Otionium bromide freeze-dried preparation for injection and preparation method of otionium bromide freeze-dried preparation

Abstract

The invention discloses an otiammonium bromide freeze-dried preparation for injection and a preparation method of the otiammonium bromide freeze-dried preparation. The preparation method comprises the following steps: firstly, preparing an otilonium bromide solution from otilonium bromide, an excipient, cyclodextrin, a hydrochloric acid solution and water for injection, filling and then adopting an ultrasonic-assisted freeze-drying technology to obtain the otilonium bromide freeze-dried preparation for injection, and the prepared product is loose, porous, few in appearance defect, good in resolubility and stable in quality.

Description

Technical Field

[0001] The invention relates to a freeze-dried otilonium bromide preparation for injection and a preparation method thereof, and belongs to the technical field of medicine. Background Art

[0002] Otilonium bromide is developed and produced by Menarini, Italy, with the trade name of Spatamine. This compound has the functions of inhibiting calcium ion influx into intestinal smooth muscle cells, antagonizing muscarinic receptors and tachykinin NK2 receptors, and has high selectivity and strong antispasmodic effect on digestive tract smooth muscle. Otilonium bromide can exert a strong antispasmodic effect on the smooth muscle of the distal digestive tract, thereby alleviating irritable bowel or spasmodic pain in the distal digestive tract.

[0003] At present, tablets of otilonium bromide are available on the market, but the tablets are slow to take effect and need to be disintegrated, released and absorbed in the body to exert their therapeutic effects. It usually takes 45 minutes to reach 80% dissolution, which cannot quickly relieve symptoms and brings inconvenience to patients. Patent CN101053562A provides an otilonium bromide capsule, which can be quickly dispersed into small particles within 5 minutes, and the gas dissolution can reach more than 90% within 5 minutes, which can quickly exert a spasmolytic effect. This dosage form can meet the needs of some patients, but for patients with abdominal pain caused by excessive contraction of gastrointestinal smooth muscle and difficulty in eating, it is very necessary to develop a fast-acting and non-oral preparation.

[0004] Drug injections can be developed into water injection preparations and freeze-dried powder preparations. According to the description in patent EP0270503, otilonium bromide is unstable in aqueous solution for a long time. Developing otilonium bromide into a freeze-dried preparation can improve the stability of the preparation and make the product easier to store and transport. However, otilonium bromide has two crystal forms. There may be a crystal form transition process during the dissolution and pre-freezing process, which causes the prescription solution to freeze into a dense glass state, making sublimation drying difficult, and excessive water residue, which leads to a long freeze-drying time; at the same time, the formation of a dense glass state will also make the dried product easy to agglomerate, resulting in unqualified product re-dissolution and affecting product quality. Summary of the invention

[0005] In view of the above problems, the present invention provides a freeze-dried otilonium bromide preparation for injection and a preparation method thereof. The present invention firstly prepares an otilonium bromide solution by using otilonium bromide, an excipient, cyclodextrin, a hydrochloric acid solution and water for injection, and then obtains the freeze-dried otilonium bromide preparation for injection by using an ultrasonic-assisted freeze-drying technology after filling. The prepared product is loose and porous, has few appearance defects, good resolubility and stable quality.

[0006] The technical scheme of the present invention is: a freeze-dried otilonium bromide preparation for injection, characterized in that its components and weight portions are: 5-30 parts of otilonium bromide, 10-20 parts of excipients, 80-90 parts of cyclodextrin, and pH 6.0-7.0.

[0007] Furthermore, the excipient is at least one of mannitol, sucrose and trehalose, preferably a combination of any two.

[0008] Furthermore, the cyclodextrin is at least one of α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin.

[0009] Furthermore, the present invention is obtained by using ultrasonic-assisted freeze-drying technology, and the raw materials and weight portions used are: 5-30 parts of otilonium bromide, 10-20 parts of excipients, 80-90 parts of cyclodextrin, hydrochloric acid solution adjusted to pH 6.0-7.0, and an appropriate amount of water for injection.

[0010] Further, the preparation method thereof:

[0011] 1) Preparation of Otilonium Bromide Solution

[0012] Add cyclodextrin and excipients to water for injection, stir and dissolve, and then disperse evenly; then add hydrochloric acid solution to adjust the pH to 6.0-7.0, then add otilonium bromide, add water for injection to make up the volume, stir and disperse evenly, and then sterilize and filter;

[0013] 2) Filling

[0014] The filtered otilonium bromide solution is divided into vials by a filling machine, half-stoppered, and put into a box for freeze drying;

[0015] 3) Freeze-drying

[0016] First, cool down to 0~-10℃ and keep warm for 50~70min; then cool down to -30~-40℃, turn on ultrasound intermittently during the cooling process, and keep warm for 210~360min; control the vacuum degree to 0.3~0.5mbar, heat up to -10~-15℃, turn on ultrasound intermittently during the heating process, and keep warm for 480~540min; control the vacuum degree to 0.1~0.2mbar, heat up to 15~25℃, turn on ultrasound intermittently during the heating process, and keep warm for 120~270min;

[0017] 4) After freeze-drying, the sample is taken out of the box to obtain the freeze-dried preparation of otilonium bromide for injection.

[0018] Furthermore, ultrasound is intermittently turned on, and the ultrasound conditions are: 15-30 KHz, turned on for 2-5 minutes, and stopped for 8-25 minutes.

[0019] Common excipients such as mannitol, sucrose and trehalose are used as freeze-dried preparations. Due to their high phase separation and crystallization tendency during the freeze-drying process, this property makes this type of excipient very easy to co-crystallize with the compound olbromidrium, resulting in the formation of crystal water in the freeze-dried product. The crystal water is very difficult to remove in the formed skeleton structure, resulting in defects such as re-dissolution and collapse in the obtained product. Therefore, the present invention adopts the method of adding a cyclic oligosaccharide in the freeze-drying process. Due to its amphiphilicity, it can act as a surfactant as well as an amorphous filler. In addition, the common excipients are easy to crystallize to form a freeze-dried skeleton during the freeze-drying process, and the ultrasonic-assisted freeze-drying technology is combined to obtain a sample with few appearance defects, good resolubility, and loose porosity.

[0020] The technical effect of the present invention is: otilonium bromide solution is prepared by using otilonium bromide, excipient, cyclodextrin, hydrochloric acid solution and water for injection, and after filling, ultrasonic assisted freeze drying technology is used to obtain a freeze-dried otilonium bromide preparation for injection. Experiments have shown that the product prepared by the present invention is loose and porous, has few appearance defects, has good re-solubility, and the quality of the freeze-dried otilonium bromide preparation for injection prepared under accelerated storage conditions is stable. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 Appearance picture of the freeze-dried preparation of otilonium bromide for injection prepared for prescription 1-1;

[0022] Figure 2 Appearance picture of the lyophilized preparation of otilonium bromide for injection prepared for prescription 1-2;

[0023] Figure 3 Appearance picture of the freeze-dried preparation of otilonium bromide for injection prepared for prescription 1-3;

[0024] Figure 4 Appearance picture of the freeze-dried otilonium bromide for injection prepared for prescription 1-4;

[0025] Figure 5 This is a picture of the appearance of the freeze-dried otilonium bromide preparation for injection prepared in Example 2;

[0026] Figure 6 This is a picture of the appearance of the freeze-dried otilonium bromide preparation for injection prepared in Example 3;

[0027] Figure 7 This is a picture of the appearance of the freeze-dried otilonium bromide preparation for injection prepared in Example 4. DETAILED DESCRIPTION

[0028] In order to more clearly describe the purpose, technical solutions and advantages of the present invention, the present invention is further explained in conjunction with embodiments.

[0029] Example 1: Prescription Screening

[0030] Table 1: Prescription screening of lyophilized otilonium bromide for injection

[0031]

[0032] The preparation method is as follows:

[0033] 1) Preparation of Otilonium Bromide Solution

[0034] Control the temperature at 10-20°C, add 80% of the water for injection into a beaker, then add the prescribed amount of cyclodextrin and excipients (mannitol, sucrose, trehalose, added according to the prescription), stir to dissolve, and then use a cantilever high-speed disperser to disperse for 20 minutes at a speed of 800 rpm.

[0035] After adjusting the pH of the solution to 6.0-7.0 with 1M HCl, add the prescribed amount of otilonium bromide under stirring, and add water for injection to make the volume to 1000 ml. Use the high-speed disperser again to disperse at high speed for 15 minutes at a speed of 500 rpm.

[0036] After dispersion is completed, the solution is sterilized and filtered through a 0.22 μm filter and waits for filling.

[0037] 2) Filling

[0038] The filtered otilonium bromide solution was dispensed into 10 ml vials by a filling machine, half-stoppered, and put into a freezer for freeze drying.

[0039] 3) Freeze-drying

[0040] The temperature was lowered to 0°C in 30 minutes and kept warm for 60 minutes. The temperature was lowered to -40°C in 40 minutes, and ultrasonic waves were intermittently turned on during the cooling process (15KHz, turned on for 2 minutes, stopped for 8 minutes), and then kept warm for 240 minutes. The vacuum degree was controlled to be 0.3-0.5mbar, and the temperature was raised to -10°C in 30 minutes. Ultrasonic waves were intermittently turned on during the heating process (25KHz, turned on for 2 minutes, stopped for 13 minutes), and kept warm for 480 minutes. The vacuum degree was controlled to be 0.14mbar, and the sample was heated to 15-25°C within 30 minutes. Ultrasonic waves were intermittently turned on during the heating process (30KHz, turned on for 5 minutes, stopped for 25 minutes), and kept warm for 120 minutes.

[0041] 4) After freeze-drying, the sample is pressed out of the box to obtain the freeze-dried otilonium bromide preparation for injection.

[0042] Prescription screening results:

[0043] 1) The sample prepared under the conditions of prescription 1-1 showed floating and re-dissolving phenomena. It may be that the crystal form of otilonium bromide changed during the pre-freezing process, causing the prescription solution to freeze into a dense glass state. The prescription contained more mannitol and sucrose and did not contain cyclodextrin. The skeleton formed during the freeze-drying process may form a eutectic compound, resulting in more residual water during the sublimation drying process, which caused the product to re-dissolve after freeze-drying (see Figure 1 );

[0044] 2) The sample prepared under the conditions of prescription 1-2 collapsed. It is possible that the crystal form of otilonium bromide changed during the pre-freezing process, causing the prescription solution to freeze into a dense glass state. During the sublimation drying process, the product agglomerated, causing the freeze-dried product to collapse (see Figure 2 );

[0045] 3) The samples prepared under the conditions of prescription 1-3 showed shrinkage. It is possible that the skeleton of the samples collapsed during the freeze-drying process due to the presence of only one cyclodextrin and otilonium bromide solution, which caused the product to shrink (see Figure 3 );

[0046] 4) The samples prepared under the conditions of prescription 1-4 are loose and porous, with few appearance defects (see Figure 4 ), which is the best prescription. It can be seen that the excipient and cyclodextrin need to be coordinated, and the amount of excipient needs to be reduced and the amount of cyclodextrin needs to be increased to obtain a sample that meets the requirements.

[0047] Embodiment 2:

[0048] Table 2: Formula of Otilonium Bromide Lyophilized Preparation for Injection in Example 2

[0049] raw material Dosage Otilonium Bromide 20g sucrose 10g Mannitol 10g Cyclodextrin (β-cyclodextrin) 80g 1M HCl Adjust pH to 6.0-7.0 Water for injection Make up to 1000ml

[0050] Example 2 The formula of the lyophilized otilonium bromide preparation for injection is shown in Table 2, and its preparation method is as follows:

[0051] Steps 1), 2) and 4) are the same as those in Example 1.

[0052] Step 3) Different freeze-drying processes were used for investigation:

[0053] Freeze-drying process 1: control the temperature to -10°C for 60 minutes and keep it warm for 60 minutes; control the temperature to -30°C for 40 minutes, turn on the ultrasound intermittently during the cooling process (15KHz, turn on for 2 minutes, stop for 8 minutes), and keep it warm for 240 minutes; control the vacuum degree to 0.3-0.5mbar, control the temperature to -15°C for 45 minutes, turn on the ultrasound intermittently during the heating process (25KHz, turn on for 2 minutes, stop for 13 minutes), and keep it warm for 480 minutes; control the vacuum degree to 0.14mbar, heat the sample to 15-25°C within 30 minutes, turn on the ultrasound intermittently during the heating process (30KHz, turn on for 5 minutes, stop for 25 minutes), and keep it warm for 120 minutes.

[0054] Freeze-drying process 2: control the temperature to -10℃ for 60min and keep it warm for 60min; control the temperature to -30℃ for 40min and keep it warm for 240min; control the vacuum degree to 0.3-0.5mbar, control the temperature to -15℃ for 45min and keep it warm for 480min; control the vacuum degree to 0.14mbar, raise the temperature of the sample to 15-25℃ within 30min and keep it for 120min.

[0055] Conclusion: The sample prepared by freeze-drying process 1 under the conditions of this example is loose and porous, with few appearance defects (see Figure 5 ), the sample obtained in freeze-drying process 2 was partially melted, so the subsequent freeze-drying process adopted ultrasonic assisted freeze-drying technology.

[0056] Embodiment 3:

[0057] Table 3: Formula of Otilonium Bromide Lyophilized Preparation for Injection in Example 3

[0058]

[0059]

[0060] Example 3 The formula of the lyophilized otilonium bromide preparation for injection is shown in Table 3, and its preparation method is the same as that of Example 2. Conclusion: The sample prepared under the conditions of this example is loose and porous, with few appearance defects (see Figure 6 ).

[0061] Embodiment 4:

[0062] Table 4: Formula of Otilonium Bromide Lyophilized Preparation for Injection in Example 4

[0063] raw material Dosage Otilonium Bromide 20g sucrose 5g Trehalose 5g Cyclodextrin (β-cyclodextrin) 90g 1M HCl Adjust pH to 6.0-7.0 Water for injection Make up to 1000ml

[0064] The formula of the lyophilized otilonium bromide preparation for injection of Example 4 is shown in Table 4, and its preparation method is as follows:

[0065] Steps 1), 2) and 4) are the same as those in Example 1.

[0066] Step 3) Freeze-drying process: control the temperature to -10°C for 60 minutes and keep it warm for 60 minutes; control the temperature to -40°C for 30 minutes, intermittently turn on the ultrasound during the cooling process (15KHz, turn on for 2 minutes, stop for 8 minutes), and keep it warm for 360 minutes; control the vacuum degree to 0.3-0.5mbar, control the temperature to -10°C for 30 minutes, intermittently turn on the ultrasound during the heating process (25KHz, turn on for 2 minutes, stop for 13 minutes), and keep it warm for 480 minutes; control the vacuum degree to 0.14mbar, heat the sample to 15-25°C within 30 minutes, intermittently turn on the ultrasound during the heating process (30KHz, turn on for 5 minutes, stop for 25 minutes), and keep it warm for 240 minutes.

[0067] Conclusion: The samples prepared under the conditions of this example are loose and porous, with few appearance defects (see Figure 7 ).

[0068] Then, the samples of Examples 1-4 (the best recipe of Examples 1-4 is selected in Example 1, the same below) are tested respectively, as shown below.

[0069] 1. pH and moisture detection

[0070] The pH and moisture content of the samples of Examples 1-4 were tested according to the standards of the Chinese Pharmacopoeia 2020 edition, and the test results are shown in Table 5. The pH was 6.0-7.0, and the water content was up to 3.01%.

[0071] Table 5: pH and moisture test results of samples of Examples 1-4

[0072] Example pH Moisture Example 1 6.89 2.13％ Example 2 6.02 1.89％ Example 3 6.16 3.01％ Example 4 6.70 2.56％

[0073] 2. Check the resolubility results

[0074] The samples of Examples 1-4 were tested for resolubility, and the results are shown in Table 6.

[0075] Table 6: Resolubility test results of samples from Examples 1-4

[0076]

[0077] Conclusion: According to the test results in Table 6, otilonium bromide for injection has good resolubility and stability.

[0078] 3. Otilonium bromide stability storage results

[0079] Otilonium bromide contains known impurities and contains an ester group, which may degrade during the stability storage process to form impurity I, the structure of which is shown below:

[0080]

[0081] The related substances of the samples of Examples 1-4 under accelerated placement conditions were detected using the following chromatographic conditions: HPLC chromatographic conditions: Hypersil TM ODS C 18 Chromatographic column (4.6×250mm, 5μm); buffer salt-methanol (30:70) as mobile phase, pH 6, wherein the buffer salt is: 0.5mol / L sodium acetate trihydrate solution containing 5mmol / L sodium 1-heptanesulfonate; flow rate: 1.0ml per minute; detection wavelength: 254nm; column temperature: 30℃; injection volume: 10μl.

[0082] Table 7: Related substance detection results of samples of Examples 1-4 under accelerated placement conditions

[0083]

[0084]

[0085] The test results are shown in Table 7. Conclusion: Under the accelerated storage condition, the degradation impurity (impurity I) of otilonium bromide for injection increased slightly, but the result was still less than 0.1%, which met the requirements, and other impurities did not change significantly, indicating that the quality of the prepared otilonium bromide for injection freeze-dried preparation was stable and met the requirements.

Claims

1. A freeze-dried preparation of otilonium bromide for injection, characterized in that: The components and weight proportions thereof are: 5-30 parts of otilonium bromide, 10-20 parts of excipients, 80-90 parts of cyclodextrin, and pH value of 6.0-7.

0.

2. The otilonium bromide lyophilized preparation for injection according to claim 1, characterized in that: The excipient is at least one of mannitol, sucrose and trehalose.

3. The otilonium bromide lyophilized preparation for injection according to claim 1, characterized in that: The cyclodextrin is at least one of α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin.

4. The method for preparing the freeze-dried otilonium bromide for injection according to any one of claims 1 to 3, characterized in that: The preparation is obtained by adopting ultrasonic-assisted freeze-drying technology. The raw materials and weight portions thereof are: 5-30 parts of otilonium bromide, 10-20 parts of excipients, 80-90 parts of cyclodextrin, a hydrochloric acid solution adjusted to pH 6.0-7.0, and an appropriate amount of water for injection.

5. The preparation method according to claim 4, characterized in that: 1) Preparation of Otilonium Bromide Solution Add cyclodextrin and excipients to water for injection, stir and dissolve until uniformly dispersed; then add hydrochloric acid solution to adjust pH to 6.0-7.0, then add otilonium bromide, add water for injection to make up to volume, stir and disperse until uniformly dispersed, and then sterilize and filter; 2) Filling The filtered otilonium bromide solution is divided into vials by a filling machine, half-stoppered, and put into a box for freeze drying; 3) Freeze-drying First, cool down to 0~-10℃ and keep warm for 50~70min; then cool down to -30~-40℃, turn on ultrasound intermittently during the cooling process, and keep warm for 210~360min; control the vacuum degree to 0.3~0.5mbar, heat up to -10~-15℃, turn on ultrasound intermittently during the heating process, and keep warm for 480~540min; control the vacuum degree to 0.1~0.2mbar, heat up to 15~25℃, turn on ultrasound intermittently during the heating process, and keep warm for 120~270min; 4) After freeze-drying, the sample is taken out of the box to obtain the freeze-dried preparation of otilonium bromide for injection.

6. The preparation method according to claim 5, characterized in that: The intermittent ultrasound is started under the following conditions: 15-30 KHz, started for 2-5 minutes, and stopped for 8-25 minutes.

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