Pharmaceutical composition comprising tenofovir alafenamide fumarate, preparation method therefor, and use thereof

Abstract

A pharmaceutical composition comprising tenofovir alafenamide fumarate, which consists of tenofovir alafenamide fumarate, a filler, a binder, a glidant, a disintegrant, and a lubricant, thereby avoiding the problems of sticking and tablet lamination associated with traditional dry and wet granulation processes, while also exhibiting formulation stability.

Description

Pharmaceutical compositions containing tenofovir alafenamide fumarate, preparation methods and applications Technical Field

[0001] This invention belongs to the field of pharmaceuticals, specifically relating to pharmaceutical compositions containing tenofovir alafenamide fumarate, their preparation methods, and their applications. Background Technology

[0002] The domestically approved tenofovir alafenamide fumarate formulation is in tablet form, 25mg in strength, suitable for treating chronic hepatitis B in adults and adolescents (aged 12 years and older, weighing at least 35kg). Therefore, long-term medication is required, with a dosage of one tablet once daily, placing high demands on patient adherence. Currently, there are no oral antiviral drugs for hepatitis B that can be administered once weekly. This invention, through scientific experimentation and trials, has surprisingly discovered that tenofovir alafenamide fumarate can be developed into a once-weekly oral dosage form, significantly improving long-term patient adherence while exhibiting ideal safety, efficacy, and formulation stability, meeting clinical needs and filling a market gap.

[0003] However, for the development of tenofovir alafenamide fumarate for once-weekly administration, a drug content of at least seven times the recommended level is needed to achieve substantial efficacy and good safety. Both domestic and international patents focus on developing 25mg tablets, with the active pharmaceutical ingredient (API) comprising no more than 20% of the formulation. Considering the inherent poor compressibility, poor flowability, and tendency to stick and dissolve in the API, increasing the content of tenofovir alafenamide fumarate easily leads to technical problems such as increased formulation development difficulty and low dissolution rates. Therefore, significant work is still needed to resolve these technical issues. Summary of the Invention

[0004] To address the above-mentioned problems, the present invention provides a pharmaceutical composition containing tenofovir alafenamide fumarate, comprising the following components by weight percentage: 40.0%–60.0% tenofovir alafenamide fumarate, 1.0%–8.0% disintegrant, 0.1%–3.0% flow aid, 0.5%–6.0% lubricant, 0.5%–5.0% binder, and the balance being filler;

[0005] The disintegrant is one or a mixture of more than one of crostomethyl cellulose sodium, crostopolyvinyl ketone, and low-substituted hydroxypropyl cellulose;

[0006] The flow aid is one or a mixture of more than one of silica or talc.

[0007] The adhesive is one or a mixture of more than one of polyvinylpyrrolidone or hydroxypropyl methylcellulose;

[0008] The lubricant is one or a mixture of more than one of sodium stearate fumarate or magnesium stearate; the filler is divided into an external phase filler and an internal phase filler, both of which are lactose.

[0009] This drug composition only needs to be taken once a week, greatly improving patient compliance. Considering that the original formulation, tenofovir alafenamide fumarate tablets, is 25 mg once daily, based on biopharmaceutics, pharmacology, and clinical development experience, a once-weekly dosage was developed, with a minimum dose of 25 mg × 7 days (175 mg). Research revealed that the original formulation has a tablet core weight of 200 mg. To facilitate patient administration, this invention uses the original formulation's tablet weight as a reference and developed a 90 mg dosage, 2 tablets once a week.

[0010] If a once-daily drug is to be developed for once-weekly use, the absorption of the formulation in the human body needs to be considered, especially ensuring 100% efficacy. The original manufacturer conducted antiviral studies on different doses of tenofovir alafenamide fumarate (8mg–120mg) and the marketed product TDF 300mg. They found that the minimum effective concentration of TFV in plasma at a dose of 8mg TAF under steady-state conditions was 2.1 ng / mL, and that TDF at 300mg had similar anti-hepatitis B virus activity. Therefore, to bridge efficacy, the first objective of this invention is: after a single dose of the formulation of this invention, the concentration of TFV in plasma should not be lower than 2.1 ng / mL one week later, thus bridging efficacy.

[0011] The dosage of this invention was developed from the original 25mg formulation to a 90mg tablet. Due to the increased dosage, drug dissolution may be reduced. In order to ensure that the absorption of tenofovir alafenamide in vivo is not affected by dissolution, the technical objective of this invention is: to achieve rapid in vitro release of tenofovir alafenamide tablets using imported registration standard methods, with a release rate not less than 85% within 15 minutes.

[0012] In addition, due to the increase in specifications and the reduction in excipients, and the fact that tenofovir alafenamide fumarate is prone to sticking and impaction, it is necessary to solve the sticking and impaction problem during the tableting process; furthermore, tenofovir alafenamide fumarate is unstable, and with the increase in dosage, the impurity limit control is lower, so it is necessary to select appropriate formulations and processes to improve product stability. Objective 3 of this invention: to develop products with stable production processes and good stability.

[0013] Therefore, the main technical objectives of this invention are as follows:

[0014] 1. The pharmaceutical composition of the present invention, when prepared into tablets, ensures that the concentration of TFV in plasma is not lower than the effective concentration of 2.1 ng / mL one week after a single dose, demonstrating bridging effectiveness.

[0015] 2. The pharmaceutical composition of the present invention, when prepared into tablets, shall be subjected to the dissolution and release assay (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II) using 0.05 mol / L acetate buffer (pH 4.5) in 500 ml as the dissolution medium and a rotation speed of 75 rpm. The dissolution rate shall not be less than 85% after 15 minutes.

[0016] 3. The pharmaceutical composition of the present invention is used to prepare tablets, and the manufacturing process is stable and the tablets have good stability.

[0017] The inventors conducted a series of formulation and process QbD studies based on the determined formulation composition to determine the range of each formulation composition.

[0018] Furthermore, the present invention provides a pharmaceutical composition containing tenofovir alafenamide fumarate, comprising the following components by weight percentage: 40.0% to 60.0% tenofovir alafenamide fumarate, 1.0% to 8.0% disintegrant, 0.1% to 3.0% flow aid, 0.5% to 6.0% lubricant, 0.5% to 5.0% binder, and the balance being filler.

[0019] Furthermore, the present invention provides a pharmaceutical composition containing tenofovir alafenamide fumarate, characterized in that it comprises the following components by weight percentage: 45.0% to 60.0% tenofovir alafenamide fumarate, 1.0% to 6.0% disintegrant, 0.5% to 3.0% flow aid, 1.0% to 5.0% lubricant, 1.0% to 4.0% binder, and the balance being filler.

[0020] Furthermore, the present invention provides a pharmaceutical composition containing tenofovir alafenamide fumarate, comprising the following components by weight percentage: 45.0% to 60.0% tenofovir alafenamide fumarate, 1.0% to 5.0% disintegrant, 0.5% to 2.0% flow aid, 1.0% to 4.0% lubricant, 1.0% to 3.0% binder, with the balance being filler.

[0021] Furthermore, the present invention provides a tenofovir alafenamide fumarate pharmaceutical composition comprising the following components by weight percentage: 45.0% to 60.0% tenofovir alafenamide fumarate, 2.0% to 4.0% disintegrant, 0.5% to 1.5% flow aid, 1.0% to 3.0% lubricant, 1.0% to 2.0% binder, and the balance being filler.

[0022] Furthermore, in the above-mentioned pharmaceutical composition containing tenofovir alafenamide fumarate, the lubricant is magnesium stearate; and the binder is povidone.

[0023] The povidone can be selected from K30, K25 or K90.

[0024] Furthermore, in the above-mentioned pharmaceutical composition containing tenofovir alafenamide fumarate, the lactose comprises spray-dried lactose and granulated lactose.

[0025] Furthermore, in the above-mentioned pharmaceutical composition containing tenofovir alafenamide fumarate, the formulation has an internal and external phase structure, wherein the external phase structure includes a lubricant, a flow aid, a disintegrant, and an external phase filler; and the internal phase structure includes tenofovir alafenamide fumarate, an internal phase filler, and a binder.

[0026] Furthermore, the pharmaceutical composition has an internal and external structure, wherein the internal additives are tenofovir alafenamide fumarate, crospovidone, and granulated lactose G200, and the external additives are colloidal silica, crospovidone sodium carboxymethyl cellulose, a lubricant, and spray-dried lactose F100.

[0027] Furthermore, the present invention provides a formulation comprising the above-described pharmaceutical composition, the formulation further comprising a pharmaceutically acceptable coating material.

[0028] The coating material can be a gastrosoluble film coating powder, with a weight ratio ranging from drug composition to coating material of 1:0.01-0.1.

[0029] Based on the characteristics of tenofovir alafenamide fumarate, namely poor flowability and stickiness, and the need to address stickiness and layering issues during formulation development, the inventors of this invention have developed a wet granulation preparation method for the aforementioned internal and external additive structures. This preparation method comprises the following steps:

[0030] 1) Mix the prescribed amount of tenofovir alafenamide fumarate and the internal phase filler to obtain material 1;

[0031] 2) Granulation solution: Dissolve the prescribed amount of the binder in purified water to prepare a granulation solution; (This is a conventional technique in the art)

[0032] 3) Add the granulation solution to the material 1 to granulate, and obtain material 2;

[0033] 4) The material 2 is wet-granulated to obtain material 3;

[0034] 5) After drying the material 3, dry granulation is performed to obtain an internal phase mixture;

[0035] 6) After mixing the prescribed amounts of the gliding agent, the disintegrant, and the external phase filler with the internal phase mixture, the lubricant is added for total mixing, and then the mixture is compressed into tablets to obtain the pharmaceutical composition.

[0036] One specific preparation method is:

[0037] (1) Pass the prescribed amount of tenofovir alafenamide fumarate and lactose through a 20-60 mesh sieve and add them to a wet granulator for mixing. The stirring speed is 75-400 rpm, the cutting speed is 100-500 rpm, and the mixing time is 5 min.

[0038] (2) Granulation solution: Dissolve the prescribed amount of povidone K30 in the required purified water and set aside.

[0039] (3) Granulate the material from step (1) using the granulation solution from step 2. The addition time is 4 to 6 minutes, the stirring speed is 75 to 400 rpm, and the shearing speed is 100 to 500 rpm. After all the granulation solution has been added, keep the speed constant and continue granulation for 0.5 to 1.5 minutes.

[0040] (4) The material from step 3 is wet-granulated through a comil with a screen aperture of 6350μm and a rotation speed of 1750rpm.

[0041] (5) Add the material from step 4 into a fluidized bed and dry it until the moisture content is less than 3%.

[0042] (6) Dry granulation of the dry particles from step 5, with a sieve aperture of 1016-1575 μm and a rotation speed of 1000-4000 rpm, to obtain internal phase mixture 1.

[0043] (7) The prescribed amounts of colloidal silica, cross-linked sodium carboxymethyl cellulose and lactose are passed through a 20-60 mesh sieve and added to the conical hopper along with the internal phase mixture 1 for mixing at a speed of 15 rpm for 10-20 min.

[0044] (8) Pass the prescribed amount of magnesium stearate through a 40-60 mesh sieve and add it to the hopper of step 7 for total mixing. The mixing speed is 15 rpm and the mixing time is 5-10 min.

[0045] (10) Finally, use an 8mm round punch to compress the tablets to obtain the desired tablets.

[0046] (11) The core can be selectively coated.

[0047] The present invention further provides the use of the above-described pharmaceutical composition or formulation, or the pharmaceutical composition prepared by the above-described preparation method, in the preparation of antiretroviral drugs.

[0048] The viruses mentioned are: HBV, HIV, etc.

[0049] The present invention has explored the following technologies:

[0050] In the early stages of formulation development, the inventors, based on the excipient composition of the reference formulation and the compatibility results of the raw materials and excipients, preliminarily determined the formulation composition and investigated direct mixing tableting, dry granulation, and wet granulation processes (Example 1). They found that in the direct mixing tableting process, sticking occurred in the first tablet, and the sticking was severe. Dry granulation could not produce strips, as the powder adhered to the rollers, which was caused by the active pharmaceutical ingredient. The wet granulation process significantly improved the sticking, but the sticking phenomenon still occurred. To address the punching problem, the inventors optimized the formulation using a wet granulation process, including investigating the ratio of internal microcrystalline particles to lactose, increasing tablet weight, increasing the filler dosage (reducing the proportion of active pharmaceutical ingredient), and increasing the amount of magnesium stearate as a lubricant. However, none of these methods resolved the punching issue. Increasing the amount of the gliding agent silica and the external microcrystalline cellulose while increasing the tablet weight resulted in no punching (Formula 7) when the active pharmaceutical ingredient proportion was approximately 30%, and good compressibility was observed. However, the content decreased significantly before, during, and after compression, leading to stratification, possibly due to excessive gliding agent. Formula 6 indicated that reducing the amount of gliding agent silica would cause punching. Based on this observation, the inventors found that colloidal silica as a gliding agent cannot simultaneously solve both punching and tablet stratification problems.

[0051] Microcrystalline cellulose is widely used in tablets due to its good compressibility. In this invention patent, microcrystalline cellulose is in the internal phase, resulting in poor granulation. The results of the study on different microcrystalline / lactose ratios in Example 2 show that the more microcrystalline cellulose in the internal phase, the more fine powder is produced even with increased water content, exceeding 73%, leading to sticking and condensation. Example 4 solved the sticking and condensation problem by not adding microcrystalline cellulose to the internal phase, but the presence of microcrystalline cellulose in the external phase caused a new problem during tableting—stratification. It is speculated that this is due to differences in particle size, density, or flowability between the internal and external phase excipients. Therefore, the inventors replaced the external phase microcrystalline cellulose PH102 with finer microcrystalline cellulose PH101, higher density dicalcium phosphate, and better flowability spray-dried lactose for further research. Surprisingly, when the external phase filler was replaced with spray-dried lactose, the stratification phenomenon was significantly improved—no stratification occurred, and tableting was smooth, thus obtaining the tenofovir alafenamide fumarate pharmaceutical composition of the present invention (Formula 12). The final tenofovir alafenamide fumarate pharmaceutical composition consists of the active ingredient tenofovir alafenamide fumarate, a disintegrant, a binder, a flow aid, and a lubricant; the remainder is a filler, which is lactose.

[0052] In the above-mentioned pharmaceutical composition, the filler lactose has two types: the internal phase lactose is granulated lactose G200, and the external phase lactose is spray-dried lactose F100. The formulation amount of the internal phase granulated lactose is 0.5 to 3 times that of the external phase granulated lactose, i.e., G200:F100 = 3:(1 to 6).

[0053] The above-mentioned pharmaceutical composition is preferably an immediate-release tablet, with a preferred dosage range of 60–240 mg / tablet. The amount of filler can be adjusted according to changes in tablet weight.

[0054] The inventors scaled up the formula and conducted preliminary human trials. After a single dose of 180 mg, the plasma tenofovir concentration was 3.66 ng / mL one week later.

[0055] The above-mentioned drug composition, when compressed into tablets, only needs to be taken once a week, and after one week the concentration of tenofovir in human plasma is not less than the effective concentration of 2.1 ng / mL.

[0056] This patented formulation has the following six technical features:

[0057] 1. The pharmaceutical composition of the present invention, when prepared into tablets, results in a plasma TFV concentration greater than the effective concentration of 2.1 ng / mL one week after a single dose.

[0058] 2. The pharmaceutical composition of the present invention, when prepared into tablets, is subjected to the dissolution and release assay (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II), using 0.05 mol / L acetate buffer (pH 4.5), 500 ml as the dissolution medium, and a rotation speed of 75 rpm. The dissolution rate is greater than 85% after 15 minutes.

[0059] 3. The pharmaceutical composition of the present invention has a raw material ratio of more than 45% w / w, smaller tablet weight, smaller size, and fewer inactive excipients, which greatly improves safety and medication compliance.

[0060] 4. The pharmaceutical composition of the present invention, when prepared into tablets, only needs to be taken once a week to achieve effectiveness, greatly improving medication adherence.

[0061] 5. The pharmaceutical composition of the present invention, when prepared into tablets, has more stringent control over related substances compared to the reference formulation, with degradation impurities being 7.2 times lower than the limit of the reference formulation, and meets the stability requirement of 6 months of accelerated processing, thus solving the problem of increased risk of related substances caused by wet granulation as described in existing literature. Detailed Implementation

[0062] The following examples are used to further illustrate the present invention, but are not limited to it.

[0063] In the following examples, tenofovir alafenamide fumarate was supplied by Shanghai Disano; povidone was supplied by Ashland; lactose was supplied by Metformin; microcrystalline cellulose was supplied by DuPont; dicalcium phosphate was supplied by Spartan; colloidal silica was supplied by Evonik; cross-linked sodium carboxymethyl cellulose was supplied by JRS; magnesium stearate was supplied by Peter Greven; and Opadry was supplied by Calocarboxy.

[0064] The composition of the reference formulation is shown in the table below.

[0065] Table 1. Formulation composition of the reference formulation

[0066] The preparation method is as follows: tenofovir alafenamide fumarate is mixed with microcrystalline cellulose, partially croscarmellose sodium, lactose monohydrate and partially magnesium stearate, granulated by dry method, then mixed with the remaining croscarmellose sodium and magnesium stearate, compressed into tablets, and finally coated.

[0067] Domestic and international patents all develop 25mg dosage forms, and the target product can be obtained using dry granulation, wet granulation, and direct powder compression. However, the proportion of active pharmaceutical ingredient (API) in the formulation is no more than 20%. The tenofovir alafenamide fumarate drug composition developed in this invention patent has an API proportion of approximately 40%, and the API itself is quite viscous and has poor flowability, which poses a significant challenge to formulation development. In order to screen for the optimal process, dry granulation, wet granulation, and direct powder compression were first investigated, as detailed in Example 1.

[0068] Example 1 - Study of Different Processes

[0069] Direct mixing tableting, dry granulation, and wet granulation are commonly used processes for oral solid dosage forms. To screen for a suitable process, the inventors conducted research on each. Referring to the original tablet formulation, lactose monohydrate and microcrystalline cellulose were used as fillers; croscarmellose sodium was used as a disintegrant; magnesium stearate was used as a lubricant; and a flow aid was added to improve the flowability of the material. Formulation 1 is direct mixing tableting, using lactose F100. Formulations 2 and 3 are wet granulation and dry granulation, respectively, using granulation lactose G200. Povidone K30 was selected as the wet granulation binder. Detailed formulation compositions are shown in Table 2.

[0070] Table 2. Composition of Formulations for Different Processes * It is used in the process but is not present in the final formulation. $ Direct compression uses microcrystalline cellulose PH102 with a larger particle size, while wet granulation and dry granulation use PH101 with a smaller particle size.

[0071] The preparation method of process 1 - direct pressure is as follows:

[0072] (1) Pass the prescribed amount of materials other than magnesium stearate through a 40-mesh sieve and add them to a mixer for mixing at 15 rpm for 20 min.

[0073] (2) Pass the prescribed amount of magnesium stearate through a 60-mesh sieve and add it to the hopper of step 1 for total mixing. The mixing speed is 10 rpm and the mixing time is 5 min.

[0074] (3) Finally, compress the tablets to obtain the desired tablets.

[0075] The preparation method of process 2 - wet granulation is as follows.

[0076] (1) Pass the prescribed amounts of tenofovir alafenamide fumarate, lactose and internal phase microcrystalline cellulose through a 30-mesh sieve and add them to a wet granulator for mixing. The stirring speed is 130 rpm, the cutting speed is 500 rpm, and the mixing time is 5 min.

[0077] (2) Granulation solution: Dissolve the prescribed amount of povidone in purified water and set aside.

[0078] (3) Granulate the material from step (1) using the granulation solution from step 2. The addition time is 4 min, the stirring speed is 200 rpm, and the shearing speed is 550 rpm. After all the granulation solution has been added, keep the speed constant and continue granulation for 0.5 min.

[0079] (4) The material from step 3 is wet-granulated through a comil with a screen aperture of 6350μm and a rotation speed of 1750rpm.

[0080] (5) Add the material from step 4 into a fluidized bed and dry it until the moisture content is less than 3%.

[0081] (6) The material from step 5 is dry-granulated through a comil with a screen aperture of 1016 μm and a rotation speed of 1750 rpm to obtain an internal phase mixture 1.

[0082] (7) The prescribed amounts of colloidal silica, external phase microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose are passed through a 30-mesh sieve and added to the conical hopper along with the internal phase mixture 1 for mixing at a speed of 15 rpm for 10 min.

[0083] (8) Pass the prescribed amount of magnesium stearate through a 40-mesh sieve and add it to the hopper of step 7 for total mixing. The mixing speed is 15 rpm and the mixing time is 5 min.

[0084] (10) Finally, use an 8mm round punch to compress the tablets to obtain the desired tablets.

[0085] The preparation method of process 3 - dry granulation is as follows.

[0086] (1) Pass the internal phase auxiliary materials through a 30-mesh sieve, add them to the mixing hopper and mix at 15 rpm for 10 min.

[0087] (2) Granulate the material from step 1 using a dry granulator. Main pressure: 6.0~10.0 MPa; main shaft speed: 10 rpm / min. The density of the strip is 0.50 g / cm³. 3 ~0.90g / cm 3 .

[0088] (3) The material from step 2 was dry-granulated through a comil with a screen aperture of 1016 μm and a rotation speed of 1750 rpm to obtain an internal phase mixture 1.

[0089] (4) Add the external phase material through a 40-mesh sieve and mix it together with mixture 1 into the mixing hopper for total mixing. The mixing speed is 15 rpm and the mixing time is 10 min.

[0090] (5) Finally, use an 8mm round punch to compress the tablets to obtain the desired tablets.

[0091] The basic evaluation results of the above prescription after being compressed into tablets are shown in the table below.

[0092] Table 3. Evaluation Results of Basic Items for Different Processes

[0093] Conclusion: Formulation 1 exhibited significant sticking and punching in the first tablet during direct compression, making normal tableting impossible. Formulation 3, using the same process as the original drug (dry granulation), showed almost no formation of the tablet strips, with severe powder adhesion on the rollers. This further proves that the active pharmaceutical ingredient (API) itself is quite viscous, especially with high drug loading, making dry granulation impossible. Increasing the amount of internal phase microcrystals and lactose to reduce the API proportion would increase tablet weight, thus reducing oral compliance. Furthermore, considering the poor compressibility of the API, the filler undergoes two rounds of rolling, resulting in high brittleness and difficulty in transportation. Formulation 2, after wet granulation, significantly improved the tableting effect, but sticking and punching still occurred. Based on these findings, the inventors determined to use a wet granulation process and optimize the internal phase microcrystal / lactose ratio.

[0094] Example 2 - Investigation of the microcrystalline cellulose / lactose ratio

[0095] Microcrystalline cellulose is a plastic material with good compressibility but poor flowability, while lactose is a brittle material with good flowability. The two are often used together in marketed drugs. In order to solve the sticking phenomenon, the inventors investigated formulations with different ratios of internal phase microcrystalline cellulose / lactose. The formulation composition is shown in the table below.

[0096] Table 4. Composition of formulations with different microcrystalline cellulose / lactose ratios

[0097] *Used during the process, but not in the final formulation.

[0098] See prescription 2 for the process.

[0099] The particle size distribution and density of formulations 2, 3 and 4 are shown in Table 5.

[0100] Table 5. Comparison of properties of internal phase materials with different microcrystalline cellulose / lactose ratios

[0101] Conclusion: The above results show that the more microcrystalline cellulose there is, the more water is required, and the more fine powder is produced. When the fine powder content is ≥73.6%, all three formulations exhibit sticking and clogging. Therefore, changing the microcrystalline / lactose ratio cannot improve the sticking and clogging phenomenon.

[0102] Example 3 - Prescription Optimization 1

[0103] Example 2 shows that changing the ratio of internal phase microcrystalline cellulose to lactose does not improve the sticking phenomenon, which may be due to the high proportion of raw materials (a search revealed that the proportion of active pharmaceutical ingredients in all current formulation patents or prescriptions is no more than 20%). Therefore, optimization is carried out in the following three directions: Prescription 5: Based on prescription 2, increase the amount of external phase microcrystalline cellulose and reduce the proportion of raw materials; Prescription 6: Based on prescription 5, increase the amount of lubricant; Prescription 7: Based on prescription 6, increase the amount of flow aid. Detailed prescription composition is shown in the table below.

[0104] Table 6. Optimized Prescription Composition

[0105] *Used during the process, but not in the final formulation.

[0106] Process reference formula 2 process.

[0107] Table 7. Evaluation Results of Basic Items for Different Optimized Prescriptions

[0108] Conclusion: Formulations 5 and 6 showed some improvement in adhesion and punching, but adhesion and punching still occurred after approximately 10 minutes of compression. Formulation 7 did not show adhesion and punching, and exhibited good compressibility and brittleness; however, a new problem arose during compression—stratification. This was presumably due to excessive flow aid (2%), but formulation 6 showed adhesion and punching even with a flow aid concentration of 1%. Therefore, it can be concluded that increasing the flow aid silica can improve compressibility and resolve adhesion and punching, but it will cause stratification. Adjusting the amount of external excipients cannot simultaneously solve both adhesion and tableting stratification problems. The next step is to optimize the internal formulation composition.

[0109] Example 4 - Internal Phase Optimization 2 (Removal of Internal Phase Microcrystalline Cellulose)

[0110] Results from formulations 2, 3, and 4 showed that the more internal microcrystalline cellulose there was, the more water was required during granulation, and the more fine powder was produced. Based on this finding, the inventors removed the internal microcrystalline cellulose. Simultaneously, to reduce the risk of tablet delamination, the amount of external colloidal silica was reduced to 0.5%, and the amount of external filler was also reduced, resulting in a tablet weight of 190 mg. The formulation composition is shown in the table below.

[0111] Table 8. Removal of Microcrystalline Formulation Composition

[0112] *Used during the process, but not in the final formulation.

[0113] Prescription 8 and Prescription 9 are derived from the same batch of internal phase particles.

[0114] The process is described as follows:

[0115] (1) Mix the prescribed amount of tenofovir alafenamide fumarate and lactose together through a 30-mesh sieve and add them to a wet granulator for mixing. The stirring speed is 300 rpm, the cutting speed is 500 rpm, and the mixing time is 5 min.

[0116] (2) Granulation solution: Dissolve the prescribed amount of povidone in purified water and set aside.

[0117] (3) Granulate the material from step (1) using the granulation solution from step 2. The addition time is 5 min, the stirring speed is 300 rpm, and the shearing speed is 500 rpm. After all the granulation solution has been added, keep the speed constant and continue granulation for 1.0 min.

[0118] (4) The material from step 3 is wet-granulated through a comil with a screen aperture of 6350μm and a rotation speed of 1750rpm.

[0119] (5) Add the material from step 4 into a fluidized bed and dry it until the moisture content is less than 3%.

[0120] (6) The material from step 5 is dry-granulated through a comil with a screen aperture of 1016 μm and a rotation speed of 1750 rpm to obtain an internal phase mixture 1.

[0121] (7) The prescribed amounts of colloidal silica, microcrystalline cellulose (prescription 8) and cross-linked sodium carboxymethyl cellulose are passed through a 30-mesh sieve and added to the conical hopper along with the internal phase mixture 1 for mixing at a speed of 15 rpm for 10 min.

[0122] (8) Pass the prescribed amount of magnesium stearate through a 40-mesh sieve and add it to the hopper of step 7 for total mixing. The mixing speed is 15 rpm and the mixing time is 5 min.

[0123] (10) Finally, use an 8mm round punch to compress the tablets to obtain the desired tablets.

[0124] Table 9. Evaluation Results of Basic Items in Prescriptions 8 and 9

[0125] Conclusion: Formulation 9, without any filler in the external phase, exhibited sticking and punching phenomena; Formulation 8 did not show sticking and punching phenomena, and had good compressibility and brittleness with a fragmentation rate of 68.7%, but stratification was observed during tableting, which is considered to be the influence of the external phase filler. The next step is to investigate the effect of different types of fillers on tableting stratification.

[0126] Example 5 - Effect of different types of external phase fillers

[0127] Tableting separation is generally affected by significant differences in particle size, density, flowability, and specific gravity between the internal and external phases. Therefore, the effects of microcrystalline cellulose PH101 with smaller particle size, calcium hydrogen phosphate with higher density, and spray-dried lactose with better flowability on the tableting effect were investigated. The formulation composition is shown in the table below.

[0128] Table 10. Formulation composition of different filler types

[0129] *Used during the process, but not in the final formulation.

[0130] For the process, please refer to Formula 8.

[0131] The evaluation results of the basic items of prescriptions 10 to 12 are shown in the table below.

[0132] Table 11. Evaluation Results of Basic Items for Different Types of Fillers

[0133] Conclusion: Analysis of the content before, during, and after tableting showed that microcrystalline cellulose PH101 and dicalcium phosphate significantly improved tablet separation, but the risk of separation still existed. Surprisingly, when the external phase filler was spray-dried lactose F100, no separation was observed during tableting, and the tablets exhibited good compressibility. To further verify whether separation occurred during the tableting process of Formulation 12, 10 tablets were randomly selected for content uniformity determination; the data are shown in the table below.

[0134] Table 12. Results of content uniformity of prescription 12

[0135] The content uniformity results showed that the uniformity of formulation 12 was very good. The next step is to conduct a dissolution test, which is carried out as follows.

[0136] Dissolution test method: Take the test sample and perform the dissolution and release test according to the Chinese Pharmacopoeia 2020 edition, using 500 mL of pH 4.5 acetate buffer as the dissolution medium and rotating at 75 rpm. Take samples at different time points, filter through a 0.45 μm filter membrane, and use the filtrate as the test solution. Take an appropriate amount of tenofovir alafenamide fumarate reference standard, dissolve and dilute it to approximately 0.12 mg / mL in methanol / dissolution medium (30:70), and set aside. Measure the UV absorbance of the test solution at 260 nm and calculate the sample dissolution rate.

[0137] Table 13. Dissolution data for Formula 12

[0138] Dissolution data show that Formulation 12 dissolves very rapidly, with a dissolution rate of over 85% within 15 minutes, meeting Development Target 2.

[0139] Therefore, prescription 12 is the prescription determined by this invention patent.

[0140] The next step is to conduct formulation and process QbD studies on target formulation 12.

[0141] Example 6 - Investigation of Colloidal Silica Levels

[0142] Formula 7 found that although colloidal silica can solve the sticking problem, it has the potential for delamination. The inventors investigated the effect of different levels of colloidal silica (0.5%, 1.0% and 1.5%) on tableting. The formulation composition is shown in the table below.

[0143] Table 14. Formulation composition for different levels of gliding agents

[0144] *Removed during the process and not present in the final product. Refer to Formula 12 for the process.

[0145] The evaluation results of the basic prescription items are shown in the table below.

[0146] Table 15. Evaluation Results of Basic Items for Different Levels of Drifting Agents

[0147] Conclusion: The above data show that 0.5%–1.5% w / w colloidal silica resulted in smooth tableting without sticking or delamination, and the dissolution rate at 15 min was greater than 85%. However, the content uniformity decreased with increasing flow aid dosage, but all met the quality standards of the Chinese Pharmacopoeia. The formulation of this patented invention, with a colloidal silica content of 0.5%–1.5% w / w, meets the tablet quality standards.

[0148] Example 7 - Investigation of cross-linked carboxymethyl cellulose sodium (CCNa) levels

[0149] CCNa, as a disintegrant, directly affects the disintegration time of tablets, and thus the dissolution rate. To screen for the optimal disintegrant level, the inventors investigated the effects of different CCNa levels (2%, 3%, and 4% w / w) on tablet disintegration and dissolution. The formulation composition is shown in the table below.

[0150] Table 16. Formulation composition at different disintegrant levels

[0151] *Removed during the process and not present in the final product. Refer to Formula 12 for the process.

[0152] The evaluation results of the basic prescription items are shown in the table below.

[0153] Table 17. Evaluation Results of Basic Items for Different Levels of Drifting Agents

[0154] Conclusion: The above data show that tableting proceeds smoothly with 2.0%–4.0% w / w CCNa. However, disintegration slows down when CCNa is 4% w / w. This may be because the disintegrant CCNa increases viscosity upon contact with water, thus affecting the disintegration time. However, the dissolution rate at 15 minutes is unaffected, remaining above 85%. The formulation of this patented invention, with 2.0%–4.0% w / w croscarmellose sodium (CCNa), meets the tablet quality standards.

[0155] Example 8 - Investigation of magnesium stearate levels

[0156] Magnesium stearate, as a hydrophobic excipient, helps lubricate during tableting and prevents sticking. However, excessive lubrication or excessive addition may affect tablet hardness, disintegration, dissolution, and friability. The inventors investigated the effects of different levels of magnesium stearate (1%, 2%, and 3% w / w) on tablet quality. The formulation composition is shown in the table below.

[0157] The content uniformity of prescriptions 10 and 13-15 is shown in the table below.

[0158] Table 18. Investigation of different magnesium stearate levels

[0159] *Removed during the process and not present in the final product. Refer to Formula 12 for the process.

[0160] The evaluation results of the basic prescription items are shown in the table below.

[0161] Table 19. Evaluation Results of Basic Items at Different Magnesium Stearate Levels

[0162] Conclusion: The above data show that tableting is smooth with magnesium stearate content ranging from 1.0% to 3.0% w / w. At 3% w / w, disintegration is slower, friability is worse, and compressibility decreases, but the dissolution rate at 15 minutes is unaffected, remaining above 85%. The formulation of this patented invention, with magnesium stearate content ranging from 1.0% to 3.0% w / w, meets the tablet quality standards.

[0163] Example 9 - Formula Scale-up and Stability Study

[0164] Through extensive testing and screening, the inventors solved the problems of adhesion and tablet delamination, and finally determined the target formulation (Formulation 12). The next step is to scale up the formulation and conduct human pre-trials to bridge the effectiveness of the target formulation.

[0165] Considering that the original formulation was also a coated tablet, a coating process was applied to the tablet cores for the scaled-up batch. The formulation composition of the 10,000-tablet scaled-up batch is shown in the table below.

[0166] Table 20. Composition of the 10,000-tablet dosage formula

[0167] *Used during the process, but not in the final formulation.

[0168] The tablet core manufacturing process follows the process described in Formula 12. The resulting tablets are coated using Opadry OY-LS-28914-CN. The coating process is described below:

[0169] 1. Preparation of coating solution: Prepare a coating solution with a solid content of 20% by mixing coating powder and purified water at a ratio of 18:82 (W:W) and stir continuously.

[0170] 2. Preheating: Set the coating pan speed to 3 rpm (2-4 rpm), the air inlet temperature to 45-55℃, the air inlet frequency to 1100 rpm, the air outlet frequency to 1900 rpm, and control the material temperature at 40-50℃ for 30 minutes.

[0171] 3. Spraying: Set the coating pan speed to 10 rpm (8–12 rpm), inlet air temperature to 55–65℃, inlet air frequency to 1100 rpm, and exhaust air frequency to 1900 rpm. Set the peristaltic pump speed to 4.5 rpm, the ejector pin pressure to 0.2 MPa, and the atomization pressure to 0.2 MPa. Turn on the peristaltic pump and spray, and control the material temperature at 40–50℃ for coating. After coating, continue drying for 30 minutes.

[0172] Table 21. Evaluation Results of Basic Items in Prescription 13

[0173] Notes: ND: Not detected; LOQ: 0.05%

[0174] After the coated tablets were released, they were packaged in 30ml HDPE bottles with 2g desiccant bags and placed under accelerated conditions (40℃ / 75%RH) to investigate changes in key quality attributes such as content, related substances, and dissolution.

[0175] The stability results of prescription 13 are shown in the table below.

[0176] Table 22. Stability results of prescription 13

[0177] Conclusion: The above data show that the scaled-up formulation, after being placed under accelerated conditions for 6 months, meets the tablet quality standards and fulfills development target 3, achieving a dissolution rate of over 85% at 15 minutes.

[0178] The next step is to conduct preliminary human trials on the amplified tablets to verify their effectiveness.

[0179] Validity verification:

[0180] Study objective: To investigate the pharmacokinetic characteristics of multiple doses (test drug: tenofovir alafenamide fumarate tablets, strength: 90 mg) in healthy Chinese subjects under fasting conditions.

[0181] Experimental design: The experiment adopted a single-center, multiple-dose, open-label design.

[0182] Experimental drug:

[0183] Generic name: Tenofovir alafenamide fumarate tablets; Specification: 90mg / tablet, 2 tablets / dose, once a week; Batch number: ASN230401;

[0184] Production Date: April 20, 2023; Expiry Date: Tentatively until April 11, 2025; Storage Conditions: Store below 30℃.

[0185] Number of participants: 4 planned, 7 screened, 4 completed, and 4 analyzed.

[0186] Study Methods: Subjects were given two tenofovir alafenamide fumarate tablets (90 mg, prescription 13) weekly for four consecutive cycles on the mornings of days 1, 8, 15, and 22.

[0187] Subjects should fast overnight for at least 10 hours the night before each administration cycle, and take two tablets of the test drug (90mg) with 240mL of warm water while maintaining an upright position on an empty stomach.

[0188] Conclusion: The above results show that when the test formulation is administered once a week, there is almost no accumulation of tenofovir in plasma. After one week of administration on the first day, the plasma concentration of tenofovir was 3.66 ng / mL. After four weeks of continuous administration, the plasma concentration of tenofovir was 4.15 ng / mL, which is greater than the effective concentration of 2.1 ng / mL.

[0189] The above description is only a preferred embodiment of the present invention. It should be noted that, for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A pharmaceutical composition containing tenofovir alafenamide fumarate, characterized in that, It includes the following components by weight percentage: tenofovir alafenamide fumarate 40.0%–60.0%, disintegrant 1.0%–8.0%, flow aid 0.1%–3.0%, lubricant 0.5%–6.0%, binder 0.5%–5.0%, and the balance being filler; The disintegrant is one or a mixture of more than one of crostomethyl cellulose sodium, crostopolyvinyl ketone, and low-substituted hydroxypropyl cellulose; The flow aid is one or a mixture of more than one of silica or talc. The adhesive is one or a mixture of more than one of polyvinylpyrrolidone or hydroxypropyl methylcellulose; The lubricant is one or a mixture of more than one of sodium stearate fumarate or magnesium stearate; the filler is divided into an external phase filler and an internal phase filler, both of which are lactose.

2. The pharmaceutical composition according to claim 1, characterized in that, It includes the following components by weight percentage: tenofovir alafenamide fumarate 45.0%–60.0%, disintegrant 1.0%–6.0%, flow aid 0.5%–3.0%, lubricant 1.0%–5.0%, binder 1.0%–4.0%, and the balance being filler.

3. The pharmaceutical composition according to claim 1, characterized in that, It includes the following components by weight percentage: tenofovir alafenamide fumarate 45.0%–60.0%, disintegrant 1.0%–5.0%, flow aid 0.5%–2.0%, lubricant 1.0%–4.0%, binder 1.0%–3.0%, and the balance being filler.

4. The pharmaceutical composition according to claim 1, characterized in that, It includes the following components by weight percentage: tenofovir alafenamide fumarate 45.0%–60.0%, disintegrant 2.0%–4.0%, flow aid 0.5%–1.5%, lubricant 1.0%–3.0%, binder 1.0%–2.0%, and the balance being filler.

5. The pharmaceutical composition according to claim 1, characterized in that, The lactose includes spray-dried lactose and granulated lactose.

6. The pharmaceutical composition according to claim 1, characterized in that, The formulation has an internal and external phase structure. The external phase structure includes a lubricant, a flow aid, a disintegrant, and an external phase filler. The internal phase structure includes tenofovir alafenamide fumarate, an internal phase filler, and a binder.

7. A formulation comprising the pharmaceutical composition according to any one of claims 1-6, characterized in that, The formulation also includes a pharmaceutically acceptable coating material.

8. The method for preparing the pharmaceutical composition according to claim 1, characterized in that, It consists of the following steps: 1) Mix the prescribed amount of tenofovir alafenamide fumarate and the internal phase filler to obtain material 1; 2) Granulation solution: Dissolve the prescribed amount of the binder in purified water to prepare a granulation solution; 3) Add the granulation solution to the material 1 to granulate, and obtain material 2; 4) The material 2 is wet-granulated to obtain material 3; 5) After drying the material 3, dry granulation is performed to obtain an internal phase mixture; 6) After mixing the prescribed amounts of the gliding agent, the disintegrant, and the external phase filler with the internal phase mixture, the lubricant is added for total mixing, and then the mixture is compressed into tablets to obtain the pharmaceutical composition.

9. The use of a pharmaceutical composition according to any one of claims 1-6, or a formulation according to claim 7, or a pharmaceutical composition prepared by the preparation method according to claim 8, in the preparation of an antiretroviral drug.

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