CN103142544B - Ubenimex capsule composition and preparation method thereof - Google Patents
Ubenimex capsule composition and preparation method thereof Download PDFInfo
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- CN103142544B CN103142544B CN201310063849.9A CN201310063849A CN103142544B CN 103142544 B CN103142544 B CN 103142544B CN 201310063849 A CN201310063849 A CN 201310063849A CN 103142544 B CN103142544 B CN 103142544B
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 36
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- SZYSLWCAWVWFLT-UTGHZIEOSA-N [(2s,3s,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)-2-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxolan-2-yl]methyl octadecanoate Chemical compound O([C@@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@]1(COC(=O)CCCCCCCCCCCCCCCCC)O[C@H](CO)[C@@H](O)[C@@H]1O SZYSLWCAWVWFLT-UTGHZIEOSA-N 0.000 claims abstract description 18
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims abstract description 18
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims abstract description 17
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- Medicinal Preparation (AREA)
Abstract
The invention discloses an ubenimex capsule composition. Each unit preparation of ubenimex capsule consists of 10-30mg of ubenimex, 85-105mg of lactose, 95-118mg of microcrystalline cellulose, 8-10mg of croscarmellose sodium, 6-7mg of polacrilin potassium, 4.5-5.5mg of povidone, 1-2.5mg of sodium lauryl sulfate, 0.2-0.7mg of sucrose stearate and 3-4mg of magnesium stearate. According to the invention, the prepared ubenimex capsule can be used for effectively promoting the dissolution of ubenimex and improving the bioavailability; spray drying at 20-25 DEG C is adopted for granulation, the granulation efficiency is improved, the damage of ubenimex caused by high temperature is avoided, and the drug stability is improved; by combining an inner disintegrating agent and an outer disintegrating agent, the disintegrating speed of capsule is further increased, and the shortcomings of common capsule dissolution and disintegrating lag are overcome; and compared with prior art, the method is more suitable for industrial mass production.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to a kind of ubenimex capsule composition and preparation method thereof.
Background technology
Ubenimex, its chemical name is: N-[(2S, 3R)-3-amino-2-hydroxy-4-phenyl butyryl]-L-Leu; Molecular formula: C
16h
24n
2o
4; Molecular weight: 308.37; Its structural formula is as follows:
Ubenimex is the dipeptide compound be isolated from the culture fluid of the netted streptomycete of Fructus Canarii albi by Japanese scholars Mei Ze shore husband in 1976, the inhibition aminopeptidase B of contestable and leucine peptidase and caspase etc., inducing apoptosis of tumour cell and promotion host immune function.But combined with chemotherapy, radiotherapy and be united and applied in leukemia, multiple myeloma, myelodysplastic syndrome and hematopoietic stem cell transplantation after, and other patients with solid tumor.
Ubenimex odorless, bitter in the mouth, slightly soluble in water, oral absorption is good, rapid, and blood drug level peaking after 1 hour, approximately have 15% to be metabolised to the hydroxyl ubenimex in liver, and 80%～85% is original shape discharges from urine, domestic existing capsule and tablet listing.CN101601649B discloses a kind of Ubenimex fat emulsion injection and preparation method thereof, the fat milk mean diameter made is in the 300nm left and right, be applicable to swallow, the patient in stupor or digestive system obstacle, but complicated process of preparation, the production cost of said preparation are high, in patent, the long-time stability of this injection are not investigated simultaneously.CN101002931B discloses a kind of Ubenimex tablet and preparation method thereof, and the tablet surface made is bright and clean, but this preparation process need, by the pastille wet granular in 80 ℃ of bakings 4 hours, easily impact ubenimex stability.
Therefore this area, in the urgent need to developing the capsule of this medicine, makes it can bring into play the characteristics that capsule is covered the adverse drug taste, can improve medicine stability again, increases dissolubility and the dissolution of ubenimex in capsule, improves its bioavailability.
Summary of the invention
The technical problem that is difficult to make general formulation for insoluble anti-tumor medicament in prior art, the invention provides a kind of ubenimex capsule composition and preparation method thereof, the ubenimex dissolubility is significantly improved, thereby improved dissolution, improved bioavailability, and this preparation method is simple, but normal-temperature operation, increase medicine stability, be applicable to large production.
The invention discloses following technical scheme:
A kind of ubenimex capsule composition, the ubenimex capsule of per unit preparation is comprised of following component:
Ubenimex 10-30mg, lactose 85-105mg, microcrystalline Cellulose 95-118mg, cross-linking sodium carboxymethyl cellulose 8-10mg, polacrilin potassium 6-7mg, polyvidone 4.5-5.5mg, sodium lauryl sulphate 1-2.5mg, sucrose stearate 0.2-0.7mg, magnesium stearate 3-4mg.
Further, the ubenimex capsule of per unit preparation is comprised of following component:
Ubenimex 10-15mg, lactose 100-105mg, microcrystalline Cellulose 103-118mg, cross-linking sodium carboxymethyl cellulose 8-10mg, polacrilin potassium 6.5-7mg, polyvidone 5-5.5mg, sodium lauryl sulphate 1-1.5mg, sucrose stearate 0.2-0.5mg, magnesium stearate 3.5-4mg.
Further, the ubenimex capsule of per unit preparation is comprised of following component: ubenimex 10mg, lactose 105mg, microcrystalline Cellulose 118mg, cross-linking sodium carboxymethyl cellulose 10mg, polacrilin potassium 7mg, polyvidone 5.5mg, sodium lauryl sulphate 1mg, sucrose stearate 0.2mg, magnesium stearate 4mg.
Perhaps, in ubenimex capsule composition of the present invention, the ubenimex capsule of per unit preparation is comprised of following component: ubenimex 15mg, lactose 100mg, microcrystalline Cellulose 105mg, cross-linking sodium carboxymethyl cellulose 10mg, polacrilin potassium 7mg, polyvidone 5mg, sodium lauryl sulphate 1.5mg, sucrose stearate 0.3mg, magnesium stearate 3.5mg.
Perhaps, the ubenimex capsule of per unit preparation is comprised of following component: ubenimex 30mg, lactose 85mg, microcrystalline Cellulose 95mg, cross-linking sodium carboxymethyl cellulose 8mg, polacrilin potassium 6mg, polyvidone 4.5mg, sodium lauryl sulphate 2.5mg, sucrose stearate 0.7mg, magnesium stearate 3mg.
Perhaps, the ubenimex capsule of per unit preparation is comprised of following component: ubenimex 20mg, lactose 90mg, microcrystalline Cellulose 103mg, cross-linking sodium carboxymethyl cellulose 8mg, polacrilin potassium 6.5mg, polyvidone 5mg, sodium lauryl sulphate 1.5mg, sucrose stearate 0.5mg, magnesium stearate 3.5mg.
Perhaps, the ubenimex capsule of per unit preparation is comprised of following component: ubenimex 25mg, lactose 90mg, microcrystalline Cellulose 95mg, cross-linking sodium carboxymethyl cellulose 8mg, polacrilin potassium 6.5mg, polyvidone 4.5mg, sodium lauryl sulphate 2.5mg, sucrose stearate 0.5mg, magnesium stearate 3mg.
The invention also discloses the preparation method of ubenimex capsule composition, its preparation method comprises the following steps:
1) polyvidone of recipe quantity is mixed with to 12% PVP solution with 16% alcoholic solution, then the sodium lauryl sulphate of recipe quantity and sucrose stearate are dissolved in this solution, the ubenimex that finally adds recipe quantity, be uniformly dispersed it, makes the pastille binding agent;
2) lactose of recipe quantity, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and polacrilin potassium are crossed respectively to 80～100 mesh sieves, after mix homogeneously, make blank mixed accessories;
3) the pastille binding agent of step 1) gained is mixed and dry granulating by the high-pressure sprayer of spray dryer and the blank mixed accessories of step 2 gained;
4) by 18 mesh sieve granulate for the granule of step 3) gained;
5) step 4) gained granule is added to the magnesium stearate mix homogeneously, encapsulated.
Wherein, the described baking temperature of step 3) is 20～25 ℃, and pellet moisture is lower than 2.0%, and be 4～5 minutes drying time.
As everyone knows, the ubenimex capsule is insoluble drug, and this inventor has been carried out to a large amount of screenings, has finally determined prescription and the ratio of product of the present invention, in technical scheme disclosed by the invention:
Described diluent is lactose and microcrystalline Cellulose, and its Main Function is the volume that increases capsule, is beneficial to be shaped, and also can promote the disintegrate of capsule, improves stripping.
Described disintegrating agent is cross-linking sodium carboxymethyl cellulose and polacrilin potassium, and its Main Function is to make quick from capsule, the abundant stripping of active constituents of medicine.
Described binding agent is polyvidone, and its Main Function is to make grain forming, improves material fluidity.
Described solubilizing agent is sodium lauryl sulphate and sucrose stearate, and its Main Function is the dissolution that increases insoluble drug, improves bioavailability.
Described lubricant is magnesium stearate, and its Main Function is to make particle lubrication, increases mobility of particle, improves capsule dress sample compliance.
The ubenimex capsule prepared by prescription of the present invention and technique has the following advantages:
1) add surfactant in the prescription, the dissolution of 15min is about 2 times of commercially available ubenimex capsule (Bestatin), effectively promotes the stripping of ubenimex, has improved bioavailability.
2) preparation technology adopts 20～25 ℃ of spray-drying processes, has improved granulation efficiency, and has avoided the destruction of high temperature to ubenimex, has improved the stability of medicine.
3) in pelletization, by interior, with disintegrating agent and additional disintegrating agent, combine, further improved the disintegration rate of capsule, overcome the shortcoming that general capsule stripping and disintegrate lag behind.
4) product ubenimex capsule manufacture cost of the present invention is low, is applicable to industrialized great production, and the patent medicine low price, be conducive to alleviate patient economy burden.
The specific embodiment
Embodiment below in conjunction with the specific embodiment is described in further detail the present invention, but limitation of the present invention not, all any this areas of doing according to the disclosure of invention be equal to replacement, all belong to protection scope of the present invention.The per unit preparation contains ubenimex 10～30mg, and following table is prepared into the prescription consumption of 1000, unit: g for each embodiment.
| Component | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 |
| Ubenimex | 10 | 15 | 20 | 25 | 30 |
[0038]?
| Lactose | 105 | 100 | 90 | 90 | 85 |
| Microcrystalline Cellulose | 118 | 105 | 103 | 95 | 95 |
| Cross-linking sodium carboxymethyl cellulose | 10 | 10 | 8 | 8 | 8 |
| Polacrilin potassium | 7 | 7 | 6.5 | 6.5 | 6 |
| Polyvidone | 5.5 | 5 | 5 | 4.5 | 4.5 |
| Sodium lauryl sulphate | 1 | 1.5 | 1.5 | 2.5 | 2.5 |
| Sucrose stearate | 0.2 | 0.3 | 0.5 | 0.5 | 0.7 |
| Magnesium stearate | 4 | 3.5 | 3.5 | 3 | 3 |
Embodiment 1
Preparation technology:
1) polyvidone of recipe quantity is mixed with to 12% PVP solution with 16% alcoholic solution, then the sodium lauryl sulphate of recipe quantity and sucrose stearate are dissolved in this solution, the ubenimex that finally adds recipe quantity, be uniformly dispersed it, makes the pastille binding agent;
2) lactose of recipe quantity, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and polacrilin potassium are crossed respectively to 80～100 mesh sieves, after mix homogeneously, make blank mixed accessories;
3) by the pastille binding agent of step 1) gained, the blank mixed accessories of the high-pressure sprayer by spray dryer and step 2 gained mixes and the granule that is 1.0% in 25 ℃ of dry 5min to moisture;
4) by 18 mesh sieve granulate for the granule of step 3) gained;
5) step 4) gained granule is added to the magnesium stearate mix homogeneously, encapsulated.
Embodiment 2
Preparation technology is with embodiment 1 step, and wherein in step 3, baking temperature is 24 ℃, and the time is 5min, and moisture is reduced to 0.5%.
Embodiment 3
Preparation technology is with embodiment 1 step, and wherein in step 3, baking temperature is 23 ℃, and the time is 4min, and moisture is reduced to 1.3%.
Embodiment 4
Preparation technology is with embodiment 1 step, and wherein in step 3, baking temperature is 24 ℃, and the time is 4min, and moisture is reduced to 1.5%.
Embodiment 5
Preparation technology is with embodiment 1 step, and wherein in step 3, baking temperature is 20 ℃, and the time is 5min, and moisture is reduced to 1%.
Comparative Examples 1: dissolution contrast test
Commercially available ubenimex capsule: Nippon Kayaku K. K produces, trade name Bestatin, specification 30mg, lot number Y10860.
For investigating the dissolution of ubenimex capsule of the present invention, press two appendix XC three therapeutic methods of traditional Chinese medicine algoscopys of Chinese Pharmacopoeia version in 2010, get respectively the ubenimex capsule of the embodiment of the present invention 1～5 preparation, with each 6 of commercially available ubenimex capsules, accumulation dissolution to each time point compares test, specific as follows:
The ubenimex capsule that various embodiments of the present invention are made and 6 of commercially available ubenimex capsules be take respectively hydrochloric acid solution pH1.0 as medium, rotating speed is 50rpm, through 5,10,15,20, the 30min sampling, use high effective liquid chromatography for measuring, result is as shown in table 1, when its result shows 15 minutes, the average dissolution of ubenimex capsule of the present invention has reached 91-99%, and the dissolution of commercially available ubenimex capsule is only 54% of labelled amount, the more commercially available ubenimex capsule of ubenimex capsule of the present invention has advantages of that dissolution rate is faster, dissolution increases.
Table 1 ubenimex capsule stripping curve relatively
Comparative Examples 2: stability contrast test
Commercially available ubenimex capsule: Nippon Kayaku K. K produces, trade name Bestatin, specification 30mg, lot number Y10860.
Investigate the stability of ubenimex capsule of the present invention with the embodiment of the present invention 3,4 and commercially available capsule, ubenimex capsule and the commercially available capsule of embodiment 3,4 preparations are placed in to 40 ℃ of relative humidity 5% accelerated tests 6 months, press Chinese Pharmacopoeia version in 2010, use high performance liquid chromatography, respectively its content, related substance and 30min dissolution are detected to (content of Chinese Pharmacopoeia version regulation ubenimex in 2010 should be the 90.0%-110.0% of labelled amount, 80% that the stripping limit of 30 minutes is labelled amount).Testing result is as shown in table 2:
Table 2 ubenimex capsule composition accelerated test relatively
By table 2, can find out, in ubenimex capsule prepared by the present invention, the content of ubenimex is 98.9%-101.3%, the content of related substance is 0.04%-0.20%, and the dissolution of 30 minutes is 98%-101%, all obviously is better than the regulation of Chinese Pharmacopoeia version in 2010 about content and stripping limit; And the content of commercially available product ubenimex capsule is 95.3%-99.7%, the content of related substance is 0.12%-0.95%, and the dissolution of 30min is 82%-96%.Therefore, ubenimex capsule of the present invention all obviously is better than commercially available ubenimex capsule on content, related substance, dissolution, has stable in properties, and the second best in quality characteristics, be more suitable in industrialized great production.
Claims (9)
1. a ubenimex capsule, is characterized in that, the ubenimex capsule of per unit preparation is comprised of following component:
Ubenimex 10-30mg, lactose 85-105mg, microcrystalline Cellulose 95-118mg, cross-linking sodium carboxymethyl cellulose 8-10mg, polacrilin potassium 6-7mg, polyvidone 4.5-5.5mg, sodium lauryl sulphate 1-2.5mg, sucrose stearate 0.2-0.7mg, magnesium stearate 3-4mg.
2. ubenimex capsule according to claim 1, is characterized in that, the ubenimex capsule of per unit preparation is comprised of following component:
Ubenimex 10-15mg, lactose 100-105mg, microcrystalline Cellulose 103-118mg, cross-linking sodium carboxymethyl cellulose 8-10mg, polacrilin potassium 6.5-7mg, polyvidone 5-5.5mg, sodium lauryl sulphate 1-1.5mg, sucrose stearate 0.2-0.5mg, magnesium stearate 3.5-4mg.
3. ubenimex capsule according to claim 1, is characterized in that, the ubenimex capsule of per unit preparation is comprised of following component:
Ubenimex 30mg, lactose 85mg, microcrystalline Cellulose 95mg, cross-linking sodium carboxymethyl cellulose 8mg, polacrilin potassium 6mg, polyvidone 4.5mg, sodium lauryl sulphate 2.5mg, sucrose stearate 0.7mg, magnesium stearate 3mg.
4. ubenimex capsule according to claim 1, is characterized in that, the ubenimex capsule of per unit preparation is comprised of following component:
Ubenimex 10mg, lactose 105mg, microcrystalline Cellulose 118mg, cross-linking sodium carboxymethyl cellulose 10mg, polacrilin potassium 7mg, polyvidone 5.5mg, sodium lauryl sulphate 1mg, sucrose stearate 0.2mg, magnesium stearate 4mg.
5. ubenimex capsule according to claim 1, is characterized in that, the ubenimex capsule of per unit preparation is comprised of following component:
Ubenimex 15mg, lactose 100mg, microcrystalline Cellulose 105mg, cross-linking sodium carboxymethyl cellulose 10mg, polacrilin potassium 7mg, polyvidone 5mg, sodium lauryl sulphate 1.5mg, sucrose stearate 0.3mg, magnesium stearate 3.5mg.
6. a method for preparing claim 1～5 any one ubenimex capsule, is characterized in that, this preparation method comprises the following steps:
A, the polyvidone of recipe quantity is mixed with to 12% PVP solution with 16% alcoholic solution, then the sodium lauryl sulphate of recipe quantity and sucrose stearate is dissolved in this solution, add the ubenimex of recipe quantity, it is uniformly dispersed, make the pastille binding agent;
B, the lactose of recipe quantity, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose and polacrilin potassium are crossed respectively to 80～100 mesh sieves, after mix homogeneously, make blank mixed accessories;
The blank mixed accessories of C, the high-pressure sprayer by the pastille binding agent of steps A gained by spray dryer and step B gained mixes and dry granulating;
D, by 18 mesh sieve granulate for the granule of step C gained;
E, step D gained granule is added to the magnesium stearate mix homogeneously, encapsulated.
7. preparation method according to claim 6, is characterized in that, the described baking temperature of step C is 20～25 ℃.
8. preparation method according to claim 6, is characterized in that, the described pellet moisture content of step C is lower than 2.0%.
9. preparation method according to claim 6, is characterized in that, step C described drying time is 4～5 minutes.
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| CN103610663B (en) * | 2013-12-10 | 2015-05-06 | 成都苑东药业有限公司 | Ubenimex capsule medicament composition and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1943562A (en) * | 2006-10-25 | 2007-04-11 | 宛六一 | Ubenimex dispersion tablet and its preparing method |
| CN101066255A (en) * | 2007-05-30 | 2007-11-07 | 深圳万乐药业有限公司 | Coated ubenimex table |
| CN101194902A (en) * | 2006-12-08 | 2008-06-11 | 天津天士力制药股份有限公司 | Dropping pills containing ubenimex and method for preparing the same |
| CN101716156A (en) * | 2010-01-08 | 2010-06-02 | 成都苑东药业有限公司 | Ubenimex dispersive tablet composition |
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- 2013-02-28 CN CN201310063849.9A patent/CN103142544B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1943562A (en) * | 2006-10-25 | 2007-04-11 | 宛六一 | Ubenimex dispersion tablet and its preparing method |
| CN101194902A (en) * | 2006-12-08 | 2008-06-11 | 天津天士力制药股份有限公司 | Dropping pills containing ubenimex and method for preparing the same |
| CN101066255A (en) * | 2007-05-30 | 2007-11-07 | 深圳万乐药业有限公司 | Coated ubenimex table |
| CN101716156A (en) * | 2010-01-08 | 2010-06-02 | 成都苑东药业有限公司 | Ubenimex dispersive tablet composition |
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| CN103142544A (en) | 2013-06-12 |
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Denomination of invention: Ubenimex capsule composition and preparation method thereof Effective date of registration: 20140619 Granted publication date: 20140108 Pledgee: Chengdu high investment financing Company limited by guarantee Pledgor: Chengdu Easton Pharmaceutical Co., Ltd. Registration number: 2014510000015 |
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