CN101461808B - Fluorofenidone solid dispersoid and preparation thereof - Google Patents
Fluorofenidone solid dispersoid and preparation thereof Download PDFInfo
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- CN101461808B CN101461808B CN2008101864710A CN200810186471A CN101461808B CN 101461808 B CN101461808 B CN 101461808B CN 2008101864710 A CN2008101864710 A CN 2008101864710A CN 200810186471 A CN200810186471 A CN 200810186471A CN 101461808 B CN101461808 B CN 101461808B
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Abstract
The invention provides a fluorofenidone solid dispersant, which comprises fluorofenidone, a solubilizer and a polymer matrix, wherein the weight ratio of the fluorofenidone to the solubilizer to the polymer matrix is 1: 0.1-0.5: 4-10. The invention also provides various preparations prepared by the fluorofenidone solid dispersant. The fluorofenidone solid dispersant can improve the solubility of the fluorofenidone in water, so that a product has high potency and good uniformity, and ensure the bioavailability of a final preparation. The preparations can be used for preparing medicines for treating fibrosis or rheumatoid diseases of liver, kidney and lung organs, have good curative effect on fibrotic diseases of various organs such as hepatocirrhosis, hepatofibrosis, renal fibrosis and so on, and have stronger effect than similar compounds.
Description
Technical field
The present invention relates to a kind of Fluorofenidone solid dispersoid and preparation thereof, belong to field of medicaments.
Background technology
Fluorofenidone (Fluorofenidone), 1-(3-fluorophenyl)-5-methyl isophthalic acid H-pyridone,
Belong to pyridine compounds, pharmaceutical research shows: this medicine all has good efficacy to multiple organ fibrosis disease such as liver cirrhosis, hepatic fibrosis, renal fibrosis etc., and effect is better than similar compound.
Because Fluorofenidone is fat-soluble extremely strong, the water solublity extreme difference, therefore when Fluorofenidone is prepared into pharmaceutical preparation, lower at the intravital dissolution rate of people, influence the smooth absorption of medicine, finally influence bioavailability of medicament.Come therefrom, just need the dissolubility of Fluorofenidone be improved, guarantee to discharge stably behind the drug oral, make medicine obtain well to absorb, reach metastable bioavailability.
Summary of the invention
The object of the present invention is to provide a kind of Fluorofenidone solid dispersoid, can improve the dissolubility of Fluorofenidone in water, make product have efficient and good homogeneous, guarantee the bioavailability of final preparation.
Another object of the present invention is to provide the preparation of Fluorofenidone.
In order to realize the object of the invention, Fluorofenidone solid dispersoid of the present invention comprises Fluorofenidone, solubilizing agent and polymer matrix, and three's weight ratio is 1: 0.1-0.5: 4-10.
Described solubilizing agent is sodium lauryl sulphate, vitamin C, tween 20, tween-21, Tween-40, Tween-60, tween-61, Tween-65, tween 80, Tween-81, tween 85, tween-120, Myrij, Brij, poloxamer, sad caprin (PEG-8), Polyethylene Glycol lithium 12-hydroxy stearate, polyoxyethylene stearic acid ester, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini or lecithin.
Described polymer matrix is Polyethylene Glycol (PEG4000, PEG6000), xanthan gum, PEG 12000, PEG20000, PVPK90, PVP 10000, PVP40000 or poloxamer188.
In order further to increase the dissolubility of Fluorofenidone, also can add cosolvent, such as ethanol, ethylene glycol, propylene glycol or glycerol, addition is 0.1-0.5 a times of Fluorofenidone amount.
Fluorofenidone solid dispersoid of the present invention is to obtain by the surface that makes the Fluorofenidone granule adhere to polymer matrix.Making the method for active drug active substance calmness on substrate is to be reduced to minimum for the gathering that makes active substance/matrix granule.Can improve the dissolution rate and the dissolubility of Fluorofenidone insoluble medicine, to improve the absorption and the bioavailability of medicine.
The preparation method of the solid dispersion of Fluorofenidone of the present invention can be solvent method, fusion method, solvent-fusion method or surperficial dispersion method.
Described solvent method is characterized in that Fluorofenidone solid dispersoid and substrate, solubilizing agent, cosolvent are dissolved in the suitable solvent, flings to solvent more fast, and wherein suitable solvent is selected from ethanol, acetone, chloroform.
The described method of flinging to solvent fast comprises rotary evaporation, heating, vacuum drying, spray drying, lyophilization.
Described fusion method is characterized in that earlier polymer matrix being heated to fusing, then Fluorofenidone is mixed with solubilizing agent, and joins in the polymer matrix, is cooled to 20-35 ℃ of cooling curing again in 5-20 minute, after lyophilization is powdered.
Described solvent-fusion method is characterized by with a small amount of solvent and dissolves Fluorofenidone, the substrate, solubilizing agent, the cosolvent that add heating and melting, then solvent evaporates is done, cooling at last, wherein said a small amount of solvent is ethanol, acetone, chloroform, dichloromethane, methanol, acetonitrile.
Described surperficial dispersion method is characterized by mixes the back pulverizing with Fluorofenidone with substrate, solubilizing agent.
Fluorofenidone solid dispersoid of the present invention can be mixed with the form through any suitable administration; for example preferred oral administration combination can be tablet, capsule, granule or powder type; it is that Fluorofenidone solid dispersoid adds disintegrating agent, fluidizer, lubricant, suspending agent, binding agent and mixes, and the powder tablet forming that obtains, is filled into capsule or makes form such as granule.According to method well known in the art, the Fluorofenidone pharmaceutical composition can also be mixed with the form of non-gastrointestinal, rectum or via intranasal application administration and other administration.This class preparation can comprise pharmaceutically acceptable excipient, and described excipient comprises filler commonly used in this based composition, fluidizer, lubricant, disintegrating agent, binding agent, suspending agent etc.The present invention also comprises slow releasing preparation and controlled release preparation.
Certainly, Fluorofenidone of the present invention also can be made the pharmaceutical composition of various dosage forms with the other drug active substance.
When Fluorofenidone of the present invention is made solid preparation (such as capsule and tablet), comprise following component and weight percentage:
Fluorofenidone solid dispersoid 1-80%,
Binding agent 1-10%,
Filler 10-80%,
Lubricant 1-5%,
Disintegrating agent 1-8%.
Described binding agent is polyvidone, methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose or hydroxyethyl-cellulose.Be preferably polyvidone or hydroxy methocel.
Described filler is lactose, xylitol, microcrystalline Cellulose, dextrin, mannitol, sorbitol, sucrose, starch, pregelatinized Starch, glucose, calcium phosphate, calcium hydrogen phosphate, calcium carbonate, and composition thereof.
Described lubricant is micropowder silica gel, magnesium stearate, stearic acid, stearyl fumarate and sodium laurylsulfate.Micropowder silica gel, magnesium stearate are preferred.
Described disintegrating agent is polyvinylpolypyrrolidone, cross-linked carboxymethyl cellulose, low-substituted hydroxypropyl methylcellulose, Explotab, pregelatinized Starch and corn starch.Polyvinylpolypyrrolidone is preferred.
When Fluorofenidone is made granule, comprise following component and weight percentage:
Fluorofenidone solid dispersoid 1-80%,
Binding agent 1-10%,
Filler 10-85%,
Solubilizing agent 1-6%,
Antiseptic 0.1-1%.
Described binding agent is polyvidone, methylcellulose, hydroxy methocel, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose.Be preferably polyvidone or hydroxy methocel.
Described filler is lactose, xylitol, microcrystalline Cellulose, dextrin, mannitol, sorbitol, sucrose, starch, pregelatinized Starch, glucose, calcium phosphate, calcium hydrogen phosphate, calcium carbonate, and composition thereof.
Described solubilizing agent is poloxamer, lecithin, vitamin C, tween 80, Tween-60, Arlacel-65, polyoxyethylene castor oil etc.Poloxamer, tween 80 are preferred.
Described antiseptic is parabens, benzoic acid, sodium benzoate, sorbic acid, benzalkonium bromide etc.Parabens is preferred.
When Fluorofenidone is made suspension, comprise following component and weight percentage:
Fluorofenidone solid dispersoid 1-80%,
Suspending agent 0.8-8%,
Solubilizing agent 0.5-6%,
Correctives 0.1-50%,
Antiseptic 0.1-1%,
Water surplus.
Described suspending agent is CMC-Na, xanthan gum, methylcellulose, sodium alginate, potassium alginate, hydroxypropyl emthylcellulose, chitin, tragacanth, agar etc.CMC-Na is preferred.
Described solubilizing agent is poloxamer, lecithin, vitamin C, tween 80, Tween-60, Arlacel-65, polyoxyethylene castor oil etc.Poloxamer, tween 80 are preferred.
Described correctives is sucrose, aspartame, stevioside, saccharin sodium etc.Sucrose, stevioside are preferred.
Described antiseptic is parabens, benzoic acid, sodium benzoate, sorbic acid, benzalkonium bromide etc.Parabens is preferred.
When Fluorofenidone is made Emulsion, comprise following component and weight percentage:
Fluorofenidone solid dispersoid 1-80%,
Semisolid matrix 10-60%,
Emulsifying agent 1-10%,
Suspending agent 1-8%,
The solvent surplus.
Described semisolid matrix comprises vaseline, hard paraffin, liquid paraffin, ceresine, Oleum Arachidis hypogaeae semen, Oleum Ricini, soybean oil, olive oil, Oleum Gossypii semen, silicone, lanoline, sodium laurylsulfate, hexadecanol, octadecanol, cellulose etc.Vaseline, silicone, lanoline, PEG, carbomer are preferred.
Described emulsifying agent comprises tragacanth, gelatin, phospholipid, apricot glue, cholesterol, Rhizoma Bletillae gel, pectin, agar, sodium alginate, methylcellulose, sodium stearate, potassium stearate, calcium stearate, enuatrol, potassium oleate, fatty acid Pyrusussuriensis smooth (20,40,60,80 etc.), Polysorbate (20,40,60,80 etc.), aluminium hydroxide, calcium hydroxide etc.Arabic gum, fatty acid Pyrusussuriensis are smooth, Polysorbate is preferred.
Described suspending agent is CMC-Na, xanthan gum, methylcellulose, sodium alginate, potassium alginate, hydroxypropyl emthylcellulose, chitin, tragacanth, agar etc.CMC-Na is preferred.
Described solvent is water, ethanol, glycerol or ethylene glycol.
When Fluorofenidone is made semi-solid preparation, comprise following component and weight percentage:
Fluorofenidone solid dispersoid 1-80%,
Semisolid matrix 10-60%,
Solubilizing agent 0.5-6%,
Water surplus.
Described semisolid matrix comprises vaseline, hard paraffin, liquid paraffin, ceresine, Oleum Arachidis hypogaeae semen, Oleum Ricini, soybean oil, olive oil, Oleum Gossypii semen, silicone, lanoline, sodium laurylsulfate, hexadecanol, octadecanol, cellulose etc.Vaseline, silicone, lanoline, PEG, carbomer are preferred.
Described solubilizing agent is poloxamer, lecithin, vitamin C, tween 80, Tween-60, Arlacel-65, polyoxyethylene castor oil etc.Poloxamer, tween 80 are preferred.
Fluorofenidone preparation of the present invention also can contain the coloring agent of the 0.0001-0.05% of gross weight.Coloring agent comprises natural pigment, synthetic food color etc.Natural pigment is preferred.
Fluorofenidone preparation of the present invention can be used as and is used for preparation treatment liver, kidney, lung organ fibrosis or rheumatoid medicine.
Contain in the preparation of the present invention when having an appointment the 3-3000mg Fluorofenidone, recommending to be administered once every day to three times is used for the treatment of fibrosis.Preferred pharmaceutical composition contains the Fluorofenidone of the 3-300mg that has an appointment, and most preferred pharmaceutical composition contains the Fluorofenidone of the 15-150mg that has an appointment.And this class preferably is administered once to three times with most preferred pharmaceutical composition and is used for the treatment of organ fibrosis every day.
Be used for that the above-mentioned Fluorofenidone pharmaceutical composition of administration every day also can be not regular to some patient's administration.For example, to treating the controlled patient of fibrosis who makes them and can implement and keep therapeutic scheme so that it avoids further infection by taking the Fluorofenidone pharmaceutical composition every day.This keep therapeutic scheme comprise every day deficiency once take the Fluorofenidone pharmaceutical composition.For example, administration in per three or four days, once just it is enough.
The present invention is in order to enlarge the scope that the patient selects medication, make things convenient for the patient to use, improve Fluorofenidone oral administration stripping situation, guarantee that medicine is relatively stable at the intravital dissolution rate of patient, can guarantee that medicine steadily is absorbed, can reach metastable bioavailability simultaneously.The same dosage form (as: powder) in the past of the Fluorofenidone preparation of the present invention's preparation is compared, and has the following advantages:
1, the Fluorofenidone powder electrostatic attracts, aggregation is strong, and angle of repose is big, and is mobile very poor, causes divided dose difficult; Make divided dose accurate after making said preparation, reduce the contact staining in the technical process simultaneously, can better guarantee product quality.
2, because Fluorofenidone is fat-soluble extremely strong, the water solublity extreme difference, soluble,very slightly in water, dissolubility be 2.44～2.55mg/ml (25 ± 1) ℃ (according to " " test method(s) of solubility test " detects in footline of the note on the use page 1 that Chinese pharmacopoeia version in 2005 is two ones and page 2 first row); Preparation of the present invention has improved the water solublity of Fluorofenidone, has greatly improved the dissolubility of Fluorofenidone in water, and its dissolubility has improved 20-30 doubly; Can guarantee to discharge stably behind the drug oral, easily mix in vivo behind the drug release, help medicine and be absorbed stably, can reach metastable bioavailability simultaneously with interior environment.
The preparation that the present invention adopts Fluorofenidone solid dispersoid to make can be used for preparation treatment liver, kidney, lung organ fibrosis or rheumatoid medicine.Multiple organ fibrosis disease such as liver cirrhosis, hepatic fibrosis, renal fibrosis etc. are all had good efficacy, and effect is better than similar compound.
The specific embodiment
Following examples are used to illustrate the present invention, but are not used for limiting the scope of the invention.
Embodiment 1
The present embodiment Fluorofenidone solid dispersoid comprises Fluorofenidone, poloxamer, ethylene glycol and polymer matrix PEG4000, and four weight ratio is 1: 0.2: 0.2: 5.
Its preparation method is the method for dissolving: with 90 ℃ of fusings of PEG4000 heating, then Fluorofenidone, poloxamer and ethylene glycol are mixed, and join among the PEG4000 earlier, be cooled to 35 ℃ of cooling curings more rapidly in 20 minutes, after lyophilization is powdered.
Dissolubility detects: get excessive this Fluorofenidone solid dispersoid and put in the tool plug conical flask, add the 100ml purified water, respectively at 25 ℃ and 37 ℃ of constant temperature vibrations 48 hours, get supernatant and filter dilution back detection Fluorofenidone concentration, each sample is parallel does three parts.After testing, 25 ℃ of dissolubility of Fluorofenidone solid dispersoid are 51.2 ± 1.66mg/ml, and 37 ℃ of dissolubility are 63.1 ± 1.79mg/ml, and with method check Fluorofenidone crude drug dissolubility in water, the result is 2.44～2.55mg/ml (25 ℃); 3.14～3.16mg/ml (37 ℃).
Embodiment 2
Preparation process is with embodiment 1, and different is, Fluorofenidone solid dispersoid comprises Fluorofenidone, tween 80 and PVP10000, and three's weight ratio is 1: 0.1: 4.
The dissolubility method of inspection is with embodiment 1, and 25 ℃ of dissolubility of Fluorofenidone solid dispersoid are 53.5 ± 1.58mg/ml, and 37 ℃ of dissolubility are 78.5 ± 1.62mg/ml.
Embodiment 3
Preparation process is with embodiment 1, and different is that Fluorofenidone solid dispersoid comprises Fluorofenidone, polyoxyethylene castor oil, glycerol and xanthan gum, and each weight ratio is 1: 0.5: 0.5: 10.
The dissolubility method of inspection is with embodiment 1, and 25 ℃ of dissolubility of Fluorofenidone solid dispersoid are 48.7 ± 1.98mg/ml, and 37 ℃ of dissolubility are 61.4 ± 1.83mg/ml.
Embodiment 4
The present embodiment Fluorofenidone solid dispersoid comprises Fluorofenidone, lecithin, PEG12000, and three's weight ratio is 1: 0.3: 7.
Its preparation method is solvent method, and is as follows: Fluorofenidone, lecithin, PEG12000 are dissolved in the ethanol, and 60 ℃ of rotary evaporations are flung to ethanol promptly.
The dissolubility method of inspection is with embodiment 1, and 25 ℃ of dissolubility of Fluorofenidone solid dispersoid are 49.8 ± 1.56mg/ml, and 37 ℃ of dissolubility are 63.2 ± 1.78mg/ml.
Embodiment 5
The present embodiment Fluorofenidone solid dispersoid comprises Fluorofenidone, Tween-40, PEG600, and three's weight ratio is 1: 0.4: 7.
Its preparation method is surperficial dispersion method, and is as follows: it is characterized by Fluorofenidone is mixed the back pulverizing with Tween-40, PEG600.
The dissolubility method of inspection is with embodiment 1, and 25 ℃ of dissolubility of Fluorofenidone solid dispersoid are 48.9 ± 1.66mg/ml, and 37 ℃ of dissolubility are 62.1 ± 1.75mg/ml.
Embodiment 6
The present embodiment Fluorofenidone solid dispersoid comprises Fluorofenidone, Polyethylene Glycol lithium 12-hydroxy stearate, poloxamer 188, and three's weight ratio is 1: 0.1: 4.
Its preparation method is solvent-a dissolve method, as follows: that Fluorofenidone is dissolved in the small amount of acetone, add again among 53 ℃ of fused poloxamer 188,60 ℃ of rotary evaporation 0.5h, rapidly it is inclined to-20 ℃ of freezing 0.5h on the corrosion resistant plate of-20 ℃ of pre-coolings, it is taken out room temperature vacuum drying 24h promptly.
The dissolubility method of inspection is with embodiment 1, and 25 ℃ of dissolubility of Fluorofenidone solid dispersoid are 52.3 ± 1.91mg/ml, and 37 ℃ of dissolubility are 76.2 ± 1.83mg/ml.
Embodiment 7
By 25 milligrams of Fluorofenidone capsules of Fluorofenidone solid dispersoid preparation of embodiment 1, component is as follows:
| Composition | Amount % (w/w) | Amount/grain |
| Fluorofenidone solid dispersoid | 12.50 | 25mg |
| Microcrystalline Cellulose | 40.00 | 80mg |
| Lactose | 30.00 | 60mg |
| Polyvidone | 4.00 | 8mg |
| Low-substituted hydroxypropyl cellulose | 10.00 | 20.0mg |
| Magnesium stearate | 0.90 | 1.8mg |
| Silicon dioxide | 2.0 | 4.0mg |
| Purified water | In right amount | In right amount |
| Amount to | 100.00 | 200.00mg |
The capsule preparation process of present embodiment is as follows:
1. the preparation of binding agent: take by weighing the polyvidone of recipe quantity, add in the purified water, heated and stirred makes dissolving, and is standby.
2. mix: take by weighing Fluorofenidone solid dispersoid, microcrystalline Cellulose, lactose, the low-substituted hydroxypropyl cellulose of recipe quantity, the back of sieving respectively is with the equivalent method mix homogeneously that progressively increases.
3. granulate: add the binding agent stirring of having prepared and make suitable soft material, with 20 mesh sieve system wet granulars.
4. dry granulate: the wet granular that has prepared behind dry about 3.5h about 55 ℃, is taken out with 18 mesh sieve granulate.
5. total mixing: in dried granule, add residue adjuvant mix homogeneously.
6. capsule subpackage: the loading amount by every 200mg is carried out packing.
Embodiment 8
Preparation process is with embodiment 4, and different is that 50 milligrams of Fluorofenidone capsule contents are as follows:
| Composition | Amount % (w/w) | Amount/grain |
| Fluorofenidone solid dispersoid | 25.00 | 50mg |
| Pregelatinized Starch | 28.00 | 56mg |
| Lactose | 30.00 | 60mg |
| Polyvidone | 4.00 | 8mg |
| Polyvinylpolypyrrolidone | 10.00 | 20.0mg |
| Silicon dioxide | 1.50 | 3.00mg |
| Purified water | In right amount | In right amount |
| Amount to | 100.00 | 200.00mg |
Embodiment 9
Preparation process is with embodiment 4, and different is that 100 milligrams of Fluorofenidone capsule contents are as follows:
| Composition | Amount % (w/w) | Amount/piece |
| Fluorofenidone solid dispersoid | 50.00 | 100mg |
| Microcrystalline Cellulose | 10.00 | 20mg |
| Lactose | 20.00 | 40mg |
| Polyvidone | 5.00 | 10mg |
| Polyvinylpolypyrrolidone | 6.00 | 12mg |
| Low-substituted hydroxypropyl cellulose | 8.00 | 16mg |
| Pulvis Talci | 0.9 | 1.8mg |
| Purified water | In right amount | In right amount |
| Amount to | 100.00 | 200.00mg |
Embodiment 10
By 25 milligrams of Fluorofenidone sheets of Fluorofenidone solid dispersoid preparation of embodiment 2, component is as follows:
| Composition | Amount % (w/w) | Amount/sheet |
| Fluorofenidone solid dispersoid | 75.00 | 150mg |
| Microcrystalline Cellulose | 10.00 | 20mg |
| Lactose | 10.00 | 20mg |
| Polyvidone | 3.00 | 6mg |
| Low-substituted hydroxypropyl cellulose | 1.50 | 3mg |
| Magnesium stearate | 0.5 | 1mg |
| Purified water | In right amount | In right amount |
| Amount to | 100.00 | 200.00mg |
The Fluorofenidone sheet preparation process of present embodiment is as follows:
1. the preparation of binding agent: take by weighing the polyvidone of recipe quantity, add in the purified water, heated and stirred makes dissolving, and is standby.
2. mix: take by weighing Fluorofenidone, microcrystalline Cellulose, lactose, the low-substituted hydroxypropyl cellulose of recipe quantity, the back of sieving respectively is by the equivalent method mix homogeneously that progressively increases.
3. granulate: add the binding agent stirring of having prepared and make suitable soft material, with 20 mesh sieve system wet granulars.
4. dry granulate: the wet granular that has prepared behind dry about 3h about 55 ℃, is taken out with 18 mesh sieve granulate.
5. total mixing: in dried granule, add residue adjuvant mix homogeneously, measure semi-finished product content.
6. tabletting: the sheet by every 200mg heavily carries out tabletting.
Embodiment 11
Preparation process is with embodiment 7, and the component of different is 100 milligrams of Fluorofenidone sheets is as follows:
| Composition | Amount % (w/w) | Amount/sheet |
| Fluorofenidone solid dispersoid | 50.00 | 100mg |
| Pregelatinized Starch | 20.00 | 40mg |
| Lactose | 25.00 | 50mg |
| Polyvidone | 3.00 | 6mg |
| Low-substituted hydroxypropyl cellulose | 1.50 | 3mg |
| Magnesium stearate | 0.5 | 1mg |
| Purified water | In right amount | In right amount |
| Amount to | 100.00 | 200.00mg |
Embodiment 12
Preparation process is with embodiment 7, and the component of different is 450 milligrams of Fluorofenidone sheets is as follows:
| Composition | Amount % (w/w) | Amount/sheet |
| Fluorofenidone solid dispersoid | 25.00 | 50mg |
| Microcrystalline Cellulose | 30.00 | 60mg |
| Lactose | 15.00 | 30mg |
| Polyvidone | 3.00 | 6mg |
| Low-substituted hydroxypropyl cellulose | 1.50 | 3mg |
| Pulvis Talci | 0.5 | 1mg |
| Purified water | In right amount | In right amount |
| Amount to | 100.00 | 200.00mg |
Embodiment 13
By 150 milligrams of Fluorofenidone granules of Fluorofenidone solid dispersoid preparation of embodiment 1, constituent content is as follows:
| Composition | Amount % (w/w) | Amount/bag |
| Fluorofenidone solid dispersoid | 15.00 | 150mg |
| Sucrose | 66.00 | 660mg |
| 10% sucrose slurry sucrose amount | 10.00 | 100mg |
| Low-substituted hydroxypropyl cellulose | 6.00 | 60mg |
| Poloxamer | 2.50 | 25mg |
| Sodium benzoate | 0.5 | 5mg |
| Purified water | In right amount | In right amount |
| Amount to | 100.00 | 1000.00mg |
The particulate preparation process of present embodiment Fluorofenidone is as follows:
1. the preparation of binding agent: take by weighing the sucrose of recipe quantity, add in the purified water, heated and stirred is made 10% sucrose slurry, and is standby.
2. mix: take by weighing Fluorofenidone, sucrose, the low-substituted hydroxypropyl cellulose of recipe quantity, the back of sieving respectively is by the equivalent method mix homogeneously that progressively increases.
3. granulate: add the binding agent stirring of having prepared and make suitable soft material, with 20 mesh sieve system wet granulars.
4. dry granulate: the wet granular that has prepared behind dry about 4h about 55 ℃, is taken out and sieves with 12 order to 40 mesh sieves.
5. total mixing: in dried granule, add residue adjuvant mix homogeneously, measure semi-finished product content.
6. granule packing: carry out packing by every bag of 1g with the light blocking composite membrane.
Embodiment 14
Preparation process is with embodiment 10, and different is that 100 milligrams of particulate constituent contents of Fluorofenidone are as follows:
| Composition | Amount % (w/w) | Amount/bag |
| Fluorofenidone solid dispersoid | 10.00 | 100mg |
| Sucrose | 68.00 | 680mg |
| 10% sucrose slurry sucrose amount | 10.00 | 100mg |
| Sodium carboxymethyl cellulose | 8.00 | 80mg |
| Poloxamer | 3.50 | 35mg |
| Sodium benzoate | 0.5 | 5mg |
| Purified water | In right amount | In right amount |
| Amount to | 100.00 | 1000.00mg |
Embodiment 15
Preparation process is with embodiment 10, and different is that 50 milligrams of particulate constituent contents of Fluorofenidone are as follows:
| Composition | Amount % (w/w) | Amount/bag |
| Fluorofenidone solid dispersoid | 5.00 | 50mg |
| Sucrose | 72.00 | 720mg |
| 10% sucrose slurry sucrose amount | 10.00 | 100mg |
| Sodium carboxymethyl cellulose | 8.00 | 80mg |
| Poloxamer | 4.20 | 42mg |
| Sodium benzoate | 0.80 | 8mg |
| Purified water | In right amount | In right amount |
| Amount to | 100.00 | 1000.00mg |
Embodiment 16
By 150 milligrams of Fluorofenidone suspensions of Fluorofenidone solid dispersoid preparation of embodiment 1, component is as follows:
| Composition | Amount % (w/w) | Amount/bottle |
| Fluorofenidone solid dispersoid | 15.00 | 1500mg |
| CMC-Na | 1.00 | 100mg |
| Tragacanth | 0.50 | 50mg |
| Tween 80 | 1.00 | 100mg |
| Stevioside | 0.10 | 10mg |
| Sodium benzoate | 0.50 | 50mg |
| Purified water | 81.90 | 8190mg |
| Amount to | 100.00 | 10000mg |
Preparation method is as follows:
Recipe quantity CMC-Na and tragacanth are put in the 1000mg purified water swelling spend the night, A liquid.
The recipe quantity Fluorofenidone with the moistening of recipe quantity Tween 80, is added low amounts of water, A liquid, fully mix, add recipe quantity sodium benzoate and stevioside, adding purified water to gross weight is 10000mg.Sterilization, fill promptly gets the Fluorofenidone suspension.
Embodiment 17
Preparation process is with embodiment 13, and the component of different is 100 milligrams of Fluorofenidone suspensions is as follows:
| Composition | Amount % (w/w) | Amount/bottle |
| Fluorofenidone solid dispersoid | 10.00 | 1000mg |
| CMC-Na | 0.80 | 80mg |
| Tragacanth | 0.50 | 50mg |
| Tween 80 | 0.80 | 80mg |
| Stevioside | 0.10 | 10mg |
| Sodium benzoate | 0.50 | 50mg |
| Purified water | 87.30 | 8730mg |
| Amount to | 100.00 | 10000mg |
Embodiment 18
Preparation process is with embodiment 13, and the component of different is 50 milligrams of Fluorofenidone suspensions is as follows:
| Composition | Amount % (w/w) | Amount/bottle |
| Fluorofenidone solid dispersoid | 10.00 | 1000mg |
| CMC-Na | 0.60 | 60mg |
| Tragacanth | 0.50 | 50mg |
| Tween 80 | 0.60 | 60mg |
| Stevioside | 0.10 | 10mg |
| Sodium benzoate | 0.50 | 50mg |
| Purified water | 87.70 | 8770mg |
| Amount to | 100.00 | 10000mg |
Embodiment 19
By 150 milligrams of Fluorofenidone Emulsions of Fluorofenidone solid dispersoid preparation of embodiment 1, component is as follows:
| Composition | Amount % (w/w) | Amount/bottle |
| Fluorofenidone solid dispersoid | 15.00 | 1500mg |
| Soybean oil | 15.00 | 1500mg |
| Decanoyl/octanoyl glycerides | 15.00 | 1500mg |
| Phospholipid | 6.00 | 600mg |
| Tragacanth | 0.20 | 20mg |
| Glycerol | 4.00 | 400mg |
| Ethylene glycol | 4.00 | 400mg |
| Organosilicon | 0.60 | 60mg |
| Purified water | 40.20 | 4020mg |
| Amount to | 100.00 | 10000mg |
Preparation method is as follows:
Swelling in the recipe quantity tragacanth adding 1000mg water is spent the night, standby;
Recipe quantity Fluorofenidone crude drug, soybean oil, decanoyl/octanoyl glycerides, phospholipid are mixed, be heated to 60 ℃, standby as oil phase;
Recipe quantity glycerol, ethylene glycol, tragacanth solution, organosilicon under agitation are added to the water successively, and constantly stir, till being dissolved into uniform liquid fully, standby as water;
Earlier oil phase is put under the high speed shear emulsifying separating apparatus, opened and stir, then water is slowly added in the oil phase, rotating speed is controlled at 10000 rev/mins, sheared 10 minutes, the opaque shape liquid of milky, be the Fluorofenidone emulsion.
Embodiment 20
The component of 100 milligrams of Fluorofenidone Emulsions is as follows:
| Composition | Amount % (w/w) | Amount/bottle |
| Fluorofenidone solid dispersoid | 10.00 | 1000mg |
| Soybean oil | 10.00 | 1000mg |
| Decanoyl/octanoyl glycerides | 12.00 | 1200mg |
| Phospholipid | 4.00 | 400mg |
| Tragacanth | 0.20 | 20mg |
| Glycerol | 4.00 | 400mg |
| Ethylene glycol | 4.00 | 400mg |
| Organosilicon | 0.60 | 60mg |
| Purified water | 55.20 | 5520mg |
| Amount to | 100.00 | 10000mg |
Preparation method is as follows:
Swelling in the recipe quantity tragacanth adding 1000mg water is spent the night, standby;
Recipe quantity Fluorofenidone crude drug, soybean oil, decanoyl/octanoyl glycerides, phospholipid are mixed, be heated to 60 ℃, standby as oil phase;
Recipe quantity glycerol, ethylene glycol, tragacanth solution, organosilicon under agitation are added to the water successively, and constantly stir, till being dissolved into uniform liquid fully, standby as water;
Earlier oil phase is put under the high speed shear emulsifying separating apparatus, opened and stir, then water is slowly added in the oil phase, rotating speed is controlled at 10000 rev/mins, sheared 8 minutes, the opaque shape liquid of milky, be the Fluorofenidone emulsion.
Embodiment 21
50 milligrams of Fluorofenidone Emulsion components are as follows:
| Composition | Amount % (w/w) | Amount/bottle |
| Fluorofenidone solid dispersoid | 5.00 | 500mg |
| Soybean oil | 5.00 | 1000mg |
| Decanoyl/octanoyl glycerides | 10.00 | 1000mg |
| Phospholipid | 3.00 | 300mg |
| Tragacanth | 0.20 | 20mg |
| Glycerol | 4.00 | 400mg |
| Ethylene glycol | 4.00 | 400mg |
| Organosilicon | 0.60 | 60mg |
| Purified water | 68.20 | 6820mg |
| Amount to | 100.00 | 10000mg |
Preparation method is as follows:
Swelling in the recipe quantity tragacanth adding 1000mg water is spent the night, standby;
Recipe quantity Fluorofenidone crude drug, soybean oil, decanoyl/octanoyl glycerides, phospholipid are mixed, be heated to 60 ℃, standby as oil phase;
Recipe quantity glycerol, ethylene glycol, tragacanth solution, organosilicon under agitation are added to the water successively, and constantly stir, till being dissolved into uniform liquid fully, standby as water;
Earlier oil phase is put under the high speed shear emulsifying separating apparatus, opened and stir, then water is slowly added in the oil phase, rotating speed is controlled at 10000 rev/mins, sheared 8 minutes, the opaque shape liquid of milky, be the Fluorofenidone emulsion.
Embodiment 22
By 150 milligrams of Fluorofenidone semi-solid preparations of Fluorofenidone solid dispersoid preparation of embodiment 1, component is as follows:
| Composition | Amount % (w/w) | Amount/bottle |
| Fluorofenidone solid dispersoid | 15.00 | 1500mg |
| Vaseline | 10.00 | 1000mg |
| Lanoline | 15.00 | 1500mg |
| Carbomer | 10.00 | 1000mg |
| PEG4000 | 15.00 | 1500mg |
| Purified water | 45.00 | 4500mg |
| Amount to | 100.00 | 10000.00mg |
Preparation method is as follows:
The Fluorofenidone crude drug is ground into fine powder, sieves, add the vaseline of recipe quantity, fully mix homogeneously gets mixture A.
Take by weighing recipe quantity lanoline, carbopol, PEG4000 and water, fully mix, get mixture B.
With A and the abundant mix homogeneously of B, sterilization, fill makes external Fluorofenidone semi-solid preparation.
Embodiment 23
Preparation process is with embodiment 19, and different is that 100 milligrams of Fluorofenidone semi-solid preparations are as follows:
| Composition | Amount % (w/w) | Amount/bottle |
| Fluorofenidone solid dispersoid | 10.00 | 1000mg |
| Vaseline | 10.00 | 1000mg |
| Lanoline | 15.00 | 1500mg |
| Carbomer | 10.00 | 1000mg |
| PEG4000 | 15.00 | 1500mg |
| Purified water | 50.00 | 5000mg |
| Amount to | 100.00 | 10000.00mg |
Embodiment 24
Preparation process is with embodiment 19, and different is that 50 milligrams of Fluorofenidone semi-solid preparation components are as follows:
| Composition | Amount % (w/w) | Amount/bottle |
| Fluorofenidone solid dispersoid | 5.00 | 500mg |
| Vaseline | 10.00 | 1000mg |
| Lanoline | 15.00 | 1500mg |
| Carbomer | 10.00 | 1000mg |
| PEG4000 | 15.00 | 1500mg |
| Purified water | 55.00 | 5500mg |
| Amount to | 100.00 | 10000.00mg |
Though above the present invention is described in detail with a general description of the specific embodiments, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements all belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.
Claims (7)
1. Fluorofenidone solid dispersoid, it is characterized in that, it comprises Fluorofenidone, solubilizing agent and polymer matrix, three's weight ratio is 1: 0.1-0.5: 4-10, described solubilizing agent is a sodium lauryl sulphate, vitamin C, tween 20, tween-21, Tween-40, Tween-60, tween-61, Tween-65, tween 80, Tween-81, tween 85, tween-120, Myrij, Brij, poloxamer, sad caprin, the Polyethylene Glycol lithium 12-hydroxy stearate, polyoxyethylene stearic acid ester, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini or lecithin; Described polymer matrix is PEG4000, PEG6000, xanthan gum, PEG12000, PEG20000, PVPK90, PVP10000, PVP40000 or poloxamer 188.
2. Fluorofenidone solid dispersoid according to claim 1 is characterized in that, also comprises cosolvent, and such as ethanol, propylene glycol or glycerol, addition is 0.1-0.5 a times of Fluorofenidone amount.3. the preparation method of the described Fluorofenidone solid dispersoid of claim 1 is characterized in that, by solvent method, fusion method, solvent-fusion method or the preparation of surperficial dispersion method.
4. by any preparation that described Fluorofenidone solid dispersoid is made of claim 1-3, it is characterized in that, comprise following component and weight percentage:
Fluorofenidone solid dispersoid 1-80%,
Binding agent 1-10%,
Filler 10-80%,
Lubricant 1-5%,
Disintegrating agent 1-8%.
5. by any preparation that described Fluorofenidone solid dispersoid is made of claim 1-3, it is characterized in that, comprise following component and weight percentage:
Fluorofenidone solid dispersoid 1-80%,
Binding agent 1-10%,
Filler 10-85%,
Solubilizing agent 1-6%,
Antiseptic 0.1-1%.
6. by any preparation that described Fluorofenidone solid dispersoid is made of claim 1-3, it is characterized in that, comprise following component and weight percentage:
Fluorofenidone solid dispersoid 1-80%,
Suspending agent 0.8-8%,
Solubilizing agent 0.5-6%,
Correctives 0.1-50%,
Antiseptic 0.1-1%,
Water surplus.
7. by any preparation that described Fluorofenidone solid dispersoid is made of claim 1-3, it is characterized in that, comprise following component and weight percentage:
Fluorofenidone solid dispersoid 1-80%,
Semisolid matrix 10-60%,
Emulsifying agent 1-10%,
Suspending agent 1-8%,
The solvent surplus.
8. by any preparation that described Fluorofenidone solid dispersoid is made of claim 1-3, it is characterized in that, comprise following component and weight percentage:
Fluorofenidone solid dispersoid 1-80%,
Semisolid matrix 10-60%,
Solubilizing agent 0.5-6%,
Water surplus.
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| CN2008101864710A CN101461808B (en) | 2007-12-21 | 2008-12-19 | Fluorofenidone solid dispersoid and preparation thereof |
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