CN113350290A - Aprepitant solid dispersion composition and preparation method thereof - Google Patents

Aprepitant solid dispersion composition and preparation method thereof Download PDF

Info

Publication number
CN113350290A
CN113350290A CN202010147817.7A CN202010147817A CN113350290A CN 113350290 A CN113350290 A CN 113350290A CN 202010147817 A CN202010147817 A CN 202010147817A CN 113350290 A CN113350290 A CN 113350290A
Authority
CN
China
Prior art keywords
aprepitant
solid dispersion
composition
dispersion composition
total weight
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202010147817.7A
Other languages
Chinese (zh)
Inventor
程增江
满艳哲
孔华
程思奇
赵京华
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Corbeille Park Beijing Medical Technology Co ltd
Original Assignee
Corbeille Park Beijing Medical Technology Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Corbeille Park Beijing Medical Technology Co ltd filed Critical Corbeille Park Beijing Medical Technology Co ltd
Priority to CN202010147817.7A priority Critical patent/CN113350290A/en
Publication of CN113350290A publication Critical patent/CN113350290A/en
Pending legal-status Critical Current

Links

Images

Classifications

    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics

Abstract

The invention discloses an aprepitant solid dispersion composition and a preparation method thereof. The aprepitant and the water-soluble polymer are subjected to hot-melt extrusion technology to prepare the solid dispersion composition containing amorphous aprepitant. In the solid dispersion composition, the weight ratio of aprepitant to the water-soluble polymer is 1: 0.2-1: 10, the aprepitant exists in an amorphous state, the medicine is dissolved out very quickly, and the stability is good. Also provides an oral preparation containing the solid dispersion, which has simple preparation process, does not use any organic solvent, has very quick dissolution and good stability under proper packaging conditions.

Description

Aprepitant solid dispersion composition and preparation method thereof
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a preparation method of an aprepitant solid dispersion composition.
Background
Aprepitant capsules are drugs developed by merck corporation in 2003 for marketing to prevent postoperative nausea and vomiting, or in combination with other antiemetics to prevent nausea and vomiting induced by chemotherapeutic drugs. Aprepitant is a selective high-affinity substance P/neurokinin-1 (NK1) receptor inhibitor, has low affinity to 5-hydroxytryptamine (5HT3), dopamine and corticoid receptors, can pass through a blood brain barrier to occupy NK-1 receptors in the brain, and has the complete antiemetic control rate which is 14.98 percent higher than that of 5-hydroxytryptamine receptor antagonist drugs. The molecular formula of aprepitant is C23H21F7N4O3Molecular weight of 534.4267, and structural formula as follows:
Figure BDA0002401379640000011
after aprepitant is orally taken, the peak time (Tmax) is 4 hours, the pharmacokinetic characteristic of the aprepitant is nonlinear, and the plasma protein binding rate is more than 95%. The medicine has large distribution volume, and is mainly cleared by drug metabolism, and the metabolic pathways include CYP3A4 (major pathway), CYP1A2 and CYP2C19 (minor pathway). Although aprepitant has a very good clinical curative effect, the aprepitant is a BCS IV drug, the solubility is very poor, and a preparation with high oral bioavailability is difficult to prepare.
To increase bioavailability, the most common method used today is to reduce the particle size of the starting material and prepare a solid dispersion. WO2003049718 discloses a nanoparticle composition containing aprepitant, wherein a surface stabilizer is adsorbed on the surface of the aprepitant, so that the particle size is smaller than 1000 nm. US5145684 and US8258132 disclose aprepitant nanoparticles prepared by wet milling in the presence of a deflocculant. Although wet grinding can significantly reduce the average particle size to several hundred nanometers, thereby increasing the water solubility, the preparation process is cumbersome, such as the resulting nanoparticles must be separated from the grinding media, which is time and energy consuming and not easily scalable. CN105534987 discloses an aprepitant oral pharmaceutical preparation, which adopts ethanol dissolution and reduced pressure drying to prepare solid dispersion, thereby achieving the purpose of improving bioavailability, but a large amount of organic solvent ethanol is used in the preparation process. CN107205951 discloses a novel pharmaceutical composition, which is prepared by adding a surfactant and an organic solvent. CN104586814B discloses a method for preparing aprepitant capsules, which uses an organic solvent, diethylene glycol monoethyl ether. Therefore, although the samples prepared by these methods are considered to exhibit good pharmacokinetic properties in the above documents, the inventors have considered that the process is complicated, large-scale production operations are not easy, and an organic solvent is introduced.
The hot melt extrusion technology is also called melt extrusion technology, and refers to a technology for mixing auxiliary materials such as medicines, polymers and the like in a molten state, and extruding the mixture into a product under certain pressure, speed and shape. CN102525879B provides an aprepitant solid dispersion composition and a preparation method thereof, and the aprepitant solid dispersion composition is prepared by a hot-melt extrusion method. However, in the solid dispersion prepared in the document, the drug aprepitant still exists in a crystal form, the drug solubility is still lower than that of an amorphous state, and in terms of the implementation effect of the invention, only about 83% of the drug aprepitant is dissolved in 15min, and the dissolution is slow. Since the solubility of the amorphous drug is significantly higher than that of the crystalline drug, the dissolution rate is significantly increased. Therefore, it is urgent to provide an oral aprepitant formulation containing an amorphous drug, capable of ensuring a very rapid dissolution rate, and having a simple preparation process.
Disclosure of Invention
In view of the defects of the prior art, the invention provides an amorphous aprepitant-containing solid dispersion composition which comprises aprepitant and a water-soluble polymer.
According to the invention, the water-soluble polymer, preferably a mixture of one, two or more of polyvinyl alcohol, Soluplus, hydroxypropyl cellulose (HPC); further preferably hydroxypropyl cellulose (HPC); for example, hydroxypropyl cellulose having a molecular weight of less than 200000, for example, the following types of hydroxypropyl cellulose can be used: HPC-SSL, HPC-SL, HPC-L.
According to the present invention, the water-soluble polymer has a Tg value (glass transition temperature) or melting point of more than 50 ℃, more preferably a Tg value or melting point of 50 to 250 ℃, even more preferably a Tg value or melting point of 80 to 200 ℃, and most preferably a Tg value or melting point of 90 to 200 ℃. The water-soluble polymer may be any water-soluble polymer as long as one of the Tg value and the melting point satisfies the above-mentioned condition, and a person skilled in the art can determine whether to select an appropriate water-soluble polymer according to the Tg value or the melting point by a known technique.
According to the present invention, in the solid dispersion composition, the weight ratio of aprepitant to water-soluble polymer is 1:0.2 to 1:10, for example 1:0.5 to 1:8, preferably 1:0.5 to 1:5, more preferably 1:1 to 1: 5.
According to the present invention, the aprepitant solid dispersion composition may be a bulk solid, a flake solid, or a bar solid, or may be a powdery solid.
The aprepitant solid dispersion composition according to the invention, wherein aprepitant is present in a solid amorphous form and not in a liquid form or a crystalline form.
According to the present invention, the aprepitant solid dispersion composition further optionally comprises one, two or more of a filler, a disintegrant and a lubricant.
According to the present invention, the aprepitant solid dispersion composition may be prepared by a hot-melt extrusion method. Wherein the heating temperature can be 100-300 ℃, preferably 150-250 ℃, and more preferably 170-220 ℃.
The invention also provides a preparation method of the aprepitant solid dispersion composition, which comprises the step of hot-melt extruding aprepitant and a water-soluble polymer.
According to the invention, the temperature during hot-melt extrusion can be 100-300 ℃, preferably 150-250 ℃, and more preferably 170-220 ℃.
The hot melt extrusion step may be performed using an extruder. Suitable extruders include single screw extruders, intermeshing screw extruders or other multi-screw extruders, preferably twin screw extruders, to maximize the extrusion of the material being extruded, which may be co-rotating or counter-rotating and (optionally) equipped with kneading units. Particularly preferred is an PHARMA HME series twin screw extruder from Thermo Scientific.
The invention also provides a preparation which comprises the aprepitant solid dispersion composition and pharmaceutically acceptable auxiliary materials, such as one or two or more of a filling agent, a disintegrating agent and a lubricating agent.
According to the invention, the preparation is an oral preparation, such as granules, capsules, tablets and the like.
According to the invention, the formulation comprises aprepitant in an amount of about 20% to about 40% by total weight of the formulation, a water-soluble polymer in an amount of about 15% to about 60% by total weight of the composition, a lubricant in an amount of about 0% to about 1% by total weight of the composition, a disintegrant in an amount of about 0% to about 10% by total weight of the composition, and a filler in an amount of about 15% to about 50% by total weight of the composition. Preferably, the formulation comprises aprepitant in an amount from about 30% to about 50% by total weight of the formulation, a water-soluble polymer in an amount from about 30% to about 50% by total weight of the composition, a lubricant in an amount from about 0.1% to about 0.5% by total weight of the composition, a disintegrant in an amount from about 0% to about 5% by total weight of the composition, and a filler in an amount from about 15% to about 40% by total weight of the composition.
According to the invention, the formulation has the following in vitro dissolution profile: the accumulative dissolution rate of aprepitant reaches more than 70% in 15 minutes, and the accumulative dissolution rate reaches more than 80% in 30 minutes; preferably, the accumulative dissolution rate of aprepitant reaches more than 80% at 15 minutes, and the accumulative dissolution rate reaches more than 90% at 30 minutes; more preferably, the cumulative dissolution of aprepitant at 15 minutes is 90% or more, and the cumulative dissolution at 30 minutes is 90% or more.
The filler is selected from one or more of microcrystalline cellulose, lactose, mannitol, starch and dextrin. Preferably one or more of microcrystalline cellulose, lactose, mannitol, more preferably one or more of microcrystalline cellulose, mannitol, most preferably a mixture of microcrystalline cellulose and mannitol.
The disintegrant is selected from one or more of sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose and corn starch. Preferably one or more of sodium carboxymethyl starch, croscarmellose sodium and low substituted hydroxypropyl cellulose, more preferably one or more of sodium carboxymethyl starch and croscarmellose sodium, and most preferably sodium carboxymethyl starch.
The invention also provides a preparation method of the preparation, which comprises the following steps: pulverizing the solid dispersion composition, mixing with pharmaceutically acceptable adjuvants such as one or two or more of filler, disintegrant and lubricant, and making into oral preparation such as tablet, capsule, granule, etc. by processing (such as granulating, tabletting, capsule filling, and coating).
In the context of the present invention, the terms "solid dispersion composition" and "solid dispersion" are used interchangeably and refer to a solid dispersion composition of the present invention comprising aprepitant and a water-soluble polymer.
Advantageous effects
The aprepitant solid dispersion composition and the preparation containing the aprepitant solid dispersion composition have the advantages that the aprepitant exists in an amorphous state, the dissolution speed is very high, the stability is good, and the oral bioavailability is high. In addition, the preparation process of the solid dispersion composition and the preparation does not need to add an organic solvent or micronize, and the preparation method is simple in process and easy for large-scale production.
Drawings
Figure 1 shows the XRD pattern of aprepitant drug substance.
Figure 2 shows the XRD pattern of the solid dispersion of comparative example 2.
Figure 3 shows the XRD pattern of the solid dispersion of example 2.
Figure 4 shows the XRD pattern of HPC-SL.
Figure 5 shows the XRD pattern of the solid dispersion of example 2 after being left for 10 days under light conditions.
FIG. 6 shows an XRD pattern of the solid dispersion of example 2 after being left at high temperature for 10 days
Fig. 7 shows an XRD pattern of the solid dispersion of example 2 after being left under high humidity conditions for 10 days.
Detailed Description
Hereinafter, the solid dispersion of aprepitant composition of the present invention will be described in further detail with reference to specific examples. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.
Comparative example 1: preparation of micronized aprepitant bulk drug
The prescription is as follows:
composition of matter Single dose/mg
Aprepitant 80
Hydroxypropyl cellulose-SL 14
Sodium dodecyl sulfate 1
Mannitol 55
Microcrystalline cellulose 55
Sodium starch glycolate 10
Total weight of contents 215
The preparation process comprises the following steps:
the aprepitant bulk drug is crushed by a jet mill, so that the particle size of the bulk drug is reduced to the micron level, and the particle size D90 of the bulk drug is controlled to be below 5 mu m. And the micronized raw material medicines are adopted for preparation of the prescription.
Weighing 1000 times of single dose of each component according to the formula ratio, performing wet granulation by using water as a wetting agent, drying by a fluidized bed, mixing the dried granules with additional sodium dodecyl sulfate, manually filling gelatin hollow capsules, and taking the capsules for a dissolution test.
The dissolution measurement method comprises the following steps: determining the dissolution rate of the aprepitant capsule by adopting a high performance liquid chromatography, wherein the chromatographic condition is the same as that of a content determination method, and an octadecylsilane chemically bonded silica chromatographic column is used; water acetonitrile (40:60) is used as a mobile phase; the flow rate was 1.0ml per minute; the detection wavelength is 210 nm; and calculating the dissolution rate of aprepitant in the test solution by peak area according to an external standard method.
Dissolution medium: 2.2% sodium lauryl sulfate solution, volume of medium: 900ml, paddle speed 100 rpm. The dissolution determination method is the second method of the dissolution and release determination method of 0931 in the four general rules of the chinese pharmacopoeia 2015 edition. The results are detailed in table 1.
Table 1: dissolution data for capsules prepared in comparative example 1
Time (min) Cumulative dissolution (%)
5 1.2
10 6.5
15 8.1
30 10.5
As can be seen from the data in Table 1, after the bulk drug is micronized, the aprepitant capsule drug prepared by the traditional wet granulation process is low in dissolution, and the dissolution rate in 30min is just 10%.
Comparative example 2: preparation of aprepitant solid dispersion by taking povidone K30 as carrier polymer
The prescription is as follows:
is composed ofIs divided into Single dose/mg
Aprepitant 80
Povidone 160
Sodium dodecyl sulfate 1
Mannitol 40
Microcrystalline cellulose 40
Sodium starch glycolate 10
Total weight of contents 331
Weighing aprepitant raw material medicine according to the amount which is 1000 times of single dose, sieving the aprepitant raw material medicine by a 60-mesh sieve to remove larger particles in the raw material medicine, and then mixing the aprepitant raw material medicine with povidone K30 according to the weight ratio of 1: 2, were mixed in the weight ratio of (1). Setting the heating temperature of a double-screw extruder to be 200 ℃, adding the mixture into the double-screw extruder, mixing, melting and extruding in the extruder, adopting a standard circular caliber neck mold to obtain a strip-shaped transparent extrudate, placing the extrudate in a disc, naturally cooling at room temperature, and solidifying. Then placing the strip-shaped extrudate into a pulverizer to be pulverized, sieving the pulverized extrudate by a 60-mesh sieve, and reserving the solid dispersion composition below the 60-mesh sieve for later use; mixing the pulverized solid dispersion composition with additional adjuvants such as microcrystalline cellulose, mannitol, carboxymethyl starch sodium and sodium dodecyl sulfate at a ratio of 240:40:40:10:1, filling into capsule, and performing dissolution curve detection. The dissolution test method was the same as that in comparative example 1.
The solid dispersion composition has an XRD pattern as shown in figure 2. As can be seen from the map, the drug aprepitant exists in a crystal form.
Table 2: dissolution data for capsules prepared in comparative example 2
Time (min) Cumulative dissolution (%)
5 36.0
10 60.6
15 74.6
30 88.0
The drug dissolution of the capsule prepared from the solid dispersion composition of aprepitant and povidone K30 is much faster than that of the aprepitant capsule prepared by micronization of the bulk drugs, but the aprepitant capsule can not be completely dissolved in 30 min.
Examples 1 to 4: preparation of aprepitant solid dispersion by using hydroxypropyl cellulose as carrier polymer
Taking aprepitant raw material, sieving with a 60-mesh sieve for later use, and sieving hydroxypropyl cellulose HPC-SL with a 60-mesh sieve for later use. Mixing aprepitant and HPC-SL in different proportions, setting the heating temperature of a double-screw hot-melt extruder to be 200 ℃, then placing the mixture into the double-screw hot-melt extruder, carrying out mixing melting and extrusion to obtain a strip-shaped transparent extrudate, placing the extrudate into a disc, naturally cooling and solidifying at room temperature, then transferring the extrudate into a crusher for crushing, sieving by a 60-mesh sieve, and taking the solid dispersion composition below the 60-mesh sieve for later use. Mixing the solid dispersion composition with additional adjuvants including microcrystalline cellulose, mannitol, carboxymethyl starch sodium and sodium dodecyl sulfate at a certain ratio, filling into capsule, and performing dissolution curve detection.
Table 3: the formulations of examples 1-4 (in the tables, the single dose formulations and the units of the materials are mg)
Figure BDA0002401379640000081
Figure BDA0002401379640000091
The XRD pattern of the solid dispersion of example 2 is shown in fig. 3. As can be seen from the map, the drug aprepitant exists in an amorphous form.
Effect example 1: dissolution test of solid dispersions and capsules of examples 1-4
The solid dispersion and the capsule in each example were simultaneously subjected to dissolution curve test. The dissolution test method was the same as that in comparative example 1.
Table 4: dissolution data for the solid dispersions of examples 1-4 and the corresponding capsules
Figure BDA0002401379640000092
Effect example 2: stability study of the solid Dispersion of example 2
The solid dispersion prepared in example 2 was placed under high temperature, high humidity and light conditions, and the influence factor was examined, and the dissolution and related substances were examined. The results are shown in Table 5 below.
Table 5: stability test results of solid Dispersion of example 2
Figure BDA0002401379640000101
The stability results in table 5 show that, when the aprepitant solid dispersion is exposed for 10 days under high temperature and illumination conditions, the related substances and the dissolution curve of the aprepitant solid dispersion have no obvious change; under the condition of high humidity of 75 percent, related substances of the solid dispersion composition are obviously changed, and the early stage of dissolution is obviously reduced due to moisture absorption of the solid dispersion; however, the dissolution of the drug of the sample packaged by the aluminum plastic packaging bag is unchanged under the high-temperature high-humidity compound condition, which indicates that the composition is easy to absorb moisture, but the composition is stable under the packaging condition by isolating moisture from entering.
Further, fig. 5 shows an XRD pattern of the solid dispersion of example 2 after being left under light conditions for 10 days, fig. 6 shows an XRD pattern of the solid dispersion of example 2 after being left under high temperature conditions for 10 days, and fig. 7 shows an XRD pattern of the solid dispersion of example 2 after being left under high humidity conditions for 10 days. From these maps, it can be seen that the drug aprepitant in the solid dispersion still exists in an amorphous form and has good stability after being placed under light, high temperature or high humidity conditions for 10 days.
Effect example 3: bioavailability assay of the capsules of example 2
Using the capsules of example 2 with commercially available aprepitant capsules (
Figure BDA0002401379640000112
) And (4) carrying out bioavailability experiments, taking beagle dogs as tested animals, and carrying out experiments by adopting a double-cycle crossing method. The specific experimental method is as follows:
a healthy male beagle dog (n ═ 6) weighing 10-11kg, aged 1-3 years and not exposed to any drug within the last 6 months was selected for an in vivo pharmacokinetic study. Fasted conditions, beagle dogs were fasted overnight (without restriction of water). Will be provided withBeagle dogs were randomly divided into two groups, and given 20ml of water together with the drug, one group was given 1 capsule preparation of example 2, and the other group was given a commercial aprepitant capsule ((R))
Figure BDA0002401379640000113
80mg) of 1 pellet and fasting for a further 4 hours (without restriction of water). At a predetermined time point 2.5ml of blood was withdrawn from the hind limb vein and placed in a negative pressure tube coated with anticoagulant (heparin) for later use. And (3) treating the plasma sample to remove proteins and interfering substances, and analyzing and detecting the treated plasma sample by using a liquid chromatograph-mass spectrometer. The results of the physical pharmacokinetic experiments on beagle dogs are shown in table 6 below.
Table 6: results of pharmacokinetic experiments of different aprepitant formulations in beagle dogs
Figure BDA0002401379640000111
As can be seen from the data in Table 6, the Tmax in beagle dogs administered with the capsule of example 2 is reduced compared with the aprepitant capsule sold in the market, and the Cmax and the AUC are both obviously increased and are both increased by about 1.5 times compared with the animal group with the aprepitant capsule sold in the market, which shows that the capsule containing the aprepitant solid dispersion prepared by the invention has obvious bioavailability advantage. The activity of the medicine is increased, the specification of the preparation can be reduced while the same effective effect is ensured, and the production cost is reduced.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (9)

1. An aprepitant solid dispersion composition comprising aprepitant and a water-soluble polymer, wherein the aprepitant exists in an amorphous state;
preferably, the weight ratio of aprepitant to water-soluble polymer is 1: 0.2-1: 10, such as 1: 0.5-1: 8, preferably 1: 0.5-1: 5, and more preferably 1: 1-1: 5.
2. The solid dispersion composition according to claim 1, the water soluble polymer being selected from one, a mixture of two or more of polyvinyl alcohol, Soluplus, hydroxypropyl cellulose (HPC); preferably hydroxypropyl cellulose (HPC); for example hydroxypropyl cellulose with a molecular weight below 200000, for example hydroxypropyl cellulose of the following type: HPC-SSL, HPC-SL, HPC-L;
preferably, wherein the water-soluble polymer has a Tg (glass transition temperature) or melting point of greater than 50 deg.C, more preferably a Tg or melting point of from 50 deg.C to 250 deg.C, even more preferably a Tg or melting point of from 80 deg.C to 200 deg.C, and most preferably a Tg or melting point of from 90 deg.C to 200 deg.C.
3. The solid dispersion composition of claim 1 or 2, further optionally comprising one, two or more of a filler, a disintegrant, and a lubricant.
4. The solid dispersion composition of any one of claims 1-3, which is preparable by a hot melt extrusion process; preferably, the heating temperature may be 100 to 300 ℃, preferably 150 to 250 ℃, and more preferably 170 to 220 ℃.
5. The solid dispersion composition of any one of claims 1-4, wherein aprepitant is present in a solid amorphous form.
6. A process for preparing a solid dispersion composition as claimed in any one of claims 1 to 5, comprising the step of hot melt extruding aprepitant with a water soluble polymer;
preferably, the temperature during hot-melt extrusion can be 100-300 ℃, preferably 150-250 ℃, and more preferably 170-220 ℃.
7. An aprepitant solid dispersion composition obtained by the preparation method of claim 6.
8. A formulation comprising the aprepitant solid dispersion composition of any one of claims 1-5 and 7 and pharmaceutically acceptable excipients, such as one, two or more of a filler, a disintegrant, and a lubricant;
preferably, the formulation is an oral formulation, such as a granule, capsule or tablet;
preferably, the formulation comprises aprepitant in an amount from about 20% to about 40% by total weight of the formulation, a water-soluble polymer in an amount from about 15% to about 60% by total weight of the composition, a lubricant in an amount from about 0% to about 1% by total weight of the composition, a disintegrant in an amount from about 0% to about 10% by total weight of the composition, and a filler in an amount from about 15% to about 50% by total weight of the composition; more preferably, the formulation comprises aprepitant in an amount from about 30% to about 50% by total weight of the formulation, a water-soluble polymer in an amount from about 30% to about 50% by total weight of the composition, a lubricant in an amount from about 0.1% to about 0.5% by total weight of the composition, a disintegrant in an amount from about 0% to about 5% by total weight of the composition, and a filler in an amount from about 15% to about 40% by total weight of the composition.
9. A method of preparing the formulation of claim 8, comprising the steps of: pulverizing the solid dispersion composition, mixing with pharmaceutically acceptable adjuvants such as one or two or more of filler, disintegrant and lubricant, and making into preparation by conventional preparation processing.
CN202010147817.7A 2020-03-05 2020-03-05 Aprepitant solid dispersion composition and preparation method thereof Pending CN113350290A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202010147817.7A CN113350290A (en) 2020-03-05 2020-03-05 Aprepitant solid dispersion composition and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202010147817.7A CN113350290A (en) 2020-03-05 2020-03-05 Aprepitant solid dispersion composition and preparation method thereof

Publications (1)

Publication Number Publication Date
CN113350290A true CN113350290A (en) 2021-09-07

Family

ID=77523810

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202010147817.7A Pending CN113350290A (en) 2020-03-05 2020-03-05 Aprepitant solid dispersion composition and preparation method thereof

Country Status (1)

Country Link
CN (1) CN113350290A (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115025048A (en) * 2022-07-28 2022-09-09 上海智同医药科技有限公司 Aprepitant ternary solid dispersion
WO2024002054A1 (en) * 2022-06-27 2024-01-04 Taigen Biotechnology Co., Ltd. Pharmaceutical composition comprising a cap-dependent endonuclease inhibitor

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008104512A2 (en) * 2007-02-27 2008-09-04 Sandoz Ag Novel polymorphs of aprepitant and processes for preparation
US20090209541A1 (en) * 2006-06-16 2009-08-20 Dr. Reddy's Laboratories Ltd. Aprepitant compositions
CN102525880A (en) * 2010-12-31 2012-07-04 江苏正大天晴药业股份有限公司 Aprepitant solid dispersion composition
WO2016120013A1 (en) * 2015-01-30 2016-08-04 Pharmathen S.A. Pharmaceutical composition comprising aprepitant and method for the preparation thereof
WO2017194681A1 (en) * 2016-05-12 2017-11-16 Alfred E. Tiefenbacher (Gmbh & Co. Kg) Composition containing aprepitant
JP2019073445A (en) * 2017-10-12 2019-05-16 日本化薬株式会社 Pharmaceutical composition containing aprepitant as active ingredient

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090209541A1 (en) * 2006-06-16 2009-08-20 Dr. Reddy's Laboratories Ltd. Aprepitant compositions
WO2008104512A2 (en) * 2007-02-27 2008-09-04 Sandoz Ag Novel polymorphs of aprepitant and processes for preparation
CN102525880A (en) * 2010-12-31 2012-07-04 江苏正大天晴药业股份有限公司 Aprepitant solid dispersion composition
WO2016120013A1 (en) * 2015-01-30 2016-08-04 Pharmathen S.A. Pharmaceutical composition comprising aprepitant and method for the preparation thereof
WO2017194681A1 (en) * 2016-05-12 2017-11-16 Alfred E. Tiefenbacher (Gmbh & Co. Kg) Composition containing aprepitant
JP2019073445A (en) * 2017-10-12 2019-05-16 日本化薬株式会社 Pharmaceutical composition containing aprepitant as active ingredient

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024002054A1 (en) * 2022-06-27 2024-01-04 Taigen Biotechnology Co., Ltd. Pharmaceutical composition comprising a cap-dependent endonuclease inhibitor
CN115025048A (en) * 2022-07-28 2022-09-09 上海智同医药科技有限公司 Aprepitant ternary solid dispersion
CN115025048B (en) * 2022-07-28 2023-12-15 上海智同医药科技有限公司 Ternary solid dispersion of aprepitant

Similar Documents

Publication Publication Date Title
AU2009236289B2 (en) Oral pharmaceutical compositions in a solid dispersion comprising preferably posaconazole and HPMCAS
CN104721142B (en) Rivaroxaban solid dispersion and preparation method thereof
KR102089112B1 (en) Hypromellose acetate succinate for use as hot-melt extrusion carrier, hot-melt extrusion composition, and method for producing hot-melt extrudate
JP6522853B2 (en) SOMCL-9112 solid dispersion, method for producing the same, and SOMCL-9112 solid preparation containing the same
Sun et al. Nimodipine semi-solid capsules containing solid dispersion for improving dissolution
EP3120871B1 (en) Solid dispersion
CN113350290A (en) Aprepitant solid dispersion composition and preparation method thereof
CN102525880B (en) Aprepitant solid dispersion composition
CN113164394B (en) Vilazodone solid dispersion and preparation method thereof
CN108324720B (en) Aprepitant pharmaceutical composition and method for improving bioavailability thereof
CN110917152B (en) CYP17 inhibitor tablet and preparation method thereof
CN108078934B (en) Ziprasidone hydrochloride solid dispersible tablet and hot-melt extrusion method thereof
US5684040A (en) Compositions in the form of solid solutions
CN115427022B (en) Pharmaceutical compositions, methods of preparation and methods of use thereof
CN107951841B (en) Nimodipine solid dispersion and preparation method of nimodipine solid dispersion tablet
CN104586770A (en) Hot-melt extrusion preparation of pazopanib hydrochloride and preparation method of hot-melt extrusion preparation
CN104603138A (en) Crystalline forms of hcv inhibitor
CN104623684A (en) Preparation method of Empagliflozin and mannitol composition
CN108785256B (en) Solid dispersion and preparation method thereof
CN115869264A (en) Meloxicam solid dispersion and preparation method thereof
CN114533735A (en) Lurasidone hydrochloride pharmaceutical composition and preparation method thereof
CN107875126A (en) A kind of carbamazepine solid dispersions and its preparation
CN108175751B (en) Bufogenin solid dispersion and preparation method thereof
CN104208072A (en) Megestrol acetate hot-melt extrusion preparation
CN106511291A (en) Acotiamide hydrochloride controlled release tablet and preparation method thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
RJ01 Rejection of invention patent application after publication

Application publication date: 20210907

RJ01 Rejection of invention patent application after publication