CN103908446A - Oral solid pharmaceutical composition containing Fingolimod - Google Patents
Oral solid pharmaceutical composition containing Fingolimod Download PDFInfo
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- CN103908446A CN103908446A CN201210592982.9A CN201210592982A CN103908446A CN 103908446 A CN103908446 A CN 103908446A CN 201210592982 A CN201210592982 A CN 201210592982A CN 103908446 A CN103908446 A CN 103908446A
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- fty720
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- microcrystalline cellulose
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Abstract
The invention relates to the field of chemical pharmaceutical preparations, especially to an oral solid pharmaceutical composition containing Fingolimod or its pharmaceutically acceptable salt. Specifically, the invention relates to a pharmaceutical composition containing Fingolimod or its pharmaceutically acceptable salt, microcrystalline cellulose and (or) other pharmaceutical excipients or carriers. The pharmaceutical composition provided by the invention has the characteristics of stable preservation performance, high content uniformity, and excellent dissolution performance.
Description
Technical field
The present invention relates to chemicals medicine field, particularly relate to a kind of oral solid drug composition that contains FTY720 or its officinal salt.
Background technology
FTY720 (Fingolimod), chemical name is 2-amino-2-(2-[4-octyl phenyl] ethyl)-1,3-PD, molecular formula is C
19h
33nO
2, its structural formula is as follows:
FTY720 and officinal salt thereof are a kind of immunosuppressant newly developed in recent years, mechanism of action uniqueness, and immunosuppressive effect is powerful, and toxic and side effects is little etc.This medicine selectivity reduces the lymphocyte number in peripheral blood and tissue, the existence of significant prolongation laboratory animal transplant organ, do not damage viral immunne response and immunological memory function simultaneously, side effect is low, and demonstrates good synergism with clinical line immunosuppressive drugs such as CsA, FK506, RAD.Foreign study proves, FTY720 and officinal salt thereof can be used for the autoimmune diseasees such as rejection after treating organs is transplanted and multiple sclerosis, ulcerative colitis, rheumatoid arthritis, and potential applicability in clinical practice is wide.
In formulation art, conventional filler comprises starch based, dextrin, lactose, mannitol, microcrystalline Cellulose, inorganic salts and sugar alcohol etc.And FTY720 is primary amine compounds, lactose has incompatibility as filler and uncle's amine substance, and the U.S. rad of Maillard(very easily occurs) reaction; Dextrin, as filler, because its cohesive is very strong, can affect the stripping of FTY720 in addition, therefore can not use.
Commercially available fingolimod hydrochloride and officinal salt capsule trade name GILENYA thereof, developed by Novartis company of the U.S., in its prescription adjuvant, comprises sugar alcohol and magnesium stearate, and wherein sugar alcohol is filler, and magnesium stearate is lubricant.The patent CN200480009237.0 of Novartis company application discloses the solid composite medicament of a kind of FTY720 and officinal salt and sugar alcohol, but the stability to medicine, the uniformity and bioavailability etc. do not study in great detail this patent.
Patent CN200510082716.1 discloses a kind of FTY720 pharmaceutical preparation, it uses inorganic salts as filler, inorganic salts in the standby preparation of this legal system may disturb the detection of principal agent and related substance, be unfavorable for quality control, and the impurity content of seeing its preparation from its application text is higher, related substance has all reached more than 4%.
Patent CN201010290748.1 discloses FTY720 ointment, ointment and preparation method thereof, is external medicine preparation.
In addition, due to the specification less (specification of former triturate is 0.5mg) of FTY720 and officinal salt solid composite medicament thereof, adjuvant materials are larger, and the difficulty of controlling uniformity of dosage units is very large, can cause that each intake is inconsistent to affect the treatment, increase untoward reaction.On market, need quality controllable, safety, FTY720 or its officinal salt pharmaceutical preparation that bioavailability is good badly.
Summary of the invention
The problem to be solved in the present invention is to provide FTY720 or its officinal salt oral solid drug composition that a kind of retention is stable, uniformity of dosage units is high, bioavailability good, drug safety is high.
The inventor finds after deliberation, and the solid orally ingestible that FTY720 or its officinal salt and microcrystalline Cellulose are mixed to get can make no matter FTY720 is the performance that can keep good in preparation or in storage; The pharmaceutical composition that the microcrystalline cellulose of FTY720 or its officinal salt and PH101, two kinds of models of PH200 is mixed with, the drug content uniformity is higher; FTY720 or its officinal salt are mixed in the proper ratio with cellulose derivative, and the dissolution of principal agent is relatively good.
Therefore, the present invention relates to a kind of oral solid drug composition that contains FTY720 and officinal salt thereof, it comprises FTY720 and officinal salt and microcrystalline Cellulose, or also comprises cellulose derivative, or also comprises optionally other pharmaceutic adjuvants or carrier.
To achieve the above object of the invention, the present invention realizes by the following technical solutions:
With the total restatement of pharmaceutical composition, in pharmaceutical composition of the present invention, contain FTY720 or its officinal salt and mass percent 70%～99.9% microcrystalline Cellulose; Wherein FTY720 or its officinal salt mass percent preferably 0.1%～5%; Microcrystalline Cellulose mass percent preferably 75%～95.0%, more preferably 80%～90.0%.
In pharmaceutical composition of the present invention, microcrystalline Cellulose uses as filler.On market, the model of conventional microcrystalline Cellulose has PH101, PH102, PH103, PH105, PH112, PH113, PH200, PH301, PH302.Being used in combination of the preferred PH101 of microcrystalline Cellulose model of the present invention, two kinds of models of PH200, more preferably the weight ratio being used in combination of PH101, two kinds of models of PH200 is 3:1 ~ 1:3, most preferably 1:1.
Preferably, the present composition also comprises binding agent, the total weight of the amount of its use based on compositions preferably 1%～20%, more preferably 5%～15%, most preferably 10%.The kind of binding agent comprises that cellulose derivative is as microcrystalline Cellulose, methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl-cellulose and hydroxy propyl cellulose.Other binding agents comprise polyvidone, polyvinylpyrrolidone, gelatin, natural gum, gelatinized corn starch, Polyethylene Glycol etc.Present composition binding agent preferable methyl cellulose, hydroxypropyl cellulose or hydroxypropyl emthylcellulose, most preferably hydroxypropyl cellulose.
Preferably, the present composition also comprises lubricant, the total weight of the amount of its use based on compositions preferably 0.1%～5%, more preferably 0.5%～2%, most preferably 1%.The kind of lubricant comprises for example draws together stearic acid, magnesium stearate, calcium stearate, zinc stearate, glyceryl palmitostearate, sodium stearyl fumarate, Canola oil, hydrogenated vegetable oil, as the mixture of castor oil hydrogenated (or 101), mineral oil, sodium laurylsulfate, magnesium oxide, silica sol, Polyethylene Glycol, polyvinyl alcohol, sodium benzoate, Pulvis Talci, poloxamer or any above-mentioned substance.The preferred stearic acid of present composition lubricant, magnesium stearate, Pulvis Talci, magnesium oxide, colloidal silica, most preferably magnesium stearate.
The present composition can be that the form of powder, granule or piller or unit dosage form are as tablet or capsule.Compositions of the present invention be suitable for being well encapsulated into can be Orally administered capsule shells, particularly glutoid shell in.The present composition can be pressed into tablet.Tablet can be optionally by coating, for example, for example, carry out coating with Pulvis Talci or polysaccharide (cellulose) or hydroxypropyl emthylcellulose coating material.
Further, pharmaceutical composition of the present invention is under unit dosage form, and each unit dose, by the FTY720 or its pharmaceutical salts that suitably also have 0.3 to 20mg, wherein preferably contains 0.5 to 10mg FTY720 or its pharmaceutical salts.
Further, the preferred FTY720 hydrochlorate of pharmaceutical composition FTY720 officinal salt of the present invention.
In addition, pharmaceutical composition of the present invention, can be for the preparation of prevention or treating organs or tissue grafts rejection, graft versus host disease, autoimmune disease, inflammatory diseases, viral myocarditis or have a medicine of the viral disease that viral myocarditis causes.Can also be for the preparation of the medicine for the treatment of or prevention multiple sclerosis.
Detailed Description Of The Invention:
FTY720 officinal salt of the present invention comprises inorganic acid salt example hydrochloric acid salt, hydrobromate and sulfate; Acylate is as acetate, fumarate, maleate, benzoate, citrate, malate, mesylate and benzene sulfonate; Or also comprise that when in place slaine is as sodium salt, potassium salt, calcium salt and aluminum salt, amine salt is as triethylamine salt, and dibasic aminoacid salt is as lysinate.The preferred FTY720 hydrochlorate of pharmaceutical composition active component of the present invention.
1, adjuvant Study on Compatibility
The inventor, writing out a prescription in research process, has carried out adjuvant compatibility test with FTY720 hydrochlorate (principal agent), each model microcrystalline Cellulose, starch, sugar alcohol (comprising mannitol etc.), inorganic salt (comprising sodium chloride, potassium chloride etc.).With reference to " chemicals medicine investigative technique guideline ", by FTY720 hydrochlorate and various adjuvant by 1:5(weight ratio) be placed in respectively in cillin bottle, under illumination (4500 ± 100Lx), 60 DEG C of high temperature, high humidity (RH90 ± 5%) condition, place 10 days, sampling, HPLC method detects the related substance of mixture under each influence factor's condition.Testing result is in table 1:
Table 1 supplementary material compatibility test related substance testing result
Note: be meansigma methods with the numerical value of subscript " a " in table, for example numerical value shown in " principal agent+microcrystalline Cellulose " a line is principal agent and the various model microcrystalline Cellulose meansigma methods of mixed powder institute's measured value after correlation test respectively.
As shown in Table 1, lower 10 days of influence factor's condition and related substance comparison in 0 day, the related substance of principal agent fingolimod hydrochloride and microcrystalline Cellulose, the mixed powder of cellulose derivative changes little, substantially do not rise appreciably, the compatibility that principal agent and microcrystalline Cellulose, cellulose derivative are described is good, and principal agent and microcrystalline Cellulose, cellulose derivative mixed-powder keep good performance in storage.And principal agent and sugar alcohol, inorganic salt or starch are placed after 10 days after mixing under the each condition of influence factor, the maximum list that related substance detects is mixed and total assorted obvious increase that has.
2, adjuvant only uses the prescription of microcrystalline Cellulose as filler
Microcrystalline Cellulose is widely used in pharmaceutical preparation, be mainly in oral tablet and capsule as adhesive or filler, not only can be used for wet granulation but also can be used for direct compression or be filled in capsule.Inventor finds that microcrystalline Cellulose can be used as the unique adjuvant of drug regimen of the present invention except principal agent, in the time that the microcrystalline Cellulose mass percent in pharmaceutical composition changes in 70%～99.9% scope, especially while variation in 75.0%～95.0% scope, while further variation in 80.0%～90.0% scope, principal agent and the microcrystalline Cellulose compatibility be good, and both mixed powder storge qualities are stable.
A preferred embodiment of pharmaceutical composition of the present invention, that FTY720 hydrochlorate is mixed by weight 5:95 with microcrystalline Cellulose PH200, preparation method is identical with the preparation method of patent CN200510082716.1 embodiment 1, prepares a collection of capsule (batch be defined as " 1 ").And prepare a collection of capsule (batch be defined as " 2 ") according to prescription, the preparation method of patent CN200510082716.1 embodiment 1.Above-mentioned two batches of capsules are investigated after 40 hours 60 DEG C of heating, check the changes of contents situation of impurity and FTY720 hydrochlorate, the results are shown in Table 2.
The analytical data of 2 batch 1 of contrast table and batch 2 products is known, it is pharmaceutical composition prepared by filler that the present invention adopts microcrystalline Cellulose PH200, and adopting sodium chloride with patent CN200510082716.1 is to have better bin stability compared with the compositions prepared of filler.In addition, microcrystalline Cellulose is a kind of nontoxic and non-irritating material, after oral, do not absorb, almost there is no potential toxicity, if and inorganic salt long-term taking or absorption too much have relevant side effect, the present invention adopts microcrystalline Cellulose as filler, adopts inorganic salt as compared with filler with patent CN200510082716.1, has the strong characteristic of safety low-poison property.
Table 2 present composition contrasts stability synopsis with patented product
| Batch | Appearance luster | Total impurities (%) | Content (%) |
| 1 | White powder/granule | 0.16 | 100.4 |
| 2 | White powder/granule | 0.35 | 98.7 |
3, adjuvant also makes prescription with lubricator except using microcrystalline Cellulose
The inventor also makes prescription with lubricator be studied in detail adjuvant except using microcrystalline Cellulose.When inventor finds that the mass percent of pharmaceutical composition lubricant of the present invention changes in 0.1%～5% scope, especially while variation in 0.5%～2% scope, further in the time that mass percent is 1% compositions except keeping stable memory property, its powder flowbility is good, is beneficial to and is filled to capsule or tablet machine tabletting.In addition, the preferred stearic acid of lubricant, magnesium stearate, Pulvis Talci, magnesium oxide, colloidal silica, most preferably magnesium stearate.
An embodiment of pharmaceutical composition of the present invention, that FTY720 hydrochlorate, microcrystalline Cellulose PH200 and magnesium stearate are mixed by weight 1.2:96.8:2, recording its mobility (angle of repose °) is 36.6 °, and being filled in capsule process, powder flowbility is good, is easy to fill; And another embodiment is that FTY720 hydrochlorate, microcrystalline Cellulose PH200 are mixed by weight 1.2:96.8, recording its mobility (angle of repose °) is 45.8 °, and being filled in capsule process, static is large, fills difficulty.The interpolation of visible magnesium stearate has improved the mobility of pharmaceutical composition greatly.
A preferred embodiment of pharmaceutical composition of the present invention is by weight 1.2:96.8:2 mixing granulation by FTY720 hydrochlorate, microcrystalline Cellulose PH200 and magnesium stearate.The a collection of compositions of the identical preparation of preparation technology of preparation method and patent CN200480009237.0 embodiment 1 (batch be defined as " 3 ").And prepare a collection of compositions (batch be defined as " 4 ") according to prescription, the preparation method of patent CN200480009237.0 embodiment 1.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, the results are shown in Table 3.
Table 3 present composition contrasts stability synopsis with patented product
| Batch | Appearance luster | Total impurities (%) | Content (%) |
| 3 | White powder/granule | 0.14 | 100.2 |
| 4 | White powder/granule | 0.57 | 99.3 |
The analytical data of 3 batch 3 of contrast table and batch 4 products is known, and the pharmaceutical composition that the present invention adopts microcrystalline Cellulose PH200 to replace Marine Crystal to prepare has better bin stability.
4, adjuvant also uses the prescription of binding agent except microcrystalline Cellulose
Inventor is in the process of test, consider that preparation technology can adopt granulation fill, in prescription, may use binding agent, just the kind of binding agent is screened in test, find that cellulose derivative is good as binding agent and the principal agent compatibility, in storage, keep good performance (in table 1) with the mixed-powder of principal agent.Therefore the inventor is studied in detail as the formula of binding agent cellulose derivative.When inventor finds that the mass percent of pharmaceutical composition binding agent of the present invention changes in 1%～20% scope, storge quality is more stable.In addition, binding agent preferable methyl cellulose, hydroxypropyl cellulose or hydroxypropyl emthylcellulose, most preferably hydroxypropyl cellulose.
A preferred embodiment of pharmaceutical composition of the present invention is by weight 0.5:96.5:3 mixing granulation by FTY720 hydrochlorate, microcrystalline Cellulose PH200 and hyprolose.This technique is except not adding magnesium stearate, replaces outside Marine Crystal with microcrystalline Cellulose PH200, adopts with the identical preparation technology of patent CN200480009237.0 embodiment 3 and prepares a collection of compositions (batch be defined as " 5 ").And prepare a collection of compositions (batch be defined as " 7 ") according to prescription, the preparation technology of patent CN200480009237.0 embodiment 3.Above-mentioned two batches of compositionss are investigated after 40 hours 60 DEG C of heating, check the changes of contents situation of impurity and FTY720 hydrochlorate, the results are shown in Table 4.
In addition, inventor is also to except microcrystalline Cellulose, and adjuvant also uses the prescription of binding agent and lubricant to be studied in detail simultaneously.A preferred embodiment of pharmaceutical composition of the present invention, by FTY720 hydrochlorate, microcrystalline Cellulose PH200 and hyprolose, magnesium stearate is mixed by weight 0.5:95.5:3:1.5, adopts with the identical preparation technology of patent CN200480009237.0 embodiment 3 and prepares a collection of compositions (batch be defined as " 6 ").Said composition is investigated after 40 hours 60 DEG C of heating, checks the changes of contents situation of impurity and FTY720 hydrochlorate, the results are shown in Table 4.
Table 4 present composition contrasts stability synopsis with patented product
| Batch | Appearance luster | Total impurities (%) | Content (%) |
| 5 | White powder/granule | 0.14 | 101.7 |
| 6 | White powder/granule | 0.15 | 100.3 |
| 7 | White powder/granule | 0.55 | 98.3 |
The analytical data of 4 batch 5 of contrast table and batch 7 products, and the analytical data of 4 batch 6 of contrast table and batch 7 products is known, the pharmaceutical composition that the present invention adopts microcrystalline Cellulose PH200 to replace Marine Crystal to prepare has better bin stability.
5, the research of pharmaceutical composition uniformity of dosage units of the present invention
In order to ensure patient's health and safety, while taking medicine, all must accurately the medicine of suitable dosage be offered to patient at every turn.And for example, in pharmaceutical composition unit dosage form FTY720 of the present invention or the less situation of its officinal salt content (0.5mg), the difficulty of controlling uniformity of dosage units is very large.Inventor has carried out emphatically the comprehensive study of uniformity of dosage units to the pharmaceutical composition of the present invention below unit dose 10mg.
Inventor is unexpected to be found to combine and uses microcrystalline Cellulose that model is PH101 and PH200 as filler, can meet pharmaceutical composition prepare flow and content in preparation process all with the requirement of degree, be especially that 1:1, effect is more best in the usage ratio of two model microcrystalline Cellulose.In table 5, enumerated three embodiments of pharmaceutical composition of the present invention, and three kinds of capsules of preparation have been carried out to analyzing and testing, testing result is in table 6.
The prescription of three embodiments of table 5 present composition
| Prescription composition | Prescription 1 | Prescription 2 | Prescription 2 |
| Fingolimod hydrochloride | 0.6g | 0.6g | 0.6g |
| Microcrystalline Cellulose PH101 | -- | 20.0g | 20.0g |
| Microcrystalline Cellulose PH200 | 40g | 20.0g | 20.0g |
| Hyprolose | -- | 1.25g | 1.25g |
| Magnesium stearate | 0.4g | 0.4g | 0.4g |
| System altogether | 500 | 500 | 500 |
| Preparation method | Technique 1 | Technique 2 | Technique 3 |
Technique 1: fingolimod hydrochloride ground 200 mesh sieves; Get the principal agent of recipe quantity and the microcrystalline Cellulose equivalent mix homogeneously that progressively increases, add recipe quantity magnesium stearate, mix homogeneously.No. 4 capsule fills.
Technique 2(wet granulation): fingolimod hydrochloride ground 200 mesh sieves; Get the principal agent of recipe quantity and the hyprolose of recipe quantity, the microcrystalline Cellulose equivalent mix homogeneously that progressively increases, water is wetting agent, and 20 mesh sieves are granulated, and 50 DEG C dry.20 mesh sieve granulate, add recipe quantity magnesium stearate, mix homogeneously.No. 4 capsule fills.
Technique 3: fingolimod hydrochloride ground 200 mesh sieves; Get the principal agent of recipe quantity and the hyprolose of recipe quantity, the microcrystalline Cellulose equivalent mix homogeneously that progressively increases, add recipe quantity magnesium stearate, mix homogeneously.No. 4 capsule fills.
The index of correlation of three kinds of capsules of table 6 the present invention is investigated result
Analysis result shows, prescription 2 adopt two kinds of model microcrystalline Cellulose of PH101 and PH200 to mix to use can take into account simultaneously mobility and content all with spend.In addition, in pharmaceutical composition, add after hyprolose adopting process 2(wet granulation) and technique 3(dry granulation) mobility, uniformity of dosage units all meet the requirements, related substance is without significant change.
6, the research of pharmaceutical composition dissolution of the present invention
Dissolution is an inherent index evaluating drug quality, it is a kind of Test in vitrop of simulating oral fixing preparation disintegrate and stripping in gastrointestinal tract, dissolution has become the in vitro method of evaluating solid preparation bioavailability, dissolution, as a kind of means of quality of the pharmaceutical preparations control, can be distinguished the difference of same drug bioavailability effectively.Inventor has investigated emphatically pharmaceutical composition of the present invention, has especially investigated the granule that adopts pharmaceutical composition of the present invention to prepare, the dissolution of Tablet and Capsula agent.
Inventor finds in test, and cellulose derivative except as binding agent, also has a certain impact to the dissolution of pharmaceutical composition of the present invention in pharmaceutical composition of the present invention.When cellulose derivative is methylcellulose, hydroxypropyl cellulose or hydroxypropyl emthylcellulose, when its mass percent in compositions changes in 5%～15% scope, more progressive in the time that mass percent is 10%, dissolution the best of its pharmaceutical composition.
A preferred embodiment of pharmaceutical composition of the present invention, by weight 0.67:88.:33:10.0:1.0 by FTY720 hydrochlorate, microcrystalline Cellulose PH200, hyprolose, magnesium stearate, by technique 2(wet granulation), and adopt basket method, rotating speed 100rpm, medium volume 500ml, 30 minutes sample times, investigation 0.1N HCl adds 0.2% (W/V) SLS and pH6.8PBS adds the dissolution under 0.2% (W/V) SLS ambient condition.Dissolution is investigated and be the results are shown in Table 7.
Table 7 granule dissolution of the present invention is investigated result
From table 7 analytical data, the granule that this embodiment obtains can effectively stripping in official hour, has good dissolution.
Detailed description of the invention
Below by embodiment, the present invention will be further described, but embodiment does not limit the scope of the invention.
Embodiment 1
Adjuvant only uses the pharmaceutical composition of microcrystalline Cellulose:
Preparation method: micronized FTY720 hydrochlorate is crossed to 200 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and the microcrystalline Cellulose equivalent mix homogeneously that progressively increases, obtain pharmaceutical composition of the present invention.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.14, and drug content is 99.9%.
By said composition by required dosage tabletting or be packed in capsule.
Embodiment 2
Adjuvant only uses the pharmaceutical composition of microcrystalline Cellulose:
Preparation method: micronized FTY720 hydrochlorate is crossed to 200 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and the microcrystalline Cellulose equivalent mix homogeneously that progressively increases, obtain pharmaceutical composition of the present invention.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.13%, and drug content is 101.9%.
By said composition by required dosage tabletting or be packed in capsule.
Embodiment 3
Adjuvant only uses the pharmaceutical composition of microcrystalline Cellulose:
Preparation method: micronized FTY720 hydrochlorate is crossed to 300 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and the microcrystalline Cellulose equivalent mix homogeneously that progressively increases, obtain pharmaceutical composition of the present invention.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.15%, and drug content is 102.2%.
By said composition by required dosage tabletting or be packed in capsule.
Embodiment 4
Adjuvant only uses the pharmaceutical composition of microcrystalline Cellulose:
Preparation method: micronized FTY720 hydrochlorate is crossed to 300 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and the microcrystalline Cellulose equivalent mix homogeneously that progressively increases, obtain pharmaceutical composition of the present invention.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.11%, and drug content is 102.2%.
By said composition by required dosage tabletting or be packed in capsule.
Embodiment 5
Adjuvant only uses the pharmaceutical composition of microcrystalline Cellulose:
Preparation method: micronized FTY720 hydrochlorate is crossed to 100 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and the microcrystalline Cellulose equivalent mix homogeneously that progressively increases, obtain pharmaceutical composition of the present invention.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.14%, and drug content is 100.3%.
By said composition by required dosage tabletting or be packed in capsule.
Embodiment 6
Adjuvant only uses the pharmaceutical composition of microcrystalline Cellulose:
Preparation method: micronized FTY720 hydrochlorate is crossed to 80 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and the microcrystalline Cellulose equivalent mix homogeneously that progressively increases, obtain pharmaceutical composition of the present invention.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.14%, and drug content is 100.3%.
By said composition by required dosage tabletting or be packed in capsule.
Embodiment 7
Adjuvant only uses the pharmaceutical composition of microcrystalline Cellulose:
Preparation method: micronized FTY720 hydrochlorate is crossed to 80 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and the microcrystalline Cellulose equivalent mix homogeneously that progressively increases, obtain pharmaceutical composition of the present invention.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.13%, and drug content is 102.4%.
By said composition by required dosage tabletting or be packed in capsule.
Embodiment 8
Adjuvant, except using microcrystalline Cellulose, also makes pharmaceutical composition with lubricator:
Preparation method: micronized FTY720 hydrochlorate is crossed to 200 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and the microcrystalline Cellulose equivalent mix homogeneously that progressively increases, add recipe quantity magnesium stearate, mix homogeneously obtains pharmaceutical composition of the present invention.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.12%, and drug content is 101.2%.
By said composition by required dosage tabletting or be packed in capsule.
Embodiment 9
Adjuvant, except using microcrystalline Cellulose, also makes pharmaceutical composition with lubricator:
Preparation method: micronized FTY720 hydrochlorate is crossed to 200 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and the microcrystalline Cellulose equivalent mix homogeneously that progressively increases, add recipe quantity magnesium stearate, mix homogeneously obtains pharmaceutical composition of the present invention.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.13%, and drug content is 100.5%.
By said composition by required dosage tabletting or be packed in capsule.
Embodiment 10
Adjuvant, except using microcrystalline Cellulose, also makes pharmaceutical composition with lubricator:
Preparation method: micronized FTY720 hydrochlorate is crossed to 200 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and the microcrystalline Cellulose equivalent mix homogeneously that progressively increases, add recipe quantity magnesium stearate, mix homogeneously obtains pharmaceutical composition of the present invention.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.12%, and drug content is 100.2%.
By said composition by required dosage tabletting or be packed in capsule.
Embodiment 11
Adjuvant, except using microcrystalline Cellulose, also makes pharmaceutical composition with lubricator:
Preparation method: micronized FTY720 hydrochlorate is crossed to 200 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and the microcrystalline Cellulose equivalent mix homogeneously that progressively increases, add recipe quantity stearic acid, mix homogeneously obtains pharmaceutical composition of the present invention.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.13%, and drug content is 100.1%.
By said composition by required dosage tabletting or be packed in capsule.
Embodiment 12
Adjuvant, except using microcrystalline Cellulose, also makes pharmaceutical composition with lubricator:
Preparation method: micronized FTY720 hydrochlorate is crossed to 200 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and the microcrystalline Cellulose equivalent mix homogeneously that progressively increases, add recipe quantity Pulvis Talci, mix homogeneously obtains pharmaceutical composition of the present invention.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.15%, and drug content is 99.8%.
By said composition by required dosage tabletting or be packed in capsule.
Embodiment 13
Adjuvant, except using microcrystalline Cellulose, also makes pharmaceutical composition with lubricator:
Preparation method: micronized FTY720 hydrochlorate is crossed to 200 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and the microcrystalline Cellulose equivalent mix homogeneously that progressively increases, add recipe quantity magnesium oxide, mix homogeneously obtains pharmaceutical composition of the present invention.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.13%, and drug content is 100.7%.
By said composition by required dosage tabletting or be packed in capsule.
Embodiment 14
Adjuvant, except using microcrystalline Cellulose, also makes pharmaceutical composition with lubricator:
Preparation method: micronized FTY720 hydrochlorate is crossed to 200 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and the microcrystalline Cellulose equivalent mix homogeneously that progressively increases, add recipe quantity colloidal silica, mix homogeneously obtains pharmaceutical composition of the present invention.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.13%, and drug content is 100.6%.
By said composition by required dosage tabletting or be packed in capsule.
Embodiment 15
Adjuvant, except using microcrystalline Cellulose, also makes pharmaceutical composition with lubricator:
Preparation method: micronized FTY720 hydrochlorate is crossed to 200 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and the microcrystalline Cellulose equivalent mix homogeneously that progressively increases, add recipe quantity magnesium stearate, mix homogeneously obtains pharmaceutical composition of the present invention.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.13%, and drug content is 102.3%.
By said composition by required dosage tabletting or be packed in capsule.
Embodiment 16
Adjuvant, except using microcrystalline Cellulose, also makes pharmaceutical composition with lubricator:
Preparation method: micronized FTY720 hydrochlorate is crossed to 200 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and the microcrystalline Cellulose equivalent mix homogeneously that progressively increases, add recipe quantity magnesium stearate, mix homogeneously obtains pharmaceutical composition of the present invention.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.12%, and drug content is 102.1%.
By said composition by required dosage tabletting or be packed in capsule.
Embodiment 17
Adjuvant, except using microcrystalline Cellulose, also uses the pharmaceutical composition of binding agent:
Preparation method: micronized FTY720 hydrochlorate is crossed to 200 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and microcrystalline Cellulose, the hypromellose equivalent mix homogeneously that progressively increases, obtain pharmaceutical composition of the present invention.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.13%, and drug content is 100.6%.
By said composition by required dosage tabletting or be packed in capsule
Embodiment 18
Adjuvant, except using microcrystalline Cellulose, also uses the pharmaceutical composition of binding agent:
Preparation method: micronized FTY720 hydrochlorate is crossed to 200 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and microcrystalline Cellulose, the hypromellose equivalent mix homogeneously that progressively increases, obtain pharmaceutical composition of the present invention.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.12%, and drug content is 100.4%.
By said composition by required dosage tabletting or be packed in capsule.
Embodiment 19
Adjuvant, except using microcrystalline Cellulose, also uses the pharmaceutical composition of binding agent:
Preparation method: micronized FTY720 hydrochlorate is crossed to 200 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and microcrystalline Cellulose, the hypromellose equivalent mix homogeneously that progressively increases, obtain pharmaceutical composition of the present invention.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.14%, and drug content is 102.4%.
By said composition by required dosage tabletting or be packed in capsule.
Embodiment 20
Adjuvant, except using microcrystalline Cellulose, also uses the pharmaceutical composition of binding agent:
Preparation method: micronized FTY720 hydrochlorate is crossed to 200 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and microcrystalline Cellulose, the hypromellose equivalent mix homogeneously that progressively increases, obtain pharmaceutical composition of the present invention.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.12%, and drug content is 102.8%.
By said composition by required dosage tabletting or be packed in capsule.
Embodiment 21
Adjuvant, except using microcrystalline Cellulose, also uses the pharmaceutical composition of binding agent:
Preparation method: micronized FTY720 hydrochlorate is crossed to 200 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and microcrystalline Cellulose, the hypromellose equivalent mix homogeneously that progressively increases, obtain pharmaceutical composition of the present invention.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.12%, and drug content is 100.4%.
By said composition by required dosage tabletting or be packed in capsule.
Embodiment 22
Adjuvant, except using microcrystalline Cellulose, also uses the pharmaceutical composition of binding agent:
Preparation method: micronized FTY720 hydrochlorate is crossed to 200 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and microcrystalline Cellulose, the methylcellulose equivalent mix homogeneously that progressively increases, obtain pharmaceutical composition of the present invention.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.12%, and drug content is 101.3%.
By said composition by required dosage tabletting or be packed in capsule.
Embodiment 23
Adjuvant, except using microcrystalline Cellulose, also uses the pharmaceutical composition of binding agent:
Preparation method: micronized FTY720 hydrochlorate is crossed to 200 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and microcrystalline Cellulose, the methylcellulose equivalent mix homogeneously that progressively increases, obtain pharmaceutical composition of the present invention.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.12%, and drug content is 99.98%.
By said composition by required dosage tabletting or be packed in capsule.
Embodiment 24
Adjuvant, except using microcrystalline Cellulose, also uses the pharmaceutical composition of binding agent:
Preparation method: micronized FTY720 hydrochlorate is crossed to 200 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and microcrystalline Cellulose, the hydroxypropyl emthylcellulose equivalent mix homogeneously that progressively increases, obtain pharmaceutical composition of the present invention.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.14%, and drug content is 100.3%.
By said composition by required dosage tabletting or be packed in capsule.
Embodiment 25
Adjuvant, except using microcrystalline Cellulose, also uses the pharmaceutical composition of binding agent:
Preparation method: micronized FTY720 hydrochlorate is crossed to 200 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and microcrystalline Cellulose, the hydroxypropyl emthylcellulose equivalent mix homogeneously that progressively increases, obtain pharmaceutical composition of the present invention.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.13%, and drug content is 100.9%.
By said composition by required dosage tabletting or be packed in capsule.
Embodiment 26
Adjuvant, except using microcrystalline Cellulose, also uses the pharmaceutical composition of binding agent and lubricant simultaneously:
Preparation method: micronized FTY720 hydrochlorate is crossed to 200 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and microcrystalline Cellulose, the hyprolose equivalent mix homogeneously that progressively increases, add mix homogeneously to obtain pharmaceutical composition of the present invention the magnesium stearate of recipe quantity.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.12%, and drug content is 100.2%.By said composition by required dosage tabletting or be packed in capsule.Detect by " Chinese Pharmacopoeia " annex X E Content uniformity test, uniformity of dosage units (A+1.8S) is 13.9.
Embodiment 27
Adjuvant, except using microcrystalline Cellulose, also uses the pharmaceutical composition of binding agent and lubricant simultaneously:
Preparation method: micronized FTY720 hydrochlorate is crossed to 200 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and microcrystalline Cellulose, the hyprolose equivalent mix homogeneously that progressively increases, add mix homogeneously to obtain pharmaceutical composition of the present invention the magnesium stearate of recipe quantity.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.14%, and drug content is 102.2%.By said composition by required dosage tabletting or be packed in capsule.Detect by " Chinese Pharmacopoeia " annex X E Content uniformity test, uniformity of dosage units (A+1.8S) is 16.9.
Embodiment 28
Adjuvant, except using microcrystalline Cellulose, also uses the pharmaceutical composition of binding agent and lubricant simultaneously:
Preparation method: micronized FTY720 hydrochlorate is crossed to 200 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and microcrystalline Cellulose, the hyprolose equivalent mix homogeneously that progressively increases, add mix homogeneously to obtain pharmaceutical composition of the present invention the Pulvis Talci of recipe quantity.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.13%, and drug content is 101.4%.By said composition by required dosage tabletting or be packed in capsule.Detect by " Chinese Pharmacopoeia " annex X E Content uniformity test, uniformity of dosage units (A+1.8S) is 17.2.
Embodiment 29
Adjuvant, except using microcrystalline Cellulose, also uses the pharmaceutical composition of binding agent and lubricant simultaneously:
Preparation method: micronized FTY720 hydrochlorate is crossed to 200 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and microcrystalline Cellulose, the hyprolose equivalent mix homogeneously that progressively increases, add mix homogeneously to obtain pharmaceutical composition of the present invention the colloidal silica of recipe quantity.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.14%, and drug content is 99.99%.By said composition by required dosage tabletting or be packed in capsule.Detect by " Chinese Pharmacopoeia " annex X E Content uniformity test, uniformity of dosage units (A+1.8S) is 16.6.
Embodiment 30
Adjuvant, except using microcrystalline Cellulose, also uses the pharmaceutical composition of binding agent and lubricant simultaneously:
Preparation method: micronized FTY720 hydrochlorate is crossed to 200 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and microcrystalline Cellulose, the hydroxypropyl emthylcellulose equivalent mix homogeneously that progressively increases, add mix homogeneously to obtain pharmaceutical composition of the present invention the colloidal silica of recipe quantity.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.13%, and drug content is 101.4%.By said composition by required dosage tabletting or be packed in capsule.Detect by " Chinese Pharmacopoeia " annex X E Content uniformity test, uniformity of dosage units (A+1.8S) is 6.1.
Embodiment 31
Adjuvant, except using microcrystalline Cellulose, also uses the pharmaceutical composition of binding agent and lubricant simultaneously:
Preparation method: micronized FTY720 hydrochlorate is crossed to 200 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and microcrystalline Cellulose, the hyprolose equivalent mix homogeneously that progressively increases, add mix homogeneously to obtain pharmaceutical composition of the present invention the magnesium stearate of recipe quantity.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.12%, and drug content is 102.3%.Said composition is packed in capsule by required dosage.Detect by " Chinese Pharmacopoeia " annex X E Content uniformity test, uniformity of dosage units (A+1.8S) is 2.3.The dissolution of said preparation is in table 8.
Embodiment 32
Adjuvant, except using microcrystalline Cellulose, also uses the pharmaceutical composition of binding agent and lubricant simultaneously:
Preparation method: micronized FTY720 hydrochlorate is crossed to 200 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and microcrystalline Cellulose, the hyprolose equivalent mix homogeneously that progressively increases, add mix homogeneously to obtain pharmaceutical composition of the present invention the magnesium stearate of recipe quantity.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.12%, and drug content is 102.1%.Said composition is packed in capsule by required dosage.Detect by " Chinese Pharmacopoeia " annex X E Content uniformity test, uniformity of dosage units (A+1.8S) is 2.2.The dissolution of said preparation is in table 8.
Embodiment 33
Adjuvant, except using microcrystalline Cellulose, also uses the pharmaceutical composition of binding agent and lubricant simultaneously:
Preparation method: micronized FTY720 hydrochlorate is crossed to 200 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and microcrystalline Cellulose, the hyprolose equivalent mix homogeneously that progressively increases, add mix homogeneously to obtain pharmaceutical composition of the present invention the magnesium stearate of recipe quantity.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.12%, and drug content is 100.2%.Said composition is packed in capsule by required dosage.Detect by " Chinese Pharmacopoeia " annex X E Content uniformity test, uniformity of dosage units (A+1.8S) is 2.2.The dissolution of said preparation is in table 8.
Embodiment 34
Adjuvant, except using microcrystalline Cellulose, also uses the pharmaceutical composition of binding agent and lubricant simultaneously:
Preparation method: micronized FTY720 hydrochlorate is crossed to 200 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and microcrystalline Cellulose, the hyprolose equivalent mix homogeneously that progressively increases, add mix homogeneously to obtain pharmaceutical composition of the present invention the magnesium stearate of recipe quantity.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.12%, and drug content is 100.4%.Said composition is packed in capsule by required dosage.Detect by " Chinese Pharmacopoeia " annex X E Content uniformity test, uniformity of dosage units (A+1.8S) is 2.2.The dissolution of said preparation is in table 8.
Embodiment 35
Patent CN200480009237.0 embodiment 3 composite formulas:
Preparation method: micronized FTY720 hydrochlorate is crossed to 200 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and Marine Crystal, the hyprolose equivalent mix homogeneously that progressively increases, add mix homogeneously to obtain pharmaceutical composition of the present invention the magnesium stearate of recipe quantity.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.52%, and drug content is 98.23%.Said composition is packed in capsule by required dosage.Detect by " Chinese Pharmacopoeia " annex X E Content uniformity test, uniformity of dosage units (A+1.8S) is 21.2.The dissolution of said preparation is in table 8.
Embodiment 36
Patent CN200510082716.1 embodiment 5 composite formulas:
Preparation method: micronized FTY720 hydrochlorate is crossed to 200 mesh sieves.The FTY720 hydrochlorate of recipe quantity and potassium sulfate, the micropowder silica gel equivalent mix homogeneously that progressively increases is obtained to pharmaceutical composition of the present invention.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.32%, and drug content is 98.11%.Said composition is packed in capsule by required dosage.Detect by " Chinese Pharmacopoeia " annex X E Content uniformity test, uniformity of dosage units (A+1.8S) is 31.2.The dissolution of said preparation is in table 8.。
Embodiment 37
Embodiment 31～36 compositionss have been carried out to influence factor's test in the present invention and accelerated test is investigated:
(1) hot test
Get the embodiment of the present invention 31～36 compositionss and be placed in 60 DEG C of calorstats and place 10 days, in sampling in the 5th day, 10 days, appearance character, dissolution, content and the related substance of sample for reference.The results are shown in Table 8:
Table 8 hot test result
Conclusion: embodiment 31～34 compositionss are placed 5 days in 60 DEG C of calorstats, 10 days, with result comparison in 0 day, compositions appearance character, content, related substance, dissolution are substantially unchanged, show this product under 60 DEG C of hot conditionss, place 10 days stable, embodiment 35～36 compositionss content and related substance under this condition changes greatly by contrast.
(2) high wet test
Get the embodiment of the present invention 31～36 compositionss and be placed under 25 DEG C of relative humidity RH90 ± 5% conditions and place 10 days, in sampling in the 5th day, 10 days, appearance character, dissolution, content and the related substance of sample for reference.The results are shown in Table 9:
Table 9 high humidity result of the test
Under 25 DEG C of relative humidity RH90 ± 5% conditions of conclusion: embodiment 31～34 compositions, place 5 days, 10 days, with result comparison in 0 day, compositions appearance character, content, related substance, dissolution are substantially unchanged, show this product under 60 DEG C of hot conditionss, place 10 days stable, embodiment 35～36 compositionss content and related substance under this condition changes greatly by contrast.
(2) highlight test
Get the embodiment of the present invention 31～36 compositionss and be placed under 4500 ± 100Lx strong illumination condition and place 10 days, in sampling in the 5th day, 10 days, appearance character, dissolution, content and the related substance of sample for reference.The results are shown in Table 9:
Table 10 highlight test result
Conclusion: embodiment 31～34 compositionss are placed 5 days under 4500 ± 100Lx strong illumination condition, 10 days, with result comparison in 0 day, compositions appearance character, content, related substance, dissolution are substantially unchanged, show this product under 60 DEG C of hot conditionss, place 10 days stable, embodiment 35～36 compositionss content and related substance under this condition changes greatly by contrast.
Embodiment 38
Adjuvant, except using microcrystalline Cellulose, also uses the pharmaceutical composition of binding agent and lubricant simultaneously:
Preparation method: micronized FTY720 hydrochlorate is crossed to 200 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and microcrystalline Cellulose, the hyprolose equivalent mix homogeneously that progressively increases, add mix homogeneously to obtain pharmaceutical composition of the present invention the magnesium stearate of recipe quantity.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.12%, and drug content is 101.8%.Said composition is packed in capsule by required dosage.Detect by " Chinese Pharmacopoeia " annex X E Content uniformity test, uniformity of dosage units (A+1.8S) is 3.7.
Embodiment 39
Adjuvant, except using microcrystalline Cellulose, also uses the pharmaceutical composition of binding agent and lubricant simultaneously:
Preparation method: micronized FTY720 hydrochlorate is crossed to 200 mesh sieves.By the FTY720 hydrochlorate of recipe quantity and microcrystalline Cellulose, the hyprolose equivalent mix homogeneously that progressively increases, add mix homogeneously to obtain pharmaceutical composition of the present invention the magnesium stearate of recipe quantity.60 DEG C of heating were investigated after 40 hours, checked the changes of contents situation of impurity and FTY720 hydrochlorate, and check result shows that said composition impurity content is 0.12%, and drug content is 100.2%.Said composition is packed in capsule by required dosage.Detect by " Chinese Pharmacopoeia " annex X E Content uniformity test, uniformity of dosage units (A+1.8S) is 2.9.
Claims (27)
1. the oral solid drug composition being suitable for, it comprises:
(1) FTY720 or its officinal salt;
(2) mass percent is 70.0%～99.9% microcrystalline Cellulose.
2. oral solid drug composition as claimed in claim 1, it comprises:
(1) mass percent is 0.1%～5% FTY720 or its officinal salt;
(2) mass percent is 65.0%～99.9% microcrystalline Cellulose.
3. oral solid drug composition as claimed in claim 1 or 2, is characterized by that to comprise mass percent be 75.0%～95.0% microcrystalline Cellulose.
4. oral solid drug composition as claimed in claim 3, is characterized by that to comprise mass percent be 80.0%～90.0% microcrystalline Cellulose.
5. as claim 1 to 4 any one oral solid drug composition, the model that it is characterized by described microcrystalline Cellulose is selected from PH101, PH102, PH103, PH105, PH112, PH113, PH200, PH301, PH302.
6. as claim 1 to 4 any one oral solid drug composition, it is characterized by microcrystalline Cellulose is the combination of PH101, two kinds of models of PH200.
7. oral solid drug composition as claimed in claim 6, the weight ratio that it is characterized by microcrystalline Cellulose PH101 and microcrystalline Cellulose PH200 is 3:1 ~ 1:3.
8. oral solid drug composition as claimed in claim 7, the weight ratio that it is characterized by microcrystalline Cellulose PH101 and microcrystalline Cellulose PH200 is 1:1.
9. as claim 1 to 8 any one oral solid drug composition, it is characterized by and comprise binding agent.
10. oral solid drug composition as claimed in claim 9, is characterized by that to comprise mass percent be 1%～20% binding agent.
11. oral solid drug compositions as claimed in claim 10, is characterized by that to comprise mass percent be 5%～15% binding agent.
12. oral solid drug compositions as claimed in claim 11, is characterized by that to comprise mass percent be 10% binding agent.
13. oral solid drug compositions as described in claim 8 to 12, is characterized by described binding agent and are selected from methylcellulose, hydroxypropyl cellulose or hydroxypropyl emthylcellulose.
14. oral solid drug compositions as claimed in claim 13, it is characterized by described binding agent is hydroxypropyl cellulose.
15. as claim 1 to 14 any one oral solid drug composition, it is characterized by and comprises lubricant.
16. oral solid drug compositions as claimed in claim 15, is characterized by that to comprise mass percent be 0.1%～5% lubricant.
17. oral solid drug compositions as claimed in claim 16, is characterized by that to comprise mass percent be 0.5%～2% lubricant.
18. oral solid drug compositions as claimed in claim 17, is characterized by that to comprise mass percent be 1% lubricant.
19. oral solid drug compositions as described in claim 15 to 18, is characterized by described lubricant and are selected from stearic acid, magnesium stearate, Pulvis Talci, magnesium oxide, colloidal silica.
20. oral solid drug compositions as claimed in claim 19, it is characterized by described lubricant is magnesium stearate.
21. as described in claim 1 to 20 any one oral solid drug composition, wherein compositions is tablet, capsule or particle form.
22. as described in claim 1 to 20 any one oral solid drug composition, wherein compositions is unit dosage form.
23. oral solid drug compositions as claimed in claim 22, its compositions is unit dosage form and contains 0.3 to 20mg FTY720 or its officinal salt.
24. oral solid drug compositions as claimed in claim 23, its compositions is unit dosage form and contains 0.5 to 10mg FTY720 or its officinal salt.
25. as described in claim 1 to 24 any one oral solid drug composition, the preferred FTY720 hydrochlorate of FTY720 officinal salt described in it.
26. as described in claim 1 to 25 any one oral solid drug composition, it is for the preparation of prevention or treating organs or tissue grafts rejection, graft versus host disease, autoimmune disease, inflammatory diseases, viral myocarditis or there is a purposes in the medicine of the viral disease that viral myocarditis causes.
27. as described in claim 1 to 25 any one oral solid drug composition, for the preparation for the treatment of or prevention multiple sclerosis medicine in purposes.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201210592982.9A CN103908446A (en) | 2012-12-31 | 2012-12-31 | Oral solid pharmaceutical composition containing Fingolimod |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106619558A (en) * | 2017-02-27 | 2017-05-10 | 佛山市弘泰药物研发有限公司 | Fingolimod gastric-soluble pellets and preparation method thereof |
| CN106794159A (en) * | 2014-08-22 | 2017-05-31 | 广东东阳光药业有限公司 | A kind of FTY720 solid composite and preparation method thereof |
-
2012
- 2012-12-31 CN CN201210592982.9A patent/CN103908446A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106794159A (en) * | 2014-08-22 | 2017-05-31 | 广东东阳光药业有限公司 | A kind of FTY720 solid composite and preparation method thereof |
| CN106619558A (en) * | 2017-02-27 | 2017-05-10 | 佛山市弘泰药物研发有限公司 | Fingolimod gastric-soluble pellets and preparation method thereof |
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