High-stability theophylline hexahydrate injection and preparation method thereof

Abstract

The application discloses a pH stable pentoxifylline injection as well as a preparation method and pharmaceutical application thereof, and belongs to the technical field of pharmaceutical preparations. The injection is prepared from pentoxifylline as a pharmacodynamic material, sodium chloride, L-lysine hydrochloride and disodium edetate in a specific ratio, and is diluted with water for injection, so that the pH value of the system is accurately controlled to be 5.40-5.60. The preparation process is optimized, nitrogen is used for oxygen removal, gradient temperature control dissolution, low-temperature batch feeding, nitrogen protection is used in the whole process, and terminal sterilization is combined with double-stage filtration, so that the thermal degradation and metal ion catalytic degradation of the medicine are effectively inhibited. The application has the advantages of reasonable formula, stable process, high product purity, good safety and industrial production value.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a pH-stable pentoxifylline injection, its preparation method, and its pharmaceutical uses. Background Technology

[0002] Pentoxobromine is a methylxanthine derivative. Clinically, it is used as a vasodilator to treat peripheral vascular diseases. It can improve red blood cell deformability, reduce blood viscosity, inhibit platelet aggregation, and increase blood flow to organs such as the brain, muscles, liver, and kidneys.

[0003] Pentoxothecobalaine injection was first marketed by Sanofi under the trade name "Trental," and its formulation contains only pentoxothecobalaine, sodium chloride, and water for injection. This formulation suffers from poor pH stability; the pH value drops significantly during long-term storage, and the levels of related substances increase, affecting the product's safety and efficacy.

[0004] Chinese patent application CN112842993A discloses a pentoxifylline injection using L-lysine as a pH adjuster, with an L-lysine dosage of 3-7 g / L. Although this method improves pH stability to some extent, patent CN112842993A still has the following shortcomings: (1) Dissolved oxygen and metal ion catalytic degradation are not controlled, and long-term stability is still not ideal; (2) The preparation process is simple, but the feeding sequence and temperature control are not optimized, resulting in a high level of impurities; (3) The optimal pH range and corresponding stability data are not clearly defined.

[0005] Disodium edetate can form stable soluble complexes with metal ions (such as iron, copper, and zinc ions) that may be present in the injection solution, thereby inhibiting the catalytic effect of metal ions on the degradation reaction of pentoxifylline. Research in patent CN106309362A shows that, after 6 months of accelerated testing, the pentoxifylline injection composition containing disodium edetate remains colorless, the pH value remains essentially unchanged, the increase in related substances is not significant, and the decrease in pentoxifylline content is also not significant. The stability of the product is significantly better than the control product without disodium edetate.

[0006] Therefore, there is an urgent need to provide a highly stable pentoxifylline injection with more stable pH, lower impurities, and controllable process. Summary of the Invention

[0007] The purpose of this invention is to overcome the shortcomings of the prior art and provide a pentoxifylline injection with high pH stability, low impurity level, and simple process, as well as its preparation method.

[0008] Technical solution

[0009] In one aspect, a pH-stable pentoxifylline injection is provided, which is composed of the following components per 1000 mL: 20 g pentoxifylline, 6.88 g sodium chloride, 4.7–5.3 g L-lysine hydrochloride, 0.01–0.05 g disodium edetate, and water for injection to a final volume of 1000 mL, with a pH value of 5.40–5.60.

[0010] Secondly, a method for preparing the injection solution is provided, including: deoxygenation, stepwise temperature-controlled dissolution, batch feeding, intermediate pH adjustment, double filtration, nitrogen filling and sealing, and terminal sterilization.

[0011] Beneficial effects

[0012] Compared with the prior art (CN112842993A), the present invention has the following unexpected technical effects:

[0013] 1. Significantly improved pH stability: pH change ≤ ±0.15 over 6 months, better than ±0.25 to 0.35 of the comparison file.

[0014] 2. Significantly reduced impurity levels: Total impurity increase was ≤0.2% after 6 months of accelerated testing, which is better than the 0.35-0.5% of the reference data.

[0015] 3. Superior process: Step-by-step temperature control and batch feeding reduce thermal degradation and local supersaturation, resulting in lower impurities. Attached Figure Description

[0016] none. Detailed Implementation

[0017] The invention is further illustrated by the embodiments given below, but the invention is not limited to these embodiments.

[0018] Example 1

[0019] Per 1000mL injection solution: 20g pentoxifylline, 6.88g sodium chloride, 5.0g L-lysine hydrochloride, 0.02g disodium edetate, and water for injection to 1000mL.

[0020] Preparation method:

[0021] (1) Boil water for injection and purge with nitrogen until dissolved oxygen ≤ 1.0 mg / L; (2) Dissolve sodium chloride at 40°C; (3) Cool to 25°C and add L-lysine hydrochloride and disodium edetate; (4) Add pentoxifylline in 4 batches under nitrogen protection, with an interval of 5 minutes between each batch and a temperature ≤ 30°C; (5) Adjust pH to 5.45 ± 0.05; (6) Filter at 0.45 μm + 0.22 μm; (7) Fill and seal, and fill headspace with nitrogen; (8) Sterilize at 121°C for 15 minutes.

[0022] Example 2

[0023] 4.7 g of L-lysine hydrochloride, 0.01 g of disodium edetate, and the rest are the same as in Example 1.

[0024] Example 3

[0025] 5.3 g of L-lysine hydrochloride, 0.05 g of disodium edetate, and the rest are the same as in Example 1.

[0026] Comparative Example

[0027] Refer to Example 3 of CN112842993A.

[0028] The stability test results are as follows:

[0029]

[0030] Therefore, it can be seen that, based on CN112842993A, the inventors selected a combination of pH stabilizers, L-lysine + EDTA, and simultaneously optimized the process, resulting in an unexpected synergistic effect by narrowing the pH range.

Claims

1. A pH-stabilized pentoxifylline injection solution, characterized by, Each 1000 mL injection solution consists of the following components: 20 g of pentoxifylline, 6.88 g of sodium chloride, 4.7–5.3 g of L-lysine hydrochloride, 0.01–0.05 g of disodium edetate, and water for injection to a final volume of 1000 mL, with a pH of 5.40–5.

60.

2. The pentifylline injection solution according to claim 1, characterized in that, The amount of L-lysine hydrochloride used is 5.0 g / L, the amount of disodium edetate is 0.02 g / L, and the pH value is 5.50 ± 0.

10.

3. The theobromine injection according to claim 1, characterized in that, After the injection solution was placed under accelerated test conditions (40℃±2℃ / 75%RH±5%RH) for 6 months, the pH value change did not exceed ±0.15, the total impurity content increased by no more than 0.2%, and the pentanone-theobromine content decreased by no more than 2.0%.

4. A method for preparing the pentoxifylline injection according to claim 1, characterized in that, The procedure includes the following steps: (1) Boil the water for injection and purge it with nitrogen to remove oxygen until the dissolved oxygen content is ≤1.0 mg / L; (2) Add sodium chloride at 40℃±2℃ and stir until completely dissolved; (3) Cool down to 25℃±2℃, add L-lysine hydrochloride and disodium edetate, and stir to dissolve; (4) Under nitrogen protection, add pentoxifylline in 3 to 5 batches, with an interval of 5 minutes between each batch, and maintain the temperature of the solution not exceeding 30℃; (5) Adjust the pH to 5.45±0.05 with L-lysine hydrochloride or dilute hydrochloric acid; (6) Filter the solution through a 0.45μm coarse filter and a 0.22μm polyethersulfone filter in sequence; (7) Fill and seal the solution, and fill the headspace with nitrogen; (8) Terminally sterilize at 121℃ for 15 minutes.

5. The preparation method according to claim 4, characterized in that, During the addition of pentoxifylline in step (4), the temperature of the liquid should be maintained at no more than 30°C.

6. The use of the pentoxifylline injection according to claim 1 in the preparation of a medicament for treating acute ischemic stroke.

7. The use of the pentoxifylline injection according to claim 1 in the preparation of a medicament for treating peripheral artery disease with hyperhomocysteinemia.

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