A kind of megestrol acetate dispersible tablet and preparation method thereof

Abstract

The present invention relates to a megestrol acetate dispersible tablet and a preparation method thereof, and relates to the field of medical technology. The tablet comprises megestrol acetate, a main molecule inclusion compound, a filler, a disintegrant and a lubricant; megestrol acetate and the main molecule inclusion compound are fully dissolved in water, and the water is removed by a spray drying process to obtain a solid inclusion compound; the drying is continued to obtain an inclusion compound powder; the inclusion compound powder is mixed with a filler, a disintegrant and a lubricant, and the tablet is obtained by tablet pressing. The present application utilizes the hole structure of the main molecule inclusion compound to contain megestrol acetate inside to form a molecular capsule. Megestrol acetate and the main molecule inclusion compound are mixed in a specific ratio to form an inclusion compound, and the air inlet temperature, atomization pressure and flow rate are set in the later spray drying step, which is conducive to increasing the solubility of the drug, improving the stability of the drug and improving the bioavailability. The present application does not require micronization of the raw material drug, reduces the processing difficulty and cost, has simple steps and saves production time.

Description

Technical Field

[0001] The invention relates to the technical field of medicines, and in particular to a megestrol acetate dispersible tablet and a preparation method thereof. Background Art

[0002] Megestrol acetate is a progestogen drug with a molecular formula of C 24 H 32 O4 is mainly used to treat advanced breast cancer and advanced endometrial cancer. It also has a certain effect on renal cancer, prostate cancer and ovarian cancer. It can improve the appetite and cachexia of patients with advanced tumors, enhance the patient's demand for and intake of food, and thus improve the patient's nutritional status. Megestrol acetate mainly controls the development and growth of ovarian follicles by affecting the secretion of pituitary gonadotropin, thereby reducing the production of estrogen; it acts on estrogen receptors, preventing their synthesis and reuse, interfering with their binding with estrogen, and inhibiting the growth of tumor cells.

[0003] Megestrol acetate is a poorly soluble drug. Mechanical crushing or micronization is often used to reduce the size of drug particles to increase the dispersion of the drug in the preparation, increase the dissolution rate, and thus improve the bioavailability. However, this method is difficult to achieve the ideal drug dissolution requirements. In addition, the megestrol acetate raw material itself has high aggregation, and it is not easy to disperse evenly during the mixing process with the excipients. It takes more mixing time to ensure the uniform content of the tablets, and the production efficiency is low.

[0004] Patent application CN115531333A discloses a megestrol acetate dispersible tablet and a preparation method thereof, wherein the dispersible tablet comprises: megestrol acetate micropowder, mannitol, microcrystalline cellulose, talcum powder, sodium lauryl sulfate, caprate, flavoring agent, polyvinyl pyrrolidone, and lubricant; during the preparation process, carbon dioxide is introduced into the megestrol acetate solution until the pressure reaches 15-20MPa, the temperature is raised to 45-50°C, the pressure is maintained for 5-8h, the pressure is released, the temperature is lowered, the filtration is performed, and the megestrol acetate micropowder is obtained. The micropowder process is complicated, the particle size of the particles after micronization is very small, and the processing difficulty and cost are high; and the surface area of ​​the drug particles after micronization increases, which may lead to a decrease in the chemical stability of the drug, and oxidation, hydrolysis and other reactions are prone to occur, affecting the effectiveness and safety of the drug.

[0005] Patent application CN111643463A discloses a megestrol acetate dispersible tablet and a preparation method thereof, wherein megestrol acetate, microcrystalline cellulose and lactose are crushed, sieved and mixed uniformly according to the prescribed dosage, and then other auxiliary materials such as cross-linked carboxymethyl cellulose sodium, low-substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose, talcum powder and magnesium stearate are added, ethanol is used as a wetting agent to prepare a soft material, granulate, dry, granulate and tablet to obtain a dispersible tablet. Compared with the inclusion compound dispersible tablet, this patent method has the disadvantages of poor stability and low bioavailability.

[0006] Therefore, it is necessary to develop a megestrol acetate dispersible tablet with high production efficiency, high dissolution, good stability and high bioavailability. Summary of the invention

[0007] The object of the present invention is to provide a megestrol acetate dispersible tablet and a preparation method thereof. The megestrol acetate dispersible tablet obtained by the method has high production efficiency, high solubility, good stability and high bioavailability, and solves the problems of difficult micronization process, slow dissolution rate, poor stability and complicated preparation method in the prior art. To achieve this object, the present invention adopts the following technical scheme:

[0008] The first aspect of the present invention provides a megestrol acetate dispersible tablet, comprising megestrol acetate, a main molecule inclusion compound, a filler, a disintegrant and a lubricant;

[0009] The main molecule inclusion complex includes one or more of cyclodextrin, hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, and glucosyl-β-cyclodextrin; the filler includes one or more of lactose, microcrystalline cellulose, corn starch, and silicon dioxide; the disintegrant includes one or more of sodium carboxymethyl starch and cross-linked sodium carboxymethyl cellulose; the lubricant includes one or more of magnesium stearate and talc.

[0010] As an embodiment of the present invention, the main molecule inclusion compound is hydroxypropyl-β-cyclodextrin; the filler is lactose; the disintegrant is sodium carboxymethyl starch; and the lubricant is magnesium stearate.

[0011] As an embodiment of the present invention, the weight contents of the components of the megestrol acetate tablets are: 160 parts of megestrol acetate, 160-480 parts of main molecule inclusion complex, 35-45 parts of filler, 15-45 parts of disintegrant, and 3.7-7.3 parts of lubricant.

[0012] As an embodiment of the present invention, the weight content of each component of the megestrol acetate tablets is: the weight content of each component of the megestrol acetate tablets is: 160 parts of megestrol acetate, 160-480 parts of hydroxypropyl-β-cyclodextrin, 35-45 parts of lactose, 15-45 parts of sodium carboxymethyl starch, and 3.7-7.3 parts of magnesium stearate.

[0013] The second aspect of the present invention provides a method for preparing megestrol acetate dispersible tablets, the preparation method comprising the following steps:

[0014] Step 1, preparing a solid inclusion compound: fully dissolving megestrol acetate, the main molecule inclusion compound and water, and spray drying to remove water to obtain a solid inclusion compound;

[0015] Step 2, drying: further drying the solid inclusion compound to obtain inclusion compound powder;

[0016] Step 3: Total mixing and tableting: The inclusion compound powder is mixed with a filler, a disintegrant and a lubricant, and tableted by a tablet press to obtain megestrol acetate dispersible tablets.

[0017] Inclusion complex is a special complex formed by a drug molecule being completely included in the cavity structure of another molecule. This inclusion complex consists of a host molecule and a guest molecule. The host molecule (i.e., host molecule inclusion complex) has a cavity structure sufficient to accommodate the guest molecule (i.e., megestrol acetate) to form a molecular capsule. The inclusion complex formed by megestrol acetate and the host molecule inclusion complex can significantly increase the solubility of the drug, improve the stability of the drug, regulate the release rate of the drug, and improve the bioavailability.

[0018] As an embodiment of the present invention, in the step 1: the ratio of megestrol acetate to the main molecule inclusion complex is 1:1, 1:2 or 1:3, preferably 1:2.

[0019] As an embodiment of the present invention, in step 1: the spray drying inlet air temperature is 105°C-135°C, preferably 120°C, the atomization pressure is 0.3-0.5MPa, preferably 0.4MPa, and the flow rate is 50-80g / min, preferably 65g / min.

[0020] As an embodiment of the present invention, in the step 2: the drying air inlet temperature is 60-80°C, preferably 70°C.

[0021] As an embodiment of the present invention, the drying is performed until the material temperature is greater than 50°C.

[0022] As an embodiment of the present invention, in step 3: the main pressure of the tablet press is 15-20KN, and the tablet hardness is 8-12KG. Compared with the prior art solution, the present invention has the following beneficial effects:

[0023] 1. The present application fully dissolves megestrol acetate and the main molecule inclusion compound in water; the main molecule inclusion compound has high solubility in water, and the megestrol acetate is contained in the inclusion compound by utilizing the hole structure of the main molecule inclusion compound to form a molecular capsule. Megestrol acetate and the main molecule inclusion compound are mixed in a specific ratio to form an inclusion compound, and the inlet air temperature, atomization pressure, and flow rate are set in the later spray drying step, which is conducive to increasing the solubility of the drug, improving the stability of the drug, adjusting the release rate of the drug, and improving the bioavailability.

[0024] 2. The present application does not require micronization of the megestrol acetate API, thereby simplifying the process while ensuring the solubility of the drug, reducing the processing difficulty and cost, simplifying the steps, and saving production time; it can also avoid the agglomeration of the micronized particles due to their small particle size, thereby causing poor fluidity, which is beneficial to improving the quality and stability of the drug. DETAILED DESCRIPTION

[0025] The present invention is further described below in conjunction with examples, but the embodiments of the present invention are not limited thereto.

[0026] The raw materials, reagents, materials and equipment used in the examples can all be purchased through commercial channels.

[0027] Example 1

[0028] The present embodiment provides a megestrol acetate dispersible tablet and a preparation method thereof, the preparation method comprising the following steps:

[0029] Step 1, preparing a solid inclusion compound: fully dissolving 160 parts of megestrol acetate, 320 parts of hydroxypropyl-β-cyclodextrin and 1600 parts of water, setting the inlet air temperature to 120° C., the atomization pressure to 0.4 MPa, and the flow rate to 65 g / min for spray drying, and removing water to obtain a solid inclusion compound;

[0030] Step 2, drying: the solid inclusion compound is further dried, the air inlet temperature is adjusted to 70°C, and other parameters remain unchanged. When the temperature of the solid inclusion compound is 55°C, spray drying is stopped to obtain inclusion compound powder;

[0031] Step 3: Total mixing and tableting: Mix the inclusion compound powder with 40 parts of lactose, 30 parts of sodium carboxymethyl starch, and 5.5 parts of magnesium stearate, and compress the mixture into megestrol acetate dispersible tablets by a tablet press. The main pressure of the tablet press is 17KN, and the tablet hardness is 10KG.

[0032] Example 2

[0033] The present embodiment provides a megestrol acetate dispersible tablet and a preparation method thereof, the preparation method comprising the following steps:

[0034] Step 1, preparing a solid inclusion compound: fully dissolving 160 parts of megestrol acetate, 160 parts of cyclodextrin and 1280 parts of water, setting the inlet air temperature to 120°C, the atomization pressure to 0.4 MPa, and the flow rate to 65 g / min for spray drying, and removing water to obtain a solid inclusion compound;

[0035] Step 2, drying: the solid inclusion compound is further dried, the air inlet temperature is adjusted to 70°C, and other parameters remain unchanged. When the temperature of the solid inclusion compound is 55°C, spray drying is stopped to obtain inclusion compound powder;

[0036] Step 3: Total mixing and tableting: Mix the inclusion compound powder with 35 parts of microcrystalline cellulose, 15 parts of cross-linked carboxymethyl cellulose sodium, and 3.7 parts of talc, and compress the mixture into megestrol acetate dispersible tablets by a tablet press. The main pressure of the tablet press is 15KN, and the tablet hardness is 8KG.

[0037] Example 3

[0038] The present embodiment provides a megestrol acetate dispersible tablet and a preparation method thereof, the preparation method comprising the following steps:

[0039] Step 1, preparing a solid inclusion compound: fully dissolving 160 parts of megestrol acetate, 480 parts of glucosyl-β-cyclodextrin and 1920 parts of water, spray drying, setting the air inlet temperature to 120°C, the atomization pressure to 0.4 MPa, and the flow rate to 65 g / min, and removing water to obtain a solid inclusion compound;

[0040] Step 2, drying: the solid inclusion compound is further dried, the air inlet temperature is adjusted to 70°C, and other parameters remain unchanged. When the temperature of the solid inclusion compound is 55°C, spray drying is stopped to obtain inclusion compound powder;

[0041] Step 3: Total mixing and tableting: Mix the inclusion compound powder with 45 parts of corn starch, 45 parts of sodium carboxymethyl starch, and 7.3 parts of magnesium stearate, and compress the mixture into megestrol acetate dispersible tablets using a tablet press. The main pressure of the tablet press is 20KN, and the tablet hardness is 12KG.

[0042] Example 4

[0043] The present embodiment provides a megestrol acetate dispersible tablet and a preparation method thereof, the preparation method comprising the following steps:

[0044] Step 1, preparing a solid inclusion compound: fully dissolving 160 parts of megestrol acetate, 320 parts of hydroxypropyl-β-cyclodextrin and 1600 parts of water, setting the inlet air temperature to 105°C, the atomization pressure to 0.3MPa, and the flow rate to 50g / min for spray drying, and removing water to obtain a solid inclusion compound;

[0045] Step 2, drying: continue to dry the solid inclusion compound, adjust the air inlet temperature to 60°C, and keep other parameters unchanged. When the temperature of the solid inclusion compound reaches 60°C, stop spray drying to obtain inclusion compound powder;

[0046] Step 3: Total mixing and tableting: Mix the inclusion compound powder with 40 parts of lactose, 30 parts of sodium carboxymethyl starch, and 5.5 parts of magnesium stearate, and compress the mixture into megestrol acetate dispersible tablets by a tablet press. The main pressure of the tablet press is 17KN, and the tablet hardness is 10KG.

[0047] Example 5

[0048] The present embodiment provides a megestrol acetate dispersible tablet and a preparation method thereof, the preparation method comprising the following steps:

[0049] Step 1, preparing a solid inclusion compound: fully dissolving 160 parts of megestrol acetate, 320 parts of hydroxypropyl-β-cyclodextrin and 1600 parts of water, setting the inlet air temperature to 135° C., the atomization pressure to 0.5 MPa, and the flow rate to 80 g / min for spray drying, and removing water to obtain a solid inclusion compound;

[0050] Step 2, drying: the solid inclusion compound is further dried, the air inlet temperature is adjusted to 80°C, and other parameters remain unchanged. When the temperature of the solid inclusion compound is 60°C, the spray drying is stopped to obtain the inclusion compound powder;

[0051] Step 3: Total mixing and tableting: Mix the inclusion compound powder with 40 parts of lactose, 30 parts of sodium carboxymethyl starch, and 5.5 parts of magnesium stearate, and compress the mixture into megestrol acetate dispersible tablets by a tablet press. The main pressure of the tablet press is 17KN, and the tablet hardness is 10KG.

[0052] Comparative Example 1

[0053] The present embodiment provides a megestrol acetate dispersible tablet and a preparation method thereof, the preparation method comprising the following steps:

[0054] Step 1, preparing a solid inclusion compound: fully dissolving 160 parts of megestrol acetate, 320 parts of β-cyclodextrin and 1600 parts of water, setting the inlet air temperature to 120°C, the atomization pressure to 0.4 MPa, and the flow rate to 65 g / min for spray drying, and removing water to obtain a solid inclusion compound;

[0055] Step 2, drying: the solid inclusion compound is further dried, the air inlet temperature is adjusted to 70°C, and other parameters remain unchanged. When the temperature of the solid inclusion compound is 55°C, spray drying is stopped to obtain inclusion compound powder;

[0056] Step 3: Total mixing and tableting: Mix the inclusion compound powder with 40 parts of lactose, 30 parts of sodium carboxymethyl starch, and 5.5 parts of magnesium stearate, and compress the mixture into megestrol acetate dispersible tablets by a tablet press. The main pressure of the tablet press is 17KN, and the tablet hardness is 10KG.

[0057] Comparative Example 2

[0058] The present embodiment provides a megestrol acetate dispersible tablet and a preparation method thereof, the preparation method comprising the following steps:

[0059] 160 parts of megestrol acetate, 40 parts of anhydrous lactose, 80 parts of ethyl cellulose, 10 parts of sodium carboxymethyl starch, and 5 parts of magnesium stearate. The preparation process is as follows.

[0060] ① Micro-crushing: Megestrol acetate is crushed by air flow mill with air inlet pressure of 0.5Mpa;

[0061] ② Premixing: add megestrol acetate, anhydrous lactose, and microcrystalline cellulose into a wet granulation mixer in sequence, start stirring and chopping for 10 minutes;

[0062] ③ Wet granulation: stirring speed 10rpm, chopping 15rpm, adding appropriate amount of water for granulation;

[0063] ④ Whole grains after drying;

[0064] ⑤Total mixing: mix the dry granules obtained in ③ with the additional auxiliary materials sodium carboxymethyl starch and magnesium stearate;

[0065] ⑥ Tablet pressing: The main pressure of the tablet press is 15-20KN, and the tablet hardness is 8-12KG.

[0066] Dissolution rate study

[0067] The dispersible tablets prepared in Examples 1 to 5 and Comparative Examples 1 to 2 were tested for dissolution rate.

[0068] The specific method of dissolution rate in this application is as follows: refer to the dissolution and release determination method of the 2020 edition of the Chinese Pharmacopoeia (General Rule 0931 Method 2), and the dissolution conditions are as follows: 900 mL of 1% sodium dodecyl sulfate solution is used as the dissolution medium, the speed is 75 revolutions per minute, and the operation is carried out according to the law. Samples are taken for testing at 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, and 60 minutes after tableting. The relevant indicators obtained are detailed in Table 1:

[0069] Table 1 - Dissolution rate indicators

[0070]

[0071] Conclusion: The megestrol acetate dispersible tablets prepared in Examples 1 to 5 have a faster dissolution rate than those in Comparative Examples 1 to 2, so that the megestrol acetate is absorbed faster in the human body, thereby achieving a quick onset of action and improving bioavailability. Comparative Example 1 uses β-cyclodextrin as the main molecule inclusion compound, while Comparative Example 2 does not use the main molecule inclusion compound. In Examples 1 to 5, megestrol acetate and the main molecule inclusion compound are mixed in a specific ratio to form an inclusion compound, and specific prescription ingredients and quantities of fillers, disintegrants, and lubricants are combined, and specific spray drying parameters are set to obtain megestrol acetate dispersible tablets with better dissolution effect.

[0072] Stability test

[0073] The megestrol acetate dispersible tablets prepared in Examples 1 to 5 and Comparative Examples 1 to 2 were subjected to accelerated tests at 40° C. for 3 months. The test results are shown in Table 2 below.

[0074] Table 2 - Accelerated test results

[0075]

[0076]

[0077] As shown in Table 2, when accelerated for 3 months, the contents of comparative examples 1 to 2 decreased, while the contents of samples of embodiments 1 to 5 of the present invention did not change significantly, indicating that the present invention utilizes megestrol acetate and the main molecule inclusion compound to form an inclusion compound, so that the stability of the prepared dispersible tablet is better than that of the commercially available one, and there is no need to micronize megestrol acetate.

[0078] Bioavailability study

[0079] The megestrol acetate dispersible tablets prepared in Example 1 and Comparative Example 2 were subjected to a relative bioavailability experiment on 36 healthy volunteers under fasting conditions, and each group (n=18) was administered 160 mg of megestrol acetate dispersible tablets prepared in Example 1 and Comparative Example 2, respectively (the megestrol acetate dispersible tablets prepared in Example 1 and Comparative Example 2 were cross-tested). The average blood concentration of megestrol acetate is shown in Table 3.

[0080] Table 3: Mean blood drug concentrations

[0081]

[0082]

[0083] It can be seen from Table 3 that, compared with the megestrol acetate dispersible tablets prepared in Comparative Example 2, the megestrol acetate dispersible tablets in Example 1 of the present invention significantly improve the oral absorption bioavailability of the drug.

Claims

1. A megestrol acetate dispersible tablet, characterized in that: It includes megestrol acetate, a main molecule inclusion compound, a filler, a disintegrant and a lubricant; The main molecule inclusion complex includes one or more of cyclodextrin, hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, and glucosyl-β-cyclodextrin; the filler includes one or more of lactose, microcrystalline cellulose, corn starch, and silicon dioxide; the disintegrant includes one or more of sodium carboxymethyl starch and cross-linked sodium carboxymethyl cellulose; the lubricant includes one or more of magnesium stearate and talc.

2. A megestrol acetate dispersible tablet according to claim 1, characterized in that: The main molecular inclusion compound is hydroxypropyl-β-cyclodextrin; the filler is lactose; the disintegrant is sodium carboxymethyl starch; and the lubricant is magnesium stearate.

3. A megestrol acetate dispersible tablet according to claim 2, characterized in that, The weight contents of the components of the megestrol acetate tablets are: 160 parts of megestrol acetate, 160-480 parts of main molecule inclusion compound, 35-45 parts of filler, 15-45 parts of disintegrant, and 3.7-7.3 parts of lubricant.

4. A megestrol acetate dispersible tablet according to claim 3, characterized in that, The weight content of each component of the megestrol acetate tablet is as follows: the weight content of each component of the megestrol acetate tablet is as follows: 160 parts of megestrol acetate, 160-480 parts of hydroxypropyl-β-cyclodextrin, 35-45 parts of lactose, 15-45 parts of sodium carboxymethyl starch, and 3.7-7.3 parts of magnesium stearate.

5. A method for preparing the megestrol acetate dispersible tablets according to any one of claims 1 to 4, characterized in that: The preparation method comprises the following steps: Step 1, preparing a solid inclusion compound: fully dissolving megestrol acetate, the main molecule inclusion compound and water, and spray drying to remove water to obtain a solid inclusion compound; Step 2, drying: further drying the solid inclusion compound to obtain inclusion compound powder; Step 3: Total mixing and tableting: Mix the inclusion compound powder with the filler, disintegrant and lubricant, and compress the mixture into megestrol acetate dispersible tablets using a tablet press.

6. The preparation method according to claim 5, characterized in that: In the step 1, the ratio of megestrol acetate to the main molecule inclusion complex is 1:1, 1:2 or 1:3, preferably 1:

2.

7. The preparation method according to claim 5, characterized in that: In the step 1, the spray drying air inlet temperature is 105°C-135°C, preferably 120°C, the atomization pressure is 0.3-0.5MPa, preferably 0.4MPa, and the flow rate is 50-80g / min, preferably 65g / min.

8. The preparation method according to claim 5, characterized in that: In the step 2: the drying air inlet temperature is 60-80°C, preferably 70°C.

9. The preparation method according to claim 8, characterized in that: The drying step is performed until the material temperature is greater than 50°C.

10. The preparation method according to claim 9, characterized in that: In the step 3: the main pressure of the tablet press is 15-20KN, and the tablet hardness is 8-12KG.

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