CN101822833B - Medicament compound containing theophylines and statins - Google Patents
Medicament compound containing theophylines and statins Download PDFInfo
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- CN101822833B CN101822833B CN2010101626616A CN201010162661A CN101822833B CN 101822833 B CN101822833 B CN 101822833B CN 2010101626616 A CN2010101626616 A CN 2010101626616A CN 201010162661 A CN201010162661 A CN 201010162661A CN 101822833 B CN101822833 B CN 101822833B
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- aminophylline
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- rosuvastatin
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- statins
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Abstract
The invention relates to a medicament containing theophylines and statins. In the invention, the theophylines and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor form a compound to obtain excellent synergistic effect. The medicament compound greatly reduces the toxic and side effect of aminophylline when used alone, and the pharmacy security is improved.
Description
Technical field
The invention belongs to medical technical field, a kind of new pharmaceutical composition for the treatment of respiratory system disease of specific design.
Background technology
Asthma is a kind of common respiratory system disease, and sickness rate has trend of rising year by year.Pathogenesis of asthma mechanism is very complicated, and is not clear and definite fully as yet so far.Once think a kind of airway smooth muscle dysfunction disease the 1950's, the essence that has proposed asthma the beginning of the eighties is airway hyperreactivity.Thinking that at present asthma is the air flue chronic inflammation disease that various kinds of cell and cell component participate in, is feature with pulmonary's reversibility airflow obstruction, the gentle road of air flue mucosa inflammation high response.
Theophylline class medicine is applied to the history in year surplus in the of clinical existing 60 as a kind of suppressing panting calming medicine.Along with novel anti-asthmatic medicament is continually developed, this type of medicine treatment status clinically descends to some extent.But because its low price is still the important drugs for the treatment of bronchial asthma in a lot of places at present.Intravenous injection aminophylline antiasthmatic effect is fast, good effect, and is clinical commonly used.But safety range is little, and the effective plasma level concentration range is narrow, and therapeutic index is narrow, and (10～20mg/ml), the factor that influences its pharmacokinetics is more, and body internal diabetes removal rates individual difference is bigger.If improper use, Chang Yi causes serious toxic and side effects, even threat to life.Clinical medicine dose is difficult to grasp.
The mechanism of action of theophylline class medicine is not thoroughly illustrated as yet, but result of study recently thinks that the antiasthmatic effect of theophylline class medicine is main relevant with following mechanism.(1) activity of inhibition phosphodiesterase; (2) antagonism adenosine receptor; (3) concentration of reduction intracellular calcium; (4) release of stimulation of endogenous catecholamine; (5) suppress mastocyte and discharge inflammatory mediator; (6) antiinflammatory action.
Theophylline class medicine and derivant thereof have more than 300 kinds.Theophylline class medicine comparatively commonly used clinically at present comprises Slow-release Theophylline, aminophylline, diprophylline (diprophylline), brontyl, Oxtriphylline, Glynazan, tripropyl xanthine and doxofylline etc.
Statins is that 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor is an effective treatment means that reduces coronary heart disease risk, it can suppress HMG-CoA competitively, has the effect that better reduces low-density lipoprotein cholesterol (LDL-C) than other anticholesteremic agents.Find that in pharmacological research statins not only has good effect for reducing blood fat, but also has the thrombotic effect of anti-inflammatory response, stabilize plaque and inhibition, its mechanism of action comprises: increase nitricoxide synthase (nitric oxide syn2thase, NOS) expression, reduce endothelin-1 (endothelin-1, ET-A) and reactive oxygen intermediate (reactive oxygen species, ROS) synthetic; Reduce c reactive protein (C-reactive p rotein, level CRP); The growth and smooth muscle cell (the vascular smooth muscle cell that suppress macrophage, VSMC) migration and having increased since first statins mevastatin in 1976 comes out, statins was developed to for the 3rd generation, be usually used in clinical having at present: lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, newer Rosuvastatin and Pitavastatin in addition.Statins is evident in efficacy, side effect is little, has become the choice drug of transferring fat, and in clinical application research, has constantly found the purposes that it is new.
Thereby it is low to seek to develop a kind of cost, and good effect can suppress the medicine of asthmatic patient airway remodeling, fundamentally cures asthma, alleviates patient's misery and huge medical expense, and is significant.
Summary of the invention
The present invention is not obvious in order to solve the curative effect that exists in the existing theophylline class clinical drug treatment, the shortcoming that side effect is big, and provide a kind of good effect, long action time, side reaction bronchial asthma Therapeutic Method still less.
In order to realize purpose of the present invention, the inventor provides a kind of pharmaceutical composition that contains the treatment bronchial asthma of the following active component of effective dose:
1) theophylline class medicine;
2) 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor.Wherein the mass ratio of theophylline class medicine and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor is 1: 0.001-10.
In the above-mentioned pharmaceutical composition, described theophylline class medicine is one or more in aminophylline, brontyl, Oxtriphylline, Glynazan, diprophylline, tripropyl xanthine and the doxofylline, preferred aminophylline.
The HMG-CoA reductase inhibitor is one or more in lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, Rosuvastatin or the Pitavastatin, preferred Rosuvastatin.
The inventor is according to the result of clinical trial, and with the proper dosage proportioning, it is manufactured becomes the compound preparation that makes things convenient for the patient to take with theophylline class medicine and statins class medicine.
Pharmaceutical composition recited above, preferred aminophylline and Rosuvastatin weight ratio are 1: 0.01-1.
Compound preparation of the present invention, oral administration and intestinal external administration can both reach good effect.Several dosage forms such as the preferred double-layer tablet of oral administration, slow releasing tablet, dispersible tablet, oral cavity disintegration tablet, capsule, slow releasing capsule, soft capsule or drop pill wherein.
Above-mentioned described double-layer tablet, dispersible tablet, capsule also comprises adjuvant commonly used such as starch, L-HPC (low-substituted hydroxypropyl cellulose), magnesium stearate, microcrystalline Cellulose, PVP (polyvinylpyrrolidone), micropowder silica gel, carboxymethyl starch sodium, the tertiary butyl-4-hydroxy methyl phenyl ethers anisole, Pulvis Talci, vitamin E, the Henan gelling starch, carboxymethyl starch sodium, lactose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, crospolyvinylpyrrolidone, in the crosslinked carboxymethyl fecula sodium adjuvant one or more.
Above-mentioned described slow releasing tablet and slow releasing capsule are preferred following slow-release auxiliary material hexadecanol, octadecanol, HPMC-4M (hydroxypropyl emthylcellulose-4M), HPMC-15M (one or more in hydroxypropyl emthylcellulose-15M), glyceryl monostearate, ethyl cellulose, acrylic resin RS100, acrylic resin RL100, polyvinyl alcohol or the ethylene-vinyl acetate copolymer;
Preferred one or more in following adjuvant vitamin E, PEG400, PEG-3 oleate (Polyethylene Glycol-3 olein), glycerol, gelatin, propylene glycol or the PEG-60 glyceryl isostearate (Polyethylene Glycol-60 glyceryl isostearate) in the development of soft capsule;
Preferred one or more among following adjuvant PEG-1500 (Polyethylene Glycol-1500), PEG-2000 (Polyethylene Glycol-2000), PEG-4000 (Polyethylene Glycol-4000) or the PEG-6000 (Polyethylene Glycol-6000) in the development of drop pill.
Because asthma is a kind of chronic disease, needs long-term prescription.Asthmatic patient can produce repel psychology to taking medicine for a long time, for covering the bitterness of medicine, increases mouthfeel, and the inventor is also with the oral tablet coating, comprising: sweet tablet, film coating.Increased patient's compliance behind the coating greatly.
The intestinal external administration can be injection, injection powder pin, spray, aerosol, powder spray, buccal tablet.Its preparation method and pharmaceutic adjuvant are common method and adjuvant thereof.
The advantage that the present invention treats the pharmaceutical composition of bronchial asthma is embodied in the following aspects:
The compound recipe that shows theophylline class medicine and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor by animal experimental data has good synergism, show evident in efficacy through a large amount of zooperies, and reduced theophylline class amount of drug (the independent conventional amount used of using: aminophylline 0.3-0.6g/ days, the conventional amount used of using of aminophylline is 0.1-0.3g/ days in the pharmaceutical composition of the present invention, the conventional amount used of using of Rosuvastatin is 1-10mg/ days), side effect significantly reduces, and has increased the safety of medication.
Secondly, rapid-action, long action time; Animal experiment shows to have improved Rats survival rate and prolonged to draw to be breathed heavily incubation period.
The 3rd, because when forming immobilised compound, the dosage of each single medicine all has minimizing, thereby the incidence rate of drug side effect reduces; About medical expense, reduce when using separately owing to used drug dose ratio, and production and packing cost reduction, therefore, medical expense not only can not increase, and has decline on the contrary, and the benefit/expense ratio of feasible treatment is significantly improved.Therefore patient's treatment compliance increases greatly, and quality of life also will obviously improve.
The specific embodiment
For a better understanding of the present invention, below by description to preferred embodiment of the present invention, detailed explanation the present invention, but do not limit the present invention in any form.
The preparation of embodiment 1 tablet
Pravastatin 6g
Aminophylline 150g
Microcrystalline Cellulose 200g
Carboxymethyl starch sodium 10g
Magnesium stearate 4g
8% starch slurry is an amount of
Preparation technology: pravastatin, aminophylline and microcrystalline cellulose excipients, carboxymethyl starch sodium mix homogeneously, add an amount of starch slurry system soft material, right mistake 16 mesh sieves are granulated.Wet granular is 60 ℃ of dryings, and dried granule is crossed 16 mesh sieve granulate, sifts out the fine powder in the dry granular, with the magnesium stearate mixing, and then with dried granule mixing, tabletting, promptly.
The preparation of embodiment 2 tablets
Rosuvastatin 1.5g
Aminophylline 150g
Microcrystalline Cellulose 200g
Carboxymethyl starch sodium 10g
Magnesium stearate 4g
8% starch slurry is an amount of
Preparation technology: pravastatin, aminophylline and microcrystalline cellulose excipients, carboxymethyl starch sodium mix homogeneously, add an amount of starch slurry system soft material, right mistake 16 mesh sieves are granulated.Wet granular is 60 ℃ of dryings, and dried granule is crossed 16 mesh sieve granulate, sifts out the fine powder in the dry granular, with the magnesium stearate mixing, and then with dried granule mixing, tabletting, promptly.
The preparation of embodiment 3 tablets
Rosuvastatin 75g
Aminophylline 75g
Microcrystalline Cellulose 200g
Carboxymethyl starch sodium 10g
Magnesium stearate 4g
8% starch slurry is an amount of
Preparation technology: pravastatin, aminophylline and microcrystalline cellulose excipients, carboxymethyl starch sodium mix homogeneously, add an amount of starch slurry system soft material, right mistake 16 mesh sieves are granulated.Wet granular is 60 ℃ of dryings, and dried granule is crossed 16 mesh sieve granulate, sifts out the fine powder in the dry granular, with the magnesium stearate mixing, and then with dried granule mixing, tabletting, promptly.
The preparation of embodiment 4 bilayer tablets
A, simvastatin 3g
Hydroxypropyl emthylcellulose-4M 40g
Microcrystalline Cellulose 30g
The ethanol solution of 6%PVP is an amount of
Magnesium stearate 2g
Preparation technology: simvastatin is crossed 100 mesh sieves, hydroxypropyl cellulose-4M, microcrystalline Cellulose are crossed 80 mesh sieves, take by weighing the simvastatin of recipe quantity and hydroxypropyl cellulose-4M, microcrystalline Cellulose mix homogeneously, adding the 6%PVP ethanol solution granulates in right amount, 60 ℃ of dryings, 16 mesh sieves are put in order dried granule, add the magnesium stearate of recipe quantity in the dried granule.
B, diprophylline 300g
Lactose 20g
Sodium carboxymethyl cellulose 60g
95% alcoholic solution of 6%PVP is an amount of
Magnesium stearate 2g
Preparation technology: diprophylline is crossed 100 mesh sieves, sodium carboxymethyl cellulose, lactose are crossed 80 mesh sieves, take by weighing the diprophylline of recipe quantity and sodium carboxymethyl cellulose, lactose mix homogeneously, 95% alcoholic solution that adds 6%PVP is granulated in right amount, 60 ℃ of dryings, 16 mesh sieves are put in order dried granule, add the magnesium stearate of recipe quantity in the dried granule.
C, with above-mentioned a, two kinds of components of b adopt the bi-layer tablet press punching press promptly to get double-layer tablet.
The preparation of embodiment 5 bilayer tablets
A, brontyl 50g
Lactose 30g
Hydroxypropyl emthylcellulose-15M 20g
The 95% alcoholic solution 150g of 6%PVP
Rikemal B 200 2g
Preparation technology: brontyl is crossed 100 mesh sieves, lactose, hydroxypropyl emthylcellulose-15M cross 80 mesh sieves, take by weighing the brontyl of recipe quantity and lactose, hydroxypropyl emthylcellulose-15M mix homogeneously, 95% alcoholic solution that adds 6%PVP is granulated in right amount, 60 ℃ of dryings, 16 mesh sieves are put in order dried granule, add the Rikemal B 200 of recipe quantity in the dried granule.
B, atorvastatin 50g
Hydroxypropyl cellulose 30g
Dextrin 40g
The 95% alcoholic solution 100g of 6%PVP
Pulvis Talci 4g
Preparation technology: atorvastatin is crossed 100 mesh sieves, hydroxypropyl cellulose, dextrin are crossed 80 mesh sieves, take by weighing the atorvastatin of recipe quantity and hydroxypropyl cellulose, dextrin mix homogeneously, 95% alcoholic solution that adds 6%PVP is granulated in right amount, 60 ℃ of dryings, 16 mesh sieves are put in order dried granule, add the Pulvis Talci of recipe quantity in the dried granule.
C, with above-mentioned a, two kinds of components of b adopt the bi-layer tablet press punching press promptly to get double-layer tablet.
The preparation of embodiment 6 capsules
A, Glynazan 150g
Celphere 250g
7%PVP solution (solvent is 90% ethanol) 200g
Preparation technology: Glynazan is crossed 120 mesh sieves, and recipe quantity takes by weighing, and pours in the hopper.Drive granulating and coating machine (Taiwan unit becomes machinery plant), go into wind pressure 0.5bar, 30 ℃ of inlet air temperature, spray gun pressure (CYL) 3bar, atomizing pressure (CAP1) 0.8bar, pour celphere into, pelletize, blanking velocity 4rpm, the pump 12% of wriggling, rotary speed 145rpm, spray 7%PVP solution (solvent is 90% ethanol).Pelletize finishes, 50 ℃ of oven dry, discharging.
B, lovastatin 3g
Celphere 90g
7%PVP solution (solvent is 90% ethanol) 50g
Preparation technology: lovastatin is crossed 120 mesh sieves, and recipe quantity takes by weighing, and pours in the hopper.Drive the granulating and coating machine, go into wind pressure 0.5bar, 30 ℃ of inlet air temperature, CYL3bar, CAP10.8bar pours celphere into, pelletize, blanking velocity 4rpm, the pump 6% of wriggling, rotary speed 160rpm, spray 7%PVP solution (solvent is 90% ethanol).Pelletize finishes, 45 ℃ of oven dry, discharging.
C, the piller that a and b are made adopts hard capsule medicine filling machine to be respectively 150mg according to the weight that contains Glynazan and lovastatin in per two capsules and 3mg fills, and gets final product.
Embodiment 7 statinses and the medication combined use of theophylline class are to the pharmacodynamic experiment of experimental rat model of asthma
Experiment purpose:
Utilize the content of measuring the lung tissue of rats hydroxyproline, differential blood count, the swimming time of rat is observed speed and is sent out the inhibitory action of investigating the bronchial asthma that theophylline class medicine and statins compound recipe bring out ovalbumin the incubation period of phase symptoms of asthma and asthma.
Be subjected to the reagent thing:
The pharmaceutical composition of Rosuvastatin and aminophylline compound recipe.
Group is provided with:
Blank group, model group, Dexamethasone group, aminophylline group, Rosuvastatin group, aminophylline and the high, medium and low dosage group of Rosuvastatin compound recipe.
Gastric infusion dosage:
Dexamethasone 1.08mg/kg, aminophylline 23mg/kg, Rosuvastatin 0.46mg/kg, aminophylline and the high, medium and low dosage of Rosuvastatin compound recipe are respectively 46mg/kg aminophylline+0.92mg/kg Rosuvastatin, 23mg/kg aminophylline+0.46mg/kg Rosuvastatin, 11.5mg/kg aminophylline+0.23mg/kg Rosuvastatin.
Operating procedure:
The preparation of rat asthmatic model: 96 SD rats, body weight are 200～240g, are divided into 8 groups at random by body weight, 12 every group.Each group is 5% ovalbumin of lumbar injection prepared fresh (1ml/ only) respectively, and the normal control group is strengthened once after 5 days at intraperitoneal injection of saline 1ml.Atomizing sucks 1% ovalbumin normal saline after 10 days, once a day, 15min/ time, continuous 35 days.Each organizes gastric infusion respectively simultaneously, 10ml/kg, and continuous irrigation stomach 35 days, normal control group and model group give normal saline and irritate stomach, 10ml/kg, continuous irrigation stomach 35 days.
Rat speed is sent out bringing out of phase asthma: attack with 1% ovalbumin and the atomizing of 2% acetylcholine, bring out asthma, observe the incubation period and the symptoms of asthma of each group.
Observation index:
Draw and breathe heavily incubation period, be placed on each group rat in the hermetic container respectively, put into 4 at every turn, again with 1% egg protein solution spray, appoint animal to suck voluntarily, until asthma attack, record the dyspneic time occurs from being atomised to, carry out this 5th, 10,15 day of detecting respectively at excitation phase, gets the meansigma methods that detects for three times and be drawing of every rat and breathe heavily incubation period.
The variation of rat body weight and the comparison of survival rate before and after the test.
Measure body weight and lung body index, put to death animal, cut off skin of chest, open the thoracic cavity, peel off lung tissue, take by weighing the lung tissue weight in wet base, and calculate lung body index.Computational methods are as follows: body weight before body weight difference=test back body weight-test; Lung body index=lung weight/test back body weight (g) * 100%
Experimental result and statistical analysis:
1. aminophylline and Rosuvastatin compound recipe are attacked the preclinical influence in back to sensitization rat antigen
In the rat of test group, aminophylline and Rosuvastatin compound recipe high dose have significant coordinate repression to symptoms of asthma, have prolonged the incubation period of bronchial asthma morbidity greatly.Concrete experimental result sees Table 1.
Table 1 aminophylline and Rosuvastatin compound recipe are attacked the back to sensitization rat antigen and are dived
The influence of phase
*Compare P＜0.05 with model group,
※Compare P＜0.05 with Dexamethasone group,
﹠amp;Compare P＜0.05 with the aminophylline group
#Compare P＜0.05 with the Rosuvastatin group.
2. aminophylline and Rosuvastatin compound recipe are to the influence of the variation of rat body weight before and after the experiment
Respectively organize rat body weight no significant difference before experiment as seen from Table 2, after surplus raising in January, body weight all has growth in various degree, wherein increases obviously with normal control group and aminophylline and Rosuvastatin compound recipe group especially, and there were significant differences (p＜0.05) than other several groups.
Table 2 aminophylline and Rosuvastatin compound recipe are to the influence (unit: g) of the variation of rat body weight before and after the experiment
Annotate: respectively organize body weight there was no significant difference (p＞0.05) before the experiment, respectively organizing body weight after the experiment has significant difference (p＜0.05), and respectively organizing the body weight difference before and after the experiment has significant difference (p＜0.05).
*Compared significant difference with the normal control group, △ has compared significant difference with the asthmatic model group, ▲ compared significant difference ， ﹠amp with Dexamethasone group; Compared significant difference with aminophylline group group, ◆ compared significant difference with each group of compound recipe.
3. aminophylline and Rosuvastatin compound recipe are to survival of rats rate before and after the experiment relatively
Asthmatic model group and aminophylline group respectively have a rat to cause death in excitation process because of dyspnea; Rosuvastatin group and Dexamethasone group respectively have two rats tangible loss of appetite to occur in the experiment later stage, lose weight with lower jaw part ulcer, and in the unexpected death in the 5th day that excitation experiment is carried out, dissection turns out to be the lung tissue pyogenic infection and causes death; Normal control group and compound recipe group Rats survival rate are 100%.See table 3 for details.
Table 3 survival of rats rate
4. aminophylline and Rosuvastatin compound recipe are to Mus lung body index before and after the experiment relatively
As can be seen from Table 4: compare with the normal control group, the lung body index of asthmatic model group is obviously greater than the former, and prompting asthma attack phase lungs weight in wet base more normally increases, and exists significantly pulmonary edema; Compare with the asthmatic model group, the lung body index of each medication group all is significantly less than the former, and Dexamethasone group and aminophylline group are compared lung body index there was no significant difference for two groups, but in control asthma, all can effectively alleviate pulmonary edema; Each group of compound recipe is compared for two groups with Dexamethasone group and aminophylline group, and lung body index is significantly less than the latter, and the effect that each group of prompting compound recipe alleviates pulmonary edema obviously is better than the latter.
Table 4 induced lung body index
Annotate: respectively organizing lung body index after the experiment has significant difference (p＜0.05),
*Compared significant difference with the normal control group, △ has compared significant difference with the asthmatic model group, ▲ compared significant difference with Dexamethasone group or aminophylline group, ◆ compared significant difference with the compound recipe group, ● compared significant difference with the Rosuvastatin group.
Aminophylline of in embodiment 7, being set forth and statins compound recipe, aminophylline can be by brontyl, Oxtriphylline, Glynazan, multiple theophylline class medicines such as tripropyl xanthine and doxofylline replace, statins also can be lovastatin, simvastatin, pravastatin, Pitavastatin or atorvastatin, can obtain good concertedness effect equally, and they all have good therapeutic effect to experimental rat model of asthma or chronic obstructive pulmonary disease rat.
Claims (2)
1. the application of pharmaceutical composition in preparation treatment bronchial asthma medicine is characterized in that containing the following active component of effective dose:
1) theophylline class medicine;
2) 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor;
Described theophylline class medicine is an aminophylline, and described HMG-CoA reductase inhibitor is a Rosuvastatin, and described aminophylline and Rosuvastatin weight ratio are 1: 0.02.
2. application as claimed in claim 1 is characterized in that described pharmaceutical composition is oral formulations or intestinal external administration preparation, and described oral formulations is double-layer tablet, slow releasing tablet, dispersible tablet, oral cavity disintegration tablet, capsule or drop pill; Described intestinal external administration preparation is injection, spray, aerosol, powder spray or buccal tablet.
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| 俞森洋.《茶碱类药物》.《现代呼吸治疗学》.科学技术文献出版,2003,第1117页及第1121－1124页. * |
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