CN103536549A - Erlotinib composition freeze-dried powder for injection - Google Patents

Abstract

The invention provides an erlotinib composition freeze-dried powder for injection, and belongs to the field of medicine and medicine preparation technology. The erlotinib composition freeze-dried powder comprises following raw materials, by weight, 4 to 6 parts of erlotinib, 2 to 3 parts of chitosan nanoparticle, and 91 to 94 parts of injection water. Advantages of the erlotinib composition freeze-dried powder are that: the erlotinib composition is prepared by mixing erlotinib with the chitosan nanoparticle at a ratio of 2:1, and is made into a freeze-dried injection for utilization in clinic as an antitumor medicine; the erlotinib composition is composed of erlotinib, the chitosan nanoparticle and injection water; the chitosan nanoparticle can be used as skeleton agent, synergist and solubiliser of erlotinib, and possesses a certain degree of antitumor activity, so that synergistic antitumor effect is realized by combining the chitosan nanoparticle with erlotinib.

Description

Injection Erlotinib composite freeze-dried powder

Technical field:

The present invention relates to medicine and medicine manufacture technology field, relate in particular to a kind of injection Erlotinib composite freeze-dried powder.

Background technology:

Erlotinib (Erlotinih), chemical name is N-(3-acetylene phenyl)-6,7-bis-(2-methoxy ethoxy)-4-quinazoline amine, has chemical constitution as follows, is a kind of human epidermal growth factor acceptor tyrosine kinase domain selective depressant.

Research to the nonsmall-cell lung cancer of Erlotinib sensitivity shows, activates the main cause of anti-apoptosis pathway when epidermal growth factor recipient tyrosine kinase domain gene suddenlys change.Within 2004, first Erlotinib goes on the market in the U.S. with the form of hydrochlorate, is mainly applicable to the treatment of local late period or Metastatic Nsclc and cancer of pancreas.But because its untoward reaction (as infected and infect, gastrointestinal tract is abnormal, abnormal liver function etc.) is larger, greatly limited the clinical practice of Erlotinib.

Experiment showed, that oligo-chitosan has the effect that suppresses and treat to some pernicious cancerous cell, normal host's organ is had no side effect substantially, especially hexa polyose has the effect of very strong inhibition tumor.Blood vessel is generally passed through in the transfer of cancerous cell, and chitosan, as a kind of good polycation electrolyte, can be adsorbed on the surface of cells of vascular wall, thus the transfer of anticancer.And the metabolic characteristic of cancerous cell is to take sugared anerobic glycolysis as main, in metabolism, generate lactic acid, so cancerous cell is generally acidity around.And lymphocyte in human body can kill cancerous cell, and lymphocyte has best activity under slightly aobvious alkaline environment, thereby in cancerous cell sour environment around, lymphocytic activity has been subject to inhibition.And the contained amino basic group of chitosan, suitably the physical chemistry balance in control agent, makes body fluid pH shift to a little alkali side, strengthens lymphocytic physiologically active, has created the environment of lymphocyte attack cancerous cell.Chitosan and derivant thereof have good biocompatibility, degradability and tissue adherence, be widely used in antineoplastic drug carrier slow-release material system, the multiple antitumor drug such as chitosan and derivant thereof can load amycin, epirubicin, 5-fluorouracil, paclitaxel, obviously improve tumor chemotherapeutic drug therapeutic effect.

Summary of the invention:

An object of the present invention is to provide a kind of injection Erlotinib lyophilized powder compositions, said composition principal agent is: Erlotinib, chitosan nano.Technical problem to be solved by this invention realizes by the following technical solutions.

An Erlotinib composite freeze-dried powder, is characterized in that, the material composition that comprises following weight portion:

4～6 parts of Erlotinibs

2～3 parts of chitosan nanos

91～94 parts of waters for injection

The invention provides a kind of preparation method of Erlotinib freeze-dried composition, adopt following technical scheme:

(1) preparation of chitosan nano:

1, will after the pulverizing of chitosan powder, through 100 eye mesh screens, sieve;

2, the chitosan powder that takes 100g at room temperature (20 ℃) adds 0.1mol/l acetic acid solution 40L, and magnetic agitation, dissolves chitosan completely, obtains chitosan acetic acid solution (C=2.5g/L);

3, with 1%NaOH, regulate pH=5.0;

4, add 1% sodium tripolyphosphate 1667g to chitosan acetic acid solution under stirring, making chitosan/sodium tripolyphosphate mass ratio is 6:1, and the electrostatic interaction by zwitterion is cross-linked into nanoparticle;

5,, by 4 ℃ of high speed centrifugations of above-mentioned colloid solution (18000r/min) 30min, collect lower sediment, with after pure water washing 3 times, cooling final vacuum dry (30 ℃ following) obtains chitosan nano, moisture is lower than 2%, particle diameter≤100nm, and zeta current potential is about 15mv;

(2) preparation of injection Erlotinib composite freeze-dried powder:

(1) chitosan nano of recipe quantity is slowly joined in the water for injection of recipe quantity, stir while adding to dissolving;

(2) add Erlotinib the extremely clarification of stirring and dissolving of recipe quantity;

(3) with the buffer salt of sodium dihydrogen phosphate and sodium hydrogen phosphate, adjust pH to 5.1, add 0.1% active carbon to stir 30 minutes, filtering active carbon, medicinal liquid is again through 0.45 μ m and 0.22 μ m filtering with microporous membrane, detect intermediate content, by Erlotinib, every bottle of 0.1g calculates loading amount;

(4) according to testing requirement fill, after half tamponade, send in freezer dryer, be cooled to-40 ℃, be incubated 2 as a child, be slowly warming up to-5 ℃～0 ℃ sublimation drying, then be warming up to after 35 ℃, be incubated 3 hours, lyophilization finishes, outlet.

Beneficial effect of the present invention is:

The invention provides the compositions that a kind of Erlotinib mixes in 2:1 ratio with chitosan nano, and make injection freeze-dried powder as antitumor drug for clinical, the prescription of said composition consists of Erlotinib, chitosan nano, water for injection, chitosan nano can be used as skeleton agent, synergist, the solubilizing agent of Erlotinib, chitosan nano itself has certain anti-tumor activity, after combining, plays synergistic antitumor effect with Erlotinib.

The specific embodiment:

Following examples are used for illustrating the present invention, yet these embodiment do not limit the scope of the invention.

The preparation of embodiment mono-, injection Erlotinib composite freeze-dried powder, in 1000.

1.prescription:

Erlotinib 100g

Chitosan nano 50g

Water for injection 2000ml

2. preparation technology:

(1) chitosan nano that takes 50g slowly joins in the water for injection of 2000ml, stirs while adding to dissolving.

(2) add Erlotinib the extremely clarification of stirring and dissolving of 100g.

(3) with the buffer salt of sodium dihydrogen phosphate and sodium hydrogen phosphate, adjust PH to 5.1, add 0.1% active carbon to stir 30 minutes, filtering active carbon, medicinal liquid is again through 0.45 μ m and 0.22 μ m filtering with microporous membrane, detect intermediate content, by Erlotinib, every bottle of 0.1g calculates loading amount.

(4) according to testing requirement fill, after half tamponade, send in freezer dryer, be cooled to-40 ℃, be incubated 2 as a child, be slowly warming up to-5 ℃～0 ℃ sublimation drying, then be warming up to after 35 ℃, be incubated 3 hours, lyophilization finishes, outlet.

The preparation of embodiment bis-, injection Erlotinib composite freeze-dried powder, in 1000.

1. write out a prescription:

Erlotinib 80g

Chitosan nano 40g

Water for injection 2000ml

2. preparation technology:

(1) chitosan nano that takes 40g slowly joins in the water for injection of 2000ml, stirs while adding to dissolving.

(2) add Erlotinib the extremely clarification of stirring and dissolving of 80g.

(3) with the buffer salt of sodium dihydrogen phosphate and sodium hydrogen phosphate, adjust PH to 5.1, add 0.1% active carbon to stir 30 minutes, filtering active carbon, medicinal liquid is again through 0.45 μ m and 0.22 μ m filtering with microporous membrane, detect intermediate content, by Erlotinib, every bottle of 0.08g calculates loading amount.

(4) according to testing requirement fill, after half tamponade, send in freezer dryer, be cooled to-40 ℃, be incubated 2 as a child, be slowly warming up to-5 ℃～0 ℃ sublimation drying, then be warming up to after 35 ℃, be incubated 3 hours, lyophilization finishes, outlet.

The preparation of embodiment tri-, injection Erlotinib composite freeze-dried powder, in 1000.

1.prescription:

Erlotinib 120g

Chitosan nano 60g

Water for injection 2000ml

2. preparation technology:

(1) chitosan nano that takes 20g slowly joins in the water for injection of 2000ml, stirs while adding to dissolving.

(2) add Erlotinib the extremely clarification of stirring and dissolving of 40g.

(3) with the buffer salt of sodium dihydrogen phosphate and sodium hydrogen phosphate, adjust PH to 5.1, add 0.1% active carbon to stir 30 minutes, filtering active carbon, medicinal liquid is again through 0.45 μ m and 0.22 μ m filtering with microporous membrane, detect intermediate content, by Erlotinib, every bottle of 0.12g calculates loading amount.

(4) according to testing requirement fill, after half tamponade, send in freezer dryer, be cooled to-40 ℃, be incubated 2 as a child, be slowly warming up to-5 ℃～0 ℃ sublimation drying, then be warming up to after 35 ℃, be incubated 3 hours, lyophilization finishes, outlet.

Experimental data

Test example one: the stability of Erlotinib composite freeze-dried powder

The Erlotinib composite freeze-dried powder that embodiment 1 is made and conventional little liquid drugs injection carry out study on the stability, and influence factor adopts under 4500LX illumination and places 10 days, and the 5th day and the tenth day sampling and measuring, result was as table 1 respectively.

Table 1 Erlotinib composite freeze-dried powder and the comparison of conventional little liquid drugs injection stability

Above result shows, Erlotinib composite freeze-dried powder of the present invention adds can rebuild rapidly to obtain the injection of clear after water; Under identical experiment condition, the stability of injectable powder is obviously better than little liquid drugs injection.This good dissolubility and stability, both guaranteed the safety of medication, also extended the effect duration of Erlotinib.

Test example 2: the general security of Erlotinib composite freeze-dried powder

The Erlotinib composite freeze-dried powder that embodiment 3 is made is done general security experiment, and experimental result shows nonirritant, without anaphylactic reaction, also without haemolysis.

More than show and described ultimate principle of the present invention, principal character and advantage of the present invention.The technical staff of the industry should understand; the present invention is not restricted to the described embodiments; what in above-described embodiment and description, describe is only preference of the present invention; be not used for limiting the present invention; without departing from the spirit and scope of the present invention; the present invention also has various changes and modifications, and these changes and improvements all fall in the claimed scope of the invention.The claimed scope of the present invention is defined by appending claims and equivalent thereof.

Claims (2)

1. an injection Erlotinib composite freeze-dried powder, is characterized in that, the material composition that comprises following weight portion:

4～6 parts of Erlotinibs

2～3 parts of chitosan nanos

91～94 parts of waters for injection.

2. a preparation method for injection Erlotinib composite freeze-dried powder described in claim 1, is characterized in that, comprises the steps:

(1) preparation of chitosan nano:

(1) will after the pulverizing of chitosan powder, through 100 eye mesh screens, sieve;

(2) take the chitosan powder 100g of above-mentioned mistake 100 eye mesh screens, add 0.1mol/L acetic acid solution 40L under room temperature, magnetic agitation, dissolves chitosan completely, obtains chitosan acetic acid solution;

(3) with 1%NaOH, regulate pH=5.0;

(4) add 1% sodium tripolyphosphate 1667g to chitosan acetic acid solution under stirring, obtain colloid solution, making chitosan/sodium tripolyphosphate mass ratio is 6:1, and the electrostatic interaction by zwitterion is cross-linked into nanoparticle;

(5) by 4 ℃ of high speed centrifugation 30min of above-mentioned colloid solution, collect lower sediment, with after pure water washing 3 times, the dry chitosan nano that obtains in cooling juxtaposition drying under reduced pressure case, moisture is lower than 2%, particle diameter≤100nm, zeta current potential is about 15mv;

(2) preparation of injection Erlotinib composite freeze-dried powder:

(1) chitosan nano of recipe quantity is slowly joined in the water for injection of recipe quantity, stir while adding to dissolving;

(2) add Erlotinib the extremely clarification of stirring and dissolving of recipe quantity;

(3) with the buffer salt of sodium dihydrogen phosphate and sodium hydrogen phosphate, adjust pH to 5.1, add 0.1% active carbon to stir 30 minutes, filtering active carbon, medicinal liquid is again through 0.45 μ m and 0.22 μ m filtering with microporous membrane, detect intermediate content, by Erlotinib, every bottle of 0.1g calculates loading amount;

(4) according to testing requirement fill, after half tamponade, send in freezer dryer, be cooled to-40 ℃, be incubated 2 as a child, be slowly warming up to-5 ℃～0 ℃ sublimation drying, then be warming up to after 35 ℃, be incubated 3 hours, lyophilization finishes, outlet.