[0027] Embodiment (prescription quantity is 1000):
[0028] Eight specific prescriptions:
[0029] Prescription A:
[0030] Alfuzosin Hydrochloride 0.1g
[0031] Microcrystalline cellulose (filler) 48g
[0032] Sodium carboxymethyl starch (disintegrant) 0.5g
[0033] Magnesium stearate (lubricant) 0.9g
[0034] Micropowder silica gel (glidant) 0.5g
[0035] Preparation process: the main drug passes through a 120-mesh sieve, the filler and disintegrant pass through a 100-mesh sieve, weigh the prescribed amount of filler and disintegrant and mix evenly, and then mix the prescribed amount of the main drug with it in an equal-volume incremental method , add the prescribed amount of lubricant, mix well, and press into tablets. Dispersible tablet dispersion time limit is 3.0min.
[0036] Prescription B:
[0037] Alfuzosin Hydrochloride 1g
[0038] Microcrystalline cellulose (filler) 80g
[0039] Hydroxypropylcellulose (disintegrant) 3g
[0040] 2% PVP k30 Absolute ethanol solution (adhesive) 30g
[0041] Magnesium stearate (lubricant) 0.8g
[0042] Preparation process: the main drug passes through a 120-mesh sieve, the filler and disintegrant pass through a 100-mesh sieve, weigh the prescribed amount of filler and disintegrant and mix evenly, and then mix the prescribed amount of the main drug with it in an equal-volume incremental method , add an appropriate amount of binder to granulate, add the prescribed amount of lubricant after drying, mix well, and press into tablets. Dispersible tablet dispersion time limit is 2.8min.
[0043] Prescription C:
[0044] Alfuzosin Hydrochloride 2.5g
[0045] Microcrystalline cellulose (filler) 90g
[0046] Cross-linked polyvinylpyrrolidone (disintegrant) 5g
[0047] 5% starch slurry (adhesive) 40g
[0048] Magnesium stearate (lubricant) 0.5g
[0049] The preparation process is the same as that of prescription B. The time limit for dispersing tablets is 2.5 minutes.
[0050] Prescription D:
[0051] Alfuzosin Hydrochloride 10g
[0052] Microcrystalline cellulose (filler) 78g
[0053] Cross-linked polyvinylpyrrolidone (disintegrant) 10g
[0054] 2% PVP k30 Aqueous solution (adhesive) 50g
[0055] Magnesium stearate (lubricant) 1g
[0056] Preparation process: the main drug is passed through a 120-mesh sieve, the filler and disintegrant are passed through a 100-mesh sieve, the prescription amount of the main drug, filler and disintegrant is weighed and mixed evenly, an appropriate amount of binder is added to granulate, and the prescription is added after drying The amount of lubricant is mixed evenly, and the tablets are obtained. Dispersible tablet dispersion time limit is 2.0min.
[0057] Prescription E:
[0058] Alfuzosin Hydrochloride 30g
[0059] Lactose (filler) 48g
[0060] Sodium carboxymethyl starch (disintegrant) 20g
[0061] 2% PVP k30 Aqueous solution (adhesive) 50g
[0062] Magnesium stearate (lubricant) 1g
[0063] The preparation process is the same as that of prescription D. Dispersible tablet dispersion time limit is 2.2min.
[0064] Prescription F:
[0065] Alfuzosin Hydrochloride 50g
[0066] Lactose (filler) 34g
[0067] Cross-linked polyvinylpyrrolidone (disintegrant) 60g
[0068] 5% PVP k30 Absolute ethanol solution (adhesive) 100g
[0069] Magnesium stearate (lubricant) 1g
[0070] The preparation process is the same as that of prescription D. Dispersible tablet dispersion time limit is 1.0min.
[0071] Prescription G:
[0072] Alfuzosin Hydrochloride 70g
[0073] Microcrystalline cellulose (disintegrant) 242g
[0074] Preparation process: The main drug is passed through a 120-mesh sieve, and the disintegrant is passed through a 100-mesh sieve. The prescription amount of the main drug and the disintegrant is weighed and mixed evenly, and an appropriate amount of absolute ethanol is added to make granules. Dispersible tablet dispersion time limit is 0.7min.
[0075] Prescription H:
[0076] Alfuzosin Hydrochloride 100g
[0077] Cross-linked polyvinylpyrrolidone (disintegrant) 560g
[0078] 6% PVP k30 Aqueous solution (adhesive) 500g
[0079] Magnesium stearate (lubricant) 6g
[0080] Micronized silica gel (flow aid) 4g
[0081] The preparation process is the same as that of prescription D. Dispersible tablet dispersion time limit is 0.1min.
[0082] Dispersion Uniformity and In Vitro Dissolution Test of Alfuzosin Hydrochloride Dispersible Tablets
[0083] 1. Inspection of dispersion uniformity of alfuzosin hydrochloride dispersible tablets
[0084] Alfuzosin Hydrochloride Dispersible Tablets (prescriptions A to H), the uniformity of dispersion test method is as follows: Take 2 tablets of this product, shake in 100m1 water, in 20℃±1℃ water, it should be completely disintegrated in 3 minutes and pass through. No. 2 sieve. Please refer to Notes 1 to 8 in the attached table for details.
[0085] 2. Determination of in vitro dissolution of alfuzosin hydrochloride dispersible tablets
[0086] Alfuzosin hydrochloride dispersible tablets (prescription A~H), its in vitro dissolution test method is as follows: take this product according to the dissolution test method (the second method of appendix XC of the second part of the Chinese Pharmacopoeia version in 2000), with hydrochloric acid solution (9 → 1000) 500ml is a solvent, and the rotating speed is 50 revolutions per minute. Operate according to the law. After 30 minutes, get 10ml of the solution, filter, and get the subsequent filtrate as the test solution. According to spectrophotometry (Chinese Pharmacopoeia version two appendix IVA in 2000), measure absorbance at 244nm wavelength place; In addition, accurately weigh an appropriate amount of alfuzosin hydrochloride reference substance dried to constant weight through 105 ℃, with hydrochloric acid solution (9 → 1000 ) was dissolved and quantitatively diluted to make a solution containing 5 μg per 1 ml. The absorbance was measured by the same method, and the dissolution amount of each tablet was calculated. The limit was 80% of the labeled amount, which should meet the requirements. Please refer to the descriptions 1 to 8 of the attached drawings for details.
[0087] Table 1: In vitro cumulative dissolution rate and dispersion time limit of formulation A
[0088] time (min)
[0089] Table 2: In vitro cumulative dissolution rate and dispersion time limit of formulation B
[0090]
[0091] Table 3: In vitro cumulative dissolution rate and dispersion time limit of formulation C
[0092] time (min)
[0093] Table 4: In vitro cumulative dissolution rate and dispersion time limit of formulation D
[0094] time (min)
[0095] Table 5: In vitro cumulative dissolution rate and dispersion time limit of formulation E
[0096] time (min)
[0097] Table 6: In vitro cumulative dissolution rate and dispersion time limit of formulation F
[0098] time (min)
[0099] Table 7: In vitro cumulative dissolution rate and dispersion time limit of formulation G
[0100] time (min)
[0101] Scatter time limit
[0102] Table 8: In vitro cumulative dissolution rate and dispersion time limit of formulation H
[0103]
[0104] Pharmacokinetic study of alfuzosin dispersible tablets and alfuzosin ordinary tablets in healthy volunteers
[0105] 1. Subject selection criteria: healthy males aged 18 to 40 years old, with a weight difference of ±10% from the standard weight, avoiding overweight or underweight subjects, passing the comprehensive physical examination, and in good mental state, 2 weeks before the test Stop taking any medicine until the end of the test, no smoking, no alcoholism.
[0106] 2. Drugs and sources
[0107] Test preparation: Alfuzosin Hydrochloride Dispersible Tablets, provided by Shandong New Times Pharmaceutical Co., Ltd. Specifications: 2.5mg/tablet, the above-mentioned dispersion time limit and in vitro dissolution test are all qualified, and meet the quality standards for clinical research.
[0108] Reference preparation: Alfuzosin Hydrochloride Tablets, provided by Lunan Pharmaceutical Co., Ltd., specification: 2.5mg/tablet.
[0109] 3. Administration method
[0110] 18 subjects were paired in pairs according to their body weight, and they took the reference preparation Alfuzosin Hydrochloride Tablets (2.5 mg) orally every single time, and every time they took the test preparation Alfuzosin Hydrochloride Dispersible Tablets (2.5 mg) orally, according to random numbers, for one week Post-cross medication.
[0111] 4. Sample Collection
[0112] Start fasting after a light diet on the night before the experiment, take the medicine according to the prescribed dose on an empty stomach at 8:00 in the morning on the day of the experiment, take the reference preparation or the test preparation with 250ml of warm water, drink water 2 hours after taking the medicine, and drink water after 4 hours Have a uniform light diet. Each group of subjects collected 3ml of venous blood before the drug and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 18 hours after the drug, put it in a heparinized test tube, centrifuged for 5 minutes, and took the plasma 0.5ml, add 0.2ml of absolute ethanol, then add 0.5ml of 0.1mol/L NaOH solution, vortex for 1 minute, add 4ml of ether and continue shaking for 1 minute, centrifuge (2500 rpm, 20 minutes) to take the organic phase, Repeat the extraction once, place in a water bath at 40°C, blow dry with N2, and dissolve the residue with 0.5ml acetonitrile-0.02mol/L phosphate buffer (1:9) for sample analysis.
[0113]5. Data processing and statistical analysis The area under the alfuzosin hydrochloride plasma concentration-time curve (AUC) value is calculated by the trapezoidal method, in which AUC0~12 is calculated from the measured value of alfuzosin in plasma samples in vivo, and AUC12~∞ is calculated according to The k value of the slope of the lnc-t straight line at the tail of the elimination phase and the alfuzosin plasma concentration at the 12h point were calculated. Taking the AUC0~∞ of alfuzosin ordinary tablets as a reference, calculate the relative bioavailability of alfuzosin dispersible tablets. NDST5.0 statistical analysis program was selected, and the main pharmacokinetic parameters Tmax, Cmax and AUC0~∞ were analyzed by three-way analysis of variance and double one-sided t-test (significance level α=0.05). The results are shown in the table below.
[0114] Alfuzosin Ordinary Tablets
[0115] Compared with ordinary film group, P<0.05. There are significant differences.
[0116] The relative bioavailability of alfuzosin dispersible tablets and ordinary tablets is 123.15%.
[0117] 6. Conclusion
[0118] Alfuzosin hydrochloride dispersible tablet of the present invention is compared with existing alfuzosin hydrochloride common tablet, has significantly improved the absorption rate of medicine, makes its clinical curative effect more rapid; Timing and dosage set the stage. The bioavailability of the present invention is also greatly improved, which may be more obvious in elderly patients with decreased gastrointestinal absorption function. In addition, among the 18 volunteers, none of the gastrointestinal adverse reactions such as nausea, stomach pain and diarrhea occurred when taking the dispersible tablet; and 2 volunteers had nausea and stomach pain when taking the ordinary tablet. This shows that the gastrointestinal irritation of the alfuzosin hydrochloride dispersible tablet is significantly reduced.
