CN104644562A - Axitinib composition and preparation method thereof - Google Patents

Abstract

The invention discloses axitinib particles and a preparation method thereof. Axitinib is used for treating advanced renal cell carcinoma. At present, only axitinib tablets are sold. Aiming at dysphagia patients, compared with the above two dosage forms, the axitinib particles have obvious advantages and can improve drug compliance of patients.

Description

A kind of Axitinib composition and method of making the same

Technical field

The present invention relates to a kind of Axitinib pharmaceutical composition and preparation method thereof.

Background technology

Renal cell carcinoma (renal cell carcinoma, RCC) is a kind of modal cancer kidney.The whole world has every year and is diagnosed as RCC more than 210,000 people, causes people more than 100,000 nearly dead.Half a century in the past, the incidence rate of RCC constantly rises, and only in the U.S., since nineteen fifty, its incidence rate and fatality rate just add 126% and 36.5% respectively.The Natural history of treated of RCC is difficult to expect, its clinical manifestation is intricate again, except local symptom (pain, hematuria and renal swelling block), more commonly general (heating, anemia, hepatopathy and neuromuscular disease) and incretion symptom (erythrocytosis, hypertension and hypercalcemia).Therefore, although diagnostic method achieves progress in recent years, nearly 30%RCC shifts when going to a doctor, and most likely shifts after locality cancer (I ~ III phase) row radical nephrectomy, and the effective treatment seeking advanced renal cell carcinoma (ARCC) is very urgent.

ARCC often tolerates chemotherapy and cytokine such as interleukin II (interleukin-2, IL-2) or interferon-' alpha ' (interferon-α, INF α).Xi Peier in ARCC-forest-road (vonHippel-Lindau, VHL) disappearance of gene function causes VEGF (vascular endothelial growthfactor, VEGF) approach imbalance, vegf protein overexpression and tumor vessel hypertrophy.The antiangiogenic drugs of targeting VEGF pathway comprises vegf receptor (VEGFreceptor, VEGFR) clinical practice of inhibitor (Sutent Sorafenib and pazopanib) and Avastin, so far, Axitinib has been the 7th medicine of FDA approval treatment ARCC, significantly improves the therapeutic effect of patient.

Axitinib (axitinib, trade name Inlyta ^?), researched and developed by Pfizer, in approval listing in Huo U.S. food Drug Administration January 27 in 2012 (FDA), be used for the treatment of the ARCC that other drug is failed to respond to any medical treatment.This product is a kind of 2nd generation VEGFR inhibitor of oral medication, and selectively acting, in VEGFR1, VEGFR2 and VEGFR3, by suppressing endothelial cell proliferation and the survival of VEGF mediation, plays the effect suppressing tumor growth and cancer progression.Multinomial clinical experimental study shows, Axitinib shows clinical activity to the ARCC patient accepting too much to plant Drug therapy invalid.

The chemistry of Axitinib is called: N-methyl-2-((3-((1E)-2-(pyridine-2-base) ethylene)-1H-indazole-6-base) sulfur) benzene, and its structural formula is:

From organization web inquiries such as FDA, EMEA, only has the list marketing of Axitinib tablet at present.Tablet format is, specification is 1mg, 5mg.But clinically for some patients particularly child, old man, or other dysphagia patients, tablet greatly reduces the compliance of patient consumes.In addition owing to not containing correctives in slice, thin piece, and medicine has bitterness, therefore takes for patient and also creates inconvenience.

Summary of the invention

The invention provides a kind of Axitinib granule, its object is to provide a kind of steady quality, the patient being applicable to swallowing takes.Still further provides the preparation method of its granule, adopt traditional equipment to produce, be applicable to carrying out large-scale production.

The present invention discloses a kind of Axitinib granule, contains Axitinib as active component in granule, and filler, lubricant, disintegrating agent and correctives.

Its filler is one or more in lactose, sucrose, mannitol, sorbitol.Preferred mannitol, lactose.Correctives is used for covering the bitterness of medicine, and it is selected from one or more in Aspartane, Mentholum, glucide, saccharin sodium.Preferably from Mentholum, Aspartane.Disintegrating agent is mainly selected from polyvinylpolypyrrolidone, and lubricant mainly comprises silicon dioxide and magnesium stearate.

For improving liquidity or ensureing in dry granulation, material and machine have good lubricant effect.

In order to obtain the suitable granule of particle diameter, simultaneously also in order to ensure the stability of loading amount, the ratio of medicine in prescription is between 0.5-1.5%, the ratio of filler is between 75-95%, disintegrating agent is between 5-15% in the ratio of prescription in addition, the ratio of correctives is between 0.5-5%, and the ratio of lubricant is between 0.5-3%.

Axitinib granule prepared by the present invention has following features: formulation disintegrates is rapid, can dissolve in water fast.

Containing correctives in granule, can cover the bitterness of Axitinib, relative tablet has better mouthfeel, is conducive to the Compliance improving patient.

Drug-eluting speed and tablet class seemingly, all can ensure the hydrochloric acid medium at pH1.0,50rpm, 1000ml, paddle method

Under condition, 15min stripping is greater than 85%.Product and former bioequivalence of grinding tablet can be ensured.

According to the present invention, prepare Axitinib granule and can adopt dry method granulation processes or wet granulation process.

Prepare Axitinib granule with dry method granulation processes, comprise following steps:

A, raw material to be mixed with adjuvant,

B, prepare tablet by roll-in method,

C, tablet sieve and obtain granule,

Mixing with other adjuvants of D, Selective feeding,

E, the pack of mixed granule is prepared as finished product.

For meticulous or excessively thick granule, the sizing system that can be carried by dry granulating machine is sieved, and thin granule can carry out secondary roll-in, and thick granule can crush and screen further.Thus obtain the material meeting granularity requirement.

Prilling prepares Axitinib granule in a wet process, comprises following steps:

A, raw material to be mixed with adjuvant,

B, prepare soft material by wet granulator,

C, soft material sieve and obtain granule, and dry,

Mixing with other adjuvants of D, dried Selective feeding,

E, the pack of mixed granule is prepared as finished product.

For wet granulation process, need to control well the size of screen cloth, sieve to adopt and wave comminutor, be generally recommended as the screen cloth between 10-20 order.Also can adopt rotating pelletizer in addition, rotating pelletizer is recommended as the aperture of 3.0*3.0.Can ensure like this to prepare suitable granularity.

Simulate the disintegration rate of preparation in water by disintegration tester in addition, and contrast the disintegration rate of tablet.By the method come modal patient take after mixing it with water medicine time, the rate of dispersion of preparation in water.Correction data in concrete visible embodiment.

Find in test, medicine is in high humidity environment, and impurity can rise, and therefore in order to ensure that granule has good stability, granule is sub-packed in the bag of aluminium material, can effectively starvation and moisture, thus ensures the stability that medicine is good.

Detailed description of the invention

Below in conjunction with embodiment, the present invention is described in further detail, but working of an invention mode is not limited thereto.

Embodiment 1-2

Table 1

Preparation technology:

1, Axitinib, lactose, polyvinylpolypyrrolidone mixes in wet granulation pot,

2, polyvidone and aspartame dissolving are distributed to 95% alcoholic solution, join in granulation pot and granulate, prepare granule,

3, the granule of step " 2 " gained is carried out drying, granulate,

4, additional for granule silicon dioxide is mixed,

5, by mixed material-filling in bag.

To embodiment 1, the granules of 2 preparations, and formerly grind the detection that sheet carries out stripping curve, detection method is: dissolution medium volume: 1000ml, and dissolution medium is the hydrochloric acid solution of pH1.0, and rotating speed is 50rpm, paddle method.Stripping curve the results are shown in Table 2.

Table 2

Embodiment 3 ~ 4

Table 3

Preparation technology:

1, by Axitinib, mannitol, lactose, polyvinylpolypyrrolidone, Mentholum, magnesium stearate mixes,

2, after mixing, material dry granulating machine carries out roll extrusion and obtains tablet,

3, the tablet of step " 2 " gained is carried out pulverizing and obtains granule,

4, additional silicon dioxide, and mix,

5, by mixed material-filling in bag.

To embodiment 3, the preparation of 4 preparations, carry out the detection of stripping curve, detection method is: dissolution medium volume:

1000ml, dissolution medium is the hydrochloric acid solution of pH1.0, and rotating speed is 50rpm, paddle method.

Table 4

In addition the contrast that sheet carries out disintegration time is ground, method with former to embodiment 1 ~ 4: adopt disintegration tester, water temperature is 25 degrees Celsius (simulated environment temperature), and disintegration tester screen cloth is 20 orders.By observing preparation all by screen cloth, timing.The results are shown in Table 5

Sample	Time
		Embodiment 1 sample	Be less than 1min
Embodiment 2 sample	Be less than 1min
		Embodiment 3 sample	Be less than 1min
Embodiment 4 sample	Be less than 1min
		Formerly grind sample 15mg	9min~13min
Formerly grind sample 45mg	6min~7min

Visible, granule is according to easily dispersion, and tablet then needs the long period just by 20 eye mesh screens, and thus can infer, for the patient of dysphagia, granule is taken after mixing it with water more convenient.

Study on the stability (40 DEG C, 75% relative humidity) is carried out to embodiment 1, paper examines outward appearance, impurity, dissolution, also detects jitter time in disintegration tester in addition, the results are shown in following table:

Result shows, medicine stability is good, additionally by disintegration tester jitter time, after medicine carries out accelerated test, there is no caking, and the dispersion of disintegration tester Chinese medicine is very fast, illustrates that medicine can comparatively fast disperse, is beneficial to patient and takes.

Claims (8)

1. an Axitinib granule, is characterized in that containing Axitinib and pharmaceutically acceptable adjuvant.

2. Axitinib granule as claimed in claim 1, is characterized in that Axitinib accounts for the 0.5-1.5% of total formulation weight amount.

3. Axitinib granule as claimed in claim 1, is characterized in that described pharmaceutically acceptable adjuvant comprises correctives.

4. Axitinib granule as claimed in claim 3, is characterized in that one or more that correctives is selected from Aspartane, Mentholum, glucide, saccharin sodium.

5. Axitinib granule as claimed in claim 1, is characterized in that being prepared by dry method granulation processes.

6. Axitinib granule as claimed in claim 1, is characterized in that being prepared by wet granulation process.

7. prepare a method for the dry method granulation processes of Axitinib granule as claimed in claim 1, it is characterized in that comprising following steps:

A, raw material to be mixed with adjuvant;

B, prepare tablet by roll-in method;

C, tablet sieve and obtain granule;

D, optionally to mix with other adjuvants;

E, the pack of mixed granule is prepared as finished product.

8. prepare a method for the wet granulation process of Axitinib as claimed in claim 1, it is characterized in that comprising following steps:

A, raw material to be mixed with adjuvant;

B, prepare soft material by wet granulator;

C, soft material sieve and obtain granule, and dry;

D, optionally to mix with other adjuvants;

E, the pack of mixed granule is prepared as finished product.