Letemovir pharmaceutical composition and preparation method thereof

Abstract

The invention discloses a letemovir composition and a preparation method thereof. The specific dosage form of the letemovir composition is granules. Through dosage form, prescription and process optimization, the preparation is better in taste, easier to take, faster in dissolution and more stable in quality, the effectiveness and safety of clinical medication are guaranteed, and the applicable crowd of the medicine is expanded. Meanwhile, the preparation process designed by the invention is convenient to operate and easy to industrially amplify.

Description

Technical Field

[0001] The present invention relates to a Letermovir composition and a preparation method thereof, and in particular to a Letermovir pharmaceutical composition capable of improving medication compliance and a preparation method thereof. Background Art

[0002] Cytomegalovirus (CMV) is one of the main pathogens infecting solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients. However, the prevention and treatment of CMV infection after transplantation are limited in types, drug toxicity and cross-resistance.

[0003] Letermovir ((4S)-2-{8-fluoro-2-[4-(3-methoxyphenyl)-1-piperazinyl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydro)-4-quinazolinyl}acetic acid, C 29 H 28 F4N4O4) is an inhibitor of the viral terminase complex, which inhibits the replication behavior at the end of the viral life cycle by targeting the pUL56 subunit of the terminase complex. Its antiviral activity is highly specific to CMV and there is no cross-resistance with other anti-CMV drugs.

[0004]

[0005] The taste of Letermovir API is extremely bitter and difficult to cover up. The original CN105555771 uses coating to cover up the taste. The API is crushed and the median value of the particle size distribution does not exceed 10μm, which is more likely to bring a long-lasting and strong bitter taste. At the same time, the original dosage form is larger (240mg and 480mg), and its coated tablets are hard in appearance and larger in shape, which is not suitable for the elderly and patients with swallowing difficulties. Summary of the invention

[0006] Purpose of the invention: The present invention aims to provide a Letermovir pharmaceutical composition having good taste, easy to take, and equivalent to the original formulation and a preparation method thereof.

[0007] Technical solution: The Letermovir pharmaceutical composition of the present invention comprises, by weight, 24 to 48 parts of Letermovir, 5 to 45 parts of a first filler, 3 to 45 parts of a second filler, 1 to 10 parts of a binder, 1 to 8 parts of a disintegrant, 0.75 to 2.5 parts of a lubricant, 1 to 5 parts of a flavoring agent, 0.1 to 0.5 parts of a fragrance and 2 to 4 parts of a coating agent; the first filler is selected from pregelatinized starch, cyclodextrin, mannitol, microcrystalline cellulose, lactose, calcium hydrogen phosphate, calcium sulfate dihydrate, calcium sulfate trihydrate or corn starch, and the second filler is selected from sucrose, honey sorbitol, stevioside, xylitol, ethyl cellulose, polyacrylic acid resin, stearic acid, stearyl alcohol, glyceryl monostearate, glyceryl monooleate, carboxymethyl ethylcellulose or hydroxypropyl methylcellulose phthalate.

[0008] In the prescription designed by the present invention, an amorphous raw material drug is used and the particle size D 50 The particle size is 80-100 μm, and the API does not need special control of the particle size. The prescription design window is wide, which makes the preparation process operation window wide.

[0009] Preferably, the binder is selected from pregelatinized starch, gelatin, povidone, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, ethyl cellulose or polyethylene glycol.

[0010] Preferably, the disintegrant is selected from sodium carboxymethyl starch, croscarmellose sodium, crospovidone, carboxymethyl cellulose calcium or low-substituted hydroxypropyl cellulose.

[0011] Preferably, the lubricant is selected from magnesium stearate, silicon dioxide or talc.

[0012] Preferably, the flavoring agent is selected from sucralose, saccharin sodium, aspartame, sodium cyclamate or acesulfame potassium.

[0013] Preferably, the fragrance is selected from mint flavor, lemon flavor, strawberry flavor, pineapple flavor, orange flavor, lemon flavor or watermelon flavor.

[0014] Preferably, the first filler is selected from cyclodextrin or calcium hydrogen phosphate, and the second filler is selected from sucrose or polyacrylic acid resin.

[0015] More preferably, the first filler is selected from cyclodextrin, and the second filler is selected from sucrose.

[0016] Preferably, the binder is selected from hydroxypropyl cellulose or ethyl cellulose, the disintegrant is selected from cross-linked polyvinylpyrrolidone or low-substituted hydroxypropyl cellulose, the lubricant is selected from magnesium stearate, the flavoring agent is selected from cyclamate, the fragrance is selected from lemon essence, and the coating agent is selected from an aqueous coating agent.

[0017] More preferably, the aqueous coating agent comprises an aqueous dispersion of ethyl acrylate-methyl methacrylate copolymer, an aqueous dispersion of ethyl cellulose, triethyl citrate, hypromellose and talc.

[0018] More preferably, the aqueous coating agent comprises ethyl cellulose, hydroxypropyl methyl cellulose, ethyl acrylate-methyl methacrylate copolymer aqueous dispersion, talc, yellow iron oxide (E172), triethyl citrate, and triacetin.

[0019] Preferably, the composition of the Letermovir pharmaceutical composition by weight percentage is 24% Letermovir, 42% cyclodextrin, 22% sucrose, 5% hydroxypropyl cellulose, 3.05% low-substituted hydroxypropyl cellulose, 0.75% magnesium stearate, 3% cyclamate, 0.2% lemon flavor and 2% to 4% of their total weight of an aqueous coating agent.

[0020] More preferably, the composition of the unit preparation of the Letermovir pharmaceutical composition is 240 mg of Letermovir, 420 mg of cyclodextrin, 220 mg of sucrose, 50 mg of hydroxypropyl cellulose, 30.5 mg of low-substituted hydroxypropyl cellulose, 7.5 mg of magnesium stearate, 30 mg of cyclamate, 2 mg of lemon essence and 20-40 mg of an aqueous coating agent.

[0021] The preparation method of the Letermovir pharmaceutical composition of the present invention comprises the following steps:

[0022] (1) Granulation: mixing temovir, the first filler, the second filler, the disintegrant, the binder and the flavoring agent, adding a pharmaceutically acceptable solvent to granulate and shape the particles to obtain wet granules;

[0023] (2) coating and loading aromatics: drying and coating the wet granules obtained in step (1), then loading the aromatic solution on the surface of the coated granules and drying to obtain aromatic coated granules;

[0024] (3) Final mixing: adding the aromatic coated granules obtained in step (2) to the lubricant and mixing well to obtain the termovir pharmaceutical composition.

[0025] Among them, in the preparation process designed by the present invention, an amorphous raw material drug is used and the particle size D 50 The particle size is 80 to 100 μm, the raw materials do not need special crushing, are not easy to inhale and are more convenient to operate.

[0026] The specific operation method of step (2) is as follows

[0027] (i) Preparation of aqueous coating liquid (taste masking layer): Ethyl acrylate-methyl methacrylate copolymer aqueous dispersion, ethyl cellulose aqueous dispersion, triethyl citrate and hydroxypropyl methylcellulose were added to purified water in sequence and dispersed completely; talc was added to purified water and homogenized with a homogenizer for 6 minutes; the two suspensions were mixed and passed through an 80-mesh sieve.

[0028] (ii) Coating: set the heater temperature to 65.0-80.0°C, the air inlet temperature to 45.0-60.0°C, the air inlet frequency to 16.0-24.0 Hz, the spray speed to 6-14 r / min, the atomization pressure to 0.10-0.18 MPa, and maintain the material temperature to 23.0-32.0°C.

[0029] (iii) Preparation of alcohol coating solution (fragrance fixing layer): Add lemon essence into ethanol solution and disperse it evenly.

[0030] (iv) Preparation of flavor-fixing layer-masked granules: Spray the aromatic agent onto the surface of the coated granules with ethanol and then dry them to obtain the granules.

[0031] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0032] The present invention designs a Letermovir granule pharmaceutical composition, which optimizes the dosage form, prescription and process, so that the preparation has a better taste, is easier to take, dissolves more quickly and has more stable quality, thereby ensuring the effectiveness and safety of clinical medication and expanding the applicable population of the drug. At the same time, the preparation process designed by the present invention is easy to operate and easy to scale up industrially. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 The electronic tongue evaluation curves are for the granules prepared in Example 1 of the present invention, the tablets prepared in Comparative Examples 1 and 2, the raw material drug and the original reference preparation. DETAILED DESCRIPTION

[0034] The technical solution of the present invention is further described below in conjunction with embodiments.

[0035] Letermovir API comes from Jiangsu Zhengji Pharmaceutical Co., Ltd., purity: 100%, particle size D 50 The particle size of the mixture is 80-100 μm; the other auxiliary materials and reagents are commercially available.

[0036] Example 1

[0037] 1. Prescription composition

[0038]

[0039]

[0040] 2. Preparation method

[0041] (1) Preparation of soft material: The prescribed amount of letermovir, cyclodextrin, sucrose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose and sodium cyclamate are placed in a high shear wet granulator and mixed evenly. A mixture of ethanol and / or isopropyl alcohol and water in any proportion is added to the mixed materials. The solution is added in the form of atomization and the mixing is continued to be evenly prepared to prepare a soft material.

[0042] (2) Preparation of granules: A mobile granulator is used to prepare wet granules, and the sieve is 20 mesh;

[0043] (3) Drying of granules: The granules are dried in a fluidized bed, the material temperature is controlled at 30-50°C, the granule moisture is controlled at 1%-3%, and the granules are sized using a 20-mesh screen;

[0044] (4) Fluidized bed coating

[0045] (i) The aqueous coating liquid (taste masking layer) is prepared as follows: ethyl acrylate-methyl methacrylate copolymer aqueous dispersion, ethyl cellulose aqueous dispersion, triethyl citrate (TEC), and hydroxypropyl methylcellulose (HPMC) are added to purified water in sequence and completely dispersed; talc is added to purified water and homogenized with a homogenizer for 6 minutes; the two suspensions are mixed and passed through an 80-mesh sieve;

[0046] (ii) The preparation method of the alcohol coating solution (fragrance fixing layer) is as follows: lemon essence is added to the ethanol solution and completely dispersed;

[0047] (iii) Coating process parameters: set the heater temperature to 65.0-80.0°C, the air inlet temperature to 45.0-60.0°C, the air inlet frequency to 16.0-24.0 Hz, the spray speed to 6-14 r / min, the atomization pressure to 0.10-0.18 MPa, and maintain the material temperature to 23.0-32.0°C;

[0048] (5) Mixing: Add lubricant to the coated granules and mix well to obtain the granules;

[0049] (6) Bagging: filling with aluminum-plastic composite film.

[0050] Observation with the naked eye showed that the granules obtained were round, uniform in color, uniform in size and smooth in surface.

[0051] Comparative Example 1

[0052] Letermovir tablets were prepared according to the formulation prescription and dry granulation process disclosed in CN105555771.

[0053] 1. Prescription composition

[0054]

[0055]

[0056] 2. Preparation method

[0057] (1) Pretreatment: weigh the raw materials and excipients according to the formula and process them to the corresponding particle size (particle size: D 50 <10μm);

[0058] (2) Premixing: Transfer the added raw materials and auxiliary materials to the hopper mixer for mixing;

[0059] (3) Dry granulation: The mixed raw and excipients were granulated using a dry granulator and granulated through a 2.0 mm granulation screen at a granulation speed of 100 rpm;

[0060] (4) Granulation: Use a mobile granulator at a granulation speed of 300 rpm to granulate through a 1.5 mm sieve for secondary granulation;

[0061] (5) Total mixing: Add the additional prescribed amount of auxiliary materials and the granulated materials into the mixer and mix at a speed of 15 r / min for 6 min;

[0062] (6) Select a suitable mold for tableting, with a theoretical tablet weight of 600 mg;

[0063] (7) Select a coating solution with a solid content of 10% for coating, and control the coating weight gain to 2% to 4%.

[0064] Comparative Example 2

[0065] Letermovir tablets were prepared according to the formulation prescription and wet granulation process disclosed in CN105555771.

[0066] 1. Prescription composition

[0067]

[0068] 2. Preparation method

[0069] (1) Pretreatment: weigh the raw materials and excipients according to the formula and process them to the corresponding particle size (particle size: D 50 <10μm);

[0070] (2) Wet granulation: The raw materials and excipients are transferred to a wet granulator for mixing, and a wetting agent is added to prepare granules;

[0071] (3) Drying: placing the prepared particles in an oven to dry;

[0072] (4) Granulation: Use a mobile granulator at a granulation speed of 300 rpm to granulate through a 1.5 mm sieve for secondary granulation;

[0073] (5) Total mixing: Add the additional prescribed amount of auxiliary materials and the granulated materials into the mixer and mix at a speed of 15 r / min for 6 min;

[0074] (6) Select a suitable mold for tableting, with a theoretical tablet weight of 600 mg;

[0075] (7) Select a coating solution with a solid content of 10% for coating, and control the coating weight gain to 2% to 4%.

[0076] Example 2: In vitro dissolution evaluation of the formulation

[0077] 1. Dissolution conditions

[0078] Dissolution medium: pH 4.5 acetic acid buffer, which is prepared according to the "Guidelines for In Vitro Dissolution" and the method of "Chinese Pharmacopoeia".

[0079] Determination method: Pulp method, rotation speed 100r / min, temperature 37.0±0.5℃, sampling at 5min, 10min, 15min, 30min, and 45min respectively.

[0080] Detection method: Test according to the high performance liquid chromatography method of the Chinese Pharmacopoeia, with a limit of 80% of the labeled amount.

[0081] 2. Dissolution results

[0082] Table 1 Percentage equivalent to the labeled amount (sample n = 12)

[0083]

[0084] As shown in Table 1, the dissolution rate of the Letermovir granules prepared in Example 1 was faster than that of the tablets prepared in the comparative example.

[0085] Example 3: Taste-masking effect evaluation test of the preparation

[0086] 1. Experimental methods

[0087] (1) Samples: original reference preparation, raw material drug, granules prepared in Example 1, tablets prepared in Comparative Examples 1 and 2.

[0088] (2) Original reference preparation

[0089] Trade name: Premin, production unit: MSD, specification: 240mg.

[0090] (3) Detection

[0091] Using electronic tongue combined with sensory evaluation of volunteers.

[0092] Sensory testing method 1: 12 healthy volunteers were randomly selected and subjected to a strict bitterness sensitivity screening; the oral tasting evaluation + ranking method was used. A single-dose package of the original reference preparation was taken and the volunteers were asked to put it in their mouths to fully experience the taste of the reference preparation. The bitterness level was measured immediately after taking the drug (0 seconds) and 30 seconds after the drug was completely dissolved. After spitting it out, rinse the mouth several times. When it was confirmed that there was no bitterness in the mouth, the bitterness value of the self-made preparation sample was measured again.

[0093] Table 2 Bitterness rating table

[0094] Taste Description grade Level Bitterness Value Taste characteristics Category Description Almost no bitterness I [0.5，1.5) Light taste A (no bitterness or slightly bitter) Slightly bitter II [1.5，2.5) Light / slightly bitter / Acceptable bitterness III [2.5，3.5) Slightly bitter / bitter B (Tolerable bitterness) Bitter, but still acceptable IV [3.5，4.5) Bitter / very bitter C (very bitter) Unbearable suffering V [4.5，5.5] Very bitter Ding (unbearable bitterness)

[0095] Electronic tongue detection method 2: The electronic tongue evaluation method evaluates the taste masking effect through the signal difference between the original drug and the taste masking drug. Its working principle is that the electronic tongue system simulates the tongue to identify the taste masking drug in the solution through a chemical sensor array with different selectivity, transmits the measurement results to the computer for analysis, and uses software to process the signal calculation results for evaluation. The present invention adopts the ASTREE II electronic tongue system of Alpha MOS Company of France and uses the five-flavor sensor array to analyze the sample. The sensor array includes 1 astringent, bitter, and composite sensor, 3 electrochemical sensors and 1 Ag / AgCl reference electrode to analyze and detect the sample.

[0096] 2. Experimental results

[0097] Table 3 Sensory evaluation results

[0098]

[0099] As shown in Table 3 and Figure 1 As shown, the bitterness masking effect of the reference preparation is not good; the tablets prepared in Comparative Example 1 can mask the bitterness, but will produce a strong astringent taste; the granules prepared in Example 1 have the best bitterness masking effect and will not produce other miscellaneous tastes.

[0100] The main difference between sensory evaluation analysis and electronic tongue evaluation analysis is in smell. Sweeteners and aromatics mainly mask the perception of bad taste by generating taste or olfactory nerve impulses in the brain center and confusing the nerve impulses generated by other bad tastes, thereby playing a masking role. That is, during the sensory test, lemon flavor can produce an aromatic odor, thereby confusing the nerve impulses generated by other bad tastes to mask the perception of bad taste. However, during the electronic tongue test, the measurement results did not show that lemon flavor has a masking effect on drugs. The reason is that the combination of bitter or astringent molecules in the sample particles with the artificial lipid membrane of the exclusive sensor and the change in potential value are not affected by these two components. It can be seen that sensory evaluation has the advantages of being direct and comprehensive, and electronic tongue evaluation has the advantages of being accurate and precise. The evaluation results of the two complement and verify each other. The combined use of technology can make the evaluation results more objective and reasonable.

[0101] Example 4: Stability evaluation of formulations

[0102] 1. Experimental methods

[0103] (1) Sample processing

[0104] The granules prepared in Example 1 and the tablets prepared in Comparative Examples 1 and 2 were placed in an oven at 45° C. and dried for 6 h to ensure that their water contents were close.

[0105] (2) Moisture absorption and weight gain

[0106] Place the weighing bottle in a stability test chamber at 25°C / 90%RH for 24 hours to keep the relative humidity inside constant at 90%. Place dry granules (fine powder) or tablets with a thickness of more than 2 mm at the bottom of the weighing bottle, weigh them accurately and place them in the above-mentioned dryer (with the weighing bottle lid open). After 10 days, accurately weigh the mass of the bottle and the sample, and calculate the moisture absorption weight gain.

[0107] (3) Related substances

[0108] According to the sampling method specified in the "Chinese Pharmacopoeia", the above samples were sampled separately, and the content of relevant substances was tested according to the high performance liquid chromatography method of the "Chinese Pharmacopoeia" (equivalent to the percentage of the labeled amount).

[0109] 2. Experimental results

[0110] Table 4 Stability evaluation results

[0111] Sample source Example 1 Comparative Example 1 Comparative Example 2 10-day moisture absorption weight gain (%) 3.0 10.5 15.2 0 day impurity content (%) 0.12 0.12 0.35 10-day impurity content (%) 0.12 0.12 0.50

[0112] As shown in Table 4, when prepared by different processes, although the impurities in the formulation did not change significantly, the particles prepared in Comparative Example 1 obviously absorbed moisture under the conditions of temperature 25°C / humidity 90% RH, so the formulation and process designed by the present invention are more stable.

[0113] In summary, the present invention optimizes the dosage form, prescription and process of the preparation, adopts a process mode of wet granulation and granule coating, and the obtained granules have a regular appearance and a good taste, which increases the patient's compliance with the medication. The dissolution curve fitting shows that the in vitro dissolution behavior is similar to that of the original preparation, the quality is stable, and the preparation process is convenient, which is suitable for large-scale industrial production.

Claims

1. A Letermovir pharmaceutical composition, characterized in that: The invention comprises, by weight, 24 to 48 parts of letermovir, 5 to 45 parts of a first filler, 3 to 45 parts of a second filler, 1 to 10 parts of a binder, 1 to 8 parts of a disintegrant, 0.75 to 2.5 parts of a lubricant, 1 to 5 parts of a flavoring agent, 0.1 to 0.5 parts of a fragrance and 2 to 4 parts of a coating agent; the first filler is selected from pregelatinized starch, cyclodextrin, mannitol, microcrystalline cellulose, lactose, calcium hydrogen phosphate, calcium sulfate dihydrate, calcium sulfate trihydrate or corn starch, and the second filler is selected from sucrose, honey sorbitol, stevioside, xylitol, ethyl cellulose, polyacrylic acid resin, stearic acid, stearyl alcohol, glyceryl monostearate, glyceryl monooleate, carboxymethyl ethyl cellulose or hydroxypropyl methylcellulose phthalate.

2. The Letermovir pharmaceutical composition according to claim 1, characterized in that The adhesive is selected from pregelatinized starch, gelatin, povidone, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose or polyethylene glycol.

3. The Letermovir pharmaceutical composition according to claim 1, characterized in that The disintegrant is selected from sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, calcium carboxymethyl cellulose or low-substituted hydroxypropyl cellulose.

4. The Letermovir pharmaceutical composition according to claim 1, characterized in that The lubricant is selected from magnesium stearate, silicon dioxide or talc.

5. The Letermovir pharmaceutical composition according to claim 1, characterized in that The flavor corrector is selected from sucralose, saccharin sodium, aspartame, sodium cyclamate or acesulfame potassium.

6. The Letermovir pharmaceutical composition according to claim 1, characterized in that The aromatic agent is selected from mint essence, lemon essence, strawberry essence, pineapple essence, orange essence, lemon essence or watermelon essence.

7. The Letermovir pharmaceutical composition according to claim 1, characterized in that The first filler is selected from cyclodextrin or calcium hydrogen phosphate, and the second filler is selected from sucrose or polyacrylic acid resin.

8. The Letermovir pharmaceutical composition according to claim 1, characterized in that The binder is selected from hydroxypropyl cellulose or ethyl cellulose, the disintegrant is selected from cross-linked polyvinylpyrrolidone or low-substituted hydroxypropyl cellulose, the lubricant is selected from magnesium stearate, the flavoring agent is selected from cyclamate, the fragrance is selected from lemon essence, and the coating agent is selected from an aqueous coating agent.

9. The Letermovir pharmaceutical composition according to claim 1, characterized in that The composition by weight percentage is 24% of letermovir, 42% of cyclodextrin, 22% of sucrose, 5% of hydroxypropyl cellulose, 3.05% of low-substituted hydroxypropyl cellulose, 0.75% of magnesium stearate, 3% of cyclamate, 0.2% of lemon essence and 2% to 4% of the total weight of the aqueous coating agent.

10. The Letermovir pharmaceutical composition according to claim 9, characterized in that The composition of the unit preparation is 240 mg of letermovir, 420 mg of cyclodextrin, 220 mg of sucrose, 50 mg of hydroxypropyl cellulose, 30.5 mg of low-substituted hydroxypropyl cellulose, 7.5 mg of magnesium stearate, 30 mg of cyclamate, 2 mg of lemon flavor and 20-40 mg of aqueous coating agent.

11. A method for preparing the Letermovir pharmaceutical composition according to claim 1, characterized in that: The following steps are involved: (1) Granulation: mixing temovir, the first filler, the second filler, the disintegrant, the binder and the flavoring agent, adding a pharmaceutically acceptable solvent to granulate and shape the particles to obtain wet granules; (2) coating and loading aromatics: drying and coating the wet granules obtained in step (1), then loading the aromatic solution on the surface of the coated granules and drying to obtain aromatic coated granules; (3) Final mixing: adding the aromatic coated granules obtained in step (2) to the lubricant and mixing well to obtain the termovir pharmaceutical composition.

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