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A kind of atorvastatin calcium composition, preparation and preparation method thereof

A technology of atorvastatin calcium and composition, applied in the field of medicine, can solve the problems of reduced clinical safety, lack of any lipid-lowering activity, aggravated gastrointestinal irritation, etc., to reduce the incidence of adverse reactions and avoid the dissolution rate The difference is too large, the effect of reducing gastrointestinal adverse reactions

Active Publication Date: 2021-09-24
北京海晶生物医药科技有限公司
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  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This lactone compound does not have any lipid-lowering activity and also causes the well-known myalgia side effects of statins
Especially when excipients are added to make corresponding dosage forms, the contact of statins with excipients will lead to a decrease in the stability of atorvastatin calcium
Calcium carbonate was added to the prescription of the original research product to improve its stability, but in the process of stability investigation, we found that the level of related substances in the original research product increased significantly, indicating that the simple addition of alkaline substance calcium carbonate can improve the potency of atorvastatin calcium. limited stabilizing effect
In addition, it has been reported in the literature that adding a large amount of alkaline substances such as calcium carbonate will react with gastric acid in the body, leading to adverse reactions such as constipation, flatulence, and indigestion.
[0005] Invention patent CN1642526A (WO2003 / 068191) discloses atorvastatin calcium preparations stabilized by basic metal additives. Atorvastatin calcium exists in an amorphous form and is prepared into other forms of preparations after simply mixing with basic metals in the prescription. This preparation process cannot fundamentally solve the problem of atorvastatin calcium instability
However, it does not solve the problem of instability of atorvastatin calcium preparations. In this case, increasing its bioavailability will cause increased side effects of atorvastatin calcium and reduce clinical safety.
[0007] Invention patent CN103690485A discloses oral proliposome containing atorvastatin calcium and its preparation method, and invention patent CN103690513A discloses atorvastatin calcium nano-lipid carrier and its preparation method. Statin calcium liposome improves its stability. The preparation process of this method is relatively complicated, and a large amount of surfactant is used, which increases the irritation to the gastrointestinal tract.
[0008] Invention patents CN104983702A, CN104983690A, CN105030698A, and CN105030728A all disclose a pharmaceutical preparation prepared by using a new crystal form of atorvastatin calcium, which improves the stability of the atorvastatin calcium preparation. It is possible to transform into the existing crystal form, and the probability that the prepared pharmaceutical preparation is not equivalent to the original research product is high, and its safety and effectiveness need to be verified
[0009] Invention patent CN1630510B discloses atorvastatin calcium in pharmaceutical form, its composition and pharmaceutical preparations containing atorvastatin calcium. In the disclosed technical scheme, atorvastatin calcium is micronized and then added to make 900ml The pH of the 0.001M HCl aqueous solution with a pH of about 3 is raised to a pH equal to or greater than the pKa+1 or greater pH-adjusting substance of atorvastatin calcium, and this method can improve the potency of atorvastatin calcium to a certain extent Stability, but a large number of alkaline excipients are added to the prescription, which increases the adverse reactions in the gastrointestinal tract
[0010] In summary, the atorvastatin calcium preparation composition and preparation method reported in existing research reports and patent literature cannot fundamentally solve the problem of atorvastatin calcium stability, and at the same time, there is a large amount of basic auxiliary materials added. The existence of adverse reactions in the gastrointestinal tract

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  • A kind of atorvastatin calcium composition, preparation and preparation method thereof
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  • A kind of atorvastatin calcium composition, preparation and preparation method thereof

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preparation example Construction

[0048] Secondly, the present invention provides a kind of preparation method of the composition of atorvastatin calcium, and this preparation method comprises following preparation steps:

[0049] (1) Suspend or dissolve atorvastatin calcium, micronized basic auxiliary materials, Tween and optional hydroxypropyl cellulose in a composite solvent of an appropriate amount of methanol and purified water, spray dry, and sieve to obtain mixture;

[0050] (2) Prepared by uniformly mixing the above atorvastatin calcium mixture with other remaining auxiliary materials.

[0051] In one embodiment, the basic auxiliary material is the basic auxiliary material obtained after the micronization step, and the sieving treatment is to pass through a 100-mesh sieve.

[0052] In one embodiment, the optional hydroxypropyl cellulose in step (1) means that hydroxypropyl cellulose can be added or not added in this step, and methanol and purified The volume ratio of water is 1:1-5, preferably 1:3. ...

Embodiment 1

[0064] prescription:

[0065] Raw materials parts by weight Atorvastatin Calcium 1 calcium carbonate 2.75 Microcrystalline Cellulose PH101 5.50 lactose 2.85 Croscarmellose sodium (additional) 0.41 twain 0.04 Hypromellose EF 0.311 Croscarmellose sodium (additional) 0.41 Magnesium stearate 0.04

[0066] Preparation Process:

[0067] (1) Micronize the calcium carbonate in the prescription to less than 20 μm.

[0068] (2) Suspend atorvastatin calcium and micronized calcium carbonate, hydroxypropyl cellulose EF, and Tween in a mixed solvent of an appropriate amount of methanol and purified water, wherein the volume ratio of methanol to purified water is 1:3 , stirred evenly, and spray-dried to obtain a mixture. The spray-drying parameters were 70° C. of inlet air temperature, 40° C. of outlet air temperature, 35 Hz of induced air frequency, 40 Hz of blast air frequency, and 300 Hz of atomization frequency. The o...

Embodiment 2

[0072] prescription:

[0073] Raw materials parts by weight Atorvastatin Calcium 1 calcium silicate 3.03 Microcrystalline Cellulose PH101 6.34 Lactose 312 3.02 Crospovidone (internal addition) 0.40 twain 0.05 Hypromellose ELF 0.312 Crospovidone (additional) 0.33 Magnesium stearate 0.05

[0074] Preparation Process:

[0075] (1) Micronize the calcium carbonate in the prescription to less than 20 μm.

[0076] (2) Suspend atorvastatin calcium and micronized calcium silicate, hydroxypropyl cellulose ELF, and Tween in a mixed solvent of an appropriate amount of methanol and purified water, wherein the volume ratio of methanol to purified water is 1 : 3, stir evenly, spray dry to obtain mixture, spray dry parameters are 70 ℃ of air inlet temperature, 40 ℃ of air outlet temperature, 35 Hz of induced wind frequency, 40 Hz of blast frequency, 300 Hz of atomization frequency, gained mixture passes 100 mesh sieves.

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Abstract

The invention relates to a stable atorvastatin calcium composition, preparation and preparation method thereof. The invention adopts the micronization of the active ingredient and the basic auxiliary material in the prescription, and then suspends or dissolves them in a mixed solvent of methanol and purified water The atorvastatin calcium preparation is prepared by spray drying, which has better stability than the original research product, reduces adverse reactions, and improves patient compliance; at the same time, it has better dissolution uniformity and bioequivalence Tests show that this product is biologically equivalent to the original research product.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a composition, a preparation and a preparation method of atorvastatin calcium. Background technique [0002] Atorvastatin calcium is the third-generation statin blood lipid-regulating drug. It is a selective and competitive inhibitor of HMG-CoA reductase. Acid monoacyl-CoA reductase) and cholesterol synthesis, thereby reducing plasma cholesterol and lipoprotein levels, and by increasing the liver LDL receptors on the cell surface to enhance the uptake and metabolism of LDL. [0003] Atorvastatin calcium can reduce plasma total cholesterol, LDL-C (low-density lipoprotein cholesterol) and Apolipoprotein B can also reduce the levels of very low-density lipoprotein cholesterol and triacylglycerol, and can increase the levels of plasma high-density lipoprotein cholesterol and apolipoprotein to varying degrees. Compared with other lipid-regulating drugs, atorvastatin cal...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K47/02A61K47/38A61K31/40A61P3/06
CPCA61K31/40A61K47/02A61K47/38A61P3/06
Inventor 曹相林李萍高万峰张中领商丹丹
Owner 北京海晶生物医药科技有限公司
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