CN108309933A - A kind of oral megestrol acetate nanosuspension and preparation method thereof - Google Patents
A kind of oral megestrol acetate nanosuspension 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
- A61K9/10—Dispersions; Emulsions
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- 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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- A61K9/0012—Galenical forms characterised by the site of application
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F21/00—Dissolving
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- B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
- B01F35/90—Heating or cooling systems
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
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Abstract
A kind of oral megestrol acetate nanosuspension and preparation method thereof, the oral megestrol acetate nanosuspension includes a effective amount of ultramicronising megestrol acetate, wetting agent, suspending agent, deflocculant, pH adjusting agent, corrigent, bacteriostatic agent, aromatic, purified water, just suspension is made after dissolving mixing respectively by partial material, then it is handled through high speed shear and thick suspension is made, it is most handled through microjet high pressure afterwards and oral megestrol acetate suspension is made, it is small with solid grain size, bioavilability is high, it is evenly distributed, stable system, feature in good taste, its average particle size is less than 500nm, and dispersion degree is small, the preparation method of the product is simple for process, easily realize industrialized production.
Description
Specification
Technical field
The invention belongs to field of pharmaceutical technology, and in particular to a kind of oral megestrol acetate nanosuspension and its preparation
Method.
Background technology
Megestrol acetate (Megestrol Acetate, MA) is a kind of important synthetic progestin class drug, main to use
In the treatment of advanced breast cancer and carcinoma of endometrium, the appetite and cachexia of late tumor patient can be improved, to dysfunctional uterine
Bleeding, irregular menstruation, endometrial hyperplasia, endometriosis and other diseases also have certain curative effect.Megestrol acetate is 37
DEG C water in solubility be 2mg/ml, solubility in blood is 24 μ g/ml, since its solubility is low, causes it opposite
Lower bioavilability.The common method for improving insoluble drug bioavilability has micronization technology and nanosuspension
Technology.After drug micronization, surface free energy is larger, has the tendency that spontaneous coalescence, reduces micronizing effect.At present by indissoluble
Property drug utilization highly-water-soluble carrier material be prepared into suspension, improve that drug solubility, to accelerate drug-eluting speed effect prominent
Go out.The existing main You Shiguibao companies of the megestrol acetate suspension oral mixed suspension listed in 1993 on American market at present
The oral administration mixed suspension MEGACE ES of liquid MEGACE (megace) and Par companies listing in 2005.The MEGACE ES of Par companies are adopted
The nanoparticle of megestrol acetate is prepared with nanometer wet grinding technology, and then increases its bioavilability.
105769763 A of Chinese invention patent CN (application publication number) disclose a kind of " megestrol acetate nanometer suspension
Liquid and its preparation method and application " is directed to invent a kind of megestrol acetate nanosuspension, is by tumer pregnant
It is made through nano-level grinder grinding after ketone and stabiliser solution mixing, acetic acid in the megestrol acetate nanosuspension of the invention
The average grain diameter 1000nm of megestrol acetate is hereinafter, significantly improve the dissolution rate of megestrol acetate, and then improve acetic acid
The oral administration biaavailability of megestrol acetate.
It is mixed that a kind of oral megestrol acetate flocculation is disclosed in 2001/0048931 A1 of United States Patent (USP) US (publication number)
Suspension is directed to invent a kind of comprising megestrol acetate, surfactant and including at least polyethylene glycol, propylene second two
A kind of megestrol acetate flocculating suspension of substance in alcohol, glycerine and sorbierite.
A kind of megestrol acetate suspension is disclosed in 2002/0028794 A1 of United States Patent (USP) US (publication number), wherein
Be related to having invented it is a kind of include 10~200mg/ml, 0.04~0.4%w/v wetting agents, 1.2~1.8%w/v suspending agents acetic acid
Megestrol acetate suspension.
But the above method improves the dissolution rate and bioavilability of megestrol acetate well not yet, needs exist for
A kind of method is further to improve the dissolution rate and bioavilability of megestrol acetate.
Invention content
It is an object of the present invention to overcome prior art deficiencies, provide a kind of particle fine uniform, biological utilisation
Spend high, stablizing and in good taste oral megestrol acetate suspension.It is a further object to provide one kind
Make the method for taking orally megestrol acetate suspension.
In order to solve the above technical problems, the technical solution adopted by the present invention is：
A kind of oral megestrol acetate nanosuspension, which is characterized in that comprising a effective amount of ultramicronising tumer
Progesterone, wetting agent, suspending agent, deflocculant, pH adjusting agent, corrigent, bacteriostatic agent, aromatic, purified water；The tumer
Progesterone grain size is less than 500nm；The acid megestrol acetate suspension contains 20.0~160.0mg/ of following component megestrol acetate
Ml, 1.0~4.8mg/ml of wetting agent, 10.0~20.0mg/ml of suspending agent, 1.5~2.5mg/ml of deflocculant, pH adjusting agent
3.0~15.0mg/ml, 0.15~100.0mg/ml of corrigent, 1.0~2.0mg/ml of bacteriostatic agent, 2.0~8.0mg/ of aromatic
Ml, remaining be purified water.
Above-mentioned oral megestrol acetate nanosuspension, which is characterized in that the wetting agent is lecithin, dodecyl
One or more of sodium sulphate, Tweens wetting agent, spans wetting agent, the Tweens wetting agent are Tween-20, spit
One or more of temperature -40, Tween-60 and Tween-80；The spans wetting agent is Arlacel-20, Arlacel-40, sapn-
One or more of 60 and Arlacel-80；
And/or the suspending agent is glue class suspending agent, sodium alginate, cellulose family suspending agent, polyethylene glycol family macromolecule
One or more of suspending agent and polyvinylpyrrolidone, the glue class suspending agent be xanthans, gelatin, carrageenan, Ah
One or more of primary glue is drawn, the fiber-like suspending agent is methylcellulose, sodium carboxymethylcellulose, hydroxy propyl cellulose
Element, the polyethylene glycols polymeric retention aid suspension are PEG4000 and/or PEG6000；
And/or the deflocculant is one kind in sodium citrate, tartrate, phosphate, carbonate, glycinate
Or it is several；
And/or the pH adjusting agent is citric acid, malic acid, citric acid, acetic acid, lactic acid, potassium carbonate, sodium carbonate, carbonic acid
One or more of hydrogen sodium, saleratus, potassium citrate, sodium citrate；
And/or the corrigent is sucrose, Steviosin, triterpene glucoside, Sucralose, one kind in xylitol or several
Kind；
And/or the bacteriostatic agent is sorbic acid, potassium sorbate, nisin, sodium benzoate, one in benzoic acid
Kind is several；
And/or the aromatic is one or more of fruity essence.
Preferably, the wetting agent is Tween-80；
Preferably, and/or, the suspending agent is PEG6000；
Preferably, and/or, the deflocculant is sodium citrate；
Preferably, and/or, the pH adjusting agent is the mixture of citric acid and sodium citrate；
Preferably, and/or, the corrigent is sucrose；
Preferably, and/or, the bacteriostatic agent is sodium benzoate；
Preferably, and/or, the aromatic is flavoring apple essence agent.
Above-mentioned oral megestrol acetate nanosuspension, which is characterized in that the oral megestrol acetate nanometer is mixed
Suspension contains 40.0~100.0mg/ml of following component megestrol acetate, 2.0~3.5mg/ml of Tween-80, PEG600014.0
0.8~2.0mg/ml of mixture, the sucrose of~18.0mg/ml, 1.8~2.2mg/ml of sodium citrate, citric acid and sodium citrate
50.0~100.0mg/ml, 1.0~2.0mg/ml of sodium benzoate, 3.5~6.0mg/ml of flavoring apple essence, remaining be purified water.
The preparation method of above-mentioned oral megestrol acetate nanosuspension, which is characterized in that include the following steps：
(1) all required materials are weighed respectively, it is spare；
(2) partial purification water is added in the wetting agent for weighing step (1), and ultrasonic wave dissolves by heating；
(3) partial purification water is added in the suspending agent for weighing step (1), and ultrasonic wave dissolves by heating；
(4) partial purification water is added in deflocculant, pH adjusting agent, the corrigent weighed step (1), and ultrasonic Wave heating is molten
Solution；
(5) remaining purified water is added in the bacteriostatic agent for weighing step (1), and ultrasonic wave dissolves by heating；
(6) solution made from step (4) is added in solution made from step (3), is stirred evenly；
(7) solution made from step (5) is added in solution made from step (6), is stirred evenly；
(8) aromatic is added in solution made from step (7), is stirred evenly；
(9) solution made from step (2) is added in solution made from step (8) and is stirred evenly；
(10) megestrol acetate that step (1) weighs is added in solution made from step (9) and is stirred evenly, is made
First suspension；
(11) just suspension is made in step (10) and thick suspension is made by high speed shear；
(12) the obtained thick suspension of step (11) is high-pressure homogeneous through microjet, it is mixed that oral megestrol acetate nanometer is made
Suspension；
The grain size of the megestrol acetate bulk pharmaceutical chemicals is less than 800nm.
The preparation method of above-mentioned oral megestrol acetate nanosuspension, which is characterized in that the ultrasound Wave heating is molten
The condition of solution is：Frequency 150Hz~250Hz, 35 DEG C~60 DEG C of temperature, 15~30min of time.
The preparation method of above-mentioned oral megestrol acetate nanosuspension, which is characterized in that the item of the high speed shear
Part is：10~30 minutes, 10000~20000rpm of rotating speed, shear temperature was solution temperature.
The preparation method of above-mentioned oral megestrol acetate nanosuspension, which is characterized in that the microjet high pressure is equal
The condition of matter is：150~250Mpa of pressure, cycle-index 20~30 times.
Preferably, the condition of above-mentioned ultrasonic wave heating for dissolving is：Frequency 200Hz, 35 DEG C of temperature, time 15；
Preferably, the condition of above-mentioned high speed shear is：10min, rotating speed 10000；
Preferably, the high-pressure homogeneous condition of above-mentioned microjet is：Pressure 250Mpa, cycle-index 25 times.
The present invention operation principle be：Wetting agent can reduce solid material surface tension or interfacial tension, allow the water to open up
It is opened on solid material surface, solid material is enable to be dissolved in water faster；Suspending agent is mostly polymer substance, in water may be used
The sticky suspension formulation for forming high degree of dispersion, to limit the decrease speed of active principle in suspension；Due to mixed in suspension
Presence or the ion in adsorbent solution of outstanding microparticle surfaces free group and the ion with identical charges, while counter ion is distributed
Around it, it is easy to cause to flocculate, deflocculant is a kind of electrolyte, it can increase electrokinetic potential, reduces flocculating degree；
PH adjusting agent can not only assign product tart flavour, but also can enhance the stability of system by regulating and controlling pH value；Corrigent and aromatic
The palatable mouthfeel of product and attracting fragrance can be assigned；Bacteriostatic agent can inhibit the growth of microorganism, to extend product
Shelf-life.
Ultrasonic wave heating for dissolving is by ultrasonic wave and heating double action, the jolting rate and movement speed of acceleration molecular
Degree, puies forward high molecular diffusion velocity, to accelerate to dissolve；High speed shear technology is made immiscible by quick shear action
Material moment is equably fully dispersed, emulsification, homogeneous, dissolving；Microjet high pressure homogenization technique is exactly huge by carrying
The high pressure microjet of energy is acted in some way on the substance by homogeneous, during which the high velocity turbulent flow of accompanied by intense make material by
Power is big and uniform, so the suspension that solid grain size is small, is evenly distributed, stablizes can be obtained.
It is an advantage of the invention that：The megestrol acetate suspension solid grain size of preparation is small, bioavilability is high, divides
Cloth uniformly, it is stable system, in good taste and simple for process, easily realize industrialized production.
Specific implementation mode
Below by embodiment, technical scheme of the present invention is described in further detail, the embodiment described is
For illustrating the present invention, and it is not considered as limitation of the present invention.
Following embodiment uses ultrasonic wave separating apparatus to carry out ultrasonic wave heating for dissolving processing, is stirred using high speed shearing emulsification
It mixes machine and carries out high speed shear processing, the high-pressure homogeneous processing of microjet is carried out using microjet high pressure homogenizer.
Embodiment 1
(1) megestrol acetate 20.0000g, lecithin 1.0000g, xanthans 10.0000g, sodium tartrate are weighed
1.5000g, malic acid 0.5000g, Steviosin 0.1500g, potassium sorbate 1.0000g, lemon extract 2.0000g, purified water
963.85g, it is spare.
(2) partial purification water is added in lecithin, setting Ultrasonic Conditions are frequency 150Hz, 35 DEG C of temperature, time
15min carries out ultrasonic wave heating for dissolving；
(3) partial purification water is added in xanthans, setting Ultrasonic Conditions are frequency 150Hz, 35 DEG C of temperature, time
15min carries out ultrasonic wave heating for dissolving；
(4) partial purification water being added in sodium tartrate, malic acid, Steviosin, setting Ultrasonic Conditions are frequency 150Hz,
35 DEG C, time 15min of temperature carries out ultrasonic wave heating for dissolving；
(5) remaining purified water is added in potassium sorbate, setting Ultrasonic Conditions are frequency 150Hz, 35 DEG C of temperature, time
15min carries out ultrasonic wave heating for dissolving；
(6) solution made from step (4) is added in solution made from step (3), is stirred evenly；
(7) solution made from step (5) is added in solution made from step (6), is stirred evenly；
(8) lemon extract is added in solution made from step (7), is stirred evenly；
(9) solution made from step (2) is added in solution made from step (8) and is stirred evenly；
(10) megestrol acetate that step (1) weighs is added in solution made from step (9) and is stirred evenly, is made
First suspension；
(11) setting high speed shear condition is 10min, rotating speed 10000rpm, and just suspension, which is made, in step (10) passes through high speed
Thick suspension is made in shearing；
(12) the setting high-pressure homogeneous condition of microjet is 150Mpa, 20 times, thick suspension is made in step (11) and is penetrated through micro-
Flow high-pressure homogeneous, obtained oral megestrol acetate nanosuspension.
Oral megestrol acetate nanosuspension sweet mouthfeel obtained is tasty and refreshing, has citris aromas；Pass through granularity point
Cloth instrument measures, average grain diameter 400nm, and powder of the grain size less than 400nm accounts for 90% or more；After the above suspension is placed 35 days,
It does not precipitate.
Embodiment 2
(1) megestrol acetate 40.0000g, Tween-20 2.0000g, sodium alginate 15.0000g, sodium phosphate are weighed
1.5000g, acetic acid 1.0000g, sucrose 50.0000g, sorbic acid 1.5000g, lemon extract 3.5000g, purified water 885.50g,
It is spare.
(2) partial purification water is added in Tween-20, setting Ultrasonic Conditions are frequency 200Hz, 40 DEG C of temperature, time
20min carries out ultrasonic wave heating for dissolving；
(3) partial purification water is added in sodium alginate, setting Ultrasonic Conditions are frequency 200Hz, 40 DEG C of temperature, time
20min carries out ultrasonic wave heating for dissolving；
(4) partial purification water is added in sodium phosphate, acetic acid, sucrose, setting Ultrasonic Conditions are frequency 200Hz, temperature 40
DEG C, time 20min carries out ultrasonic wave heating for dissolving；
(5) remaining purified water is added in sorbic acid, setting Ultrasonic Conditions are frequency 200Hz, 40 DEG C of temperature, time
20min carries out ultrasonic wave heating for dissolving；
(6) solution made from step (4) is added in solution made from step (3), is stirred evenly；
(7) solution made from step (5) is added in solution made from step (6), is stirred evenly；
(8) lemon extract is added in solution made from step (7), is stirred evenly；
(9) solution made from step (2) is added in solution made from step (8) and is stirred evenly；
(10) megestrol acetate that step (1) weighs is added in solution made from step (9) and is stirred evenly, is made
First suspension；
(11) setting high speed shear condition is 15min, rotating speed 10000rpm, and just suspension, which is made, in step (10) passes through high speed
Thick suspension is made in shearing；
(12) the setting high-pressure homogeneous condition of microjet is 200Mpa, 25 times, thick suspension is made in step (11) and is penetrated through micro-
Flow high-pressure homogeneous, obtained oral megestrol acetate nanosuspension.
Oral megestrol acetate nanosuspension sweet mouthfeel obtained is tasty and refreshing, has citris aromas；Pass through granularity point
Cloth instrument measures, average grain diameter 300nm, and powder of the grain size less than 300nm accounts for 90% or more；After the above suspension is placed 35 days,
It does not precipitate.
Embodiment 3
(1) megestrol acetate 60.0000g, Tween-40 3.0000g, PEG400016.0000g, sodium carbonate are weighed
It is 2.0000g, lactic acid 1.0000g, triterpene glucoside 0.4000g, nisin 1.5000g, lemon extract 5.0000g, pure
Change water 911.10g, it is spare.
(2) partial purification water is added in Tween-40, setting Ultrasonic Conditions are frequency 250Hz, temperature 50 C, time
20min carries out ultrasonic wave heating for dissolving；
(3) partial purification water is added in PEG4000, setting Ultrasonic Conditions are frequency 250Hz, temperature 50 C, time
20min carries out ultrasonic wave heating for dissolving；
(4) partial purification water is added in sodium carbonate, lactic acid, Siraitia grosvenorii soap, setting Ultrasonic Conditions are frequency 250Hz, temperature
50 DEG C, time 20min of degree carries out ultrasonic wave heating for dissolving；
(5) nisin being added remaining purified water, setting Ultrasonic Conditions are frequency 250Hz, temperature 50 C, when
Between 20min, carry out ultrasonic wave heating for dissolving；
(6) solution made from step (4) is added in solution made from step (3), is stirred evenly；
(7) solution made from step (5) is added in solution made from step (6), is stirred evenly；
(8) lemon extract is added in solution made from step (7), is stirred evenly；
(9) solution made from step (2) is added in solution made from step (8) and is stirred evenly；
(10) megestrol acetate that step (1) weighs is added in solution made from step (9) and is stirred evenly, is made
First suspension；
(11) setting high speed shear condition is 20min, rotating speed 15000rpm, and just suspension, which is made, in step (10) passes through high speed
Thick suspension is made in shearing；
(12) the setting high-pressure homogeneous condition of microjet is 200Mpa, 30 times, thick suspension is made in step (11) and is penetrated through micro-
Flow high-pressure homogeneous, obtained oral megestrol acetate nanosuspension.
Oral megestrol acetate nanosuspension sweet mouthfeel obtained is tasty and refreshing, has citris aromas；Pass through granularity point
Cloth instrument measures, average grain diameter 250nm, and powder of the grain size less than 250nm accounts for 90% or more；After the above suspension is placed 35 days,
It does not precipitate.
Embodiment 4
(1) megestrol acetate 80.0000g, Tween-60 3.5000g, PEG600016.0000g, Chinese holly edge acid sodium are weighed
2.0000g, citric acid 1.5000g, Sucralose 0.1500g, sodium benzoate 1.5000g, flavoring apple essence 3.5000g, purified water
891.85g, it is spare.
(2) partial purification water is added in Tween-60, setting Ultrasonic Conditions are frequency 250Hz, temperature 60 C, time
25min carries out ultrasonic wave heating for dissolving；
(3) partial purification water is added in PEG6000, setting Ultrasonic Conditions are frequency 250Hz, temperature 60 C, time
25min carries out ultrasonic wave heating for dissolving；
(4) partial purification water being added in Chinese holly edge acid sodium, Chinese holly edge acid, chlorine sucrose, setting Ultrasonic Conditions are frequency 250Hz,
Temperature 60 C, time 25min carry out ultrasonic wave heating for dissolving；
(5) remaining purified water is added in sodium benzoate, setting Ultrasonic Conditions are frequency 250Hz, temperature 60 C, time
25min carries out ultrasonic wave heating for dissolving；
(6) solution made from step (4) is added in solution made from step (3), is stirred evenly；
(7) solution made from step (5) is added in solution made from step (6), is stirred evenly；
(8) flavoring apple essence is added in solution made from step (7), is stirred evenly；
(9) solution made from step (2) is added in solution made from step (8) and is stirred evenly；
(10) megestrol acetate that step (1) weighs is added in solution made from step (9) and is stirred evenly, is made
First suspension；
(11) setting high speed shear condition is 30min, rotating speed 15000rpm, and just suspension, which is made, in step (10) passes through high speed
Thick suspension is made in shearing；
(12) the setting high-pressure homogeneous condition of microjet is 250Mpa, 20 times, thick suspension is made in step (11) and is penetrated through micro-
Flow high-pressure homogeneous, obtained oral megestrol acetate nanosuspension.
Oral megestrol acetate nanosuspension sweet mouthfeel obtained is tasty and refreshing, has apple fragrance；Pass through granularity point
Cloth instrument measures, average grain diameter 200nm, and powder of the grain size less than 200nm accounts for 90% or more；After the above suspension is placed 35 days,
It does not precipitate.
Embodiment 5
(1) megestrol acetate 80.0000g, Tween-80 3.5000g, PEG600014.0000g, Chinese holly edge acid sodium are weighed
1.8000g, citric acid 0.6000g, sodium citrate 0.2000g, sucrose 50.0000g, sodium benzoate 2.0000g, flavoring apple essence
4.5000g, purified water 843.40g, it is spare.
(2) partial purification water is added in Tween-80, setting Ultrasonic Conditions are frequency 200Hz, 35 DEG C of temperature, time
15min carries out ultrasonic wave heating for dissolving；
(3) partial purification water is added in PEG6000, setting Ultrasonic Conditions are frequency 200Hz, 35 DEG C of temperature, time
15min carries out ultrasonic wave heating for dissolving；
(4) partial purification water is added in Chinese holly edge acid sodium, citric acid, sodium citrate, sucrose, setting Ultrasonic Conditions are frequency
200Hz, 35 DEG C, time 15min of temperature carry out ultrasonic wave heating for dissolving；
(5) remaining purified water is added in sodium benzoate, setting Ultrasonic Conditions are frequency 250Hz, temperature 60 C, time
25min carries out ultrasonic wave heating for dissolving；
(6) solution made from step (4) is added in solution made from step (3), is stirred evenly；
(7) solution made from step (5) is added in solution made from step (6), is stirred evenly；
(8) flavoring apple essence is added in solution made from step (7), is stirred evenly；
(9) solution made from step (2) is added in solution made from step (8) and is stirred evenly；
(10) megestrol acetate that step (1) weighs is added in solution made from step (9) and is stirred evenly, is made
First suspension；
(11) setting high speed shear condition is 30min, rotating speed 20000rpm, and just suspension, which is made, in step (10) passes through high speed
Thick suspension is made in shearing；
(12) the setting high-pressure homogeneous condition of microjet is 250Mpa, 25 times, thick suspension is made in step (11) and is penetrated through micro-
Flow high-pressure homogeneous, obtained oral megestrol acetate nanosuspension.
Oral megestrol acetate nanosuspension sweet mouthfeel obtained is tasty and refreshing, has apple fragrance；Pass through granularity point
Cloth instrument measures, average grain diameter 150nm, and powder of the grain size less than 150nm accounts for 90% or more；After the above suspension is placed 35 days,
It does not precipitate.
Embodiment 6
(1) megestrol acetate 100.0000g, Tween-80 3.0000g, PEG600018.0000g, Chinese holly edge acid sodium are weighed
2.2000g, citric acid 1.0000g, sodium citrate 0.4000g, sucrose 75.0000g, sodium benzoate 1.5000g, flavoring apple essence
6.0000g, purified water 792.90g, it is spare.
(2) partial purification water is added in Tween-80, setting Ultrasonic Conditions are frequency 200Hz, 35 DEG C of temperature, time
15min carries out ultrasonic wave heating for dissolving；
(3) partial purification water is added in PEG6000, setting Ultrasonic Conditions are frequency 200Hz, 35 DEG C of temperature, time
15min carries out ultrasonic wave heating for dissolving；
(4) partial purification water is added in Chinese holly edge acid sodium, citric acid, sodium citrate, sucrose, setting Ultrasonic Conditions are frequency
200Hz, 35 DEG C, time 15min of temperature carry out ultrasonic wave heating for dissolving；
(5) remaining purified water is added in sodium benzoate, setting Ultrasonic Conditions are frequency 200Hz, 35 DEG C of temperature, time
15min carries out ultrasonic wave heating for dissolving；
(6) solution made from step (4) is added in solution made from step (3), is stirred evenly；
(7) solution made from step (5) is added in solution made from step (6), is stirred evenly；
(8) flavoring apple essence is added in solution made from step (7), is stirred evenly；
(9) solution made from step (2) is added in solution made from step (8) and is stirred evenly；
(10) megestrol acetate that step (1) weighs is added in solution made from step (9) and is stirred evenly, is made
First suspension；
(11) setting high speed shear condition is 10min, rotating speed 10000rpm, and just suspension, which is made, in step (10) passes through high speed
Thick suspension is made in shearing；
(12) the setting high-pressure homogeneous condition of microjet is 250Mpa, 25 times, thick suspension is made in step (11) and is penetrated through micro-
Flow high-pressure homogeneous, obtained oral megestrol acetate nanosuspension.
Oral megestrol acetate nanosuspension sweet mouthfeel obtained is tasty and refreshing, has apple fragrance；Pass through granularity point
Cloth instrument measures, average grain diameter 150nm, and powder of the grain size less than 150nm accounts for 90% or more；After the above suspension is placed 35 days,
It does not precipitate.
Embodiment 7
(1) megestrol acetate 80.0000g, Tween-80 2.0000g, PEG600016.0000g, Chinese holly edge acid sodium are weighed
2.0000g, citric acid 1.5000g, sodium citrate 0.5000g, sucrose 100.0000g, sodium benzoate 1.8000g, flavoring apple essence
5.0000g, purified water 791.2g, it is spare.
(2) partial purification water is added in Tween-80, setting Ultrasonic Conditions are frequency 200Hz, 35 DEG C of temperature, time
15min carries out ultrasonic wave heating for dissolving；
(3) partial purification water is added in PEG6000, setting Ultrasonic Conditions are frequency 200Hz, 35 DEG C of temperature, time
15min carries out ultrasonic wave heating for dissolving；
(4) partial purification water is added in Chinese holly edge acid sodium, citric acid, sodium citrate, sucrose, setting Ultrasonic Conditions are frequency
200Hz, 35 DEG C, time 15min of temperature carry out ultrasonic wave heating for dissolving；
(5) remaining purified water is added in sodium benzoate, setting Ultrasonic Conditions are frequency 200Hz, temperature 45 C, time
25min carries out ultrasonic wave heating for dissolving；
(6) solution made from step (4) is added in solution made from step (3), is stirred evenly；
(7) solution made from step (5) is added in solution made from step (6), is stirred evenly；
(8) flavoring apple essence is added in solution made from step (7), is stirred evenly；
(9) solution made from step (2) is added in solution made from step (8) and is stirred evenly；
(10) megestrol acetate that step (1) weighs is added in solution made from step (9) and is stirred evenly, is made
First suspension；
(11) setting high speed shear condition is 20min, rotating speed 10000rpm, and just suspension, which is made, in step (10) passes through high speed
Thick suspension is made in shearing；
(12) the setting high-pressure homogeneous condition of microjet is 250Mpa, 30 times, thick suspension is made in step (11) and is penetrated through micro-
Flow high-pressure homogeneous, obtained oral megestrol acetate nanosuspension.
Oral megestrol acetate nanosuspension sweet mouthfeel obtained is tasty and refreshing, has apple fragrance；Pass through granularity point
Cloth instrument measures, average grain diameter 150nm, and powder of the grain size less than 150nm accounts for 90% or more；After the above suspension is placed 35 days,
It does not precipitate.
Embodiment 8
(1) megestrol acetate 100.0000g, Arlacel-40 4.0000g, polyvinylpyrrolidone 16.0000g, Chinese holly are weighed
Edge acid sodium 2.0000g, malic acid 1.5000g, potassium citrate 0.5000g, xylitol 100.0000g, benzoic acid 1.8000g, sweet tea
Orange essence 8.0000g, purified water 766.2g, it is spare.
For making step with embodiment 6, oral megestrol acetate nanosuspension sweet mouthfeel obtained is tasty and refreshing, has sweet tea
Orange perfume gas；It is measured by particles distribution instrument, average grain diameter 200nm, powder of the grain size less than 200nm accounts for 90% or more；More than
After suspension is placed 35 days, do not precipitate.
Embodiment 9
(1) megestrol acetate 120.0000g, lauryl sodium sulfate 4.4000g, suspension agent composition (poly- second are weighed
Glycol, xanthans, hydroxypropyl cellulose, according to 1:1:1 ratio is mixed) 18.0000g, deflocculant mixture (citron
Sour sodium, sodium tartrate, sodium carbonate, according to 1:1:1 ratio is mixed) 2.3000g, pH adjusting agent mixture (citric acid, lemon
Lemon acid potassium, sodium citrate, according to 6:1:1 ratio is mixed) 1.6g, flavoring agent composition (sucrose, xylitol, Steviosin,
According to 25:24:1 ratio is mixed) 10.0000g, antibacterial agent composition (benzoic acid, sodium benzoate, according to 1:1 ratio
Mixed) 1.8000g, mixing aromatic (orange flavor, lemon extract, according to according to 1:1 ratio is mixed)
5.0000g, purified water 836.90g, it is spare.
For making step with embodiment 6, oral megestrol acetate nanosuspension sweet mouthfeel obtained is tasty and refreshing, has sweet tea
Orange and citris aromas；Measured by particles distribution instrument, average grain diameter 250nm, grain size less than 250nm powder account for 90% with
On；After the above suspension is placed 35 days, do not precipitate.
Embodiment 10
(1) megestrol acetate 160.0000g, humectant mixture (lecithin, lauryl sodium sulfate, tween-are weighed
80, according to 1:1:2 ratio is mixed) 4.8000g, suspension agent composition (polyethylene glycol, sodium alginate, gelatin, according to 2:
1:1 ratio is mixed) 20.0000g, deflocculant mixture (sodium citrate, sodium tartrate, sodium carbonate, according to 3:1:1
Ratio mixed) 2.5000g, pH adjusting agent mixture (malic acid, citric acid, sodium citrate, according to 2:1:1 ratio
Mixed) 1.6000g, flavoring agent composition (Steviosin, triterpene glucoside, according to 1:2 ratio is mixed)
0.2000g, antibacterial agent composition (sorbic acid, sodium sorbate, nisin, according to 1:1：1 ratio is mixed)
1.8000g, mixing aromatic (orange flavor, lemon extract, according to according to 1:4 ratio is mixed) 8.0000g, purified water
801.10g, it is spare.
For making step with embodiment 6, oral megestrol acetate nanosuspension sweet mouthfeel obtained is tasty and refreshing, has lemon
Lemon fragrance；It is measured by particles distribution instrument, average grain diameter 250nm, powder of the grain size less than 250nm accounts for 90% or more；More than
After suspension is placed 35 days, do not precipitate.
Claims (9)
1. a kind of oral megestrol acetate nanosuspension, which is characterized in that comprising a effective amount of ultramicronising tumer pregnant
Ketone, wetting agent, suspending agent, deflocculant, pH adjusting agent, corrigent, bacteriostatic agent, aromatic, purified water；The tumer it is pregnant
Ketone grain size is less than 500nm；The acid megestrol acetate suspension contains following component：20.0~160.0mg/ of megestrol acetate
Ml, 1.0~4.8mg/ml of wetting agent, 10.0~20.0mg/ml of suspending agent, 1.5~2.5mg/ml of deflocculant, pH adjusting agent
0.5~2.0mg/ml, 0.15~100.0mg/ml of corrigent, 1.0~2.0mg/ml of bacteriostatic agent, 2.0~8.0mg/ml of aromatic,
Remaining is purified water.
2. oral megestrol acetate nanosuspension according to claim 1, which is characterized in that the wetting agent is ovum
One or more of phosphatide, lauryl sodium sulfate, Tweens wetting agent, spans wetting agent, the Tweens wetting agent
For one or more of Tween-20, Tween-40, Tween-60 and Tween-80；The spans wetting agent is Arlacel-20, department
One or more of disk -40, Arlacel-60 and Arlacel-80；
And/or the suspending agent is glue class suspending agent, sodium alginate, cellulose family suspending agent, polyethylene glycols macromolecule suspending
One or more of agent and polyvinylpyrrolidone, the glue class suspending agent are xanthans, gelatin, carrageenan, Arab
One or more of glue, the fiber-like suspending agent are methylcellulose, sodium carboxymethylcellulose, hydroxypropyl cellulose, institute
It is PEG4000 and/or PEG6000 to state polyethylene glycols polymeric retention aid suspension；
And/or the deflocculant is sodium citrate, tartrate, phosphate, carbonate, one kind in glycinate or several
Kind；
And/or the pH adjusting agent is citric acid, malic acid, citric acid, acetic acid, lactic acid, potassium carbonate, sodium carbonate, bicarbonate
One or more of sodium, saleratus, potassium citrate, sodium citrate；
And/or the corrigent is one or more of sucrose, Steviosin, triterpene glucoside, Sucralose, xylitol；
And/or the bacteriostatic agent be sorbic acid, potassium sorbate, nisin, sodium benzoate, one kind in benzoic acid or
It is several；
And/or the aromatic is one or more of fruity essence.
3. megestrol acetate suspension according to claim 2, which is characterized in that the wetting agent is Tween-80；
And/or the suspending agent is PEG6000；
And/or the deflocculant is sodium citrate；
And/or the mixture that the pH adjusting agent is citric acid and sodium citrate；
And/or the corrigent is sucrose；
And/or the bacteriostatic agent is sodium benzoate；
And/or the aromatic is flavoring apple essence agent.
4. oral megestrol acetate nanosuspension according to claim 3, which is characterized in that the oral tumer
Ground progesterone nanosuspension contains following component：40.0~100.0mg/ml of megestrol acetate, 2.0~3.5mg/ of Tween-80
Ml, PEG600014.0~18.0mg/ml, 1.8~2.2mg/ml of sodium citrate, citric acid and sodium citrate mixture 0.8~
1.8mg/ml, sucrose 50.0mg~100.0mg/ml, 1.5~2.0mg/ml of sodium benzoate, 3.5~6.0mg/ml of flavoring apple essence,
Remaining is purified water.
5. the preparation method of oral megestrol acetate nanosuspension according to claim 1, which is characterized in that including
Following steps：
(1) all required materials are weighed respectively, it is spare；
(2) partial purification water is added in the wetting agent for weighing step (1), and ultrasonic wave dissolves by heating；
(3) partial purification water is added in the suspending agent for weighing step (1), and ultrasonic wave dissolves by heating；
(4) partial purification water is added in deflocculant, pH adjusting agent, the corrigent weighed step (1), and ultrasonic wave dissolves by heating；
(5) remaining purified water is added in the bacteriostatic agent for weighing step (1), and ultrasonic wave dissolves by heating；
(6) solution made from step (4) is added in solution made from step (3), is stirred evenly；
(7) solution made from step (5) is added in solution made from step (6), is stirred evenly；
(8) aromatic is added in solution made from step (7), is stirred evenly；
(9) solution made from step (2) is added in solution made from step (8) and is stirred evenly；
(10) megestrol acetate that step (1) weighs is added in solution made from step (9) and is stirred evenly, be made just mixed
Suspension；
(11) just suspension is made in step (10) and thick suspension is made by high speed shear；
(12) the obtained thick suspension of step (11) is high-pressure homogeneous through microjet, oral megestrol acetate nanometer suspension is made
Liquid；
The grain size of the megestrol acetate bulk pharmaceutical chemicals is less than 800nm.
6. the preparation method of oral megestrol acetate nanosuspension according to claim 5, which is characterized in that described
Ultrasonic wave dissolve by heating condition be：Frequency 150Hz~250Hz, 35 DEG C~60 DEG C of temperature, 15~30min of time.
7. the preparation method of oral megestrol acetate nanosuspension according to claim 5, which is characterized in that described
The condition of high speed shear is：10~30min, 10000~20000rpm of rotating speed, shear temperature are solution temperature.
8. the preparation method of oral megestrol acetate nanosuspension according to claim 5, which is characterized in that described
The high-pressure homogeneous condition of microjet is：150~250Mpa of pressure, cycle-index 20~30 times.
9. taking orally the preparation method of megestrol acetate nanosuspension, feature according to claim 5~7 any one of them
It is, the condition that the ultrasonic wave dissolves by heating is：Frequency 200Hz, 35 DEG C of temperature, time 15；The condition of the high speed shear
It is：10min, rotating speed 10000；The high-pressure homogeneous condition of the microjet is：Pressure 250Mpa, cycle-index 25 times.
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| 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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