CN105769763A - Megestrol acetate nanosuspension and preparation method and application thereof - Google Patents
Megestrol acetate nanosuspension and preparation method and application thereof Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
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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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
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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
- A61K47/30—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
- A61K47/38—Cellulose; Derivatives thereof
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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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
Abstract
The invention discloses a megestrol acetate nanosuspension.The megestrol acetate nanosuspension is prepared by mixing megestrol acetate and a stabilizer solution and then grinding the mixture through a nanometer grinder.The stabilizer is a mixture obtained by mixing cellulose derivatives and anionic surfactants according to the mass ratio of 10: (1-2); the cellulose derivatives are hydroxypropyl methyl cellulose and hydroxyl propyl cellulose, and the mass ratio of hydroxypropyl methyl cellulose to hydroxyl propyl cellulose is 10: (1-10); the anionic surfactants are lauryl sodium sulfate and sodium deoxycholate, and the mass ratio of lauryl sodium sulfate to sodium deoxycholate is 10: (1-5).The invention further discloses a preparation method and application of the megestrol acetate nanosuspension.According to the megestrol acetate nanosuspension, the average grain diameter of megestrol acetate is below 1,000 nm, the dissolution rate of megestrol acetate is remarkably increased, and then the oral bioavailability of megestrol acetate is improved.
Description
Technical field
The invention belongs to pharmaceutical technology field, be specifically related to a kind of megestrol acetate nanosuspension and its preparation method and application.
Background technology
Megestrol acetate (megestrolacetate, MA) it is a kind of progestogens medicine, it is mainly used in treatment advanced breast cancer and advanced endometrial carcinoma, appetite and the cachexia of late tumor patient can be improved, renal carcinoma, carcinoma of prostate and ovarian cancer are also had certain curative effect.Megestrol acetate is as a kind of insoluble drug, and dissolution is the key step that restriction medicine absorbs in vivo, thus the dissolution improving medicine can be obviously improved the absorption of medicine, thus improving bioavailability.
Existing various methods improve the bioavailability of megestrol acetate at present, as described in documents below:
Chinese invention patent CN104208072A (publication number) discloses " a kind of megestrol acetate hot-melt extruded preparation ", it is directed to invent a kind of megestrol acetate hot-melt extruded preparation, the megestrol acetate hot-melt extruded thing of preparation, megestrol acetate dissolubility in water can be significantly improved, improve its bioavailability.
Chinese invention patent CN101671382A (publication number) discloses " ultra-micronized megestrol acetate and the pharmaceutical composition containing it ", it is directed to the ultra-micronized megestrol acetate having invented a kind of particle diameter less than 10 μm, and prepare into suitable pharmaceutical dosage form with pharmaceutically acceptable adjuvant, wherein comprise dispersible tablet, ordinary tablet and capsule etc..
Chinese invention patent CN1436534A (publication number) discloses " megestrol acetate capsule composition ", it is directed to invent a kind of megestrol acetate capsule, content is oleagenous suspension, wherein megestrol acetate uses micronized crude drug, said preparation is rapid-action, overcomes the shortcoming that conventional tablet bioavailability is low simultaneously.
Chinese invention patent CN1180521A (publication number) discloses " Pharmaceutical composition containing megestrol acetate ", it is directed to invent a kind of megestrol acetate Pharmaceutical composition, main preparation technology is after being melted by Polyethylene Glycol, add megestrol acetate and other pharmaceutic adjuvant of powdery, prepare into capsule or tablet.
But said method is but without dissolution and the bioavailability of well improving megestrol acetate, need exist for a kind of method to improve dissolution and the bioavailability of megestrol acetate further.
Summary of the invention
The technical problem to be solved is in that for above-mentioned the deficiencies in the prior art, it is provided that a kind of megestrol acetate nanosuspension.In this suspension, cellulose derivative is as space multistory stabilizer, can increase interparticle sterically hindered, anion surfactant is as charge stable agent, increasing the Charge repulsion between particle, two kinds of stabilizers are used in combination, in the nanosuspension of preparation, the particle diameter of medicine is less, below mean diameter 1000nm, significantly improves the dissolution rate of megestrol acetate, and then improves the oral administration biaavailability of megestrol acetate；The Stabilization of charge stable agent simultaneously is influenced by temperature less, it is ensured that the stability of nanoparticle in subsequent fluidized bed pelletization, the granule of preparation has good dispersibility again in gastro-intestinal Fluid.
For solving above-mentioned technical problem, the technical solution used in the present invention is: a kind of megestrol acetate nanosuspension, it is characterized in that, grinding through nano-level grinder after being mixed by megestrol acetate and stabiliser solution and make, described stabilizer is that cellulose derivative and anion surfactant are according to 10:(1～2) the mixture of mass ratio mixing；Described cellulose derivative is hydroxypropyl methylcellulose and hydroxypropyl cellulose, the mass ratio of hydroxypropyl methylcellulose and hydroxypropyl cellulose is 10:(1～10), described anion surfactant is the mass ratio of sodium lauryl sulphate and NaTDC, sodium lauryl sulphate and NaTDC is 10:(1～5).
Above-mentioned a kind of megestrol acetate nanosuspension, it is characterized in that, described stabilizer is that cellulose derivative and anion surfactant are according to 10:(1～1.5) the mixture of mass ratio mixing, the mass ratio of described hydroxypropyl methylcellulose and hydroxypropyl cellulose is 10:(4～7), the mass ratio of described sodium lauryl sulphate and NaTDC is 10:(3～5).
Above-mentioned a kind of megestrol acetate nanosuspension, it is characterized in that, the mixture that described stabilizer is cellulose derivative and anion surfactant mixes according to the mass ratio of 10:1.2, the mass ratio of described hydroxypropyl methylcellulose and hydroxypropyl cellulose is 10:5, and the mass ratio of described sodium lauryl sulphate and NaTDC is 10:4.
Above-mentioned a kind of megestrol acetate nanosuspension, it is characterised in that in described megestrol acetate nanosuspension, the concentration of megestrol acetate is 1mg/mL～400mg/mL；In described megestrol acetate suspension, megestrol acetate is 50:(1～2 with the mass ratio of stabilizer).
Above-mentioned a kind of megestrol acetate nanosuspension, it is characterised in that in described megestrol acetate nanosuspension, the particle mean size of megestrol acetate is below 1000nm.
It addition, present invention also offers a kind of method preparing above-mentioned megestrol acetate nanosuspension, it is characterised in that comprise the following steps:
Step one, stabilizer is dissolved in purified water, is uniformly mixing to obtain stabiliser solution；
Step 2, megestrol acetate is scattered in stabiliser solution described in step one, is uniformly mixing to obtain thick suspension；
Step 3, suspension thick described in step 2 is placed in the grinding chamber of nano-level grinder, grinds 30min～120min with the rotating speed of 1500rpm～3500rpm, obtain megestrol acetate nanosuspension.
Further, the invention provides the application in pharmaceutical preparation of a kind of above-mentioned megestrol acetate nanosuspension, the dosage form of described pharmaceutical preparation is quick-release tablet.
Above-mentioned application, it is characterised in that after described quick-release tablet is mixed homogeneously with adjuvant by megestrol acetate nanosuspension, after adopting fluidized bed granulation, tabletting is made；Described adjuvant includes filler, disintegrating agent and lubricant.
Above-mentioned application, it is characterised in that described filler is one or more in starch, dextrin, lactose, mannitol and microcrystalline Cellulose, in quick-release tablet, the weight/mass percentage composition of filler is 20%～70%；Described disintegrating agent is one or more in crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium and low-substituted hydroxypropyl methylcellulose, and in quick-release tablet, the weight/mass percentage composition of disintegrating agent is 1%～10%；Described lubricant is one or more in magnesium stearate, micropowder silica gel, Pulvis Talci and Polyethylene Glycol, and in quick-release tablet, the weight/mass percentage composition of lubricant is 0.1%～2%.
Above-mentioned application, it is characterised in that in described quick-release tablet, the weight/mass percentage composition of filler is 40%～70%, the weight/mass percentage composition of disintegrating agent is 3%～6%, and the weight/mass percentage composition of lubricant is 0.5%～1%.
The present invention compared with prior art has the advantage that
1, below the mean diameter 1000nm of megestrol acetate in the megestrol acetate nanosuspension of the present invention, significantly improves the dissolution rate of megestrol acetate, and then improves the oral administration biaavailability of megestrol acetate.
2, the megestrol acetate nanometer suspension liquid and preparation method thereof of the present invention is simple, it is easy to industrial amplification production.
3, megestrol acetate is in the process ground, particle diameter is reduced to Nano grade, produce very big surface area, there is self-assemble and reduce the trend of surface Gibbs free energy, stabilizer can be adsorbed on the gathering of the surface prevention drug particle of Nano grade medicine ion, and in the present invention, cellulose derivative is as space multistory stabilizer, it is possible to increase interparticle sterically hindered, anion surfactant, as charge stable agent, increases the Charge repulsion between particle.Two kinds of stabilizers are used in combination, in the nanosuspension of preparation, the particle diameter of medicine is less, the Stabilization of charge stable agent simultaneously is influenced by temperature less, can ensure that the stability of nanoparticle in subsequent fluidized bed pelletization, the granule of preparation has good dispersibility again in gastro-intestinal Fluid.
4, the present invention adopts fluid bed drying granulating process, megestrol acetate nanosuspension is prepared into other pharmaceutic adjuvant the granule of applicable tabletting, it is pressed into tablet further, achieving the solidification of nanosuspension, perfection solves nanosuspension difficult problem of physical stability difference in placement process.Meanwhile, compared with other peroral dosage form, tablet has convenient transport, the advantages such as patient compliance is good.
By the examples below, technical scheme is described in further detail.
Detailed description of the invention
Embodiment 1
The megestrol acetate nanosuspension of the present embodiment, megestrol acetate and stabiliser solution grind through nano-level grinder after mixing and make, the mixture that described stabilizer is cellulose derivative and anion surfactant mixes according to the mass ratio of 10:1；Described cellulose derivative is hydroxypropyl methylcellulose and hydroxypropyl cellulose, the mass ratio of hydroxypropyl methylcellulose and hydroxypropyl cellulose is 10:1, described anion surfactant is the mass ratio of sodium lauryl sulphate and NaTDC, sodium lauryl sulphate and NaTDC is 10:1；In described megestrol acetate nanosuspension, the concentration of megestrol acetate is 400mg/mL；In described megestrol acetate suspension, megestrol acetate is 50:1 with the mass ratio of stabilizer.
The preparation method of the megestrol acetate nanosuspension of the present embodiment comprises the following steps:
Step one, 10g hydroxypropyl methylcellulose, 1g hydroxypropyl cellulose, 1g sodium lauryl sulphate and 0.1g NaTDC are dissolved in 900g purified water, are uniformly mixing to obtain stabiliser solution；
Step 2,605g megestrol acetate is scattered in stabiliser solution described in step one, is uniformly mixing to obtain thick suspension；
Step 3, suspension thick described in step 2 is placed in the grinding chamber of nano-level grinder, grinds 120min with the rotating speed of 1500rpm, obtain megestrol acetate nanosuspension.
The application in pharmaceutical preparation of the megestrol acetate nanosuspension of the present embodiment, the dosage form of described pharmaceutical preparation is quick-release tablet；After described quick-release tablet is mixed homogeneously with adjuvant by megestrol acetate nanosuspension, after adopting fluidized bed granulation, tabletting is made；Described adjuvant includes filler, disintegrating agent and lubricant；Described filler is microcrystalline Cellulose, and in quick-release tablet, the weight/mass percentage composition of filler is 20%；Described disintegrating agent is low-substituted hydroxypropyl methylcellulose, and in quick-release tablet, the weight/mass percentage composition of disintegrating agent is 10%；Described lubricant is Pulvis Talci, and in quick-release tablet, the weight/mass percentage composition of lubricant is 2%.
Embodiment 2
The present embodiment is identical with embodiment 1, wherein it is different in that: described filler is starch, dextrin, lactose or mannitol, or it is starch, dextrin, lactose, at least two in mannitol and microcrystalline Cellulose, disintegrating agent is crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose or carboxymethyl starch sodium, or it is crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, at least two in carboxymethyl starch sodium and low-substituted hydroxypropyl methylcellulose, lubricant is magnesium stearate, micropowder silica gel or Polyethylene Glycol, or it is magnesium stearate, micropowder silica gel, at least two in Pulvis Talci and Polyethylene Glycol.
Embodiment 3
The megestrol acetate nanosuspension of the present embodiment, megestrol acetate and stabiliser solution grind through nano-level grinder after mixing and make, the mixture that described stabilizer is cellulose derivative and anion surfactant mixes according to the mass ratio of 10:1.2；Described cellulose derivative is hydroxypropyl methylcellulose and hydroxypropyl cellulose, the mass ratio of hydroxypropyl methylcellulose and hydroxypropyl cellulose is 10:5, described anion surfactant is the mass ratio of sodium lauryl sulphate and NaTDC, sodium lauryl sulphate and NaTDC is 10:4；In described megestrol acetate nanosuspension, the concentration of megestrol acetate is 200mg/mL；In described megestrol acetate suspension, megestrol acetate is 50:2 with the mass ratio of stabilizer.
The preparation method of the megestrol acetate nanosuspension of the present embodiment comprises the following steps:
Step one, 10g hydroxypropyl methylcellulose, 5g hydroxypropyl cellulose, 1.285g sodium lauryl sulphate and 0.515g NaTDC are dissolved in 1.66kg purified water, are uniformly mixing to obtain stabiliser solution；
Step 2,420g megestrol acetate is scattered in stabiliser solution described in step one, is uniformly mixing to obtain thick suspension；
Step 3, suspension thick described in step 2 is placed in the grinding chamber of nano-level grinder, grinds 30min with the rotating speed of 3500rpm, obtain megestrol acetate nanosuspension.
The application in pharmaceutical preparation of the megestrol acetate nanosuspension of the present embodiment, the dosage form of described pharmaceutical preparation is quick-release tablet；After described quick-release tablet is mixed homogeneously with adjuvant by megestrol acetate nanosuspension, after adopting fluidized bed granulation, tabletting is made；Described adjuvant includes filler, disintegrating agent and lubricant；Described filler is starch and microcrystalline Cellulose (mass ratio is 5:14), and in quick-release tablet, the weight/mass percentage composition of filler is 50%；Described disintegrating agent is carboxymethyl starch sodium, and in quick-release tablet, the weight/mass percentage composition of disintegrating agent is 5%；Described lubricant is micropowder silica gel, and in quick-release tablet, the weight/mass percentage composition of lubricant is 0.8%.
Embodiment 4
The present embodiment is identical with embodiment 3, wherein it is different in that: described filler is starch, dextrin, lactose, one in mannitol and microcrystalline Cellulose or more than three kinds, or it is dextrin, lactose, in mannitol and microcrystalline Cellulose two kinds, or it is dextrin, the mixture of a kind of and starch in lactose and mannitol, disintegrating agent is crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose or low-substituted hydroxypropyl methylcellulose, or it is crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, at least two in carboxymethyl starch sodium and low-substituted hydroxypropyl methylcellulose, lubricant is magnesium stearate, Pulvis Talci or Polyethylene Glycol, or it is magnesium stearate, micropowder silica gel, at least two in Pulvis Talci and Polyethylene Glycol.
Embodiment 5
The megestrol acetate nanosuspension of the present embodiment, megestrol acetate and stabiliser solution grind through nano-level grinder after mixing and make, the mixture that described stabilizer is cellulose derivative and anion surfactant mixes according to the mass ratio of 10:1.5；Described cellulose derivative is hydroxypropyl methylcellulose and hydroxypropyl cellulose, the mass ratio of hydroxypropyl methylcellulose and hydroxypropyl cellulose is 10:4, described anion surfactant is the mass ratio of sodium lauryl sulphate and NaTDC, sodium lauryl sulphate and NaTDC is 10:3；In described megestrol acetate nanosuspension, the concentration of megestrol acetate is 200mg/mL；In described megestrol acetate suspension, megestrol acetate is 50:1.5 with the mass ratio of stabilizer.
The preparation method of the megestrol acetate nanosuspension of the present embodiment comprises the following steps:
Step one, 6.2g hydroxypropyl methylcellulose, 2.47g hydroxypropyl cellulose, 1g sodium lauryl sulphate and 0.3g NaTDC are dissolved in 1330g purified water, are uniformly mixing to obtain stabiliser solution；
Step 2,332g megestrol acetate is scattered in stabiliser solution described in step one, is uniformly mixing to obtain thick suspension；
Step 3, suspension thick described in step 2 is placed in the grinding chamber of nano-level grinder, grinds 60min with the rotating speed of 2500rpm, obtain megestrol acetate nanosuspension.
The application in pharmaceutical preparation of the megestrol acetate nanosuspension of the present embodiment, the dosage form of described pharmaceutical preparation is quick-release tablet；After described quick-release tablet is mixed homogeneously with adjuvant by megestrol acetate nanosuspension, after adopting fluidized bed granulation, tabletting is made；Described adjuvant includes filler, disintegrating agent and lubricant；Described filler is starch, dextrin, lactose, mannitol and microcrystalline Cellulose (mass ratio is 5:2:2:1:10), and in quick-release tablet, the weight/mass percentage composition of filler is 40%；Described disintegrating agent is crospolyvinylpyrrolidone, and in quick-release tablet, the weight/mass percentage composition of disintegrating agent is 6%；Described lubricant is magnesium stearate and Polyethylene Glycol (mass ratio is 1:1), and in quick-release tablet, the weight/mass percentage composition of lubricant is 1%.
Embodiment 6
The present embodiment is identical with embodiment 5, wherein it is different in that: described filler is starch, dextrin, lactose, one in mannitol and microcrystalline Cellulose, two kinds, three kinds or four kinds, disintegrating agent is cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium or low-substituted hydroxypropyl methylcellulose, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, at least two in carboxymethyl starch sodium and low-substituted hydroxypropyl methylcellulose, lubricant is magnesium stearate, micropowder silica gel, one in Pulvis Talci and Polyethylene Glycol, three kinds or four kinds, or for micropowder silica gel and Pulvis Talci, or it is magnesium stearate and micropowder silica gel, or it is magnesium stearate and Pulvis Talci, or it is Pulvis Talci and Polyethylene Glycol, or for micropowder silica gel and Polyethylene Glycol.
Embodiment 7
The megestrol acetate nanosuspension of the present embodiment, megestrol acetate and stabiliser solution grind through nano-level grinder after mixing and make, the mixture that described stabilizer is cellulose derivative and anion surfactant mixes according to the mass ratio of 10:1；Described cellulose derivative is hydroxypropyl methylcellulose and hydroxypropyl cellulose, the mass ratio of hydroxypropyl methylcellulose and hydroxypropyl cellulose is 10:7, described anion surfactant is the mass ratio of sodium lauryl sulphate and NaTDC, sodium lauryl sulphate and NaTDC is 10:5；In described megestrol acetate nanosuspension, the concentration of megestrol acetate is 100mg/mL；In described megestrol acetate suspension, megestrol acetate is 50:2 with the mass ratio of stabilizer.
The preparation method of the megestrol acetate nanosuspension of the present embodiment comprises the following steps:
Step one, 8.8g hydroxypropyl methylcellulose, 6.2g hydroxypropyl cellulose, 1g sodium lauryl sulphate and 0.5g NaTDC are dissolved in 3700g purified water, are uniformly mixing to obtain stabiliser solution；
Step 2,412.5g megestrol acetate is scattered in stabiliser solution described in step one, is uniformly mixing to obtain thick suspension；
Step 3, suspension thick described in step 2 is placed in the grinding chamber of nano-level grinder, grinds 90min with the rotating speed of 2000rpm, obtain megestrol acetate nanosuspension.
The application in pharmaceutical preparation of the megestrol acetate nanosuspension of the present embodiment, the dosage form of described pharmaceutical preparation is quick-release tablet；After described quick-release tablet is mixed homogeneously with adjuvant by megestrol acetate nanosuspension, after adopting fluidized bed granulation, tabletting is made；Described adjuvant includes filler, disintegrating agent and lubricant；Described filler is lactose, mannitol and microcrystalline Cellulose (mass ratio is 1:1:1), and in quick-release tablet, the weight/mass percentage composition of filler is 70%；Described disintegrating agent is cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium and low-substituted hydroxypropyl methylcellulose (mass ratio is 2:1:2), and in quick-release tablet, the weight/mass percentage composition of disintegrating agent is 3%；Described lubricant is magnesium stearate, micropowder silica gel, Pulvis Talci and Polyethylene Glycol (mass ratio is 1:1:1:2), and in quick-release tablet, the weight/mass percentage composition of lubricant is 0.5%.
Embodiment 8
nullThe present embodiment is identical with embodiment 7，Wherein it is different in that: described filler is starch、Dextrin、Lactose、One in mannitol and microcrystalline Cellulose、Two kinds、Four kinds or five kinds，Or it is starch、Dextrin、In mannitol and microcrystalline Cellulose three kinds，Or it is starch、The mixture of two kinds in dextrin and microcrystalline Cellulose and lactose，Or it is the mixture of a kind of and lactose in starch and dextrin and mannitol，Disintegrating agent is crospolyvinylpyrrolidone、Cross-linking sodium carboxymethyl cellulose、One in carboxymethyl starch sodium and low-substituted hydroxypropyl methylcellulose、Two kinds or four kinds，Or it is crospolyvinylpyrrolidone、Carboxymethyl starch sodium and low-substituted hydroxypropyl methylcellulose，Or it is crospolyvinylpyrrolidone、Cross-linking sodium carboxymethyl cellulose and low-substituted hydroxypropyl methylcellulose，Or it is crospolyvinylpyrrolidone、Cross-linking sodium carboxymethyl cellulose and carboxymethyl starch sodium，Lubricant is magnesium stearate、Micropowder silica gel、The one of Pulvis Talci and Polyethylene Glycol、Two or three.
Embodiment 9
The megestrol acetate nanosuspension of the present embodiment, megestrol acetate and stabiliser solution grind through nano-level grinder after mixing and make, the mixture that described stabilizer is cellulose derivative and anion surfactant mixes according to the mass ratio of 10:2；Described cellulose derivative is hydroxypropyl methylcellulose and hydroxypropyl cellulose, the mass ratio of hydroxypropyl methylcellulose and hydroxypropyl cellulose is 10:10, described anion surfactant is the mass ratio of sodium lauryl sulphate and NaTDC, sodium lauryl sulphate and NaTDC is 10:5；In described megestrol acetate nanosuspension, the concentration of megestrol acetate is 1mg/mL；In described megestrol acetate suspension, megestrol acetate is 50:1 with the mass ratio of stabilizer.
The preparation method of the megestrol acetate nanosuspension of the present embodiment comprises the following steps:
Step one, 3.75g hydroxypropyl methylcellulose, 3.75g hydroxypropyl cellulose, 1g sodium lauryl sulphate and 0.5g NaTDC are dissolved in 450kg purified water, are uniformly mixing to obtain stabiliser solution；
Step 2,450g megestrol acetate is scattered in stabiliser solution described in step one, is uniformly mixing to obtain thick suspension；
Step 3, suspension thick described in step 2 is placed in the grinding chamber of nano-level grinder, grinds 90min with the rotating speed of 2000rpm, obtain megestrol acetate nanosuspension.
The application in pharmaceutical preparation of the megestrol acetate nanosuspension of the present embodiment, the dosage form of described pharmaceutical preparation is quick-release tablet；After described quick-release tablet is mixed homogeneously with adjuvant by megestrol acetate nanosuspension, after adopting fluidized bed granulation, tabletting is made；Described adjuvant includes filler, disintegrating agent and lubricant；Described filler is lactose, mannitol and microcrystalline Cellulose (mass ratio is 1:1:1), and in quick-release tablet, the weight/mass percentage composition of filler is 70%；Described disintegrating agent is cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium and low-substituted hydroxypropyl methylcellulose (mass ratio is 2:1:2), and in quick-release tablet, the weight/mass percentage composition of disintegrating agent is 1%；Described lubricant is magnesium stearate, micropowder silica gel, Pulvis Talci and Polyethylene Glycol (mass ratio is 1:1:1:2), and in quick-release tablet, the weight/mass percentage composition of lubricant is 0.1%.
Embodiment 10
nullThe present embodiment is identical with embodiment 9，Wherein it is different in that: described filler is starch、Dextrin、Lactose、One in mannitol and microcrystalline Cellulose、Two kinds、Four kinds or five kinds，Or it is starch、Dextrin、In mannitol and microcrystalline Cellulose three kinds，Or it is starch、The mixture of two kinds in dextrin and microcrystalline Cellulose and lactose，Or it is the mixture of a kind of and lactose in starch and dextrin and mannitol，Disintegrating agent is crospolyvinylpyrrolidone、Cross-linking sodium carboxymethyl cellulose、One in carboxymethyl starch sodium and low-substituted hydroxypropyl methylcellulose、Two kinds or four kinds，Or it is crospolyvinylpyrrolidone、Carboxymethyl starch sodium and low-substituted hydroxypropyl methylcellulose，Or it is crospolyvinylpyrrolidone、Cross-linking sodium carboxymethyl cellulose and low-substituted hydroxypropyl methylcellulose，Or it is crospolyvinylpyrrolidone、Cross-linking sodium carboxymethyl cellulose and carboxymethyl starch sodium，Lubricant is magnesium stearate、Micropowder silica gel、The one of Pulvis Talci and Polyethylene Glycol、Two or three.
Adopting laser granulometry that the granularity of the megestrol acetate nanosuspension of the present invention is measured, result is following table such as:
The granularity of table 1 megestrol acetate nanosuspension
| Embodiment | d10(nm) | d50(nm) | d90(nm) | Mean(nm) |
| 1 | 125 | 375 | 800 | 350 |
| 3 | 136 | 355 | 765 | 341 |
| 5 | 150 | 401 | 851 | 420 |
| 7 | 145 | 420 | 890 | 450 |
| 9 | 155 | 412 | 875 | 433 |
From table 1 it follows that the mean diameter of megestrol acetate is below 1000nm in the megestrol acetate nanosuspension prepared of the present invention.
The megestrol acetate quick-release tablet of the present invention is carried out Dissolution Rate Testing and bioavailability study:
One, Dissolution Rate Testing
Precision weighs megestrol acetate quick-release tablet 20mg prepared by the present invention, adopts two annex XC dissolution method the second methods of version Chinese Pharmacopoeia in 2015 to test.With 900mL mass concentration be 1% sodium dodecyl sulfate solution for dissolution medium, rotating speed 100r min-1Dissolution medium temperature is maintained at (37.0 ± 0.5) DEG C, separately sampled 10mL when 5min, 10min, 20min, 30min, 45min, 60min, supplements the sodium lauryl sulphate dissolution medium that 10mL mass concentration is 1% simultaneously, and the sample of taking-up is through 0.45 μm of filtering with microporous membrane.Precision measures filtrate 2mL, puts in 50mL measuring bottle, adds the sodium dodecyl sulfate solution that mass concentration is 1% and is diluted to scale, shakes up, as need testing solution.Additionally, precision weighs megestrol acetate reference substance (marketed tablet) 20mg, put in 100mL measuring bottle, add methanol dissolve and be diluted to scale, precision measures 2.0mL, puts in 50mL measuring bottle, is diluted to scale with the sodium dodecyl sulfate solution that mass concentration is 1%, shake up, as reference substance solution.Taking above two solution respectively, according to UV-VIS spectrophotometry two annex IVA of version Chinese Pharmacopoeia in 2015, measure A value respectively at the wavelength place of 292nm, calculate the dissolution of every, result is in Table 2.
The megestrol acetate quick-release tablet of table 2 present invention and the dissolution results of marketed tablet
| Time (min) | Embodiment 1 | Embodiment 3 | Embodiment 5 | Embodiment 7 | Embodiment 9 | Marketed tablet |
| 5 | 42.35% | 45.16% | 43.16% | 45.22% | 42.56% | 25.13% |
| 10 | 69.76% | 70.25% | 71.50% | 68.76% | 69.25% | 43.1% |
| 20 | 90.67% | 93.25% | 91.25% | 92.67% | 90.85% | 69.25% |
| 30 | 93.2% | 94.35% | 94.10% | 94.55% | 93.14% | 79.15% |
| 45 | 94.28% | 95.42% | 96.28% | 95.98% | 94.36% | 83.05% |
| 60 | 97.5% | 97.9% | 97.88% | 96.68% | 96.95% | 88.27% |
Can be seen that from the data of table 2, compare with commercially available megestrol acetate tablet, the dissolution of the quick-release tablet of the present invention significantly improves, and when 30 minutes, the dissolution of marketed tablet is only 79.15%, and the dissolution of the megestrol acetate quick-release tablet of the present invention has reached more than 90%.
Two, pharmacokinetic trial in animal body
Adopt LC-MS technology, have studied 6 beagle dogs oral self-control megestrol acetate quick-release tablet (40mg/ is only) internal pharmacokinetics process afterwards, and using commercially available megestrol acetate tablet as compareing (two period crossover administrations), determine the concentration of megestrol acetate in 6 Beagle dog oral administration different time blood plasma, its pharmacokinetic parameter is calculated according to blood drug level, wherein peak time (Tmax) and maximum plasma concentration (Cmax) all represent with measured value, under Cot curve, area (AUC) is for adding up from method result of calculation.By the pharmacokinetic parameters result of calculation of test preparation (T) and reference preparation (R) in Table 3.
Table 3 is the pharmacokinetic parameters of (40mg/ is only) after beagle dog oral administration
As can be seen from Table 3, compared with commercially available megestrol acetate tablet, the megestrol acetate quick-release tablet of the present invention significantly improves the oral organism-absorbing availability of medicine.
The above; it it is only presently preferred embodiments of the present invention; not the present invention is imposed any restrictions, every any simple modification, change and equivalent structure change above example made according to the technology of the present invention essence, all still fall within the protection domain of technical solution of the present invention.
Claims (10)
1. a megestrol acetate nanosuspension, it is characterized in that, grinding through nano-level grinder after being mixed by megestrol acetate and stabiliser solution and make, described stabilizer is that cellulose derivative and anion surfactant are according to 10:(1～2) the mixture of mass ratio mixing；Described cellulose derivative is hydroxypropyl methylcellulose and hydroxypropyl cellulose, the mass ratio of hydroxypropyl methylcellulose and hydroxypropyl cellulose is 10:(1～10), described anion surfactant is the mass ratio of sodium lauryl sulphate and NaTDC, sodium lauryl sulphate and NaTDC is 10:(1～5).
2. a kind of megestrol acetate nanosuspension according to claim 1, it is characterized in that, described stabilizer is that cellulose derivative and anion surfactant are according to 10:(1～1.5) the mixture of mass ratio mixing, the mass ratio of described hydroxypropyl methylcellulose and hydroxypropyl cellulose is 10:(4～7), the mass ratio of described sodium lauryl sulphate and NaTDC is 10:(3～5).
3. a kind of megestrol acetate nanosuspension according to claim 2, it is characterized in that, the mixture that described stabilizer is cellulose derivative and anion surfactant mixes according to the mass ratio of 10:1.2, the mass ratio of described hydroxypropyl methylcellulose and hydroxypropyl cellulose is 10:5, and the mass ratio of described sodium lauryl sulphate and NaTDC is 10:4.
4. a kind of megestrol acetate nanosuspension according to claim 1,2 or 3, it is characterised in that in described megestrol acetate nanosuspension, the concentration of megestrol acetate is 1mg/mL～400mg/mL；In described megestrol acetate suspension, megestrol acetate is 50:(1～2 with the mass ratio of stabilizer).
5. a kind of megestrol acetate nanosuspension according to claim 1,2 or 3, it is characterised in that in described megestrol acetate nanosuspension, the particle mean size of megestrol acetate is below 1000nm.
6. the method for the megestrol acetate nanosuspension prepared as described in claim 1,2 or 3, it is characterised in that comprise the following steps:
Step one, stabilizer is dissolved in purified water, is uniformly mixing to obtain stabiliser solution；
Step 2, megestrol acetate is scattered in stabiliser solution described in step one, is uniformly mixing to obtain thick suspension；
Step 3, suspension thick described in step 2 is placed in the grinding chamber of nano-level grinder, grinds 30min～120min with the rotating speed of 1500rpm～3500rpm, obtain megestrol acetate nanosuspension.
7. the application in pharmaceutical preparation of the megestrol acetate nanosuspension as described in claim 1,2 or 3, the dosage form of described pharmaceutical preparation is quick-release tablet.
8. application according to claim 7, it is characterised in that after described quick-release tablet is mixed homogeneously with adjuvant by megestrol acetate nanosuspension, after adopting fluidized bed granulation, tabletting is made；Described adjuvant includes filler, disintegrating agent and lubricant.
9. application according to claim 7, it is characterised in that described filler is one or more in starch, dextrin, lactose, mannitol and microcrystalline Cellulose, in quick-release tablet, the weight/mass percentage composition of filler is 20%～70%；Described disintegrating agent is one or more in crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium and low-substituted hydroxypropyl methylcellulose, and in quick-release tablet, the weight/mass percentage composition of disintegrating agent is 1%～10%；Described lubricant is one or more in magnesium stearate, micropowder silica gel, Pulvis Talci and Polyethylene Glycol, and in quick-release tablet, the weight/mass percentage composition of lubricant is 0.1%～2%.
10. application according to claim 9, it is characterised in that in described quick-release tablet, the weight/mass percentage composition of filler is 40%～70%, the weight/mass percentage composition of disintegrating agent is 3%～6%, and the weight/mass percentage composition of lubricant is 0.5%～1%.
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| CN109432018A (en) * | 2018-12-25 | 2019-03-08 | 中国人民解放军第四军医大学 | Nanosuspension of insoluble drug and its preparation method and application |
| CN111904931A (en) * | 2020-07-06 | 2020-11-10 | 中国人民解放军军事科学院军事医学研究院 | Megestrol acetate nanocrystal oral suspension, and preparation method and application thereof |
| CN112891309A (en) * | 2019-11-19 | 2021-06-04 | 北京化工大学 | Megestrol acetate nano dry suspension and preparation method thereof |
| CN113274351A (en) * | 2020-02-20 | 2021-08-20 | 东曜药业有限公司 | Oral megestrol acetate suspension and preparation method thereof |
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| CN112891309A (en) * | 2019-11-19 | 2021-06-04 | 北京化工大学 | Megestrol acetate nano dry suspension and preparation method thereof |
| CN112891309B (en) * | 2019-11-19 | 2022-07-26 | 北京化工大学 | Megestrol acetate nano dry suspension and preparation method thereof |
| CN113274351A (en) * | 2020-02-20 | 2021-08-20 | 东曜药业有限公司 | Oral megestrol acetate suspension and preparation method thereof |
| CN113274351B (en) * | 2020-02-20 | 2024-04-12 | 东曜药业有限公司 | Oral megestrol acetate suspension and preparation method thereof |
| CN111904931A (en) * | 2020-07-06 | 2020-11-10 | 中国人民解放军军事科学院军事医学研究院 | Megestrol acetate nanocrystal oral suspension, and preparation method and application thereof |
| CN111904931B (en) * | 2020-07-06 | 2022-09-20 | 中国人民解放军军事科学院军事医学研究院 | Megestrol acetate nanocrystal oral suspension, and preparation method and application thereof |
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