CN1939302A - Siromosi medicinal composition and its making method - Google Patents
Siromosi medicinal composition and its making method Download PDFInfo
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- CN1939302A CN1939302A CN 200510105774 CN200510105774A CN1939302A CN 1939302 A CN1939302 A CN 1939302A CN 200510105774 CN200510105774 CN 200510105774 CN 200510105774 A CN200510105774 A CN 200510105774A CN 1939302 A CN1939302 A CN 1939302A
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Abstract
A composite medicine in the form of tablet or capsule is prepared from sirolimus, the carrier chosen from povidone K30, poloxamer 188 and vitamin-E polyethanediol succinate, and auxiliary. Its preparing process is also disclosed.
Description
Technical field
The present invention relates to pharmaceutical composition that utilizes the preparation of sirolimus series compound and preparation method thereof.
Background technology
Sirolimus be proved have immunosuppressant in vivo, anti-repulsion, antifungal and anti-inflammatory activity, and can suppress thymocyte proliferation external.Therefore, these preparations can be used for the treatment of or inhibition of transplant rejection, for example alloplast of kidney, heart, liver, lung, bone marrow, pancreas (islet cells), cornea, small intestinal and skin, and valvular xenograft; Treatment or inhibition host versus graft disease; Treatment or inhibition autoimmune disease, for example lupus, rheumatoid arthritis, diabetes, myasthenia gravis and multiple sclerosis; Treatment or inflammation-inhibiting, for example psoriasis, dermatitis, eczema, seborrhea, inflammatory bowel, pneumonia (comprising asthma, chronic obstructive pulmonary disease, emphysema, adult respiratory distress syndrome, bronchitis etc.), uveitis; The treatment solid tumor comprises sarcoma and cancer, for example astrocytoma, carcinoma of prostate, breast carcinoma, small cell lung cancer and ovarian cancer; Adult T-cell leukemia/lymphoma; Fungus; With the too much disease of blood vessel hyperplasia, for example restenosis and atherosclerosis.
U.S. FDA is the immunosuppressant when approval on August 25th, 2000 sirolimus sheet is used for organ transplantation.
Sirolimus and series compound thereof dissolubility in water is extremely low, belongs to the strong-hydrophobicity chemical compound.When sirolimus and series compound thereof adopt traditional adjuvant and traditional handicraft to prepare ordinary preparation, when oral these preparations of human body, the amount that enters blood flow may be less, and dissolution rate often is difficult to prediction, and the bioavailability curve is irregular and variability is very big, shortcoming such as stable inadequately.Sirolimus and derivant oral solid formulation thereof that present nothing can be taken easily.
Because the oil-soluble of sirolimus and water solublity are all very poor, so only there is a spot of sirolimus preparation to be proved to be gratifying.United States Patent (USP) 5,516,770 and 5,530,006 discloses the intravenous injection of sirolimus, United States Patent (USP) 5,536,729 and 5,559,121 disclose the liquid oral medicine of sirolimus.Lower and undulatory property is restricted greatly its medical value because of its bioavailability.
P Guitard discloses the method for preparing the pharmaceutical composition that contains the sirolimus solid dispersion in US6004973, US6197781, three pieces of patents of US2003/000835, what these patents adopted is with dissolution with solvents medicine and carrier, after solvent volatilized, the solid dispersion that the medicine that obtains and carrier form is made tablet, capsule etc. after being ground into granule less than 0.5mm again.
W.O.98/56358 (Nagi AS) discloses the sirolimus solid preparation of oral administration, has wherein comprised the sugar-coat composition by sirolimus, one or more sugar and one or more binding agents.The suspension of sirolimus with the sugar-coat composition of compositions such as sugar, binding agent is sprayed onto on the blank core that does not contain the active medicine sirolimus, after the drying, makes tablet, capsule etc.
The monoacyl of sirolimus and diacyl derivant (according to Chemical Abstract nomenclature principle, bit esterified 31 and 42) have shown useful as antifungal agents (United States Patent (USP) 4,316; 885); can be used for preparing the water-soluble prodrug (United States Patent (USP) 4,650,803) of sirolimus.United States Patent (USP) 5,118,678 disclose carbamate useful as immunosuppressants, antiinflammatory, antifungal and the antitumor agent of sirolimus.United States Patent (USP) 5,100,883 disclose the fluorinated esters of sirolimus.United States Patent (USP) 5,118,677 disclose the carboxylic acid amide esters of sirolimus.United States Patent (USP) 5,130,307 disclose the amino ester of sirolimus.United States Patent (USP) 5,117,203 disclose the sulphonic acid ester and the sulfamate of sirolimus.United States Patent (USP) 5,194,447 disclose the sulfonylcarbamic acid ester of sirolimus.WO94/02136 discloses the sirolimus that 16-O-replaces.United States Patent (USP) 5,258,389 disclose the sirolimus (O-aromatic radical) that 40-O-replaces.WO 92/05179 discloses the sirolimus carboxylate.United States Patent (USP) 5,151,413 disclose the acetal form of sirolimus.United States Patent (USP) 5,120,842 disclose the sirolimus silyl ether.WO 93/11130 discloses methylene sirolimus and derivant.WO94/02385 and 95/14023 discloses the sirolimus alkenyl derivative.United States Patent (USP) 5,256,790 disclose the sirolimus of 32-O-dihydro or replacement.
United States Patent (USP) 5,100,899 disclose the method for using sirolimus and derivant inhibition graft-rejection thereof.
Summary of the invention
The objective of the invention is to prepare and have the Siromosi medicinal composition of dissolution rate in vitro faster, and conveniently take, said composition have higher bioavailability and undulatory property less.
The pharmaceutical composition that the present invention relates to contains the sirolimus or derivatives thereof as active component, and the adjuvant that contains mounting medium and other effects is as non-active ingredient.
The active component that the present invention adopts is the sirolimus or derivatives thereof.The derivant of sirolimus comprises the pharmaceutically selectable derivant of sirolimus.Comprise particularly: (the hydroxyl usefulness-OR1 on the cyclohexyl ring of sirolimus replaces the derivant that CCI-779 (for sirolimus), O-replace, and is hydroxyalkyl, hydroxyl alkoxyalkyl, acyl aminoalkyl, aminoalkyl at this R1.), 40-O-(2-hydroxyl) ethyl-sirolimus, 40-O-(3-hydroxyl)-propyl group-sirolimus, 40-O-[2-(2-hydroxyl) ethyoxyl] ethyl-sirolimus and 40-O-(2-acetylamino ethyl)-sirolimus; The sirolimus derivant also can be the derivant that 26-or 28-replace.
Preferably, the active component of the present invention's employing is: sirolimus, CCI-779 (for sirolimus), 40-O-(2-hydroxyl) ethyl sirolimus, 32-deoxidation sirolimus and 16-penta-2-alkynes oxygen-32 (S)-dihydro sirolimus.
More preferably, the active component of the present invention's employing is: sirolimus, CCI-779 (for sirolimus), 40-O-(2-hydroxyl) ethyl sirolimus.
The sirolimus amount that exists among the present invention is at 0.01～30% (in w/w) of amount of formulation.0.1～10% (w/w) of optimal amount in the preparation composition.
The mounting medium of solid dispersion can be high molecular polymer, surfactant, saccharide, sterols, cholic acid class, organic acid etc.The present invention adopts mounting medium combination and mounting medium and other effect adjuvant combinations, makes the combination of this pharmaceutical composition have special property, and can directly prepare solid preparation, adopts certain preparation method, makes this pharmaceutical composition have good performance.It can be one or more that the present invention adopts mounting medium and other effect adjuvants, and the mounting medium that is fit to and other effect adjuvants are as described below.
In force, mounting medium can be one or more water soluble polymers.The water soluble polymer that is fit to comprises polyvidone (PVP), and preferred mean molecule quantity is 8000～50000; Polyethylene Glycol (PEG) comprises mean molecule quantity between 1000～9000, and preferred mean molecule quantity is 1800～7000; Cyclodextrin comprises beta-schardinger dextrin-or alpha-cyclodextrin.For example the beta-schardinger dextrin-of Shi Heing has beta-schardinger dextrin-, HP-, methyl-beta-schardinger dextrin-, DM-, glycosyl-beta-schardinger dextrin-etc., preferred beta-schardinger dextrin-, HP-; Hydroxypropyl emthylcellulose xyxylene ester; Cellulose derivative such as hydroxypropyl emthylcellulose (HPMC) can obtain result preferably with the HPMC of low apparent kinetics viscosity, as in the solution viscosity value of 20 ℃ of 2% weight concentration at 100cps, preferably below 50cps.
Mounting medium can be one or more surfactants, for example a kind of nonionic, cation, anion or two kinds of ionic surfactants.The surfactant that is fit to comprises:
Poloxamer 188 (Poloxamer188) in polyoxyethylene-polyoxypropylene copolymer analog.
Vitamin E polyethylene glycol succinic acid ester in the vitamin derivative (TPGS).
Gelucire 44/14 in the polyglycolyzed glyceride, Gelucire 53/10, Gelucire 35/10, preferred Gelucire 44/14.
Lecithin, for example soybean lecithin, Ovum Gallus domesticus Flavus lecithin, preferably soya lecithin.
Mounting medium can be saccharide, for example mannitol.
Mounting medium can be a sterols, for example the ethyoxyl cholesterol.
Mounting medium can be the cholic acid class, comprises cholic acid or its salt, for example cholic acid, hydroxyacetic acid or its salt, sodium cholate.
Mounting medium can be an organic acid, for example citric acid, succinic acid.
Mounting medium can be other, for example sodium lauryl sulphate.
It is about 30% that the consumption of mounting medium of the present invention in preparation generally is up to, and for example weight is 1%～10%.
Optimum mounting medium comprises 30 POVIDONE K 30 BP/USP 30, poloxamer 188 or vitamin E polyethylene glycol succinic acid ester or its combination in any.
The weight ratio of sirolimus and derivant thereof and mounting medium of the present invention is no more than 1: 20 usually, preferably is no more than 1: 10, and optimum is lower than 1: 5.
Pharmaceutical composition of the present invention contains the adjuvant of other effects.
The adjuvant of other effects can be one or more pharmaceutically useful filleies, wherein a kind of or wherein several compositions of sucrose, lactose, microcrystalline Cellulose, starch, dextrin for example, general maximum about 99% of the gross weights that account for of filler loading, for example 50%～90%, optimum is 70%～90% of a weight of formulation.
The adjuvant of other effects can be one or more disintegrating agents.Disintegrating agent comprises polyvinylpolypyrrolidone, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose.
The adjuvant of other effects can be one or more lubricants, for example, magnesium stearate or colloidal silica, it is about 3% that weight reaches as high as, generally 0.1～3.0%
The adjuvant of other effects can be one or more aromatic, for example fragrant citrus essence, Herba Menthae essence etc.
The adjuvant of other effects can be one or more food colorings, is modulated into the color of pleasing the people, for example beta-carotene etc.
The adjuvant of other effects can be one or more antioxidant or stabilizing agent, and antioxidant comprises butylated hydroxytoluene, DL-alpha-tocopherol, propyl gallate, ascorbyl palmitate and fumaric acid, and stabilizing agent is that malonic acid is fit to.
Pharmaceutical composition of the present invention can be made any traditional preparation that makes things convenient for dosage form to take for can directly making the solid dispersion of solid preparation.For example, tablet, capsule, granule or powder agent etc.
On the other hand, the invention provides sirolimus preparation of compositions method, can obtain directly to make the solid dispersion compositions of solid preparation, make this pharmaceutical composition have good performance.In the invention process, sirolimus or derivatives thereof, mounting medium are dissolved in solvent or the mixed solvent, solvent can be the mixed solvent of one or more solvent compositions, and the dissolving of the mounting medium in sirolimus or derivatives thereof and solvent order can change.The solvent that is applicable to preparation solid dispersion of the present invention can be a water; Available organic solvent comprises: alcohols, for example methanol, ethanol or isopropyl alcohol; Esters, for example ethyl acetate; Ethers, for example ether; Ketone, for example acetone; Or halogenated hydrocarbon, for example dichloromethane.A kind of more convenient mixed solvent is the mixed solvent that ethanol/water is formed, weight ratio between about 1: 10 to about 10: 1, for example 1: 5 to 5: 1.
In the invention process, with the sirolimus or derivatives thereof, one or more mounting mediums are dissolved in the ethanol-water solution, typical situation is that sirolimus or derivatives thereof and the weight ratio of mounting medium in solvent are between 1: 0.1 to 1: 20, this solution adds in the adjuvant that can be used as solid preparation, in the mixed-powder as microcrystalline Cellulose and lactose, this solution of some situation can be simultaneously as the binding agent of solid preparation, by suitable drying means, make sirolimus or derivatives thereof solid dispersion compositions, with other auxiliary materials and mixing, direct compression be filled in the gelatine capsule or the bag of packing in.
Drying means can be that technical methods such as vacuum drying, spray drying or fluid bed drying are realized.
In the invention process, sirolimus or derivatives thereof and mounting medium, other effect adjuvant combinations, the pharmaceutical composition that is different from other documents, and can make sirolimus or derivatives thereof compositions realize the solid dispersion form, make sirolimus or derivatives thereof solid dispersion compositions, acquisition can directly be prepared into the sirolimus or derivatives thereof compositions of solid preparation.Aspect cumulative in vitro stripping percentage rate and the dissolubility water two, embody sirolimus or derivatives thereof composition properties.
Below will provide the present invention to prepare the specific embodiment of solid dispersion, measure each embodiment sample cumulative in vitro stripping percentage rate and the dissolubility in water simultaneously, wherein dissolution medium is the phosphate buffer (0.005molL-1 of 0.1% sodium lauryl sulphate, pH6.5), the temperature of mensuration dissolubility is 25 ℃.
The dissolubility in water of sirolimus crude drug (25 ℃) records less than 1.0 μ gmL-1, and sirolimus crude drug cumulative in vitro stripping percentage rate sees Table 1.
Table 1 sirolimus crude drug cumulative in vitro stripping situation (n=6)
| Dissolution time (min) | 10 | 20 | 30 | 45 |
| Stripping percentage rate (%) | 10.2 | 13.7 | 16.4 | 18.9 |
The specific embodiment
Embodiment 1
Sirolimus or its series compound 1g
Polyvidone-K30 5g
Microcrystalline Cellulose 50g
Lactose 50g
Carboxymethyl starch sodium 3g
Microcrystalline Cellulose, lactose, carboxymethyl starch sodium are crossed 80 mesh sieves, take by weighing microcrystalline Cellulose 50g, lactose 50g, carboxymethyl starch sodium 3g respectively, mixing.Sirolimus or its series compound, polyvidone-K30 are dissolved in the solution of alcohol-water (8: 2) preparation as binding agent, add above-mentioned filler mixture, the preparation soft material, cross 18 mesh sieve system wet granulars, dry, 20 mesh sieve granulate, or the electric heating spray dryer carries out spray drying, makes dried particles.Add lubricant, fluidizer, tabletting makes sirolimus tablet (claiming compositions A).During the granule that makes can also incapsulate or in the sachet of packing into, make capsule or sachet.
The dissolubility (25 ℃) of said composition A tablet in water records 4.2 μ gmL
-1, compositions A tablet cumulative in vitro stripping percentage rate sees Table 2.
Table 2 compositions A tablet cumulative in vitro stripping situation (n=6)
| Dissolution time (min) | 10 | 20 | 30 | 45 |
| Stripping percentage rate (%) | 46.8 | 80.5 | 89.5 | 92.3 |
Embodiment 2
Sirolimus or its series compound 1g
Polyvidone-K30 10g
Microcrystalline Cellulose 50g
Lactose 50g
Carboxymethyl starch sodium 3g
Microcrystalline Cellulose, lactose, carboxymethyl starch sodium are crossed 80 mesh sieves, take by weighing microcrystalline Cellulose 50g, lactose 50g, carboxymethyl starch sodium 3g respectively, mixing.Sirolimus or its series compound, polyvidone-K30 are dissolved in the solution of alcohol-water (8: 2) preparation as binding agent, add above-mentioned filler mixture, the preparation soft material, cross 18 mesh sieve system wet granulars, dry, 20 mesh sieve granulate, or the electric heating spray dryer carries out spray drying, makes dried particles.Add lubricant, fluidizer, tabletting makes sirolimus tablet (claiming compositions B).During the granule that makes can also incapsulate or in the sachet of packing into, make capsule or sachet.
The dissolubility (25 ℃) of said composition B tablet in water records 5.6 μ gmL
-1, compositions B tablet cumulative in vitro stripping percentage rate sees Table 3.
Table 3 compositions B tablet cumulative in vitro stripping situation (n=6)
| Dissolution time (min) | 10 | 20 | 30 | 45 |
| Stripping percentage rate (%) | 42.5 | 78.9 | 88.4 | 91.7 |
Embodiment 3
Sirolimus or its series compound 1g
Poloxamer-188 5g
Microcrystalline Cellulose 50g
Lactose 50g
Polyvidone-K30 is an amount of
Carboxymethyl starch sodium 3g
Microcrystalline Cellulose, lactose, carboxymethyl starch sodium are crossed 80 sieves, take by weighing microcrystalline Cellulose 50g, lactose 50g, carboxymethyl starch sodium 3g respectively, mixing.Get the 5g poloxamer-188 in beaker,, after the fusion, in stirring, add medicine 1g, mixing fully with anhydrous alcohol solution 65 ℃ of water-baths.Add above-mentioned filler mixture, behind the mixing, place 2-3h, take out and put 30-35 ℃ of vacuum drying, take out and pulverize, cross 80 mesh sieves in the refrigerator frozen coating.It is an amount of to add 10% polyvidone-K30 alcohol-water (8: 2), and the preparation soft material is crossed 18 mesh sieves, system wet granular, 50 ℃ of dryings, 20 mesh sieve granulate.Add lubricant, fluidizer, tabletting makes sirolimus tablet (claiming compositions C).During the granule that makes can also incapsulate or in the sachet of packing into, make capsule or sachet.
The dissolubility (25 ℃) of said composition C tablet in water records 2.4 μ gmL
-1, compositions C tablet cumulative in vitro stripping percentage rate sees Table 4.
Table 4 compositions C tablet cumulative in vitro stripping situation (n=6)
| Dissolution time (min) | 10 | 20 | 30 | 45 |
| Stripping percentage rate (%) | 42.1 | 77.8 | 87.4 | 88.6 |
Embodiment 4
Sirolimus or its series compound 1g
Poloxamer-188 10g
Microcrystalline Cellulose 50g
Lactose 50g
Polyvidone-K30 is an amount of
Carboxymethyl starch sodium 3g
Microcrystalline Cellulose, lactose, carboxymethyl starch sodium are crossed 80 mesh sieves, take by weighing microcrystalline Cellulose 50g, lactose 50g, carboxymethyl starch sodium 3g respectively, mixing.Get the 10g poloxamer-188 in beaker,, after the fusion, in stirring, add medicine 1g, mixing fully with anhydrous alcohol solution 65 ℃ of water-baths.Add above-mentioned filler mixture, behind the mixing, place 2-3h, take out and put 30-35 ℃ of vacuum drying, take out and pulverize, cross 80 mesh sieves in the refrigerator frozen coating.It is an amount of to add 10% polyvidone-K30 alcohol-water (8: 2), and the preparation soft material is crossed 18 mesh sieves, system wet granular, 50 ℃ of dryings, 20 mesh sieve granulate.Add lubricant, fluidizer, tabletting makes sirolimus tablet (claiming compositions D).During the granule that makes can also incapsulate or in the sachet of packing into, make capsule or sachet.
The dissolubility (25 ℃) of said composition D tablet in water records 2.0 μ gmL
-1, compositions D tablet cumulative in vitro stripping percentage rate sees Table 5.
Table 5 compositions D tablet cumulative in vitro stripping situation (n=6)
| Dissolution time (min) | 10 | 20 | 30 | 45 |
| Stripping percentage rate (%) | 40.3 | 74.9 | 83.1 | 87.6 |
Embodiment 5
Sirolimus or its series compound 1g
Vitamin E polyethylene glycol succinic acid ester (TPGS) 5g
Microcrystalline Cellulose 50g
Lactose 50g
Polyvidone-K30 is an amount of
Carboxymethyl starch sodium 3g
Microcrystalline Cellulose, lactose, carboxymethyl starch sodium are crossed 80 mesh sieves, take by weighing microcrystalline Cellulose 50g, lactose 50g, carboxymethyl starch sodium 3g respectively, mixing.Get the 5g vitamin E polyethylene glycol succinic acid ester in beaker,, after the fusion, in stirring, add medicine 1g, mixing fully with anhydrous alcohol solution 60 ℃ of water-baths.Add above-mentioned filler mixture, behind the mixing, place 2-3h, take out and put 30-35 ℃ of vacuum drying, take out and pulverize, cross 80 mesh sieves in the refrigerator frozen coating.It is an amount of to add 10% polyvidone-K30 alcohol-water (8: 2), and the preparation soft material is crossed 18 mesh sieves, system wet granular, 50 ℃ of dryings, 20 mesh sieve granulate.Add lubricant, fluidizer, tabletting makes sirolimus tablet (claiming compositions E).During the granule that makes can also incapsulate or in the sachet of packing into, make capsule or sachet.
The dissolubility (25 ℃) of said composition E tablet in water records 18.0 μ gmL
-1, compositions E tablet cumulative in vitro stripping percentage rate sees Table 6.
Table 6 compositions E tablet cumulative in vitro stripping situation (n=6)
| Dissolution time (min) | 10 | 20 | 30 | 45 |
| Stripping percentage rate (%) | 52.3 | 84.1 | 91.2 | 93.6 |
Embodiment 6
Sirolimus or its series compound 1g
Vitamin E polyethylene glycol succinic acid ester (TPGS) 10g
Microcrystalline Cellulose 50g
Lactose 50g
Polyvidone-K30 is an amount of
Carboxymethyl starch sodium 3g
Microcrystalline Cellulose, lactose, carboxymethyl starch sodium are crossed 80 mesh sieves, take by weighing microcrystalline Cellulose 50g, lactose 50g, carboxymethyl starch sodium 3g respectively, mixing.Get the 10g vitamin E polyethylene glycol succinic acid ester in beaker,, after the fusion, in stirring, add medicine 1g, mixing fully with anhydrous alcohol solution 60 ℃ of water-baths.Add above-mentioned filler mixture, behind the mixing, place 2-3h, take out and put 30-35 ℃ of vacuum drying, take out and pulverize, cross 80 mesh sieves in the refrigerator frozen coating.It is an amount of to add 10% polyvidone-K30 alcohol-water (8: 2), and the preparation soft material is crossed 18 mesh sieves, system wet granular, 50 ℃ of dryings, 20 mesh sieve granulate.Add lubricant, fluidizer, tabletting makes sirolimus tablet (title composition F).During the granule that makes can also incapsulate or in the sachet of packing into, make capsule or sachet.
The dissolubility (25 ℃) of said composition F tablet in water records 20.3 μ gmL-1, and composition F tablet cumulative in vitro stripping percentage rate sees Table 7.
Table 7 composition F tablet cumulative in vitro stripping situation (n=6)
| Dissolution time (min) | 10 | 20 | 30 | 45 |
| Stripping percentage rate (%) | 65.2 | 86.5 | 91.3 | 93.7 |
Embodiment 7
Sirolimus or its series compound 1g
Gelucire 44/14 5g
Microcrystalline Cellulose 50g
Lactose 50g
Polyvidone-K30 is an amount of
Carboxymethyl starch sodium 3g
Microcrystalline Cellulose, lactose, carboxymethyl starch sodium are crossed 80 mesh sieves, take by weighing microcrystalline Cellulose 50g, lactose 50g, carboxymethyl starch sodium 3g respectively, mixing.Get 5g Gelucire 44/14 in beaker,, after the fusion, in stirring, add medicine 1g, mixing fully with anhydrous alcohol solution 60 ℃ of water-baths.Add above-mentioned filler mixture, behind the mixing, place 2-3h, take out and put 30-35 ℃ of vacuum drying, take out and pulverize, cross 80 mesh sieves in the refrigerator frozen coating.It is an amount of to add 10% polyvidone-K30 alcohol-water (8: 2), and the preparation soft material is crossed 18 mesh sieves, system wet granular, 50 ℃ of dryings, 20 mesh sieve granulate.Add lubricant, fluidizer, tabletting makes sirolimus tablet (claiming compositions G).During the granule that makes can also incapsulate or in the sachet of packing into, make capsule or sachet.
The dissolubility (25 ℃) of said composition G tablet in water records 1.5 μ gmL
-1, compositions G tablet cumulative in vitro stripping percentage rate sees Table 8.
Table 8 compositions G tablet cumulative in vitro stripping situation (n=6)
| Dissolution time (min) | 10 | 20 | 30 | 45 |
| Stripping percentage rate (%) | 40.5 | 71.6 | 81.2 | 84.9 |
Embodiment 8
Sirolimus or its series compound 1g
PEG4000 5g
Microcrystalline Cellulose 50g
Lactose 50g
Polyvidone-K30 is an amount of
Carboxymethyl starch sodium 3g
Microcrystalline Cellulose, lactose, carboxymethyl starch sodium are crossed 80 mesh sieves, take by weighing microcrystalline Cellulose 50g, lactose 50g, carboxymethyl starch sodium 3g respectively, mixing.Get 5g PEG4000 in beaker,, after the fusion, in stirring, add medicine 1g, mixing fully with anhydrous alcohol solution 60 ℃ of water-baths.Add above-mentioned filler mixture, behind the mixing, place 2-3h, take out and put 30-35 ℃ of vacuum drying, take out and pulverize, cross 80 mesh sieves in the refrigerator frozen coating.It is an amount of to add 10% polyvidone-K30 alcohol-water (8: 2), and the preparation soft material is crossed 18 mesh sieves, system wet granular, 50 ℃ of dryings, 20 mesh sieve granulate.Add lubricant, fluidizer, tabletting makes sirolimus tablet (claiming compositions H).During the granule that makes can also incapsulate or in the sachet of packing into, make capsule or sachet.
The dissolubility (25 ℃) of said composition H tablet in water records 1.2 μ gmL
-1, compositions H tablet cumulative in vitro stripping percentage rate sees Table 9.
Table 9 compositions H tablet cumulative in vitro stripping situation (n=6)
| Dissolution time (min) | 10 | 20 | 30 | 45 |
| Stripping percentage rate (%) | 40.1 | 69.2 | 80.8 | 83.4 |
Embodiment 9
Sirolimus or its series compound 1g
HPMC 10g
Microcrystalline Cellulose 50g
Lactose 50g
Carboxymethyl starch sodium 3g
Microcrystalline Cellulose, lactose, carboxymethyl starch sodium are crossed 80 mesh sieves, take by weighing microcrystalline Cellulose 50g, lactose 50g, carboxymethyl starch sodium 3g respectively, mixing.Sirolimus or its series compound, HPMC are dissolved in the solution of alcohol-water (8: 2) preparation as binding agent, add above-mentioned filler mixture, the preparation soft material is crossed 18 mesh sieves, system wet granular, drying, 20 mesh sieve granulate, or the electric heating spray dryer carries out spray drying, makes dried particles.Add lubricant, fluidizer, tabletting makes sirolimus tablet (title composition I).During the granule that makes can also incapsulate or in the sachet of packing into, make capsule or sachet.
The dissolubility (25 ℃) of said composition I tablet in water records 4.1 μ gmL
-1, composition I tablet cumulative in vitro stripping percentage rate sees Table 10.
Table 10 composition I tablet cumulative in vitro stripping situation (n=6)
| Dissolution time (min) | 10 | 20 | 30 | 45 |
| Stripping percentage rate (%) | 47.2 | 81.3 | 90.1 | 92.9 |
Embodiment 10
Sirolimus or its series compound 1g
Sodium laurylsulfate 5g
Microcrystalline Cellulose 50g
Lactose 50g
Polyvidone-K30 is an amount of
Carboxymethyl starch sodium 3g
Microcrystalline Cellulose, lactose, carboxymethyl starch sodium are crossed 80 mesh sieves, take by weighing microcrystalline Cellulose 50g, lactose 50g, carboxymethyl starch sodium 3g respectively, mixing.Sirolimus or its series compound, sodium laurylsulfate are dissolved in the solution of alcohol-water (5: 5), add above-mentioned filler mixture, and behind the mixing, 40 ℃ of vacuum dryings or electric heating spray dryer carry out spray drying, make dried particles.Take out and pulverize, cross 80 mesh sieves.It is an amount of to add 10% polyvidone-K30 alcohol-water (8: 2), and the preparation soft material is crossed 18 mesh sieves, system wet granular, 50 ℃ of dryings, 20 mesh sieve granulate.Add lubricant, fluidizer, tabletting makes sirolimus tablet (claiming compositions J).During the granule that makes can also incapsulate or in the sachet of packing into, make capsule or sachet.+
The dissolubility (25 ℃) of said composition J tablet in water records 50.1 μ gmL
-1, compositions J tablet cumulative in vitro stripping percentage rate sees Table 11.
Table 11 compositions J tablet cumulative in vitro stripping situation (n=6)
| Dissolution time (min) | 10 | 20 | 30 | 45 |
| Stripping percentage rate (%) | 68.2 | 89.7 | 93.9 | 95.5 |
Embodiment 11
Sirolimus or its series compound 1g
Cholate 5g
Microcrystalline Cellulose 50g
Lactose 50g
Polyvidone-K30 is an amount of
Carboxymethyl starch sodium 3g
Microcrystalline Cellulose, lactose, carboxymethyl starch sodium are crossed 80 mesh sieves, take by weighing microcrystalline Cellulose 50g, lactose 50g, carboxymethyl starch sodium 3g respectively, mixing.Sirolimus or its series compound, cholate are dissolved in the solution of alcohol-water (5: 5), add above-mentioned filler mixture, and behind the mixing, 40 ℃ of vacuum dryings or electric heating spray dryer carry out spray drying, make dried particles.Take out and pulverize, cross 80 mesh sieves.It is an amount of to add 10% polyvidone-K30 alcohol-water (8: 2), and the preparation soft material is crossed 18 mesh sieves, system wet granular, 50 ℃ of dryings, 20 mesh sieve granulate.Add lubricant, fluidizer, tabletting makes sirolimus tablet (claiming compositions K).During the granule that makes can also incapsulate or in the sachet of packing into, make capsule or sachet.
The dissolubility (25 ℃) of said composition K tablet in water records 1.9 μ gmL
-1, compositions K tablet cumulative in vitro stripping percentage rate sees Table 12.
Table 12 compositions K tablet cumulative in vitro stripping situation (n=6)
| Dissolution time (min) | 10 | 20 | 30 | 45 |
| Stripping percentage rate (%) | 42.3 | 73.6 | 85.7 | 87.4 |
Embodiment 12
Sirolimus or its series compound 1g
Polyvidone-K30 5g
Poloxamer-188 5g
Microcrystalline Cellulose 50g
Lactose 50g
Carboxymethyl starch sodium 3g
Microcrystalline Cellulose, lactose, carboxymethyl starch sodium are crossed 80 mesh sieves, take by weighing microcrystalline Cellulose 50g, lactose 50g, carboxymethyl starch sodium 3g respectively, mixing.Sirolimus or its series compound, polyvidone-K30, poloxamer-188 are dissolved in the solution of alcohol-water (8: 2) preparation as binding agent, add above-mentioned filler mixture, the preparation soft material, cross 18 mesh sieve system wet granulars, dry, 20 mesh sieve granulate, or the electric heating spray dryer carries out spray drying, makes dried particles.Add lubricant, fluidizer, tabletting makes sirolimus tablet (claiming compositions L).During the granule that makes can also incapsulate or in the sachet of packing into, make capsule or sachet.
The dissolubility (25 ℃) of said composition L tablet in water records 3.1 μ gmL
-1, compositions L tablet cumulative in vitro stripping percentage rate sees Table 13.
Table 13 compositions L tablet cumulative in vitro stripping situation (n=6)
| Dissolution time (min) | 10 | 20 | 30 | 45 |
| Stripping percentage rate (%) | 46.1 | 79.7 | 89.3 | 90.6 |
Embodiment 13
Sirolimus or its series compound 1g
Polyvidone-K30 5g
Vitamin E polyethylene glycol succinic acid ester (TPGS) 5g
Microcrystalline Cellulose 50g
Lactose 50g
Carboxymethyl starch sodium 3g
Microcrystalline Cellulose, lactose, carboxymethyl starch sodium are crossed 80 mesh sieves, take by weighing microcrystalline Cellulose 50g, lactose 50g, carboxymethyl starch sodium 3g respectively, mixing.Sirolimus or its series compound, polyvidone-K30, vitamin E polyethylene glycol succinic acid ester are dissolved in the solution of alcohol-water (8: 2) preparation as binding agent, add above-mentioned filler mixture, the preparation soft material, cross 18 mesh sieve system wet granulars, dry, 20 mesh sieve granulate, or the electric heating spray dryer carries out spray drying, makes dried particles.Add lubricant, fluidizer, tabletting makes sirolimus tablet (claiming compositions M).During the granule that makes can also incapsulate or in the sachet of packing into, make capsule or sachet.
The dissolubility (25 ℃) of said composition M tablet in water records 24.8 μ gmL
-1, compositions M tablet cumulative in vitro stripping percentage rate sees Table 14.
Table 14 compositions M tablet cumulative in vitro stripping situation (n=6)
| Dissolution time (min) | 10 | 20 | 30 | 45 |
| Stripping percentage rate (%) | 67.8 | 88.1 | 92.6 | 94.8 |
Embodiment 14
Sirolimus or its series compound 1g
HPMC 5g
Poloxamer-188 5g
Microcrystalline Cellulose 50g
Lactose 50g
Carboxymethyl starch sodium 3g
Microcrystalline Cellulose, lactose, carboxymethyl starch sodium are crossed 80 mesh sieves, take by weighing microcrystalline Cellulose 50g, lactose 50g, carboxymethyl starch sodium 3g respectively, mixing.Sirolimus or its series compound, HPMC, poloxamer-188 are dissolved in the solution of alcohol-water (8: 2) preparation as binding agent, add above-mentioned filler mixture, the preparation soft material, cross 18 mesh sieve system wet granulars, dry, 20 mesh sieve granulate, or the electric heating spray dryer carries out spray drying, makes dried particles.Add lubricant, fluidizer, tabletting makes sirolimus tablet (claiming compositions N).During the granule that makes can also incapsulate or in the sachet of packing into, make capsule or sachet.
The dissolubility (25 ℃) of said composition N tablet in water records 3.6 μ gmL
-1, compositions N tablet cumulative in vitro stripping percentage rate sees Table 15.
Table 15 compositions N tablet cumulative in vitro stripping situation (n=6)
| Dissolution time (min) | 10 | 20 | 30 | 45 |
| Stripping percentage rate (%) | 45.2 | 80.5 | 89.7 | 91.6 |
Embodiment 15
Sirolimus or its series compound 1g
HPMC 5g
Vitamin E polyethylene glycol succinic acid ester (TPGS) 5g
Microcrystalline Cellulose 50g
Lactose 50g
Carboxymethyl starch sodium 3g
Microcrystalline Cellulose, lactose, carboxymethyl starch sodium are crossed 80 mesh sieves, take by weighing microcrystalline Cellulose 50g, lactose 50g, carboxymethyl starch sodium 3g respectively, mixing.Sirolimus or its series compound, HPMC, vitamin E polyethylene glycol succinic acid ester are dissolved in the solution of alcohol-water (8: 2) preparation as binding agent, add above-mentioned filler mixture, the preparation soft material, cross 18 mesh sieve system wet granulars, dry, 20 mesh sieve granulate, or the electric heating spray dryer carries out spray drying, makes dried particles.Add lubricant, fluidizer, tabletting makes sirolimus tablet (claiming compositions O).During the granule that makes can also incapsulate or in the sachet of packing into, make capsule or sachet.
The dissolubility (25 ℃) of said composition O tablet in water records 22.3 μ gmL
-1, compositions O tablet cumulative in vitro stripping percentage rate sees Table 16.
Table 16 compositions O tablet cumulative in vitro stripping situation (n=6)
| Dissolution time (min) | 10 | 20 | 30 | 45 |
| Stripping percentage rate (%) | 61.5 | 87.5 | 91.4 | 93.8 |
Claims (8)
1. Siromosi medicinal composition contains sirolimus or its pharmaceutically selectable derivant as active component, contains one or more water soluble polymers or one or more surfactants as mounting medium, contains the adjuvant of other effects.
2. compositions as claimed in claim 1 is characterized in that: the active component that is adopted is sirolimus or CCI-779 or 40-O-(2-hydroxyl) ethyl sirolimus or 32-deoxidation sirolimus or 16-penta-2-alkynes oxygen-32 (S)-dihydro sirolimus.
3. compositions as claimed in claim 2 is characterized in that: the active component that is adopted is sirolimus or CCI-779 or 40-O-(2-hydroxyl) ethyl sirolimus.
4. as each described compositions of claim 1-3, it is characterized in that: contain 0.01～30% (in the w/w) of sirolimus amount in the compositions in amount of formulation.
5. compositions as claimed in claim 4 is characterized in that: the sirolimus amount is at 0.1～10% (w/w) of amount of formulation in the compositions.
6. as each described compositions of claim 1-3, it is characterized in that: the mounting medium of selecting for use in the said composition is a kind of or its combination in any of 30 POVIDONE K 30 BP/USP 30 or poloxamer 188 or vitamin E polyethylene glycol succinic acid ester.
7. compositions as claimed in claim 6 is characterized in that: the adjuvant that said composition adopts is one or more the compositions in sucrose or lactose or microcrystalline Cellulose or starch or the dextrin.
8. the preparation of compositions method of each of a claim 1-7, it is characterized in that: sirolimus or derivatives thereof, one or more mounting mediums are dissolved in the ethanol-water solution, this solution adds in the adjuvant that can be used as solid preparation, dry, make sirolimus or derivatives thereof solid dispersion compositions, with other auxiliary materials and mixing, direct compression be filled in the gelatine capsule or the bag of packing in.
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| Application Number | Priority Date | Filing Date | Title |
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| CN200510105774A CN100581545C (en) | 2005-09-29 | 2005-09-29 | Siromosi medicinal composition and its making method |
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| CN200510105774A CN100581545C (en) | 2005-09-29 | 2005-09-29 | Siromosi medicinal composition and its making method |
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| CN1939302A true CN1939302A (en) | 2007-04-04 |
| CN100581545C CN100581545C (en) | 2010-01-20 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101129362B (en) * | 2007-08-16 | 2010-10-06 | 江苏信孚药业有限公司 | Sirolimus dispersible tablets and method of producing the same |
| CN102100665A (en) * | 2011-01-14 | 2011-06-22 | 华南理工大学 | Eye drops containing vitamin E derivatives and preparation method thereof |
| CN102125693A (en) * | 2011-01-25 | 2011-07-20 | 福建科瑞药业有限公司 | Tiagabine hydrochloride pharmaceutical composition and preparation method thereof |
| CN102499919A (en) * | 2011-10-13 | 2012-06-20 | 嘉兴富特吉生物科技有限公司 | Medicine combination containing low sirolimus dose for treating or preventing fibrotic diseases |
| CN102718777A (en) * | 2012-06-21 | 2012-10-10 | 福建省微生物研究所 | Method for preparing iodo sirolimus crystals |
| CN103099790A (en) * | 2011-11-11 | 2013-05-15 | 山东新时代药业有限公司 | Tablet containing everolimus and preparation method thereof |
| WO2015016694A1 (en) | 2013-08-02 | 2015-02-05 | Laboratorio Raam De Sahuayo, S.A. De C.V. | Stable solid immunosuppressor composition |
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| CN101129362B (en) * | 2007-08-16 | 2010-10-06 | 江苏信孚药业有限公司 | Sirolimus dispersible tablets and method of producing the same |
| CN102100665A (en) * | 2011-01-14 | 2011-06-22 | 华南理工大学 | Eye drops containing vitamin E derivatives and preparation method thereof |
| CN102100665B (en) * | 2011-01-14 | 2012-05-30 | 华南理工大学 | Eye drops containing vitamin E derivatives and preparation method thereof |
| CN102125693A (en) * | 2011-01-25 | 2011-07-20 | 福建科瑞药业有限公司 | Tiagabine hydrochloride pharmaceutical composition and preparation method thereof |
| CN102499919A (en) * | 2011-10-13 | 2012-06-20 | 嘉兴富特吉生物科技有限公司 | Medicine combination containing low sirolimus dose for treating or preventing fibrotic diseases |
| CN103099790A (en) * | 2011-11-11 | 2013-05-15 | 山东新时代药业有限公司 | Tablet containing everolimus and preparation method thereof |
| CN103099790B (en) * | 2011-11-11 | 2015-09-02 | 山东新时代药业有限公司 | A kind of tablet containing everolimus and preparation method thereof |
| CN102718777A (en) * | 2012-06-21 | 2012-10-10 | 福建省微生物研究所 | Method for preparing iodo sirolimus crystals |
| WO2015016694A1 (en) | 2013-08-02 | 2015-02-05 | Laboratorio Raam De Sahuayo, S.A. De C.V. | Stable solid immunosuppressor composition |
| US20160235722A1 (en) * | 2013-08-02 | 2016-08-18 | Laboratorio Raam De Sahuayo, S.A. De C.V. | Stable Solid Immunosuppressor Composition |
| CN108815160A (en) * | 2018-07-18 | 2018-11-16 | 严鹏科 | A kind of rapamycin liposome nano granule and preparation method thereof |
| EP3991750A4 (en) * | 2019-06-26 | 2022-08-03 | Ricoh Company, Ltd. | Pharmaceutical composition |
| CN115518044A (en) * | 2022-08-15 | 2022-12-27 | 方达医药技术（苏州）有限公司 | Composition for improving solubility of everolimus and freeze-drying process thereof |
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|---|---|
| CN100581545C (en) | 2010-01-20 |
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Assignee: Fujian Kerui Pharmaceutical Co.,Ltd. Assignor: Fujian Microorganism Inst. Contract record no.: 2010350000312 Denomination of invention: Siromosi medicinal composition and its making method Granted publication date: 20100120 License type: Exclusive License Open date: 20070404 Record date: 20101224 |
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