CN103372014B - A kind of energy Fast Stripping, stable Vardenafil hydrochloric acid oral solid formulation and preparation method thereof - Google Patents
A kind of energy Fast Stripping, stable Vardenafil hydrochloric acid oral solid formulation and preparation method thereof Download PDFInfo
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Abstract
The present invention relates to a kind of Vardenafil hydrochloric acid oral solid formulation that is stable, Fast Stripping and preparation method thereof.Said preparation for active drug with Vardenafil hydrochloric acid trihydrate, is equipped with the adjuvants such as filler, disintegrating agent, antioxidant, correctives, fluidizer, lubricant, adopts pharmaceutically acceptable preparation technology.Formula of the present invention and preparation technology can improve the dissolution rate of oral formulations, and medicine discharges fast, also can improve the stability of medicine.
Description
Technical field
The present invention relates to oral solid formulation of a kind of Vardenafil hydrochloric acid that is stable, Fast Stripping and preparation method thereof.
Background technology
Vardenafil hydrochloric acid is the potent phosphodiesterase 5 inhibitor of a kind of high selectivity of Bayer Bitterfeld GmbH drugmaker exploitation listing, is used for the treatment of male penis erection dysfunction.Erectile Dysfunction (ED) is a kind of common disease, and patient can not carry out normal sexual life, can badly influence physical and mental health and the quality of life of patient.
Vardenafil hydrochloric acid in U.S. FDA approval listing on August 19th, 2003, at present in the listing of more than 70, whole world country.Vardenafil hydrochloric acid is one of best-selling drugs of the whole world three large anti-ED diseases at present, has onset rapid, and drug effect continues, better tolerance, the features such as side effect is little, safe and reliable, and taking convenience, the impact of unable to take food thing and ethanol.Domestic approval listing Vardenafil hydrochloric acid sheet (specification 5mg, 10mg and 20mg) in 2005, trade name " Ai Lida ".Prescription is Vardenafil hydrochloric acid trihydrate, microcrystalline Cellulose, polyvinylpolypyrrolidone, colloidal silica, magnesium stearate, hypromellose, Polyethylene Glycol, titanium dioxide, yellow iron oxide, and red iron oxide, in the Vardenafil hydrochloric acid tablet 5 minutes of existing prescription composition preparation, stripping is lower than 80%, do not reach Fast Stripping, the object of quick acting.
CN1681481A discloses a kind of method of Vardenafil hydrochloric acid trihydrate medicine for the preparation of comprising solid form, the gas processing of its requirement humidity carries out 0.5 ~ 6 month, and require to carry out under 16 ~ 30 DEG C of conditions, in this patent, preparation method is more special, all requirement is had to temperature and humidity, and it is unstable according to tablet product in stability put procedure of this formula preparation, impurity Vardenafil hydrochloric acid N-oxide is above standard limit 0.3%, medicine stripping in pH1.2 hydrochloric acid solution (900ml) is slow in addition, within 5 minutes, stripping is lower than 80%, the object of quick acting can not be reached.
CN101141950A discloses a kind of Vardenafil oral cavity disintegration tablet, containing Vardenafil hydrochloric acid trihydrate, commercially available premixing auxiliary material polyvinylpolypyrrolidone, mannitol, sorbitol and colloidal silica, aspartame, Mint Essence, magnesium stearate, the production technology announced in this technology is simple, but the cost of premixing auxiliary material is higher, substantially increases production cost, is unfavorable for production and sales.US2010159003A1 discloses a kind of Vardenafil sheet, containing Vardenafil hydrochloric acid trihydrate (crossing 40 mesh sieves), and filler anhydrous calcium phosphate, lactose monohydrate; Disintegrating agent cross-linking sodium carboxymethyl cellulose (sodium carboxymethylcellulose pyce); Flux-regulating agent silicon dioxide, magnesium stearate lubricant, and coating Opadry II, though production technology is simple in this invention, due to the composition not containing antioxidant, can not ensure the stability of product in preparation and storage.
CN1984661A discloses a kind of Co ntrolled release preparation of Vardenafil, containing micronization Vardenafil hydrochloric acid trihydrate, matrix polymer is as hydroxypropyl emthylcellulose etc., compression aids is as microcrystalline Cellulose, lactose, magnesium stearate, silicon dioxide etc., and/or the excipient of pH-value dependent release is as citric acid, Fructus Vitis viniferae acid, succinic acid, tartaric acid etc., the thermoplastic carrier be applicable to is as polyvinylpyrrolidone, vinyl acetate co-polymer, phthalate, cellulose etc., the application of this technology can reach the slow releasing of medicine, but Vardenafil needs to discharge onset fast, therefore in clinical practice, advantage is not possessed.
Summary of the invention
For the deficiency that prior art exists, the invention provides a kind of energy Fast Stripping, stable Vardenafil hydrochloric acid oral solid formulation and preparation method thereof.The Vardenafil hydrochloric acid oral solid formulation of gained of the present invention, not only significantly improve pharmaceutical preparation in the stability of producing and in storage, also significantly improve the 5min dissolution of medicine in pH1.2 and pH6.8 dissolution medium, to reach the object of Fast Stripping and onset.
Technical scheme of the present invention is as follows:
A kind of energy Fast Stripping, stable Vardenafil hydrochloric acid oral solid formulation, wherein containing Vardenafil hydrochloric acid 1 ~ 10%, filler 75 ~ 90%, disintegrating agent 1 ~ 10%, antioxidant 0.01 ~ 0.02%, correctives 0 ~ 4%, fluidizer 0 ~ 1%, lubricant 0.1 ~ 2%, each constituent content is mass percent; Described antioxidant be selected from butylated hydroxyarisol (BHA), two fourth cresols (BHT), sodium sulfite, sodium pyrosulfite one or more.
According to the present invention, described Vardenafil hydrochloric acid is Vardenafil hydrochloric acid trihydrate, carries out micronization processes, and granularity is D
90≤ 40 μm.
Vardenafil hydrochloric acid oral solid formulation of the present invention can be made into tablet, granule or chewable tablet.
According to Vardenafil hydrochloric acid oral solid formulation of the present invention, preferably, described antioxidant mass percent 0.02%.
According to Vardenafil hydrochloric acid oral solid formulation of the present invention, preferably containing disintegrating agent mass percent in tablet is 4 ~ 8%.
According to Vardenafil hydrochloric acid oral solid formulation of the present invention, preferably containing disintegrating agent 4 ~ 8% in chewable tablet, correctives 1 ~ 4%, is mass percent.
According to Vardenafil hydrochloric acid oral solid formulation of the present invention, preferably containing correctives mass percent 0.5 ~ 2% in granule.
Described filler is selected from one or more in microcrystalline Cellulose, lactose, mannitol or pregelatinized Starch, one or more wherein in preferably microcrystalline cellulose, lactose or mannitol.
Described disintegrating agent is selected from one or more in cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, carboxymethyl starch sodium, crosslinked carboxymethyl fecula sodium or crospolyvinylpyrrolidone, wherein preferred crospolyvinylpyrrolidone.
Described antioxidant preferred tertiary BHA.
Described correctives is selected from one or more in aspartame, cyclamate, cherry essence, vanilla, Fructus Citri Limoniae essence or flavoring banana essence.
Described fluidizer is selected from micropowder silica gel or Pulvis Talci.
Described lubricant is selected from one or more in magnesium stearate, castor oil hydrogenated, carnaubic acid wax or Glyceryl Behenate; Wherein preferred magnesium stearate.
Antioxidant is added in Vardenafil hydrochloric acid oral solid formulation of the present invention, the effect significantly improving product stability in preparation and storage can be played on the one hand, the oxidative degradation of principal agent Vardenafil hydrochloric acid trihydrate can be avoid or reduced on the other hand, serve the generation significantly reducing N-oxide impurity in preparation and storage, thus ensure that the level of product single impurity N-oxide and total impurities in preparation and storage is better than or is equal to imported product
Vardenafil hydrochloric acid oral solid formulation of the present invention, adopts pharmaceutically acceptable preparation technology, is selected from wet granulation, dry-pressing granulation or directly mixes powder tabletting.Described Vardenafil hydrochloric acid oral solid formulation tablet, makes coated tablet further by adding coating material.
Described wet granulation technology adds binding agent in drug powder, powder coalesced together form the method for granule by the bridge formation of binding agent or cementation.
Described dry-pressing granulating process is after being mixed homogeneously with appropriate powdered filler, lubricant or binding agent etc. by drug powder, is pressed into bulk or large lamellar, and then is ground into the granule of suitable size with suitable equipment.
Described directly mixed powder tablet forming technique is after being mixed with proper auxiliary materials by drug powder, the method for direct compression without granulation.The preparation technology of Vardenafil hydrochloric acid oral solid formulation of the present invention is not limited only to above three kinds of methods.
According to the present invention, preferably, a kind of Vardenafil hydrochloric acid oral solid formulation, prescription constituent mass percentage ratio is as follows:
Vardenafil hydrochloric acid 5 ~ 10%, filler 80 ~ 90%, disintegrating agent 4 ~ 8%, antioxidant 0.01 ~ 0.02%, correctives 1 ~ 3%, fluidizer 0.1 ~ 1%, lubricant 0.1 ~ 0.5%, each amounts of components sum is 100%.Wherein said Vardenafil hydrochloric acid is Vardenafil hydrochloric acid trihydrate, carries out micronization processes, and granularity is D
90≤ 40 μm.
According to the present invention, preferred scheme is as follows further:
I, a kind of Vardenafil hydrochloric acid sheet, prescription constituent mass percentage ratio is as follows:
Vardenafil hydrochloric acid trihydrate 7.93%, microcrystalline Cellulose 84.53%, cross-linking sodium carboxymethyl cellulose 6.02%, butylated hydroxyarisol 0.02%, micropowder silica gel 0.50%, carnaubic acid wax 1.00%.
Above-mentioned Vardenafil hydrochloric acid sheet Opadry coating powder 03B62319 is carried out coating, can obtain Vardenafil hydrochloric acid Film coated tablets, the consumption of Opadry coating powder is 3% of above-mentioned Vardenafil hydrochloric acid sheet total amount.
II, a kind of Vardenafil hydrochloric acid sheet, prescription constituent mass percentage ratio is as follows:
Vardenafil hydrochloric acid trihydrate 7.90%, mannitol 84.58%, crospolyvinylpyrrolidone 6.00%, two fourth cresols 0.02%, micropowder silica gel 0.50%, magnesium stearate 1.00%.
Above-mentioned Vardenafil hydrochloric acid sheet Opadry coating powder 03B62319 is carried out coating, can obtain Vardenafil hydrochloric acid Film coated tablets, the consumption of Opadry coating powder is 3% of above-mentioned Vardenafil hydrochloric acid sheet total amount.
III, a kind of Vardenafil hydrochloric acid chewable tablet, prescription constituent mass percentage ratio is as follows:
Vardenafil hydrochloric acid trihydrate 5.93%, mannitol and microcrystalline Cellulose 85.05%, crospolyvinylpyrrolidone 6.00%, butylated hydroxyarisol 0.02%, cherry essence and aspartame 2.00%, magnesium stearate 1.00%.Wherein, the mass ratio of preferred mannitol and microcrystalline Cellulose is 5: 1, and the ratio between cherry essence and aspartame is 1: 1.
IV, a kind of Vardenafil hydrochloric acid granule, prescription constituent mass percentage ratio is as follows:
Vardenafil hydrochloric acid trihydrate 6.44%, mannitol and microcrystalline Cellulose 86.55%, crosslinked carboxymethyl fecula sodium 5.00%, butylated hydroxyarisol 0.01%, aspartame 1.00%, magnesium stearate 1.00%.Wherein, the mass ratio of preferred mannitol and microcrystalline Cellulose is 4: 1.
The present invention also provides the preparation method of Vardenafil hydrochloric acid oral solid formulation, and the Vardenafil hydrochloric acid oral solid formulation that this preparation method obtains can obtain Fast Stripping and improve stability.
The preparation method of Vardenafil hydrochloric acid oral solid formulation of the present invention, uses jet mill to carry out comminution by gas stream Vardenafil hydrochloric acid trihydrate, makes granularity reach D
90≤ 40 μm; Get each component by proportioning, adopt dry-pressing to granulate or directly mix powder tablet forming technique, wherein:
Granule: the particle filling of gained of dry-pressing being granulated is dressed up bag and made Vardenafil hydrochloric acid granule; Or,
Chewable tablet: the granule of gained of dry-pressing being granulated carries out tabletting and makes Vardenafil hydrochloric acid chewable tablet, or by each component directly mixed powder tabletting, make Vardenafil hydrochloric acid chewable tablet; Or,
Tablet: the granule of gained of dry-pressing being granulated carries out tabletting or by each component directly mixed powder tabletting, make Vardenafil hydrochloric acid tablet, or Vardenafil hydrochloric acid Film coated tablets made by coating further.
Vardenafil hydrochloric acid oral solid formulation of the present invention is Vardenafil hydrochloric acid sheet, Vardenafil hydrochloric acid chewable tablet or Vardenafil hydrochloric acid granule.
In Vardenafil hydrochloric acid oral solid formulation prescription of the present invention, antioxidant improves the stability of solid preparation.The content mass percent of described antioxidant is 0.01 ~ 0.02%, preferably 0.02%; If the too low < 0.01% of antioxidant content mass percent, then can not play the effect improving stability; And if antioxidant content mass percent > 0.02%, be then unfavorable for the clinical practice of Vardenafil hydrochloric acid oral drugs.Described antioxidant plays stabilizing agent in Vardenafil hydrochloric acid oral solid formulation, reduces the generation of N-oxide impurity, improves the stability in preparation production and storage.
Vardenafil hydrochloric acid oral solid formulation of the present invention adopts pharmaceutically acceptable preparation technology, the micronization processes of Vardenafil hydrochloric acid raw material, and the granularity obtained is D
90≤ 40 μm, the Fast Stripping of medicine can be ensured, the stripping curve in the different dissolution medium of pH1.2 with pH6.8 with
all similar, can reduce or avoid the risk of inequivalence in Bioequivalence Test thus, and reaches the fast object of clinical onset of action.
Accompanying drawing explanation
Fig. 1 embodiment 1, comparative experimental example and
the stripping curve comparison diagram of sheet in pH1.2 dissolution medium;
Fig. 2 embodiment 1, comparative experimental example and
the stripping curve comparison diagram of sheet in pH6.8 dissolution medium;
Fig. 3 embodiment 1, comparative experimental example and
40 DEG C of accelerated stability comparison diagrams of sheet;
Fig. 4 embodiment 2, comparative experimental example and
the stripping curve comparison diagram of sheet in pH1.2 dissolution medium;
Fig. 5 embodiment 2, comparative experimental example and
the stripping curve comparison diagram of sheet in pH6.8 dissolution medium;
Fig. 6 embodiment 2, comparative experimental example and
40 DEG C of accelerated stability comparison diagrams of sheet;
Fig. 7 embodiment 3, comparative experimental example and
the stripping curve comparison diagram of sheet in pH1.2 dissolution medium;
Fig. 8 embodiment 3, comparative experimental example and
the stripping curve comparison diagram of sheet in pH6.8 dissolution medium;
Fig. 9 embodiment 3, comparative experimental example and
40 DEG C of accelerated stability comparison diagrams of sheet;
Figure 10 embodiment 4, comparative experimental example and
the stripping curve comparison diagram of sheet in pH1.2 dissolution medium;
Figure 11 embodiment 4, comparative experimental example and
the stripping curve comparison diagram of sheet in pH6.8 dissolution medium;
Figure 12 embodiment 4, comparative experimental example and
40 DEG C of accelerated stability comparison diagrams of sheet.
Detailed description of the invention
Following examples only for further illustrating the present invention, but do not limit the present invention.In embodiment, supplementary material used is commercial products, and device therefor is this area conventional equipment.
Embodiment 1. Vardenafil hydrochloric acid tablet recipe forms: specification 20mg (in Vardenafil), recipe quantity is 1000.
Get recipe quantity Vardenafil hydrochloric acid trihydrate and cross jet mill pulverizing, make granularity D
90≤ 40 μm, cross 40 mesh sieves and remove agglomerate, for subsequent use; Get recipe quantity microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, tert-butyl group BHA cross 40 mesh sieves, for subsequent use; Get recipe quantity micropowder silica gel and 60 mesh sieves crossed by carnaubic acid wax, for subsequent use.
Preparation method: by above-mentioned Vardenafil hydrochloric acid trihydrate, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, the tert-butyl group BHA handled well; be placed in hopper mixer mix homogeneously; dry-pressing granulator is granulated; granulate; then micropowder silica gel is added in transfer of granules material bin mixer; carnaubic acid wax is added again, mixer mix homogeneously, tabletting after mix homogeneously.
Opadry 03B62319 (coating material) is used to carry out coating to suppressed Vardenafil hydrochloric acid sheet, the consumption of Opadry coating powder 03B62319 is 3% of above-mentioned Vardenafil hydrochloric acid sheet total amount, i.e. 9.00g, in coating process, sheet bed tempertaure controls at 35 ~ 40 DEG C, and Vardenafil hydrochloric acid Film coated tablets made by coating.
Embodiment 2. Vardenafil hydrochloric acid tablet recipe forms: specification 20mg (in Vardenafil), recipe quantity is 1000.
Get recipe quantity Vardenafil hydrochloric acid trihydrate and cross jet mill pulverizing, make granularity D
90≤ 40 μm, cross 40 mesh sieves and remove agglomerate, for subsequent use; Get recipe quantity mannitol, crospolyvinylpyrrolidone, two fourth cresols cross 40 mesh sieves, for subsequent use; Get recipe quantity micropowder silica gel and magnesium stearate crosses 60 mesh sieves, for subsequent use.
Preparation method: by above-mentioned Vardenafil hydrochloric acid trihydrate, mannitol, crospolyvinylpyrrolidone, the two fourth cresols handled well, be placed in hopper mixer mix homogeneously, cross 60 mesh sieves, add micropowder silica gel, after 60 mesh sieves after mix homogeneously, add magnesium stearate, mixer mix homogeneously, tabletting.
Opadry 03B62319 (coating material) is used to carry out coating to suppressed Vardenafil hydrochloric acid sheet, the consumption of Opadry coating powder 03B62319 is 3% of above-mentioned Vardenafil hydrochloric acid sheet total amount, i.e. 9.00g, in coating process, sheet bed tempertaure controls at 35 ~ 40 DEG C, and Vardenafil hydrochloric acid Film coated tablets made by coating.
Embodiment 3. Vardenafil hydrochloric acid chewable tablet prescription forms: specification 20mg (in Vardenafil), recipe quantity is 1000.
Get recipe quantity Vardenafil hydrochloric acid trihydrate and cross jet mill pulverizing, make granularity D
90≤ 40 μm, cross 40 mesh sieves and remove agglomerate, for subsequent use; Get recipe quantity mannitol, microcrystalline Cellulose, crospolyvinylpyrrolidone, tert-butyl group BHA cross 40 mesh sieves, for subsequent use; Get recipe quantity cherry essence, aspartame, magnesium stearate cross 60 mesh sieves, for subsequent use.
Preparation method: by above-mentioned Vardenafil hydrochloric acid trihydrate, mannitol, microcrystalline Cellulose, crospolyvinylpyrrolidone, tert-butyl group BHA, cherry essence, the aspartame handled well; be placed in hopper mixer mix homogeneously; dry-pressing granulator is granulated; granulate; cross 60 mesh sieves; add magnesium stearate, mixer mix homogeneously, Vardenafil hydrochloric acid chewable tablet made by tabletting.
Embodiment 4. Vardenafil hydrochloric acid granule prescription forms: specification 20mg (in Vardenafil), recipe quantity is 1000 bags.
Get recipe quantity Vardenafil hydrochloric acid trihydrate and cross jet mill pulverizing, make granularity D
90≤ 40 μm, cross 40 mesh sieves and remove agglomerate, for subsequent use; Get recipe quantity mannitol, microcrystalline Cellulose, crosslinked carboxymethyl fecula sodium, tert-butyl group BHA cross 40 mesh sieves, for subsequent use; Get recipe quantity aspartame, magnesium stearate crosses 60 mesh sieves, for subsequent use.
Preparation method: by above-mentioned Vardenafil hydrochloric acid trihydrate, mannitol, microcrystalline Cellulose, crosslinked carboxymethyl fecula sodium, tert-butyl group BHA, the aspartame handled well; be placed in hopper mixer mix homogeneously; dry-pressing granulator is granulated; granulate; cross 60 mesh sieves; add magnesium stearate, mixer mix homogeneously.Fill becomes bag to make Vardenafil hydrochloric acid granule.
Comparative experimental example: not containing the Vardenafil hydrochloric acid sheet of antioxidant
Vardenafil hydrochloric acid tablet recipe forms: specification 20mg (in Vardenafil), recipe quantity is 1000.
Preparation method:
Vardenafil hydrochloric acid trihydrate is crossed 40 mesh sieves, and microcrystalline Cellulose, crospolyvinylpyrrolidone, micropowder silica gel, magnesium stearate cross 60 mesh sieves.Vardenafil hydrochloric acid trihydrate, microcrystalline Cellulose, crospolyvinylpyrrolidone is taken by recipe quantity; put mixer mixing; dry-pressing granulator is granulated; granulate; cross 60 mesh sieves, add micropowder silica gel, after mix homogeneously, add magnesium stearate (crossing 60 mesh sieves); tabletting after mix homogeneously, Vardenafil hydrochloric acid Film coated tablets made by coating.
One, the mensuration of Vardenafil hydrochloric acid oral solid formulation In Vitro Dissolution curve.
Dissolution in vitro experimental technique is as follows: according to dissolution method (Chinese Pharmacopoeia version in 2010 two annex XC second methods), with 0.1mol/L hydrochloric acid solution and pH6.8 phosphate buffer 900ml for dissolution medium, when dissolution medium temperature reaches 37 DEG C ± 1 DEG C, drop into sample, open and stir, rotating speed is 50 turns per minute, announce stripping sample point according to FDA and sample 10ml respectively at when 5min, 10min, 15min, 20min, 30min, filter, get filtrate 5ml and be diluted to 10ml as need testing solution, equivalent supplements synthermal fresh dissolution medium; Separately get Vardenafil hydrochloric acid reference substance and be about 13.2mg in 100ml measuring bottle, add ethanol and make dissolving and be diluted to scale, in contrast product storing solution.Get the reference substance solution that reference substance storing solution 5ml is settled to 50ml with 0.1mol/L hydrochloric acid solution prepares for diluent dilutes.Get above-mentioned solution according to spectrophotography (Chinese Pharmacopoeia version in 2010 two annex IV), at 245nm wavelength, place measures trap respectively, calculates dissolution, in table 1 ~ 4.Vardenafil hydrochloric acid oral solid formulation of the present invention (embodiment 1 ~ 4), comparative experimental example and commercialized product
the In Vitro Dissolution curve of (sheet, specification 20mg) is shown in accompanying drawing 1 ~ 12.
Table 1 embodiment 1, comparative experimental example and
the accumulation dissolution (%) of sheet (20mg)
Table 2 embodiment 2, comparative experimental example and
the accumulation dissolution (%) of sheet (20mg)
Table 3 embodiment 3, comparative experimental example and
the accumulation dissolution (%) of sheet (20mg)
Table 4 embodiment 4, comparative experimental example and
the accumulation dissolution (%) of sheet (20mg)
From above data, the stripping curve of embodiment 1 ~ 4 in 2 kinds of different dissolution mediums all with
sheet similar (15min stripping > 85% or stripping similar factors > 50), dissolution rate be obviously better than comparative experimental example and
sheet, 5min dissolution significantly improves, and can reach the object of quick acting.
Two, the Content and related substances determination of Vardenafil hydrochloric acid oral solid formulation.
(1) assay:
According to high effective liquid chromatography for measuring (Chinese Pharmacopoeia version in 2010 two annex VD).
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are filler, (get 0.8g ammonium acetate is dissolved in 900ml water Acetate Solution A, add 100 acetonitriles again, mixing), (get 0.8g ammonium acetate is dissolved in 100ml water Acetate Solution B, add 900ml acetonitrile again, mixing), carry out eluting by with Gradient:
| Time (min) | A％ | B％ |
| 0 | 80 | 20 |
| 20 | 0 | 100 |
Pillar reequilibrate 10 minutes, determined wavelength 245nm, column temperature 40 DEG C.Get system suitability solution 10 μ l injection liquid chromatography, impurity Vardenafil hydrochloric acid N-oxide (being called for short N-oxide) and the separating degree of Vardenafil hydrochloric acid are greater than 5.0, theoretical cam curve must not lower than 12000 by Vardenafil hydrochloric acid sheet, and the relative standard deviation of content reference substance solution continuous sample introduction gained peak area must not be greater than 1.5% (n=6).
Impurity reference substance Vardenafil hydrochloric acid raw material midbody A by-product benzene sulfonyl derivant (being called for short benzene sulfonyl derivant) is got in the preparation of system suitability solution respectively and each 10.0mg of N-oxide is placed in 50ml measuring bottle, dissolve (ultrasonic 10 minutes) with diluent and be diluted to scale, get this solution 2ml in 100ml measuring bottle, scale is diluted to, as impurity storing solution with diluent.Get 24.0mg Vardenafil hydrochloric acid reference substance in 100ml measuring bottle, add 10ml impurity storing solution, dissolve (ultrasonic 10 minutes) with diluent and be diluted to scale, shaking up, to obtain final product.
The preparation precision of content reference substance solution takes Vardenafil hydrochloric acid reference substance and is about 24mg, puts in 100ml measuring bottle, adds appropriate diluent, ultrasonic 10 minutes, is diluted to scale, shakes up, to obtain final product with diluent.
Need testing solution preparation gets this product 10 in 500ml measuring bottle, adds appropriate solvent, ultrasonic 10 minutes, is diluted to scale with diluent, filters through 0.45 μm of filter membrane, gets subsequent filtrate 2.5ml dilution and is settled to 10ml as need testing solution.
Algoscopy gets reference substance solution and each 10 μ l of need testing solution injection liquid chromatography respectively, and record chromatogram, by external standard method with calculated by peak area, to obtain final product.
(2) determination of related substances:
Precision measures the need testing solution 3ml under assay item, 1000ml solution (0.3%) is in contrast diluted to diluent, according to method under assay item, get contrast solution 10 μ l injection liquid chromatography, the content of impurity is calculated by the main constituent Self-control method of the correction up factor, impurity benzene sulfonyl derivant and N-oxide all must not cross 0.3%, and other single impurity must not cross 0.2%, and total impurities must not cross 1.0%.
Table 5 Vardenafil hydrochloric acid oral solid formulation is the related substance of (40 DEG C, 75%) and content under acceleration environment
From above data, embodiment 1 ~ 4 at 40 DEG C, the accelerated stability impurity level under RH75% condition with
sheet is compared, and its impurity level is better than or is equal to
sheet; The impurity level of embodiment 1 ~ 4 is obviously better than comparative experimental example, the sufficient proof stability action of antioxidant in Vardenafil hydrochloric acid oral formulations.
Claims (2)
1. energy Fast Stripping, a stable Vardenafil hydrochloric acid oral solid formulation, is characterized in that, prescription constituent mass percentage ratio is one of following:
Vardenafil hydrochloric acid sheet: Vardenafil hydrochloric acid trihydrate 7.93%, microcrystalline Cellulose 84.53%, cross-linking sodium carboxymethyl cellulose 6.02%, butylated hydroxyarisol 0.02%, micropowder silica gel 0.50%, carnaubic acid wax 1.00%; Or,
Vardenafil hydrochloric acid sheet: Vardenafil hydrochloric acid trihydrate 7.90%, mannitol 84.58%, crospolyvinylpyrrolidone 6.00%, two fourth cresols 0.02%, micropowder silica gel 0.50%, magnesium stearate 1.00%; Or,
Vardenafil hydrochloric acid chewable tablet: Vardenafil hydrochloric acid trihydrate 5.93%, mannitol and microcrystalline Cellulose 85.05%, crospolyvinylpyrrolidone 6.00%, butylated hydroxyarisol 0.02%, cherry essence and aspartame 2.00%, magnesium stearate 1.00%; Or,
Vardenafil hydrochloric acid granule: Vardenafil hydrochloric acid trihydrate 6.44%, mannitol and microcrystalline Cellulose 86.55%, crosslinked carboxymethyl fecula sodium 5.00%, butylated hydroxyarisol 0.01%, aspartame 1.00%, magnesium stearate 1.00%;
Described Vardenafil hydrochloric acid trihydrate, carries out micronization processes, and granularity is D
90≤ 40 μm.
2. the preparation method of Vardenafil hydrochloric acid oral solid formulation described in claim 1, uses jet mill to carry out comminution by gas stream Vardenafil hydrochloric acid trihydrate, makes granularity reach D
90≤ 40 μm; Get each component by proportioning adopt dry-pressing to granulate or directly mix powder tablet forming technique, wherein:
Granule: the particle filling of gained of dry-pressing being granulated is dressed up bag and made Vardenafil hydrochloric acid granule; Or,
Chewable tablet: the granule of gained of dry-pressing being granulated carries out tabletting and makes Vardenafil hydrochloric acid chewable tablet, or by each component directly mixed powder tabletting make Vardenafil hydrochloric acid chewable tablet; Or,
Tablet: the granule of gained of dry-pressing being granulated carries out tabletting, or by each component directly mixed powder tabletting make Vardenafil hydrochloric acid tablet, or Vardenafil hydrochloric acid Film coated tablets made by coating further.
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| CN110193015A (en) * | 2018-02-27 | 2019-09-03 | 广州朗圣药业有限公司 | A kind of Vardenafil hydrochloric acid oral disnitegration tablet and preparation method thereof |
| CN108272765B (en) * | 2018-04-26 | 2021-02-02 | 江西杏林白马药业股份有限公司 | Pharmaceutical composition containing vardenafil hydrochloride, orally disintegrating tablet, and preparation and application thereof |
| JP7391521B2 (en) * | 2019-03-12 | 2023-12-05 | 東和薬品株式会社 | Pharmaceutical composition for treating erectile dysfunction |
| JP7336241B2 (en) * | 2019-04-02 | 2023-08-31 | 富士化学工業株式会社 | Method for producing tablet containing vardenafil |
| CN110507626B (en) * | 2019-09-19 | 2020-08-18 | 山东创新药物研发有限公司 | Preparation method of stable vardenafil hydrochloride trihydrate pharmaceutical composition |
| CN114460205A (en) * | 2022-02-17 | 2022-05-10 | 南京嘉晨医药科技有限公司 | Method for detecting dissolution curve of vardenafil hydrochloride orally disintegrating tablet |
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