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CN110193013B - Deacetylmycoepoxyethane solid dispersion and preparation method thereof - Google Patents

Deacetylmycoepoxyethane solid dispersion and preparation method thereof Download PDF

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CN110193013B
CN110193013B CN201910590818.6A CN201910590818A CN110193013B CN 110193013 B CN110193013 B CN 110193013B CN 201910590818 A CN201910590818 A CN 201910590818A CN 110193013 B CN110193013 B CN 110193013B
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凌榕镔
陈秋君
邱恒涛
叶英
朱海健
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Lipin Pharmaceutical Xiamen Co ltd
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Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a solid dispersion of deacetylmycoepoxyethane and a preparation method thereof. The invention provides a solid dispersion of deacetylmycoepoxyethane, which comprises the following components: (a) the deacetyl fungal epoxyethyl ester with the structural formula shown as A or a derivative thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient,
Figure DDA0002116063710000011
(b) hydrophilic polymer carrier and (c) surfactant. According to the solid dispersion of the acetyl fungi epoxy ethyl ester provided by the invention, the solubilizing component is added, so that the absorption effect of the acetyl fungi epoxy ethyl ester is greatly improved, the utilization rate of the acetyl fungi epoxy ethyl ester is improved, and the solid dispersion has a good application prospect.

Description

Deacetylmycoepoxyethane solid dispersion and preparation method thereof
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a solid dispersion of deacetylmycoepoxyethane and a preparation method thereof.
Background
Breast cancer is a malignant tumor which occurs in mammary epithelial tissues, the number of new cases is about 167.1 ten thousand every year, the breast cancer is located at the beginning of female cancer, the incidence rate of the breast cancer in the whole world is always on an increasing trend from the end of the 70 th 20 th century, and the breast cancer is an important disease which threatens the health of women at present.
The deacetylmycoepoxydiene is fungus with skeleton obtained by separating fermentation liquor of marine mangrove endophytic fungus A123The compound has novel structure and is rare in natural products, and the chemical name of the compound is 2- (8-methyl-9-oxa-bicyclo [ 4.2.1)]Nona-2, 4-dien-7-yl) -6-oxo-3, 6-dihydro-2H-pyrone of formula C14H16O4Molecular weight is 248, and chemical structural formula is as follows:
Figure BDA0002116063690000011
the deacetylated fungi epoxyethyl ester has strong anti-tumor activity in animal in vitro and in vivo tests. According to the requirements of the technical guidance principle of non-clinical research of cytotoxic antitumor drugs issued by the national ministry of health, the evaluation of the in vivo and in vitro antitumor activity of the deacetylmycoepoxyethyl ester is carried out. Test results show that the in vitro cytotoxic activity range of the deacetylmycoepoxyethane to 14 tested tumor strains is 1-12 mu g/ml; animal in vivo tests of 4 tumor strains show that the deacetylmycoepoxyethyl has obvious or extremely obvious curative effects (the relative tumor proliferation rate T/C is less than 40%) on human breast cancer MCF-7 and breast cancer MDA-MB-231, which indicates that the deacetylmycoepoxyethyl has better curative effect on breast cancer, and in the therapeutic dose, the deacetylmycoepoxyethyl has no obvious influence on the body weight and organs of experimental animals, and indicates that the deacetylmycoepoxyethyl has lower toxic and side effects.
The deacetylmycoepoxyethane is a poorly soluble drug, has poor oral absorption, slow in vivo absorption and low bioavailability, and seriously influences the curative effect. The dissolution requirement can not be achieved by controlling the grain diameter of the deacetylmycoepoxyethane and the solubilization mode of the prescription.
Chinese patent CN101953808B discloses an injection of deacetylmycoepoxyethane and its preparation method, which comprises placing deacetylmycoepoxyethane, surfactant and suspending agent in a container, adding water, predispersing, homogenizing, adding freeze-drying protective agent, stirring to dissolve, subpackaging, freezing, and freeze-drying to obtain the final product.
A solid dispersion is a solid substance proposed in 1961 as a highly dispersed poorly soluble drug in a suitable solid carrier material. The solubility and the dispersion state of the medicine are one of main reasons influencing the bioavailability in vivo, and the solid dispersion technology can enable the medicine to form a highly dispersed state in a high molecular carrier, and can effectively increase the solubility and the dissolution speed of the insoluble medicine, thereby improving the bioavailability of the medicine.
The preparation method of the solid dispersion has various preparation methods and various and complicated optional auxiliary materials, and although a plurality of patents about the solid dispersion are published, applicable prescriptions and preparation processes selected for different drug properties are very different, and research and test are needed according to the characteristics of the drug. There has been no report on the solubilizing technique of ethyl oxiranate of acetylfungi so far.
Therefore, it is necessary to develop a solid dispersion of a desacetyl fungal oxiranyl ester compound with significantly improved bioavailability to solve the problem of poor absorption of the active ingredient by mammals.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a solid dispersion of deacetylmycoepoxyethane and a preparation method thereof. According to the solid dispersion of the acetyl fungi epoxy ethyl ester provided by the invention, the solubilizing component is added, so that the absorption effect of the acetyl fungi epoxy ethyl ester is greatly improved, the utilization rate of the acetyl fungi epoxy ethyl ester is improved, and the solid dispersion has a good application prospect.
The technical scheme of the invention is as follows:
a deacetylated fungal epoxyethyl ester solid dispersion, comprising:
(a) the deacetyl fungal epoxyethyl ester with the structural formula shown as A or a derivative thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient,
Figure BDA0002116063690000031
(b) hydrophilic polymer carrier and (c) surfactant.
Further, the weight ratio of (a), (b) and (c) is 1: (3-8): (0.1-2).
Further, the hydrophilic polymer carrier is methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose succinate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, potassium carboxymethylcellulose, cellulose acetate succinate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyacrylic acid copolymer, poly (meth) acrylic acid polymer, polyvinylpyrrolidone/povidone, vinylpyrrolidone homopolymer, vinylpyrrolidone copolymer, vinylpyrrolidone-vinylacetate copolymer, gelatin, sodium alginate, soluble starch, acacia, dextrin, hyaluronic acid, sodium chondroitin sulfate, propylene glycol alginate, sodium alginate, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl acetate, hydroxypropyl methylcellulose, polyvinyl acetate, polyvinyl pyrrolidone, polyvinyl acetate, polyvinyl alcohol, and the like, One or more of agar, tragacanth, xanthan gum, methacrylate copolymer, polyoxyethylene, polyoxypropylene, copolymer of ethylene oxide and propylene oxide, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene glycol, chitosan, polyvinylpyrrolidone-vinyl acetate copolymer, hydroxypropyl methyl cellulose acetate, and cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate; the surfactant is sodium dodecyl sulfate, sodium lauryl sulfate, polyoxyethylene sorbitan long-chain fatty acid ester, TPGS1000One or more of cholate, sodium glycocholate and polyoxyethylene-15 propylene glycol.
Further, the hydrophilic polymer carrier is one or more of a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, hydroxypropyl methyl cellulose, polyethylene glycol and copovidone; the surfactant is sodium dodecyl sulfate and TPGS1000One or two of them.
Further, the solid dispersion of the deacetylmycoepoxyethane can be prepared into tablets, patches, capsules, pills, granules or powder.
A preparation method of the solid dispersion of the deacetylmycoepoxyethane comprises the following steps:
s1, dissolving the (a), (b) and (c) serving as solutes in a solvent, and uniformly mixing to obtain a mixed solution;
s2, treating the mixed solution prepared in the step S1 by film cooling, spray coagulation, hot melt extrusion, melt coagulation, solvent evaporation or solvent melting method to obtain the product.
Further, the preparation method of the solid dispersion of the deacetylmycoepoxyethane comprises the following steps:
s1, dissolving the (a), (b) and (c) serving as solutes in a solvent, and uniformly mixing to obtain a mixed solution;
s2, treating the mixed liquid prepared in the step S1 by a spray drying method to obtain the plant growth regulator.
Further, the solvent in step S1 is selected from one or more of ethanol, acetone, isopropanol, methanol, dichloromethane, and chloroform; the solvent evaporation method in the step S2 is one of drying, vacuum drying, rotary evaporation, hot plate heating, spray drying, freeze drying, supercritical anti-solvent, co-precipitation, electrostatic spinning, spray cold drying, ultra-fast cold drying, and fluid bed coating.
Further, the volume ratio of the solute to the solvent in the step S1 is 10-50%; the solvent is one or two of acetone and ethanol.
Further, the deacetyl fungal epoxyethyl ester is amorphous deacetyl fungal epoxyethyl ester.
Compared with the prior art, the invention has the following beneficial effects:
(1) the solid dispersion of the acetyl fungi epoxy ethyl ester provided by the invention is simple in composition, and the bioavailability of the solid dispersion of the acetyl fungi epoxy ethyl ester compound can be obviously improved.
(2) The effective component of the deacetylated fungal epoxyethyl ester solid dispersion provided by the invention is a deacetylated fungal epoxyethyl ester amorphous structure, which is beneficial to the absorption and utilization of active components by human bodies, and further improves the utilization rate of the deacetylated fungal epoxyethyl ester solid dispersion.
(3) The preparation method of the deacetylated fungal epoxyethyl ester solid dispersion provided by the invention is simple and convenient to operate, easy to realize industrial production and good in application prospect.
Drawings
FIG. 1 XRPD patterns of formulas 1-1 ~ 1-5 and API in example 1, wherein a, b, c, d, e correspond to XRPD patterns of formula 1-1, formula 1-2, formula 1-3, formula 1-4 and formula 1-5, respectively, and wherein WL is 1.54060;
FIG. 2 XRPD patterns of prescriptions 2-1 to 2-4 and API in example 2, wherein a, b, c and d correspond to XRPD patterns of prescriptions 2-1, 2-2, 2-3 and 2-4 respectively, and WL is 1.54060;
FIG. 3 XRPD patterns for prescriptions 3-1 to 3-5 and API in example 3, a, b, c, d, e correspond to XRPD patterns for prescription 3-1, prescription 3-2, prescription 3-3, prescription 3-4 and prescription 3-5, respectively, wherein WL is 1.54060;
FIG. 4 XRPD patterns of formulas 4-1 to 4-3 and API in example 4, wherein a, b and c correspond to XRPD patterns of formula 4-1, formula 4-2 and formula 4-3, respectively, and WL is 1.54060.
Detailed Description
The present invention will be described in further detail with reference to the following examples. It should not be understood that the scope of the above-described subject matter of the present invention is limited to the following examples.
In the following examples, the deacetylmycoepoxyethyl ester is abbreviated as DAM, the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer is abbreviated as Soluplus, hydroxypropyl methylcellulose is abbreviated as HPMC, polyvinylpyrrolidone/povidone is abbreviated as PVP, polyethylene glycol is abbreviated as PEG, polyvinyl alcohol is abbreviated as PVA, sodium carboxymethylcellulose is abbreviated as CMC-Na, and sodium dodecyl sulfate is abbreviated as SDS.
Example 1 preparation of DAM solid Dispersion
The preparation method comprises the following steps: mixing DAM and Soluplus according to the proportion of the prescription in Table 1, adding 30% acetone solution (solid content is kept at 10%) of the prescription amount, and stirring to dissolve to obtain a mixed solution; the mixture was spray-dried with a spray dryer. The operating parameters are as follows: inlet temperature: 100 ℃, outlet temperature: 60 ℃, air suction force: 100%, nitrogen flow rate: 350L/h, feeding speed: 15 percent (5mL/min), taking out, and cooling to room temperature in a drier to obtain the solid dispersion.
Formulas 1-1 to 1-5 are described as examples 1-1 to 1-5, respectively.
Table 1 recipe ratio of example 1
Composition of Prescription 1-1 Prescription 1-2 Prescription 1-3 Prescription 1-4 Prescription 1-5
DAM(g) 5 5 5 5 5
Soluplus(g) 5 10 15 25 40
30% acetone (mL) 90 135 180 270 405
Composition ratio 1:1 1:2 1:3 1:5 1:8
Example 2 preparation of DAM solid Dispersion
The preparation method comprises the following steps: mixing DAM, Soluplus and TPGS1000Uniformly mixing according to the proportion of the prescription in the table 2, adding 30% acetone solution (keeping the solid content at 10%) of the prescription amount, and stirring to dissolve the acetone solution to prepare a mixed solution; the mixture was spray-dried with a spray dryer. The operating parameters are as follows: inlet temperature: 100 ℃, outlet temperature: 60 ℃, air suction force: 100%, nitrogen flow rate: 350L/h, feeding speed: 15 percent (5mL/min), taking out, and cooling to room temperature in a drier to obtain the solid dispersion.
Formulas 2-1 to 2-4 are described as examples 2-1 to 2-4, respectively.
Table 2 recipe ratio of example 2
Composition of Prescription 2-1 Prescription 2-2 Prescription 2-3 Prescription 2-4
DAM(g) 5 5 5 5
Soluplus(g) 25 25 25 25
TPGS1000(g) 0.1 0.5 2.5 10
30% acetone (mL) 225.9 229.5 247.5 315
Composition ratio 1:5:0.02 1:5:0.1 1:5:0.5 1:5:2
Example 3 preparation of DAM solid Dispersion
The preparation method comprises the following steps: mixing DAM, HPMC, PVP, PEG, PVA, CMC-Na, TPGS1000Uniformly mixing according to the proportion of the prescription in the table 3, adding 30% acetone solution (keeping the solid content at 10%) of the prescription amount, and stirring to dissolve the acetone solution to prepare a mixed solution; the mixture was spray-dried with a spray dryer. The operating parameters are as follows: inlet temperature: 100 ℃, outlet temperature: 60 ℃, air suction force: 100%, nitrogen flow rate: 350L/h, feeding speed: 15 percent (5mL/min), taking out, and cooling to room temperature in a drier to obtain the solid dispersion.
Formulas 3-1 to 3-5 are described as examples 3-1 to 3-5, respectively.
Table 3 recipe ratio of example 3
Figure BDA0002116063690000061
Figure BDA0002116063690000071
Example 4 preparation of DAM solid Dispersion
The preparation method comprises the following steps: mixing DAM, Soluplus, SDS, lecithin and sodium deoxycholate uniformly according to the proportion of the prescription in Table 4, adding 30% acetone solution (keeping the solid content at 10%) of the prescription amount, and stirring to dissolve the acetone solution to prepare a mixed solution; the mixture was spray-dried with a spray dryer. The operating parameters are as follows: inlet temperature: 100 ℃, outlet temperature: 60 ℃, air suction force: 100%, nitrogen flow rate: 350L/h, feeding speed: 15 percent (5mL/min), taking out, and cooling to room temperature in a drier to obtain the solid dispersion.
Formulas 4-1 to 1-3 are described as examples 4-1 to 1-3, respectively.
Table 4 recipe ratio of example 4
Composition of Prescription 4-1 Prescription 4-2 Prescription 4-3
DAM(g) 5 5 5
Soluplus(g) 25 25 25
SDS(g) 2.5
Lecithin (g) 2.5
Deoxycholic acid sodium salt (g) 2.5
30% acetone (mL) 270 270 270
Composition ratio 1:5:0.5 1:5:0.5 1:5:0.5
Example 5 preparation of DAM capsules
The preparation method comprises the following steps: DAM, the DAM solid dispersions of examples 1-4, the DAM solid dispersions of examples 2-1 to 2-4, the DAM solid dispersions of examples 3-1 to 3-5, and the DAM solid dispersions of examples 4-1 to 4-3 were filled in 0# capsules so that the amount of DAM in each capsule was 0.05g, and these were referred to as examples 5-1 to 5-14, respectively.
Test example I solubility test of DAM solid Dispersion and tablet
1. Test materials: DAM solid dispersions prepared in examples 1-1 to 4-3.
2. The test method comprises the following steps: respectively taking 100mg of test material solid dispersion samples, placing the samples in 20ml penicillin bottles, adding 10ml of purified water, magnetically stirring to dissolve the samples, respectively sampling for 0 hour, 18 hours and 24 hours, and detecting the content by using a high performance liquid chromatography, wherein the detection results are shown in Table 5.
TABLE 5 solubility comparison of different formulations
Figure BDA0002116063690000081
As can be seen from table 5, the solubility of the DAM solid dispersion is significantly better than that of the DAM as the raw material drug, and as can be seen from fig. 1 to 4, the DAM solid dispersion provided by the invention is amorphous and has high solubility, and meanwhile, the invention uses Soluplus, hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG) and copovidone (PVP) as hydrophilic polymer carriers, and uses TPGS1000And SDSThe solid dispersion prepared by the surfactant has the most obvious effect of improving the solubility of the DAM, and test results show that the solubility of the DAM solid dispersion provided by the invention is obviously improved, and the DAM solid dispersion has good application value.
Test example two animal drug test of DAM solid Dispersion
1. Test materials: DAM capsules prepared in example 5.
2. Test grouping and methods: 56 beagle dogs with the age of 10-12 months are selected and averagely divided into 14 groups, 4 dogs in each group are respectively administered with 10mg/kg of test material, the test material is recorded as an example 5-1 to 5-14, blood is taken before (0min) and 15min, 30min, 1h, 2h, 4h, 6h, 8h and 24h after each administration, the concentration of DAM in blood plasma is determined by an LC-MS/MS method, the AUC value of the prepared DAM solid dispersion is calculated, and the result of a pharmacokinetic test is shown in Table 6.
TABLE 6 comparison of bioavailability Effect of different prescription DAM tablets
Figure BDA0002116063690000091
As can be seen from Table 6, the AUC of each of examples 5-4 to 5-9 and examples 5-12 is higher than 956hr ng/ml and far higher than that of example 5-1, and the AUC of the rest of the components is lower than 763hr ng/ml, which shows that the DAM solid dispersion prepared by the invention has the advantages of remarkably improved absorptivity, remarkably increased utilization rate and good application prospect.
The foregoing embodiments are merely illustrative of the principles and utilities of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or change the above-mentioned embodiments without departing from the spirit and scope of the present invention. Accordingly, it is intended that all equivalent modifications or changes which can be made by those skilled in the art without departing from the spirit and technical spirit of the present invention be covered by the claims of the present invention.

Claims (6)

1. A deacetyl fungal epoxyethyl ester solid dispersion, comprising:
(a) the deacetyl fungus epoxy ethyl ester with the structural formula shown as A as an active ingredient, (b) a hydrophilic polymer carrier, (c) a surfactant;
Figure 565716DEST_PATH_IMAGE001
A
the weight ratio of (a), (b) and (c) is 1: (3-8): (0.1-2);
the hydrophilic polymer carrier is a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and the surfactant is TPGS1000；
Or, the hydrophilic polymer carrier is hydroxypropyl methyl cellulose, and the surfactant is TPGS1000；
Or the hydrophilic polymer carrier is polyvinylpyrrolidone, and the surfactant TPGS1000；
Or the hydrophilic polymer carrier is polyethylene glycol, and the surfactant is TPGS1000；
Or the hydrophilic polymer carrier is a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and the surfactant is sodium dodecyl sulfate;
the deacetylated fungal epoxy ethyl ester in the solid dispersion is amorphous deacetylated fungal epoxy ethyl ester.
2. The solid dispersion of desacetyl fungal oxiranes according to claim 1, wherein the solid dispersion of desacetyl fungal oxiranes is formulated as a tablet, patch, capsule, pill, granule or powder.
3. A method of preparing the solid dispersion of the deacetyl fungal oxiranyl ester according to any of claims 1-2, comprising the steps of:
s1, dissolving the (a), (b) and (c) serving as solutes in a solvent, and uniformly mixing to obtain a mixed solution;
s2, treating the mixed solution prepared in the step S1 by film cooling, spray coagulation, hot melt extrusion, melt coagulation, solvent evaporation or solvent melting method to obtain the product.
4. The method of preparing the solid dispersion of desacetyl fungal oxiranes according to claim 3, comprising the steps of:
s1, dissolving the (a), (b) and (c) serving as solutes in a solvent, and uniformly mixing to obtain a mixed solution;
s2, treating the mixed liquid prepared in the step S1 by a spray drying method to obtain the plant growth regulator.
5. The method for preparing the solid dispersion of the desacetylfungal epoxyethyl ester according to claim 3, wherein the solvent in the step S1 is one or more selected from ethanol, acetone, isopropanol, methanol, dichloromethane and chloroform; the solvent evaporation method in the step S2 is one of drying, vacuum drying, rotary evaporation, hot plate heating, spray drying, freeze drying, supercritical anti-solvent, co-precipitation, electrostatic spinning, spray cold drying, ultra-fast cold drying, and fluid bed coating.
6. The method for preparing the solid dispersion of the desacetyl fungal oxiranyl ester in accordance with claim 3, wherein the volume ratio of the solute to the solvent in the step S1 is 10-50%; the solvent is one or two of acetone and ethanol.
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