CN106667908A - Supersaturated solid self-emulsifying preparation and preparation method thereof - Google Patents
Supersaturated solid self-emulsifying preparation 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
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
- A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
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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
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
Abstract
The invention discloses a supersaturated solid self-emulsifying preparation and a preparation method thereof. The supersaturated solid self-emulsifying preparation is prepared from a devitrification inhibitor and a difficult-to-dissolve medicine solid self-emulsifying system, wherein the difficult-to-dissolve medicine solid self-emulsifying system is prepared from mesoporous silicon dioxide SBA-15 and a difficult-to-dissolve medicine liquid self-emulsifying transmitting system; the liquid self-emulsifying transmitting system is composed of a difficult-to-dissolve medicine, an oil phase, an emulsifying agent and an auxiliary emulsifying agent; the devitrification inhibitor is an amphiphilic high molecular polymer Soluplus. The devitrification inhibitor Soluplus has a crystallization inhibiting effect through inhibiting nucleation of the supersaturated difficult-to-dissolve medicine and the growth speed of crystals; a supersaturated state of a medicine solution is kept and the absorption of the difficult-to-dissolve medicine is guaranteed; the bioavailability is high and the supersaturated solid self-emulsifying preparation has good development and application prospects.
Description
Technical field
The invention belongs to technical field of medicine, more particularly it relates to a kind of supersaturated solid self-emulsifying system
Agent and preparation method thereof.
Background technology
Oral administration is a kind of method of administration most common, that most simple, patient is most easily accepted by.Medicine enters stomach and intestine by oral administration
Firstly the need of by course of dissolution after road, can just be absorbed by organisms, and then play drug effect.Biopharmaceutics Classification system
BCS II class medicines in (Biopharmaceutical classification system, BCS) have low solubility, height
Permeability, its speed limit link for often turning into such drug absorption in gastral process in leaching.Statistics shows, BCS II
Class medicine proportion in marketed drug is 40%, and this ratio of medicine is up to 70% in research and development.BCS II class medicines
It is that pharmacological active substance can not the main cause as medicine that bioavilability is low caused by the poor solubility of thing.Therefore such as
What effectively improves the solubility and dissolution rate of BCS II class medicines, and then it is study of pharmacy to improve its oral administration biaavailability
Important content.
Insoluble medicine solid self-emulsifiable preparation (Solid self-emulsifying drug delivery system,
SSEDDS), the system has self-emulsifying technology (improving dissolution and bioavilability) and solid pharmaceutical preparation (good stability, storage side concurrently
Just, compliance is good) double dominant, and overcome liquid self-emulsifying drug delivery systemses presence shortcomings.
But in insoluble drug SSEDDS, medicine is present in solid phase carrier with unformed shape, due to no lattice energy
Constraint, the rapid dissolution of drug molecule, self-emulsifying composition meet water after from the spontaneous emulsification of solid phase carrier desorption formed O/W emulsions,
Drug molecule is further solubilized among emulsion droplet, causes medicine apparent solubility in the gastrointestinal tract considerably beyond its balance dissolving
Degree, forms supersaturated solution.The solution belongs to thermodynamic unstable system, medicine can spontaneous precipitation crystal, make the apparent of medicine
Solubility is intended to extremely low equilbrium solubility, causes drug concentration to reduce, and absorbs and reduces, the vivo biodistribution of final influence medicine
Availability and curative effect of medication.Therefore medicine is maintained in the hypersaturated state of intestines and stomach, it is ensured that medicine has time enough through stomach and intestine
Road absorbs the purpose that bioavilability is improved to reach, and has very important significance.
The content of the invention
Based on this, in order to overcome the defect of above-mentioned prior art, the invention provides a kind of supersaturated solid self-emulsifying system
Agent and preparation method thereof.
In order to realize foregoing invention purpose, this invention takes following technical scheme：
A kind of supersaturated solid self-emulsifying preparation, by crystallization inhibitor and insoluble medicine solid self-emulsifying drug delivery systemses (Solid
Self-emulsifying drug delivery system, SSEDDS) it is prepared from；The insoluble medicine solid is certainly newborn
Change system is by mesoporous silicon oxide SBA-15 and insoluble drug liquid self-emulsifying transmission system (Self-emulsifying
Drug delivery system, SEDDS) it is prepared from, the liquid self-emulsifying transmission system is 1~2 by mass ratio:1~
4:1~4:3~6 insoluble drug, oil phase, emulsifying agent and assistant for emulsifying agent composition, the insoluble drug liquid self-emulsifying are passed
Delivery system is 1~4 with the mass ratio of mesoporous silicon oxide SBA-15:1, the crystallization inhibitor is amphipathy macromolecule polymer
Soluplus, the crystallization inhibitor is 0.2~2 with the weight ratio of insoluble drug：1.
Wherein in some embodiments, the crystallization inhibitor is 0.5~2 with the weight ratio of insoluble drug：1.
Wherein in some embodiments, the crystallization inhibitor is 1 with the weight ratio of insoluble drug:1.
Wherein in some embodiments, the insoluble drug liquid self-emulsifying transmission system and mesoporous silicon oxide SBA-
15 mass ratio is 2~3:1.
Wherein in some embodiments, the mass ratio of the liquid self-emulsifying transmission system and mesoporous silicon oxide SBA-15
It is 3:1.
Wherein in some embodiments, the mass ratio of the insoluble drug, oil phase, emulsifying agent and assistant for emulsifying agent is 1.5
~2:2~3:2~3:3~4.
Wherein in some embodiments, the mass ratio of the insoluble drug, oil phase, emulsifying agent and assistant for emulsifying agent is 1.5:
2.55:2.55:3.4。
Wherein in some embodiments, the insoluble drug is BCS II class medicines, and its solubility is low, fat-soluble height.
Wherein in some embodiments, the insoluble drug is fenofibrate, celecoxib or carbamazepine.
Wherein in some embodiments, the oil phase is Capmul MCM C8, oleic acid, ethyl oleate, the acid of medium chain triglyceride three
One or more in ester, triglycerin caprylic/capric ester, propylene ethyl glycol month decylate.
Wherein in some embodiments, the emulsifying agent is Tween 80, polyoxyethylene oleate, ethyoxyl polyoxyethylene
One or more in glyceride, LABRAFIL M 1944CS.
Wherein in some embodiments, the assistant for emulsifying agent is ethanol, propane diols, polyethylene glycol (PEG), isopropanol, sweet
One or more in oil, ethylene glycol monomethyl ether (Transcutol), Dimethyl isosorbide.
Wherein in some embodiments, the liquid self-emulsifying transmission system by insoluble drug, ethyl oleate,
Cremophor RH40 and Transcutol HP are constituted.
Present invention also offers the preparation method of above-mentioned supersaturated solid self-emulsifying preparation, technical side in detail below is taken
Case：
A kind of preparation method of supersaturated solid self-emulsifying preparation, comprises the following steps：
(1) oil phase, emulsifying agent, assistant for emulsifying agent are well mixed, obtain the oily solution of homogeneous clarification；By insoluble drug
Add in above-mentioned oily solution, after being well mixed, complete drug dissolution is treated in 30~40 DEG C of water-bath balances, obtain final product the slightly solubility medicine
The liquid self-emulsifying transmission system of thing, the mass ratio of the insoluble drug, oil phase, emulsifying agent and assistant for emulsifying agent is 1~2:1~
4:1~4:3~6；
(2) by the liquid self-emulsifying transmission system of the insoluble drug of step (1), absolute ethyl alcohol is added, is stirred at room temperature down,
Mesoporous silicon oxide SBA-15 is added, 20~30h is kept stirring for and is reached adsorption equilibrium, removed in 35~50 DEG C of drying molten
Agent, obtains final product insoluble medicine solid self-emulsifying drug delivery systemses, liquid self-emulsifying transmission system and the mesoporous dioxy of the insoluble drug
The mass ratio of SiClx SBA-15 is 1~4:1；
(3) it is 0.2~2 by crystallization inhibitor and insoluble drug weight ratio：1 ratio, crystallization inhibitor is added
State in insoluble medicine solid self-emulsifying drug delivery systemses, obtain final product the supersaturated solid self-emulsifying preparation.
Compared with prior art, the invention has the advantages that：
1st, supersaturated solid self-emulsifying preparation of the invention is by adding crystallization inhibitor Soluplus, from thermodynamics
Say, Soluplus reduces system degree of supersaturation by increasing the equilbrium solubility of insoluble drug, reduces the crystallization of medicine
Driving force；Said from aerodynamic point, stronger hydrogen bond action is there may be between Soluplus and insoluble drug, played and suppress
With the effect for delaying crystallization；Crystallization inhibitor Soluplus is fast by suppressing the nucleation and crystal growth of supersaturated insoluble drug
Rate presses down brilliant effect to reach, and maintains the hypersaturated state of drug solution, it is ensured that the absorption of insoluble drug, bioavilability is high,
It is expected to develop into product, the clinically low caused low drug effect of insoluble drug bioavilability is solved the problems, such as, with clinical practice
Real value；
2nd, the preparation method process is simple of supersaturated solid self-emulsifying preparation of the invention, with good development and application
Prospect.
Brief description of the drawings
Fig. 1 is fenofibrate supersaturation concentration-time graph (A) and supersaturation concentration-time song in test example of the present invention 1
Area AUCss (B) under line；
Fig. 2 is that blood concentration-time of the different fenofibrate formulations in test example of the present invention 3 in Beagle dog bodies becomes
Change curve, wherein, super-SSEDDS is FNB supersaturation solid self-emulsifying preparations, and SSEDDS is the FNB for not adding crystallization inhibitor
Solid self-emulsifying preparation.
Specific embodiment
The present invention is further discussed below with specific embodiment below in conjunction with the accompanying drawings, the present invention does not address part and is applied to existing skill
Art.It is given below specific embodiment of the invention, but embodiment is merely to be described in further detail this explanation, is not intended to limit this
The claim of invention.
In following examples, unless otherwise specified, raw material derives from commercially available.
The fenofibrate of embodiment 1 supersaturation solid self-emulsifying preparation
The construction method of the fenofibrate supersaturation solid self-emulsifying preparation of the present embodiment is comprised the following steps：
With fenofibrate (FNB) as insoluble drug, oil phase is ethyl oleate, and emulsifying agent is Cremophor RH40, is helped
Emulsifying agent is Transcutol HP.Its preparation method is comprised the following steps：
Oil phase 2.55g, emulsifying agent 2.55g, assistant for emulsifying agent 3.4g mixing are weighed respectively, and the oily for obtaining homogeneous clarification is molten
Liquid, weighs 1.5g insoluble drugs FNB and adds above-mentioned solution dissolving, obtains final product insoluble drug liquid SEDDS.Weigh on 3.0g
Insoluble drug liquid SEDDS is stated, 10mL absolute ethyl alcohols are added, 1.0g solidified carrier SBA-15 are added, drying removes solvent, i.e.,
Obtain insoluble drug SSEDDS.Weigh crystallization inhibitor amphipathy macromolecule polymer Soluplus 1.0g and add and be equal to
In the above-mentioned insoluble drug SSEDDS of 1.0g FNB, the fenofibrate supersaturation solid self-emulsifying preparation of the present embodiment is obtained final product.
The celecoxib of embodiment 2 supersaturation solid self-emulsifying preparation
The construction method of the celecoxib supersaturation solid self-emulsifying preparation of the present embodiment is comprised the following steps：
With celecoxib as insoluble drug, oil phase is ethyl oleate, and emulsifying agent is Cremophor RH40, assistant for emulsifying agent
It is Transcutol HP.Its preparation method is comprised the following steps：
Oil phase 3.0g, emulsifying agent 3.0g, assistant for emulsifying agent 4.0g mixing are weighed respectively, obtain the oily solution of homogeneous clarification,
Weigh 2.0g insoluble drugs celecoxib and add above-mentioned solution dissolving, obtain final product insoluble drug liquid SEDDS.Weigh 3.0g
Above-mentioned insoluble drug liquid SEDDS, adds 10mL absolute ethyl alcohols, adds 1.0g solidified carrier SBA-15, and drying removes solvent,
Obtain final product insoluble drug SSEDDS.Weigh crystallization inhibitor amphipathy macromolecule polymer Soluplus0.8g and add and be equal to
In the above-mentioned insoluble drug SSEDDS of 1.0g celecoxibs, the celecoxib supersaturation solid self-emulsifying system of the present embodiment is obtained final product
Agent.
The carbamazepine of embodiment 3 supersaturation solid self-emulsifying preparation
The construction method of the carbamazepine supersaturation solid self-emulsifying preparation of the present embodiment is comprised the following steps：
With carbamazepine as insoluble drug, oil phase is ethyl oleate, and emulsifying agent is Cremophor RH40, assistant for emulsifying agent
It is Transcutol HP.Its preparation method is comprised the following steps：
Oil phase 2.5g, emulsifying agent 2.5g, assistant for emulsifying agent 3.5g mixing are weighed respectively, obtain the oily solution of homogeneous clarification,
Weigh 1.5g insoluble drugs carbamazepine and add above-mentioned solution dissolving, obtain final product insoluble drug liquid SEDDS.Weigh 3.5g
Above-mentioned insoluble drug liquid SEDDS, adds 10mL absolute ethyl alcohols, adds 1.0g solidified carrier SBA-15, and drying removes solvent,
Obtain final product insoluble drug SSEDDS.Weigh crystallization inhibitor amphipathy macromolecule polymer Soluplus1.5g and add and be equal to
In the above-mentioned insoluble drug SSEDDS of 1.0g carbamazepines, the carbamazepine supersaturation solid self-emulsifying system of the present embodiment is obtained final product
Agent.
The fenofibrate of embodiment 4 supersaturation solid self-emulsifying preparation
The construction method of the fenofibrate supersaturation solid self-emulsifying preparation of the present embodiment is comprised the following steps：
With fenofibrate (FNB) as insoluble drug, oil phase is ethyl oleate, and emulsifying agent is Cremophor RH40, is helped
Emulsifying agent is Transcutol HP.Its preparation method is comprised the following steps：
Oil phase 2.6g, emulsifying agent 2.4g, assistant for emulsifying agent 3.3g mixing are weighed respectively, obtain the oily solution of homogeneous clarification,
Weigh 1.7g insoluble drugs FNB and add above-mentioned solution dissolving, obtain final product insoluble drug liquid SEDDS.Weigh 2.9g above-mentioned
Insoluble drug liquid SEDDS, adds 10mL absolute ethyl alcohols, adds 1.0g solidified carrier SBA-15, and drying removes solvent, obtains final product
Insoluble drug SSEDDS.Weigh crystallization inhibitor amphipathy macromolecule polymer Soluplus0.6g and add and be equal to
In the above-mentioned insoluble drug SSEDDS of 1.0gFNB, the fenofibrate supersaturation solid self-emulsifying preparation of the present embodiment is obtained final product.
The external supersaturation experiment of the fenofibrate supersaturation solid self-emulsifying preparation of the embodiment 1 of test example 1
Precision weighs the fenofibrate supersaturation solid self-emulsifying preparation of the embodiment 1 for being equal to FNB100mg, supersaturation
Dissolution medium is 200mL deionized waters, and rotating speed 100rpm, 37 ± 0.5 DEG C of temperature samples 2mL respectively at 0,1,2,3,4,5,6h.
Filtered with 0.22 μm of teflon membrane filter, take subsequent filtrate 0.5mL, 10mL is diluted to using absolute ethyl alcohol immediately, at 286nm
UV absorption is determined, Each point in time fenofibrate concentration is calculated.Parallel three parts, to eliminate error.
Figure 1A and B are respectively supersaturation concentration-time changing curve and area AUCss under supersaturation concentration-time graph,
Result shows, when the mass ratio of Soluplus and FNB is when 0 increases to 1, AUCss with the increase of Soluplus consumptions by
It is cumulative plus, show within this range, the crystalline rate of FNB slows down gradually, Soluplus maintain hypersaturated state ability with
The increase of its consumption and increase.When the mass ratio of Soluplus and FNB is when 1 increases to 10, AUCss is with Soluplus consumptions
Increase and without conspicuousness change, show within this range, the crystalline rate of FNB is basically unchanged, Soluplus maintain supersaturation
The ability of state keeps constant.Therefore in supersaturated solid self-emulsifying system, determine the matter of crystallization inhibitor Soluplus and FNB
Amount is than being 1:1.
The fenofibrate supersaturation solid self-emulsifying preparation of the embodiment 1 of test example 2 emulsification test again
Method according to embodiment 1 builds fenofibrate liquid self-emulsifying systems.Take and be equal to 0.3mL liquid self-emulsifyings
Supersaturated solid self-emulsifying preparation, adds 200mL water, and rotating speed is 50rpm, treats that it is emulsified completely, observes emulsion outward appearance.Gained sample
Product stand overnight, and taking supernatant carries out particle size determination.Table 1 be solid self-emulsifying and supersaturated solid self-emulsifying system particle diameter and
Polydispersity coefficient.
The particle diameter and polydispersity coefficient (n=3) of the solid self-emulsifying of table 1 and supersaturated solid self-emulsifying system
The result of table 1 shows that after Soluplus is added, the particle diameter of emulsion droplet is increased slightly, it may be possible to due to part Soluplus
Polymer segment be embedded in emulsion droplet surface, certain hydration is caused, so as to increased the space steric effect of emulsion droplet.
The PDI of two kinds of particle diameters is respectively less than 0.20, shows the homogeneous grain diameter of emulsion, and the addition of crystallization inhibitor Soluplus is not to system
Emulsification behavior produce conspicuousness influence.
The Beagle dogs Internal pharmacokinetics research of the fenofibrate supersaturation solid self-emulsifying preparation of the embodiment 1 of test example 3
By test preparation for the mass ratio of the crystallization inhibitor Soluplus and FNB prepared in embodiment 1 is 1:1 FNB mistakes
Saturation solid self-emulsifying preparation super-SSEDDS and plus crystallization inhibitor FNB solid self-emulsifying preparations SSEDDS.
Take two preparation dual crossing experimental designs, 6 Beagle dogs are randomly divided into two groups, every group three, for body
Interior pharmacokinetic studies.Fasting (can't help water) 12h before experiment, the cleaning phase is two weeks.Every Beagle dog give respectively equivalent to
The solid self-emulsifying preparation of 100mgFNB, supersaturated solid self-emulsifying preparation.After administration set time point (0,0.25,0.50,
0.75th, 1,1.5,2,3,4,6,8,24h) blood 4mL is taken in the negative pressure taking blood vessel containing liquaemin in hind leg femoral vein, it is well mixed
5000rpm, is centrifuged 5min afterwards, upper plasma is taken, in -20 DEG C of Refrigerator stores with to be analyzed.Plasma containing drug sample 0.5mL is taken, essence
The internal standard Indomethacin working solution (50 μ g/mL) of 50 μ L of close addition, 200 μ L concentration are the hydrochloric acid solution of 1mol/L, in vortice
Upper vibration mixes 5min.4mL absolute ethers are added, vortex 5min, 8000rpm centrifugation 5min takes supernatant, dense through Nitrogen evaporator
Contracting volatilizes solvent.200 μ L mobile phases are added to redissolve, vortex 5min is centrifuged 5min through 16000rpm, supernatant is taken, using efficient
The haemoconcentration of liquid-phase chromatographic analysis FNB acid.
Chromatographic condition：Chromatographic column：Phenomenex C18 (250mm × 4.6mm, 5 μm)；Mobile phase：Acetonitrile：0.1% vinegar
Acid=65:35；Detection wavelength：286nm；Flow velocity：1mL/min；Column temperature：40℃；Sample size：50μL.
Fig. 2 is that blood concentration-time change curve result of the different FNB preparations in Beagle dog bodies shows, two kinds
The blood concentration-time plots changes of preparation are consistent, and the blood concentration of supersaturated preparation is higher than solid self-emulsifying preparation.
The pharmacokinetic parameters of each preparation are further calculated using WinNonlin V3.3 softwares, by blood medicine in Beagle dog bodies
Concentration time curve result carries out compartment model fitting, as a result shows that the fitting coefficient of compartment model is smaller, and in each group
The compartment model of Beagle dogs is inconsistent, therefore the present invention is finally fitted using non-compartment model, calculates pharmacokinetic parameters.
Table 2 is the pharmacokinetic parameters of plasma drug level after Beagle dogs are administered orally.
The pharmacokinetic parameters (n=5) of plasma drug level after the Beagle dogs of table 2 oral administration
The result of table 2 shows that there was no significant difference for Cmax, Tmax of SSEDDS and super-SSEDDS, super-SSEDDS
AUC0 → ∞ be higher than SSEDDS, show to add Soluplus in solid self-emulsifying system, can further improve the suction of FNB
Receive.In solid self-emulsifying system, model drug FNB is distributed in self-emulsifying skeleton with unformed shape, due to not having lattice beam
Tie up, the dissolution rate of medicine is very fast.Meanwhile, the solidified carrier material SBA-15 that the present invention is used has specific surface area higher,
Be conducive to the entrance of hydrone, further increase the release of medicine and self-emulsifying composition.The rapid release of medicine, causes stomach and intestine
Considerably beyond its equilbrium solubility, the addition of crystallization inhibitor Soluplus maintains system to the apparent solubility of medicine in road
Hypersaturated state, it is ensured that the absorption of FNB.
Each technical characteristic of embodiment described above can be combined arbitrarily, to make description succinct, not to above-mentioned reality
Apply all possible combination of each technical characteristic in example to be all described, as long as however, the combination of these technical characteristics is not deposited
In contradiction, the scope of this specification record is all considered to be.
Embodiment described above only expresses several embodiments of the invention, and its description is more specific and detailed, but simultaneously
Can not therefore be construed as limiting the scope of the patent.It should be pointed out that coming for one of ordinary skill in the art
Say, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to protection of the invention
Scope.Therefore, the protection domain of patent of the present invention should be determined by the appended claims.
Claims (8)
1. a kind of supersaturated solid self-emulsifying preparation, it is characterised in that by crystallization inhibitor and insoluble medicine solid self-emulsifying
System is prepared from；The insoluble medicine solid self-emulsifying drug delivery systemses are by mesoporous silicon oxide SBA-15 and insoluble drug liquid
Self-emulsifying transmission system is prepared from, and the liquid self-emulsifying transmission system is 1~2 by mass ratio:1~4:1~4:3~6
Insoluble drug, oil phase, emulsifying agent and assistant for emulsifying agent composition, the insoluble drug liquid self-emulsifying transmission system with it is mesoporous
The mass ratio of silica SBA-15 is 1~4:1, the crystallization inhibitor is amphipathy macromolecule polymer Soluplus, institute
It is 0.2~2 that crystallization inhibitor is stated with the weight ratio of insoluble drug:1.
2. supersaturated solid self-emulsifying preparation according to claim 1, it is characterised in that the crystallization inhibitor and indissoluble
Property medicine weight ratio be 0.5~2：1.
3. supersaturated solid self-emulsifying preparation according to claim 2, it is characterised in that the crystallization inhibitor and indissoluble
Property medicine weight ratio be 1:1.
4. supersaturated solid self-emulsifying preparation according to claims 1 to 3, it is characterised in that the insoluble drug liquid
Body self-emulsifying transmission system is 3 with the mass ratio of mesoporous silicon oxide SBA-15:1.
5. supersaturated solid self-emulsifying preparation according to claims 1 to 3, it is characterised in that the insoluble drug, oil
The mass ratio of phase, emulsifying agent and assistant for emulsifying agent is 1.5~2:2~3:2~3:3~4.
6. supersaturated solid self-emulsifying preparation according to claims 1 to 3, it is characterised in that the insoluble drug is
Fenofibrate, celecoxib or carbamazepine.
7. supersaturated solid self-emulsifying preparation according to claims 1 to 3, it is characterised in that the oil phase is single octanoic acid
In glyceride, oleic acid, ethyl oleate, median chain triglyceride oil, triglycerin caprylic/capric ester, propylene ethyl glycol month decylate
One or more；The emulsifying agent is Tween 80, polyoxyethylene oleate, ethyoxyl polyoxyethylene glyceride, poly- second two
One or more in alcohol glyceride；The assistant for emulsifying agent is ethanol, propane diols, polyethylene glycol, isopropanol, glycerine, ethylene glycol
One or more in single ethylether, Dimethyl isosorbide.
8. the preparation method of the supersaturated solid self-emulsifying preparation described in any one of claim 1~7, it is characterised in that including
Following steps：
(1) oil phase, emulsifying agent, assistant for emulsifying agent are well mixed, obtain the oily solution of homogeneous clarification；Insoluble drug is added
In above-mentioned oily solution, after being well mixed, complete drug dissolution is treated in 30~40 DEG C of water-bath balances, obtain final product the insoluble drug
Liquid self-emulsifying transmission system, the mass ratio of the insoluble drug, oil phase, emulsifying agent and assistant for emulsifying agent is 1~2:1~4:1
~4:3~6；
(2) by the liquid self-emulsifying transmission system of the insoluble drug of step (1), absolute ethyl alcohol is added, is stirred at room temperature down, added
Mesoporous silicon oxide SBA-15, is kept stirring for 20~30h and reaches adsorption equilibrium, removes solvent in 35~50 DEG C of drying, i.e.,
Obtain insoluble medicine solid self-emulsifying drug delivery systemses, the liquid self-emulsifying transmission system and mesoporous silicon oxide of the insoluble drug
The mass ratio of SBA-15 is 1~4:1；
(3) it is 0.2~2 by crystallization inhibitor and insoluble drug weight ratio：1 ratio, above-mentioned difficulty is added by crystallization inhibitor
In soluble drug solid self-emulsifying system, the supersaturated solid self-emulsifying preparation is obtained final product.
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| CN109924491A (en) * | 2019-04-01 | 2019-06-25 | 东南大学 | A kind of dihydromyricetin solid-state self-emulsifying material and its preparation method and application |
| CN110664755A (en) * | 2019-11-06 | 2020-01-10 | 周华锋 | Protein polypeptide self-microemulsion and preparation method and application thereof |
| CN110833527A (en) * | 2018-08-16 | 2020-02-25 | 郑州泰丰制药有限公司 | Ulipristal acetate supersaturated solid self-emulsifying preparation and preparation method thereof |
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| CN110833527A (en) * | 2018-08-16 | 2020-02-25 | 郑州泰丰制药有限公司 | Ulipristal acetate supersaturated solid self-emulsifying preparation and preparation method thereof |
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| CN110664755A (en) * | 2019-11-06 | 2020-01-10 | 周华锋 | Protein polypeptide self-microemulsion and preparation method and application thereof |
| CN110664755B (en) * | 2019-11-06 | 2021-11-05 | 周华锋 | Protein polypeptide self-microemulsion and preparation method and application thereof |
| CN113116826A (en) * | 2021-04-20 | 2021-07-16 | 河北医科大学 | A topical carbamazepine nanometer preparation and its preparation method |
| CN113750043A (en) * | 2021-09-18 | 2021-12-07 | 山东省药学科学院 | Celecoxib self-emulsifying oral liquid and preparation method thereof |
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