WO2014090176A1 - Nanoscale platinum drug and preparation method thereof - Google Patents

Abstract

A nanoscale platinum drug particle and a preparation method thereof. In the nanoscale platinum drug particle, silicon dioxide aerogel is used as a carrier of the platinum drug. The silicon dioxide aerogel has porosity of 95% to 99%, a pore diameter of 10 to 50nm, a specific surface area of 200 to 1000 m²/g, and a density of 3 to 300 kg/m³; a colloidal particle diameter of a formed network is 1 to 50nm. The platinum drug is absorbed in pores of the silicon dioxide aerogel to form the nanoscale platinum drug particle with a diameter less than 100nm. The preparation method comprises: dissolving the platinum drug in a 1.5%(W/V) Nacl solution, adding the silicon dioxide aerogel, drying after complete adsorption, adding purified water and delivering the mixture to an emulsifying machine for emulsification, then homogenizing mixture by using a high-pressure homogenizer, and drying the obtained homogenate to obtain the nanoscale platinum drug particle.

Description

 Nano platinum drug and preparation method thereof

 Technical field

 The invention relates to an anti-tumor platinum medicine, in particular to a nano-scale platinum medicine and a preparation method thereof.

 Background technique

Chemotherapy is one of the important means to treat malignant tumors. Platinum drugs have important application value in the treatment of malignant tumors. The therapeutic mechanism mainly relies on the cytotoxic effect of platinum-based chemotherapy drugs on cells. Platinum drugs currently used mainly in clinical practice include cisplatin, a traditional platinum preparation, carboplatin, a substitute for cisplatin, and oxaliplatin. Platinum drugs are cell cycle non-specific drugs that act on cells. DNA The process of replication, and damage to its cell membrane, has a strong spectrum of anti-cancer effects, and is a first-line drug for genitourinary tumors, digestive tract tumors, and cancerous pleural effusions. It has been widely used in clinical practice and has become the most commonly used anticancer drug. one. In clinical applications, platinum drugs are usually administered intravenously, but because of the low quality of platinum drugs, they run too fast in the blood circulation, do not exert anticancer effects well, and intravenous administration, systemic chemotherapy It has large side effects and often has nephrotoxicity, myelosuppression and severe digestive tract reactions, such as frequent nausea and vomiting. Studies have shown that the concentration of cisplatin in tissues is consistent with its anticancer effects and toxic side effects.

People have been looking for an effective way to reduce the adverse effects of anti-tumor platinum drugs, such as changing the dosage form. Because the oral bioavailability of platinum drugs is extremely low, the preparation of oral platinum drugs has been a difficult problem that cannot be overcome in the pharmaceutical field at home and abroad. The research of nanomedicine is a new and vital direction in drug research. The drug is mainly loaded into the nano drug carrier by encapsulation and adsorption. Due to the size of the nano drug, the diameter of the capillary (6-8μm) is still small, so it can be easily introduced into various tissues and organs of the human body for controlled release, which greatly improves the bioavailability of the drug. Studies have shown that tumor tissue has a diameter of 100nm to 1000nm micropores, and in most normal healthy tissues, the intercellular gap is less than 10nm . Thus, by preparing drug-loaded nanoparticles between these two sizes, it is possible to selectively deliver the therapeutic agent to the tumor tissue.

The nano drug is a nano-sized particle prepared by dissolving, encapsulating or adsorbing the drug on a carrier, and the paclitaxel is made into a nano-particle preparation, which can greatly improve the absorption of paclitaxel. At present, there are many research reports on this direction, but it still fails to fundamentally solve the problem of low oral bioavailability of paclitaxel. After oral administration, a large part of nanoparticles are not absorbed and directly excreted, only a small part of nanometers. The granules are absorbed, and if the drug absorption fluctuates at a low level, the percentage error of the absorbed dose will be significant. For a given dose, if the particulate uptake exceeds the expected value, then the toxicity will occur; The amount of absorption is less or the drug concentration is lower than the therapeutic dose range, resulting in treatment failure.

 Summary of the invention

In view of the low solubility of platinum drugs, low oral bioavailability, and the serious toxic side effects of existing platinum drug injections, a first object of the present invention is to provide a novel nano-scale platinum drug particle.

In order to achieve the above object, the present invention provides a nano-scale platinum-based drug particle, characterized in that a silica aerogel is used as a carrier of a platinum-based drug, and the porosity of the silica aerogel is 95 ～. 99%, a pore diameter of 10 to 50 nm, a specific surface area of 200 to 1000 m ² /g, a density of 3 to 300 kg / m ³ , a colloidal particle diameter of 1 to 50 nm, and the platinum drug is adsorbed in the second The form in the pores of the silica aerogel forms platinum-based drug particles having a diameter of less than 100 nm.

 Further, the mass ratio of the platinum drug to the silica aerogel is 1: 0.5 to 20.

 The above-mentioned nano-sized platinum drug particles can be formulated into a pharmaceutically acceptable oral preparation.

 Further, the oral preparation is a tablet, a pill, a powder, a capsule, a granule or a suspension.

 The above-mentioned nano-sized platinum drug particles can be formulated into a pharmaceutically acceptable injection or suppository.

 Another object of the present invention is to provide a method for producing the above-described nano-scale platinum-based drug particles, characterized in that the method comprises the following steps:

 (1) dissolving the platinum drug in a 1.5% (w/v) NaCl solution;

 (2) adding a silica aerogel to the above NaCl solution;

 (3) after the platinum drug and the silica aerogel are completely adsorbed, dried;

 (4) adding purified water to the dried product, and feeding it into an emulsifier to emulsify;

 (5) feeding the emulsion obtained in the step (4) to a high-pressure homogenizer for homogenization;

 (6) After the homogenized liquid obtained in the step (5) is dried, nanometer-scale platinum drug particles are obtained.

 When the silica aerogel described in the step (2) is hydrophobic, it is necessary to pass 300 ～ before adding the NaCl solution. The heat treatment at 1000 ° C causes the alkyl group on the surface to disappear and is hydrophilic.

 Further, the ratio of the mass of the platinum drug to the volume of the 1.5% (w/v) NaCl solution is 1:5 ~ 200.

 Further, the drying in the step (3) is natural drying, oven drying or freeze drying.

 Further, the amount of purified water added in the step (4) is 20 to 200 ml/g of the platinum drug.

 Further, the drying in the step (6) is spray drying.

 Beneficial effects:

 1 For the first time, the present invention successfully prepares nano-scale platinum drugs by using silica aerogel as a carrier. Unlike the existing nano-scale platinum drugs, the nano-scale platinum drugs have a diameter of 100 nm. In the following, the nanometer level in the field of materials science is achieved, and it is a nano-scale platinum drug in the true sense. Although particles smaller than 1 μm in diameter are called nanoparticles, there is a tendency to develop particles smaller than 100 nm. Particles, because these particles will exhibit some unique physical properties and thus exhibit potentially different and useful biological properties. For example, due to the microcirculation of the capillaries of the body and the limitation of the cell barrier, the optimal particle size of the drug particles that can enter the blood circulation and be absorbed by the body is 10-100nm. Therefore, the nano-scale platinum-based drug of the present invention has a qualitative leap in bioavailability.

 2, the nano-scale platinum drug particles of the invention can be loaded up to 90% The above is that the existing liposome nanoparticles, polymer nanoparticles and the like are unmatched, and the drug loading amount is comparable to that of the nanocrystalline drug suspension, but the production method is simpler and the cost is lower.

 3. In the nano-scale platinum drug particles of the present invention, the platinum-based drug is loaded in numerous nano-scale cavities of the silica aerogel to form an independent group which does not agglomerate. 'Nanodispersion' The structure is extremely stable, which directly solves the international problem of preparation of micro-nano drug research, such as agglomeration cannot be medicine, and difficult-to-dissolve drugs are difficult to improve bioavailability. The nano-scale platinum drug is an efficient, low-toxic, economical, and has ' Targeting function of anti-tumor drugs, which are 'nanodispersed' The new physical mechanism solves the problem of dissolution and absorption of platinum drugs, making full use of its efficacy and unprecedented oral bioavailability, realizing the targeted aggregation from systemic toxicity to tumor sites in the treatment of platinum drugs against tumors. It solves the international pharmaceutical problems of low platinum biopharmaceutical injections with low bioavailability, poor side effects, poor efficacy and high treatment costs after decades of efforts at home and abroad.

 4 Oral anti-tumor drugs have long been regarded as the most advanced technology in the pharmaceutical field, and can not be attacked for decades. The nano-scale platinum-based medicine provided by the invention realizes a new oral mechanism with nano-uptake as the main absorption mode, and Nanosolid dispersion ' The new structure makes the solubility of platinum drugs greatly increased, and can be absorbed orally. It breaks through the international exclusion zone that platinum drugs can not absorb orally. For the first time, the bioavailability of oral replacement injection is directly realized at the material level. The emergence of platinum-based oral dosage forms in place of injections can make the family chemotherapy that people have been expecting for many years to be truly realized, bringing revolutionary advances in anti-tumor drugs. Moreover, under the premise that the original clinical drug and the original indication are unchanged or broader, the injection and oral administration meet the trend of the drug, the patient compliance is greatly improved, and it is easy to be clinically accepted. The oral dosage form overcomes the defects of the injection molding type manufacturing process, high requirements of workshop equipment and packaging, and high production cost.

 5 The precursor of the silica aerogel used as a carrier in the nano-scale platinum-based medicine of the present invention is a silicon which is inexpensive, easy to obtain, and has been widely used in medicines and foods, and has many years of use in national and international standards. The base medicine edible auxiliary material is also one of the excipients described in the "Handbook of Pharmaceutical Excipients", so the safety of the nano-scale platinum-based medicine of the present invention is reliable.

The antitumor effect of the nanoscale platinum-based drug of the present invention is demonstrated by an anti-tumor nude mouse experiment. The silica aerogels used in the experiments are all selected from silica aerogels having the following properties: porosity 95 to 99%, a pore diameter of 10 to 50 nm, a specific surface area of 200 to 1000 m ² /g, a density of 3 to 300 kg / m ³ , and a colloidal particle diameter of 1 to 50 nm.

1.  1. Material: Balb/c, nude mouse, female, weight (18±2) g , purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.; experimental cisplatin injection, purchased from Jiangsu Haosen Pharmaceutical Co., Ltd. (National Medicine Standard: H20040813); experimental nano-cisplatin as the embodiment of the present invention 1 The dry powder obtained.

1. 2. Establishment of animal model A sufficient amount of tumor cells were collected, resuspended in a centrifuge tube with PBS, and subcutaneously inoculated into the back of nude mice at 2 × 10 ⁶ cells/0.1 ml per spot.

1.  3. Experimental grouping and drug administration plan After the tumor model is established, the tumor diameter of the nude mice is 4 ~ 6mm, according to 5 / Group, group. Refer to the drug usage and dosage, the latest "Clinical Oncology Manual" related literature and previous experimental results, oral bioavailability according to 20% to 30% , determine the dosing regimen; blank group (only one, for each group), injection of cisplatin group, once a day, intraperitoneal injection; nano-cisplatin group, oral gavage, once a day.

1. 4. Detection method Animals were normally reared after administration, and the general state of the animals was observed every day, and the body weight of the animals was recorded. The tumor diameter (vernier caliper) was measured twice a week to calculate the tumor volume (v): v = ( ab ² ) /2 (where a is the long diameter of the tumor and b is the short diameter of the tumor). The relative tumors (RTV) of each group were compared: RTV=v _t /v ₀ , where v ₀ is the tumor volume measured on the day of the cage administration (Day 0 ), and v _t is the tumor volume at each measurement;

 The tumor inhibition rate (VIR) was calculated from the relative tumor volume: VIR= ( 1- RTV treatment group / RTV Negative control group) × 100%

 5. Experimental results

 5.1 cisplatin treatment of human metastatic nude mice liver cancer BEL-7402 experimental results are shown in Table 1 and Figure 4

 Table 1

Relative tumor inhibition rate %
	Dose	Time		4d		7d		11d		14d		17d		21d
24d	28d
Oral nano cisplatin	5mg/kg	A	44.05	34.16	43.47	24.5	20.59	30.96	21.13	15.38
	20mg/kg	B	31.85	33.94	69.9	74.5	76.34	74.08	70.94	52.21
Injection of cisplatin	1mg/kg	C	25.68	26.26	39.46	18.33	25.66	11.94	8.44	4.7

 Note: Oral nano-cisplatin 5mg/kg, after 14 days of administration, the drug was stopped for 7 days, and then continued for 9 days, 5 only / Group

 Oral nano-cisplatin 20mg/kg, 1 death, withdrawal after 14 days of administration, no longer administered, 5 / group;

 Cisplatin 1 mg/kg was injected, and the drug was discontinued for 7 days after 14 days of administration, and then continued for 9 days, 6 rats/group.

 5.2 cisplatin treatment of human metastasis in nude mice non-small cell lung cancer NCI-1299 experimental results are shown in Table 2 and Figure 5

 Table 2

Relative tumor inhibition rate %
Oral nano cisplatin	Dose		Time		4d		7d		11d	14d
	10mg/kg	A	-13.03	21.35	31.59	43.28

 Note: Oral nano-cisplatin 10mg/kg, administered for 14 days, weight loss 14.2%, 5 / group.

 5.3 Cisplatin treatment of human metastasis of cervical cancer in nude mice Hela results are shown in Table 3 and Figure 6

 table 3

Relative tumor inhibition rate %
	Dose		Time		4d		7d		11d
14d	17d
Oral nano cisplatin	10mg/kg	A	11.41	34.59	10.04	45.84	21.66
Injection of cisplatin	10mg/kg	B	22.36	Death after 4 days of continuous administration

 Note: Oral nano-cisplatin 10mg/kg, continuous administration for 14 days, no death, 5 / group.

 5.4 Discussion of results

 1. In the experiment, the anti-tumor drugs should be used as large as possible in order to quickly kill the characteristics of cancer cells, and the dosage according to the maximum tolerance (MTD) The anti-cancer effect of the positive control commercial drug is designed to achieve the best level, and the safety of the two drugs is compared with the anti-cancer effect of the oral nano drug of the present invention.

 2 The experimental results show that the relative tumor inhibition rate of the oral nano-preparation of the invention is superior to that of the commercial injection drug, and the side effects are also significantly reduced, suggesting that the oral nano-drug of the invention has a good effect of improving the quality of life and prolonging the survival of the patient.

 DRAWINGS

 Figure 1 is an electron micrograph of a silica aerogel of the present invention;

 Figure 2 is an electron micrograph of the cisplatin raw material solution;

 Figure 3 is a photomicrograph of a nanoscale cisplatin of the present invention;

 Figure 4 is a graph showing the relative tumor inhibition rate of human metastatic nude mouse liver cancer BEL-7402 in the results of an anti-tumor nude mouse experiment;

 Figure 5 is an experimental study of anti-tumor nude mice. Human metastasis nude mice non-small cell lung cancer NCI-1299 Relative tumor inhibition rate curve;

 Figure 6 is a graph showing the relative tumor inhibition rate of human metastatic nude mouse cervical cancer Hela in the results of an anti-tumor nude mouse experiment.

 detailed description

 The invention will be further described in detail below with reference to the accompanying drawings, which are intended to illustrate the invention.

The silica aerogels used in the following examples are each selected from silica aerogels having a porosity of 95 to 99%, a pore diameter of 10 to 50 nm, and a specific surface area of 200 to 1000 m ² /g. The density of the colloidal particles of the network is from 3 to 300 kg / m ³ and the diameter of the colloidal particles is from 1 to 50 nm.

 Example 1

 The nano-scale platinum drug of the present embodiment is prepared as follows:

 1 , cisplatin bulk drug (Shandong Platinum Pharmaceutical Co., Ltd.) 1g, adding 1.5% (w / v) of NaCl solution 20ml dissolved;

 2, adding 2 g of silica aerogel after heat treatment at 500 ° C for adsorption;

 3. After the adsorption is complete, dry in an oven at 60 ° C;

 4, after drying, add 100ml of purified water, 25000rpm / min ordinary emulsifier emulsified, 5min ;

 5, high pressure homogenizer (Shanghai Donghua GYB 30-6S), 400bar, cycle 6 times, 10min ;

 6. Spray the homogenized liquid in an experimental spray dryer (Shanghai Shunyi Science and Technology SP-1500). Parameters: temperature 130 ° C, flow rate 500ml / h, nozzle: 0.75mm, after drying to obtain nano-scale cisplatin particles.

 Example 2

 The nano-scale platinum drug of the present embodiment is prepared as follows:

 1. Carboplatin bulk drug (Shandong Platinum Pharmaceutical Co., Ltd.) 1g, adding 1.5% (w/v) NaCl solution 5ml dissolved;

 2. Add 0.5 g of silica aerogel after heat treatment at 1000 ° C for adsorption;

 3. After the adsorption is complete, it is naturally dry;

 4, after drying, add 20ml of purified water, 25000rpm / min ordinary emulsifier emulsified, 5min;

 5, high pressure homogenizer (Shanghai Donghua GYB 30-6S), 400bar, cycle 8 times, 10min ;

 6. Spray the homogenized liquid in an experimental spray dryer (Shanghai Shunyi Science and Technology SP-1500). Parameters: temperature 130 ° C, flow rate 500ml/H, nozzle: 0.75mm, after drying, nano-scale carboplatin particles were obtained.

 Example 3

 The nano-scale platinum drug of the present embodiment is prepared as follows:

 1 , oxaliplatin bulk drug (Shandong Platinum Pharmaceutical Co., Ltd.) 1g, adding 1.5% (w / v) of NaCl solution 150ml dissolved;

 2, adding hydrophilic silica aerogel 15g for adsorption;

 3. After the adsorption is complete, freeze-dry;

 4, after drying, add 150ml of purified water, 25000rpm/min emulsification machine, 5min ;

 5, high pressure homogenizer (Shanghai Donghua GYB 30-6S), 400bar, cycle 7 times, 10min ;

 6. Spray the homogenized liquid in an experimental spray dryer (Shanghai Shunyi Science and Technology SP-1500). Parameters: temperature 130 ° C, flow rate 500ml/H, nozzle: 0.75mm, after drying, nano-sized oxaliplatin particles were obtained.

 Example 4

 The nano-scale platinum drug of the present embodiment is prepared as follows:

 1 , cisplatin bulk drug (Shandong Platinum Pharmaceutical Co., Ltd.) 1g, adding 1.5% (w / v) of NaCl solution 200ml dissolved;

 2. Adding 20 g of silica aerogel after heat treatment at 300 ° C for adsorption;

 3. After the adsorption is complete, dry in an oven at 60 ° C;

 4, after drying, add 200ml of purified water, 25000rpm / min ordinary emulsifier emulsified, 5min ;

 5, high pressure homogenizer (Shanghai Donghua GYB 30-6S), 400bar, cycle 6 times, 10min ;

 6. Spray the homogenized liquid in an experimental spray dryer (Shanghai Shunyi Science and Technology SP-1500). Parameters: temperature 130 ° C, flow rate 500ml / h, nozzle: 0.75mm, after drying to obtain nano-scale cisplatin particles.

 Example 5

 The nano-scale platinum drug of the present embodiment is prepared as follows:

 1 , cisplatin bulk drug (Shandong Platinum Pharmaceutical Co., Ltd.) 1g, adding 1.5% (w / v) of NaCl solution 70ml dissolved;

 2. Add 7 g of silica aerogel after heat treatment at 700 ° C for adsorption;

 3. After the adsorption is complete, freeze-dry;

 4, another 6g of PEG-4000 is added to 400ml of absolute ethanol to dissolve;

 5. Add the lyophilized solid from step 3 to the above PEG-4000 ethanol solution and emulsify it for 3 minutes. ;

 6. Dry the emulsion of step 5 in a 60 ° C electric heating oven for 12 hours;

 7. Grinding step 6 The dried solid is passed through a 200 mesh sieve to obtain nano-sized cisplatin particles.

 Example 6

 Examples 1 to 5 The obtained nano-sized platinum drug particles are uniformly mixed with an appropriate amount of microcrystalline cellulose, starch and magnesium stearate, and then tableted by a tableting machine to obtain a nano-sized platinum drug tablet of the present invention.

 Example 7

 Examples 1 to 5 The obtained nano-sized platinum drug particles are directly loaded into a hard capsule shell to obtain a nano-scale platinum drug capsule of the present invention.

 Example 8

 Examples 1 to 5 The obtained nano-sized platinum-based drug particles are added to an aqueous solution and stirred uniformly to obtain a nano-scale platinum-based drug suspension of the present invention. The suspension may be administered orally as it is, or may be prepared as an injection according to the preparation standard of the injection.

 Example 9

 Nanoscale platinum drug particles obtained in Examples 1 to 5 and an appropriate amount of Witepsol The nano-scale platinum drug suppository of the present invention is prepared by a hot melt method.

Claims (10)

1. A nano-scale platinum drug particle characterized in that a silica aerogel is used as a carrier of a platinum drug, and the silica aerogel has a porosity of 95 to 99% and a pore diameter of 10 to 50 nm. a specific surface area of 200 to 1000 m ² /g, a density of 3 to 300 kg / m ³ , a colloidal particle diameter of the composition network of 1 to 50 nm, the platinum drug is adsorbed in the pore of the silica aerogel The form forms platinum-based drug particles having a diameter of less than 100 nm.
2. The nano-sized platinum-based drug particle according to claim 1, wherein a mass ratio of the platinum drug to the silica aerogel is 1:0.5 to 20.
3. A pharmaceutically acceptable oral preparation prepared from the nano-plated platinum drug particles according to claim 1 or 2.
4. The oral preparation according to claim 3, wherein the oral preparation is a tablet, a pill, a powder, a capsule, a granule or a suspension.
5. A pharmaceutically acceptable injection or suppository made of the nano-plated platinum drug particles according to claim 1 or 2.
6. The method for preparing nano-scale platinum-based drug particles according to any one of claims 1 to 5, characterized in that the method comprises the following steps:

   (1) dissolving the platinum drug in a 1.5% (w/v) NaCl solution;

   (2) adding a silica aerogel to the above NaCl solution;

   (3) After the platinum drug and the silica aerogel are completely adsorbed, dried;

   (4) adding purified water to the dried product, and feeding it into an emulsifier to emulsify;

   (5) feeding the emulsion obtained in the step (4) to a high-pressure homogenizer for homogenization;

   (6) After the homogenized liquid obtained in the step (5) is dried, nanometer-scale platinum drug particles are obtained.
7. The method for preparing nano-scale platinum-based drug particles according to claim 6, wherein when the silica aerogel described in the step (2) is hydrophobic, it is required to pass 300~ before adding the NaCl solution. Heat treatment at 1000 ° C makes it hydrophilic.
8. The method for preparing nano-scale platinum-based drug particles according to claim 6, wherein the ratio of the mass of the platinum-based drug to the volume of the 1.5% (w/v) NaCl solution is 1:5 to 200 .
9. The method for preparing nano-scale platinum-based drug particles according to claim 6, wherein the amount of purified water added in the step (4) is 20 to 200 ml/g of a platinum drug.
10. The method for producing nano-scale platinum-based drug particles according to claim 6, wherein the drying in the step (6) is spray drying.

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