CN102579355B - Mitoxantrone nano calcium hydrophosphate preparation and preparation method thereof - Google Patents
Mitoxantrone nano calcium hydrophosphate preparation and preparation method thereof Download PDFInfo
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- CN102579355B CN102579355B CN 201210073797 CN201210073797A CN102579355B CN 102579355 B CN102579355 B CN 102579355B CN 201210073797 CN201210073797 CN 201210073797 CN 201210073797 A CN201210073797 A CN 201210073797A CN 102579355 B CN102579355 B CN 102579355B
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Abstract
The invention relates to a mitoxantrone nano calcium hydrophosphate preparation and a preparation method thereof. The method comprises the following steps of: adding mitoxantrone into a calcium chloride aqueous solution, performing ultrasonic dispersion uniformly, adding the calcium chloride aqueous solution containing the mitoxantrone into an organic phase, and performing ultrasound treatment uniformly to obtain an emulsion A, wherein a molar ratio of calcium chloride to the mitoxantrone is (5:1)-(1:1), and the volume ratio of the calcium chloride aqueous solution to the organic phase is (1:50)-(1:200); adding a sodium hydrogen phosphate aqueous solution of which the volume is equal to that of the calcium chloride aqueous solution containing the mitoxantrone into the organic phase, and performing ultrasound treatment uniformly to obtain an emulsion B; adding the emulsion B into the emulsion A slowly under the condition of magneton stirring, and stirring for 0.5 to 2 hours; and adding the mixed solution into ethanol for demulsification, centrifuging, washing by using the ethanol, and drying samples naturally. A process for preparing the mitoxantrone nano calcium hydrophosphate preparation is simple, the particle diameter of the preparation is 40 to 150 nanometers, and the medicine carrying rate is 20 to 40 percent.
Description
Technical field
The present invention relates to medical technical field, relate to more specifically mitoxantrone nanometer calcium hydrogen phosphate preparation and preparation method thereof.
Background technology
Since the seventies in last century, China's cancer mortality is sustainable growth trend always, the annual number of dying from cancer is respectively 700,000,1,170,000 and 1,500,000 at the beginning of the seventies, the nineties and 21 century, and cancer has become the No.1 killer of serious threat China people ' s health.Therefore prevention and treatment cancer are the significant problems that China and even the whole world will face.
The chemotherapeutics that the treatment cancer is commonly used is a lot, and wherein mitoxantrone is that a kind of effectively antitumor drug, especially the treatment of breast carcinoma and malignant lymphoma is had good curative effect.Yet chemotherapeutics also can cause to the normal cell of human body great infringement in killing tumor cell, thereby causes other side effect, and human body is damaged.
MA is a kind of anthraquinone anti-cancer agent, and its structure and antitumaous effect and amycin are close, because of its without the amino sugar structure, do not produce free radical, and the inhibition lipid peroxidation arranged, therefore lower to cardiac toxicity.Its mechanism of action shows, visual MA is cell cycle nonspecific agent (CCNSA), and because it can kill the cancerous cell of any cell cycle, propagation all is suppressed with non-proliferative cell.Somatoblast is more responsive to this product than resting cell, and the S later stage is the most responsive to mitoxantrone.It is by following two kinds of mechanism to the effect of malignant cell:
(1) embed: as intercalator, thereby it can be embedded between the DNA base blocking dna synthetic with transcribe (transcription), cause the glue of DNA chain to connect and the destruction of chain structure.
(2) enzyme suppresses: can suppress the activity of II type topoisomerase (topoisomerase), thereby cause the disintegrate of genomic DNA.
The development of nanometer medicament is shaped with the problem that solves these long-term puzzlement people of chemical therapy toxic side effect of hoping.The nanometer medicament refers to utilize and has at least one dimension to be in nanoscale scope (1-100nm) in the three dimensions or be base material by the nano material that they consist of as elementary cell, comes medicament-carried and new medicinal preparation preparation.This novel pharmaceutical preparation can utilize high-permeability and retention effect (the enhanced permeability and retention effect of solid tumor, EPR), selectively permeate and be trapped in the tumor tissues position, thereby can increase drug effect and reduce system's side effect.Thereby we wish by the research to mitoxantrone nanometer calcium hydrogen phosphate preparation, can improve existing nanometer treatment technology with this.
Summary of the invention
The objective of the invention is to design and prepare a kind of novel mitoxantrone nanometer calcium hydrogen phosphate preparation.Present technique is compared with existing preparation method, and the calcium hydrogen phosphate nanoparticle that makes is more even, and particle diameter is less (100 nanometers are following) also, thereby better applied research can be arranged aspect pharmaceutical carrier.
The preparation method of mitoxantrone nanometer calcium hydrogen phosphate preparation, step is as follows:
1) configure respectively 100～900 mMs every liter calcium chloride and sodium hydrogen phosphate aqueous solution, for subsequent use.
2) get a certain amount of calcium chloride and add corresponding mitoxantrone (calcium chloride and mitoxantrone mol ratio are 5: 1～1: 1), after ultra-sonic dispersion is even, the calcium chloride water that will contain the mitoxantrone medicine joins in the corresponding organic facies (calcium chloride water and organic facies volume ratio are 1: 50～1: 200), ultrasonic even, form the A emulsion, for subsequent use.
3) get sodium hydrogen phosphate aqueous solution with the calcium chloride water equal volume that contains the mitoxantrone medicine, it joined in the corresponding organic facies amount and the step 2 of organic facies) organic facies of getting is identical, ultrasonicly evenly forms the B emulsion, and is for subsequent use.
4) under the condition that magneton stirs, the B emulsion is slowly added in the A emulsion, after the adding, stirred 0.5～2 hour.
5) mixed solution in the step 4 is added breakdown of emulsion in the ethanol, then centrifugal, at last sample is dried naturally.
Annotate: wherein organic facies is by hexanol, and surfactant triton X-100 and cyclohexane extraction form according to volume ratio at 1: 1: 2.
Whole preparation process simple and fast, manufacturing cycle the longest is three hours, productive rate is high.Prepared mitoxantrone nanometer calcium hydrogen phosphate particle diameter is between 40 to 100 nanometers, and particle size distribution is even.
The present invention is with the advantage that traditional emulsion process prepares nanoparticle:
1, adopt this technique to prepare mitoxantrone nanometer calcium hydrogen phosphate preparation, preparation process is extremely simple.By calcium chloride and sodium hydrogen phosphate are formed emulsion with organic facies respectively, then with the method for two kinds of emulsion mix homogeneously, can greatly improve the stability of emulsion droplet in the emulsion, the more traditional emulsion process of the particle diameter of preparation is more even, thus use safer effectively.
2, prepared calcium hydrogen phosphate has good biocompatibility and biodegradability.Calcium hydrogen phosphate can be made calsium supplement and be taken by people, has safe and reliable performance, and under the acid condition of tumor tissues, calcium hydrogen phosphate can degrade rapidly to discharge the medicine of embedding, thereby improves therapeutic effect.
Therefore, compare with existing mitoxantrone pharmaceutical preparation, it is simple that the mitoxantrone nanometer calcium hydrogen phosphate preparation that the present invention relates to has preparation technology, the carrying drug ratio high, and the preparation particle diameter is between 40 to 150 nanometers, and carrying drug ratio is 20% to 40%.Be expected to effectively reduce the toxic and side effects of mitoxantrone, therefore the treatment of cancer is had extremely important researching value.
Description of drawings
Fig. 1: according to the stereoscan photograph of the mitoxantrone nanometer calcium hydrogen phosphate preparation of previous method preparation.
Fig. 2: according to the stereoscan photograph of the mitoxantrone nanometer calcium hydrogen phosphate preparation of embodiment 3 preparation.
The specific embodiment
The present invention is described further below in conjunction with specific embodiment.
Embodiment 1:
1) configure respectively 100 mMs every liter calcium chloride and sodium hydrogen phosphate aqueous solution, for subsequent use.
2) get 0.1 milliliter calcium chloride and add corresponding mitoxantrone (calcium chloride and mitoxantrone mol ratio are 5: 1), after ultra-sonic dispersion was even, the calcium chloride water that will contain the mitoxantrone medicine joined in 5 milliliters of organic faciess, and is ultrasonic even, form the A emulsion, for subsequent use.
3) get sodium hydrogen phosphate aqueous solution with the calcium chloride water equal volume that contains the mitoxantrone medicine, it is joined in 5 milliliters of organic faciess, ultrasonicly evenly form the B emulsion, for subsequent use.
4) under the condition that magneton stirs, the B emulsion is slowly added in the A emulsion, after the adding, stirred 2 hours.
5) mixed solution in the step 4 is added breakdown of emulsion in the ethanol, then centrifugal, at last sample is dried naturally.
Embodiment 2:
1) configure respectively 200 mMs every liter calcium chloride and sodium hydrogen phosphate aqueous solution, for subsequent use.
2) get 0.2 milliliter calcium chloride and add corresponding mitoxantrone (calcium chloride and mitoxantrone mol ratio are 5: 1), after ultra-sonic dispersion was even, the calcium chloride water that will contain the mitoxantrone medicine joined in 5 milliliters of organic faciess, and is ultrasonic even, form the A emulsion, for subsequent use.
3) get sodium hydrogen phosphate aqueous solution with the calcium chloride water equal volume that contains the mitoxantrone medicine, it is joined in 5 milliliters of organic faciess, ultrasonicly evenly form the B emulsion, for subsequent use.
4) under the condition that magneton stirs, the B emulsion is slowly added in the A emulsion, after the adding, stirred 2 hours.
5) mixed solution in the step 4 is added breakdown of emulsion in the ethanol, then centrifugal, at last sample is dried naturally.
Embodiment 3:
1) configure respectively 300 mMs every liter calcium chloride and sodium hydrogen phosphate aqueous solution, for subsequent use.
2) get 0.3 milliliter calcium chloride and add corresponding mitoxantrone (calcium chloride and mitoxantrone mol ratio are 3: 1), after ultra-sonic dispersion was even, the calcium chloride water that will contain the mitoxantrone medicine joined in 10 milliliters of organic faciess, and is ultrasonic even, form the A emulsion, for subsequent use.
3) get sodium hydrogen phosphate aqueous solution with the calcium chloride water equal volume that contains the mitoxantrone medicine, it is joined in 10 milliliters of organic faciess, ultrasonicly evenly form the B emulsion, for subsequent use.
4) under the condition that magneton stirs, the B emulsion is slowly added in the A emulsion, after the adding, stirred 1 hour.
5) mixed solution in the step 4 is added breakdown of emulsion in the ethanol, then centrifugal, at last sample is dried naturally.
The sample of preparation is compared with Fig. 1 of prior art production as shown in Figure 2, and particle diameter is more evenly controlled, all below 100 nanometers.
Embodiment 4:
1) configure respectively 450 mMs every liter calcium chloride and sodium hydrogen phosphate aqueous solution, for subsequent use.
2) get 0.3 milliliter calcium chloride and add corresponding mitoxantrone (calcium chloride and mitoxantrone mol ratio are 3: 1), after ultra-sonic dispersion was even, the calcium chloride water that will contain the mitoxantrone medicine joined in 10 milliliters of organic faciess, and is ultrasonic even, form the A emulsion, for subsequent use.
3) get sodium hydrogen phosphate aqueous solution with the calcium chloride water equal volume that contains the mitoxantrone medicine, it is joined in 10 milliliters of organic faciess, ultrasonicly evenly form the B emulsion, for subsequent use.
4) under the condition that magneton stirs, the B emulsion is slowly added in the A emulsion, after the adding, stirred 1 hour.
5) mixed solution in the step 4 is added breakdown of emulsion in the ethanol, then centrifugal, at last sample is dried naturally.
Embodiment 5:
1) configure respectively 600 mMs every liter calcium chloride and sodium hydrogen phosphate aqueous solution, for subsequent use.
2) get 0.5 milliliter calcium chloride and add corresponding mitoxantrone (calcium chloride and mitoxantrone mol ratio are 3: 1), after ultra-sonic dispersion was even, the calcium chloride water that will contain the mitoxantrone medicine joined in 10 milliliters of organic faciess, and is ultrasonic even, form the A emulsion, for subsequent use.
3) get sodium hydrogen phosphate aqueous solution with the calcium chloride water equal volume that contains the mitoxantrone medicine, it is joined in 10 milliliters of organic faciess, ultrasonicly evenly form the B emulsion, for subsequent use.
4) under the condition that magneton stirs, the B emulsion is slowly added in the A emulsion, after the adding, stirred 0.5 hour.
5) mixed solution in the step 4 is added breakdown of emulsion in the ethanol, then centrifugal, at last sample is dried naturally.
Embodiment 6:
1) configure respectively 750 mMs every liter calcium chloride and sodium hydrogen phosphate aqueous solution, for subsequent use.
2) get 0.5 milliliter calcium chloride and add corresponding mitoxantrone (calcium chloride and mitoxantrone mol ratio are 3: 1), after ultra-sonic dispersion was even, the calcium chloride water that will contain the mitoxantrone medicine joined in 20 milliliters of organic faciess, and is ultrasonic even, form the A emulsion, for subsequent use.
3) get sodium hydrogen phosphate aqueous solution with the calcium chloride water equal volume that contains the mitoxantrone medicine, it is joined in 20 milliliters of organic faciess, ultrasonicly evenly form the B emulsion, for subsequent use.
4) under the condition that magneton stirs, the B emulsion is slowly added in the A emulsion, after the adding, stirred 0.5 hour.
5) mixed solution in the step 4 is added breakdown of emulsion in the ethanol, then centrifugal, at last sample is dried naturally.
Embodiment 7:
1) configure respectively 900 mMs every liter calcium chloride and sodium hydrogen phosphate aqueous solution, for subsequent use.
2) get 0.5 milliliter calcium chloride and add corresponding mitoxantrone (calcium chloride and mitoxantrone mol ratio are 5: 1), after ultra-sonic dispersion was even, the calcium chloride water that will contain the mitoxantrone medicine joined in 20 milliliters of organic faciess, and is ultrasonic even, form the A emulsion, for subsequent use.
3) get sodium hydrogen phosphate aqueous solution with the calcium chloride water equal volume that contains the mitoxantrone medicine, it is joined in 20 milliliters of organic faciess, ultrasonicly evenly form the B emulsion, for subsequent use.
4) under the condition that magneton stirs, the B emulsion is slowly added in the A emulsion, after the adding, stirred 0.5 hour.
5) mixed solution in the step 4 is added breakdown of emulsion in the ethanol, then centrifugal, at last sample is dried naturally.
Embodiment 8:
Morphologic observation, particle diameter and measure of spread thereof.
Extracting sample solution takes out precipitate after ultracentrifugation separates, adding distil water makes dispersion on a small quantity, drips sample preparation on the carbon supporting film, under transmission electron microscope, observe its pattern state and take pictures, the result as described in Figure 2:
The microemulsion sample of getting preparation is an amount of, and then dilution measures microemulsion particle diameter and distribution with the particle size determination instrument.
Observe the spheroidal particle that mitoxantrone nano-calcium phosphate microemulsion is even rule under the transmission electron microscope.
The mitoxantrone nano-calcium phosphate microemulsion particle diameter that experiment records evenly distributes in the 40-100nm scope.
Embodiment 9:
The mensuration of drug loading
Get supernatant, add a certain amount of Hcl, make drug release out, measure the absorbance A of amycin, thereby obtained the content of minocycline hydrochloride by the concentration of the out medicine of the relation of drug level and absorbance, then:
Shown in the drug loading of this experiment is calculated as follows:
The amount of obtained Nano particles of calcium carbonate: 0.8-1mg, light absorption value X are 0.272-0.288, and the drug level computing formula is: the drug level that y=0.2192X+0.004 calculates is 0.06362-0.06713mg/ml
Medicine gross mass: 0.1909-0.2014
Claims (2)
1. the preparation method of a mitoxantrone nanometer calcium hydrogen phosphate preparation, step is as follows:
1) configure respectively 100～900 mMs every liter calcium chloride and sodium hydrogen phosphate aqueous solution, for subsequent use;
2) get calcium chloride water and add mitoxantrone, calcium chloride and mitoxantrone mol ratio are 5:1～1:1, after ultra-sonic dispersion is even, the calcium chloride water that will contain mitoxantrone joins in the organic facies, calcium chloride water and organic facies volume ratio are 1:50～1:200, ultrasonic even, form the A emulsion, for subsequent use;
3) get sodium hydrogen phosphate aqueous solution with the calcium chloride water equal volume that contains mitoxantrone, it joined in the organic facies amount and the step 2 of organic facies) organic facies of getting is identical, ultrasonicly evenly forms the B emulsion, and is for subsequent use;
4) under the condition that magneton stirs, the B emulsion is slowly added in the A emulsion, after the adding, stirred 0.5～2 hour;
5) mixed solution in the step 4) is joined breakdown of emulsion in the ethanol, then centrifugal and use washing with alcohol, at last sample is dried naturally;
Above-mentioned organic facies is by hexanol, and surfactant triton X-100 and cyclohexane extraction are according to volume ratio 1:1:2.
2. the mitoxantrone nanometer calcium hydrogen phosphate preparation of the method for claim 1 preparation is characterized in that the preparation particle diameter between 40 to 150 nanometers, and carrying drug ratio is 20% to 40%.
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