CN106619521B - Itraconazole enteric solubility solid dispersions and its preparation method and application - Google Patents
Itraconazole enteric solubility solid dispersions and its preparation method and application Download PDFInfo
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- CN106619521B CN106619521B CN201611255033.6A CN201611255033A CN106619521B CN 106619521 B CN106619521 B CN 106619521B CN 201611255033 A CN201611255033 A CN 201611255033A CN 106619521 B CN106619521 B CN 106619521B
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- itraconazole
- solid dispersions
- enteric solubility
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- surfactant
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Classifications
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- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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Abstract
The invention discloses a kind of Itraconazole enteric solubility solid dispersions and its preparation method and application, the solid dispersions are prepared by Itraconazole, enteric solubility macromolecule carrier and the surfactant as active constituent.The solid dispersions are made by torching mark, and Itraconazole is present in solid dispersions with unformed shape.Beagle dog vivo biodistribution availability experiment show Itraconazole enteric solubility solid dispersions with respect to reference preparation (commercially available capsule) relative bioavailability be 180%, enteric solubility macromolecule carrier and surfactant in the solid dispersions can not only improve the dissolution rate of Itraconazole, Itraconazole can also be inhibited in the recrystallization of gastrointestinal tract, to improve bioavilability, adverse reaction is reduced.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of Itraconazole enteric solubility solid dispersions and its preparation side
Method and application.
Background technique
Its chemical name is 4- [4- [4- [4- [[cis-2- (2,4- dichloros for Itraconazole (English name: Itraconazole)
Phenyl) -2- (1H-1,2,4- triazol-1-yl methyl) -1,3- dioxolanes -4- base] methoxyl group] phenyl] piperazine -1- base] benzene
Base] -2- [(1RS) -1- methyl-propyl] -1,2,4- triazole -3- ketone.Molecular formula: C35H38Cl2N8O4, molecular weight: 705.63, tool
There are following chemical structures:
Itraconazole is artificial synthesized triazole derivative, is a kind of broad-spectrum antifungal medicine of synthesis, antimicrobial spectrum with
Ketoconazole is similar, plays antibacterial activity by changing fungal cell's membrane permeability, equal to the pathogen of superficial part, deep fungal infection
There is antibacterial activity, can inhibit the synthesis of fungal cell membrane ergosterol, to play antifungal effect.Itraconazole has extremely strong
Hydrophobic effect, dissolution rate is minimum in water, mainly improves its dissolution rate by various formulation methods at present.
In order to improve the water-soluble to improve its bioavilability of Itraconazole, patent ZL98806999.7 discloses one kind
Diameter is 0.5-10 μm, the itraconazole particles of amorphous form.But the itraconazole particles are made with pharmaceutical excipient
After tablet, it cannot disperse the short time, there are problems that difficulties in dispersion.
Patent ZL200610065136.6 discloses a kind of composition of the oral administration containing Itraconazole, the composition
Contain 40-69.9wt% solid dispersions, the osmosis inducing agent of 0.1-30wt%, the disintegrating agent of 0.1-30wt%, the solid
The Itraconazole of 1 parts by weight by being dispersed in the hydroxypropyl methyl cellulose and 0.01-5 weight of 0.1-10 parts by weight by dispersion
In the absorption enhancement agent composition of part and with amorphous preparation.The preparation method of the composition needs that Itraconazole is first prepared into her
Triaconazole dispersion, then by the dispersion and other auxiliary material mixing granulations, tabletting, and for dispersion each in composition, infiltration
The additional amount of saturating inducer, disintegrating agent etc. carries out strict control, to reach preferable dissolution rate and bioavilability, preparation process
It is complicated.
Patent ZL200910076988.9 discloses a kind of Itraconazole composite powder and preparation method thereof, by Itraconazole
Drug is first dissolved in organic solvent, and the aqueous solution of hydrophilicity condiment is added, and is settled out the suspension of itraconazole particles, dry
After obtain powder, diameter of particle is 0.5-15 μm, is by the partial size that powder is dispersed in water the itraconazole particles of acquisition
100nm-1μm.Composite granule dissolution rate with higher, but using polyvinylpyrrolidone as hydrophilic carrier, have higher
Cost.
Patent ZL200910305827.2 discloses a kind of Itraconazole composition and preparation method thereof, and the composition is by her
Triaconazole, starch, mannitol, sucrose, Steviosin composition, preparation process is simple, and pharmaceutic adjuvant safety used is free of to human body
Harmful organic solvent, cost is relatively low, and stability is good, but dissolution rate will reach 85% or more, needs more than 100 minutes time,
Dissolution rate need to be improved.
The dosage form of Itraconazole listing has injection, capsule and oral solution.Commercial product (Capsule) it is to adopt
With solid dispersions technique improve Itraconazole solubility, but the oral absorption of said preparation by gastrointestinal tract environment influenced compared with
Greatly, oral administration biaavailability individual difference is significant.The main reason is that Itraconazole solubility is to pH and its dependence, in neutral pH
Under the conditions of the saturation solubility of its aqueous solution be about 0.1ug/ml, be respectively in gastric acid solution and the saturation solubility in intestinal juice
5ug/ml and 0.25ug/ml.Itraconazole dissolves out rapidly under one's belt, so that Itraconazole be made to form thermodynamic instability under one's belt
Supersaturated solution, the Itraconazole dissolved again crystallization cause absorb reduce so as to cause bioavilability reduction.When her
After triaconazole goes to enteron aisle from stomach, solubility reduces rapidly and accelerates Itraconazole and recrystallizes from supersaturated solution.Therefore,
Insoluble drug hypersaturated state in the gastrointestinal tract is maintained, is that drug has the saturating intestinal absorption of time enough to improve bioavilability
Effect become field of medicaments research hotspot and difficult point.
For the bottleneck of amorphous solid dispersion gastrointestinal tract crystallization, researchers are by screening different carrier material solutions
The certainly problem, but simple acted on by polymer carrier inhibition drug in gastrointestinal tract crystallization is not obvious.
Summary of the invention
Based on this, in order to overcome the defects of the prior art described above, the present invention provides a kind of enteric solubility Itraconazole solids
Dispersion, enteric solubility carrier and surfactant in the solid dispersions, which can cooperate with, inhibits Itraconazole gastrointestinal tract crystallization.
For achieving the above object, this invention takes technical solutions in detail below:
A kind of Itraconazole enteric solubility solid dispersions are by Itraconazole, surfactant and enteric solubility macromolecule
What carrier was prepared, the Itraconazole is in the amorphous carrier for being dispersed in the solid dispersions.
In wherein some embodiments, the enteric solubility Itraconazole solid dispersions are by following components in percentage by weight
It is prepared: Itraconazole 10-40%, enteric solubility polymer carrier 55%-85%, surfactant 2%-20%, institute
Stating enteric solubility macromolecule carrier is acetic acid hydroxypropyl methylcellulose succinate, hypromellose phthalate or propylene
Acid resin；The surfactant is Tween 80, sodium taurocholate, polyethylene glycol/caprolactam/vinyl acetate copolymerized
Object, alpha-tocofecol succinic acid macrogol ester, poloxamer F188 or lauryl sodium sulfate.
In wherein some embodiments, the acetic acid hydroxypropyl methylcellulose succinate is acetic acid hydroxypropyl methylcellulose amber
Acid esters LF type, acetic acid hydroxypropyl methylcellulose succinate MF type or acetic acid hydroxypropyl methylcellulose succinate HF type；The propylene
Acid resin is acrylic resin L100 type, acrylic resin L100-55 type or acrylic resin S100 type.
In wherein some embodiments, the solid dispersions are prepared by following components in percentage by weight: Yi Qu
Health azoles 20-35%, enteric solubility polymer carrier 60%-75%, surfactant 5%-15%.
In wherein some embodiments, the solid dispersions are prepared by following components in percentage by weight: Yi Qu
Health azoles 20-30%, enteric solubility polymer carrier 65%-75%, surfactant 5%-10%.
In wherein some embodiments, the solid dispersions are prepared by following components in percentage by weight: Yi Qu
Health azoles 25%, enteric solubility polymer carrier 65%, surfactant 10%.
The present invention also provides the preparation methods of above-mentioned Itraconazole enteric solubility solid dispersions, take following technical side
Case:
A kind of preparation method of above-mentioned Itraconazole enteric solubility solid dispersions, comprising the following steps: weigh her according to the ratio
Triaconazole, enteric solubility polymer carrier and surfactant, grinding make to be uniformly mixed, and physical mixture is made；It is added double
In screw rod hot-melt extruded machine, physical mixture is squeezed out, crushed 80-120 mesh after cooling to get the solid of the Itraconazole
Dispersion.
In wherein some embodiments, the extrusion temperature of the hot-melt extruded machine is 140 DEG C -185 DEG C, hot-melt extruded machine
Screw speed is 80-160 revs/min.
In wherein some embodiments, the extrusion temperature of the hot-melt extruded machine is 160 DEG C -170 DEG C, hot-melt extruded machine
Screw speed is 100-140 revs/min.
The present invention also provides above-mentioned Itraconazole enteric solubility solid dispersions to prepare the application in Itraconazole preparation.
It is subjected on a kind of Itraconazole preparation, including above-mentioned Itraconazole enteric solubility solid dispersions and pharmacy
Auxiliary material, after conventional machining directly or indirectly be added be made.
In wherein some embodiments, the dosage form of the Itraconazole preparation is granule, tablet, capsule, oral solution
Etc. any peroral dosage form.
Compared with prior art, the invention has the following advantages:
1, the present inventor is by a large amount of creative experiments, using enteric solubility macromolecule carrier and surface-active
Agent screens as raw material and obtains most suitable component proportion, and Itraconazole enteric solubility solid dispersions, Yi Qukang is prepared
Azoles is present in solid dispersions as an amorphous form, can not only improve Itraconazole in the concentration of gastrointestinal tract supersaturated solution,
Itraconazole can also be inhibited in the recrystallization of gastrointestinal tract, to improve bioavilability, gastrointestinal tract supersaturation inhibition is tied again
Brilliant effect is better than listing preparation capsule；
2, Itraconazole solid dispersions of the invention are using torching mark preparation gained, and preparation method is simple,
No solvent residue, it is environmental-friendly, it is suitable for industrialized production.
Detailed description of the invention
Fig. 1 is Itraconazole bulk pharmaceutical chemicals, hypromellose phthalate raw material powder, Bo Luosha in embodiment 1
The X ray diffracting spectrum of nurse (F188) raw material powder, Itraconazole enteric solubility solid dispersion powder；
(A) is the TG curve graph of enteric solubility polymer carrier in Fig. 2；It (B) is the TG curve graph of each surfactant；
A is Itraconazole bulk pharmaceutical chemicals, each Itraconazole enteric solubility solid dispersions of embodiment 1-6 and commercially available capsule in Fig. 3
DSC curve；(B) under the condition of high temperature and high humidity for Itraconazole enteric solubility solid dispersions in embodiment 1-6 and commercially available capsule
Place 3 months DSC curve figures；
Fig. 4 is Itraconazole enteric solubility solid dispersions in embodiment 5, the Itraconazole enteric of surfactant is not added
Property solid dispersions and listing preparation capsuleSimulated gastrointestinal tract supersaturation curve graph；
Fig. 5 is Itraconazole enteric solubility solid dispersions capsule and listing preparation capsule in embodiment 5In the intracorporal Itraconazole blood concentration-time curve graph of beasle dog.
Specific embodiment
It is further discussed below the present invention in the following with reference to the drawings and specific embodiments, the present invention does not address place and is suitable for existing skill
Art.It is given below specific embodiments of the present invention, but embodiment is not intended to limit this merely to this explanation is described in further detail
The claim of invention.
The embodiment of the present invention is raw materials used as follows:
Itraconazole is commercial product；
Hypromellose phthalate (HPMCP), acetic acid hydroxypropyl methylcellulose succinate (HPMCAS) are purchased from
Japan XINYUE；
Acrylic resin (Eudragit) is purchased from German goldschmidt chemical corporation.
Polyethylene glycol/caprolactam/vinyl acetate co-polymer (Soluplus), alpha-tocofecol succinic acid ester are poly-
Ethylene glycol (TPGS), poloxamer (F188) are purchased from BASF Aktiengesellschaft；
Lauryl sodium sulfate is purchased from Tianjin good fortune morning chemical reagent factory；
Sodium taurocholate is purchased from Shanghai Mike woods biology Co., Ltd；
Tween 80 is purchased from Tianjin great Mao chemical reagent factory.
1 Itraconazole enteric solubility solid dispersions of embodiment
A kind of Itraconazole enteric solubility solid dispersions of the present embodiment, by following components in percentage by weight preparation
At Itraconazole 10%, enteric solubility polymer carrier 80%, surfactant 10%, wherein enteric solubility macromolecule carrier
Material is hypromellose phthalate, and surfactant is poloxamer F188.
The Itraconazole enteric solubility solid dispersions the preparation method is as follows:
1) 1.2g Itraconazole, 9.6g hypromellose phthalate, 1.2g poloxamer F188, grinding are weighed
Make to be uniformly mixed, physical mixture is made；
2) extrusion temperature of twin screw hot melt extruder is set as 160 DEG C, starts screw rod after reaching preset temperature, screw rod turns
Speed is 150 revs/min, and manufactured physical mixture is added in twin screw hot melt extruder, and mixture is in item by screw rod
Shape squeezes out；
3) bar of hot-melt extruded is crossed 80 meshes and obtains Itraconazole enteric solubility solid dispersions through pulverization process.
The Itraconazole enteric solubility solid dispersions powder x-ray diffraction that the present embodiment is prepared evaluates Itraconazole
Each state of matter in solid dispersions: using X-ray diffraction analysis method to auxiliary material, Itraconazole bulk pharmaceutical chemicals, Itraconazole intestines
Soluble solids dispersion is characterized, and analysis result is as shown in Figure 1.Itraconazole bulk pharmaceutical chemicals are observed that from X-ray map
In have apparent crystal diffraction peak, the Itraconazole enteric solubility solid dispersions of preparation illustrate Itraconazole without crystal diffraction peak
It is dispersed in enteric solubility polymer carrier and surfactant with a kind of noncrystalline state of high degree of dispersion.
2 Itraconazole enteric solubility solid dispersions of embodiment
A kind of Itraconazole enteric solubility solid dispersions of the present embodiment, by following components in percentage by weight preparation
At Itraconazole 20%, enteric solubility polymer carrier 60%, surfactant 20%, wherein enteric solubility macromolecule carrier
Material is acetic acid hydroxypropyl methylcellulose succinate (LF type), and surfactant is sodium taurocholate.
The solid dispersions of the Itraconazole the preparation method is as follows:
1) 2.4g Itraconazole, 7.2g acetic acid hydroxypropyl methylcellulose succinate (LF type), 2.4g sodium taurocholate, grinding are weighed
Make to be uniformly mixed, physical mixture is made；
2) extrusion temperature of twin screw hot melt extruder is set as 170 DEG C, starts screw rod after reaching preset temperature, screw rod turns
Speed is 100 revs/min, and manufactured physical mixture is added in twin screw hot melt extruder, and mixture is in item by screw rod
Shape squeezes out；
3) bar of hot-melt extruded is crossed 80 meshes and obtains Itraconazole enteric solubility solid dispersions through pulverization process.
3 Itraconazole enteric solubility solid dispersions of embodiment
A kind of Itraconazole enteric solubility solid dispersions of the present embodiment, by following components in percentage by weight preparation
At Itraconazole 36.4%, enteric solubility polymer carrier 50%, surfactant 13.6%, wherein enteric solubility macromolecule
Carrier material is acrylic resin (Eudragit L100-55), and surfactant is Tween 80.
The Itraconazole enteric solubility solid dispersions the preparation method is as follows:
1) 4.8g Itraconazole is weighed, 6.6g acrylic resin (Eudragit L100-55), 1.8g Tween 80, grinding makes
It is uniformly mixed, physical mixture is made；
2) extrusion temperature of twin screw hot melt extruder is set as 175 DEG C, starts screw rod after reaching preset temperature, screw rod turns
Speed is 120 revs/min, and manufactured physical mixture is added in twin screw hot melt extruder, and mixture is in item by screw rod
Shape squeezes out；
3) bar of hot-melt extruded is crossed 80 meshes and obtains Itraconazole enteric solubility solid dispersions through pulverization process.
4 Itraconazole enteric solubility solid dispersions of embodiment
A kind of Itraconazole enteric solubility solid dispersions of the present embodiment, by following components in percentage by weight preparation
At Itraconazole 30%, enteric solubility polymer carrier 65%, surfactant 5%, wherein enteric solubility macromolecule carrier material
Material is acrylic resin (Eudragit S100), and surfactant is lauryl sodium sulfate.
The Itraconazole enteric solubility solid dispersions the preparation method is as follows:
1) 3.6g Itraconazole is weighed, 7.8g acrylic resin (Eudragit S100), 0.6g lauryl sodium sulfate,
Grinding makes to be uniformly mixed, and physical mixture is made；
2) extrusion temperature of twin screw hot melt extruder is set as 165 DEG C, starts screw rod after reaching preset temperature, screw rod turns
Speed is 80 revs/min, and manufactured physical mixture is added in twin screw hot melt extruder, and mixture is in a strip shape by screw rod
It squeezes out；
3) bar of hot-melt extruded is crossed 80 meshes and obtains Itraconazole enteric solubility solid dispersions through pulverization process.
5 Itraconazole enteric solubility solid dispersions of embodiment
A kind of Itraconazole enteric solubility solid dispersions of the present embodiment, by following components in percentage by weight preparation
At Itraconazole 20%, enteric solubility polymer carrier 70%, surfactant 10%, wherein enteric solubility macromolecule carrier
Material is acetic acid hydroxypropyl methylcellulose succinate (MF type), and surfactant is alpha-tocofecol succinic acid ester polyethylene glycol.
The Itraconazole enteric solubility solid dispersions the preparation method is as follows:
1) 2.4g Itraconazole, 8.4g acetic acid hydroxypropyl methylcellulose succinate (MF type), 1.2g alpha-tocopherol amber are weighed
Amber acid esters polyethylene glycol, grinding make to be uniformly mixed, and physical mixture is made；
2) extrusion temperature of twin screw hot melt extruder is set as 170 DEG C, starts screw rod after reaching preset temperature, screw rod turns
Speed is 100 revs/min, and manufactured physical mixture is added in twin screw hot melt extruder, and mixture is in item by screw rod
Shape squeezes out；
3) it by the bar of hot-melt extruded through pulverization process, sieves with 100 mesh sieve to obtain Itraconazole enteric solubility solid dispersions.
6 Itraconazole enteric solubility solid dispersions of embodiment
A kind of Itraconazole enteric solubility solid dispersions of the present embodiment, by following components in percentage by weight preparation
At Itraconazole 25%, enteric solubility polymer carrier 60%, surfactant 15%, wherein enteric solubility macromolecule carrier
Material is acetic acid hydroxypropyl methylcellulose succinate (HF type), and surfactant is polyethylene glycol/caprolactam/acetic acid
Vinyl ester copolymers.
The Itraconazole enteric solubility solid dispersions the preparation method is as follows:
1) 3g Itraconazole, 7.2g acetic acid hydroxypropyl methylcellulose succinate (MF type), 1.8g polyethylene glycol/ethylene are weighed
Base caprolactam/vinyl acetate co-polymer, grinding make to be uniformly mixed, and physical mixture is made；
2) extrusion temperature of twin screw hot melt extruder is set as 175 DEG C, starts screw rod after reaching preset temperature, screw rod turns
Speed is 120 revs/min, and manufactured physical mixture is added in twin screw hot melt extruder, and mixture is in item by screw rod
Shape squeezes out；
3) bar of hot-melt extruded is crossed 80 meshes and obtains Itraconazole enteric solubility solid dispersions through pulverization process.
The thermal stability of 7 Itraconazole of embodiment, enteric solubility high molecular material and surfactant
With synchronous solving to the thermal stability of Itraconazole, enteric solubility polymer carrier and surfactant into
Row characterization.Suitable sample is taken respectively, is placed in aluminium crucible, using blank aluminium crucible as reference, in the stream of nitrogen gas of 40ml/min
In, it with the heating rate of 10 DEG C/min, is scanned in the range of 30 DEG C to 300 DEG C, records sample with the change of temperature quality
Change.
As a result as shown in Fig. 2, Itraconazole enteric solubility high molecular material and surfactant are point before 200 DEG C
Solution illustrates drug used in the present invention, enteric solubility high molecular material and surfactant in the at a temperature of heat of preparation process
Stability is good.
8 Itraconazole preparation of embodiment
Itraconazole enteric solubility solid dispersions 50g in Example 5, is packed into the capsule shells of commercial product, prepares her
Triaconazole capsule.
Comparative example does not add the Itraconazole enteric solubility solid dispersions of surfactant
The Itraconazole enteric solubility solid dispersions that surfactant is not added of this comparative example, by following weight percent
Component is prepared: Itraconazole 20%, enteric solubility polymer carrier 80%, and wherein enteric solubility polymer carrier is
Acetic acid hydroxypropyl methylcellulose succinate (MF type).
This be not added surfactant Itraconazole enteric solubility solid dispersions the preparation method is as follows:
1) 2.4g Itraconazole, 9.6g acetic acid hydroxypropyl methylcellulose succinate (MF type) are weighed, grinding makes to be uniformly mixed,
Physical mixture is made；
2) extrusion temperature of twin screw hot melt extruder is set as 170 DEG C, starts screw rod after reaching preset temperature, screw rod turns
Speed is 100 revs/min, and manufactured physical mixture is added in twin screw hot melt extruder, and mixture is in item by screw rod
Shape squeezes out；
3) it by the bar of hot-melt extruded through pulverization process, sieves with 100 mesh sieve to obtain the Itraconazole that surfactant is not added
Enteric solubility solid dispersions.
The experiment of 1 high temperature and humidity physical stability of test example
By Itraconazole enteric solubility solid dispersions in 1-6 of the embodiment of the present invention and commercially available under the conditions of 40 DEG C of 75%RH
After preparation capsule (dress of unpacking) is stored 3 months, table is mutually carried out using object of the differential scanning calorimetry to Itraconazole in each prescription
Sign.
Experimental method: taking solid dispersions 5-10mg, is placed in aluminium crucible, and using blank aluminium crucible as reference substance, In
In the nitrogen stream of 40ml/min, with the heating rate of 10 DEG C/min, 180 DEG C are risen to from room temperature.Record sample varies with temperature
Neither endothermic nor exothermic situation.
Experimental result is as shown in Figure 3, the results showed that commercial preparation capsule unpack fill before Itraconazole exist with amorphous state
(A), after placing 3 months under the condition of high temperature and high humidity, occur the melting peak (B) of crystalline state Itraconazole on DSC curve, show
Itraconazole has recrystallized in capsule.However, the Itraconazole solid dispersions in the present invention are under the condition of high temperature and high humidity
After placing three months, Itraconazole still maintains amorphous state.Prove the object of Itraconazole enteric solubility solid dispersions of the invention
It manages stability and is better than commercial preparation capsule.
The in-vitro simulated stomach of test example 2-intestines supersaturation experiment
Experimental method: precision weighs Itraconazole enteric solubility solid dispersions in embodiment 5, the surface that is not added of comparative example is lived
Property agent Itraconazole enteric solubility solid dispersions and piller in the capsule of commercial preparation it is appropriate (containing Itraconazole 5mg), satiety
With degree be 20,100 revs/min of revolving speed, 37 ± 0.5 DEG C of bath temperature.Preceding 2 hours dissolution mediums are the hydrochloric acid solution of pH=1.2
750ml is subsequently added into 0.2M sodium radio-phosphate,P-32 solution 250ml, pH is adjusted to 6.8.Respectively 5,15,30,60,90,120,125,
150,180,240,300 minutes when sample 5ml.It is filtered with 0.22 μm of teflon membrane filter, discards primary filtrate 3ml, take filtrate
1ml, after 2 times of methanol dilution, with the concentration of high performance liquid chromatography measurement different time points Itraconazole in the solution.
Experimental result: Fig. 4 is that table is not added in Itraconazole enteric solubility solid body dispersion, comparative example prepared by embodiment 5
The Itraconazole enteric solubility solid dispersions of face activating agent and sell the experiment of the in-vitro simulated stomach of capsule-intestines supersaturation as a result, result
Display commercial preparation discharges whole drugs in simulate the gastric juice, and when pH is changed into 6.8, the concentration of Itraconazole is reduced rapidly,
This is because the dissolution rate moment of drug reduces, accelerate Itraconazole crystallization from supersaturated solution.Yi Qu prepared by embodiment 5
Health azoles enteric solubility solid dispersions discharge sub-fraction in simulate the gastric juice, and when pH is changed into 6.8, the concentration of Itraconazole is fast
Speed improves, this is because discharging rapidly out drug after the dissolution of enteric solubility carrier reaches hypersaturated state, but due to carrier and table
Under the action of the activating agent of face, Itraconazole can be very good to maintain hypersaturated state in simulated intestinal fluid.In contrast, upper Chinese system of weights
When pH switchs to 6.8, the concentration of Itraconazole reduces agent capsules, and Itraconazole recrystallizes from supersaturated solution, shows to list
Preparation capsule maintains Itraconazole poor in the effect of gastrointestinal tract hypersaturated state.However surfactant is not added in comparative example
Itraconazole enteric solubility solid dispersions are in simulation gastro-intestinal Fluid, and due to not adding surfactant, drug is in simulate the gastric juice
Only dissolve out it is micro, and in simulated intestinal fluid cannot continue keep hypersaturated state, bioavilability is obviously than having added surface-active
The Itraconazole enteric solubility solid dispersions of agent want low.Therefore, the Itraconazole enteric solubility solid dispersions in embodiment 5 maintain
Itraconazole is obviously preferable in the effect of gastrointestinal tract hypersaturated state.
The experiment of 3 beasle dog interior medicine dynamics of test example
Experimental method: 6 healthy adult beasle dogs, half male and half female, weight range 8-10kg.Fasting 12 hours before testing,
Two groups are randomly divided into, is taken a blood sample in hind leg vein.It is tested using single dose crossover, dosage is 100mg Itraconazole.Point
The itraconazole (by test preparation) and commercially available capsule (reference preparation) of the preparation of embodiment 7 are not swallowed, and the interval cleaning phase is one
Week.After medication, in 0.5,1,2,3,4,6,8,10,12,4ml is taken a blood sample respectively for 24 hours in 5ml heparin sodium vacuum blood collection tube.Whole blood
3000rpm is centrifuged 15min at 4 DEG C, pipettes 500 μ l of supernatant (i.e. blood plasma) in 7ml centrifuge tube, the internal standard that 40 μ l are added is molten
Liquid, adds the 0.8mol/L solution of zinc sulfate of 80 μ l, and vortex 30s is mixed.Addition 5ml extract liquor (n-hexane: methylene chloride=
7:3) extracted, vortex 5min, after in 8000rpm be centrifuged 10min.After pipetting supernatant extract liquor, 1ml extract liquor is added,
Vortex 2min is centrifuged 10min then at 8000rpm.Merge extract liquor twice, is placed in 35 DEG C of vacuum ovens and volatilizes solvent.In
It volatilizes and the resuspension of 250 μ l mobile phases is added in residue, vortex 2min crosses 0.22 μm of filter membrane to 200 μ l internal lining pipes, sample introduction measurement.
Chromatographic condition: HPLC-UV measurement, chromatographic column: Phenomenex-C18 (5 μm, 4.6 × 250nm), it is additional
Security Guard-C18 fill-type pre-column (5 μm, 4 × 3mm)；Mobile phase acetonitrile-pH6.7 phosphate-buffered salt (62:38, v/
v)；Flow velocity 1.000ml/min；Column temperature: 30 DEG C；Detection wavelength: 263nm；Sample volume: 20 μ l.
Experimental result: the blood concentration-time curve of Itraconazole is as shown in figure 5, with Itraconazole enteric of the invention
Property solid dispersions preparation itraconazole the intracorporal blood concentration of beasle dog be higher than commercial preparation capsule, it was demonstrated that this hair
Itraconazole solid dispersions in bright can preferably maintain the supersaturation concentration of Itraconazole in the gastrointestinal tract, to improve life
Object availability.
Each technical characteristic of embodiment described above can be combined arbitrarily, for simplicity of description, not to above-mentioned reality
It applies 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, all should be considered as described in this specification.
The embodiments described above only express several embodiments of the present invention, and the description thereof is more specific and detailed, but simultaneously
It cannot therefore be construed as limiting the scope of the patent.It should be pointed out that coming for those of ordinary skill in the art
It says, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to protection of the invention
Range.Therefore, the scope of protection of the patent of the invention shall be subject to the appended claims.
Claims (10)
1. a kind of Itraconazole enteric solubility solid dispersions, which is characterized in that the enteric solubility Itraconazole solid dispersions by
Following components in percentage by weight is prepared: Itraconazole 10-40%, enteric solubility polymer carrier 55%-85%, table
Face activating agent 2%-20%, the enteric solubility macromolecule carrier are acetic acid hydroxypropyl methylcellulose succinate MF type；
The surfactant is alpha-tocofecol succinic acid macrogol ester.
2. Itraconazole enteric solubility solid dispersions according to claim 1, which is characterized in that the solid dispersions by
Following components in percentage by weight is prepared: Itraconazole 20-35%, enteric solubility polymer carrier 60%-75%, table
Face activating agent 5%-15%.
3. Itraconazole enteric solubility solid dispersions according to claim 2, which is characterized in that the solid dispersions by
Following components in percentage by weight is prepared: Itraconazole 20-30%, enteric solubility polymer carrier 65%-75%, table
Face activating agent 5%-10%.
4. Itraconazole enteric solubility solid dispersions according to claim 3, which is characterized in that the solid dispersions by
Following components in percentage by weight is prepared: Itraconazole 20%, enteric solubility polymer carrier 70%, surfactant
10%.
5. Itraconazole enteric solubility solid dispersions according to any one of claims 1 to 4, which is characterized in that the intestines
The preparation method of dissolubility Itraconazole solid dispersions the following steps are included: weigh Itraconazole, enteric solubility macromolecule according to the ratio
Carrier material and surfactant, grinding make to be uniformly mixed, and physical mixture is made；It is added in twin screw hot melt extruder, squeezes
Physical mixture out crushed 80-120 mesh after cooling to get the solid dispersions of the Itraconazole.
6. the preparation method of the described in any item Itraconazole enteric solubility solid dispersions of Claims 1 to 5, which is characterized in that
The following steps are included: weighing Itraconazole, enteric solubility polymer carrier and surfactant according to the ratio, grinding keeps mixing equal
It is even, physical mixture is made；It is added in twin screw hot melt extruder, squeezes out physical mixture, crushed 80-120 mesh after cooling
Sieve the solid dispersions to get the Itraconazole.
7. the preparation method of Itraconazole enteric solubility solid dispersions according to claim 6, which is characterized in that the heat
The extrusion temperature of molten extruder is 140 DEG C -185 DEG C, and the screw speed of hot-melt extruded machine is 80-160 revs/min.
8. the preparation method of Itraconazole enteric solubility solid dispersions according to claim 7, which is characterized in that the heat
The extrusion temperature of molten extruder is 160 DEG C -170 DEG C, and the screw speed of hot-melt extruded machine is 100-140 revs/min.
9. the described in any item Itraconazole enteric solubility solid dispersions of Claims 1 to 5 are in preparing Itraconazole preparation
Using.
10. application according to claim 9, which is characterized in that the dosage form of the Itraconazole preparation is granule, piece
Agent, capsule or oral solution.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6027747A (en) * | 1997-11-11 | 2000-02-22 | Terracol; Didier | Process for the production of dry pharmaceutical forms and the thus obtained pharmaceutical compositions |
| CN105126110A (en) * | 2015-07-29 | 2015-12-09 | 中山大学 | Solid dispersion of itraconazole and preparation method and application of solid dispersion |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6027747A (en) * | 1997-11-11 | 2000-02-22 | Terracol; Didier | Process for the production of dry pharmaceutical forms and the thus obtained pharmaceutical compositions |
| CN105126110A (en) * | 2015-07-29 | 2015-12-09 | 中山大学 | Solid dispersion of itraconazole and preparation method and application of solid dispersion |
Non-Patent Citations (1)
| Title |
|---|
| Investigation of Polymer-Surfactant and Polymer-Drug-Surfactant Miscibility for Solid Dispersion;Suhas G. Gumaste, et.al;《The AAPS Journal》;20160614;第3-4页"film casting"部分以及表1；第7-9页"HPMCAS-ITZ-Poloxamer 188"部分 * |
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