pH value close to that of tears, and is more comfortable to use; has better stability, a stable pH value during storage, no demulsification, and stable quality.

[0009] The inventors have investigated the commonly used pH adjusters or buffers for ophthalmic preparations, including sodium hydroxide, sodium dihydrogen phosphate-sodium hydroxide, sodium dihydrogen phosphate-disodium hydrogen phosphate, hydrochloric acid-disodium hydrogen phosphate, citric acid-sodium citrate, boric acid-borax, sodium acetate-sodium hydroxide, etc., and found that although these pH adjusters or buffers can adjust the pH value of ophthalmic preparations, they will cause unknown impurities in the preparations and will seriously affect the stability of the emulsion system, or cause demulsification, or cause degradation reactions of the active ingredients. It is speculated that the above-mentioned pH adjusters or buffers have undergone esterification reactions with certain excipients, or the acids or bases therein will catalyze the esterification reactions of the excipients.

[0010] The inventors surprisingly found that an appropriate amount of sodium acetate as a buffer can make the pH value of the ophthalmic composition close to neutral, improve the comfort of using the medicine, and maintain the stability of the emulsion system without demulsification, degradation reaction of the active ingredients, and generation of unknown impurities. The pH value and quality are stable during storage.

[0011] In accordance with the provisions of 9001 of the General Rules of Part IV of the 2020 edition of the "Chinese Pharmacopoeia", the ophthalmic composition of the present invention was subjected to an influencing factor test (high temperature 50°C), an accelerated test (40°C±2°C / RH25%±5%) and a long-term test (25°C±2°C / RH40%±5%). The results showed that the pH value of the ophthalmic composition of the present invention was similar to that of tears, and did not change significantly during storage. The preparation was stable, with few impurities, the emulsion system was stable, and no demulsification occurred.

[0012] Based on the above findings, the present invention provides an ophthalmic composition in the form of an aqueous solution, which is composed of cyclosporine, medium-chain triglycerides, polyoxyethylene (40) hydrogenated castor oil, polyethylene glycol 400, glycerol, sodium acetate and water. The medium-chain triglycerides are used as an oil phase solvent, polyoxyethylene (40) hydrogenated castor oil is used as an emulsifier, polyethylene glycol 400 is used as an auxiliary emulsifier, glycerol is used as an osmotic pressure regulator, sodium acetate is used as a buffer, and water is used as a solvent.

[0013] In certain embodiments, the ophthalmic composition consists of 0.05 w / v% to 0.1 w / v% cyclosporine, 0.2 w / v% to 1.2 w / v% medium chain triglycerides, 0.8 w / v% to 3 w / v% polyoxyethylene (40) hydrogenated castor oil, 0.4 w / v% to 1.5 w / v% polyethylene glycol 400, 1.6 w / v% to 2.4 w / v% glycerol, 0.1 w / v% to 0.4 w / v% sodium acetate and the balance water.

[0014] In certain embodiments, the content of cyclosporine in the ophthalmic composition is 0.05 w / v%, 0.09 w / v% or 0.1 w / v%.

[0015] In certain embodiments, the ophthalmic composition consists of 0.05 w / v% cyclosporine, 0.2 w / v% to 0.6 w / v% medium chain triglycerides, 0.8 w / v% to 1.5 w / v% polyoxyethylene (40) hydrogenated castor oil, 0.4 w / v% to 0.75 w / v% polyethylene glycol 400, 2 w / v% to 2.4 w / v% glycerol, 0.1 w / v% to 0.3 w / v% sodium acetate and the balance water.

[0016] In certain embodiments, the ophthalmic composition consists of 0.09 w / v% cyclosporine, 0.4 w / v% to 1.2 w / v% medium chain triglycerides, 0.8 w / v% to 3 w / v% polyoxyethylene (40) hydrogenated castor oil, 0.4 w / v% to 1.5 w / v% polyethylene glycol 400, 1.6 w / v% to 2.2 w / v% glycerol, 0.1 w / v% to 0.4 w / v% sodium acetate and the balance water.

[0017] In certain embodiments, the ophthalmic composition consists of 0.1 w / v% cyclosporine, 0.4 w / v% to 1.2 w / v% medium chain triglycerides, 0.8 w / v% to 3 w / v% polyoxyethylene (40) hydrogenated castor oil, 0.4 w / v% to 1.5 w / v% polyethylene glycol 400, 1.6 w / v% to 2.2 w / v% glycerol, 0.1 w / v% to 0.4 w / v% sodium acetate and the balance water.

[0018] In certain embodiments, the ophthalmic composition consists of 0.05 w / v% cyclosporine, 0.2 w / v% medium chain triglycerides, 0.8 w / v% polyoxyethylene (40) hydrogenated castor oil, 0.4 w / v% polyethylene glycol 400, 2.4 w / v% glycerol, 0.1 w / v% sodium acetate and the balance water.

[0019] In certain embodiments, the ophthalmic composition consists of 0.05 w / v% cyclosporine, 0.4 w / v% medium chain triglycerides, 1 w / v% polyoxyethylene (40) hydrogenated castor oil, 0.5 w / v% polyethylene glycol 400, 2.2 w / v% glycerol, 0.15 w / v% sodium acetate and the balance water.

[0020] In certain embodiments, the ophthalmic composition consists of 0.05 w / v% cyclosporine, 0.6 w / v% medium chain triglycerides, 1.5 w / v% polyoxyethylene (40) hydrogenated castor oil, 0.75 w / v% polyethylene glycol 400, 2 w / v% glycerol, 0.3 w / v% sodium acetate and the balance water.

[0021] In certain embodiments, the ophthalmic composition consists of 0.09 w / v% cyclosporine, 0.4 w / v% medium chain triglycerides, 0.8 w / v% polyoxyethylene (40) hydrogenated castor oil, 0.4 w / v% polyethylene glycol 400, 2.2 w / v% glycerol, 0.1 w / v% sodium acetate and the balance water.

[0022] In certain embodiments, the ophthalmic composition consists of 0.09 w / v% cyclosporine, 0.8 w / v% medium chain triglycerides, 2 w / v% polyoxyethylene (40) hydrogenated castor oil, 1 w / v% polyethylene glycol 400, 1.8 w / v% glycerol, 0.3 w / v% sodium acetate and the balance water.

[0023] In certain embodiments, the ophthalmic composition consists of 0.09 w / v% cyclosporine, 1.2 w / v% medium chain triglycerides, 3 w / v% polyoxyethylene (40) hydrogenated castor oil, 1.5 w / v% polyethylene glycol 400, 1.6 w / v% glycerol, 0.4 w / v% sodium acetate and the balance water.

[0024] In certain embodiments, the ophthalmic composition consists of 0.1 w / v% cyclosporine, 0.4 w / v% medium chain triglycerides, 0.8 w / v% polyoxyethylene (40) hydrogenated castor oil, 0.4 w / v% polyethylene glycol 400, 2.2 w / v% glycerol, 0.1 w / v% sodium acetate and the balance water.

[0025] In certain embodiments, the ophthalmic composition consists of 0.1 w / v% cyclosporine, 0.8 w / v% medium chain triglycerides, 2 w / v% polyoxyethylene (40) hydrogenated castor oil, 1 w / v% polyethylene glycol 400, 1.8 w / v% glycerol, 0.3 w / v% sodium acetate and the balance water.

[0026] In certain embodiments, the ophthalmic composition consists of 0.1 w / v% cyclosporine, 1.2 w / v% medium chain triglycerides, 3 w / v% polyoxyethylene (40) hydrogenated castor oil, 1.5 w / v% polyethylene glycol 400, 1.6 w / v% glycerol, 0.4 w / v% sodium acetate and the balance water.

[0027] In certain embodiments, the pH of the ophthalmic composition is 6.0 to 7.5, preferably 6.4 to 7.3, more preferably 6.5 to 7.2, and even more preferably 6.5 to 7.0.

[0028] The present invention also provides a method for preparing the ophthalmic composition, comprising:

[0029] (1) dissolving cyclosporine in medium chain triglycerides;

[0030] (2) adding polyoxyethylene (40) hydrogenated castor oil and polyethylene glycol 400 to the mixture obtained in (1);

[0031] (3) Dissolve glycerol and sodium acetate in water;

[0032] (4) adding the mixture obtained in (2) to the mixture obtained in (3);

[0033] (5) Add water to make up the total amount and mix well.

[0034] The present invention also provides the use of the ophthalmic composition in preparing a drug for treating immune rejection after corneal transplantation or ocular surface inflammatory diseases (such as dry eye, conjunctivitis) or in preparing a drug for preventing postoperative inflammation of the ocular surface.

[0035] The present invention also provides that the ophthalmic composition can be used as eye drops, for example, for treating immune rejection after corneal transplantation or ocular surface inflammatory diseases (such as dry eye, conjunctivitis), or for preventing postoperative inflammation of the ocular surface.

[0036] In the present invention, unless otherwise specified, the term "%" refers to w / v% (weight / volume percentage), expressed as g / 100 mL. For example, a composition containing 0.1% cyclosporine means that the content of cyclosporine in the composition is 0.1 g / 100 mL, that is, 100 mL of the composition contains 0.1 g of cyclosporine.

[0037] In the present invention, the term "Polyoxyl (40) Hydrogenated Castor Oil" refers to polyoxyethylene glycerol trihydroxystearate, which also contains a small amount of polyethylene glycol trihydroxystearate and free polyethylene glycol. It is prepared by reacting 1 mol of glycerol trihydroxystearate with 40-45 mol of ethylene oxide, and meets the quality standards specified in the 2020 edition of the "Chinese Pharmacopoeia".

[0038] In the present invention, the term "medium chain triglyceride" refers to, for example, medium chain fatty acid (MCFA carbon chain is 6-12 carbon atoms) and glycerol esterification to form medium chain fatty acid triglyceride (also known as medium chain triglyceride, MCT). The medium chain fatty acid molecules connected to the three hydroxyl groups of the glycerol molecule can be the same or different. Medium chain triglyceride can be a single medium chain fatty acid triglyceride or a mixture of multiple medium chain fatty acid triglycerides. Preferably, the term "medium chain triglyceride" refers to a mixture of triglycerides obtained by esterification of caprylic acid, capric acid and glycerol, referred to as caprylic capric acid glyceride or caprylic capric acid triglyceride. More preferably, the term "medium chain triglyceride" refers to the definition in the 2020 edition of the "Chinese Pharmacopoeia": Caprylic acid (C8H2O2) separated from the fatty oil extracted from the hard dry part of the endosperm of coconut Cocos nucifera L. or the dry part of the endosperm of oil palm Elaeisguineensis Jacq 16 O2), decanoic acid (C 10 H 20 O2) and other saturated fatty acids, and glycerol esterification to obtain a triglyceride mixture, which contains caprylic acid (C8H 16 O2) and decanoic acid (C 10 H 20 The total amount of O2) shall not be less than 95.0%.

[0039] The ophthalmic composition of the present invention has one or more of the following advantages:

[0040] (1) The ophthalmic composition of the present invention has a pH value close to that of tears and is comfortable to use;

[0041] (2) The ophthalmic composition of the present invention has better stability, a stable pH value during storage, no demulsification, and can maintain stable quality under high temperature conditions, accelerated conditions and long-term conditions. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 The chromatogram of related substances of cyclosporine eye drops of Example 3 is shown;

[0043] Figure 2The chromatograms of related substances of cyclosporine eye drops of Comparative Examples 1 to 8 are shown. DETAILED DESCRIPTION

[0044] The embodiments of the present invention will be described in detail below with reference to examples. Those skilled in the art will understand that the following examples are only used to illustrate the present invention and are not to be regarded as limiting the scope of the present invention. However, the following examples all fall within the scope of the present invention.

[0045] Although many materials and operating methods used in the following examples are well known in the art, the present invention is still described in as much detail as possible. It is clear to those skilled in the art that the materials and operating methods used in the following examples are well known in the art unless otherwise specified.

[0046] In the embodiments or test examples of the present invention, when describing eye drops, "%" refers to the percentage of weight / volume, expressed as g / 100 mL. For example, 0.1% cyclosporine eye drops means that 100 mL of the eye drops contain 0.1 g of cyclosporine. For another example, adding 0.1% sodium acetate buffer means that 0.1 g of sodium acetate is added as a buffer in 100 mL of the eye drops.

[0047] Cyclosporine used in the examples of the present invention was purchased from Jiangsu Jiuyang Biopharmaceutical Co., Ltd. (batch number: 240708DXI), medium chain triglycerides were purchased from Liaoning Xinxing Pharmaceutical Co., Ltd. (batch number: 230802-2-01), polyoxyethylene (40) hydrogenated castor oil was purchased from BASF (batch number: 67319775L0), polyethylene glycol 400 was purchased from Hunan Erkang Pharmaceutical Co., Ltd. (batch number: 102820240703), glycerol was purchased from Hunan Erkang Pharmaceutical Co., Ltd. (batch number: 000120240806), and sodium acetate was purchased from Taishan Xinning Pharmaceutical Co., Ltd. (batch number: 20221010).

[0048] Examples 1-5: Preparation of 0.05% cyclosporine eye drops

[0049] Element Example 1 Example 2 Example 3 Example 4 Example 5 Cyclosporine 0.05g 0.05g 0.05g 0.05g 0.05g Medium Chain Triglycerides 0.2g 0.2g 0.4g 0.6g 0.6g Polyoxyethylene (40) hydrogenated castor oil 0.8g 0.8g 1g 1.5g 1.5g Polyethylene glycol 400 0.4g 0.4g 0.5g 0.75g 0.75g glycerin 2.4g 2.4g 2.2g 2g 2g Sodium acetate 0.05g 0.1g 0.15g 0.3g 0.5g water Up to 100mL Up to 100mL Up to 100mL Up to 100mL Up to 100mL

[0050] The preparation method is as follows:

[0051] (1) dissolving cyclosporine in medium chain triglycerides and stirring evenly;

[0052] (2) adding polyoxyethylene (40) hydrogenated castor oil and polyethylene glycol 400 to the mixture obtained in (1) and stirring evenly;

[0053] (3) Dissolve glycerol and sodium acetate in part of the water and stir evenly;

[0054] (4) adding the mixture obtained in (2) to the mixture obtained in (3) and stirring evenly;

[0055] (5) Add water to 100 mL and stir evenly;

[0056] (6) Sterilize by filtering with a 0.22 μm pore size filter.

[0057] Examples 6-10: Preparation of 0.09% cyclosporine eye drops

[0058] Element Example 6 Example 7 Example 8 Example 9 Example 10 Cyclosporine 0.09g 0.09g 0.09g 0.09g 0.09g Medium Chain Triglycerides 0.4g 0.4g 0.8g 1.2g 1.2g Polyoxyethylene (40) hydrogenated castor oil 0.8g 0.8g 2g 3g 3g Polyethylene glycol 400 0.4g 0.4g 1g 1.5g 1.5g glycerin 2.2g 2.2g 1.8g 1.6g 1.6g Sodium acetate 0.05g 0.1g 0.3g 0.4g 0.5g water Up to 100mL Up to 100mL Up to 100mL Up to 100mL Up to 100mL

[0059] The preparation method is the same as that of Example 1-5.

[0060] Examples 11-15: Preparation of 0.1% cyclosporine eye drops

[0061] Element Embodiment 11 Example 12 Example 13 Embodiment 14 Embodiment 15 Cyclosporine 0.1 g 0.1g 0.1g 0.1g 0.1g Medium Chain Triglycerides 0.4g 0.4g 0.8g 1.2g 1.2g Polyoxyethylene (40) hydrogenated castor oil 0.8g 0.8g 2g 3g 3g Polyethylene glycol 400 0.4g 0.4g 1g 1.5g 1.5g glycerin 2.2g 2.2g 1.8g 1.6g 1.6g Sodium acetate 0.05g 0.1g 0.3g 0.4g 0.5g water Up to 100mL Up to 100mL Up to 100mL Up to 100mL Up to 100mL

[0062] The preparation method is the same as that of Example 1-5.

[0063] Comparative Examples 1-8: Based on Example 3, the type of buffer was adjusted, and the pH was adjusted to neutral, i.e., 6.9-7.1, with a pH adjuster to obtain Comparative Examples 1-8.

[0064]

[0065] The preparation methods of Comparative Examples 1 to 8 are as follows:

[0066] (1) dissolving cyclosporine in medium chain triglycerides and stirring evenly;

[0067] (2) adding polyoxyethylene (40) hydrogenated castor oil and polyethylene glycol 400 to the mixture obtained in (1) and stirring evenly;

[0068] (3) Dissolve glycerol and buffer (if any) in part of the water and stir evenly;

[0069] (4) adding the mixture obtained in (2) to the mixture obtained in (3) and stirring evenly;

[0070] (5) adding a pH adjuster to adjust the pH value of the mixture obtained in (4) to neutral, i.e., 6.9 to 7.1;

[0071] (6) Add water to make up to 100 mL and stir evenly.

[0072] In the above comparative examples, comparative example 1 is that no buffer is added and the pH value is not adjusted; comparative example 2 is that no buffer is added and the pH value is adjusted to 6.9-7.1 with sodium hydroxide; comparative example 3 is that sodium dihydrogen phosphate is used as a buffer and the pH value is adjusted to 6.9-7.1 with sodium hydroxide; comparative example 4 is that sodium dihydrogen phosphate and disodium hydrogen phosphate are used as buffers and the pH value does not need to be adjusted; comparative example 5 is that disodium hydrogen phosphate is used as a buffer and the pH value is adjusted to 6.9-7.1 with hydrochloric acid; comparative example 6 is that boric acid and borax are used as buffers and the pH value does not need to be adjusted; comparative example 7 is that sodium citrate is used as a pH adjuster and the pH value is adjusted to 6.9-7.1 with citric acid; comparative example 8 is that sodium acetate is used as a buffer and the pH value is adjusted to 6.9-7.1 with sodium hydroxide.

[0073] Test Example 1: Stability Study

[0074] According to the guidelines for stability testing of raw materials and preparations in Part IV of the 2020 edition of the Chinese Pharmacopoeia, 9001, the samples of the examples were taken for influencing factor tests (high temperature 50°C), accelerated tests (temperature 40°C±2°C, relative humidity 25%±5%) and long-term tests (temperature 25°C±2°C, relative humidity 40%±5%).

[0075] (I) Accelerated test results

[0076] Table 1. Accelerated test results of 0.05% cyclosporine eye drops of Examples 1 to 5

[0077]

[0078]

[0079] Table 2. Accelerated test results of 0.09% cyclosporine eye drops of Examples 6 to 10

[0080]

[0081] Table 3. Accelerated test results of 0.1% cyclosporine eye drops of Examples 11 to 15

[0082]

[0083] The results of the accelerated test are shown in Tables 1 to 3. The results show:

[0084] (1) The results of Examples 2 to 4, Examples 7 to 9, and Examples 12 to 14, including properties, pH value, osmotic pressure molar concentration, related substances and contents, all meet the limit requirements;

[0085] (2) In Examples 1, 6, and 11, where 0.05% sodium acetate was added as a buffer, the buffering capacity of the solution was relatively weak, and the pH value of the preparation continued to decrease during storage. After accelerated storage for 6 months, the pH value did not meet the limit requirement, and the stability was relatively poor.

[0086] (3) In Examples 5, 10, and 15, in which 0.5% sodium acetate was added as a buffer, the emulsion system of the preparations was unstable during storage, and demulsification occurred after 3 months, indicating poor stability.

[0087] (II) Long-term test

[0088] Table 4. Long-term test results of 0.05% cyclosporine eye drops of Examples 2 to 4

[0089]

[0090]

[0091] Table 5. Long-term test results of 0.09% cyclosporine eye drops of Examples 7 to 9

[0092]

[0093]

[0094] Table 6. Long-term test results of 0.1% cyclosporine eye drops of Examples 12 to 14

[0095]

[0096]

[0097] The long-term test results are shown in Tables 4 to 6. The results show:

[0098] (1) The results of Examples 2 to 4, Examples 7 to 9, and Examples 12 to 14, including properties, pH value, osmotic pressure molar concentration, related substances and contents, all meet the limit requirements;

[0099] (2) As the amount of sodium acetate increased, the decreasing trend of pH value during storage slowed down;

[0100] (3) The eye drop samples of Examples 2 to 4, Examples 7 to 9, and Examples 12 to 14 did not experience demulsification.

[0101] Figure 1The chromatogram of related substances of cyclosporine eye drops of Example 3 is shown. It can be found that except for the peak of the main degradation impurity cyclosporine A, after storage for 30 days under high temperature conditions (temperature 50°C), storage for 6 months under accelerated conditions (temperature 40°C±2°C, relative humidity 25%±5%), and storage for 24 months under long-term conditions (temperature 25°C±2°C, relative humidity 40%±5%), the interference peak of unknown impurities has no obvious change, and no other impurity peaks are generated.

[0102] The results of the above-mentioned accelerated tests and long-term tests indicate that the addition of 0.1% to 0.4% sodium acetate buffer can not only make the pH value of the preparation approximately neutral, thus ensuring the comfort of medication, but also improve the stability of the pH value of the preparation, so that the pH value of the preparation meets the limit requirements during storage; and also ensure the stability of the emulsion system, so that demulsification will not occur.

[0103] Test Example 2: Comparative Study on the Quality of Cyclosporine Eye Drops in Comparative Examples 1 to 8

[0104] Table 7. Quality test results of cyclosporine eye drops of comparative examples 1 to 8 (day 0)

[0105]

[0106] The results of the comparative test of the quality of cyclosporine eye drops of Comparative Examples 1-8 are shown in Table 7. The results show:

[0107] (1) Comparative Example 1 did not add a buffer and a pH adjuster, resulting in a low pH value and poor medication comfort;

[0108] (2) In Comparative Example 2, only a pH adjuster was added without a buffer, resulting in a pH value after volume adjustment that was about 0.8 lower than the pH value of 6.9 to 7.1 before volume adjustment, and the stability of the pH value of the preparation could not be guaranteed;

[0109] (3) Comparative Examples 2, 3, 5, 7, and 8 all have poor compatibility of auxiliary materials and the presence of large unknown impurities due to the addition of strong acid or strong base as pH adjuster, Comparative Example 4 has added phosphate as buffer, and Comparative Example 6 has added boric acid and borax as buffer.

[0110] Figure 2 The chromatograms of related substances of the cyclosporine eye drops of Comparative Examples 1 to 8 are shown, and it can be found that the cyclosporine eye drops of Comparative Examples 2 to 8 have large unknown impurity interference peaks.

[0111] The above test results show that if no buffer is added and the pH value is not adjusted, the pH value of the preparation is low and the comfort of medication is poor; if no buffer is added and only the pH adjuster is used to adjust the pH value, the stability of the pH value of the preparation cannot be guaranteed; using buffer systems such as sodium dihydrogen phosphate-sodium hydroxide, sodium dihydrogen phosphate-disodium hydrogen phosphate, hydrochloric acid-disodium hydrogen phosphate, boric acid-borax, citric acid-sodium citrate, sodium acetate-sodium hydroxide as buffers and pH adjusters will produce large unknown impurities and interfere with the determination of related substances.

[0112] Test Example 3: Irritation Investigation

[0113] The cyclosporine eye drops of Examples 2 to 4, Examples 7 to 9, and Comparative Examples 12 to 14 were tested to observe whether the cyclosporine eye drops were irritating to rabbits after being instilled into their eyes, so as to provide a basis for the evaluation of medication comfort and safety.

[0114] Evaluation method: Three male Japanese white rabbits were selected, and cyclosporine eye drops were instilled into the left eyes of the three animals in the treatment group, 6 times a day, 1 drop each time, with an interval of at least 1 hour, for 7 consecutive days. The eyes were examined before the first administration and 1h, 2h, 4h, 24h, 48h, and 72h after the last administration.

[0115] Table 8. Eye irritation response scoring table

[0116]

[0117] Table 9. Eye irritation evaluation criteria

[0118] Irritation level integral Non-irritating 0～3 Mild irritant 4～8 Moderate irritation 9～12 Intensity of stimulation 13～16

[0119] Table 10. Statistics of irritation test scores

[0120]

[0121] The eye irritation reaction was scored and evaluated according to the standards in Tables 8 and 9, and the results are shown in Table 10. The results showed that the addition of 0.1% to 0.4% sodium acetate buffer had a better medication comfort and no obvious irritation to rabbit eyes.

[0122] Although the specific embodiments of the present invention have been described in detail, it will be understood by those skilled in the art that various modifications and substitutions may be made to those details based on all the teachings disclosed, and these changes are within the scope of protection of the present invention. The full scope of the present invention is given by the attached claims and any equivalents thereof.

Claims

1. An ophthalmic composition in the form of an aqueous solution, comprising cyclosporine, medium chain triglycerides, polyoxyethylene (40) hydrogenated castor oil, polyethylene glycol 400, glycerol, sodium acetate and water.

2. The ophthalmic composition according to claim 1, comprising 0.05 w / v% to 0.1 w / v% cyclosporine, 0.2 w / v% to 1.2 w / v% medium chain triglycerides, 0.8 w / v% to 3 w / v% polyoxyethylene (40) hydrogenated castor oil, 0.4 w / v% to 1.5 w / v% polyethylene glycol 400, 1.6 w / v% to 2.4 w / v% glycerol, 0.1 w / v% to 0.4 w / v% sodium acetate and the balance water.

3. The ophthalmic composition according to claim 2, wherein the content of cyclosporine is 0.05 w / v%, 0.09 w / v% or 0.1 w / v%.

4. The ophthalmic composition of claim 3, comprising 0.05 w / v% cyclosporine, 0.2 w / v% to 0.6 w / v% medium chain triglyceride, 0.8 w / v% to 1.5 w / v% polyoxyethylene (40) hydrogenated castor oil, 0.4 w / v% to 0.75 w / v% polyethylene glycol 400, 2 w / v% to 2.4 w / v% glycerol, 0.1 w / v% to 0.3 w / v% sodium acetate and the balance water.

5. The ophthalmic composition of claim 3, comprising 0.09 w / v% cyclosporine, 0.4 w / v% to 1.2 w / v% medium chain triglycerides, 0.8 w / v% to 3 w / v% polyoxyethylene (40) hydrogenated castor oil, 0.4 w / v% to 1.5 w / v% polyethylene glycol 400, 1.6 w / v% to 2.2 w / v% glycerol, 0.1 w / v% to 0.4 w / v% sodium acetate and the balance water.

6. The ophthalmic composition of claim 3, comprising 0.1 w / v% cyclosporine, 0.4 w / v% to 1.2 w / v% medium chain triglycerides, 0.8 w / v% to 3 w / v% polyoxyethylene (40) hydrogenated castor oil, 0.4 w / v% to 1.5 w / v% polyethylene glycol 400, 1.6 w / v% to 2.2 w / v% glycerol, 0.1 w / v% to 0.4 w / v% sodium acetate and the balance water.

7. The ophthalmic composition of claim 3, comprising 0.05 w / v% cyclosporine, 0.2 w / v% medium chain triglyceride, 0.8 w / v% polyoxyethylene (40) hydrogenated castor oil, 0.4 w / v% polyethylene glycol 400, 2.4 w / v% glycerol, 0.1 w / v% sodium acetate and the balance water, or The composition is composed of 0.05w / v% cyclosporine, 0.4w / v% medium chain triglyceride, 1w / v% polyoxyethylene (40) hydrogenated castor oil, 0.5w / v% polyethylene glycol 400, 2.2w / v% glycerol, 0.15w / v% sodium acetate and the balance water, or The composition is composed of 0.05w / v% cyclosporine, 0.6w / v% medium chain triglyceride, 1.5w / v% polyoxyethylene (40) hydrogenated castor oil, 0.75w / v% polyethylene glycol 400, 2w / v% glycerol, 0.3w / v% sodium acetate and the balance water, or The composition is composed of 0.09w / v% cyclosporine, 0.4w / v% medium chain triglyceride, 0.8w / v% polyoxyethylene (40) hydrogenated castor oil, 0.4w / v% polyethylene glycol 400, 2.2w / v% glycerol, 0.1w / v% sodium acetate and the balance water, or The composition is composed of 0.09w / v% cyclosporine, 0.8w / v% medium chain triglyceride, 2w / v% polyoxyethylene (40) hydrogenated castor oil, 1w / v% polyethylene glycol 400, 1.8w / v% glycerol, 0.3w / v% sodium acetate and the balance water, or The composition is composed of 0.09w / v% cyclosporine, 1.2w / v% medium chain triglyceride, 3w / v% polyoxyethylene (40) hydrogenated castor oil, 1.5w / v% polyethylene glycol 400, 1.6w / v% glycerol, 0.4w / v% sodium acetate and the balance water, or The composition is composed of 0.1w / v% cyclosporine, 0.4w / v% medium chain triglyceride, 0.8w / v% polyoxyethylene (40) hydrogenated castor oil, 0.4w / v% polyethylene glycol 400, 2.2w / v% glycerol, 0.1w / v% sodium acetate and the balance water, or The composition is composed of 0.1w / v% cyclosporine, 0.8w / v% medium chain triglyceride, 2w / v% polyoxyethylene (40) hydrogenated castor oil, 1w / v% polyethylene glycol 400, 1.8w / v% glycerol, 0.3w / v% sodium acetate and the balance water, or The composition is composed of 0.1 w / v% cyclosporine, 1.2 w / v% medium chain triglyceride, 3 w / v% polyoxyethylene (40) hydrogenated castor oil, 1.5 w / v% polyethylene glycol 400, 1.6 w / v% glycerol, 0.4 w / v% sodium acetate and the balance water.

8. The ophthalmic composition according to any one of claims 1 to 7, which has a pH of 6.0 to 7.5, preferably 6.4 to 7.3, more preferably 6.5 to 7.2, and even more preferably 6.5 to 7.

0.

9. A method for preparing the ophthalmic composition according to any one of claims 1 to 8, comprising: (1) dissolving cyclosporine in medium chain triglycerides; (2) adding polyoxyethylene (40) hydrogenated castor oil and polyethylene glycol 400 to the mixture obtained in (1); (3) Dissolve glycerol and sodium acetate in water; (4) adding the mixture obtained in (2) to the mixture obtained in (3); (5) Add water to make up the total amount and mix well.

10. Use of the ophthalmic composition according to any one of claims 1 to 8 in the preparation of a medicament for treating immune rejection after corneal transplantation or ocular surface inflammatory diseases (such as dry eye, conjunctivitis) or in the preparation of a medicament for preventing postoperative inflammation of the ocular surface.

Images