CN1891212A - Oral preparation and its preparing method - Google Patents
Oral preparation and its preparing method Download PDFInfo
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- CN1891212A CN1891212A CN 200510082716 CN200510082716A CN1891212A CN 1891212 A CN1891212 A CN 1891212A CN 200510082716 CN200510082716 CN 200510082716 CN 200510082716 A CN200510082716 A CN 200510082716A CN 1891212 A CN1891212 A CN 1891212A
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Abstract
The present invention relates to an immunosuppressant preparation and its preparation method. In the concrete, it is an oral preparation, including 2-p-octylphenethyl-2-aminopropanediol hydrochloride as immunosuppressant, inorganic salt and/or other medicinal auxiliary material or carrier.
Description
Invention field
The present invention relates to a kind of immunosuppressant agent formulation and preparation method thereof.Specifically, the present invention relates to a kind of oral formulations, it comprises 2-as immunosuppressant to octyl group phenethyl 2-amino-propanediol hydrochloride (abbreviating FTY720 as), inorganic salt, and/or other pharmaceutic adjuvant or carrier.
Background technology
2-abbreviates FTY720 as to octyl group phenethyl 2-amino-propanediol hydrochloride, and it is a kind of immunosuppressant newly developed in recent years, the mechanism of action uniqueness, and immunosuppressive effect is powerful, and toxic and side effects is little.This medicine selectivity reduces the peripheral circulation lymphocyte number, the existence of significant prolongation laboratory animal transplant organ, do not damage simultaneously immunne response and immunological memory function to virus, toxic and side effects is low, and demonstrate good synergism with clinical line immunosuppressive drugs such as CsA, FK506, RAD, first phase clinical trial result the renal transplant patient is good, and potential applicability in clinical practice is wide.But FTY720 is if use separately with common medicinal supplementary material such as lactose, mannitol, HPMC, starch, Icing Sugar, dextrin, microcrystalline Cellulose, magnesium stearate, micropowder silica gel etc. or share when being made into oral solid formulation, can cause the impurity in the solid preparation of making to increase or active component content reduction, i.e. active ingredient instability in the preparation.
Summary of the invention
The purpose of this invention is to provide a kind of 2-that can make to octyl group phenethyl 2-amino-propanediol hydrochloride stable formulation and preparation method thereof in oral formulations.
The inventor now unexpectedly finds to mix with medicinal inorganic salt as the FTY720 of immunosuppressant the solid orally ingestible that obtains after deliberation can make no matter the preparation that contains FTY720 is can both keep good stable in preparation or in storing.
Therefore, the present invention relates to a kind of oral formulations, it comprises 2-as immunosuppressant to octyl group phenethyl 2-amino-propanediol hydrochloride, medicinal inorganic salt, or optionally other pharmaceutic adjuvant or carrier.
The invention still further relates to a kind of method for preparing oral formulations, it comprises 2-is mixed with medicinal inorganic salt octyl group phenethyl 2-amino-propanediol hydrochloride.
According to the present invention, in total formulation weight, FTY720 content is preferably 0.01 weight %-20 weight % in the preparation of the present invention.Medicinal inorganic salt content is preferably 80 weight %-99.99 weight %.Medicinal inorganic salt has for example: the mixture of two or more of sodium chloride, potassium chloride, calcium sulfate, sodium sulfate, potassium sulfate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium hydrogen phosphate, calcium hydrogen phosphate etc. or they.
Further, the form of preparation of the present invention is said for example and is tablet, capsule or granule.
Say that further preparation of the present invention also can be unit dosage forms (amount) form, as every, every or every bag, and in unit dosage forms, 2-is 0.1mg-5mg to the specification or the content of octyl group phenethyl 2-amino-propanediol hydrochloride.
The preparation method of preparation of the present invention is more specifically said and comprised: respectively at 50～80 ℃ of dryings, control moisture is crossed 60～180 mesh sieves below 2%, granulates behind the mixing with FTY720 and medicinal inorganic salt, the back tabletting or be filled into capsule or direct packaging gets final product of granulating; Or be pressed into little bulk with rolling process behind the mixing, be ground into the granule of 20～60 order sizes then, tabletting or be filled into capsule or direct packaging gets final product.
The specific embodiment
The following examples are used for further specifying the present invention, but it does not mean that any limitation of the invention.
Embodiment:
For the ease of investigating, to contain active substance be 1 milligram/every or every for the preparation tablet made of each prescription or capsule in the present embodiment.Each the prescription all make 1000 or.
Embodiment 1 (prescription 1)
FTY720 1g, sodium chloride 20g, respectively at 60 ℃ of dryings 4 hours, control moisture was below 2%, cross 80 mesh sieves, equivalent incremental method mixing adds suitable quantity of water system soft material, crosses 30 mesh sieves and granulates, 60 ℃ of dryings 30 minutes, 24 order granulate are by the required dosage tabletting or be filled into capsule and get final product.60 ℃ of heating were investigated in 4 hours and five days, checked impurity and FTY720 changes of contents, and the result does not have significant change (seeing Table 7).
Embodiment 2 (prescription 2)
FTY720 1g, potassium chloride 20g, respectively at 60 ℃ of dryings 4 hours, control moisture was below 2%, cross 80 mesh sieves, equivalent incremental method mixing adds suitable quantity of water system soft material, crosses 30 mesh sieves and granulates, 60 ℃ of dryings 30 minutes, 24 order granulate are by the required dosage tabletting or be filled into capsule and get final product.60 ℃ of heating were investigated in 4 hours and five days, checked impurity and FTY720 changes of contents, and the result does not have significant change (seeing Table 7).
Embodiment 3 (prescription 3)
FTY720 1g, sodium chloride 10g, potassium chloride 10g was respectively at 60 ℃ of dryings 4 hours, control moisture is crossed 80 mesh sieves below 2%, and equivalent incremental method mixing adds suitable quantity of water system soft material, cross 30 mesh sieves and granulate, 60 ℃ of dryings 30 minutes, 24 order granulate are by the required dosage tabletting or be filled into capsule and get final product.60 ℃ of heating were investigated in 4 hours and five days, checked impurity and FTY720 changes of contents, and the result does not have significant change (seeing Table 7).
Embodiment 4 (prescription 4)
FTY720 1g, calcium sulfate 20g, respectively at 60 ℃ of dryings 4 hours, control moisture was crossed 80 mesh sieves below 2%, equivalent incremental method mixing, the aqueous solution system soft material that adds an amount of 5% 30 POVIDONE K 30 BP/USP 30 is crossed 30 mesh sieves and is granulated, 60 ℃ of dryings 30 minutes, 24 order granulate are by the required dosage tabletting or be filled into capsule and get final product.60 ℃ of heating were investigated in 4 hours and five days, checked impurity and FTY720 changes of contents, content significant change as a result (seeing Table 7).
Embodiment 5 (prescription 5)
FTY720 1g, potassium sulfate 18g, micropowder silica gel 2g, respectively at 60 ℃ of dryings 4 hours, control moisture was crossed 80 mesh sieves below 2%, and equivalent incremental method mixing is by the required dosage tabletting or be filled into capsule and get final product.60 ℃ of heating were investigated in 4 hours and five days, checked impurity and FTY720 changes of contents, the significant change of FTY720 content as a result.
Embodiment 6 (prescription 6)
FTY720 1g, potassium dihydrogen phosphate 18g, microcrystalline Cellulose 2g was respectively at 60 ℃ of dryings 4 hours, control moisture is crossed 80 mesh sieves, equivalent incremental method mixing below 2%, be pressed into little bulk with rolling process, be ground into the granule of 20～60 order sizes then, by the required dosage tabletting or be filled into capsule and get final product.60 ℃ of heating 4 hours and five days are investigated, inspection impurity and FTY720 changes of contents, FTY720 content change (seeing Table 7) as a result.
Embodiment 7 (prescription 7)
FTY720 1g, calcium hydrogen phosphate 18g, micropowder silica gel 2g, respectively at 60 ℃ of dryings 4 hours, control moisture was crossed 80 mesh sieves below 2%, and equivalent incremental method mixing is by the required dosage tabletting or be filled into capsule and get final product.60 ℃ of heating 4 hours and five days are investigated, inspection impurity and FTY720 changes of contents, FTY720 content change (seeing Table 7) as a result.
Embodiment 8 (prescription 8)
FTY720 1g, lactose 20g, mixing, in 60 ℃ of dryings 4 hours, control moisture was crossed 80 mesh sieves below 2%, and equivalent incremental method mixing is by the required dosage tabletting or be filled into capsule and get final product.60 ℃ of heating were investigated in 4 hours and five days, checked impurity and FTY720 changes of contents, FTY720 content and impurity significant change as a result (seeing Table 7).
Embodiment 9 (prescription 9)
FTY720 1mg, mannitol 20g, mixing, in 60 ℃ of dryings 4 hours, control moisture was crossed 80 mesh sieves below 2%, and equivalent incremental method mixing is by the required dosage tabletting or be filled into capsule and get final product.60 ℃ of heating were investigated in 4 hours and five days, checked impurity and FTY720 changes of contents, FTY720 content and impurity significant change as a result (seeing Table 7).
Embodiment 10 (prescription 10)
FTY720 1g, lactose 19.8g, HPMC 0.2g is respectively at 60 ℃ of dryings, control moisture is crossed 80 mesh sieves, equivalent incremental method mixing below 2%, be pressed into little bulk with rolling process, be ground into the granule of 20～60 order sizes then, by the required dosage tabletting or be filled into capsule and get final product.60 ℃ of heating were investigated in 4 hours and five days, checked impurity and FTY720 changes of contents, FTY720 content and impurity significant change as a result (seeing Table 7).
Embodiment 11 (prescription 11)
FTY720 1g, mannitol 19.8g, HPMC 0.2g is respectively at 60 ℃ of dryings, control moisture is crossed 80 mesh sieves, equivalent incremental method mixing below 2%, be pressed into little bulk with rolling process, be ground into the granule of 20～60 order sizes then, by the required dosage tabletting or be filled into capsule and get final product.60 ℃ of heating were investigated in 4 hours and five days, checked impurity and FTY720 changes of contents, FTY720 content and impurity significant change as a result (seeing Table 7).
Embodiment 12 (prescription 12)
FTY720 1g, lactose 17g, mannitol 2.8g, HPMC0.2g, respectively at 60 ℃ of dryings, control moisture is crossed 80 mesh sieves, equivalent incremental method mixing below 2%, be pressed into little bulk with rolling process, be ground into the granule of 20～60 order sizes then, by the required dosage tabletting or be filled into capsule and get final product.60 ℃ of heating were investigated in 4 hours and five days, checked impurity and FTY720 changes of contents, FTY720 content and impurity significant change as a result (seeing Table 7).
Embodiment 13 (prescription 13)
FTY720 1g, amylum pregelatinisatum 19.8g, HPMC0.2g is respectively at 60 ℃ of dryings, control moisture is crossed 80 mesh sieves, equivalent incremental method mixing below 2%, be pressed into little bulk with rolling process, be ground into the granule of 20～60 order sizes then, by the required dosage tabletting or be filled into capsule and get final product.60 ℃ of heating were investigated in 4 hours and five days, checked impurity and FTY720 changes of contents, FTY720 content and impurity significant change as a result (seeing Table 7).
Embodiment 14 (prescription 14)
FTY720 1g, sodium tartrate 19g, microcrystalline Cellulose 1g was respectively at 60 ℃ of dryings 4 hours, control moisture is crossed 80 mesh sieves, equivalent incremental method mixing below 2%, be pressed into little bulk with rolling process, be ground into the granule of 20～60 order sizes then, by the required dosage tabletting or be filled into capsule and get final product.60 ℃ of heating were investigated in 4 hours and five days, checked impurity and FTY720 changes of contents, FTY720 content and impurity significant change as a result (seeing Table 7).
Embodiment 15
The arbitrary FTY720 tablet of embodiment of the invention 1-3, capsule and granule have carried out influence factor's test and accelerated test is investigated, and the result is as follows:
The content of active substance that below is used to investigate tablet, capsule and the granule of experiment be 1 milligram/every,, bag.
Influence factor's test
Get the arbitrary FTY720 tablet of embodiment of the invention 1-3, capsule and granule and place under high temperature (60 ℃), high humidity (RH=92.5%), illumination (4500LX) condition, outward appearance, impurity, dissolution, content were investigated in sampling respectively in 0 day, 5 days, 10 days.The results are shown in Table 1～table 3.
Table 1 FTY720 sheet influence factor result of the test
| Time (my god) | The investigation project | Outward appearance | Impurity (%) | Dissolution (%) | Content % |
| 0 | White tablets | 0.41 | 98.8 | 100.9 | |
| 5 | Hot and humid illumination | White tablets white tablets white tablets | 0.45 0.43 0.47 | 99.4 97.2 100.4 | 98.7 100.5 99.2 |
| 10 | Hot and humid illumination | White tablets white tablets white tablets | 0.42 0.44 0.49 | 98.6 97.9 99.3 | 99.5 100.3 98.9 |
Table 2 FTY720 capsule influence factor result of the test
| Time (my god) | The investigation project | Outward appearance | Impurity (%) | Dissolution (%) | Content % |
| 0 | Hard capsule case, content are white powder or granule. | 0.42 | 99.2 | 100.6 | |
| 5 | Hot and humid illumination | Hard capsule case, content are white powder or granule.Hard capsule case, content are white powder or granule.Hard capsule case, content are white powder or granule. | 0.42 0.45 0.47 | 98.6 99.5 100.4 | 99.7 98.3 100.2 |
| 10 | Hot and humid illumination | Hard capsule case, content are white powder or granule.Hard capsule case, content are white powder or granule.Hard capsule case, content are white powder or granule. | 0.43 0.43 0.48 | 98.5 99.2 100.6 | 101.5 97.9 100.4 |
Table 3 FTY720 granule influence factor result of the test
| Time (my god) | The investigation project | Outward appearance | Impurity (%) | Content % |
| 0 | White powder/granule | 0.41 | 100.5 | |
| 5 | Hot and humid illumination | White powder/granule white powder/granule white powder/granule | 0.46 0.42 0.48 | 99.2 99.7 100.8 |
| 10 | Hot and humid illumination | White powder/granule white powder/granule white powder/granule | 0.43 0.47 0.42 | 101.6 99.5 98.4 |
The arbitrary preparation of conclusion: embodiment of the invention 1-3 is through high temperature (60 ℃), high humidity (RH=92.5%) and illumination (4500LX) influence factor test.Preparation of the present invention was as a result placed 10 days under high temperature (60 ℃), high humidity (RH=92.5%), illumination (4500LX) condition, and each investigation project has no significant change steady quality.
Accelerated test
The sample of the arbitrary FTY720 tablet of embodiment of the invention 1-3, capsule and granule simulation listing packing is put in 40 ℃, the constant incubator of RH=75%, respectively at sampling in 0,1,2,3,6 month, investigate outward appearance, impurity, dissolution, content, the results are shown in Table 4～table 6.
Table 4 FTY720 sheet accelerated test result
| Lot number | Time (moon) | The investigation project | |||
| Appearance luster | Impurity (%) | Dissolution (%) | Content (%) | ||
| 030807 | 0 1 2 3 6 | White tablets white tablets white tablets white tablets white tablets | 0.42 0.49 0.53 0.61 0.69 | 98.6 99.2 97.5 98.4 99.2 | 101.3 100.2 99.8 98.6 100.7 |
| 030808 | 0 1 2 3 6 | White tablets white tablets white tablets white tablets white tablets | 0.42 0.47 0.53 0.63 0.68 | 97.3 98.2 99.8 101.4 99.6 | 100.2 99.5 99.7 99.3 100.1 |
| 030809 | 0 1 2 3 6 | White tablets white tablets white tablets white tablets white tablets | 0.41 0.46 0.55 0.62 0.70 | 100.2 98.4 97.1 98.6 97.5 | 98.8 100.2 100.6 98.7 99.4 |
Table 5 FTY720 capsule accelerated test result
| Lot number | Time (moon) | The investigation project | |||
| Appearance luster | Impurity (%) | Dissolution (%) | Content (%) | ||
| 030810 | 0 1 2 3 6 | White powder/granule white powder/granule white powder/granule white powder/granule white powder/granule | 0.39 0.47 0.56 0.63 0.71 | 98.2 99.0 98.5 98.9 99.6 | 100.2 100.7 98.8 99.2 100.3 |
| 030811 | 0 1 2 3 6 | White powder/granule white powder/granule white powder/granule white powder/granule white powder/granule | 0.40 0.46 0.54 0.64 0.71 | 98.4 97.2 98.8 100.2 99.1 | 99.4 98.5 98.7 99.8 100.9 |
| 030812 | 0 1 2 3 6 | White powder/granule white powder/granule white powder/granule white powder/granule white powder/granule | 0.40 0.46 0.57 0.63 0.72 | 97.8 98.1 97.9 98.2 98.5 | 99.8 100.7 98.4 99.7 98.4 |
Table 6 FTY720 granule accelerated test result
| Lot number | Time (moon) | The investigation project | |||
| Appearance luster | Impurity (%) | Melting | Content (%) | ||
| 030814 | 0 1 2 3 6 | White powder/granule white powder/granule white powder/granule white powder/granule white powder/granule | 0.40 0.45 0.54 0.62 0.71 | The clarification of solution settled solution settled solution settled solution settled solution | 100.2 100.6 99.8 99.4 99.7 |
| 030815 | 0 1 2 3 6 | White powder/granule white powder/granule white powder/granule white powder/granule white powder/granule | 0.41 0.45 0.56 0.62 0.72 | The clarification of solution settled solution settled solution settled solution settled solution | 101.3 100.5 100.2 98.6 99.3 |
| 030816 | 0 1 2 3 6 | White powder/granule white powder/granule white powder/granule white powder/granule white powder/granule | 0.40 0.47 0.56 0.63 0.74 | The clarification of solution settled solution settled solution settled solution settled solution | 98.4 99.2 100.1 100.6 99.3 |
The arbitrary preparation of conclusion: embodiment of the invention 1-3 was preserved 6 months under temperature is 40 ℃, the condition of relative humidity 75%, and the removal of impurity slightly increases, and other every investigation projects have no significant change steady quality.
The different prescription of table 7 FTY720 preparation is investigated the comparative test result
| The preparation of embodiment | Investigation project (60 ℃ were heated 4 hours) | Investigation project (placing 5 days for 60 ℃) | ||
| Impurity (%) | Content (%) | Impurity (%) | Content (%) | |
| 1 | 0.49 | 100.1 | 0.51 | 99.91 |
| 2 | 0.47 | 99.98 | 0.48 | 99.96 |
| 3 | 0.45 | 100.2 | 0.47 | 100.1 |
| 4 | 0.47 | 96.6 | 0.87 | 93.4 |
| 5 | 0.46 | 90.8 | 0.66 | 84.2 |
| 6 | 0.45 | 97.2 | 0.85 | 97.1 |
| 7 | 0.52 | 96.4 | 1.32 | 94.7 |
| 8 | 1.50 | 90.4 | 2.74 | 79.4 |
| 9 | 1.76 | 87.5 | 3.08 | 83.2 |
| 10 | 1.86 | 87.7 | 3.18 | 73.6 |
| 11 | 2.43 | 92.5 | 3.64 | 85.3 |
| 12 | 1.79 | 90.8 | 8.71 | 76.7 |
| 13 | 1.99 | 88.9 | 10.4 | 70.2 |
| 14 | 2.87 | 90.2 | 6.76 | 81.6 |
Conclusion:
It is interference-free that the preparation of the embodiment of the invention 1～3 not only makes in the preparation activity substance content measure, and the degraded of active substance is also not obvious; Under various investigation conditions the quality of formulation products all be in stable, and advantage such as prescription is simple, preparation technology is easy, with low cost.
Claims (8)
1. oral formulations, it 2-that comprises formula I is to octyl group phenethyl-2-amino-propanediol hydrochloride
And medicinal inorganic salt.
2. the oral formulations of claim 1, it also comprises optionally pharmaceutic adjuvant or carrier.
3. claim 1 or 2 oral formulations wherein in total formulation weight, contain the medicinal inorganic salt of the 2-of 0.01 weight %-20 weight % to octyl group phenethyl-2-amino-propanediol hydrochloride and 80 weight %-99.99%.
4. the oral formulations arbitrary according to claim 1-3, wherein inorganic salt is selected from two or more mixture of sodium chloride, potassium chloride, calcium sulfate, sodium sulfate, potassium sulfate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium hydrogen phosphate, calcium hydrogen phosphate or they.
5. the oral formulations of claim 4, wherein said preparation is tablet, capsule or granule.
6. the oral formulations of claim 5, wherein said preparation is unit dosage forms or unit dose.
7. the oral formulations of claim 6, wherein unit dosage forms or dosage contain 0.1-5mg2-to octyl group phenethyl-2-amino-propanediol hydrochloride.
8. the preparation method of an oral agents preparation, it comprises: with 2-to octyl group phenethyl-2-amino-propanediol hydrochloride (FTY720) and medicinal inorganic salt respectively at 50～80 ℃ of dryings, control moisture is below 2%, select through 60～180 mesh sieves, powder behind the mixing is granulated, the back tabletting or be filled into capsule or direct packaging becomes granule to get final product of granulating.
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| CN1891212B CN1891212B (en) | 2010-10-13 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010078711A1 (en) * | 2008-12-29 | 2010-07-15 | 北京富卡生物技术有限公司 | Amino methanol derivants and salts thereof and their preparation methods and medical use |
| CN103315985A (en) * | 2013-05-16 | 2013-09-25 | 南京市鼓楼医院 | Application of Fingolimod in preparing medicine for inhibiting liver cancer intrahepatic metastasis |
| WO2020043325A1 (en) * | 2018-08-31 | 2020-03-05 | Pharmathen S.A. | Pharmaceutical composition comprising an immunomodulatory agent and method for the preparation thereof |
| EP3733161A1 (en) * | 2007-10-12 | 2020-11-04 | Novartis AG | Compositions comprising sphingosine 1 phosphate (s1p) receptor modulators |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ATE414508T1 (en) * | 2003-04-08 | 2008-12-15 | Novartis Pharma Gmbh | SOLID PHARMACEUTICAL DOSH FORMS CONTAINING AN S1P RECEPTOR AGONIST AND A SUGAR ALCOHOL |
| CN1241903C (en) * | 2003-10-14 | 2006-02-15 | 马启明 | Method for preparing 2-para octylphenyl ehtyl-2-amino propanediol |
-
2005
- 2005-07-07 CN CN2005100827161A patent/CN1891212B/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3733161A1 (en) * | 2007-10-12 | 2020-11-04 | Novartis AG | Compositions comprising sphingosine 1 phosphate (s1p) receptor modulators |
| WO2010078711A1 (en) * | 2008-12-29 | 2010-07-15 | 北京富卡生物技术有限公司 | Amino methanol derivants and salts thereof and their preparation methods and medical use |
| CN103315985A (en) * | 2013-05-16 | 2013-09-25 | 南京市鼓楼医院 | Application of Fingolimod in preparing medicine for inhibiting liver cancer intrahepatic metastasis |
| WO2020043325A1 (en) * | 2018-08-31 | 2020-03-05 | Pharmathen S.A. | Pharmaceutical composition comprising an immunomodulatory agent and method for the preparation thereof |
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| CN1891212B (en) | 2010-10-13 |
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