CN106794182B - 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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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- 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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- A61K47/00—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
- A61K47/36—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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- A—HUMAN NECESSITIES
- 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
- A61K47/50—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
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
A pharmaceutical composition and its preparation method are provided. The pharmaceutical composition comprises 6-acetyl-8-cyclopentyl-5-methyl-2- (5-piperazin-1-yl-pyridin-2-ylamino) -8H-pyrido [2,3-d]Solid dispersion prepared from pyrimidine-7-ketone, disintegrant, diluent, adhesive, glidant or lubricant.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a pharmaceutical preparation containing a cyclin inhibitor and a preparation method thereof.
Background
Cyclin-dependent kinases (CDKs) share 13 members, all belong to the serine/threonine protein kinase family, and rely on binding to cyclins to promote phase transition in the cell cycle, initiate DNA synthesis, regulate cellular transcription, and other key functions.
The critical role played by CDKs in the proliferation and death of all cells, including healthy and tumor cells, is that a broad spectrum of CDK inhibitors, especially in patients who have not been genetically screened, has been shown to be difficult to demonstrate with a high therapeutic window. The dosage is larger, the toxicity is too high, and the dosage is smaller and the drug effect is not good. It becomes particularly important to selectively inhibit portions of the CDK. Of course, because most CDK isoforms have relatively similar chemical structures, increasing the selectivity of CDK inhibitors is another challenge.
The compound of the formula I is a targeted CDK4/6 inhibitor, can selectively inhibit cyclin-dependent kinases 4 and 6(CDK4/6), restores cell cycle control, and blocks tumor cell proliferation. The compound acts on MDA-MB-435 breast cancer cells, can effectively reduce phosphorylation of Rb at Ser780 and Ser795 sites, and IC50 is 66nM and 63nM respectively.
The solubility of the compound of the formula I in water is about 9 mu g/ml, and the compound is insoluble or almost insoluble, which directly influences the absorption and bioavailability of the compound in vivo, and the solubilization methods of the difficult-to-dissolve medicines mainly comprise ① micronization technology, ② salt formation into ester, ③ solid dispersion, inclusion compound and other solubilization technologies.
Disclosure of Invention
The invention aims to solve the problem of solubilization of the active ingredients of the composition as a poorly soluble medicine and provide a pharmaceutical composition capable of improving in-vivo bioavailability.
The technical scheme of the invention is realized by the following modes:
the pharmaceutical composition comprises a solid dispersion prepared from a compound shown in a formula I, a disintegrant, a diluent, a binder, a lubricant and a glidant, wherein the weight ratio of each component is as follows:
optionally, the composition may further comprise a flavoring agent, a coloring agent or a coating material, and most preferably, the sum of the weight percentages of the components is 100%.
Preferably, the weight ratio of each component is as follows:
optionally, the composition may further comprise a flavoring agent, a coloring agent or a coating material, and most preferably, the sum of the weight percentages of the components is 100%.
Preferably, the solid dispersion comprises a compound shown in the formula I and a carrier material, wherein the material comprises one or more of polyethylene glycol, poloxamer, polyvinylpyrrolidone, stearic acid, shellac, glycerogelatin and glyceryl monostearate, preferably, the weight ratio of the compound shown in the formula I to the carrier material is 1: 1-1: 6, and more preferably, the weight ratio of the compound shown in the formula I to the carrier material is 1: 1-1: 4.
Preferably, the diluent is selected from at least one of sugar, sugar alcohol, starch and cellulose, more preferably, the diluent is selected from at least one of lactose, microcrystalline cellulose and starch, and the dosage of the diluent is 15-50%.
Preferably, the binder is at least one of cellulose derivatives and povidone, more preferably, the binder is at least one selected from hydroxypropyl cellulose and povidone, and the dosage of the binder is 2-10%.
Preferably, the disintegrant is at least one of cellulose derivatives and starch derivatives, and more preferably, the disintegrant is at least one selected from crospovidone, carboxymethyl starch sodium and croscarmellose sodium, and the dosage of the disintegrant is 1-15%.
Preferably, the lubricant is stearate, and more preferably, the lubricant is magnesium stearate, and the dosage of the magnesium stearate is 0.1-2.5%.
Preferably, the glidant is at least one of micropowder silica gel and silicon dioxide, and the dosage of the glidant is 1-5%.
The solid dispersion is prepared by hot-melt granulation of a hot-melt extrusion granulator, a spray-type solid dispersion preparation machine or an ebullient granulation dryer, wherein the pharmaceutical dosage form is a tablet or a capsule.
Preferably, the preparation method of the solid dispersion is as follows:
(1) uniformly mixing the compound of formula I and a carrier material;
(2) preparing the mixture obtained in the step (1) into a solid dispersion by a hot melt extrusion granulator, a hot melt granulation, a spray type solid dispersion preparation machine or a boiling granulation dryer.
It is also an object of the present invention to provide a process for preparing said pharmaceutical composition by wet granulation, the process comprising:
(1) uniformly mixing the solid dispersion obtained in the step (2) of the claim 12 with a diluent and a disintegrating agent, adding a binding agent, granulating, and drying at 45 ℃ for 1 h;
(2) optionally, drying the dried particles of screening step (1);
(3) mixing the dried granules of step (2), glidant and lubricant in a mixer to obtain a final mixture;
(4) optionally, filling the mixture of step (3) above by a suitable capsule filling machine to prepare capsules;
(5) optionally, tabletting the mixture of step (3) above by compressing it on a suitable tabletting machine to produce tablet cores;
(6) optionally, the core tablet of step (5) is film coated with a film coating.
It is also an object of the present invention to provide an alternative process for the preparation of said pharmaceutical composition, said composition being prepared by dry granulation, the process comprising:
(1) compacting the solid dispersion of step (2) of claim 12, diluent, disintegrant and binder in a suitable roller press;
(2) breaking the ribbon obtained during step (1) into granules by means of a suitable grinding or sieving step;
(3) optionally, mixing step (2), lubricant and glidant in a mixer to obtain a final mixture;
(4) optionally, filling the mixture of step (3) above by a suitable capsule filling machine to prepare capsules;
(5) optionally, tabletting the mixture of step (3) above by compressing it on a suitable tabletting machine to produce tablet cores;
(6) optionally, the core tablet of step (5) is film coated with a film coating.
It is also an object of the present invention to provide an alternative process for preparing said pharmaceutical composition, said composition being prepared by a direct mixing process, comprising the steps of:
(1) mixing the solid dispersion obtained in step (2) of claim 12, a binder, a diluent, a disintegrant, a lubricant and a glidant in a hopper mixer to obtain a mixture;
(2) optionally, filling the mixture of step (1) above by a suitable capsule filling machine to prepare capsules;
(3) optionally, tabletting the mixture of step (1) above by compressing it on a suitable tabletting machine to produce tablet cores;
(4) optionally, the core tablet of step (3) is film coated with a film coating.
It is also an object of the present invention to provide another pharmaceutical composition comprising a cyclodextrin inclusion complex prepared from a compound of formula I.
Preferably, the preparation method of the clathrate compound is selected from one of spray drying and freeze drying.
A great deal of research shows that the solid dispersion and the inclusion compound prepared by the invention can obviously increase the solubility of the compound and improve the bioavailability in vivo.
After a great deal of experiments, the inventor finds that after the active ingredients and the carrier materials are prepared into the solid dispersion containing the active ingredients by adopting a hot-melt extrusion granulator, a hot-melt granulation and spray type solid dispersion preparation machine or a boiling granulation dryer, the solubility of the medicine can be obviously increased, the absorption of the medicine can be increased, and the bioavailability of the medicine in vivo can be improved.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to specific examples. The following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the invention.
Example 1
1.1 preparation method
200g of API and 200g of PEG4000 are added into a hot melt extrusion instrument for hot melt extrusion to obtain a solid dispersion, and the solid dispersion is crushed and sieved by a 100-mesh sieve for standby.
1000 tablets per granule of the formula: weighing 50g of the solid dispersion, 50g of lactose, 15g of microcrystalline cellulose, 8g of hydroxypropyl cellulose and 8g of carboxymethyl starch sodium, putting into a wet granulator, stirring for 20min, adding 50% ethanol water for granulation, drying with a fluidized bed at 50 ℃ for 10min, granulating with a 1.0mm screen, adding 4g of silicon dioxide and 1g of magnesium stearate, controlling the content, and filling into capsules or tabletting.
1.2 solubility
| API | Solid dispersion | Physical mixture | |
| Equilibrium solubility (. mu.g/ml) | 8.9 | 239 | 10.1 |
| Multiple of | / | 26.9 | 1.1 |
1.3 dissolution results
The capsule is used for dissolution rate investigation, and the capsule is prepared by referring to XC second method and paddle method which is an annex of the second part of Chinese pharmacopoeia 2010 edition, wherein the stirring speed is 75rpm, the dissolution medium is 900mL of buffer solution with the pH value of 4.5, and the sampling time point is 45 min.
Example 2
2.1 preparation method
200g of API and 200g of PEG4000 are added into a hot melt extrusion instrument for hot melt extrusion to obtain a solid dispersion, and the solid dispersion is crushed and sieved by a 100-mesh sieve for standby.
1000 tablets per granule of the formula: weighing 200g of the solid dispersion, 50g of lactose, 25g of microcrystalline cellulose, 4g of hydroxypropyl cellulose and 4g of carboxymethyl starch sodium, putting into a wet granulator, stirring for 20min, adding 50% ethanol water for granulation, drying by a fluidized bed at 50 ℃ for 10min, granulating by a 1.0mm screen, adding 2g of silicon dioxide and 1g of magnesium stearate, controlling the content, and filling into capsules or tabletting.
2.2 dissolution results
The capsule is used for dissolution rate investigation, and the capsule is prepared by referring to XC second method and paddle method which is an annex of the second part of Chinese pharmacopoeia 2010 edition, wherein the stirring speed is 75rpm, the dissolution medium is 900mL of buffer solution with the pH value of 4.5, and the sampling time point is 45 min.
Example 3
3.1 preparation method
200g of API and 200g of PEG4000 are added into a hot melt extrusion instrument for hot melt extrusion to obtain a solid dispersion, and the solid dispersion is crushed and sieved by a 100-mesh sieve for standby.
1000 tablets per granule of the formula: weighing 50g of the solid dispersion, 30g of microcrystalline cellulose, 20g of starch, 12g of povidone and 20g of crospovidone, putting into a wet granulator, stirring for 20min, adding 50% ethanol water for granulation, drying at 50 ℃ for 10min by a fluidized bed, granulating by a 1.0mm screen, adding 3g of silicon dioxide and 1g of magnesium stearate, controlling the content, and filling into capsules or tabletting.
3.2 dissolution results
The capsule is used for dissolution rate investigation, and the capsule is prepared by referring to XC second method and paddle method which is an annex of the second part of Chinese pharmacopoeia 2010 edition, wherein the stirring speed is 75rpm, the dissolution medium is 900mL of buffer solution with the pH value of 4.5, and the sampling time point is 45 min.
Example 4
4.1 preparation method
200g of API and 200g of PEG4000 are added into a hot melt extrusion instrument for hot melt extrusion to obtain a solid dispersion, and the solid dispersion is crushed and sieved by a 100-mesh sieve for standby.
1000 tablets per granule of the formula: weighing 50g of the solid dispersion, 20g of lactose, 30g of starch, 12g of povidone and 20g of crospovidone, putting into a wet granulator, stirring for 20min, adding 50% ethanol water for granulation, drying with a fluidized bed at 50 ℃ for 10min, granulating by using a 1.0mm screen, adding 3g of silicon dioxide and 1g of magnesium stearate, controlling the content, and filling into capsules or tabletting.
4.2 dissolution results
The capsule is used for dissolution rate investigation, and the capsule is prepared by referring to XC second method and paddle method which is an annex of the second part of Chinese pharmacopoeia 2010 edition, wherein the stirring speed is 75rpm, the dissolution medium is 900mL of buffer solution with the pH value of 4.5, and the sampling time point is 45 min.
Example 5
5.1 preparation method
Adding 100g of API and 100g of poloxamer into a hot-melt extrusion instrument for hot-melt extrusion to obtain a solid dispersion, and crushing the solid dispersion and sieving the solid dispersion with a 100-mesh sieve for later use.
1000 tablets per granule of the formula: weighing 50g of the solid dispersion, 30g of lactose, 20g of microcrystalline cellulose, 12g of povidone and 20g of crospovidone, putting into a wet granulator, stirring for 20min, adding 50% ethanol water for granulation, drying with a fluidized bed at 50 ℃ for 10min, granulating by using a 1.0mm screen, adding 3g of silicon dioxide and 1g of magnesium stearate, controlling the content, and filling into capsules or tabletting.
5.2 solubility
| API | Solid dispersion | Physical mixture | |
| Equilibrium solubility (. mu.g/ml) | 8.9 | 187 | 10.1 |
| Multiple of increase | / | 21.0 | 1.1 |
5.3 dissolution results
The capsule is used for dissolution rate investigation, and the capsule is prepared by referring to XC second method and paddle method which is an annex of the second part of Chinese pharmacopoeia 2010 edition, wherein the stirring speed is 75rpm, the dissolution medium is 900mL of buffer solution with the pH value of 4.5, and the sampling time point is 45 min.
Example 6
6.1 preparation method
Adding 50g of API and 100g of poloxamer into a hot-melt extrusion instrument for hot-melt extrusion to obtain a solid dispersion, and crushing the solid dispersion and sieving the solid dispersion with a 100-mesh sieve for later use.
1000 tablets per granule of the formula: weighing 75g of the solid dispersion, 30g of lactose, 20g of microcrystalline cellulose, 12g of povidone and 20g of crospovidone, putting into a wet granulator, stirring for 20min, adding 50% ethanol water for granulation, drying with a fluidized bed at 50 ℃ for 10min, granulating by using a 1.0mm screen, adding 3g of silicon dioxide and 1g of magnesium stearate, controlling the content, and filling into capsules or tabletting.
6.2 solubility
| API | Solid dispersion | Physical mixture | |
| Equilibrium solubility (. mu.g/ml) | 8.9 | 249 | 10.1 |
| Multiple of increase | / | 28.0 | 1.1 |
6.3 dissolution results
The capsule is used for dissolution rate investigation, and the capsule is prepared by referring to XC second method and paddle method which is an annex of the second part of Chinese pharmacopoeia 2010 edition, wherein the stirring speed is 75rpm, the dissolution medium is 900mL of buffer solution with the pH value of 4.5, and the sampling time point is 45 min.
Example 7
7.1 preparation method
Adding 50g of API and 200g of poloxamer into a hot-melt extrusion instrument for hot-melt extrusion to obtain a solid dispersion, and crushing the solid dispersion and sieving the solid dispersion with a 100-mesh sieve for later use.
1000 tablets per granule of the formula: weighing 125g of the solid dispersion, 30g of lactose, 20g of microcrystalline cellulose, 12g of povidone and 20g of crospovidone, putting into a wet granulator, stirring for 20min, adding 50% ethanol water for granulation, drying with a fluidized bed at 50 ℃ for 10min, granulating by using a 1.0mm screen, adding 3g of silicon dioxide and 1g of magnesium stearate, controlling the content, and filling into capsules or tabletting.
7.2 solubility
| API | Solid dispersion | Physical mixture | |
| Equilibrium solubility (. mu.g/ml) | 8.9 | 272 | 10.1 |
| Multiple of increase | / | 30.6 | 1.1 |
7.3 dissolution results
The capsule is used for dissolution rate investigation, and the capsule is prepared by referring to XC second method and paddle method which is an annex of the second part of Chinese pharmacopoeia 2010 edition, wherein the stirring speed is 75rpm, the dissolution medium is 900mL of buffer solution with the pH value of 4.5, and the sampling time point is 45 min.
Example 8
8.1 preparation method
50g of API and 100g of Kollidon VA 64 are added into a hot melt extruder for hot melt extrusion to obtain a solid dispersion, and the solid dispersion is crushed and sieved by a 100-mesh sieve for later use.
1000 tablets per granule of the formula: weighing 75g of the solid dispersion, 30g of lactose, 20g of microcrystalline cellulose, 12g of hydroxypropyl cellulose and 20g of crospovidone, compacting the mixture, crushing into granules, adding 2.5g of silicon dioxide and 1g of magnesium stearate, controlling the content, and filling into capsules or tabletting.
8.2 solubility
| API | Solid dispersion | Physical mixture | |
| Equilibrium solubility (. mu.g/ml) | 8.9 | 222 | 10.1 |
| Multiple of increase | / | 24.9 | 1.1 |
8.3 dissolution results
The capsule is used for dissolution rate investigation, and the capsule is prepared by referring to XC second method and paddle method which is an annex of the second part of Chinese pharmacopoeia 2010 edition, wherein the stirring speed is 75rpm, the dissolution medium is 900mL of buffer solution with the pH value of 4.5, and the sampling time point is 45 min.
Example 9
9.1 preparation method
Dissolving 50g of API and 150g of povidone in a methanol/dichloromethane mixed solvent, spray-drying to obtain a solid dispersion, and crushing and sieving the solid dispersion by a 100-mesh sieve for later use.
1000 tablets per granule of the formula: weighing 100g of the solid dispersion, 30g of lactose, 30g of microcrystalline cellulose and 10g of croscarmellose sodium, compacting the mixture, crushing into granules, adding 1.5g of magnesium stearate, controlling the content, and filling into capsules or tabletting.
9.2 solubility
9.3 dissolution results
The capsule is used for dissolution rate investigation, and the capsule is prepared by referring to XC second method and paddle method which is an annex of the second part of Chinese pharmacopoeia 2010 edition, wherein the stirring speed is 75rpm, the dissolution medium is 900mL of buffer solution with the pH value of 4.5, and the sampling time point is 45 min.
Example 10
10.1 preparation method
Dissolving 50g of API and 100g of povidone in a methanol/dichloromethane mixed solvent, spray-drying to obtain a solid dispersion, and crushing and sieving the solid dispersion by a 100-mesh sieve for later use.
1000 tablets per granule of the formula: weighing 75g of the solid dispersion, 30g of lactose, 20g of microcrystalline cellulose, 3g of hydroxypropyl cellulose and 6g of croscarmellose sodium, compacting the mixture, crushing into granules, adding 1.0g of magnesium stearate, controlling the content, and filling into capsules or tabletting.
10.2 solubility
| API | Solid dispersion | Physical mixture | |
| Equilibrium solubility (. mu.g/ml) | 8.9 | 204 | 10.1 |
| Multiple of increase | / | 22.9 | 1.1 |
10.3 dissolution results
The capsule is used for dissolution rate investigation, and the capsule is prepared by referring to XC second method and paddle method which is an annex of the second part of Chinese pharmacopoeia 2010 edition, wherein the stirring speed is 75rpm, the dissolution medium is 900mL of buffer solution with the pH value of 4.5, and the sampling time point is 45 min.
Example 11
11.1 preparation method
Dissolving 50g of API and 50g of povidone in a methanol/dichloromethane mixed solvent, spray-drying to obtain a solid dispersion, and crushing and sieving the solid dispersion by a 100-mesh sieve for later use.
1000 tablets per granule of the formula: weighing 50g of the solid dispersion, 30g of lactose, 20g of microcrystalline cellulose, 6g of hydroxypropyl cellulose and 10g of croscarmellose sodium, putting into a wet granulator, stirring for 20min, adding 50% ethanol water for granulation, drying with a fluidized bed at 50 ℃ for 10min, granulating with a 1.0mm screen, adding 2g of silicon dioxide and 1g of magnesium stearate, controlling the content, and filling into capsules or tabletting.
11.2 solubility
| API | Solid dispersion | Physical mixture | |
| Equilibrium solubility (. mu.g/ml) | 8.9 | 203 | 10.1 |
| Multiple of increase | / | 22.8 | 1.1 |
11.3 dissolution results
The capsule is used for dissolution rate investigation, and the capsule is prepared by referring to XC second method and paddle method which is an annex of the second part of Chinese pharmacopoeia 2010 edition, wherein the stirring speed is 75rpm, the dissolution medium is 900mL of buffer solution with the pH value of 4.5, and the sampling time point is 45 min.
Example 12
12.1 preparation method
Dissolving 50g of API and 50g of povidone in a methanol/dichloromethane mixed solvent, spray-drying to obtain a solid dispersion, and crushing and sieving the solid dispersion by a 100-mesh sieve for later use.
1000 tablets per granule of the formula: weighing 50g of the solid dispersion, 50g of lactose, 50g of microcrystalline cellulose, 10g of hydroxypropyl cellulose and 20g of crospovidone, adding 2g of silicon dioxide and 1g of magnesium stearate, controlling the content, and filling into capsules or tabletting.
12.2 solubility
| API | Solid dispersion | Physical mixture | |
| Equilibrium solubility (. mu.g/ml) | 8.9 | 203 | 10.1 |
| Multiple of increase | / | 22.8 | 1.1 |
12.3 dissolution results
The capsule is used for dissolution rate investigation, and the capsule is prepared by referring to XC second method and paddle method which is an annex of the second part of Chinese pharmacopoeia 2010 edition, wherein the stirring speed is 75rpm, the dissolution medium is 900mL of buffer solution with the pH value of 4.5, and the sampling time point is 45 min.
Example 13
13.1 preparation method
Preheating 100g of microcrystalline cellulose PH200 in a boiling pellet dryer, dissolving 50g of API and 150g of povidone in a methanol/dichloromethane mixed solvent, spraying into the boiling pellet dryer, and drying to obtain a solid dispersion for later use after the solution is sprayed.
1000 tablets per granule of the formula: weighing 100g of the solid dispersion, 50g of lactose, 30g of microcrystalline cellulose, 10g of hydroxypropyl cellulose and 10g of crospovidone, adding 2g of silicon dioxide and 1g of magnesium stearate, controlling the content, and filling into capsules or tabletting.
13.2 solubility
| API | Solid dispersion | Physical mixture | |
| Equilibrium solubility (. mu.g/ml) | 8.9 | 297 | 10.1 |
| Multiple of increase | / | 33.4 | 1.1 |
13.3 dissolution results
The capsule is used for dissolution rate investigation, and the capsule is prepared by referring to XC second method and paddle method which is an annex of the second part of Chinese pharmacopoeia 2010 edition, wherein the stirring speed is 75rpm, the dissolution medium is 900mL of buffer solution with the pH value of 4.5, and the sampling time point is 45 min.
Example 14
14.1 preparation method
Preheating 100g of microcrystalline cellulose PH200 in a boiling pellet dryer, dissolving 50g of API and 150g of povidone in a methanol/dichloromethane mixed solvent, spraying into the boiling pellet dryer, and drying to obtain a solid dispersion for later use after the solution is sprayed.
1000 tablets per granule of the formula: weighing 100g of the solid dispersion, 20g of lactose, 10g of microcrystalline cellulose, 10g of hydroxypropyl cellulose and 5g of carboxymethyl starch sodium, putting into a wet granulator, stirring for 20min, adding 50% ethanol water for granulation, drying with a fluidized bed at 50 ℃ for 10min, granulating with a 1.0mm screen, adding 2g of silicon dioxide and 1g of magnesium stearate, controlling the content, and filling into capsules or tabletting.
14.2 solubility
| API | Solid dispersion | Physical mixture | |
| Equilibrium solubility (. mu.g/ml) | 8.9 | 297 | 10.1 |
| Multiple of increase | / | 33.4 | 1.1 |
14.3 dissolution results
The capsule is used for dissolution rate investigation, and the capsule is prepared by referring to XC second method and paddle method which is an annex of the second part of Chinese pharmacopoeia 2010 edition, wherein the stirring speed is 75rpm, the dissolution medium is 900mL of buffer solution with the pH value of 4.5, and the sampling time point is 45 min.
Example 15
15.1 preparation method
Preheating 100g of microcrystalline cellulose PH200 in a boiling pellet dryer, dissolving 50g of API and 150g of povidone in a methanol/dichloromethane mixed solvent, spraying into the boiling pellet dryer, and drying to obtain a solid dispersion for later use after the solution is sprayed.
1000 tablets per granule of the formula: weighing 100g of the solid dispersion, 20g of lactose, 10g of microcrystalline cellulose, 10g of hydroxypropyl cellulose and 5g of carboxymethyl starch sodium, compacting the mixture, crushing into granules, adding 1.0g of magnesium stearate, controlling the content, and filling into capsules or tabletting.
15.2 solubility
| API | Solid dispersion | Physical mixture | |
| Equilibrium solubility (. mu.g/ml) | 8.9 | 297 | 10.1 |
| Multiple of increase | / | 33.4 | 1.1 |
15.3 dissolution results
The capsule is used for dissolution rate investigation, and the capsule is prepared by referring to XC second method and paddle method which is an annex of the second part of Chinese pharmacopoeia 2010 edition, wherein the stirring speed is 75rpm, the dissolution medium is 900mL of buffer solution with the pH value of 4.5, and the sampling time point is 45 min.
Example 16
50g of API and 50g of β -cyclodextrin are dissolved in a methanol/dichloromethane mixed solvent, spray-dried to prepare an inclusion compound, and the inclusion compound is crushed and sieved by a 100-mesh sieve for standby.
1000 tablets per granule of the formula: weighing 50g of the clathrate compound, 50g of lactose, 50g of microcrystalline cellulose, 8g of hydroxypropyl cellulose and 15g of crospovidone, adding 2g of silicon dioxide and 1g of magnesium stearate, controlling the content, and filling into capsules or tabletting.
16.2 solubility
| API | Inclusion compound | Physical mixture | |
| Equilibrium solubility (. mu.g/ml) | 8.9 | 298 | 10.1 |
| Multiple of increase | / | 33.5 | 1.1 |
16.3 dissolution results
The capsule is used for dissolution rate investigation, and the capsule is prepared by referring to XC second method and paddle method which is an annex of the second part of Chinese pharmacopoeia 2010 edition, wherein the stirring speed is 75rpm, the dissolution medium is 900mL of buffer solution with the pH value of 4.5, and the sampling time point is 45 min.
Example 17
50g of API, 20g of β -cyclodextrin and 30g of mannitol are dissolved in a methanol/dichloromethane mixed solvent, freeze-dried to prepare an inclusion compound, and the inclusion compound is crushed and sieved by a 100-mesh sieve for standby.
1000 tablets per granule of the formula: weighing 50g of the clathrate compound, 30g of lactose, 20g of microcrystalline cellulose, 8g of hydroxypropyl cellulose and 15g of croscarmellose sodium, putting into a wet granulator, stirring for 20min, adding 50% ethanol water for granulation, drying with a fluidized bed at 50 ℃ for 10min, granulating with a 1.0mm screen, adding 2g of silicon dioxide and 1g of magnesium stearate, controlling the content, and filling into capsules or tabletting.
17.2 solubility
| API | Inclusion compound | Physical mixture | |
| Equilibrium solubility (. mu.g/ml) | 8.9 | 278 | 10.1 |
| Multiple of increase | / | 31.2 | 1.1 |
17.3 dissolution results
The capsule is used for dissolution rate investigation, and the capsule is prepared by referring to XC second method and paddle method which is an annex of the second part of Chinese pharmacopoeia 2010 edition, wherein the stirring speed is 75rpm, the dissolution medium is 900mL of buffer solution with the pH value of 4.5, and the sampling time point is 45 min.
Claims (10)
1. A pharmaceutical composition comprising a solid dispersion prepared from a compound of formula i, a disintegrant, diluent, binder, glidant, or lubricant:
the pharmaceutical composition comprises the following components in percentage by weight:
the solid dispersion comprises a compound shown in a formula I and a carrier material, wherein the carrier material is selected from one or more of polyethylene glycol, poloxamer and polyvinylpyrrolidone;
the diluent is selected from at least one of lactose, microcrystalline cellulose and starch;
the adhesive is selected from at least one of hydroxypropyl cellulose and povidone;
the disintegrant is at least one selected from crospovidone, carboxymethyl starch sodium and croscarmellose sodium;
the lubricant is magnesium stearate;
the glidant is at least one of micropowder silica gel and silicon dioxide.
2. The pharmaceutical composition according to claim 1, which comprises a solid dispersion prepared from a compound of formula i, a disintegrant, a diluent, a binder, a lubricant or a glidant, wherein the weight ratio of the components is as follows:
3. the pharmaceutical composition of claim 1, wherein the weight ratio of the compound of formula i to the carrier material is 1:1 to 1: 6.
4. The pharmaceutical composition according to claim 3, wherein the weight ratio of the compound of formula I to the carrier material is 1:1 to 1: 4.
5. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is formulated as a tablet or capsule.
6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the solid dispersion is prepared by a hot melt extrusion granulator, a spray type solid dispersion preparation machine or a boiling granulation dryer.
7. The pharmaceutical composition of claim 6, wherein the solid dispersion is prepared by the following method:
1) uniformly mixing a compound of formula I and a carrier material;
2) preparing the mixture obtained in the step 1) into a solid dispersion by hot-melt granulation of a hot-melt extrusion granulator, a spray-type solid dispersion preparation machine or an ebullient granulation dryer.
8. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 4, wherein the composition is prepared by wet granulation by the following process:
1) uniformly mixing the solid dispersion obtained in the step 2) of the claim 7 with a diluent and a disintegrating agent, adding a binding agent for granulation, and drying at 45 ℃ for 1 h;
2) optionally, drying and sieving the dried particles of step 1);
3) mixing the dried granules of step 2), glidant and lubricant in a mixer to obtain a final mixture;
4) optionally, filling the mixture of step 3) above through a suitable capsule filling machine to prepare capsules;
5) optionally, tabletting the mixture of step 3) above by compressing it on a suitable tabletting machine to obtain tablet cores;
6) optionally, the core tablet of step 5) is film coated with a film coating.
9. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 4, wherein the composition is dry granulated by the following process:
1) compacting the solid dispersion obtained in step 2) of claim 7, diluent, disintegrant and binder in a suitable roller press;
2) breaking the ribbon obtained during step 1) into granules by means of a suitable grinding or sieving step;
3) optionally, mixing step 2), lubricant and glidant in a mixer to obtain a final mixture;
4) optionally, filling the mixture of step 3) above through a suitable capsule filling machine to prepare capsules;
5) optionally, tabletting the mixture of step 3) above by compressing it on a suitable tabletting machine to obtain tablet cores;
6) optionally, the core tablet of step 5) is film coated with a film coating.
10. A process for preparing a pharmaceutical composition according to any one of claims 1 to 4, wherein the composition is prepared by a direct mixing process comprising the steps of:
1) mixing the solid dispersion obtained in step 2) of claim 7, a binder, a diluent, a disintegrant, a lubricant and a glidant in a hopper mixer to obtain a mixture;
2) optionally, filling the mixture of step 1) above through a suitable capsule filling machine to prepare capsules;
3) optionally, tabletting the mixture of step 1) above by compressing it on a suitable tabletting machine to obtain tablet cores;
4) optionally, the core tablet of step 3) is film coated with a film coating.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
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| CN2014106254798 | 2014-11-07 | ||
| CN201410625479.8A CN105616419A (en) | 2014-11-07 | 2014-11-07 | 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 |
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| CN106794182B true CN106794182B (en) | 2020-02-14 |
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| 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 |
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| 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 |
| US10449195B2 (en) | 2016-03-29 | 2019-10-22 | Shenzhen Pharmacin Co., Ltd. | Pharmaceutical formulation of palbociclib and a preparation method thereof |
| CN109078006B (en) * | 2016-03-29 | 2021-04-20 | 深圳市药欣生物科技有限公司 | Medicinal preparation of palbociclib 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 |
| CN114306245A (en) | 2020-09-29 | 2022-04-12 | 深圳市药欣生物科技有限公司 | Pharmaceutical composition of amorphous solid dispersion and preparation method thereof |
| CN114404380B (en) * | 2021-12-30 | 2023-04-18 | 重庆华森制药股份有限公司 | Terazosin hydrochloride capsule and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2007129062A1 (en) * | 2006-05-08 | 2007-11-15 | Astex Therapeutics Limited | Pharmaceutical combinations of diazole derivatives for cancer treatment |
| 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 |
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| EP1648889B1 (en) * | 2003-07-11 | 2008-10-29 | Warner-Lambert Company LLC | Isethionate salt of a selective cdk4 inhibitor |
| CN101146794A (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 |
| TWI471321B (en) * | 2009-06-08 | 2015-02-01 | Abbott Gmbh & Co Kg | Pharmaceutical dosage form for oral administration of a bcl-2 family inhibitor |
| WO2011156786A2 (en) * | 2010-06-10 | 2011-12-15 | Afraxis, 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 |
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2014
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| 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 |
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| CN106794182A (en) | 2017-05-31 |
| TW201617069A (en) | 2016-05-16 |
| TWI727935B (en) | 2021-05-21 |
| CN105616419A (en) | 2016-06-01 |
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