CN102085193B - Tibolone orally disintegrating tablets and method for preparing same - Google Patents
Tibolone orally disintegrating tablets and method for preparing same Download PDFInfo
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- CN102085193B CN102085193B CN 200910241388 CN200910241388A CN102085193B CN 102085193 B CN102085193 B CN 102085193B CN 200910241388 CN200910241388 CN 200910241388 CN 200910241388 A CN200910241388 A CN 200910241388A CN 102085193 B CN102085193 B CN 102085193B
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Abstract
The invention provides tibolone orally disintegrating tablets and a method for preparing the same. The tibolone orally disintegrating tablets comprise tibolone serving as a main ingredient and a disintegrating agent, a bulking agent, a flavoring agent and the like serving as auxiliary ingredients. The preparation method comprises the steps of mixing, direct tabletting, coating and the like. The tibolone orally disintegrating tablets have the formulation advantages that the tablets can be disintegrated or dissolved in the mouth without water and enter the alimentary tract along with the swallowing action, and the in-vivo behavior of the tablets is the same as that of the common tablets. The tibolone orally disintegrating tablets have the characteristics of convenience of taking, rapid absorption, high bioavailability and the like, and can improve the adaptability of patients and offer more options for doctors and patients in clinical administration.
Description
Technical field
The present invention relates to a kind of tibolone oral cavity disintegration tablet and preparation method thereof, belong to technical field of medicine.
Background technology
Tibolone can be stablized the hypothalamus-pituitary system of women after climacteric ovarian function decline.This central action is the synthesis result of the multiple hormone characteristic that has from tibolone, for example estrogen activity, progestin reach weak androgenic activity, these characteristics will be confirmed by following various effect: tibolone is in every day during oral 2.5 milligrams of dosage, can suppress postmenopausal women's Gonadotropin Level and suppress the ovulation of women at fertile age.The tibolone of this dosage does not stimulate postmenopausal women's endometrium.Only there is the only a few patient slight uterus hypertrophy to occur; The degree of its hypertrophy does not increase along with the prolongation of medicine time.Simultaneously also observe tibolone to the stimulation of vaginal mucosa.The tibolone of same dosage has the effect that suppresses postmenopausal women's bone loss.Menopausal symptom particularly vasomotor symptoms such as hectic fever, hyperhidrosis etc. all is suppressed, and libido and emotion are also had good effect.
The development of oral cavity disintegration tablet starts from late 1970s, has the characteristics such as rapid-action, taking convenience due to it, and existing tens these kinds are gone on the market in various countries at present.China SFDA with oral cavity disintegration tablet as a kind of novel form, national medicine is examined the application that more than 300 this kind accepted at the center, this market is developing growth rapidly.
Oral cavity disintegration tablet (orally disintegrating tablets) is called for short oral cavity disintegration tablet, is that a kind of water that do not need in the oral cavity can disintegrate or the tablet of dissolving.The preparation characteristic of oral cavity disintegration tablet is: do not need water or only need use a small amount of water, also need not to chew, medicine is placed in the oral cavity, after meeting the rapid dissolving of saliva or disintegrate, along with autonomous and involuntary swallowing act of user enter digestive system and absorb after onset, be particularly useful for the patient's medication under the special environments such as old man, child, dysphagia or drinking-water inconvenience.Compare with conventional tablet, the advantage of oral cavity disintegration tablet is: rapid-action, bioavailability is high, taking convenience, and reducing medicine stimulates esophagus and gastrointestinal.
Summary of the invention
The purpose of this invention is to provide a kind of tibolone oral cavity disintegration tablet and preparation method thereof.
Tibolone oral cavity disintegration tablet of the present invention is made by the supplementary material medicine of following weight portion:
Tibolone 100, lactose 120-160, mannitol 350-400, microcrystalline Cellulose 250-300, low-substituted hydroxypropyl cellulose 60-70, aspartame 1-4, magnesium stearate 8-12;
Preferably, medicine of the present invention is to be made by the supplementary material medicine of following weight ratio:
Tibolone 100, lactose 120, mannitol 350, microcrystalline Cellulose 250, low-substituted hydroxypropyl cellulose 60, aspartame 1, magnesium stearate 8;
Perhaps:
Tibolone 100, lactose 160, mannitol 400, microcrystalline Cellulose 300, low-substituted hydroxypropyl cellulose 70, aspartame 4, magnesium stearate 12;
Perhaps:
Tibolone 100, lactose 140, mannitol 375, microcrystalline Cellulose 275, low-substituted hydroxypropyl cellulose 65, aspartame 2.5, magnesium stearate 10.
Another object of the present invention is to provide the preparation method of this tibolone oral cavity disintegration tablet, and the preparation method of medicine of the present invention is as follows:
(a) tibolone, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, mannitol, magnesium stearate in 105 ℃ of dryings 1 hour, were pulverized 100 mesh sieves, and it is standby that lactose and aspartame were pulverized 100 mesh sieves;
(b) take in proportion the low-substituted hydroxypropyl cellulose of tibolone, mannitol, lactose, aspartame, 1/3 amount, the microcrystalline Cellulose mixing of 1/3 amount, get mixed material;
(c) add 50% alcoholic solution in step (b) gained mixed material, make suitable soft material, granulate with 32 mesh sieves, wet grain is in 45 ± 5 ℃ of dryings, with 32 mesh sieve granulate;
(d) with the microcrystalline Cellulose of step (c) gained granule and surplus, the low-substituted hydroxypropyl cellulose of surplus, the magnesium stearate mix homogeneously of proportional quantities;
(e) semi-finished product chemical examination, tabletting and get final product.
The supplementary material part by weight of tibolone oral cavity disintegration tablet of the present invention and preparation method are through a large amount of strict screening tests, process certification, just obtain after stability study, be not just can directly obtain by preparation teaching material or other reference material, through screening test, process certification, stability study proved invention supplementary material ratio is reasonable, stable preparation process, finished product preparation is stable, meets galenic pharmacy and State Food and Drug Administration for the preparation guideline requirement of oral cavity disintegration tablet.
After tibolone orally disintegrating tablet preparation of the present invention is completed, carried out quality research, worked out the method for inspection of indices, and carried out the methodology checking of each index detection method according to the guideline of Chinese Pharmacopoeia and new drug research, all methods all meet the analysis of pharmaceutical dosage forms requirement, detect and study according to the tibolone oral cavity disintegration tablet of these methods to development.
1. little sample testing:
1.1 repeat the sample assay
According to supplementary material formula and the preparation method of embodiment 1, repeat to have prepared three batch samples in a small amount, its quality index to be checked, result is all up to specification, and the check detailed results sees Table 1.
Table 1 repeats the sample assay
| Investigate index | Outward appearance | Hardness (kg) | Disintegration (S) | Dissolution (%) | Uniformity of dosage units | Content (%) | Related substance (%) |
| 061101 | Unilateral bright and clean, neat in edge | 1.85～2.4 | 25 | 96.81 | Up to specification | 100.72 | 0.24 |
| 061102 | Unilateral bright and clean, neat in edge | 1.61～2.17 | 29 | 96.35 | Up to specification | 100.18 | 0.26 |
| 061103 | Unilateral bright and clean, neat in edge | 1.84～2.36 | 27 | 96.83 | Up to specification | 100.22 | 0.25 |
The repeated trials confirmation, this prescription is reasonable, and this technique is more stable, can prepare the oral cavity disintegration tablet that conforms to quality requirements, and can amplify this prescription, with the stability of further this technique of checking and the reasonability of prescription.
1.2 influence factor's test
Test take 0601101 batch as test sample carries out the influence factor, experimental condition is 60 ℃ of high temperature, 92.5% high humidity, 4500Lx illumination, respectively at 0 day, 5 days, 10 days sampling and measuring, under 92.5% super-humid conditions, the sample moisture absorption is serious, can't take a sample in the time of the 5th day, therefore change under 75% super-humid conditions and test, result of the test sees Table 2.
Table 2 influence factor result of the test
Conclusion: through influence factor test, result shows, this product prescription rationally, process stabilizing.Meet the oral cavity disintegration tablet quality standard.
2. pilot plant test
2.1 supplementary material formula and preparation method according to embodiment 1, the preparation of test agent in carried out producing under the pilot-scale condition with reference to the guideline of new drug research three batches, and according to testing through the method for inspection of fully checking, assay sees the following form 3.
Table 3 tibolone oral cavity disintegration tablet pilot scale sample survey result
By as seen from Table 3, the preparation method of tibolone oral cavity disintegration tablet sheet of the present invention, the every detection index of the tibolone oral cavity disintegration tablet of producing is all qualified, can produce the medicine that meets the tablet formulation requirement, and as seen this process stabilizing, can be used for producing in enormous quantities.
2.2 the test agent accelerated test assay of 6 months in three batches that is: is pressed commercially available back, places the assay of 6 months under 40 ℃ of temperature and relative humidity 75% ± 5% condition.See Table 4.
The table 4 three batch sample accelerated tests assay of 6 months
| Lot number | Outward appearance | Content (%) | Dissolution (%) | Disintegration (s) | Related substance (%) |
| 080901 | Unchanged | 99.63 | 95.8 | 29 | 0.38 |
| 080902 | Unchanged | 99.94 | 94.7 | 32 | 0.43 |
| 080903 | Unchanged | 99.12 | 93.9 | 33 | 0.39 |
| Reference preparation | Unchanged | 87.14 | 67.2 | 637 | 2.17 |
2.3 the assay that three batch samples kept sample 36 months for a long time, that is: the assay after room temperature under the commercially available back condition is placed 36 months naturally.See Table 5.
Table 5 keeps sample for a long time and checked result in 36 months
| Lot number | Outward appearance | Content (%) | Dissolution (%) | Disintegration (s) | Related substance (%) |
| 080901 | Unchanged | 99.94 | 99.62 | 20 | 0.31 |
| 080902 | Unchanged | 100.25 | 99.50 | 22 | 0.30 |
| 080903 | Unchanged | 100.18 | 99.51 | 25 | 0.32 |
| Reference preparation | Unchanged | 85.14 | 63.2 | 737 | 2.37 |
By the result of table 4 and table 5 as seen, tibolone oral cavity disintegration tablet of the present invention indices under extreme storage condition and room temperature naturalness still meets the preparation requirement of tablet, reference preparation defective phenomenon all occurs in the last index of experiment, therefore, the tibolone oral cavity disintegration tablet has solved the stability problem of this medicine, but and large-scale production.
Can be confirmed by above experiment: tibolone orally disintegrating tablet preparation prescription of the present invention is reasonable, and stable preparation process, feasible is suitable for batch production.
The specific embodiment
Following embodiment is used for illustrating the preparation of tibolone oral cavity disintegration tablet of the present invention, but it can not consist of any restriction to scope of the present invention.
Embodiment 1
The supplementary material part by weight:
Tibolone 100 grams, lactose 140 grams, mannitol 375 grams, microcrystalline Cellulose 275 grams, low-substituted hydroxypropyl cellulose 65 grams, aspartame 2.5 grams, magnesium stearate 10 grams.
Preparation method:
(a) tibolone, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, mannitol, magnesium stearate in 105 ℃ of dryings 1 hour, were pulverized 100 mesh sieves, and it is standby that lactose and aspartame were pulverized 100 mesh sieves;
(b) take in proportion the low-substituted hydroxypropyl cellulose of tibolone, mannitol, lactose, aspartame, 1/3 amount, the microcrystalline Cellulose mixing of 1/3 amount, get mixed material;
(c) add 50% alcoholic solution in step (b) gained mixed material, make suitable soft material, granulate with 32 mesh sieves, wet grain is in 45 ± 5 ℃ of dryings, with 32 mesh sieve granulate;
(d) with the microcrystalline Cellulose of step (c) gained granule and surplus, the low-substituted hydroxypropyl cellulose of surplus, the magnesium stearate mix homogeneously of proportional quantities;
(e) semi-finished product chemical examination, tabletting and get final product.
Assay: outward appearance: white tablets; Tablet weight variation: up to specification; Disintegration and leach granularity: up to specification; Dissolution: 98.12%; Related substance: 0.27%; Content: 99.87%.
Embodiment 2
The supplementary material part by weight:
Tibolone 100 grams, lactose 120 grams, mannitol 350 grams, microcrystalline Cellulose 250 grams, low-substituted hydroxypropyl cellulose 60 grams, aspartame 1 gram, magnesium stearate 8 grams
Preparation method:
(a) tibolone, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, mannitol, magnesium stearate in 105 ℃ of dryings 1 hour, were pulverized 100 mesh sieves, and it is standby that lactose and aspartame were pulverized 100 mesh sieves;
(b) take in proportion the low-substituted hydroxypropyl cellulose of tibolone, mannitol, lactose, aspartame, 1/3 amount, the microcrystalline Cellulose mixing of 1/3 amount, get mixed material;
(c) add 50% alcoholic solution in step (b) gained mixed material, make suitable soft material, granulate with 32 mesh sieves, wet grain is in 45 ± 5 ℃ of dryings, with 32 mesh sieve granulate;
(d) with the microcrystalline Cellulose of step (c) gained granule and surplus, the low-substituted hydroxypropyl cellulose of surplus, the magnesium stearate mix homogeneously of proportional quantities;
(e) semi-finished product chemical examination, tabletting and get final product.
Assay: outward appearance: white tablets; Tablet weight variation: up to specification; Disintegration and leach granularity: up to specification; Dissolution: 99.02%; Related substance: 0.26%; Content: 99.66%.
Embodiment 3
The supplementary material part by weight
Tibolone 100 grams, lactose 160 grams, mannitol 400 grams, microcrystalline Cellulose 300 grams, low-substituted hydroxypropyl cellulose 70 grams, aspartame 4 grams, magnesium stearate 12 grams;
Preparation method:
(a) tibolone, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, mannitol, magnesium stearate in 105 ℃ of dryings 1 hour, were pulverized 100 mesh sieves, and it is standby that lactose and aspartame were pulverized 100 mesh sieves;
(b) take in proportion the low-substituted hydroxypropyl cellulose of tibolone, mannitol, lactose, aspartame, 1/3 amount, the microcrystalline Cellulose mixing of 1/3 amount, get mixed material;
(c) add 50% alcoholic solution in step (b) gained mixed material, make suitable soft material, granulate with 32 mesh sieves, wet grain is in 45 ± 5 ℃ of dryings, with 32 mesh sieve granulate;
(d) with the microcrystalline Cellulose of step (c) gained granule and surplus, the low-substituted hydroxypropyl cellulose of surplus, the magnesium stearate mix homogeneously of proportional quantities;
(e) semi-finished product chemical examination, tabletting and get final product.
Assay: outward appearance: white tablets; Tablet weight variation: up to specification; Disintegration and leach granularity: up to specification; Dissolution: 99.41%; Related substance: 0.25%; Content: 99.78%.
Claims (5)
1. tibolone oral cavity disintegration tablet is characterized in that this medicine supplementary material weight ratio is:
Tibolone 100, lactose 120-160, mannitol 350-400, microcrystalline Cellulose 250-300,
Low-substituted hydroxypropyl cellulose 60-70, aspartame 1-4, magnesium stearate 8-12.
2. tibolone oral cavity disintegration tablet according to claim 1 is characterized in that the supplementary material weight ratio of this medicine is:
Tibolone 100, lactose 120, mannitol 350, microcrystalline Cellulose 250,
Low-substituted hydroxypropyl cellulose 60, aspartame 1, magnesium stearate 8.
3. tibolone oral cavity disintegration tablet according to claim 1 is characterized in that the supplementary material weight ratio of this medicine is:
Tibolone 100, lactose 160, mannitol 400, microcrystalline Cellulose 300,
Low-substituted hydroxypropyl cellulose 70, aspartame 4, magnesium stearate 12.
4. tibolone oral cavity disintegration tablet according to claim 1 is characterized in that the supplementary material weight ratio of this medicine is:
Tibolone 100, lactose 140, mannitol 375, microcrystalline Cellulose 275,
Low-substituted hydroxypropyl cellulose 65, aspartame 2.5, magnesium stearate 10.
5. the preparation method of according to claim 1-4 described tibolone oral cavity disintegration tablets of any one is characterized in that this tibolone oral cavity disintegration tablet makes through following steps:
(a) tibolone, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, mannitol, magnesium stearate in 105 ℃ of dryings 1 hour, were pulverized 100 mesh sieves, and it is standby that lactose and aspartame were pulverized 100 mesh sieves;
(b) take in proportion the low-substituted hydroxypropyl cellulose of tibolone, mannitol, lactose, aspartame, 1/3 amount, the microcrystalline Cellulose mixing of 1/3 amount, get mixed material;
(c) add 50% alcoholic solution in step (b) gained mixed material, make suitable soft material, granulate with 32 mesh sieves, wet grain is in 45 ± 5 ℃ of dryings, with 32 mesh sieve granulate;
(d) with the microcrystalline Cellulose of step (c) gained granule and surplus, the low-substituted hydroxypropyl cellulose of surplus, the magnesium stearate mix homogeneously of proportional quantities;
(e) semi-finished product chemical examination, tabletting and get final product.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 200910241388 CN102085193B (en) | 2009-12-08 | 2009-12-08 | Tibolone orally disintegrating tablets and method for preparing same |
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| CN 200910241388 CN102085193B (en) | 2009-12-08 | 2009-12-08 | Tibolone orally disintegrating tablets and method for preparing same |
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| US10736907B2 (en) * | 2016-05-04 | 2020-08-11 | Novalon S.A. | Use of sugar-alcohols in tibolone compositions |
| CN114767693B (en) * | 2022-04-29 | 2023-07-28 | 浙江和沐康医药科技有限公司 | Tibolone composition for improving stability and dissolution behavior and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1253503A (en) * | 1997-04-22 | 2000-05-17 | 阿克佐诺贝尔公司 | Stabilized tibolone compositions |
| CN1476826A (en) * | 2003-07-30 | 2004-02-25 | 北京中西经纬释药技术有限公司 | Oral disintegrant tablet and its preparation method |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1253503A (en) * | 1997-04-22 | 2000-05-17 | 阿克佐诺贝尔公司 | Stabilized tibolone compositions |
| CN1476826A (en) * | 2003-07-30 | 2004-02-25 | 北京中西经纬释药技术有限公司 | Oral disintegrant tablet and its preparation method |
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