CN104415345A - Multi-element compound and preparation method thereof - Google Patents
Multi-element compound and preparation method thereof Download PDFInfo
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- CN104415345A CN104415345A CN201310393190.3A CN201310393190A CN104415345A CN 104415345 A CN104415345 A CN 104415345A CN 201310393190 A CN201310393190 A CN 201310393190A CN 104415345 A CN104415345 A CN 104415345A
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- pioglitazone hydrochloride
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Abstract
The invention belongs to the technical field of pharmaceutical preparations and particularly relates to a multi-element compound containing a surfactant as well as a preparation method and application of the multi-element compound containing the surfactant. The multi-element compound comprises pioglitazone hydrochloride, polyvinylpyrrolidone compounds and a surfactant at a weight ratio of 1 to (0.5-10) to (0.5-10). By virtue of a differential scanning calorimetry technique and a powder X-ray diffraction technique, results prove that pioglitazone hydrochloride in the multi-element compound presents an unformed state, and the dissolution rate of pioglitazone hydrochloride which is an indissolvable drug is increased; the wetting and the dissolution of the drug can be commonly accelerated by the utilized polymers and surfactant; dissolution rate of pioglitazone hydrochloride can be remarkably increased by the multi-element unformed pioglitazone hydrochloride compound, so that the bioavailability of the drug can be improved.
Description
Technical field
The invention belongs to pharmaceutical preparations technology field, be specifically related to a kind of the multiple element compound containing surfactant and its production and use, more specifically relate to a kind of the multiple element compound containing pioglitazone hydrochloride, high molecular polymer and surfactant and its production and use.
Background technology
At pharmaceutical field, about have the problem that the medicine of more than 80% has water-soluble low, numerous have the molecule of pharmacologically active to cause low bioavailability in vivo due to its low water solublity.The dissolubility that medicine is low causes drug molecule just to be drained before arrival site of action, thus reduces its Absorption and curative effect.In order to solve the problems of dissolution of insoluble drug, people attempt have employed a lot of preparation means and are improved.What current application was more is solid dispersion, the solubilizing agent of cyclodextrin inclusion compound, medicine is with cosolvent, liposome, micelle, microemulsion, become Ficus caricaL etc. to medicine.In these preparation techniques, the technology had at present for industrialization mainly comprises solid dispersion, microemulsion and liposome technology.And preparation industry it is envisaged that cost, can the effect etc. of commercial application and solubilising.From then on angle analysis, solid dispersions technique is optimal solubilization technique beyond doubt.And for technology such as liposomees, although also can reach good solubilizing effect, its high expense, greatly reduces the universality that it applies.
Adding of polymeric matrix is the essential condition forming solid dispersion or complex.Some polymer itself has certain crystal diffraction peak, as polyethylene glycols and polyoxyethylene polyoxypropylene ether block copolymer class.And some polymer may show unformed character due to the arrangement randomness of self repetitive, as hydroxypropyl methylcellulose cellulose family and polyvinylpyrrolidone class.Drug molecule and polymer support can come to interact with carrier by intermolecular force, reach close contact physically.Intermolecular force can be reflected on hydrogen bond action, also may show in dipolar interaction.Hydrogen bond action is the modal intermolecular interaction form of expression.Polymer can as the acceptor of hydrogen, and medicine is as the donor of hydrogen, and vice versa.The polymer that the present invention adds is polyvinylpyrrolidone class, containing five yuan of pyrrole rings, is mainly the acceptor of hydrogen, and drug molecule pioglitazone hydrochloride itself is containing secondary amide (NH) and hydrochlorate, can give active hydrogen.This design is the stripping that can increase insoluble drug in theoretical basis.Both possible interaction mechanisms are for forming hydrogen bond, and structure is as follows:
Medicine high degree of dispersion is in the polymer conducive to the contact area increasing medicine and dissolution medium.The degree of solubilising is also relevant with both ratios.Water-soluble polymer needs certain ratio just can reach the solubilising of medicine usually.Polymer, except increasing insoluble drug dissolubility, also serves the effect suppressing unformed drug crystallization.Different polymer suppresses the degree of unformed drug crystallization different from mechanism.This suppression crystalline polamer the mechanism increasing stability comprise the reinforcement of intermolecular force, drug molecule mobility weaken the reduction etc. with drug molecule free energy.
Add the stripping that surfactant can promote insoluble drug jointly in the polymer, make the adding of surfactant medicine and polymer support more easily contact with dissolution medium when stripping, thus add the dispersibility of medicine.
Summary of the invention
The object of the present invention is to provide a kind of the multiple element compound significantly strengthening insoluble drug dissolution.
Another object of the present invention is the preparation method providing this multiple element compound.
Medicine of the present invention is dispersed in the joint vector that polymer and surfactant formed with unformed form, and the carrier of this associating can improve the water solublity of medicine, improves the dissolution of medicine, more effectively plays therapeutical effect.
The multiple element compound of the present invention, comprising pioglitazone hydrochloride, polymer and surfactant, the weight ratio of pioglitazone hydrochloride, polymer and surfactant is 1:(0.5 ~ 10): (0.5 ~ 10).
Described the multiple element compound exists in powder form.Can be in solid dispersion, clathrate, lyophilization powder and spray-dried powders any one, be preferably solid dispersion class powder.
Described polymer support comprises the conventional high molecular polymer of pharmacy, comprise polyvinylpyrrolidone--type polymer, be selected from: comprise polyvinylpyrrolidone k12, PVP k17, polyvinylpyrrolidone k30, any one in polyvinylpyrrolidone k90.
Described surfactant is the surfactant that pharmaceutics is conventional, this surfactant can be polysorbate 20, the smooth class of fatty acid Pyrusussuriensis, sodium lauryl sulphate, tween 80, Myrij class, D-alpha-tocopherol cetomacrogol 1000 succinate, be preferably sodium lauryl sulphate and D-alpha-tocopherol cetomacrogol 1000 succinate, then be preferably D-alpha-tocopherol cetomacrogol 1000 succinate.
The particle diameter of described the multiple element compound is less than 250 μm.
Described the multiple element compound measures through differential scanning calorimetry (DSC) and powder X-ray derivatization method (PXRD), and medicine exists with unformed form.
Described the multiple element compound mainly adopts solvent to volatilize method and is prepared.
Described solvent is waved dry process step and is comprised: by polymer, pioglitazone hydrochloride and surfactant dissolves in solvent, becomes the solution of homogeneous phase, puts into round bottom eggplant-shape bottle, outer heating in water bath to 50 ~ 60 DEG C.Under constantly rotating, solvent starts evaporation, and solvent evaporated, can form solid matter inside beaker.Scrape solid matter, put into 60 DEG C of baking oven inner dryings 24 hours, remove residual solvent further, then use mortar to grind, and cross 80 mesh sieves, be drying to obtain the multiple element compound.
The solvent adopted in described preparation method comprises methanol, ethanol, normal propyl alcohol, isopropyl alcohol, n-butyl alcohol, chloroform, dichloromethane and acetone.
The present invention has the following advantages:
Pioglitazone hydrochloride and polymer support define stable amorphous state complex, be scattered in polymer support medicaments uniformity, medicine exists as an amorphous form, significantly increases dissolution rate and the dissolubility of insoluble drug, thus bioavailability in the body that may increase medicine.Polymer support have passed intermolecular force can suppress the crystallization of medicine under amorphous state to some extent, thus the medicine storage stability improved.
Accompanying drawing explanation
Figure 1A is the DSC figure of pioglitazone hydrochloride;
Figure 1B is the DSC figure of amorphous state pioglitazone hydrochloride complex;
Fig. 2 is the PXRD figure of embodiment 1 amorphous state pioglitazone hydrochloride complex;
Fig. 3 is the PXRD figure of embodiment 2 amorphous state pioglitazone hydrochloride complex;
Fig. 4 is the PXRD figure of pioglitazone hydrochloride;
Fig. 5 is the stripping comparison diagram of embodiment 1 ~ embodiment 4 amorphous state complex and pioglitazone hydrochloride;
The complex containing surfactant of Fig. 6 to be embodiment 3 with PVPK90 be carrier and embodiment 5 are containing the stripping comparison diagram of the complex of surfactant;
The complex containing surfactant of Fig. 7 to be embodiment 3 with PVPK90 be carrier does not contain the initial dissolution rate figure of the complex of surfactant with embodiment 5.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is described further, and embodiment is only indicative, never means that it limits the scope of the invention by any way.
embodiment 1
The ternary pioglitazone hydrochloride complex being carrier with polyvinylpyrrolidone k12, comprising:
Pioglitazone hydrochloride 500mg
Polyvinylpyrrolidone k12 500mg
D-alpha-tocopherol cetomacrogol 1000 succinate 250mg
Described amorphous state complex particle diameter is less than 200 μm.
Preparation process comprises: 1. by the pioglitazone hydrochloride of formula ratio, PVP K30 and D-alpha-tocopherol cetomacrogol 1000 succinate are dissolved in 10mL ethanol, become the solution of homogeneous phase, put into round bottom eggplant-shape bottle, outer heating in water bath to 50 ~ 60 DEG C; 2., under constantly rotating, organic solvent starts evaporation, evaporation time about 2 hours, and solvent evaporated, can form solid state white color substance inside beaker; 3. solid matter is scraped, put into 60 DEG C of baking oven inner dryings 24 hours, further the contained residual minim organic solvent of evaporation, then use mortar to grind, and cross 80 mesh sieves, be namely able to the ternary pioglitazone hydrochloride complex containing surfactant that polyvinylpyrrolidone K12 is carrier.
embodiment 2
The ternary pioglitazone hydrochloride complex being carrier with polyvinylpyrrolidone k30, comprising:
Pioglitazone hydrochloride 700mg
Polyvinylpyrrolidone k30 1400mg
D-alpha-tocopherol cetomacrogol 1000 succinate 350mg
Described amorphous state complex particle diameter is less than 200 μm.
Preparation process comprises: 1. by the pioglitazone hydrochloride of formula ratio, PVP K30 and D-alpha-tocopherol cetomacrogol 1000 succinate are dissolved in 15mL chloroform, become the solution of homogeneous phase, put into round bottom eggplant-shape bottle, outer heating in water bath to 50 ~ 60 DEG C; 2., under constantly rotating, organic solvent starts evaporation, evaporation time about 2.5 hours, and solvent evaporated, can form solid state white color substance inside beaker; 3. solid matter is scraped, put into 60 DEG C of baking oven inner dryings 24 hours, further the contained residual minim organic solvent of evaporation, then use mortar to grind, and cross 80 mesh sieves, be namely able to the ternary pioglitazone hydrochloride complex containing surfactant that PVP K30 is carrier.
embodiment 3
The ternary pioglitazone hydrochloride complex being carrier with polyvinylpyrrolidone k90, comprising:
Pioglitazone hydrochloride 600 mg
Polyvinylpyrrolidone k90 1400 mg
D-alpha-tocopherol cetomacrogol 1000 succinate 400 mg
Described amorphous state complex particle diameter is less than 200 μm.
Preparation process comprises: 1. by the pioglitazone hydrochloride of formula ratio, PVP K90 and D-alpha-tocopherol cetomacrogol 1000 succinate are dissolved in 17mL methanol, become the solution of homogeneous phase, put into round bottom eggplant-shape bottle, outer heating in water bath to 55 ~ 60 DEG C; 2., under constantly rotating, organic solvent starts evaporation, evaporation time about 3 hours, and solvent evaporated, can form solid state white color substance inside beaker; 3. solid matter is scraped, put into 60 DEG C of baking oven inner dryings 24 hours, further the contained residual minim organic solvent of evaporation, then use mortar to grind, and cross 80 mesh sieves, be namely able to the ternary pioglitazone hydrochloride complex containing surfactant that PVP K90 is carrier.
embodiment 4
The ternary pioglitazone hydrochloride complex being carrier with copovidone VA64, comprising:
Pioglitazone hydrochloride 1000mg
Copovidone VA64 1000mg
D-alpha-tocopherol cetomacrogol 1000 succinate 500mg
Described amorphous state complex particle diameter is less than 200 μm.
Preparation process comprises: 1. by the pioglitazone hydrochloride of formula ratio, copovidone VA64 and D-alpha-tocopherol cetomacrogol 1000 succinate are dissolved in 20mL methanol, become the solution of homogeneous phase, put into round bottom eggplant-shape bottle, outer heating in water bath to 50 ~ 55 DEG C; 2., under constantly rotating, organic solvent starts evaporation, evaporation time about 2.5 hours, and solvent evaporated, can form solid state white color substance inside beaker; 3. solid matter is scraped, put into 60 DEG C of baking oven inner dryings 24 hours, further the contained residual minim organic solvent of evaporation, then use mortar to grind, and cross 80 mesh sieves, be namely able to the ternary pioglitazone hydrochloride complex containing surfactant that copovidone VA64 is carrier.
embodiment 5
The binary pioglitazone hydrochloride complex being carrier with polyvinylpyrrolidone k90, comprising:
Pioglitazone hydrochloride 800mg
Polyvinylpyrrolidone k90 1600mg
Described amorphous state complex particle diameter is less than 200 μm.
Preparation process comprises: 1. the pioglitazone hydrochloride of formula ratio and PVP K30 are jointly dissolved in 15mL ethanol, become the solution of homogeneous phase, put into round bottom eggplant-shape bottle, outer heating in water bath to 55 ~ 60 DEG C; 2., under constantly rotating, ethanol starts evaporation, evaporation time about 3 hours, and evaporate to dryness organic solvent, can form solid state white color substance inside beaker; 3. solid matter is scraped, put into 60 DEG C of baking oven inner dryings 24 hours, further the contained residual minim organic solvent of evaporation, then use mortar to grind, and cross 80 mesh sieves, be namely able to the binary pioglitazone hydrochloride complex not containing surfactant that PVP K90 is carrier.
embodiment 6
Differential scanning calorimetry (DSC)
By the polynary pioglitazone hydrochloride complex of the embodiment of the present invention 1 and 2, pioglitazone hydrochloride by differential scanning calorimeter (DSC822e, prunus mume (sieb.) sieb.et zucc. Teller, Sweden) measure the unformed state of medicine, DSC instrument is interior mark with indium, the test sample of 5mg is placed in aluminum dish, put into DSC instrument, heating rate is 10 DEG C/min, and temperature range is 30-220 DEG C.DSC result of the test as shown in Figure 1.
Tested by DSC, we find that the fusing point peak of the present invention's various amorphous state pioglitazone hydrochloride complex Chinese medicine all disappears, and also imply that the formation of these polynary unformed states of complex Chinese medicine.
embodiment 7
Powder x-ray diffraction test (PXRD)
By the amorphous state pioglitazone hydrochloride complex of the embodiment of the present invention 1 and embodiment 2, pioglitazone hydrochloride by D/Max-2500 type x-ray diffractometer (Rigaku, Tokyo, Japan) measure the unformed status of medicine, this instrument uses Cu K alpha ray to be emission source
standard to operate in voltage be 40kV and electric current is carry out under 100mA.Scanning speed is 8 °/min, and sweep limits is 10 ~ 60 ° of 2 θ.Get about 50mg testing sample powder, be pressed into thin slice, put into X-ray diffraction instrument and measure.PXRD result of the test as shown in Figure 2, Figure 3 and Figure 4.
Tested by PXRD, we find that the crystal peak of the present invention's various amorphous state pioglitazone hydrochloride complex Chinese medicine all disappears, and further demonstrate the amorphous formation of medicine.
embodiment 8
Dissolution rate
By polynary pioglitazone hydrochloride complex obtained for the embodiment of the present invention 1 ~ 4 according to Chinese Pharmacopoeia version in 2010 two XC first method dissolution methods, (huge sky is sent out to adopt ZRS-8G type digestion instrument, Tianjin, China) be dissolution medium with pure water, rotating speed is 50 turns per minute, and dissolution medium temperature is 37 DEG C.Under equal conditions test 3 times.The dissolution test result of each embodiment as shown in Figure 5.Add surfactant and do not add the dissolution results of surfactant as shown in Figure 6.Each embodiment 5min initial dissolution rate as shown in Figure 7.
Found by stripping experiment, the present invention's various amorphous state pioglitazone hydrochloride complex has been significantly increased the dissolution rate of pioglitazone hydrochloride, and increase rate is at 4 ~ 6 times (Fig. 5).After adding surfactant, the dissolution rate of complex is significantly strengthened (Fig. 6), and the originally dissolution rate of each complex containing surfactant is all obviously strengthened (Fig. 7).These stripping description of tests, the multiple element compound containing surfactant provided by the present invention can improve the dissolution rate of medicine significantly, is conducive to the absorption of human body, can increases the bioavailability in body, increases therapeutic effect.
Claims (11)
1. a multiple element compound, is characterized in that: containing pioglitazone hydrochloride, high molecular polymer and surfactant; The weight ratio of described pioglitazone hydrochloride, high molecular polymer and surfactant is 1:(0.5 ~ 10): (0.5 ~ 10).
2. the multiple element compound according to claim 1, is characterized in that, described complex exists in powder form.
3. the multiple element compound according to claim 1, is characterized in that, described complex to be selected from solid dispersion, clathrate, lyophilization powder, spray-dried powders any one, is preferably solid dispersion.
4. the multiple element compound according to claim 1, is characterized in that: described complex particle diameter is less than 250 μm.
5. the multiple element compound according to claim 1, is characterized in that, described high molecular polymer is polyvinylpyrrolidone--type polymer.
6. the multiple element compound according to claim 5, is characterized in that, described high molecular polymer is selected from: polyvinylpyrrolidone k12, PVP k17, polyvinylpyrrolidone k30, any one in polyvinylpyrrolidone k90.
7. the multiple element compound according to claim 1, described surfactant is selected from polysorbate 20, the smooth class of fatty acid Pyrusussuriensis, sodium lauryl sulphate, tween 80, Myrij class, D-alpha-tocopherol cetomacrogol 1000 succinate; Be preferably sodium lauryl sulphate or D-alpha-tocopherol cetomacrogol 1000 succinate; Be preferably D-alpha-tocopherol cetomacrogol 1000 succinate again.
8. the multiple element compound according to claim 1, described pioglitazone hydrochloride exists with unformed form.
9. the preparation method of the multiple element compound according to any one of claim 1-8, is characterized in that, described method is that solvent volatilizes method.
10. preparation method according to claim 9, described solvent volatilizes method step and comprises: by polymer, pioglitazone hydrochloride and surfactant dissolves in solvent, becomes the solution of homogeneous phase, and under constantly rotating, solvent evaporated, obtains the multiple element compound.
11. preparation methoies according to claim 9 or 10, any one in described solvent selected from methanol, ethanol, normal propyl alcohol, isopropyl alcohol, n-butyl alcohol, chloroform, dichloromethane and acetone.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112461947A (en) * | 2020-10-27 | 2021-03-09 | 山东省药学科学院 | Method for measuring dissolution curve of pioglitazone hydrochloride tablet |
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2013
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| CN101167731A (en) * | 2007-10-22 | 2008-04-30 | 林海平 | Dispersible tablet containing metformin and glibenclamide and preparation method thereof |
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| CN102892764A (en) * | 2010-03-25 | 2013-01-23 | 弗特克斯药品有限公司 | Solid forms of (r)-1(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-n-(1-(2,3-dihyderoxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1h-indol-5-yl) cyclopropanecarboxamide |
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Application publication date: 20150318 |