CN102824343A - Solid pharmaceutical composition containing benzimidazole derivative - Google Patents
Solid pharmaceutical composition containing benzimidazole derivative Download PDFInfo
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- CN102824343A CN102824343A CN2011101620224A CN201110162022A CN102824343A CN 102824343 A CN102824343 A CN 102824343A CN 2011101620224 A CN2011101620224 A CN 2011101620224A CN 201110162022 A CN201110162022 A CN 201110162022A CN 102824343 A CN102824343 A CN 102824343A
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Abstract
The invention relates to a benzimidazole derivative containing solid pharmaceutical composition for adjusting drug dissolution and/or raising stability, a preparation method thereof, and an application in preparation of drugs for treating circulatory diseases.
Description
Technical field
The present invention relates to solid composite medicament that improves drug dissolution and/or stability and preparation method thereof, and the purposes that is used for preparing antihypertensive drug.
Background technology
Blood circulation diseases, satisfactory again angiopathy is meant the disease of heart, blood vessel and the sanguimotor neural mechanism of adjusting.See at most with heart disease, hypertension.Blood circulation diseases is a commonly encountered diseases, and especially proportion is very big in internal disease.The normal protracted course of disease of heart disease, influence life and work, case fatality rate is also high, and along with the control of infectious disease, cardiovascular disease shared status in human mortality's reason is more outstanding.Blood circulation diseases can be divided into congenital and posteriority two big classes.Congenital cardiovascular diseases is that cardiovascular injuries is in period of fetus due to the abnormal development.Acquired cardiovascular disease is like coronary atherosclerotic heart disease, rheumatic heart disease, hypertension and hypertensive heart disease.
Angiotensin II causes vasoconstriction and the blood pressure that raises through the angiotensin-ii receptor on the cell membrane.Thus, angiotensin ii receptor antagonist can be the active drug of treatment blood circulation diseases such as hypertension etc.RAS is participated in control systemic blood pressure, body fluid volume, electrolyte balance etc. with RAAS in homeostasis.Based on Angiotensin II with effective vasoconstriction effect through being positioned at the fact of the angiotensin-ii receptor rising blood pressure on the cell membrane; Disclosed the relation between renin angiotensin and the hypertension at present; Thus, the Hangzhoupro short of money agent of Angiotensin II has been used to treat the hypertension that angiotensin brings out.Up to now; The administration of clinical administered through oral is already used has the active medicine in Angiotensin II Hangzhoupro short of money; As the preferred chemical constitution of strong expression Angiotensin II antagonistic activity, known have the structure of acidic group such as tetrazole radical, carboxyl etc. on the xenyl side chain, used (Ruth R.Wexler etc. such as medicine with such architectural feature such as losartan, Candesartan Cilexetil, Olmesartan medoxomil clinically; Journal of Medicinal Chemistry; Vol.39, p.625 (1996), JP-A-4-364171, JP-A-5-78328 etc.).JP-A-5-271228 has described wherein that the acidic group on the xenyl side chain is a 5-oxo-4,5-dihydro-1,2,4-uh two tell-chemical compound of 3-base, it has shown long-term and intensive Angiotensin II antagonistic activity and antihypertensive activity behind the oral administration.In addition, W003/047573 has described the benzo miaow described in the JP-A-5-271228 and tells derivant and except the angiotensin-ii receptor antagonistic activity, also have the insulin sensitizing agent activity.
A Qishatan (English name Azilsartan) is a kind of angiotensin ii receptor antagonist medicine that is in the treatment vascular hypertension in the research and development; Through of the vasoconstrictive effect that combine block Angiotensin II of selective exclusion Angiotensin II with vascular smooth muscle AT1 receptor; Be used to treat vascular hypertension, also be at present unique clinical angiotensin ii receptor antagonist in latter stage (husky smooth type) medicine that is in more.
Drug products need have effectiveness, safety and stability.The effectiveness of drug products, safety and stability; Not only closely related with safety with the effectiveness of active ingredient itself; And receive from preparation medicament The properties, all be very important such as the influence of the stability of active ingredient in preparation, the dissolution characteristic of medicine from preparation etc.For example, even preparation satisfies the quality of certain level after preparation just, if the active ingredient in preparation decomposes in time, effectiveness and the safety said preparation according to drug products is problematic so.For the dissolution characteristic of medicine from preparation, when medicine when stripping is too slow from preparation, this medicine may not reach valid density and may not realize desired effect in blood.When the medicine stripping is too fast, possibly cause the interior blood drug level of body to increase sharply, the risk of side effect also possibly increase.
For the method that improves the stability of active ingredient in preparation; It is known adding the pH regulator agent; Only disclose employing fumaric acid and sodium hydroxide among the patent documentation CN101677961A, or monosodium fumarate uses simultaneously active component to be A Qishatan ester potassium salt as the method for stabilizing agent.Simultaneously, this patent documentation is claimed the dissolution that has improved medicine, but its specific embodiment that provides is the dissolution experiment under high pH (pH 6.8) condition, fails to prove its stripping advantage in the human body environment.Measure the dissolution of pharmaceutical composition under low pH condition that this patent application provides, it is very limited to know that it improves effect.
CN101528262A discloses the solid composite medicament that comprises effective ingredient, low melting point grease-like material and low viscosity adhesive, and improves the method for effective ingredient by stripping in the solid composite.Wherein, the drug dissolution matter that comprises the solid dosage forms of low melting point grease-like material improves, but its specific embodiment that provides is the dissolution experiment under high pH (pH 6.8) condition, fails to prove its stripping advantage in the human body environment.Measure the dissolution of pharmaceutical composition under low pH condition that this patent application provides, it is very limited to know that it improves effect.
Summary of the invention
The object of the present invention is to provide a kind of solid composite medicament, it comprises the chemical compound of formula (I) expression, the dissolution and/or the stability that it is characterized in that regulating medicine,
Wherein,
R
1Be the monocycle nitrogen heterocycle, this heterocyclic radical has can be by the hydrogen atom of deprotonation, R
2Be carboxyl, and R
3Be low alkyl group, preferred formula (I) chemical compound is A Qishatan;
Said dissolution regulated quantity is 5%～100%, preferred 10%～90%.Said regulated quantity is recruitment or reduction amount, and said dissolution is the dissolution in pH1～10 dissolution mediums, and preferred pH is 4～8.
Wherein comprise at least a non-active ingredient and regulate dissolution; Described non-active ingredient is selected from ethyl cellulose, cellulose acetate, HPMCP, cellulose ethanoate phthalic acid ester, carboxymethylethylcellulose, EUDRAGIT L100-55, ethyl acrylate-methyl methacrylate-methacrylic acid trimethyl ammonium ethyl ester chloride copolymer, methyl methacrylate-ethyl acrylate copolymer, methacrylic acid-acrylic acid methyl ester .-methylmethacrylate copolymer, hydroxypropyl cellulose acetas succinate and/or polyvinyl acetate phthalic acid ester, and said non-active ingredient can be present in the surface of pharmaceutical composition or be dispersed in pharmaceutical composition inside.
A preferred version of the present invention is that the particle diameter d (0.5) of chemical compound after micronization processes of formula (I) expression is less than or equal to 200 μ m, is preferably d (0.5) and is less than or equal to 50 μ m, and more preferably d (0.5) is less than or equal to 5 μ m; D (0.9) is less than or equal to 300 μ m, is preferably d (0.9) and is less than or equal to 50 μ m, and more preferably d (0.9) is less than or equal to 10 μ m.
A preferred version of the present invention is that the particle diameter d (0.5) of chemical compound after the nanorize technical finesse of formula (I) expression is less than or equal to 1 μ m, is preferably d (0.5) and is less than or equal to 500nm; D (0.9) is less than or equal to 1 μ m, is preferably d (0.9) and is less than or equal to 700nm.
Another preferred version of the present invention is the interior clathrate that forms of void structure that formula (I) chemical compound is wrapped up in cyclodextrin and derivant thereof; Wherein said cyclodextrin and derivant thereof are selected from alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, 2; 6 dimethyl-s, 2; 6 trimethyl beta-schardinger dextrin-s, monosaccharide groups beta-schardinger dextrin-, disaccharidase base beta-schardinger dextrin-, maltotriose glycosyl beta-schardinger dextrin-, two monosaccharide groups beta-schardinger dextrin-s, disaccharide base beta-schardinger dextrin-, 2; 3; 6-trimethoxy beta-schardinger dextrin-, 2-oxygen-(2-hydroxypropyl)-beta-schardinger dextrin-and/or HP-are preferably beta-schardinger dextrin-and/or HP-.Further, the chemical compound and the cyclodextrin weight ratio of formula (I) expression are 1: 20～1: 2; Be preferably 1: 10～1: 4; More preferably 1: 8～1: 4.
Another preferred version of the present invention is that this solid composite medicament comprises cosolvent and/or stabilizing agent and is selected from sodium lauryl sulphate, sarcosyl, poloxamer, polysorbas20, Tween 80, span, polyoxyethylene hydrogenated Oleum Ricini, Oleum Ricini and gathers hydrocarbon oxygen ester, sodium carbonate, sodium bicarbonate, calcium hydrogen phosphate, magnesium carbonate, magnesium hydroxide, maleic acid and sodium hydroxide, fumaric acid and sodium hydroxide, citric acid and sodium hydroxide, tartaric acid and sodium hydroxide, maleic acid list sodium, monosodium fumarate, sodium tartrate, citric acid list sodium, propyl gallate, ethylenediaminetetraacetic acid, disodiumedetate, Butylated hydroxyanisole, sodium sulfite, sodium sulfite, sodium pyrosulfite and/or ascorbic acid, preferred sodium carbonate, sodium bicarbonate, maleic acid and sodium hydroxide, fumaric acid and sodium hydroxide, citric acid and sodium hydroxide, maleic acid list sodium, monosodium fumarate and/or citric acid list sodium.Further, said cosolvent and/or stabilizing agent addition are the 0.01%-20% of solid composite medicament gross weight, preferred 0.01%-10%.
Another object of the present invention is to a kind of method for preparing described pharmaceutical composition, it is characterized in that chemical compound with formula (I) expression disperses and/or is embedded in the compositions in the each component, forms the method for solid composite.
Another object of the present invention is to provide the purposes of described pharmaceutical composition in the medicine of preparation treatment blood circulation diseases, the preferred hypertension of said disease.
Description of drawings
Fig. 1: raw material particle size is to the influence of preparation stripping behavior
Fig. 2: clathrate is to the influence of preparation stripping behavior
Fig. 3: cosolvent is to the influence of preparation stripping behavior
The contrast of Fig. 4: embodiment 3 and Comparative Examples 2 stripping behaviors
The specific embodiment
To adopt comminution by gas stream to handle (d (0.5)≤2.61 μ m; D (0.9)≤5.24 μ m) A Qishatan (64g); With mannitol (200g), microcrystalline Cellulose (30g), cross-linking sodium carboxymethyl cellulose (16g) mix homogeneously, adopting 5% hydroxy propyl cellulose aqueous solution is binding agent, granulates; Fluid bed drying, 1.0mm screen cloth granulate.Behind granulate, add magnesium stearate 3.3g, mix homogeneously in the granule.The gained mixture obtains having the plain sheet of following composition through 10.0mm drift tabletting.
The composition of preparation (every 159.63mg)
Embodiment 2
With A Qishatan (64g), with beta-schardinger dextrin-(384g) mix homogeneously, add 768g water, grind 6h to semi-solid, 40 ℃ of drying under reduced pressure get solid.With suitable quantity of water, methanol wash gained solid, drying under reduced pressure obtains clathrate.Get clathrate an amount of (containing A Qishatan 32g), with mannitol (100g), microcrystalline Cellulose (15g), cross-linking sodium carboxymethyl cellulose (8g) mix homogeneously, adopting 5% hydroxy propyl cellulose aqueous solution is binding agent, granulates fluid bed drying, 1.0mm screen cloth granulate.Behind granulate, add magnesium stearate 3.3g, mix homogeneously in the granule.The gained mixture obtains having the plain sheet of following composition through 10.0mm drift tabletting.
The composition of preparation (every 345.5mg)
Embodiment 3
With A Qishatan (64g), with mannitol (90g), microcrystalline Cellulose (90g), cross-linking sodium carboxymethyl cellulose (15g), sodium carbonate (40g) mix homogeneously, adopting 5% hydroxy propyl cellulose aqueous solution is binding agent, granulates fluid bed drying, 1.0mm screen cloth granulate.Behind granulate, add magnesium stearate 3g, mix homogeneously in the granule.The gained mixture obtains having the plain sheet of following composition through 7.0mm drift tabletting.
The composition of preparation (every 156mg)
Embodiment 4
With A Qishatan (64g),, add magnesium stearate 3g, mix homogeneously with mannitol (90g), microcrystalline Cellulose (90g), cross-linking sodium carboxymethyl cellulose (15g), sodium carbonate (40g) mix homogeneously.The gained mixture obtains having the plain sheet of following composition through 7.0mm drift tabletting.
The composition of preparation (every 151mg)
With A Qishatan (64g); With mannitol (90g), microcrystalline Cellulose (90g), cross-linking sodium carboxymethyl cellulose (15g), sodium lauryl sulphate (40g) mix homogeneously, adopting 5% hydroxy propyl cellulose aqueous solution is binding agent, granulates; Fluid bed drying, 1.0mm screen cloth granulate.Behind granulate, add magnesium stearate 3g, mix homogeneously in the granule.The gained mixture obtains having the plain sheet of following composition through 7.0mm drift tabletting.
The composition of preparation (every 155mg)
Embodiment 6
With A Qishatan (64g),, adopt 5% hydroxy propyl cellulose aqueous solution (to contain 2.5% citric acid with mannitol (90g), microcrystalline Cellulose (90g), cross-linking sodium carboxymethyl cellulose (15g) mix homogeneously; 0.83% sodium hydroxide) is binding agent; Granulate fluid bed drying, 1.0mm screen cloth granulate.Behind granulate, add magnesium stearate 3g, mix homogeneously in the granule.The gained mixture obtains having the plain sheet of following composition through 7.0mm drift tabletting.
The composition of preparation (every 158.5mg)
Embodiment 7
With A Qishatan (64g),, adopt 5% hydroxy propyl cellulose aqueous solution (to contain 2.5% maleic acid with mannitol (90g), microcrystalline Cellulose (90g), cross-linking sodium carboxymethyl cellulose (15g) mix homogeneously; 0.83% sodium hydroxide) is binding agent; Granulate fluid bed drying, 1.0mm screen cloth granulate.Behind granulate, add magnesium stearate 3g, mix homogeneously in the granule.The gained mixture obtains having the plain sheet of following composition through 7.0mm drift tabletting.
The composition of preparation (every 158.5mg)
Embodiment 8
With A Qishatan (64g),, adopt 5% hydroxy propyl cellulose aqueous solution (to contain 2.5% fumaric acid with mannitol (90g), microcrystalline Cellulose (90g), cross-linking sodium carboxymethyl cellulose (15g) mix homogeneously; 0.83% sodium hydroxide) is binding agent; Granulate fluid bed drying, 1.0mm screen cloth granulate.Behind granulate, add magnesium stearate 3g, mix homogeneously in the granule.The gained mixture obtains having the plain sheet of following composition through 7.0mm drift tabletting.
The composition of preparation (every 158.5mg)
Embodiment 9
With A Qishatan (64g),, adopt 5% hydroxy propyl cellulose aqueous solution (to contain 2.5% fumaric acid with mannitol (90g), microcrystalline Cellulose (90g), cross-linking sodium carboxymethyl cellulose (15g) mix homogeneously; 0.83% sodium hydroxide) is binding agent; Granulate fluid bed drying, 1.0mm screen cloth granulate.Behind granulate, add magnesium stearate 3g, mix homogeneously in the granule.The gained mixture obtains plain sheet through 9.0mm drift tabletting.EUDRAGIT S100 A type and EUDRAGIT S100 Type B are dissolved in 95% ethanol, constantly are stirred to dissolving fully, slowly add, continue to be stirred to dissolving, subsequent use.Get Pulvis Talci, triethyl citrate is added to the residue ethanol water, mixes the back with homogenize 10 minutes, slowly joins then in the copolymer solution, continues stirring 30 minutes.Plain sheet placed carry out coating in the high-efficiency coating pot, obtain the coated tablet of following composition.
The composition of label (every 317mg)
The composition of coatings (every 332.9mg)
With A Qishatan (64g),, adopt 5% hydroxy propyl cellulose aqueous solution (to contain 2.5% fumaric acid with mannitol (90g), microcrystalline Cellulose (90g), cross-linking sodium carboxymethyl cellulose (15g) mix homogeneously; 0.83% sodium hydroxide) is binding agent; Granulate fluid bed drying, 1.0mm screen cloth granulate.Behind granulate, add magnesium stearate 3g, mix homogeneously in the granule.The gained mixture obtains plain sheet through 10.0mm drift tabletting.EUDRAGIT S100 A type and EUDRAGIT S100 Type B are dissolved in 95% ethanol, constantly are stirred to dissolving fully, slowly add, continue to be stirred to dissolving, subsequent use.Get Pulvis Talci, triethyl citrate is added to the residue ethanol water, mixes the back with homogenize 10 minutes, slowly joins then in the copolymer solution, continues stirring 30 minutes.Plain sheet placed carry out coating in the high-efficiency coating pot, obtain the coated tablet of following composition.
The composition of label (every 317mg)
The composition of coatings (every 320.2mg)
Embodiment 11
With A Qishatan (64g), EUDRAGIT S100 A type (18.65g), EUDRAGIT S100 Type B (55.95g), magnesium stearate (1.4g) mix homogeneously, the gained mixture obtains having the plain sheet of following composition through 7.0mm drift tabletting.
The composition of preparation (every 140mg)
Embodiment 12
With A Qishatan (64g), calcium hydrogen phosphate (67.6g), pregelatinized Starch (7g), magnesium stearate (1.4g) mix homogeneously, the gained mixture obtains having the plain sheet of following composition through 7.0mm drift tabletting.
The composition of preparation (every 140mg)
Embodiment 13
With A Qishatan (64g), with hydroxypropyl-beta-schardinger dextrin-(256g) mix homogeneously, add 512g water, grind 6h to semi-solid, 40 ℃ of drying under reduced pressure get solid.With suitable quantity of water, methanol wash gained solid, drying under reduced pressure obtains clathrate.Get clathrate an amount of (containing A Qishatan 32g), with mannitol (100g), microcrystalline Cellulose (15g), cross-linking sodium carboxymethyl cellulose (8g) mix homogeneously, adopting 5% hydroxy propyl cellulose aqueous solution is binding agent, granulates fluid bed drying, 1.0mm screen cloth granulate.Behind granulate, add magnesium stearate 3.3g, mix homogeneously in the granule.The gained mixture obtains having the plain sheet of following composition through 10.0mm drift tabletting.
The composition of preparation (every 290mg)
Embodiment 14
To adopt nanorize to handle (d (0.5)≤290nm; The A Qishatan (64g) of d (0.9)≤520nm); With mannitol (200g), microcrystalline Cellulose (30g), cross-linking sodium carboxymethyl cellulose (16g) mix homogeneously, adopting 5% hydroxy propyl cellulose aqueous solution is binding agent, granulates; Fluid bed drying, 1.0mm screen cloth granulate.Behind granulate, add magnesium stearate 3.3g, mix homogeneously in the granule.The gained mixture obtains having the plain sheet of following composition through 10.0mm drift tabletting.
The composition of preparation (every 159.6mg)
Comparative Examples 1
With the A Qishatan that adopted 60 mesh sieves (64g), with mannitol (200g), microcrystalline Cellulose (30g), cross-linking sodium carboxymethyl cellulose (16g) mix homogeneously, adopting the hydroxy propyl cellulose aqueous solution is binding agent, granulates fluid bed drying, 1.0mm screen cloth granulate.Behind granulate, add magnesium stearate 3.3g, mix homogeneously in the granule.The gained mixture obtains having the plain sheet of following composition through 7.0mm drift tabletting.
The composition of preparation (every 159.6mg)
Comparative Examples 2
Experimental example 1
Measure the approximate solubility of A Qishatan in different medium, as follows.
With reference to 2010 editions approximate solubility assay methods of Chinese Pharmacopoeia: in quantitative each medium, add excessive A Qishatan, powerful jolting in per 5 minutes is 30 seconds under 25 ℃ of conditions.After 30 minutes, with 0.45 μ m filtering with microporous membrane, HPLC measures A Qishatan concentration in the subsequent filtrate.
The approximate solubility of table 1 A Qishatan in different medium
| Medium | Approximate solubility (μ g/ml) |
| 0.1M hydrochloric acid | 4.92 |
| The pH4.5 acetate buffer | 3.7 |
| PH4.5 acetate buffer+1% sodium lauryl sulphate | 54.8 |
| PH4.5 acetate buffer+5% sodium lauryl sulphate | 173.0 |
| Water | 20.0 |
| The pH5.8 acetate buffer | 79.02 |
| The pH6.0 acetate buffer | 126.8 |
| The pH6.2 acetate buffer | 263.8 |
| The pH6.8 phosphate buffer | 832.73 |
Can be known that by The above results pH4.5 acetate buffer+5% sodium lauryl sulphate can satisfy the sink conditions of the following specification preparation of 37mg, the pH6.8 phosphate buffer then can satisfy the sink conditions of the following specification preparation of 250mg.
Experimental example 2
The medicine stripping behavior evaluation condition of the plain sheet that obtains in embodiment 1 and the Comparative Examples 1 is following:
Dissolution medium: pH4.5 acetate buffer+5% sodium lauryl sulphate, pH6.8 phosphate buffer
Dissolution medium volume: 900ml
Dissolving-out method: with reference to 2010 editions dissolution determination methods of Chinese Pharmacopoeia, select dissolution determination second method (being the oar method), rotating speed is 50rpm.
Adopt the HPLC method to measure stripping curve and see Fig. 1.
As shown in Figure 1, reduce can significantly improve the stripping behavior of A Qishatan under low pH condition (pH4.5) behind the raw material particle size.
Experimental example 3
The medicine stripping behavior evaluation condition of the plain sheet that obtains in embodiment 2 and the Comparative Examples 1 is following:
Dissolution medium: pH4.5 acetate buffer+5% sodium lauryl sulphate
Dissolution medium volume: 900ml
Dissolving-out method: with reference to 2010 editions dissolution determination methods of Chinese Pharmacopoeia, select dissolution determination second method (being the oar method), rotating speed is 50rpm.
Adopt the HPLC method to measure stripping curve and see Fig. 2.
As shown in Figure 2, adopting beta-schardinger dextrin-is significantly to improve A Qishatan stripping behavior with this understanding behind the enclose material preparation clathrate.
Experimental example 4
The plain sheet that obtains in embodiment 2 and the Comparative Examples 1 is carried out damp-prrof packing, place respectively under 40 ℃, the 60 ℃ conditions, respectively at sampling in 7 days, 14 days, through the recruitment of HPLC method mensuration catabolite, the result saw table 2.
Table 2 clathrate is to the influence of preparation stability
The result shows that adopting beta-schardinger dextrin-is can improve A Qishatan stability behind the enclose material preparation clathrate, suppresses degraded.
Experimental example 5
The medicine stripping behavior evaluation condition of the plain sheet that obtains in embodiment 3 and the Comparative Examples 1 is following:
Dissolution medium: pH4.5 acetate buffer, pH4.5 acetate buffer+5% sodium lauryl sulphate
Dissolution medium volume: 900ml
Dissolving-out method: with reference to 2010 editions dissolution determination methods of Chinese Pharmacopoeia, select dissolution determination second method (being the oar method), rotating speed is 50rpm.
Adopt the HPLC method to measure stripping curve and see Fig. 3.
As shown in Figure 3, adopt sodium carbonate can significantly improve A Qishatan stripping behavior with this understanding as cosolvent.
Experimental example 6
The plain sheet that obtains in embodiment 7 and the Comparative Examples 1 is carried out damp-prrof packing, place respectively under 40 ℃, the 60 ℃ conditions, respectively at sampling in 7 days, 14 days, through the recruitment of HPLC method mensuration catabolite, the result saw table 3.
Table 3 stabilizing agent is to the influence of preparation stability
The result shows that adopting maleic acid and sodium hydroxide is that stabilizing agent can significantly improve A Qishatan stability.
Experimental example 7
The plain sheet that obtains in embodiment 6,8 and the Comparative Examples 1 is carried out damp-prrof packing, place respectively under 40 ℃, the 60 ℃ conditions, respectively at sampling in 7 days, through the recruitment of HPLC method mensuration catabolite, the result saw table 4.
Table 4 stabilizing agent is to the influence of preparation stability
The result shows that adopting fumaric acid or citric acid and sodium hydroxide is that stabilizing agent can improve A Qishatan stability.
Experimental example 8
The medicine stripping behavior evaluation condition of the plain sheet that obtains in embodiment 3, Comparative Examples 1 and the Comparative Examples 2 is following:
Dissolution medium: pH4.5 acetate buffer+5% sodium lauryl sulphate, pH6.8 phosphate buffer
Dissolution medium volume: 900ml
Dissolving-out method: with reference to 2010 editions dissolution determination methods of Chinese Pharmacopoeia, select dissolution determination second method (being the oar method), rotating speed is 50rpm.
Adopt the HPLC method to measure stripping curve and see Fig. 4.
As shown in Figure 4, Comparative Examples 2 technical schemes are all suitable than Comparative Examples 1 stripping behavior under high pH (pH6.8) condition, under low pH (pH4.5) condition to improve stripping limited, explain that the adding polyethylene glycol 6000 is not remarkable as the cosolvent effect.Embodiment 3 adopts sodium carbonate suitable than Comparative Examples 2 stripping behavior under high pH (pH6.8) condition as cosolvent, better improve under low pH (pH4.5) condition A Qishatan stripping, have beyond thought effect.
Claims (19)
1. solid composite medicament, the chemical compound that it comprises formula (I) expression is characterized in that regulating the dissolution of medicine and/or improves stability.
Wherein, R
1Be the monocycle nitrogen heterocycle, this heterocyclic radical has can be by the hydrogen atom of deprotonation, R
2Be carboxyl, and R
3Be C
1-10Low alkyl group.
2. solid composite medicament according to claim 1, wherein said dissolution regulated quantity is 5%-100%, is preferably 10%-90%.
3. according to the said solid composite medicament of claim 2, wherein said leaching condition is pH1～10, preferred pH4～8.
4. according to the said solid composite medicament of claim 1, wherein comprise at least a non-active ingredient and regulate dissolution.
5. according to the said solid composite medicament of claim 4, wherein said non-active ingredient is selected from ethyl cellulose, cellulose acetate, HPMCP, cellulose ethanoate phthalic acid ester, carboxymethylethylcellulose, EUDRAGIT L100-55, ethyl acrylate-methyl methacrylate-methacrylic acid trimethyl ammonium ethyl ester chloride copolymer, methyl methacrylate-ethyl acrylate copolymer, methacrylic acid-acrylic acid methyl ester .-methylmethacrylate copolymer, hydroxypropyl cellulose acetas succinate and/or polyvinyl acetate phthalic acid ester.
6. solid composite medicament according to claim 5, wherein said non-active ingredient can be present in the surface of pharmaceutical composition or be dispersed in pharmaceutical composition inside.
7. solid composite medicament according to claim 1, wherein said formula (I) chemical compound is A Qishatan.
8. according to any described solid composite medicament of claim 1～7, the particle diameter d (0.5) of the chemical compound of its Chinese style (I) expression is less than or equal to 200 μ m, is preferably d (0.5) and is less than or equal to 50 μ m, and more preferably d (0.5) is less than or equal to 5 μ m.
9. according to any described solid composite medicament of claim 1～7, the particle diameter d (0.9) of the chemical compound of its Chinese style (I) expression is less than or equal to 300 μ m, is preferably d (0.9) and is less than or equal to 50 μ m, and more preferably d (0.9) is less than or equal to 10 μ m.
10. according to any described solid composite medicament of claim 1～7, the chemical compound particle diameter d (0.5) of its Chinese style (I) expression is less than or equal to 1 μ m, is preferably d (0.5) and is less than or equal to 500nm.
11. according to any described solid composite medicament of claim 1～7, the chemical compound particle diameter d (0.9) of its Chinese style (I) expression is less than or equal to 1 μ m, is preferably d (0.9) and is less than or equal to 700nm.
12. according to any described solid composite medicament of claim 1～7, the chemical compound of its Chinese style (I) expression is wrapped up in the interior clathrate that forms of void structure of cyclodextrin and derivant thereof.
13. solid composite medicament according to claim 12, wherein said cyclodextrin and derivant thereof are selected from alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, 2,6 two.Methyl beta-schardinger dextrin-, 2; 6 trimethyl beta-schardinger dextrin-s, monosaccharide groups beta-schardinger dextrin-, disaccharidase base beta-schardinger dextrin-, maltotriose glycosyl beta-schardinger dextrin-, two monosaccharide groups beta-schardinger dextrin-s, disaccharide base beta-schardinger dextrin-, 2; 3; 6-trimethoxy beta-schardinger dextrin-, 2-oxygen-(2-hydroxypropyl)-beta-schardinger dextrin-and/or HP-are preferably beta-schardinger dextrin-and/or HP-.
14. solid composite medicament according to claim 12, the chemical compound and the cyclodextrin weight ratio of wherein said formula (I) expression are 1: 20～1: 2; Be preferably 1: 10～1: 4; More preferably 1: 8～1: 4.
15. according to any described solid composite medicament of claim 1～7, it comprises cosolvent and/or stabilizing agent.
16. solid composite medicament according to claim 15; Wherein said cosolvent and/or stabilizing agent are selected from sodium lauryl sulphate, sarcosyl, poloxamer, polysorbas20, Tween 80, span, polyoxyethylene hydrogenated Oleum Ricini, Oleum Ricini and gather hydrocarbon oxygen ester, sodium carbonate, sodium bicarbonate, calcium hydrogen phosphate, magnesium carbonate, magnesium hydroxide, maleic acid and sodium hydroxide, fumaric acid and sodium hydroxide, citric acid and sodium hydroxide, tartaric acid and sodium hydroxide, maleic acid list sodium, monosodium fumarate, sodium tartrate, citric acid list sodium, propyl gallate, ethylenediaminetetraacetic acid, disodiumedetate, Butylated hydroxyanisole, sodium sulfite, sodium sulfite, sodium pyrosulfite and/or ascorbic acid, preferred sodium carbonate, sodium bicarbonate, maleic acid and sodium hydroxide, fumaric acid and sodium hydroxide, citric acid and sodium hydroxide, maleic acid list sodium, monosodium fumarate and/or citric acid list sodium.
17. solid composite medicament according to claim 15, wherein said cosolvent and/or stabilizing agent addition are the 0.01%-20% of solid composite medicament gross weight, preferred 0.01%-10%.
18. a method for preparing like any described pharmaceutical composition of claim 1～17 is characterized in that chemical compound with formula (I) expression disperses and/or is embedded in the compositions in the each component, forms solid composite.
19. according to the purposes of any described pharmaceutical composition of claim 1～17 in the medicine of preparation treatment blood circulation diseases, the preferred hypertension of said disease.
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011101620224A CN102824343A (en) | 2011-06-16 | 2011-06-16 | Solid pharmaceutical composition containing benzimidazole derivative |
| JP2014511719A JP2014515359A (en) | 2011-05-23 | 2012-05-18 | Solid pharmaceutical composition comprising a benzimidazole derivative |
| CN201280002761.XA CN103096878B (en) | 2011-05-23 | 2012-05-18 | Solid pharmaceutical composition containing benzimidazole derivative |
| KR1020137032234A KR20140030237A (en) | 2011-05-23 | 2012-05-18 | Solid pharmaceutical composition containing benzimidazole derivative |
| PCT/CN2012/075716 WO2012159552A1 (en) | 2011-05-23 | 2012-05-18 | Solid pharmaceutical composition containing benzimidazole derivative |
| HK13110090.3A HK1182638A1 (en) | 2011-05-23 | 2013-08-28 | Solid pharmaceutical composition containing benzimidazole derivative |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2011101620224A CN102824343A (en) | 2011-06-16 | 2011-06-16 | Solid pharmaceutical composition containing benzimidazole derivative |
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| CN102824343A true CN102824343A (en) | 2012-12-19 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN2011101620224A Pending CN102824343A (en) | 2011-05-23 | 2011-06-16 | Solid pharmaceutical composition containing benzimidazole derivative |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103096878A (en) * | 2011-05-23 | 2013-05-08 | 江苏恒瑞医药股份有限公司 | Solid pharmaceutical composition containing benzimidazole derivative |
| CN106176604A (en) * | 2016-08-30 | 2016-12-07 | 佛山市弘泰药物研发有限公司 | A kind of Azilsartan potassium salt self-micro emulsion formulation and preparation method thereof |
-
2011
- 2011-06-16 CN CN2011101620224A patent/CN102824343A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103096878A (en) * | 2011-05-23 | 2013-05-08 | 江苏恒瑞医药股份有限公司 | Solid pharmaceutical composition containing benzimidazole derivative |
| CN106176604A (en) * | 2016-08-30 | 2016-12-07 | 佛山市弘泰药物研发有限公司 | A kind of Azilsartan potassium salt self-micro emulsion formulation and preparation method thereof |
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Application publication date: 20121219 |