CN101485641B - Finasteride and doxazosin compound controlled release capsule and use thereof - Google Patents
Finasteride and doxazosin compound controlled release capsule and use thereof Download PDFInfo
- Publication number
- CN101485641B CN101485641B CN2009100002256A CN200910000225A CN101485641B CN 101485641 B CN101485641 B CN 101485641B CN 2009100002256 A CN2009100002256 A CN 2009100002256A CN 200910000225 A CN200910000225 A CN 200910000225A CN 101485641 B CN101485641 B CN 101485641B
- Authority
- CN
- China
- Prior art keywords
- doxazosin
- finasteride
- medicine
- controlled release
- capsule
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a finasteride-doxazosin controlled-release capsule, and belongs to the technical field of medicines. Common micro pills of finasteride and slow release micro pills of doxazosin are mixed and encapsulated to prepare the controlled-release capsule, wherein the weight ratio of the finasteride medicine to the doxazosin medicine in the capsule is 1:0.625-2.5. The composite capsule preparation utilizes high molecular polymers as auxiliary materials of the controlled-release preparation, the finasteride as the common micro pill and the doxazosin as the slow release micro pill; tests verify that: effective constituents of the two medicines not only can be mutually cooperated to achieve better curative effects, but also can stably release the medicines, avoid the difference between blood concentration at wave crest and wave hollow, and reduce toxic and side effects of the medicines on human body are reduced; moreover, the controlled-release capsule can also reduce the medicine taking time of a patient and improve compliance of taking medicines. The finasteride-doxazosin controlled-release capsule can be used as a medicine to treat hypertension and benign hyperplasia of prostate.
Description
Technical field:
The invention belongs to medical technical field, relate to a kind of preparation that is used for the treatment of the medicine of hypertension and benign prostatic hyperplasia, be specifically related to by finasteride and the compound capsule preparations of doxazosin with controlled release ability.
Background technology:
Benign prostatic hyperplasia is common male's Senile disease, main cause is the growth at age and the existence that the function testis is arranged, caused urinating blocked, its main cause has two aspects: the one, and the testosterone that testis produces, under the effect of α 1 reductase, be transformed into dihydrotestosterone, act on prostate and make prostatic hyperplasia.Outgrowth body of gland is charged into bladder, and the compressing urethra causes bladder outlet mechanical obstruction.Be that neck of bladder, back urethra, body of prostate and peplos contain abundant α receptor on the other hand, because of being subjected to the stimulation of mechanical obstruction, the α receptor excitement of above-mentioned position is increased its tension force, functional blocking appears, thereby the symptom benign prostatic hyperplasia that blocks that increases the weight of to urinate causes dysuric reason, mainly be that mechanical obstruction and mechanical obstruction due to the prostatic hyperplasia stimulates neck of bladder, back urethra, the position receptor of body of prostate etc., make its generation irritability cause above-mentioned position tension force and increase, and functional result of blocking occurs.In the therapeutic process, be difficult to determine to be mechanical obstruction clinically, still functional blocking.Therefore have only two main causes that solve benign prostatic hyperplasia patient urinary tract obstruction simultaneously in the treatment, just can receive better therapeutic effect.
Finasteride is a kind of synthetic 5 α-steroid hormone chemical compound, the alternative 5 that suppresses, the process that makes testosterone change into 5 is obstructed, the androgen level descends in the prostatic cell, prostate specific antigen in the serum (PSA) reduces, the prostate volume that increases dwindles, and the urine flow rate increases.Doxazosin is a kind of long-acting selectivity α receptor blocking agent, and mitigation capability blocks.Be applicable to treatment and control benign prostatic hyperplasia, loose prostate is dwindled, improve the relevant symptom of prostatic hyperplasia.Clinical showing: the medication of prostatic hyperplasia patient treatment is after 4 months, prostate gland symptoms decreased average 30%, and its weight is compared and is alleviated 27%, and advantage is that toxicity is little, and is safe and reliable.
Doxazosin is long lasting α 1 receptor blocking agent, this product selectively acting is in joint back α 1-adrenoceptor, this product acts on the a1-adrenoceptor of prostate and neck of bladder smooth muscle, make neck of bladder, prostate, capsula prostatica smooth muscle loosening, urethra and bladder resistance lower, thereby alleviate the urethral obstruction symptom that prostatic hyperplasia causes.
Clinical pharmacology experiment proves that also finasteride and two kinds of medicines of doxazosin can couplings, and mutual synergism arranged, compare with every kind of medicine of independent use, two kinds of drug combinations have reduced the incidence rate of prostatic hyperplasia progress significantly, and have delayed the progress of prostatic hyperplasia.But the adverse reaction rate of drug combination uses finasteride or doxazosin height more separately, because doxazosin has tangible hypotensive effect, bigger to orthostatic blood pressure and heart rate influence, absorb very fast, peak time 2-3 hour, can cause the blood pressure rapid drawdown, cause the postural hypotension untoward reaction, the patient does not tolerate.That common untoward reaction has is weak, postural hypotension, peripheral edema, dizzy, libido reduction, rhinitis, abnormal ejaculation, sexual impotence and sexual function are unusual.
Existing BeiJing SaiKe Pharmacy Co., Ltd is in the research of carrying out finasteride and doxazosin compound formulation, patent application 200410074655.X discloses both compound recipe ordinary preparations, and the proportioning and the preparation process of tablet and conventional capsule agent are disclosed in an embodiment, demonstration is that two kinds of medicines and pharmaceutic adjuvant directly are mixed and made into common compound preparation.Common compound preparation reflects has demonstrate,proved the mutual synergism of two kinds of medicines aspect therapeutic effect, yet, not overcoming the untoward reaction of drug combination, medicine strengthens the toxicity of human body.
Summary of the invention:
The purpose of this invention is to provide a kind of finasteride doxazosin controlled release capsule, it is a kind of new compound controlled release preparation, said preparation not only can be brought into play better therapeutic by the mutual synergism of two kinds of effective ingredients, also can steadily discharge medicine, avoid the difference of crest and trough blood drug level, reduce the toxicity of medicine, can reduce patient's medicine time, improve the compliance of taking medicine human body.
Finasteride doxazosin controlled release capsule of the present invention, be by the finasteride common pellets be loaded on capsulae vacuus after the doxazosin slow-release micro-pill mixes and form, the mass ratio of finasteride medicine and doxazosin medicine is 1: 0.625～2.5 in the capsule.
Wherein, described doxazosin slow-release micro-pill is by being the ball heart with the medicament pellet that contains the doxazosin medicine, is the slow-release micro-pill that coating material is prepared from the high molecular polymer that is dissolved in organic solvent.
Described organic solvent can be methanol, ethanol, any one or a few aqueous solution of any one or a few mixing or its in isopropyl alcohol and the acetone; What described coating material was ethyl cellulose and hydroxypropyl emthylcellulose by weight (1: 6)～(3: 1) is compound.
Described medicament pellet is mixed after wet granulation forms by medicine and filler, adhesive; Medicine described here is doxazosin or its pharmaceutical salts, and pharmaceutical salts can be hydrochlorate, sulfate, mesylate, maleate; Preferred Carclura.
Described filler is selected from one or more the mixing in lactose, mannitol, xylitol, sorbitol, Icing Sugar, dextrin, starch, pregelatinized Starch, microcrystalline Cellulose and the inorganic salt.
Described adhesive is selected from one or more the mixing in starch slurry, methylcellulose, hydroxypropyl cellulose, hypromellose, ethyl cellulose, polyvidone, gelatin and the Polyethylene Glycol.
Wherein, described finasteride common pellets is the ball heart with blank micropill, is mixed into coating material and makes with finasteride medicine, adhesive and organic solvent.
Described organic solvent is a methanol, ethanol, isopropyl alcohol, acetone or wherein any one or a few mixing or its any one or a few aqueous solution; Adhesive is one or more in starch slurry, methylcellulose, hydroxypropyl cellulose, hypromellose, ethyl cellulose, polyvidone, gelatin, the Polyethylene Glycol etc.
Also comprise auxiliary agent in the described coating material, described cosolvent is one or more in sodium lauryl sulphate, tween (Tween), span (Span), phospholipid, poloxalkol, tristerin, the sucrose fatty acid ester etc.
Another purpose of the present invention is to provide the application of finasteride doxazosin controlled release capsule in preparation treatment hypertension and benign prostatic hyperplasia medicine.
Adopt above technical scheme, in the complex capsule preparation of the present invention, finasteride is rapid release (common) micropill, doxazosin is a slow-release micro-pill, utilize the high molecular polymer of optimizing to come control drug release time and degree as the slow releasing preparation adjuvant, experiment shows: two kinds of effective ingredients not only can be worked in coordination with the performance better therapeutic mutually, also can steadily discharge medicine, avoid the difference of crest and trough blood drug level, reduce the toxicity of medicine human body; In addition, can reduce patient's medicine time, improve the compliance of taking medicine.Can be used for new drug as treatment hypertension and benign prostatic hyperplasia.
Description of drawings:
Fig. 1 is blood drug level-time graph behind the different compound preparations of the oral finasteride doxazosin of Beagle dog.
Fig. 2 is blood pressure-time graph behind the different compound preparations of the oral finasteride doxazosin of Beagle dog.
The specific embodiment:
The present invention mainly is devoted to improve the pharmacokinetic properties of the two preparation when the design compound preparation, make the plasma drug level parameter more steady, reduces the side effect that common compound preparation has.
Therefore, compound controlled release preparation provided by the invention, be that two kinds of composition and effectivenesses are made micropill respectively, by using different film coating mode and material, wherein a kind of medicine is made slow-release micro-pill, control the rate of release of two kinds of medicines with this, and utilize the difference of two kinds of drug releasing rates, make this pharmaceutical composition reach ideal synergy, the synergism that had so both possessed compound medicine can effectively improve benign prostate hyperplasia (BPH) and patient's lower urinary tract symptom fast, significantly reduces the generation of first-dose response and side effect, safety and toleration have been improved again, with curative effect and safety desired combination.
The present invention uses the film packaging technique to prepare the controlled release compound preparation, is specially the controlled release compound capsule, and compound controlled release capsule provided by the invention is made up of two kinds of different micropills.At first, the present invention determines doxazosin in two kinds of medicines is made slow-release micro-pill, and another kind of medicine finasteride is a common pellets, because the rate of release of medicine is fast, also can be described as fast release micropill, helps fast and effeciently to improve disease.The finasteride fast release micropill is by the drug coating technology medicine evenly to be wrapped on the celphere to make; The doxazosin slow-release micro-pill is by extruding spheronization technique doxazosin to be made micropill, realizes the target of medicament slow release then by the high molecular polymer coating.
Below with specific embodiment compound controlled release capsule of the present invention and preparation thereof are described.
Embodiment 1: the preparation of finasteride fast release micropill
Finasteride micropill coating preparation technology: the medicine in will filling a prescription, adhesive, cosolvent and organic solvent mix (by prescription) and make coating solution; Will be in fluid bed with above-mentioned coating solution with blank sugar pill ball core coating.During coating, may command micropill finasteride medicament contg is at 1～60wt%.
Here, medicine is a finasteride; Adhesive can be selected from one or more mixing in starch slurry, methylcellulose, hydroxypropyl cellulose, hypromellose, ethyl cellulose, polyvidone, gelatin, the Polyethylene Glycol etc.; When the medicine dissolution degree is not enough, can add cosolvent, cosolvent is selected from one or more mixing in sodium lauryl sulphate, tween (Tween), span (Span), phospholipid, poloxalkol, tristerin, the sucrose fatty acid ester etc.; Organic solvent is selected from methanol, ethanol, and isopropyl alcohol, any one or a few aqueous solution of any one or a few mixing or its in the acetone, organic solvent can use separately also can mix by arbitrary proportion and use.
Prescription A:
Finasteride 3.90g
Hydroxypropyl cellulose 0.04g
Ethanol 40g
Isopropyl alcohol: water=9: 1 10g
Prescription B:
Finasteride 3.90g
Hypromellose 0.10g
Sodium lauryl sulphate 0.20g
Isopropyl alcohol 40g
Prescription C:
Finasteride 3.90g
Polyvidone 0.10g
Acetone 40g
Prescription D:
Finasteride 3.90g
Methylcellulose 0.04g
Tween 80 0.20g
Ethanol: water=75: 25 60g
Prescription E:
Finasteride 3.90g
Ethyl cellulose 0.10g
Tristerin 0.20g
Methanol 50g
The preparation of embodiment 2, doxazosin slow-release micro-pill
Doxazosin slow-release micro-pill coating preparation technology: at first medicine and filler, adhesive are carried out wet granulation after mixing, extrude the round as a ball medicament pellet that is prepared into then, after the medicament pellet drying, with fluid bed coating solution coating, the coating weightening finish is 5-17%.Can control and contain doxazosin medicine 1～60wt% in the micropill.
Here, the medicament pellet Chinese medicine is doxazosin or its pharmaceutical salts, and pharmaceutical salts can be hydrochlorate, sulfate, mesylate, maleate, preferred Carclura; Filler is selected from one or more the mixing in lactose, mannitol, xylitol, sorbitol, Icing Sugar, dextrin, starch, pregelatinized Starch, microcrystalline Cellulose, the inorganic salt etc., and adhesive is selected from one or more in starch slurry, methylcellulose, hydroxypropyl cellulose, hypromellose, ethyl cellulose, polyvidone, gelatin, the Polyethylene Glycol etc.
Coating solution is dissolved in the organic solvent by high molecular polymer to be made, and wherein, high molecular polymer is ethyl cellulose and the compound use of hydroxypropyl emthylcellulose, and its usage ratio is 1: 6～3: 1 (by weight).Organic solvent can be methanol, ethanol, and isopropyl alcohol, any one or a few aqueous solution of any one or a few mixing or its in the acetone, solvent can use separately also can mix by arbitrary proportion and use.。
Prescription 1:
Medicament pellet
Doxazosin 4.00g
Icing Sugar 62.00g
Starch 24.04g
Hyprolose 10.0g
Coating solution
Ethyl cellulose 10.0g
Hydroxypropyl emthylcellulose 10.0g
Ethanol: water=75: 25 380.0g
Prescription 2:
Medicament pellet
Carclura 5.0g
Icing Sugar 55.0g
Microcrystalline Cellulose 25.0g
Hypromellose 15.0g
Coating solution
Ethyl cellulose 10.0g
Hydroxypropyl emthylcellulose 10.0g
Acetone 380.0g
Prescription 3:
Medicament pellet
Doxazosin 4.0g
Lactose 70.0g
Microcrystalline Cellulose 20.0g
Polyvidone 6.0g
Coating solution
Ethyl cellulose 10.0g
Hydroxypropyl emthylcellulose 10.0g
95% ethanol 380.0g
Prescription 4:
Medicament pellet
Doxazosin 4.0g
Mannitol 75.0g
Pregelatinized Starch 18.0g
Methylcellulose 3.0g
Coating solution
Ethyl cellulose 10.0g
Hydroxypropyl emthylcellulose 10.0g
Isopropyl alcohol 380.0g
Prescription 5:
Medicament pellet
Doxazosin hydrochlorate 4.5g
Lactose 92.5g
Ethyl cellulose 3.0g
Coating solution
Ethyl cellulose 15.0g
Hydroxypropyl emthylcellulose 5.0g
Acetone 380.0g
Prescription 6:
Medicament pellet
Doxazosin 4.00g
Microcrystalline Cellulose 85.04g
Polyvidone 11.0g
Coating solution
Ethyl cellulose 15.0g
Hydroxypropyl emthylcellulose 5.0g
Isopropyl alcohol 380.0g
Prescription 7:
Medicament pellet
Doxazosin 4.0g
Starch 80.0g
Hypromellose 16.0g
Coating solution
Ethyl cellulose 5.0g
Hydroxypropyl emthylcellulose 15.0g
Dehydrated alcohol 380.0g.
Embodiment 3: the preparation of finasteride doxazosin controlled release capsule
Two kinds of micropill according to the form below 1 group modes that embodiment 1 and 2 prepares are respectively distinguished mix homogeneously by the amount of two kinds of medicines, the capsulae vacuus of packing into then, each capsule charge weight is 100mg.
Table 1: finasteride-doxazosin compound controlled release capsule
Experimental section
Experiment one, the different proportioning compound recipes of finasteride doxazosin are to the influence of prostatic hyperplasia
80 of Adult SD male rats, body weight 70-110g.Be divided into 8 groups at random according to table 2.Except that normal group, all the other 7 groups of rats are cooked the castration operation respectively: rat through the capable aseptic operation of scrotum, is extractd bilateral testes with 3.0% chloral hydrate intraperitoneal injection of anesthesia (10ml/kg).Performing the operation began medication: model group castrated rats subcutaneous injection testosterone propionate 5mg/kg (dosage is 2ml/kg) in back 7 days, irritated stomach (20ml/kg) with solvent simultaneously; Positive group castrated rats in the subcutaneous injection testosterone propionate with doxazosin (Doxazosin, Dox), (Finasteride Fin) irritates stomach, every day 1 time finasteride.Proportioning group castrated rats prescription with various dose in the subcutaneous injection testosterone propionate is irritated stomach, every day 1 time.The rats in normal control group subcutaneous injection is irritated stomach with normal saline, every day 1 time with oil.The subcutaneous injection volume is 2ml/kg, and the gastric infusion volume is 20ml/kg.
Behind the administration 14d, the execution animal is cutd open and gets prostata tissue, weighs, and drainage is surveyed volume, calculates the prostate coefficient, and prostate coefficient=prostate quality/body weight * 100 calculates prostatic hyperplasia suppression ratio (%)
Suppression ratio (%)=(administration group coefficient-normal group coefficient) ÷ (model group coefficient-normal group coefficient) * 100%
Table 2 doxazosin (Dox), finasteride (Fin) proportioning synopsis
The result: above-mentioned experimental result as shown in Table 3.Compare with model control group, Dox 2.0-4.0mg/kg has the effect trend that reduces to the increase of prostate coefficient, the increase that prostate is mentioned, the prostatic hyperplasia suppression ratio is 3.1-18.5%, but not seeing has biostatistics's difference, shows that Dox2.0-4.0mg/kg does not have the influence (P＞0.05) of significance to prostatic hyperplasia;
Fin 5.0mg/kg has significantly the increase of the increase of prostate coefficient, prostate volume and reduces (P＜0.05 or P＜0.01), the prostatic hyperplasia suppression ratio is 53.1%, 2.5mg/kg dosage prostatic hyperplasia suppression ratio is 13.1%, but do not see significance biostatistics difference is arranged, show that Fin5.0mg/kg is an effective dose, Fin2.5mg/kg is an ineffective dose;
The compound recipe that Dox and Fin form, at Dox: Fin (2: 5 and 4: 5) after ratio is compound, increase to the prostate coefficient, the increase of prostate volume has highly significant to reduce (P＜0.01), the prostatic hyperplasia suppression ratio is respectively 84.6%, 93.1%, be higher than Dox 2.0mg/kg dosage (3.1%) far away, Dox 4.0mg/kg dosage (18.5%) and Fin 5.0mg/kg dosage (53.1%), and has significance biostatistics difference (P＜0.01), the prostatic hyperplasia suppression ratio is obviously improved, be increased to 84.6%-93.1% by 3.1%-53.1%, and have dose relationship to show and synergism occurred after compound, drug effect significantly improves;
Fin ineffective dose 2.5mg/kg (13.1%) and invalid Dox (2-4mg/kg, 3.1% and 18.5%) compound back all can produce significantly effect, be increased to 28.5%-36.9% by 3.1%-18.5%, and have significance biostatistics difference (P＜0.01) show form compound recipe after drug action dosage obviously reduce.
The compound recipe that conclusion: Dox and Fin form has the obvious synergistic effect to prostatic hyperplasia.Forming the effective ratio dosage range of compound recipe is Dox (2-4mg/kg): Fin (2.5-5.0mg/kg), and useful effect dosage obviously reduces behind the formation compound recipe.
The different proportioning compound recipes of embodiment two, finasteride doxazosin are to the influence of urinary function
Male SD rat 250-300g is according to body weight, and random packet (referring to table 2) is fixed with urethane 1.5g/kg intraperitoneal injection of anesthesia layback position.Row duodenal intubation art is in order to administration.In hypogastric region pubic symphysis place, vertically cut skin, do otch along hunter's line, open the abdominal cavity, expose bladder.In the pore-creating of bladder top, will make the two-chamber sleeve pipe by oneself and insert bladder and fix with the fine rule ligation.Cannula cavity links to each other with the constant current peristaltic pump through silica gel tube, continues the perfusion normal saline with the 0.20ml/min flow velocity.The sleeve pipe exocoel links to each other with eight road physiology monitors through threeway and pressure transducer, and each parameter of record bladder changes.After treating that intravesical pressure is stablized 30min, duodenal intubation administration, record administration forward and backward bladder urinate pressure (VMP, cmH
2O), urinate at interval (ICI, min) and urinate capacity (VMV, situation of change ml).Experimental data is represented with measured value and rate of change, with significant difference between t test evaluation group.
The result: above-mentioned experimental result is listed in table 4.Show that compare with the blank group, Dox 4.0mg/kg can significantly reduce rat bladder VMP (P＜0.01), the reduction amplitude is 13.2% ± 7.8%, obviously shorten (P＜0.01), the shortening amplitude is 9.2% ± 8.5% obvious VMV (P＜0.01) of minimizing, and the minimizing amplitude is 10.8% ± 26.4%; 2.0mg/kg dosage is seen significance biostatistics difference is not arranged, show that Dox4.0mg/kg is an effective dose, Dox2.0mg/kg is an ineffective dose;
Fin 2.5-5.0mg/kg has the effect trend that reduces to rat bladder VMP, ICI, VMV, but does not see biostatistics's difference there is (P＞0.05), shows that Fin2.5-5.0mg/kg does not have the influence of significance to the rat urine function;
The compound recipe that Dox and Fin form, after Dox: Fin (4: 5) ratio is compound, there is highly significant to reduce (P＜0.01) to rat bladder VMP, ICI, VMV, amplitude of variation is respectively 16.2% ± 9.8%, 12.2% ± 10.3%, 15.8% ± 20.4%, is higher than Dox 4.0mg/kg effect dosage and Fin 5.0mg/kg dosage; After Dox effective dose 4mg/kg and invalid Fin (2.5-5.0mg/kg) are compound, rat bladder VMP, ICI, VMV effect are obviously strengthened, and dose relationship is arranged.Show synergism to have occurred after compound, drug effect significantly improves;
The compound back of Fin ineffective dose 2.5-5.0mg/kg and invalid Dox dosage 4mg/kg all can produce significantly and act on, and rat bladder VMP, ICI, VMV is had significantly reduce (P＜0.01), show the formation compound recipe after drug action dosage obviously reduce.
The compound recipe that conclusion: Dox and Fin form has the obvious synergistic effect to the rat urine function.Forming the effective ratio dosage range of compound recipe is Dox (2-4mg/kg): Fin (2.5-5.0mg/kg), and useful effect dosage obviously reduces behind the formation compound recipe.
The pharmacokinetic of embodiment three, finasteride doxazosin controlled release compound preparation and common compound preparation
Select normal Beagle dog (male and female half and half) for use, every group 6, select common compound preparation (2.5mg finasteride and the pure product of 2mg doxazosin are simply mixed) and controlled release compound preparation of the present invention (capsule 4) for use, carry out the per os gastric infusion, Dox and Fin carry out compound according to 2: 2.5 ratios.Dog is got 4.5mg/kg dosage, each treated animal respectively at administration after according to above-mentioned time point before taking medicine 0h and take medicine the back 0.25,0.50,1.0,1.5,2.0,2.5,3,4,6,8,10,12,24,36,48,60,72h, and get blood from vein, and centrifugal, isolate blood plasma.Get 1ml blood plasma and measure drug level as follows.And before taking medicine, measure blood pressure (mmHg) with the back 0.50,1.0,2.0,4,6,8,10 of taking medicine, 24h.
The accurate plasma sample 1ml that adds in centrifuge tube, inner mark solution (medroxyprogesterone acetate 2ug/ml) 20ul, the vortex mixing adds NaOH (0.1mol/L) solution 0.1ml, and the vortex mixing adds people's acetic acid ethyl ester 5ml, and vortex 3min is in the centrifugal 5min of 4000r/min.Divide and get organic facies 4ml in another centrifuge tube, in 50 ℃ of water-baths, dry up with nitrogen current.Residue dissolves with 100ul mobile phase, and the centrifugal 3min of 16000r/min draws supernatant and is transferred in the automatic sampler sample bottle, carries out LC-MS and analyzes.Blood drug level-time data is carried out the pharmacokinetics model and is differentiated, and calculate main pharmacokinetic parameters with DAS 2.1 pharmacy and statistical procedure pharmacokinetics resume module.
Result: blood drug level-time graph behind the different compound preparations of the oral finasteride doxazosin of Beagle dog
See Fig. 1; Pharmacokinetic parameters sees Table 5, and the monitoring of blood pressure value is seen Fig. 2.
The different compound preparation pharmacokinetic parameters of table 5
From Fig. 1 blood drug level-time graph and table 5 pharmacokinetic parameter as can be seen, after doxazosin is made slow releasing preparation, peak reaching time of blood concentration Tmax obviously prolongs, extend to 10h by 3h, reaching peak concentration Cmax obviously reduces, be reduced to 26.02 μ g/L by 58.01 μ g/L, eliminate half-life t/2 β in vivo and obviously accelerate, add near 15.487h by 21.965h; The following area AUC of curve obviously increases during medicine, is increased to 973.875ug/L*h by 703.57ug/L*h.Above result shows, controlled release compound preparation of the present invention, and doxazosin has tangible slow release effect in vivo.
From the blood pressure-time supervision curve (Fig. 2) of correspondence as can be seen, the normal contraction blood pressure of animal is descended rapidly, fall reaches 41%, causes abnormity burst hypotension, and 10h just begins later on progressively to recover normal; Descend and the blood pressure appearance is slight in 3h after the administration of compound slow-releasing preparation, the maximum fall of normal arterial pressure is 10.8% in the 10h, and whole medication process blood pressure near normal, is not seen hypotension substantially.Under the normal condition, blood pressure occur 10%～20% drop to diurnal blood pressure rhythm and pace of moving things normal type, can not produce tangible sense of discomfort, surpassing 20% be unusually, side reactions such as tangible discomfort can occur; The doxazosin result of slow release in vivo is described in the controlled release compound preparation of the present invention, has reduced because side effect such as the caused hypotension of doxazosin fast Absorption have kept better curative effect concentration to lower toxic concentration, and guaranteed stable curative effect.
Claims (7)
1. finasteride doxazosin controlled release capsule, be by the finasteride common pellets be loaded on capsulae vacuus after the doxazosin slow-release micro-pill mixes and form, the mass ratio of finasteride medicine and doxazosin medicine is 1: 0.625～2.5 in the capsule;
Described doxazosin slow-release micro-pill is by being the ball heart with the medicament pellet that contains the doxazosin medicine, is the slow-release micro-pill that coating material is prepared from the high molecular polymer that is dissolved in organic solvent; Described high molecular polymer is made up of by weight 1: 6～3: 1 ethyl cellulose and hydroxypropyl emthylcellulose;
Described finasteride common pellets is the ball heart with blank micropill, is mixed into coating material and makes with finasteride medicine, adhesive and organic solvent; Described adhesive is one or more the mixing in starch slurry, methylcellulose, hydroxypropyl cellulose, hypromellose, ethyl cellulose, polyvidone, gelatin and the Polyethylene Glycol etc.;
Described organic solvent is a methanol, ethanol, one or more aqueous solution of one or more mixing or its in isopropyl alcohol and the acetone.
2. finasteride doxazosin controlled release capsule according to claim 1 is characterized in that, the medicament pellet of described doxazosin slow-release micro-pill is mixed after wet granulation forms by medicine and filler, adhesive; Described medicine is doxazosin or its hydrochlorate, sulfate, mesylate or maleate.
3. finasteride doxazosin controlled release capsule according to claim 2 is characterized in that described medicine is a Carclura.
4. finasteride doxazosin controlled release capsule according to claim 2, it is characterized in that described filler is selected from one or more the mixing in lactose, mannitol, xylitol, sorbitol, Icing Sugar, dextrin, starch, pregelatinized Starch and the microcrystalline Cellulose.
5. finasteride doxazosin controlled release capsule according to claim 2, it is characterized in that described adhesive is selected from one or more the mixing in starch slurry, methylcellulose, hydroxypropyl cellulose, hypromellose, ethyl cellulose, polyvidone, gelatin and the Polyethylene Glycol.
6. according to the described finasteride doxazosin of claim 1 controlled release capsule, it is characterized in that, also comprise cosolvent in the described finasteride common pellets coating material, described cosolvent is one or more in sodium lauryl sulphate, tween, span, phospholipid, poloxalkol, tristerin and the sucrose fatty acid ester.
7. the application of the arbitrary described finasteride doxazosin controlled release capsule of claim 1 to 6 in preparation treatment hypertension and benign prostatic hyperplasia medicine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100002256A CN101485641B (en) | 2008-09-08 | 2009-01-12 | Finasteride and doxazosin compound controlled release capsule and use thereof |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810212265 | 2008-09-08 | ||
| CN200810212265.2 | 2008-09-08 | ||
| CN2009100002256A CN101485641B (en) | 2008-09-08 | 2009-01-12 | Finasteride and doxazosin compound controlled release capsule and use thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101485641A CN101485641A (en) | 2009-07-22 |
| CN101485641B true CN101485641B (en) | 2011-05-18 |
Family
ID=40888805
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009100002256A Expired - Fee Related CN101485641B (en) | 2008-09-08 | 2009-01-12 | Finasteride and doxazosin compound controlled release capsule and use thereof |
| CN2009100002275A Expired - Fee Related CN101485642B (en) | 2008-09-08 | 2009-01-12 | Method for preparing compound controlled release capsule for treating benign prostatic hyperplasia and the compound controlled release capsule |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009100002275A Expired - Fee Related CN101485642B (en) | 2008-09-08 | 2009-01-12 | Method for preparing compound controlled release capsule for treating benign prostatic hyperplasia and the compound controlled release capsule |
Country Status (1)
| Country | Link |
|---|---|
| CN (2) | CN101485641B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BRPI1103204A2 (en) * | 2011-06-03 | 2014-02-25 | Eurofarma Lab S A | PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF BENIGNA PROSTATIC HYPERPLASIA |
| CN105902553A (en) * | 2016-05-29 | 2016-08-31 | 山东仁和堂药业有限公司 | Compound finasteride tablets and preparation process thereof |
-
2009
- 2009-01-12 CN CN2009100002256A patent/CN101485641B/en not_active Expired - Fee Related
- 2009-01-12 CN CN2009100002275A patent/CN101485642B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN101485642B (en) | 2011-09-28 |
| CN101485641A (en) | 2009-07-22 |
| CN101485642A (en) | 2009-07-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1286451C (en) | Pharmaceutical formulation for efficient administration of apomorphine, 6aR-(-)-N-propyl-norepomorphine and their derivatives and pro-drugs thereof | |
| JP2012500230A (en) | Gastric retention drug release system and method and use thereof | |
| ES2427628T3 (en) | New compositions of 1- [2- (2,4-dimethyl-phenylsulfanyl) -phenyl] piperazine | |
| CN102526058A (en) | Anti-inflammatory analgesic medicinal composition containing lornoxicam and esomeprazole | |
| KR20150058271A (en) | Drug delivery systems and methods for treatment of bladder voiding dysfunction and other lower urinary tract disorders by using trospium | |
| AU2002309429A1 (en) | Pharmaceutical formulation for the efficient administration of apomorphine, 6aR-(-)-N-propyl-norapomorphine and their derivatives and pro-drugs thereof | |
| KR102466192B1 (en) | Combination therapy for the treatment of hepatocellular carcinoma | |
| KR20180008918A (en) | Combinations of beta3 adrenergic receptor agonists and muscarinic receptor antagonists for treating overactive bladder | |
| CN104902928A (en) | Co-micronisation product comprising ulipristal acetate | |
| CN101485641B (en) | Finasteride and doxazosin compound controlled release capsule and use thereof | |
| CN106822907B (en) | Two-phase release preparation containing racecadotril and preparation method thereof | |
| AU2009297562B2 (en) | Agent for preventing and/or treating functional gastrointestinal disorder | |
| CN101485659A (en) | Medicament composition of amlodipine and simvastatin as well as preparation method and application thereof | |
| WO2008052431A1 (en) | Use of composition comprising amlodipine in preparing medicaments for treating a lower urinary tract disorder | |
| CN104288106A (en) | Floating and sustained-release pellet, pharmaceutical composition containing pellet and preparation method of pharmaceutical composition | |
| CN108853043B (en) | Medicine for treating central diabetes insipidus and application thereof | |
| CN101590038B (en) | Oral sustained release hypotensive composition | |
| US20080131511A1 (en) | Pharmaceutical Composition for Treatment of Tear and Salivary Fluid Drying | |
| CN101007014B (en) | A compound puerarin preparation | |
| CN100540003C (en) | Pharmaceutical composition containing amlodipine and terazosin | |
| CN100391459C (en) | Doxazosin Mesylate Sustained Release Preparation | |
| CN119033716A (en) | Pharmaceutical composition containing eplerenone and tadalafil, and preparation method and application thereof | |
| CN104606144A (en) | Oral slow-release rotundine preparation | |
| CN120189513A (en) | Pharmaceutical composition and application thereof in preparing compound preparation | |
| CN101322703A (en) | Granisetron hydrochloride mouth spray |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20110518 Termination date: 20210112 |