An injectable temperature-sensitive gel foam sclerosing agent

Abstract

The present application belongs to the field of pharmaceutical preparations, and particularly relates to an injectable temperature-sensitive gel foam sclerosing agent. The injectable temperature-sensitive gel foam sclerosing agent comprises lauromacrogol air foam and poloxamer 407, and is a new treatment strategy formed by combining the advantages of foam sclerosing agents and temperature-sensitive gels. In the process of compounding components, it is accidentally found that, under the synergistic effect of specific concentrations and components, lauromacrogol is the main foaming agent, poloxamer 407 is attached to the liquid film surface layer of the foam, the foam volume is basically unchanged, and the poloxamer 407 and lauromacrogol air foam are mutually synergistic, the stability of the foam is increased, and the action time of the drug at the lesion site is significantly prolonged.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulations, and specifically relates to an injectable temperature-sensitive gel foam hardener. Background Technology

[0002] Venous malformations are the most common congenital slow-flow vascular malformations in clinical practice, with over 40% occurring in the head and neck region. Larger or more specifically located venous malformations often lead to significant cosmetic deformities and functional impairments, severely impacting patients' quality of life. Currently, the mainstream international treatment for venous malformations is sclerotherapy, with commonly used sclerosing agents including polidocanol and bleomycin. However, when liquid sclerosing agents are directly injected into the veins, their concentration is severely diluted by the blood and they are quickly carried away by the blood flow, resulting in a short duration of action at the lesion site, thus significantly affecting the therapeutic effect. To overcome these drawbacks of liquid sclerosing agents, two solutions have emerged: foam sclerosing agents and gel sclerosing agents.

[0003] Gel sclerotherapy involves injecting a gel carrying a sclerosing agent into the lesion cavity. The gel acts as a sustained-release carrier of the sclerosing agent, prolonging the drug's action time. This strategy is exemplified by using medical fibrin gel to carry bleomycin. The disadvantages of this method are that the gel is a solid, solid-like substance; its surface layer contacts the lesion tissue to exert an effective therapeutic effect, while the interior of the gel does not provide therapeutic benefit and may even produce adverse effects. Furthermore, the gel degradation time is excessively long, typically several months, when in reality only a few days are sufficient to achieve the desired therapeutic effect. Excessive retention time can lead to adverse reactions.

[0004] Another solution is to mix the liquid sclerosing agent with air to create a foam sclerosing agent. Compared to liquid sclerosing agents, foam sclerosing agents require about 1 / 10 of the drug dosage, can remain on the lesion site for a longer time, have a longer duration of action, better efficacy, and fewer side effects. However, foam is unstable and usually decomposes into liquid and air within minutes, severely affecting the treatment outcome. Summary of the Invention

[0005] This invention combines the two methods mentioned above. Inspired by the temperature-sensitive properties of poloxamer, this invention provides an injectable temperature-sensitive gel foam curing agent, referred to as gel foam.

[0006] Compared to solid gels, gel foams retain the advantages of sustained drug release while overcoming the disadvantages of their solid state. Besides the innovative concept, gel foams also present several technical challenges. Firstly, ensuring that the foam remains liquid in vitro within a polidocanol-based air foam system and rapidly gels in vivo is crucial. Secondly, preventing the gel foam from becoming a solid gel after gelation in vivo, thus eliminating its advantages, is also essential.

[0007] To address the aforementioned technical problems, this invention prepares a foam hardener at room temperature. By combining various components, a synergistic effect is achieved. After injection into the body, the gel foam hardener gels and becomes semi-solid. Compared with traditional foam hardeners, it not only retains the latter's advantages but also overcomes its disadvantages, namely, it will not be washed away by the blood, thus ensuring the duration of drug action at the lesion site.

[0008] Specifically, the technical solution of the present invention is as follows:

[0009] An injectable temperature-sensitive gel foam curing agent, comprising polidocanol air foam and poloxamer 407 (P407).

[0010] Furthermore, the polydocanol air foam comprises a 1% (by volume) polydocanol (POL) solution and air, and the mass of the poloxamer 407 used accounts for 19% to 21% of the volume of the 1% (by volume) polydocanol solution.

[0011] Furthermore, the polycinnamic acid air foam is an aggregate of multiple small bubbles, each with a liquid film on its surface; the poloxamer 407 is attached to the surface of the liquid film.

[0012] Furthermore, the injectable temperature-sensitive gel foam curing agent transforms from a fluid foam to a semi-solid gel foam at ≥37.5℃; even further, the period for the injectable temperature-sensitive gel foam curing agent to transform from a fluid foam to a semi-solid gel foam at 37.5℃ is 10.0s to 62.7s. The semi-solid gel foam is characterized by: transferring the prepared P407-POL temperature-sensitive gel foam into a glass test tube and placing it in a constant-temperature controlled water bath at 37.5℃; inverting and tilting the test tube every 5 seconds at a 60° angle to the horizontal plane to test the foam's fluidity; if the foam does not flow within 5 seconds after the test tube is inverted, it is considered a semi-solid gel foam.

[0013] Crucially, the inventiveness of this invention also lies in the fact that the injectable temperature-sensitive gel foam curing agent prepared by this invention does not rely on the known foaming effect of poloxamer 407 to form foam. On the other hand, if poloxamer 407 exerts its foaming effect, the technical effect described in this invention cannot be achieved. Specifically, this is manifested in the following ways:

[0014] The concentration of poloxamer 407 used in this invention is 19%–21% (W / V), which is relatively high. It is known that poloxamer 407 is a high-molecular-weight nonionic surfactant, readily soluble in water, and possesses certain foaming properties. If poloxamer 407 is used as the main foaming agent in the system of this invention, rapid gelation after the gel foam hardener is injected into the body will lead to the instantaneous disintegration of the foam system and solidification of the gel. This not only eliminates the advantages of the foam formulation but also introduces the defect of prolonged adhesion of the solid gel. Therefore, during the compounding process, this invention unexpectedly discovered that under specific concentrations and synergistic effects of the components, polidocanol is the main foaming agent, while poloxamer 407 adheres to the liquid film surface of the foam. After gelation in vivo, the foam volume remains essentially unchanged. This indicates that poloxamer 407 only becomes semi-solid on the liquid film surface, which not only increases foam stability but also significantly prolongs the duration of drug action at the lesion site due to its adhesion effect.

[0015] The present invention also provides a method for preparing the above-mentioned injectable temperature-sensitive gel foam curing agent, the steps of which are as follows:

[0016] S1: Weigh poloxamer 407 and dissolve it in 1% (volume) polycinnamic acid solution to obtain P407-POL solution;

[0017] S2: Prepare foam from P407-POL solution using the Tessari method, with a liquid-to-gas ratio of 1:4 to 1:1.

[0018] The Tessari method is a widely used foam preparation method in clinical practice. Specifically, a certain volume of P407-POL solution is drawn into one syringe, and air is drawn into another syringe at an appropriate liquid-to-gas ratio. Then, the two syringes are connected to a three-way valve, and the solution is injected back and forth at a uniform speed to produce foam.

[0019] Preferably, in the preparation process of the injectable temperature-sensitive gel foam hardener of the present invention, the liquid-to-gas ratio is 1:1.

[0020] The beneficial effects of this invention are as follows:

[0021] This invention provides an injectable temperature-sensitive gel foam sclerosing agent. The foam is stable and fine, and is in a fluid state at room temperature for easy injection. After injection into the body, it responds to temperature and gels into a semi-solid state, while maintaining the foam shape, thus fixing the foam to the lesion site. This significantly prolongs the drug's action time and provides better therapeutic effects. Attached Figure Description

[0022] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0023] Figure 1 For example 1, the liquid precipitation time for different P407 mass concentrations is given. The results are expressed as mean ± standard deviation, n = 5. * indicates that the difference between the 1%, 3%, and 5% groups and the 0% group is statistically significant, P < 0.05 (*) or 0.01 (**) or 0.001 (***).

[0024] Figure 2 For FHT with different P407 mass concentrations in Example 1, the results are expressed as mean ± standard deviation, n = 5, * indicates that the difference between the 1%, 3%, and 5% groups and the 0% group is statistically significant, P < 0.05 (*) or 0.01 (**) or 0.001 (***);

[0025] Figure 3 The appearance of thermosensitive gel foam at different temperatures: a, 25℃; b, 37.5℃;

[0026] Figure 4 The gelation time of P407-POL thermosensitive gel foam with different concentrations;

[0027] Figure 5 The in vitro dissolution process of P407-POL thermosensitive gel foam with different concentrations;

[0028] Figure 6 Fourier transform infrared spectra of P407, polycinnamic acid alcohol, and P407-POL hydrogel. Detailed Implementation

[0029] The present invention will now be described through specific embodiments. Unless otherwise specified, all technical means used in this invention are methods well known to those skilled in the art. Furthermore, the embodiments should be understood as illustrative, not limiting, of the scope of the invention; the essence and scope of the invention are defined only by the claims. For those skilled in the art, various changes or modifications to the material composition and dosage in these embodiments without departing from the essence and scope of the invention also fall within the protection scope of this invention.

[0030] Reagents and instruments used in this invention

[0031] 1% Podocanol Injection (Shaanxi Tianyu Pharmaceutical Co., Ltd., China)

[0032] Poloxamer 407 (Beijing Solarbio Technology Co., Ltd., China)

[0033] 10mL disposable sterile medical syringe (Shandong Weigao Group Medical Polymer Products Co., Ltd., China)

[0034] Medical three-way valve (Shandong Weigao Group Medical Polymer Products Co., Ltd., China)

[0035] Centrifuge tubes (Wuxi Nice Life Science Co., Ltd., China)

[0036] Analytical balance (Mettler Toledo, USA)

[0037] Vortex mixer (Haimen Qilinbell Instrument Manufacturing Co., Ltd., China)

[0038] Constant temperature refrigerator (Haier Group, China)

[0039] Electric thermostatic water bath (Shanghai Jinghong Experimental Equipment Co., Ltd., China)

[0040] Thermostatic Shaker (New Brunswick Scientific, USA)

[0041] Pointer push-pull force gauge (Nanjing Suche Measurement Instrument Co., Ltd., China)

[0042] Vacuum freeze dryer (Beijing Sihuan Qihang Technology Co., Ltd., China)

[0043] Fourier transform infrared spectrometer (Thermo Fisher Scientific, USA)

[0044] Example 1

[0045] The effect of poloxamer 407 on the performance of polydocanol air foam

[0046] An injectable temperature-sensitive gel foam curing agent, the preparation and testing steps are as follows:

[0047] (1) Solution preparation: Accurately weigh 0.5g, 1g, 3g and 5g of P407, and dissolve them in 10mL of 1% polidocanol injection to prepare P407-POL solutions with mass concentrations of 0%, 0.5%, 1%, 3% and 5% (W / V). After thoroughly stirring the mixture with a vortex mixer, place it in a refrigerator at 4℃ for 24 hours to obtain a uniform and stable solution.

[0048] (2) Foam preparation: All hardened foams were prepared using the Tessari method. Two 10mL disposable sterile medical syringes were connected using a medical three-way valve. The angle between the two syringes when connected was 90°. The valve at the other end was closed. A certain volume of solution and air was drawn at a liquid-to-air ratio of 1:4. That is, a certain volume of solution was drawn into one syringe and four times the volume of air was drawn into the other syringe. Then, the two syringes were pushed back and forth at a uniform speed 20 times (one syringe pushing back and forth is counted as one time) to obtain foam.

[0049] (3) Record experimental data: When the foam preparation is complete, push all the foam into a syringe, then immediately disconnect the syringe containing all the foam from the T-connector and place it vertically upside down on the test tube rack so that the rubber piston of the syringe is at the bottom. Start timing from this point and record the liquid precipitation time, that is, the time when the liquid phase appears at the bottom of the syringe and can be observed with the naked eye; and the foam half-life time (FHT), that is, the time required for half of the original volume of the hardened solution to return to the liquid state.

[0050] (4) In order to avoid the impact of different experimental conditions on foam stability, the entire experiment was completed by the same person. Each experiment was repeated 5 times, and a new syringe and three-way valve from the same production batch were used before each experiment.

[0051] (5) Statistical analysis: SPSS 26.0 software package was used for statistical analysis of the data. The results of the preliminary experiment showed that the liquid precipitation time and FHT of each group of foam did not conform to the normal distribution. Therefore, the Kruskal-Wallis test was used to detect the difference in data of each group. The significance of the statistical analysis was set as P<0.05.

[0052] Experimental results

[0053] (1) Liquid precipitation time. The liquid precipitation time of foams prepared from 5 groups of solutions was measured, such as... Figure 1 As shown in the figure, the liquid precipitation times for each group were 17.1±1.2s, 26.7±0.9s, 36.9±2.7s, 60.3±3.2s, and 82.9±2.2s, respectively. There was no statistically significant difference between the group with 0.5% P407 and the control group (P>0.05), while the groups with 1%, 3%, and 5% P407 showed statistically significant differences compared to the control group (P<0.05). The liquid precipitation time of the foam produced by each group of solutions increased with increasing P407 concentration.

[0054] (2) Foam half-life. The half-life of FHT prepared from 5 groups of solutions was determined, such as... Figure 2 As shown in the figure, the FHT of polidocanol in the control group without P407 was 143.2±4.2 s. After adding 0.5% P407, it became 191.6±5.1 s, with no statistically significant difference (P>0.05). However, after adding 1%, 3%, and 5% P407, the FHT became 209.4±9.4 s, 301.6±10.8 s, and 400.6±8.4 s, respectively, all of which showed statistically significant differences compared to the control group (P<0.05). Similar to the liquid precipitation time results, the FHT of the foams produced by each group of solutions also increased with increasing P407 concentration, and the foams became finer and more uniform.

[0055] Example 2

[0056] (1) Solution preparation: Accurately weigh 1.9g, 2.0g, and 2.1g of P407, and add them to 10mL of 1% polidocanol injection under ice bath conditions. Use a vortex mixer to thoroughly stir the mixture and then store it in a 4℃ refrigerator for 24 hours to allow it to fully dissolve, thereby preparing homogeneous and stable solutions with P407 mass concentrations of 19%, 20%, and 21% (W / V).

[0057] (2) Foam preparation: Take the prepared solution out of the 4℃ refrigerator and let it stand in the room for 30 minutes to allow the solution to return to the room temperature of 25℃. Then, use the Tessari method to prepare all the temperature-sensitive gel foams. After repeated experiments, the optimal liquid-to-air ratio for preparing foam is found to be 1:1. That is, a certain volume of solution is drawn into one syringe and the same volume of air is drawn into another syringe. Then, the two syringes are pushed back and forth at a uniform speed 50 times to obtain foam.

[0058] (3) Gelation Time: The gelation time of P407-POL thermosensitive gel foams with different mass concentrations was determined using the inverted test tube method. 4 mL of the prepared P407-POL thermosensitive gel foam was transferred into a glass test tube and placed in a constant-temperature water bath at 37.5℃. The test tube was inverted and tilted every 5 seconds, forming a 60° angle with the horizontal plane, to test the foam's fluidity. If the foam did not flow within 5 seconds of inversion, it indicated that gelation had occurred, and this time was recorded as the gelation time. Each experiment was repeated 5 times. After each experiment, the test tubes were cleaned and completely dried. New syringes and three-way valves from the same batch were used for each experiment to prepare the thermosensitive gel foam.

[0059] (4) In vitro dissolution experiment: To study the in vitro drug dissolution behavior of thermosensitive gel foam, 4 mL of prepared P407-POL thermosensitive gel foam of different mass concentrations was placed in a test tube and placed in a constant temperature water bath at 37.5℃ until complete gel formation. The weight of the test tube at this point was measured. Then, 2 mL of physiological saline preheated to 37.5℃ was added to the test tube as the release medium, and the mixture was gently shaken at 75 rpm on a constant temperature shaker at 37.5℃. Every 10 minutes, all the release medium was removed, and the test tube walls were completely dried with filter paper. The weight of the test tube at this point was measured. Then, 2 mL of physiological saline preheated to 37.5℃ was added to the test tube again as the release medium to continue the study. This process was repeated until the weight of the remaining thermosensitive gel foam in the test tube was less than 10% of the initial weight. The degree of dissolution of the thermosensitive gel foam at a specific time was calculated using the following formula:

[0060]

[0061] In the formula, M0 represents the initial weight of the thermosensitive gel foam and the test tube, M tThe weights of the thermosensitive gel foam and the test tube at a specific time point are given, and M is the weight of the empty test tube. Each experiment was repeated three times. After each experiment, the test tubes were cleaned and completely dried. New syringes and three-way valves from the same batch were used to prepare the thermosensitive gel foam for each experiment.

[0062] (5) Analysis of drug binding mechanism: To investigate whether the binding between P407 and polidocanol in the thermosensitive gel foam is physical or chemical, and whether new substances are generated after binding, the prepared P407-POL hydrogel was freeze-dried into powder using a vacuum freeze dryer. Fourier transform infrared spectroscopy was performed on the P407, polidocanol, and freeze-dried hydrogel samples. The Fourier transform infrared spectrometer was started, and transparent thin films of the P407, polidocanol, and freeze-dried hydrogel sample powders were prepared using the potassium bromide pressing method and placed in the sample holder of the instrument. The signal of the blank background was scanned first, and then the signals of the three samples were scanned, recording the values ​​between 4000 and 450 cm⁻¹. -1 Between 1cm -1 The transmittance data were processed using OMNIC software, and Fourier transforms were performed to obtain the infrared spectra of the three samples. The infrared spectra were then merged and the absorption peaks were analyzed using ORIGIN software.

[0063] (6) Statistical analysis: SPSS 26.0 software package was used for statistical analysis of the data. Kruskal-Wallis test was used to detect the differences between the groups. The significance of the statistical analysis was set at P<0.05.

[0064] Experimental results

[0065] (1) Appearance of thermosensitive gel foam at different temperatures. From Figure 3 As can be seen, the P407-POL thermosensitive gel foam is a fluid with good flowability at room temperature (25°C), and the foam can flow under gravity when the test tube is tilted. When the temperature is increased to 37.5°C, it becomes a semi-solid gel. After the test tube is tilted, it remains unchanged and does not flow. The volume change before and after observation by scale is <5%. This indicates that under the specific concentration and synergistic effect of the components in this embodiment, polidocanol is the main foaming agent, while poloxamer 407 is attached to the liquid film surface of the foam. After gelation in the body, the foam volume remains basically unchanged, and poloxamer 407 only becomes semi-solid on the liquid film surface. When the temperature is reduced to 25°C, it can return to the initial fluid state.

[0066] (2) Gelation time. The gelation time of P407-POL thermosensitive gel foams of different concentrations was measured at temperatures ranging from 25℃ to 37.5℃, as follows: Figure 4As shown in the figure. Preliminary experimental results indicate that P407-POL air foam with a mass concentration below 19% cannot form gel foam at 37.5℃; however, when the P407 mass concentration reaches 22% or higher, the P407-POL solution has already formed a semi-solid gel at room temperature. Therefore, a P407 mass concentration range of 19% to 21% is a suitable concentration range for preparing thermosensitive gel foam. The gelation time results show that at 37.5℃, the gelation time required for a P407 mass concentration of 19% is 57.0 ± 5.7 s, the gelation time for a concentration of 20% is 34.0 ± 4.2 s, and the gelation time for a concentration of 21% is 10.0 ± 0.0 s. The gelation time of P407-POL thermosensitive gel foam decreases with increasing P407 concentration.

[0067] (3) In vitro dissolution curves. In vitro dissolution curves of P407-POL thermosensitive gel foams at different concentrations were measured, as shown below. Figure 5 As shown in the results, the 19% concentration of the thermosensitive gel foam achieved a dissolution rate of over 90% after 50 minutes, while the 20% and 21% concentrations only achieved this after 60 minutes. The in vitro dissolution trends of the three concentrations of thermosensitive gel foam were roughly the same, but the higher the P407 concentration, the lower the in vitro dissolution rate.

[0068] (4) Binding mechanisms between components. Infrared spectra of P407, polidocanol, and P407-POL hydrogel were measured, such as... Figure 6 As shown.

[0069] The structural formula of P407 is HO(C2H4O). a (C3H6O) b (C2H4O) a H. Analysis of the infrared spectrum of P407 shows that at 3694 cm⁻¹... -1 The absorption peak appearing nearby originates from the stretching vibration of the hydrogen bond in the OH group, at 2878 cm⁻¹. -1 The absorption peaks appearing nearby correspond to the stretching vibrations of hydrogen bonds in CH, at 1280 and 1108 cm⁻¹. -1 The absorption peaks appearing nearby originate from the stretching vibrations of COC, while those at 1462, 950, and 843 cm⁻¹ are also present. -1 The absorption peaks that appear nearby are caused by the CH bending vibration.

[0070] The structural formula of polidocanol is C 12 H 25 (C2H4O)9OH. In the infrared spectrum of polidocanol, it can be seen that at 3591 cm⁻¹... -1 The absorption peak appearing nearby originates from the stretching vibration of the hydrogen bond in the OH group, at 2863 cm⁻¹.-1 The absorption peaks appearing nearby correspond to the stretching vibrations of hydrogen bonds in CH, at 1296 and 1103 cm⁻¹. -1 The absorption peaks appearing nearby are caused by the stretching vibrations of COC, at 1457, 945, and 852 cm⁻¹. -1 The absorption peaks that appear nearby originate from the bending vibration of CH.

[0071] When comparing the lyophilized sample of P407-POL hydrogel with the infrared spectra of P407 and polidocanol, although characteristic signals of both initial polymers were observable, most of the characteristic signals were closer to those of P407 because P407 had the highest proportion in the final mixture. No new characteristic peaks were found in the infrared spectrum of the P407-POL hydrogel, indicating that no chemical reaction occurred between P407 and polidocanol during hydrogel formation. The two polymers combined physically, without the formation of any new products.

[0072] In summary, the addition of P407 in this invention improves the stability of 1% polidocanol air foam, and this improvement is significantly enhanced when the P407 concentration is greater than 1%. Most importantly, mixing 19-21% P407 with 1% polidocanol produces a temperature-sensitive gel foam curing agent that is flowable at 25°C and non-flowable at 37.5°C. The two components are physically combined without a chemical reaction, and poloxamer 407 adheres only to the surface of the foam's liquid film and does not act as the primary foaming agent. At a P407 concentration of 21%, this temperature-sensitive gel foam curing agent exhibits good flowability at room temperature (25°C) and can be smoothly injected using a syringe with a needle diameter of at least 1.2 mm. Upon injection into a 37.5°C environment, the temperature-sensitive gel foam rapidly forms a gel within 10 seconds and can remain at the lesion site for more than 60 minutes, making it an ideal choice for clinical applications.

Claims

1. An injectable temperature-sensitive gel foam curing agent, characterized in that, Including polidocanol air foam and poloxamer 407; The polycinnarizine air foam comprises 1% (by volume) polycinnarizine solution and air, with poloxamer 407 having a mass-volume fraction of 19%-21% relative to the 1% (by volume) polycinnarizine solution.

2. The injectable temperature-sensitive gel foam curing agent as described in claim 1, characterized in that, The polyoxymethylene air foam is an aggregate of multiple small bubbles, each with a liquid film on its surface; the poloxamer 407 is attached to the surface of the liquid film.

3. The injectable temperature-sensitive gel foam hardener as described in claim 1, characterized in that, The injectable temperature-sensitive gel foam hardener changes from a fluid foam to a semi-solid gel foam at ≥37.5℃.

4. The injectable temperature-sensitive gel foam curing agent as described in claim 3, characterized in that, The injectable temperature-sensitive gel foam curing agent has a cycle of 10.0s-62.7s from flowing foam to semi-solid gel foam at 37.5℃.

5. The injectable temperature-sensitive gel foam curing agent as described in claim 1, characterized in that, The preparation method of the injectable temperature-sensitive gel foam hardener is as follows: S1: Weigh poloxamer 407 and dissolve it in 1% (volume) polycinnamic acid solution to obtain P407-POL solution; S2: Prepare foam from P407-POL solution using the Tessari method, with a liquid-to-gas ratio of 1:4 to 1:1.

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