WO2007143895A1

WO2007143895A1 - Supersaturated solution of gemcitabine hydrochloride and prepraration method thereof

Info

Publication number: WO2007143895A1
Application number: PCT/CN2007/001604
Authority: WO
Inventors: Zuohong Han; Qingmin Yang; Baoming Liu; Guiting Zhang; Minghui Zhang; Jingyi Wang
Original assignee: Qilu Pharmaceutical (Hainan) Co., Ltd.
Priority date: 2006-06-12
Filing date: 2007-05-17
Publication date: 2007-12-21
Also published as: CN101088492A; CN102406603B; CN101088492B; CN102406603A

Abstract

A stable supersaturated solution of gemcitabine hydrochloride, which is prepared by dissolving completely gemcitabine hydrochloride in a medium by heating it at pH 4-8 to give a supersaturated solution of gemcitabine having a concentrate of 15-45g/L.

Description

Gemcitabine hydrochloride stable supersaturated solution and preparation method thereof

The invention relates to a supersaturated solution of a medicament and a preparation method thereof, in particular to a supersaturated solution containing gemcitabine hydrochloride and a preparation method thereof.

Background technique

Gemcitabine, the English name Gemcitabine, has the chemical name 2'-deoxy^', -difluoroadenosine (P-isomer), the molecular formula is C ₉ HnF ₂ N ₃ 0 ₄ , and the molecular weight is 299.66.

Gemcitabine is an anti-tumor drug produced by Lilly Pharmaceuticals of the United States. In 1996, the US FDA approved it as a first-line drug for the treatment of pancreatic cancer. In 1998, it was approved as a drug for the treatment of non-small cell lung cancer. China approved the import in 1999, and the domestically produced imitation products were approved for clinical trial on June 15, 2000.

Gemcitabine produced at home and abroad is a freeze-dried powder injection of gemcitabine hydrochloride. The reason is that the gemcitabine hydrochloride solution is unstable and cannot be stored for a long time. It was reported that gemcitabine hydrochloride was partitioned to 86% in a 0.1 hydrochloric acid solution at 40 ° C for 4 weeks, and decomposed to 72% under alkaline conditions of 0.1 N sodium hydroxide.

The injection preparations of the medicines are solution type and dry powder, and the unstable medicines use dry powders, so that the medicine can be stored for a long time. Comparison of dry powder and aqueous solution: 1) complicated process and high production cost; 2) need to inject solution to dissolve, inconvenient to use, increase the chance of pollution; 3) aqueous solution of gemcitabine hydrochloride pH 2.5~3.0, room temperature (25±2. C) Poor placement stability; 4) The solubility of gemcitabine hydrochloride at pH>4 is reduced, only 15g/L below 23°C (g/L means the mass per gigaliter of solution containing gemcitabine, below The same), can not meet the requirements for the preparation of higher concentration injections. Therefore, a large number of studies have been conducted in order to solve the stability of the gemcitabine hydrochloride solution and to improve its solubility in a pH > 4 environment.

CN00133414X discloses a gemcitabine solution preparation, the main contents of which are: gemcitabine base and a solvent for dissolving gemcitabine base. Its production process is to use gemcitabine Water, ethanol, propylene glycol, etc. are dissolved.

CN1650883A discloses a gemcitabine hydrochloride solution-type injection containing a basic substance or a weak acid salt as a stabilizer. The literature uses gemcitabine hydrochloride as a raw material, dissolves in water for injection, adds stabilizer and isotonic agent, adjusts the pH value of the solution to 3.6 ~ 7. ⁵ , and obtains a stable solution injection, and its stability meets the requirements. Comparing gemcitabine hydrochloride into a solution injection and gemcitabine base to prepare a solution injection, it is not necessary to convert the gemcitabine hydrochloride drug substance into gemcitabine base, thereby reducing the production process and reducing the cost. This document considers that the problem of unstable gemcitabine hydrochloride injection at home and abroad under alkaline conditions is solved.

O2005014010 discloses a pharmaceutical composition of gemcitabine hydrochloride containing cyclodextrin as a solubilizer. The composition has a solubility of 40 g/L of gemcitabine hydrochloride at pH 4 to 9, and is stable at room temperature (25 ± 2 °C) for two years.

When preparing the injection according to CN1650883A, the solubility of gemcitabine hydrochloride was only 15g/L at 23 °C and pH 4 ~ 7. It is not easy to prepare a high concentration of injection, and the prepared solution was allowed to stand at 60 °C for 10 days. obviously increase. According to WO2005014010, the solubility of gemcitabine hydrochloride can reach 40g/L, but cyclodextrin should be added as a solubilizer; a large number of studies have proved that cyclodextrin has certain nephrotoxicity, so cyclodextrin should be avoided in the preparation.

Summary of the invention

The present invention is directed to the deficiencies of the prior art, and provides a gyrcitabine hydrochloride supersaturated solution and a preparation method thereof.

The gemcitabine hydrochloride supersaturated solution of the present invention is characterized in that the quantitative gemcitabine hydrochloride is completely dissolved in the solvent under the condition of pH 4-8, and the concentration is higher than the concentration of gemcitabine hydrochloride at 23 ° C (concentration with gemcitabine) Calculate, the same as below) to 45 g / L of gemcitabine hydrochloride supersaturated solution.

The above-mentioned super-saturated solution of gemcitabine hydrochloride needs to be sterilized by hot filtration. Before cooling, it can be directly filled into the final container according to a single package dosage; the obtained product is cooled after cooling. Gemcitabine hydrochloride solid precipitated. According to the literature ^=艮道, the concentration of gemcitabine hydrochloride is only 15g/L (as calculated by gemcitabine) at 23°C and pH4~8. The gemcitabine hydrochloride supersaturated solution of the present invention is characterized by a concentration of more than 15 g/L (as calculated by gemcitabine) at 23 ° C, up to 45 g / L (based on gemcitabine).

Preferably, the concentration of the gemcitabine hydrochloride supersaturated solution is 20 to 40 g/L (calculated as gemcitabine).

Preferably, the solvent is water or a biocompatible isotonic aqueous solution. The pH is preferably 5 to 7, most preferably H 6 .

Preferably, the above-mentioned gemcitabine hydrochloride dissolution heating temperature is 30 to 90 ° C, more preferably 45 to 80. C.

Preferably, the gemcitabine hydrochloride supersaturated solution is filled with nitrogen and/or an antioxidant is added to further inhibit the degradation of gemcitabine hydrochloride, wherein the antioxidant is selected from the group consisting of pharmaceutically acceptable substances.

The above antioxidants include, but are not limited to, sulfites, ascorbic acid and derivatives, thio compounds, amino acids, phenols, amines or chelating agents. The sulfites are selected from the group consisting of sodium hydrogen sulfite, sodium sulfite,

The ascorbic acid derivative is selected from the group consisting of ascorbic acid or D-isoascorbic acid; the thio compound is selected from one or more of thioglycerol, 2-mercaptoethanol, 5-thio-D-glucose or thioglycolic acid; From one or more of L-cysteine or a salt thereof, L-methionine, L-arginine, L-tryptophan; the amine is selected from pyridoxamine hydrochloride; the chelating agent is selected from B Disodium diamine tetraacetate or sodium calcium edetate.

The above antioxidant is added in an amount of 0.01% to 0.5% / V, mass to volume ratio. The gemcitabine hydrochloride supersaturated solution of the invention is prepared by completely dissolving the quantitative gemcitabine hydrochloride in water or a biocompatible isotonic aqueous solution at a pH of 4-8 and a heating temperature of 30-90 ° C to form a supersaturated solution. The concentration of gemcitabine is 15 ~ 45g / L, and it is filtered by sterilizing heat. It can be directly filled into the final container seal at a single package dose before cooling. This will not precipitate crystals. To further increase the stability of the gyrcitabine hydrochloride supersaturated solution, nitrogen can be charged and/or an antioxidant can be added to the final container. The residual oxygen content of the nitrogen in the ampoule is < 0.5%, and the selection and dosage of the antioxidant are as described above.

The above dissolution temperature should not be too high. If the temperature reaches Ι ΟΟ Ό and the holding time exceeds 5 hours, the degradation material increases significantly. The ρΗ of the solution should not be too high. When ρΗ is adjusted to above 8 and the holding time at 100 °C for more than 4 hours, the degradation material is also significantly increased.

As is well known to those skilled in the art, to better control the pH of the solution, buffers such as: carbonates, phosphates, lactates, acetates, citrates, maleates, etc. may be added. . The pH range should not exceed 8 and not less than 4. Preferably, the pH is selected from pH 5 to 7, and the pH is 6. One or a combination of buffers may be used alone.

Additionally, as is well known to those skilled in the art, isotonic agents, such as: sodium chloride, dextrose, mannitol, physiologically tolerated potassium, calcium, magnesium solutions may be added to the solution. One or a combination of isotonic agents may be used alone.

The gemcitabine hydrochloride supersaturated solution provided by the invention has the characteristics of stable and high concentration, and can be used for preparing a pharmaceutical preparation for intravenous administration.

Stability of gemcitabine hydrochloride supersaturated solution First, the physical stability of the saturated solution (precipitation crystallization) was observed. First, the content of gemcitabine hydrochloride and its degradation substances were determined by high performance liquid chromatography.

In the stability test, the content of gemcitabine and related substances was determined by high performance liquid chromatography. Wa ters color PAN, C18 column, measuring wavelength 268nm, mobile phase: ammonium acetate buffer - methanol = 90: 10.

Tables 1 and 2 are the physical and chemical stability test data of the injection of the present invention, respectively, to illustrate the beneficial effects of the present invention. Table 1. Prepared by using the gemcitabine hydrochloride supersaturated solution of the present invention and the prior art

Table 2. Comparison of chemical stability of samples prepared by using the gemcitabine hydrochloride supersaturated solution of the present invention and the prior art

The aqueous solution of gemcitabine hydrochloride has a pH of about 2.7, and the degradation at 100 °C for 2 hours is more than 20%, and the chemical stability is poor. As described in the patent CN1650883AH and the patent WO20O5014010, the chemical stability of the aqueous solution of gemcitabine hydrochloride is better at pH 4-8, 100 °C 2h. Degradation of about 3%, however, at 23 ° C, pH 4 ~ 8, the concentration of gemcitabine hydrochloride in water is up to 15g / L (in gemcitabine), can not meet the requirements for the preparation of high concentration injection. Surprisingly, the concentration of the gemcitabine hydrochloride supersaturated solution of the present invention can reach 45 g/L (calculated as gemcitabine), and no solid precipitation occurs at room temperature for a long period of time. When the gemcitabine hydrochloride solution is heated to at least 30 ° C, a supersaturated solution of gemcitabine concentration of 15 ~ 45 g / L can be obtained at pH 4 - 8, and the solution is directly dispensed in a single package dose. The final container is sealed, and the obtained supersaturated solution does not precipitate gemcitabine hydrochloride solid. When added with antioxidant, its chemical stability is much better than that of gemcitabine hydrochloride injection prepared according to CN1650883A.

The invention firstly prepares a certain concentration of a stable supersaturated solution of gemcitabine hydrochloride, and adding an antioxidant can further increase the stability of the solution. The supersaturated solution can be used for the preparation of a solution-type injection of gemcitabine hydrochloride. The supersaturated solution contains an antioxidant as a stabilizer, and is prepared by heating and dissolving into a supersaturated solution containing gemcitabine hydrochloride. The supersaturated solution can be used to prepare a pharmaceutical preparation for intravenous administration.

detailed description

The invention is further illustrated by the following examples, which should not be construed as limiting the invention.

Example 1: Take 227.7 mg of gemcitabine hydrochloride (containing 200 mg of gemcitabine), dissolve it with 6 ml of water for injection, add 0.09 g of sodium chloride, add 0.5 N of sodium hydroxide, adjust the pH to 4.5, and heat the solution to 30 to 40 ° C. The precipitated crystals were completely dissolved, and the volume was adjusted to 10 ml with water for injection. Then, it was filtered by hot sterilization, and dispensed in 10 ml of ampoule, 10 ml each, and sealed. The concentration of gemcitabine was 20 g/L. Example 2: Take 341.6 mg of gemcitabine hydrochloride (containing 300 mg of gemcitabine), dissolve it with 6 ml of water for injection, add 0.09 g of sodium chloride, add 0.5 N of sodium hydroxide, adjust the pH to 6.0, and heat the solution to 50-6 (TC). The precipitated crystals were completely dissolved, and the volume was adjusted to 10 ml with water for injection. Then, the mixture was filtered in a hot solution, and placed in an ampoule, and filled with nitrogen (residual oxygen in an ampoule filled with nitrogen gas < 5.0%), and sealed. The concentration of gemcitabine was 30g/L.

Example 3: Take 455 mg of gemcitabine hydrochloride (containing 400 mg of gemcitabine), dissolve it with 6 ml of water for injection, add 0.09 g of sodium chloride, add 0.5 sodium hydroxide, adjust the pH to 5, 5, and heat the solution to 60-80 ° C. The precipitated crystals were completely dissolved and diluted to 10αι1 with water for injection. Then, the mixture was filtered and disintegrated in 5 ml of ampoule, each 5 ml, filled with nitrogen (the residual oxygen content of the ampoule filled with nitrogen gas < 5.0%), and sealed. The concentration of gemcitabine is 40 g/L.

Example 4: 512 mg of gemcitabine hydrochloride (containing gemcitabine 450 mg), dissolved in 6 ml of water for injection, adding 10 mg of L-arginine and 0.09 g of sodium chloride, then adding 0.5 N of sodium hydroxide to adjust the pH to 8.0, and heating the above solution To 45 to 50 ° C, the precipitated crystals were completely dissolved, and the volume was adjusted to 10 ml with water for injection. Then heat and sterilize, filter, dispense in ampoules, and seal. The concentration of gemcitabine is 45 g/L.

Example 5: Take 455 mg of gemcitabine hydrochloride (containing 400 mg of gemcitabine), dissolve it with 6 ml of physiological saline, add 10 mg of L-arginine, then add 0.5 sodium hydroxide, adjust the pH to 6.0, and heat the solution to 45-50 ° C. The precipitated crystals were completely dissolved and made up to 10 ml with physiological water. Then, the mixture was filtered and placed in a 5 ml vial, 5 ml each, and filled with nitrogen (residual oxygen in the ampoule filled with nitrogen gas < 5.0%), and sealed. The concentration of gemcitabine is 40 g/L.

Example 6: Take 455 mg of gemcitabine hydrochloride (containing 400 mg of gemcitabine), dissolve it with 6 ml of water for injection, add 15 mg of sodium sulfite and 0.09 g of sodium chloride, add 0.5 N of sodium hydroxide, adjust the pH to 7.0, and heat the solution to 45~5. (TC, so that the precipitated crystals are completely dissolved, and the volume is adjusted to 10 ml with water for injection. Filtered, dispensed in ampoules, filled with nitrogen (residual oxygen in the ampoule filled with nitrogen gas < 5.0%), sealed. The concentration of gemcitabine was 40 g/L.

Example 7: Gemcitabine hydrochloride 455 mg (containing gemcitabine 400 mg) was dissolved in 6 ml of water for injection, 5 mg of thioglycolic acid and 0.09 g of sodium chloride were added, then 0.5 N sodium hydroxide was added to adjust the pH to 6.0, and the solution was heated to 45~. The precipitated crystals were completely dissolved at 50 ° C, and the volume was adjusted to 10 ml with water for injection. Then heat and sterilize and filter, dispense in 10ml vial, each 5ml, seal. The concentration of gemcitabine was 40 g/L.

Example 8: 455 mg of gemcitabine hydrochloride (containing 400 mg of gemcitabine), dissolved in 6 ml of physiological saline, and added 5 mg of L-arginine, 20 mg of L-methionine and 0.09 g of sodium chloride, and then added 0.5 N of sodium hydroxide to adjust the pH to 4.5, normalize the saline to 10ml. The solution is heated to 80 to 90 ° C, so that the precipitated crystals are completely dissolved, then filtered by hot sterilization, dispensed in an ampoule, and sealed. The concentration of gemcitabine is 40 g/L.

Example 9: Take 455 mg of gemcitabine hydrochloride (containing 400 mg of gemcitabine), 0.9 mg of disodium edetate, dissolve with 6 ml of physiological saline at 50-60 ° C, add 10 mg of L-arginine, and then add 0.7 ml of 1N sodium hydroxide. Adjust the pH to 7.0 and dilute to 10 ml with 50~60Ό physiological saline. Then heat and filter, disassemble in an ampoule, and seal. The concentration of gemcitabine is 40 g/L.

Example 10: 512 mg of gemcitabine hydrochloride (containing gemcitabine 450 mg), dissolved in 6 ml of calcium phosphate buffer (pH 6.0), added with 20 mg of ascorbic acid and 0.09 g of sodium chloride, and added with 0.5 N sodium hydroxide to adjust the pH to 5.0. The solution was heated to 45 ~ 50 ° C to completely dissolve the precipitated crystals, and the volume was adjusted to 10 ml with phosphate buffer. Then, the mixture was filtered and disintegrated in an ampoule, and nitrogen was filled (the residual oxygen content of the nitrogen in the ampoule was < 5.0%) and sealed. The concentration of gemcitabine is 45 g/L.

Example 11: Take 455 mg of gemcitabine hydrochloride (containing gemcitabine 400 mg), dissolve it with 6 ml of phosphate buffer (pH 6.0), add 50 mg of pyridoxamine hydrochloride and 0.09 g of sodium chloride, and then add 0.5 N sodium hydroxide to adjust pH 6.0, the above solution is heated At 45 to 50 ° C, the precipitated crystals were completely dissolved, and the volume was adjusted to 10 ml with a phosphate buffer. Then heat and sterilize the filter, dispense in the ampoule, and seal. Gemcitabine concentration is 40g/L _o

The products prepared in the above examples can be used as pharmaceutical applications for intravenous administration. Example 12: Stability test of gemcitabine hydrochloride supersaturated solution of the present invention The physical and chemical stability of the gemcitabine hydrochloride supersaturated injection solution prepared in the examples of the present invention was obtained according to the aforementioned stability study method, as shown in Table 3. Stability test results of gemcitabine hydrochloride supersaturated solution

Stability under different test conditions

Sample test content Physical stability Chemical stability (% gemcitabine content)

2 ~ 8 ° C 3 months 0 days 40. C3 months Example 1 Crystal precipitation 99.8% 96.5% Example 2 Crystal precipitation 100.5% 97.9% Example 3 Crystal precipitation 97.6% Example 4 Crystal precipitation 99.7%

Example 5 Crystal precipitation 99.9% 99.3% Example 6 Crystal precipitation 100.7% 98.7% Example 7 Crystal precipitation 100.2% 99.5% Example 8 Crystal precipitation 100.6% 99.3% Example 9 Crystal precipitation 99.8% 98.3% Example 10 Crystal Free Precipitation 100.4% 99.2% Example 11 Crystal Free Precipitation 99.6% 99.0%

Claims

Rights request

A gemcitabine hydrochloride supersaturated solution, characterized in that the gemcitabine hydrochloride supersaturated solution is prepared by the following method: under the condition of pH 4-8, the quantitative gemcitabine hydrochloride is completely dissolved in the solvent by heating, and the concentration is exceeded. Gemcitabine hydrochloride is at 23. The saturated concentration at C is at most 45 g/L (as calculated by gemcitabine) of a gyrcitabine hydrochloride supersaturated solution.

2. The gemcitabine hydrochloride supersaturated solution according to claim 1, wherein the supersaturation concentration is 20 to 40 g/L (calculated as gemcitabine).

3. The gemcitabine hydrochloride supersaturated solution according to claim 1, wherein the solvent is water or a biocompatible isotonic aqueous solution.

The gemcitabine hydrochloride supersaturated solution according to claim 1, wherein the pH is 5 to 7, preferably pH 6.

The gyrcitabine hydrochloride supersaturated solution according to claim 1, wherein the heating temperature is 30 to 90 ° C, preferably 45 to 80 ° C.

The gemcitabine hydrochloride supersaturated solution according to claim 1, characterized in that the gemcitabine hydrochloride supersaturated solution is filled with nitrogen gas and/or an antioxidant is added.

7. The gemcitabine hydrochloride supersaturated solution according to claim 6, wherein the antioxidant is selected from the group consisting of sulfites, ascorbic acid and derivatives thereof, thioides, amino acids, phenols, amines and chelates. mixture.

8. The gemcitabine hydrochloride supersaturated solution according to claim 7, wherein the sulfite is selected from the group consisting of sodium hydrogen sulfite, sodium sulphate, sodium metabisulfite, and sodium citrate. The ascorbic acid derivative is selected from the group consisting of ascorbic acid and D-isoascorbic acid; and the thio compound is selected from one or more of thioglycerol, 2-mercaptoethanol, 5-thio-D-glucose and thioglycolic acid.

9. The gemcitabine hydrochloride supersaturated solution according to claim 7, characterized by Wherein the amino acid is selected from one or more of L-cysteine or a salt thereof, L-methionine, L-arginine and L-tryptophan; the amine is selected from pyridoxamine salt The chelating agent is selected from the group consisting of disodium edetate and sodium calcium edetate.

10. A method for preparing a gemcitabine hydrochloride supersaturated solution, which comprises completely dissolving the quantitative gemcitabine hydrochloride in water or a biocompatible isotonic aqueous solution at a pH of 4 to 8 and a heating temperature of 30 to 90 °C. A supersaturated solution is formed, the concentration of gemcitabine is 15~45g/L, and the bacteria are sterilized by hot filtration. The mixture is directly filled into the final container and sealed in a single package dose before cooling.

The use of the gemcitabine hydrochloride supersaturated solution according to any one of claims 1 to 9 for the preparation of a pharmaceutical preparation for intravenous administration.