A vinblastine suspension and a preparation method thereof
By preparing vinpocetine suspension, the problem of vinpocetine's poor water solubility was solved by using specific excipients and high-pressure homogenization technology, achieving high bioavailability and stability of oral liquid formulations, suitable for oral administration.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- SOUTHEAST UNIV CHENGXIAN COLLEGE
- Filing Date
- 2026-03-26
- Publication Date
- 2026-06-09
AI Technical Summary
Vinpocetine is poorly soluble in water, resulting in poor oral bioavailability. Currently available liquid formulations are mainly injections, and there is a lack of liquid formulations suitable for oral administration, limiting the improvement of bioavailability.
The formulation of vinpocetine suspension, containing mannitol as a suspending agent, polyethylene glycol succinate as a solubilizing agent, and sodium cross-linked carboxymethyl cellulose as a stabilizer, is used to prepare nanoparticles with a particle size of 200-300 nm through high-pressure homogenization and pH adjustment, forming a spatially stable structure and improving solubility and dispersibility.
It significantly improves the bioavailability of vinpocetine, achieving efficient absorption of oral liquid formulations, excellent stability and dispersibility, and reducing individual differences and toxic side effects.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical preparation technology, and in particular to a vinpocetine suspension and its preparation method. Background Technology
[0002] Vinpocetine, chemically known as ethyl(13as,13bs)-13a-ethyl-2,3,5,6-13a,13b hexahydro-1H-indole[3,2,1-de]pyridine[3,2,1-ij][1,5]-diazanaphthalene-12-carboxylic acid, is an indole alkaloid. Scientific research has confirmed that vinpocetine has a selective effect on cerebral blood vessels, selectively improving cerebral blood circulation, promoting cerebral energy metabolism, regulating neurotransmitter system function, and protecting the brain from ischemic and hypoxic damage in multiple ways. It has good efficacy in preventing and treating sequelae of cerebral hemorrhage, cerebral arteriosclerosis, and hyperviscosity syndrome, and also has effects such as improving memory, mood, and age-related hearing and visual abnormalities.
[0003] However, vinpocetine is a poorly soluble drug, almost insoluble in water, which severely affects its dissolution and absorption, resulting in poor oral bioavailability. According to the Ostwald-Freundrich equation, the drug dissolution rate is inversely proportional to the drug particle size. Reducing the drug particle size can significantly increase its dissolution rate, thereby significantly improving the drug's bioavailability, reducing individual variability, and decreasing toxic side effects.
[0004] Currently, research on the bioavailability of vinpocetine mainly focuses on the research and improvement of drug formulations, such as vinpocetine sustained-release tablets, vinpocetine dispersible tablets, vinpocetine lyophilized powder for injection, vinpocetine drop pills, vinpocetine cocrystal complexes, and vinpocetine injections. The main improvement method is to change the pharmaceutical excipients. However, the improvement of bioavailability in oral formulations such as vinpocetine sustained-release tablets, dispersible tablets, and drop pills is limited. Liquid formulations show a more significant improvement in drug bioavailability. Currently, the main liquid dosage form of vinpocetine is an injection, suitable for intravenous or intramuscular injection; there is no liquid dosage form suitable for oral administration.
[0005] Therefore, developing a liquid formulation of vinpocetine that can be directly administered orally, and whose bioavailability is significantly higher than existing oral vinpocetine formulations, is of great significance for the medicinal use of vinpocetine. Summary of the Invention
[0006] The purpose of this invention is to provide a vinpocetine suspension and its preparation method, aiming to expand the dosage forms of vinpocetine and improve its bioavailability.
[0007] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a vinpocetine suspension, comprising the following raw materials in parts by mass: Vinpocetine 5.2~12.6 parts, suspending agent 32~45 parts, solubilizer 1.3~3.5 parts, stabilizer 4.8~6.5 parts, water 220~250 parts.
[0008] Preferably, the suspending agent is mannitol.
[0009] Preferably, the cosolvent is vitamin E polyethylene glycol succinate.
[0010] Preferably, the stabilizer is croscarmellose sodium.
[0011] Preferably, it also includes a pH adjuster, said pH adjuster comprising one or more of sodium citrate, sodium tartrate and sodium citrate.
[0012] Preferably, the amount of pH adjuster used is such that the pH value of the vinpocetine suspension is 3.5 to 5.5.
[0013] Preferably, the particle size D of the vinpocetine suspension is... 50 It is 200~300nm.
[0014] The present invention also provides a method for preparing the vinpocetine suspension, comprising the following steps: 1) The suspending agent, solubilizer, and stabilizer are sequentially dispersed in water to obtain an aqueous dispersion; 2) Add vinpocetine to the aqueous dispersion, homogenize under high pressure, and then adjust the pH value with a pH adjuster to obtain vinpocetine suspension.
[0015] Preferably, the pressure of the high-pressure homogenization in step 2) is 30,000 to 40,000 psi, and the number of high-pressure homogenization cycles is 4 to 7.
[0016] The beneficial effects of this invention are: The vinpocetine suspension of this invention is suitable for oral administration. The excipients in the suspension include a suspending agent, a solubilizer, and a stabilizer. The solubilizer inhibits the aggregation of vinpocetine nanoparticles while improving their solubility and dispersion uniformity in water. The suspending agent and stabilizer together construct a spatially stable structure, ensuring the suspension and dispersion of the vinpocetine nanoparticles and resisting their sedimentation. Through the synergistic effect of the suspending agent, solubilizer, and stabilizer, nanoscale distribution and uniform dispersion and suspension of vinpocetine are achieved, significantly improving its bioavailability. High-pressure homogenization achieves the nanoscale distribution of vinpocetine, with a particle size D... 50 Reaching 200~300nm. Detailed Implementation
[0017] This invention provides a vinpocetine suspension, comprising the following raw materials in parts by mass: Vinpocetine 5.2~12.6 parts, suspending agent 32~45 parts, solubilizer 1.3~3.5 parts, stabilizer 4.8~6.5 parts, water 220~250 parts.
[0018] In this invention, the vinpocetine suspension is preferably suitable for oral administration.
[0019] In this invention, the vinpocetine suspension comprises, by weight, the following raw materials: 5.2-12.6 parts of vinpocetine, preferably 6-11.3 parts, more preferably 7.5-10.5 parts, and even more preferably 8-9.5 parts; 32-45 parts of suspending agent, preferably 34-42 parts, more preferably 36-40 parts, and even more preferably 38 parts; 1.3-3.5 parts of solubilizer, preferably 1.5-3.2 parts, more preferably 1.8-3 parts, and even more preferably 2-2.5 parts; 4.8-6.5 parts of stabilizer, preferably 5-6.3 parts, more preferably 5.2-6 parts, and even more preferably 5.5-5.8 parts; and 220-250 parts of water, preferably 225-245 parts, more preferably 230-240 parts, and even more preferably 235 parts.
[0020] In this invention, the suspending agent is preferably mannitol. Mannitol promotes the suspension and dispersion of nanoparticles, which helps to improve the stability of nanoparticles.
[0021] In this invention, the co-solvent is preferably vitamin E polyethylene glycol succinate. Vitamin E polyethylene glycol succinate improves the solubility and dispersibility of vinpocetine nanoparticles in water by inhibiting their aggregation.
[0022] In this invention, the stabilizer is preferably croscarmellose sodium. Croscarmellose sodium, as a stabilizer, increases the viscosity of the suspension system, resists the sedimentation of vinpocetine nanoparticles, and together with mannitol forms a spatially stable structure, providing a uniformly dispersed suspension system.
[0023] In this invention, a pH adjuster is preferably also included, wherein the pH adjuster preferably includes one or more of sodium citrate, sodium tartrate and sodium citrate.
[0024] In this invention, the amount of pH adjuster is preferably such that the pH value of the vinpocetine suspension is 3.5 to 5.5, more preferably 4 to 5, and even more preferably 4.5.
[0025] In this invention, the particle size D of the vinpocetine suspension is... 50 Preferably, the wavelength is 200~300nm, more preferably 220~280nm, and even more preferably 250nm.
[0026] The present invention also provides a method for preparing the vinpocetine suspension, comprising the following steps: 1) The suspending agent, solubilizer, and stabilizer are sequentially dispersed in water to obtain an aqueous dispersion; 2) Add vinpocetine to the aqueous dispersion, homogenize under high pressure, and then adjust the pH value with a pH adjuster to obtain vinpocetine suspension.
[0027] In this invention, the pressure of the high-pressure homogenization in step 2) is preferably 30,000 to 40,000 psi, more preferably 32,000 to 38,000 psi, and even more preferably 35,000 psi; the number of high-pressure homogenizations is preferably 4 to 7 times, and even more preferably 5 to 6 times.
[0028] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.
[0029] The water used in the embodiments and comparative examples of this invention is sterile water.
[0030] Example 1
[0031] The raw materials of vinpocetine suspension by mass are: 12.6 parts vinpocetine, 38 parts mannitol, 1.3 parts vitamin E polyethylene glycol succinate, 5.5 parts croscarmellose sodium, and 220 parts water.
[0032] The preparation method of vinpocetine suspension is as follows: Mannitol, vitamin E polyethylene glycol succinate, and croscarmellose sodium are dispersed in water to obtain an aqueous dispersion. Vinpocetine is added to the aqueous dispersion, and the mixture is homogenized five times under high pressure at 35,000 psi. Then, the pH value is adjusted to 4.5 using sodium tartrate to obtain the final product.
[0033] Example 2
[0034] The raw materials of vinpocetine suspension by mass are: 8 parts vinpocetine, 32 parts mannitol, 2 parts vitamin E polyethylene glycol succinate, 6.5 parts croscarmellose sodium, and 250 parts water.
[0035] The preparation method of vinpocetine suspension is as follows: Mannitol, vitamin E polyethylene glycol succinate, and croscarmellose sodium are dispersed in water to obtain an aqueous dispersion. Vinpocetine is added to the aqueous dispersion, and the mixture is homogenized four times under high pressure at 40,000 psi. Then, the pH value is adjusted to 3.5 using sodium tartrate to obtain the final product.
[0036] Example 3
[0037] The raw materials of vinpocetine suspension by mass are: 5.2 parts vinpocetine, 45 parts mannitol, 3.5 parts vitamin E polyethylene glycol succinate, 4.8 parts croscarmellose sodium, and 235 parts water.
[0038] The preparation method of vinpocetine suspension is as follows: Mannitol, vitamin E polyethylene glycol succinate, and croscarmellose sodium are dispersed in water to obtain an aqueous dispersion. Vinpocetine is added to the aqueous dispersion, and the mixture is homogenized under high pressure at 30,000 psi seven times. Then, the pH value is adjusted to 5.1 using sodium tartrate to obtain the final product.
[0039] Comparative Example 1
[0040] Mannitol is omitted in Example 1, and everything else is the same as in Example 1.
[0041] Comparative Example 2
[0042] The croscarmellose sodium carboxymethyl cellulose in Example 1 is omitted, and everything else is the same as in Example 1.
[0043] Comparative Example 3
[0044] In Example 1, 5.5 parts of cross-linked sodium carboxymethyl cellulose were replaced with 12 parts of serine phospholipids, and the rest were the same as in Example 1.
[0045] Comparative Example 4
[0046] Replace 1.3 parts of vitamin E polyethylene glycol succinate in Example 1 with 1.8 parts of tartaric acid, otherwise remain the same as in Example 1.
[0047] Comparative Example 5
[0048] The mannitol in Example 1 was modified to 52 parts, and the cross-linked sodium carboxymethyl cellulose was modified to 6.2 parts, with the other parts remaining the same as in Example 1.
[0049] Comparative Example 6
[0050] The mannitol in Example 1 was modified to 32 parts, the cross-linked sodium carboxymethyl cellulose was modified to 9 parts, and the rest was the same as in Example 1.
[0051] The particle size of vinpocetine in the vinpocetine suspension was determined using a Zetasizer 3000 laser particle size analyzer, and the polydispersity index (PDI) of vinpocetine was determined by dynamic light scattering (DLS) method. The test results are shown in Table 1.
[0052] Table 1. Particle size of vinpocetine suspension
[0053] Note: Three parallel comparative experiments were set up for each group. Table 1 shows the average values of the three parallel comparative experiments.
[0054] Stability evaluation: 100 mL of vinpocetine suspension was placed at 40℃ and 75% relative humidity for 6 months and an accelerated stability test was performed. Changes in particle size, pH value, and related substances were evaluated according to the Chinese Pharmacopoeia. The sedimentation volume ratio after standing for 3 hours was determined according to the Chinese Pharmacopoeia for oral suspensions. The stability evaluation results are shown in Tables 2 and 3.
[0055] Table 2. Changes in particle size, pH value, and related substances of vinpocetine suspension.
[0056] Table 3 Sedimentation volume ratio of vinpocetine suspension after standing for 3 hours
[0057] Note: Three parallel comparative experiments were set up for each group. Tables 2 and 3 show the average values of the three parallel comparative experiments.
[0058] As shown in Tables 2 and 3, the vinpocetine particles in Examples 1-3 were in the range of 219-231 nm, with small particle size and low PDI, indicating a narrow particle size distribution and excellent stability. In accelerated testing over 6 months, the particle size increase was controlled within +5 nm, and the pH and related substance content fluctuated little. The sedimentation volume ratio after 3 hours fully met the quality requirements. In contrast, Comparative Examples 1-3, due to the disruption of the spatially stable structure constructed by the suspending agent and stabilizer, caused particle agglomeration, resulting in a significant increase in particle size and a marked rise in PDI. Under prolonged static conditions, these particles were prone to agglomeration and sedimentation, and the content of related substances increased rapidly, indicating extremely poor stability. Comparative Example 4, using tartaric acid as a co-solvent, could not form a synergistic system with mannitol and croscarmellose sodium, failing to achieve uniform suspension and dispersion, leading to larger particle size and poor stability. Comparative Examples 5-6, due to changes in the dosage of suspending agent and stabilizer, formed an unbalanced spatially stable network, which could not support the suspension and dispersion of vinpocetine, resulting in larger particle size and poorer stability.
[0059] Bioavailability evaluation: Twenty-one Wistar rats (healthy, clean-grade, weighing 250±20g) were randomly divided into 7 groups of 3 rats each. Before the experiment, the rats were fasted for 12 hours and then orally administered vinpocetine suspension (Example 1) orally (Comparative Examples 1-6) at a dose of 8 mg / kg. Venous blood samples were collected at 0.25h, 0.5h, 1h, 2h, 3h, 4h, 6h, and 8h after administration. Blood drug concentrations were determined using high-performance liquid chromatography (HPLC), and the average blood drug concentration from the three rats was recorded. The test results are shown in Tables 4 and 5.
[0060] Table 4. Blood concentrations of vinpocetine (μg / mL)
[0061] Table 5 Pharmacokinetic parameters of vinpocetine
[0062] As shown in Tables 4 and 5, the bioavailability of vinpocetine in Example 1 was significantly higher than that in Comparative Examples 1-6. Comparative Examples 1-3 altered the types and amounts of suspending agents and stabilizers, thereby disrupting the spatially stable structure constructed by the suspending agents and stabilizers. Comparative Example 4 selected tartaric acid as a co-solvent, which could not form a synergistic system with mannitol and cross-linked sodium carboxymethyl cellulose. Comparative Examples 1-4 reduced the dispersibility of the suspension, resulting in poor dispersibility of vinpocetine nanoparticles and decreased bioavailability. Comparative Examples 5-6 changed the amounts of suspending agents and stabilizers. Although they constructed a synergistic spatial structure network of suspending agents, stabilizers, and co-solvents, they did not achieve equilibrium and stability, failing to support the suspension and dispersion of vinpocetine and instead reducing bioavailability. These results indicate that the vinpocetine suspension of the present invention, by using specific excipients (suspending agents, co-solvents, and stabilizers) and strictly controlling their ratio, synergistically imparts uniform and excellent suspension dispersibility to vinpocetine, significantly improving its bioavailability.
[0063] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.
Claims
1. A vinpocetine suspension, characterized in that, By weight, it contains the following ingredients: Vinpocetine 5.2~12.6 parts, suspending agent 32~45 parts, solubilizer 1.3~3.5 parts, stabilizer 4.8~6.5 parts, water 220~250 parts.
2. The vinpocetine suspension according to claim 1, characterized in that, The suspending agent is mannitol.
3. The vinpocetine suspension according to claim 1 or 2, characterized in that, The cosolvent is vitamin E polyethylene glycol succinate.
4. The vinpocetine suspension according to claim 3, characterized in that, The stabilizer is croscarmellose sodium cellulose.
5. The vinpocetine suspension according to claim 4, characterized in that, It also contains a pH adjuster, which includes one or more of sodium citrate, sodium tartrate, and sodium citrate.
6. The vinpocetine suspension according to claim 1 or 5, characterized in that, The amount of pH adjuster used is such that the pH value of the vinpocetine suspension is 3.5 to 5.
5.
7. The vinpocetine suspension according to claim 6, characterized in that, The particle size D of the vinpocetine suspension 50 It is 200~300nm.
8. The method for preparing the vinpocetine suspension according to any one of claims 1 to 7, characterized in that, It includes the following steps: 1) The suspending agent, solubilizer, and stabilizer are sequentially dispersed in water to obtain an aqueous dispersion; 2) Add vinpocetine to the aqueous dispersion, homogenize under high pressure, and then adjust the pH value with a pH adjuster to obtain vinpocetine suspension.
9. The preparation method according to claim 8, characterized in that, Step 2) The pressure of the high-pressure homogenization is 30,000~40,000 psi, and the number of high-pressure homogenization cycles is 4~7.