CN114366723A - Microsphere containing pirarubicin hydrochloride as well as preparation method and application thereof - Google Patents
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Abstract
The invention belongs to the technical field of medical materials, and discloses a microsphere containing pirarubicin hydrochloride, a preparation method and application thereof. A microsphere containing pirarubicin hydrochloride comprises polyhydroxyalkanoate and pirarubicin hydrochloride loaded on the polyhydroxyalkanoate. The method adopts the polyhydroxyalkanoate to load the pirarubicin hydrochloride, and controls the proportion of an oil phase and a water phase in the preparation, the selection of the surfactant and the concentration of the surfactant, so that the prepared microspheres have uniform particle size and the encapsulation rate is more than 99.90 percent; the inhibition effect on the tumor is better than that of the pirarubicin hydrochloride injection.
Description
Technical Field
The invention belongs to the technical field of medical materials, and particularly relates to a pirarubicin hydrochloride-containing microsphere as well as a preparation method and application thereof.
Background
The methods for treating solid tumors are more, and related research reports are also more. Among the various treatments, chemotherapy remains one of the common options. Conventional chemotherapy, although used for a long time, has not established the therapeutic effect on solid tumors, and the fundamental problem is that conventional chemotherapy cannot achieve an effective drug concentration at the tumor site and maintain a sufficient duration of action. Because the effect of chemotherapy depends not only on the sensitivity of the drug, the action time and the drug concentration of the drug at the tumor site are more important, while the conventional chemotherapy can not achieve the above goal, and the inappropriate chemotherapy with low dose can not only induce the drug resistance of tumor cells, but also stimulate the diffusion and metastasis of tumors.
The local application of chemotherapy drugs, especially the local slow release, has become the focus of the current solid tumor chemotherapy. The local chemotherapy can prolong the action time of the medicine on the tumor part and improve the medicine concentration, thereby realizing the aim which cannot be realized by the conventional chemotherapy and reducing the chance of inducing the drug resistance generation of tumor cells or stimulating the tumor diffusion and metastasis due to the low-dose chemotherapy.
At present, the biodegradable sustained and controlled release preparation mostly uses solid polymers as sustained release carriers, such as polyglycolic acid, polylactic acid or copolymers thereof and the like. However, these sustained release carriers have certain limitations, such as poor hydrophilicity, large molecular polarity, poor processability, high price, uncontrollable degradation period and other disadvantages of polylactic acid (PLA).
Pirarubicin hydrochloride is an antitumor drug, and can be used for treating head and neck tumors, breast cancer, gastric cancer, bladder cancer, renal pelvis and ureter tumors, ovarian cancer, uterine cancer, acute leukemia and malignant lymphoma. The preparation of the sustained and controlled release preparation of the pirarubicin hydrochloride has more difficulties, and the prepared microspheres have nonuniform grain diameter and low entrapment rate by adopting polylactic acid as a sustained release carrier, thereby seriously influencing the sustained release and the good function of the medicament.
Therefore, it is highly desirable to provide a microsphere containing pirarubicin hydrochloride, which has uniform particle size, high encapsulation efficiency and good sustained release effect.
Disclosure of Invention
The present invention is directed to solving at least one of the problems of the prior art described above. Therefore, the invention provides the pirarubicin hydrochloride-containing microsphere which is uniform in particle size, high in encapsulation efficiency and good in slow release effect.
In a first aspect, the invention provides a microsphere containing pirarubicin hydrochloride.
Specifically, the microsphere containing pirarubicin hydrochloride comprises polyhydroxyalkanoate and pirarubicin hydrochloride loaded on the polyhydroxyalkanoate.
Preferably, the mass of the pirarubicin hydrochloride accounts for 1% -8% of the mass of the polyhydroxyalkanoate; more preferably, the mass of the pirarubicin hydrochloride accounts for 2% -5% of the mass of the polyhydroxyalkanoate.
Preferably, the polyhydroxyalkanoate is selected from at least one of a copolymer of hydroxybutyrate and hydroxyvalerate (PHBV), a copolyester of 3-hydroxybutyrate with 3-hydroxyhexanoate (phbhfx), a copolyester of 3-hydroxybutyrate and 4-hydroxybutyrate (P34HB), a copolymer of 3-hydroxybutyrate, 3-hydroxyhexanoate and 3-hydroxyvalerate (phvhhx), a polyhydroxyhexanoate (PHHx) or a Polyhydroxyoctanoate (PHO).
The invention provides a preparation method of a microsphere containing pirarubicin hydrochloride in a second aspect.
Specifically, the preparation method of the microsphere containing pirarubicin hydrochloride comprises the following steps:
dissolving polyhydroxyalkanoate and pirarubicin hydrochloride in a solvent, and mixing to obtain an oil phase;
dissolving a surfactant in water to obtain a water phase;
and mixing the oil phase and the water phase, homogenizing and curing to obtain the pirarubicin hydrochloride-containing microspheres.
Preferably, the solvent is selected from at least one of N-methylpyrrolidone, dichloromethane, chloroform or acetonitrile.
Preferably, the dissolving process is to dissolve the polyhydroxyalkanoate and the pirarubicin hydrochloride in the solvent respectively to obtain a polyhydroxyalkanoate solution and a pirarubicin hydrochloride solution.
Preferably, in the polyhydroxyalkanoate solution, the mass concentration of the polyhydroxyalkanoate is 10-50 mg/mL.
Preferably, in the pirarubicin hydrochloride solution, the mass concentration of the pirarubicin hydrochloride is 1-8 mg/mL.
Preferably, the surfactant is selected from at least one of an anionic surfactant, a cationic surfactant, or a nonionic surfactant. Further preferably, the surfactant is selected from at least one of stearic acid, sodium dodecylbenzenesulfonate, quaternary ammonium compounds, lecithin, betaine, alkyl glucoside (APG), fatty acid glyceride, fatty acid sorbitan (span), polysorbate (tween), or polyvinyl alcohol; more preferably, the surfactant is polyvinyl alcohol.
Preferably, in the water phase, the mass fraction of the surfactant is 1.8% -8%; further preferably, in the aqueous phase, the mass fraction of the surfactant is 1.8% -5%.
Preferably, the volume ratio of the oil phase to the aqueous phase is 1: (3-15); further preferably, the volume ratio of the oil phase to the aqueous phase is 1: (5-12).
In a third aspect, the invention provides an application of microspheres containing pirarubicin hydrochloride.
In particular to application of the microsphere containing pirarubicin hydrochloride in preparing anticancer drugs.
A medicament comprising said microspheres comprising pirarubicin hydrochloride.
Compared with the prior art, the invention has the following beneficial effects:
the method adopts the polyhydroxyalkanoate to load the pirarubicin hydrochloride, and controls the proportion of an oil phase and a water phase in the preparation, the selection of the surfactant and the concentration of the surfactant (polyvinyl alcohol), so that the prepared microspheres have uniform particle size, the encapsulation rate is more than 99.90 percent, and the in-vitro release time is more than or equal to 30 days; the inhibition effect on the tumor is better than that of the pirarubicin hydrochloride injection.
Drawings
FIG. 1 is a light mirror image of the emulsion obtained in step (3) of example 1;
FIG. 2 is a diagram of a light mirror during curing of the emulsion obtained in step (3) of example 1;
FIG. 3 is a photograph of a cured optical mirror of the emulsion obtained in step (3) of example 1;
FIG. 4 is a graph showing the distribution of the particle size of pirarubicin hydrochloride-containing microspheres prepared in example 1;
FIG. 5 is a light mirror image during curing of the emulsion obtained in step (3) of comparative example 1.
Detailed Description
In order to make the technical solutions of the present invention more apparent to those skilled in the art, the following examples are given for illustration. It should be noted that the following examples are not intended to limit the scope of the claimed invention.
The starting materials, reagents or apparatuses used in the following examples are conventionally commercially available or can be obtained by conventionally known methods, unless otherwise specified.
Example 1
A microsphere containing pirarubicin hydrochloride, wherein the pirarubicin hydrochloride is loaded by polyhydroxyalkanoate.
A preparation method of microspheres containing pirarubicin hydrochloride comprises the following steps:
(1) dissolving polyhydroxyalkanoate (3-hydroxybutyric acid and 4-hydroxybutyrate copolyester) in dichloromethane to prepare a polyhydroxyalkanoate solution with the mass concentration of 30mg/mL, and dissolving pirarubicin hydrochloride in dichloromethane to prepare a pirarubicin hydrochloride solution with the concentration of 3.4 mg/mL; then, 30mL of polyhydroxyalkanoate solution is mixed with 10mL of pirarubicin hydrochloride solution to obtain an oil phase.
(2) And (3) dissolving polyvinyl alcohol in water to obtain a water phase with the mass fraction of the polyvinyl alcohol being 2%.
(3) 30mL of the oil phase was poured into 280mL of the water phase, and stirred using an overhead stirrer with a stirring blade width of 6.5 cm. 300r/min, stirring for 42 min. Making it into a homogeneous emulsion. FIG. 1 is a light mirror image of an emulsion, and it can be seen from FIG. 1 that there are a plurality of microspheres in the emulsion, which are not yet cured. And then adding 280mL of water into the prepared emulsion, stirring by using an overhead stirrer, stirring at 180r/min for 40h, and volatilizing the organic solvent in an open beaker to solidify to obtain the pirarubicin hydrochloride-containing microspheres. FIG. 2 is a light mirror image during the emulsion curing process, and FIG. 3 is a light mirror image after the emulsion curing. FIG. 4 is a distribution diagram of the particle size of the prepared pirarubicin hydrochloride-containing microspheres, and as can be seen from FIG. 4, the average particle size of the microspheres is 56um, the span value is 0.68, the particle size is uniform and controllable, and the stability of treatment can be ensured.
Example 2
A microsphere containing pirarubicin hydrochloride, wherein the pirarubicin hydrochloride is loaded by polyhydroxyalkanoate.
A preparation method of microspheres containing pirarubicin hydrochloride comprises the following steps:
(1) dissolving polyhydroxyalkanoate (3-hydroxybutyric acid and 4-hydroxybutyrate copolyester) in dichloromethane to prepare a polyhydroxyalkanoate solution with the mass concentration of 30mg/mL, and dissolving pirarubicin hydrochloride in dichloromethane to prepare a pirarubicin hydrochloride solution with the concentration of 3.4 mg/mL; then, 30mL of polyhydroxyalkanoate solution is mixed with 10mL of pirarubicin hydrochloride solution to obtain an oil phase.
(2) And (3) dissolving polyvinyl alcohol in water to obtain a water phase with the mass fraction of the polyvinyl alcohol being 3%.
(3) 30mL of the oil phase was poured into 280mL of the water phase, and stirred using an overhead stirrer with a stirring blade width of 6.5 cm. 300r/min, stirring for 42 min. Making it into a homogeneous emulsion. And then adding 280mL of water into the prepared emulsion, stirring by using an overhead stirrer, stirring at 180r/min for 40h, and volatilizing the organic solvent in an open beaker to solidify to obtain the pirarubicin hydrochloride-containing microspheres.
Example 3
A microsphere containing pirarubicin hydrochloride, wherein the pirarubicin hydrochloride is loaded by polyhydroxyalkanoate.
A preparation method of microspheres containing pirarubicin hydrochloride comprises the following steps:
(1) dissolving polyhydroxyalkanoate (copolyester of 3-hydroxybutyric acid and 3-hydroxyhexanoic acid) in dichloromethane to prepare a polyhydroxyalkanoate solution with the mass concentration of 30mg/mL, and dissolving pirarubicin hydrochloride in dichloromethane to prepare a pirarubicin hydrochloride solution with the concentration of 3.4 mg/mL; then, 30mL of polyhydroxyalkanoate solution is mixed with 10mL of pirarubicin hydrochloride solution to obtain an oil phase.
(2) And (3) dissolving polyvinyl alcohol in water to obtain a water phase with the mass fraction of the polyvinyl alcohol being 2.5%.
(3) 30mL of the oil phase was poured into 280mL of the water phase, and stirred using an overhead stirrer with a stirring blade width of 6.5 cm. 300r/min, stirring for 42 min. Making it into a homogeneous emulsion. And then adding 280mL of water into the prepared emulsion, stirring by using an overhead stirrer, stirring at 180r/min for 40h, and volatilizing the organic solvent in an open beaker to solidify to obtain the pirarubicin hydrochloride-containing microspheres.
Example 4
A microsphere containing pirarubicin hydrochloride, wherein the pirarubicin hydrochloride is loaded by polyhydroxyalkanoate.
A preparation method of microspheres containing pirarubicin hydrochloride comprises the following steps:
(1) dissolving polyhydroxyalkanoate (copolyester of 3-hydroxybutyric acid and 3-hydroxyhexanoic acid) in dichloromethane to prepare a polyhydroxyalkanoate solution with the mass concentration of 40mg/mL, and dissolving pirarubicin hydrochloride in dichloromethane to prepare a pirarubicin hydrochloride solution with the concentration of 5.0 mg/mL; then, 30mL of polyhydroxyalkanoate solution is mixed with 10mL of pirarubicin hydrochloride solution to obtain an oil phase.
(2) And (3) dissolving polyvinyl alcohol in water to obtain a water phase with the mass fraction of the polyvinyl alcohol being 2.5%.
(3) 30mL of the oil phase was poured into 280mL of the water phase, and stirred using an overhead stirrer with a stirring blade width of 6.5 cm. 300r/min, stirring for 42 min. Making it into a homogeneous emulsion. And then adding 280mL of water into the prepared emulsion, stirring by using an overhead stirrer, stirring at 180r/min for 40h, and volatilizing the organic solvent in an open beaker to solidify to obtain the pirarubicin hydrochloride-containing microspheres.
Comparative example 1
Comparative example 1 differs from example 1 in that the mass fraction of polyvinyl alcohol in the aqueous phase is 1.5% and the rest of the preparation process is the same as in example 1.
Specifically, the preparation method of the composition containing pirarubicin hydrochloride comprises the following steps:
(1) dissolving polyhydroxyalkanoate (3-hydroxybutyric acid and 4-hydroxybutyrate copolyester) in dichloromethane to prepare a polyhydroxyalkanoate solution with the mass concentration of 30mg/mL, and dissolving pirarubicin hydrochloride in dichloromethane to prepare a pirarubicin hydrochloride solution with the concentration of 3.4 mg/mL; then, 30mL of polyhydroxyalkanoate solution is mixed with 10mL of pirarubicin hydrochloride solution to obtain an oil phase.
(2) And (3) dissolving polyvinyl alcohol in water to obtain a water phase with the mass fraction of the polyvinyl alcohol being 1.5%.
(3) 30mL of the oil phase was poured into 280mL of the water phase, and stirred using an overhead stirrer with a stirring blade width of 6.5 cm. 300r/min, stirring for 42 min. Making it into a homogeneous emulsion. And then adding 280mL of water into the prepared emulsion, stirring by using an overhead stirrer, stirring at 180r/min for 40h, and volatilizing the organic solvent in an open beaker to solidify to obtain the composition containing the pirarubicin hydrochloride. FIG. 5 is a light mirror image of the emulsion during the solidification process, wherein the emulsion is broken during the solidification process, and the prepared emulsion is unstable and can not be solidified into microspheres. As can be seen from comparative example 1, it is important to show the mass fraction of polyvinyl alcohol in the aqueous phase, and the polyvinyl alcohol with an appropriate concentration can stabilize the emulsion during the curing process without breaking the emulsion.
Comparative example 2
Comparative example 2 differs from example 1 in that 80mL of aqueous phase are taken and the preparation is otherwise the same as in example 1. Specifically, the preparation method of the composition containing pirarubicin hydrochloride comprises the following steps:
(1) dissolving polyhydroxyalkanoate (3-hydroxybutyric acid and 4-hydroxybutyrate copolyester) in dichloromethane to prepare a polyhydroxyalkanoate solution with the mass concentration of 30mg/mL, and dissolving pirarubicin hydrochloride in dichloromethane to prepare a pirarubicin hydrochloride solution with the concentration of 3.4 mg/mL; then, 30mL of polyhydroxyalkanoate solution is mixed with 10mL of pirarubicin hydrochloride solution to obtain an oil phase.
(2) And (3) dissolving polyvinyl alcohol in water to obtain a water phase with the mass fraction of the polyvinyl alcohol being 2%.
(3) 30mL of the oil phase was poured into 80mL of the water phase, and stirred using an overhead stirrer with a stirring blade width of 6.5 cm. 300r/min, stirring for 42 min. Making it into a homogeneous emulsion. And then adding 280mL of water into the prepared emulsion, stirring by using an overhead stirrer, stirring at 180r/min for 40h, and volatilizing the organic solvent in an open beaker to solidify to obtain the composition containing the pirarubicin hydrochloride.
Product effectiveness testing
The microspheres containing pirarubicin hydrochloride prepared in examples 1-4 and the composition containing pirarubicin hydrochloride prepared in comparative examples 1-2 are tested, and the test contents comprise: balling property, drug loading rate and encapsulation rate.
(1) Balling property
Whether or not balling can be realized is observed by a microscope in the preparation process. Tests show that the microspheres prepared by the methods provided in examples 1-4 have good sphericity. Whereas comparative examples 1 and 2 did not produce microspheres.
(2) Drug loading
The drug loading of the microspheres containing pirarubicin hydrochloride was tested by liquid chromatography.
Drug loading is the amount of drug contained in the microspheres/weight of the microspheres.
The test parameters are: an Elite Hypersil ODS 2C 18 column 5 μm, 4.6X 150mm, purified with methanol: water (50:50) as a mobile phase, at a flow rate of 1.0ml/min, at a wavelength of 237nm for ultraviolet detection.
And (3) testing results: pirarubicin hydrochloride is linear in the range of 0.005-0.35umol/ml, r is 0.9992, and the lowest detection limit is 0.005 umol/ml. The process recoveries at low, medium and high concentrations (0.03, 0.1, 0.3umol/ml) were 101.33%, 102.43% and 102.04%, respectively, with daytime and intraday RSD < 4% and 1%, respectively.
(3) Encapsulation efficiency
The encapsulation efficiency is the drug content of the microsphere/theoretical drug content of the microsphere.
The results of the drug loading and encapsulation efficiency tests are shown in table 1.
TABLE 1
| Example 1 | Example 2 | Example 3 | Example 4 | Comparative example 1 | Comparative example 2 | |
| Drug loading | 1.5％ | 1.5％ | 1.48％ | 1.49％ | / | / |
| Encapsulation efficiency | 99.92％ | 99.90％ | 99.95％ | 99.90％ | 0 | 0 |
As can be seen from Table 1, the microspheres prepared in examples 1 to 4 have a drug loading of 1.48% or more and an encapsulation efficiency of 99.90% or more; the comparative example can not prepare ideal microspheres and can not make the pirarubicin hydrochloride well release.
Meanwhile, the microsphere containing the pirarubicin hydrochloride provided by the invention is subjected to preliminary in vitro release time and in vivo tumor inhibition tests. The in vitro release time is tested by simulating a physiological environment; in vivo tumor inhibition test, the microsphere provided by the invention is compared with pirarubicin hydrochloride injection. Through preliminary experiments, the in vitro release time of the microsphere containing the pirarubicin hydrochloride is longer than 30 days, the tumor inhibition rate can reach more than 50%, and the effect of the microsphere is superior to that of the pirarubicin hydrochloride injection.
Claims (10)
1. The microsphere containing pirarubicin hydrochloride is characterized by comprising polyhydroxyalkanoate and pirarubicin hydrochloride loaded on the polyhydroxyalkanoate.
2. The microsphere of claim 1, wherein the pirarubicin hydrochloride is present in an amount of 1% to 8% by weight of the polyhydroxyalkanoate.
3. The microspheres of claim 1, wherein the polyhydroxyalkanoate is selected from at least one of a hydroxybutyrate and hydroxyvalerate copolymer, a 3-hydroxybutyrate copolyester with 3-hydroxyhexanoic acid, a 3-hydroxybutyrate and 4-hydroxybutyrate copolyester, a 3-hydroxybutyrate, 3-hydroxyhexanoic acid and 3-hydroxyvaleric acid copolymer, a polyhydroxyhexanoate or polyhydroxyoctanoate.
4. The method for preparing pirarubicin hydrochloride-containing microspheres according to any one of claims 1-3, comprising the steps of:
dissolving polyhydroxyalkanoate and pirarubicin hydrochloride in a solvent, and mixing to obtain an oil phase;
dissolving a surfactant in water to obtain a water phase;
and mixing the oil phase and the water phase, homogenizing and curing to obtain the pirarubicin hydrochloride-containing microspheres.
5. The preparation method according to claim 4, wherein the dissolving process comprises dissolving the polyhydroxyalkanoate and the pirarubicin hydrochloride in a solvent respectively to obtain a polyhydroxyalkanoate solution and a pirarubicin hydrochloride solution; preferably, the mass concentration of the polyhydroxyalkanoate is 10-50 mg/mL; the mass concentration of the pirarubicin hydrochloride is 1-8 mg/mL.
6. The method according to claim 4, wherein the surfactant is at least one selected from the group consisting of an anionic surfactant, a cationic surfactant and a nonionic surfactant.
7. The method according to claim 4, wherein the surfactant is present in the aqueous phase at a mass fraction of 1.8% to 8%.
8. The method according to claim 4, wherein the volume ratio of the oil phase to the aqueous phase is 1: (3-15).
9. Use of microspheres containing pirarubicin hydrochloride according to any one of claims 1 to 3 in the preparation of an anti-cancer medicament.
10. A medicament comprising microspheres containing pirarubicin hydrochloride according to any one of claims 1 to 3.
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