Silymarin solid dispersion as well as silymarin ophthalmic gel and preparation method thereof

Abstract

The invention discloses a silymarin solid dispersion, silymarin ophthalmic gel and a preparation method of the silymarin ophthalmic gel. The silymarin ophthalmic gel comprises the following components in parts by weight: 0.1-10 parts of a silymarin solid dispersion, 0.5-20 parts of a gel matrix, 1-80 parts of a preservative, 0.5-10 parts of a humectant and 0.5-2 parts of a buffer agent, and the silymarin solid dispersion is prepared by dispersing silymarin and analogues thereof in a hydrophilic carrier material through a melting method. The solubility of silymarin and analogues thereof is improved through a solid dispersion technology, the problem of poor stability of silymarin and analogues thereof is solved, the bioavailability of the silymarin and analogues thereof in local eye application is improved, and the prepared eye gel product can effectively eliminate oxygen free radicals on the eye surface, inhibit lipid peroxidation and increase the content of superoxide dismutase so as to delay senescence. The preparation process is simple, large-scale production is easy, the residence time of the medicine in eyes is prolonged, the bioavailability is improved, and meanwhile the medication compliance of a patient is improved.

Description

Technical Field

[0001] The invention belongs to the technical field of ophthalmic pharmaceutical preparations, and particularly relates to a silymarin solid dispersion and a silymarin ophthalmic gel and a preparation method thereof. Background Art

[0002] As one of the most sensitive organs in the human body, the eyes are exposed to a variety of external stimuli every day, such as light (especially blue light), pollution, and stress. These factors will continuously trigger an "oxidative stress response" in the eye tissues, accelerating the aging process. Among them, the retina, lens, cornea and other tissues will continuously produce "free radicals" (such as reactive oxygen species ROS) during the metabolism process. Long-term accumulation will lead to ① retinal damage, triggering inflammation and cell apoptosis, and increasing the risk of age-related macular degeneration (AMD); ② lens opacity, leading to protein cross-linking and denaturation, forming cataracts; ③ corneal aging, destroying the lipid and protein structure of corneal epithelial cells, reducing corneal transparency, causing dry eye syndrome and corneal degeneration; ④ aging of the skin around the eyes, free radicals accelerate the degradation of collagen and elastic fibers, leading to wrinkles, sagging, and dark circles; ⑤ electronic screens and ultraviolet light in the blue light will directly stimulate the retina to produce excessive free radicals, which is also an important cause of premature eye aging in the modern population.

[0003] Silymarin is a flavonoid extracted and isolated from the fruit of the Asteraceae plant, Silybum marianum. It consists of four isomers: silybin, silybinin, silybintin, and silymarinol, with silybin as the main component. Silymarin has strong antioxidant and anti-aging effects. It can increase superoxide dismutase (SOD) levels by scavenging oxygen free radicals, inhibiting lipid peroxidation and 5-lipoxygenase activity, and acting as a chain-interrupting antioxidant or free radical scavenger.

[0004] Silymarin is highly lipophilic and has good mucosal permeability, but its solubility in water is extremely low (approximately 40 μg / mL), resulting in poor absorption and low bioavailability, which affects the drug's clinical efficacy. Various methods have been used to prepare new dosage forms to improve the bioavailability of silymarin, such as silymarin phospholipid complexes, water-soluble silymarin derivatives, silymarin liposomes, silymarin microemulsions, and silymarin suspensions. However, these technologies are currently only used for systemic administration and have not yet been applied to topical ophthalmic administration. Summary of the Invention

[0005] The purpose of the present invention is to overcome the shortcomings of the prior art and provide a silymarin solid dispersion and a silymarin ophthalmic gel and a preparation method thereof, which solve the problems of poor solubility, low bioavailability and long administration cycle of silymarin and its analogs in the above-mentioned background art.

[0006] The technical solution adopted by the present invention to solve the technical problem is: providing a stable silymarin eye gel, which comprises the following components in parts by weight:

[0007]

[0008] The silymarin solid dispersion is prepared by dispersing silymarin and its analogs, including isomers such as silybin, silybin, silybintin and silymarinol, in a hydrophilic carrier material through a melting method.

[0009] In a preferred embodiment of the present invention, the carrier material includes one or more of polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 20000, mannitol, Tween 80, polyvinyl pyrrolidone (PVP), poloxamer and hypromellose (HPMC).

[0010] In a preferred embodiment of the present invention, the mass ratio of silymarin and its analogues to the carrier material is 1:0.5-10; wherein,

[0011] The mass ratio of silymarin and its analogs to polyethylene glycol 4000 is 1:2-10;

[0012] The mass ratio of silymarin and its analogs to polyethylene glycol 6000 is 1:2-10;

[0013] The mass ratio of silymarin and its analogs to polyethylene glycol 20000 is 1:2-10;

[0014] The mass ratio of silymarin and its analogues to mannitol is 1:0.5-4;

[0015] The mass ratio of silymarin and its analogs to Tween 80 is 1:0.5-1;

[0016] The mass ratio of silymarin and its analogs to polyvinylpyrrolidone (PVP) is 1:2-10;

[0017] The mass ratio of silymarin and its analogs to poloxamer is 1:2-10;

[0018] The mass ratio of the silymarin and its analogues to hydroxypropyl methylcellulose (HPMC) is 1:0.5-4.

[0019] In a preferred embodiment of the present invention, the gel matrix includes acrylic polymers (such as carbomer) or cellulose derivatives (such as HPMC).

[0020] In a preferred embodiment of the present invention, the preservative is one or more of ethylparaben, chlorobutanol, benzalkonium bromide and benzalkonium chloride.

[0021] In a preferred embodiment of the present invention, the moisturizing agent is one or more of glycerin, propylene glycol, hyaluronic acid, and sorbitol.

[0022] In a preferred embodiment of the present invention, the buffer is at least one of boric acid, citric acid, borax, sodium citrate, and sodium dihydrogen phosphate.

[0023] The present invention also provides a method for preparing the above-mentioned stable silymarin ophthalmic gel, comprising the following steps:

[0024] Step 1: Add the gel matrix to water for injection, heat to 60-80°C to prepare a slurry, and cool for use;

[0025] Step 2: Heat the water for injection to 60-80°C, add the preservative and stir until dissolved, then add the buffer and stir until dissolved, add the moisturizer and stir, cool, add the silymarin solid dispersion and stir until dissolved;

[0026] Step 3: Mix the solutions of step 1 and step 2, stir evenly, adjust the pH value to 5.0-6.5, add water for injection, continue stirring until uniform, and filter with a 0.22 μm microporous filter membrane to obtain silymarin eye gel.

[0027] In a preferred embodiment of the present invention, the preparation method of the silymarin solid dispersion in step 3 comprises the following steps:

[0028] Silymarin and its analogs are mixed with a hydrophilic carrier material, heated in a water bath at 60-70° C. until completely melted, stirred to fully disperse and mix evenly, quickly poured into an aluminum crucible placed on an ice-salt bath, cooled, and frozen in a -20° C. refrigerator for 2 hours, vacuum dried for 4-6 hours, and sieved through a 40-mesh sieve to obtain the silymarin solid dispersion.

[0029] In a preferred embodiment of the present invention, the heating temperature in step 1 and step 2 is preferably 80°C.

[0030] In a preferred embodiment of the present invention, in step 4, a 10% wt sodium hydroxide solution is used to adjust the pH value.

[0031] The present invention also provides a silymarin solid dispersion, which is prepared by dispersing silymarin and its analogs in a hydrophilic carrier material by a melt method; the silymarin and its analogs include isomers such as silybin, silybin, silybintin and silymarinol; the carrier material includes one or more of polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 20000, mannitol, Tween 80, polyvinyl pyrrolidone, poloxamer and hypromellose; wherein,

[0032] The mass ratio of silymarin and its analogs to polyethylene glycol 4000, polyethylene glycol 6000, and polyethylene glycol 20000 is 1:2-10;

[0033] The mass ratio of silymarin and its analogues to mannitol is 1:0.5-4;

[0034] The mass ratio of silymarin and its analogs to Tween 80 is 1:0.5-1;

[0035] The mass ratio of silymarin and its analogues to polyvinyl pyrrolidone is 1:2-10;

[0036] The mass ratio of silymarin and its analogs to poloxamer is 1:2-10;

[0037] The mass ratio of the silymarin and its analogues to the hypromellose is 1:0.5-4.

[0038] In a preferred embodiment of the present invention, the mass ratio of silymarin and its analogs to Tween 80 is 1:1.

[0039] The silymarin solid dispersion and silymarin ophthalmic gel of the present invention are used as antioxidant drugs for delaying aging. The usage and dosage of the silymarin ophthalmic gel are as follows: external eye drops, 2-3 drops / time, 1-2 times / week.

[0040] Compared with the background technology, this technical solution has the following advantages:

[0041] 1. The silymarin ophthalmic gel of the present invention optimizes the defects of silymarin and its analogs in the prior art, such as poor solubility and low bioavailability; by adopting the form of silymarin solid dispersion, the solubility and stability of silymarin and its analogs are significantly improved.

[0042] 2. The silymarin ophthalmic gel preparation of the present invention overcomes the limitations of traditional ophthalmic preparations. The silymarin solid dispersion combined with the sustained-release performance of the gel structure gives silymarin and its analogs a longer half-life, can continuously and effectively release silymarin and its analogs, prolong the retention time of the drug in the eye, improve bioavailability, greatly reduce the dosage concentration and frequency of administration, reduce the patient's use burden, and increase medication compliance.

[0043] 3. The silymarin ophthalmic gel preparation of the present invention has certain positive effects on anti-oxidation and delaying the progression of aging.

[0044] 4. The preparation process of the present invention is relatively simple, the preparation cost is low, it is convenient for industrial production, and it is conducive to large-scale promotion and application, and promotes technological innovation. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 These are the dissolution test results of silymarin in Examples 1-4.

[0046] Figure 2 These are the dissolution test results of silymarin in Examples 5-8.

[0047] Figure 3 These are the dissolution test results of silymarin in Examples 9-12.

[0048] Figure 4 These are the dissolution test results of silymarin in Examples 13-16.

[0049] Figure 5 These are the dissolution test results of silymarin in Examples 17-20.

[0050] Figure 6 These are the dissolution test results of silymarin in Examples 21-22.

[0051] Figure 7 These are the dissolution test results of silymarin in Examples 23-24.

[0052] Figure 8 These are the dissolution test results of silymarin in Examples 25-26.

[0053] Figure 9 These are the rheological property test results of Examples 28-30 and Comparative Example 1.

[0054] Figure 10 These are the release curves of Examples 31-32 and Comparative Example 2. DETAILED DESCRIPTION

[0055] In order to enable those skilled in the art to better understand the solutions of the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the accompanying drawings of the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts should fall within the scope of protection of the present invention.

[0056] The hydrophilic carrier materials used in the following examples are polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 20000, mannitol, Tween 80, polyvinyl pyrrolidone (PVP), poloxamer, and hydropropyl methylcellulose (HPMC). Silymarin and its analogs are commercially available, including isomers such as silybin, silybinin, silybintin, and silymarinol.

[0057]

Solubility test

[0058] To test the solubility of silymarin in the above carrier materials, silymarin and the carrier materials were mixed in a ratio of 1:5 (m / m), placed in a stoppered flask filled with 25 mL of distilled water, and shaken in a constant temperature air bath shaker at 37°C and a speed of 100 r / min for 72 h. After removal, centrifugation (4000 r·min -1 ) for 10 min, dilute the supernatant appropriately with mobile phase, shake well, take 10 μL and inject into liquid chromatograph according to the above determination method, record the chromatographic peak area, and calculate the content of silymarin and its analogues in each carrier.

[0059] Silymarin solubility determination method:

[0060] Chromatographic column: Diamonsil C18 (250×4.6, 5μm),

[0061] Mobile phase: methanol-water-glacial acetic acid (55:48:0.5)

[0062] Flow rate: 1.0 ml min -1

[0063] Injection volume: 15 μL

[0064] Detection wavelength: 287nm

[0065] Column temperature: 25.0°C

[0066] Table 1 Silymarin solubility test results

[0067]

[0068]

[0069] The test results in Table 1 show that the above carriers have a certain solubilizing effect on the solubility of silymarin, and Tween 80 has the best solubilizing effect.

[0070] Examples 1 to 26

[0071] This group of examples provides a silymarin solid dispersion, which is prepared by dispersing silymarin and its analogs in a hydrophilic carrier material via a melt process. The specific preparation method comprises the following steps:

[0072] Silymarin was mixed with the hydrophilic carrier material according to the proportions in Table 2, and the sample was placed in a small beaker, heated in a 70°C water bath until completely melted, and stirred to fully disperse and mix evenly. The mixture was quickly poured into an aluminum crucible placed on an ice-salt bath, cooled, and frozen in a -20°C refrigerator for 2 hours, vacuum dried, and sieved through a 40-mesh sieve for later use.

[0073] Table 2 Proportions of silymarin and carrier materials in Examples 1 to 26

[0074]

[0075]

[0076]

Dissolution test

[0077] The dissolution test of the silymarin solid dispersion prepared in this group of examples in pH 6.8 phosphate buffer was carried out using a dissolution method. The results showed that when the ratio of silymarin to polyethylene glycol carrier was higher than 1:8, the dissolution rate of silymarin in the prepared solid dispersion was accelerated and the cumulative dissolution amount was the largest ( Figures 1 to 3 ); The dissolution rate of the solid dispersion prepared with polyvinyl pyrrolidone and Tween 80 as carriers was significantly improved ( Figure 4 and Figure 8 ), and the other vectors showed no significant differences ( Figures 5 to 7 ).

[0078] Examples 27 to 30

[0079] In this group of examples, a silymarin solid dispersion prepared with Tween 80 as a carrier (the mass ratio of silymarin to the carrier is 1:1), carbomer 940 and hydroxypropyl methylcellulose (K4M) as a gel matrix, and gel matrix solutions with different mass concentrations (mass fraction, unit: %) were prepared to prepare silymarin ophthalmic gel.

[0080] Table 3

[0081]

[0082]

[0083] Comparative Example 1

[0084] Silymarin solid dispersion solution without added gel matrix.

[0085]

Surface tension measurement

[0086] Visual observation showed that the gel in Example 27 was emulsified. The surface tension of Examples 28 to 30 and Comparative Example 1 was further measured using a surface tension meter. The test results are shown in the following table.

[0087] Table 4 Surface tension measurement results

[0088] Example 28 Example 29 Example 30 Comparative Example 1 Surface tension (mN / m) 58.79 46.28 40.42 70.78

[0089] The table shows that HPMC reduces the surface tension of silymarin solid dispersion solutions. The higher the concentration, the greater the reduction in surface tension. Lower surface tension improves spreadability, forming a uniform gel layer around the eyes and enabling slow and sustained drug release.

[0090]

Rheological property test

[0091] The examples 28 to 30 and comparative example 1 were measured using a TA rheometer with a preset temperature of 32°C. The rheological curves are shown in Figure 2. Figure 9 The results show that the rheological properties of Example 30 can not only alleviate the blinking pain caused by high-viscosity eye drops for ocular administration, but also facilitate the uniform distribution of the drug on the surface of the eyeball.

[0092] Examples 31-32

[0093] In this group of examples, the ratio of HPMC K4M was optimized based on Examples 29 and 30, and silymarin ophthalmic gel was prepared with 2 parts of chlorobutanol as a preservative, 1 part of glycerin as a humectant, and 0.5 parts of borate as a buffer.

[0094] Comparative Example 2

[0095] The difference between Comparative Example 2 and Examples 31 and 32 is that HPMC K4M is not added to the silymarin ophthalmic preparation.

[0096]

Release curve test

[0097] The release curves of Examples 31 and 32 and Comparative Example 2 were investigated. The results are as follows: Figure 10 As shown, when the addition amount of HPMC K4M is 1.5%, it has a good sustained-release effect, and Comparative Example 2 has no sustained-release ability, so Example 32 is the optimal formula.

[0098]

Stability Characterization

[0099] Example 32 and Comparative Example 2 were subjected to accelerated tests and long-term tests:

[0100] 1. Accelerated testing

[0101] Test method: The homemade silymarin eye gel in simulated market packaging was placed at 40°C and 75% relative humidity for 6 months, and samples were taken at 0, 1, 2, 3, and 6 months for testing.

[0102] 2. Long-term testing

[0103] Test method: Self-made silymarin eye gel in simulated market packaging was placed at 25°C and 60% relative humidity for 12 months. Samples were taken at the 0th, 3rd, 6th, 9th and 12th month for testing.

[0104] The results are shown in Tables 5 and 6 (the dosage of the main drug was 105-110). The content of the main drug in the silymarin ophthalmic gel obtained in Example 32 did not change significantly, while the content of the main drug in Comparative Example 2 decreased significantly.

[0105] Table 5

[0106]

[0107]

[0108] Table 6

[0109]

[0110] In summary, the present invention discloses a stable silymarin ophthalmic gel preparation. During its preparation, the silymarin ophthalmic gel preparation of the present invention utilizes the advantages of solid dispersion technology to significantly improve the solubility and stability of silymarin and its analogs, achieving a long-lasting sustained-release function, delaying the drug's residence time on the ocular surface, and increasing the drug's accumulated concentration on the ocular surface, thereby providing a more effective novel pharmaceutical preparation for anti-oxidation and anti-aging.

[0111] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A stable silymarin ophthalmic gel, characterized by: In parts by weight, it comprises the following components: The silymarin solid dispersion is prepared by dispersing silymarin and its analogues in a hydrophilic carrier material through a melting method. The silymarin and its analogues include silybin, silybin, silybintin and silymarinol.

2. The stable silymarin ophthalmic gel according to claim 1, characterized in that: The carrier material includes one or more of polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 20000, mannitol, Tween 80, polyvinyl pyrrolidone, poloxamer and hypromellose.

3. The stable silymarin ophthalmic gel according to claim 2, characterized in that: The mass ratio of silymarin and its analogues to the carrier material is 1:0.5-10; wherein, The mass ratio of silymarin and its analogs to polyethylene glycol 4000, polyethylene glycol 6000, and polyethylene glycol 20000 is 1:2-10; The mass ratio of silymarin and its analogues to mannitol is 1:0.5-4; The mass ratio of silymarin and its analogs to Tween 80 is 1:0.5-1; The mass ratio of silymarin and its analogues to polyvinyl pyrrolidone is 1:2-10; The mass ratio of silymarin and its analogs to poloxamer is 1:2-10; The mass ratio of the silymarin and its analogues to the hypromellose is 1:0.5-4.

4. The stable silymarin ophthalmic gel according to claim 1, characterized in that: The gel matrix includes acrylic polymers or cellulose derivatives.

5. The stable silymarin ophthalmic gel according to claim 1, characterized in that: The preservative is one or more of ethylparaben, chlorobutanol, benzalkonium bromide and benzalkonium chloride.

6. The stable silymarin ophthalmic gel according to claim 1, characterized in that: The moisturizing agent is one or more of glycerin, propylene glycol, hyaluronic acid and sorbitol.

7. The stable silymarin ophthalmic gel according to claim 1, characterized in that: The buffer is at least one of boric acid, citric acid, borax, sodium citrate, and sodium dihydrogen phosphate.

8. The method for preparing a stable silymarin ophthalmic gel according to any one of claims 1 to 7, characterized in that: The steps include: Step 1: Add the gel matrix to water for injection, heat to 60-80°C to prepare a slurry, and cool for use; Step 2: Heat the water for injection to 60-80°C, add the preservative and stir until dissolved, then add the buffer and stir until dissolved, add the moisturizer, stir, cool, and finally add the silymarin solid dispersion and stir until dissolved; Step 3: Mix the solutions of step 1 and step 2, stir evenly, adjust the pH value to 5.0-6.5, add water for injection, continue stirring until uniform, and filter with a 0.22 μm microporous filter membrane to obtain silymarin eye gel.

9. The method for preparing a stable silymarin ophthalmic gel according to claim 8, characterized in that: In step 3, the preparation method of silymarin solid dispersion comprises the following steps: Silymarin and its analogs are mixed with a hydrophilic carrier material, heated in a water bath at 60-70° C. until completely melted, stirred to fully disperse and mix evenly, quickly poured into an aluminum crucible placed on an ice-salt bath, cooled, and frozen in a -20° C. refrigerator for 2 hours, vacuum dried for 4-6 hours, and sieved through a 40-mesh sieve to obtain the silymarin solid dispersion.

10. A silymarin solid dispersion, characterized in that: The invention discloses a method for preparing a silymarin and its analogs by dispersing them in a hydrophilic carrier material through a melt process; the silymarin and its analogs include silybin, silybin, silybintin and silymarinol; the carrier material includes one or more of polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 20000, mannitol, Tween 80, polyvinyl pyrrolidone, poloxamer and hypromellose; wherein, The mass ratio of silymarin and its analogs to polyethylene glycol 4000, polyethylene glycol 6000, and polyethylene glycol 20000 is 1:2-10; The mass ratio of silymarin and its analogues to mannitol is 1:0.5-4; The mass ratio of silymarin and its analogs to Tween 80 is 1:0.5-1; The mass ratio of silymarin and its analogues to polyvinyl pyrrolidone is 1:2-10; The mass ratio of silymarin and its analogs to poloxamer is 1:2-10; The mass ratio of the silymarin and its analogues to the hypromellose is 1:0.5-4.

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