CN101057833A - Solid dispersion preparation - Google Patents
Solid dispersion preparation Download PDFInfo
- Publication number
- CN101057833A CN101057833A CN 200710093774 CN200710093774A CN101057833A CN 101057833 A CN101057833 A CN 101057833A CN 200710093774 CN200710093774 CN 200710093774 CN 200710093774 A CN200710093774 A CN 200710093774A CN 101057833 A CN101057833 A CN 101057833A
- Authority
- CN
- China
- Prior art keywords
- solid dispersion
- water
- weight
- tablet
- soluble polymer
- 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.)
- Pending
Links
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Provided are a granule or a tablet of a solid dispersion that allows a drug in a preparation to be rapidly dissolved without impairing the dissolution of the solid dispersion, and a method for producing the same. More specifically, provided are a granule of a solid dispersion comprising a poorly soluble drug, a water-soluble polymer, an excipient and a disintegrator, wherein a content of the water-soluble polymer is 1 to 10% by weight and a content of the disintegrator is 15 to 50% by weight; a tablet of a solid dispersion comprising a poorly soluble drug, a water-soluble polymer, an excipient and a disintegrator, wherein a content of the water-soluble polymer is 1 to 5% by weight and a content of the disintegrator is 15 to 50% by weight; and a method for producing a granule or tablet of a solid dispersion comprising spraying a water-soluble polymer solution in which a poorly soluble drug has been dispersed or dissolved, on a mixed powder of an excipient and a disintegrator, and granulating and drying the resultant preparation.
Description
Technical field
The present invention relates to a kind of solid preparation that is used to improve poorly soluble medicine dissolution that is produced, relate in particular to a kind of solid preparation that contains disintegrate fast and allow the solid dispersion of medicine dissolution.
Background technology
Poorly soluble medicine degree of crystallinity height and dissolubility in water is extremely low.Therefore, very low by trap in its bioavailability of preparation of these medication preparation or the body, make that drug effect is insufficient and become problem.As the technology that addresses this is that, people have developed solid dispersion, and wherein poorly soluble drug molecule is scattered in polymer support such as the cellulose derivative with unbodied state.
Conventional solid dispersion uses with capsular dosage form, and this capsule contains the cosolvent that will be dissolved with poorly soluble medicine and carrier and carries out the solid that spray drying obtains, and perhaps uses with himself fine grained or particle form.As the general dosage form of solid preparation, said preparation most preferably is tablet, because tablet prescribes easily, and gives with fixed dosage easily, and the patient also is easy to handle and take.
Be known that, under situation by the tablet of solid dispersion powder preparation, the porosity of tablet is often very low, and this is not only owing to the specific surface area that reduces, but also owing to plastic deformation of amorphous drug molecule in mold process and the strong combination between the carrier polymer.This low-porosity makes that hydrone slowly infiltrates tablet in drug administration process, and the disintegrate of tablet is also very slow, so solid dispersion can not be brought into play the internal action that it improves stripping.In addition, in hydration or process in leaching, the viscosity that is used as the water-soluble or enteric polymer of carrier increases, thereby in process in leaching, forms a kind of hydrogel layer on the surface of tablet, makes that the infiltration of water is further stoped.
At the solution of these problems, Japanese patent application (PCT country stage) the open No.2005-517690 of examination proposes not a kind ofly to contain solid dispersion powder, disintegrating agent and contain the excipient of pore former and the tablet that obtains by spray drying.In addition, Japanese patent application is not examined open No.5-262642/1993 and is proposed a kind of powder that adds water-soluble polymer matrix and can add excipient and disintegrating agent as required in poorly soluble medicine.Yet the addition that strengthens polymer or water-soluble polymer matrix as the concentration of carrier is very big, so the rate of dissolution of medicine is tending towards reducing.In addition, Japanese patent application (PCT country's stage) is not examined among the open No.2005-517690, obtain the solid dispersion powder by spray drying, the solid dispersion powder with need compression and crushed mixture after other components are mixed, be formed for the particulate powder of tabletting.The particle diameter of the solid dispersion powder of spray drying preparation is very little in this way, therefore when simply mix with excipient, causes and emanates and make component not be evenly distributed on the powder that is used for tabletting.In addition, this method makes complicated operation, and solid dispersion may be in compression recrystallization.In addition, add disintegrating agent behind the solid dispersion in preparation because the high bond strength of carrier, when solid dispersion assemble and in tablet in conjunction with the time, can form aggregation in the disintegrating procedue and be dispersed in the water, thereby reduce the stripping of medicine.
Japanese patent application is not examined open No.2004-67606 and is proposed a kind of fine grain tablet that contains, this fine grained is injected on the mixed-powder of excipient and disintegrating agent by the solution that will contain itraconazole (a kind of poorly soluble medicine), water-soluble polymer and enteric polymer, makes product pelletize and dry and obtain.Yet the addition of disintegrating agent seldom needs just to make in 360 minutes medicine stripping from tablet.Therefore, the disintegrative of this tablet does not improve.
People such as Hirasawa (Journal of the Pharmaceutical Society of Japan, 124 (1), 19～23 (2004)) a kind of tablet is proposed, the alcoholic dispersion of this tablet by will containing nilvadipine (a kind of poorly soluble medicine), polyvinylpolypyrrolidone and methylcellulose be as in the mixed-powder that is added in conjunction with liquid such as lactose, methylcellulose and the low materials such as hydroxypropyl cellulose that replace, and said mixture stirring and pelletize are prepared.Nilvadipine is solvable in ethanol, but polyvinylpolypyrrolidone and methylcellulose are insoluble in ethanol.Therefore, as if because do not reach common dissolved state, alcoholic acid effect is just as the reagent that is used to disperse and dilute amorphous nilvadipine.For unbodied drug molecule being scattered in the polymer as carrier, being necessary to make drug molecule and polymer all to be dissolved in the cosolvent and reaching common dissolved state.Therefore, as if the solid dispersion of the amorphous nilvadipine of record does not have enough dissolubility in Journal of thePharmaceutical Society of Japan 124 (1), 19～23 (2004).In addition, because the addition of water-soluble polymer is very big, so be difficult to obtain the preparation of rapidly dissolvable.
Summary of the invention
Because above-mentioned situation, obtain the present invention, the invention provides and a kind ofly allow the quick stripping of medicine in the preparation and can not weaken the granule or the tablet of the solid dispersion of solid dispersion stripping and the method for preparing said preparation.
For addressing the above problem, the present inventor furthers investigate, discovery is when water-soluble polymer that is used as the solid dispersion carrier that adds scheduled volume respectively and disintegrating agent, the disintegrative of the tablet that obtains by the mold pressing solid dispersion does not reduce, and granule and tablet have excellent dissolubility.Therefore, finished the present invention.
More specifically, the invention provides a kind of granule of solid dispersion, contain poorly soluble medicine, water-soluble polymer, excipient and disintegrating agent, the content of wherein said water-soluble polymer is 1～10 weight %, and the content of described disintegrating agent is 15～50 weight %; A kind of tablet of solid dispersion contains poorly soluble medicine, water-soluble polymer, excipient and disintegrating agent, and the content of wherein said water-soluble polymer is 1～5 weight %, and the content of described disintegrating agent is 15～50 weight %; And a kind of method for preparing the granule or the tablet of solid dispersion, be included in jet spread on the mixed-powder of excipient and disintegrating agent or be dissolved with the water-soluble polymer solution of poorly soluble medicine, and make product pelletize and dry.
According to the present invention, obtain having the solid preparation of excellent solubility, when it is granule, have high-dissolvability; When it was tablet, in 10 minutes, disintegratable also discharged the poorly soluble medicine of at least 70 weight % after introducing dissolution medium.
The specific embodiment
Following more detailed description the present invention.
The dissolubility of poorly soluble medicine in water that the present invention uses is extremely low, and the trap during conventional oral administration is very poor.For example, the poorly soluble medicine meaning of regulation is the medicine of " almost insoluble or insoluble " or " atomic molten " in the Japanese Pharmacopoeia the 14th edition.In Japanese Pharmacopoeia the 14th edition, " dissolubility " of term medicine meaning is in 20 ± 5 ℃ solvent, every jolting in 5 minutes once, and each jolting 30 seconds, the dissolution of solid powdered medicine in 30 minutes.If medicine is " almost insoluble or insoluble ", the amount of dissolving 1g or the required solvent of 1ml medicine (being water in this manual) so is 10, more than the 000ml.If medicine is " atomic molten ", the amount of dissolving 1g or the required solvent of 1ml medicine so is 1, more than the 000ml, but less than 10,000ml.
The object lesson of the poorly soluble medicine that the present invention uses includes but not limited to nifedipine, phenacetin, phenytoin, Digitoxin, nilvadipine, diazepam, griseofulvin and chloromycetin.
In the present invention, because the molecular dispersion of poorly soluble medicine becomes amorphous form, so water-soluble polymer is as carrier.Water-soluble polymer is a kind of following polymer: when this polymer being added to required half of stripping to whole calorimetric water (70 ℃ or higher) and stir and during dispersed mixture, simultaneously under the situation of used hot water amount less than required whole amounts, stir the cold water or the frozen water that add surplus down, this polymer is by the 14th edition regulation of Japanese pharmacopeia " extremely dissolved (dissolving the required water yield of 1g or 1ml medicine less than 1ml) ", " free dissolved (the dissolving 1g or the required water yield of 1ml medicine be 1ml or more and less than 10ml) ", or " dissolved (and the dissolving 1g or the required water yield of 1ml medicine be 10ml or more and less than 30ml) ".Its object lesson can comprise alkylcellulose, as methylcellulose; Hydroxy alkyl cellulose is as hydroxyethyl-cellulose and hydroxypropyl cellulose; The hydroxyalkyl alkylcellulose is as hydroxyethylmethyl-cellulose and hydroxypropyl emthylcellulose; Polyvinyl alcohol; And polyvinylpyrrolidone.Wherein, hydroxypropyl emthylcellulose is particularly preferred.
The content of water-soluble polymer can change with the dosage form of solid preparation.If solid preparation is a particle form, so preferred content can be 1～10 weight % of preparation total amount.If solid preparation is a tablet form, so preferred content can be 1～5 weight % of preparation.If the content of water-soluble polymer less than 1 weight %, is difficult to obtain the poorly soluble medicine of complete amorphous state so in solid dispersion.If content is greater than 10 weight % under the granule situation, or content is greater than 5 weight % under the tablet situation, and the ratio of water-soluble polymer becomes big in the preparation so, and the size that particulate dosage can become big or tablet can become greatly, therefore not preferred this situation.
If with poorly soluble medicine as 1, the weight ratio preferred 1～5 of water-soluble polymer and poorly soluble medicine so.If the ratio of water-soluble polymer is less than 1, poorly soluble medicine is not complete amorphous state in solid dispersion so.If this ratio is greater than 5, the ratio of water-soluble polymer becomes big in the preparation so, thereby the change of preparation size is big, and this preparation that routine is used is not suitable for.
Preferred those of solvent that are used to prepare the solid dispersion that contains water-soluble polymer and poorly soluble medicine make poorly soluble medicine be able to fine dissolving therein and water-soluble polymer also is able to dissolved solvent therein.The example of these solvents comprises the mixed solvent of methanol, ethanol, dichloromethane, acetone and composition thereof and they and water.Dissolubility in solvent carries out suitable selection to solvent according to poorly soluble medicine and water-soluble polymer.
The addition of solvent is preferably and makes solid concentration is 3～18 weight %, and being preferably especially and making solid concentration is 3.5～12 weight %.
The example of the excipient that the present invention uses comprises lactose, corn starch, sucrose, mannitol, anhydrous calcium phosphate, crystalline cellulose and their mixture.Preferred especially the use contained lactose and corn starch with 7: 3 blended mixed-powders of weight ratio.
With respect to the preparation total amount, the content of excipient is preferably 30～90 weight %, is preferably 42.5～78.5 weight % especially.If the content of excipient is less than 30 weight %, the quantitative change of disintegrating agent is too much so, thereby the flowability of granulated powder is poor.If the content of excipient is greater than 90 weight %, the quantitative change of disintegrating agent is little so, thereby can not get expecting to improve the effect of dissolubility.
The disintegrating agent example that the present invention uses comprises carboxymethyl cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, cross-linking sodium carboxymethyl cellulose, have hydroxypropyl cellulose (L-HPC), hydroxypropyl starch, carboxymethyl starch sodium, polyvinylpolypyrrolidone and their mixture of low replacement of the propoxyl of 5～16 weight %.
As the disintegrating agent that the present invention uses, the preferred especially low hydroxypropyl cellulose that replaces because it makes granule have high fluidity, and is guaranteed the high stripping of medicine from the mold pressing preparation.Preferred especially bulking volume density is that 0.40g/ml or bigger and jolt ramming volume density are the hydroxypropyl cellulose of 0.60g/ml or bigger low replacement.
Term herein " bulking volume density " means the volume density that is in the loose packing state, height at 23cm, with sample by 24 mesh sieves of Japanese Industrial Standards (JIS) evenly pack into diameter 5.03cm, the height 5.03cm (volume 100ml) the rustless steel hydrostatic column, after making the upper surface flush of sample and container, weigh and measure described bulking volume density.Term " jolt ramming volume density " means the volume density that is in tight filling state, and the container that is under the loose packing state by jolt ramming obtains closely to load state.Described " jolt ramming " means the operation that sample is closely loaded, and promptly by the container that sample is housed is fallen from predetermined height repeatedly, thereby applies a light impulsive force to container bottom.In the reality, after the upper surface flush of sample and container is finished and is weighed when measuring bulking volume density, lid (member of the powder test set that a kind of Hosokawa Micron Corporation produces) is covered on container, powder is added to the top edge of this lid, jolt ramming height 1.8cm, jolt ramming 180 times.After finishing jolt ramming, remove lid, make the upper surface flush of powder and container after, weigh.Volume density under this state is as the jolt ramming volume density.The powder test set (PT-D) that these operations can use Hosokawa Micron Corporation to produce carries out.
In addition, the preferred compressed degree is 35% or the hydroxypropyl cellulose of lower low replacement.The degree of compression herein means the reduction rate of volume, and it obtains by following equation:
The degree of compression (%)={ (the loose b.d. of jolt ramming b.d.-)/jolt ramming b.d.} * 100
Wherein b.d. means volume density.
With respect to the preparation total amount, the content of disintegrating agent is preferably 15～50 weight %, is preferably 20～40 weight % especially.If the content of disintegrating agent less than 15 weight %, a little less than the improvement effect to dissolubility, can not get desired effects so.If the content of disintegrating agent is greater than 50 weight %, the flowability of the granulated powder that obtains so reduces, and this is not preferred for the powder that is used for tabletting.
If necessary, can add lubricant in the tablet of solid dispersion of the present invention.The example of lubricant comprises magnesium stearate, sucrose fatty acid ester, Polyethylene Glycol, Talcum and stearic acid.
With respect to the amount of removing preparation behind the lubricant, the amount of lubricant is preferably 0.5～2 weight %.If the addition of lubricant can not get sufficient lubricating property so less than 0.5 weight %, thereby the gained preparation adheres on mortar or the pestle in the tabletting process.If the amount of lubricant is greater than 2 weight %, hardness or disintegrative reduce so.
Below, the granule of preparation solid dispersion of the present invention and the method for tablet are described.
Can or be dissolved with the water-soluble polymer solution of poorly soluble medicine by jet spread on the mixed-powder of excipient and disintegrating agent, and make product pelletize and dry and obtain the granule of solid preparation of the present invention.More specifically, jet spread or be dissolved with the water-soluble polymer solution of poorly soluble medicine on the excipient that is flowing in comminutor and the mixed-powder of disintegrating agent makes product pelletize and dry, carries out the particle diameter adjustment then.
The example of comminutor comprises fluidized bed prilling coating equipment, high-speed stirred Granulation Equipments and rotating granulation equipment.Preferred especially fluid bed granulating and coating equipment.
The granule conduct of using said method to obtain is used for the powder of tabletting, and by the optional lubricant of adding in granule, and the mold pressing granule obtains tablet of the present invention in tablet machine.Pulverize when improving powder properties, stripping etc. when needs, before tabletting, can use suitable pulverizer to pulverize the granule that obtains by said method.Described pulverizer comprises cutter formula pulverizer, roller pulverizer, ball mill, jet mill, screen mill and bead mill.
When the granule of the solid dispersion that obtains like this according to " dissolution test, the method 2 " described in the Japanese Pharmacopoeia the 14th edition evaluation, give dissolved drug concentration in back 5 minutes can for dosage 70% or bigger.Therefore, show high stripping.
When the tablet of the solid dispersion that obtains according to " slaking test " described in the Japanese Pharmacopoeia the 14th edition evaluation, give tablet possibility disintegrate in back 10 minutes, and when estimating this tablet according to " dissolution test; method 2 " described in the Japanese Pharmacopoeia the 14th edition, give dissolved drug concentration in back 10 minutes can for dosage 70% or bigger.Therefore, show high disintegrative and high stripping.
In order to cover taste or to cover abnormal smells from the patient, make that perhaps preparation is an enteric coated preparation, perhaps realize the slow release of preparation, can use known method that the solid preparation that the present invention obtains is carried out coating.The example of coating materials comprises enteric polymer, as Cellacefate, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, Hydroxypropyl Methylcellulose Phathalate, HPMC-AS and carboxymethylethylcellulose; The gastric solubility polymer is as polyethylene acetal lignocaine acetas (polyvinyl acetaldiethylaminoacetate) and methacrylic acid aminoalkyl ester copolymer; And above-mentioned water-soluble polymer.
Specifically describe the present invention below by embodiment and comparative example, yet the present invention is not limited to these examples.
Embodiment 1 and comparative example 1
By dissolving 1.2g nifedipine and 2.4g hydroxypropyl emthylcellulose (the HPMC) (methoxyl group of the propoxyl of 8.7 weight % and 28.8 weight % in the mixed solvent that contains 8: 2 second alcohol and water of weight ratio, 6mPas), or 12g nifedipine and 24g hydroxypropyl emthylcellulose (the HPMC) (methoxyl group of the hydroxypropyl of 8.7 weight % and 28.8 weight %, 6mPas), preparation solid dispersion liquid solution.The solid dispersion liquid solution is injected in mobile by the low hydroxypropyl cellulose (L-HPC) (propoxyls of 10.9 weight %) that replaces, lactose (Pharmatose that DMV International makes) and corn starch (Nihon Shokuhin Kako Co. in fluidized bed prilling coating equipment (the Multiplex MP-01 that POWREXCORPORATION makes), Ltd. the corn starch W of Zhi Zaoing) on the mixture that constitutes, make product pelletize and dry.Then, (hole: sieve control particle diameter 500 μ m) obtains granule to use 30 orders.As a comparative example, contain its amount outside prescribed limit of the present invention and by the similar manner manufacturing as the granule of the hydroxypropyl cellulose of the low replacement of disintegrating agent.
Table 1 shows when using the evaluation of orifice plate slamp value to have every kind of each 20g of gained granule of different formulations, the result of fluidity evaluating.Here, the orifice plate slamp value refers to be used to estimate the index of powder flowbility, and the hourglass shape funnel by the 20g sample being placed the hole be plugged (internal diameter: 42mm, highly: 90mm), make sample be downward through hole and mobile and obtain based on the hole dimension evaluation.
Mobile evaluation " well " refers to the good fluidity of powder and flows downward fast, refers to that mobile difference and powder are not downward through the hole and estimate " poor ".
Table 1
| Form | Always (g) | Mobile | ||||||
| Nifedipine (g) | HPMC (g) | L-HPC (g) | Lactose (g) | Corn starch (g) | ||||
| Embodiment 1 | Prescription A | 1.2 | 2.4 | 48 | 131.9 | 56.5 | 240 | Well |
| Prescription B | 12 | 24 | 48 | 109.2 | 46.8 | 240 | Well | |
| Prescription C | 12 | 24 | 96 | 75.6 | 32.4 | 240 | Well | |
| Comparative example 1 | Prescription D | 12 | 24 | - | 142.8 | 61.2 | 240 | Well |
| Prescription E | 12 | 24 | 24 | 126 | 54 | 240 | Well | |
| Prescription F | 12 | 24 | 144 | 42 | 18 | 240 | Difference | |
Embodiment 2 and comparative example 2
In the granule that embodiment 1 and comparative example 1 obtain, the 1890mg granule of testing to have good fluidity according to the oar method of dissolution test in the Japanese Pharmacopoeia the 14th edition (containing the 94.5mg nifedipine).As the condition of dissolution test, rotating speed is set to 100rpm, and 900ml water is as test fluid.Be reference purpose, also press similar manner test 94.5mg nifedipine powder self.Table 2 shows the result.
(prescription A～C) shows and is higher than comparative example 2 particulate strippings the granule of all embodiment 2.On the other hand, wherein show and the similar value of prescription D that wherein adds the low hydroxypropyl cellulose that replaces as the amount of the hydroxypropyl cellulose of the low replacement of disintegrating agent prescription E less than prescribed limit of the present invention, so dissolubility not raising basically.The bigger prescription F of amount for wherein hanging down the hydroxypropyl cellulose that replaces causes obstruction in fluidized bed prilling, therefore be difficult to carry out good pelletize.
Consequently, obviously the granule of solid dispersion of the present invention has excellent dissolubility.
Table 2
| Stripping (%) | ||||||||||
| Time (minute) | 0 | 2 | 5 | 10 | 15 | 20 | 30 | 45 | 60 | |
| Embodiment 2 | Prescription A | 0 | 67.4 | 71.6 | 70.6 | 68.3 | 67.3 | 65.2 | 62.9 | 62.0 |
| Prescription B | 0 | 53.7 | 71.3 | 69.7 | 66.7 | 65.9 | 61.8 | 60.8 | 59.5 | |
| Prescription C | 0 | 65.8 | 73.1 | 70.4 | 68.3 | 67.7 | 65.9 | 64.0 | 61.6 | |
| Comparative example 2 | Prescription D | 0 | 46.9 | 59.8 | 61.2 | 59.8 | 58.2 | 57.0 | 54.9 | 54.1 |
| Prescription E | 0 | 56.5 | 58.2 | 60.2 | 59.0 | 57.4 | 55.3 | 54.1 | 52.3 | |
| Prescription F | - | - | - | - | - | - | - | - | - | |
| Nifedipine self | 0 | 0.6 | 3.4 | 9.3 | 10 | 10.6 | 11.9 | 11.9 | 11.9 | |
Embodiment 3 and comparative example 3
By dissolving 1.2g nifedipine and 2.4g hydroxypropyl emthylcellulose (HPMC) (methoxyl groups of the propoxyl of 8.7 weight % and 28.8 weight %) in the mixed solvent that contains 8: 2 second alcohol and water of weight ratio, or 6g nifedipine and 12g hydroxypropyl emthylcellulose (HPMC) (methoxyl groups of the hydroxypropyl of 8.7 weight % and 28.8 weight %), preparation solid dispersion liquid solution.The solid dispersion liquid solution is injected on the mixture that mobile hydroxypropyl cellulose (L-HPC) (propoxyls of 10.9 weight %) by low replacement, lactose (Pharmatose that DMV International makes) and corn starch (Nihon Shokuhin Kako Co., the corn starch W that Ltd. makes) have constituted in fluidized bed prilling coating equipment (the Multiplex MP-01 that POWREX CORPORATION makes).Make product pelletize and dry, use 30 orders (hole: sieve control particle diameter 500 μ m).Obtain granule like this.Use granule as the powder that is used for tabletting, the magnesium stearate of 0.5 weight % be added to the powder that is used for tabletting as lubricant, mix product, and in rotary tablet machine (Vergo that Kikusui Seisakusho Ltd. makes) treatment mixture.Consequently, make the 210mg tablet.As a comparative example, contain its amount outside prescribed limit of the present invention and by the similar manner manufacturing as the tablet of the hydroxypropyl emthylcellulose of water-soluble polymer.The hardness and the disintegrative of test gained tablet.The results are shown in table 3.
(prescription G～I) shows suitable hardness and excellent disintegrative to the tablet that obtains among the embodiment 3.
On the other hand, contain its amount outside prescribed limit of the present invention and the tablet that obtains in the comparative example 3 as the hydroxypropyl emthylcellulose of water-soluble polymer (prescription J～L) shows lower disintegrative.
Table 3
| Form | Always (g) | Hardness (kgf) | Disintegration time (minute) | ||||||
| Nifedipine (g) | HPMC (g) | L-HPC (g) | Lactose (g) | Corn starch (g) | |||||
| Embodiment 3 | Prescription G | 1.2 | 2.4 | 48 | 131.9 | 56.5 | 240 | 7 | 4.3 |
| Prescription H | 6 | 12 | 48 | 121.8 | 52.2 | 240 | 7.4 | 7.4 | |
| Formula I | 6 | 12 | 96 | 88.2 | 37.8 | 240 | 6.1 | 7.1 | |
| Comparative example 3 | Prescription J | 6 | 12 | - | 155.4 | 66.6 | 240 | 10 | 24.4 |
| Prescription K | 12 | 24 | 48 | 109.2 | 46.8 | 240 | 10 | 21.6 | |
| Prescription L | 12 | 24 | 96 | 75.6 | 32.4 | 240 | 9.4 | 25.3 | |
Embodiment 4 and comparative example 4
By the mode identical, the 1890mg tablet (containing the 47.25mg nifedipine) that obtains in embodiment 3 and the comparative example 3 is carried out dissolution test with embodiment 2.In addition, be reference purpose, also press similar manner test 47.25mg nifedipine powder self.The results are shown in table 4.
(prescription G～I) shows never the stripping result than particulate powder difference to the tablet that obtains among the embodiment 4.In addition, improve stripping by the amount that improves disintegrating agent.For the prescription J that wherein adds the hydroxypropyl cellulose of the low replacement that is used as disintegrating agent, dissolubility does not improve basically.
On the other hand, for containing its amount outside prescribed limit of the present invention and as the prescription J and the K of the hydroxypropyl emthylcellulose of water-soluble polymer, in test, on tablet surface, form the hydrogel of water-soluble polymer, therefore pass in time, begin slow release and allow stripping from the surface, thereby in conventional embodiment, observe the elongated and stripping of disintegration time and improve insufficient.
Therefore, obviously the tablet of solid dispersion of the present invention has excellent disintegrative and excellent dissolubility.
Table 4
| Stripping (%) | ||||||||||
| Time (minute) | 0 | 2 | 5 | 10 | 15 | 20 | 30 | 45 | 60 | |
| Embodiment 4 | Prescription G | 0 | 42.0 | 74.6 | 83.9 | 79.3 | 76.9 | 70.7 | 71.5 | 70.7 |
| Prescription H | 0 | 41.4 | 66.3 | 71.2 | 72.1 | 63.8 | 65.4 | 67.1 | 63.0 | |
| Formula I | 0 | 39.8 | 69.6 | 81.2 | 79.5 | 77.9 | 77.0 | 78.7 | 84.5 | |
| Comparative example 4 | Prescription J | 0 | 7.5 | 21.8 | 42.8 | 50.3 | 49.5 | 52.8 | 51.1 | 50.3 |
| Prescription K | 0 | 7.6 | 17.1 | 25.4 | 31.2 | 33.1 | 35.0 | 35.9 | 36.6 | |
| Prescription L | 0 | 9.2 | 17.8 | 25.9 | 30.4 | 33.2 | 35.4 | 39.9 | 39.1 | |
| Nifedipine self | 0 | 0.6 | 3.4 | 9.3 | 10 | 10.6 | 11.9 | 11.9 | 11.9 | |
Claims (10)
1. the granule of a solid dispersion contains poorly soluble medicine, water-soluble polymer, excipient and disintegrating agent, and the content of wherein said water-soluble polymer is 1～10 weight %, and the content of described disintegrating agent is 15～50 weight %.
2. the granule of solid dispersion as claimed in claim 1, wherein said water-soluble polymer is selected from alkylcellulose, hydroxy alkyl cellulose, hydroxyalkyl alkylcellulose, polyvinyl alcohol and polyvinylpyrrolidone.
3. the granule of solid dispersion as claimed in claim 1 or 2, wherein said disintegrating agent are the hydroxypropyl celluloses of low replacement with propoxyl of 5～16 weight %.
4. to be bulking volume density be the hydroxypropyl cellulose of the low replacement of 0.60g/ml at least for 0.40g/ml and jolt ramming volume density at least for the granule of solid dispersion as claimed in claim 3, wherein said disintegrating agent.
5. particulate method for preparing solid dispersion may further comprise the steps: jet spread or be dissolved with the water-soluble polymer solution of poorly soluble medicine on the mixed-powder of excipient and disintegrating agent; And make the product pelletize also dry.
6. the tablet of a solid dispersion contains poorly soluble medicine, water-soluble polymer, excipient and disintegrating agent, and the content of wherein said water-soluble polymer is 1～5 weight %, and the content of described disintegrating agent is 15～50 weight %.
7. the tablet of solid dispersion as claimed in claim 6, wherein said water-soluble polymer is selected from alkylcellulose, hydroxy alkyl cellulose, hydroxyalkyl alkylcellulose, polyvinyl alcohol and polyvinylpyrrolidone.
8. as the tablet of claim 6 or 7 described solid dispersion, wherein said disintegrating agent is the hydroxypropyl cellulose of low replacement with propoxyl of 5～16 weight %.
9. to be bulking volume density be the hydroxypropyl cellulose of the low replacement of 0.60g/ml at least for 0.40g/ml and jolt ramming volume density at least for the tablet of solid dispersion as claimed in claim 8, wherein said disintegrating agent.
10. method for preparing the tablet of solid dispersion may further comprise the steps: jet spread or be dissolved with the water-soluble polymer solution of poorly soluble medicine on the mixed-powder of excipient and disintegrating agent; And make the product pelletize also dry.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2006116272 | 2006-04-20 | ||
| JP2006116272 | 2006-04-20 | ||
| JP2007087957 | 2007-03-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101057833A true CN101057833A (en) | 2007-10-24 |
Family
ID=38864238
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200710093774 Pending CN101057833A (en) | 2006-04-20 | 2007-04-18 | Solid dispersion preparation |
Country Status (2)
| Country | Link |
|---|---|
| JP (1) | JP5576963B2 (en) |
| CN (1) | CN101057833A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109157516A (en) * | 2018-11-05 | 2019-01-08 | 天津双硕医药科技有限公司 | A kind of Cilostazol oral solid drug composition |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH07118154A (en) * | 1993-10-22 | 1995-05-09 | Dainippon Pharmaceut Co Ltd | Solid dispersion and granular preparation |
| JP2004067606A (en) * | 2002-08-08 | 2004-03-04 | Zensei Yakuhin Kogyo Kk | Orally administrable itraconazole preparation |
| DK1683524T3 (en) * | 2003-11-14 | 2011-03-14 | Ajinomoto Kk | Solid-form dispersion or phenyalanine derivative solid form medical preparation |
-
2007
- 2007-04-18 CN CN 200710093774 patent/CN101057833A/en active Pending
-
2013
- 2013-05-08 JP JP2013098337A patent/JP5576963B2/en active Active
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109157516A (en) * | 2018-11-05 | 2019-01-08 | 天津双硕医药科技有限公司 | A kind of Cilostazol oral solid drug composition |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2013147512A (en) | 2013-08-01 |
| JP5576963B2 (en) | 2014-08-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101057834B (en) | Solid preparation comprising enteric solid dispersion | |
| JP5612462B2 (en) | Particulate material for dosage forms | |
| US8663698B2 (en) | Solid dispersion preparation | |
| CN101120922B (en) | Solid dosage form comprising solid dispersion and method for producing the same | |
| TW200534878A (en) | Direct compression formulation and process | |
| TW201023897A (en) | Directly compressible granular microcrystalline cellulose based excipient, manufacturing process and use thereof | |
| US20170112768A1 (en) | Directly compressible granular microcrystalline cellulose based excipient, manufacturing process and use thereof | |
| KR101136659B1 (en) | Solid preparation comprising solid dispersion and method for producing the same | |
| EP2207533B1 (en) | Directly compressible high functionality granular microcrystalline cellulose based excipient, manufacturing process and use thereof | |
| CN101057833A (en) | Solid dispersion preparation | |
| EP2379061B1 (en) | Precompacted fast-disintegrating formulations of compounds with a low oral bioavailability | |
| CN116801867A (en) | Solid tablet dosage form of riluzole | |
| JP5711969B6 (en) | Directly compressible, highly functional, granular microcrystalline cellulose-based excipient, manufacturing process and use thereof | |
| CA2768452A1 (en) | Material and process for incorporation of low dosage active pharmaceutical ingredients and use thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20071024 |