A dry suspension containing tigoprazan and hydrotalcite, and its preparation method and application

Abstract

The present invention relates to the technical field of pharmaceutical preparations, and specifically relates to a dry suspension containing tigolacine and hydrotalcite, and a preparation method and application thereof. The dry suspension contains the following components in parts by weight: 300-500 parts of hydrotalcite, 50 parts of tigolacine, 354-584 parts of filler, 40-70 parts of disintegrant, 10 parts of stabilizer, 10 parts of suspending agent, 1 part of flavoring agent, and 5 parts of lubricant, and is obtained by dry granulation. The present invention inhibits gastric acid secretion by inhibiting H + / K + -ATPase by tigolacine and neutralizes gastric acid by hydrotalcite. The combined use achieves a synergistic effect, can more effectively relieve related symptoms such as reflux esophagitis, has a quick effect and few side effects.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and particularly relates to a dry suspension containing tigolacine and hydrotalcite, and a preparation method and application thereof. Background Art

[0002] Reflux esophagitis is a common digestive system disease, which refers to the reflux of gastric contents into the esophagus, resulting in chronic inflammation caused by damage to the esophageal mucosa. In severe cases, it can lead to esophageal ulcers, strictures, and even canceration. Its typical symptoms are heartburn and reflux. The disease is prone to recurrence, and the symptoms of many patients at night cannot be controlled, seriously affecting the quality of life and physical health. The prevalence of this disease in the general population is as high as 6.4%. Currently, the commonly used clinical treatment methods include drug treatment and lifestyle changes. However, the existing drug treatment methods still have certain limitations, such as side effects, drug resistance and other problems. Therefore, the development of new, safe and effective drugs is an important direction for the treatment of reflux esophagitis.

[0003] As a novel mechanism acid-suppressing drug, tigolacine reversibly binds to H + / K + -ATPase by competing with potassium ions, and can simultaneously inhibit both its resting and activated states, thereby persistently inhibiting gastric acid secretion. Compared with traditional acid-suppressing drugs such as proton pump inhibitors (PPIs), it shows more advantages in clinical practice. According to clinical studies: tigolacine has a fast onset of action in Chinese subjects, with a rapid onset within 30 minutes, while other acid-suppressing drugs generally take 1.5 to 4 hours to take effect. At the same time, tigolacine is more convenient to take, not affected by the eating time and metabolic genotype, bringing a more convenient choice for patients with a busy work and fast-paced life.

[0004] Hydrotalcite is a white or off-white granular powder, odorless and tasteless. Its pharmacological action is to neutralize gastric acid. It is mainly applicable to acute and chronic gastritis, reflux esophagitis, peptic ulcer, heartburn and gastric discomfort related to gastric acid, and can relieve symptoms such as gastric pain, acid reflux, nausea, vomiting, abdominal distension caused by excessive gastric acid.

[0005] Hydrotalcite is an antacid, and it has the following several functions: 1) Neutralize gastric acid and can treat gastric inflammation or ulcers caused by excessive gastric acid secretion; 2) Maintain the gastric pH and keep the gastric pH between 3 and 5; 3) Adsorption and binding effect, hydrotalcite can directly inhibit the activity of pepsin by adsorbing and binding it, which is beneficial to the repair of the ulcer surface; 4) Hydrotalcite can stimulate the gastric mucosa, increase the synthesis of prostaglandin E2, and enhance the protection of the gastric mucosa.

[0006] Patent application CN115209875A discloses a pharmaceutical composition for delayed release of ticlopidine and immediate release of clopidogrel, the dosage forms of which include tablets, granules and capsules. However, this method is only suitable for improving the stomach discomfort caused by taking clopidogrel, and is not suitable for common stomach diseases.

[0007] Patent application CN117159461A discloses a hydrotalcite suspension and preparation method, which has a simple prescription and an efficient preparation process. Patent CN115569146A discloses an oral suspension of hydrotalcite, which combines simethicone, hydrotalcite and omeprazole, and has good stability and embedding effect, but its therapeutic effect is unknown.

[0008] Currently, there is no dry suspension combining tigolaxant and aluminum carbonate on the market, so it is necessary to study the mechanism of the combination of the two drugs in order to obtain a composite dry suspension with higher stability, bioavailability and better efficacy. Summary of the invention

[0009] The purpose of the present invention is to provide a tigolasan aluminum carbonate dry suspension and a preparation method and application thereof. The dry suspension is prepared by mixing tigolasan and aluminum carbonate in a certain proportion and then dry granulating the mixture. + / K + -ATPase to inhibit gastric acid secretion and aluminum carbonate magnesium to neutralize gastric acid. The combined use can achieve a synergistic effect, which can more effectively relieve reflux esophagitis and other related symptoms with rapid effects and few side effects.

[0010] To achieve the above object, the present invention provides a dry suspension containing teoglasan and hydrotalcite, which comprises the following components by weight: 300-500 parts of hydrotalcite, 50 parts of teoglasan, 354-584 parts of filler, 40-70 parts of disintegrant, 10 parts of stabilizer, 10 parts of suspending agent, 1 part of flavoring agent and 5 parts of lubricant.

[0011] Tigorazine reversibly inhibits H by competing with potassium ions. + / K + -ATPase, thereby inhibiting gastric acid secretion; aluminum carbonate can be quickly converted into aluminum hydroxide and magnesium hydroxide in the stomach, which can exert a fast, mild and long-lasting anti-acid effect. The combined use of tigolasan and aluminum carbonate can produce a synergistic effect and improve the therapeutic effect. At the same time, the new mechanism of action of tigolasan can effectively reduce gastric acid secretion and alleviate gastroesophageal reflux symptoms; aluminum carbonate can neutralize gastric acid and protect the gastric mucosa. The combination of the two can treat reflux esophagitis from different mechanisms and improve the efficacy. The combination of the two drugs can reduce gastric acid secretion while relieving symptoms such as heartburn, acid reflux, nausea, vomiting, and abdominal distension caused by excessive gastric acid, treating both the symptoms and the root causes, and quickly relieving symptoms.

[0012] Furthermore, the filler is anhydrous lactose, the disintegrant is sodium carboxymethyl starch, the stabilizer is colloidal silicon dioxide, the suspending agent is xanthan gum, the flavoring agent is sucralose, and the lubricant is magnesium stearate.

[0013] Furthermore, by weight parts, the dry suspension containing tigolacine and hydrotalcite contains the following components: 300 - 500 parts of hydrotalcite, 50 parts of tigolacine, 354 - 584 parts of anhydrous lactose, 40 - 70 parts of sodium carboxymethyl starch, 10 parts of colloidal silicon dioxide, 10 parts of xanthan gum, 1 part of sucralose, 5 parts of magnesium stearate, and the total amount is 1000 parts.

[0014] Furthermore, by weight parts, the dry suspension containing tigolacine and hydrotalcite contains the following components: 500 parts of hydrotalcite, 50 parts of tigolacine, 384 parts of anhydrous lactose, 40 parts of sodium carboxymethyl starch, 10 parts of colloidal silicon dioxide, 10 parts of xanthan gum, 1 part of sucralose, 5 parts of magnesium stearate. Under this preferred formulation, hydrotalcite has good stability. After being compounded with tigolacine, it can effectively improve the stability of tigolacine and extend its shelf life. Hydrotalcite can also promote the dissolution and absorption of tigolacine in vivo, improve the bioavailability of tigolacine, and thus improve the therapeutic effect.

[0015] The present invention also provides a preparation method of the dry suspension containing tigolacine and hydrotalcite, which includes the following steps:

[0016] (1) Crushing to make the particle size of tigolacine satisfy D90 = 10 - 40 μm and the particle size of hydrotalcite satisfy D90 = 5 - 50 μm; passing anhydrous lactose through an 80 - mesh sieve.

[0017] (2) Mixing hydrotalcite, tigolacine, anhydrous lactose, sodium carboxymethyl starch, colloidal silicon dioxide, xanthan gum, and sucralose to obtain mixed powder 1; adding magnesium stearate to mixed powder 1 and mixing to obtain mixed powder 2.

[0018] (3) Adding mixed powder 2 to a dry granulator for dry granulation, sieving, and obtaining the sized dry suspension granules for granule filling.

[0019] Furthermore, in step (1), after crushing, the particle size of tigolacine satisfies D90 = 15 μm and the particle size of hydrotalcite satisfies D90 = 10 μm.

[0020] Furthermore, in step (2), the mixing is carried out in a hopper mixer at a rotation speed of 10 rpm for 20 min to obtain mixed powder 1; adding magnesium stearate to mixed powder 1 and mixing at a rotation speed of 10 rpm for 5 min to obtain mixed powder 2.

[0021] Further, in step (3), the pressure of the pressing wheel of the dry granulator is 3 - 5 MPa, the gap between the pressing wheels is 1 - 2 mm, the rotation speed of granulation is 400 - 600 rpm, and the aperture of the sieve for sieving is 1.25 - 1.5 mm.

[0022] The present invention also provides the application of the above dry suspension containing tigecycline and hydrotalcite. The dry suspension is used to prepare a drug for treating reflux esophagitis, gastric acid, gastritis, and / or gastric ulcer, and has a significantly better therapeutic effect on reflux esophagitis than the drugs in the prior art.

[0023] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0024] 1. By combining tigecycline and hydrotalcite, the present invention treats reflux esophagitis from different mechanisms, treating both the symptoms and the root cause, quickly relieving symptoms, and improving the curative effect. The dry suspension adopted by the present invention is convenient for transportation, carrying, and taking, has good stability, fast absorption, and high bioavailability, and can exert the drug efficacy faster and better in the body.

[0025] 2. Good stability: Hydrotalcite has good stability. After being compounded with tigecycline, it can effectively improve the stability of tigecycline and extend its shelf life.

[0026] 3. High bioavailability: Hydrotalcite can promote the dissolution and absorption of tigecycline in the body, improve the bioavailability of tigecycline, and thus improve the therapeutic effect.

[0027] 4. Simple preparation process: The present invention adopts dry granulation, which is convenient to operate and is conducive to industrial production. Specific embodiments

[0028] The present invention will be further explained and illustrated below through specific examples and comparative examples, but this is not a limitation on the scope of protection requested by the claims of the present invention. Those skilled in the art can make any modifications, equivalent replacements, or improvements based on the basic idea of the present invention, and all should be included in the protection scope of the present invention.

[0029] The tigecycline raw material used in the present invention is sourced from Shandong Luoxin Pharmaceutical Group Hengxin Pharmaceutical Co., Ltd. (registration number Y20200000121), and the hydrotalcite raw material is sourced from Hunan Jiudian Hongyang Pharmaceutical Co., Ltd. (registration number Y20190021360). The excipients used in the following examples and comparative examples are all commercially available excipients, meeting the pharmaceutical, injectable standards, or pharmacopoeia standards.

[0030] Examples 1 - 3 and Comparative Examples 1 - 3

[0031] A tigecycline hydrotalcite dry suspension, the composition of which is shown in the formula in Table 1. The preparation method is as follows:

[0032] (1) Pulverize to make the particle size D90 of tigecycline = 15 μm, the particle size D90 of hydrotalcite = 10 μm; anhydrous lactose is passed through an 80-mesh sieve.

[0033] (2) Put the raw and auxiliary materials except magnesium stearate into a hopper mixer, rotate at 10 rpm, and mix for 20 min to obtain mixed powder 1; add magnesium stearate to mixed powder 1, rotate at 10 rpm, and mix for 5 min to obtain mixed powder 2.

[0034] (3) Add mixed powder 2 to a dry granulator for dry granulation, control the pressure of the pressing wheel at 3 - 5 MPa, the gap of the pressing wheel at 1 - 2 mm, pass the pressed cake after dry pressing through a sizing machine, the sizing rotation speed is 400 - 600 rpm, and the screen aperture is 1.3 mm, and perform granule filling on the sized dry suspension granules.

[0035] Table 1: Prescription information table of examples and comparative examples (single-dose dosage / mg)

[0036]

[0037]

[0038] I. Content uniformity and stability investigation

[0039] (1) Content uniformity investigation

[0040] Take the dry suspension samples at the granule filling stage of Examples 1 - 3 and Comparative Examples 1 - 3, sample according to the "Technical Guidelines for the Study of Mixing Uniformity and In-Process Dosage Unit Uniformity of Chemical Oral Solid Preparations", with a total of 20 sampling points in the whole batch, and 7 dosage unit samples are taken at each sampling point. According to the content uniformity inspection method in General Chapter 0941 of the Fourth Part of the Chinese Pharmacopoeia 2020 Edition, detect the content uniformity of the samples.

[0041] Table 2: Content uniformity test results of Examples 1 - 3 and Comparative Examples 1 - 3

[0042] Sample Average content % (n = 140) L = A + 2.2S Standard Average content = 100% ± 10% L = A + 2.2S ≤ 20 Example 1 101.12 1.31 Example 2 99.81 1.76 Example 3 99.13 2.33 Comparative Example 1 99.32 7.16 Comparative Example 2 98.49 2.45 Comparative Example 3 99.95 1.79

[0043] It can be seen from the data in Table 2 that the average content and content uniformity of Examples 1 - 3 and Comparative Examples 1 - 3 all meet the requirements, that is, the API is evenly distributed in the granules, indicating that the mixing process and the dry granulation process meet the requirements of uniform particle distribution.

[0044] (2) Stability investigation

[0045] The dry suspensions of Examples 1 to 3 and Comparative Examples 1 to 3 were sampled for long-term stability (temperature 25 ± 2°C, relative humidity 60 ± 10%), and the changes in their sedimentation volume ratio, redispersibility, dissolution, content, and related substances were recorded.

[0046] The specific test procedure is as follows:

[0047] Method for measuring the sedimentation volume ratio: Disperse 1000 mg of dry suspension granules in 9 ml of water, shake well and place in a graduated cylinder. Measure the volume V0 (H0) of the suspension. After standing for a certain time, observe the volume V (H) of the sediment when the sedimentation surface no longer changes. The sedimentation volume ratio F = V / V0 = H / H0. The Chinese Pharmacopoeia (2020 Edition) stipulates that for oral suspensions, the F value shall not be less than 0.90 after standing for 3 h.

[0048] Method for measuring redispersibility: Invert and flip the suspension that has been standing for 90 min after measuring the sedimentation volume ratio (±180° is one time), and record the number of flips required for the sediment at the bottom of the test tube to be completely redispersed. If the required number is 1 time, the redispersibility is 100%. Thereafter, for each additional time, the redispersibility decreases by 5%.

[0049] Method for measuring dissolution data: Determine by the paddle method as specified in General Chapter 0931 Dissolution and Release in the Fourth Part of the Chinese Pharmacopoeia (2020 Edition). Take 1 g of the dry suspensions of Examples 1 - 3 respectively, disperse in 9 ml of water, and then add them to 900 ml of hydrochloric acid solution with pH 1.2 respectively. The stirring paddle speed is 50 rpm. Sample and replenish the liquid at the predetermined time. The samples taken are filtered through a 0.45 μm microporous membrane filter, and the content of tigolacine is determined by high performance liquid chromatography after adding an appropriate amount of internal standard substance to the filtrate.

[0050] Table 3: Stability test results of Examples 1 to 3 and Comparative Examples 1 to 3

[0051]

[0052] It can be seen from the data in Table 3 that the sedimentation volume ratio and redispersibility of Examples 1 - 3 meet the requirements, and the properties are stable under long-term sampling conditions; the sedimentation volume ratio and redispersibility of Comparative Examples 1 - 3 do not meet the requirements, that is, too high a proportion of hydrotalcite, too high a proportion of anhydrous lactose, or too low a proportion of sodium carboxymethyl starch in the dry suspension will affect the sedimentation volume ratio and redispersibility of the suspension, thus affecting the quality of the product.

[0053] Table 4: Changes in dissolution of Examples 1 - 3 over time

[0054]

[0055] As can be seen from the data in Table 4, the cumulative dissolution of the samples of Examples 1-3 in the pH 1.0 medium within 15 minutes over 0-6 months was greater than 85%, belonging to rapid dissolution.

[0056] Table 5: Content changes of Examples 1-3 over time

[0057]

[0058] Table 6: Changes in the related substance content of Examples 1-3 over time

[0059]

[0060] As can be seen from the data in Table 5 and Table 6, the content and related substances of Examples 1-3 meet the requirements under long-term storage conditions, indicating that the dry suspension of the present invention has stable properties and a low risk of degradation under long-term storage conditions.

[0061] II. Clinical efficacy observation

[0062] Sixty patients with reflux esophagitis diagnosed as LA grades A / B / C / D by endoscopic examination were selected as subjects. They were randomly divided into two groups at a ratio of 1:1 (the ratio of patients with grades A, B, C, and D in the two groups, as well as the ratio of the total number of patients in the two groups), and received the tegoprazan and hydrotalcite dry suspension in Example 1 (1000 mg each time) and tegoprazan tablets (50 mg, Taixinzan) of Shandong Luoxin, one tablet each time, once a day for 4 weeks or 8 weeks. Subjects who achieved endoscopic healing after 4 weeks terminated the study treatment, and those who did not achieve endoscopic healing continued treatment for 4 weeks. The main efficacy index was the cumulative endoscopic healing rate at 8 weeks, defined as the proportion of patients with erosive healing determined by upper gastrointestinal endoscopy after 8 weeks of study treatment (erosive healing means the absence of erosion and mucosal damage according to the LA classification). The secondary efficacy indexes included the healing rate within 4 weeks, symptom and health-related quality of life evaluation, etc. Compared with the tegoprazan tablets (50 mg, Taixinzan) of Shandong Luoxin, the efficacy of the tegoprazan and hydrotalcite dry suspension in Example 1 in treating Chinese patients with reflux esophagitis in terms of erosive healing, symptom improvement, and quality of life improvement after 4 weeks or 8 weeks was evaluated. A total of 60 subjects were included in the main efficacy population (full analysis set), and they received either tegoprazan tablets (50 mg, Taixinzan) of Shandong Luoxin once a day or the tegoprazan and hydrotalcite dry suspension in Example 1 once a day. The demographic characteristics and baseline disease characteristics of the two groups of subjects were similar. The average age of the subjects was 46.9 ± 11.5 years old, 73.4% were male, and 24.6% were positive for Helicobacter pylori. The proportion of patients with baseline LA grades was 45.2% for grade A, 46.4% for grade B, 7.7% for grade C, and 0.8% for grade D.

[0063] The research results showed that the cumulative endoscopic healing rate of the tegoprazan and hydrotalcite dry suspension group in Example 1 after 8 weeks of treatment (96.1%) was better than that of the tegoprazan tablet (50 mg, Taixinzan) group of Shandong Luoxin (91.8%).

[0064] After 4 weeks of treatment, 78.2% of the patients in the tegoprazan and hydrotalcite dry suspension group in Example 1 achieved endoscopic healing and stopped treatment, while the figure for the tegoprazan tablet (50 mg, Taixinzan) group of Shandong Luoxin was 75.8%.

[0065] In summary, the effect of the tegoprazan and hydrotalcite dry suspension group in Example 1 in treating reflux esophagitis was better than that of the tegoprazan tablet (50 mg, Taixinzan) group of Shandong Luoxin.

[0066] Finally, it should be noted that the above examples are only used to illustrate the technical solutions of the present invention and are not intended to limit them; although the present invention has been described in detail with reference to the foregoing examples, those of ordinary skill in the art should understand that they can still modify the technical solutions described in the foregoing examples, or perform equivalent replacements for some of the technical features; and these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the various embodiments of the present invention.

Claims

1. A dry suspension containing tegrassen and hydrotalcite, characterized in that: The composition comprises the following components by weight: 500 parts of hydrotalcite, 50 parts of tigolasan, 384 parts of anhydrous lactose, 40 parts of sodium starch glycolate, 10 parts of colloidal silicon dioxide, 10 parts of xanthan gum, 1 part of sucralose, and 5 parts of magnesium stearate; The dry suspension containing tegrassen and hydrotalcite is prepared by the following steps: (1) grinding so that the particle size of tigolasan satisfies D90=15 μm, the particle size of hydrotalcite satisfies D90=10 μm, and the anhydrous lactose passes through a 80-mesh sieve; (2) aluminum carbonate, tegrassen, anhydrous lactose, sodium starch glycolate, colloidal silicon dioxide, xanthan gum, and sucralose are mixed to obtain mixed powder 1; magnesium stearate is added to mixed powder 1, and mixed to obtain mixed powder 2; (3) Dry granulating the mixed powder 2, sieving, and filling the obtained dry mixed suspension granules; In step (2), the mixing is carried out in a hopper mixer at a speed of 10 rpm for 20 minutes to obtain mixed powder 1; magnesium stearate is added to mixed powder 1 at a speed of 10 rpm for 5 minutes to obtain mixed powder 2; In step (3), the dry granulation is carried out in a dry granulator, the pressure of the pressing wheel of the dry granulator is 3-5 MPa, the gap between the pressing wheels is 1-2 mm, the granulation speed is 400-600 rpm, and the sieve mesh size is 1.25-1.5 mm.

2. Use of the dry suspension containing tegoraxan and hydrotalcite according to claim 1 in the preparation of a medicament for treating reflux esophagitis, gastric acid, gastritis and / or gastric ulcer.

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