A clarithromycin taste-masked solid dispersion and a method for preparing the same

Abstract

The application provides a clarithromycin taste-masking solid dispersion and a preparation method thereof, and belongs to the technical field of medicine preparation. TM One or more of HPC; the mass ratio of the clarithromycin and the auxiliary material is 1-2:1-8. The application adopts hot melt extrusion (HME) to prepare a CLA amorphous solid dispersion (SD). By comparing the differences in the Hansen solubility parameters, the polymers used for HME are preliminarily selected to predict the miscibility of the drug and the polymers. E100 is selected as the polymer because it combines the taste-masking effect and the solubility.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical preparation, in particular to a clarithromycin taste-masking solid dispersion and a preparation method thereof. BACKGROUND

[0002] Clarithromycin (CLA) is one of the most commonly used macrolide antibiotics for children, but has the disadvantage of heavy bitter taste and poor solubility. It has a short elimination half-life (2.6-4.4 hours), poor water solubility and reduced bioavailability after oral administration (<55%). Previously, attempts have been made to optimize the release process of CLA, but the problem of limited solubility has still not been effectively solved. Therefore, the use of hot melt extrusion technology can be a good way to overcome the above-mentioned disadvantages associated with CLA.

[0003] Hot melt extrusion (HME) is a continuous process in which a mixture of powdered drugs and excipients is delivered by a heated rotating screw to uniformly mix the materials. Compared with traditional methods, HME has multiple advantages, namely (1) no organic solvents are used, and thus the non-aqueous process is green without solvent residues (2) the intensive mixing of components can promote the uniform dispersion of molecules and the conversion of drugs to amorphous, thereby achieving greater solubility and bioavailability (3) low production cost and small footprint. SUMMARY

[0004] To solve the above problems, the present application provides a clarithromycin taste-masking solid dispersion and a preparation method thereof. The present application uses excipients as carrier materials, so that the release amount of clarithromycin is small, and the bitter taste of clarithromycin is masked.

[0005] To achieve the above-mentioned purposes, the present application provides the following technical solutions:

[0006] The present application provides a clarithromycin taste-masking solid dispersion, which is prepared by hot melt extrusion of clarithromycin and excipients;

[0007] The excipients include E100, EPO and Klucel TM one or more of HPC;

[0008] The mass ratio of the clarithromycin to the excipients is 1: ~ 2: 1 ~ 8.

[0009] Preferably, the mass ratio of the clarithromycin to the excipients is 1:2 ~ 4.

[0010] Preferably, the mass ratio of the clarithromycin to the excipients is 1:1.5.

[0011] The present application also provides a preparation method of the clarithromycin taste-masking solid dispersion according to the above technical solutions, which comprises the following steps:

[0012] mixing the clarithromycin and the excipient to obtain a mixture;

[0013] hot-melt extruding the mixture to obtain a taste-masked solid dispersion of clarithromycin;

[0014] The hot-melt extruding condition comprises: temperature of 130-220℃, rotation speed of 25-100rpm.

[0015] Preferably, the temperature is 150℃.

[0016] Preferably, the temperature is 160-200℃.

[0017] Preferably, the temperature is 180℃.

[0018] Preferably, the rotation speed is 75rpm.

[0019] Preferably, the rotation speed is 50rpm.

[0020] The present application has the following advantages:

[0021] The present application adopts hot-melt extrusion (HME) to prepare CLA amorphous solid dispersion. By comparing the difference of Hansen solubility parameters, the polymer used for HME is preliminarily selected to predict the miscibility of the drug and the polymer. Eudragit® E100 is selected as the polymer because it combines the taste-masking effect and solubility. In addition, this polymer improves the solubility. Orthogonal experiment is adopted to optimize the formulation and process, and the screw rotation speed, extrusion temperature and drug percentage are independent variables, and the content, dissolution rate and extrusion diameter are dependent variables. The best extrusion parameters are as follows: temperature of 150℃, screw rotation speed of 75rpm, mass ratio of clarithromycin and Eudragit® E100 of 1:1.5. Thermogravimetric study confirms the stability of CLA and Eudragit® E100 at the extrusion temperature adopted. Differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) studies on the powdered solid dispersion show that the crystalline CLA is converted into amorphous form. Fourier transform infrared spectroscopy (FTIR) results show that the formation of hydrogen bonds between clarithromycin and the polymer leads to the stabilization of clarithromycin in its amorphous form. Compared with the physical mixture, the dissolution rate study of the HME extrudate extruded using simulated saliva medium shows less release at the end (the less the drug release, the better the taste masking effect). In addition, the in-vitro taste masking evaluation results of the product show that the physical mixture has strong bitter taste compared with the HME formulation, which indicates that Eudragit® E100 has the potential to be used as a taste-masking polymer in the form of melt extrusion. Eudragit® E100 as a taste-masking polymer in the form of melt extrusion has the potential.

[0022] Structure ​​​

[0023] 1. Pure clarithromycin in TGA exhibited a significant thermal event due to drug degradation at around 250°C. The processing temperature in this experiment was below the decomposition temperature, suggesting that the drug did not degrade during extrusion. Figure 4 ).

[0024] 2. The DSC temperature plot of clarithromycin shows an endothermic peak at 229°C corresponding to the drug's melting point. This sharp peak indicates that pure clarithromycin is in crystalline form. The absence of a melting point peak for CLA during the extrusion process indicates the absence of crystalline CLA in the solid dispersion. This may be due to the complete conversion of crystalline CLA to its amorphous form. Figure 5 ).

[0025] 3. PXRD confirmed that no crystallization properties of the drug were observed. The unique peak of E100 confirms its amorphous nature, and the reduced drug crystal behavior can be clearly seen in the PXRD pattern of the solid dispersion. Figure 6 ).

[0026] 4. FTIR confirmed that no crystallization properties of the drug were observed. The unique peak at E100 confirms its amorphous nature. The reduced crystal behavior of the drug is clearly visible in the PXRD pattern of the solid dispersion. Figure 7 ).

[0027] 5. SEM images of pure clarithromycin show the size of the drug crystals. On the other hand, SEM images of the solid dispersion show uniformly dispersed drug particles with enhanced surface area, which is important for representative dissolution and bioavailability in drug delivery. Figure 8 ). Attached Figure Description

[0028] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the accompanying drawings used in the embodiments will be briefly described below.

[0029] Figure 1 Dissolution profiles of clarithromycin solid dispersions under different process formulations and conditions; the lower the drug release in HME particles of clarithromycin formulation, the better the taste masking efficiency of the polymer, which makes... E100 has become an important candidate for HME in developing taste-masking formulations; therefore, polymers with good taste-masking effects were selected. E100 was used to prepare CLA-SD; dissolution curves of clarithromycin solid dispersion with different polymers; dissolution curves of clarithromycin solid dispersion at different temperatures; from Figure 1It can be seen from the figure that the solubility of the obtained extrusion is the highest at a lower temperature of 130℃, which may be related to the fact that CLA cannot be uniformly dispersed at a lower temperature, but when the temperature reaches 160℃, the continuous increase in temperature will increase the solubility and reduce the taste masking effect, therefore, the barrel temperature is set at about 160℃; the dissolution curves of the solid dispersion of clarithromycin at different screw speeds, from Figure 1 It can be seen from the figure that the cumulative solubility is the lowest when the screw speed is 75rpm, indicating that the taste masking effect is better, therefore, the screw speed is set in the range of about 75rpm; the dissolution curves of the solid dispersion of clarithromycin at different proportions. From Figure 1 It can be seen from the figure that when the proportion is 1:1, the release of clarithromycin is the least, proving that the bitterness masking effect is good, and the increase or decrease of the proportion of clarithromycin will reduce the masking effect, therefore, the drug loading is set at about 1:1.

[0030] Figure 2 In (a), the average scores given by the volunteers to CLA, PM and SD, the higher the score, the heavier the bitter taste, it can be seen that CLA and PM (physical mixture) have little effect on improving the bitter taste, and the bitter taste score is significantly reduced after forming SD (solid dispersion) by hot melt extrusion technology, proving that the taste masking effect is obvious, (b) dissolution of CLA, PM and SD. The release of the simulated drug in the oral cavity is significantly lower than that of CLA when SD is formed, indicating that the taste masking effect of clarithromycin bitterness is obvious;

[0031] Figure 3 In (a), the electronic tongue "taste map": signal comparison between CLA, PM and SD (PCA analysis of electrode response), (b) electronic tongue taste radar chart, in Figure 3 (b), the larger the test value, the heavier the bitter taste, it can be seen from the figure that CLA and PM have the strongest bitter taste, and the SD prepared by HME has the smallest bitter taste value, indicating that the masking effect is obvious, the in vitro electronic tongue evaluation is in good agreement with the in vivo test, and the best taste masking formula can be determined. The electronic tongue can prove to be an effective method for developing delicious and pleasant products;

[0032] Figure 4 The pure clarithromycin in the TGA curve shows a significant thermal event at about 250℃ caused by drug degradation, the processing temperature of this experiment is lower than the decomposition temperature, so it can be considered that the drug will not be degraded during the extrusion process;

[0033] Figure 5 The absence of the melting point peak of CLA in the obtained extrusion process indicates that there is no crystalline CLA in the solid dispersion, which may be due to the complete conversion of crystalline CLA to amorphous form;

[0034] Figure 6No unique peaks of Eudragit E100 were observed, thus confirming its amorphous nature. The PM peaks correspond to pure crystalline CLA, but some peaks are weaker, and the decrease in drug crystalline behavior is evident from the PXRD pattern of SD, as all the unique peaks show a decrease in intensity;

[0035] Figure 7 This indicates that there can be hydrogen bonding interactions between CLA and E100 in the HME prepared solid dispersion;

[0036] Figure 8 The SEM image of SD shows uniformly dispersed drug particles with enhanced surface area, which is important for representative solubility and bioavailability in drug delivery;

[0037] Figure 9 Drug release profile of the drug prepared into solid dispersion with different excipients;

[0038] Figure 10 DSC thermogram of the drug prepared into solid dispersion with different excipients. DETAILED DESCRIPTION

[0039] The present application provides a taste-masked clarithromycin solid dispersion prepared by hot melt extrusion of clarithromycin and excipients; the excipients include Eudragit E100, EPO and Klucel TM HPC; the mass ratio of the clarithromycin and E100 is 1-2:1-8. In the present application, the mass ratio of the clarithromycin and excipients is preferably 1:2-4. In the present application, the mass ratio of the clarithromycin and excipients is preferably 1:1.5. The present application does not have special limitations on the source of the clarithromycin, and a conventional commercially available product can be used, such as that purchased from Shengxing Pharmaceutical (China). The present application does not have special limitations on the source of the E100, and in the specific embodiments of the present application, the E100 is derived from Evonik Pharma Polymers (Germany).

[0040] The present application also provides a preparation method of the above-mentioned technical solution of the taste-masked clarithromycin solid dispersion, which comprises the following steps:

[0041] Mixing the clarithromycin and excipients to obtain a mixture;

[0042] Hot melt extruding the mixture to obtain the taste-masked clarithromycin solid dispersion;

[0043] The hot melt extrusion conditions include a temperature of 130-220°C and a rotation speed of 25-100 rpm.

[0044] In the present application, the temperature is preferably 150°C. In the present application, the temperature is preferably 160-200°C, more preferably 180°C. In the present application, the rotation speed is preferably 75 rpm. In the present application, the rotation speed is preferably 50 rpm.

[0045] The present application preferably uses a co-rotating twin-screw extruder (ZSK 25, Coperion, USA) to perform hot melt extrusion on the mixture.

[0046] In order to further illustrate the present application, the present application is described in detail below in conjunction with examples, but they should not be understood as limiting the scope of protection of the present application.

[0047] Example 1

[0048] Clarithromycin (CLA) was purchased from Shengxing Pharmaceutical (China), E100 and EPO was derived from Evonik Pharma Polymers (Germany), cross-linked polyvinylpyrrolidone (PVP VA64) and Klucel TM HPC was donated by Ashland (USA), Soluplus was derived from BASF (Germany), and HPLC solvents were analytical grade and purchased from Quanshi Professional Solvents (China).

[0049] 1. Carrier screening

[0050] In this example, E100 particles release less clarithromycin than pure clarithromycin within the end dissolution time interval in Figure 1 The lower the drug release in the HME particles of the clarithromycin formulation, the better the taste masking efficiency of the polymer, which makes E100 an important candidate for developing taste-masked formulations by HME. Therefore, the polymer E100 with good taste masking effect was selected to prepare CLA-SD.

[0051] PVP VA64, HPC, EPO, Soluplus and E100 were selected as carrier materials and mixed uniformly at a drug material ratio of 1:3 (physical mixture) The lower the drug release in the HME particles of the clarithromycin formulation, the better the taste masking efficiency of the polymer, which makes E100 an important candidate for developing taste-masked formulations by HME. Therefore, the polymer E100 with good taste masking effect was selected to prepare CLA-SD.

[0052] Set the extruder temperature range to 200℃ and the screw speed to 50rpm. After the extruder is turned on, allow it to balance for 60 minutes. Then, feed the physical mixture into the extruder through the feeder. Allow the extrudate to cool and solidify, then crush and sieve it. Finally, dry and store it in a cool, dark place.

[0053] Depend on Figure 9 Therefore, when clarithromycin and different excipients are prepared into solid dispersions using hot melt extrusion technology, different dispersions are obtained due to the different properties of the excipients. Water-soluble carriers increase drug release, thus reducing the masking effect, such as PVP VA64 and Soluplus. Conversely, solid dispersions formed from poorly soluble excipients generally reduce the solubility of clarithromycin, thereby improving the masking effect. For example, eutectic excipients... E100, EPO, HPC)

[0054] Figure 10 The results were obtained by extruding various excipients at the optimal drug-to-material ratio of 1.5:1 and the optimal process parameters of 160℃ and 75rpm. Solid dispersions of different excipients were obtained.

[0055] It can be observed that the endothermic peaks specific to CLA have all disappeared, indicating that a stable solid dispersion has been formed. This suggests that the optimal process parameters are suitable for the preparation of the above excipient solid dispersions.

[0056] 2. Temperature selection

[0057] Generally, higher temperatures provide more heat energy, which is more conducive to the binding of drugs and carriers. However, it should also be considered that high temperatures can degrade drugs and carriers. Figure 1 As can be seen, the solubility of the extruded material is highest at a lower temperature of 130°C. This may be related to the fact that CLA cannot be uniformly dispersed with the carrier at lower temperatures. However, when the temperature reaches 160°C, further increases in temperature will increase solubility but reduce the masking effect. Therefore, the barrel temperature is set at 160°C.

[0058] by Using E100 as a carrier, CLA and E100 was mixed at a drug-to-material ratio of 1:3 (physical mixture). The extrusion temperatures were set at 130℃, 160℃, 180℃, 200℃, and 220℃. When the temperature reached 160℃, further increases in temperature would increase solubility and reduce the masking effect. Therefore, the barrel temperature was set at approximately 160℃. The screw speed was fixed at 50 rpm. After the extruder was started, it was allowed to equilibrate for 60 minutes. The physical mixture was then fed into the barrel through the feeder for extrusion. The extrudate was cooled, shaped, pulverized, sieved, and dried in a cool, dark place for storage.

[0059] 3. Speed ​​Selection

[0060] Screw speed affects the shear force and residence time of the material in the barrel. When the screw speed is too slow, the residence time of the material in the barrel is longer, allowing for more complete absorption of heat energy, but some mechanical energy will also be lost under the action of shear force. Furthermore, for heat-resistant materials, excessive residence time can lead to degradation. If the screw speed is too fast, the drug may not be able to completely melt and mix, but the mechanical energy will be greater. Figure 1 As can be seen, the cumulative solubility is lowest at a screw speed of 75 rpm, indicating a better masking effect. Therefore, the screw speed should be set within the range of 75 rpm.

[0061] by Using E100 as a carrier, CLA and E100 was mixed at a drug-to-material ratio of 1:3 (physical mixture). Screw speeds were set at 25, 50, 75, and 100 rpm. The lowest cumulative solubility was observed at 75 rpm, indicating a better masking effect. Therefore, the screw speed was set within the range of approximately 75 rpm. The extrusion temperature was fixed at 160℃. After the extruder was started and allowed to equilibrate for 60 minutes, the physical mixture was fed into the extruder through a feeder. The extrudate was cooled, shaped, pulverized, sieved, and dried in a cool, dark place for storage.

[0062] 4. Selection of drug-to-material ratio

[0063] from Figure 1 The results show that clarithromycin release is minimal when the ratio is 1:1, demonstrating a good bitterness masking effect. Increasing or decreasing the clarithromycin ratio reduces the masking effect. Therefore, the drug loading ratio is set at 1:1.

[0064] by Using E100 as a carrier, CLA and E100 was mixed uniformly at drug-to-material mass ratios of 2:1, 1:1, 1:2, 1:4, and 1:8 (physical mixture). When the ratio was 1:1, clarithromycin release was minimal, demonstrating good bitterness masking. Increasing or decreasing the clarithromycin ratio reduced the masking effect. Therefore, the drug loading was set at 1:1. The extruder temperature was set to 160℃, and the screw speed was fixed at 75 rpm. After the extruder was started and allowed to equilibrate for 60 minutes, the physical mixture was fed into the extruder through a feeder. The extrudate was cooled, shaped, pulverized, sieved, and dried in a cool, dark place for storage.

[0065] The final prescription was subsequently determined through orthogonal experiments.

[0066] An orthogonal array experimental design was employed to conduct a univariate experimental study. Screw speed, extrusion temperature, and drug percentage were selected as independent variables, while drug content, dissolution rate, and extrusion diameter were selected as dependent variables. The interactions between the independent variables were investigated. Finally, the effect of each variable on the dependent variable and the interactions between the variables were evaluated.

[0067] Table 1 shows that, using simulated saliva dissolution as a quantitative indicator, range R and variance analysis indicate that the order of factors affecting the cumulative dissolution rate of clarithromycin is C>A>B. That is, the primary and secondary factors affecting the cumulative dissolution rate of clarithromycin are the drug loading ratio, barrel temperature, and screw speed. All factors have an impact, but the differences are not significant. The optimal process combination is A1B2C3. The barrel temperature is 150℃, the screw speed is 75 rpm, and CLA and... The ratio of E100 carriers is 1:1.5.

[0068] The optimal conditions are: barrel temperature 150℃, screw speed 75rpm, CLA and The ratio of E100 carriers is 1:1.5.

[0069] Table 1 2 3 Multifactor experimental design.

[0070]

[0071] Table 2 2 3 Results of multi-factor experiment.

[0072]

[0073]

[0074] Example 2

[0075] Bitterness comparison

[0076] 1. Tasting

[0077] Initially, volunteers were asked to taste purified API solutions, pure water (blank), and various solid dispersion solutions (CLA net content 125 mg). After selecting eligible subjects and undergoing a 12–24 hour cleanse period, individuals were randomly (blindly) asked to taste products (CLA, PM, and SD), where PM (physical mixture) and SD (solid dispersion), and were asked to score the various sample solutions. The scoring results showed that clarithromycin had a strong bitter taste, with a mean score of 4.63 ± 0.51.

[0078] The primary method for evaluating the taste of taste-masking agents is to assess their masking effect using a human taste evaluation panel. Typically, a group of healthy volunteers (<20 people) place the drug in their mouths for a period of time (30-60 seconds) before spitting it out. Based on their taste experience, they select different taste levels and rate the effect. The average masking effect is then calculated by combining the results from all participants. Taste levels are generally categorized as "not bitter, slightly bitter, bitter, very bitter, extremely bitter," corresponding to scores of 1, 2, 3, 4, and 5, respectively.

[0079] Table 3 Bitterness Evaluation Criteria

[0080] Bitterness intensity Score Not bitter 1 Slightly bitter 2 Bitter 3 Very bitter 4 Extremely bitter 5

[0081] However, the SD of the optimal formulation prepared by HME is in Figure 2 The average score for (a) was 2.87 ± 0.64. The results of the human panel study confirm that when using... When E100 was used as a taste-masking polymer for HME extrusion, the effective taste-masking effect of clarithromycin was observed. Data analysis showed that both active pharmaceutical ingredients (APIs) had a significant inhibitory effect on bitterness (P<0.05).

[0082] The polymer exhibits effective taste masking ability. Furthermore, the HME formulation also demonstrates excellent CLA masking performance. Figure 2 In (a), sensory data obtained from the panel members showed that SD was significantly more effective at masking odors than pure CLA. This can be attributed to... E100 (pH < 4.5) exhibits pH-dependent solubility properties because healthy human saliva has a pH of 7.4. SD's sensory score is within the taste masking range (below 3), which is considered satisfactory.

[0083] 2. Dissolution rate

[0084] To evaluate the effect of the HME process on CLA taste masking, in vitro dissolution profiles were performed on HME loaded with 450 mg equivalent CLA as an API, and compared with those of HME particles containing a physical mixture (with the same API concentration). The dissolution profiles are shown below. Figure 2 As shown in (b). This result indicates that the solubility of CLA in a salivary environment decreased after SD was prepared using HME, demonstrating that SD has a taste-masking effect. According to the guidelines of the International Federation of Pharmaceutical Associations, dissolution values ​​can be used to determine a rough baseline for bitterness.

[0085] In this study, SD showed significantly reduced solubility compared to pure CLA, indicating reduced drug release in the salivary environment. Figure 2 As shown in (b), the lower the release of the SD drug prepared by HME, the better the taste masking efficiency, which makes... E100 has become an important polymer for HME in developing taste masking formulations. In previous studies, dissolution studies were used as an assessment of taste masking and compared with the results of electronic tongue, and the two assessment methods ultimately reached consistent conclusions.

[0086] 3. Electronic tongue

[0087] A novel in vitro approach to assess the taste masking efficiency of various drug formulations and avoid problems associated with human group members is the use of an array of electronic sensors called an electronic tongue. Other researchers have conducted similar studies, in which principal component analysis (PCA) of products is presented via PCA maps to determine the taste masking efficacy of various components. For the purpose of studying pure CLA, PM and stretched SD were processed as described in the previous section. The taste signals of different samples are represented on taste maps projected based on PCA, as shown in the figure. Figure 3 (a) In this diagram, these figures show the relative redistribution and bitterness proximity for each formulation. According to the figures... Figure 3 As shown in (a), the extruded product (SD) and clarithromycin were well separated, indicating significant differences in distance and taste. Furthermore, the taste profile revealed a significant difference between SD and CLA.

[0088] PM and CLA are very close together, while SD is relatively far from them. This implies a significant evolution in flavor and improved masking for pure CLA. Figure 3 In (b), the higher the experimental value, the stronger the bitterness. The graph clearly shows that CLA and PM have the strongest bitterness, while the SD prepared by HME has the lowest bitterness value, indicating a significant masking effect. The in vitro electronic tongue evaluation showed good agreement with the in vivo test, enabling the determination of the optimal taste masking formulation. The electronic tongue can prove to be an effective method for developing palatable and enjoyable products.

[0089] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. People can obtain other embodiments based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A taste-masked solid dispersion of clarithromycin, characterized in that, prepared by hot-melt extrusion from clarithromycin and an excipient; the excipient is Eudragit® E100; the mass ratio of clarithromycin to excipient is 1:1.5; the preparation method of the clarithromycin taste-masked solid dispersion, comprising the following steps: mixing the clarithromycin and the excipient to obtain a mixture; hot-melt extruding the mixture to obtain the clarithromycin taste-masked solid dispersion; the hot-melt extrusion conditions include: temperature of 150°C, rotation speed of 75 rpm.

Images