CN102038663B - Carbazole sulfonamide antineoplastic agent capsules and preparation method - Google Patents

Abstract

The invention belongs to the field of pharmaceutic preparations and relates to a preparation method of the antineoplastic agent, in particular to carbazole sulfonamide antineoplastic agent capsules and a preparation method thereof. The carbazole sulfonamide antineoplastic agent capsules are characterized in that: lactose and beta-cyclodextrin are added into a carbazole sulfonamide medicine, namely N-(2,6-dimethypyridine-3-yl)-9-methylcarbazole-3-sulfamide; the materials are mixed and ground into micro powder; the micro powder is granulated, and the granulates are formed into capsules; and the dissolution rate of the capsules are improved.

Description

A kind of carbazole sulfonamide series antineoplastic medicament capsule and preparation method thereof

Technical field

The invention belongs to field of pharmaceutical preparations, relate to a kind of method for preparing of anti-tumor agent, be specifically related to a kind of carbazole sulfonamide series antineoplastic medicament capsule and preparation method thereof.

Background technology

Antitubulin is one type of effectively antitumor drug; Along with paclitaxel extensive use clinically; With to the structure of microtubule and the deep understanding of function, be that the research and development of the antitumor drug of target spot have caused the concern of whole world drugmaker day by day with the tubulin.

At present, paclitaxel and vinca Antitubulin have been successfully applied to all kinds of tumors of clinical treatment, but it is as a kind of macromolecular natural product; Its synthetic difficulty is big; Bioavailability is low, toxic side effect, particularly; The appearance of multidrug resistant glycoprotein makes its therapeutic receive serious challenge.Therefore, synthesizing new is necessary to the effective micromolecule Antitubulin of all kinds of tumors.

Chinese patent discloses patent of invention: carbazole sulfonamide derivative and preparation method thereof (Granted publication CN 1807413B); Carbazole sulfonamide derivative is one type of new micromolecule Antitubulin, not only has anti-microtubule effect, also has notable antitumor activity; And it is little to have molecular weight; Synthetic simple, the advantage that toxic and side effects is little has a good application prospect.

N-of the present invention (2,6-dimethoxy-pyridine-3-the replaces)-capsular active component N-of 9-methyl carbazole-3-sulfonamide (2,6-dimethoxy-pyridine-3-replaces)-9-methyl carbazole-3-sulfonamide belongs to carbazole sulfonamide derivative, and its chemical structural formula is following:

This chemical compound has notable antitumor activity, but this chemical compound is very difficult water-soluble, and according to general capsules preparation technique, its capsule dissolution does not reach the requirement of pharmacopeia regulation far away.Making the capsule of processing that good dissolution arranged, is our urgency problems to be solved.

Summary of the invention

The object of the invention solves N-(2,6-dimethoxy-pyridine-3-replaces)-capsular dissolution problem of 9-methyl carbazole-3-sulfonamide exactly.

We find: with N-(2,6-dimethoxy-pyridine-3-replaces)-9-methyl carbazole-3-sulfonamide, and lactose, beta-schardinger dextrin-is milled to micropowder after mixing, and can promote its dissolution.Than using lactose, a kind of will the getting well in the beta-schardinger dextrin-separately.

We find: with N-(2,6-dimethoxy-pyridine-3-replaces)-9-methyl carbazole-3-sulfonamide, beta-schardinger dextrin-is milled to micropowder after mixing, and adds lactose again in above-mentioned micropowder, continues to be milled to micropowder, and its dissolution is best.

Its reason possibly be: micronized N-(2,6-dimethoxy-pyridine-3-replaces)-9-methyl carbazole-3-sulfonamide mixes with the micropowder beta-schardinger dextrin-, in wet-granulation process moistening time of ethanol water; Beta-schardinger dextrin-has played clathration; Clathrate has good wettability, so medicine obtained solubilising, simultaneously; Lactose micropowder is a water soluble adjuvant; Adsorbing the particle of a large amount of water soluble adjuvants around the micronized drug particle, so just can prevent the mutual gathering of tiny drug particle, it stably is present in the mixture.When water soluble adjuvant dissolved, tiny drug particle just directly was exposed in the dissolution medium, so dissolving (going out) speed is accelerated greatly.Therefore, beta-schardinger dextrin-, lactose has played synergism to the dissolution of drug particle.

We find: N-when milling (2,6-dimethoxy-pyridine-3-replaces)-9-methyl carbazole-3-sulfonamide, and lactose, the charge ratio of beta-schardinger dextrin-is: 1: 1～10: 1～3, W/W is better.

Can also include filler in the adjuvant, binding agent, disintegrating agent, lubricant.

Said filler is starch, Icing Sugar, cellulose derivative; Said binding agent is starch, gelatin, cellulose derivative, dextrin; Said disintegrating agent is starch, cellulose derivative, sodium lauryl sulphate; Said lubricant is Polyethylene Glycol, magnesium stearate, Pulvis Talci, micropowder silica gel.

(2,6-dimethoxy-pyridine-3-replaces)-9-methyl carbazole-3-sulfonamide capsule preparation method thereof is following for N-:

(1) with N-(2,6-dimethoxy-pyridine-3-replaces)-9-methyl carbazole-3-sulfonamide, beta-schardinger dextrin-is milled to micropowder after mixing;

(2) lactose is added in the above-mentioned micropowder, continues to be milled to micropowder, cross 200 mesh sieves;

(3) micropowder that (2) is prepared, and crossed filler, binding agent, the disintegrating agent mix homogeneously of 100 mesh sieves, adding ethanol water system soft material, 14 mesh sieves are granulated, 50 ℃～60 ℃ dryings, 14 mesh sieve granulate;

(4) the adding mix lubricant is even, detection level; Confirm that according to testing result capsule loads scope, carry out capsule and load, detects qualified after, pack, promptly get.

Above-mentioned method for preparing can obtain following useful effect 1:

We will be according to N-(2,6-dimethoxy-pyridine-3-the replaces)-9-methyl carbazole-3-sulfonamide capsule (A sample) of embodiment 1 formulation;

Embodiment 1 prescription deletion beta-schardinger dextrin-, the N-of preparation (2,6-dimethoxy-pyridine-3-replaces)-9-methyl carbazole-3-sulfonamide capsule (B sample);

Embodiment 1 prescription deletion lactose, the N-of preparation (2,6-dimethoxy-pyridine-3-replaces)-9-methyl carbazole-3-sulfonamide capsule (C sample);

, but do not mill the N-of preparation (2,6-dimethoxy-pyridine-3-replaces)-9-methyl carbazole-3-sulfonamide capsule (D sample) according to embodiment 1 prescription;

A, B, C, D sample are carried out the dissolution comparative test simultaneously, and according to the method for Chinese Pharmacopoeia version regulation in 2005, in simulated gastric fluid (0.1mol/L hydrochloric acid solution), result of the test is seen table 1:

Table 1

Sample	Dissolution (meansigma methods)
		A	93％
B	67％
		C	72％
D	43％

Can find out from last table: use beta-schardinger dextrin-simultaneously, lactose, and mill, promoted the dissolution of sample greatly.

Above-mentioned method for preparing can obtain following useful effect 2:

We will carry out study on the stability according to N-(2,6-dimethoxy-pyridine-3-the replaces)-9-methyl carbazole-3-sulfonamide capsule (A sample) of embodiment 1 formulation:

Test one: hot test

Get N-(2,6-dimethoxy-pyridine-3-replaces)-9-methyl carbazole-3-sulfonamide capsule, in the horizontalization ware, be positioned in 60 ℃ of thermostatic drying chambers 10 days, in sampling in the 5th and the 10th day, detect a stability emphasis inspection item, with comparison in 0 day, the result saw table 2:

Table 2 hot test result

The result shows, these article are 60 ℃ of hot conditions held 10 days, outward appearance, content, and the basic no change of dissolution, related substance does not have significant change yet, shows that these article are comparatively stable to 60 ℃ of high temperature.

Test two: high wet test

Get N-(2,6-dimethoxy-pyridine-3-the replaces)-9-methyl carbazole-3-sulfonamide capsule of listing In Aluminium Foil Packing, in the horizontalization ware, be put in and fill KNO ₃In the exsiccator of saturated solution (25 ℃, RH 92.5%),, detect a stability emphasis inspection item in sampling in the 5th and the 10th day 25 ℃ of condition held 10 days, with 0 day relatively, the result sees table 3:

Table 3 high humidity (RH 92.5%) result of the test

The result shows, these article are in RH92.5% condition held, outward appearance, content, and the basic no change of dissolution, related substance does not have significant change yet, shows that these article are by stable to high humidity (RH 92.5%) under the listing In Aluminium Foil Packing condition.

Test three: strong illumination test

Get N-(2,6-dimethoxy-pyridine-3-replaces)-9-methyl carbazole-3-sulfonamide capsule, in the horizontalization ware, be put under the clarity detector light canopy; Regulate illumination 4500Lx, under this condition, placed 10 days; Detect in sampling in the 5th and the 10th day, with comparison in 0 day, the result saw table 4:

Table 4 exposure experiments to light result

The result shows, N-(2,6-dimethoxy-pyridine-3-replaces)-9-methyl carbazole-3-sulfonamide capsule under the strong illumination condition 10 days, with 0 day relatively, outward appearance, content, related substance, the basic no change of dissolution show that these article are stable to high light.

Conclusion:

Test shows: (2,6-dimethoxy-pyridine-3-replaces)-9-methyl carbazole-3-sulfonamide capsule is stable to high temperature, strong illumination to N-, also is stable by listing In Aluminium Foil Packing condition to high humidity.

Test shows: N-of the present invention (2,6-dimethoxy-pyridine-3-replaces)-9-methyl carbazole-3-sulfonamide capsule is write out a prescription and technology, can guarantee the quality of these article.

The specific embodiment

Following embodiment is used for further narrating the present invention, but does not do any restriction.

Embodiment 1 N-(2,6-dimethoxy-pyridine-3-replaces)-9-methyl carbazole-capsular preparation of 3-sulfonamide

Prescription: (1000)

N-(2,6-dimethoxy-pyridine-3-replaces)-9-methyl carbazole-3-sulfonamide 50g

Beta-schardinger dextrin-100g

Lactose 250g

Low-substituted hydroxypropyl cellulose 10g

Magnesium stearate 4g

Preparation technology:

(1) with 50g N-(2,6-dimethoxy-pyridine-3-replaces)-9-methyl carbazole-3-sulfonamide, the 100g beta-schardinger dextrin-is milled to micropowder after mixing.

(2) lactose 250g is added in the above-mentioned micropowder, continues to be milled to micropowder, cross 200 mesh sieves.

(3) micropowder that (2) is prepared, and crossed the low-substituted hydroxypropyl cellulose 10g mix homogeneously of 100 mesh sieves, adding 50% ethanol water system soft material, 14 mesh sieves are granulated, 50 ℃～60 ℃ dryings, 14 mesh sieve granulate.

(4) granule that (3) is prepared adds magnesium stearate 4g mix homogeneously, and content is surveyed in censorship; Confirm that according to testing result capsule loads scope, carry out capsule and load, detects qualified after, pack, promptly get.

Embodiment 2 N-(2,6-dimethoxy-pyridine-3-replaces)-9-methyl carbazole-capsular preparation of 3-sulfonamide

Prescription: (1000)

N-(2,6-dimethoxy-pyridine-3-replaces)-9-methyl carbazole-3-sulfonamide 100g

Beta-schardinger dextrin-100g

Lactose 100g

Microcrystalline Cellulose 15g

Magnesium stearate 6g

Preparation technology:

(1) with 100g N-(2,6-dimethoxy-pyridine-3-replaces)-9-methyl carbazole-3-sulfonamide, the 100g beta-schardinger dextrin-is milled to micropowder after mixing.

(2) lactose 100g is added in the above-mentioned micropowder, continues to be milled to micropowder.Cross 200 mesh sieves.

(3) micropowder that (2) is prepared, and crossed the microcrystalline Cellulose 15g mix homogeneously of 100 mesh sieves, adding 50% ethanol water system soft material, 14 mesh sieves are granulated, 50 ℃～60 ℃ dryings, 14 mesh sieve granulate.

(4) granule that (3) is prepared adds magnesium stearate 6g mix homogeneously, and content is surveyed in censorship; Confirm that according to testing result capsule loads scope, carry out capsule and load, detects qualified after, pack, promptly get.

Embodiment 3 N-(2,6-dimethoxy-pyridine-3-replaces)-9-methyl carbazole-capsular preparation of 3-sulfonamide

Prescription: (1000)

N-(2,6-dimethoxy-pyridine-3-replaces)-9-methyl carbazole-3-sulfonamide 50g

Beta-schardinger dextrin-150g

Lactose 350g

Low-substituted hydroxypropyl cellulose 12g

Micropowder silica gel 6g

Preparation technology:

(1) with 50g N-(2,6-dimethoxy-pyridine-3-replaces)-9-methyl carbazole-3-sulfonamide, the 150g beta-schardinger dextrin-is milled to micropowder after mixing.

(2) lactose 350g is added in the above-mentioned micropowder, continues to be milled to micropowder.Cross 200 mesh sieves.

(3) micropowder that (2) is prepared, and crossed the low-substituted hydroxypropyl cellulose 12g mix homogeneously of 100 mesh sieves, adding 50% ethanol water system soft material, 14 mesh sieves are granulated, 50 ℃～60 ℃ dryings, 14 mesh sieve granulate.

(4) granule that (3) is prepared adds micropowder silica gel 6g mix homogeneously, and content is surveyed in censorship; Confirm that according to testing result capsule loads scope, carry out capsule and load, detects qualified after, pack, promptly get.

Claims (4)

1. a carbazole sulfonamide series antineoplastic medicament capsule is made up of active constituents of medicine and adjuvant, it is characterized in that: active constituents of medicine is N-(2,6-dimethoxy-pyridine-3-replaces)-9-methyl carbazole-3-sulfonamide; Contain lactose in the adjuvant, beta-schardinger dextrin-; After N-(2,6-dimethoxy-pyridine-3-replaces)-9-methyl carbazole-3-sulfonamide, lactose, beta-schardinger dextrin-mix, be milled to micropowder; The charge ratio of N-when milling (2,6-dimethoxy-pyridine-3-replaces)-9-methyl carbazole-3-sulfonamide, lactose, beta-schardinger dextrin-is: 1: 1～10: 1～3, and W/W.

2. capsule according to claim 1 is characterized in that: include filler, binding agent, disintegrating agent, lubricant in the adjuvant.

3. capsule according to claim 2 is characterized in that: said filler is starch, Icing Sugar, cellulose derivative; Said binding agent is starch, gelatin, cellulose derivative, dextrin; Said disintegrating agent is starch, cellulose derivative, sodium lauryl sulphate; Said lubricant is Polyethylene Glycol, magnesium stearate, Pulvis Talci, micropowder silica gel.

4. according to the capsule described in the claim 3, it is characterized in that: its preparation method is following:

(1) with N-(2,6-dimethoxy-pyridine-3-replaces)-9-methyl carbazole-3-sulfonamide, beta-schardinger dextrin-is milled to micropowder after mixing;

(2) lactose is added in the above-mentioned micropowder, continues to be milled to micropowder, cross 200 mesh sieves;

(3) micropowder that (2) is prepared, and crossed the filler of 100 mesh sieves, binding agent disintegrating agent mix homogeneously adds ethanol water system soft material, and 14 mesh sieves are granulated, 50 ℃～60 ℃ dryings, 14 mesh sieve granulate;

(4) the adding mix lubricant is even, detection level; Confirm that according to testing result capsule loads scope, carry out capsule and load, detects qualified after, pack, promptly get.