阅读说明：本技术 一种适用于注射的药用乳糖及其制备方法 (Medicinal lactose suitable for injection and preparation method thereof ) 是由 庄贤韩 王瑞云 刘伦俊 于 2018-07-04 设计创作，主要内容包括：本发明属于医药领域,具体涉及一种适用于注射的药用乳糖及其制备方法。本发明人经研究发现,采用活性炭吸附和钛棒过滤相结合方法,可去除乳糖中存在的残留微量蛋白和其他杂质,纯化所得的乳糖可用于注射剂产品。亦即,本发明制备方法获得的药用乳糖,杂质蛋白的含量小于或等于200ppm,较佳地,杂质蛋白含量小于或等于100ppm；所述乳糖中内毒素含量小于或等于5EU/g,较佳情况下,内毒素含量小于或等于0.5EU/g,可适用于注射。(The invention belongs to the field of medicines, and particularly relates to medicinal lactose suitable for injection and a preparation method thereof. The inventor finds that residual trace protein and other impurities in the lactose can be removed by adopting a method combining activated carbon adsorption and titanium rod filtration, and the lactose obtained by purification can be used for injection products. That is, the content of impurity protein in the medicinal lactose obtained by the preparation method of the invention is less than or equal to 200ppm, preferably, the content of impurity protein is less than or equal to 100 ppm; the content of endotoxin in the lactose is less than or equal to 5EU/g, preferably less than or equal to 0.5EU/g, and the lactose is suitable for injection.)

1. A process for the preparation of pharmaceutical lactose suitable for injection, comprising the steps of: (1) dissolving: adding lactose raw material into water, dissolving until lactose is saturated; (2) adsorption: adding activated carbon into the lactose aqueous solution obtained in the step (1), and uniformly mixing to obtain a mixed solution of lactose and activated carbon; (3) and (3) filtering: filtering the mixed solution of lactose and active carbon obtained in the step (2), and collecting clear filtrate to obtain a lactose saturated aqueous solution; (4) and (3) crystallization: cooling and crystallizing the lactose saturated aqueous solution obtained in the step (3) to obtain a mixed solution of lactose crystals; (5) and (3) dehydrating: dehydrating the mixed liquid of the lactose crystals obtained in the step (4) to obtain wet lactose; (6) and (3) drying: and (5) drying the wet lactose obtained in the step (5) to obtain the wet lactose.

2. The preparation method according to claim 1, wherein in the step (1), the weight ratio of the lactose raw material to the water is (0.5-2.5): 1.

3. the method according to claim 1, wherein in the step (2), the weight ratio of the lactose aqueous solution to the activated carbon is 100: (0.1 to 1).

4. The method according to claim 1, wherein in the step (2), the mixed solution of lactose and activated carbon obtained in the step (2) is filtered through a titanium rod.

5. The preparation method according to claim 1, wherein in the step (4), the cooling is performed to 30 to 60 ℃ for cooling crystallization.

6. The process according to claim 1, wherein in the step (5), the mixture of lactose crystals obtained in the step (4) is transferred to a centrifuge and dehydrated.

7. The preparation method according to claim 1, wherein in the step (6), the wet lactose obtained in the step (5) is transferred to a fluidized drying oven and dried; preferably, the hot air temperature of the fluidized drying furnace is 60-100 ℃.

8. The method of claim 1, further comprising any one or more of the following features: 1) in the step (1), the lactose raw material is put into water which is heated to 40-45 ℃, and the obtained lactose aqueous solution is continuously heated to 95-100 ℃ until lactose is saturated; 2) in the step (1), the lactose raw material is selected from any one or more of medicinal lactose, analytically pure lactose or chemically pure lactose; 3) in the step (2), the active carbon is medicinal active carbon; 4) in the step (2), the lactose aqueous solution and the active carbon are uniformly mixed by adopting a heating mode; 5) and (4) transferring the lactose saturated aqueous solution obtained in the step (3) into a crystallizing tank, and cooling and crystallizing.

9. Use of the preparation method according to any one of claims 1 to 8 for preparing lactose for injection.

10. A lactose for injection prepared by the method of any one of claims 1 to 8.

Technical Field

The invention belongs to the field of medicines, and particularly relates to medicinal lactose suitable for injection and a preparation method thereof.

Background

Lactose belongs to disaccharide, has almost no physiological activity, is a common pharmaceutic adjuvant, is mainly used as a filler or a diluent in an oral solid preparation, and is also used for direct compression of the oral solid preparation. Less commonly used in injections, but more commonly used in some lyophilized formulations. Lactose, which is present in amorphous form without damaging the main active ingredient due to its high glass transition temperature during lyophilization, plays a role as a "lyoprotectant" in such lyophilized formulations.

Lactose is mainly derived from animal milk and is an accessory product of milk, and the safety problem becomes the biggest limitation of applying the lactose to medical products, and the safety problem mainly comprises two aspects, namely lactose intolerance caused by gastrointestinal tract, and anaphylaxis caused by residual allergens (including protein impurities and other impurities, such as endotoxin) in the lactose to human bodies. When the injection is used, a series of adverse reactions such as urticaria, fever, shock and the like are easily caused, so that the application of lactose as an injection auxiliary material is greatly limited. Therefore, it is highly desirable to develop a new purification process to obtain lactose with high purity that can be used for injection.

In the refining process of lactose, the application of active carbon is indispensable, the active carbon has developed pore structure, large specific surface area and rich internal microporous structure, can adsorb pigments, impurities, inorganic metal ions, partial organic matters and the like, is used as a high-quality adsorbent and is widely applied to the processes of medicament decolorization, purification and refining. The literature reports that the activated carbon can adsorb protein in water, and the larger the protein concentration is, the larger the adsorption amount is.

The traditional process for removing protein and endotoxin and reducing microorganism indexes can generally adopt a physical filtration method such as an ultrafiltration membrane or adsorption method by using active carbon, resin and the like, and has the advantages of reducing new pyrogens and new impurities in the production process as much as possible, and on the premise of achieving the process purpose and the quality standard, the simpler process steps and the better production raw and auxiliary materials are used.

Through experiments, the lactose serving as the pharmaceutical adjuvant is taken as a raw material, and the pharmaceutical adjuvant for injection is obtained by selecting proper water and activated carbon and carrying out recrystallization refining. And the first-class solvent and the second-class solvent designated by ICH are not added in the crystallization, so that the pollution of three wastes is less. The product has stable quality and high yield.

In order to reduce the risk of using lactose in injection, a new lactose purification process is urgently needed to prepare lactose with good safety for the medical use of injection.

Disclosure of Invention

In order to overcome the problems in the prior art, the invention aims to provide medicinal lactose and a preparation method thereof, wherein the preparation method of the medicinal lactose belongs to a refining method of medicinal auxiliary materials, and particularly belongs to the medicinal auxiliary material lactose for injection and the refining method thereof. The medicinal lactose prepared by the invention has low impurity protein content and low endotoxin content, is safe and effective, and can be used for injection.

In order to achieve the above objects and other related objects, the present invention adopts the following technical solutions:

in a first aspect of the present invention, there is provided a process for the preparation of pharmaceutical lactose suitable for injection, comprising the steps of:

(1) dissolving: adding lactose raw material into water, dissolving until lactose is saturated;

(2) adsorption: adding activated carbon into the lactose aqueous solution obtained in the step (1), and uniformly mixing to obtain a mixed solution of lactose and activated carbon;

(3) and (3) filtering: filtering the mixed solution of lactose and active carbon obtained in the step (2), and collecting clear filtrate to obtain a lactose saturated aqueous solution;

(4) and (3) crystallization: cooling and crystallizing the lactose saturated aqueous solution obtained in the step (3) to obtain a mixed solution of lactose crystals;

(5) and (3) dehydrating: dehydrating the mixed liquid of the lactose crystals obtained in the step (4) to obtain wet lactose;

(6) and (3) drying: and (5) drying the wet lactose obtained in the step (5) to obtain the wet lactose.

In one embodiment, in step (1), the lactose raw material is put into water which has been heated to 40-45 ℃, and the resulting aqueous lactose solution is further heated to 95-100 ℃ until lactose is saturated.

In one embodiment, in the step (1), the weight ratio of the lactose raw material to the water in the feeding process is (0.5-2.5): 1.

in one embodiment, in the step (1), the weight ratio of the lactose raw material to the water in the feeding process is (0.5-1.5): 1.

in one embodiment, in the step (1), the weight ratio of the lactose raw material to the water in the feeding process is (1.5-2.5): 1.

in one embodiment, in step (1), the weight ratio of lactose starting material to water at the time of dosing is 0.5, 1.5 or 2.5.

In one embodiment, in step (1), the lactose raw material is selected from any one or combination of pharmaceutical lactose, analytically pure lactose or chemically pure lactose. The lactose starting material is available commercially.

In one embodiment, in step (2), the activated carbon is pharmaceutical activated carbon. Can be obtained by commercial route.

In one embodiment, in step (2), the lactose aqueous solution is mixed with the activated carbon by heating.

In one embodiment, in step (2), the weight ratio of the aqueous lactose solution to the activated carbon is 100: (0.1 to 1).

In one embodiment, in step (2), the weight ratio of the aqueous lactose solution to the activated carbon is 100: (0.3 to 1).

In one embodiment, in step (2), the weight ratio of the aqueous lactose solution to the activated carbon is 100: (0.5 to 1).

In one embodiment, in step (2), the weight ratio of the aqueous lactose solution to the activated carbon is 100: (0.8 to 1).

In one embodiment, in step (2), the weight ratio of the aqueous lactose solution to the activated carbon is 100: (0.1-0.8).

In one embodiment, in step (2), the weight ratio of the aqueous lactose solution to the activated carbon is 100: (0.1-0.5).

In one embodiment, in step (2), the weight ratio of the aqueous lactose solution to the activated carbon is 100: (0.1-0.3).

In one embodiment, in step (2), the weight ratio of the aqueous lactose solution to the activated carbon is 100: (0.3-0.8).

In one embodiment, in step (2), the weight ratio of the aqueous lactose solution to the activated carbon is 100: (0.3-0.5).

In one embodiment, in step (2), the weight ratio of the aqueous lactose solution to the activated carbon is 100: (0.5-0.8).

In one embodiment, in step (2), the weight ratio of the aqueous lactose solution to the activated carbon is 100:0.1, 100: 0.3, 100:0.5, 100:0.8 and 100: 1.

In one embodiment, in step (3), the mixed solution of lactose and activated carbon obtained in step (2) is filtered through a titanium rod.

In one embodiment, the titanium rod is a micron titanium rod.

In one embodiment, in the step (4), the lactose saturated aqueous solution obtained in the step (3) is transferred to a crystallizing tank for cooling crystallization.

In one embodiment, in the step (4), the cooling temperature is 30-60 ℃, and the cooling crystallization is carried out.

In one embodiment, in the step (4), the cooling temperature is 30-40 ℃, and the cooling crystallization is carried out.

In one embodiment, in the step (4), the cooling temperature is 40-60 ℃, and the cooling crystallization is carried out.

In one embodiment, in step (5), the mixed solution of lactose crystals obtained in step (4) is transferred to a centrifuge for dehydration.

In one embodiment, in the step (6), the lactose wet sugar obtained in the step (5) is transferred to a fluidized drying oven and dried. So as to obtain the medicinal lactose which has low impurity protein content and qualified endotoxin and is suitable for injection.

In one embodiment, the hot air temperature of the fluidized drying furnace is 60-100 ℃.

In a second aspect of the invention, there is provided the use of the aforementioned preparation process for the preparation of lactose for injection.

In a third aspect of the invention, there is provided a medicinal lactose suitable for injection prepared by the aforementioned preparation method.

In one embodiment, the pharmaceutically acceptable lactose suitable for injection is lactose monohydrate, lactose anhydrous, or a combination thereof.

In one embodiment, the pharmaceutical lactose suitable for injection contains less than or equal to 200ppm of contaminating proteins. Preferably, the impurity protein is less than or equal to 100 ppm. The impurity protein is residual impurity protein or introduced protein impurity in the lactose production process.

In one embodiment, the pharmaceutical lactose suitable for injection has an endotoxin content of less than or equal to 5 EU/g. Preferably, the endotoxin content is less than or equal to 0.5 EU/g.

Compared with the prior art, the invention has the following beneficial effects:

the inventor finds that residual trace protein and other impurities in the lactose can be removed by adopting a method combining activated carbon adsorption and titanium rod filtration, and the lactose obtained by purification can be used for injection products. That is, the content of impurity protein in the medicinal lactose obtained by the preparation method of the invention is less than or equal to 200ppm, preferably, the content of impurity protein is less than or equal to 100 ppm; the content of endotoxin in the lactose is less than or equal to 5EU/g, preferably less than or equal to 0.5EU/g, and the lactose is suitable for injection.

Detailed Description

Before the present embodiments are further described, it is to be understood that the scope of the invention is not limited to the particular embodiments described below; it is also to be understood that the terminology used in the examples is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention. Test methods in which specific conditions are not specified in the following examples are generally carried out under conventional conditions or under conditions recommended by the respective manufacturers.

When numerical ranges are given in the examples, it is understood that both endpoints of each of the numerical ranges and any value therebetween can be selected unless the invention otherwise indicated. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition to the specific methods, devices, and materials used in the examples, any methods, devices, and materials similar or equivalent to those described in the examples may be used in the practice of the invention in addition to the specific methods, devices, and materials used in the examples, in keeping with the knowledge of one skilled in the art and with the description of the invention.

Unless otherwise indicated, the experimental methods, detection methods, and preparation methods disclosed herein all employ techniques conventional in the art of molecular biology, biochemistry, chromatin structure and analysis, analytical chemistry, cell culture, recombinant DNA technology, and related arts. These techniques are well described in the literature, and may be found in particular in the study of the MOLECULAR CLONING, Sambrook et al: a LABORATORY MANUAL, Second edition, Cold Spring harbor LABORATORY Press, 1989and Third edition, 2001; ausubel et al, Current PROTOCOLS Inmolecular BIOLOGY, John Wiley & Sons, New York, 1987and periodic updates; the series METHODS IN ENZYMOLOGY, Academic Press, San Diego; wolffe, CHROMATINSTRUCUTURE AND FUNCTION, Third edition, Academic Press, San Diego, 1998; (iii) Methods Inenzymolygy, Vol.304, Chromatin (P.M. Wassarman and A.P.Wolffe, eds.), academic Press, San Diego, 1999; and METHODS IN MOLECULAR BIOLOGY, Vol.119, chromatography protocols (P.B.Becker, ed.) Humana Press, Totowa, 1999, etc.