CN111184703B

CN111184703B - Arsenic trioxide slow-release pill and preparation method thereof

Info

Publication number: CN111184703B
Application number: CN201811371963.7A
Authority: CN
Inventors: 周晋; 姜嫣嫣; 刘晓; 周萍; 高建华; 海鑫
Original assignee: Harbin Yida Pharmaceutical Ltd By Share Ltd; Fudan University
Current assignee: Harbin Yida Pharmaceutical Ltd By Share Ltd; Fudan University
Priority date: 2018-11-15
Filing date: 2018-11-15
Publication date: 2023-03-28
Anticipated expiration: 2038-11-15
Also published as: CN111184703A

Abstract

The invention belongs to the field of medical technology and pharmaceutical preparations, and relates to an arsenic trioxide sustained-release pellet and a preparation method and application thereof. The invention is made into arsenic trioxide slow-release pellets by a medicine pellet core containing arsenic trioxide and a slow-release coating layer wrapping the pellet core, wherein the medicine pellet core consists of arsenic trioxide, a filling agent and an adhesive, and the slow-release coating layer consists of an enteric high molecular material or a water-insoluble high molecular material, a plasticizer, a pore-forming agent and/or an anti-sticking agent. The arsenic trioxide slow-release pill can realize the release degree ranges of 10 to 30 percent (0.5 to 2 hours), 40 to 60 percent (4 to 8 hours) and more than or equal to 90 percent (24 hours). The prepared sustained-release pellets are used for preparing oral medicines for treating acute non-lymphocytic leukemia, and the curative effect of the acute promyelocytic leukemia is most obvious; and can be used for preparing oral medicines for treating chronic myelocytic leukemia, chronic myelogenous leukemia, liver cancer, lung cancer, pancreatic cancer, colon cancer, breast cancer, cervical cancer, etc.

Description

Arsenic trioxide slow-release pill and preparation method thereof

Technical Field

The invention belongs to the field of medical technology and pharmaceutical preparations, and relates to an arsenic trioxide sustained-release pellet as well as a preparation method and application thereof.

Background

The prior art discloses that Arsenic Trioxide (ATO) is widely used for treating Acute Promyelocytic Leukemia (APL), and a large number of experimental studies show that APL treated by the arsenic trioxide has a remarkable curative effect. Research shows that ATO has a dose-dependent dual effect on acute promyelocytic leukemia cells, low-concentration ATO can induce partial differentiation of the cells under the long-term action, and high-concentration ATO can induce apoptosis; when low concentration (0.1-0.5 mu mol/L) is applied to a cell line, ATO can induce the differentiation of human acute promyelocytic leukemia cells by attacking the PML part of a PML-RAR alpha fusion product and destroying the chimeric protein, ATO with higher concentration (concentration between 0.5-2 mu mol/L and realized in the first few hours after ATO infusion) can induce the apoptosis of leukemia cells, the apoptosis mechanism is the formation of arsenic induced Reactive Oxygen Species (ROS) to damage DNA and RNA, and the apoptosis can also be induced by inducing a mitochondrial caspase system; the research also shows that ATO of 2 mu mol/L acts for 24 hours, the apoptosis rate is 7 percent, the acting time is 48 hours, the apoptosis rate is 20 percent, the acting time is 72 hours, and the apoptosis rate is 60 percent. Under the effective concentration, the longer the action time is, the better the apoptosis promoting effect is.

The dosage of arsenous acid and sodium chloride injection on the market in China for treating leukemia is reported to be 10mg once a day for an adult, and the dosage is diluted by 5 percent glucose injection or 500ml of 0.9 percent sodium chloride injection and then is subjected to intravenous drip. The ATO intravenous drip method comprises a traditional infusion method and a continuous slow drip method (volume 50, phase 11 of 6 months in 2015 of Chinese pharmacy), wherein the traditional intravenous infusion method is used for infusing 0.16mg/kg of ATO once a day, the infusion is completed within about 2 hours, after the infusion is performed for about 4 hours (peak reaching time), the peak concentration of blood plasma can reach 5-7 mu mol/L, the concentration far exceeds the apoptosis concentration (2 mu mol/L) of leukemia cells, severe adverse reactions such as severe threat to normal tissue organs can be generated, some patients can have severe adverse reactions such as hypercalcemia, disseminated Intravascular Coagulation (DIC), torsades de pointes, cardiogenic sudden cardiac death and the like, even the life of the patients is threatened, and some patients can have critical adverse reactions such as leukemia cell stasis syndrome-like hypercalcemia, fatal intracranial hemorrhage, central nervous system infiltration of leukemia and the like. Pharmacokinetic studies show that plasma arsenic is rapidly removed after ATO reaches the peak, the plasma concentration half-life period is 0.89 +/-0.29 h, the removal half-life period is 12.13 +/-3.31h, and the peripheral blood arsenic content is 0.3 mu mol/L after 12h, so that the traditional drip infusion method has serious defects in the aspects of safety and effectiveness. At present, a continuous slow infusion method is mostly adopted for administration of ATO clinically, namely for adult patients, 10mg of ATO is diluted in 500mL of 5% glucose injection, infusion is carried out 2 times a day, each time, infusion is carried out at the speed of 8 drops/min, the infusion is completed within about l 8-20 h, the two times are separated by 2h, a treatment course is formed in four weeks, and the intermittent treatment lasts for 1-2 weeks.

In view of the problems of clinical application of ATO injection, oral administration is a more convenient and safer administration route, but at present, there is no ATO oral preparation on the market at home and abroad. The compound Huangdai tablet is a common oral Chinese medicinal compound preparation containing arsenic, the common dosage is 15 tablets per time and 3 times a day, according to the literature report (the academic report of the liberty and pharmacology, 2002, volume 18, period 5), the compound Huangdai tablet contains 4 mg/tablet of realgar, healthy volunteers take 10 tablets per time, namely 40mg of realgar is taken, and the amount of arsenic is about 25mg. Measuring the average actually measured peak concentration to be 0.57 +/-0.02 mu mol/L, the fitting peak concentration to be 0.54 +/-0.016 mu mol/L, the actually measured peak reaching time to be 8h and the fitting peak reaching time to be 7.4499 +/-0.3184 h; therefore, there are problems that the administration dose is large, the administration is frequent, and it is difficult to ensure a sustained and stable effective blood concentration (2. Mu. Mol/L), and the like.

In conclusion, the common injection and the common oral preparation of ATO have the problems of safety, effectiveness or compliance in clinical application, compared with the common sustained-release preparation, the sustained-release preparation can reduce the administration times, slowly and continuously release medicine in vivo after administration, can effectively reduce the peak-valley concentration, can avoid toxic and side effects exceeding the treatment concentration range, can keep in the effective concentration range for a long time, continuously exert the safe and effective treatment effect, and can greatly improve the medication compliance of patients. However, at present, the research report of an ATO oral sustained-release preparation is not seen at home and abroad, and no medicine is available on the market. Therefore, the development of an ATO oral sustained-release preparation has extremely high clinical application value in the aspects of ensuring the curative effect, reducing the toxic and side effects, improving the compliance of patients and the like.

Based on the current situation of the prior art, the inventor of the application intends to provide an arsenic trioxide sustained-release pellet and a preparation method and application thereof.

Disclosure of Invention

The invention aims to provide an arsenic trioxide sustained-release pellet and a preparation method and application thereof aiming at the current situation and defects of the prior art. The invention solves the problems of long administration time of an ATO injection, low patient compliance, frequent administration of an oral preparation, low bioavailability, easy occurrence of gastrointestinal adverse reactions, damage to normal tissue cells caused by overhigh blood concentration, and the like.

The purpose of the invention is realized by the following technical scheme.

On one hand, the invention provides an arsenic trioxide sustained-release pellet, which consists of a drug pellet core containing ATO and a sustained-release coating layer coated outside the pellet core, wherein the sustained-release coating layer consists of an enteric polymer material or a water-insoluble polymer material, and the weight of the sustained-release coating layer accounts for 1-30% of the weight of the drug pellet core.

Preferably, in the medicinal pill core, the ATO accounts for 1 to 7 parts by weight, the filler accounts for 93 to 99 parts by weight, and the adhesive accounts for 4 to 15 percent of the sum of the ATO and the filler.

Preferably, the filler is a mixture of one or more of microcrystalline cellulose, starch, stearic acid, pregelatinized starch, lactose, sucrose and sodium carboxymethylcellulose.

Preferably, the binder or wetting agent is selected from a mixture of one or more of hypromellose, povidone, hyprolose and water.

Preferably, the enteric polymer material or the water-insoluble polymer material contained in the sustained-release coating layer is selected from acrylic resin, the enteric polymer material is preferably one or a mixture of more of Eudragit L30D, L100 and S100, and the water-insoluble polymer material is preferably one or a mixture of more of Eudragit RL30D, NE30D and RS 30D.

Preferably, the plasticizer is selected from a mixture of one or more of polyethylene glycol, triethyl citrate, dibutyl sebacate, glycerol, diethyl phthalate and propylene glycol. The pore-forming agent and/or the antisticking agent is selected from one or a mixture of more of talcum powder, magnesium stearate, micro-powder silica gel and hydrogenated castor oil. The dispersion medium is selected from one or more of water and organic solvent.

Preferably, the dosage of the enteric polymer material or the water-insoluble polymer material in the sustained-release coating layer accounts for 1-30%, preferably 6-20% of the weight of the drug pellet core, the dosage of the plasticizer accounts for 0-40%, preferably 5-20% of the dosage of the enteric polymer material or the water-insoluble polymer material, the dosage of the anti-sticking agent accounts for 0-50% of the dosage of the enteric polymer material or the water-insoluble polymer material, the dosage of the pore-forming agent accounts for 0-60%, preferably 20-50% of the dosage of the enteric polymer material or the water-insoluble polymer material, and the balance is a dispersion medium.

Preferably, said sustained-release pellets are characterized by a drug pellet core selected between 10 and 50 mesh screens, preferably 18 to 35 mesh screens.

Preferably, the sustained-release pellets are characterized in that the length-diameter ratio of the drug-containing pellets is 1-1.

In another aspect, the present invention provides a method for preparing the above arsenic trioxide sustained-release pellets, which comprises the steps of: 1) Mixing ATO and a filling agent, adding an adhesive solution to prepare a soft material, and preparing a medicinal pill core by an extrusion rounding method; 2) Sieving the dry medicine pill core prepared in the step 1) to obtain a medicine pill core of 10-50 meshes; 3) Preparing a coating solution of the slow-release coating layer; 4) And (3) spraying and coating the coating liquid prepared in the step 3) on the medicament pill core obtained by sieving in the step 2) to obtain the arsenic trioxide slow-release pill.

In another aspect, the invention provides the use of the arsenic trioxide sustained-release pellets in the preparation of medicaments for treating acute promyelocytic leukemia, chronic promyelocytic leukemia, liver cancer, lung cancer, pancreatic cancer, colon cancer, breast cancer and cervical cancer; preferably, the medicament is a sustained release capsule.

In one embodiment of the invention, the arsenic trioxide sustained-release pellets comprise the following components: 1 to 7 portions of ATO, 93 to 99 portions of filler and 4 to 15 percent of adhesive.

In one embodiment of the invention, the preparation method of the provided arsenic trioxide sustained-release pellets comprises the following steps:

the first step is as follows: preparing a medicine pill core, namely weighing ATO, a filling agent, an adhesive and/or a wetting agent according to a formula, stirring and mixing in a wet granulator to prepare a soft material, transferring the soft material into an extruder, extruding the soft material through a screen (the aperture is 0.4-2.0 mm), transferring the extruded cylindrical strip-shaped material into an extrusion spheronizer, spheronizing to obtain a spherical medicine pill core, drying the medicine pill core, and sieving to obtain 18-35-mesh pellets;

the second step is that: a slow-release coating layer, the formulation of the coating solution contains enteric polymer materials or water-insoluble polymer materials for controlling the drug release rate, the polymers can be prepared into solution for use, or aqueous dispersions of the polymers can be used, other polymers are sometimes added into the coating solution, or a plurality of polymers are adopted for multilayer coating, so that the coated pellets release the drug at a proper rate; the method comprises the following specific steps: taking a proper amount of the medicinal pellet core, placing the medicinal pellet core in a fluidized bed, starting a fan, heating and making the pellet in a fluidized state, starting a liquid supply pump and spraying coating liquid after the pellet reaches a set material temperature, closing the liquid supply when the pellet meets the weight gain requirement of a formula, and placing the coated pellet in an oven for aging to obtain the medicinal pellet;

the third step is that: the coated pellets are filled into capsules to prepare the sustained-release capsules.

In the present invention, the coating amount of the polymer is a main factor for determining the drug release rate, and the coating amount of the polymer in the actual coating operation depends on whether the coated pellets reach the release degree specified by the product quality standard. Experiments show that the prepared drug pill core can quickly and completely release drugs, and after the ATO pill core is coated by acrylic resin, especially the coating of polymers such as Eudragit (Eudragit) L30D, L100 and S100, eudragit (Eudragit) RL30D, NE30D, RS3OD and the like can effectively control the release of the drugs; when the wrapping amount of the polymer is 1-5%, the release degree range of the prepared arsenic trioxide sustained-release pellets is as follows: 20 to 45 percent (0.5 to 2 hours), 60 to 85 percent (4 to 8 hours) and more than or equal to 95 percent (24 hours); when the wrapping amount is 6-20%, the range of the release degree which can be achieved is as follows: 10 to 30 percent (0.5 to 2 hours), 40 to 60 percent (4 to 8 hours) and more than or equal to 90 percent (24 hours); when the wrapping amount of the polymer is 21-30%, the release degree range of the prepared arsenic trioxide sustained-release pellets is as follows: 1-20% (0.5-2 h), 30-50% (4-8 h) and more than or equal to 70% (24 h) (as shown in figure 1);

in the invention, the formula of the coating liquid also has certain influence on the drug release rate of the sustained-release pellet, and a proper amount of plasticizer, such as polyethylene glycol, triethyl citrate, dibutyl sebacate, glycerol, diethyl phthalate and the like, is added into the coating liquid, and the proper amount is 10-30% (w/w) of the polymer; the coating liquid is also added with a proper amount of antisticking agent, such as talcum powder, magnesium stearate, micro-powder silica gel, hydrogenated castor oil and the like, and the proper amount is 20-40% (w/w) of the polymer.

The invention provides an arsenic trioxide sustained-release pellet and a preparation method thereof, and the arsenic trioxide sustained-release pellet can reduce the administration times and maintain the effective blood concentration for a long time, thereby achieving the purposes of improving the curative effect, reducing the toxic and side effect and improving the medication compliance of patients. The arsenic trioxide sustained-release pellets provided by the invention have no obvious burst release phenomenon, can completely release the drug within 24 hours, have simple preparation process and are easy for industrial production.

Description of the drawings:

figure 1 is a 24h release profile of ATO drug pellet cores and sustained release pellets weighted by different coatings.

Detailed description of the preferred embodiments

The invention is further illustrated below with reference to specific examples. It will be understood by those skilled in the art that these examples are merely illustrative of the present invention and do not limit the scope of the present invention in any way.

Example 1

In the arsenic trioxide sustained-release pellet provided by the embodiment, the composition of the prescription of the drug pellet core and the preparation method thereof are as follows:

TABLE 1 medicinal pill core prescription composition

The preparation method of the pill core comprises the following steps: the preparation method of the medicine pill core of each prescription by adopting an extrusion rounding method comprises the following specific operations: the main medicine and the auxiliary materials are mixed evenly according to the prescription proportion, and then the adhesive (the solution with 10 percent of PVP prepared by deionized water is used as the adhesive) is added. After the soft material is prepared, extruding the mixture in an extruder through a screen of the extruder, rolling the obtained strip-shaped object in a rolling machine, taking out the strip-shaped object, drying the strip-shaped object, and screening pellets of 18-35 meshes for later use. The yield of the pill core prepared by each prescription is not less than 90 percent.

Example 2

In the arsenic trioxide sustained-release pellet provided by the embodiment, the coating solution formula of the sustained-release layer and the preparation method thereof are as follows:

TABLE 2 coating solution prescription composition

And (3) coating process: the coating liquid of the different prescriptions is wrapped outside the medicine pill core, and the specific operation is as follows: the fluidized bed was opened, 500g of ATO pellet cores (18 to 35 mesh) prepared according to the pharmaceutical pellet core formulation 1 of example 1 were fed into the fluidized bed, and coated with a coating solution by spraying, and then oven-aged for 24 hours at 50 ℃ (coating solution formulation 1), 40 ℃ (coating solution formulation 2), 25 ℃ (coating solution formulation 3), and 40 ℃ (coating solution formulation 4), respectively.

Example 3

In this example, a proper amount of sustained-release pellets with different polymer wrapping amounts are taken and encapsulated, and the release degree is measured, and the specific result is shown in fig. 1;

the release rate was determined according to the general rule of section 4 of the "Chinese pharmacopoeia" 2015 edition by using a first method for measuring dissolution rate and release rate, using 1000ml of phosphate buffer solution of pH 7 as a solvent and 100 rpm as a rotation speed, and operating according to the method.

Claims

1. An arsenic trioxide slow release pellet is characterized by consisting of a drug pellet core containing arsenic trioxide ATO and a slow release coating layer coated outside the pellet core,

wherein the content of the first and second substances,

the medicine pill core consists of arsenic trioxide ATO, a filling agent and an adhesive or wetting agent, wherein the arsenic trioxide ATO accounts for 1-10 parts by weight, the filling agent accounts for 90-99 parts by weight, and the sum of the two parts by weight is 100 parts by weight; the adhesive or wetting agent is 2 to 30 percent of the total weight of the arsenic trioxide ATO and the filler;

the slow release coating layer of the drug pill core consists of an enteric polymer material or a water-insoluble polymer material, a plasticizer, a pore-forming agent and/or an anti-sticking agent and a dispersion medium; the weight of the enteric polymer material or the water-insoluble polymer material in the slow-release coating layer accounts for 1-30% of the weight of the medicinal pill core.

2. The sustained-release arsenic trioxide pellets according to claim 1, wherein the filler in the core of the drug pellet is selected from the group consisting of microcrystalline cellulose, starch, stearic acid, pregelatinized starch, lactose, sucrose and mixtures of one or more of sodium carboxymethylcellulose.

3. The arsenic trioxide sustained-release pellets according to claim 1, wherein the binder or wetting agent in the drug pellet core is selected from one or more of hypromellose, povidone, hyprolose, water or ethanol.

4. The arsenic trioxide sustained-release pellet according to claim 1, wherein the enteric polymer material in the sustained-release coating layer is enteric acrylic resin selected from the group consisting of Eudragit L30D, L100, S100, and the water-insoluble polymer material is one or more of ethyl cellulose, eudragit NE30D, RL30D, RS30D, NM 30D.

5. The sustained-release arsenic trioxide pellets according to claim 1, wherein the plasticizer is selected from one or more of polyethylene glycol, triethyl citrate, dibutyl sebacate, glycerin, diethyl phthalate and propylene glycol;

the pore-forming agent and/or the antisticking agent is one or a mixture of more of talcum powder, magnesium stearate, micro-powder silica gel and hydrogenated castor oil;

the dispersion medium is selected from one or a mixture of water and an organic solvent.

6. The arsenic trioxide sustained-release pellets according to claim 1, wherein the dosage of the enteric polymer material or the water-insoluble polymer material in the sustained-release coating layer accounts for 1-30% of the weight of the drug pellet core.

7. The arsenic trioxide sustained-release pellets according to claim 6, wherein the dosage of the enteric polymer material or the water-insoluble polymer material in the sustained-release coating layer is 6-20% of the weight of the drug pellet core.

8. The sustained-release arsenic trioxide pellets according to claim 1, wherein the amount of the plasticizer is 0 to 40 percent of the amount of the enteric polymer material or the water-insoluble polymer material, the amount of the anti-sticking agent is 0 to 60 percent of the amount of the enteric polymer material or the water-insoluble polymer material, the amount of the pore-forming agent is 0 to 60 percent of the amount of the enteric polymer material or the water-insoluble polymer material, and the balance is the dispersion medium.

9. The arsenic trioxide sustained-release pellets according to claim 1, wherein the drug pellet core is 10-50 mesh.

10. The arsenic trioxide sustained-release pellet as claimed in claim 1, wherein the length-diameter ratio of the drug pellet core is 1.

11. The process for preparing sustained-release pellets of arsenic trioxide according to any of the claims 1 to 10, which comprises the following steps:

1) Mixing ATO and a filling agent, adding an adhesive solution, mixing to prepare a soft material, and then adopting an extrusion rolling method, wherein the diameter of a sieve pore of an extruder is 0.4-2.0 mm to prepare a medicine pill core;

2) Sieving the medicinal pill cores prepared in the step 1), and taking pill cores of 10-50 meshes;

3) Preparing a coating solution of the slow-release coating layer;

4) And (3) spraying and coating the coating solution prepared in the step 3) on the medicament pill core obtained by sieving in the step 2) to prepare the arsenic trioxide slow-release pill.

12. Use of sustained-release pellets of arsenic trioxide according to any of claims 1 to 10 for the manufacture of a medicament for the treatment of acute non-lymphocytic leukemia.

13. The use according to claim 12, wherein the acute non-lymphocytic leukemia is acute promyelocytic leukemia.

14. Use of the arsenic trioxide sustained release pellets of any one of claims 1 to 10 for the preparation of oral medicaments for the treatment of chronic myelogenous leukemia and the acute phase of chronic granulocytes, liver cancer, lung cancer, pancreatic cancer, colon cancer, breast cancer, cervical cancer.

15. Use according to claim 12 or 14, wherein the medicament is a slow release capsule.