CN103735523B - Peretinoin medicinal composition - Google Patents
Peretinoin medicinal composition Download PDFInfo
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- CN103735523B CN103735523B CN201310718283.9A CN201310718283A CN103735523B CN 103735523 B CN103735523 B CN 103735523B CN 201310718283 A CN201310718283 A CN 201310718283A CN 103735523 B CN103735523 B CN 103735523B
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- pelretin
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Abstract
The invention provides a peretinoin medicinal composition. The medicinal composition is a peretinoin dropping pill preparation, and comprises active medicine peretinoin and a matrix. The dripping drill is prepared by heating and melting the medicine and the matrix, dripping into a condensate which cannot be uniformly mixed with the medicine and the matrix, concentrating and condensing to prepare the preparation. The peretinoin medicinal composition can be kept stable for a long time, and is quick in drug release, simple in production equipment and convenient to operate.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to a kind of cancer treatment drug pelretin acid drop pill pharmaceutical composition.
Background technology
Pelretin acid (peretinoin, NIK-333) is the medicine of the Hepatoma therapy recurrence of being developed by Japanese Kowa company Ltd.Peretinoin is a kind of acyclic retinoic acid, similar vitamin A, main target molecule is retinoic acid receptor α, and this compound demonstrates affinity to retinoic acid associated proteins and retinoic acid receptor, has induction and apoptosis-induced effect to hepatocarcinoma.Peretinoin II/III clinical trial phase peretinoin suppresses the effect that hepatocarcinoma (HCC) recurs to be evaluated, and result shows the generation that it can prevent from newly sending out liver neoplasm.In these subgroups of test are analyzed, we can see the curative effect of peretinoin more clearly, and it supports II/III clinical trial phase data.Also infer that peretinoin can not only suppress HCC to recur from result of the test, and the cancer that liver cirrhosis can also be suppressed to cause occurs.Peretinoin chemical name (2E, 4E, 6E, 10E)-3,7,11,15-tetramethyl-2,4,6,10,14-16 oxopentanoic acid, structural formula is as follows:
Pelretin acid is water insoluble faint yellow to yellow Powdered crystallization, and the material unstable to light, heat or oxygen, meets water or organic solvent easily decomposes, and for ensuring drug quality, pelretin processed with acid is become the stability that need ensure pelretin acid during pharmaceutical preparation.CN1674886 discloses the soft capsule preparation of pelretin acid, and be dispersed in soybean oil, Semen arachidis hypogaeae wet goods vegetable oil by pelretin acid suspendible, then enclose in the capsule shells containing opacifier, wherein dispersant is the surfactants such as glyceryl monostearate.But because pelretin acid can not be dissolved in oil, in said preparation, active medicine is dispersed in vegetable oil, causes disintegration time longer, oral absorption can be comparatively slow, and soft capsule preparation technology is relatively complicated, needs to prepare capsule shells.Therefore, have and need to find pelretin acid can being made stable and being more suitable for the dosage form of oral absorption of other.
Summary of the invention
The invention provides the pharmaceutical composition of a kind of cancer treatment drug pelretin acid, this pharmaceutical composition is pelretin acid dropping pill formulation, and the dropping pill formulation of pelretin acid can maintain a long-term stability, and release is rapid, and production equipment is simple, easy to operate.
A kind of Peretinoin medicinal composition provided by the invention, is characterized in that, this pharmaceutical composition is pelretin acid dropping pill formulation.Be made up of the acid of active medicine pelretin and substrate in described pelretin acid dropping pill formulation, substrate is one or more in water-soluble base, fat-soluble substrate, surfactant, at least one, the most preferably combination of water-soluble base and surfactant in preferred water soluble base and surfactant; Described water-soluble base is selected from Polyethylene Glycol, sodium stearate, gelatin, poloxamer or its combination, preferred Polyethylene Glycol, and Polyethylene Glycol can be PEG4000, PEG6000, PEG8000, PEG10000; Described fat-soluble substrate is selected from glyceryl monostearate, stearic acid, insect wax, hydrogenated vegetable oil, octadecanol, hexadecanol or its combination, preferred glyceryl monostearate; Described surfactant is selected from poloxamer or tween 80, preferred poloxamer.In pelretin acid dropping pill formulation of the present invention, the acid of active medicine pelretin and the mass fraction of substrate are than being 1:0.5 ~ 10, preferred 1:3 ~ 8, most preferably 1:4 ~ 5.Time in substrate containing surfactant, the ratio of quality and the number of copies of surfactant and active medicine is for being 1:0.05 ~ 0.5.
Preferably, pelretin acid dropping pill formulation comprises the acid of active medicine pelretin, Macrogol 4000, poloxamer, and its mass fraction is than being 1:4 ~ 5:0.1 ~ 0.5.
The preparation method of pelretin acid dropping pill formulation of the present invention is mixed homogeneously for the acid of active medicine pelretin is placed in container with substrate and is heated to 50 ~ 70 DEG C, heat while stirring to whole melting, fused solution is inserted pill dripping machine fluid reservoir, in 50 ~ 70 DEG C of lower instillation cooling mediums of insulation, wash ball after cooling, lucifuge mode is packed.Cooling medium used in the present invention, must be safe and harmless, and do not have an effect with principal agent, principal agent and substrate all should be insoluble in condensed fluid, the density of condensed fluid should be moderate, and drop pill can be made slowly to increase in condensed fluid can decline, and can select oiliness condensed fluid or aqueous condensed fluid.Oiliness condensed fluid can be selected from liquid paraffin, dimethicone, Semen Maydis wet goods, preferred liquid paraffin.Aqueous condensed fluid can be selected from aqueous solution, the alcoholic solution of variable concentrations, diluted acid, dilute alkaline soln, preferred dilute alkaline soln (as 5% sodium hydroxide).When substrate adopt be water-soluble base time, cooling medium selects oiliness condensed fluid usually, when substrate adopt oil-soluble substrate time, cooling medium adopts aqueous condensed fluid usually.The pill dripping machine (as the DWJ-2000S-D type Multifunctional drop pills production experimental machine that Yantai hundred Yao Tai Chinese medicine Science and Technology Ltd. produces) that pill dripping machine of the present invention can adopt self-control or buy.The present invention finds, melt temperature when preparing drop pill and the insulation operative temperature of pill dripping machine remain between 50 ~ 70 DEG C, preferably 60 DEG C, can make the rapid melting of the mixture of medicine and substrate and active medicine does not produce structure changes.Between the employing internal diameter 6.0 ~ 9.0mm of pill dripping machine, the dropper between external diameter 6.5 ~ 9.8mm, all can prepare roundness good, weight differential is qualified, and unit dose is at the drop pill of 3 ~ 100 mg.
Because pelretin acid is to photo-labile, the drop pill that the present invention prepares need adopt lucifuge mode to pack, as In Aluminium Foil Packing, and brown bottle, black bottle packaging etc.The present invention is all undertaken by under the condition of above-mentioned packaging by drop pill to the investigation of the stability of obtained drop pill.
Adopt different substrates on the impact of drop pill quality to investigate, several conventional water-soluble base and fat-soluble matrix composition drop pill are selected respectively, get the raw materials ready than for 1:5 with pelretin acid and substrate mass fraction, drop pill is prepared by above-mentioned preparation method, investigate active medicine content, dissolve scattered time limit and rounding rate in product, the parameters such as pill weight variation, the results are shown in following table:
| Substrate | Active medicine content | Dissolve scattered time limit | Rounding rate | Pill weight variation |
| PEG 2000 | 16.66% | 346 S | 82% | ±6.5% |
| PEG 4000 | 16.66% | 360 S | 94% | ±7.0% |
| PEG 8000 | 16.66% | 380 S | 88% | ±7.1% |
| PEG 10000 | 16.66% | 392 S | 85% | ±7.2% |
| Sodium stearate | 16.66% | 402 S | 85% | ±6.0% |
| Poloxamer | 16.66% | 310 S | 89% | ±6.4% |
| Glyceryl monostearate | 16.66% | 644 S | 85% | ±7.3% |
| Insect wax | 16.66% | 662 S | 83% | ±7.0% |
| Hydrogenated vegetable oil | 16.66% | 680 S | 82% | ±7.2% |
| Octadecanol | 16.66% | 842 S | 84% | ±7.3% |
| PEG 4000+ poloxamer | 16.66% | 338 S | 95% | ±6.8% |
| PEG 4000+ Tween 80 | 16.66% | 340 S | 96% | ±6.9% |
| Glyceryl monostearate+poloxamer | 16.66% | 592 S | 88% | ±7.0% |
As seen from the above table, the drop pill dissolution velocity adopting water-soluble base comparatively to adopt oil-soluble substrate to obtain is faster, and the use of surfactant can accelerate disintegrate, is more conducive to oral absorption; The more oil-soluble substrate of roundness of water-soluble base is higher, and after identical prescription adds surfactant, roundness can improve; The weight differential of different substrates all meets the requirements.In addition, in the drop pill that all substrate obtains, active medicine content does not change, and can ensure the stable of active medicine, illustrate that the dosage form of drop pill is the dosage form of applicable pelretin acid.The substrate that those skilled in the art can select other different according to demand and adjuvant prepare sustained-release and controlled release drop pill, solution drop pill, suppository drop pill, hard capsule drop pill, coated drop pill, elaioplast drop ball, enteric coating drop pill, dry-pressing coated drop pill etc.
The invention provides a kind of pharmaceutical composition of pelretin acid, this pharmaceutical composition is pelretin acid dropping pill formulation, is made up of the acid of active medicine pelretin and substrate.The preparation of drop pill is by after medicine and substrate heating and melting, instill in the condensed fluid do not mixed mutually, shrink condensation and the preparation made, preparation process can be avoided introducing the disadvantageous water of stability or organic reagent, the acid of active component pelretin is present in substrate in preparation process always, avoids more contact light and oxygen; Dropping pill formulation possesses good dissolubility as solid dispersion, and release is rapid, is more conducive to oral absorption, improves drug bioavailability; Pelretin acid drop pill is adopted lucifuge material packaging, medicine can be kept steady in a long-term, thus ensure safety and the effectiveness of Clinical practice.
Below in conjunction with the embodiment of detailed description of the invention, the present invention will be further described.
Detailed description of the invention
embodiment 1
Prescription: pelretin acid 100 g, polyethylene glycol 6000 400 g
Preparation process is as follows:
1) first PEG 6000 is heated to about 60 DEG C in water-soluble, adds pelretin acid, constantly stir and make whole melting, filtered while hot, the pill dripping machine (the DWJ-2000S-D type Multifunctional drop pills production experimental machine that Yantai hundred Yao Tai Chinese medicine Science and Technology Ltd. produces) adopting self-control or buy, puts in fluid reservoir, be incubated at 60 DEG C, with in the mouth of pipe, external diameter is respectively 9.0mm, the dropper dripping of 9.8mm, drip in the liquid coolant of liquid paraffin, be condensed into ball, wash ball with liquid paraffin, to obtain final product;
2) pack with two aluminum bag and get product;
3) check weight differential and dissolve scattered time limit, weight differential is between ± 7.5%, and dissolve scattered time limit meansigma methods is 365 seconds.
embodiment 2
Prescription: pelretin acid 100 g, glyceryl monostearate 300 g
Preparation process is as follows:
1) first glyceryl monostearate is heated to about 55 DEG C in water-soluble, adds pelretin acid, constantly stir and make whole melting, filtered while hot, the pill dripping machine (the DWJ-2000S-D type Multifunctional drop pills production experimental machine that Yantai hundred Yao Tai Chinese medicine Science and Technology Ltd. produces) adopting self-control or buy, puts in fluid reservoir, be incubated at 60 DEG C, with in the mouth of pipe, external diameter is respectively 9.0mm, the dropper dripping of 9.8mm, drip in the liquid coolant of liquid paraffin, be condensed into ball, wash ball with liquid paraffin, to obtain final product;
2) pack with brown bottle, inflated with nitrogen gets product;
3) check weight differential and dissolve scattered time limit, weight differential is between ± 7.5%, and dissolve scattered time limit meansigma methods is 623.5 seconds.
embodiment 3
Prescription: pelretin acid 50 g, Macrogol 4000 200 g, poloxamer 10 g
Preparation process is as follows:
1) first Polyethylene Glycol is heated to about 60 DEG C in water-soluble, first adds poloxamer, stirring and dissolving, then add pelretin acid, constantly stir and make whole melting, filtered while hot, the pill dripping machine (the DWJ-2000S-D type Multifunctional drop pills production experimental machine that Yantai hundred Yao Tai Chinese medicine Science and Technology Ltd. produces) adopting self-control or buy, puts in fluid reservoir, is incubated at 60 DEG C, with in the mouth of pipe, external diameter is respectively 8.0mm, the dropper dripping of 8.8mm, drip in the liquid coolant of liquid paraffin, be condensed into ball, wash ball, to obtain final product;
2) pack with brown bottle, fill nitrogen and get product;
3) check weight differential and dissolve scattered time limit, weight differential is between ± 7.5%, and dissolve scattered time limit meansigma methods is 343 seconds.
embodiment 4
Prescription: pelretin acid 50 g, Macrogol 4000 250 g, poloxamer 20 g
Preparation process is as follows:
1) first Polyethylene Glycol is heated to about 60 DEG C in water-soluble, first add poloxamer, stirring and dissolving, then pelretin acid is added, continuous stirring makes whole melting, filtered while hot, the pill dripping machine (the DWJ-2000S-D type Multifunctional drop pills production experimental machine that Yantai hundred Yao Tai Chinese medicine Science and Technology Ltd. produces) adopting self-control or buy, puts in fluid reservoir, be incubated at 60 DEG C, with in the mouth of pipe, external diameter is respectively 8.0mm, the dropper dripping of 8.8mm, drip in the liquid coolant of dimethicone, be condensed into ball, wash ball, to obtain final product;
2) pack with two aluminum bag and get product;
3) check weight differential and dissolve scattered time limit, weight differential is between ± 7.5%, and dissolve scattered time limit meansigma methods is 321 seconds.
embodiment 5
Prescription: pelretin acid 30 g, Macrogol 4000 240 g
Preparation process is as follows:
1) first Polyethylene Glycol is heated to about 60 DEG C in water-soluble, then adds pelretin acid, constantly stir and make whole melting, filtered while hot, the pill dripping machine (the DWJ-2000S-D type Multifunctional drop pills production experimental machine that Yantai hundred Yao Tai Chinese medicine Science and Technology Ltd. produces) adopting self-control or buy, puts in fluid reservoir, be incubated at 60 DEG C, with in the mouth of pipe, external diameter is respectively 7.0mm, the dropper dripping of 7.8mm, drip in the liquid coolant of liquid paraffin, be condensed into ball, wash ball, to obtain final product;
2) pack with brown bottle, fill nitrogen and get product;
3) check weight differential and dissolve scattered time limit, weight differential is between ± 7.5%, and dissolve scattered time limit meansigma methods is 345 seconds.
embodiment 6
Prescription: pelretin acid 100 g, poloxamer 200 g
Preparation process is as follows:
1) first poloxamer is heated to about 60 DEG C in water-soluble, adds pelretin acid, constantly stir and make whole melting, filtered while hot, the pill dripping machine (the DWJ-2000S-D type Multifunctional drop pills production experimental machine that Yantai hundred Yao Tai Chinese medicine Science and Technology Ltd. produces) adopting self-control or buy, puts in fluid reservoir, be incubated at 60 DEG C, with in the mouth of pipe, external diameter is respectively 7.0mm, the dropper dripping of 7.8mm, drip in the liquid coolant liquid paraffin of 5% sodium hydroxide, be condensed into ball, wash ball, to obtain final product;
2) pack with brown bottle, fill nitrogen and get product;
3) check weight differential and dissolve scattered time limit, weight differential is between ± 7.5%, and dissolve scattered time limit meansigma methods is 302 seconds.
embodiment 7
Prescription: pelretin acid 50 g, glyceryl monostearate 250 g
Preparation process is as follows:
1) first glyceryl monostearate is heated to about 60 DEG C in water-soluble, adds pelretin acid, constantly stir and make whole melting, filtered while hot, the pill dripping machine (the DWJ-2000S-D type Multifunctional drop pills production experimental machine that Yantai hundred Yao Tai Chinese medicine Science and Technology Ltd. produces) adopting self-control or buy, puts in fluid reservoir, be incubated at 60 DEG C, with in the mouth of pipe, external diameter is respectively 6.0mm, the dropper dripping of 6.5mm, drip in aqueous solution liquid, be condensed into ball, wash ball with liquid paraffin, to obtain final product;
2) pack with bottle, fill nitrogen and get product;
3) check weight differential and dissolve scattered time limit, weight differential is between ± 7.5%, and dissolve scattered time limit meansigma methods is 650 seconds.
embodiment 8
Prescription: pelretin acid 80 g, octadecanol 240 g
Preparation process is as follows:
1) first octadecanol is heated to about 65 DEG C in water-soluble, adds pelretin acid, constantly stir and make whole melting, filtered while hot, the pill dripping machine (the DWJ-2000S-D type Multifunctional drop pills production experimental machine that Yantai hundred Yao Tai Chinese medicine Science and Technology Ltd. produces) adopting self-control or buy, puts in fluid reservoir, be incubated at 60 DEG C, with in the mouth of pipe, external diameter is respectively 6.0mm, the dropper dripping of 6.5mm, drip in aqueous solution, be condensed into ball, wash ball by the liquid coolant of 5% sodium hydroxide, to obtain final product;
2) pack with brown bottle, fill nitrogen and get product;
3) check weight differential and dissolve scattered time limit, weight differential is between ± 7.5%, and dissolve scattered time limit meansigma methods is 723 seconds.
embodiment 9 stability test
Test is by " Chinese Pharmacopoeia " 2000 editions two annex XIXC medicine stability test guideline designs.
Test item: related substance, content.
Detection method: in stability, related substance detection method is HPLC method, this method is for checking related substance (the maximum list detected respectively at 260nm and 310nm place is assorted and total assorted).
Accelerated test: get pelretin acid drop pill prepared by the embodiment of the present invention 1 ~ 6, band packaging puts into relative humidity 75%, and temperature is 40
oplace 6 months in C climatic chamber, detect indices in sampling in 1,3,6 month, it the results are shown in following table.
Can be seen by above result, under each embodiment 6 months acceleration environments, in put procedure, detect maximum unknown impuritie, total assorted all meet the requirements that (oxidative degradation impurity is less than 0.4% in 260nm place, unknown impuritie is less than 0.1%, total mixing is less than 0.5%), maximum unknown impuritie detected at 310nm place, total assorted all meet the requirements that (unknown impuritie is less than 0.1%, total mixing is less than 0.3%), pelretin of the present invention acid drop pill good stability is described, is applicable to long-term preservation.
Claims (1)
1. a Peretinoin medicinal composition, it is characterized in that, this pharmaceutical composition is pelretin acid dropping pill formulation, be made up of the acid of active medicine pelretin and substrate, described substrate is made up of water-soluble base Macrogol 4000 and surface agent poloxamer, and the mass fraction of pelretin acid, Macrogol 4000, poloxamer is than being 1:4 ~ 5:0.1 ~ 0.5; The preparation method of described pelretin acid dropping pill formulation is mixed homogeneously for the acid of active medicine pelretin is placed in container with substrate and is heated to 50 ~ 70 DEG C, heat while stirring to whole melting, fused solution is inserted pill dripping machine fluid reservoir, 8.0mm is respectively with mouth of pipe internal-and external diameter under 50 ~ 70 DEG C of insulations, the dropper of 8.8mm instills in cooling medium liquid paraffin or dimethicone, wash ball after cooling, lucifuge mode is packed.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103068381A (en) * | 2010-08-11 | 2013-04-24 | 兴和株式会社 | Medicinal agent for prevention and/or treatment of hepatocellular carcinoma |
| CN103140462A (en) * | 2010-10-01 | 2013-06-05 | 帝斯曼知识产权资产管理有限公司 | Synthesis of peretinoin |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2011246432A (en) * | 2010-04-28 | 2011-12-08 | Kowa Co | Medicine for prevention and/or treatment of hepatitis c |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103068381A (en) * | 2010-08-11 | 2013-04-24 | 兴和株式会社 | Medicinal agent for prevention and/or treatment of hepatocellular carcinoma |
| CN103140462A (en) * | 2010-10-01 | 2013-06-05 | 帝斯曼知识产权资产管理有限公司 | Synthesis of peretinoin |
Non-Patent Citations (1)
| Title |
|---|
| 正交设计法研究盐酸小檗碱滴丸制备工艺;杨红等;《中外医疗》;20091231(第2期);9－10页 * |
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