Letemovir preparation composition and preparation method thereof

Abstract

The invention discloses a letemovir preparation composition which comprises the following components in percentage by weight: 20-70% of letemovir, 10-20% of filler, 10-20% of adhesive, 5-10% of disintegrating agent, 5-10% of flavoring agent, 5-10% of controlled release agent, 5-10% of lubricant, 5-10% of flow aid and 5-10% of solubilizer. 20%-70% of a filling agent; 2%-10% of an adhesive; 2%-10% of a disintegrating agent; 0.5%-5% of a flavoring agent; 0%-20% of a controlled release agent; 0.5%-5% of a lubricant; 0.5%-5% of a flow aid; and 0%-60% of a solubilizer. The Leltemovir granule can meet the requirements of prevention and treatment medication for children with dysphagia and old CMV (cytomegalovirus) infected patients without Leltemovir granules in China. The letemovir granules have the advantages of simple preparation process, stable process, better dissolution rate, good stability of finished products and the like, are suitable for industrial batch production, and can bring good social benefits and economic benefits.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical pharmacy, and in particular relates to a Letermovir pharmaceutical composition, and specifically relates to a Letermovir preparation composition and a preparation method thereof. Background Art

[0002] CMV is a double-stranded DNA virus of the herpesvirus genus, which is mainly transmitted through direct contact. CMV infection is common worldwide. The CMV seropositivity rates of healthy people over 14 years old, blood and organ donors are 83% and 86% respectively; the seropositivity rate of CMV in healthy adults in China exceeds 90%, such as the seropositivity rate of CMV in adults over 25 years old in Shanghai exceeds 97%. Humans are often latently infected with CMV in childhood, most of which have no clinical symptoms. After that, CMV can remain latent in a variety of cells for life. Under immunosuppression, CMV lurking in the body can be reactivated, causing infection and disease of the corresponding organs, and even death, leaving survivors with various sequelae. From 2006 to 2012, there were approximately 27,000 A110-HSCTs per year worldwide, of which approximately 6,400 were performed in Southeast Asia and the Western Pacific. Since 2008, the number of A110-HSCTs in China has been increasing year by year. Clinically, it is very important to properly prevent and treat CMV infection in a timely manner. The specific methods are: 1) Use antiviral drugs for prevention, but there are currently no drugs approved in China for the prevention of CMV infection after HSCT; 2) Preemptive therapy (PET), that is, actively monitoring viral replication and using anti-CMV drugs when CMV viremia is detected.

[0003] Letermovir is a novel non-nucleoside cytomegalovirus (CMV) inhibitor (3,4-dihydroquinazoline) that inhibits viral replication by preventing the terminase from cleaving newly synthesized CMV DNA into individual viral genomes and directing them into empty viral capsids. In cell culture models of infected virus strains, letermovir showed potent activity against laboratory and various CMV clinical isolates, including several strains resistant to marketed anti-CMV drugs. Letermovir has a highly specific mechanism of action, and its target (CMV DNA terminase) has no homologs in humans, so the potential toxicity associated with its mechanism of action is low. In addition, no cross-resistance was observed between letermovir and currently approved drugs for the treatment of CMV in infected cell culture models. The main reason is that the existing anti-CMV drugs are DNA polymerase inhibitors, and their resistance is related to UL54 and / or UL97, which constitute the DNA polymerase. Letermovir targets CMV DNA terminase, which is composed of UL56 and UL89. Previous in vitro studies have found that most amino acid mutations that lead to drug resistance are concentrated in a conserved region of UL56 protein 231-369. Drug-resistant mutations found in the UL89 protein alone have little effect unless they act in combination with drug-resistant mutations in UL56. In an analysis of UL56 protein sequences of 74 HCMV clinical strains, it was found that drug-resistant mutations in natural clinical strains are very rare.

[0004] Letermovir is the world's first and currently the only drug used to prevent CMV infection in CMV-seropositive allogeneic hematopoietic stem cell transplant recipients. It differs from DNA polymerase inhibitors in that letermovir is more selective for CMV and has significantly improved potency of action. As mentioned above, all currently available anti-CMV drugs have significant toxicities, such as bone marrow suppression and nephrotoxicity. Considering the challenges of PET and the toxicities associated with existing anti-CMV drugs, letermovir, as an anti-CMV drug with a new mechanism of action, is expected to meet currently unmet clinical needs.

[0005] Letermovir was originally developed by Merck Pharmaceuticals and was approved by the U.S. FDA on November 9, 2017. Its trade name is Prevymis. It is used to prevent and treat cytomegalovirus (CMV) infection and disease in allogeneic hematopoietic stem cell transplantation (HSCT) [R+] adults and children aged 6 months and older, weighing at least 6 kg, and CMV seropositive. It is also used for CMV prevention in high-risk renal transplant recipients (donor CMV seropositive / recipient CMV seronegative [D+ / R-]) aged 12 years and older and weighing at least 40 kg. Currently, the only marketed Letermovir preparations in China are oral tablets and injections.

[0006] CN110433166A discloses a pharmaceutical preparation containing a dihydroquinazoline derivative with antiviral activity, and relates to a method for preparing a pharmaceutical preparation composition for intravenous administration. CN105555771A discloses a method for preparing amorphous Letermovir and a method for preparing a solid pharmaceutical preparation (immediate release preparation) that can be administered orally. WO2022132676A1 discloses a mini tablet of a viral terminase inhibitor and a method for preparing the same, including granulation, tableting, and fluidized bed coating. The mini tablet can be packaged in capsules, pouches, or strip packaging and taken as a granule, which is suitable for patients with dysphagia such as children and elderly patients, meeting some unmet clinical needs.

[0007] Solid oral dosage forms, especially tablets and capsules, have always been the most convenient and commonly used dosage forms. However, tablets and capsules, due to their fixed content restrictions, are difficult to use for many people with dysphagia, especially children and the elderly. Granules are easy to swallow and are particularly suitable for children and elderly patients. They can provide new options for expanding the population of medication and improving the overall treatment effect of patients. The launch of granule preparations meets the medication needs of many patients who cannot swallow complete tablets and capsules.

[0008] The preparation process of mini tablets is complex, including granulation, tableting, fluidized bed coating, capsule filling or bagging, etc. In particular, the tableting and coating processes of mini tablets have high requirements on equipment performance and long production time, which further increases the preparation cost of oral letrozole granules. Summary of the invention

[0009] In view of the above-mentioned defects of the prior art, the object of the present invention is to provide a letermovir rapid-release granule preparation, which has the advantages of simple preparation process, stable process, good dissolution, good finished product stability, etc., and is suitable for industrial batch production.

[0010] In the first aspect of the present invention, a Letermovir preparation composition is provided, comprising Letermovir, characterized in that it also comprises a filler, a binder, a disintegrant, a flavoring agent, a release modifier, a lubricant, a glidant, and a solubilizer, and the weight percentage of each component is as follows:

[0011] Letermovir: 20%-70%;

[0012] Filler: 20% to 70%;

[0013] Adhesive: 2% to 10%;

[0014] Disintegrant: 2% to 10%;

[0015] Flavor corrective: 0.5% to 5%;

[0016] Modified release agent: 0% to 20%;

[0017] Lubricant: 0.5%~5%;

[0018] Glidant: 0.5% to 5%;

[0019] Solubilizer: 0%~60%.

[0020] Preferably, the weight percentage of each component is as follows:

[0021] Letermovir: 20%-70%;

[0022] Filler: 20% to 60%;

[0023] Adhesive: 2% to 8%;

[0024] Disintegrant: 2% to 8%;

[0025] Flavor corrective: 0.5% to 3%;

[0026] Modified release agent: 4% to 15%;

[0027] Lubricant: 0.5%~3%;

[0028] Flow aid: 0.5% to 3%;

[0029] Solubilizer: 20%~55%.

[0030] More preferably, the weight percentages of the components are as follows:

[0031] Letermovir: 30%-50%;

[0032] Filler: 20% to 50%;

[0033] Adhesive: 3% to 5%;

[0034] Disintegrant: 3% to 5%;

[0035] Flavor corrective: 1% to 3%;

[0036] Modified release agent: 6% to 12%;

[0037] Lubricant: 1% to 3%;

[0038] Glidant: 1% to 3%;

[0039] Solubilizer: 30%~45%.

[0040] In some specific embodiments, the Letermovir is micronized to a D90 of less than 20 μm, more preferably a D90 of less than 10 μm.

[0041] In some specific embodiments, the filler is selected from one or more of starches, celluloses, sugar alcohols, and sugars.

[0042] Preferably, the filler is selected from one or more of starch, microcrystalline cellulose, mannitol and lactose.

[0043] In some specific embodiments, the binder is selected from one or more of povidone, hydroxypropyl cellulose, and hypromellose.

[0044] In some specific embodiments, the disintegrant is selected from one or more of sodium carboxymethyl starch, cross-linked carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose, preferably cross-linked carboxymethyl cellulose sodium;

[0045] In some specific embodiments, the flavoring agent is selected from one or more of natural sweeteners, synthetic sweeteners, and ion exchange resin taste masking agents.

[0046] The natural sweetener is selected from one or more of stevioside, glycyrrhizin, simple syrup and aromatic syrup.

[0047] The synthetic sweetener is selected from one or more of saccharin sodium, sucralose, aspartame, and neotame, preferably sucralose.

[0048] The ion exchange resin taste masking agent is selected from one or more of Kyron T-104, Kyron T-114, Kyron T-134, KyronT-154, Kyron T-159, and Kyron T-123, preferably Kyron T-134.

[0049] In some specific embodiments, the release modifier is selected from one or more of Eudragit L100-55, Eudragit L100, colloidal silicon dioxide, xanthan gum, and magnesium oxide, preferably colloidal silicon dioxide, and more preferably magnesium oxide.

[0050] In some specific embodiments, the lubricant is selected from one or more of calcium stearate, magnesium stearate, and hydrogenated vegetable oil, preferably magnesium stearate.

[0051] In some specific embodiments, the glidant is preferably colloidal silicon dioxide.

[0052] In some specific embodiments, the solubilizing agent is selected from one or more of poloxamer 188, poloxamer 237, and PEG6000.

[0053] By optimizing the components and proportions of the Letermovir preparation composition, the solubility of the Letermovir preparation composition can be reduced, so that its dissolution behavior reaches a level comparable to that of tablets in the prior art.

[0054] In a second aspect of the present invention, a method for preparing a Letermovir formulation composition is provided, wherein the formulation composition is a granule, the granule is prepared by wet granulation, and the method comprises the following steps:

[0055] S1. Weigh micronized letermovir, filler, and disintegrant, and mix them to prepare a drug-containing mixed powder;

[0056] S2, preparing the binder into an aqueous solution, adding the mixed powder in step S1 to perform wet granulation;

[0057] S3, drying the prepared wet granules in an oven or fluidized bed to control the LOD within 3% to obtain drug-containing dry granules;

[0058] S4, mixing the dry particles with a flavoring agent, a lubricant, and a glidant to obtain letermovir total mixed particles;

[0059] S5, packing the total mixed granules into bags according to dosage and sealing them to obtain a finished product.

[0060] In a third aspect of the present invention, a method for preparing a Letermovir formulation composition is provided, wherein the formulation composition is a granule, the granule is prepared by dry granulation, and the method comprises the following steps:

[0061] S1. Weigh micronized letermovir, filler, disintegrant, binder and lubricant, mix them and prepare drug-containing mixed powder;

[0062] The mixed powder in steps S2 and S1 is dry granulated using a dry granulator to control the particle size of the drug-containing particles to be within the range of 300 μm to 650 μm;

[0063] S3, mixing the granules obtained by dry granulation with a flavoring agent, a lubricant, and a glidant to obtain letermovir total mixed granules;

[0064] S4, packing the total mixed granules into bags according to dosage and sealing them to obtain a finished product.

[0065] In a fourth aspect of the present invention, a method for preparing a Letermovir formulation composition is provided, wherein the formulation composition is a granule, the granule is prepared by fluidized bed boiling granulation, and the method comprises the following steps:

[0066] S1. Weigh micronized letermovir, filler, and disintegrant, and mix them to prepare a drug-containing mixed powder;

[0067] S2, preparing the binder into an aqueous solution, spraying the binder aqueous solution into the mixed powder in step S1 by fluidized bed boiling granulation to obtain granules containing letermovir, and controlling the LOD to be within 3%;

[0068] S3, mixing the dry granules prepared by boiling granulation with a flavoring agent, a lubricant, and a glidant to obtain a letermovir total mixed granule;

[0069] S4, packing the total mixed granules into bags according to dosage and sealing them to obtain a finished product.

[0070] In a fifth aspect of the present invention, a method for preparing a Letermovir formulation composition is provided, wherein the formulation composition is a granule, the granule is prepared by hot melt extrusion granulation, and the method comprises the following steps:

[0071] S1, mixing letermovir with a carrier material;

[0072] S2, setting the screw speed to about 30-300 rpm, the ratio of screw length to diameter (L / D) to 15-40, and feeding the mixed mixture of letermovir, carrier material and pharmaceutically acceptable pharmaceutical excipients into a hot melt extruder preheated to 70° C. to 120° C.;

[0073] S3, cooling the extruded mixture, crushing and sieving to obtain Letermovir pharmaceutical composition particles;

[0074] S4, mixing the Letermovir pharmaceutical composition particles with a flavoring agent, a lubricant, and a glidant to obtain Letermovir total mixed particles;

[0075] S5, packing the total mixed granules into bags according to dosage and sealing them to obtain a finished product;

[0076] The carrier material is selected from one or more of PVP, polyacrylic acid resin, cellulose, and PEG;

[0077] The weight ratio of the Letermovir to the carrier material is 1:4 to 1:1.

[0078] Preferably, the weight ratio of Letermovir to the carrier material is 1:3, more preferably 2:3.

[0079] In some specific embodiments, the PVP-based carrier material is preferably Kollidon VA64; the polyacrylic acid resin-based carrier material is preferably Eudragit E100; the cellulose-based carrier material is preferably hydroxypropyl cellulose or hydroxypropyl methyl cellulose; and the PEG-based carrier material is preferably PEG4000 or PEG6000.

[0080] In some specific embodiments, the carrier material is a mixture of hydroxypropyl cellulose and PEG6000 in a weight ratio of 1:8 to 8:1, preferably 4:6 to 6:4.

[0081] Experiments have shown that a certain ratio of carrier material and Letermovir can be processed by the hot melt extrusion process of the present invention to prepare a Letermovir preparation composition in which the drug is dissolved in the carrier material or dispersed in the carrier material at the molecular level.

[0082] The term "modifying agent" as used herein refers to a material that can speed up or slow down the release rate of Letermovir.

[0083] Compared with the prior art, the present invention has the following beneficial effects:

[0084] The present invention can fill the need for preventive and therapeutic medication for children and elderly patients with CMV infection who have difficulty swallowing and who do not have Letermovir granules in China. Letermovir granules have the advantages of simple preparation process, stable process, good dissolution, good stability of finished products, etc., are suitable for industrial mass production, and can bring good social and economic benefits.

[0085] The concept and technical effects of the present invention will be further described below in conjunction with the accompanying drawings to fully understand the purpose, features and effects of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0086] Figure 1 It is the dissolution curve of Example 1 in a medium containing 0.6% Tween 80 at pH 4.5.

[0087] Figure 2 This is the dissolution curve of Example 2 in a medium containing 0.6% Tween 80 at pH 4.5.

[0088] Figure 3 This is the dissolution curve of Example 3 in a medium containing 0.6% Tween 80 at pH 4.5.

[0089] Figure 4 This is the dissolution curve of Example 4 in a medium containing 0.6% Tween 80 at pH 4.5.

[0090] Figure 5 This is the dissolution curve of Example 5 in a medium containing 0.6% Tween 80 at pH 4.5.

[0091] Figure 6 It is a comparative diagram of the dissolution curves of the original marketed oral tablets and comparative examples 1 to 6 in a medium containing 0.6% Tween 80 at pH 4.5.

[0092] Figure 7 It is a comparative diagram of the dissolution curves of the original marketed oral tablets and Examples 1 to 5 in a medium containing 0.6% Tween 80 at pH 4.5. DETAILED DESCRIPTION

[0093] In order to make the technical means, creative features, objectives and effects of the invention easier to understand, the invention is further described below with reference to specific diagrams. However, the invention is not limited to the following implementation cases.

[0094] It should be noted that the embodiments and drawings of this specification are only used to match the contents disclosed in the specification so as to facilitate understanding and reading by persons familiar with this technology, and are not used to limit the conditions under which the present invention can be implemented. Therefore, they have no substantive technical significance. Any adjustments that are not creative should still fall within the scope of the technical contents disclosed in the present invention without affecting the effects and purposes that can be achieved by the present invention.

[0095] All kinds of reagents involved in the embodiments are commercially available products, and all commercial products can be used.

[0096] The invention provides a method for determining the dissolution curve of letermovir granules, which adopts a paddle method, wherein the dissolution medium is a pH 4.5, 0.6% Tween 80 acetate buffer solution, the volume of the dissolution medium is 500ml-900ml, and the rotation speed is 50 rpm-100 rpm.

[0097] Example 1

[0098] The granule formulation is shown in Table 1 below:

[0099] Table 1 Example 1 Granules Prescription

[0100]

[0101]

[0102] Preparation process:

[0103] 1) Micronize Temovir and weigh the prescribed amount.

[0104] 2) Weigh the prescribed amount of letermovir, microcrystalline cellulose, hypromellose, croscarmellose sodium, and poloxamer 188, place in a suitable container and mix for 5 minutes. After mixing, pass the material through a 35-mesh sieve twice.

[0105] 3) Weigh an appropriate amount of purified water and prepare the prescribed amount of povidone K29 / 32 into an 8% to 10% aqueous solution.

[0106] 4) Add the mixture in step 1 into the fluidized bed, set the inlet air temperature to 55°C to 70°C, the material temperature to 45°C to 55°C, and set the appropriate inlet air volume to fully fluidize the material. When the material temperature rises to 50°C, start boiling granulation at a spraying rate of 15 to 20 g / min.

[0107] 5) After granulation, dry until LOD is less than 3%, and use a 1600 μm granulation screen for dry granulation.

[0108] 6) Add the letermovir dry granules and the additional prescribed amount of sucralose, lemon flavor, colloidal silicon dioxide, and magnesium stearate into a multidimensional mixer and mix for 10 minutes to obtain letermovir granules.

[0109] 7) In the future, the Temovir total mixed granules will be packed into pharmaceutical aluminum composite film bags according to the filling requirements and sealed for storage.

[0110] Example 2

[0111] The granule formulation is shown in Table 2 below:

[0112] Table 2 Example 2 Granules Prescription

[0113]

[0114]

[0115] Preparation process:

[0116] 1) Micronize Temovir and weigh the prescribed amount.

[0117] 2) Weigh the prescribed amount of letermovir and colloidal silicon dioxide, place in a suitable container and mix for 5 minutes, then pass through a 35-mesh sieve twice.

[0118] 3) The mixture in step 1 was placed in a multi-dimensional mixing device and mixed for 60 minutes.

[0119] 4) Place the prescribed amount of microcrystalline cellulose, povidone K29 / 32, sucralose, lemon flavor, magnesium stearate and the mixture in step 3 in a multidimensional mixer and mix for 10 minutes to obtain a total mixed granule.

[0120] 5) In the future, the Temovir total mixed granules will be packed into pharmaceutical aluminum composite film bags according to the filling requirements and sealed for storage.

[0121] Example 3

[0122] The granule prescription is shown in Table 3 below:

[0123] Table 3 Example 3 Granules Prescription

[0124]

[0125]

[0126] Preparation process:

[0127] 1) Micronize Temovir and weigh the prescribed amount.

[0128] 2) Weigh the prescribed amount of letermovir, povidone K29 / 32, croscarmellose sodium, xanthan gum and other materials, place them in a suitable container and mix for 5 minutes. After mixing, pass the material through a 35-mesh sieve twice.

[0129] 3) After passing magnesium stearate through a 60-mesh filter, weigh the prescribed amount, then weigh microcrystalline cellulose and Eudragit L100-55, add the three materials to step 1), and continue mixing for 5 minutes.

[0130] 4) The mixture in step 3) is continuously added to a dry granulator, and the roller pressure is set to 30-70 bar, the roller gap is 1.5-2.5 mm, and the roller speed is 6-12 rpm for dry granulation. The obtained granules are sized using a 1000 μm-1600 μm sieve.

[0131] 5) Weigh the additional prescribed amount of sucralose, lemon essence, magnesium stearate and other materials, add them into a multidimensional mixer, and mix for 10 minutes to obtain letermovir granules.

[0132] 6) In the future, the Temovir total mixed granules will be packed into pharmaceutical aluminum composite film bags according to the packing requirements and sealed for storage.

[0133] Example 4

[0134] The granule formulation is shown in Table 4 below:

[0135] Table 4 Example 4 Granules Prescription

[0136]

[0137]

[0138] Preparation process:

[0139] 1) Micronize Temovir and weigh the prescribed amount.

[0140] 2) Weigh the prescribed amount of Letermovir, 888ATO and PEG6000 were placed in a suitable container and mixed for 5 minutes. After the mixing, the material was passed through a 35-mesh sieve twice.

[0141] 3) Setting the extrusion temperature of the twin-screw hot melt extruder to 85° C. to 120° C. and the screw speed to 100 to 300 rpm to prepare extruded particles.

[0142] 4) The hot melt extruded granules are crushed and sized using a 1000-1300 μm sieve.

[0143] 5) Weigh the prescribed amount of microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, and povidone K29 / 32, and add them together with the granules crushed in step 4 into a high shear wet granulator, and use purified water for wet granulation.

[0144] 6) The wet granules were dried in a fluidized bed at a material temperature of 50° C. until the LOD was less than 3%, and dry granulation was performed using a 1600 μm granulation screen.

[0145] 7) Add the additional prescribed amount of sucralose and magnesium stearate into a multi-dimensional mixer and mix for 10 minutes to obtain letermovir granules.

[0146] 8) In the future, the Temovir total mixed granules will be packed into pharmaceutical aluminum composite film bags according to the packing requirements and sealed for storage.

[0147] Example 5

[0148] The granule prescription is shown in Table 5 below:

[0149] Table 5 Example 5 Granules Prescription

[0150]

[0151]

[0152] Preparation process:

[0153] 1) Micronize Temovir and weigh the prescribed amount.

[0154] 2) Weigh the prescribed amount of letermovir, microcrystalline cellulose, hypromellose, magnesium oxide, croscarmellose sodium, povidone K29 / 32, and poloxamer 188, place in a suitable container and mix for 5 minutes. After mixing, pass the material through a 35-mesh sieve twice.

[0155] 3) Weigh an appropriate amount of purified water and prepare a 5% aqueous solution with the remaining amount of povidone K29 / 32.

[0156] 4) Add the mixture in step 1 into a high shear wet granulator and mix for 5 minutes.

[0157] 5) Start the high shear wet granulator and slowly add the prepared 5% povidone K29 / 32 aqueous solution into the granulator for wet granulation.

[0158] 6) The wet granules were dried in a fluidized bed at a material temperature of 50° C. until the LOD was less than 3%, and dry granulation was performed using a 1600 μm granulation screen.

[0159] 7) Add the letermovir dry granules and the additional prescribed amount of sucralose, colloidal silicon dioxide, and magnesium stearate into a multidimensional mixer and mix for 10 minutes to obtain letermovir granules.

[0160] 8) In the future, the Temovir total mixed granules will be packed into a medicinal PE / AL / PET composite film bag according to the filling quantity requirements and sealed for storage.

[0161] Comparative Example:

[0162] Different Letermovir pharmaceutical compositions were prepared according to the prescriptions in Tables 6 and 7 below as comparative examples.

[0163] Table 6 Comparative Example 1, Comparative Example 2, Comparative Example 3 Ingredients

[0164]

[0165]

[0166] Table 7 Comparative Example 4, Comparative Example 5, Comparative Example 6 Ingredients

[0167] Prescription ingredients Comparative Example 4 Comparative Example 5 Comparative Example 6 Letermovir 120mg 120mg 120mg Microcrystalline Cellulose PH101 210mg 391mg 250mg Ethyl cellulose 90mg --- --- Xanthan gum --- 13mg --- Magnesium oxide --- --- 45mg Povidone K29 / 32 --- 40mg --- Hydroxypropyl methylcellulose 60mg --- 55mg PEG6000 120mg --- 130mg Magnesium Stearate --- 30mg --- Sucralose --- 3mg --- Lemon flavor --- 3mg --- Total 600mg 600mg 750mg

[0168] Comparative Example 3 contains colloidal silicon dioxide as a release modifier. The mixture of the letermovir powder is wrapped by a water-transfer film formed by the colloidal silicon dioxide through a long mixing time, thereby slowing down the release rate of the mixed powder of the letermovir.

[0169] Comparative Example 6 contains magnesium oxide as a release modifier, which can adjust the pH of the Letermovir pharmaceutical composition and utilize the pH-dependent dissolution of Letermovir to slow down the release rate of the Letermovir pharmaceutical composition.

[0170] In Comparative Examples 1, 2, 4 and 5, Eudragit, ethyl cellulose and xanthan gum were used as release modifiers, respectively, to form a swollen sustained-release gel layer in the Letermovir pharmaceutical composition, thereby slowing down the release rate of the Letermovir pharmaceutical composition.

[0171] Results and discussion: Figure 6 The figure shows the dissolution curves of six comparative examples in a pH 4.5 medium containing 0.6% Tween 80. Comparative Examples 3 and 6 have similar in vitro dissolution release behaviors to the original marketed oral tablets.

[0172] Comparative Example:

[0173] Different Letermovir pharmaceutical compositions were prepared according to the prescriptions in Table 8 below as comparative examples.

[0174] Table 8 Comparative Example 7, Comparative Example 8, Comparative Example 9, Comparative Example 10 Ingredients

[0175]

[0176]

[0177] Comparative Example 7: A pharmaceutical composition of Letermovir was prepared according to the method described in Example 2.

[0178] Comparative Example 8: A pharmaceutical composition of Letermovir was prepared according to the method described in Example 3.

[0179] Comparative Example 9: A pharmaceutical composition of Letermovir was prepared according to the method described in Example 1.

[0180] Comparative Example 10: A pharmaceutical composition of Letermovir was prepared according to the method described in Example 4.

[0181] As shown in the experimental data in Table 9 below, the pharmaceutical compositions prepared by different processes of powder mixing, wet granulation, boiling granulation, and hot melt extrusion, when left open at 40°C / 75%RH for 1 month, the impurity degradation was 0.24%, 0.39%, 0.38%, and 0.06% respectively compared with 0 days. Among them, the pharmaceutical composition prepared by hot melt extrusion process showed significantly less growth in impurity degradation compared with other preparation processes. This indicates that the hot melt extrusion process can wrap Letermovir in a carrier material to avoid direct contact between Letermovir and humid air, thereby improving the stability of the Letermovir pharmaceutical composition.

[0182] Table 9 Comparison of the stability of pharmaceutical compositions prepared by different preparation processes

[0183]

[0184] By the attached Figures 1 to 6 The experimental results show that the pharmaceutical composition can be prepared by powder mixing, dry granulation, wet granulation, boiling granulation, hot melt extrusion and other processes. The prepared granules can be adjusted under pH 4.5, 0.6% Tween 80 dissolution conditions to make the release behavior of the prepared granules basically consistent with that of the marketed tablets by adjusting the composition components.

[0185] The preferred specific embodiments of the present invention are described in detail above. It should be understood that ordinary technicians in the field can make many modifications and changes based on the concept of the present invention without creative work. Therefore, all technical solutions that can be obtained by technicians in the technical field based on the concept of the present invention through logical analysis, reasoning or limited experiments on the basis of the prior art should be within the scope of protection determined by the claims.

Claims

1. A Letermovir preparation composition comprising Letermovir, characterized in that: It also contains fillers, binders, disintegrants, flavoring agents, release modifiers, lubricants, glidants, and solubilizers. The weight percentages of each component are as follows: Letermovir: 20%-70%; Filler: 20% to 70%; Adhesive: 2% to 10%; Disintegrant: 2% to 10%; Flavor corrective: 0.5% to 5%; Modified release agent: 0% to 20%; Lubricant: 0.5%~5%; Flow aid: 0.5% to 5%; Solubilizer: 0%~60%.

2. The Letermovir preparation composition according to claim 1, characterized in that The weight percentage of each component is as follows: Letermovir: 20%-70%; Filler: 20% to 60%; Adhesive: 2% to 8%; Disintegrant: 2% to 8%; Flavor corrective: 0.5% to 3%; Modified release agent: 4% to 15%; Lubricant: 0.5%~3%; Flow aid: 0.5% to 3%; Solubilizer: 20%~55%.

3. The Letermovir formulation composition according to claim 2, characterized in that The weight percentage of each component is as follows: Letermovir: 30%-50%; Filler: 20% to 50%; Adhesive: 3% to 5%; Disintegrant: 3% to 5%; Flavor corrective: 1% to 3%; Modified release agent: 6% to 12%; Lubricant: 1% to 3%; Glidant: 1% to 3%; Solubilizer: 30%~45%.

4. The Letermovir preparation composition according to any one of claims 1 to 3, characterized in that: The Letermovir is micronized to a D90 of less than 20 μm.

5. The Letermovir preparation composition according to any one of claims 1 to 3, characterized in that: The filler is selected from one or more of starches, celluloses, sugar alcohols, and sugars.

6. The Letermovir preparation composition according to any one of claims 1 to 3, characterized in that: The binder is selected from one or more of povidone, hydroxypropyl cellulose and hypromellose.

7. The Letermovir preparation composition according to any one of claims 1 to 3, characterized in that: The disintegrant is selected from one or more of sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose.

8. The Letermovir preparation composition according to any one of claims 1 to 3, characterized in that: The flavor corrector is selected from one or more of natural sweeteners, synthetic sweeteners, and ion exchange resin taste masking agents.

9. The Letermovir preparation composition according to any one of claims 1 to 3, characterized in that: The release modifier is selected from one or more of Eudragit L100-55, Eudragit L100, colloidal silicon dioxide, xanthan gum, and magnesium oxide, preferably colloidal silicon dioxide, and more preferably magnesium oxide.

10. The Letermovir preparation composition according to any one of claims 1 to 3, characterized in that: The lubricant is selected from one or more of calcium stearate, magnesium stearate, and hydrogenated vegetable oil, preferably magnesium stearate.

11. The Letermovir preparation composition according to any one of claims 1 to 3, characterized in that: The glidant is preferably colloidal silicon dioxide.

12. The Letermovir preparation composition according to any one of claims 1 to 3, characterized in that: The solubilizing agent is selected from one or more of poloxamer 188, poloxamer 237, and PEG6000.

13. The method for preparing the Letermovir preparation composition according to any one of claims 1 to 12, characterized in that: The preparation composition is a granule, which is prepared by hot melt extrusion granulation, and the method comprises the following steps: S1, mixing letermovir with a carrier material; S2, setting the screw speed to about 30-300 rpm, the ratio of screw length to diameter (L / D) to 15-40, and feeding the mixed mixture of letermovir, carrier material and pharmaceutically acceptable pharmaceutical excipients into a hot melt extruder preheated to 70° C. to 120° C.; S3, cooling the extruded mixture, crushing and sieving to obtain Letermovir pharmaceutical composition particles; S4, mixing the Letermovir pharmaceutical composition particles with a flavoring agent, a lubricant, and a glidant to obtain Letermovir total mixed particles; S5, packing the total mixed granules into bags according to dosage and sealing them to obtain a finished product; The carrier material is selected from one or more of PVP, polyacrylic acid resin, cellulose, and PEG; the weight ratio of Letermovir to the carrier material is 1:4 to 1:1.

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