CN108066289B

CN108066289B - Posaconazole solid dispersion, preparation method thereof and posaconazole enteric-coated preparation

Info

Publication number: CN108066289B
Application number: CN201711495634.9A
Authority: CN
Inventors: 梁兆丰; 童伟勤; 赖颖强
Original assignee: Guangzhou Bositao Controlled Release Pharmaceutical Co ltd
Current assignee: Guangzhou Bositao Controlled Release Pharmaceutical Co ltd
Priority date: 2017-12-28
Filing date: 2017-12-28
Publication date: 2021-01-26
Anticipated expiration: 2037-12-28
Also published as: CN108066289A

Abstract

The invention discloses a posaconazole solid dispersion, a preparation method thereof and a posaconazole enteric-coated preparation, and relates to the field of posaconazole preparations. The invention discloses a posaconazole solid dispersion which is prepared by carrying out hot melting, spraying and freezing on raw materials, wherein the raw materials comprise the following components in parts by weight: 100-200 parts of posaconazole active ingredient, 300-400 parts of enteric material and 1-15 parts of plasticizer. The posaconazole solid dispersion has a good dissolution rate in intestinal tracts and lower content of impurity components, and improves the bioavailability of posaconazole.

Description

Posaconazole solid dispersion, preparation method thereof and posaconazole enteric-coated preparation

Technical Field

The invention relates to the field of posaconazole preparations, in particular to a posaconazole solid dispersion, a preparation method thereof and a posaconazole enteric preparation.

Background

Invasive fungal infections, also known as deep fungal infections or systemic fungal infections. In recent years, immunosuppressed patients have been increasing with the abuse of large doses of immunosuppressive agents, chemotherapeutic drugs, and broad spectrum antibiotics.

Posaconazole (Posaconazole) under the trade name Posaconazole

Is a novel triazole antifungal drug developed by Mr. Probaba corporation (Shimorshadong pharmacy), is approved by FDA to be on the market in 2006, 9 and 15 days, and is used for fungal infection caused by refractory diseases or other drug resistance, such as aspergillosis, tuberculosis, fusarium and the like. Posaconazole was the first FDA approved antibacterial agent for the prevention of lesions caused by invasive Aspergillus and, like other azole antibacterial agents, was also a heme cofactor that passed through the active site of lanosterol 14 α -demethylase (CYP51 or Ergllp)In combination, inhibit the biosynthesis of fungal ergosterol, and destroy the formation and integrity of cell membrane, thereby playing an antibacterial role.

Posaconazole overcomes the problems of narrow antibacterial spectrum and drug resistance of the first generation of triazole drugs, and the broad-spectrum antifungal effect of posaconazole is proved in vitro and in vivo and has effects on candida, various aspergillus and other common and very common pathogenic fungi.

Posaconazole is a weakly basic compound with a high solubility in the acidic environment of the stomach, about 0.8mg/ml, but when posaconazole dissolved in the stomach reaches the intestinal tract (pH of about 6.5), a large amount of dissolved posaconazole precipitates out with a solubility of less than 1 μ g/ml. The intestinal tract is the main part of the absorption of posaconazole, and the poor solubility in the intestinal tract causes the low bioavailability of posaconazole.

Thus, the preparation of oral formulations of posaconazole has hitherto suffered from the poor solubility of posaconazole in the intestinal tract.

In view of this, the invention is particularly proposed.

Disclosure of Invention

The invention aims to provide a posaconazole solid dispersion which is prepared by carrying out hot melting, spraying and freezing on raw materials, wherein the posaconazole solid dispersion has a better dissolution rate in intestinal tracts and lower content of impurity components, and the bioavailability of posaconazole is improved.

Another object of the present invention is to provide a process for preparing the above-mentioned posaconazole solid dispersion.

Another object of the present invention is to provide an enteric posaconazole preparation, which comprises the above-mentioned solid posaconazole dispersion.

The invention is realized by the following steps:

the posaconazole solid dispersion is prepared by carrying out hot melting, spraying, freezing and curing on raw materials, wherein the raw materials comprise the following components in parts by weight: 100-200 parts of posaconazole active ingredient, 300-400 parts of enteric material and 1-15 parts of plasticizer.

A process for the preparation of a solid dispersion of posaconazole as described above, which comprises:

carrying out hot melting treatment on a physical mixture formed by mixing the posaconazole active ingredient, the enteric material and the plasticizer to obtain a hot-melt mixture;

and (3) atomizing, freezing and solidifying the hot-melt mixture to obtain the posaconazole solid dispersion.

An enteric posaconazole preparation, which comprises the above-mentioned posaconazole solid dispersion and pharmaceutically acceptable auxiliary materials.

The invention has the following beneficial effects:

the invention provides a posaconazole solid dispersion which is prepared by carrying out hot melting, spraying, freezing and curing on raw materials, wherein the raw materials comprise the following components in parts by weight: 100-200 parts of posaconazole active ingredient, 300-400 parts of enteric material and 1-15 parts of plasticizer. The posaconazole solid dispersion has a good dissolution rate in intestinal tracts, and the bioavailability of posaconazole is improved;

in addition, the invention provides a preparation method of the posaconazole solid dispersion, which adopts a hot-melt spray freezing technology, carries out hot-melt treatment on a physical mixture formed by mixing the active ingredient of posaconazole, an enteric material and a plasticizer, and carries out atomization treatment, freezing treatment and solidification treatment on the obtained hot-melt mixture to obtain the posaconazole solid dispersion; the preparation method reduces the impurity content, controls the quality of the intermediate, overcomes the defects of low efficiency and high loss rate in the hot-melting extrusion process, and has the characteristics of more uniform particle size and high yield.

Drawings

In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.

FIG. 1 shows an enteric solid oral tablet of posaconazole according to example 1 of the present inventionProposaconazole preparation

Comparing results of in vitro dissolution curves;

FIG. 2 shows a posaconazole enteric solid oral tablet and a posaconazole precursor developer provided in examples 1 to 3 and comparative example 1 of the present invention

Comparing results of in vitro dissolution curves;

FIG. 3 shows the posaconazole enteric solid oral tablet and the posaconazole pro-drug formulation provided in examples 1 and 4 and comparative example 2 of the present invention

And (5) comparing the in vitro dissolution curves.

Detailed Description

In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.

The following is a detailed description of the posaconazole solid dispersion, the preparation method thereof and the posaconazole enteric-coated preparation of the embodiment of the invention.

Solid dispersion technology is a common method for increasing the dissolution rate and bioavailability of poorly soluble drugs. Hot Melt Extrusion (HME) is a solid dispersion technique for preparing a solid dispersion of an insoluble drug by mixing and extruding a bulk drug and a carrier adjuvant in a high-temperature molten state. Posaconazole enteric-coated tablet developed by Xianlingbaoya company

The method adopts a hot-melt extrusion technology, takes an enteric material HPMC-AS AS a hot-melt extrusion carrier to prepare the posaconazole solid dispersion, and improves the dissolution and absorption of the posaconazole solid dispersion in intestinal tractsAnd (6) harvesting.

However, the prior art has the following problems:

1. the shear mixing process of hot melt extrusion involves high-intensity mechanical force, and the molecular structure of materials is easily damaged and denatured, so that the content of related materials is increased. The Sarode and the like find that the content of free succinic acid and acetic acid of the HPMC-AS is obviously increased along with the increase of the rotating speed from 100r/min to 300r/min and the increase of the temperature from 160 ℃ to 200 ℃ in the hot-melt extrusion process, the color of an extruded product is obviously deepened, the dissolution rate of the prepared solid dispersion is correspondingly slowed down, and the bioavailability of the posaconazole is reduced;

2. the hot-melt extrusion intermediate obtained by the hot-melt extrusion process needs to be crushed into particles, the crushing process reduces the continuity of the whole process, the crushing step is easy to generate heat, and the intermittent crushing and the addition of dry ice or liquid nitrogen for protection are needed, so that the operational difficulty of the process is increased, and the efficiency is reduced. The heat generated during crushing can cause the particles to be thermally melted and adhered to the wall of the cavity body again, so that the material loss can be caused and the recovery is difficult; secondly, the wall-sticking materials are difficult to be crushed again, so the control difficulty of the granularity is larger.

The hot melt spray freezing technology is a preparation technology developed on the basis of spray drying, and is the biggest difference from the spray drying technology in that the hot melt spray freezing technology adopts cold air flow to solidify products and does not need to use any solvent. It can disperse the active components in the molten material, spray it in the cooling tower by atomizer, exchange heat with the air in the cooling tower, and solidify to obtain semi-finished product or finished product.

The basic principle of the hot-melt spray freezing technology is as follows: the evenly mixed melting auxiliary materials and other materials are dispersed into mist-shaped liquid drops through an atomizer at a certain temperature, and the mist-shaped liquid drops are fully contacted with cold air in a freezing chamber to carry out heat exchange, so that the mist-shaped liquid drops are rapidly solidified, and gas-solid separation is completed in a cyclone separator to obtain superfine powder or fine particle semi-finished products or finished products.

Based on the above, in order to overcome the above problems, the invention provides a posaconazole solid dispersion prepared by adopting a hot-melt spray freezing technology, a preparation method thereof and a posaconazole enteric-coated preparation.

On one hand, the invention provides a posaconazole solid dispersion which is prepared by carrying out hot melting, spraying and freezing on raw materials, wherein the raw materials comprise the following components in parts by weight: 100-200 parts of posaconazole active ingredient, 300-400 parts of enteric material and 1-15 parts of plasticizer.

Preferably, in some embodiments of the present invention, the raw materials comprise, in parts by weight: 100-125 parts of posaconazole active ingredient, 300-325 parts of enteric material and 5-10 parts of plasticizer.

The granules prepared in the proportioning range have uniform granularity and ideal dissolution effect.

Further, in some embodiments of the present invention, the enteric material is selected from one or both of cellulosic enteric materials and acrylic resin enteric materials.

Preferably, in some embodiments of the present invention, the cellulose enteric material is selected from one or more of cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate and hydroxypropylmethylcellulose phthalate.

Preferably, in some embodiments of the present invention, the acrylic enteric material is selected from the group consisting of those available under the trade name

E100、

L100-55、

L100 and

one or more of acrylic resin enteric materials of S100.

Further, in some embodiments of the invention, the plasticizer is selected from one or more of hydroxypropyl methylcellulose E3, hydroxypropyl methylcellulose E5, hydroxypropyl methylcellulose E15, hydroxypropyl cellulose EXF, hydroxypropyl cellulose ELF, hydroxypropyl cellulose LXF, hydroxypropyl cellulose JXF, hydroxypropyl cellulose HXF, povidone K17, povidone K30, and povidone K90.

The plasticizer has the functions of adjusting the dissolution rate and improving the rheological property of the molten material, and the main functions of the plasticizer are as follows: 1) the melting point of the mixed material is reduced in the hot melting spraying stage, the material is softened, the viscosity of the molten material is reduced, the rheological property of the molten material is improved, the mechanical resistance is reduced, and the production is facilitated; 2) as most of the selected plasticizers are hydrophilic materials, hydrophilic channels can be formed in the tablet to play a role in moisture absorption, and the dissolution of the product can be improved in the dissolution stage.

Further, in some embodiments of the present invention, the posaconazole active ingredient is a posaconazole solvate, a posaconazole prodrug, a crystalline form of posaconazole, amorphous posaconazole, or a mixture of crystalline form of posaconazole and amorphous posaconazole.

However, it should be noted that the posaconazole active ingredient is not limited to the above form, and can be posaconazole in other forms, which are all within the scope of the present invention.

In another aspect, the present invention provides a method for preparing the above posaconazole solid dispersion, which comprises:

and atomizing, freezing and solidifying the hot-melt mixture to obtain the posaconazole solid dispersion.

The posaconazole solid dispersion obtained by the preparation method is uniformly mixed with additional auxiliary materials to prepare the corresponding posaconazole enteric-coated preparation. Such as dry direct compression to obtain enteric solid oral posaconazole tablet or capsule.

Further, in some embodiments of the present invention, the temperature of the hot melt process is 135-145 ℃;

preferably, the atomization pressure of the atomization treatment is 0.18 bar-0.24 bar;

preferably; the condensation temperature of the freezing treatment is-16 ℃ to 0 ℃.

Within the range of the parameters, the prepared posaconazole solid dispersion has the characteristics of uniform particles, high recovery rate, ideal dissolution effect, low impurity content and the like.

In some embodiments of the present invention, the temperature of the hot melt process may be any one or a range between any two of 135 ℃, 136 ℃, 137 ℃, 138 ℃, 139 ℃, 140 ℃, 141 ℃, 142 ℃, 143 ℃, 144 ℃, 145 ℃, and the like.

In some embodiments of the invention, the atomization pressure of the atomization process may be any one or a range between any two of 0.18bar, 0.19bar, 0.20bar, 0.21bar, 0.22bar, 0.23bar, and 0.24bar, and the like.

In some embodiments of the invention, the freezing process has a condensation temperature in the range of any one or any two of-16 ℃, -14 ℃, -12 ℃, -10 ℃, -8 ℃, -6 ℃, -4 ℃, -2 ℃, and 0 ℃.

Preferably, in some embodiments of the present invention, the temperature of the hot melt process is 140 ℃, the atomization pressure of the atomization process is 0.18bar, and the condensation temperature of the freezing process is-8 ℃.

In another aspect, the invention provides an enteric posaconazole preparation, which comprises the above posaconazole solid dispersion and pharmaceutically acceptable auxiliary materials.

Further, in some embodiments of the invention, the excipients include fillers, binders, disintegrants, lubricants, and coating materials.

Preferably, in some embodiments of the present invention, the adjuvant comprises, in parts by weight: 50-100 parts of a filler, preferably 50-80 parts; 50-100 parts of adhesive, preferably 50-80 parts; 10-40 parts of disintegrating agent, preferably 20-30 parts of disintegrating agent and 1-10 parts of lubricating agent, preferably 2-5 parts of lubricating agent.

Preferably, in some embodiments of the invention, the filler is selected from one or more of lactose monohydrate, anhydrous lactose, microcrystalline cellulose, starch, partially pregelatinized starch, and mannitol.

Preferably, in some embodiments of the invention, the binder is selected from one or more of hydroxypropyl methylcellulose E3, hydroxypropyl methylcellulose E5, hydroxypropyl methylcellulose E15, hydroxypropyl cellulose EXF, hydroxypropyl cellulose ELF, hydroxypropyl cellulose LXF, hydroxypropyl cellulose JXF, hydroxypropyl cellulose HXF, povidone K17, povidone K30 and povidone K90.

Preferably, in some embodiments of the present invention, the disintegrant is selected from one or more of low substituted hydroxypropyl cellulose among cellulose derivatives, croscarmellose sodium, sodium carboxymethyl starch of starch derivatives, and crospovidone of povidone type.

Preferably, in some embodiments of the invention, the disintegrant is selected from one or both of croscarmellose sodium and sodium carboxymethyl starch.

Preferably, in some embodiments of the present invention, the lubricant is selected from one or more of magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, sodium lauryl sulfate, talc and silicon dioxide.

Further, in some embodiments of the invention, the above enteric posaconazole formulation is a solid oral tablet or capsule.

Preferably, in some embodiments of the present invention, the enteric material is an acrylic resin having an enteric function, the plasticizer is hydroxypropyl cellulose, the filler is microcrystalline cellulose, the binder is hydroxypropyl cellulose, the disintegrant is croscarmellose sodium, and the lubricant is magnesium stearate.

Preferably, in some embodiments of the present invention, the acrylic resin soluble pH environment is between pH 5.0 and pH 7.0;

wherein, the acrylic resin used as the enteric material corresponds to the commodity model of

E100、

S100、

L100 or

L100-55。

Wherein hydroxypropyl cellulose EXF is used as plasticizer and has the corresponding trade name of

HPC EXF。

In a further aspect, the present invention provides a preparation method of the above enteric posaconazole preparation, which comprises:

and (3) primarily mixing the posaconazole solid dispersion with a filling agent, an adhesive and a disintegrating agent to obtain a primary mixture, and adding a lubricant into the primary mixture for total mixing to obtain a total mixture.

Further, in some embodiments of the invention, the above preparation method further comprises: and tabletting the total mixture to obtain a tablet core, and performing film coating treatment on the tablet core to obtain a finished tablet.

Of course, in some embodiments of the invention, the total mixture is granulated and the granules are filled into capsules to give finished capsules.

It should be noted that the dosage form of the posaconazole enteric preparation can be reasonably selected according to actual requirements, such as the administration mode.

In conclusion, the posaconazole solid dispersion provided by the invention is prepared by carrying out hot melting, spraying, freezing and curing on raw materials, has low content of impurities such as dehydroxysaconazole, benzylated posaconazole and the like, has a good dissolution rate in intestinal tracts, and effectively improves the bioavailability of posaconazole.

The preparation method of the posaconazole solid dispersion provided by the invention adopts a hot-melt spray freezing technology to prepare the raw materials into the solid dispersion, reduces the impurity content in the posaconazole solid dispersion, has controllable quality of an intermediate, overcomes the defects of low efficiency and high loss rate in a hot-melt extrusion process, and has the characteristics of more uniform particle size and high yield.

The posaconazole solid dispersion preparation provided by the invention is prepared by mixing the posaconazole solid dispersion and pharmaceutically acceptable auxiliary materials, has low content of impurities such as dehydroxysaconazole, benzylated posaconazole and the like, has a good dissolution rate in intestinal tracts, and effectively improves the bioavailability of posaconazole.

The features and properties of the present invention are described in further detail below with reference to examples.

Example 1

The embodiment provides a posaconazole enteric solid oral tablet which is prepared by mixing a posaconazole solid dispersion and auxiliary materials;

wherein the posaconazole solid dispersion consists of 100g of posaconazole and 325g of acrylic resin (A)

L100-55) and 5g of hydroxypropyl cellulose (f)

HPC EXF) is prepared by hot melting, spraying, freezing and solidifying;

the auxiliary materials comprise: 70g of hydroxypropyl cellulose (f)

HPC EXF), 70g microcrystalline cellulose, 28g croscarmellose sodium, 2g magnesium stearate, 16g

Yellow coating material and proper amount of purified water, wherein the purified water is used for preparing the coating liquid.

The present embodiment provides a preparation method of the above posaconazole enteric solid oral tablet, which comprises the following steps:

1 preparation of Posaconazole solid Dispersion

1.1. And (3) sieving the posaconazole, the acrylic resin and the hydroxypropyl cellulose ester by a 30-mesh sieve, putting the mixture into a mixing tank according to the formula dosage, and mixing for 10 minutes at the speed of 20rpm/min to obtain a physical mixture.

1.2. Transferring the physical mixture into a mixing chamber of a hot-melt spray granulator (MS-220 type), setting the hot-melt temperature at 140 ℃, setting the pump speed of a circulating pump at 15, starting a stirring paddle, and stirring at 300rpm/min for 8 minutes to obtain a molten mixture.

At the same time, the freezing system was turned on and the freezing temperature was set to-8 ℃.

1.3. Starting the atomizer (two-fluid airflow atomizer), setting the atomization pressure to be 0.18Bar, setting the rotating speed of the fan to be 2500rpm, and collecting the materials in the charging barrel to obtain the posaconazole solid dispersion.

2 preparing the finished product of the enteric posaconazole preparation

2.1 putting the obtained posaconazole solid dispersion, the microcrystalline cellulose and the croscarmellose sodium in the amount of the formula into a mixing tank, mixing at the speed of 20rpm/min for 10 minutes, adding magnesium stearate for lubrication, and mixing at the speed of 20rpm/min for 5 minutes to obtain a final mixture.

2.2 mixing the final mixture in a rotary tablet press (C)&C800) Tabletting with 17mm × 8mm mold to obtain posaconazole tablet

And performing film coating on the yellow solution to obtain the posaconazole enteric solid oral tablet.

Examination of dissolution Effect

1 dissolution test

The prepared posaconazole enteric solid oral tablet and the posaconazole raw preparation are mixed

In vitro dissolution comparison, referring to the in vitro dissolution method recommended by FDA in USA, the posaconazole enteric solid oral tablet needs to be dissolved in 750mL of 0.01N hydrochloric acid medium for 2h, and then 250mL of 0.2M phosphate buffer solution is added to make the dissolved bodyThe dissolution is continued for 1h when the pH value of 1000mL is 6.8 +/-0.05, and the dissolution method is as follows:

the internal method development was carried out with reference to the in vitro dissolution method published by the FDA in the united states, using Sodium Dodecyl Sulfate (SDS) as a surfactant, and the procedure was as follows:

the first stage is as follows: taking 6 posaconazole enteric solid oral tablet samples prepared in example 1, carrying out an acid resistance test under the dissolution test conditions, taking 10mL of medium after 2 hours, filtering the medium through 0.22 mu microporous filter membrane, discarding 8mL, reserving 2mL, transferring the medium to a quartz cuvette with the diameter of 2mm, carrying out detection at the wavelength of 262nm, and calculating by using a control solution with the concentration of 0.1mg/mL, wherein the dissolution (acid resistance) is detected according to the following formula:

dissolution (acid resistance)%, sample absorbance x control concentration x dissolution medium volume)/(control absorbance x labeled amount) × 100%

And a second stage: after 2 hours, 250mL of SDS-containing phosphate medium with the same temperature is added to the original medium, so that the surfactant mass concentration is 0.3% and the pH value is 6.8 +/-0.05, 10mL of the medium is taken at different sampling time points, the medium is filtered through a 0.22 mu m microporous filter membrane, 7mL of the medium is discarded, 2mL of the medium is reserved and transferred to a 2mm quartz cuvette, the detection is carried out at the wavelength of 262nm, the control solution with the concentration of 0.1mg/mL is used for calculation, and the dissolution rate detection formula is as follows:

calculation of dissolution

Dissolution% (% sample absorbance × control concentration × dissolution medium volume)/(control absorbance × labeled amount) × 100%

The results are shown in tables 1 and 2.

TABLE 1

TABLE 2

As can be seen from tables 1 and 2, the in vitro dissolution behavior of the posaconazole enteric preparation prepared by the method of the embodiment 1 of the invention is consistent with that of the original preparation, and the curative effect of the drug is not affected while the process is optimized.

2 detection of impurities

The impurities generated in the posaconazole process are mainly three types: hydroxy triazole impurities, desposaconazole and benzylated posaconazole. The comparison between the posaconazole enteric-coated tablets prepared in example 1 and the original preparation in terms of related substances is shown in table 3 below.

TABLE 3

Related substances	Original preparation	Example 1
			Total impurities	2.2％	1.5％
Impurities of the class of hydroxy triazoles	0.5％	0.6％
			Dexposaconazole	0.7％	0.3％
Benzylated posaconazole	0.5％	0.3％

The dehydroposaconazole and the benzylated posaconazole may be associated with mechanical forces in the process, which externally applied mechanical forces catalyse the radical reactions of posaconazole. The airflow effect of the preparation method of the posaconazole enteric solid oral tablet provided in example 1 has much less influence on posaconazole than the hot-melt extrusion process, and thus the resulting dehydroxysaconazole and benzylated posaconazole are lower than those of the original formulation.

From the above results, it can be seen that the posaconazole enteric solid oral tablet provided in example 1 of the present invention has a dissolution effect consistent with that of the commercially available posaconazole enteric preparation, but also has a lower content of impurities such as desposaconazole and benzylated posaconazole.

Example 2

The preparation method of posaconazole enteric solid oral tablet provided in this example is substantially the same as that of example 1, except that hydroxypropyl cellulose, a plasticizer, is used

HPC EXF was used in an amount of 10 g.

The results of the dissolution test of the posaconazole enteric solid oral tablet obtained in this example are shown in fig. 2.

Example 3

HPC EXF was used in an amount of 15 g.

Comparative example 1

This comparative example provides a posaconazole enteric solid oral tablet substantially the same as in example 1, except that hydroxypropylcellulose is used as the plasticizer

HPC EXF was used in an amount of 0 g.

The results of the dissolution test of the posaconazole enteric solid oral tablet obtained in the comparative example are shown in figure 2.

As can be seen from FIG. 2, the enteric solid oral posaconazole tablet and the original posaconazole formulation provided in example 1

Hydroxypropyl cellulose containing plasticizer with similar dissolution effect

The dissolution effect of the posaconazole enteric solid oral tablets of HPC EXF (examples 1-3) was better than that of the posaconazole enteric solid oral tablets without plasticizer (comparative example 1).

Example 4

The preparation method of the enteric solid oral posaconazole tablet provided in this example is substantially the same as that of example 1, except that in this example, the atomization pressure of the atomization treatment is 0.24 bar.

The results of the dissolution test of the posaconazole enteric solid oral tablet obtained in this example are shown in fig. 3.

Comparative example 2

The preparation method of the enteric solid oral posaconazole tablet provided by the comparative example is basically the same as that of example 1, except that in the present example, the atomization pressure of the atomization treatment is 0.12 bar.

The results of the dissolution test of the posaconazole enteric solid oral tablet obtained in the comparative example are shown in figure 3.

As can be seen from FIG. 3, the solutions of posaconazole enteric solid oral tablets provided in examples 1 and 4Preparation for producing effect and posaconazole

Similarly, the dissolution effect of the posaconazole enteric-coated solid oral tablet prepared at the 0.18bar atomizing pressure in example 1 and the dissolution effect of the posaconazole enteric-coated solid oral tablet prepared at the 0.24bar atomizing pressure in example 4 are both better than that of the posaconazole enteric-coated solid oral tablet prepared at the 0.12bar atomizing pressure in comparative example 2.

To sum up, the preparation method of the enteric posaconazole preparation provided by the embodiment of the invention adopts the hot-melt spray freezing technology, the raw materials are firstly prepared into the solid dispersion, and the solid dispersion is mixed with the auxiliary materials to prepare the enteric posaconazole solid oral tablet, and compared with the prior art, the preparation method has the following beneficial effects:

(1) the content of related substances is reduced, and the quality of the intermediate is controllable. The preparation method is characterized in that a hot melt spray freezing technology is used for preparing the posaconazole solid dispersion, the mixing stage is carried out in a material storage chamber of equipment, and the stirring and mixing of a stirring paddle and the circular flow motion of gas of an atomizer form a structure which is compared with a hot melt extrusion technology, so that the shearing force of a screw on materials is avoided, the posaconazole and auxiliary materials thereof are protected from being damaged by mechanical force on the aspect of a molecular structure, the generation of related substances is reduced, and the quality controllability of an intermediate is improved.

(2) The defects of low efficiency and high loss rate in the hot-melting extrusion process are overcome. When the solid dispersion is prepared by hot-melt extrusion, the prepared intermediate needs to be crushed into particles by a crusher, the particle size needs to be controlled by the aperture of a screen mesh of the crusher, more heat is generated during crushing in most cases, the particles need to be crushed discontinuously and protected by adding dry ice or liquid nitrogen, the operational difficulty of the process is increased, and the particles can be adhered to the wall of a cavity body by hot melting again due to the heat generated during crushing, so that the material loss and the recovery are caused; secondly, the wall-sticking materials are difficult to be crushed again, so the control difficulty of the granularity is larger. The hot-melt freezing spray granulation can be used for one-step granulation, and the granules are controlled by the atomizing pressure during spraying, so that the prepared granules are more uniform in granularity and high in yield.

The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. 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

1. The posaconazole solid dispersion is characterized by being prepared from raw materials through hot melting, spraying, freezing and curing, wherein the raw materials comprise the following components in parts by weight: 100-125 parts of posaconazole active ingredient, 300-325 parts of enteric material and 5-10 parts of plasticizer;

the enteric material is Eudragit^®L100-55; the plasticizer is hydroxypropyl cellulose EXF;

wherein the temperature of the hot melting treatment is 135-145 ℃, the atomization pressure of the atomization treatment is 0.18-0.24 bar, and the condensation temperature of the freezing treatment is-16-0 ℃.

2. The posaconazole solid dispersion according to claim 1, wherein the posaconazole active ingredient is a posaconazole solvate, a posaconazole prodrug, a crystalline form of posaconazole, amorphous posaconazole, or a mixture of crystalline form of posaconazole and amorphous posaconazole.

3. The process for preparing a posaconazole solid dispersion according to any one of claims 1 to 2, which comprises:

atomizing, freezing and solidifying the hot-melt mixture to obtain the posaconazole solid dispersion;

4. An enteric posaconazole formulation, comprising the solid posaconazole dispersion according to any one of claims 1 to 2 and a pharmaceutically acceptable excipient.

5. The enteric posaconazole formulation according to claim 4, wherein the excipients comprise a filler, a binder, a disintegrant, a lubricant and a coating material.

6. The enteric posaconazole formulation according to claim 5, wherein the filler is selected from one or more of lactose monohydrate, anhydrous lactose, microcrystalline cellulose, starch, partially pregelatinized starch and mannitol.

7. The enteric posaconazole formulation according to claim 5, wherein the binder is selected from one or more of hydroxypropyl methylcellulose E3, hydroxypropyl methylcellulose E5, hydroxypropyl methylcellulose E15, hydroxypropyl cellulose EXF, hydroxypropyl cellulose ELF, hydroxypropyl cellulose LXF, hydroxypropyl cellulose JXF, hydroxypropyl cellulose HXF, povidone K17, povidone K30 and povidone K90.

8. The enteric posaconazole formulation according to claim 5, wherein the disintegrant is one or more selected from the group consisting of low-substituted hydroxypropyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, and crospovidone.

9. The enteric posaconazole formulation according to claim 5, wherein the lubricant is one or more selected from the group consisting of magnesium stearate, stearic acid, calcium stearate, sodium stearyl fumarate, sodium lauryl sulfate, talc and silica.

10. The enteric posaconazole formulation according to any one of claims 4 to 9, wherein the excipients comprise, in parts by weight: 50-100 parts of a filler, 50-100 parts of a binder, 10-40 parts of a disintegrating agent and 1-10 parts of a lubricant.

11. The enteric posaconazole formulation according to claim 10, wherein the excipients comprise: 50-80 parts of a filler, 50-80 parts of a binder, 20-30 parts of a disintegrating agent and 2-5 parts of a lubricant.