CN115944599A - Idebenone dripping pill and its application - Google Patents
Idebenone dripping pill and its application Download PDFInfo
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- CN115944599A CN115944599A CN202310060402.XA CN202310060402A CN115944599A CN 115944599 A CN115944599 A CN 115944599A CN 202310060402 A CN202310060402 A CN 202310060402A CN 115944599 A CN115944599 A CN 115944599A
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- polyethylene glycol
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- dripping pill
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- 239000006187 pill Substances 0.000 title claims abstract description 117
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
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Abstract
The invention discloses a dripping pill of idebenone, which comprises the following components: the idebenone dripping pill is prepared from idebenone, a matrix material and a surfactant, wherein the matrix material is selected from polyethylene glycols with different molecular weights, the surfactant is selected from polyethylene glycol monostearate and/or polyethylene glycol-15 hydroxystearate, the dripping pill is formed by condensation by a melt dripping method, and condensate is selected from one or more of liquid paraffin, dimethyl silicone oil and methyl silicone oil. The idebenone dripping pill prepared by screening the matrix material and the surfactant has good roundness, no obvious tailing, excellent solubility and small content difference. Compared with tablets, oral films, capsules, oral liquids and the like prepared by the prior art, the invention provides a better choice for idebenone oral preparations.
Description
Technical Field
The invention belongs to the technical field of medicines, and relates to an idebenone dripping pill and application thereof.
Background
Idebenone (Idebenone, IDB) with the chemical name 2- (10-hydroxydecyl) -5, 6-dimethoxy-3-methyl-1, 4-benzoquinone. The medicine was developed by Nippon martian industries, inc. in 80 s of the 19 th century, and belongs to the coenzyme Q10 derivatives. Idebenone activates brain mitochondrial activity in vivo, increases ATP production, and inhibits the production of peroxidized lipids by brain mitochondria, exerting antioxidant and other functions (Suno M and Nagaoka a, arch, gerntol, geriatr,1989, 8.
Idebenone functions in cells and tissues through two pathways: the cytochrome reductase (P450 detoxification enzyme) is subjected to single electron reduction to generate unstable semiquinone and further generate superoxide, so that the extremely strong toxicity is caused, and the pathway can be prevented by a two-electron reduction mechanism in cells; idebenone performs a two-electron reduction mechanism by NAD (P) H quinone oxidoreductase 1 (NQO 1), forming stable hydroquinones, and the activated molecule donates electrons to scavenge free radicals or activate the mitochondrial respiratory transport chain to produce ATP (Gueven and Woolley k.redox Biol,2015, 4.
Idebenone can be used for treating brain function damage caused by chronic cerebrovascular disease and brain trauma, and improving mental behavior disorders such as subjective symptom, language, anxiety, depression, hypomnesis, and intelligence decline. 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 research shows that idebenone has good therapeutic effect on a plurality of models of hepatic fibrosis and non-alcoholic fatty liver disease (NASH) (Wang Shuzhen, et al, CN112707806B; jiang, XJ. J Biochem Mol Toxicol,2021,35 (10): e 22876), and is expected to be used for treating hepatic fibrosis or NASH patients.
The currently approved oral formulation of idebenone on the market is idebenone tablets (30 mg/tablet). Idebenone is a strongly 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 bulky, difficult to swallow, poor in patient compliance and inconvenient for clinical use.
Hitherto, a great deal of research has been conducted on the prescription and process of idebenone preparations in the form of tablets, capsules and the like, but no attempt has been made to prepare idebenone into dripping pills. The dripping pill is a spherical or quasi-spherical preparation prepared by heating, melting and mixing the raw materials and matrix, and dripping into immiscible and non-interacting condensing medium. The dripping pill has the advantages of small volume, convenient carrying, oral or sublingual administration, good patient compliance, etc. However, there is a significant contradiction between the drug loading and the dissolution time of the drop pills, and the optimal balance must be achieved through systematic research and creative work on specific drugs. In addition, the preparation of the dripping pill also needs to overcome the problems of poor content uniformity, low roundness and the like caused by improper prescription or process.
Disclosure of Invention
The invention provides an idebenone dripping pill aiming at the defects of the prior art, and solves the problems of long dissolving time limit, poor roundness and the like in the preparation process of the idebenone dripping pill.
The specific technical scheme of the invention is as follows:
a dripping pill of idebenone is characterized in that the dripping pill comprises: idebenone and a matrix material, wherein the dripping pill is formed by condensation by a melting dripping method, and the condensate is selected from oil condensate.
The matrix material is selected from polyethylene glycols of different 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 1000-6000, and the condensate is preferably methyl silicone oil, dimethyl silicone oil or liquid paraffin.
According to a specific example of the present invention, the polyethylene glycol is one or more selected from polyethylene glycol 1000, polyethylene glycol 1500, polyethylene glycol 2000, polyethylene glycol 3000, polyethylene glycol 4000, and polyethylene glycol 6000.
The research of the invention finds that the prepared dripping pill is difficult to stir uniformly by singly using the polyethylene glycol as the matrix, and the dripping pill has round appearance and no trailing phenomenon when the molecular weight of the polyethylene glycol (1000-1500) is lower, but has soft hardness, and can be softened, deformed and cracked along with the rise of temperature. When the molecular weight of polyethylene glycol is increased (4000-6000), the roundness of the appearance of the dripping pill is reduced, a tailing phenomenon occurs, and the dissolving time is prolonged. Especially when polyethylene glycol 6000 is adopted, the drug loading is only 10 percent, and the requirement of the dissolution and dispersion time limit of the dropping pill in Chinese pharmacopoeia 2020 edition cannot be met.
The present inventors have surprisingly found that the above problems can be solved by adding a surfactant.
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 polyethylene glycol monostearate and/or polyethylene glycol-15 hydroxystearate.
The preferable dropping pill of the invention is selected from the following combinations: idebenone, polyethylene glycol 4000 and/or polyethylene glycol 6000, and polyethylene glycol monostearate and/or polyethylene glycol-15 hydroxystearate.
The dropping pill comprises the following components in parts by weight:
1-60 parts of idebenone, 1-90 parts of polyethylene glycol and 1-70 parts of surfactant. Preferably 3 to 50 parts of idebenone, 1 to 60 parts of polyethylene glycol and 1 to 55 parts of surfactant.
Further preferably, 5 to 25 parts of idebenone, 5 to 60 parts of polyethylene glycol and 5 to 55 parts of surfactant. (ii) a More preferably, the detergent composition comprises 10 to 20 parts of idebenone, 5 to 50 parts of polyethylene glycol and 5 to 50 parts of surfactant.
In a specific example of the invention, the dropping pill comprises the following components in parts by weight: 10 parts of idebenone, 6000 parts of polyethylene glycol and 40 parts of polyethylene glycol monostearate;
or, the dropping pill comprises the following components in parts by weight: 10 parts of idebenone, 4000 parts of polyethylene glycol and 40 parts of polyethylene glycol-15 hydroxystearate;
or, the dropping pill comprises the following components in parts by weight: 10 parts of idebenone, 6000 parts of polyethylene glycol and 40 parts of polyethylene glycol-15 hydroxystearate.
The invention also aims to provide a pharmaceutical composition which contains the idebenone dripping pill and pharmaceutically acceptable auxiliary materials. The composition can be further coated and processed into coated dripping pill and/or filled into empty capsule to be processed into capsule dosage form after controlling the size.
The idebenone dripping pill is prepared by heating and melting idebenone and polyethylene glycol (surfactant can be further added) by adopting a solid dispersion technology, dripping the idebenone and the polyethylene glycol into condensate, condensing and forming the idebenone and removing the condensate on the surface of the dripping pill, and specifically comprises the following steps:
s1, heating idebenone, polyethylene glycol and a surfactant to be molten, uniformly stirring, and standing for defoaming;
s2, after defoaming, dripping 45-60 drops of the whole mixture by a dripper every minute, and cooling and forming in a condensate.
Preferably, the heating temperature in the S1 is 90 ℃, and the stirring time is 1.5 hours. Preferably, 45 to 50 drops of the dripping pills in the S2 are dripped per minute, and the temperature of condensate is 0 ℃.
The advantages of the invention are as follows:
(1) The research of the invention finds that when the drop pill is prepared by using a melt dropping method, the appearance of the drop pill prepared by combining most of water-soluble substrates and oily condensate or non-aqueous substrates and aqueous condensate is difficult to meet the requirement, and most of the drop pills can not form complete spheres or sphere-like shapes. Through a large number of experimental screens, the invention discovers that the dropping pills prepared by using polyethylene glycols as a matrix and selecting methyl silicone oil, dimethyl silicone oil or liquid paraffin as a condensate can be in a complete spherical shape.
(2) The research of the invention finds that the dropping pill prepared by singly using the polyethylene glycol as the matrix is difficult to be uniformly stirred. Although the dropping pill has round appearance and no tailing phenomenon when the molecular weight of the polyethylene glycol is lower (1000-1500) the polyethylene glycol has soft hardness and can be softened, deformed and cracked along with the rise of the temperature. When the molecular weight of polyethylene glycol is increased (4000-6000 polyethylene glycol), the roundness of the appearance of the dropping pill is reduced, a tailing phenomenon exists, the dissolving time is prolonged, and especially when the medicine carrying capacity of the polyethylene glycol 6000 is only 10%, the dissolving time limit of the dropping pill in China pharmacopoeia 2020 edition cannot be met. The present inventors have surprisingly found that the above problems can be solved by adding a surfactant. The use of the surfactant can obviously shorten the dissolution time limit of the dripping pill.
(3) Because of the strong lipid solubility of idebenone, it is necessary to stir idebenone in a molten matrix for 3-4 hours during the preparation of idebenone dripping pills to dissolve and disperse idebenone in the matrix. The research of the invention finds that the use of the surfactant can also obviously shorten the stirring time, and the content difference of the finished dripping pills is small. Good homogeneity can also be achieved by reducing the stirring time to within 1.5 hours.
(4) According to the invention, through screening of the matrix and the condensate and optimization of the matrix and the formula, the polyethylene glycol is used as the matrix, and the surfactant is added, the prepared idebenone dropping pill has the advantages of good roundness, no obvious tailing, excellent solubility and small content difference. Compared with tablets, oral films, capsules, oral liquids and the like prepared by the prior art, the invention provides a better choice for idebenone oral preparations.
Drawings
FIG. 1 is a diagram of a real object of idebenone dripping pill prepared by PEG6000 as matrix.
FIG. 2 is a diagram of idebenone dripping pill prepared by adding polyethylene glycol monostearate into PEG6000 as matrix.
FIG. 3 shows PEG6000 as matrix added with polyethylene glycol-15 hydroxystearate
The obtained idebenone dripping pill is in physical picture.
FIG. 4 is a diagram of idebenone dripping pill prepared with PEG4000 as matrix.
FIG. 5 is a diagram of idebenone dripping pill prepared by adding polyethylene glycol monostearate into PEG4000 as matrix.
FIG. 6 shows PEG4000 as matrix with PEG-15 hydroxystearate
The obtained idebenone dripping pill is in physical picture.
Detailed Description
The specific steps of the present invention are illustrated below by way of examples, but the specific embodiments are not limited by the examples.
Terms used in the present invention generally have meanings commonly understood by those of ordinary skill in the art, unless otherwise specified.
The present invention is described in further detail below with reference to specific examples and with reference to the data. It will be understood that these examples are intended to illustrate the invention and are not intended to limit the scope of the invention in any way.
In the following examples, various procedures and methods not described in detail are conventional methods well known in the art.
Unless otherwise indicated, the raw materials and equipment described in the embodiments of the present invention are known products and can be obtained by purchasing commercially available products.
EXAMPLE 1 screening of different substrates and condensate
The preparation method comprises the following steps:
s1, heating a substrate to 90 ℃; adding idebenone while stirring; stirring for 3 hours; standing for defoaming;
s2, after defoaming, dripping 45 drops of the whole mixture by a dripper every minute, cooling and forming in a condensate at 0 ℃, wiping off the condensate adhered to the surface, and preparing the dripping pill.
The formation of the dripping pills from different non-aqueous bases and aqueous condensates is shown in Table 1. The results show that the dripping pills prepared from the non-aqueous substrate and the aqueous condensate have unqualified appearance and cannot be spherical.
TABLE 1
| Non-aqueous base | Condensate liquid | Molding conditions |
| Stearic acid | Water (W) | The larger the drop distance, the bigger the hemisphere is, and the hemisphere floats on the surface |
| Glyceryl monostearate | Water (W) | Can be formed into sphere-like shape, and can be melted at 90 deg.C, but can be solidified quickly |
| Beeswax | Water (W) | Spherical and ellipsoidal in water, but has fast condensation and solidified without dropping a few drops |
| Cetyl alcohol (cetyl alcohol) | Water (W) | Hemispherical grain shape |
| Stearyl alcohol | Water (W) | Triangular hollow hemisphere |
The formation of the dripping pills from different aqueous bases and oily condensates is shown in Table 2. In addition, the melting points of common aqueous matrix polyvinylpyrrolidone (PVP K30), urea and beta-cyclodextrin are 130 ℃, 132.7 ℃ and 255-265 ℃, respectively, and the water bath cannot reach a molten state and cannot be directly dripped; the carboxymethyl starch sodium can not be melted when heated to 90 ℃ and can not be directly dripped. Note: polyethylene glycol-15 hydroxystearate (trade name: solutol-HS 15, abbreviation)
)。
TABLE 2
The results show that poloxamer 127, span 85/span 80, polyethylene glycol-15 hydroxystearate, stearic acid and polyethylene glycol monostearate have poor sphericity in liquid paraffin and methyl silicone oil, and polyethylene glycol-15 hydroxystearate, polyoxyethylene monostearate and polyethylene glycols have poor sphericity in dibutyl phthalate. The polyethylene glycols have good balling property in liquid paraffin and are better in balling property in methyl silicone oil and dimethyl silicone oil. Therefore, the invention selects the methyl silicone oil as the condensate and takes the polyethylene glycol 1000-6000 as the matrix to further study the dissolution time limit of the dropping pill.
Example 2 Effect of polyethylene glycol bases of different molecular weights on the Properties of idebenone dropping pills
1. Preparing the dripping pills to be tested
The idebenone dripping pills are weighed as formula 1 to formula 8 according to the following mixture ratio of table 3.
TABLE 3
The preparation method comprises the following steps:
the following preparation methods are adopted in the formulas 1 to 8:
s1, heating a substrate to 90 ℃; adding idebenone while stirring; stirring for 3 hours; standing for defoaming;
and S2, after defoaming, dripping 45 drops of the whole mixture by a dripper per minute, cooling and forming in methyl silicone oil at the temperature of 0 ℃, wiping off condensate adhered to the surface, and preparing 3000 dropping pills.
2. Evaluation of appearance quality of dropping pill
The evaluation method comprises the following steps: evaluating the appearance quality of the dripping pills in the prescription, wherein the evaluation items comprise: hardness (-softer + moderate + + harder), pill roundness (+ round + + more round), pill tailing condition (+ tailing-no tailing), uniformity (-non-uniform + + more uniform).
3. Determination of dissolution time limit of dripping pill
Hanging a hanging basket special for the dropping pill on a metal support through a stainless steel shaft at the upper end, immersing the hanging basket into a 1000 ml beaker, wherein artificial gastric juice with the temperature of 37 +/-1 ℃ is contained in the beaker, adjusting the position of the hanging basket to enable a screen mesh to be 25mm away from the bottom of the beaker when the hanging basket descends, and adjusting the height of a liquid level to enable the screen mesh to be 15 mm below the liquid level when the hanging basket ascends. Except for other provisions, 6 samples were taken and placed in the glass tubes of the above hanging basket, 1 sample was added to each tube, and the disintegration tester was immediately started for examination, and the results are shown in table 1.
The preparation method of the artificial gastric juice comprises the following steps: taking 16.4 ml of dilute hydrochloric acid, adding about 800 ml of water and 10 g of pepsin, shaking up, adding water to dilute into 1000 ml, and preparing the traditional Chinese medicine composition before use.
4. Results and analysis
TABLE 4 drop pill Property data
| Number of | Uniformity of the film | Degree of roundness | Hardness of | Tailing situation | Dissolving time limit (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 |
As shown in Table 4, the uniformity of the prepared dripping pill is poor and it is difficult to stir uniformly by using polyethylene glycol alone as the matrix. Although the dropping pill has round appearance and no tailing phenomenon when the molecular weight of the polyethylene glycol is lower, the dropping pill has softer hardness and can be softened, deformed and cracked along with the rise of the temperature. When the molecular weight of polyethylene glycol is increased, the roundness of the appearance of the dropping pill is reduced, a tailing phenomenon exists, the dissolving time is prolonged, and particularly, when the medicine carrying quantity of polyethylene glycol 6000 is only 10%, the dissolving time limit of the dropping pill in Chinese pharmacopoeia 2020 edition cannot be met.
Example 3 Effect of different surfactants on idebenone drop pill Properties
1. Idebenone dripping pills with different proportions are prepared by the method in the example 2 (the surfactant is added in the step S1). The idebenone dripping pills are weighed according to the proportion of the following table 5, namely 15 to 58.
TABLE 5
TABLE 6 dropping pill Property data
The results show that the addition of the surfactant has little influence on the properties of the idebenone dripping pills prepared from the low molecular weight polyethylene glycol substrate, but can effectively improve the roundness, hardness, dissolving time limit and dripping pill tailing conditions of the idebenone dripping pills prepared from the high molecular weight polyethylene glycol substrate. Wherein, although tween (20, 60, 80), span (20, 60, 80, 85) and poloxamer (F68, F127) can improve roundness and tailing conditions, the dissolving time is not obviously influenced. The polyethylene glycol monostearate and the polyethylene glycol-15 hydroxystearate can not only improve the uniformity and improve the roundness and trailing conditions, but also obviously shorten the dissolving time of the high-molecular polyethylene glycol dripping pill, and the effect of the polyethylene glycol-15 hydroxystearate is better.
Example 4 Effect of surfactant content on Properties of idebenone drop pills made of high molecular weight polyethylene glycol
1. Idebenone dripping pills with different proportions are prepared by the method in the example 3.
The idebenone dripping pills are 59-64 in the proportion shown in the following table 7.
TABLE 7
TABLE 8 drop pill data
| Numbering | Uniformity of the film | Degree of roundness | Hardness of | Tailing situation | Dissolving time limit (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 |
The physical diagrams of the dripping pills of the formula 59-64 are shown in figure 1-figure 6.
From the results in table 8, it can be seen that increasing the dosage of polyethylene glycol monostearate or polyethylene glycol-15 hydroxystearate can significantly shorten the dissolution time limit of the dripping pills prepared from a single high molecular weight polyethylene glycol substrate (PEG 4000 or PEG 6000). In addition, the appearance of the dripping pill is obviously improved, and the uniformity is also obviously improved.
Example 5 Effect of different drug Loading on idebenone drop pill Properties
Based on the experimental result of example 4, the drug loading of the dropping pill prepared by using polyethylene glycol 4000 and polyethylene glycol 6000 as the matrix is increased, and the improvement effect of the surfactant on the dropping pill prepared by using the high molecular weight polyethylene glycol matrix (PEG 4000 or PEG 6000) is further verified.
1. Idebenone dripping pills with different proportions are prepared by the method in the reference example 3 (wherein the stirring time of S1 is shortened to 1.5 h).
The idebenone dripping pill formula 65-formula 76 is weighed according to the following mixture ratio of the following table 9.
TABLE 9
TABLE 10 drop pill data
| Numbering | Uniformity of the film | Degree of roundness | Hardness of | Tailing situation | Dissolving time limit (min) |
| Formulation 65 | ++ | ++ | ++ | - | 3.01 |
| Formulation 66 | ++ | ++ | ++ | - | 5.85 |
| Formulation 67 | ++ | ++ | ++ | - | 14.38 |
| Formulation 68 | ++ | ++ | ++ | - | 5.38 |
| Formulation 69 | ++ | ++ | ++ | - | 16.70 |
Although the dissolution time of the high drug loading dropping pill prepared by the high molecular weight polyethylene glycol substrate (PEG 4000 or PEG 6000) is obviously prolonged along with the increase of the drug loading, as can be seen from Table 10, the dissolution time limit of the dropping pill is obviously shortened while the drug loading of the dropping pill is improved by adding the surfactant polyethylene glycol-15 hydroxystearate. In addition, due to the good solubility of the polyethylene glycol-15 hydroxystearate to the idebenone, the stirring time for preparing a uniform molten medicine liquid is shortened from 3 hours to 1.5 hours, the content difference of the prepared idebenone dripping pills is smaller, and the dissolution time limit is shortened to be within 17 minutes. The idebenone dripping pill prepared from the polyethylene glycol-15 hydroxystearate and PEG4000 or PEG6000 has better roundness, moderate hardness and no tailing condition, and has the characteristic of high drug loading rate, thereby achieving ideal effect.
In conclusion, the invention provides an idebenone dripping pill preparation which has excellent uniformity and appearance quality, high drug loading capacity and short dissolving time.
The above description is only a preferred embodiment of the present invention, and it should be understood that the present invention is not limited to the above description, which should be interpreted as a limitation, for a person skilled in the art to which the present invention pertains, and the following detailed description of the present invention and the accompanying drawings are included.
Claims (10)
1. A dripping pill of idebenone is characterized in that the dripping pill comprises: the idebenone dripping pill is prepared from idebenone, a matrix material and a surfactant, wherein the matrix material is selected from polyethylene glycols with different molecular weights, the surfactant is selected from polyethylene glycol monostearate and/or polyethylene glycol-15 hydroxystearate, the dripping pill is formed by condensation by a melt dripping method, and condensate is selected from one or more of liquid paraffin, dimethyl silicone oil and methyl silicone oil.
2. The dripping pill according to claim 1, wherein the matrix material is selected from one or more of polyethylene glycol 1000 to 6000.
3. The dripping pill according to claim 2, wherein the matrix material 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.
4. The dripping pill according to claim 3, wherein the dripping pill is selected from the group consisting of: idebenone, polyethylene glycol 4000 and/or polyethylene glycol 6000, polyethylene glycol monostearate and/or polyethylene glycol-15 hydroxystearate.
5. The dripping pill according to claim 1, wherein the dripping pill comprises the following components in parts by weight: 1-60 parts of idebenone, 1-90 parts of polyethylene glycol and 1-70 parts of surfactant.
6. The dripping pill according to claim 5, wherein the dripping pill comprises the following components in parts by weight: 5-25 parts of idebenone, 5-60 parts of polyethylene glycol and 5-55 parts of surfactant.
7. The dripping pill according to claim 6, wherein the dripping pill comprises the following components in parts by weight: 10-20 parts of idebenone, 5-50 parts of polyethylene glycol and 5-50 parts of surfactant.
8. The dripping pill according to claim 1, wherein the dripping pill comprises the following components in parts by weight: 10 parts of idebenone, 6000 parts of polyethylene glycol and 40 parts of polyethylene glycol monostearate;
or, the dropping pill comprises the following components in parts by weight: 20 parts of idebenone, 10 parts of polyethylene glycol 4000 and 10 parts of polyethylene glycol-15 hydroxystearate;
or, the dropping pill comprises the following components in parts by weight: 20 parts of idebenone, 6000 parts of polyethylene glycol and 40 parts of polyethylene glycol-15 hydroxystearate.
9. A pharmaceutical composition characterized by comprising the idebenone dripping pill of any one of claims 1 to 8 and a pharmaceutically acceptable adjuvant.
10. Use of idebenone dripping pill as claimed in any one of claims 1 to 8 in the preparation of a medicament for the treatment of liver fibrosis and non-alcoholic fatty liver disease.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310060402.XA CN115944599A (en) | 2023-01-17 | 2023-01-17 | Idebenone dripping pill and its application |
| PCT/CN2023/136542 WO2024152776A1 (en) | 2023-01-17 | 2023-12-05 | Idebenone dripping pill and use thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202310060402.XA CN115944599A (en) | 2023-01-17 | 2023-01-17 | Idebenone dripping pill and its application |
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| WO (1) | WO2024152776A1 (en) |
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|---|---|---|---|---|
| WO2024152776A1 (en) * | 2023-01-17 | 2024-07-25 | 中国药科大学 | Idebenone dripping pill and use thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1891946A1 (en) * | 2006-08-14 | 2008-02-27 | Santhera Pharmaceuticals (Schweiz) AG | Transmucosal administration of 2,3-dimethoxy-5-methyl-6-(10-hydroxydecyl)-1,4-benzoquinone |
| EP2246048A1 (en) * | 2009-04-30 | 2010-11-03 | Santhera Pharmaceuticals (Schweiz) AG | Quinone derivative 2,3-dimethoxy-5-methyl-6-(10-hydroxydecyl)-1,4-benzoquinone for the treatment of primary progressive multiple sclerosis |
| CN115944599A (en) * | 2023-01-17 | 2023-04-11 | 中国药科大学 | Idebenone dripping pill and its application |
-
2023
- 2023-01-17 CN CN202310060402.XA patent/CN115944599A/en active Pending
- 2023-12-05 WO PCT/CN2023/136542 patent/WO2024152776A1/en unknown
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|---|---|---|---|---|
| WO2024152776A1 (en) * | 2023-01-17 | 2024-07-25 | 中国药科大学 | Idebenone dripping pill and use thereof |
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