Pharmaceutical composition containing propofol fumarate tenofovir as well as preparation method and application of pharmaceutical composition

Abstract

The invention provides a pharmaceutical composition containing propofol fumarate and tenofovir, the pharmaceutical composition is composed of propofol fumarate and tenofovir, a filler, an adhesive, a flow aid, a disintegrating agent and a lubricant, the appropriate filler is adopted in the prescription, the problems of sticking and tabletting layering in traditional dry and wet granulation are effectively avoided, and the pharmaceutical composition is suitable for large-scale production. And meanwhile, the preparation has ideal safety, effectiveness and preparation stability, fills up corresponding market and technical vacancies, and has a wide industrial application prospect.

Description

Technical Field

[0001] The invention belongs to the field of medicines, and in particular relates to a pharmaceutical composition containing tenofovir alafenamide fumarate, a preparation method and an application thereof. Background Art

[0002] The tenofovir alafenamide fumarate preparation approved for marketing in China is a tablet with a specification of 25 mg, which is suitable for treating chronic hepatitis B in adults and adolescents (aged 12 years and above, weighing at least 35 kg), so long-term medication is required, and the usage and dosage is "once a day, one tablet at a time", which has high requirements for the patient's medication compliance. There is no oral anti-hepatitis B virus drug on the market that can be administered once a week. Through scientific experiments and attempts, the present invention surprisingly found that tenofovir alafenamide fumarate can be developed into an oral dosage form that can be administered once a week, which greatly improves the patient's long-term medication compliance, and at the same time has ideal safety, effectiveness and formulation stability, meets clinical needs and fills the market gap.

[0003] However, the development of a drug for once-a-week administration of tenofovir alafenamide fumarate requires at least 7 times the drug content to achieve considerable effectiveness and good safety. Domestic and foreign patents are all for the development of 25mg tablets, and the proportion of raw materials in the prescription is no more than 20%. Considering the poor compressibility, poor fluidity and easy sticking of tenofovir alafenamide raw materials, increasing the content of tenofovir alafenamide fumarate is likely to cause technical problems such as difficulty in prescription development and low dissolution, so a lot of work is still needed to solve the corresponding technical problems. Summary of the invention

[0004] In view of the above problems, the present invention provides a pharmaceutical composition containing tenofovir alafenamide fumarate, comprising the following components in weight percentage: 40.0% to 60.0% of tenofovir alafenamide fumarate, 1.0% to 8.0% of disintegrant, 0.1% to 3.0% of glidant, 0.5% to 6.0% of lubricant, 0.5% to 5.0% of binder, and the balance is filler;

[0005] The disintegrant is one or a mixture of more than one of cross-linked carboxymethyl cellulose sodium, cross-linked polyvinylpyrrolidone, and low-substituted hydroxypropyl cellulose;

[0006] The glidant is one or a mixture of more than one of silicon dioxide or talc;

[0007] The binder is one or a mixture of more than one of povidone or hypromellose;

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

[0009] The pharmaceutical composition only needs to be taken once a week, which greatly improves the patient's compliance. Considering that the original preparation of tenofovir alafenamide fumarate tablets is 25 mg, once a day, according to biopharmaceutics, pharmacology and clinical development experience, a specification of once-a-week administration is developed, and the dosage should be at least 25 mg×7 days (175 mg). It is found that the core weight of the original preparation is 200 mg. In order to facilitate patients to take, the present invention takes the tablet weight of the original preparation as a reference and develops a specification of 90 mg, once a week, 2 tablets / time.

[0010] If a once-a-day drug is developed into a once-a-week drug, the absorption of the preparation in the human body must be considered, especially the effectiveness must be 100% guaranteed. The original research company conducted a study on the antiviral ability of different doses of tenofovir alafenamide fumarate (8mg-120mg) and the marketed product TDF 300mg, and found that the minimum effective concentration of TFV in plasma at a dose of 8mg TAF under steady-state conditions was 2.1ng / mL, which had similar anti-hepatitis B virus activity as the marketed 300mg TDF. In order to bridge the effectiveness, the goal 1 of the present invention is: after a single dose of the preparation of the present invention, the concentration of TFV in plasma must not be less than 2.1ng / mL after one week, then the effectiveness can be bridged.

[0011] The dosage of the present invention is developed into a 90mg tablet from the original preparation of 25mg. Due to the increase in specifications, the drug dissolution may decrease. In order to prevent the absorption of tenofovir alafenamide in the body from being affected by dissolution, the technical goal 2 of the present invention is to adopt the method of import registration standards to achieve rapid release of tenofovir alafenamide tablets in vitro, which shall not be less than 85% in 15 minutes.

[0012] In addition, due to the increase in specifications and the reduction in auxiliary materials, and the easy sticking of the tenofovir alafenamide fumarate raw materials, the sticking problem in the tableting process needs to be solved; in addition, tenofovir alafenamide fumarate is unstable. As the dosage increases, the impurity limit control is lower, and it is necessary to select a suitable formula and process to improve the stability of the product. Objective 3 of the present invention: to develop a product with stable production process and good stability.

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

[0014] 1. After a single dose of the tablets prepared from the pharmaceutical composition of the present invention, the concentration of TFV in plasma should not be lower than the effective concentration of 2.1 ng / mL one week later, bridging effectiveness.

[0015] 2. The pharmaceutical composition of the present invention is prepared into tablets, and the dissolution and release rate are determined according to the dissolution and release rate determination method (Method 2, Part 4, General Rules 0931, Chinese Pharmacopoeia 2020 Edition), using 0.05 mol / L acetate buffer (pH 4.5), 500 ml as the dissolution medium, the rotation speed is 75 revolutions per minute, and the dissolution rate in 15 minutes shall not be less than 85%.

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

[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 ingredients in weight percentage: 40.0% to 60.0% of tenofovir alafenamide fumarate, 1.0% to 8.0% of disintegrant, 0.1% to 3.0% of glidant, 0.5% to 6.0% of lubricant, 0.5% to 5.0% of 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 ingredients in weight percentage: 45.0% to 60.0% of tenofovir alafenamide fumarate, 1.0% to 6.0% of disintegrant, 0.5% to 3.0% of glidant, 1.0% to 5.0% of lubricant, 1.0% to 4.0% of binder, and the balance is filler.

[0020] Furthermore, the present invention provides a pharmaceutical composition containing tenofovir alafenamide fumarate, comprising the following ingredients in weight percentage: 45.0% to 60.0% of tenofovir alafenamide fumarate, 1.0% to 5.0% of disintegrant, 0.5% to 2.0% of glidant, 1.0% to 4.0% of lubricant, 1.0% to 3.0% of binder, and the balance being filler.

[0021] Furthermore, the present invention provides a tenofovir alafenamide fumarate pharmaceutical composition, comprising the following components in weight percentage: 45.0% to 60.0% of tenofovir alafenamide fumarate, 2.0% to 4.0% of disintegrant, 0.5% to 1.5% of glidant, 1.0% to 3.0% of lubricant, 1.0% to 2.0% of 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 polyvidone can be selected from K30, K25 or K90.

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

[0025] Furthermore, in the above-mentioned pharmaceutical composition containing tenofovir alafenamide fumarate, the prescription is an internal and external phase structure, the external phase structure includes a lubricant, a glidant, a disintegrant and an external phase filler; the internal phase structure includes tenofovir alafenamide fumarate, an internal phase filler, and a binder.

[0026] Furthermore, the pharmaceutical composition is an internal and external addition structure, wherein the internal addition is tenofovir alafenamide fumarate, cross-linked polyvinylpyrrolidone and granulated lactose G200, and the external addition is colloidal silicon dioxide, cross-linked sodium carboxymethyl cellulose, a lubricant and spray-dried lactose F100.

[0027] Furthermore, the present invention further provides a preparation containing the above pharmaceutical composition, wherein the preparation also contains a pharmaceutically acceptable coating material.

[0028] The coating material may be a gastric soluble film coating powder, and the weight ratio range is pharmaceutical composition: coating material = 1:0.01-0.1.

[0029] The inventors of the present invention have developed a wet granulation preparation method based on the characteristics of tenofovir alafenamide fumarate, i.e., poor fluidity and stickiness, and the problems of stickiness and stratification need to be solved during the formulation development process. The inventors have developed a wet granulation preparation method for the above-mentioned internal and external addition structures, and the preparation method comprises the following steps:

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

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

[0032] 3) adding the granulation liquid to the material 1 for granulation to obtain material 2;

[0033] 4) wet granulating the material 2 to obtain material 3;

[0034] 5) drying the material 3 and performing dry granulation to obtain an internal phase mixture;

[0035] 6) After mixing the prescribed amount of the glidant, the disintegrant and the external phase filler with the internal phase mixture, the lubricant is added, the mixture is mixed and then tabletted to obtain the pharmaceutical composition.

[0036] One of the specific preparation methods is:

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

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

[0039] (3) Granulate the material in step (1) with the granulation liquid in step 2, with the liquid addition time of 4 to 6 minutes, stirring speed of 75 to 400 rpm, and shear speed of 100 to 500 rpm. After all the granulation liquid is added, keep the speed unchanged and continue granulation for 0.5 to 1.5 minutes.

[0040] (4) The material in step 3 is wet granulated through a comil with a sieve size of 6350 μm and a rotation speed of 1750 rpm.

[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) The dry particles in step 5 are dry sized with a sieve aperture of 1016 to 1575 μm and a rotation speed of 1000 to 4000 rpm to obtain an internal phase mixture 1.

[0043] (7) Pass the prescribed amount of colloidal silicon dioxide, crosslinked sodium carboxymethyl cellulose and lactose through a 20-60 mesh sieve and add them into a conical hopper together with the internal phase mixture 1 and mix them 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 into the hopper in step 7 for total mixing at a speed of 15 rpm for 5-10 min.

[0045] (10) Finally, an 8 mm round punch was used for tableting to obtain the desired tablets.

[0046] (11) The core tablet may be optionally coated.

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

[0048] The viruses include: HBV, HIV, etc.

[0049] The present invention has carried out the following technical exploration:

[0050] In the early stage of formula development, the inventors preliminarily determined the formula composition based on the excipient composition of the reference preparation and the compatibility results of the raw and excipients, and investigated the direct mixing tableting process, dry granulation process and wet granulation process (Example 1). It was found that the first tablet of the direct mixing tableting process had a sticking phenomenon, and the sticking was serious. The dry granulation process could not produce a ribbon, and the material powder stuck to the roller, which was caused by the raw material. The wet granulation process had a significant improvement in sticking, but the sticking phenomenon also occurred. In order to solve the sticking phenomenon, the inventors chose the wet granulation process and carried out a series of prescription optimizations, including investigating the ratio of microcrystalline / lactose in the internal phase, increasing the tablet weight, increasing the filler dosage (reducing the proportion of the raw material prescription), and increasing the amount of lubricant magnesium stearate, but none of them could solve the sticking problem. However, on the basis of increasing the tablet weight, the amount of the glidant silicon dioxide and the external phase microcrystalline cellulose was increased. When the proportion of the raw material was about 30%, no sticking phenomenon was found (prescription 7), and the compressibility was good, but the content before, during, and after tableting showed a significant downward trend, resulting in stratification, which may be caused by too much glidant. Prescription 6 suggests that using a reduced amount of glidant silicon dioxide will cause sticking. Based on this phenomenon, the inventors found that the glidant colloidal silicon dioxide cannot solve the problems of sticking and tableting stratification at the same time.

[0051] Microcrystalline cellulose is commonly used in tablets due to its good compressibility. In the present invention, microcrystalline cellulose is in the internal phase, and the granulation effect is poor. The results of the study of different microcrystalline / lactose ratios in Example 2 show that the more microcrystalline in the internal phase, the more fine powder will be produced even if the amount of water added increases. More than 73% is fine powder, resulting in sticking. In Example 4, the problem of sticking is solved by not adding microcrystalline cellulose to the internal phase, but the microcrystalline cellulose in the external phase causes a new problem in tableting - stratification. It is speculated that this is caused by the difference in particle size, density or fluidity of the internal and external phase excipients. Therefore, the inventors replaced the external phase microcrystalline cellulose PH102 with finer particle size microcrystalline cellulose PH101, calcium hydrogen phosphate with greater density and spray-dried lactose with better fluidity for research respectively. Surprisingly, it was found that when the external phase filler was replaced with spray-dried lactose, the stratification phenomenon was significantly improved - no stratification phenomenon occurred, and the tableting was smooth, thereby obtaining the tenofovir alafenamide fumarate pharmaceutical composition (prescription 12) of the present invention. The final tenofovir alafenamide fumarate pharmaceutical composition is composed of an active ingredient tenofovir alafenamide fumarate, a disintegrant, a binder, a glidant, and a lubricant; the rest is a filler, and the filler is lactose.

[0052] In the above-mentioned pharmaceutical composition, the filler lactose has two types, wherein the inner phase lactose is granulated lactose G200, and the outer phase lactose is spray-dried lactose F100, and the prescription amount of the inner phase granulated lactose accounts for 0.5 to 3 times of the outer phase granulated lactose, that is, G200:F100=3:(1 to 6).

[0053] The above-mentioned pharmaceutical composition is preferably an immediate release tablet, and the dosage range is preferably 60 to 240 mg / tablet. The amount of filler can be adjusted according to the change of tablet weight.

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

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

[0056] This patented development formula has the following 6 technical features:

[0057] 1. After a single dose of the tablets prepared from the pharmaceutical composition of the present invention, the concentration of TFV in plasma is greater than the effective concentration of 2.1 ng / mL one week later.

[0058] 2. The pharmaceutical composition of the present invention is used to prepare tablets. According to the dissolution and release determination method (Method 2, Part 4, General Rules 0931, Chinese Pharmacopoeia 2020 Edition), 0.05 mol / L acetate buffer (pH 4.5), 500 ml is used as the dissolution medium, the rotation speed is 75 revolutions per minute, and the solubility in 15 minutes is greater than 85%.

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

[0060] 4. The pharmaceutical composition of the present invention is prepared into tablets, which only need to be taken once a week to achieve effectiveness, greatly improving the compliance of taking the medicine.

[0061] 5. The pharmaceutical composition of the present invention is used to prepare tablets, and the related substances are more strictly controlled than those of the reference preparation, the degradation impurities are lower than 7.2 times the limit of the reference preparation, and the accelerated stability for 6 months is met, which solves the problem that wet granulation recorded in existing literature can increase the risk of related substances. DETAILED DESCRIPTION

[0062] The following examples are used to further illustrate the present invention but are not intended to limit the present invention.

[0063] In the following examples, tenofovir alafenamide fumarate was supplied by Shanghai Desano; povidone was supplied by Ashland; lactose was supplied by Meggle; microcrystalline cellulose was supplied by DuPont; calcium hydrogen phosphate was supplied by Spirax; colloidal silicon dioxide was supplied by Evonik; croscarmellose sodium was supplied by JRS; magnesium stearate was supplied by Peter Greven; and Opadry was supplied by Colorcon.

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

[0065] Table 1. Composition of the reference preparation

[0066]

[0067] The preparation method is as follows: tenofovir alafenamide fumarate is mixed with microcrystalline cellulose, part of cross-linked sodium carboxymethyl cellulose, lactose monohydrate and part of magnesium stearate, dry granulated, then mixed with the remaining cross-linked sodium carboxymethyl cellulose and magnesium stearate, tableted, and finally coated.

[0068] Domestic and foreign patents are all about developing a 25mg dosage form. The target product can be obtained by dry granulation, wet granulation and direct powder compression, but the proportion of raw materials in the prescription is no more than 20%. The tenofovir alafenamide fumarate pharmaceutical composition developed by the present invention has a raw material proportion of about 40%, and the raw material itself is relatively sticky and has poor fluidity, which brings great challenges to the formulation development. In order to screen the optimal process, dry granulation, wet granulation and direct powder compression were first investigated, as shown in Example 1.

[0069] Example 1 - Different process studies

[0070] Direct mixing tableting, dry granulation and wet granulation are commonly used processes for oral solid preparations. In order to screen suitable processes, the inventors have studied them respectively, referring to the original tablet formulation composition, lactose monohydrate and microcrystalline cellulose as fillers; cross-linked sodium carboxymethyl cellulose as a disintegrant, magnesium stearate as a lubricant, and additional glidants are added to improve the fluidity of the material. Prescription 1 is direct mixing tableting, and lactose F100 is selected. Prescriptions 2 and 3 are wet granulation and dry granulation, respectively, and granulated lactose G200 is selected. At the same time, povidone K30 is selected as a wet granulation binder. The detailed formulation composition is shown in Table 2.

[0071] Table 2. Composition of different process prescriptions

[0072]

[0073] * Used during the process, not present in the final preparation.

[0074] $ Direct compression uses microcrystalline cellulose PH102 with a larger particle size, while wet granulation and dry granulation use PH101 with a smaller particle size.

[0075] The preparation method of process 1-direct pressing is as follows:

[0076] (1) Pass the materials in the prescription amount other than magnesium stearate through a 40-mesh sieve and add them into a mixer for mixing at a speed of 15 rpm for 20 min.

[0077] (2) Pass the prescribed amount of magnesium stearate through a 60-mesh sieve and add it into the hopper in step 1 for total mixing at a speed of 10 rpm for 5 min.

[0078] (3) Finally, the desired tablets are obtained by tableting.

[0079] The preparation method of process 2-wet granulation is as follows.

[0080] (1) The prescribed amount of tenofovir alafenamide fumarate, lactose and internal phase microcrystalline cellulose were passed through a 30-mesh sieve and added to a wet granulator for mixing. The stirring speed was 130 rpm, the cutting speed was 500 rpm, and the mixing time was 5 min.

[0081] (2) Granulation liquid: Dissolve the prescribed amount of povidone in purified water and set aside.

[0082] (3) Granulate the material in step (1) with the granulation liquid in step 2, with a liquid addition time of 4 min, a stirring speed of 200 rpm, and a shear speed of 550 rpm. After all the granulation liquid is added, keep the speed unchanged and continue granulation for 0.5 min.

[0083] (4) The material in step 3 is wet granulated through a comil with a sieve size of 6350 μm and a rotation speed of 1750 rpm.

[0084] (5) Add the material from step 4 into a fluidized bed and dry it until the moisture content is less than 3%.

[0085] (6) The material in step 5 is dry granulated by comil with a sieve aperture of 1016 μm and a rotation speed of 1750 rpm to obtain an internal phase mixture 1.

[0086] (7) The prescribed amount of colloidal silicon dioxide, external phase microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose were passed through a 30-mesh sieve together with the internal phase mixture 1 and added into a conical hopper for mixing at a speed of 15 rpm for 10 min.

[0087] (8) Pass the prescribed amount of magnesium stearate through a 40-mesh sieve and add it into the hopper in step 7 for total mixing at a speed of 15 rpm for 5 min.

[0088] (10) Finally, an 8 mm round punch was used for tableting to obtain the desired tablets.

[0089] Process 3 - Dry granulation preparation method is as follows.

[0090] (1) The internal phase and auxiliary materials are screened through a 30-mesh screen and added to a mixing hopper for mixing at a speed of 15 rpm for 10 min.

[0091] (2) The material in step 1 is granulated by a dry granulator, with a main pressure of 6.0-10.0 MPa and a main shaft speed of 10 rpm / min.

[0092] Strip density 0.50g / cm 3 ~0.90g / cm 3 .

[0093] (3) The material of step 2 is dry granulated by comil, with a sieve aperture of 1016 μm and a rotation speed of 1750 rpm to obtain an internal phase mixture 1.

[0094] (4) Pass the external phase material through a 40-mesh filter and add it into the mixing hopper together with mixture 1 for total mixing at a speed of 15 rpm for 10 min.

[0095] (5) Finally, an 8 mm round punch is used for tableting to obtain the desired tablets.

[0096] The evaluation results of the basic items after the above prescription was compressed into tablets are shown in the following table

[0097] Table 3. Evaluation results of basic items of different processes

[0098]

[0099] Conclusion: In the direct tableting process, the first tablet of prescription 1 showed obvious sticking phenomenon, and it could not be tableted normally. Prescription 3 used the same process as the original research (dry granulation), and the ribbon was almost impossible to form, and the roller had serious sticky powder. Further proof was that the API itself was sticky, especially with high drug loading, and dry granulation could not be carried out normally. It was necessary to increase the amount of internal phase microcrystals and lactose to reduce the proportion of API, but the tablet weight would increase, and oral compliance would decrease. At the same time, considering the poor compressibility of API, the filler was rolled twice, resulting in high brittleness of the finished product, which was not easy to transport; Prescription 2 significantly improved the tableting effect after wet granulation, but sticking phenomenon still occurred. Based on the above findings, the inventors determined to use the wet granulation process to optimize the ratio of internal phase microcrystals / lactose.

[0100] Example 2 - Investigation of the ratio of microcrystalline cellulose to lactose

[0101] Microcrystalline cellulose is a plastic material with good compressibility but poor fluidity. Lactose is a brittle material with good fluidity but good flowability. The two are often used together and appear in marketed drugs. In order to solve the sticking phenomenon, the inventors investigated the formulations of different ratios of microcrystalline cellulose / lactose in the internal phase. The formulation composition is shown in the table below.

[0102] Table 4. Formulation composition of different microcrystalline cellulose / lactose ratios

[0103]

[0104]

[0105] *Used during processing, not present in the final preparation.

[0106] See recipe 2 for process

[0107] The particle size distribution and density of Prescription 2, Prescription 3 and Prescription 4 are shown in Table 5.

[0108] Table 5. Comparison of internal phase material properties at different microcrystalline cellulose / lactose ratios

[0109]

[0110] Conclusion: The above results show that the more microcrystalline cellulose there is, the more water is needed to add and the more fine powder is produced. When the fine powder is ≥73.6%, the above three prescriptions all show sticking phenomenon. Therefore, changing the ratio of microcrystalline / lactose cannot improve the sticking phenomenon.

[0111] Example 3-Prescription Optimization 1

[0112] Example 2 shows that changing the ratio of microcrystalline / lactose in the internal phase cannot improve the sticking phenomenon, which may be caused by the high proportion of raw materials (the proportion of all formulation patents or prescription raw materials in the prescription is not more than 20%). Therefore, optimization is carried out in the following three directions: Prescription 5: On the basis of Prescription 2, increase the amount of microcrystalline cellulose in the external phase and reduce the proportion of raw materials; Prescription 6: On the basis of Prescription 5, increase the amount of lubricant; Prescription 7: On the basis of Prescription 6, increase the amount of glidant. The detailed prescription composition is shown in the table below.

[0113] Table 6. Optimized prescription composition

[0114]

[0115] *Used during processing, not present in the final preparation.

[0116] The process refers to recipe 2 process.

[0117] Table 7. Evaluation results of basic items of different optimized prescriptions

[0118]

[0119] Conclusion: The sticking phenomenon of prescriptions 5 and 6 was improved, but sticking was still found after about 10 minutes of tableting; no sticking was found in prescription 7, and the compressibility and friability were good, but a new problem occurred during the tableting process - stratification. It is speculated that there is too much flow aid (2%), which causes excessive flow, but prescription 6 shows that when the flow aid is 1%, sticking occurs during tableting. Therefore, it can be concluded that adding the flow aid silicon dioxide can improve compressibility and solve the sticking phenomenon, but it will cause stratification. The problem of sticking and tableting stratification cannot be solved at the same time by adjusting the amount of external phase excipients. The next step is to optimize the composition of the internal phase prescription.

[0120] Example 4 - Internal Phase Optimization 2 (Removal of Internal Phase Microcrystalline Cellulose)

[0121] The results of Prescription 2, Prescription 3 and Prescription 4 show that the more microcrystalline in the internal phase, the more water is needed for granulation, and the more fine powder is produced. Based on this finding, the inventor removed the internal phase microcrystalline cellulose, and in order to reduce the risk of tableting stratification, the amount of colloidal silicon dioxide in the external phase was reduced to 0.5%, and the amount of external phase filler was reduced, and the tablet weight was set to 190 mg. The composition of the prescription is shown in the table below.

[0122] Table 8. Removal of microcrystal formulation composition

[0123]

[0124] *Used during processing, not present in the final preparation.

[0125] Prescription 8 and Prescription 9 are derived from the same batch of internal phase particles.

[0126] The process is described as follows:

[0127] (1) The prescribed amount of tenofovir alafenamide fumarate and lactose were passed through a 30-mesh sieve and added to a wet granulator for mixing. The stirring speed was 300 rpm, the cutting speed was 500 rpm, and the mixing time was 5 min.

[0128] (2) Granulation liquid: Dissolve the prescribed amount of povidone in purified water and set aside.

[0129] (3) Granulate the material in step (1) with the granulation liquid in step 2, with the liquid addition time of 5 min, stirring speed of 300 rpm, and shear speed of 500 rpm. After all the granulation liquid is added, keep the speed unchanged and continue granulation for 1.0 min.

[0130] (4) The material in step 3 is wet granulated through a comil with a sieve size of 6350 μm and a rotation speed of 1750 rpm.

[0131] (5) Add the material from step 4 into a fluidized bed and dry it until the moisture content is less than 3%.

[0132] (6) The material in step 5 is dry granulated by comil with a sieve aperture of 1016 μm and a rotation speed of 1750 rpm to obtain an internal phase mixture 1.

[0133] (7) The prescribed amount of colloidal silicon dioxide, microcrystalline cellulose (prescription 8) and cross-linked sodium carboxymethyl cellulose were passed through a 30-mesh sieve and added to a conical hopper together with the internal phase mixture 1 and mixed at a speed of 15 rpm for 10 minutes.

[0134] (8) Pass the prescribed amount of magnesium stearate through a 40-mesh sieve and add it into the hopper in step 7 for total mixing at a speed of 15 rpm for 5 min.

[0135] (10) Finally, an 8 mm round punch was used for tableting to obtain the desired tablets.

[0136] Table 9. Evaluation results of basic items of prescription 8 and prescription 9

[0137]

[0138] Conclusion: In prescription 9, no filler was added to the external phase, and sticking phenomenon occurred; in prescription 8, no sticking phenomenon was found, and the compressibility and friability were both good, with a fineness of 68.7%. However, stratification was found during the tableting process, which was considered to be the influence of the external phase filler. The next step is to investigate the influence of different types of fillers on tableting stratification.

[0139] Example 5 - Effect of different filler types on the external phase

[0140] Tableting stratification is generally affected by the large differences in particle size, density, fluidity and specific gravity between the inner and outer phases. Therefore, the effects of microcrystalline cellulose PH101 with a smaller particle size, calcium hydrogen phosphate with a higher density, and spray-dried lactose with better fluidity on tableting were investigated. The formulation composition is shown in the table below.

[0141] Table 10. Prescription composition of different filler types

[0142]

[0143]

[0144] *Used during processing, not present in the final preparation.

[0145] For the process, please refer to recipe 8.

[0146] The evaluation results of the basic items of Prescriptions 10 to 12 are shown in the table below.

[0147] Table 11. Evaluation results of basic items of different filler types

[0148]

[0149] Conclusion: From the content before, during and after tableting, it can be seen that microcrystalline cellulose PH101 and calcium hydrogen phosphate have significantly improved the tableting stratification, but there is still a risk of stratification; surprisingly, when the external phase filler is spray-dried lactose F100, no stratification was found during the tableting process, and the compressibility was good. In order to further verify whether the prescription 12 was stratified during the tableting process, 10 tablets were randomly selected for content uniformity determination, and the data are shown in the table below.

[0150] Table 12. Content uniformity results of formulation 12

[0151]

[0152]

[0153] The content uniformity results showed that the uniformity of formulation 12 was very good. The next step was to conduct a dissolution test as follows.

[0154] Dissolution test method: Take the test sample, follow the dissolution and release test method of the 2020 edition of the Chinese Pharmacopoeia, use 500mL pH4.5 acetate buffer as the dissolution medium, rotate at 75rpm, operate according to the law, take samples at different time points, filter through a 0.45μm filter membrane, and take the filtrate as the test solution; take an appropriate amount of tenofovir alafenamide fumarate reference substance, add methanol / dissolution medium (30:70) to dissolve and dilute to about 0.12mg / mL for use. Determine the ultraviolet absorbance of the test solution at 260nm and calculate the sample solubility.

[0155] Table 13. Dissolution data of Formulation 12

[0156]

[0157] The dissolution data showed that Formulation 12 had very rapid dissolution, greater than 85% in 15 minutes, meeting development goal 2.

[0158] Therefore, prescription 12 is the confirmed prescription of the present invention.

[0159] Next, the formulation and process QbD study was conducted on the target formulation 12.

[0160] Example 6 - Investigation of colloidal silicon dioxide levels

[0161] Prescription 7 found that although colloidal silicon dioxide can solve the sticking problem, there is a potential stratification phenomenon. The inventors investigated the effects of different colloidal silicon dioxide levels (0.5%, 1.0% and 1.5%) on tableting. The formulation composition is shown in the table below.

[0162] Table 14. Formulation composition of different glidant levels

[0163]

[0164]

[0165] * Removed during processing and not present in final product. Refer to recipe 12 process.

[0166] The evaluation results of the basic items of the prescription are shown in the table below.

[0167] Table 15. Evaluation results of basic items at different levels of glidants

[0168]

[0169] Conclusion: The above data show that 0.5% to 1.5% w / w colloidal silicon dioxide can be tableted smoothly without sticking and stratification, and the 15-min dissolution rate is greater than 85%. However, as the amount of flow aid increases, the content uniformity deteriorates, and all meet the quality standards of the Chinese Pharmacopoeia. The patented prescription of this invention, the amount of colloidal silicon dioxide is 0.5% to 1.5% w / w, which meets the tablet quality standards.

[0170] Example 7 - Investigation of Cross-linked Sodium Carboxymethyl Cellulose (CCNa) Levels

[0171] As a disintegrant, CCNa directly affects the disintegration time of tablets, and further affects the dissolution rate of tablets. In order to screen the optimal level of disintegrant, 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.

[0172] Table 16. Formulation composition of different disintegrant levels

[0173]

[0174]

[0175] * Removed during processing and not present in final product. Refer to recipe 12 process.

[0176] The evaluation results of the basic items of the prescription are shown in the table below.

[0177] Table 17. Evaluation results of basic items at different levels of glidants

[0178]

[0179] Conclusion: The above data show that 2.0% to 4.0% w / w CCNa can compress tablets smoothly, but when CCNa is 4% w / w, disintegration becomes slower. This may be because the disintegrant CCNa produces viscosity after contacting water, thus affecting the disintegration time, but the dissolution rate in 15 minutes has no effect and is greater than 85%. The patented prescription of the present invention, the amount of cross-linked sodium carboxymethyl cellulose (CCNa) of 2.0% to 4.0% w / w, meets the tablet quality standards.

[0180] Example 8 - Investigation of Magnesium Stearate Levels

[0181] Magnesium stearate, as a hydrophobic excipient, helps lubricate and prevent sticking during tableting, but excessive lubrication or excessive addition may affect the hardness, disintegration, dissolution and friability of the tablets. The inventors investigated the effects of different magnesium stearate levels (1%, 2% and 3% w / w) on tablet quality. The formulation composition is shown in the table below.

[0182] The content uniformity of prescription 10 and prescription 13-15 is shown in the table below.

[0183] Table 18. Investigation of different magnesium stearate levels

[0184]

[0185]

[0186] * Removed during processing and not present in final product. Refer to recipe 12 process.

[0187] The evaluation results of the basic items of the prescription are shown in the table below.

[0188] Table 19. Evaluation results of basic items at different magnesium stearate levels

[0189]

[0190] Conclusion: The above data show that 1.0% to 3.0% w / w magnesium stearate can compress smoothly. When magnesium stearate is 3% w / w, disintegration slows down, friability deteriorates, and compressibility decreases, but the dissolution rate in 15 minutes is not affected, which is greater than 85%. The patented prescription of the present invention, with magnesium stearate content of 1.0% to 3.0% w / w, meets the tablet quality standard.

[0191] Example 9 - Formulation Scale-up and Stability Studies

[0192] The inventors solved the problems of sticking and tableting delamination through a large number of experimental screenings and finally determined the target prescription (prescription 12). The next step is to scale up the prescription and conduct human pre-tests to bridge the effectiveness of the target prescription.

[0193] Considering that the original preparation is also a coated tablet, the tablet cores of the scaled-up batch were coated. The formulation composition of the scaled-up batch of 10,000 tablets is shown in the table below.

[0194] Table 20. Prescription composition for batch size of 10,000 tablets

[0195]

[0196]

[0197] *Used during processing, not present in the final preparation.

[0198] The core process refers to the process of prescription 12. The prepared tablets are coated with Opadry OY-LS-28914-CN. The coating process is described as follows:

[0199] 1. Preparation of coating solution: Prepare a coating solution with a solid content of 20% according to the ratio of coating powder to purified water = 18:82 (W:W), and continue stirring.

[0200] 2. Preheating: Set the coating pan speed to 3rpm (2-4rpm), the inlet air temperature to 45-55℃, the inlet air frequency to 1100rpm, the exhaust air frequency to 1900rpm, control the material temperature at 40-50℃, and preheat for 30 minutes.

[0201] 3. Spraying: Set the coating pan speed to 10rpm (8-12rpm), the air inlet temperature to 55-65℃, the air inlet frequency to 1100rpm, and the exhaust frequency to 1900rpm. Set the peristaltic pump speed to 4.5rpm, the ejector pressure to 0.2MPa, and the atomization pressure to 0.2MPa. Turn on the peristaltic pump and spray liquid, and control the material temperature at 40-50℃ for coating. After coating, continue drying for 30 minutes.

[0202] Table 21. Evaluation results of basic items of prescription 13

[0203]

[0204]

[0205] Note: ND: Not Detected; LOQ: 0.05%

[0206] After the release of the coated tablets, 30 ml HDPE bottles with 2 g dry bags were used as packaging and placed under accelerated conditions (40°C / 75% RH) to examine changes in key quality attributes such as content, related substances and dissolution.

[0207] The stability results of Formulation 13 are shown in the table below.

[0208] Table 22. Stability results of Formulation 13

[0209]

[0210] Conclusion: The above data show that the scaled-up formulations met tablet quality standards and development goal 3 after being placed under accelerated conditions for 6 months. The dissolution rate reached more than 85% in 15 minutes.

[0211] The next step is to conduct human pilot trials on the enlarged tablets to verify their effectiveness.

[0212] Validity Verification:

[0213] Study objective: To investigate the in vivo pharmacokinetic characteristics of multiple doses of tenofovir alafenamide fumarate tablets (experimental drug: tenofovir alafenamide fumarate tablets, specification: 90 mg) in healthy Chinese subjects under fasting conditions.

[0214] Experimental design: The trial adopted a single-center, multiple-dose, open-label design.

[0215] Trial Drugs:

[0216] Generic name: Tenofovir Alafenamide Fumarate Tablets; Specification: 90 mg / tablet, 2 tablets / time, once a week; Batch number: ASN230401;

[0217] Production date: 2023.04.20; Valid until: tentatively until 2025.04.118; Storage conditions: Store below 30℃

[0218] Number of subjects: 4 planned, 7 screened, 4 completed, and 4 analyzed.

[0219] Research method: The subjects were given 2 tablets of tenofovir alafenamide fumarate tablets (specification: 90 mg, prescription 13) per week for 4 consecutive cycles, respectively in the morning of D1, D8, D15 and D22.

[0220] The subjects fasted for at least 10 hours the night before each cycle of drug administration, and took 2 tablets of the test drug (specification: 90 mg) with 240 mL of warm water while keeping the upper body in an upright position on an empty stomach.

[0221] Conclusion: The above results show that the test preparation is taken once a week, and there is almost no accumulation of tenofovir in plasma. After taking it on the first day, the concentration of tenofovir in plasma is 3.66ng / mL after one week. After taking it for 4 consecutive weeks, the concentration of tenofovir in plasma is 4.15ng / mL, which is greater than the effective concentration of 2.1ng / mL.

[0222] The above description is only a preferred embodiment of the present invention. It should be pointed out that, for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A pharmaceutical composition containing tenofovir alafenamide fumarate, characterized in that: The invention comprises the following components in weight percentage: 40.0% to 60.0% of tenofovir alafenamide fumarate, 1.0% to 8.0% of a disintegrant, 0.1% to 3.0% of a glidant, 0.5% to 6.0% of a lubricant, 0.5% to 5.0% of a binder, and the balance is a filler; The disintegrant is one or a mixture of more than one of cross-linked carboxymethyl cellulose sodium, cross-linked polyvinylpyrrolidone, and low-substituted hydroxypropyl cellulose; The glidant is one or a mixture of more than one of silicon dioxide or talc; The binder is one or a mixture of more than one of povidone or hypromellose; The lubricant is one or a mixture of sodium stearyl 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 The invention comprises the following components in percentage by weight: 45.0% to 60.0% of tenofovir alafenamide fumarate, 1.0% to 6.0% of a disintegrant, 0.5% to 3.0% of a glidant, 1.0% to 5.0% of a lubricant, 1.0% to 4.0% of a binder, and the balance is a filler.

3. The pharmaceutical composition according to claim 1, characterized in that The invention comprises the following components in percentage by weight: 45.0% to 60.0% of tenofovir alafenamide fumarate, 1.0% to 5.0% of a disintegrant, 0.5% to 2.0% of a glidant, 1.0% to 4.0% of a lubricant, 1.0% to 3.0% of a binder, and the balance is a filler.

4. The pharmaceutical composition according to claim 1, characterized in that The invention comprises the following components in percentage by weight: 45.0% to 60.0% of tenofovir alafenamide fumarate, 2.0% to 4.0% of a disintegrant, 0.5% to 1.5% of a glidant, 1.0% to 3.0% of a lubricant, 1.0% to 2.0% of a binder, and the balance is a 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 prescription is an internal and external phase structure, wherein the external phase structure includes a lubricant, a glidant, a disintegrant and an external phase filler; and the internal phase structure includes tenofovir alafenamide fumarate, an internal phase filler and a binder.

7. A preparation containing the pharmaceutical composition according to any one of claims 1 to 6, characterized in that: The formulation further comprises 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) mixing a prescribed amount of tenofovir alafenamide fumarate and the internal phase filler to obtain material 1; 2) Granulation liquid: dissolving the prescribed amount of the binder in purified water to prepare a granulation liquid; 3) adding the granulation liquid to the material 1 for granulation to obtain material 2; 4) wet granulating the material 2 to obtain material 3; 5) drying the material 3 and performing dry granulation to obtain an internal phase mixture; 6) After mixing the prescribed amount of the glidant, the disintegrant and the external phase filler with the internal phase mixture, the lubricant is added, the mixture is mixed and then tabletted to obtain the pharmaceutical composition.

9. Use of the pharmaceutical composition according to any one of claims 1 to 6, or the preparation according to claim 7, or the pharmaceutical composition prepared by the preparation method according to claim 8 in the preparation of antiretroviral drugs.

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