阅读说明：本技术 一种含氟伐他汀钠的复方制剂制备方法 (Preparation method of compound preparation containing fluvastatin sodium ) 是由 鲁光英 于 2021-08-03 设计创作，主要内容包括：本发明提供了一种含氟伐他汀钠的复方制剂制备方法,所述复方制剂包括重量比例为1:0.1—0.8的氟伐他汀钠和环磷酰胺混合均匀即可。本发明通过氟伐他汀钠联合低剂量的环磷酰胺组合,达到抑制肿瘤生长的目的,为鼻咽癌的治疗提供了一个新的且更为有效的解决方案,该制剂用于鼻咽癌的治疗,比单独使用环磷酰胺有效性高,副作用小,特别适用于有高血脂的鼻咽癌患者的治疗。(The invention provides a preparation method of a compound preparation containing fluvastatin sodium, wherein the compound preparation comprises fluvastatin sodium and cyclophosphamide which are uniformly mixed according to the weight ratio of 1: 0.1-0.8. The fluvastatin sodium is combined with the cyclophosphamide with low dose to achieve the aim of inhibiting the growth of tumors, a new and more effective solution is provided for the treatment of the nasopharyngeal carcinoma, and the preparation is used for the treatment of the nasopharyngeal carcinoma, has higher effectiveness and less side effect than the single use of the cyclophosphamide, and is particularly suitable for the treatment of the patients with the nasopharyngeal carcinoma with hyperlipidemia.)

1. A preparation method of a compound preparation containing fluvastatin sodium is characterized by comprising the following steps: the compound preparation comprises fluvastatin sodium and cyclophosphamide which are mixed uniformly according to the weight ratio of 1: 0.1-0.8.

2. The method for preparing the fluvastatin sodium-containing compound preparation according to claim 1, which comprises the following steps: the weight ratio of fluvastatin sodium to cyclophosphamide is 1: 0.2-0.4.

3. The process for preparing fluvastatin sodium-containing compound preparation according to claim 1 or 2, wherein: the preparation method of the tablet comprises the following steps: taking microcrystalline cellulose, silicon dioxide and hydroxypropyl methylcellulose at a ratio of 7:3: 1; uniformly mixing microcrystalline cellulose and silicon dioxide, adding fluvastatin sodium according to the component amount by an equivalent incremental method, and uniformly mixing; weighing hydroxypropyl methylcellulose, preparing into 5% water solution, pressing solid powder into pellet, coating hydroxypropyl methylcellulose on the pellet by fluidized bed medicine feeding method, and spraying CAP film to obtain enteric fluvastatin sodium pellet;

sieving silicon dioxide or magnesium stearate with 60 mesh sieve; adding appropriate amount of ethanol into microcrystalline cellulose or lactose to prepare into granule; firstly, adding enteric fluvastatin sodium pellets and lactose particles into a mixer for mixing, then adding cyclophosphamide according to the component parts, setting a proper rotating speed, mixing for 20 minutes, then adding silicon dioxide or magnesium stearate, continuing mixing for 5 minutes, and tabletting by using a circular shallow concave die with the diameter of 9mm, wherein the hardness is 7-10 kg/cm 2.

4. The method for preparing the compound preparation containing fluvastatin sodium according to claim 3, which comprises the following steps: the compound preparation formulation comprises a solid preparation, a liquid preparation, an injection, an external transdermal preparation, a tablet and a capsule formulation.

Technical Field

The invention relates to the technical field of organic matter synthesis pharmacy, in particular to a preparation method of a compound preparation containing fluvastatin sodium.

Background

Nasopharyngeal carcinoma refers to malignant tumors occurring at the top and side walls of the nasopharyngeal cavity, is one of high-incidence malignant tumors in China, has the incidence rate of otorhinolaryngological malignant tumors, is a multi-incidence area in Guangdong, Guangxi, Fujian, Hunan and the like, is more than a woman, is mostly middle-aged people and also has juvenile patients, and is researched: the etiology is related to ethnic susceptibility (yellow people are more sick than white people), genetic factors, EB virus infection and the like, the malignancy degree of nasopharyngeal carcinoma is higher, and common clinical symptoms of nasal obstruction, blood in nasal discharge, ear stuffiness and blockage, hearing loss, diplopia, headache and the like can appear in early stage of cervical lymph node metastasis. Nasopharyngeal carcinoma is mostly of moderate sensitivity to radiotherapy, which is the first choice for treatment of nasopharyngeal carcinoma. However, surgical resection and chemotherapy are indispensable for the treatment of more differentiated cancers, later disease processes and recurrence after radiotherapy.

Cyclophosphamide is the most commonly used antineoplastic agent of alkylating agent, after entering human body, it is hydrolyzed by excessive phosphoramide enzyme or phosphatase existing in liver or tumor, decomposes and releases chloroethylphosphamide (or named as phosphoramide nitrogen mustard) with strong alkylation, and generates cytotoxicity to tumor cells, and is clinically used for malignant lymphoma, multiple myeloma, leukemia, breast cancer, ovarian cancer, cervical cancer, prostate cancer, colon cancer, bronchial cancer, nasopharyngeal carcinoma, lung cancer, etc., and the antineoplastic spectrum is wide, and is the first so-called "latent" broad-spectrum antineoplastic agent. It is a first-line medicine for treating nasopharyngeal carcinoma, and is mainly used in the chemotherapy stage of late stage nasopharyngeal carcinoma.

Fluvastatin sodium is the first totally-synthesized HMG-CoA reductase inhibitor, is a common hypolipidemic drug, is used for primary hypercholesterolemia and mixed dyslipidemia which cannot be completely controlled by diet, has a good hypolipidemic effect, and is rarely recorded for treating nasopharyngeal carcinoma.

Disclosure of Invention

Aiming at the defects and problems in the prior art, the invention provides a preparation method of a compound preparation containing fluvastatin sodium, and when cyclophosphamide is applied to treat nasopharyngeal carcinoma, patients simultaneously use fluvastatin sodium, the two have obvious synergistic effect.

In order to achieve the purpose, the invention provides the following technical scheme:

a preparation method of a compound preparation containing fluvastatin sodium comprises the step of uniformly mixing fluvastatin sodium and cyclophosphamide according to the weight ratio of 1: 0.1-0.8.

In the technical scheme, the weight ratio of fluvastatin sodium to cyclophosphamide is 1: 0.2-0.4.

A compound preparation containing fluvastatin sodium is in the form of solid preparation, liquid preparation, injection, external transdermal preparation, tablet or capsule.

In the technical scheme, the preparation method of the tablet comprises the following steps: taking microcrystalline cellulose, silicon dioxide and hydroxypropyl methylcellulose at a ratio of 7:3: 1; uniformly mixing microcrystalline cellulose and silicon dioxide, adding fluvastatin sodium according to the component amount by an equivalent incremental method, and uniformly mixing; weighing hydroxypropyl methylcellulose, preparing into 5% water solution, pressing solid powder into pellet, coating hydroxypropyl methylcellulose on the pellet by fluidized bed medicine feeding method, and spraying CAP film to obtain enteric fluvastatin sodium pellet;

sieving silicon dioxide or magnesium stearate with 60 mesh sieve; adding appropriate amount of ethanol into microcrystalline cellulose or lactose to prepare into granule; firstly, adding enteric fluvastatin sodium pellets and lactose particles into a mixer for mixing, then adding cyclophosphamide according to the component parts, setting a proper rotating speed, mixing for 20 minutes, then adding silicon dioxide or magnesium stearate, continuing mixing for 5 minutes, and tabletting by using a circular shallow concave die with the diameter of 9mm, wherein the hardness is 7-10 kg/cm 2.

The fluvastatin sodium is combined with the cyclophosphamide with low dose to achieve the aim of inhibiting the growth of tumors, a new and more effective solution is provided for the treatment of the nasopharyngeal carcinoma, and the preparation is used for the treatment of the nasopharyngeal carcinoma, has higher effectiveness and less side effect than the single use of the cyclophosphamide, and is particularly suitable for the treatment of the patients with the nasopharyngeal carcinoma with hyperlipidemia.

Detailed Description

The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

The preparation method of the compound preparation containing fluvastatin sodium shown as the example comprises the following steps:

example 1: a method for preparing a compound preparation containing fluvastatin sodium comprises the step of uniformly mixing fluvastatin sodium and cyclophosphamide according to the weight ratio of 1: 0.1-0.8, wherein in the preferred embodiment, the weight ratio of the fluvastatin sodium to the cyclophosphamide is 1: 0.2-0.4.

The compound preparation can be prepared into various dosage forms, including solid preparations, liquid preparations, injections, external transdermal preparations and other administration types, and 2 medicaments can be orally taken, preferably prepared into oral preparations, preferably conventional dosage forms such as tablets, capsules and the like, fluvastatin sodium is prepared into enteric pellets and dispersed in the tablets, and the tablets also contain related auxiliary materials which can be used by persons skilled in the art in the tablet process such as fillers, lubricants, disintegrants and the like.

The preparation method of the tablet comprises the following steps: taking microcrystalline cellulose, silicon dioxide and hydroxypropyl methylcellulose at a ratio of 7:3: 1; uniformly mixing microcrystalline cellulose and silicon dioxide, adding fluvastatin sodium according to the component amount by an equivalent incremental method, and uniformly mixing; weighing hydroxypropyl methylcellulose, preparing into 5% water solution, pressing solid powder into pellet, coating hydroxypropyl methylcellulose on the pellet by fluidized bed medicine feeding method, and spraying CAP film to obtain enteric fluvastatin sodium pellet;

sieving silicon dioxide or magnesium stearate with 60 mesh sieve; adding appropriate amount of ethanol into microcrystalline cellulose or lactose to prepare into granule; firstly, adding enteric fluvastatin sodium pellets and lactose particles into a mixer for mixing, then adding cyclophosphamide according to the component parts, setting a proper rotating speed, mixing for 20 minutes, then adding silicon dioxide or magnesium stearate, continuing mixing for 5 minutes, and tabletting by using a circular shallow concave die with the diameter of 9mm, wherein the hardness is 7-10 kg/cm 2.

Mechanism and background of the invention: the inventor discovers that in the process of collecting medical records of medicine use, when patients who use cyclophosphamide to treat nasopharyngeal carcinoma use fluvastatin sodium, the side effect of the patients suffering from the nasopharyngeal carcinoma is obviously lighter, the two have obvious synergy, the effective rate of the cyclophosphamide is obviously improved, so that the nasopharyngeal carcinoma rats are consciously fed with food containing compound preparations, and after a contrast test with rats fed with the cyclophosphamide alone, the fluvastatin sodium can obviously improve the effectiveness of the cyclophosphamide, and the fluvastatin sodium and the cyclophosphamide can synergistically control the growth of the nasopharyngeal carcinoma through the action mechanism of inhibiting the generation and growth of tumor vessels, so that the remarkable synergistic nasopharyngeal carcinoma resisting effect is generated, and meanwhile, the toxic and side effect of the cyclophosphamide can be effectively reduced.

The test data is as follows: test for influence of combination of fluvastatin sodium and cyclophosphamide on nasopharyngeal carcinoma rats

Dividing nasopharyngeal carcinoma rats into 3 groups, each group comprises 4 rats, wherein 1 group is fed with equal amount of adjuvant; 2 groups are fed with cyclophosphamide 4 mg/kg; the 3 groups were fed fluvastatin sodium 0.5mg/Kg and cyclophosphamide 4mg/kg. once a day for 21 days, and the body weights of the nude mice before and after treatment and the tumor volumes after the administration were measured as follows:

TABLE 1 comparison of body weights of groups of nude mice before and after treatment

Group of	Number only	Before treatment (g)	After treatment (g)
				1	4	212.6	194.3
2	4	208.7	244.6
				3	4	211.1	256.7

It can be seen that the rats of groups 2 and 3 treated with the drug showed significant weight gain, especially in rats treated with fluvastatin sodium and cyclophosphamide.

Table 2 comparison of tumor volumes after administration to groups of nude mice:

group of	Number only	Volume after administration (mm)3)
			1	4	1810.4
2	4	1632.7
			3	4	1466.8

Thus: fluvastatin sodium can obviously improve the effectiveness of cyclophosphamide, fluvastatin sodium combined with cyclophosphamide can synergistically control the growth of nasopharyngeal carcinoma by inhibiting the action mechanism of tumor angiogenesis and growth, generate obvious synergistic nasopharyngeal carcinoma resisting action, and simultaneously can effectively reduce the toxic and side effects of cyclophosphamide.

The above description is only for the specific embodiments of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention, and all the changes or substitutions should be covered within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.