Granisetron sustained-release medicine for relieving chemotherapy or postoperative nausea and vomiting

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a granisetron sustained-release drug for relieving chemotherapy or postoperative vomiting. The sustained-release medicine comprises granisetron, medium-chain fatty acid triglyceride, carnauba wax, an adhesive and a diluent. The sustained-release medicine is relatively low in content of related substances, good in stability after an acceleration test and capable of being completely released within 24 hours, the medicine taking frequency within one day is reduced, and the problem of long-term medicine taking of patients, especially chemotherapy or postoperative haematemesis and vomiting patients is solved.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a granisetron sustained-release medicine for relieving nausea and vomiting after chemotherapy or surgery. Background Art

[0002] Granisetron hydrochloride (1-methyl-N-[endo-9-methyl-9-azabicyclo(3,3,1)nonane-3-yl]-1H-indazole-3-carboxamide) is a highly selective 5-HT3 receptor (5-hydroxytryptamine 3 receptor) antagonist, which is used for nausea and vomiting caused by radiotherapy and cytotoxic chemotherapy. Its structural formula is shown below

[0003]

[0004] Granisetron hydrochloride is a highly selective 5-HT3 receptor antagonist, mainly used to control nausea and vomiting (CINV) caused by chemotherapy, radiotherapy or surgery. It has a very high selectivity for 5-HT3 receptors, much higher than its affinity for other 5-HT receptors (such as 5-HT1, 5-HT2, etc.) and other neural receptors (such as α1, α2 receptors, β-adrenergic receptors, dopamine D2 receptors, etc.). Therefore, it can effectively inhibit the activation of 5-HT3 receptors in the central nervous system and vagus nerve endings due to the release of 5-HT by enterochromaffin cells, thereby alleviating the symptoms of nausea and vomiting.

[0005] Although granisetron has shown good efficacy in treatment, especially good tolerability in adults and children, its short half-life (approximately 4 to 6 hours) requires frequent administration, which reduces patient compliance to a certain extent, especially in the prevention of delayed chemotherapy-induced vomiting (delayed CINV). In addition, the oral formulation of granisetron has some shortcomings, such as poor patient compliance due to high-frequency administration, and relatively low bioavailability of oral drugs due to the first-pass effect. Although granisetron is also available in suppository form, the irregular absorption of suppositories may cause discomfort to patients, and if the suppository reaches the colon, it will still undergo first-pass elimination, resulting in further reduction in bioavailability.

[0006] Therefore, although granisetron is an effective and well-tolerated drug, its pharmacokinetic properties still have certain limitations, especially when frequent dosing is required, which may have an adverse effect on the patient's treatment compliance. Therefore, it is of great significance to provide a granisetron sustained-release tablet with complete release, good stability and simple preparation process. Summary of the invention

[0007] In view of the problems existing in the prior art and in the granisetron hydrochloride sustained-release preparation, the present invention provides a granisetron sustained-release drug, especially a sustained-release tablet capable of stably dissolving. Accelerated tests show that the sustained-release tablet has stable quality, is suitable for long-term storage, and is suitable for large-scale industrial production.

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

[0009] A sustained-release medicine containing granisetron, the sustained-release medicine comprises granisetron, medium-chain fatty acid triglyceride, carnauba wax, a diluent and a binder; calculated by weight, the ratio of granisetron, medium-chain fatty acid triglyceride, carnauba wax and the diluent is 1:2:2-8:145-190, and an appropriate amount of the binder.

[0010] Furthermore, in a preferred embodiment of the present invention, the binder in the sustained-release drug is a 0.5-1% chitosan ethanol solution, and more preferably a 0.75% chitosan ethanol solution.

[0011] Furthermore, in a preferred embodiment of the present invention, the diluent in the sustained-release drug is one or a combination of hypromellose, inulin lactone, lactose, mannitol, microcrystalline cellulose, silicon dioxide, and calcium hydrogen phosphate; preferably a combination of hypromellose, inulin lactone and microcrystalline cellulose, calculated by weight ratio, the hypromellose, inulin lactone and microcrystalline cellulose are 1:1:5-17.

[0012] Furthermore, in a preferred embodiment of the present invention, the sustained-release drug comprises granisetron, medium-chain fatty acid triglycerides, carnauba wax, hypromellose, inulin, microcrystalline cellulose and deacetylated chitosan ethanol solution; calculated by weight, the ratio of granisetron, medium-chain fatty acid triglycerides, carnauba wax, hypromellose, inulin and microcrystalline cellulose is 1:2:5:15:15:180, and an appropriate amount of 0.75% deacetylated chitosan ethanol solution.

[0013] Furthermore, in a preferred embodiment of the present invention, the sustained-release drug comprises granisetron, medium-chain fatty acid triglycerides, carnauba wax, hypromellose, inulin, microcrystalline cellulose and chitosan ethanol solution; calculated by weight, the ratio of granisetron, medium-chain fatty acid triglycerides, carnauba wax, hypromellose, inulin and microcrystalline cellulose is 1:2:8:20:20:100, and an appropriate amount of 0.5% chitosan ethanol solution.

[0014] Furthermore, in a preferred embodiment of the present invention, the sustained-release drug comprises granisetron, medium-chain fatty acid triglycerides, carnauba wax, hypromellose, inulin, microcrystalline cellulose and chitosan ethanol solution; calculated by weight, the ratio of granisetron, medium-chain fatty acid triglycerides, carnauba wax, hypromellose, inulin and microcrystalline cellulose is 1:2:2:8:8:126, and an appropriate amount of 1% chitosan ethanol solution.

[0015] Furthermore, the sustained-release drug is selected from one of tablets, capsules, and granules.

[0016] Furthermore, the preparation method of the tablet comprises the following steps:

[0017] 1) Heat and melt medium chain fatty acid triglyceride and carnauba wax, then add inulin lactone and granisetron hydrochloride, stir evenly, cool and grind into powder, and set aside;

[0018] 2) Add hydroxypropyl methylcellulose and microcrystalline cellulose and stir evenly, add 0.5-1% ethanol solution of deacetylated chitosan as a binder to granulate, dry, sieve, and granulate for later use;

[0019] 3) Then, magnesium stearate is added, stirred evenly, and tabletted to obtain tablets.

[0020] Compared with the prior art, the present invention has the following outstanding advantages:

[0021] The granisetron hydrochloride sustained-release preparation provided by the present invention, especially in the sustained-release tablet machine, has high uniformity, good stability, and stable drug release, greatly improves the medication compliance of patients, reduces the number of medication times, and ensures the continuity and stability of drug efficacy. The results of the accelerated test prove that it has stable quality, is suitable for long-term storage, and can support industrial large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 : In vitro cumulative dissolution rate (%) of each example at 1h, 2h, 4h, 6h, 8h, 12h, 16h, 20h and 24h.

[0023] Figure 2 : Total impurity content (%) of related substances in each embodiment at the accelerated time of 0 month, 1 month, 2 months, 3 months and 6 months. DETAILED DESCRIPTION

[0024] The following specific implementation modes are listed to further illustrate the present invention, but do not limit the scope of the present invention in any way. Those skilled in the art can make various modifications or improvements based on the basic idea of ​​the present invention, but as long as they do not deviate from the basic idea of ​​the present invention, they are all within the scope of the present invention.

[0025] Example 1: A sustained-release tablet containing granisetron hydrochloride (1000 tablets), the preparation process is as follows:

[0026]

[0027]

[0028] Preparation process:

[0029] 1) Heat medium chain fatty acid triglyceride and carnauba wax to 50°C to melt, then add inulin lactone and granisetron hydrochloride, stir evenly, cool and grind, and set aside;

[0030] 2) Add hydroxypropyl methylcellulose and microcrystalline cellulose and stir evenly, add 0.5% ethanol solution of deacetylated chitosan as a binder to granulate, dry, sieve, and set aside;

[0031] 3) Weighing, then adding 1% of the total weight of magnesium stearate, stirring evenly, and tableting to obtain tablets.

[0032] Example 2: A sustained-release tablet containing granisetron hydrochloride (1000 tablets), the preparation process is as follows:

[0033] Element Weight(g) Granisetron Hydrochloride 1 Medium chain triglycerides 2 Carnauba wax 8 Hydroxypropyl methylcellulose 20 Inulin 20 Microcrystalline Cellulose 100 Chitosan alcohol solution Moderate

[0034] Preparation process:

[0035] 1) Heat medium chain fatty acid triglyceride and carnauba wax to 55°C to melt, then add inulin lactone and granisetron hydrochloride, stir evenly, cool and grind, and set aside;

[0036] 2) Add hydroxypropyl methylcellulose and microcrystalline cellulose and stir evenly, add 0.75% ethanol solution of deacetylated chitosan as a binder to granulate, dry, sieve, and set aside;

[0037] 3) Weighing, then adding 1% of the total weight of magnesium stearate, stirring evenly, and tableting to obtain tablets.

[0038] Example 3: A sustained-release tablet containing granisetron hydrochloride (1000 tablets), the preparation process is as follows:

[0039]

[0040]

[0041] Preparation process:

[0042] 1) Heat medium chain fatty acid triglyceride and carnauba wax to 60°C to melt, then add inulin lactone and granisetron hydrochloride, stir evenly, cool and grind, and set aside;

[0043] 2) Add hydroxypropyl methylcellulose and microcrystalline cellulose and stir evenly, add 1% ethanol solution of deacetylated chitosan as a binder to granulate, dry, sieve, and set aside;

[0044] 3) Weighing, then adding 1% of the total weight of magnesium stearate, stirring evenly, and tableting to obtain tablets.

[0045] Example 4: A sustained-release tablet containing granisetron hydrochloride (1000 tablets), the preparation process is as follows:

[0046] Element Weight(g) Granisetron Hydrochloride 1 Medium chain triglycerides 2 Carnauba wax 8 Hydroxypropyl methylcellulose 20 Inulin 20 Microcrystalline Cellulose 100 Chitosan alcohol solution Moderate

[0047] Preparation process:

[0048] 1) Heat medium chain fatty acid triglyceride and carnauba wax to 60°C to melt, then add inulin lactone and granisetron hydrochloride, stir evenly, cool and grind, and set aside;

[0049] 2) Add hydroxypropyl methylcellulose and microcrystalline cellulose and stir evenly, add 1% ethanol solution of deacetylated chitosan as a binder to granulate, dry, sieve, and put the granules into capsules to obtain the product.

[0050] Comparative Example 1: A sustained-release tablet containing granisetron hydrochloride (1000 tablets), the preparation process is as follows:

[0051] Element Weight(g) Granisetron Hydrochloride 1 Carnauba wax 8 Hydroxypropyl methylcellulose 20 Inulin 20 Microcrystalline Cellulose 100 Chitosan alcohol solution Moderate

[0052] The preparation process is the same as that of Example 2.

[0053] Comparative Example 2: A sustained-release tablet containing granisetron hydrochloride (1000 tablets), the preparation process is as follows:

[0054] Element Weight(g) Granisetron Hydrochloride 1 Medium chain triglycerides 2 Hydroxypropyl methylcellulose 20 Inulin 20 Microcrystalline Cellulose 100 Chitosan alcohol solution Moderate

[0055] The preparation process is the same as that of Example 2.

[0056] Comparative Example 3: A sustained-release tablet containing granisetron hydrochloride (1000 tablets), the preparation process is as follows:

[0057] Element Weight(g) Granisetron Hydrochloride 1 Medium chain triglycerides 5 Carnauba wax 2 Hydroxypropyl methylcellulose 20 Inulin 20 Microcrystalline Cellulose 100 Chitosan alcohol solution Moderate

[0058] The preparation process is the same as that of Example 2.

[0059] Comparative Example 4: A sustained-release tablet containing granisetron hydrochloride (1000 tablets), the preparation process is as follows:

[0060] Element Weight(g) Granisetron Hydrochloride 1 Medium chain triglycerides 2 Carnauba wax 8 Hydroxypropyl methylcellulose 20 Microcrystalline Cellulose 100 Chitosan alcohol solution Moderate

[0061] The preparation process is the same as that of Example 2.

[0062] Comparative Example 5: A sustained-release tablet containing granisetron hydrochloride (1000 tablets), the preparation process is as follows:

[0063] Element Weight(g) Granisetron Hydrochloride 1 Medium chain triglycerides 2 Carnauba wax 8 Hydroxypropyl methylcellulose 20 Inulin 20 Microcrystalline Cellulose 100 Ethyl cellulose in ethanol Moderate

[0064] The preparation process is the same as that of Example 2.

[0065] Comparative Example 6: A sustained-release tablet containing granisetron hydrochloride (1000 tablets), the preparation process is as follows:

[0066] Element Weight(g) Granisetron Hydrochloride 1 Stearic acid 2 Glyceryl Monostearate 8 Hydroxypropyl methylcellulose 20 Inulin 20 Microcrystalline Cellulose 100 Chitosan alcohol solution Moderate

[0067] The preparation process is the same as that of Example 2.

[0068] Comparative Example 7: A sustained-release tablet containing granisetron hydrochloride (1000 tablets), the preparation process is as follows:

[0069] Element Weight(g) Granisetron Hydrochloride 1 Medium chain triglycerides 2 Carnauba wax 8 Hydroxypropyl methylcellulose 15 Inulin 5 Microcrystalline Cellulose 150 Chitosan alcohol solution Moderate

[0070] The preparation process is the same as that of Example 2.

[0071] Verification Example

[0072] 1) Investigation of in vitro release characteristics of tablets

[0073] Dissolution test: Take the tablets obtained in Examples 1-7, refer to the test apparatus of the second method of the fourth part 0931 dissolution test method of the 2020 edition of the Chinese Pharmacopoeia, use water as the dissolution medium, the rotation speed is 60 revolutions per minute, and sample 5mL (add equal amount of medium) at 1, 2, 4, 6, 8, 12, 16, 20, and 24h, filter through a 0.45μm microporous membrane, and use high performance liquid chromatography, with a KromasilC18 column (4.6mm×250mm, 5μm) as the chromatographic column, and the mobile phase is 0.02mol / L potassium dihydrogen phosphate (pH=3.0): acetonitrile (volume ratio 3:1), the flow rate is 1.0ml / min, and the detection wavelength is 291nm for determination. The results of the determination are shown in Figure 1 .

[0074] Figure 1 The tablets obtained in Examples 1-3 and Comparative Examples 1-7 can stably release the drug completely within 24 hours, thus achieving a sustained-release effect and reducing the number of medication times.

[0075] 2): Study on the stability of tablets.

[0076] Grind the product, add mobile phase (0.25% (ml / ml) triethylamine in 0.05 mol / L sodium acetate solution (adjust pH to 6.0 with glacial acetic acid)-methanol (50:50)) to dissolve and dilute to make a solution containing about 0.5 mg per 1 ml as the test solution; accurately measure an appropriate amount of granisetron hydrochloride, add mobile phase to quantitatively dilute to make a solution containing 5 μg per 1 ml as the control solution.

[0077] According to the chromatographic conditions under the content determination item, accurately measure 20μl of the test solution and the control solution and inject them into the liquid chromatograph respectively, and record the chromatogram to twice the retention time of the main component peak. If there are impurity peaks in the chromatogram of the test solution, the sum of the areas of the impurity peaks shall not be greater than the main peak area of ​​the control solution (1.0%).

[0078] Accelerated conditions: Place at 40±2℃ and 75±5% (accelerated) for 6 months. Take samples at the end of the 0th, 3rd and 6th month to measure the maximum single impurity, total impurities and content. The results are as follows: Figure 2 shown.

[0079] Figure 2 : The results show that the impurity growth of the tablets obtained in Examples 1-3 and Comparative Examples 1-7 meets the quality requirements after being placed under accelerated conditions, and the content of Examples 1-3 is below 0.5%, which is lower than the requirement of 1% in the 2020 edition of the Chinese Pharmacopoeia. This shows that the tablets obtained by the present invention have high stability.

Claims

1. A sustained-release drug containing granisetron, characterized in that: The sustained-release drug comprises granisetron, medium-chain fatty acid triglycerides, carnauba wax, a diluent and a binder; calculated by weight, the ratio of granisetron, medium-chain fatty acid triglycerides, carnauba wax and the diluent is 1:2:2-8:145-190, and an appropriate amount of binder.

2. The sustained-release drug according to claim 1, characterized in that: The binder in the sustained-release medicine is 0.5-1% deacetylated chitosan ethanol solution.

3. The sustained-release drug according to claim 1, characterized in that: The diluent is one or a combination of hypromellose, inulin, lactose, mannitol, microcrystalline cellulose, silicon dioxide, and calcium hydrogen phosphate; preferably a combination of hypromellose, inulin and microcrystalline cellulose, calculated by weight ratio, the hypromellose, inulin and microcrystalline cellulose are 1:1:5-17.

4. The sustained-release drug according to claim 1, characterized in that: The sustained-release drug comprises granisetron, medium-chain fatty acid triglycerides, carnauba wax, hypromellose, inulin, microcrystalline cellulose and chitosan ethanol solution; calculated by weight, the ratio of granisetron, medium-chain fatty acid triglycerides, carnauba wax, hypromellose, inulin and microcrystalline cellulose is 1:2:5:15:15:

180.

5. The sustained-release drug according to claim 1, characterized in that: The sustained-release drug comprises granisetron, medium-chain fatty acid triglycerides, carnauba wax, hydroxypropyl methylcellulose, inulin lactone, microcrystalline cellulose and chitosan ethanol solution; calculated by weight, the ratio of granisetron, medium-chain fatty acid triglycerides, carnauba wax, hydroxypropyl methylcellulose, inulin lactone and microcrystalline cellulose is 1:2:8:20:20:100, and an appropriate amount of 0.5% chitosan ethanol solution.

6. The sustained-release drug according to claim 1, characterized in that: The sustained-release drug comprises granisetron, medium-chain fatty acid triglycerides, carnauba wax, hydroxypropyl methylcellulose, inulin lactone, microcrystalline cellulose and chitosan ethanol solution; calculated by weight, the ratio of granisetron, medium-chain fatty acid triglycerides, carnauba wax, hydroxypropyl methylcellulose, inulin lactone and microcrystalline cellulose is 1:2:2:8:8:126, and an appropriate amount of 1% chitosan ethanol solution.

7. The sustained-release drug according to any one of claims 1 to 7, characterized in that: The sustained-release drug is prepared with pharmaceutically acceptable excipients into tablets, capsules and dispersible tablets.

8. The sustained-release drug according to claim 7, characterized in that The preparation method of the tablet comprises the following steps: 1) Heat and melt medium chain fatty acid triglyceride and carnauba wax, then add inulin lactone and granisetron hydrochloride, stir evenly, cool and grind into powder, and set aside; 2) Add hydroxypropyl methylcellulose and microcrystalline cellulose and stir evenly, add 0.5-1% ethanol solution of deacetylated chitosan as a binder to granulate, dry, sieve, and granulate for later use; 3) Then, magnesium stearate is added, stirred evenly, and tabletted to obtain tablets.

9. The sustained-release drug according to claim 7, characterized in that: The preparation method of the tablet comprises the following steps: 1) Heat medium chain fatty acid triglyceride and carnauba wax to 55°C to melt, then add inulin lactone and granisetron hydrochloride, stir evenly, cool and grind, and set aside; 2) Add hydroxypropyl methylcellulose and microcrystalline cellulose and stir evenly, add 0.75% ethanol solution of deacetylated chitosan as a binder to granulate, dry, sieve, and set aside; 3) Weighing, then adding 1% of the total weight of magnesium stearate, stirring evenly, and pressing into tablets to obtain tablets.

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