CN101244049A - Clenbuterol hydrochloride double-layer sustained release tablets and preparation thereof - Google Patents
Clenbuterol hydrochloride double-layer sustained release tablets and preparation thereof Download PDFInfo
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Abstract
The invention discloses a clenbuterol hydrochloride two-layer slow release tablet used for easing asthma, which comprises two layers, namely, a quick release layer and a slow release layer; wherein, the quick release layer comprises 0.02 to 0.1% clenbuterol hydrochloride, 0.1 to 15% disintegrating agent and 10 to 25 filler (the percentages are all calculated against the overall weight of the two-layer tablet). The slow release layer comprises 0.03 to 0.15 clenbuterol hydrochloride, 40 to 70% slow release material and 2 to 25% filler, where all the percentages are also calculated against the overall weight of the two-layer tablet. In the clenbuterol hydrochloride two-layer slow release tablet, the quick release layer has the advantages of quickly releasing the drug, generating instant effects, and alleviating the symptoms rapidly; while the slow release layer has the advantages of slowly releasing the drug, stabilizing the blood drug level, reducing the side effects, lowering the use times, and improving the compliance of the patients when using the drug.
Description
Technical field
The present invention relates to a kind of medicine for the treatment of bronchial asthma, relate in particular to and a kind ofly can treat clenbuterol hydrochloride double-layer sustained release tablets of bronchial asthma and preparation method thereof, described double-layer sustained release tablets wherein one deck is a release layer, and another layer is a slow release layer.
Background technology
Bronchial asthma is a kind of common anaphylactic disease.During morbidity, owing to bronchial muscular spasm, mucosa swelling, the tube chamber stenosis is narrow, and it is long-pending to add that secretions stagnates, and causes ventilation to block dyspnea.In recent years, because environmental pollution is serious day by day, the sickness rate of bronchial asthma is in rising trend.Therefore, the drug research of treatment bronchial asthma is one of duty-bound mission of pharmacy worker always.Clenbuterol hydrochloride has another name called clenbuterol, clenbuterol hydrochloride, clenbuterol, Clenbuterol, Celenbuterol, peace diprophylline, and English name Clenbuterol Hydrochloride is potent selective ' beta '3 adrenergic β
2Receptor stimulating agent, can cause the bronchial smooth muscle diastole, be used for the treatment of bronchial asthma, asthmatic bronchitis and the emophysematous bronchitis of companion etc., the bronchial smooth muscle to spastic contraction when asthma attack is particularly responsive, can remove spasm, relieving asthma, make respiratory function recover normal.Clenbuterol hydrochloride also can have facilitation to bronchial epithelial ciliary movement, promotes the respiratory tract defense function, have eliminate the phlegm, the effect of antitussive.
Existing clenbuterol hydrochloride preparation mainly contains conventional tablet, aerosol, suppository, membrane, patch (Chinese patent CN1634005A), the shortcoming of these preparations is that action time is short, the ordinary tablet antiasthmatic effect was only kept 4～6 hours, aerosol sucks and kept 2～4 hours, the blood drug level shakiness causes serious side reaction easily.
The chemistry of clenbuterol hydrochloride is called α-[(uncle's fourth amino) methyl]-4-amino-3,5-dichlorbenzyl alcohol hydrochlorate, during clinical practice, drug dose is little, but side effect is big, symptoms such as blood drug level muscular tremor, nervous, cardiopalmus, headache may occur, feels sick when surpassing treatment blood drug level scope, vomiting, particularly bigger for disease patient's danger such as hypertension, heart disease, hyperthyroidism, glaucoma, prostate hyperplasia, may increase the weight of the state of an illness, therefore, adopt slow releasing agent, make its blood drug level steady, just can reduce the generation of side effect effectively.But, dyspnea during the asthma patient outbreak, painful unusually, therefore, need preparation to have the rapid release effect, rapidly relief of symptoms.
In order to overcome above-mentioned shortcoming, the invention provides a kind of double-layer sustained release tablets, wherein one deck is a release layer, another layer is a slow release layer.
Summary of the invention
The object of the present invention is to provide a kind of clenbuterol hydrochloride double-layer sustained release tablets, wherein one deck is a release layer, can rapid delivery of pharmaceuticals, have rapid-action, the effect of relief of symptoms rapidly, another layer is a slow release layer, drug slow discharges, and makes blood drug level steady, reduces side effect, and can reduce access times, improve the compliance of patient's medication.
Being characterized as of clenbuterol hydrochloride double-layer sustained release tablets of the present invention, release layer are a kind ofly mouthful to collapse the type preparation, can be contained in the oral cavity or Sublingual, discharge medicine rapidly and produce curative effect.The weight ratio of release layer and slow release layer is 1: 2～1: 6, and the thickness ratio of release layer and slow release layer is 1: 0.5～1: 2, and the clenbuterol hydrochloride weight ratio in release layer and the slow release layer is 0.1: 1～1: 0.1.Thereby rapid-action, the slow purpose stably of blood drug level then.
In the clenbuterol hydrochloride double-layer sustained release tablets of the present invention, release layer contains the clenbuterol hydrochloride that accounts for bilayer tablet gross weight 0.02～0.1%; 0.1～15% disintegrating agent and 10～25% filler.Disintegrating agent is preferably one or more the mixture in cross-linking sodium carboxymethyl cellulose (CCNa), polyvinylpolypyrrolidone (PVPP), carboxymethyl starch sodium (CMS Na), low hydroxypropyl cellulose (L-HPC), starch, hydroxypropyl starch, citric acid, sodium bicarbonate, sodium lauryl sulphate and the veegum that replaces.Filler is preferably one or more mixture in microcrystalline Cellulose, lactose, starch, mannitol, pregelatinized Starch, Icing Sugar, dextrin, calcium sulfate, the glucose.In addition, can also contain one or more mixture in magnesium stearate, Pulvis Talci, micropowder silica gel, stevioside and the aspartame in the release layer.
The slow release layer of clenbuterol hydrochloride double-layer sustained release tablets contains the clenbuterol hydrochloride that accounts for bilayer tablet gross weight 0.03～0.15%; 40～70% slow-release material and 2～25% filler.Slow-release material is preferably hydroxypropyl methylcellulose, carbomer, the mixture of one or more in ethyl cellulose, polyacrylic resin class, Brazil wax, stearyl alcohol, glyceryl monostearate, Polyethylene Glycol, polyethylene glycol mono stearate, triglyceride, cellulose acetate peptide acid esters (CAP), hydroxypropyl methylcellulose peptide acid esters (HPMCP), Hydroxypropyl Methyl Cellulose Phthalate (HPMCAS), methylcellulose (MC), alginate, chitosan, polrvinyl chloride, polyethylene, hexadecanol, the octadecanol.Its filler is preferably one or more the mixture in pregelatinized Starch, lactose, microcrystalline Cellulose, starch, calcium sulfate, dextrin, calcium hydrogen phosphate, magnesium stearate and the micropowder silica gel.
In the preferred embodiment of the invention, wherein, described release layer contains the clenbuterol hydrochloride that accounts for bilayer tablet gross weight 0.02～0.07%, 0.6～6% disintegrating agent and 10～20% filler; Described slow release layer contains the clenbuterol hydrochloride that accounts for bilayer tablet gross weight 0.03～0.1%, 50～65% slow-release material and 8～25% filler.
The present invention also provides a kind of preparation method of above-mentioned clenbuterol hydrochloride double-layer sustained release tablets, it is characterized by, and this method comprises:
After the component of release layer was mixed, by direct powder compression, perhaps tabletting behind dry granulation or the wet granulation prepared described release layer;
After the component of slow release layer is mixed, by direct powder compression, perhaps granulate after dry granulation, wet granulation, the fusion or the system piller after tabletting, prepare described slow release layer;
The release layer and the slow release layer of above-mentioned preparation are made double-layer tablet.
In the external stripping curve of clenbuterol hydrochloride double-layer sustained release tablets of preparation, release in 2 hours release in about 50%, 5 hour release in about 70%, 10 hour is about 90%, shows to have tangible slow release effect.Common clenbuterol hydrochloride sheet is nearly 100% release within an hour.
Stability test shows: in 6 months the accelerated test content of clenbuterol hydrochloride be 0 month 96%, in 12 months the long term test content of clenbuterol hydrochloride be 0 month 97%, other every indexs are all up to specification, prove that this clenbuterol hydrochloride double-layer sustained release tablets is stable.
In vivo test shows: blood drug level reaches 20ng/ml, and the clenbuterol hydrochloride double-layer sheet only needs 1.5 hours, and common clenbuterol hydrochloride sheet needs 3 hours, illustrates that the clenbuterol hydrochloride double-layer sheet is rapid-action.In addition, clenbuterol hydrochloride double-layer sheet curve when the intravital medicine of people is steady, and blood drug level remains within the 30ng/ml.The blood drug level of common clenbuterol hydrochloride sheet maximum reaches 44ng/ml, but 20 hours blood drug level is with nearly 0, and 20 hours blood drug level of clenbuterol hydrochloride double-layer sheet has 20ng/ml.Curve was more steady when the clenbuterol hydrochloride double-layer sheet was described than the medicine of ordinary tablet, and administration time can prolong and side effect reduces.
So in the clenbuterol hydrochloride double-layer sustained release tablets of the present invention, its release layer can rapid delivery of pharmaceuticals, have rapid-action, the effect of relief of symptoms rapidly; The slow release layer Chinese medicine slowly discharges, and blood drug level is steady, and side effect reduces, and can reduce access times, improves the compliance of patient's medication.
Description of drawings
Fig. 1 is the external stripping curve figure that the embodiment of the invention 20 is measured.
Curve comparison diagram when Fig. 2 is the body giving drugs into nose of the embodiment of the invention 21 and common clenbuterol hydrochloride sheet.
Fig. 3 is the stability test result's of the expression embodiment of the invention 22 figure.
The specific embodiment
Below, will the present invention be further detailed by embodiment, but the present invention is not limited to these embodiment, in the illustrated scope of claim of the present invention, can carry out various changes or be equal to replacement.
Embodiment 1
Prescription 1:
Preparation technology: principal agent and all adjuvants are crossed 100 mesh sieves respectively.With the clenbuterol hydrochloride in the release layer and other adjuvants in the release layer with the equivalent method mix homogeneously that progressively increases, direct powder compression system release layer, thickness is 0.15cm.Get the clenbuterol hydrochloride in the slow release layer, the equivalent method of progressively increasing adds ethyl cellulose, carbomer and lactose, and 75% ethanol 15ml makes soft material, 16 mesh sieve grains, and 45 ℃ of dryings, 18 mesh sieve granulate, tabletting system slow release layer after the adding magnesium stearate, thickness is 0.17cm.This clenbuterol hydrochloride double-layer sustained release tablets of preparation on the double-layer sustained release tablet machine.
Embodiment 2
Prescription 2:
Preparation technology: earlier principal agent and all adjuvants are crossed 100 mesh sieves respectively.With the clenbuterol hydrochloride in the release layer and other adjuvants in the release layer with the equivalent method mix homogeneously that progressively increases, direct powder compression system release layer, thickness is 0.14cm.Get the clenbuterol hydrochloride in the slow release layer, the equivalent method of progressively increasing adds polyacrylic resin and pregelatinized Starch, and water 15ml is a wetting agent system soft material, 16 mesh sieve grains, and 65 ℃ of dryings, 18 mesh sieve granulate, tabletting system slow release layer after the adding magnesium stearate, thickness is 0.18cm.This clenbuterol hydrochloride double-layer sustained release tablets of preparation on the double-layer sustained release tablet machine.
Embodiment 3
Prescription 3:
Preparation technology: earlier principal agent and all adjuvants are crossed 100 mesh sieves respectively.With the equivalent method mix homogeneously that progressively increases, 3% starch slurry 10ml makes soft material with the clenbuterol hydrochloride in the release layer and other adjuvants in the release layer, and 16 mesh sieves are granulated, 55 ℃ of dryings, and 18 mesh sieve granulate, the system release layer, thickness is 0.14cm.Get the clenbuterol hydrochloride in the slow release layer, the equivalent method of progressively increasing adds hydroxypropyl methylcellulose and calcium hydrogen phosphate, and ethanol 15ml makes soft material, 16 mesh sieve grains, and 45 ℃ of dryings, 18 mesh sieve granulate add microcrystalline Cellulose, and tabletting system slow release layer behind the mixing, thickness are 0.18cm.This clenbuterol hydrochloride double-layer sustained release tablets of preparation on the double-layer sustained release tablet machine.
Embodiment 4
Prescription 4:
Preparation technology: earlier principal agent and all adjuvants are crossed 100 mesh sieves respectively.With the equivalent method mix homogeneously that progressively increases, 5% starch slurry 12ml makes soft material with the clenbuterol hydrochloride in the release layer and other adjuvants in the release layer, and 16 mesh sieves are granulated, 55 ℃ of dryings, and 18 mesh sieve granulate, the system release layer, thickness is 0.15cm.Get the clenbuterol hydrochloride in the slow release layer, the equivalent method of progressively increasing adds other adjuvants such as hydroxypropyl methylcellulose, dextrin and microcrystalline Cellulose, mix homogeneously, and direct powder compression system slow release layer, thickness are 0.15cm.This clenbuterol hydrochloride double-layer sustained release tablets of preparation on the double-layer sustained release tablet machine.
Prescription 5:
Preparation technology: earlier principal agent and all adjuvants are crossed 100 mesh sieves respectively.With the clenbuterol hydrochloride in the release layer and other adjuvants in the release layer with the equivalent method mix homogeneously that progressively increases, direct powder compression system release layer, thickness is 0.15cm.Get the clenbuterol hydrochloride in the slow release layer, the equivalent method of progressively increasing adds other adjuvants such as hydroxypropyl methylcellulose, ethyl cellulose and pregelatinized Starch, mix homogeneously, and dry granulation is pressed into thin slice earlier, and cross 18 mesh sieves and granulate, the system slow release layer, thickness is 0.18cm.This clenbuterol hydrochloride double-layer sustained release tablets of preparation on the double-layer sustained release tablet machine.
Embodiment 6
Prescription 6:
Preparation technology: earlier principal agent and all adjuvants are crossed 100 mesh sieves respectively.With the equivalent method mix homogeneously that progressively increases, 10% starch slurry 15ml makes soft material with the clenbuterol hydrochloride in the release layer and other adjuvants in the release layer, and 16 mesh sieves are granulated, 40 ℃ of dryings, and 18 mesh sieve granulate, the system release layer, thickness is 0.16cm.Get the clenbuterol hydrochloride in the slow release layer, the equivalent method of progressively increasing is mixed with ethyl cellulose, hydroxypropyl methylcellulose, mannitol, dry granulation, and 18 order granulate, tabletting system slow release layer after the adding magnesium stearate, thickness is 0.18cm.This clenbuterol hydrochloride double-layer sustained release tablets of preparation on the double-layer sustained release tablet machine.
Embodiment 7
Prescription 7:
Preparation technology: earlier principal agent and all adjuvants are crossed 100 mesh sieves respectively.With the clenbuterol hydrochloride in the release layer and other adjuvants in the release layer with the equivalent method mix homogeneously that progressively increases, direct powder compression system release layer, thickness is 0.12cm.Get the clenbuterol hydrochloride in the slow release layer, add ethyl cellulose, pregelatinized Starch, water system soft material is granulated; dry granulate, hydroxypropyl methylcellulose is granulated dry granulate with ethanol system soft material; with two kinds of granule mix homogeneously, add the micropowder silica gel fluidizer, tabletting system slow release layer, thickness are 0.18cm.This clenbuterol hydrochloride double-layer sustained release tablets of preparation on the double-layer sustained release tablet machine.
Embodiment 8
Prescription 8:
Preparation technology: earlier principal agent and all adjuvants are crossed 100 mesh sieves respectively.With the clenbuterol hydrochloride in the release layer and other adjuvants in the release layer with the equivalent method mix homogeneously that progressively increases, direct powder compression system release layer, thickness is 0.14cm.Get the clenbuterol hydrochloride in the slow release layer, the equivalent method of progressively increasing is mixed with ethyl cellulose, hydroxypropyl methylcellulose, mannitol, dry granulation, and 18 order granulate, tabletting system slow release layer after the adding magnesium stearate, thickness is 0.15cm.This clenbuterol hydrochloride double-layer sustained release tablets of preparation on the double-layer sustained release tablet machine.
Embodiment 9
Prescription 9:
Preparation technology: earlier principal agent and all adjuvants are crossed 100 mesh sieves respectively.Get clenbuterol hydrochloride in the release layer and other adjuvants in the release layer with the equivalent method mix homogeneously that progressively increases, direct powder compression system release layer, thickness is 0.10cm.Get the clenbuterol hydrochloride in the slow release layer, the equivalent method of progressively increasing adds other adjuvants such as hydroxypropyl methylcellulose, ethyl cellulose and lactose, mix homogeneously, 50% ethanol 25ml makes soft material, and 16 mesh sieves are granulated, 60 ℃ of dryings, 18 mesh sieve granulate system slow release layers, thickness is 0.18cm.This clenbuterol hydrochloride double-layer sustained release tablets of preparation on the double-layer sustained release tablet machine.
Prescription 10:
Preparation technology: earlier principal agent and all adjuvants are crossed 100 mesh sieves respectively.Get clenbuterol hydrochloride in the release layer and other adjuvants in the release layer with the equivalent method mix homogeneously that progressively increases, direct powder compression system release layer, thickness is 0.12cm.Get the clenbuterol hydrochloride in the slow release layer, the equivalent method of progressively increasing adds polyacrylic resin and pregelatinized Starch, dry granulation, and 18 mesh sieve granulate, tabletting system slow release layer after the adding magnesium stearate, thickness is 0.19cm.This clenbuterol hydrochloride double-layer sustained release tablets of preparation on the double-layer sustained release tablet machine.
Embodiment 11
Prescription 11:
Preparation technology: earlier principal agent and all adjuvants are crossed 100 mesh sieves respectively.With the clenbuterol hydrochloride in the release layer and other adjuvants in the release layer with the equivalent method mix homogeneously that progressively increases, dry granulation, 18 mesh sieve granulate, the system release layer, thickness is 0.12cm.Get the clenbuterol hydrochloride in the slow release layer, the equivalent method of progressively increasing adds Brazil wax, stearyl alcohol, and 50～60 ℃ of fusions add microcrystalline Cellulose and granulate, and 40 ℃ of dryings are made slow release layer behind the 18 mesh sieve granulate, and thickness is 0.18cm.This clenbuterol hydrochloride double-layer sustained release tablets of preparation on the double-layer sustained release tablet machine.
Embodiment 12
Prescription 12:
Preparation technology: earlier principal agent and all adjuvants are crossed 100 mesh sieves respectively.With the clenbuterol hydrochloride in the release layer and other adjuvants in the release layer with the equivalent method mix homogeneously that progressively increases, direct powder compression system release layer, thickness is 0.15cm.Get the clenbuterol hydrochloride in the slow release layer, the equivalent method of progressively increasing adds glyceryl monostearate and calcium sulfate, mix homogeneously, and 50～60 ℃ of fusions are granulated, and 40 ℃ of dryings add magnesium stearate system slow release layer behind the 18 mesh sieve granulate, and thickness is 0.15cm.This clenbuterol hydrochloride double-layer sustained release tablets of preparation on the double-layer sustained release tablet machine.
Embodiment 13
Prescription 13:
Preparation technology: earlier principal agent and all adjuvants are crossed 100 mesh sieves respectively.With the equivalent method mix homogeneously that progressively increases, 5% starch slurry 12ml makes soft material with the clenbuterol hydrochloride in the release layer and other adjuvants in the release layer, and 16 mesh sieves are granulated, 55 ℃ of dryings, and 18 mesh sieve granulate, the system release layer, thickness is 0.14cm.Get the clenbuterol hydrochloride in the slow release layer, the equivalent method of progressively increasing adds Polyethylene Glycol and triglyceride, mix homogeneously, and 60 ℃ of fusions are granulated, 40 ℃ of dryings, 18 mesh sieve granulate add starch and dextrin, and tabletting system slow release layer, thickness are 0.15cm.This clenbuterol hydrochloride double-layer sustained release tablets of preparation on the double-layer sustained release tablet machine.
Embodiment 14
Prescription 14:
Preparation technology: earlier principal agent and all adjuvants are crossed 100 mesh sieves respectively.With the clenbuterol hydrochloride in the release layer and other adjuvants in the release layer with the equivalent method mix homogeneously that progressively increases, direct powder compression system release layer, thickness is 0.15cm.Get the clenbuterol hydrochloride in the slow release layer, the equivalent method of progressively increasing adds CAP, MC, and dextrin adds alcohol granulation, and 40 ℃ of dryings add the microcrystalline Cellulose mix homogeneously behind the 18 mesh sieve granulate, and tabletting system slow release layer, thickness are 0.15cm.This clenbuterol hydrochloride double-layer sustained release tablets of preparation on the double-layer sustained release tablet machine.
Prescription 15:
Preparation technology: earlier principal agent and all adjuvants are crossed 100 mesh sieves respectively.With the clenbuterol hydrochloride in the release layer and other adjuvants in the release layer with the equivalent method mix homogeneously that progressively increases, dry granulation, 18 mesh sieve granulate, the system release layer, thickness is 0.14cm.Get the clenbuterol hydrochloride in the slow release layer, the equivalent method of progressively increasing adds HPMCP, mix homogeneously, and 60 ℃ of fusions add dextrin, and extruding system piller adds microcrystalline Cellulose system slow release layer, and thickness is 0.16cm.This clenbuterol hydrochloride double-layer sustained release tablets of preparation on the double-layer sustained release tablet machine.
Embodiment 16
Prescription 16:
Preparation technology: earlier principal agent and all adjuvants are crossed 100 mesh sieves respectively.With the equivalent method mix homogeneously that progressively increases, 5% starch slurry 12ml makes soft material with the clenbuterol hydrochloride in the release layer and other adjuvants in the release layer, and 16 mesh sieves are granulated, 55 ℃ of dryings, and 18 mesh sieve granulate, the system release layer, thickness is 0.13cm.Get the clenbuterol hydrochloride in the slow release layer, the equivalent method of progressively increasing adds HPMCAS, mix homogeneously, and 60 ℃ of fusions, extruding system piller adds microcrystalline Cellulose and starch system slow release layer, and thickness is 0.17cm.This clenbuterol hydrochloride double-layer sustained release tablets of preparation on the double-layer sustained release tablet machine.
Embodiment 17
Prescription 17:
Preparation technology: earlier principal agent and all adjuvants are crossed 100 mesh sieves respectively.With the clenbuterol hydrochloride in the release layer and other adjuvants in the release layer with the equivalent method mix homogeneously that progressively increases, dry granulation, the system release layer, thickness is 0.14cm.Get the clenbuterol hydrochloride in the slow release layer, the equivalent method of progressively increasing adds other adjuvants such as hydroxypropyl methylcellulose, sodium alginate and microcrystalline Cellulose, mix homogeneously, water system soft material, 16 mesh sieves are granulated, 55 ℃ of dryings, 18 mesh sieve granulate add magnesium stearate tabletting system slow release layer, and thickness is 0.18cm.This clenbuterol hydrochloride double-layer sustained release tablets of preparation on the double-layer sustained release tablet machine.
Embodiment 18
Prescription 18:
Preparation technology: earlier principal agent and all adjuvants are crossed 100 mesh sieves respectively.With the equivalent method mix homogeneously that progressively increases, 5% starch slurry 8ml makes soft material with the clenbuterol hydrochloride in the release layer and other adjuvants in the release layer, and 16 mesh sieves are granulated, 65 ℃ of dryings, and 18 mesh sieve granulate, the system release layer, thickness is 0.14cm.Get the clenbuterol hydrochloride in the slow release layer, the equivalent method of progressively increasing adds polyvinyl chloride, 55 ℃ of fusions, and it is agglomerating to add the starch stirring, granulate, 40 ℃ of dryings, 18 order granulate add the micropowder silica gel mix homogeneously, and tabletting system slow release layer, thickness are 0.15cm.This clenbuterol hydrochloride double-layer sustained release tablets of preparation on the double-layer sustained release tablet machine.
Embodiment 19
Prescription 19:
Preparation technology: earlier principal agent and all adjuvants are crossed 100 mesh sieves respectively.With the clenbuterol hydrochloride in the release layer and other adjuvants in the release layer with the equivalent method mix homogeneously that progressively increases, direct compression system release layer, thickness is 0.15cm.Get the clenbuterol hydrochloride in the slow release layer, the equivalent method of progressively increasing adds hexadecanol and octadecanol, 60 ℃ of fusions, and granulate in the cooling back, and 18 order granulate add magnesium stearate tabletting system slow release layer, and thickness is 0.15cm.This clenbuterol hydrochloride double-layer sustained release tablets of preparation on the double-layer sustained release tablet machine.
With the prescription of embodiment 1 and the clenbuterol hydrochloride double-layer sustained release tablets of prepared, be dissolution medium with 0.001mol/LHCl 500ml, per minute 100 changes, and measures external stripping curve, See Figure 1.In external stripping curve, release in 2 hours release in 50%, 5 hour release 90% in 70%, 10 hour.
Embodiment 21
Prescription and prepared clenbuterol hydrochloride double-layer sustained release tablets with embodiment 3 carry out in vivo test to the healthy volunteer, carry out reference with ordinary tablet.
The processing of plasma sample: get the 15mL centrifuge tube and add 0.2mol/L NaOH solution 2mL successively, 0.5mg/L mark liquid 100 μ L in the hydroquinone, anticoagulant heparin blood plasma sample 1mL, mixing, (8: 2) extracting solution 8mL adds diethyl ether-ethanol, capping is extracted 20min with ultrasonoscope, the centrifugal 15min of 3000 commentaries on classics/min; Getting supernatant is transferred in another clean tube, add the washing of 0.2mol/L NaOH 2mL mixing, the centrifugal 5min of 3000 commentaries on classics/min, getting supernatant layer is transferred in the clean tube, put logical nitrogen in 60 ℃ of water-baths, volatilize, residual with the dissolving of 0.1mL mobile phase, get 20 μ L and measure, use internal standard method with peak area quantification for high performance liquid chromatograph.
Chromatographic condition: Hypersil silicagel column 150mm * 4.6mm, particle diameter 3 μ m; Mobile phase: acetonitrile: water: 5mol/L ammonium acetate (90: 10: 0.1); Flow velocity 0.8ml/min; UV-detector wavelength: 243nm; Column temperature is a room temperature.
Curve is seen Fig. 2 during the body giving drugs into nose, and test shows: blood drug level reaches 20ng/ml, and the clenbuterol hydrochloride double-layer sheet only needs 1.5 hours, and common clenbuterol hydrochloride sheet needs 3 hours, illustrates that the clenbuterol hydrochloride double-layer sheet is rapid-action.In addition, clenbuterol hydrochloride double-layer sheet curve when the intravital medicine of people is steady, and blood drug level remains within the 30ng/ml.The blood drug level of common clenbuterol hydrochloride sheet maximum reaches 44ng/ml, but 20 hours blood drug level is with nearly 0, and 20 hours blood drug level of clenbuterol hydrochloride double-layer sheet has 20g/ml.Curve was more steady when the clenbuterol hydrochloride double-layer sheet was described than the medicine of ordinary tablet, and administration time can prolong and side effect reduces.
Embodiment 22
Clenbuterol hydrochloride double-layer sustained release tablets with embodiment 6 prescriptions and prepared carries out stability test, the result shows: in 6 months the accelerated test content of clenbuterol hydrochloride be 0 month 96%, in 12 months the long term test content of clenbuterol hydrochloride be 0 month 97%, other every indexs are all up to specification, prove that this clenbuterol hydrochloride double-layer sustained release tablets is stable.The results are shown in Figure 3.
Claims (10)
1. a clenbuterol hydrochloride double-layer sustained release tablets is characterized in that, comprises release layer and slow release layer.
2. clenbuterol hydrochloride double-layer sustained release tablets as claimed in claim 1 is characterized in that, the weight ratio of release layer and slow release layer is 1: 2～1: 6; The thickness ratio of release layer and slow release layer is 1: 0.5～1: 2; Clenbuterol hydrochloride weight ratio in release layer and the slow release layer is 0.1: 1～1: 0.1.
3. clenbuterol hydrochloride double-layer sustained release tablets as claimed in claim 1 or 2 is characterized in that, described release layer contains the clenbuterol hydrochloride that accounts for bilayer tablet gross weight 0.02～0.1%, 0.1～15% disintegrating agent and 10～25% filler.
4. clenbuterol hydrochloride double-layer sustained release tablets as claimed in claim 3 is characterized in that, described release layer is a kind ofly mouthful to collapse the type preparation, can be contained in the oral cavity or Sublingual, discharges medicine rapidly and produces curative effect.
5. clenbuterol hydrochloride double-layer sustained release tablets as claimed in claim 3 is characterized in that, described release layer also contains one or more the mixture in magnesium stearate, Pulvis Talci, micropowder silica gel, stevioside and the aspartame.
6. clenbuterol hydrochloride double-layer sustained release tablets as claimed in claim 3, it is characterized in that the contained disintegrating agent of described release layer is one or more the mixture in cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, carboxymethyl starch sodium, low hydroxypropyl cellulose, starch, hydroxypropyl starch, citric acid, sodium bicarbonate, sodium lauryl sulphate and the veegum that replaces; The contained filler of described release layer is one or more mixture in microcrystalline Cellulose, lactose, starch, mannitol, pregelatinized Starch, Icing Sugar, dextrin, calcium sulfate, the glucose.
7. clenbuterol hydrochloride double-layer sustained release tablets as claimed in claim 1 or 2 is characterized in that, described slow release layer contains the clenbuterol hydrochloride that accounts for bilayer tablet gross weight 0.03～0.15%, 40～70% slow-release material and 2～25% filler.
8. clenbuterol hydrochloride double-layer sustained release tablets as claimed in claim 7, it is characterized in that, the contained slow-release material of described slow release layer is a hydroxypropyl methylcellulose, carbomer, ethyl cellulose, the polyacrylic resin class, Brazil wax, stearyl alcohol, glyceryl monostearate, Polyethylene Glycol, polyethylene glycol mono stearate, triglyceride, cellulose acetate peptide acid esters, hydroxypropyl methylcellulose peptide acid esters, Hydroxypropyl Methyl Cellulose Phthalate, methylcellulose, alginate, chitosan, polrvinyl chloride, polyethylene, hexadecanol, the mixture of one or more in the octadecanol; The contained filler of described slow release layer is one or more the mixture in pregelatinized Starch, lactose, microcrystalline Cellulose, starch, calcium sulfate, dextrin, calcium hydrogen phosphate, magnesium stearate and the micropowder silica gel.
9. clenbuterol hydrochloride double-layer sustained release tablets as claimed in claim 1 or 2 is characterized in that, described release layer contains the clenbuterol hydrochloride that accounts for bilayer tablet gross weight 0.02～0.07%, 0.6～6% disintegrating agent and 10～20% filler; Described slow release layer contains the clenbuterol hydrochloride that accounts for bilayer tablet gross weight 0.03～0.1%, 50～65% slow-release material and 8～25% filler.
10. the preparation method as any described clenbuterol hydrochloride double-layer sustained release tablets of claim 1～9 is characterized in that, this method comprises:
After the component of release layer was mixed, by direct powder compression, perhaps tabletting behind dry granulation or the wet granulation prepared described release layer;
After the component of slow release layer is mixed, by direct powder compression, perhaps granulate after dry granulation, wet granulation, the fusion or the system piller after tabletting, prepare described slow release layer;
The release layer and the slow release layer of above-mentioned preparation are made double-layer tablet.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100375498A CN101244049B (en) | 2007-02-14 | 2007-02-14 | Clenbuterol hydrochloride double-layer sustained release tablets and preparation thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100375498A CN101244049B (en) | 2007-02-14 | 2007-02-14 | Clenbuterol hydrochloride double-layer sustained release tablets and preparation thereof |
Publications (2)
| Publication Number | Publication Date |
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| CN101244049A true CN101244049A (en) | 2008-08-20 |
| CN101244049B CN101244049B (en) | 2010-11-10 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN2007100375498A Expired - Fee Related CN101244049B (en) | 2007-02-14 | 2007-02-14 | Clenbuterol hydrochloride double-layer sustained release tablets and preparation thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110201691A1 (en) * | 2008-03-27 | 2011-08-18 | The University Of Leicester | Modulation of fibroblast activity |
| CN102772395A (en) * | 2011-05-09 | 2012-11-14 | 中国人民解放军军事医学科学院毒物药物研究所 | Sustained release preparation containing ambroxol hydrochloride and clenbuterol hydrochloride, and preparation method thereof |
| CN105997958A (en) * | 2016-07-12 | 2016-10-12 | 中国人民解放军白求恩医务士官学校 | Oral cavity external preparation and preparation method thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20010107754A (en) * | 2000-05-26 | 2001-12-07 | 민경윤 | Process for preparing rapidly disintegrating tablet for oral administration |
| CN1419908A (en) * | 2002-12-19 | 2003-05-28 | 王登之 | Oral cavity disintegrating tablet of clenbuterol hydrochloride for treating asthma, and preparing method thereof |
| CN1579401A (en) * | 2003-08-11 | 2005-02-16 | 李亦武 | Cought and asthma relieaving preparation and its preparation method |
-
2007
- 2007-02-14 CN CN2007100375498A patent/CN101244049B/en not_active Expired - Fee Related
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110201691A1 (en) * | 2008-03-27 | 2011-08-18 | The University Of Leicester | Modulation of fibroblast activity |
| US9555013B2 (en) * | 2008-03-27 | 2017-01-31 | The University Of Leicester | Modulation of fibroblast activity |
| CN102772395A (en) * | 2011-05-09 | 2012-11-14 | 中国人民解放军军事医学科学院毒物药物研究所 | Sustained release preparation containing ambroxol hydrochloride and clenbuterol hydrochloride, and preparation method thereof |
| CN105997958A (en) * | 2016-07-12 | 2016-10-12 | 中国人民解放军白求恩医务士官学校 | Oral cavity external preparation and preparation method thereof |
| CN105997958B (en) * | 2016-07-12 | 2019-03-26 | 中国人民解放军白求恩医务士官学校 | A kind of oral cavity external preparation and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101244049B (en) | 2010-11-10 |
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