CN102793929B

CN102793929B - Method for preparing stable amorphous drug preparation

Info

Publication number: CN102793929B
Application number: CN2012103279703A
Authority: CN
Inventors: 卢恩先; 李守峰
Original assignee: Shanghai Aucta Pharmaceuticals Co Ltd
Current assignee: Shanghai Aokeda Pharmaceutical Technology Co ltd
Priority date: 2012-09-07
Filing date: 2012-09-07
Publication date: 2013-12-11
Anticipated expiration: 2032-09-07
Also published as: CN102793929A

Abstract

The invention belongs to the technical field of drug preparation, in particular to a method for preparing a stable amorphous drug preparation. According to the method, a small quantity of micromolecule auxiliary materials are added to an amorphous pharmaceutical preparation, such as citric acid, succinic acid, sorbitol and the like, which can be used for effectively stabilizing the amorphous pharmaceutical preparation. Compared with macromolecule auxiliary materials, the micromolecule auxiliary materials can have better interaction and compatibility with drug molecules, so that the micromolecule auxiliary materials can be used for better stabilizing the amorphous drug preparation. The invention also provides an optimization method of an amorphous drug preparation prescription, and the optimization process comprises the following steps of: screening proper micromolecule auxiliary materials according to different drugs, and determining an optimal dosage of the screened micromolecule auxiliary materials.

Description

A kind of method of stablizing amorphous state pharmaceutical preparation for preparing

Technical field

The invention belongs to field of medicine preparing technology, be specifically related to a kind of preparation method of amorphous state pharmaceutical preparation.

Background technology

In recent years, along with the appearance of more insoluble drugs, amorphous state pharmaceutical preparation is more and more paid close attention to.Amorphous state pharmaceutical preparation can improve the dissolubility of insoluble drug, thereby increases absorption and the bioavailability of medicine.Amorphous state pharmaceutical preparation applied range, be applicable to the exploitation of early stage new drug and the improvement of later stage preparation.

The pharmaceutical preparation of preparation amorphous state, usual method is first medicine and adjuvant to be dissolved in solvent, then uses spray drying, then through lyophilization or rotary evaporation, except desolventizing.Also having a kind of method more commonly used is to melt extrusion molding, first medicine and adjuvant is at high temperature melted, then cooling fast.If but preparation technology is improper or preparation prescription is bad, medicine can crystallize out in preparation process, thereby can not get amorphous state pharmaceutical preparation.

Although amorphous state pharmaceutical preparation has a lot of advantages, amorphous state pharmaceutical preparation is very unstable, and it, can spontaneous crystallizing out in storage process in metastable condition.Therefore prepare a stable amorphous state pharmaceutical preparation is the difficult problem of pharmacy circle always.Solution commonly used is to add a large amount of high polymer adjuvants to stablize amorphous state pharmaceutical preparation at present.Selected macromolecule material should have higher vitrification point, can and drug molecule certain interaction (by hydrogen bond, ionic bond or other modes) and compatibility are preferably arranged.But process like this, the stability of amorphous state pharmaceutical preparation is still not ideal enough, and technique is more complicated also.

Summary of the invention

The object of the invention is to propose the simple preparation of a kind of technique and stablize the method for amorphous state pharmaceutical preparation.

The present invention finds after deliberation, no matter, in preparation or storage process, adds a small amount of micromolecule adjuvant (as citric acid, succinic acid, sorbitol etc.) in the formula of amorphous state pharmaceutical preparation, can effectively stablize amorphous state pharmaceutical preparation.With high polymer adjuvant, compare, micromolecule adjuvant and drug molecule can have better interaction and compatibility.Therefore, the micromolecule adjuvant can better be stablized amorphous state pharmaceutical preparation.But the vitrification point of micromolecule adjuvant is lower, add a large amount of micromolecule adjuvants can make the vitrification point of amorphous state pharmaceutical preparation reduce, thereby production is made troubles to preparation.So prescription need to be optimized.Optimizing process comprises: the suitable micromolecule adjuvant according to different drug screenings; Determine the optimum amount that filters out the micromolecule adjuvant.

Selected micromolecule adjuvant should have good interaction with medicine.Interaction comprises hydrogen bond, ionic bond, nonpolar bond etc.The interaction power can be calculated or obtain by experiment by molecular structural formula.Experimental technique more commonly used is the melting point depression method.The used in amounts of micromolecule adjuvant will obtain by experiment.More direct method is to investigate by phasor.

The method of amorphous state pharmaceutical preparation is stablized in the preparation that the present invention proposes, and specifically can have following 2 kinds:

Preparation method I, concrete steps are:

1. by medicine, micromolecule adjuvant and high polymer adjuvant are dissolved in suitable solvent;

2. use spray drying, the method for lyophilization or rotary evaporation is except desolventizing;

3. resulting solid conservation carries out drying in vacuum desiccator;

4. the solid abrasive of gained is become to fine powder, then cross 35 purpose sieves.

Preparation method II, concrete steps are:

1. hybrid medicine, micromolecule adjuvant and high polymer adjuvant;

2. said mixture is added to hot-melt extruded granulator, make granule;

3. the solid particle that grinds gained becomes fine powder, then crosses 35 purpose sieves;

4. resulting powder is kept in vacuum desiccator and carries out drying.

Add the micromolecule adjuvant can be than being easier to successful preparation amorphous state preparation.And can make the amorphous state preparation keep stable in storage and transportation.

The accompanying drawing explanation

Fig. 1 is the screening phasor of carbamide amorphous state preparation.Blue triangle represents that the gained solid contains crystal formation, and red square represents that the gained solid is the amorphous state preparation.

Fig. 2 is the phasor of condition after lower 3 months that carbamide amorphous state preparation is stored in 40 ℃ of temperature and 75% humidity.Blue triangle represents that the gained solid contains crystal formation, and red square represents that the gained solid is the amorphous state preparation.

Fig. 3 is the Lapatinib amorphous state formulation X optical diffraction figure made.

Fig. 4 is Lapatinib amorphous state preparation and the dissolution of Lapatinib crude drug in water.

The X-ray diffraction pattern (with the comparison that start) of Fig. 5 after to be Lapatinib amorphous state preparation store 2 weeks under the condition of 40 ℃ and 75% humidity.

The specific embodiment

Below by specific embodiment, further introduce the inventive method.

embodiment 1:carbamide (urea) amorphous state preparation

The molecule of carbamide is very little, is easy to crystallization.Also do not report at present amorphous state carbamide.The technology of application this patent, the amorphous state preparation of carbamide is by successful preparation, and good stability is arranged.

Prescription screening:

1. carbamide, citric acid (citric acid) and hydroxypropyl emthylcellulose (HPMC) are dissolved in methanol, wherein, 10 % that the addition of citric acid is gross weight～30 %, 60 % that the addition of hydroxypropyl emthylcellulose is gross weight～80 %;

2. solvent methanol volatilizees at normal temperatures, obtains carbamide amorphous state preparation;

3. carbamide amorphous state preparation is kept in vacuum desiccator; Temperature is 24 ℃ ~ 28 ℃, preferably 25 ℃;

Detect whether obtain pure amorphous state preparation with microscope and powder x-ray diffraction.Fig. 1 is the screening phasor of carbamide amorphous state preparation.

As seen from Figure 1, do not add micromolecule adjuvant citric acid, only in the situation that urea content, lower than gross weight 10%, just can obtain the amorphous state preparation.Added citric acid, urea content still can form the amorphous state preparation up to gross weight 60%.The carbamide amorphous state preparation obtained is stored in the condition of 40 ℃ of temperature and 75% humidity and studies the stability of preparation over lower 3 months.Fig. 2 is that carbamide amorphous state preparation stores the phasor after 3 months under the condition of 40 ℃ of temperature and 75% humidity.As can be seen from Figure 2, when the citric acid that adds gross weight 10% or 20%, very stable containing the amorphous state preparation of gross weight 20% carbamide.The carbamide amorphous state preparation that there is no citric acid, after storing certain hour, carbamide can crystallize out.This shows, micromolecule adjuvant citric acid can help the preparation of carbamide amorphous state preparation and improve the stability of carbamide amorphous state preparation.

embodiment 2: Lapatinib amorphous state preparation

Lapatinib (lapatinib) is a kind of oral micromolecule epidermal growth factor (EGFR:ErbB-1, ErbB-2) tyrosine kinase inhibitor, the late period be used for the treatment of or metastatic breast cancer.Lapatinib belongs to insoluble drug, and in 25 ° of C water, dissolubility is<0.030 mg/mL.Therefore, the bioavailability of Lapatinib lower (<25%).Be prepared into the dissolubility that the amorphous state preparation can improve Lapatinib, thereby improve its bioavailability.

Lapatinib amorphous state preparation prescription is as table 1:

Table 1 Lapatinib amorphous state preparation prescription

?	20120629-2	20120629-4	20120629-6
				Two p-methyl benzenesulfonic acid Lapatinibs	100mg	100mg	500mg
PVPK30	700mg	600mg	3000mg
				Monohydrate potassium	---	100mg	500mg

Preparation method is as follows:

1. Lapatinib (lapatinib), PVPK30 and monohydrate potassium are dissolved in the methanol and water mixed solvent of 54 ℃ ~ 58 ℃ (preferably 55 ℃).In mixed solvent, the weight ratio of first alcohol and water is 40:1 v/v;

2. remove desolventizing with Rotary Evaporators;

3. the solid dispersion obtained is kept in vacuum desiccator dry 22 ~ 26 hours, preferably dry 24 hours;

4. the abrasive solid dispersion, cross 35 mesh sieves, obtains the solid dispersion powder.

The Lapatinib amorphous state formulation X optical diffraction figure made as shown in Figure 3.20120629-2 also has the crystal of a small amount of Lapatinib as can be seen from Figure 3.20120629-4 is amorphous state completely.Therefore add a small amount of micromolecule adjuvant in prescription, citric acid, can contribute to prepare noncrystal preparation.

20120629-6 is the prescription that 20120629-4 amplifies.Fig. 4 is 20120629-6 and the dissolution of Lapatinib crude drug in water.The dissolution of 20120629-6 in water, up to 150ug/ml, is 5 times of Lapatinib crude drug dissolution as can be seen from Figure 4.So Lapatinib amorphous state preparation probably improves Lapatinib bioavailability in vivo.

Lapatinib amorphous state preparation, 20120629-6 is placed under the condition of 40 ℃ and 75% humidity and stores 2 weeks its stability tests of investigation.Fig. 5 shows that Lapatinib amorphous state preparation is stable with this understanding.

Claims

1. one kind prepares the method for stablizing amorphous state pharmaceutical preparation, it is characterized in that adding appropriate micromolecule adjuvant in the formula of amorphous state pharmaceutical preparation;

The concrete steps of preparation are:

(1) carbamide, citric acid and hydroxypropyl emthylcellulose are dissolved in methanol, wherein, the addition of citric acid is gross weight 10%～30%, 60 % that the addition of hydroxypropyl emthylcellulose is gross weight～80 %;

(2) solvent methanol volatilizees at normal temperatures, obtains carbamide amorphous state preparation;

(3) carbamide amorphous state preparation is kept in vacuum desiccator; Temperature is 24 ℃--28 ℃;

Perhaps,

(1), by Lapatinib, PVPK30 and monohydrate potassium are dissolved in 54 ℃--and in the methanol and water mixed solvent of 58 ℃, in mixed solvent, the weight ratio of first alcohol and water is 40:1 v/v;

(2) remove desolventizing with Rotary Evaporators;

(3) solid dispersion obtained is kept at dry 22--26 hour in vacuum desiccator;

(4) abrasive solid dispersion, cross 35 mesh sieves, obtains the solid dispersion powder; Make Lapatinib amorphous state preparation;

Wherein, described Lapatinib is 100mg, and PVPK30 is 600mg, and monohydrate potassium is 100mg, or described Lapatinib is 500mg, and PVPK30 is 3000mg, and monohydrate potassium is 500mg.