HPPH lyophilized powder injection for injection and preparation method thereof

Abstract

Disclosed are a HPPH lyophilized powder injection for injection and the preparation method thereof. The HPPH lyophilized powder injection contains HPPH, auxiliary solvents, solubilizing agents, excipients, and pH adjusting agents. The HPPH lyophilized powder injection is loose and has good resolubility, low moisture, and good stability.

Claims

1. A HPPH lyophilized powder injection, comprising HPPH, auxiliary solvents, solubilizing agents, excipients and pH adjusting agents, wherein the weight percentages of HPPH, auxiliary solvents, solubilizing agents, and excipients are as follows: TABLE-US-00011 HPPH 0.05%~3.50% auxiliary solvents 0.05%~0.50% solubilizing agents  0.80%~28.00% excipients  70.00%~99.00%.

2. The HPPH lyophilized powder injection according to claim 1, wherein the weight percentages of HPPH, auxiliary solvents, solubilizing agents, and excipients are: TABLE-US-00012 HPPH 0.08%~2.50% auxiliary solvents 0.08%~0.25% solubilizing agents  0.95%~25.00% excipients  70.00%~99.00%.

3. A HPPH lyophilized powder injection, wherein the proportions of each raw material are: TABLE-US-00013 HPPH 0.50~7.50 g solvents 30.00~150.00 g auxiliary solvents 0.50~0.65 g solubilizing agents 5.00~100.00 g excipients 300.00~500.00 g pH adjusting agents q.s., adjusting the pH value to 6.0~8.0 water for injection added until 5000 ml in total prepared in total 1000 bottles.

4. The HPPH lyophilized powder injection according to claim 3, wherein the proportions of each raw material are: TABLE-US-00014 HPPH 4.00~6.00 g solvents 100.00~150.00 g auxiliary solvents 0.51~0.56 g solubilizing agents 25.00~50.00 g excipients 350.00~400.00 g pH adjusting agents q.s., adjusting the pH value to 6.5~7.5 water for injection added until 5000 ml in total prepared in total 1000 bottles.

5. The HPPH lyophilized powder injection according to claim 3, wherein the solvent is 95%˜100% (v/v) ethanol.

6. The HPPH lyophilized powder injection according to claim 1, wherein the auxiliary solvent is sodium carbonate.

7. The HPPH lyophilized powder injection according to claim 1, wherein the solubilizing agent is polyoxyethylene castor oil, tweens or polyethylene glycol stearate 15.

8. The HPPH lyophilized powder injection according to claim 1, wherein the excipient is mannitol, lactose or dextran.

9. The HPPH lyophilized powder injection according to claim 1, wherein the pH adjusting agent is phosphoric acid, hydrochloric acid or acetic acid.

10. The HPPH lyophilized powder injection according to claim 7, wherein the solubilizing agent is polyoxyethylene castor oil or polyethylene glycol stearate 15.

11. The HPPH lyophilized powder injection according to claim 8, wherein the excipient is mannitol.

12. The HPPH lyophilized powder injection according to claim 9, wherein the pH adjusting agent is phosphoric acid.

Description

EXAMPLES

(1) The present invention will be further illustrated by the following examples. It should be noted that the following examples are only intended to illustrate the present invention rather than to limit the scope of the present invention in any way.

Example 1

(2) TABLE-US-00005 HPPH 5.0 g absolute alcohol 150.0 g sodium carbonate 0.56 g polyoxyethylene castor oil (EL) 50.0 g mannitol 300.0 g phosphoric acid q.s., adjusting the pH value to 7.0 water for injection added until 5000 ml in total Prepared in total 1000 bottles

(3) a) transferring a prescribed amount of mannitol into a compounding tank filled with 2000 ml of water for injection, stirring until dissolved, then obtaining Solution {circle around (1)};

(4) b) weighing and placing a prescribed amount of HPPH into the compounding tank, adding a prescribed amount of absolute alcohol, stirring, adding prescribed amounts to of sodium carbonate solution and polyoxyethylene castor oil, further stirring until dissolved, then obtaining Solution {circle around (2)}; and

(5) c) adding Solution {circle around (2)} into Solution {circle around (1)}, stirring, adding water for injection to reach 5000 ml, then adding in drops the phosphoric acid aqueous solution to adjust the pH value of the solution to 7.0; filtering and sterilizing the solution, followed by putting is the solution into the liquid storage tank, subpackaging, partial stoppering, lyophilizing, stoppering and packaging. In which, the lyophilizing step is as follows:

(6) 1) pre-lyophilizing: pre-lyophilizing the products at −40˜−50° C. for 3 hours to make the products frozen and compacted;

(7) 2) the first drying: after the pre-lyophilizing of the products, starting the vacuum pump to evacuate until the degree of vacuum reaches 20˜30 Pa, increasing the temperature of the products to −5° C. and maintaining for 28 hours; and

(8) 3) desorption drying: gradually warming up the products to reach the temperature of 20° C., and maintaining for 5 hours.

Example 2

(9) TABLE-US-00006 HPPH 1.0 g 96% alcohol 30 g sodium carbonate 0.50 g Tween 80 5.00 g dextran 500 g phosphoric acid q.s., adjusting the pH value to 6.5 water for injection added until 5000 ml in total Prepared in total 1000 bottles

(10) a) transferring a prescribed amount of dextran into a compounding tank filled with 2500 ml of water for injection, stirring until dissolved, then obtaining Solution {circle around (1)};

(11) b) weighing and placing a prescribed amount of HPPH into the compounding tank, adding a prescribed amount of 96% alcohol, stirring, adding prescribed amounts of sodium carbonate solution and Tween 80, further stirring until dissolved, then obtaining Solution {circle around (2)}; and

(12) c) adding Solution {circle around (2)} into Solution {circle around (1)}, stirring, adding water for injection to reach 5000 ml, then adding in drops the phosphoric acid aqueous solution to adjust the pH value of the solution to 6.5; filtering and sterilizing the solution, followed by putting the solution into the liquid storage tank, subpackaging, partial stoppering, lyophilizing, stoppering and packaging. In which, the lyophilizing step is as follows:

(13) 1) pre-lyophilizing: pre-lyophilizing the products at −40˜−50° C. for 3.5 hours to make the products frozen and compacted;

(14) 2) the first drying: after the pre-lyophilizing of the products, starting the vacuum pump to evacuate until the degree of vacuum reaches 20˜30 Pa, improving the temperature of the products to −5° C. and maintaining for 29 hours; and

(15) 3) desorption drying: gradually warning up the products to reach the temperature of 20° C., and maintaining for 4 hours.

Example 3

(16) TABLE-US-00007 HPPH 7.5 g 95% alcohol 100 g sodium carbonate 0.63 g polyethylene glycol stearate 15 100 g mannitol 500 g phosphoric acid q.s., adjusting the pH value to 7.8 water for injection added until 5000 ml Prepared in total 1000 bottles

(17) a) transferring a prescribed amount of mannitol into a compounding tank filled with 3000 ml of water for injection, stirring until dissolved, then obtaining Solution {circle around (1)};

(18) b) weighing and placing a prescribed amount of HPPH into the compounding tank, adding a prescribed amount of 95% alcohol, stirring, adding prescribed amounts of sodium carbonate solution and polyethylene glycol stearate 15, further stirring until dissolved, then obtaining Solution {circle around (2)}; and

(19) c) adding Solution {circle around (2)} into Solution {circle around (1)}, stirring, adding water for injection to reach 5000 ml, then adding in drops the phosphoric acid aqueous solution to adjust the pH value of the solution to 7.8; filtering and sterilizing the solution, followed by putting the solution into the liquid storage tank, subpackaging, partial stoppering, lyophilizing, stoppering and packaging. In which, the lyophilizing step is as follows:

(20) 1) pre-lyophilizing: pre-lyophilizing the products at −40˜−50° C. for 4 hours to make the products frozen and compacted;

(21) 2) the first drying: after the pre-lyophilizing of the products, starting the vacuum pump to evacuate until the degree of vacuum reaches 20˜30 Pa, increasing the temperature of the products to −5° C. and maintaining for 31 hours; and

(22) 3) desorption drying: gradually warming up the products to reach the temperature of 20° C., and maintaining for 3 hours.

Example 4

(23) TABLE-US-00008 HPPH 5.0 g 96% alcohol 80.0 g sodium carbonate 0.55 g polyoxyethylene castor oil (EL) 30.0 g mannitol 400.0 g phosphoric acid q.s. water for injection added until 5000 ml in total Prepared in total 1000 bottles

(24) a) transferring a prescribed amount of mannitol into a compounding tank filled with 4000 ml of water for injection, stirring until dissolved, then obtaining Solution {circle around (1)};

(25) b) weighing and placing a prescribed amount of HPPH into the compounding tank, adding a prescribed amount of 96% alcohol, stirring, adding prescribed amounts of sodium carbonate solution and polyoxyethylene castor oil, further stirring until dissolved, then obtaining Solution {circle around (2)}; and

(26) c) adding Solution {circle around (2)} into Solution {circle around (1)}, stirring, adding water for injection to reach 5000 ml, then adding in drops the phosphoric acid aqueous solution to adjust the pH value of the solution to 7.3; filtering and sterilized the solution, followed by putting the solution into the liquid storage tank, subpackaging, partial stoppering, lyophilizing, stoppering and packaging. In which, the lyophilizing step is as follows:

(27) 1) pre-lyophilizing: pre-lyophilizing the products at −40˜−45° C. for 2.5 hours to make the products frozen and compacted;

(28) 2) the first drying: after the pre-lyophilizing of the products, starting the vacuum pump to evacuate until the degree of vacuum reaches 20˜30 Pa, increasing the is temperature of the products to −5° C. and maintaining for 29 hours; and

(29) 3) desorption drying: gradually warming up the products to reach the temperature of 20° C., and maintaining for 4 hours.

Example 5 Study of Stability

(30) Place the lyophilized powder injections obtained by Examples 1-4 as well as the bulk solution before being lyophilized respectively under the conditions of 40° C. and 5° C. Conduct the study of stability, and the measured data about stability are as follows:

(31) TABLE-US-00009 Total Impurity % 1 2 4 6 Sample Temperature 0 day week weeks weeks weeks lyophilized 40° C. 0.33 0.46 0.61 0.74 1.18 powder  5° C. 0.33 0.35 0.44 0.48 0.51 injection of Example 1 unlyophilized 40° C. 0.33 1.43 2.17 2.21 2.20 bulk solution  5° C. 0.33 0.59 0.75 0.92 1.68 of Example 1 lyophilized 40° C. 0.31 0.43 0.78 0.85 1.42 powder  5° C. 0.31 0.35 0.41 0.52 0.62 injection of Example 2 unlyophilized 40° C. 0.38 2.30 2.75 3.14 4.01 bulk solution  5° C. 0.38 0.77 0.85 1.19 1.82 of Example 2 lyophilized 40° C. 0.32 0.41 0.68 1.01 1.22 powder  5° C. 0.32 0.34 0.35 0.47 0.55 injection of Example 3 unlyophilized 40° C. 0.31 1.34 1.95 2.64 2.57 bulk solution  5° C. 0.31 0.45 0.90 1.28 1.75 of Example 3 lyophilized 40° C. 0.35 0.66 0.72 0.96 1.11 powder  5° C. 0.35 0.35 0.45 0.48 0.50 injection of Example 4 unlyophilized 40° C. 0.37 1.92 2.02 2.03 2.22 bulk solution  5° C. 0.37 0.48 0.73 1.29 1.66 of Example 4

(32) It can be seen from the above data that, both the increasing ranges and the increasing rates of the impurities of lyophilized powder injections are far below those of the bulk solution before being lyophilized. Thus, the stability of the lyophilized powder injection is obviously higher than the stability of the bulk solution before being lyophilized. Based on a comprehensive consideration of the safety and effectiveness of the formulation, the lyophilized powder injection would be chosen as a preferred formulation.

Example 6 Study of Stability

(33) According to the proportions and technology of the formulations in Examples 2 and 4, prepare another three batches of lyophilized powder injections. Place every batch at 5° C. and conduct the study of stability. The measured data about stability are as follows:

(34) TABLE-US-00010 Total Impurity % 12 18 24 Sample Batch 0 day 3 months 6 months months months months lyophilized Batch 1 0.25 0.26 0.30 0.34 0.35 0.39 powder injection Batch 2 0.30 0.32 0.35 0.38 0.40 0.45 of Example 2 Batch 3 0.31 0.33 0.37 0.40 0.41 0.43 lyophilized Batch 1 0.24 0.26 0.29 0.30 0.31 0.35 powder injection Batch 2 0.29 0.30 0.33 0.35 0.39 0.39 of Example 4 Batch 3 0.20 0.22 0.28 0.31 0.31 0.34

(35) It can be seen from the above data that, all batched of the lyophilized powder injections have uniform qualities, and the repeatability among the batches is good. Under the condition of 5° C., the increasing rates of the impurities within 24 months are rather slow, thus the stability of the product is high.