Idebenone dripping pill and application thereof

Abstract

The present invention discloses a kind of idebenone dropping pill, comprising: idebenone, a matrix material and a surfactant, wherein the matrix material is selected from polyethylene glycol of different molecular weights, the surfactant is selected from polyethylene glycol monostearate and / or polyethylene glycol-15 hydroxystearate, the dropping pill is condensed and formed by a melt-drop method, and the condensate is selected from one or more of liquid paraffin, dimethyl silicone oil, and methyl silicone oil. The present invention selects the matrix material and the surfactant, and the obtained idebenone dropping pill has good roundness, no obvious tailing, excellent solubility, and small content difference. Compared with the tablets, oral films, capsules, oral liquids, etc. made by the prior art, the present invention provides a better choice for idebenone oral preparations.

Description

Technical Field

[0001] The invention belongs to the technical field of medicine and relates to an idebenone dripping pill and application thereof. Background Art

[0002] Idebenone (IDB), chemically known as 2-(10-hydroxydecyl)-5,6-dimethoxy-3-methyl-1,4-benzoquinone, was developed by Takeda Pharmaceutical Company in Japan in the 1880s. It is a derivative of coenzyme Q10. Idebenone can activate brain mitochondrial activity, increase ATP production, and inhibit lipid peroxide production in brain mitochondria, exerting antioxidant and other functions (Suno M and Nagaoka A, Arch. Gerontol. Geriatr, 1989, 8:299-305).

[0003] Idebenone exerts its functions in cells and tissues through two pathways: 1. Cytochrome reductase (P450 detoxification enzyme) undergoes one-electron reduction to produce unstable semiquinone, which further produces superoxide compounds, leading to extremely toxicity. This pathway can be blocked by a two-electron reduction mechanism within the cell. 2. Idebenone undergoes a two-electron reduction mechanism via NAD(P)H quinone oxidoreductase 1 (NQO1) to form stable hydroquinone. The activated molecule provides electrons to scavenge free radicals or activate the mitochondrial respiratory transport chain to produce ATP (Gueven N and Woolley K. Redox Biol, 2015, 4:289-295).

[0004] Idebenone can be used to treat brain function damage caused by chronic cerebrovascular disease and brain trauma, and can improve subjective symptoms, language, anxiety, depression, memory loss, intellectual decline and other mental and behavioral disorders. Clinical trials have shown that IDB has excellent safety, with a maximum safe dose of 2250 mg / person / day (Kutz K, J Neurol, 2009, 256 (S1): 31-35). Recent studies have found that idebenone has a good therapeutic effect in multiple models of liver fibrosis and non-alcoholic fatty liver disease (NASH) (Wang Shuzhen et al., CN112707806B; Jiang, XJ. J Biochem Mol Toxicol, 2021, 35 (10): e22876), and is expected to be used to treat patients with liver fibrosis or NASH.

[0005] The currently approved oral preparation of idebenone is idebenone tablets (30 mg / tablet). Idebenone is a strong ester-soluble drug with a solubility in water of only 8 mg·L. -1(Carbone C and Pignatello R, Drug Deliv, 2012, 9(11): 1378-1392). In addition, the tablets are large in size, difficult to swallow, and have poor patient compliance, making them inconvenient for clinical use.

[0006] To date, extensive research has been conducted on the formulation and processing of idebenone tablets, capsules, and other dosage forms, but there have been no reports of attempts to prepare idebenone as drop pills. Drop pills are spherical or quasi-spherical preparations made by heating and melting the API and a matrix, then dropping them into an immiscible, non-interactive condensing medium. Drop pills offer advantages such as small size, portability, oral or sublingual administration, and good patient compliance. However, there is a significant conflict between the drug loading and dissolution time of drop pills, requiring systematic drug-specific research and creative effort to achieve the optimal balance. Furthermore, the preparation of drop pills requires overcoming issues such as poor content uniformity and low roundness due to inappropriate formulations or processes. Summary of the Invention

[0007] The present invention addresses the deficiencies in the prior art and provides an idebenone dropping pill, which overcomes the problems of long dissolution time and poor roundness during the preparation process of the idebenone dropping pill. The prepared idebenone dropping pill has a high drug loading capacity, can be dissolved within 30 minutes, and in the preferred embodiment can be dissolved within 3 minutes at the fastest, and has a round shape and good uniformity.

[0008] The specific technical solutions of the present invention are as follows:

[0009] The invention discloses an idebenone dropping pill, characterized in that the dropping pill comprises idebenone and a matrix material, and is formed by condensation by a melt-dropping method, wherein the condensate is selected from an oily condensate.

[0010] The matrix material is selected from polyethylene glycols of varying molecular weights. Preferably, the polyethylene glycol is selected from one or more of polyethylene glycol 200-6000, and the condensate is selected from one or more of liquid paraffin, dimethyl silicone oil, vegetable oil, methyl silicone oil, and dibutyl phthalate. More preferably, the polyethylene glycol is polyethylene glycol 1000-6000, and the condensate is preferably methyl silicone oil, dimethyl silicone oil, or liquid paraffin.

[0011] In a specific example of the present invention, the polyethylene glycol is selected from one or more of polyethylene glycol 1000, polyethylene glycol 1500, polyethylene glycol 2000, polyethylene glycol 3000, polyethylene glycol 4000, and polyethylene glycol 6000.

[0012] The present invention found that the single use of polyethylene glycol as a matrix makes it difficult to stir the obtained pellets evenly. Although the pellets have a rounded appearance and no tailing phenomenon when the polyethylene glycol molecular weight (polyethylene glycol 1000-1500) is low, the pellets have a rounded appearance and no tailing phenomenon, but the hardness is softer and will soften, deform, and break as the temperature rises. When the polyethylene glycol molecular weight increases (polyethylene glycol 4000-6000), the roundness of the pellets decreases, and there is a tailing phenomenon, and the dissolution time becomes longer. Especially when polyethylene glycol 6000 is used, not only is the drug loading only 10%, but it also fails to meet the provisions of the dissolution time limit of the pellets in the Chinese Pharmacopoeia 2020 Edition.

[0013] The present invention unexpectedly discovered that the above problems can be solved by adding surfactants.

[0014] Preferably, the surfactant is selected from one or more of Tween 20, Tween 60, Tween 80, Span 20, Span 60, Span 80, Span 85, polyethylene glycol monostearate, polyethylene glycol-15 hydroxystearate, poloxamer F68, and poloxamer F127. More preferably, it is polyethylene glycol monostearate and / or polyethylene glycol-15 hydroxystearate.

[0015] The preferred dropping pills of the present invention are selected from the following combination: idebenone, polyethylene glycol 4000 and / or polyethylene glycol 6000, and polyethylene glycol monostearate and / or polyethylene glycol-15 hydroxystearate.

[0016] The weight parts of the components of the dripping pills of the present invention are as follows:

[0017] 1-60 parts of idebenone, 1-90 parts of polyethylene glycol, and 1-70 parts of a surfactant, preferably 3-50 parts of idebenone, 1-60 parts of polyethylene glycol, and 1-55 parts of a surfactant.

[0018] More preferably, the composition comprises 5 to 25 parts of idebenone, 5 to 60 parts of polyethylene glycol, and 5 to 55 parts of a surfactant. More preferably, the composition comprises 10 to 20 parts of idebenone, 5 to 50 parts of polyethylene glycol, and 5 to 50 parts of a surfactant.

[0019] In a specific example of the present invention, the dripping pills include the following ingredients in parts by weight: 10 parts of idebenone, 50 parts of polyethylene glycol 6000, and 40 parts of polyethylene glycol monostearate;

[0020] Alternatively, the dripping pills comprise the following ingredients in parts by weight: 10 parts of idebenone, 50 parts of polyethylene glycol 4000, and 40 parts of polyethylene glycol-15 hydroxystearate;

[0021] Alternatively, the dripping pills comprise the following ingredients in parts by weight: 10 parts of idebenone, 50 parts of polyethylene glycol 6000, and 40 parts of polyethylene glycol-15 hydroxystearate.

[0022] Another object of the present invention is to provide a pharmaceutical composition comprising the idebenone dropping pills of the present invention and pharmaceutically acceptable excipients. This composition can be further coated to form coated dropping pills and / or sized to form hollow capsules to form a capsule dosage form.

[0023] The idebenone dropping pills of the present invention are prepared by using solid dispersion technology to heat and melt idebenone and polyethylene glycol (a surfactant may be further added), then dripping them into a condensate to form the condensate, and then removing the condensate on the surface of the dropping pills. The steps are as follows:

[0024] S1. Heat idebenone, polyethylene glycol, and surfactant until melted, stir evenly, and let stand to defoam;

[0025] S2. After defoaming, drip the entire mixture through the dripper at a rate of 45 to 60 drops per minute, and cool in the condensate to form a solid.

[0026] Preferably, the heating temperature in S1 is 90°C and the stirring time is 1.5 hours. Preferably, the dropping pills in S2 are dripped at a rate of 45 to 50 drops per minute and the temperature of the condensate is 0°C.

[0027] The advantages of the present invention are as follows:

[0028] (1) The present invention has found that when using the melt-drop method to prepare dropping pills, the appearance of the dropping pills produced by combining most water-soluble matrices with oily condensates or non-aqueous matrices with aqueous condensates is difficult to meet the requirements, and most cannot form a complete spherical or quasi-spherical shape. Through extensive experimental screening, the present invention has found that dropping pills produced using polyethylene glycols as the matrix and methyl silicone oil, dimethyl silicone oil, or liquid paraffin as the condensate can all form a complete spherical shape.

[0029] (2) The present invention has found that the pellets made with polyethylene glycol as the matrix alone are difficult to stir evenly. Although the appearance of the pellets is round and there is no tailing phenomenon when the molecular weight of polyethylene glycol is low (polyethylene glycol 1000-1500), the hardness is relatively soft and will soften, deform and break as the temperature rises. When the molecular weight of polyethylene glycol increases (polyethylene glycol 4000-6000), the roundness of the appearance of the pellets decreases, and there is a tailing phenomenon, and the dissolution time becomes longer. In particular, when the drug loading of polyethylene glycol 6000 is only 10%, it cannot meet the provisions of the dissolution time limit of the pellets in the "Chinese Pharmacopoeia 2020 Edition". The present invention unexpectedly found that the above problems can be solved by adding surfactants. The use of surfactants can significantly shorten the dissolution time limit of the pellets.

[0030] (3) Due to the strong lipid solubility of idebenone, during the preparation of idebenone pellets, idebenone needs to be stirred in the molten matrix for 3 to 4 hours before it can be dissolved and dispersed in the matrix. The present invention found that the use of surfactants can significantly shorten the stirring time and reduce the content variation of the finished pellets. Shortening the stirring time to within 1.5 hours can also achieve good uniformity.

[0031] (4) By screening the matrix and condensate, optimizing the matrix and formulation, using polyethylene glycol as the matrix, and adding a surfactant, the present invention produces idebenone pellets with good roundness, no noticeable tailing, excellent solubility, and minimal content variation. Compared to tablets, oral films, capsules, oral liquids, etc. produced by existing technologies, the present invention provides a superior alternative for idebenone oral preparations. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 This is a photo of idebenone dripping pills made with PEG6000 as the matrix.

[0033] Figure 2 This is a photo of idebenone dripping pills made by adding polyethylene glycol monostearate to PEG6000 as the matrix.

[0034] Figure 3 Add polyethylene glycol-15 hydroxystearate to PEG6000 as a matrix Actual picture of the prepared idebenone pills.

[0035] Figure 4 This is a photo of idebenone dripping pills made with PEG4000 as the matrix.

[0036] Figure 5 This is a photo of idebenone drops made by adding polyethylene glycol monostearate to PEG4000 as the matrix.

[0037] Figure 6 Add polyethylene glycol-15 hydroxystearate to PEG4000 as a matrix Actual picture of the prepared idebenone pills. DETAILED DESCRIPTION

[0038] The specific steps of the present invention are described below by way of examples, but the specific implementation scheme is not limited by the examples.

[0039] Unless otherwise specified, the terms used in the present invention generally have the meanings commonly understood by those skilled in the art.

[0040] The present invention will be described in further detail below in conjunction with specific examples and with reference to data. It should be understood that these embodiments are only for illustrating the present invention and are not intended to limit the scope of the present invention in any way.

[0041] In the following examples, various processes and methods not described in detail are conventional methods well known in the art.

[0042] Unless otherwise specified, the raw materials, auxiliary materials and equipment described in the specific embodiments of the present invention are all known products and can be obtained by purchasing commercial products.

[0043] Example 1 Screening of different matrices and condensates

[0044] Preparation method:

[0045] S1. Heat the substrate to 90°C; add idebenone while stirring; stir for 3 hours; and allow to stand for defoaming;

[0046] S2. After defoaming, drip the entire mixture through the dripper at a rate of 45 drops per minute, cool and form in 0°C condensate, wipe off the condensate adhering to the surface, and obtain dripping pills.

[0047] The formation of pellets prepared with different non-aqueous matrices and aqueous condensates is shown in Table 1. The results show that the pellets prepared with non-aqueous matrices and aqueous condensates have unqualified appearance and cannot be spherical.

[0048] Table 1

[0049] Non-aqueous matrix Condensate Molding conditions stearic acid water The larger the drop distance, the larger the hemispherical shape and the more it floats on the surface. Glyceryl Monostearate water It can be spherical, melts at 90℃, but solidifies quickly. beeswax water It forms a spherical ellipsoid in water, but condenses quickly and solidifies within a few drops. Cetyl Alcohol (Cetyl Alcohol) water Rice-grain hemispherical Stearyl alcohol water Triangular hollow hemisphere

[0050] Table 2 shows the formation of pellets made from different aqueous matrices and oily condensates. In addition, the melting points of common aqueous matrices polyvinylpyrrolidone (PVP K30), urea, and β-cyclodextrin are 130°C, 132.7°C, and 255-265°C, respectively. They cannot be melted in a water bath and cannot be directly dripped. Sodium carboxymethyl starch cannot be melted when heated to 90°C and cannot be directly dripped. Note: Polyethylene glycol-15 hydroxystearate (trade name: Solutol-HS 15, abbreviated as ).

[0051] Table 2

[0052]

[0053]

[0054] The results showed that poloxamer 127, Span 85 / Span 80, polyethylene glycol-15 hydroxystearate, stearic acid, and polyethylene glycol monostearate had poor spheroidization in liquid paraffin and methyl silicone oil, while polyethylene glycol-15 hydroxystearate, polyoxyethylene monostearate, and polyethylene glycols all had poor spheroidization in dibutyl phthalate. Polyethylene glycols had good spheroidization in liquid paraffin, and were even better in methyl silicone oil and dimethyl silicone oil. Therefore, the present invention selected methyl silicone oil as the condensate and used polyethylene glycol 1000-6000 as the matrix to further study the dissolution time of the pills.

[0055] Example 2: Effects of polyethylene glycol matrices of different molecular weights on the properties of idebenone dripping pills

[0056] 1. Preparation of test pills

[0057] Weigh and prepare Idebenone Dropping Pills in the following proportions according to Table 3: Prescription 1 to Prescription 8.

[0058] Table 3

[0059]

[0060] Preparation method:

[0061] Prescriptions 1-8 were prepared using the following methods:

[0062] S1. Heat the substrate to 90°C; add idebenone while stirring; stir for 3 hours; and allow to stand for defoaming;

[0063] S2. After defoaming, the entire mixture was dripped through the dripper at a rate of 45 drops per minute. The mixture was cooled and formed in methyl silicone oil at 0°C. The condensate adhering to the surface was wiped off to obtain 3,000 dripping pills.

[0064] 2. Evaluation of the appearance quality of pills

[0065] Evaluation method: The appearance quality of the pills described in the prescription was evaluated, and the evaluation items included: hardness (-softer + moderate ++ harder), roundness of the pills (+round ++ more round), tailing of the pills (+tailing - no tailing), and uniformity (-uneven + uniform ++ more uniform).

[0066] 3. Determination of the dissolution time of the pills

[0067] Suspend a hanging basket for pellets from a metal stand via a stainless steel shaft at its upper end and immerse it in a 1000 ml beaker filled with artificial gastric fluid at 37 ± 1°C. Adjust the basket's position so that the screen is 25 mm from the beaker bottom when descending and 15 mm below the liquid level when ascending. Unless otherwise specified, place six test sample pellets into the glass tubes of the basket, one pellet per tube. Immediately initiate the disintegration tester and perform the disintegration test. The results are shown in Table 1.

[0068] Preparation method of artificial gastric juice: Take 16.4 ml of dilute hydrochloric acid, add about 800 ml of water and 10 grams of pepsin, shake well, and dilute with water to 1000 ml. Prepare before use.

[0069] 4. Results and Analysis

[0070] Table 4. Data on various properties of the pills

[0071] serial number Uniformity Roundness hardness Tailing Dissolution time (min) Prescription 1 - ++ - - 3.03 Prescription 2 - ++ - - 4.58 Prescription 3 - ++ - - 3.55 Prescription 4 - ++ - - 5.67 Prescription 5 - + ++ + 4.18 Prescription 6 - + ++ + 8.24 Prescription 7 - + ++ + 30.00 Prescription 8 - + ++ + 30.00

[0072] As shown in Table 4, using polyethylene glycol as the matrix alone results in poor uniformity of the pellets and makes it difficult to stir evenly. Although the pellets are round and free of tailing when the molecular weight of polyethylene glycol is low, they are soft and will soften, deform, and break as the temperature rises. When the molecular weight of polyethylene glycol increases, the roundness of the pellets decreases, and there is a tailing phenomenon, and the dissolution time becomes longer. In particular, when the drug loading of polyethylene glycol 6000 is only 10%, it cannot meet the requirements of the dissolution time limit of the pellets in the "Chinese Pharmacopoeia 2020 Edition".

[0073] Example 3: Effects of different surfactants on the properties of idebenone dripping pills

[0074] 1. Prepare idebenone dripping pills with different formulations according to the method of Example 2 (add surfactant in step S1). Weigh idebenone dripping pills formulations 15 to 58 according to the formulations in Table 5 below.

[0075] Table 5

[0076]

[0077]

[0078] Table 6 Data on properties of the pills

[0079]

[0080]

[0081]

[0082] These results indicate that the addition of surfactants has little effect on the properties of idebenone pellets prepared with a low-molecular-weight polyethylene glycol matrix, but can effectively improve the roundness, hardness, dissolution time, and tailing of idebenone pellets prepared with a high-molecular-weight polyethylene glycol matrix. While Tween (20, 60, 80), Span (20, 60, 80, 85), and Poloxamer (F68, F127) can improve roundness and tailing, they have no significant effect on dissolution time. Polyethylene glycol monostearate and polyethylene glycol-15-hydroxystearate not only improve uniformity, improve roundness, and improve tailing, but also significantly shorten the dissolution time of high-molecular-weight polyethylene glycol pellets, with polyethylene glycol-15-hydroxystearate being more effective.

[0083] Example 4: Effect of surfactant content on the properties of idebenone dripping pills prepared with high molecular weight polyethylene glycol

[0084] 1. Prepare idebenone dripping pills with different proportions according to the method of Example 3.

[0085] Weigh and prepare Idebenone Dropping Pills in the proportions of Formulations 59 to 64 according to Table 7 below.

[0086] Table 7

[0087]

[0088] Table 8 Data of the dripping pills

[0089] serial number Uniformity Roundness hardness Tailing Dissolution time (min) Prescription 59 - + ++ + 4.06 Prescription 60 - + ++ + 30.00 Prescription 61 ++ ++ + - 3.58 Prescription 62 ++ ++ + - 3.05 Prescription 63 ++ ++ + - 10.90 Prescription 64 ++ ++ + - 5.70

[0090] The actual picture of the dripping pills for prescriptions 59-64 is as follows Figures 1-6 shown.

[0091] The results in Table 8 show that increasing the dosage of polyethylene glycol monostearate or polyethylene glycol-15-hydroxystearate significantly shortens the dissolution time of pills prepared with a single high-molecular-weight polyethylene glycol matrix (PEG4000 or PEG6000). Furthermore, the appearance of the pills is significantly improved, and their uniformity is also significantly enhanced.

[0092] Example 5: Effects of different drug loadings on the properties of idebenone dripping pills

[0093] Based on the experimental results of Example 4, the drug loading of the pellets prepared using polyethylene glycol 4000 and polyethylene glycol 6000 as matrices was increased to further verify the improvement effect of surfactants on the pellets prepared using high molecular weight polyethylene glycol matrices (PEG4000 or PEG6000).

[0094] 1. Prepare idebenone dripping pills with different ratios according to the method of Example 3 (wherein the stirring time of S1 is shortened to 1.5 h).

[0095] Weigh and prepare Idebenone Dropping Pills in the proportions of Prescription 65 to Prescription 76 according to Table 9 below.

[0096] Table 9

[0097]

[0098] Table 10 Data of the dripping pills

[0099] serial number Uniformity Roundness hardness Tailing Dissolution time (min) Recipe 65 ++ ++ ++ - 3.01 Recipe 66 ++ ++ ++ - 5.85 Recipe 67 ++ ++ ++ - 14.38 Recipe 68 ++ ++ ++ - 5.38 Recipe 69 ++ ++ ++ - 16.70

[0100] Although the dissolution time of highly drug-loaded pills prepared with a high-molecular-weight polyethylene glycol matrix (PEG4000 or PEG6000) increases significantly with increasing drug loading, Table 10 shows that the addition of the surfactant polyethylene glycol-15 hydroxystearate significantly shortens the dissolution time while increasing the drug loading. Furthermore, due to the excellent solubility of polyethylene glycol-15 hydroxystearate in idebenone, the stirring time for preparing a uniform molten solution was shortened from 3 hours to 1.5 hours. The resulting idebenone pills exhibited minimal variability in content and a dissolution time of less than 17 minutes. Idebenone pills prepared with polyethylene glycol-15 hydroxystearate and PEG4000 or PEG6000 exhibited improved roundness, moderate hardness, and no tailing, while also exhibiting high drug loading, achieving the desired effect.

[0101] In summary, the present invention provides an idebenone dripping pill preparation, which has excellent uniformity and appearance quality, and has a high drug loading capacity and a short dissolution time.

[0102] The above contents are merely preferred embodiments of the present invention. For ordinary technicians in this field, according to the ideas of the present invention, there may be changes in the specific embodiments and their application scope. The contents of this specification should not be understood as limiting the present invention.

Claims

1. An idebenone dripping pill, characterized in that: The dropping pills include: idebenone, a matrix material and a surfactant, wherein the matrix material is selected from one or more of polyethylene glycol 4000-6000, and the surfactant is selected from polyethylene glycol monostearate and / or polyethylene glycol-15 hydroxystearate. The dropping pills are formed by condensation using a melt-drop method, and the condensate is selected from one or more of liquid paraffin, dimethyl silicone oil, and methyl silicone oil.

2. The dropping pill according to claim 1, characterized in that The matrix material is selected from polyethylene glycol 4000 and / or polyethylene glycol 6000.

3. The dropping pill according to claim 1, characterized in that The dropping pills comprise the following components in parts by weight: 1 to 60 parts of idebenone, 1 to 90 parts of a matrix material, and 1 to 70 parts of a surfactant.

4. The dropping pill according to claim 3, characterized in that The dropping pills comprise the following components in parts by weight: 5 to 25 parts of idebenone, 5 to 60 parts of matrix material, and 5 to 55 parts of surfactant.

5. The dropping pill according to claim 4, characterized in that The dropping pills comprise the following components in parts by weight: 10 to 20 parts of idebenone, 5 to 50 parts of matrix material, and 5 to 50 parts of surfactant.

6. The dropping pill according to claim 1, characterized in that The dripping pills include the following ingredients in parts by weight: 10 parts of idebenone, 50 parts of polyethylene glycol 6000, and 40 parts of polyethylene glycol monostearate; Alternatively, the dripping pills comprise the following ingredients in parts by weight: 20 parts of idebenone, 10 parts of polyethylene glycol 4000, and 10 parts of polyethylene glycol-15 hydroxystearate; Alternatively, the dripping pills comprise the following ingredients in parts by weight: 20 parts of idebenone, 40 parts of polyethylene glycol 6000, and 40 parts of polyethylene glycol-15 hydroxystearate.

7. A pharmaceutical composition, characterized in that Contains the idebenone dripping pills according to any one of claims 1 to 6 and pharmaceutically acceptable excipients.

8. Use of the idebenone dripping pills according to any one of claims 1 to 6 in the preparation of a medicament for treating liver fibrosis and non-alcoholic fatty liver disease.

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