Trimebutine maleate sublingual tablet and preparation method thereof

Abstract

The invention discloses a trimebutine maleate sublingual tablet and a preparation method thereof. The sublingual tablet disclosed by the invention is prepared by compounding trimebutine maleate, an auxiliary material Starlac, hydroxypropyl methylcellulose and menthol. According to the invention, the novel auxiliary material Starlac and the disintegrating agent hydroxypropyl methylcellulose are mixed for use, so that the use amount of the auxiliary material Starlac with relatively high price is reduced, and the obtained product has better hardness and disintegration performance and good quality stability.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology and relates to a trimebutine maleate sublingual tablet and a preparation method thereof. Background Art

[0002] Trimebutine maleate is a gastrointestinal antispasmodic drug developed by the French company Jouveinal (now a subsidiary of Pfizer). It was first launched in France in 1970 under the trade name DEBRIDAT. The mechanism of action of trimebutine maleate is to specifically bind to peripheral opioid receptors, reduce or reverse the anesthetic analgesic activity of agonists, and eliminate adverse reactions such as gastrointestinal dysfunction and respiratory depression caused by them. It has a bidirectional regulatory effect on gastrointestinal motility, that is, it can regulate Ca 2+ and K + Pathways inhibit acetylcholine-induced gastrointestinal smooth muscle contractions. Trimebutine can also activate peripheral opioid receptors, releasing gastrointestinal peptides such as motilin, vasoactive intestinal peptide, and gastrin, thereby inhibiting visceral nerve reflexes and raising the visceral pain threshold. Trimebutine also has low toxicity and few, mild adverse reactions. It is recommended for inflammatory abdominal pain in the "Chinese Expert Consensus on Standardized Use of Antispasmodic and Analgesic Drugs for Acute Abdominal Pain in Adults."

[0003] At present, the dosage forms of trimebutine maleate listed are mainly tablets and suspensions. Both tablets and suspensions are administered orally. This mode of administration can adapt to various populations, but patients with abdominal pain may experience nausea or restrict fluid intake, and oral administration is obviously inappropriate. There is a first-pass effect in trimebutine maleate. When administered orally, the drug is absorbed from the gastrointestinal tract and enters the liver through the portal vein system. Some drugs can be metabolized and inactivated, reducing the amount of drugs entering the systemic circulation, thereby reducing bioavailability. At the same time, trimebutine has a relatively short half-life, and oral administration requires three times a day to maintain blood drug concentration. In order to avoid the first-pass effect, patent CN102397234A provides a trimebutine maleate injection, but the injection is not as safe as the oral preparation, and the injection administration method has many restrictions, which brings more inconvenience to the patient. CN 108159003 A provides a soluble granular preparation that completely dissolves the drug in vitro to improve bioavailability. Although this method can increase bioavailability by improving the absorption of the drug after entering the small intestine, this method still cannot avoid the first-pass effect of the drug. Therefore, it is urgent to develop new dosage forms to improve the above problems. Summary of the Invention

[0004] To address the above issues, the present invention provides a new dosage form of trimebutine maleate—trimebutine maleate sublingual tablets. The sublingual tablets are compounded with trimebutine maleate, the excipient Starlac, hypromellose, and menthol. By combining the novel excipient Starlac with the disintegrant hypromellose, the present invention reduces the amount of the relatively expensive excipient Starlac, resulting in a product with improved hardness and disintegration properties, and excellent product quality stability.

[0005] The technical solution of the present invention is: a trimebutine maleate sublingual tablet, characterized in that its raw materials and weight parts are: trimebutine maleate 70, auxiliary material Starlac 44-45.5, hypromellose 3.0-4.5 and menthol 1.5-3.0.

[0006] The preferred ratio is: trimebutine maleate 70, excipient Starlac 45.5, hypromellose 3.0 and menthol 1.5.

[0007] Preparation method:

[0008] a: Pass the raw material trimebutine maleate through an 80-mesh sieve and the remaining excipients through a 60-mesh sieve;

[0009] b: Mix the excipients Starlac and hypromellose to obtain mixed powder b;

[0010] c: taking the raw material trimebutine maleate and adding it into the mixed powder b to obtain mixed powder c;

[0011] d: Menthol was added to the mixed powder c, and the mixture was mixed, and then tableted to obtain trimebutine maleate sublingual tablets.

[0012] Furthermore, the present invention uses a 6 mm round punch for tableting, and the theoretical tablet weight is 120 mg.

[0013] The disintegration time of sublingual tablets in the oral cavity is an important inspection item. Currently, sublingual tablets are prepared using common excipients, and generally there will be a situation where the disintegration time meets the requirements but the hardness does not meet the requirements. In CN1622809A and CN1981752A, the novel excipient Starlac is used. Starlac is a mixture of starch and lactose, which is obtained by spray drying. The prepared novel excipient Starlac can disintegrate faster while improving the hardness of the tablets during the preparation process of sublingual tablets. However, the current dosage of sublingual tablets using this novel excipient is large, reaching more than 90%, making the price of the prepared finished product also higher. The present invention uses the novel excipient Starlac after mixing with the disintegrant hypromellose, which reduces the dosage of the excipient Starlac, and the product hardness and disintegration performance obtained are better, and the product quality stability is good. And the use ratio of the sublingual tablet excipient Starlac is about 58% (using the lower-priced hypromellose to replace), which greatly saves cost.

[0014] The model of the hypromellose is a mixture of one or more of (1828, 2208, 2906, 2910).

[0015] Compared with commercially available trimebutine maleate tablets, suspensions, injections, and soluble granules, the present invention prepares trimebutine maleate sublingual tablets for the first time. The sublingual tablets have the following advantages:

[0016] (1) Currently, the marketed trimebutine maleate tablets (specification 100 mg) weigh about 169 mg and have a diameter of 8.2 mm, which are relatively large. However, the trimebutine maleate sublingual tablets weigh about 120 mg and have a diameter of 6 mm. They are small and flat, and only require a small amount of saliva to disintegrate and be absorbed, which increases patient compliance and makes drug administration more convenient.

[0017] (2) Trimebutine maleate sublingual tablets absorb the drug into the blood through the sublingual capillaries and directly enter the blood circulation. They have a fast onset of action, high absorption efficiency, and avoid the first-pass effect. They are safer than injections.

[0018] (3) Due to the high absorption efficiency of trimebutine maleate sublingual tablets, the tablet specifications can be reduced to achieve the same pharmacological effect, greatly reducing the toxic and side effects of the drug on the human body.

[0019] (4) The present invention provides a sublingual trimebutine maleate tablet, in which the disintegrant involved is a mixture of a new excipient Starlac and a disintegrant hypromellose, and a powder direct tableting method is adopted. This method has a simple process, low cost, and can prepare a product with stable quality. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1These are the dissolution curves of trimebutine maleate sublingual tablets in four media of Example 1;

[0021] Figure 2 The mean plasma concentration-time curve of trimebutine maleate in Beagle dogs (n=6). DETAILED DESCRIPTION

[0022] The effects are described below with reference to the examples and accompanying drawings. The excipient Starlac used in all the examples of the present invention was purchased from MEGGLE Pharmaceutical Excipients. The model of the hypromellose used was 1828.

[0023] Example 1-3:

[0024] The ingredients of trimebutine maleate sublingual tablets of Examples 1-3 and Comparative Examples 1-2 are shown in Table 1 below, wherein in Comparative Example 1, the amount of Starlac excipient is increased to replace hypromellose, and in Comparative Example 2, the amount of hypromellose excipient is increased to replace Starlac excipient.

[0025] Table 1: Ingredients of trimebutine maleate sublingual tablets of Examples 1-3 and Comparative Examples 1-2

[0026] Prescription composition Example 1 Example 2 Example 3 Comparative Example 1 Comparative Example 2 Trimebutine Maleate 70mg 70mg 70mg 70mg 70mg Starlac 45.5mg 44mg 44mg 48.5mg / Hydroxypropyl methylcellulose 3mg 3mg 4.5mg / 48.5mg Menthol 1.5mg 3mg 1.5mg 1.5mg 1.5mg

[0027] Preparation process:

[0028] a: Pass the raw material trimebutine maleate through an 80-mesh sieve and the remaining excipients through a 60-mesh sieve;

[0029] b: Mix the prescribed amount of Starlac and hypromellose to obtain mixed powder b;

[0030] c: taking the prescribed amount of raw material trimebutine maleate and adding it to the mixed powder b to obtain mixed powder c;

[0031] d: Add the prescribed amount of menthol to the mixed powder c and mix;

[0032] e: The above-mentioned total mixed powder was compressed into tablets using a 6 mm round punch, with a theoretical tablet weight of 120 mg.

[0033] The experimental results are shown in Table 2. The test methods for hardness, friability, disintegration time and content were all carried out in accordance with the Chinese Pharmacopoeia test methods.

[0034] Table 2: Experimental results of Examples 1-3 and Comparative Examples 1-2

[0035]

[0036]

[0037] The experimental results are shown in Table 2. It can be seen that the addition of hypromellose to the prescription can shorten the disintegration time, and the disintegration time of the sublingual tablet can be controlled to be less than 60S. The hardness of the resulting tablets is moderate and the friability meets the requirements. However, if the amount of the new excipient Starlac added is small, the disintegration time is greater than 1min, and the friability does not meet the requirements. Therefore, the prescription amount of Examples 1, 2 and 3 is determined. Comparative Example 1 increases the amount of Starlac excipient to replace hypromellose, and its friability, disintegration time and hardness performance are poor. Comparative Example 2 increases the amount of hypromellose excipient to replace Starlac excipient, and fails to successfully compress the tablets. Therefore, it can be seen that Starlac and hypromellose are synergistically compounded, and the best effect can be obtained by compounding them in an appropriate ratio.

[0038] Comparative Example 3-4: The new excipient Starlac was replaced by a conventional excipient (a physical mixture of lactose monohydrate and starch was used as an excipient to replace the new excipient Starlac). Specific examples are shown in Table 3 below.

[0039] Table 3: Ingredients of Trimebutine Maleate Sublingual Tablets of Comparative Examples 3-4

[0040] Prescription composition Comparative Example 3 Comparative Example 4 Trimebutine Maleate 70mg 70mg Lactose monohydrate 37.4mg 35mg starch 6.6mg 9mg Hydroxypropyl methylcellulose 3mg 4.5mg Menthol 3mg 1.5mg

[0041] Preparation process:

[0042] a: Pass the raw material trimebutine maleate through an 80-mesh sieve and the remaining excipients through a 60-mesh sieve;

[0043] b: taking the prescribed amount of lactose monohydrate, starch and hypromellose and mixing them to obtain mixed powder b;

[0044] c: taking the prescribed amount of raw material trimebutine maleate and adding it to the mixed powder b to obtain mixed powder c;

[0045] d: Add the prescribed amount of menthol to the mixed powder c and mix;

[0046] e: The above-mentioned total mixed powder was compressed into tablets using a 6 mm round punch, with a theoretical tablet weight of 120 mg.

[0047] The experimental results are shown in Table 4.

[0048] Table 4: Experimental results of Comparative Examples 3-4

[0049]

[0050]

[0051] The results in Table 4 show that when lactose monohydrate and starch are physically mixed as an excipient instead of the new excipient Starlac, the sublingual tablets obtained have a longer disintegration time and unsatisfactory friability. Therefore, the product obtained by using the new excipient Starlac instead of conventional excipients to prepare sublingual tablets meets the requirements.

[0052] Test example:

[0053] 1. According to the EP standard, the relevant substance detection results of Examples 1-3 are shown in Table 5.

[0054] Table 5: Related substance detection results of Examples 1-3

[0055]

[0056] It can be seen from the results in Table 5 that under the conditions investigated, the performance of the sublingual tablet of the present invention is relatively stable.

[0057] 2. Medium dissolution curve

[0058] The dissolution curves of the trimebutine maleate sublingual tablets of Example 1 were investigated. 500 ml of each of the four dissolution media, water, 0.1 M hydrochloric acid solution, pH 4.5 phosphate buffer, and pH 6.8 phosphate buffer, were used as the medium. A paddle method was used at 75 rpm. After 5, 10, 15, 30, and 45 minutes, 10 ml of the dissolution solution was collected, filtered, and the filtrate was collected to determine the dissolution amount. The cumulative dissolution and dissolution curve results of the four dissolution media are shown in Tables 6 and 7. Figure 1 As shown in the figure, it can be seen from the experimental results that trimebutine maleate sublingual tablets have good dissolution in the four media, and the dissolution rate can reach more than 95% in 10 minutes.

[0059] Table 6 Dissolution results of trimebutine maleate sublingual tablets in four media in Example 1

[0060]

[0061] 3. Pharmacokinetics experiments

[0062] The sublingual tablets prepared in Example 1 were compared with the marketed oral tablets (SAWAI) for in vivo pharmacokinetic evaluation.

[0063] Experimental process:

[0064] Six Beagle dogs were used, half male and half female, weighing 7.95 to 9.85 kg.

[0065] The study used a two-period crossover design with a 7-day interval between periods. Six Beagle dogs were randomly divided into two groups, with three dogs in each group. Each period, the reference formulation group received an oral dose of 100 mg / dog of the reference formulation. Approximately 0.5 mL of blood was collected from the forelimb and hindlimb veins of the dogs before dosing (0 h) and at 0.083, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, and 24 h after dosing. Each period, the test formulation group received a sublingual dose of 70 mg / dog of the test formulation. Approximately 0.5 mL of blood was collected from the forelimb and hindlimb veins of the dogs before dosing (0 h) and at 0.083, 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, and 24 h after dosing. The blood was placed in a heparinized centrifuge tube, placed in an ice box, and centrifuged within 1 h to separate the plasma (centrifugation conditions: 2-8°C, 8000 rpm, 10 min). The collected plasma was stored at -20°C until testing.

[0066] Here are the results:

[0067] The results are shown in Table 7. Compared with the reference preparation, the test preparation T max and MRT (0-t) Less than the reference preparation, while C max , AUC (0-t) and AUC (0-∞) The results were significantly higher than those of the reference preparation, while the other parameters showed no significant differences. This indicates that trimebutine maleate sublingual tablets (70 mg) can achieve higher blood drug concentrations in a shorter time than ordinary tablets (100 mg), achieving a rapid onset of action.

[0068] The average plasma concentration-time curve of trimebutine maleate in Beagle dogs is as follows Figure 2 As shown in Table 7 and Figure 2 It can be seen that the trimebutine maleate sublingual tablets of the present invention absorb the drug into the blood through the sublingual capillaries and directly enter the blood circulation, with rapid onset and high absorption efficiency.

[0069] Table 7: Comparison of main pharmacokinetic parameters of trimebutine maleate in Beagle dogs (n=6)

[0070]

[0071] “*” indicates P < 0.05 compared with the reference preparation.

Claims

1. A trimebutine maleate sublingual tablet, characterized in that: The raw materials and weight proportions thereof are: 70% trimebutine maleate, 44-45.5% of auxiliary material Starlac, 3.0-4.5% of hypromellose and 1.5-3.0% of menthol.

2. The trimebutine maleate sublingual tablet according to claim 1, characterized in that: The raw materials and weight proportions thereof are: 70% trimebutine maleate, 45.5% of auxiliary material Starlac, 3.0% of hypromellose and 1.5% of menthol.

3. The trimebutine maleate sublingual tablet according to claim 1 or 2, characterized in that: The model of the hypromellose is a mixture of one or more of 1828, 2208, 2906 and 2910.

4. The method for preparing the trimebutine maleate sublingual tablets according to any one of claims 1 to 3, characterized in that: The following steps are involved: a: Pass the raw material trimebutine maleate through an 80-mesh sieve, and pass the remaining raw materials through a 60-mesh sieve; b: Mix the auxiliary materials Starlac and hypromellose to obtain mixed powder b; c: taking the raw material trimebutine maleate and adding it into the mixed powder b to mix, to obtain mixed powder c; d: Add menthol to the mixed powder c and mix, then compress the mixture into tablets to obtain trimebutine maleate sublingual tablets.

5. The preparation method according to claim 4, characterized in that: A 6 mm round punch was used for tableting.

6. The preparation method according to claim 5, characterized in that: The theoretical tablet weight of the trimebutine maleate sublingual tablet is 120 mg.

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