CN104414990A - Stable preparation containing everolimus or derivatives of everolimus and preparation method of stable preparation - Google Patents
Stable preparation containing everolimus or derivatives of everolimus and preparation method of stable preparation Download PDFInfo
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- CN104414990A CN104414990A CN201310410583.0A CN201310410583A CN104414990A CN 104414990 A CN104414990 A CN 104414990A CN 201310410583 A CN201310410583 A CN 201310410583A CN 104414990 A CN104414990 A CN 104414990A
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Abstract
The invention relates to an oral solid preparation containing everolimus or derivatives of the everolimus. The oral solid preparation at least comprises everolimus or the derivatives of the everolimus and a water-soluble film-forming agent, wherein the everolimus or the derivatives of the everolimus serves as an active ingredient. The invention further relates to a preparation method of the oral solid preparation. The oral solid preparation containing the everolimus or derivatives of everolimus has the characteristics of good stability, ideal dissolution and simple process and is high in production efficiency and applicable to industrial production.
Description
Technical field
The present invention relates to a kind of oral solid formulation and preparation method thereof, be specifically related to preparation of everolimus or derivatives thereof and preparation method thereof.
Background technology
Everolimus (everolimus) is sirolimus (sirolimus, also known as rapamycin, i.e. rapamycin) derivant, also known as 40-0-(2-ethoxy)-rapamycin, or 40-0-(2-ethoxy)-sirolimus.
Structural formula:
Everolimus is a kind of Macrocyclolactone lactone kind medicine, structure belongs to the derivant of rapamycin, therefore is also called 40-0-(2-ethoxy)-rapamycin, and functionally it belongs to rapamycin mammal target spot (mTOR) inhibitors of kinases.Everolimus can slow down the growth of kidney cancer cell, reduces the mortality rate of 67%.By growth and the propagation of inhibition tumor cell, directly act on tumor cell; By suppressing blood vessel to occur, causing tumor vessel to distribute and reduce and play indirect action.The clinical patient treating advanced renal cell cancer failure for Sutent or Sorafenib.
Everolimus is developed by Novartis Co., Ltd of Switzerland (Novartis) the earliest, within 2003, goes on the market first in Sweden, trade name
, dosage form has tablet and dispersible tablet, and specification has 0.25mg, 0.5mg, 0.75mg and1.0mg.Subsequently, Novartis continual exploitation 2.5mg, 5mg, 10mg, trade name
in March, 2010, FDA ratifies the rejection of everolimus for preventing light moderate immune to repel the renal transplantation of kidney transplant patients's appearance of risk, trade name
2011, FDA ratified everolimus and expands indication, is used for the treatment of inoperable rare hereditary brain benign tumor subependymal giant cell astrocytoma (SEGA).Except the rejection after renal cell carcinoma and organ transplantation, everolimus is also carrying out the research to neuroendocrine tumor, lymphoma, other cancers and tuberous sclerosis, can be used as unitary agent or share with existing cancer treatment method.
Everolimus crude drug is in white extremely micro-yellow, water-soluble hardly, mainly with amorphous existence.Consider from biopharmaceutics angle, this compounds usually needs to adopt solubilising means, to improve its bioavailability in preparation process.In addition, disclosed data also shows, and everolimus chemical stability is bad, shines all more responsive, especially under conditions of high humidity, very easily degrade to wet, light and heat.Such as, commercialized product
(Novartis Co., Ltd) adopts aluminum aluminum packaging, to realize moisture effect.Except adopting except damp-prrof packing, usually by selecting adjuvant that some moisture is lower as Lactis Anhydrous, mannitol etc., or special preparation technology can also be adopted, as powder coating technology etc., thus improving product quality.
US Patent No. 6004973 discloses the rapamycin or derivatives thereof of solid dispersion form, described solid dispersion system adopts coprecipitation preparation, by rapamycin and a kind of mounting medium, if hypromellose, Hydroxypropyl methyl cellulose phtalate are with amorphous or essentially amorphous state physical bond, make tablet, capsule or powder, overcome the unpredictable rate of dissolution of conventional formulation and irregular bioavailability.But employing a large amount of organic solvents due to this technique, the solvent evaporate to dryness time is long, and power consumption is large, and complex process, quality control is more difficult, is unfavorable for suitability for industrialized production.Moreover, solid dispersion is easy " aging " in storage process, causes product stripping to delay.
Chinese patent CN201110065075 discloses a kind of oral solid formulation compositions of everolimus, and said composition comprises a kind of acid-base modifier especially, regulates the pH value of water solution of compositions to 5-6, and described preparation adopts the preparation of powder coating technology.Known to formulation scientist, due to everolimus, proportion is less in the formulation, be not easy very much mixing, and everolimus bulk density is low, can cause layering in fluidized bed coating process, has the underproof risk of uniformity of dosage units.
Chinese patent CN103099790 discloses a kind of preparation method of tablet of everolimus, described method system is sprayed onto on polyvinylpolypyrrolidone after being dissolved in organic solvent is as acetonitrile, dichloromethane, chloroform, methanol, dehydrated alcohol by everolimus, and after drying under reduced pressure and the mixing of other pharmaceutic adjuvant, tabletting obtains everolimus sheet.But organic solvent must be adopted as acetonitrile due to its technical process, dichloromethane, chloroform etc., to the toxicity of human body greatly and high volatility, therefore in production process, safety coefficient is low, operating difficulties, and needs to carry out a large amount of post processing work such as solvent recovery.In addition, as one skilled in the art will appreciate, decompression dry device complex structure, construction cost is more, thus undesirably increases production cost.
US Patent No. 20100316724 discloses a kind of immunosuppressant, and as tacrolimus, the microball preparation of sirolimus, the microsphere average grain diameter of preparation is less than or equal to 10um, and tap density is not more than 0.4g/ml.
US Patent No. 20120053198 discloses the solution of rapamycin or derivatives thereof, and said preparation system adopts the preparation of gamma-cyclodextrin inclusion technique.
Summary of the invention
The invention provides oral solid formulation of a kind of stable everolimus or derivatives thereof and preparation method thereof, it at least comprises the everolimus or derivatives thereof of 0.25-5% and is selected from the water-soluble film forming agent of copolyvidone, polyvinyl alcohol and/or polyethylene glycol-vinyl alcohol.Described preparation adopts wet granulation technology preparation, and stability is better, and stripping is desirable, and technique is simple, and production efficiency is high, is applicable to suitability for industrialized production.
According to everolimus or derivatives thereof preparation of the present invention, include and be equivalent to total formulation weight:
The everolimus or derivatives thereof of 0.25-2.5%,
The water-soluble film forming agent of 2-15%,
The diluent of 65-90%,
The disintegrating agent of 2-20%,
The lubricant of 0.5-2%.
According to the present invention, everolimus or derivatives thereof is selected from everolimus, tacrolimus, sirolimus etc., preferred everolimus.
Everolimus itself is poorly soluble.As one skilled in the art will appreciate, for insoluble drug, usually need to adopt some solubilization technique to improve stripping, as reduced crude drug particle diameter, adding surfactant, increasing the consumption of disintegrating agent, or select other special process, as solid dispersions technique, supercritical fluid technology etc.As mention in background technology US6004973 by preparing solid dispersion to improve the stripping of rapamycin or derivatives thereof, thus improve its bioavailability.
As described herein, " water-soluble film forming agent " refers to that a class has the high molecular weight water soluble polymer of filming performance.This kind of material is generally used in tablet, granule, the Coating Solution of micropill and the spray of local application.Conventional has hypromellose, hyprolose, polyvidone, copolyvidone, polyvinyl alcohol, polyethylene glycol-ethenol copolymer etc.
According to the present invention, water-soluble film forming agent is selected from: copolyvidone, polyvinyl alcohol and/or polyethylene glycol-ethenol copolymer, and its ratio accounts for the 2-15% of total formulation weight, preferred 3-12%.
According to the present invention, diluent is selected from one or more in lactose, mannitol, starch, microcrystalline Cellulose, dextrin.Preferably, diluent is mannitol, and its ratio accounts for the 65-95% of total formulation weight.
According to the present invention, disintegrating agent is selected from cross-linked carboxymethyl cellulose sodium, polyvinylpolypyrrolidone, carboxymethylstach sodium, and its ratio accounts for the 2-15% of total formulation weight.
According to the present invention, lubricant is selected from stearic acid, magnesium stearate, sodium stearyl fumarate, and its ratio accounts for total formulation weight () .5-2%.
According to a preferred embodiment of the invention a, comprise and be equivalent to total formulation weight:
The everolimus or derivatives thereof of 0.25-2.5%,
The copolyvidone of 3-15%,
The mannitol of 65-90%,
The polyvinylpolypyrrolidone of 3-15%,
The magnesium stearate of 0.5-2%.
Copolyvidone is the copolymer of water miscible l-vinyl-2-pyrrolidone and vinylacetate (3:2), molecular formula (C
6h
9nO) n/ (C
4h
6o
2) m, molecular weight 45000-70000, prepare through Raolical polymerizable.Be typically used as binding agent, consumption is 2%-5%.Owing to having had the character of polyvidone and polyvinyl acetate concurrently, both remain the good water solublity of polyvidone, caking property and film property, and due to larger than polyvidone to the affinity of hydrophobic surface, have certain solubilization.Draw moist test also to show, copolyvidone than polyvidone have relatively much lower draw moist.There is ISP (the special product chemistry of the U.S.) company commercially available prod
and BASF (German BASF) company
vA64.
Polyvinylpolypyrrolidone is water-insoluble crosslinked 1 vinyl 2 pyrrolidone homopolymer, and molecular formula is (C
6h
9nO) n, molecular weight is greater than 1000000, is obtained by " rice " (Popcorn) polyreaction.Be typically used as disintegrating agent, amount ranges 2%-5%.There is ISP company commercially available prod
xL-10, and BASF AG
cL-F etc.
The present inventor finds, after increasing copolyvidone component in everolimus preparation, can effectively improve product stripping.The present inventor is also unexpected to be found, adds water-soluble film forming agent as copolyvidone etc., effectively can improve the stability of solution in everolimus solution.Accelerated test is investigated and is also found, the Dissolution parameters of the preparation of everolimus or derivatives thereof prepared in accordance with the present invention is stablized, and related substance increases slack-off, and when the ratio of itself and crude drug is in particular range, can reach optimum efficiency, as being greater than 5:1.
According to another preferred embodiment of the invention, comprise and be equivalent to total formulation weight:
The everolimus or derivatives thereof of 0.25-2.5%,
The BHT of 0.02-0.1%,
The copolyvidone of 3-10%,
The spray-dried lactose of 65-90%,
The polyvinylpolypyrrolidone of 3-15%,
The magnesium stearate of 0.8-2%.
According to another preferred embodiment of the present invention, comprise and be equivalent to total formulation weight:
The everolimus or derivatives thereof of 0.25-2.5%,
The BHT of 0.02-0.1%,
310%
iR,
The mannitol of 65-90%,
Cross-linked carboxymethyl cellulose sodium of 3-15%,
The sodium stearyl fumarate of 0.8-2%.
As described above,
iR is polyvinyl alcohol-polyethylene glycol (3:1) graft copolymer of BASF AG's exploitation, be applied in the quick-releasing type coating of tablet and micropill mainly as film former, have viscosity low, water solublity and the better feature of pliability, be called as forth generation coated product.
On the other hand, present invention also offers the preparation method of described preparation, it is characterized in that described preparation adopts wet granulation technology preparation, specifically comprise:
A. everolimus or derivatives thereof and water-soluble film forming agent are dissolved in a solvent, obtain solution a, optionally, in solution a, add antioxidant;
B. by the pharmaceutic adjuvant mixing containing at least one diluent, add the solution a that step a obtains and granulate;
C. by wet grain drying, granulate obtains granule c, optionally, adds pharmaceutic adjuvant mixing in granule c;
D. granule c tabletting step c obtained or filled capsules.
Wet granulation technology is a kind of preparation technology of routine, and conventional has High Shear Mixer Granulator and fluidized bed granulation (also known as one-step palletizing), has technique simple, quality controllable feature, extensive use in pharmaceutical industry.According to the present invention, everolimus or derivatives thereof and a kind of water-soluble film forming agent are dissolved in a solvent, effectively ensure that the content uniformity of everolimus or derivatives thereof in preparation compositions on the one hand, effectively improve the stability of preparation compositions on the other hand.Detection in 0 day shows, the sample size uniformity prepared in accordance with the present invention is desirable, stripping curve and control formulation (Novartis Co., Ltd, 0.25mg, lot number S0001B) consistent, related substance level very low (single maximum contaminant≤0.05%), acceleration environment (40 DEG C, after placing June 75%RH), indices all conforms with the regulations.
According to a kind of embodiment of the present invention, the preparation of everolimus or derivatives thereof adopts wet granulation technology preparation, specifically comprises:
A. everolimus or derivatives thereof and water-soluble film forming agent are dissolved in a solvent, obtain solution a
1, separately by antioxidant dissolve with ethanol, obtain solution a
2, by solution a
1and a
2be mixed to get solution a;
B. by the pharmaceutic adjuvant mixing containing at least one diluent, add the solution a that step a obtains and granulate;
C. by wet grain drying, granulate obtains granule c, optionally, adds pharmaceutic adjuvant mixing in granule c;
D. the granule c obtained by step c carries out tabletting or filled capsules.
According to another embodiment of the present invention, the preparation of everolimus or derivatives thereof adopts wet granulation technology preparation, specifically comprises:
A. everolimus or derivatives thereof and water-soluble film forming agent are dissolved in a solvent, obtain solution a, preferably, in solution a, add antioxidant;
B. the pharmaceutic adjuvant containing at least one diluent is mixed in material trough, solution a even application to pharmaceutic adjuvant will carry out granulation and drying, and obtain granule b;
C. by wet grain drying, granulate obtains granule c, optionally, adds pharmaceutic adjuvant mixing in granule c;
D. the granule c obtained by step c carries out tabletting or filled capsules.
According to the present invention, everolimus or derivatives thereof accounts for the 0.25-2.5% of total formulation weight.
According to the present invention, water-soluble film forming agent is selected from copolyvidone, polyvinyl alcohol and/or polyethylene glycol-ethenol copolymer, accounts for the 2-20% of total formulation weight, preferred 3-10%.
According to the present invention, the solvent described in step a is selected from water, ethanol, acetone, isopropyl alcohol.
According to the present invention, antioxidant is selected from Butylated hydroxyanisole (BHA), 2,6-di-t-butyl-4 methylphenols (BHT), vitamin E, propyl gallate, dodecyl gallate.
According to the present invention, selected antioxidant dissolubility in water is lower, can add a small amount of cosolvent as used after dissolve with ethanol.
According to the present invention, in preparation, also comprise the diluent of the 65-95% accounting for total formulation weight, account for the disintegrating agent of the 2-20% of total formulation weight, account for the lubricant of the 0.5-2% of total formulation weight.
According to the present invention, it is characterized in that one or more that described diluent is selected from lactose, mannitol, starch, microcrystalline Cellulose, dextrin, described disintegrating agent is selected from one or more in cross-linked carboxymethyl cellulose sodium, polyvinylpolypyrrolidone, carboxymethylstach sodium, low-substituted hydroxypropyl cellulose, and described lubricant is selected from one or more in stearic acid, magnesium stearate, sodium stearyl fumarate.
Detailed description of the invention
By following examples, the present invention may be better understood, but the present invention is not limited thereto.
Embodiment 1: prepare everolimus sheet
The prescription of everolimus sheet:
The preparation technology of this embodiment is as follows:
A. will
iR dissolves in 20g water, then adds everolimus stirring and dissolving and obtain solution a;
B. lactose is poured in P1-6 granulation pot, add solution a granulation and obtain granule b;
C. granule b is transferred in Minilab fluid bed dry, then dried granule granulate is obtained granule c;
D. granule c is mixed with cross-linked carboxymethyl cellulose sodium, then add magnesium stearate and be mixed to get granule d;
E. adopt DP30A single punch tablet machine tabletting, the heavy 100mg of sheet, prepares 1000 altogether.
With everolimus, former to grind sheet (Novartis Co., Ltd, 0.25mg, lot number S0001B) be control formulation, measures the stripping curve of above-mentioned slice, thin piece in 0.4%SDS aqueous solution, the results are shown in down according to Chinese Pharmacopoeia 2010 editions two annex XC:
Result shows, consistent with prior art, and product In Vitro Dissolution prepared in accordance with the present invention is desirable.
Place June under acceleration conditions after adopting aluminum aluminum packaging according to everolimus sheet A according to the present invention, respectively at 1,2,3, sampling in June, the stripping curve of working sample.The results are shown in down:
Data show, everolimus sheet Dissolution parameters prepared in accordance with the present invention is stablized.
Embodiment 2: prepare everolimus sheet
The prescription of everolimus sheet:
The preparation technology of this embodiment is as follows:
A. by the everolimus of recipe quantity and
iR stirring and dissolving in 40g water obtains solution a
1, the BHT separately taking recipe quantity dissolves to obtain solution a in 5ml ethanol
2, by solution a
1with solution a
2be mixed to get solution a;
B. poured into by mannitol in P1-6 granulation pot, the solution a adding preparation granulates;
C. by dry at 40-50 DEG C in transfer of granules to DHG-9246A baking oven, dried granule granulate is obtained granule c;
D. granule c is mixed with polyvinylpolypyrrolidone, then add magnesium stearate and be mixed to get granule d;
E. DP30A tabletting machine is adopted, the heavy 200mg of monolithic sheet.
Embodiment 3: prepare everolimus sheet
Be prepared as follows the everolimus sheet of prescription:
The preparation technology of this embodiment is as follows:
A. by the everolimus of recipe quantity and copolyvidone, stirring and dissolving in 20g water obtains solution a
1, the BHT separately taking recipe quantity dissolves to obtain solution a in 5ml ethanol
2, by solution a
1with solution a
2be mixed to get solution a;
B. poured into by mannitol in P1-6 granulation pot, the solution a adding preparation granulates;
C. dry in transfer of granules to Minilab fluid bed, dried granule granulate is obtained granule c;
D. granule c is mixed with polyvinylpolypyrrolidone, then add magnesium stearate and be mixed to get granule d;
E. DP30A tabletting machine is adopted, the heavy 100mg of monolithic sheet.
With the former sheet (Novartis Co., Ltd, 0.50mg, lot number S0022) that grinds of everolimus for contrast, respectively above-mentioned sample E, F, G, H are placed 10 days at 40 DEG C of condition lower open mouths, adopt HPLC method to measure related substance and the content of the sample of different time points.
Further, under acceleration environment (40 DEG C, 75%RH), place March after being adopted by the said goods aluminum aluminum to pack, investigate related substance and content.
Data show, and compared with prior art, tablet stability prepared in accordance with the present invention is better.
Embodiment 4: prepare everolimus sheet
Be prepared as follows the everolimus sheet of prescription:
The preparation technology of this embodiment is as follows:
A. everolimus and copolyvidone are dissolved in suitable quantity of water, obtain solution a;
B. poured into by mannitol in P1-6 granulation pot, the solution a adding preparation granulates;
C. dry in transfer of granules to Minilab fluid bed, dried granule granulate is obtained granule c;
D. granule c is mixed with spray-dried lactose, polyvinylpolypyrrolidone, then add magnesium stearate and be mixed to get granule d;
E. adopt DP30A tabletting machine, prescription I, J, K, L, M, N, 0 monolithic sheet be heavily respectively 125mg, 125mg, 125mg, 125mg, 125mg, 250mg, 500mg.
Embodiment 5: prepare everolimus capsule
The prescription of everolimus capsule:
The preparation technology of this embodiment is as follows:
A. take the everolimus of recipe quantity, propyl gallate and polyvinyl alcohol stirring and dissolving in 80g water, obtain solution a;
B. mannitol is poured in the material trough of fluid bed, inlet temperature 50 DEG C is set, air quantity 30-40m
3/ h, atomizing pressure 0.5-0.8bar, by the solution a even application of preparation on mannitol, control leaving air temp 28-32 DEG C, until solution a has sprayed, at 45 DEG C, then continued drying obtain granule b;
C. granule b is mixed with low-substituted hydroxypropyl cellulose, then add sodium stearyl fumarate and be mixed to get granule c;
D. 3# gelatin hollow capsule filled capsules is adopted, every loading amount 100mg.
Claims (11)
1. the oral solid formulation containing everolimus or derivatives thereof, it at least comprises the everolimus or derivatives thereof being equivalent to total formulation weight 0.25%-2.5% and the water-soluble film forming agent being selected from copolyvidone, polyvinyl alcohol and/or Kollicoat IR.
2. preparation according to claim 1, is characterized in that water-soluble film forming agent accounts for the 2-15% of total formulation weight, preferred 3-10%.
3. preparation according to claim 1 and 2, is characterized in that the ratio of water-soluble film forming agent and everolimus or derivatives thereof is greater than 5:1.
4. preparation according to claim 1, is characterized in that the preferred copolyvidone of water-soluble film forming agent.
5. preparation according to claim 1, is characterized in that also comprising the diluent of the 65-95% accounting for total formulation weight, accounts for the disintegrating agent of the 2-20% of total formulation weight, accounts for the lubricant of the 0.5-2% of total formulation weight.
6. preparation according to claim 5, is characterized in that: described diluent is selected from one or more in lactose, mannitol, starch, microcrystalline Cellulose, dextrin, preferred mannitol; Described disintegrating agent is selected from one or more in cross-linked carboxymethyl cellulose sodium, polyvinylpolypyrrolidone, carboxymethylstach sodium, low-substituted hydroxypropyl cellulose, preferred polyvinylpolypyrrolidone; Described lubricant is selected from one or more in stearic acid, magnesium stearate, sodium stearyl fumarate, preferred magnesium stearate.
7. the preparation according to any one of claim 1-6, is characterized in that also comprising antioxidant.
8. preparation according to claim 7, it is characterized in that antioxidant is selected from Butylated hydroxyanisole (BHA), 2, one or more in 6-di-t-butyl-4 methylphenol (BHT), vitamin E, propyl gallate, dodecyl gallate, preferred BHT.
9. a preparation method for the preparation of the everolimus or derivatives thereof according to any one of claim 1-8, is characterized in that described preparation adopts wet granulation technology preparation, specifically comprises:
A. everolimus or derivatives thereof and water-soluble film forming agent are dissolved in a solvent, obtain solution a, optionally, in solution a, add antioxidant;
B. by the pharmaceutic adjuvant mixing containing at least one diluent, add solution a and granulate;
C. by wet grain drying, granulate obtains granule c, optionally, adds pharmaceutic adjuvant mixing in granule c;
D. granule c tabletting step c obtained or filled capsules.
10. preparation according to claim 9, is characterized in that the ratio of described water-soluble film forming agent and everolimus or derivatives thereof is greater than 5:1.
11. methods according to claim 9, is characterized in that described solvent is selected from water, ethanol, acetone, isopropyl alcohol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310410583.0A CN104414990A (en) | 2013-09-11 | 2013-09-11 | Stable preparation containing everolimus or derivatives of everolimus and preparation method of stable preparation |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310410583.0A CN104414990A (en) | 2013-09-11 | 2013-09-11 | Stable preparation containing everolimus or derivatives of everolimus and preparation method of stable preparation |
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| CN104414990A true CN104414990A (en) | 2015-03-18 |
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ID=52965817
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|---|---|---|---|
| CN201310410583.0A Pending CN104414990A (en) | 2013-09-11 | 2013-09-11 | Stable preparation containing everolimus or derivatives of everolimus and preparation method of stable preparation |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106176664A (en) * | 2016-08-31 | 2016-12-07 | 佛山市弘泰药物研发有限公司 | A kind of everolimus capsule and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1762357A (en) * | 2005-09-21 | 2006-04-26 | 深圳市天一时科技开发有限公司 | Oral medicinal formulation of moxifloxacin and its preparation method |
| US20130039951A1 (en) * | 2011-08-11 | 2013-02-14 | Dong-A Pharm. Co., Ltd. | Process Of Preparing A Stabilized And Solubilized Formulation Of Sirolimus Derivatives |
-
2013
- 2013-09-11 CN CN201310410583.0A patent/CN104414990A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1762357A (en) * | 2005-09-21 | 2006-04-26 | 深圳市天一时科技开发有限公司 | Oral medicinal formulation of moxifloxacin and its preparation method |
| US20130039951A1 (en) * | 2011-08-11 | 2013-02-14 | Dong-A Pharm. Co., Ltd. | Process Of Preparing A Stabilized And Solubilized Formulation Of Sirolimus Derivatives |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106176664A (en) * | 2016-08-31 | 2016-12-07 | 佛山市弘泰药物研发有限公司 | A kind of everolimus capsule and preparation method thereof |
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