CN105616419A - Pharmaceutical composition containing cyclin inhibitor solid dispersion, and preparation method thereof - Google Patents
Pharmaceutical composition containing cyclin inhibitor solid dispersion, and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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Abstract
The present invention discloses a pharmaceutical composition containing a cyclin inhibitor solid dispersion, and a preparation method thereof, and particularly relates to a pharmaceutical composition adopting 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazine-1-yl-pyridine-2-yl-amino)-8H-pyrido[2,3-d]pyrimidine-7-one represented by a formula I or a salt thereof as an active component, a preparation method and uses thereof, wherein the pharmaceutical composition comprises a solid dispersion, a disintegrating agent, a diluent, a binder, a glidant or a lubricant prepared from the compound represented by the formula I. According to the present invention, with the solid dispersion or clathrate technology, the dissolution of the poorly soluble drug is improved, and the bioavailability is improved. The formula I is defined in the specification.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, be specifically related to pharmaceutical preparation comprising cyclin inhibitors and preparation method thereof.
Background technology
Cell cycle protein dependent kinase (CDK) has 13 members, Dou Shu serine/threonine protein kitase family, rely on the combination with cyclin (cyclin), promote that Cell Cycle changes, start DNA synthesis and regulating cell such as transcribes at the key function.
CDKs includes the pivotal role risen in the healthy propagation with tumor cell and death, the CDK inhibitor of wide spectrum at all cells, is difficult to represent higher treatment window in particular for without the patient of genescreen. Dosage is big, and toxicity is too high, and little does not have drug effect. So optionally suppressing part CDK just to become increasingly important. Certainly because major part CDK hypotype has chemical constitution like relative proximity, the selectivity how improving CDK inhibitor is again another one challenge.
Type I compound is a kind of targeting CDK4/6 inhibitor, it is possible to Selective depression cell cycle protein dependent kinase 4 and 6 (CDK4/6), recovers cell cycle and controls, blocks tumor cell proliferation. It acts on MDA-MB-435 breast cancer cell, can effectively reduce Rb at Ser780 and Ser795 site phosphorylation, and IC50 is 66nM and 63nM respectively.
Dissolubility about 9 �� g/ml in type I compound water, insoluble or almost insoluble, this directly affects the absorption in vivo of this compound and bioavailability. The solubilization method of difficult-soluble medicine specifically includes that 1. micronization technology; 2. salt is become to become ester; 3. the solubilization technique such as solid dispersion, clathrate.
Summary of the invention
It is an object of the invention to the solubilising problem solving present composition active component as difficult-soluble medicine, it is provided that a kind of pharmaceutical composition that can improve vivo biodistribution availability.
The technical scheme is that and realized by following manner:
Pharmaceutical composition, it comprises the solid dispersion prepared by type I compound, disintegrating agent, diluent, binding agent, lubricant, fluidizer, and wherein each components by weight is as follows:
Optional, described compositions can also comprise correctives, coloring agent or coating material, it is most preferred that, the percentage by weight sum of above-mentioned each component is 100%.
Preferably, described each components by weight is as follows:
Optional, described compositions can also comprise correctives, coloring agent or coating material, it is most preferred that, the percentage by weight sum of above-mentioned each component is 100%.
Preferably, solid dispersion comprises type I compound, carrier material, described material includes one or more in Polyethylene Glycol, poloxamer, polyvinylpyrrolidone, stearic acid, Lac, glycerin gelatine, glyceryl monostearate, preferably, the weight ratio of described type I compound and carrier material is 1:1��1:6, it is furthermore preferred that the weight ratio of described type I compound and carrier material is 1:1��1:4.
Preferably, described diluent at least one in sugar, sugar alcohol, starch and cellulose, it is furthermore preferred that at least one that described diluent is in lactose, microcrystalline Cellulose, starch, its consumption is 15��50%.
Preferably, described binding agent is cellulose derivative and at least one of polyvidone apoplexy due to endogenous wind, it is furthermore preferred that at least one that described binding agent is in hydroxypropylcellulose, polyvidone, its consumption is 2��10%.
Preferably, described disintegrating agent is at least one in cellulose derivative and starch derivatives, it is furthermore preferred that at least one that described disintegrating agent is in polyvinylpolypyrrolidone, carboxymethylstach sodium, cross-linking sodium carboxymethyl cellulose, its consumption is 1��15%.
Preferably, described lubricant is stearate, it is furthermore preferred that described lubricant is magnesium stearate, its consumption is 0.1��2.5%.
Preferably, described fluidizer is at least one in micropowder silica gel and silicon dioxide, and its consumption is 1��5%.
Described solid dispersion is prepared from by the granulation of hot-melt extruded granulator hot melt, aerosol type solid dispersion preparation machine or Fluidbedgranulatingdrier, and wherein said pharmaceutical dosage form is tablet or capsule.
Preferably, the preparation method of described solid dispersion is as follows:
(1) by type I compound and carrier material mix homogeneously;
(2) by the granulation of hot-melt extruded granulator hot melt, aerosol type solid dispersion preparation machine or Fluidbedgranulatingdrier, step (1) gained mixture is prepared into solid dispersion.
Another object of the present invention also resides in a kind of method preparing described pharmaceutical composition of offer, and described compositions is by wet granulation, and method is as follows:
(1) claim 12 step (2) gained solid dispersion is mixed homogeneously with diluent, disintegrating agent, add binding agent and granulate, 45 DEG C of dry 1h;
(2) optional, that dry sieve (1) step by step is dry granule;
(3) granule, fluidizer and the lubricant that blend step (2) is dry in mixer, it is thus achieved that final mixture;
(4) optional, by the mixture of suitable capsule filling machine fill above-mentioned steps (3), prepare capsule;
(5) optional, by suppressing the mixture of above-mentioned steps (3) on suitable tablet machine, by its tabletting, thus preparing label;
(6) optional, with film coating, the label of step (5) is carried out film coating.
Another object of the present invention also resides in the method preparing described pharmaceutical composition providing another kind to substitute, and described compositions is by dry granulation, and method is as follows:
(1) compacting claim 12 step (2) gained solid dispersion, diluent, disintegrating agent and binding agent in suitable roller compactor;
(2) by suitable grinding or screening step, the ribbon that step (1) period obtains is broken into granule;
(3) optional, blend step (2), lubricant and fluidizer in mixer, it is thus achieved that final mixture;
(4) optional, by the mixture of suitable capsule filling machine fill above-mentioned steps (3), prepare capsule;
(5) optional, by suppressing the mixture of above-mentioned steps (3) on suitable tablet machine, by its tabletting, thus preparing label;
(6) optional, with film coating, the label of step (5) is carried out film coating.
Another object of the present invention also resides in the method preparing described pharmaceutical composition providing another kind to substitute, and described compositions is that the method by directly mixing prepares, and step is as follows:
(1) in hopper mixer, hybrid right requires 12 steps (2) gained solid dispersion, binding agent, diluent, disintegrating agent, lubricant and fluidizer, it is thus achieved that mixture;
(2) optional, by the mixture of suitable capsule filling machine fill above-mentioned steps (1), prepare capsule;
(3) optional, by suppressing the mixture of above-mentioned steps (1) on suitable tablet machine, by its tabletting, thus preparing label;
(4) optional, with film coating, the label of step (3) is carried out film coating.
Another object of the present invention also resides in another pharmaceutical composition of offer, and it includes the cyclodextrin clathrate prepared by type I compound.
Preferably, the preparation method of described clathrate one in spray drying or lyophilization.
The invention provides the solid dispersion of a kind of type I compound, clathrate technology and preparation method thereof, big quantity research shows, solid dispersion prepared by the present invention and clathrate can dramatically increase the dissolubility of compound, improves vivo biodistribution availability.
Inventor finds after carrying out great many of experiments; after adopting the granulation of hot-melt extruded granulator hot melt, aerosol type solid dispersion preparation machine or Fluidbedgranulatingdrier that active component and carrier material are made the solid dispersion containing active component; the dissolubility of medicine can be increased significantly, increase the absorption of medicine and improve medicine vivo biodistribution availability.
Detailed description of the invention
Below in conjunction with specific embodiment, embodiment of the present invention are described in detail. Example below is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.
Embodiment 1
1.1 preparation methoies
200gAPI, 200gPEG4000 are joined hot-melt extruded in hot-melt extruded instrument, obtains solid dispersion, pulverized 100 mesh sieves, stand-by.
1000 slice/prescriptions: weigh above-mentioned solid dispersion 50g, lactose 50g, microcrystalline Cellulose 15g, hydroxypropylcellulose 8g, carboxymethylstach sodium 8g; put in wet granulator; stirring 20min; add 50% ethanol water to granulate; 50 DEG C of fluid bed drying 10min, 1.0mm screen cloth granulate, add silicon dioxide 4g and magnesium stearate 1g; middle control content, fill capsule or tabletting.
1.2 dissolubility
| API | Solid dispersion | Physical mixture | |
| Equilbrium solubility (�� g/ml) | 8.9 | 239 | 10.1 |
| Multiple | / | 26.9 | 1.1 |
1.3 dissolution results
Carrying out dissolution investigation with above-mentioned capsule, with reference to Chinese Pharmacopoeia two annex XC the second method paddle method of version in 2010, mixing speed is 75rpm, and dissolution medium is 900mLpH4.5 buffer, and sampling time point is 45min.
Embodiment 2
2.1 preparation methoies
200gAPI, 200gPEG4000 are joined hot-melt extruded in hot-melt extruded instrument, obtains solid dispersion, pulverized 100 mesh sieves, stand-by.
1000 slice/prescriptions: weigh above-mentioned solid dispersion 200g, lactose 50g, microcrystalline Cellulose 25g, hydroxypropylcellulose 4g, carboxymethylstach sodium 4g; put in wet granulator; stirring 20min; add 50% ethanol water to granulate; 50 DEG C of fluid bed drying 10min, 1.0mm screen cloth granulate, add silicon dioxide 2g and magnesium stearate 1g; middle control content, fill capsule or tabletting.
2.2 dissolution results
Carrying out dissolution investigation with above-mentioned capsule, with reference to Chinese Pharmacopoeia two annex XC the second method paddle method of version in 2010, mixing speed is 75rpm, and dissolution medium is 900mLpH4.5 buffer, and sampling time point is 45min.
Embodiment 3
3.1 preparation methoies
200gAPI, 200gPEG4000 are joined hot-melt extruded in hot-melt extruded instrument, obtains solid dispersion, pulverized 100 mesh sieves, stand-by.
1000 slice/prescriptions: weigh above-mentioned solid dispersion 50g, microcrystalline Cellulose 30g, starch 20g, polyvidone 12g, polyvinylpolypyrrolidone 20g; put in wet granulator; stirring 20min; add 50% ethanol water to granulate; 50 DEG C of fluid bed drying 10min, 1.0mm screen cloth granulate, add silicon dioxide 3g and magnesium stearate 1g; middle control content, fill capsule or tabletting.
3.2 dissolution results
Carrying out dissolution investigation with above-mentioned capsule, with reference to Chinese Pharmacopoeia two annex XC the second method paddle method of version in 2010, mixing speed is 75rpm, and dissolution medium is 900mLpH4.5 buffer, and sampling time point is 45min.
Embodiment 4
4.1 preparation methoies
200gAPI, 200gPEG4000 are joined hot-melt extruded in hot-melt extruded instrument, obtains solid dispersion, pulverized 100 mesh sieves, stand-by.
1000 slice/prescriptions: weigh above-mentioned solid dispersion 50g, lactose 20g, starch 30g, polyvidone 12g, polyvinylpolypyrrolidone 20g; put in wet granulator; stirring 20min; add 50% ethanol water to granulate; 50 DEG C of fluid bed drying 10min, 1.0mm screen cloth granulate, add silicon dioxide 3g and magnesium stearate 1g; middle control content, fill capsule or tabletting.
4.2 dissolution results
Carrying out dissolution investigation with above-mentioned capsule, with reference to Chinese Pharmacopoeia two annex XC the second method paddle method of version in 2010, mixing speed is 75rpm, and dissolution medium is 900mLpH4.5 buffer, and sampling time point is 45min.
Embodiment 5
5.1 preparation methoies
100gAPI, 100g poloxamer is joined hot-melt extruded in hot-melt extruded instrument, obtains solid dispersion, pulverized 100 mesh sieves, stand-by.
1000 slice/prescriptions: weigh above-mentioned solid dispersion 50g, lactose 30g, microcrystalline Cellulose 20g, polyvidone 12g, polyvinylpolypyrrolidone 20g; put in wet granulator; stirring 20min; add 50% ethanol water to granulate; 50 DEG C of fluid bed drying 10min, 1.0mm screen cloth granulate, add silicon dioxide 3g and magnesium stearate 1g; middle control content, fill capsule or tabletting.
5.2 dissolubility
| API | Solid dispersion | Physical mixture | |
| Equilbrium solubility (�� g/ml) | 8.9 | 187 | 10.1 |
| Increase multiple | / | 21.0 | 1.1 |
5.3 dissolution results
Carrying out dissolution investigation with above-mentioned capsule, with reference to Chinese Pharmacopoeia two annex XC the second method paddle method of version in 2010, mixing speed is 75rpm, and dissolution medium is 900mLpH4.5 buffer, and sampling time point is 45min.
Embodiment 6
6.1 preparation methoies
50gAPI, 100g poloxamer is joined hot-melt extruded in hot-melt extruded instrument, obtains solid dispersion, pulverized 100 mesh sieves, stand-by.
1000 slice/prescriptions: weigh above-mentioned solid dispersion 75g, lactose 30g, microcrystalline Cellulose 20g, polyvidone 12g, polyvinylpolypyrrolidone 20g; put in wet granulator; stirring 20min; add 50% ethanol water to granulate; 50 DEG C of fluid bed drying 10min, 1.0mm screen cloth granulate, add silicon dioxide 3g and magnesium stearate 1g; middle control content, fill capsule or tabletting.
6.2 dissolubility
| API | Solid dispersion | Physical mixture | |
| Equilbrium solubility (�� g/ml) | 8.9 | 249 | 10.1 |
| Increase multiple | / | 28.0 | 1.1 |
6.3 dissolution results
Carrying out dissolution investigation with above-mentioned capsule, with reference to Chinese Pharmacopoeia two annex XC the second method paddle method of version in 2010, mixing speed is 75rpm, and dissolution medium is 900mLpH4.5 buffer, and sampling time point is 45min.
Embodiment 7
7.1 preparation methoies
50gAPI, 200g poloxamer is joined hot-melt extruded in hot-melt extruded instrument, obtains solid dispersion, pulverized 100 mesh sieves, stand-by.
1000 slice/prescriptions: weigh above-mentioned solid dispersion 125g, lactose 30g, microcrystalline Cellulose 20g, polyvidone 12g, polyvinylpolypyrrolidone 20g; put in wet granulator; stirring 20min; add 50% ethanol water to granulate; 50 DEG C of fluid bed drying 10min, 1.0mm screen cloth granulate, add silicon dioxide 3g and magnesium stearate 1g; middle control content, fill capsule or tabletting.
7.2 dissolubility
| API | Solid dispersion | Physical mixture | |
| Equilbrium solubility (�� g/ml) | 8.9 | 272 | 10.1 |
| Increase multiple | / | 30.6 | 1.1 |
7.3 dissolution results
Carrying out dissolution investigation with above-mentioned capsule, with reference to Chinese Pharmacopoeia two annex XC the second method paddle method of version in 2010, mixing speed is 75rpm, and dissolution medium is 900mLpH4.5 buffer, and sampling time point is 45min.
Embodiment 8
8.1 preparation methoies
50gAPI, 100gKollidonVA64 are joined hot-melt extruded in hot-melt extruded instrument, obtains solid dispersion, pulverized 100 mesh sieves, stand-by.
1000 slice/prescriptions: weigh above-mentioned solid dispersion 75g, lactose 30g, microcrystalline Cellulose 20g, hydroxypropylcellulose 12g, polyvinylpolypyrrolidone 20g, compacting said mixture, is broken into granule, adds silicon dioxide 2.5g and magnesium stearate 1g, middle control content, fill capsule or tabletting.
8.2 dissolubility
| API | Solid dispersion | Physical mixture | |
| Equilbrium solubility (�� g/ml) | 8.9 | 222 | 10.1 |
| Increase multiple | / | 24.9 | 1.1 |
8.3 dissolution results
Carrying out dissolution investigation with above-mentioned capsule, with reference to Chinese Pharmacopoeia two annex XC the second method paddle method of version in 2010, mixing speed is 75rpm, and dissolution medium is 900mLpH4.5 buffer, and sampling time point is 45min.
Embodiment 9
9.1 preparation methoies
Being dissolved in ethanol/methylene mixed solvent by 50gAPI, 150g polyvidone, spray drying prepares solid dispersion, is pulverized 100 mesh sieves, stand-by.
1000 slice/prescriptions: weigh above-mentioned solid dispersion 100g, lactose 30g, microcrystalline Cellulose 30g, cross-linking sodium carboxymethyl cellulose 10g, compacting said mixture, are broken into granule, add magnesium stearate 1.5g, middle control content, fill capsule or tabletting.
9.2 dissolubility
| API | Solid dispersion | Physical mixture | |
| Equilbrium solubility (�� g/ml) | 8.9 | 268 | 10.1 |
| Increase multiple | / | 30.1 | 1.1 |
9.3 dissolution results
Carrying out dissolution investigation with above-mentioned capsule, with reference to Chinese Pharmacopoeia two annex XC the second method paddle method of version in 2010, mixing speed is 75rpm, and dissolution medium is 900mLpH4.5 buffer, and sampling time point is 45min.
Embodiment 10
10.1 preparation method
Being dissolved in ethanol/methylene mixed solvent by 50gAPI, 100g polyvidone, spray drying prepares solid dispersion, is pulverized 100 mesh sieves, stand-by.
1000 slice/prescriptions: weigh above-mentioned solid dispersion 75g, lactose 30g, microcrystalline Cellulose 20g, hydroxypropylcellulose 3g, cross-linking sodium carboxymethyl cellulose 6g, compacting said mixture, is broken into granule, adds magnesium stearate 1.0g, middle control content, fill capsule or tabletting.
10.2 dissolubility
| API | Solid dispersion | Physical mixture | |
| Equilbrium solubility (�� g/ml) | 8.9 | 204 | 10.1 |
| Increase multiple | / | 22.9 | 1.1 |
10.3 dissolution result
Carrying out dissolution investigation with above-mentioned capsule, with reference to Chinese Pharmacopoeia two annex XC the second method paddle method of version in 2010, mixing speed is 75rpm, and dissolution medium is 900mLpH4.5 buffer, and sampling time point is 45min.
Embodiment 11
11.1 preparation method
Being dissolved in ethanol/methylene mixed solvent by 50gAPI, 50g polyvidone, spray drying prepares solid dispersion, is pulverized 100 mesh sieves, stand-by.
1000 slice/prescriptions: weigh above-mentioned solid dispersion 50g, lactose 30g, microcrystalline Cellulose 20g, hydroxypropylcellulose 6g, cross-linking sodium carboxymethyl cellulose 10g; put in wet granulator; stirring 20min; add 50% ethanol water to granulate; 50 DEG C of fluid bed drying 10min, 1.0mm screen cloth granulate, add silicon dioxide 2g and magnesium stearate 1g; middle control content, fill capsule or tabletting.
11.2 dissolubility
| API | Solid dispersion | Physical mixture | |
| Equilbrium solubility (�� g/ml) | 8.9 | 203 | 10.1 |
| Increase multiple | / | 22.8 | 1.1 |
11.3 dissolution result
Carrying out dissolution investigation with above-mentioned capsule, with reference to Chinese Pharmacopoeia two annex XC the second method paddle method of version in 2010, mixing speed is 75rpm, and dissolution medium is 900mLpH4.5 buffer, and sampling time point is 45min.
Embodiment 12
12.1 preparation method
Being dissolved in ethanol/methylene mixed solvent by 50gAPI, 50g polyvidone, spray drying prepares solid dispersion, is pulverized 100 mesh sieves, stand-by.
1000 slice/prescriptions: weigh above-mentioned solid dispersion 50g, lactose 50g, microcrystalline Cellulose 50g, hydroxypropylcellulose 10g, polyvinylpolypyrrolidone 20g, add silicon dioxide 2g and magnesium stearate 1g, middle control content, fill capsule or tabletting.
12.2 dissolubility
| API | Solid dispersion | Physical mixture | |
| Equilbrium solubility (�� g/ml) | 8.9 | 203 | 10.1 |
| Increase multiple | / | 22.8 | 1.1 |
12.3 dissolution result
Carrying out dissolution investigation with above-mentioned capsule, with reference to Chinese Pharmacopoeia two annex XC the second method paddle method of version in 2010, mixing speed is 75rpm, and dissolution medium is 900mLpH4.5 buffer, and sampling time point is 45min.
Embodiment 13
13.1 preparation method
100g microcrystalline Cellulose PH200 is put into preheating in boiling micropill drying machine, 50gAPI, 150g polyvidone is dissolved in ethanol/methylene mixed solvent, spray in boiling micropill drying machine, after solution has sprayed, dry to obtain solid dispersion, stand-by.
1000 slice/prescriptions: weigh above-mentioned solid dispersion 100g, lactose 50g, microcrystalline Cellulose 30g, hydroxypropylcellulose 10g, polyvinylpolypyrrolidone 10g, add silicon dioxide 2g and magnesium stearate 1g, middle control content, fill capsule or tabletting.
13.2 dissolubility
| API | Solid dispersion | Physical mixture | |
| Equilbrium solubility (�� g/ml) | 8.9 | 297 | 10.1 |
| Increase multiple | / | 33.4 | 1.1 |
13.3 dissolution result
Carrying out dissolution investigation with above-mentioned capsule, with reference to Chinese Pharmacopoeia two annex XC the second method paddle method of version in 2010, mixing speed is 75rpm, and dissolution medium is 900mLpH4.5 buffer, and sampling time point is 45min.
Embodiment 14
14.1 preparation method
100g microcrystalline Cellulose PH200 is put into preheating in boiling micropill drying machine, 50gAPI, 150g polyvidone is dissolved in ethanol/methylene mixed solvent, spray in boiling micropill drying machine, after solution has sprayed, dry to obtain solid dispersion, stand-by.
1000 slice/prescriptions: weigh above-mentioned solid dispersion 100g, lactose 20g, microcrystalline Cellulose 10g, hydroxypropylcellulose 10g, carboxymethylstach sodium 5g; put in wet granulator; stirring 20min; add 50% ethanol water to granulate; 50 DEG C of fluid bed drying 10min, 1.0mm screen cloth granulate, add silicon dioxide 2g and magnesium stearate 1g; middle control content, fill capsule or tabletting.
14.2 dissolubility
| API | Solid dispersion | Physical mixture | |
| Equilbrium solubility (�� g/ml) | 8.9 | 297 | 10.1 |
| Increase multiple | / | 33.4 | 1.1 |
14.3 dissolution result
Carrying out dissolution investigation with above-mentioned capsule, with reference to Chinese Pharmacopoeia two annex XC the second method paddle method of version in 2010, mixing speed is 75rpm, and dissolution medium is 900mLpH4.5 buffer, and sampling time point is 45min.
Embodiment 15
15.1 preparation method
100g microcrystalline Cellulose PH200 is put into preheating in boiling micropill drying machine, 50gAPI, 150g polyvidone is dissolved in ethanol/methylene mixed solvent, spray in boiling micropill drying machine, after solution has sprayed, dry to obtain solid dispersion, stand-by.
1000 slice/prescriptions: weigh above-mentioned solid dispersion 100g, lactose 20g, microcrystalline Cellulose 10g, hydroxypropylcellulose 10g, carboxymethylstach sodium 5g, compacting said mixture, are broken into granule, add magnesium stearate 1.0g, middle control content, fill capsule or tabletting.
15.2 dissolubility
| API | Solid dispersion | Physical mixture | |
| Equilbrium solubility (�� g/ml) | 8.9 | 297 | 10.1 |
| Increase multiple | / | 33.4 | 1.1 |
15.3 dissolution result
Carrying out dissolution investigation with above-mentioned capsule, with reference to Chinese Pharmacopoeia two annex XC the second method paddle method of version in 2010, mixing speed is 75rpm, and dissolution medium is 900mLpH4.5 buffer, and sampling time point is 45min.
Embodiment 16
Being dissolved in ethanol/methylene mixed solvent by 50gAPI, 50g beta-schardinger dextrin-, spray drying prepares clathrate, is pulverized 100 mesh sieves, stand-by.
1000 slice/prescriptions: weigh above-mentioned clathrate 50g, lactose 50g, microcrystalline Cellulose 50g, hydroxypropylcellulose 8g, polyvinylpolypyrrolidone 15g, add silicon dioxide 2g and magnesium stearate 1g, middle control content, fill capsule or tabletting.
16.2 dissolubility
| API | Clathrate | Physical mixture | |
| Equilbrium solubility (�� g/ml) | 8.9 | 298 | 10.1 |
| Increase multiple | / | 33.5 | 1.1 |
16.3 dissolution result
Carrying out dissolution investigation with above-mentioned capsule, with reference to Chinese Pharmacopoeia two annex XC the second method paddle method of version in 2010, mixing speed is 75rpm, and dissolution medium is 900mLpH4.5 buffer, and sampling time point is 45min.
Embodiment 17
Being dissolved in ethanol/methylene mixed solvent by 50gAPI, 20g beta-schardinger dextrin-, 30g mannitol, lyophilization prepares clathrate, is pulverized 100 mesh sieves, stand-by.
1000 slice/prescriptions: weigh above-mentioned clathrate 50g, lactose 30g, microcrystalline Cellulose 20g, hydroxypropylcellulose 8g, cross-linking sodium carboxymethyl cellulose 15g; put in wet granulator; stirring 20min; add 50% ethanol water to granulate; 50 DEG C of fluid bed drying 10min, 1.0mm screen cloth granulate, add silicon dioxide 2g and magnesium stearate 1g; middle control content, fill capsule or tabletting.
17.2 dissolubility
| API | Clathrate | Physical mixture | |
| Equilbrium solubility (�� g/ml) | 8.9 | 278 | 10.1 |
| Increase multiple | / | 31.2 | 1.1 |
17.3 dissolution result
Carrying out dissolution investigation with above-mentioned capsule, with reference to Chinese Pharmacopoeia two annex XC the second method paddle method of version in 2010, mixing speed is 75rpm, and dissolution medium is 900mLpH4.5 buffer, and sampling time point is 45min.
Claims (17)
1. a pharmaceutical composition, it includes the solid dispersion prepared by type I compound, disintegrating agent, diluent, binding agent, fluidizer or lubricant:
2. pharmaceutical composition according to claim 1, it comprises the solid dispersion prepared by type I compound, disintegrating agent, diluent, binding agent, lubricant or fluidizer, and each components by weight is as follows:
3. pharmaceutical composition according to claim 1, it comprises the solid dispersion prepared by type I compound, disintegrating agent, diluent, binding agent, lubricant or fluidizer, and wherein each components by weight is as follows:
4. pharmaceutical composition according to claim 1, it is characterized in that, described solid dispersion comprises type I compound and carrier material, one or more in Polyethylene Glycol, poloxamer, polyvinylpyrrolidone, stearic acid, Lac, glycerin gelatine or glyceryl monostearate of described carrier material; Preferably, the weight ratio of described type I compound and carrier material is 1:1��1:6, more preferably 1:1��1:4.
5. pharmaceutical composition according to claim 1, it is characterised in that described diluent at least one in sugar, sugar alcohol, starch and cellulose.
6. pharmaceutical composition according to claim 1, it is characterised in that described binding agent is selected from least one of cellulose derivative and polyvidone apoplexy due to endogenous wind.
7. pharmaceutical composition according to claim 1, it is characterised in that described disintegrating agent at least one in cellulose derivative and starch derivatives.
8. pharmaceutical composition according to claim 1, it is characterised in that described lubricant is stearate.
9. pharmaceutical composition according to claim 1, it is characterised in that described fluidizer at least one in micropowder silica gel and silicon dioxide.
10. the pharmaceutical composition according to any one in claim 1-9, it is characterised in that described pharmaceutical composition makes tablet or capsule.
11. the pharmaceutical composition according to any one in claim 1-9, it is characterised in that described solid dispersion is prepared from by hot-melt extruded granulator, aerosol type solid dispersion preparation machine or Fluidbedgranulatingdrier.
12. pharmaceutical composition according to claim 11, it is characterised in that the preparation method of described solid dispersion is as follows:
1) by type I compound and carrier material mix homogeneously;
2) granulated by hot-melt extruded granulator hot melt, aerosol type solid dispersion preparation machine or Fluidbedgranulatingdrier be by step 1) gained mixture prepares into solid dispersion.
13. the method for the pharmaceutical composition that preparation is according to any one in claim 1-9, it is characterised in that described compositions is by wet granulation, and method is as follows:
1) by claim 12 step 2) gained solid dispersion mixs homogeneously with diluent, disintegrating agent, and add binding agent and granulate, 45 DEG C of dry 1h;
2) optional, dry sieve step by step 1) dry granule;
3) blend step 2 in mixer) dry granule, fluidizer and lubricant, it is thus achieved that final mixture;
4) optional, by suitable capsule filling machine fill above-mentioned steps 3) mixture, prepare capsule;
5) optional, by suitable tablet machine suppress above-mentioned steps 3) mixture, by its tabletting, thus prepare label;
6) optional, with film coating to step 5) label carry out film coating.
14. the method for the pharmaceutical composition that preparation is according to any one in claim 1-9, it is characterised in that described compositions is by dry granulation, and method is as follows:
1) compacting claim 12 step 2 in suitable roller compactor) gained solid dispersion, diluent, disintegrating agent and binding agent;
2) by suitable grinding or screening step, by step 1) period obtain ribbon be broken into granule;
3) optional, blend step 2 in mixer), lubricant and fluidizer, it is thus achieved that final mixture;
4) optional, by suitable capsule filling machine fill above-mentioned steps 3) mixture, prepare capsule;
5) optional, by suitable tablet machine suppress above-mentioned steps 3) mixture, by its tabletting, thus prepare label;
6) optional, with film coating to step 5) label carry out film coating.
15. the method for the pharmaceutical composition that preparation is according to any one in claim 1-9, it is characterised in that described compositions is that the method by directly mixing prepares, and step is as follows:
1) in hopper mixer, hybrid right requires 12 steps 2) gained solid dispersion, binding agent, diluent, disintegrating agent, lubricant and fluidizer, it is thus achieved that mixture;
2) optional, by suitable capsule filling machine fill above-mentioned steps 1) mixture, prepare capsule;
3) optional, by suitable tablet machine suppress above-mentioned steps 1) mixture, by its tabletting, thus prepare label;
4) optional, with film coating to step 3) label carry out film coating.
16. a pharmaceutical composition, it includes the cyclodextrin clathrate prepared by type I compound.
17. pharmaceutical composition according to claim 16, the preparation method of described cyclodextrin clathrate one in spray drying or lyophilization.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410625479.8A CN105616419A (en) | 2014-11-07 | 2014-11-07 | Pharmaceutical composition containing cyclin inhibitor solid dispersion, and preparation method thereof |
| CN201580043440.8A CN106794182B (en) | 2014-11-07 | 2015-11-06 | Pharmaceutical composition containing cyclin inhibitor solid dispersion and preparation method thereof |
| PCT/CN2015/093952 WO2016070833A1 (en) | 2014-11-07 | 2015-11-06 | Pharmaceutical composition containing cell cycle protein inhibitor solid dispersion, and preparation method for pharmaceutical composition |
| TW104136657A TWI727935B (en) | 2014-11-07 | 2015-11-06 | A pharmaceutical composition including solid dispersion of cyclin inhibitor and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410625479.8A CN105616419A (en) | 2014-11-07 | 2014-11-07 | Pharmaceutical composition containing cyclin inhibitor solid dispersion, and preparation method thereof |
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| Publication Number | Publication Date |
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| CN105616419A true CN105616419A (en) | 2016-06-01 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410625479.8A Pending CN105616419A (en) | 2014-11-07 | 2014-11-07 | Pharmaceutical composition containing cyclin inhibitor solid dispersion, and preparation method thereof |
| CN201580043440.8A Active CN106794182B (en) | 2014-11-07 | 2015-11-06 | Pharmaceutical composition containing cyclin inhibitor solid dispersion and preparation method thereof |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201580043440.8A Active CN106794182B (en) | 2014-11-07 | 2015-11-06 | Pharmaceutical composition containing cyclin inhibitor solid dispersion and preparation method thereof |
Country Status (3)
| Country | Link |
|---|---|
| CN (2) | CN105616419A (en) |
| TW (1) | TWI727935B (en) |
| WO (1) | WO2016070833A1 (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017166451A1 (en) * | 2016-03-29 | 2017-10-05 | 深圳市华力康生物医药有限公司 | Pharmaceutical preparation of palbociclib and preparation method thereof |
| CN107510847A (en) * | 2016-06-16 | 2017-12-26 | 常州方楠医药技术有限公司 | A kind of Pharmaceutical composition that XiLin solid dispersions are won containing unformed pa and preparation method thereof |
| WO2019056163A1 (en) * | 2017-09-19 | 2019-03-28 | 浙江华海药业股份有限公司 | N-formyl palbociclib and preparation method therefor and use thereof, and palbociclib preparation and quality control method therefor |
| CN114404380A (en) * | 2021-12-30 | 2022-04-29 | 重庆华森制药股份有限公司 | Terazosin hydrochloride capsule and preparation method thereof |
| US11464779B2 (en) | 2016-03-29 | 2022-10-11 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical formulation of palbociclib and a preparation method thereof |
| US11471418B2 (en) | 2020-09-29 | 2022-10-18 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical compositions of amorphous solid dispersions and methods of preparation thereof |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1648889B1 (en) * | 2003-07-11 | 2008-10-29 | Warner-Lambert Company LLC | Isethionate salt of a selective cdk4 inhibitor |
| CN101146806A (en) * | 2005-01-21 | 2008-03-19 | 阿斯泰克斯治疗有限公司 | Pyrazole derivatives for the inhibition of CDK and GSK |
| CN101484439A (en) * | 2006-05-05 | 2009-07-15 | 阿斯泰克斯治疗有限公司 | 4- (2,6-dichloro-benzoylamino) -1h-pyrazole-3-carboxylic acid (1-methanesulphonyl-piperidin-4-yl) -amide for the treatment of cancer |
| WO2007129062A1 (en) * | 2006-05-08 | 2007-11-15 | Astex Therapeutics Limited | Pharmaceutical combinations of diazole derivatives for cancer treatment |
| TWI471321B (en) * | 2009-06-08 | 2015-02-01 | Abbott Gmbh & Co Kg | Pharmaceutical dosage form for oral administration of a bcl-2 family inhibitor |
| EP2580217A4 (en) * | 2010-06-10 | 2014-06-18 | Afraxis Holdings Inc | 6-(ethynyl)pyrido[2,3-d]pyrimidin-7(8h)-ones for the treatment of cns disorders |
| US20140220112A1 (en) * | 2013-02-01 | 2014-08-07 | Zoneone Pharma, Inc. | Transformation of drug cyclodextrin complex compositions into compositions of mixtures of lipid vesicle encapsulated drug and cyclodextrin drug complexes |
-
2014
- 2014-11-07 CN CN201410625479.8A patent/CN105616419A/en active Pending
-
2015
- 2015-11-06 CN CN201580043440.8A patent/CN106794182B/en active Active
- 2015-11-06 TW TW104136657A patent/TWI727935B/en not_active IP Right Cessation
- 2015-11-06 WO PCT/CN2015/093952 patent/WO2016070833A1/en active Application Filing
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017166451A1 (en) * | 2016-03-29 | 2017-10-05 | 深圳市华力康生物医药有限公司 | Pharmaceutical preparation of palbociclib and preparation method thereof |
| GB2564793A (en) * | 2016-03-29 | 2019-01-23 | Shenzhen Pharmacin Co Ltd | Pharmaceutical preparation of palbociclib and preparation method thereof |
| GB2564793B (en) * | 2016-03-29 | 2020-09-09 | Shenzhen Pharmacin Co Ltd | A pharmaceutical formulation of palbociclib and a preparation method thereof |
| US11464779B2 (en) | 2016-03-29 | 2022-10-11 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical formulation of palbociclib and a preparation method thereof |
| CN107510847A (en) * | 2016-06-16 | 2017-12-26 | 常州方楠医药技术有限公司 | A kind of Pharmaceutical composition that XiLin solid dispersions are won containing unformed pa and preparation method thereof |
| WO2019056163A1 (en) * | 2017-09-19 | 2019-03-28 | 浙江华海药业股份有限公司 | N-formyl palbociclib and preparation method therefor and use thereof, and palbociclib preparation and quality control method therefor |
| US11471418B2 (en) | 2020-09-29 | 2022-10-18 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical compositions of amorphous solid dispersions and methods of preparation thereof |
| CN114404380A (en) * | 2021-12-30 | 2022-04-29 | 重庆华森制药股份有限公司 | Terazosin hydrochloride capsule and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106794182A (en) | 2017-05-31 |
| TW201617069A (en) | 2016-05-16 |
| TWI727935B (en) | 2021-05-21 |
| CN106794182B (en) | 2020-02-14 |
| WO2016070833A1 (en) | 2016-05-12 |
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Application publication date: 20160601 |