CN119745803A - Leitemivir preparation composition and preparation method thereof - Google Patents

Abstract

The invention discloses a letromycin preparation composition which comprises 20-70% by weight of letromycin, 20-70% by weight of filler, 2-10% by weight of binder, 2-10% by weight of disintegrating agent, 0.5-5% by weight of flavoring agent, 0-20% by weight of release modifier, 0.5-5% by weight of lubricant, 0.5-5% by weight of glidant and 0-60% by weight of solubilizer. The invention can fill the medicine demands of domestic Leidemomvir granules for preventing and treating CMV infection patients of children and old people with dysphagia. The letromycin particles have the advantages of simple preparation process, stable process, good dissolution rate, good product stability and the like, are suitable for industrialized mass production, and can bring good social and economic benefits.

Description

Leitemivir preparation composition and preparation method thereof

Technical Field

The invention belongs to the technical field of chemical pharmacy, and particularly relates to a letromycin and pyrroside pharmaceutical composition, in particular to a letromycin and pyrroside preparation composition and a preparation method thereof.

Background

CMV is a double stranded DNA virus of the genus herpesvirus, transmitted mainly by direct contact. CMV infection is common worldwide, the serum antibody positive rate of CMV of healthy people over 14 years old and blood and organ donors is 83% and 86%, respectively, and the serum positive rate of CMV of healthy adults in China is over 90%, for example, the serum positive rate of CMV of adults over 25 years old in Shanghai city is over 97%. Humans are often recessively infected with CMV at childhood, mostly without clinical symptoms, after which CMV can be in a lifelong latent state in a variety of cells. In the immunosuppressive state, the CMV that is hidden in the body can be reactivated, causing infection and disease of the corresponding organs, even death, with the survivors left with various sequelae. In 2006-2012, there are about 2.7 tens of thousands of A110-HSCT's worldwide, with about 6,400 in southeast Asia and western Pacific regions. The number of Chinese A110-HSCT cases has increased year by year from 2008. Clinically, it is important to properly prevent and treat CMV infection in time, and the specific method is that 1) antiviral medicines are adopted for prevention, but no medicines approved for preventing CMV infection after HSCT exist in China at present, and 2) preemptive treatment (PREEMPTIVE THERAPY, PET) is carried out, namely, virus replication is actively monitored, and anti-CMV medicines are adopted for treatment when CMV viremia is detected.

Letrozole is a novel non-nucleoside Cytomegalovirus (CMV) inhibitor (3, 4-dihydroquinazoline) that prevents terminal enzymes from cleaving newly synthesized CMV DNA into individual viral genomes and directing them into empty viral capsids, thereby inhibiting viral replication. In cell culture models of infected strains, letrozole shows potent activity against laboratory and various CMV clinical isolates, including several strains resistant to marketed anti-CMV drugs. The mechanism of action of letromycin is highly specific and the target (CMVDNA terminal enzyme) to which it is directed is not homologous in humans and therefore has less potential toxicity associated with its mechanism of action. Furthermore, in the cell culture model of infection, cross-resistance between letromycin and the drugs currently approved for the treatment of CMV was not observed. The main reason is that currently available anti-CMV drugs are DNA polymerase inhibitors, the resistance of which is associated with UL54 and/or UL97, which constitute DNA polymerase. Whereas temavir is a targeted CMV DNA end enzyme consisting of UL56 and UL 89. In past in vitro studies, most amino acid mutations that lead to drug resistance have been found to be concentrated in a conserved region of UL56 protein 231-369. The effect of the drug resistance mutation found in the UL89 protein alone is small unless combined with the drug resistance mutation of UL 56. In a UL56 protein sequence analysis of 74 clinical HCMV strains, it was found that it is very rare for the natural clinical strain to generate drug resistance mutations.

Rituximab is the first global and currently the only prophylactic drug for CMV infection in CMV seropositive allogeneic hematopoietic stem cell transplant recipients. It differs from DNA polymerase inhibitors in that letromycin is more selective for CMV and has a significantly improved intensity of action. As previously mentioned, all currently available anti-CMV drugs have significant toxicity, such as myelosuppression and nephrotoxicity. Considering the challenges of PET and the toxicity associated with existing anti-CMV drugs, letrozole is expected to meet the clinical needs currently not met as an anti-CMV drug with a new mechanism of action.

Lai Mo Weiyuan developed by the pharmaceutical company Mitsador, USA FDA approval was obtained at 11/9 of 2017 under the trade name Prevymis for the prevention and treatment of Cytomegalovirus (CMV) infections and diseases in adult and pediatric patients with 6 months and above, at least 6 kg body weight, CMV seropositive allogeneic Hematopoietic Stem Cell Transplantation (HSCT) [ R+ ] and CMV prophylaxis in adult and pediatric high risk kidney transplant recipients (donor CMV seropositive/recipient CMV seronegative [ D+/R- ]) aged 12 years and above, at least 40 kg body weight. The rituximab formulation on the market is currently only marketed as oral tablets and injections in China.

CN110433166a discloses a pharmaceutical preparation containing an antiviral active dihydroquinazoline derivative, which relates to a preparation method of a pharmaceutical preparation composition for intravenous administration. CN105555771a discloses a process for the preparation of amorphous letrozole and a process for the preparation of solid pharmaceutical formulations (immediate release formulations) for oral administration. WO2022132676A1 discloses a mini-tablet of a viral-stopping enzyme inhibitor and a process for its preparation, comprising granulation, tabletting, fluid bed coating. The mini-tablet can be packaged in capsules, sachets or strip-shaped packages and taken as granules, is suitable for patients with dysphagia such as children and elderly patients, and meets the clinical demands which are partially not met.

The most convenient and commonly used dosage forms for administration have historically been solid oral dosage forms, particularly tablets and capsules, which, however, due to their fixed content limitations, present a degree of difficulty for many dysphagia people, particularly children and the elderly. The granule is particularly suitable for children and elderly patients to take because of easy swallowing, and can provide a new choice for enlarging the application population and improving the overall treatment effect of patients. The market of granular formulations meets the medication requirements of many patients who cannot swallow complete tablets and capsules.

The mini-tablet preparation process is complex and comprises the processes of granulation, tabletting, fluidized bed coating, capsule filling or bagging and the like, and especially the mini-tablet tabletting and coating processes have higher requirements on equipment performance and longer production time, so that the preparation cost of the oral letromycin granules is further increased.

Disclosure of Invention

In view of the defects in the prior art, the invention aims to provide a rituximab quick-release granule preparation which has the advantages of simple preparation process, stable process, good dissolution rate, good product stability and the like, and is suitable for industrial mass production.

In a first aspect of the present invention, there is provided a letromycin formulation composition comprising letromycin, characterized in that it further comprises filler, binder, disintegrant, flavoring agent, release-controlling agent, lubricant, glidant, solubilizing agent, the weight percentages of the components being as follows:

20% -70% of letromycin;

20% -70% of filler;

2% -10% of adhesive;

2% -10% of disintegrating agent;

0.5% -5% of flavoring agent;

0% -20% of release modifier;

0.5% -5% of lubricant;

0.5% -5% of glidant;

0% -60% of solubilizer.

Preferably, the weight percentages of the components are as follows:

20% -70% of letromycin;

20% -60% of filler;

2% -8% of adhesive;

2% -8% of disintegrating agent;

0.5% -3% of flavoring agent;

4% -15% of release modifier;

0.5% -3% of lubricant;

0.5% -3% of glidant;

20-55% of solubilizer.

More preferably, the weight percentages of the components are as follows:

30% -50% of letrozole;

20% -50% of filler;

3% -5% of adhesive;

3% -5% of disintegrating agent;

1% -3% of a flavoring agent;

6% -12% of release modifier;

1% -3% of lubricant;

1% -3% of glidant;

30% -45% of solubilizer.

In some embodiments, the letrozole is micronized to a D90 of less than 20 μm, more preferably a D90 of less than 10 μm.

In some embodiments, the filler is selected from one or more of starches, celluloses, sugar alcohols, sugars.

Preferably, the filler is selected from one or more of starch, microcrystalline cellulose, mannitol, lactose.

In some embodiments, the binder is selected from one or more of povidone, hyprolose, hypromellose.

In some embodiments, the disintegrant is selected from one or more of sodium carboxymethyl starch, croscarmellose, low substituted hydroxypropylcellulose, preferably sodium croscarmellose;

In some embodiments, the flavoring agent is selected from one or more of a natural sweetener, a synthetic sweetener, an ion exchange resin taste masking agent.

The natural sweetener is selected from one or more of stevioside, glycyrrhizin, simple syrup and aromatic syrup.

The synthetic sweetener is selected from one or more of saccharin sodium, sucralose, aspartame and neotame, preferably sucralose.

The ion exchange resin taste masking agent is selected from one or more of Kyron T-104, kyron T-114, kyron T-134, kyron T-154, kyron T-159, kyron T-123. Preferably Kyron T-134.

In some embodiments, the release modifier is selected from one or more of Eudragit L100-55, eudragit L100, colloidal silica, xanthan gum, magnesium oxide, preferably colloidal silica, more preferably magnesium oxide.

In some embodiments, the lubricant is selected from one or more of calcium stearate, magnesium stearate, hydrogenated vegetable oil, preferably magnesium stearate.

In some embodiments, the glidant is preferably colloidal silicon dioxide.

In some embodiments, the solubilizing agent is selected from one or more of poloxamer 188, poloxamer 237, PEG 6000.

By optimizing the components and proportion of the Lett-movir preparation composition, the dissolution rate of the Lett-movir preparation composition can be reduced, so that the dissolution behavior of the Lett-movir preparation composition reaches the level equivalent to that of tablets in the prior art.

In a second aspect of the present invention, there is provided a process for preparing a formulation composition of letromycin, wherein said formulation composition is in the form of granules prepared by wet granulation, the process comprising the steps of:

S1, weighing micronized letrozole, a filler and a disintegrating agent, and mixing to prepare medicine-containing mixed powder;

s2, preparing an adhesive into an aqueous solution, and adding the mixed powder obtained in the step S1 for wet granulation;

s3, drying the prepared wet particles through an oven or a fluidized bed, and controlling LOD within 3% to prepare dry particles containing medicines;

s4, mixing the dry particles with a flavoring agent, a lubricant and a glidant to obtain a lett Mo Weizong mixed particle;

s5, sealing the total mixed particles in bags according to the dosage to obtain a finished product.

In a third aspect of the present invention, there is provided a process for preparing a formulation composition of letrozole, wherein the formulation composition is in the form of granules prepared by dry granulation, the process comprising the steps of:

s1, weighing micronized letromycin, a filler, a disintegrating agent, an adhesive and a lubricant, and mixing to prepare medicine-containing mixed powder;

The mixed powder in the step S2 and the step S1 is subjected to dry granulation by using a dry granulator, and the particle size of the drug-containing particles is controlled within the range of 300-650 mu m;

S3, mixing the granules obtained by dry granulation with a flavoring agent, a lubricant and a glidant to obtain a lett Mo Weizong mixed granule;

S4, sealing the total mixed particles in bags according to the dosage to obtain a finished product.

In a fourth aspect of the present invention, there is provided a process for preparing a formulation composition of letromycin, wherein said formulation composition is in the form of granules prepared by fluid bed ebullating granulation, the process comprising the steps of:

S1, weighing micronized letrozole, a filler and a disintegrating agent, and mixing to prepare medicine-containing mixed powder;

S2, preparing an adhesive into an aqueous solution, spraying the aqueous solution of the adhesive into the mixed powder in the step S1 through fluidized bed boiling granulation to obtain particles containing the letromycin, and controlling LOD within 3%;

s3, mixing dry particles prepared by boiling granulation with a flavoring agent, a lubricant and a glidant to obtain a lett Mo Weizong mixed particle;

S4, sealing the total mixed particles in bags according to the dosage to obtain a finished product.

In a fifth aspect of the present invention, there is provided a process for preparing a formulation composition of letromycin, wherein said formulation composition is in the form of granules prepared by hot melt extrusion granulation, the process comprising the steps of:

s1, mixing the letromycin with a carrier material;

S2, setting the rotating speed of a screw to be about 30-300 rpm, and feeding a mixture of the uniformly mixed letrozole, a carrier material and pharmaceutically acceptable pharmaceutical excipients into a hot-melt extruder preheated to 70-120 ℃ with the length and diameter ratio (L/D) of the screw to be 15-40;

s3, cooling, crushing and sieving the extruded mixture to obtain letrozole pharmaceutical composition particles;

s4, mixing the particles of the Temu-M pharmaceutical composition with a flavoring agent, a lubricant and a glidant to obtain Laider Mo Weizong mixed particles;

S5, sealing the total mixed particles in bags according to the dosage to obtain a finished product;

the carrier material is selected from one or more of PVP, polyacrylic resin, cellulose and PEG;

the weight ratio of the letrozole to the carrier material is 1:4-1:1.

Preferably, the weight ratio of the letrozole to the carrier material is 1:3, more preferably 2:3.

In some embodiments, PVP-based carrier materials are selected from Kollidon VA64, polyacrylic resin-based carrier materials are selected from Eudragit E100, cellulose-based carrier materials are selected from hydroxypropyl cellulose and hydroxypropyl methylcellulose, and PEG-based carrier materials are selected from PEG4000 and PEG6000.

In some embodiments, the carrier material is a mixture of hydroxypropyl cellulose and PEG6000 in a weight ratio of 1:8-8:1, preferably 4:6-6:4.

Experiments show that the rituximab preparation composition with the pharmaceutical dissolved in the carrier material or dispersed in the carrier material at the molecular level can be prepared by the treatment of the hot-melt extrusion process of the present invention with a certain proportion of the carrier material and the rituximab.

By "modified release agent" herein is meant a material capable of accelerating or slowing the release rate of letromycin.

Compared with the prior art, the invention has the following beneficial effects:

The invention can fill the medicine demands of domestic Leidemomvir granules for preventing and treating CMV infection patients of children and old people with dysphagia. The letromycin particles have the advantages of simple preparation process, stable process, good dissolution rate, good product stability and the like, are suitable for industrialized mass production, and can bring good social and economic benefits.

The conception and technical effects of the present invention will be further described with reference to the accompanying drawings to fully understand the objects, features and effects of the present invention.

Drawings

FIG. 1 is a graph of the dissolution of example 1 in a medium containing 0.6% Tween 80 at pH 4.5.

FIG. 2 is a graph of the dissolution of example 2 in a medium containing 0.6% Tween 80 at pH 4.5.

FIG. 3 is a graph of the dissolution of example 3 in a medium containing 0.6% Tween 80 at pH 4.5.

FIG. 4 is a graph of the dissolution of example 4 in a medium containing 0.6% Tween 80 at pH 4.5.

FIG. 5 is a graph of the dissolution of example 5 in a medium containing 0.6% Tween 80 at pH 4.5.

FIG. 6 is a graph comparing dissolution curves of freshly ground and marketed oral tablets, comparative examples 1-6 in a medium containing 0.6% Tween 80 at pH 4.5.

FIG. 7 is a graph comparing dissolution curves of freshly ground and marketed oral tablets, examples 1-5, in a medium containing 0.6% Tween 80 at pH 4.5.

Detailed Description

The invention is further described with reference to the following detailed description in order to make the technical means, the inventive features, the achieved objects and the effects of the invention easy to understand. The present invention is not limited to the following examples.

It should be understood that the embodiments and drawings of the present invention are only for the purpose of understanding and reading the disclosure of the present invention, and are not intended to limit the applicable limitations of the present invention, so that the present invention is not limited to the technical essential features, and any modifications without inventive arrangements are included within the scope of the present invention without affecting the efficacy and the objects achieved.

All types of reagents involved in the examples are commercial products, and commercial products can be adopted.

The invention provides a method for measuring a dissolution curve of letromivir granules, which adopts a paddle method, wherein a dissolution medium is a buffer solution of Tween 80 acetate with pH of 4.5 and 0.6%, the volume of the dissolution medium is 500-900 mL, and the rotation speed is 50-100 rpm.

Example 1

The granule formulation is shown in table 1 below:

table 1 example 1 granule formulation

The preparation process comprises the following steps:

1) Future micronization of the termivir and weighing of the prescription.

2) Weighing the materials of the prescription amount of the letrozole, the microcrystalline cellulose, the hydroxypropyl methylcellulose, the croscarmellose sodium and the poloxamer 188, mixing for 5 minutes in a proper container, and sieving the mixed materials with a 35-mesh sieve for 2 times.

3) Weighing a proper amount of purified water, and preparing 8% -10% aqueous solution from the povidone K29/32 with the prescription amount.

4) And (3) adding the mixture obtained in the step (1) into a fluidized bed, setting the air inlet temperature to be 55-70 ℃ and the material temperature to be 45-55 ℃, and setting the proper air inlet quantity to fully fluidize the material. When the temperature of the material rises to 50 ℃, boiling granulation is started at a liquid spraying speed of 15-20 g/min.

5) After the granulation, the mixture was dried to a LOD of less than 3%, and dry granulation was carried out using a 1600 μm granulation screen.

6) Adding the Te Mo Weigan granules, the added prescription amount of sucralose, lemon essence, colloidal silicon dioxide and magnesium stearate into a multidimensional mixer, and mixing for 10min to obtain the Lepidotimod particles.

7) Filling the special Mo Weizong mixed particles into a medicinal aluminum composite film bag according to the filling amount requirement, and sealing and storing.

Example 2

The granule formulations are shown in table 2 below:

table 2 example 2 granule formulation

The preparation process comprises the following steps:

1) Future micronization of the termivir and weighing of the prescription.

2) The prescription amount of the Lepidotimod and the colloidal silicon dioxide are weighed, placed in a proper container for mixing for 5min and then screened by a 35-mesh sieve for 2 times.

3) Placing the mixture obtained in the step 1 into a multi-dimensional mixing device, and mixing for 60min.

4) And (3) placing the microcrystalline cellulose, povidone K29/32, sucralose, lemon essence, magnesium stearate and the mixture obtained in the step (3) into a multidimensional mixer, and mixing for 10 minutes to obtain total mixed particles.

5) Filling the special Mo Weizong mixed particles into a medicinal aluminum composite film bag according to the filling amount requirement, and sealing and storing.

Example 3

The granule formulation is shown in table 3 below:

Table 3 example 3 granule formulation

The preparation process comprises the following steps:

1) Future micronization of the termivir and weighing of the prescription.

2) Weighing materials such as the prescription amount of the letrozole, the povidone K29/32, the internal cross-linked sodium carboxymethyl cellulose, the xanthan gum and the like, mixing for 5min in a proper container, and sieving the mixed materials with a 35-mesh sieve for 2 times.

3) The magnesium stearate is weighed to obtain the prescription after passing through 60 meshes, then the microcrystalline cellulose and the Eudragit L100-55 are weighed, and the three materials are added into the step 1) to be mixed for 5min.

4) Continuously adding the mixture obtained in the step 3) into a dry granulating machine, setting the roller pressure to be 30-70 bar, setting the roller gap to be 1.5-2.5 mm, and performing dry granulating at the roller rotating speed of 6-12 rpm. The prepared particles are sized by using a screen with the diameter of 1000-1600 mu m.

5) The materials with the prescription amount, such as sucralose, lemon essence, magnesium stearate and the like are weighed and added into a multidimensional mixer, and the total mixing is carried out for 10 minutes to prepare the letrozole particles.

6) Filling the special Mo Weizong mixed particles into a medicinal aluminum composite film bag according to the filling amount requirement, and sealing and storing.

Example 4

The granule formulation is shown in table 4 below:

table 4 example 4 granule formulation

The preparation process comprises the following steps:

1) Future micronization of the termivir and weighing of the prescription.

2) Weighing the prescription amount of the letromycin,888ATO, PEG6000, and placing in a proper container, mixing for 5min, and sieving the mixed material with 35 mesh sieve for 2 times.

3) And setting the extrusion temperature of the twin-screw hot-melt extruder at 85-120 ℃ and the screw rotating speed at 100-300 rpm to prepare extruded particles.

4) And crushing and granulating the hot melt extruded particles by using a 1000-1300 mu m screen.

5) And (3) weighing the microcrystalline cellulose, the croscarmellose sodium and the povidone K29/32 with the prescription amount, adding the crushed granules in the step (4) into a high-shear wet granulator, and performing wet granulation by using purified water.

6) The wet granules were dried in a fluidized bed at a material temperature of 50 ℃ to a LOD of less than 3% and dry sized using a 1600 μm sizing screen.

7) Adding the externally added prescription amount of sucralose and magnesium stearate into a multidimensional mixer, and mixing for 10min to obtain the letrozole particles.

8) Filling the special Mo Weizong mixed particles into a medicinal aluminum composite film bag according to the filling amount requirement, and sealing and storing.

Example 5

The granule formulation is shown in table 5 below:

table 5 example 5 granule formulation

The preparation process comprises the following steps:

1) Future micronization of the termivir and weighing of the prescription.

2) Weighing the materials of the prescription amount of the letrozole, the microcrystalline cellulose, the hydroxypropyl methylcellulose, the magnesium oxide, the croscarmellose sodium, the endo-povidone K29/32 and the poloxamer 188, mixing for 5min, and sieving the mixed materials with a 35-mesh sieve for 2 times.

3) An appropriate amount of purified water was weighed and the remaining amount of povidone K29/32 was formulated as a 5% aqueous solution.

4) The mixture from step 1 was added to a high shear wet granulator and mixed for 5min.

5) Starting a high-shear wet granulator, and slowly adding the prepared 5% povidone K29/32 aqueous solution into the granulator for wet granulation.

6) The wet granules were dried in a fluidized bed at a material temperature of 50 ℃ to a LOD of less than 3% and dry sized using a 1600 μm sizing screen.

7) Adding the Te Mo Weigan granules, the externally-added prescription amount of sucralose, colloidal silicon dioxide and magnesium stearate into a multidimensional mixer, and mixing for 10min to obtain the Lepidotimod particles.

8) Filling the special Mo Weizong mixed particles into a medicinal PE/AL/PET composite film bag according to the filling amount requirement, and sealing and storing.

Comparative example:

different pharmaceutical compositions of letromycin were prepared as comparative examples according to the formulations of tables 6 and 7 below.

TABLE 6 ingredient tables of comparative example 1, comparative example 2, comparative example 3

TABLE 7 comparative example 4, comparative example 5, comparative example 6 composition table

Prescription composition	Comparative example 4	Comparative example 5	Comparative example 6
				Lett Morvir	120mg	120mg	120mg
Microcrystalline cellulose PH101	210mg	391mg	250mg
				Ethylcellulose	90mg	---	---
Xanthan gum	---	13mg	---
				Magnesium oxide	---	---	45mg
Povidone K29/32	---	40mg	---
				Hydroxypropyl methylcellulose	60mg	---	55mg
PEG6000	120mg	---	130mg
				Magnesium stearate	---	30mg	---
Sucralose	---	3mg	---
				Lemon essence	---	3mg	---
Total amount of	600mg	600mg	750mg

Comparative example 3 contains colloidal silica as a release modifier and the release rate of the letromycin powder mixture is slowed by the longer mixing time that the letromycin powder mixture is surrounded by a water transport film formed from the colloidal silica.

Comparative example 6 contains magnesium oxide as a release modifier which can adjust the pH of the pharmaceutical composition of letrozole, and thus slow down the release rate of the pharmaceutical composition of letrozole by utilizing the pH-dependent character of letrozole dissolution.

In comparative examples 1, 2,4, and 5, each of which was formed of ulipristine, ethylcellulose, and xanthan gum as a release-controlling agent, the release rate of the pharmaceutical composition of telco was slowed by forming a swollen gel-layer of slow release in the pharmaceutical composition of telco.

Results and discussion the graph shown in FIG. 6 illustrates the dissolution profiles of six comparative examples in a medium containing 0.6% Tween 80 at pH 4.5. Comparative example 3 and comparative example 6 have similar in vitro dissolution release behavior as the original marketed oral tablets.

Comparative example:

as a comparative example, different pharmaceutical compositions of letrozole were prepared according to the recipe of table 8 below.

TABLE 8 composition tables of comparative example 7, comparative example 8, comparative example 9, comparative example 10

Comparative example 7A pharmaceutical composition of letrozole was prepared as described in example 2.

Comparative example 8A pharmaceutical composition of letrozole was prepared as described in example 3.

Comparative example 9A pharmaceutical composition of letrozole was prepared as described in example 1.

Comparative example 10A pharmaceutical composition of letrozole was prepared as described in example 4.

The following experimental data in table 9 show that the impurity degradation of the pharmaceutical compositions prepared by the different processes of powder mixing, wet granulation, boiling granulation, hot melt extrusion was 0.24%, 0.39%, 0.38%, 0.06% respectively when left open for 1 month at 40 ℃ per 75% rh compared to 0 day. Wherein the pharmaceutical composition prepared by the hot melt extrusion process has significantly less impurity degradation and growth than other preparation processes. The method has the advantages that the Lepidotimod can be wrapped in the carrier material through a hot-melt extrusion process, so that direct contact between the Lepidotimod and moist air is avoided, and the stability of the Lepidotimod pharmaceutical composition is improved.

Table 9 comparison of stability of pharmaceutical compositions prepared by different preparation techniques

From the experimental results shown in fig. 1 to 6, the pharmaceutical composition can be prepared by using processes such as powder mixing, dry granulation, wet granulation, boiling granulation, hot melt extrusion and the like. The prepared particles can be made to be basically consistent with the release behavior of the tablet on the market by adjusting the components of the composition under the conditions of pH4.5 and 0.6 percent Tween 80 dissolution.

The foregoing describes in detail preferred embodiments of the present invention. It should be understood that numerous modifications and variations can be made in accordance with the concepts of the invention without requiring creative effort by one of ordinary skill in the art. Therefore, all technical solutions which can be obtained by logic analysis, reasoning or limited experiments based on the prior art by the person skilled in the art according to the inventive concept shall be within the scope of protection defined by the claims.

Claims (13)

1. A letromycin preparation composition comprises letromycin and is characterized by also comprising a filler, a binder, a disintegrating agent, a flavoring agent, a release regulating agent, a lubricant, a glidant and a solubilizer, wherein the weight percentages of the components are as follows:

20% -70% of letromycin;

20% -70% of filler;

2% -10% of adhesive;

2% -10% of disintegrating agent;

0.5% -5% of flavoring agent;

0% -20% of release modifier;

0.5% -5% of lubricant;

0.5% -5% of glidant;

0% -60% of solubilizer.

2. The letromycin formulation composition according to claim 1, wherein the weight percentages of the components are as follows:

20% -70% of letromycin;

20% -60% of filler;

2% -8% of adhesive;

2% -8% of disintegrating agent;

0.5% -3% of flavoring agent;

4% -15% of release modifier;

0.5% -3% of lubricant;

0.5% -3% of glidant;

20-55% of solubilizer.

3. The letromycin formulation composition according to claim 2, wherein the weight percentages of the components are as follows:

30% -50% of letrozole;

20% -50% of filler;

3% -5% of adhesive;

3% -5% of disintegrating agent;

1% -3% of a flavoring agent;

6% -12% of release modifier;

1% -3% of lubricant;

1% -3% of glidant;

30% -45% of solubilizer.

4. A letromycin formulation composition according to any one of claims 1 to 3 wherein the letromycin is micronized to a D90 of less than 20 μm.

5. A letromycin formulation composition according to any of claims 1 to 3 wherein the filler is selected from one or more of starches, celluloses, sugar alcohols and sugars.

6. A letromycin formulation composition according to any of claims 1 to 3 wherein the binder is selected from one or more of povidone, hyprolose, hypromellose.

7. A letromycin formulation composition according to any of claims 1 to 3 wherein the disintegrant is selected from one or more of sodium carboxymethyl starch, croscarmellose sodium, low substituted hydroxypropylcellulose.

8. A letromycin formulation composition according to any one of claims 1 to 3 wherein the flavouring agent is selected from one or more of natural sweetener, synthetic sweetener, ion exchange resin taste masking agent.

9. A letromycin formulation composition according to any of claims 1-3 wherein the release modifying agent is selected from one or more of ulide L100-55, ulide L100, colloidal silica, xanthan gum, magnesium oxide, preferably colloidal silica, more preferably magnesium oxide.

10. A letromycin formulation composition according to any of claims 1 to 3 wherein the lubricant is selected from one or more of calcium stearate, magnesium stearate, hydrogenated vegetable oil, preferably magnesium stearate.

11. A letromycin formulation composition according to any one of claims 1 to 3 wherein the glidant is preferably colloidal silicon dioxide.

12. A letromycin formulation composition according to any of claims 1 to 3 wherein the solubilising agent is selected from one or more of poloxamer 188, poloxamer 237, PEG 6000.

13. The method of preparing a formulation of letromycin composition as claimed in any one of claims 1 to 12 wherein the formulation is in the form of granules prepared by hot melt extrusion granulation, the method comprising the steps of:

s1, mixing the letromycin with a carrier material;

S2, setting the rotating speed of a screw to be about 30-300 rpm, and feeding a mixture of the uniformly mixed letrozole, a carrier material and pharmaceutically acceptable pharmaceutical excipients into a hot-melt extruder preheated to 70-120 ℃ with the length and diameter ratio (L/D) of the screw to be 15-40;

s3, cooling, crushing and sieving the extruded mixture to obtain letrozole pharmaceutical composition particles;

s4, mixing the particles of the Temu-M pharmaceutical composition with a flavoring agent, a lubricant and a glidant to obtain Laider Mo Weizong mixed particles;

S5, sealing the total mixed particles in bags according to the dosage to obtain a finished product;

the carrier material is selected from one or more of PVP, polyacrylic resin, cellulose and PEG, and the weight ratio of the letrozole to the carrier material is 1:4-1:1.