CN114569545B

CN114569545B - Stable mitoxantrone preparation

Info

Publication number: CN114569545B
Application number: CN202011380155.4A
Authority: CN
Inventors: 陈宁; 刘珺; 李丹; 杨战鏖; 涂菲娜; 蒋小涌; 黄权华; 赖宝林; 张翠荣; 张远杏; 刘瑞锦
Original assignee: Shenzhen Huarun Nine Chuang Pharmaceutical Co ltd; Shenzhen China Resources Gosun Pharmaceutical Co Ltd
Current assignee: Shenzhen Huarun Nine Chuang Pharmaceutical Co ltd; Shenzhen China Resources Gosun Pharmaceutical Co Ltd
Priority date: 2020-11-30
Filing date: 2020-11-30
Publication date: 2023-08-22
Anticipated expiration: 2040-11-30
Also published as: CN114569545A

Abstract

The invention relates to a stable mitoxantrone preparation, which comprises the following components in percentage by weight: mitoxantrone and/or pharmaceutically acceptable salts thereof in an amount of 0.1-20mg/ml; 3-18mg/ml of sodium chloride; acetic acid 0.015-1mg/ml; sodium acetate 0-0.15mg/ml; sodium metabisulfite 0-0.3mg/ml; sodium sulfate 0-0.6mg/ml; and (3) a solvent. The formulation of the invention can solve the technical problem of the great increase of impurities in the preparation process of the mitoxantrone preparation, has stable property and meets the requirements of clinical treatment.

Description

Stable mitoxantrone preparation

Technical Field

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a stable mitoxantrone preparation.

Background

Mitoxantrone or mitoxantrone hydrochloride was first synthesized in 1979 by Murdock and lederrle laboratories in the united states and demonstrated its antitumor activity. Mitoxantrone hydrochloride was approved by the FDA in the united states in 1987 for injection production under the trade name Novantrone. Mitoxantrone hydrochloride has the chemical name of 1, 4-dihydroxy-5, 8-bis [ [2- [ (2-hydroxyethyl) amino ] ethyl ] amino ] -9, 10-anthraquinone dihydrochloride, and the structural formula of the mitoxantrone hydrochloride is shown as formula (I).

Mitoxantrone or mitoxantrone hydrochloride is an anthracycline antitumor agent, has a molecular structure similar to doxorubicin, has a planar aromatic ring and is easy to insert into the base pair of a DNA duplex, forcing the two base pairs to separate, growing DNA, causing structural deformation and cell death. Mitoxantrone or mitoxantrone hydrochloride is a nonspecific cell cycle drug, acts on chromosome replication process, particularly blocks cells in G2 phase, can kill cancer cells of any cell cycle, inhibits proliferation and non-proliferation cells, has high curative effects on breast cancer, acute leukemia and malignant lymphoma, and is also effective on digestive tract tumors such as gastric cancer and intestinal cancer, and prostate cancer, head and neck cancer, lung cancer, liver cancer, melanoma, soft tissue sarcoma, multiple myeloma, testicular tumor and ovarian cancer.

As a pharmaceutical formulation, an aqueous solution of mitoxantrone was approved for use. However, mitoxantrone has limited stability in aqueous solutions. It is known that mitoxantrone is susceptible to oxidative degradation if no measures are taken to reduce or preferably prevent degradation. For example, the degradation is performed to an impurity I represented by formula (II), an impurity II represented by formula (III), an impurity III represented by formula (IV), or an impurity IV represented by formula (V).

Impurity I (RRT 1.5):

impurity II (RRT 0.8):

impurity III (RRT 1.4):

impurity IV (RRT 2.8):

EP0236822B1 discloses a pharmaceutical formulation comprising mitoxantrone hydrochloride, sodium metabisulfite, the chelating agents disodium edetate and glycine, which is stabilized by the addition of the antioxidant sodium metabisulfite having a fixed pH, and the chelating agents disodium edetate and glycine.

CN102397561B discloses a self-assembled nanocrystalline injection comprising mitoxantrone sulfate, glycerol, acetic acid, sodium acetate and sodium metabisulfite, or comprising mitoxantrone hydrochloride, sodium chloride, acetic acid, sodium acetate and disodium edetate, which is stabilized by adding sodium metabisulfite or disodium edetate.

In CN102397561B is disclosed a mitoxantrone hydrochloride injection for lymphatic tracking comprising mitoxantrone hydrochloride, sodium metabisulfite and hydrochloric acid, which is stabilized by adding sodium metabisulfite.

However, the above-mentioned formulations are still unsatisfactory from the viewpoint of stability. Therefore, a mitoxantrone formulation with less adverse reactions, stable properties, less impurity content and suitability for clinical needs to be redesigned.

Disclosure of Invention

In order to solve the problems in the prior art, the present invention aims to provide a stable mitoxantrone formulation.

In the present invention, unless otherwise indicated, scientific and technical terms used herein have the meanings commonly understood by one of ordinary skill in the art. Meanwhile, in order to better understand the present invention, definitions and explanations of related terms are provided below.

It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

As used herein, the term "related substances" refers to starting materials, intermediates, polymers, side reaction products, degradation products during storage, and the like, which are brought in during production.

As used herein, the terms "patient," "individual," and "subject" are used interchangeably to refer to any individual animal for which treatment is desired, more preferably a mammal (including, e.g., non-human animals such as cats, dogs, horses, rabbits, zoo animals, cattle, pigs, sheep, and non-human primates). In certain embodiments, the patient herein is a human. The patient may be suffering from, suspected of suffering from, or at risk of suffering from a thyroid tumor. As used herein, a "disorder" is any disorder that would benefit from treatment, including but not limited to chronic and acute disorders or diseases, including those pathological disorders that predispose a mammal to the disorder in question.

As used herein, "pharmaceutical formulation" refers to a formulation in a form that allows for the biological activity of the active ingredient contained therein to be effective and that does not include other components that have unacceptable toxicity to the subject to whom the formulation is administered.

As used herein, "pH adjuster" refers to a compound or mixture of compounds that can be used to ensure that the pH of the reconstitution kit is within an acceptable range for human or mammalian administration (pH of about 4.0-10.5). Suitable pH adjusting agents include pharmaceutically acceptable buffers such as TRIS (hydroxymethyl) methylglycine (tricine), phosphate or TRIS [ i.e. TRIS (hydroxymethyl) aminomethane ]; pharmaceutically acceptable acids such as pharmaceutically acceptable organic acids (e.g., formic acid, acetic acid) or mixtures thereof or inorganic acids (e.g., hydrochloric acid, phosphoric acid) or mixtures thereof, and pharmaceutically acceptable bases such as sodium carbonate, sodium bicarbonate or mixtures thereof. When the conjugate used is in the form of an acid salt, the pH adjuster may optionally be provided in a separate vial or container, such that the kit user may adjust the pH as part of a multi-step procedure.

As used herein, "pharmaceutically acceptable excipient" refers to ingredients of a pharmaceutical formulation that are non-toxic to a subject other than the active ingredient. Pharmaceutically acceptable excipients include, but are not limited to, buffers, carriers, stabilizers or preservatives.

As used herein, "pharmaceutically acceptable salt" means a salt that is not biologically or otherwise undesirable. Pharmaceutically acceptable salts include acid and base addition salts. The phrase "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients forming the formulation and/or the mammal being treated therewith.

As used herein, "pharmaceutically acceptable acid addition salts" refer to those pharmaceutically acceptable salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and organic acids selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, pamoic acid, phenylacetic acid, methanesulfonic acid "mesylate", ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

The term "pharmaceutically acceptable base addition salts" means those pharmaceutically acceptable salts formed with organic or inorganic bases. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins, such as salts of isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethylamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, and polyamine resins.

As used herein, "treatment" refers to clinical intervention that attempts to alter the natural course of a treated individual, and may be used to prevent or in the course of clinical pathology. Desirable therapeutic effects include, but are not limited to, preventing occurrence or recurrence of a disease, alleviating symptoms, reducing any direct or indirect pathological consequences of a disorder, preventing metastasis, reducing the rate of disease progression, alleviating or alleviating a disease state, and alleviating or prognosticating an improvement.

As used herein, "administration" refers to a method of administering a dose of a compound (e.g., mitoxantrone hydrochloride injection) or pharmaceutical composition (e.g., a pharmaceutical composition comprising an inhibitor or antagonist) to a subject (e.g., a patient). Administration may be by any suitable means, including parenteral, intrapulmonary, and intranasal administration, and if desired for topical treatment, intralesional administration. Parenteral infusion includes, for example, intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. Administration may be by any suitable route, for example by injection, such as intravenous or subcutaneous injection, depending in part on whether administration is brief or chronic. Various dosing regimens are contemplated herein, including, but not limited to, single or multiple administrations at different points in time, bolus administrations, and pulse infusion.

In one aspect, the invention provides a stable mitoxantrone formulation comprising the following components in percentage by weight:

in a preferred embodiment, the solvent is selected from the group consisting of: water, sodium chloride solution or dextrose solution; preferably, the water is water for injection;

in a preferred embodiment, the mitoxantrone formulation has an impurity I content of between 0 and 1.5%, the impurity I having a formula shown in formula (II):

in a preferred embodiment, the mitoxantrone formulation has an impurity II content of between 0 and 1.5%, the impurity II having a formula shown in formula (III):

in a preferred embodiment, the mitoxantrone formulation has an impurity III content of between 0 and 1.5%, the impurity III having a formula shown in formula (IV):

in a preferred embodiment, the mitoxantrone formulation has an impurity IV content of between 0% and 1.5%, the impurity IV having a formula shown in formula (V):

in a preferred embodiment, the formulation is an injection; preferably, the injection is in the form of solution, lyophilized powder, emulsion, liposome, nanoparticle, nanocrystalline, microcrystal, microsphere or gel; preferably, the solution is sodium chloride injection or glucose injection.

In a preferred embodiment, the pH of the formulation ranges between 2.5 and 5.0, preferably between 2.8 and 4.3.

In a preferred embodiment, the pharmaceutically acceptable salts are those of mitoxantrone with inorganic and organic acids.

In a preferred embodiment, the mineral acid is, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid.

In a preferred embodiment, the organic acid is selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, pamoic acid, phenylacetic acid, methanesulfonic acid "mesylate", ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid.

In a preferred embodiment, the pharmaceutically acceptable salt is selected from the group consisting of mitoxantrone hydrochloride, mitoxantrone oxalate, mitoxantrone sulfate, mitoxantrone phosphate, mitoxantrone acetate, mitoxantrone citrate; more preferably, the pharmaceutically acceptable salt is mitoxantrone hydrochloride.

In a preferred embodiment, the mitoxantrone or pharmaceutically acceptable salt thereof is present in an amount of 2 to 10mg/ml; preferably 2mg/ml, 5mg/ml or 10mg/ml.

In a preferred embodiment, the sodium chloride is present in an amount of 4-16mg/ml; preferably 4mg/ml, 8mg/ml or 16mg/ml.

In a preferred embodiment, the content of acetic acid is 0.23-0.92mg/ml; preferably 0.23mg/ml, 0.46mg/ml or 0.92mg/m

In a preferred embodiment, the sodium acetate is present in an amount of 0.05 to 0.1mg/ml; preferably 0.05mg/ml or 0.1mg/ml.

In a preferred embodiment, the sodium metabisulfite is present in an amount of 0.05-0.4mg/ml; preferably 0.1-0.3mg/ml; more preferably 0.1mg/ml, 0.2mg/ml or 0.3mg/ml.

In a preferred embodiment, the sodium sulfate is present in an amount of 0.015 to 0.045mg/ml; preferably 0.015mg/ml, 0.03mg/ml or 0.045mg/ml.

In one aspect, the invention provides the use of a mitoxantrone formulation in the manufacture of a medicament or lymphatic tracer for treating a tumour.

In a preferred embodiment, the tumor is selected from the group consisting of: breast cancer, acute leukemia, malignant lymphoma, digestive tract tumor such as gastric cancer and intestinal cancer, prostate cancer, head and neck cancer, lung cancer, liver cancer, melanoma, soft tissue sarcoma, multiple myeloma, testicular tumor and ovarian cancer.

In one aspect, the present invention provides a method of preparing a mitoxantrone formulation comprising the steps of:

(1) Respectively weighing the acetic acid, sodium acetate, sodium chloride, sodium metabisulfite and/or sodium sulfate with the prescription amount, and mixing with the prescription amount of solvent to obtain auxiliary material mixed solution; preferably, the auxiliary material is dissolved by stirring.

(2) Mixing the auxiliary material mixed solution obtained in the step (1) with the prescription amount of mitoxantrone and/or pharmaceutically acceptable salt thereof; preferably, it is dissolved by stirring; preferably, it is dissolved by stirring for 10-30 min;

in a preferred embodiment, the method further comprises: (3) filtering; preferably, the fine filtration is performed through 0.45 μm and 0.22 μm filters.

In a preferred embodiment, the method further comprises: (4) filling nitrogen; preferably, sterilization is performed at 121℃for 15min after nitrogen filling.

In a preferred embodiment, the pH of the formulation ranges between 2.8 and 4.3;

in a preferred embodiment, the injection is made to a specification of 2ml:10 mg.

Through experimental investigation, the addition of sodium metabisulfite and sodium acetate can obviously influence the content of related substances in the preparation, the content of the related substances is obviously reduced, and the combined use effect of sodium metabisulfite and sodium sulfate is optimal, wherein the mitoxantrone injection with the mitoxantrone concentration of 1-10mg/ml is prepared, degradation impurities (impurities I and III) can be controlled below 0.2% after high-temperature sterilization, and the technical problem that the impurities I and III are greatly increased in the preparation process of the mitoxantrone preparation can be solved by using the formula of the mitoxantrone injection.

Detailed Description

For purposes of clarity and conciseness, features are described herein as part of the same or separate embodiments, however, it will be understood that the scope of the invention may include some embodiments with a combination of all or some of the features described.

The experimental methods in the following examples are conventional methods unless otherwise specified. The raw materials, reagent materials and the like used in the examples described below are commercially available products unless otherwise specified.

Example 1 selection of pH of formulation

Example 1-1

Table 1 components and contents of the preparations

All the appliances and penicillin bottles are soaked with edetate disodium, the prescription amount of sodium chloride, acetic acid, sodium acetate, sodium metabisulfite and sodium acetate are weighed and added into the prescription amount of injection water, stirring is carried out to dissolve, the prescription amount of mitoxantrone hydrochloride is added after the dissolution, stirring is carried out for 30min to dissolve, fine filtering is carried out through a 0.45 mu m and 0.22 mu m filter membrane, nitrogen filling is carried out, a cover is rolled, and sterilization is carried out for 15min at 121 ℃.

Examples 1 to 2

Table 2 components and contents of the formulations

Examples 1 to 3

Table 3 Components and contents of the preparations

Examples 1 to 4

Table 4 components and contents of the preparations

The pH values of the solutions before and after sterilization of examples 1-1 to 1-4 were measured, respectively.

TABLE 5 pH of mitoxantrone hydrochloride injections of different concentrations before and after sterilization

Concentration of solution	1mg/ml	2mg/ml	5mg/ml	10mg/ml
					Before sterilization	3.7	3.6	3.4	3.5
After sterilization	3.8	3.6	3.4	3.5

Note that: mitoxantrone hydrochloride to Cheng Mituo anthraquinone has a conversion factor of 0.8591.

The above results show that the pH value is reduced with the increase of the concentration of the injection, and the pH value is not obviously different before and after sterilization.

Conclusion: combining the product characteristics, the concentration range, the pharmacodynamics experiment result and the clinical application, and finally setting the pH value control range to be 2.8-4.3; meets the requirements of 2015 edition Chinese pharmacopoeia and meets the clinical application of the product.

EXAMPLE 2 selection of antioxidant classes

Example 2-1

Table 6 components and contents of the preparations

All the appliances and penicillin bottles are soaked with edetate disodium, the prescription amount of sodium chloride, acetic acid and sodium acetate are weighed and added into the prescription amount of injection water, stirring is carried out to dissolve, the prescription amount of mitoxantrone hydrochloride is added after dissolving, stirring is carried out for 30min to dissolve, fine filtering is carried out through a filter membrane with the thickness of 0.45 mu m and 0.22 mu m, filling nitrogen is carried out, a rolling cover is carried out, and sterilization is carried out at 115 ℃ for 30 min.

Example 2-2

Table 7 components and contents of the preparations

All the appliances and penicillin bottles are soaked by edetate disodium, the prescription amount of sodium chloride, acetic acid, sodium acetate and sodium metabisulfite are weighed, added into the prescription amount of injection water, stirred to be dissolved, the prescription amount of mitoxantrone hydrochloride is added after the dissolution, stirred for 30min to be dissolved, finely filtered by a 0.45 mu m and 0.22 mu m filter membrane, filled with nitrogen, rolled and sterilized at 115 ℃ for 30 min.

Examples 2 to 3

Table 8 components and contents of the preparations

Soaking all the devices and penicillin bottles in edetate disodium, weighing the prescription amount of sodium chloride, acetic acid and edetate disodium, adding into the prescription amount of injection water, stirring to dissolve, adding the prescription amount of mitoxantrone hydrochloride after dissolving, stirring for 30min to dissolve, finely filtering with 0.45 μm and 0.22 μm filter membrane, filling nitrogen, rolling cover, and sterilizing at 115 ℃ for 30 min.

Examples 2 to 4

Table 9 components and contents of the preparations

All the appliances and penicillin bottles are soaked with edetate disodium, the prescription amount of sodium chloride, acetic acid, sodium acetate, sodium metabisulfite and sodium sulfate are weighed, added into the prescription amount of injection water, stirred to be dissolved, added with the prescription amount of mitoxantrone hydrochloride after being dissolved, stirred for 30min to be dissolved, finely filtered by a 0.45 mu m and 0.22 mu m filter membrane, filled with nitrogen, rolled and capped, and sterilized for 30min at 115 ℃.

In this example, the effect of antioxidants on the properties, pH, content and related substances of the samples in the formulations using sodium metabisulfite, disodium edentate, sodium metabisulfite+sodium sulfate as antioxidants were examined, respectively, with respect to the injection without antioxidants, and the results are shown in table 10.

TABLE 10 selection of antioxidant classes

The result shows that the relative substances of the prescription without adding the antioxidant and the sodium metabisulfite are obviously higher than those of the prescription with adding the disodium edentate, the sodium metabisulfite and the sodium sulfate simultaneously, and the relative substances of the two are basically consistent, namely, the prescription prepared by sodium metabisulfite and the sodium sulfate is basically consistent with the prescription prepared by taking the disodium edentate as the antioxidant.

EXAMPLE 3 selection of antioxidant usage

Example 3-1

Table 11 components and contents of the preparations

Example 3-2

Table 12 components and contents of the preparations

Examples 3 to 3

Table 13 components and contents of the preparations

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In this example, sodium metabisulfite with 0.005%, 0.01% and 0.015% was selected, the sodium sulfate dosage was temporarily set to 0.015%, the other auxiliary materials were the same as the prescription dosage, and the influence of sodium metabisulfite with different concentrations on the properties, pH and related substances of the sample was examined, and the results are shown in Table 14.

TABLE 14 antioxidant dosage screening

The results show that the content of sodium metabisulfite has a remarkable influence on the content of the impurities I and III, the content of the impurities is remarkably reduced along with the increase of the content of the sodium metabisulfite, and the content of the impurities I and III of 0.01% and 0.015% of sodium metabisulfite are basically consistent.

Example 4 Effect of Nitrogen charging on residual oxygen and dissolved oxygen

Example 4-1

Table 15 components and contents of the preparations

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All the appliances and penicillin bottles are soaked with edetate disodium, the prescription amount of sodium chloride, acetic acid, sodium acetate and sodium sulfate are weighed and added into the prescription amount of injection water, stirring is carried out to dissolve, the prescription amount of mitoxantrone hydrochloride is added after dissolving, stirring is carried out for 30min to dissolve, fine filtering is carried out through a 0.45 mu m and 0.22 mu m filter membrane, filling nitrogen is carried out, the residual oxygen amount is controlled to be about 2%, rolling is carried out, and sterilization is carried out for 30min at 115 ℃.

Example 4-2

Table 16 components and contents of the preparations

All the appliances and penicillin bottles are soaked with edetate disodium, the prescription amount of sodium chloride, acetic acid, sodium acetate, sodium metabisulfite and sodium sulfate are weighed and added into the prescription amount of injection water, stirring is carried out to dissolve, the prescription amount of mitoxantrone hydrochloride is added after the dissolution, stirring is carried out for 30min to dissolve, fine filtering is carried out through a 0.45 mu m and 0.22 mu m filter membrane, filling nitrogen is carried out, the residual oxygen amount is controlled to be about 2%, and the mixture is rolled and covered, and sterilization is carried out for 30min at 115 ℃.

Examples 4 to 3

Table 17 formulation components and content

Examples 4 to 4

Table 18 formulation components and contents

All the appliances and penicillin bottles in the small test are soaked with disodium edentate, the prescription amount of sodium chloride, acetic acid, sodium acetate, sodium metabisulfite and sodium sulfate are weighed, added into the prescription amount of water for injection, stirred to be dissolved, added with the prescription amount of mitoxantrone hydrochloride after being dissolved, stirred for 30min to be dissolved, finely filtered by a 0.45 mu m and 0.22 mu m filter membrane, filled with nitrogen, controlled to be about 2% of residual oxygen, rolled and sterilized at 115 ℃ for 30min, and the product is obtained.

The formulation of this example examined whether to fill nitrogen and whether to sterilize the residual oxygen and dissolved oxygen changes, and the results are shown in tables 19 and 20.

TABLE 19 residual oxygen amount variation

TABLE 20 dissolved oxygen variation

From the above results, it was found that the residual oxygen amount and the dissolved oxygen amount after sterilization were significantly reduced after adding sodium metabisulfite under nitrogen-filled conditions, and the residual oxygen amount and the dissolved oxygen amount after sterilization were not significantly different when the sodium metabisulfite was used in an amount of 0.01 to 0.03%.

EXAMPLE 5 selection of sodium sulfate usage

Example 5-1

Table 21 components and contents of the preparations

All the appliances and penicillin bottles are soaked by edetate disodium, the prescription amount of sodium chloride, acetic acid, sodium acetate and sodium metabisulfite are weighed and added into the prescription amount of injection water, stirring is carried out to dissolve, the prescription amount of mitoxantrone hydrochloride is added after dissolving, stirring is carried out for 30min to dissolve, fine filtering is carried out through a 0.45 mu m and 0.22 mu m filter membrane, filling nitrogen is carried out, the residual oxygen amount is controlled to be about 2%, rolling is carried out, and sterilization is carried out for 30min at 115 ℃.

Example 5-2

Table 22 formulation components and contents

Examples 5 to 3

Table 23 components and contents of the preparations

In this example, 0, 0.015% and 0.03% sodium sulfate were selected, the sodium sulfate usage was temporarily set to 0.015%, the other auxiliary materials were used in the same amount as the prescription, and the influence of sodium sulfate of different concentrations on the properties, pH and related substances of the sample was examined, and the results are shown in table 4.

TABLE 24 sodium sulfate dosage screening

The results show that the content of the impurity I and the impurity III is obviously influenced by the sodium sulfate, and the content of the impurity I and the impurity III is obviously reduced along with the increase of the sodium sulfate, and the content of the impurity I and the impurity III of 0.015 percent and 0.03 percent of sodium sulfate are basically consistent.

Claims

1. A stable mitoxantrone formulation comprising the following components and amounts:

the content of the impurity I in the mitoxantrone preparation is between 0 and 1.5 percent, and the structural formula of the impurity I is shown as the formula (II):

the content of an impurity II in the mitoxantrone preparation is between 0 and 1.5 percent, and the structural formula of the impurity II is shown as a formula (III):

the content of the impurity III in the mitoxantrone preparation is between 0 and 1.5 percent, and the structural formula of the impurity III is shown as a formula (IV):

the content of the impurity IV in the mitoxantrone preparation is between 0 and 1.5 percent, and the structural formula of the impurity IV is shown as a formula (V):

the preparation is injection;

the pH of the formulation ranges from 2.8 to 4.3.

2. A stable mitoxantrone formulation comprising the following components and amounts:

the preparation is injection;

the pH of the formulation ranges from 2.8 to 4.3.

3. A stable mitoxantrone formulation comprising the following components and amounts:

the preparation is injection;

the pH of the formulation ranges from 2.8 to 4.3.

4. A stable mitoxantrone formulation comprising the following components and amounts:

the preparation is injection;

the pH of the formulation ranges from 2.8 to 4.3.

5. A stable mitoxantrone formulation comprising the following components and amounts:

the preparation is injection;

the pH of the formulation ranges from 2.8 to 4.3.

6. A stable mitoxantrone formulation comprising the following components and amounts:

the preparation is injection;

the pH of the formulation ranges from 2.8 to 4.3.

7. A stable mitoxantrone formulation comprising the following components and amounts:

the preparation is injection;

the pH of the formulation ranges from 2.8 to 4.3.

8. A stable mitoxantrone formulation comprising the following components and amounts:

the preparation is injection;

the pH of the formulation ranges from 2.8 to 4.3.

9. A stable mitoxantrone formulation comprising the following components and amounts:

the preparation is injection;

the pH of the formulation ranges from 2.8 to 4.3.

10. A stable mitoxantrone formulation comprising the following components and amounts:

the preparation is injection;

the pH of the formulation ranges from 2.8 to 4.3.

11. A stable mitoxantrone formulation comprising the following components and amounts:

the preparation is injection;

the pH of the formulation ranges from 2.8 to 4.3.

12. A stable mitoxantrone formulation comprising the following components and amounts:

the preparation is injection;

the pH of the formulation ranges from 2.8 to 4.3.

13. Use of a mitoxantrone formulation according to any one of claims 1-12 in the manufacture of a medicament or lymphatic tracer for treating a tumor.

14. The use of claim 13, wherein the tumor is selected from the group consisting of: breast cancer, acute leukemia, malignant lymphoma, digestive tract tumor, prostate cancer, head and neck cancer, lung cancer, liver cancer, melanoma, soft tissue sarcoma, multiple myeloma, testicular tumor, and ovarian cancer.

15. The use of claim 14, wherein the digestive tract tumor is gastric or intestinal cancer.

16. A process for the preparation of a mitoxantrone formulation of any one of claims 1-12 comprising the steps of:

(1) Respectively weighing the acetic acid, sodium acetate, sodium chloride, sodium metabisulfite and sodium sulfate with the prescription amount, and mixing with the solvent with the prescription amount to obtain auxiliary material mixed solution;

(2) Mixing the auxiliary material mixed solution obtained in the step (1) with the prescription amount of mitoxantrone hydrochloride; it was dissolved by stirring.

17. The method for preparing a mitoxantrone formulation according to claim 16 wherein,

the method further comprises the steps of: (3) filtration, wherein the fine filtration is performed through 0.45 μm and 0.22 μm filter membranes.

18. The method for producing a mitoxantrone formulation according to claim 16 or 17 wherein,

the method further comprises the steps of: (4) filling nitrogen; sterilizing at 121deg.C for 15min after nitrogen filling.