A pharmaceutical composition of tenofovir alafenamide and preparation method thereof

Abstract

The present application provides a kind of tartaric acid propyltenofovir tablet pharmaceutical composition and preparation method thereof, the composition includes tartaric acid propyltenofovir, lactose monohydrate, microcrystalline cellulose, disintegrant and lubricant, is prepared using powder direct pressure process or dry granulation process, the prepared tartaric acid propyltenofovir tablet not only has good stability, and 15min within the unique dissolution characteristics, simultaneously still has smaller gastrointestinal irritation characteristic.

Description

Technical Field

[0001] This invention relates to a tablet pharmaceutical composition and its preparation method, specifically to a tenofovir tartrate tartrate tablet pharmaceutical composition and its preparation method, belonging to the field of pharmaceutical preparations. Background Technology

[0002] Tenofovir alafenamide, also known as tenofovir alafenamide, has the chemical name: N-[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phenoxyphosphono]-L-alanine-1-methylethyl ester; CAS Registry Number: 379270-37-8; its molecular structure is shown in Formula (I).

[0003]

[0004] Tenofovir alafenamide is an ester prodrug of tenofovir, an acyclic nucleotide reverse transcriptase inhibitor with broad-spectrum antiviral activity. It inhibits the reverse transcriptases of HIV-1 and HIV-2, as well as HBV polymerase, thereby suppressing viral replication. After oral administration, tenofovir alafenamide is hydrolyzed to tenofovir, which is then phosphorylated by cellular kinases to its pharmacologically active metabolite, tenofovir disoproxil fumarate (TRF). TRF competes with 5′-deoxyadenosine triphosphate (5′-3′-3′-4 ... Compared with the marketed similar drug tenofovir disoproxil, tenofovir alafenamide has 10 times the antiviral activity, 200 times the stability in plasma, 220 times the half-life, and nearly 10 times the accumulation in peripheral blood mononuclear cells (PBMCs). Therefore, tenofovir alafenamide has better efficacy, higher safety, and lower drug resistance for the prevention and / or treatment of hepatitis B virus (HBV) and human immunodeficiency virus (HIV / AIDS) infection.

[0005] Tenofovir alafenamide has a low solid melting point and low water solubility, which is unfavorable for the preparation and dissolution of drug formulations. Therefore, it has been developed into a salt form for use in formulations. For example, CN1443189A and CN1706855A disclose fumarate of tenofovir alafenamide. Although tenofovir alafenamide fumarate has significant improvements in water solubility and physical properties compared to the free base, its chemical stability and thermodynamic stability are poor.

[0006] According to the product information for tenofovir alafenamide fumarate tablets (Vemlidy), tenofovir alafenamide fumarate tablets can cause gastrointestinal adverse reactions, such as diarrhea, vomiting, nausea, abdominal pain, abdominal distension, and flatulence.

[0007] CN106414466B discloses a tenofovir tartrate propionate, which the inventors have discovered to have excellent physicochemical properties, as follows:

[0008]

[0009] An influencing factor test (damp heat) was conducted on tenofovir tartrate propionate, and the results are shown in the table below:

[0010] Table of Influencing Factors Test Results (40℃±2℃, Humidity 95±5%)

[0011]

[0012] The results of the influencing factors test show that tenofovir tartrate is very sensitive to damp heat, which is related to the fact that its structure contains multiple ester bonds, which are prone to hydrolysis under damp heat conditions. Therefore, water and high temperature should be avoided when preparing oral solid dosage forms of tenofovir tartrate.

[0013] The preparation of oral solid dosage forms of tenofovir tartrate involves wet granulation, dehydration and drying processes, all of which involve humid and hot conditions. Water and high temperatures cannot be avoided, making tenofovir tartrate prone to degradation, increasing related substances, and residual moisture also affects the stability of the drug during storage.

[0014] Therefore, how to obtain an oral solid dosage form of tenofovir alafenamide that can be rapidly released, has minimal gastrointestinal irritation, and exhibits good drug stability is an urgent problem to be solved in this field. Summary of the Invention

[0015] To address the aforementioned issues, the inventors, through extensive experimental research, developed a tenofovir tartrate tartrate tablet composition and its preparation method. This tenofovir tartrate tartrate tablet exhibits good stability, rapid release upon disintegration, unique dissolution characteristics within 15 minutes, and minimal irritation to the gastrointestinal tract, effectively overcoming the shortcomings of existing tenofovir tartrate oral solid dosage forms.

[0016] This invention is achieved through the following technical solution:

[0017] A pharmaceutical composition for tenofovir tartrate tablets is provided, comprising tenofovir tartrate, lactose monohydrate, microcrystalline cellulose, a disintegrant, and a lubricant; wherein the disintegrant is selected from croscarmellose sodium, croscarmellose polyvinylpyrrolidone, or croscarmellose sodium, and the lubricant is selected from magnesium stearate, micronized silica gel, or hydrogenated castor oil.

[0018] In some embodiments, the pharmaceutical composition comprises the following components by weight percentage:

[0019] Tenofovir alafenamide tartrate 2.5%-20.0%,

[0020] Lactose monohydrate 30%-60%,

[0021] Microcrystalline cellulose 20%-50%,

[0022] Disintegrant 2.0%-10.0%,

[0023] Lubricant 0.25%-3.0%.

[0024] Furthermore, the pharmaceutical composition comprises the following components by weight percentage:

[0025] Tenofovir alafenamide tartrate 2.5%-20.0%,

[0026] Lactose monohydrate 30%-60%,

[0027] Microcrystalline cellulose 20%-50%,

[0028] Disintegrant 2.0%-6.0%,

[0029] Lubricant 0.25%-2.0%.

[0030] Alternatively, the pharmaceutical composition may comprise the following components by weight percentage:

[0031] Tenofovir alafenamide tartrate 2.5%-20.0%,

[0032] Lactose monohydrate 30%-60%,

[0033] Microcrystalline cellulose 20%-50%,

[0034] Disintegrant 5.0%-9.0%,

[0035] Lubricant 0.5%-2.5%.

[0036] In one embodiment, the pharmaceutical composition comprises the following components by weight percentage:

[0037] Tenofovir tartrate 14.5%,

[0038] 50% lactose monohydrate

[0039] 30% microcrystalline cellulose

[0040] Disintegrant 4.0%,

[0041] Lubricant 1.5%.

[0042] In one embodiment, the pharmaceutical composition comprises the following components by weight percentage:

[0043] Tenofovir tartrate 14.5%,

[0044] Lactose monohydrate 47%,

[0045] 30% microcrystalline cellulose

[0046] Disintegrant 7.0%,

[0047] Lubricant 1.5%.

[0048] Furthermore, the pharmaceutical composition further comprises a gastric-soluble film-coating premix, the amount of which is added at 2%-6% of the original composition weight, preferably 2%-4%.

[0049] In some embodiments, the microcrystalline cellulose is selected from at least one of microcrystalline cellulose PH101, PH102, PH112, PH301, and PH302, preferably microcrystalline cellulose PH101; the lactose monohydrate is selected from at least one of lactose monohydrate 14SD, F100, 310NF, 312NF, 314NF, T80, and T100, preferably lactose monohydrate 14SD.

[0050] The present invention also provides a method for preparing the tenofovir tartrate tablet pharmaceutical composition, which is prepared by direct powder compression or dry granulation.

[0051] The powder direct pressing process includes the following preparation steps:

[0052] (1) Pre-treat tenofovir tartrate and pharmaceutical excipients separately;

[0053] (2) Premix the pretreated tenofovir tartrate and pharmaceutical excipients;

[0054] (3) Compress the material obtained in (2) to obtain tablet cores;

[0055] (4) Optionally, the core obtained in (3) is coated to obtain coated sheets.

[0056] The dry granulation process includes the following preparation steps:

[0057] (1) Pre-treat tenofovir tartrate and pharmaceutical excipients separately;

[0058] (2) Premix tenofovir tartrate with a portion of the disintegrant and a portion of the lubricant;

[0059] (3) Add the material obtained in (2) to a dry granulator for dry granulation;

[0060] (4) Mix the material obtained in (3) with the remaining disintegrant and the remaining lubricant;

[0061] (5) Compress the material obtained in (4) to obtain tablet cores;

[0062] (6) Optionally, the core obtained in (5) is coated to obtain coated sheets.

[0063] The pharmaceutical composition of tenofovir tartrate tartrate tablets of the present invention has very rapid dissolution characteristics (unique dissolution characteristics within 15 min). According to the "Guidelines for Exemption from Human Bioequivalence Trials" formulated by the State Food and Drug Administration in 2016, the definition of very rapid dissolution of oral solid immediate-release preparations is: using Method 1 (basket method) of Appendix General Rules (0931) of the 2020 edition of the Chinese Pharmacopoeia, with a rotation speed of 100 rpm, or Method 2 (paddle method), with a rotation speed of 50 or 75 rpm, and a dissolution medium volume of 500 ml (or less), the API can be dissolved to more than 85% of the labeled amount within 15 minutes in the dissolution medium: (1) 0.1 mol / L HCl or enzyme-free simulated gastric juice; (2) pH 4.5 buffer medium; (3) pH 6.8 buffer medium or enzyme-free simulated intestinal juice.

[0064] The tenofovir tartrate acetonate described in this invention is a hemi-tartrate salt of tenofovir acetonate, namely, the L-tenofovir alafenamide tartrate (1:2) described in the specification CN106414466B.

[0065] The tenofovir tartrate tartrate tablet pharmaceutical composition and its preparation method provided by the present invention have the following advantages:

[0066] (1) The product has good stability, which overcomes the defect that multiple ester bonds in the molecular structure of tenofovir tartrate are easily hydrolyzed by humid heat conditions, thus improving the safety of the product in clinical use.

[0067] (2) The product meets the definition of oral solid immediate-release formulations having very rapid dissolution, and has unique dissolution characteristics within 15 minutes, making it an excellent oral solid immediate-release formulation;

[0068] (3) When the product disintegrates, the drug first disperses into fine particles and then gradually dissolves. Compared with the direct disintegration of existing tablets, this greatly reduces the stimulation of the gastrointestinal tract by the drug and reduces the incidence of gastrointestinal adverse reactions such as nausea, vomiting, abdominal pain, diarrhea, abdominal distension, and flatulence of tenofovir alafenamide oral tablets.

[0069] (4) The powder is prepared by direct pressing or dry granulation, which does not involve the use of water and high temperature drying conditions. This reduces the generation of active ingredient degradation impurities during the preparation process, greatly reduces the content of related substances in the product, and significantly improves the quality. Detailed Implementation

[0070] The present invention will be further described in detail below with reference to embodiments, but this is not intended to limit the present invention. Any equivalent substitutions made in the art in accordance with the disclosure of the present invention shall fall within the protection scope of the present invention.

[0071] Example 1: Preparation of tenofovir tartrate tablets pharmaceutical composition by direct powder compression method

[0072] prescription:

[0073] Material Name Proportion Tenofovir tartrate 14.5% lactose 50.0% microcrystalline cellulose 30.0% Cross-linked carboxymethyl cellulose sodium 4.0% magnesium stearate 1.5% Chip 100.0%

[0074] Preparation process: Take all raw and auxiliary materials, sieve tenofovir tartrate, control the drying loss of microcrystalline cellulose (model: PH101) and lactose (model: 14SD) to be less than 1.0%, and control the drying loss of croscarmellose sodium to be less than 1.5%; put tenofovir tartrate raw material, microcrystalline cellulose, lactose, croscarmellose sodium, and magnesium stearate into a mixer and mix evenly; compress into tablets and control the tablet weight to be about 200mg to obtain product A1.

[0075] Example 2 Preparation of tenofovir tartrate tablet pharmaceutical composition (powder direct compression method)

[0076] prescription:

[0077] Material Name Proportion Tenofovir tartrate 14.5% lactose 50.0% microcrystalline cellulose 30.0% Cross-linked carboxymethyl cellulose sodium 4.0% magnesium stearate 1.5% Piece weight 100.0%

[0078] Preparation process: Take all raw and auxiliary materials, sieve tenofovir tartrate, control the drying loss of microcrystalline cellulose (model: PH101) and lactose (model: 14SD) to be less than 1.0%, and control the drying loss of croscarmellose sodium to be less than 1.5%; put tenofovir tartrate raw material, microcrystalline cellulose, lactose, croscarmellose sodium, and magnesium stearate into a mixer and mix evenly; compress into tablets and control the tablet weight to be about 200mg, and coat with film coating premix (gastric-soluble type) to increase the weight by 2%-4% to obtain product A2.

[0079] Example 3: Preparation of the tenofovir tartrate tartrate tablet pharmaceutical composition (direct powder compression method)

[0080] prescription:

[0081] Material Name Proportion Tenofovir tartrate 14.5% lactose 50.0% microcrystalline cellulose 30.0% Cross-linked carboxymethyl cellulose sodium 4.0% magnesium stearate 1.5% Piece weight 100.0%

[0082] Preparation process: Take all raw and auxiliary materials, sieve tenofovir tartrate, control the drying loss of microcrystalline cellulose (model: PH101) and lactose (model: 314NF) to be less than 1.0%, and control the drying loss of croscarmellose sodium to be less than 1.5%; put tenofovir tartrate raw material, microcrystalline cellulose, lactose, croscarmellose sodium, and magnesium stearate into a mixer and mix evenly; compress into tablets and control the tablet weight to be about 200mg, and coat with film coating premix (gastric-soluble type) to increase the weight by 2%-4% to obtain product A3.

[0083] Example 4 Preparation of a pharmaceutical composition of tenofovir tartrate propionate tablets (direct powder compression method)

[0084] prescription:

[0085] Material Name Proportion Tenofovir tartrate 14.5% lactose 50.0% microcrystalline cellulose 30.0% Cross-linked carboxymethyl cellulose sodium 4.0% magnesium stearate 1.5% Piece weight 100.0%

[0086] Preparation process: Take all raw and auxiliary materials, sieve tenofovir tartrate, control the drying loss of microcrystalline cellulose (model: PH102) and lactose (model: 14SD) to be less than 1.0%, and control the drying loss of croscarmellose sodium to be less than 1.5%; put tenofovir tartrate raw material, microcrystalline cellulose, lactose, croscarmellose sodium, and magnesium stearate into a mixer and mix evenly; compress into tablets and control the tablet weight to be about 200mg, and coat with film coating premix (gastric-soluble type) to increase the weight by 2%-4% to obtain product A4.

[0087] Example 5: Preparation of a pharmaceutical composition of tenofovir tartrate propionate tablets (direct powder compression method)

[0088] prescription:

[0089] Material Name Proportion Tenofovir tartrate 14.5% lactose 50.0% microcrystalline cellulose 30.0% Cross-linked carboxymethyl cellulose sodium 4.0% magnesium stearate 1.5% Piece weight 100.0%

[0090] Preparation process: Take all raw and auxiliary materials, sieve tenofovir tartrate, control the drying loss of microcrystalline cellulose (model: PH301) and lactose (model: 14SD) to be less than 1.0%, and control the drying loss of croscarmellose sodium to be less than 1.5%; put tenofovir tartrate raw material, microcrystalline cellulose, lactose, croscarmellose sodium, and magnesium stearate into a mixer and mix evenly; compress into tablets and control the tablet weight to be about 200mg, and apply film coating premix (gastric-soluble type) to increase the weight by 2%-4% to obtain product A5.

[0091] Example 6 Preparation of a pharmaceutical composition of tenofovir tartrate propionate tablets (direct powder compression method)

[0092] prescription:

[0093] Material Name Proportion Tenofovir tartrate 14.5% lactose 50.0% microcrystalline cellulose 30.0% Cross-linked carboxymethyl cellulose sodium 4.0% magnesium stearate 1.5% Piece weight 100.0%

[0094] Preparation process: Take all raw and auxiliary materials, sieve tenofovir tartrate, control the drying loss of microcrystalline cellulose (model: PH101) and lactose (model: F100) to be less than 1.0%, and control the drying loss of croscarmellose sodium to be less than 1.5%; put tenofovir tartrate raw material, microcrystalline cellulose, lactose, croscarmellose sodium, and magnesium stearate into a mixer and mix evenly; compress into tablets and control the tablet weight to be about 200mg, and apply film coating premix (gastric-soluble type) to increase the weight by 2%-4% to obtain product A6.

[0095] Example 7 Preparation of a pharmaceutical composition of tenofovir tartrate propionate tablets (direct powder compression method)

[0096] prescription:

[0097] Material Name Proportion Tenofovir tartrate 14.5% lactose 50.0% microcrystalline cellulose 30.0% Cross-linked carboxymethyl cellulose sodium 4.0% magnesium stearate 1.5% Piece weight 100.0%

[0098] Preparation process: Take all raw and auxiliary materials, sieve tenofovir tartrate, control the drying loss of microcrystalline cellulose (model: PH302) and lactose (model: 14SD) to be less than 1.0%, and control the drying loss of croscarmellose sodium to be less than 1.5%; put tenofovir tartrate raw material, microcrystalline cellulose, lactose, croscarmellose sodium, and magnesium stearate into a mixer and mix evenly; compress into tablets and control the tablet weight to be about 200mg, and apply film coating premix (gastric-soluble type) to increase the weight by 2%-4% to obtain product A7.

[0099] Example 8 Preparation of a pharmaceutical composition of tenofovir tartrate propionate tablets (direct powder compression method)

[0100] prescription:

[0101] Material Name Proportion Tenofovir tartrate 14.5% lactose 50.0% microcrystalline cellulose 30.0% Cross-linked carboxymethyl cellulose sodium 4.0% magnesium stearate 1.5% Piece weight 100.0%

[0102] Preparation process: Take all raw and auxiliary materials, sieve tenofovir tartrate, control the drying loss of microcrystalline cellulose (model: PH101) and lactose (model: 310NF) to be less than 1.0%, and control the drying loss of croscarmellose sodium to be less than 1.5%; put tenofovir tartrate raw material, microcrystalline cellulose, lactose, croscarmellose sodium, and magnesium stearate into a mixer and mix evenly; compress into tablets and control the tablet weight to be about 200mg, and apply film coating premix (gastric-soluble type) to increase the weight by 2%-4% to obtain product A8.

[0103] Example 9 Preparation of a pharmaceutical composition of tenofovir tartrate propionate tablets (direct powder compression method)

[0104] prescription:

[0105] Material Name Proportion Tenofovir tartrate 14.5% lactose 50.0% microcrystalline cellulose 30.0% Cross-linked carboxymethyl cellulose sodium 4.0% magnesium stearate 1.5% Chip 100.0%

[0106] Preparation process: Take all raw and auxiliary materials, sieve tenofovir tartrate, control the drying loss of microcrystalline cellulose (model: PH101) and lactose (model: F100) to be less than 1.0%, and control the drying loss of croscarmellose sodium to be less than 1.5%; put tenofovir tartrate raw material, microcrystalline cellulose, lactose, croscarmellose sodium, and magnesium stearate into a mixer and mix evenly; compress into tablets and control the tablet weight to be about 200mg, and add film coating premix (gastric-soluble type) to the film coating to increase the weight by about 2%-4% to obtain product A9.

[0107] Example 10 Preparation of a pharmaceutical composition of tenofovir tartrate propionate tablets (direct powder compression method)

[0108] prescription:

[0109] Material Name Proportion Tenofovir tartrate 14.5% lactose 60.0% microcrystalline cellulose 20.0% Cross-linked carboxymethyl cellulose sodium 4.0% magnesium stearate 1.5% Piece weight 100.0%

[0110] Preparation process: Take all raw and auxiliary materials, sieve tenofovir tartrate, control the drying loss of microcrystalline cellulose (model: PH301) and lactose (model: F100) to be less than 1.0%, and control the drying loss of croscarmellose sodium to be less than 1.5%; put tenofovir tartrate raw material, microcrystalline cellulose, lactose, croscarmellose sodium, and magnesium stearate into a mixer and mix evenly; compress into tablets and control the tablet weight to be about 200mg, and apply film coating premix (gastric-soluble type) to increase the weight by 2%-4% to obtain product A10.

[0111] Example 11 Preparation of a pharmaceutical composition of tenofovir tartrate propionate tablets (direct powder compression method)

[0112] prescription:

[0113] Material Name Proportion Tenofovir tartrate 14.5% lactose 30.0% microcrystalline cellulose 50.0% Cross-linked carboxymethyl cellulose sodium 4.0% magnesium stearate 1.5% Chip 100.0%

[0114] Preparation process: Take all raw and auxiliary materials, sieve tenofovir tartrate, control the drying loss of microcrystalline cellulose (model: PH302) and lactose (model: T100) to be less than 1.0%, and control the drying loss of sodium croscarmellose to be less than 1.5%; put tenofovir tartrate raw material, microcrystalline cellulose, lactose, sodium croscarmellose, and magnesium stearate into a mixer and mix evenly; compress into tablets and control the tablet weight to be about 200mg, and add film coating premix (gastric-soluble type) to the film coating to increase the weight by 2%-4% to obtain product A11.

[0115] Example 12 Preparation of a pharmaceutical composition of tenofovir tartrate propionate tablets (direct powder compression method)

[0116] prescription:

[0117] Material Name Proportion Tenofovir tartrate 2.5% lactose 41.5% microcrystalline cellulose 48.0% Sodium carboxymethyl starch 6.0% magnesium stearate 2.0% Chip 100.0%

[0118] Preparation process: Take all raw and auxiliary materials, sieve tenofovir tartrate, control the drying loss of microcrystalline cellulose (model: PH102) and lactose (model: T80) to be less than 1.0%, and control the drying loss of sodium carboxymethyl starch to be less than 1.5%; put tenofovir tartrate raw material, microcrystalline cellulose, lactose, sodium carboxymethyl starch and magnesium stearate into a mixer and mix evenly; compress into tablets and control the tablet weight to be about 50mg, and add film coating premix (gastric-soluble type) to the film coating to increase the weight by about 2%-4% to obtain product A12.

[0119] Example 13 Preparation of a pharmaceutical composition of tenofovir tartrate propionate tablets (direct powder compression method)

[0120] prescription:

[0121] Material Name Proportion Tenofovir tartrate 20.0% lactose 40.0% microcrystalline cellulose 33.75% Cross-linked polyvinylpyrrolidone 6.0% Hydrogenated castor oil 0.25% Chip 100.0%

[0122] Preparation process: Take all raw and auxiliary materials, sieve tenofovir tartrate, control the drying loss of microcrystalline cellulose (model: PH101) and lactose (model: F100) to be less than 1.0%, and control the drying loss of cross-linked polyvinylpyrrolidone to be less than 1.5%; put tenofovir tartrate raw material, microcrystalline cellulose, lactose, cross-linked polyvinylpyrrolidone, and hydrogenated castor oil into a mixer and mix evenly; compress into tablets and control the tablet weight to be about 500mg, and coat with film coating premix (gastric-soluble type) to increase the weight by about 2%-4% to obtain product A13.

[0123] Example 14 Preparation of a pharmaceutical composition of tenofovir tartrate propofol tablets (dry granulation)

[0124] prescription:

[0125] Material Name Proportion Tenofovir tartrate 14.5% Lactose monohydrate 47.0% microcrystalline cellulose 30.0% Cross-linked carboxymethyl cellulose sodium 7.0% magnesium stearate 1.5%

[0126] Preparation process: Take all raw and auxiliary materials, sieve the tenofovir tartrate acetonide raw material and set aside; control the drying loss of microcrystalline cellulose (model: PH101) and lactose (model: 14SD) to be less than 1.0%, and control the drying loss of croscarmellose sodium to be less than 1.5%; put the tenofovir tartrate acetonide raw material, microcrystalline cellulose, lactose, part of croscarmellose sodium, and part of magnesium stearate into a mixer and mix evenly; after dry granulation, add the remaining croscarmellose sodium and magnesium stearate and mix evenly, compress into tablets and control the tablet weight to be about 200mg to obtain product A14.

[0127] Example 15 Preparation of a pharmaceutical composition of tenofovir tartrate propofol tablets (dry granulation)

[0128] prescription:

[0129] Material Name Proportion Tenofovir tartrate 14.5% Lactose monohydrate 47.0% microcrystalline cellulose 30.0% Cross-linked carboxymethyl cellulose sodium 7.0% magnesium stearate 1.5% Chip 100.0%

[0130] Preparation process: Take all raw and auxiliary materials, sieve the tenofovir tartrate acetonide raw material and set aside; control the drying loss of microcrystalline cellulose (model: PH101) and lactose (model: 14SD) to be less than 1.0%, and control the drying loss of croscarmellose sodium to be less than 1.5%; put the tenofovir tartrate acetonide raw material, microcrystalline cellulose, lactose, part of croscarmellose sodium, and part of magnesium stearate into a mixer and mix evenly; after dry granulation, add the remaining croscarmellose sodium and magnesium stearate and mix evenly, compress into tablets and control the tablet weight to be about 200mg, and add film coating premix (gastric-soluble type) to the film coating with a weight gain of about 2%-4% to obtain product A15.

[0131] Example 16 Preparation of a pharmaceutical composition of tenofovir tartrate propofol tablets (dry granulation)

[0132] prescription:

[0133] Material Name Proportion Tenofovir tartrate 14.5% Lactose monohydrate 47.0% microcrystalline cellulose 30.0% Cross-linked carboxymethyl cellulose sodium 7.0% magnesium stearate 1.5% Chip 100.0%

[0134] Preparation process: Take all raw and auxiliary materials, sieve the tenofovir tartrate acetonide raw material and set aside; control the drying loss of microcrystalline cellulose (model: PH101) and lactose monohydrate (model: 310NF) to be less than 1.0%, and control the drying loss of croscarmellose sodium to be less than 1.5%; put the tenofovir tartrate acetonide raw material, microcrystalline cellulose, lactose, part of croscarmellose sodium, and part of magnesium stearate into a mixer and mix evenly; after dry granulation, add the remaining croscarmellose sodium and magnesium stearate and mix evenly, compress into tablets and control the tablet weight to be about 200mg, and add film coating premix (gastric-soluble type) to the film coating with a weight gain of about 2%-4% to obtain product A16.

[0135] Example 17 Preparation of a pharmaceutical composition of tenofovir tartrate propofol tablets (dry granulation)

[0136] prescription:

[0137] Material Name Proportion Tenofovir tartrate 14.5% Lactose monohydrate 47.0% microcrystalline cellulose 30.0% Cross-linked carboxymethyl cellulose sodium 7.0% magnesium stearate 1.5% Chip 100.0%

[0138] Preparation process: Take all raw and auxiliary materials, sieve the tenofovir tartrate acetonide raw material and set aside; control the drying loss of microcrystalline cellulose (model: PH101) and lactose monohydrate (model: F100) to be less than 1.0%, and control the drying loss of croscarmellose sodium to be less than 1.5%; put the tenofovir tartrate acetonide raw material, microcrystalline cellulose, lactose, part of croscarmellose sodium, and part of magnesium stearate into a mixer and mix evenly; after dry granulation, add the remaining croscarmellose sodium and magnesium stearate, mix evenly, compress into tablets and control the tablet weight to be about 200mg; the film coating premix (gastric-soluble type) increases the weight by about 2%-4% to obtain product A17.

[0139] Example 18 Preparation of a pharmaceutical composition of tenofovir tartrate propionate tablets (dry granulation)

[0140] prescription:

[0141] Material Name Proportion Tenofovir tartrate 14.5% Lactose monohydrate 47.0% microcrystalline cellulose 30.0% Cross-linked carboxymethyl cellulose sodium 7.0% magnesium stearate 1.5% Chip 100.0%

[0142] Preparation process: Take all raw and auxiliary materials, sieve the tenofovir tartrate acetonide raw material and set aside; control the drying loss of microcrystalline cellulose (model: PH302) and lactose monohydrate (model: 14SD) to be less than 1.0%, and control the drying loss of croscarmellose sodium to be less than 1.5%; put the tenofovir tartrate acetonide raw material, microcrystalline cellulose, lactose, part of croscarmellose sodium, and part of magnesium stearate into a mixer and mix evenly; after dry granulation, add the remaining croscarmellose sodium and magnesium stearate, mix evenly, compress into tablets and control the tablet weight to be about 200mg; the film coating premix (gastric-soluble type) increases the weight by about 2%-4% to obtain product A18.

[0143] Example 19 Preparation of a pharmaceutical composition of tenofovir tartrate propionate tablets (dry granulation)

[0144] prescription:

[0145] Material Name Proportion Tenofovir tartrate 14.5% Lactose monohydrate 47.0% microcrystalline cellulose 30.0% Cross-linked carboxymethyl cellulose sodium 7.0% magnesium stearate 1.5% Chip 100.0%

[0146] Preparation process: Take all raw and auxiliary materials, sieve the tenofovir tartrate acetonide raw material and set aside; control the drying loss of microcrystalline cellulose (model: PH101) and lactose monohydrate (model: 314NF) to be less than 1.0%, and control the drying loss of croscarmellose sodium to be less than 1.5%; put the tenofovir tartrate acetonide raw material, microcrystalline cellulose, lactose, part of croscarmellose sodium, and part of magnesium stearate into a mixer and mix evenly; after dry granulation, add the remaining croscarmellose sodium and magnesium stearate, mix evenly, compress into tablets and control the tablet weight to be about 200mg; the film coating premix (gastric-soluble type) increases the weight by about 2%-4% to obtain product A19.

[0147] Example 20 Preparation of a pharmaceutical composition of tenofovir tartrate propofol tablets (dry granulation)

[0148] prescription:

[0149] Material Name Proportion Tenofovir tartrate 14.5% Lactose monohydrate 47.0% microcrystalline cellulose 30.0% Cross-linked carboxymethyl cellulose sodium 7.0% magnesium stearate 1.5% Chip 100.0%

[0150] Preparation process: Take all raw and auxiliary materials, sieve the tenofovir tartrate acetonide raw material and set aside; control the drying loss of microcrystalline cellulose (model: PH102) and lactose monohydrate (model: 14SD) to be less than 1.0%, and control the drying loss of croscarmellose sodium to be less than 1.5%; put the tenofovir tartrate acetonide raw material, microcrystalline cellulose, lactose, part of croscarmellose sodium, and part of magnesium stearate into a mixer and mix evenly; after dry granulation, add the remaining croscarmellose sodium and magnesium stearate, mix evenly, compress into tablets and control the tablet weight to be about 200mg; the film coating premix (gastric-soluble type) increases the weight by about 2%-4% to obtain product A20.

[0151] Example 21 Preparation of a pharmaceutical composition of tenofovir tartrate propofol tablets (dry granulation)

[0152] prescription:

[0153] Material Name Proportion Tenofovir tartrate 14.5% Lactose monohydrate 30.0% microcrystalline cellulose 50.0% Sodium carboxymethyl starch 5.0% magnesium stearate 0.5% Chip 100.0%

[0154] Preparation process: Take all raw and auxiliary materials, sieve the tenofovir tartrate acetonide raw material and set aside; control the drying loss of microcrystalline cellulose (model: PH102) and lactose monohydrate (model: 310NF) to be less than 1.0%, and control the drying loss of sodium carboxymethyl starch to be less than 1.5%; put the tenofovir tartrate acetonide raw material, microcrystalline cellulose, lactose, part of sodium carboxymethyl starch, and part of magnesium stearate into a mixer and mix evenly; after dry granulation, add the remaining sodium carboxymethyl starch and magnesium stearate and mix evenly, compress into tablets and control the tablet weight to be about 200mg, and add film coating premix (gastric-soluble type) to the film coating with a weight gain of about 2%-4% to obtain product A21.

[0155] Example 22 Preparation of a pharmaceutical composition of tenofovir tartrate propofol tablets (dry granulation)

[0156] prescription:

[0157] Material Name Proportion Tenofovir tartrate 14.5% Lactose monohydrate 60.0% microcrystalline cellulose 20.0% Cross-linked polyvinylpyrrolidone 5.0% magnesium stearate 0.5% Chip 100.0%

[0158] Preparation process: Take all raw and auxiliary materials, sieve the tenofovir tartrate acetonide raw material and set aside; control the drying loss of microcrystalline cellulose (model: PH301) and lactose monohydrate (model: 312NF) to be less than 1.0%, and control the drying loss of cross-linked polyvinylpyrrolidone to be less than 1.5%; put the tenofovir tartrate acetonide raw material, microcrystalline cellulose, lactose, part of cross-linked polyvinylpyrrolidone, and part of magnesium stearate into a mixer and mix evenly; after dry granulation, add the remaining cross-linked polyvinylpyrrolidone and magnesium stearate, mix evenly, compress into tablets and control the tablet weight to be about 200mg; the film coating premix (gastric-soluble type) increases the weight by about 2%-4% to obtain product A22.

[0159] Example 23 Preparation of a pharmaceutical composition of tenofovir tartrate propionate tablets (dry granulation)

[0160] prescription:

[0161] Material Name Proportion Tenofovir tartrate 14.5% Lactose monohydrate 44.0% microcrystalline cellulose 30.0% Cross-linked carboxymethyl cellulose sodium 9.0% Micronized silica 2.5% Chip 100.0%

[0162] Preparation process: Take all raw and auxiliary materials, sieve the tenofovir tartrate acetonide raw material and set aside; control the drying loss of microcrystalline cellulose (model: PH302) and lactose monohydrate (model: 314NF) to be less than 1.0%, and control the drying loss of croscarmellose sodium to be less than 1.5%; put the tenofovir tartrate acetonide raw material, microcrystalline cellulose, lactose, part of croscarmellose sodium, and part of micronized silica gel into a mixer and mix evenly; after dry granulation, add the remaining croscarmellose sodium and micronized silica gel and mix evenly, then compress into tablets and control the tablet weight to be about 200mg. The film coating premix (gastric-soluble type) increases the weight gain by about 2%-4% to obtain product A23.

[0163] Example 24 Preparation of a pharmaceutical composition of tenofovir tartrate propofol tablets (dry granulation)

[0164] prescription:

[0165] Material Name Proportion Tenofovir tartrate 14.5 % Lactose monohydrate 47.5% microcrystalline cellulose 30.0% Cross-linked carboxymethyl cellulose sodium 7.0% Hydrogenated castor oil 1.0% Chip 100.0%

[0166] Preparation process: Take all raw and auxiliary materials, sieve the tenofovir tartrate acetonide raw material and set aside; control the drying loss of microcrystalline cellulose (model: PH112) and lactose monohydrate (model: 14SD) to be less than 1.0%, and control the drying loss of croscarmellose sodium to be less than 1.5%; put the tenofovir tartrate acetonide raw material, microcrystalline cellulose, lactose, part of croscarmellose sodium, and part of hydrogenated castor oil into a mixer and mix evenly; after dry granulation, add the remaining croscarmellose sodium and hydrogenated castor oil, mix evenly, compress into tablets and control the tablet weight to be about 200mg; the film coating premix (gastric-soluble type) increases the weight by about 2%-4% to obtain product A24.

[0167] Example 25 Preparation of a pharmaceutical composition of tenofovir tartrate tartrate tablets (dry granulation)

[0168] prescription:

[0169] Material Name Proportion Tenofovir tartrate 2.5% Lactose monohydrate 59.0% microcrystalline cellulose 30.0% Cross-linked carboxymethyl cellulose sodium 7.0% magnesium stearate 1.5% Chip 100.0%

[0170] Preparation process: Take all raw and auxiliary materials, sieve the tenofovir tartrate acetonide raw material and set aside; control the drying loss of microcrystalline cellulose (model: PH101) and lactose monohydrate (model: 14SD) to be less than 1.0%, and control the drying loss of croscarmellose sodium to be less than 1.5%; put the tenofovir tartrate acetonide raw material, microcrystalline cellulose, lactose, part of croscarmellose sodium, and part of magnesium stearate into a mixer and mix evenly; after dry granulation, add the remaining croscarmellose sodium and magnesium stearate and mix evenly, then compress into tablets and control the tablet weight to be about 50mg. The film coating premix (gastric-soluble type) increases the weight gain by about 2%-4% to obtain product A25.

[0171] Example 26 Preparation of a pharmaceutical composition of tenofovir tartrate tartrate tablets (dry granulation)

[0172] prescription:

[0173] Material Name Proportion Tenofovir tartrate 20.0% lactose 41.5% microcrystalline cellulose 30.0% Cross-linked carboxymethyl cellulose sodium 7.0% magnesium stearate 1.5% Chip 100.0%

[0174] Preparation process: Take all raw and auxiliary materials, sieve the tenofovir tartrate acetonide raw material and set aside; control the drying loss of microcrystalline cellulose (model: PH101) and lactose monohydrate (model: 14SD) to be less than 1.0%, and control the drying loss of croscarmellose sodium to be less than 1.5%; put the tenofovir tartrate acetonide raw material, microcrystalline cellulose, lactose, part of croscarmellose sodium, and part of magnesium stearate into a mixer and mix evenly; after dry granulation, add the remaining croscarmellose sodium and magnesium stearate, mix evenly, compress into tablets and control the tablet weight to be about 500mg; the film coating premix (gastric-soluble type) increases the weight by about 2%-4% to obtain product A26.

[0175] Example 27 Preparation of a pharmaceutical composition of tenofovir tartrate propionate tablets (dry granulation)

[0176] prescription:

[0177] Material Name Proportion Tenofovir tartrate 14.5% lactose 47.0% microcrystalline cellulose 30.0% Cross-linked carboxymethyl cellulose sodium 7.0% magnesium stearate 1.5% Chip 100.0%

[0178] Preparation process: Take all raw and auxiliary materials, sieve the tenofovir tartrate acetonide raw material and set aside; the auxiliary materials are not pretreated (i.e., the loss on drying is not controlled); put the tenofovir tartrate acetonide raw material, microcrystalline cellulose (model: PH101), lactose monohydrate (model: 14SD), part of the cross-linked sodium carboxymethyl cellulose, and part of the magnesium stearate into a mixer and mix evenly; after dry granulation, add the remaining cross-linked sodium carboxymethyl cellulose and magnesium stearate and mix evenly, compress into tablets and control the tablet weight to be about 200mg, and add film coating premix (gastric-soluble type) to the film coating to increase the weight by about 2%-4% to obtain product A27.

[0179] Example 28 Preparation of tenofovir tartrate tablets by wet granulation process

[0180] prescription:

[0181] Material Name Prescription dosage (mg / tablet) Proportion Tenofovir tartrate 28.9 13.32% Lactose monohydrate 100.0 46.10% microcrystalline cellulose 60.0 27.67% Sodium croscarmellose 15.0 6.92% magnesium stearate 3.0 1.38% Chip 216.9 100.00% Film-coated premix (gastric-soluble) 10.0 4.61%

[0182] Preparation method: Weigh the raw materials and excipients according to the table above, mix microcrystalline cellulose with croscarmellose sodium, then add lactose monohydrate and mix, then add tenofovir tartrate propionate and mix; add an appropriate amount of purified water for wet granulation; dry; granulate; add magnesium stearate and mix well, then compress into tablets; then coat with a suspension prepared with 75% ethanol to obtain product A28.

[0183] Example 29 Preparation of tenofovir tartrate tablets by wet granulation process

[0184] prescription:

[0185] Material Name Prescription dosage (mg / tablet) Proportion Tenofovir tartrate 28.9 11.78% Lactose monohydrate 100.0 40.75% microcrystalline cellulose 100.0 40.75% Sodium carboxymethyl starch 15.0 6.11% magnesium stearate 1.5 0.61% total 245.4 100.00%

[0186] Preparation method: Weigh the raw materials and excipients according to the table above, first mix sodium carboxymethyl starch with microcrystalline cellulose, then add lactose monohydrate and mix, then add tenofovir tartrate propionate; add an appropriate amount of purified water for wet granulation; dry; granulate; add magnesium stearate and mix well, then fill into hydroxypropyl methylcellulose capsules to obtain product A29.

[0187] Example 30: Study on the dissolution characteristics of the powder direct pressing product of the present invention

[0188] The products obtained in Examples 1-8 of this invention were used to determine their dissolution in four different dissolution media according to the dissolution test method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II). The results are shown in Table 1 below:

[0189] Table 1: Dissolution rate (%) of products from Examples 1-8 in four different media

[0190]

[0191] As shown in Table 1, among the four dissolution media, the powder direct compression method of this invention achieved a dissolution rate of over 90% at 15 minutes, fully meeting the characteristics of very rapid dissolution of oral solid immediate-release formulations. Specifically, products A3-A8 all exhibited rapid disintegration, with a dissolution rate of 30-40% at 2.5 minutes, showing a significantly faster initial release than A1 and A2. In contrast, products A1 and A2 initially dispersed into fine particles before gradually dissolving, achieving a dissolution rate of 20-25% at 2.5 minutes, with a slower initial release. The selection of microcrystalline cellulose PH101 and lactose monohydrate 14SD ensures that the drug disperses into fine particles before gradually dissolving, which is more conducive to a slower initial release of the drug after entering the body and reduces gastrointestinal irritation.

[0192] Example 31: Study on the dissolution characteristics of the dry granulation product of the present invention

[0193] The products obtained in Examples 14-21 of this invention were used to determine their dissolution in four different dissolution media according to the dissolution test method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II). The results are shown in Table 2 below:

[0194] Table 2: Dissolution rate (%) of products from Examples 14-21 in four different media

[0195]

[0196] Similar to the direct compression method for powder, as shown in Table 2 above, among the four dissolution media, the dry granulation products of this invention all have a dissolution rate of over 90% at 15 minutes, fully meeting the characteristics of very rapid dissolution of oral solid immediate-release formulations. Products A16 to A21 all exhibit rapid disintegration, with a dissolution rate of 29-43% at 2.5 minutes, and the initial release is slightly faster than that of A14 and A15. Products A14 and A15 first disperse into fine particles and then gradually dissolve during disintegration and dissolution, with a dissolution rate of 21-25% at 2.5 minutes, and the initial release is gradual. By selecting microcrystalline cellulose PH101 and lactose monohydrate 14SD, the drug first disperses into fine particles during dissolution and then gradually dissolves, which is more conducive to the gradual release of the drug in the initial stage after entering the human body and reduces the irritation to the gastrointestinal tract.

[0197] Example 32: Comparative Test of Gastrointestinal Irritation

[0198] Test method:

[0199] 1. Administration method and dosage:

[0200] Take one tablet after breakfast, with 240ml of warm water, for 15 consecutive days.

[0201] 2. Number of subjects:

[0202] 144 healthy male subjects were divided into 6 groups of 24 each, aged 18 to 55 years, and took the A2, A3, A15, and A16 products of this invention, the original commercially available product Vemlidy, and a blank preparation, respectively.

[0203] 3. Evaluation Criteria:

[0204] The number of subjects who experienced gastrointestinal irritation symptoms during medication was counted, and the results are shown in Table 3.

[0205] The gastrointestinal irritation test results of the present invention's A2, A3, A15, and A16 products, as well as the original commercially available product Vemlidy, are shown in Table 3 below:

[0206] Table 3 Results of Gastrointestinal Irritation Test

[0207] Group nausea and vomiting stomach ache Other gastrointestinal irritants (such as diarrhea, bloating, flatulence, etc.) Blank group 0 0 0 A2 0 0 1 A3 4 2 4 A15 1 0 1 A16 4 3 2 Vilid 3 2 3

[0208] The results in Table 3 show that the original commercially available product Vemlidy and the example products A3 and A16 caused significant gastrointestinal irritation, while the example products A2 and A15 caused less gastrointestinal irritation and had better patient compliance.

[0209] Example 33 Stability Comparison Test

[0210] Products from Examples 1, 2, 14, 15, 27, 28, and 29, as well as the original commercially available products, were placed at 40±2℃ and 75%±5% humidity; and at 30±2℃ and 65%±5% humidity for 3 months. The results of impurity testing are shown in Table 4 below.

[0211] Table 4: Stability Test Results

[0212]

[0213] The results in Table 4 above show that the products A1, A2, A14, and A15 of this invention, when placed at 30±2℃ and 65%±5% humidity for 3 months and at 40±2℃ and 75%±5% humidity for 3 months, have significantly lower maximum impurities and total impurities than the wet granulation products A28 and A29 and the original commercially available product, Velid, and have better stability (product A27 has slightly lower stability because the excipients were not pretreated for drying and weight loss during preparation).

Claims

1. A pharmaceutical composition for tenofovir tartrate tartrate tablets, characterized in that, The pharmaceutical composition comprises the following components by weight percentage: Tenofovir tartrate 14.5%, Lactose monohydrate 14SD 50%, Microcrystalline cellulose pH 101 30%, Cross-linked sodium carboxymethyl cellulose 4.0%, Magnesium stearate 1.5%; Each auxiliary component undergoes a pre-treatment of drying loss.

2. A pharmaceutical composition for tenofovir tartrate tartrate tablets, characterized in that, The pharmaceutical composition comprises the following components by weight percentage: Tenofovir tartrate 14.5%, Lactose monohydrate 14SD 47%, Microcrystalline cellulose pH 101 30%, Cross-linked sodium carboxymethyl cellulose 7.0%, Magnesium stearate 1.5%; Each auxiliary component undergoes a pre-treatment of drying loss.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that, It further includes a gastric-soluble film-coating premix, which is added at 2%-4% of the original composition weight.

4. A method for preparing the pharmaceutical composition according to any one of claims 1-3, characterized in that, The preparation is carried out using a dry granulation process including the following steps: (1) Tenofovir tartrate and pharmaceutical excipients were pretreated respectively. The pretreatment of pharmaceutical excipients was a drying loss pretreatment. The drying loss of microcrystalline cellulose PH101 and lactose monohydrate 14SD was controlled to be less than 1.0%, and the drying loss of croscarmellose sodium was controlled to be less than 1.5%. (2) Tenofovir tartrate acetate was premixed with microcrystalline cellulose PH101, lactose monohydrate 14SD, partially cross-linked sodium carboxymethyl cellulose and partially magnesium stearate; (3) Add the material obtained in (2) to a dry granulator for dry granulation; (4) Mix the material obtained in (3) with the remaining crosslinked sodium carboxymethyl cellulose and the remaining magnesium stearate; (5) Compress the material obtained in (4) to obtain tablet cores; (6) Optionally, the core obtained in (5) is coated to obtain coated sheets.

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