CN103655470A - Dutasteride self-microemulsion composition and preparation method thereof - Google Patents
Dutasteride self-microemulsion composition and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a self-microemulsion dutasteride orally-taken preparation and a preparation method thereof. The self-microemulsion composition comprises the following components in percent by weight: 0.05%-0.3% of dutasteride, 5%-75% of oil, 20%-60% of an emulsifier and 4%-50% of a co-emulsifier. After being cured, the self-microemulsion auxiliary materials can be prepared into preparations such as tablets or capsules; after being quickly disintegrated in a stomach, the preparation can be form emulsion drops with average grain size of 10 nm-100 nm in a gastrointestinal tract after being self-microemulsified, so that solubility and dissolution rate of the dutasteride can be improved, and absorption of the dutasteride in the gastrointestinal tract can be promoted.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to a kind of dutasteride's self-emulsion composition and oral formulations thereof, said composition comprises the dutasteride 0.05%-0.3% of percentage by weight, oily 5%-75%, emulsifying agent 20%-60%, co-emulsifier 4%-50%, and its emulsion droplet mean diameter is 10-100nm.
Technical background
Dutasteride's chemical name: (5 α, 17 β)-(two (trifluoromethyl) phenyl of 2,5-)-3-oxygen-4-azepine-androstane-1-alkene-17-Methanamide, its chemical structural formula is:
Dutasteride is 2nd generation 5 alpha-reductase depressants, the research and development of You Gelansu company, and the approval of 2002 Nianl0 Yue10You FDA Food and Drug Administrations (FDA) is gone on the market in the U.S., trade name Avodart, the commodity Avolve by name in European market.Be mainly used in clinically the treatment of prostate hyperplasia, male pattern baldness, seborrheic alopecia, hereditary alopecia, that current the first is also unique a kind of medicine that simultaneously suppresses I type and II type 5 alpha-reductases, compare with other 5α-reductase inhibitor, it is useful that dutasteride's dual function is proved to be clinically.In China, 5α-reductase inhibitor and androgen receptor antagonist have approximately occupied the share of half in anti-prostatic hyperplasia market.However, because dutasteride is water-soluble hardly, limited by its physicochemical property, its preparation bioavailability is not high, so dutasteride's preparation of development of new is very necessary.
Dutasteride's dosage form of listing is soft capsule, and commodity are called AVODART, is dutasteride is dissolved in sad list/bis-glyceride in the mixture with butylated hydroxytoluene, then is filled in soft capsule and obtains.But its dissolution is not high.
KR100962447, a kind of solid state Emulsion of self emulsifying is disclosed, by the dutasteride of 1 part of weight, the water-soluble polymeric that is selected from HPMC, PVP K17, HPC and HEC of 20-30 weight portion, the surfactant that is selected from sucrose palmitate, Myrj 45, sodium lauryl sulphate etc. of 10-20 weight portion, the oil of 40-60 weight portion, this grease separation makes from creamer from soybean oil, Trivent OCG, propenyl caprylate, add again filler and disintegrating agent to make solid state preparation, as tablet etc.This prescription is unfavorable for controlling emulsion droplet particle diameter, and limited to improving the effect of dutasteride's dissolution, the dissolution in having the dissolution fluid of surfactant is suitable with the Avodart of listing, and complicated process of preparation, and the industrialization of restriction technology is used.
KR101055412 discloses a kind of hardening composition (tablet) of dutasteride's self emulsifying, by the first coating solution and the second coating solution and oil, surfactant, stabilization agent forms, wherein the first coating solution includes dutasteride, adsorbent, pharmaceutic adjuvant, the compositions of mixtures of water-soluble polymer and water-insoluble polymerization, the second coating solution comprises not stripping property polymer of water, its preparation method is by dutasteride, oil, surfactant, stabilization agent is dissolved in organic solvent, add adsorbent and pharmaceutic adjuvant to be mixed to form cure formulations, then with the first coating solution and the second coating solution, respectively cure formulations is carried out to coating, make coated tablet.This prescription is unfavorable for controlling emulsion droplet particle diameter, has limited the raising of dutasteride's dissolution, and the dissolution in having the dissolution fluid of surfactant is suitable with the Avodart of listing, and complicated process of preparation.
Self-microemulsion drug delivery system (self-microemulsifying drug delivery system, SMEDDS) be the transparent and homogeneous being formed by oil phase, emulsifying agent and co-emulsifier, under ambient temperature and gentle agitation, meet water self-emulsifying microemulsion and form O/W type.Compare with emulsion, SMEDDS physical property is more stable, is easy to preparation.The meticulous microemulsion of oral rear formation, its advantage mainly contains: 1) spontaneous formation microemulsion under gastrointestinal tract condition; 2) slightly solubility or fat-soluble medicine are had to higher solubilising power; 3) can filtration sterilization, can be used as intravenous administration formulation; 4) higher physical stability; 5) be filled in hard capsule or soft capsule, preparation technology is simple, easily large production.
Self-microemulsion drug delivery system has the potential advantages that improve bioavailability, but form relevant with concrete reactive compound physicochemical property, biopharmaceutics character, prescription, therefore, insoluble medicine self-microemulsion drug delivery system is forward position and the difficult point field of pharmaceutics research.The present invention becomes to be prepared into mean diameter less by the male amine of insoluble drug Du Tadu, the self-microemulsion of even particle size distribution, solve dutasteride's stripping difficulty, the problem of the low grade of bioavailability, make reducing in dutasteride's consumption situation, the blood drug level of still remaining valid, reducing that dutasteride's side effect brought may.
Summary of the invention
Object of the present invention provides a kind of dutasteride's self-emulsion composition, comprising:
Dutasteride 0.05%-0.3%
Co-emulsifier 4%-50%,
Wherein percentage ratio is all weight percentage.
Wherein, described oil phase is selected from vegetable oil, modified vegetable oil, fatty acid ester, isopropyl myristate, median chain triglyceride oil (C8-C10) (referred to as MCT), Capmul MCM C8 (referred to as CMG) and their any mixture, preferred median chain triglyceride oil (C8-C10), Capmul MCM C8 or their mixture, described emulsifying agent is selected from Tween 80 (Tween80), polyoxyethylene castor oil 35(is referred to as CrEL35), polyoxyethylene hydrogenated Oleum Ricini 40 (referred to as RH40), sad certain herbaceous plants with big flowers acid polyethylene glycol glyceride, lecithin and their any mixture, preferred Tween 80, polyoxyethylene castor oil 35, polyoxyethylene hydrogenated Oleum Ricini 40 or their mixture, described co-emulsifier is selected from ethanol, propylene glycol, PEG400, Labrasol, TC (Transcotol P) and their any mixture, preferably propylene glycol, PEG400 or their mixture.
The compositions of the invention described above, the emulsion droplet mean diameter of dutasteride's self-microemulsion is 10-100nm, preferably 10-80 nm.
In one embodiment, dutasteride's self-emulsion composition of the present invention, comprise: dutasteride 0.05%-0.5%, be selected from median chain triglyceride oil (C8-C10), the oily 5%-75% of Capmul MCM C8 and their mixture, be selected from Tween 80, polyoxyethylene castor oil 35, the emulsifying agent 20%-60% of polyoxyethylene hydrogenated Oleum Ricini 40 and their mixture, be selected from propylene glycol, the co-emulsifier 4%-50% of PEG400 and their mixture, the emulsion droplet mean diameter of dutasteride's self-microemulsion is 10-100nm, preferred 10-80 nm, wherein, described percentage ratio is all weight percentage.
Another object of the present invention is to provide a kind of dutasteride's self-microemulsion oral preparation, comprise dutasteride's self-emulsion composition and/or pharmaceutic adjuvant and/or carrier, in base, dutasteride's self-emulsion composition is comprised of the component of following weight percent: dutasteride 0.05%-0.3%, oil 5%-75%, emulsifying agent 20%-60%, co-emulsifier 4%-50%, wherein, described oil phase is selected from vegetable oil, modified vegetable oil, fatty acid ester, isopropyl myristate, median chain triglyceride oil (C8-C10) (referred to as MCT), Capmul MCM C8 (referred to as CMG) and their any mixture, preferably median chain triglyceride oil (C8-C10), Capmul MCM C8 (or their mixture, described emulsifying agent is selected from Tween 80 (Tween80), polyoxyethylene castor oil 35(is referred to as CrEL35), polyoxyethylene hydrogenated Oleum Ricini 40 (referred to as RH40), sad certain herbaceous plants with big flowers acid polyethylene glycol glyceride, lecithin and their any mixture, preferably Tween 80, polyoxyethylene castor oil 35, polyoxyethylene hydrogenated Oleum Ricini 40 or their mixture, described co-emulsifier is selected from ethanol, propylene glycol, PEG400, Labrasol, TC (Transcotol P) and their any mixture, preferably propylene glycol, PEG400 or their mixture.
In a preferred embodiment, dutasteride's self-microemulsion oral preparation of the present invention, comprise dutasteride's self-emulsion composition and/or pharmaceutic adjuvant and/or carrier, in base, dutasteride's self-emulsion composition is comprised of the component of following weight percent: dutasteride 0.05%-0.3%, be selected from median chain triglyceride oil (C8-C10), the oily 5%-75% of Capmul MCM C8 and their mixture, be selected from Tween 80, polyoxyethylene castor oil 35, the emulsifying agent 20%-60% of polyoxyethylene hydrogenated Oleum Ricini 40 and their mixture, be selected from propylene glycol, the co-emulsifier 4%-50% of PEG400 and their mixture,
Dutasteride's self-microemulsion oral preparation of the invention described above, the emulsion droplet mean diameter of other male amine self-microemulsion is 10-100nm, preferably 10-80 nm.
Dutasteride's self-microemulsion oral preparation of the invention described above, described preparation can be hard capsule or soft capsule and tablet.
In one embodiment, a kind of dutasteride's self-microemulsion capsule of the present invention, comprise dutasteride's self-emulsion composition and carrier, wherein, described dutasteride's self-emulsion composition comprises: dutasteride 0.05%-0.3%, oil phase 5%-75%, emulsifying agent 20%-60%, co-emulsifier 4%-50%, wherein, described oil phase is selected from vegetable oil, modified vegetable oil, fatty acid ester, isopropyl myristate, median chain triglyceride oil (C8-C10), Capmul MCM C8 and their any mixture, preferred median chain triglyceride oil (C8-C10), Capmul MCM C8 or their mixture, described emulsifying agent is selected from Tween 80, polyoxyethylene castor oil 35, polyoxyethylene hydrogenated Oleum Ricini 40, sad certain herbaceous plants with big flowers acid polyethylene glycol glyceride, lecithin and their any mixture, preferred Tween 80, polyoxyethylene castor oil 35, polyoxyethylene hydrogenated Oleum Ricini 40 or their mixture, described co-emulsifier is selected from ethanol, propylene glycol, PEG400 (PEG400) Labrasol, TC and their any mixture, preferably propylene glycol, PEG400 or their mixture.
In above-mentioned all specific embodiments, dutasteride's self-microemulsion oral preparation of the present invention, described carrier can be capsule capsule material, the also adjuvant such as medicinal filler, described capsule capsule material is soft capsule or hard capsule.
In above-mentioned specific embodiments, dutasteride's self-microemulsion capsule of the present invention, preferably, dutasteride's self-emulsion composition is comprised of the component of following weight percent: dutasteride 0.05%-0.3%, be selected from median chain triglyceride oil (C8-C10), the oily 5%-75% of Capmul MCM C8 and their mixture, be selected from Tween 80, polyoxyethylene castor oil 35, the emulsifying agent 20%-60% of polyoxyethylene hydrogenated Oleum Ricini 40 and their mixture, be selected from propylene glycol, the co-emulsifier 4%-50% of PEG400 and their mixture, its capsule is soft capsule or hard capsule.
In above-mentioned specific embodiments, dutasteride's self-microemulsion capsule of the present invention, the emulsion droplet mean diameter of dutasteride's self-microemulsion is 10-100nm, preferably 10-80 nm.
In another embodiment, dutasteride's self-microemulsion tablet of the present invention, by dutasteride's self-emulsion composition and pharmaceutic adjuvant, formed, wherein, described dutasteride's self-emulsion composition comprises: dutasteride 0.05%-0.3%, oil phase 5%-75%, emulsifying agent 20%-60%, co-emulsifier 4%-50%, wherein, described oil phase is selected from vegetable oil, modified vegetable oil, fatty acid ester, isopropyl myristate, median chain triglyceride oil (C8-C10), Capmul MCM C8 and their any mixture, preferred median chain triglyceride oil (C8-C10), Capmul MCM C8 or their mixture, described emulsifying agent is selected from Tween 80, polyoxyethylene castor oil 35, polyoxyethylene hydrogenated Oleum Ricini 40, sad certain herbaceous plants with big flowers acid polyethylene glycol glyceride, lecithin and their any mixture, preferred Tween 80, polyoxyethylene castor oil 35, polyoxyethylene hydrogenated Oleum Ricini 40 or their mixture, described co-emulsifier is selected from ethanol, propylene glycol, PEG400 (PEG400) Labrasol, TC and their any mixture, preferably propylene glycol, PEG400 or their mixture.
In above-mentioned another specific embodiments, dutasteride's self-microemulsion tablet of the present invention, preferably, dutasteride's self-emulsion composition is comprised of the component of following weight percent: dutasteride 0.05%-0.3%, be selected from the oily 5%-75% of median chain triglyceride oil (C8-C10), Capmul MCM C8 and their mixture, be selected from the emulsifying agent 20%-60% of Tween 80, polyoxyethylene castor oil 35, polyoxyethylene hydrogenated Oleum Ricini 40 and their mixture, be selected from the co-emulsifier 4%-50% of propylene glycol, PEG400 and their mixture.
In above-mentioned another specific embodiments, dutasteride's self-microemulsion tablet of the present invention, the emulsion droplet mean diameter of dutasteride's self-microemulsion is 10-100nm, preferably 10-80 nm.
Another object of the present invention has been to provide the preparation method of a kind of dutasteride's self-microemulsion and oral formulations thereof, it is characterized in that: get appropriate dutasteride, be dissolved in co-emulsifier, add oil phase, emulsifying agent, after stirring, embedding is in hard capsule or soft capsule, make dutasteride's hard capsule or soft capsule, or add pharmaceutic adjuvant to solidify afterwards, granulate, be pressed into tablet or pack in hard capsule.
Pharmaceutic adjuvant described in the invention described above, refer to the conventional adjuvant for capsule or tablet known in the art, specifically be selected from diluent if microcrystalline Cellulose, lactose, mannitol, xylitol, soluble starch and glucose powder etc., disintegrating agent are if cross-linking sodium carboxymethyl cellulose, polyvinyl pyrrolidone etc., binding agent, lubricant are as magnesium stearate etc., its granulation, tabletting and dress capsule etc. are all the conventional meanses of this area, the adjuvant adapting with corresponding dosage form of selecting to be applicable to according to conventional knowledge.
The preparation method that this realizes the invention described above, provides following multiple specific embodiments:
Embodiment I: precision takes recipe quantity dutasteride, add recipe quantity co-emulsifier, 40 ℃ of water-baths are dissolved it, by recipe quantity, add oil phase and emulsifying agent, after stirring, obtain dutasteride's self-microemulsion, its fill is made to dutasteride's self-microemulsion hard capsule in hard capsule;
Embodiment II: precision takes recipe quantity oil phase, emulsifying agent and co-emulsifier, makes blank self-microemulsion concentrated solution after stirring, then takes recipe quantity dutasteride, after stirring and dissolving mix homogeneously, obtain dutasteride's self-microemulsion, its fill, in hard capsule, is made to dutasteride's hard capsule;
Embodiment III: precision takes recipe quantity dutasteride, add recipe quantity oil phase, 40-50 ℃ of heating in water bath makes its dissolving, by recipe quantity, add emulsifying agent and co-emulsifier, after stirring and dissolving mix homogeneously, obtain dutasteride's self-microemulsion, its fill, in hard capsule, is made to dutasteride's hard capsule;
Embodiment IV: precision takes recipe quantity dutasteride, add recipe quantity oil phase, 40-50 ℃ of water-bath makes its dissolving, by recipe quantity, add emulsifying agent and co-emulsifier, after stirring, obtain dutasteride's self-microemulsion, be press-sealed in the soft capsule that gelatin is capsule material, made dutasteride's self-microemulsion soft capsules.
In the method for the present invention of above-mentioned embodiment I-IV, dutasteride, oil phase, emulsifying agent, the co-emulsifier separately mass percent of shared compositions are:
Dutasteride 0.05%-0.3%
Co-emulsifier 4%-50%,
Wherein, described oil phase is selected from vegetable oil, modified vegetable oil, fatty acid ester, isopropyl myristate, median chain triglyceride oil (C8-C10), Capmul MCM C8 and their any mixture, preferred median chain triglyceride oil (C8-C10), Capmul MCM C8 or their mixture, described emulsifying agent is selected from Tween 80, polyoxyethylene castor oil 35, polyoxyethylene hydrogenated Oleum Ricini 40, sad certain herbaceous plants with big flowers acid polyethylene glycol glyceride, lecithin and their any mixture, preferred Tween 80, polyoxyethylene castor oil 35, polyoxyethylene hydrogenated Oleum Ricini 40 or their mixture, described co-emulsifier is selected from ethanol, propylene glycol, PEG400, TC and their any mixture, preferably propylene glycol, PEG400 or their mixture.
Particle size determination: get by above-mentioned form prepare dutasteride's self-microemulsion 1g, fall in beaker, get purified water 20ml, add in aforementioned beaker, under 50r/min condition, stir, dutasteride's self-microemulsion system becomes appearance colorless by grease at once or is with light blue opalescence and is clear solution.Adopt Ma Erwen laser particle analyzer to measure, all can form emulsion droplet mean diameter is 10-100nm, preferably 10-80 nm.
Dutasteride's self-microemulsion oral preparation tool of the present invention has the following advantages:
1, can significantly improve dutasteride's dissolution;
2, preparation technology is simple, stable and controllable for quality;
3, can significantly improve in dutasteride's body and absorb;
4, can be through Lymphatic, the removing and the first pass effect that have reduced gastrointestinal mucosa can reduce individual absorption difference;
5, in the self-microemulsion short time, stripping is rapid, complete, emulsion droplet good stability, and the emulsion droplet particle diameter forming after disperseing is little, is evenly distributed and is conducive to the interior absorption of medicine body;
6, after the solidification of dutasteride's self-microemulsion, keeping under the molten intrinsic advantage prerequisite of self-microemulsion, without adding task equipment, can realize industrial-scale production.
Accompanying drawing explanation
The stripping curve of Fig. 1 embodiment 35
The stripping curve figure of Fig. 2 embodiment 36
The emulsion droplet particle size distribution figure of the microemulsion of Fig. 3 embodiment 4
The emulsion droplet particle size distribution figure of the microemulsion of Fig. 4 embodiment 9
The emulsion droplet particle size distribution figure of the microemulsion of Fig. 5 embodiment 14
The emulsion droplet particle size distribution figure of the microemulsion of Fig. 6 embodiment 21
The emulsion droplet particle size distribution figure of the microemulsion of Fig. 7 embodiment 27
The emulsion droplet particle size distribution figure of the microemulsion of Fig. 8 embodiment 31
The emulsion droplet particle size distribution figure of the microemulsion of Fig. 9 embodiment 32
The emulsion droplet particle size distribution figure of the microemulsion of Figure 10 embodiment 33
The emulsion droplet particle size distribution figure of the microemulsion of Figure 11 embodiment 34
The specific embodiment
Following embodiment is used for further understanding the present invention, but can not limit the scope of the invention.
Comparing embodiment 1-2
Preparation method: precision takes the dutasteride of recipe quantity, adds the oil phase of recipe quantity, and 40-50 ℃ of water-bath dissolved it, after stirring and dissolving, is press-sealed in the capsule that gelatin is capsule material, makes dutasteride's self-microemulsion soft capsules or hard capsule.
Comparing embodiment 3
Preparation method:
First dutasteride, PVP K17, sucrose ester 15 are together distributed in Capryol 90, and are dissolved in the ethanol of 250g, make the mixed solution of homogenizing.Then above-mentioned solution is added in solidification forming agent microcrystalline Cellulose 256g and crospolyvinylpyrrolidone (Kollidoncl) 50g; carry out the mixed processing of 5min; granulate; in 60 ℃ of temperature, carry out drying and processing; evaporate organic solvent ethanol; and in the granulate mixture producing by above-mentioned wet granulation oven dry; fusion microcrystalline Cellulose (AvicelPh102) 34.5g; make final mixture, then on suitable tablet machine, be crushed to tablet (containing dutasteride 0.5mg/ sheet).
Embodiment 1 – 30 self-emulsion compositions
Above-mentioned dutasteride's self-microemulsion capsule (containing dutasteride 0.5mg/ capsule) can take following technique to be prepared:
Process I: precision takes recipe quantity dutasteride, add recipe quantity co-emulsifier, 40 ℃ of water-baths are dissolved it, by recipe quantity, add oil phase and emulsifying agent, after stirring, obtain dutasteride's self-microemulsion, its fill is made to dutasteride's self-microemulsion hard capsule in hard capsule.
Technique II: precision takes recipe quantity oil phase, emulsifying agent and co-emulsifier, makes blank self-microemulsion concentrated solution after stirring, then takes recipe quantity dutasteride, after stirring and dissolving mix homogeneously, obtain dutasteride's self-microemulsion, its fill, in hard capsule, is made to dutasteride's hard capsule.
Technique III: precision takes recipe quantity dutasteride, adds recipe quantity oil phase, and 40-50 ℃ of heating in water bath makes its dissolving, by recipe quantity, add emulsifying agent and co-emulsifier, after stirring and dissolving mix homogeneously, obtain dutasteride's self-microemulsion, its fill, in hard capsule, is made to dutasteride's hard capsule.
Technique IV: precision takes recipe quantity dutasteride, adds recipe quantity oil phase, and 40-50 ℃ of water-bath makes its dissolving, by recipe quantity, add emulsifying agent and co-emulsifier, after stirring, obtain dutasteride's self-microemulsion, be press-sealed in the soft capsule that gelatin is capsule material, make dutasteride's self-microemulsion soft capsules.
Prescription
Dutasteride's self-microemulsion 7g(of embodiment 19 is containing dutasteride 21mg)
Soluble starch 35g
Preparation method: soluble starch 35g, adds dutasteride's self-microemulsion 7g(of embodiment 19 containing dutasteride 21mg under stirring), after mixing, encapsulated by content, make altogether 42 of Peroral solid dosage form capsules.
Embodiment 32 Peroral solid dosage form capsules
Prescription
Dutasteride's self-microemulsion 1kg(of embodiment 21 is containing dutasteride 3g)
Glucose powder 2.4 kg
Preparation method: in top spray fluid bed, add glucose powder 2.4kg, blower fan: 15HZ, temperature of charge: 25 ℃, spray gun pressure: 0.2MPa, hydrojet flow velocity 20HZ, prepared by the dutasteride's self-microemulsion formulation and technology by embodiment 21 makes dutasteride's self-microemulsion 1kg(containing his 3g of degree) sparge on glucose powder, press content encapsulated, make altogether 6000 of Peroral solid dosage form capsules.
Embodiment 33 tablets
Prescription
Dutasteride's self-microemulsion 3.5g(of embodiment 18 is containing dutasteride 10.5mg)
Xylitol 14g
Microcrystalline Cellulose 3.5g
Cross-linking sodium carboxymethyl cellulose 0.63g
Magnesium stearate 0.21g
Preparation method: xylitol soluble starch 14g, under stirring, add dutasteride's self-microemulsion 3.5g(of embodiment 18 containing dutasteride 10.5mg), add successively again 3.5g microcrystalline Cellulose, 0.63g cross-linking sodium carboxymethyl cellulose, 0.21g magnesium stearate, after mixing, press content tabletting, must be containing 21 of tablet.
Embodiment 34 tablets
Prescription
Embodiment 21 dutasteride's self-microemulsion 1kg
Lactose 1kg
Mannitol 4kg
Polyvinyl pyrrolidone 60g
Magnesium stearate 30g
Micropowder silica gel 12g
Preparation method: in centrifugal pellet processing machine, add substrate lactose 1kg and mannitol 4kg, blower fan 10HZ, 25 ℃ of temperature of charge, spray gun pressure: 0.1MPa, hydrojet flow velocity 10HZ, by the 1kg dutasteride self-microemulsion of preparing by the formulation and technology of embodiment 21 dutasteride's self-microemulsion (containing dutasteride 3g) for sparging on mixed substrates, after having sprayed, collection material, adds in mixer, add successively 60g polyvinyl pyrrolidone, 30g magnesium stearate, 12g micropowder silica gel, after mixing, by content tabletting, must be containing 6000 of tablet.
Embodiment 35 dissolution determinations
Measure capsule and the preparation of embodiment 31,32,33,34 and the stripping behavior of dutasteride's soft capsule of listing in 0.1mol/l aqueous hydrochloric acid solution of comparing embodiment 1-3 and the random embodiment 4,9,14,21,27 selecting.Meanwhile, adopt Ma Erwen laser particle analyzer to measure comparing embodiment 3, embodiment 4,9,14,21,27,31,32,33, the 34 self-microemulsion particle diameters that form.
Data from table 1, dutasteride's self-microemulsion capsule of the present invention in 0.1mol/l hydrochloric acid solution 60min accumulation dissolution not only far away higher than the capsule of comparing embodiment 1, comparing embodiment 2, and far away higher than commercially available dutasteride's soft capsule (trade name: AVODART), simultaneously also than the embodiment 4(comparing embodiment 3 according to Korea Spro's patent KR100962447B1) the oral formulations dissolution prepared is higher, under comparatively gentle leaching condition, the 45min dissolution that does not add surfactant in dissolution medium reaches more than 65%.
Table 1 sample accumulation dissolution (%)
Table 2 self-microemulsion particle size determination result
| Sample title | Mean diameter (nm) | D90 (nm) | Particle size distribution figure |
| Comparing embodiment 3 | 440 | --- | --- |
| Embodiment 4 | 80.00 | 96.87 | Fig. 3 |
| Embodiment 9 | 12.94 | 18.17 | Fig. 4 |
| Embodiment 14 | 27.65 | 43.82 | Fig. 5 |
| Embodiment 21 | 12.99 | 19.17 | Fig. 6 |
| Embodiment 27 | 65.44 | 58.77 | Fig. 7 |
| |
16.53 | 17.32 | Fig. 8 |
| Embodiment 32 | 10.49 | 11.58 | Fig. 9 |
| Embodiment 33 | 22.74 | 24.69 | Figure 10 |
| Embodiment 34 | 13.68 | 14.57 | Figure 11 |
Embodiment 36 dissolution determinations
Relatively make embodiment 31-34 dutasteride self-micro emulsion formulation, comparing embodiment 3 and listing dutasteride soft capsule (trade name: stripping behavior AVODART) by oneself.
Table 3 sample accumulation dissolution (%)
The result of table 3 shows, dutasteride's self-microemulsion solid preparation of the present invention and listing dutasteride soft capsule (trade name: AVODART) and the preparation of comparing embodiment 3, stripping behavior is suitable in the 0.1mol/l hydrochloric acid solution that contains 2% sodium lauryl sulphate.Owing to having added surfactant in dissolution medium, can not distinguish the quality of each comparison dissolution.
Claims (10)
1. dutasteride's self-emulsion composition, comprising: dutasteride 0.05%-0.3%, oily 5%-75%, emulsifying agent 20%-60%, co-emulsifier 4%-50%, be all weight percentage.
2. compositions as claimed in claim 1, oral formulations, described grease separation is from vegetable oil, modified vegetable oil, fatty acid ester, isopropyl myristate, median chain triglyceride oil, Capmul MCM C8 and their any mixture, preferably median chain triglyceride oil, Capmul MCM C8 or their mixture.
3. compositions as claimed in claim 1, described emulsifying agent is selected from Tween 80, polyoxyethylene castor oil 35, polyoxyethylene hydrogenated Oleum Ricini 40, sad certain herbaceous plants with big flowers acid polyethylene glycol glyceride, lecithin and their any mixture, preferably Tween 80, polyoxyethylene castor oil 35, polyoxyethylene hydrogenated Oleum Ricini 40 or their mixture.
4. compositions claimed in claim 1, described co-emulsifier is selected from ethanol, propylene glycol, PEG400, TC and their any mixture, preferably propylene glycol, PEG400 or their mixture.
5. the arbitrary described compositions of claim 1 to 4, the emulsion droplet mean diameter that it is characterized in that dutasteride's self-microemulsion is 10-100nm, preferably 10-80 nm.
6. compositions claimed in claim 5, further comprises and packs described self-emulsion composition into hard capsule or soft capsule.
7. dutasteride's self-microemulsion oral preparation, comprises claim 1-5 arbitrary described compositions and pharmaceutically acceptable adjuvant or carrier.
8. oral formulations as claimed in claim 7, described preparation is hard capsule, soft capsule or tablet.
9. oral formulations as claimed in claim 7, described adjuvant comprises diluent, disintegrating agent or lubricant.
10. the preparation method of dutasteride's self-microemulsion oral preparation claimed in claim 7, it is characterized in that: dutasteride is dissolved in co-emulsifier, add oil, emulsifying agent and co-emulsifier, after stirring, become self-microemulsion, by microemulsion embedding in hard capsule or soft capsule, make dutasteride's hard capsule or soft capsule, or self-microemulsion is solidified to rear fill in capsule with pharmaceutic adjuvant, or be pressed into tablet.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2017503866A (en) * | 2014-12-23 | 2017-02-02 | ハンミ ファーム． シーオー．， エルティーディー． | Composition for self-emulsifying drug delivery system comprising dutasteride |
| CN109394723A (en) * | 2017-08-17 | 2019-03-01 | 海南皇隆制药股份有限公司 | A kind of dutasteride's soft capsule and preparation method thereof |
| CN109674762A (en) * | 2019-03-05 | 2019-04-26 | 南京正大天晴制药有限公司 | A kind of composition capsule of dutasteride and hair growth |
| CN110613695A (en) * | 2019-10-23 | 2019-12-27 | 人福普克药业（武汉）有限公司 | Dutasteride soft capsule and preparation method thereof |
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| WO2010092596A1 (en) * | 2009-02-10 | 2010-08-19 | Genepharm India Private Limited | An oral pharmaceutical composition of dutasteride |
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| WO2010092596A1 (en) * | 2009-02-10 | 2010-08-19 | Genepharm India Private Limited | An oral pharmaceutical composition of dutasteride |
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| 张晓峰 等: "自微乳化释药***（SMEDDS）的研究进展", 《现代药物与临床》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2017503866A (en) * | 2014-12-23 | 2017-02-02 | ハンミ ファーム． シーオー．， エルティーディー． | Composition for self-emulsifying drug delivery system comprising dutasteride |
| CN109394723A (en) * | 2017-08-17 | 2019-03-01 | 海南皇隆制药股份有限公司 | A kind of dutasteride's soft capsule and preparation method thereof |
| CN109394723B (en) * | 2017-08-17 | 2020-11-24 | 海南皇隆制药股份有限公司 | Dutasteride soft capsule and preparation method thereof |
| CN109674762A (en) * | 2019-03-05 | 2019-04-26 | 南京正大天晴制药有限公司 | A kind of composition capsule of dutasteride and hair growth |
| CN110613695A (en) * | 2019-10-23 | 2019-12-27 | 人福普克药业（武汉）有限公司 | Dutasteride soft capsule and preparation method thereof |
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