CN108338974B - BF061 solid dispersion, preparation method and application thereof in pharmacy - Google Patents
BF061 solid dispersion, preparation method and application thereof in pharmacy Download PDFInfo
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- CN108338974B CN108338974B CN201710055294.1A CN201710055294A CN108338974B CN 108338974 B CN108338974 B CN 108338974B CN 201710055294 A CN201710055294 A CN 201710055294A CN 108338974 B CN108338974 B CN 108338974B
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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Abstract
The invention belongs to the field of pharmaceutical preparations, and relates to a BF061 solid dispersion, a preparation method thereof and pharmaceutical application thereof. The solid dispersion comprises BF061 serving as an active ingredient and a high-molecular carrier material, wherein the high-molecular carrier material accounts for 70-90% of the mass of the BF061 solid dispersion, and is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, copolyvinylpyrrolidone-vinyl acetate, a porous silicon carrier, a polyoxyethylene polyoxypropylene ether block copolymer and the like. The determination result shows that the solid dispersion obviously improves the water solubility and the in vitro dissolution of BF 061; after the BF061 solid dispersion is orally taken by the SD rat, the blood concentration is obviously increased compared with that of the bulk drug; animal experiment results also show that the oral antithrombotic effect of the solid dispersion is equivalent to that of clopidogrel, but the bleeding side effect is obviously lower than that of clopidogrel, so that the solid dispersion is expected to be developed into a novel oral antiplatelet medicament for treating arterial thrombotic diseases such as coronary heart disease, stroke and the like.
Description
Technical Field
The invention belongs to the field of medicinal preparations, relates to a novel solid dispersion of an antiplatelet medicament BF061 and a preparation method thereof, and particularly relates to the BF061 solid dispersion and the preparation method thereof and application thereof in preparing oral preparations for preventing and treating arterial thrombotic diseases.
Background
The prior art discloses that stroke, coronary heart disease and other arterial thrombotic diseases become the first killer threatening the health of people in China with the improvement of living standard of people. Research shows that intravascular thrombosis caused by abnormal activation of platelets is the pathological basis of coronary heart disease and stroke of arterial thrombotic diseases, so that an antiplatelet drug for inhibiting platelet activation is a main means for preventing and treating the diseases; studies have also shown that the efficacy of antiplatelet drugs in coronary heart disease and stroke is established.
BF061 is an antiplatelet drug (CN 102617680A) studied before the invention and has P2Y12The receptor antagonism and phosphodiesterase inhibition dual activity, a mouse thrombus model experiment shows that the clopidogrel-containing compound has antithrombotic activity similar to that of clopidogrel, but the bleeding tendency is obviously reduced, the solubility in water is very low, and the dissolution of the drug become the rate-limiting process of the drug absorption. If administered orally, its bioavailability is inevitably low.
The solid dispersion technology is a dispersion system which is formed by highly dispersing a medicament in a solid carrier and exists in a solid form, and is mainly used for accelerating and increasing the dissolution of an insoluble medicament and improving the bioavailability of the insoluble medicament; the carrier material is generally a high molecular polymer, the property of the carrier material has great influence on the property of the solid dispersion, and the carrier material generally has the basic properties of no toxicity, no carcinogenicity, no influence on the stability of the medicine, no chemical change with the medicine, no influence on the medicine effect and content monitoring of the medicine, and the like. The solid dispersion is usually prepared by a solvent method, a melting method, a hot-melt extrusion method, or the like.
Based on the current situation of the prior art, the inventor of the application intends to provide a novel solid dispersion of an antiplatelet drug BF061 and a preparation method thereof, and particularly relates to a BF061 solid dispersion and a preparation method thereof and application thereof in preparing oral preparations for preventing and treating arterial thrombotic diseases.
Disclosure of Invention
The invention aims to provide a novel solid dispersion of an antiplatelet medicament BF061 and a preparation method thereof based on the defects in the prior art, and particularly relates to the BF061 solid dispersion, the preparation method thereof and application thereof in preparing oral preparations for preventing and treating arterial thrombotic diseases.
The invention provides a solid dispersion of a double-target anti-platelet drug BF061 and a preparation method thereof, and the prepared solid dispersion can be used for oral administration.
The invention adopts a new solid dispersion hot-melt extrusion preparation technology which is used in the field of pharmaceutical preparations in recent years, has simple process, no organic solvent and easy realization of industrial mass production; the preparation method of the invention adopts the high polymer material for preparing the solid dispersion by the hot-melt extrusion method, and particularly adopts Soluplus auxiliary material, so that the solubility and the in-vitro dissolution rate of the insoluble drug can be obviously improved.
Specifically, the invention provides a drug solid dispersion with anti-platelet activity, which is prepared from BF061 serving as an active ingredient and a high polymer carrier material, wherein the high polymer carrier material accounts for 70-90% of the mass of the BF061 solid dispersion,
in the invention, the high molecular carrier material is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), co-vinyl pyrrolidone vinyl acetate (VA64), porous silicon carrier (ParteckSLC 800), polyoxyethylene polyoxypropylene ether block copolymer (Pluronic F68);
the molecular formula of the active ingredient BF061 is shown as a formula I,
the method has the following formula I,
the molecular formula of the preferred high molecular carrier material Soluplus is shown as a formula II,
and (5) obtaining a second expression.
In the invention, the preparation method adopts a hot-melt extrusion method, and comprises the following steps:
BF061 and polymer carrier material are mixed and then added into a double-screw hot-melt extruder, the extrusion temperature of the hot-melt extruder is 120-160 ℃, the rotating speed of the screw is 30-100 r/min, and the mixture extruded by the hot-melt extruder is crushed to obtain the BF061 solid dispersion.
The solid dispersion comprises BF061 and an auxiliary material polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus). A preferred embodiment is to have a 1:5 ratio of BF061 to Soluplus. Further, the solid dispersion of the present invention may further comprise other water-soluble polymer excipients. The present invention further improves the physical properties of the solid dispersion by adding one or more water-soluble polymers. The water-soluble polymer is a water-soluble polymer commonly used in solid dispersions, and can be selected from the following polymers:
co-polyvinylpyrrolidone vinyl acetate (VA 64);
polyethylene glycol;
polyoxyethylene polyoxypropylene ether block copolymers;
polyvinylpyrrolidone;
hydroxyalkyl celluloses, such as hydroxymethyl cellulose;
hydroxyalkyl alkylcelluloses, such as hydroxypropylmethylcellulose.
The solid dispersion of the present invention is prepared by a hot-melt extrusion process.
The invention identifies the dispersion state of the medicine in the solid dispersion by X-ray diffraction (XRD) and Differential Scanning Calorimetry (DSC). The solubility and in vitro dissolution of the original drug and the solid dispersion drug are measured, and the result shows that the solid dispersion obviously improves the solubility and in vitro dissolution of BF 061. The change of blood concentration of SD rats after respectively taking BF061 bulk drug and the solid dispersion orally is measured. The anti-platelet aggregation and anti-thrombosis effects of the BF061 bulk drug, the solid dispersion and the clopidogrel which are respectively taken by SD rats are measured, and the severity of the bleeding side effect is compared. The result shows that the oral antithrombotic effect of the solid dispersion is equivalent to that of clopidogrel, but the bleeding side effect is far lower than that of clopidogrel, so that the solid dispersion is expected to be developed into a new generation of antiplatelet medicament, and can be used as an antithrombotic medicament for treating arterial thrombotic diseases such as coronary heart disease, stroke and the like.
The method of the invention does not need to use organic solvent, is environment-friendly and has no organic solvent residue.
Drawings
FIG. 1: x-ray diffraction pattern of BF061 solid dispersion powder of example 1;
FIG. 2: differential Scanning Calorimetry (DSC) of BF061 solid dispersion powder of example 1;
FIG. 3: dissolution curves of the BF061 solid dispersion and the bulk drug in 0.2% sodium dodecyl sulfate solution in example 1;
FIG. 4: the in vivo blood concentration time curve of BF061 solid dispersion and the bulk drug in example 1 after oral administration in SD rats.
Detailed Description
The raw materials used in the embodiment of the invention are as follows:
BF061 is synthesized by chemical series of the university of Compound Dan;
copolyvinylpyrrolidone vinyl acetate (VA64) was purchased from Pasteur, Germany;
the novel adjuvant polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus) was purchased from Pasteur Germany;
other reagent materials were purchased from national drug products, Inc
The invention is further illustrated by the following examples;
example 1 preparation of solid Dispersion 1 of BF061
The solid dispersion of the embodiment is prepared from BF061 and Soluplus which are used as active ingredients, wherein the Soluplus accounts for 83% of the mass of the BF061 solid dispersion;
2 g of BF061 and 10 g of Soluplus are uniformly mixed, the extrusion temperature of a double-screw hot-melt extruder is set to be 140 ℃, and the rotating speed of a screw is set to be 30 revolutions per minute. Adding the uniformly mixed materials into a hot-melt extruder, and extruding the mixture in a strip shape through a screw after the mixture is melted; cooling the hot-melt extruded strip-shaped objects, and then crushing and sieving the cooled strip-shaped objects by using a mortar to obtain BF061 solid dispersion 1 powder;
the solid dispersion powder prepared in this example was subjected to X-ray diffraction (as shown in FIG. 1) and Differential Scanning Calorimetry (DSC) (as shown in FIG. 2) to show that the drug was dispersed in the carrier material in an amorphous or molecular state.
Example 2 preparation of solid Dispersion 2 of BF061
The solid dispersion in the embodiment is prepared from BF061 serving as an active ingredient and co-polyvinylpyrrolidone vinyl acetate (VA64), wherein the VA64 accounts for 83% of the mass percentage of the BF061 solid dispersion;
1.5 g of BF061 and 7.5 g of VA64 were mixed uniformly, and the extrusion temperature of the twin-screw hot-melt extruder was set at 155 ℃ and the screw speed was set at 30 revolutions per minute. Adding the uniformly mixed materials into a hot-melt extruder, and extruding the mixture in a strip shape through a screw after the mixture is melted; and cooling the hot-melt extruded strip, and crushing and sieving the cooled strip by using a mortar to obtain BF061 solid dispersion 2 powder.
Example 3 preparation of solid Dispersion 3 of BF061
The solid dispersion in the embodiment is prepared from BF061 serving as an active ingredient and an auxiliary material porous silicon carrier (Parteck SLC 800), wherein the auxiliary material Parteck SLC800 accounts for 80% of the mass of the BF061 solid dispersion;
dissolving 0.5 g of BF061 in acetone to prepare a BF061 acetone solution, dropwise adding the solution into 2 g of adjuvant Parteck SLC800 while stirring, continuously stirring to volatilize the organic solvent, and repeating the steps. After drying overnight, the residual solvent was evaporated to give solid dispersion 3.
Example 4 preparation of solid Dispersion 4 of BF061
The solid dispersion in the embodiment is prepared from BF061 serving as an active ingredient and an auxiliary material polyoxyethylene polyoxypropylene ether block copolymer (Pluronic F68), wherein Pluronic F68 accounts for 83% of the mass of the BF061 solid dispersion;
1 g of BF061 was mixed homogeneously with 5 g of Pluronic F68, the heater temperature being set at 65 ℃. Melting the physically and uniformly mixed materials on a heater, stirring for 15 minutes, and continuously and uniformly mixing; after cooling, the obtained product was pulverized and sieved in a mortar to obtain BF061 solid dispersion 4 powder.
Example 5 solubilization of BF061 solid Dispersion
The equilibrium solubility of solid dispersions 1 and 2 in water is much higher than the bulk drug substance, as shown in table 1;
table 1: solubility of solid dispersions prepared with BF061 in combination with different excipients (Mean ± SD, n = 3).
| Solubility (. mu.g/ml) | |
| BF061 raw medicine | 22.2 ± 1.8 |
| Solid Dispersion 1 | 81.8 ± 3.2 |
| |
41.8 ± 2.5 |
| Solid Dispersion 3 | 21.9 ± 1.8 |
| |
25. 6 ± 2.4 |
The results in FIG. 3 show that: the dissolution rate of the solid dispersion 1 is obviously higher than that of the bulk drug.
Example 6 BF061 solid Dispersion 1 action of inhibiting platelet aggregation orally in rats
The purpose of this example is to demonstrate that oral administration of BF061 solid dispersion 1 to rats can inhibit ADP-induced platelet aggregation,
preparation of platelets:250-300 g SD rat takes BF061 solid dispersoid 1 in 100mg/kg dose orally, the anticoagulant adopts 3.8 percent sodium citrate solution, the plasma is obtained by centrifuging the 300 g for 5 minutes twice, the plasma is obtained by continuing to centrifuge the 900 g, and the number of the platelets is adjusted to be 2.5 × 10 by the plasma8Individual platelets/mL;
aggregation assay of platelets: platelet aggregation was performed in a platelet aggregation apparatus ((Model 400VS, Chrono-Log, Haverston, Pa.), setting parameters: stirring speed 900 rpm, temperature 37 ℃, adding 10 μ M ADP agonist, monitoring time of platelet aggregation curve was 5 minutes, and aggregation rate was defined as 100% of the normal saline control group;
as shown in Table 2, BF061 solid dispersion 1 was partially inhibited from aggregation of rat platelets induced by 10. mu.M ADP (Chono-log) when orally administered.
Table 2: BF061 solid dispersoid 1 can partially inhibit 10 mu M ADP-induced platelet aggregation of rats after being orally taken
| Group of | Platelet aggregation rate (n = 3) |
| Physiological saline control group | 95.8 ± 4.7％ |
| BF061 crude drug 100mg/kg oral administration group | 96.1 ± 8.3％ |
| BF061 solid dispersion 157 mg/kg oral group | 96.4 ± 10.8％ |
| BF061 solid dispersion 1100 mg/kg oral group | 62.5 ± 9.8 |
| Clopidogrel | |
| 10 mg/kg oral group | 39.5 ± 15.0％ |
Example 7 in vivo antithrombotic assay of BF061 solid Dispersion
A rat A-V shunt thrombus model is adopted to evaluate the oral antithrombotic effect of BF061 solid dispersion 1, 250 g of male SD rats are randomly divided into 5 groups, normal saline is respectively orally taken, 100mg/kg of BF061 bulk drug, 100mg/kg of BF061 solid dispersion 1 (prepared by Soluplus), 100mg/kg of BF061 solid dispersion 2 (prepared by Kollidon VA64), 10 mg/kg of clopidogrel are respectively taken, the carotid artery and the jugular vein of the rat are connected by a 15 cm long plastic tube, a6 cm long silk thread is arranged in the middle, blood is made to flow into the plastic tube for circulation for 15 min, and the result shows that the thrombus wet weight of the rats in all drug treatment groups is smaller than that in a normal saline control group (shown in table 3), wherein the BF061 solid dispersion 1 has the best effect and has a significant difference compared with the control group (the result of (the oral antithrombotic effect ofP< 0.01), no significant difference compared to clopidogrel group (P＞ 0.05）；
Experimental results prove that BF061 SD1 oral administration of 100mg/kg has stronger antithrombotic effect in the rat model, and the effect is similar to that of positive control clopidogrel.
Table 3: antithrombotic effect of BF061 solid dispersion after oral administration to rats
Example 8 bleeding tendency of BF061 solid Dispersion 1 after oral administration
Evaluating the bleeding side effect of BF061 by observing the bleeding time of the SD rat with the tail broken, wherein the whole observation time is 60min, and if the bleeding time exceeds 60min, the result is recorded as 60min, and is shown in Table 4;
compared with the normal saline control group, the bleeding time of the BF061 solid dispersion treatment group (intragastric administration of 100 mg/kg) has no significant difference, while the bleeding time of the rats of the clopidogrel treatment group (10 mg/kg, intragastric administration is performed 1 time in the first 1 day, intragastric administration is performed 1 time 2 hours in advance in the same day, and 2 times in total) exceeds 60min, and compared with the normal saline group and the BF061 SD group, the difference has significance, and the result combined with the rat antithrombotic model proves that: under the antithrombotic action similar to that of clopidogrel, the BF061 solid dispersion 1 has less bleeding side effect when being orally taken and hardly causes obvious bleeding.
Table 4: the BF061 solid dispersion 1 has obviously weaker side effect of oral hemorrhage than the clopidogrel
| Group of | Bleeding time (min) |
| Physiological saline control group (n = 7) | 11.2 ± 1.0 |
| BF061 solid dispersion 1100 mg/kg oral group (n = 6) | 15.9 ± 3.7 |
| |
60 ± 0 |
Example 9 BF061 solid Dispersion 1 exhibits an improved bioavailability compared to the crude drug substance
The results in fig. 4 show that in the pharmacokinetic experiments of SD rats, BF061 solid dispersion 1 prepared in example 1 has a higher peak value of blood concentration in vivo and a peak reaching time earlier than that of the bulk drug.
Claims (3)
1. A drug solid dispersion with anti-platelet activity is characterized in that the drug solid dispersion is prepared from BF061 serving as an active ingredient and a high polymer carrier material, wherein the high polymer carrier material accounts for 70-90% of the mass of the BF061 solid dispersion,
the polymer carrier material is selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), the molecular formula of the active ingredient BF061 is as shown in formula I,
the polymer carrier material is Soluplus with a molecular formula shown as a formula II
2. The method for preparing a pharmaceutical solid dispersion having antiplatelet activity according to claim 1, which comprises the steps of:
BF061 and polymer carrier material are mixed and then added into a double-screw hot-melt extruder, the extrusion temperature of the hot-melt extruder is 120-160 ℃, the rotating speed of the screw is 30-100 r/min, and the mixture extruded by the hot-melt extruder is crushed to obtain the BF061 solid dispersion.
3. Use of the pharmaceutical solid dispersion with antiplatelet activity according to claim 1 in the preparation of a medicament for preventing and treating arterial thrombotic diseases.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102204868A (en) * | 2011-05-18 | 2011-10-05 | 北京化工大学 | Hot-melt extrusion process for preparing indometacin quick release preparation from multi-element auxiliary materials |
| CN102617680A (en) * | 2011-02-01 | 2012-08-01 | 复旦大学 | Bi-functional antiplatelet aggregation medicine and application thereof |
| WO2012100654A1 (en) * | 2011-01-26 | 2012-08-02 | 北京化工大学 | Ribofuranosyl purine compound, preparation method therefor, and use thereof |
| CN102657617A (en) * | 2012-05-09 | 2012-09-12 | 北京化工大学 | Hot-melt extruded quick release preparation of nimesulide and hot-melt extruding method thereof |
-
2017
- 2017-01-24 CN CN201710055294.1A patent/CN108338974B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012100654A1 (en) * | 2011-01-26 | 2012-08-02 | 北京化工大学 | Ribofuranosyl purine compound, preparation method therefor, and use thereof |
| CN102617680A (en) * | 2011-02-01 | 2012-08-01 | 复旦大学 | Bi-functional antiplatelet aggregation medicine and application thereof |
| CN102204868A (en) * | 2011-05-18 | 2011-10-05 | 北京化工大学 | Hot-melt extrusion process for preparing indometacin quick release preparation from multi-element auxiliary materials |
| CN102657617A (en) * | 2012-05-09 | 2012-09-12 | 北京化工大学 | Hot-melt extruded quick release preparation of nimesulide and hot-melt extruding method thereof |
Non-Patent Citations (2)
| Title |
|---|
| BF061, a novel antiplatelet and antithrombotic agent targeting P2Y12 receptor and phosphodiesterase;Hu, Liang等;《Thrombosis and Haemostasis》;20110922;第106卷(第6期);第1203-1214页 * |
| BF061抗血小板、抗血栓作用及其机制的研究;胡亮;《万方数据知识服务平台》;20140318;全文 * |
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