Epristeride gastric floating tablet and preparation method thereof

Abstract

The invention discloses epristeride gastric floating tablets and a preparation method thereof, and belongs to the field of medicines. The epristeride gastric floating tablet comprises the following components in percentage by mass: 1%-15% of epristeride, 10%-50% of a sustained release agent, 20%-55% of a filling agent, 5%-20% of an adhesive, 5%-30% of a foaming agent and 0.5%-3% of a lubricating agent. The preparation method comprises the following steps: uniformly mixing the active component, the slow-release agent, the filler, the adhesive and the foaming agent, performing wet granulation by using a wetting agent, drying and sieving to obtain dry granules; and uniformly mixing the obtained particles with a lubricant, and tabletting to obtain the epristeride gastric floating tablet. The epristeride gastric floating tablet obtained by a wet preparation process can rapidly float in a hydrochloric acid medium, and the epristeride gastric floating tablet can float for a long time and can be slowly released for 12 hours. According to the epristeride gastric floating tablet disclosed by the invention, the medication frequency can be reduced, the compliance of a patient is improved, the preparation process is simple, the raw materials are easy to obtain, and commercialized large-scale production can be realized.

Description

Technical Field

[0001] The invention belongs to the field of medicine, and particularly relates to an Aprelet gastric floating tablet and a preparation method thereof. Background Art

[0002] Prostatic hyperplasia, formerly known as prostatic hypertrophy, is a common disease in middle-aged and elderly men and a benign lesion of the prostate. Currently, traditional drugs for the treatment of prostatic hyperplasia mainly include α-adrenergic receptor blockers, M receptor antagonists, 5α-reductase inhibitors (such as Apretil) and other drugs.

[0003] The chemical name of Aprelet is 17β-(N-tert-butyl-amino-formyl)androsta-3,5-diene-3-carboxylic acid, and the molecular formula is C 25 H 37 NO3 is a non-competitive 5α-reductase inhibitor. Aprelet forms a ternary complex with 5α-reductase and NADP, inhibiting the conversion of testosterone to dihydrotestosterone in the prostate, thereby reducing the content of dihydrotestosterone, and has little effect on testosterone and dihydrotestosterone in the circulating blood. Long-term use of Aprelet can reduce the size of the prostate and reduce urination resistance, thereby alleviating bladder outlet obstruction to increase urine flow rate, reduce residual urine volume, and achieve the purpose of symptom improvement.

[0004]

[0005] The trade name of Aprelet tablets is "Chuanliu", and the dosage is 5 mg once a day, once in the morning and once in the evening, before or after meals. After oral administration, Aprelet tablets can be rapidly absorbed in the digestive tract, and the drug can be detected in the serum 0.25 hours after administration. The blood drug concentration reaches the peak in 3 to 4 hours, and the elimination phase half-life (T1 / 2β) is 7.5 hours.

[0006] Gastric floating tablets are low-density gastric retention tablets. After the drug is taken orally and enters the stomach, its density is lower than that of gastric juice (1.004~1.01g / cm 3 ) and float in gastric juice. According to the different floating mechanisms, it can be divided into two types: non-effervescent floating type and effervescent floating type. Among them, the effervescent floating type uses a foaming agent (carbonate or bicarbonate) to generate gas, wrapping the drug in floating bubbles to achieve a floating effect. This floating state prolongs the residence time of the drug in the stomach, promotes the dissolution and absorption of the drug, and thus enhances the efficacy.

[0007] Aprelet has the characteristics of fast oral absorption and short half-life. Multiple administration may cause peak-to-trough fluctuations in blood drug concentration and further lead to adverse reactions. Therefore, Aprelet can be developed into gastric floating tablets to stabilize blood drug concentration to reduce adverse reactions, and reduce the number of dosing times for patients to improve patient compliance with medication.

[0008] In view of this, the present invention is proposed. Summary of the invention

[0009] The first object of the present invention is to provide an Aprelet gastric floating tablet which can float quickly in a hydrochloric acid medium and has a long floating time.

[0010] The second purpose of the present invention is to propose a method for preparing Aprelet gastric floating tablets, which is simple, the raw materials are easy to obtain, and commercial-scale mass production can be achieved.

[0011] In order to solve the above problems, the technical solution adopted by the present invention is as follows:

[0012] The invention discloses an aprelet gastric floating tablet, wherein the components and their mass ratios are: 1%-15% aprelet, 10%-50% sustained-release agent, 20%-55% filler, 5%-20% binder, 5%-30% foaming agent and 0.5%-3% lubricant.

[0013] Furthermore, the mass ratio of the sustained-release agent is 15% to 30%.

[0014] Furthermore, the sustained-release agent is selected from one or more of hydroxypropyl cellulose, polymethacrylate, polyacrylate and polystyrene.

[0015] Furthermore, the filler is selected from one or more of lactose, starch, sucrose, and pregelatinized starch.

[0016] Furthermore, the adhesive is selected from one or more of copovidone, povidone, methyl cellulose and ethyl cellulose.

[0017] Furthermore, the foaming agent is selected from one or more of carbonates and bicarbonates.

[0018] Furthermore, the lubricant is selected from one or more of magnesium stearate, micro powder silica gel and talc.

[0019] Furthermore, the floating start time is less than 5 minutes and the continuous floating time is more than 12 hours.

[0020] Furthermore, the preparation method of any of the above-mentioned Aprelet gastric floating tablets comprises the following steps:

[0021] Step 1: weigh each component according to the mass percentage of each component in the Aprelet Gastric Floating Tablets;

[0022] Step 2: Evenly mix Aprelet, the sustained-release agent, the filler, the binder and the foaming agent to obtain a mixed powder;

[0023] Step 3: wet granulating the mixed powder obtained above with a wetting agent, drying the obtained wet granules, and sieving to obtain dry granules;

[0024] Step 4: Mix the obtained dry granules with the lubricant and press into tablets to obtain Aplit gastric floating tablets.

[0025] Furthermore, in step 4, the tabletting pressure range is 3-5 kg / cm 2 .

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] 1) The Aprelet gastric floating tablets of the present invention are designed with an effervescent floating mechanism, and can float quickly in a hydrochloric acid medium with a pH of 1.0, with a floating time of less than 5 minutes and a floating time of more than 12 hours.

[0028] 2) The Aprelet gastric floating tablets of the present invention will not have a sudden release within 1 hour, and can effectively release in vitro for about 12 hours, thereby avoiding side effects caused by fluctuations in blood drug concentration.

[0029] 3) The Aprelet gastric floating tablets of the present invention have the same therapeutic effect as commercially available preparations, reduce the frequency of administration, and improve patient compliance.

[0030] 4) The preparation process of the Aprelet gastric floating tablets of the present invention is simple, the raw materials are easily available, and commercial large-scale production can be achieved. DETAILED DESCRIPTION

[0031] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific implementation methods of the present invention are described in detail below in conjunction with specific embodiments.

[0032] The following examples are carried out under conventional conditions unless otherwise specified; the reagents or instruments used are commercially available products unless otherwise specified.

[0033] The test methods used in the following examples are as follows:

[0034] In vitro floating performance test: using a dissolution apparatus, with 900 mL of hydrochloric acid with a pH of 1.0 as the experimental medium, the medium temperature is 36.5°C~37.5°C, and the rotation speed is 50 rpm / min.

[0035] Dissolution determination of Aplit gastric floating tablets: The test was carried out in accordance with the provisions of the second method of dissolution and release determination method in the fourth general rule of the 2020 edition of the Chinese Pharmacopoeia, 0931, using 900 mL of degassed 0.5% SDS, pH 1.0 hydrochloric acid solution as the gastric release medium, the medium temperature was 36.5℃~37.5℃, and the speed was 75rpm / min. 10 mL of samples were taken at 1, 2, 3, 4, 5, 6, 7, 8, 10, and 12 hours, and an equal amount of fresh medium at the same temperature was supplemented at the same time. The sample was filtered through a 0.8μm microporous membrane, and the filtrate was taken to measure the absorbance with a UV-visible photometer, with a detection wavelength of 276nm; another appropriate amount of reference substance was accurately weighed and determined in the same way, and the cumulative release was calculated by the external standard method.

[0036] Stability test: Place the Apelite gastric floating tablets in an open culture dish and place them at 60°C (high temperature conditions) and 40°C, 75% RH (accelerated conditions) for 30 days. Detect the Apelite content and related substances in the samples at 0d, 5d, 10d and 30d to examine the stability.

[0037] The prescription of Aiplete Gastric Floating Tablets is shown in Table 1 below:

[0038] Table 1 Prescription of Aplit Gastric Floating Tablets of the present invention

[0039]

[0040] Among them, the active ingredient is Aprelet; the sustained-release agent is one or more of hydroxypropyl cellulose (HPMC), polymethacrylate, polyacrylate and polystyrene; the filler is one or more of lactose, starch, sucrose, and pregelatinized starch; the binder is one or more of copovidone, povidone, methyl cellulose, and ethyl cellulose; the foaming agent is one or more of carbonate and bicarbonate; the lubricant is one or more of magnesium stearate, micro-powder silica gel and talc.

[0041] Embodiment 1~4

[0042] The components and their mass percentages of Aiplete Gastric Floating Tablets are shown in Table 2 below:

[0043] Table 2 Comparison of components and mass percentages of Aprelet Gastric Floating Tablets in Examples 1 to 4

[0044]

[0045] The preparation method of the Aprelet gastric floating tablets in the above Examples 1 to 4 is as follows:

[0046] The active ingredients, sustained-release agents, fillers, binders and foaming agents in the prescribed amounts of each example were mixed uniformly, wet granulated with a wetting agent, passed through a 24-mesh sieve, dried at 40°C (the moisture content was controlled at 2-4%), and sieved through a 24-mesh sieve; the granules obtained above were mixed uniformly with a lubricant and stirred at a temperature of 3-5 kg / cm 2 The tablets were compressed into a tablet under a pressure of , thereby obtaining the Aplit gastric floating tablets.

[0047] Embodiment 5~7

[0048] The components and their mass percentages of Aiplete Gastric Floating Tablets are shown in Table 3 below:

[0049] Table 3 Comparison of components and mass percentages of Aprelet Gastric Floating Tablets in Examples 5 to 7

[0050]

[0051] The preparation method of Aprelet gastric floating tablets in Examples 5 to 7 is the same as that in Examples 1 to 4.

[0052] Example 8

[0053] The in vitro floating performance of the Aprelet gastric floating tablets prepared in Examples 1 to 4 was tested:

[0054] Six Aprelet gastric floating tablets prepared in Examples 1 to 4 were taken and placed in the experimental medium. The floating hysteresis time of the gastric floating tablets from being placed in the medium to floating to the liquid surface and the continuous floating time in the medium were recorded to examine the floating performance of the samples. The results are shown in Table 4 below:

[0055] Table 4 Floating performance test results of samples from Example 1 to Example 4

[0056]

[0057] The results show that the samples of Examples 1 to 4 can all float quickly in a hydrochloric acid experimental medium with a pH of 1.0, the floating time is no more than 5 minutes, and the continuous floating time is more than 12 hours.

[0058] Example 9

[0059] The dissolution rate of the Aprelet gastric floating tablets prepared in Examples 1 to 4 above was measured:

[0060] Six Aprelet gastric floating tablets prepared in Examples 1 to 4 were taken to investigate their cumulative release at different time points. The test results are shown in Table 5 below:

[0061] Table 5 In vitro release results of samples from Example 1 to Example 4

[0062]

[0063] The results show that the amount of sustained-release agent in the sample of Example 2 is 10%, and the cumulative release in 1 hour reaches 42.1%, with a certain burst release phenomenon. The amount of sustained-release agent in the sample of Example 3 is 42%, and the cumulative release in 12 hours is only 64.1%, and the release rate is slow. There is no burst release phenomenon in the cumulative release of the samples of Example 1 (the amount of sustained-release agent is 15%) and Example 3 (the amount of sustained-release agent is 23%), and the cumulative release in 12 hours reaches more than 90%. The above results show that too much sustained-release agent in the floating tablet will lead to a slow release in vitro, and too little sustained-release agent will lead to a burst release in vitro. Therefore, the preferred amount of sustained-release agent is 15-30%.

[0064] Example 10

[0065] The stability test of the Aprelet gastric floating tablets prepared in the above Examples 1 to 4 was carried out, and the results are shown in Table 6 below:

[0066] Table 6 Stability test results of samples from Example 1 to Example 4

[0067]

[0068] The results showed that the Aplilet gastric floating tablets in Examples 1 to 4 were placed at 60°C (high temperature conditions) and 40°C, 75% RH (accelerated conditions) for 30 days, and the content and related substances were within the limits, indicating that the Aplilet gastric floating tablets prepared by the present invention have stable properties and reliable quality.

[0069] Embodiment 11

[0070] Experiments on benign prostatic hyperplasia (BPH) in rats

[0071] The sample prepared in Example 1 and the commercially available 5 mg Aprelet (using the product Chuanliu 5 mg tablets of Jiangsu Lianhuan Pharmaceutical) were used for comparative testing. The experimental method is as follows:

[0072] The testicles of male SD rats were removed under sterile conditions to establish a BPH rat model. Penicillin 20,000 U / kg was injected intramuscularly for 3 consecutive days. One week after the operation, testosterone propionate (0.5 mg / rat) dissolved in olive oil was injected subcutaneously once a day for 4 consecutive weeks to induce BPH. Male SD rats were divided into 4 groups, 10 rats in each group, namely, a blank group (castrated rats, intragastric administration of normal saline), a model group (castrated rats + testosterone propionate, intragastric administration of normal saline), a control group (castrated rats + testosterone propionate, administered with 1.5 mg / kg commercially available Aprelet, twice a day), and Example 1 group (castrated rats + testosterone propionate, administered with 3 mg / kg Aprelet gastric floating tablets, once a day). After 4 consecutive weeks of administration, the ventral lobe, agglutinating gland and dorsal lobe of the prostate were removed, and the wet weight was weighed. After the total weight was combined, the prostate index was calculated according to the following formula: Prostate index (%) = prostate wet weight (g) / body weight (g) × 100%, and the results are shown in Table 7 below.

[0073] Table 7 Pharmacological efficacy test results of the Aplilet gastric floating tablets prepared by the present invention and the commercially available Aplilet (n=10)

[0074]

[0075] In Table 7, = means: P < 0.001 compared with the blank group; ### means: P < 0.001 compared with the model group.

[0076] The results in Table 7 show that compared with the blank group, the prostate index of the model group was significantly increased, indicating that the rat BPH model was successfully constructed. Compared with the model group, the control group (1.5 mg / kg commercially available Aprelet, twice a day) and Example 1 (3 mg / kg Aprelet gastric floating tablets, once a day) both significantly reduced the prostate index, making it close to that of the blank group, indicating that both had good therapeutic effects. The prostate index of Example 1 was similar to that of the control group, while the frequency of medication was reduced from twice a day to once a day. Therefore, Aprelet gastric retention tablets have consistent efficacy compared with commercially available preparations, and reduce the frequency of administration, thereby improving patient compliance.

[0077] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. An Aprelet gastric floating tablet, characterized in that: The components and their mass ratios are: 1% to 15% of Aprelet, 10% to 50% of sustained-release agent, 20% to 55% of filler, 5% to 20% of binder, 5% to 30% of foaming agent and 0.5% to 3% of lubricant.

2. The Aprelet gastric floating tablet according to claim 1, characterized in that: The mass ratio of the sustained-release agent is 15% to 30%.

3. The Aprelet gastric floating tablet according to claim 1, characterized in that: The sustained-release agent is selected from one or more of hydroxypropyl cellulose, polymethacrylate, polyacrylate and polystyrene.

4. The Aprelet gastric floating tablet according to claim 1, characterized in that: The filler is selected from one or more of lactose, starch, sucrose and pregelatinized starch.

5. The Aprelet gastric floating tablet according to claim 1, characterized in that: The binder is selected from one or more of copolyvidone, povidone, methyl cellulose and ethyl cellulose.

6. The Aprelet gastric floating tablet according to claim 1, characterized in that: The foaming agent is selected from one or more of carbonates and bicarbonates.

7. The Aprelet gastric floating tablet according to claim 1, characterized in that: The lubricant is selected from one or more of magnesium stearate, micro powder silica gel and talc.

8. The Aprelet gastric floating tablet according to any one of claims 1 to 7, characterized in that: The floating start time is less than 5 minutes and the continuous floating time is more than 12 hours.

9. A method for preparing the Aprelet gastric floating tablet according to any one of claims 1 to 8, characterized in that: Here are the steps: Step 1: weigh each component according to the mass percentage of each component in the Aprelet Gastric Floating Tablets; Step 2: Evenly mix Aprelet, the sustained-release agent, the filler, the binder and the foaming agent to obtain a mixed powder; Step 3: wet granulating the mixed powder obtained above with a wetting agent, drying the obtained wet granules, and sieving to obtain dry granules; Step 4: Mix the obtained dry granules with the lubricant and press into tablets to obtain Aplit gastric floating tablets.

10. The method for preparing the Aprelet gastric floating tablet according to claim 9, characterized in that: In step 4, the tabletting pressure range is 3-5 kg / cm 2 .

Images