Pharmaceutical composition with improved stability comprising tenofovir alafenamide or pharmaceutically acceptable salt thereof

Abstract

The present invention discloses a pharmaceutical composition with improved stability that contains tenofovir alafenamide or its pharmaceutically acceptable salt.

Description

PHARMACEUTICAL COMPOSITION WITH IMPROVED STABILITY COMPRISING TENOFOVIR ALAFENAMIDE OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF

[0001] The present invention relates to a pharmaceutical composition with improved stability comprising tenofovir alafenamide or a pharmaceutically acceptable salt thereof, and more particularly to a pharmaceutical composition comprising tenofovir alafenamide succinate as an active ingredient for the treatment of chronic hepatitis B.

[0002] Tenofovir alafenamide is a compound represented by chemical formula 1 below, exhibiting antiviral activity and being used as an antiviral agent for the treatment of chronic hepatitis B.

[0003] [Chemical Formula 1]

[0004]

[0005] Various attempts have been made to improve the stability of tenofovir alafenamide by modifying the salt of tenofovir alafenamide. Particularly, International Patent Publication No. 2016 / 192692 (Patent Document 1) discloses acid addition salts of tenofovir alafenamide.

[0006] Among the various acid addition salts, tenofovir alafenamide succinate is known to undergo hydrolysis due to its unstable carboxyl-ester bond, leading to the generation of the related substances during the hydrolysis process (Non-Patent Document 1).

[0007] Thus, there is a need for the development of pharmaceutical compositions to enhance stability by preventing the generation of the related substances.

[0008] [Prior Arts]

[0009] [Patent Document]

[0010] (Patent Document 1)

[0011] International Patent Publication No. 2016 / 192692

[0012] [Non-Patent Document]

[0013] (Non-Patent Document 1) Development of Tenofovir Prodrugs as Rectal Microbicides for HIV Prevention, University of Pittsburgh (2016)

[0014] The present invention is to address the above-mentioned issues and provide a pharmaceutical composition with stability secured by using a specific additive to inhibit the generation of the related substances of tenofovir alafenamide succinate under severe and accelerated open conditions.

[0015] The technical solutions described below are disclosed to solve the technical problems above.

[0016] In one aspect, the present invention discloses a pharmaceutical composition comprising tenofovir alafenamide succinate.

[0017] The pharmaceutical composition containing tenofovir alafenamide succinate according to the present invention has the advantage of containing a specific additive to inhibit the generation of related substances, thereby improving stability and ensuring a sufficient shelf life.

[0018] The effects of the present invention are not limited to the above-mentioned effects, and various effects may be included within the range that is obvious to those skilled in the art from the description below.

[0019] Hereinafter, the Specification of the present application is described in more details.

[0020] The Specification of the present application is described specifically. The terms used in the present invention have been selected as widely used general terms as possible in consideration of the functions in the present invention, but they may vary according to the intention or precedent of those skilled in the art, the emergence of new technologies and the like. In addition, in certain cases, there is also a term arbitrarily selected by the applicant, in which case the meaning will be described in detail in the detailed description of the invention. Therefore, the terms used in the present invention should be defined based on the meanings of the terms and the contents throughout the present invention, rather than the names of the simple terms.

[0021] Unless defined otherwise, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art. Terms such as those defined in the commonly used dictionaries should be construed as having meanings consistent with the meanings in the context of the related art and shall not be construed in ideal or excessively formal meanings unless expressly defined in this application.

[0022] The numerical range includes the numerical values defined in the range. All maximum numerical limits given throughout this Specification include all lower numerical limits as if the lower numerical limits were clearly written. All minimum numerical limits given throughout this Specification include all higher numerical limitations as if the higher numerical limit were clearly written. All numerical limitations given throughout this Specification will include all better numerical ranges within the broader numerical range, as if the narrower numerical limitations were clearly written.

[0023] Hereinafter, each description and embodiment disclosed in the present invention may also be applied to other descriptions and embodiments for each. Therefore, all combinations of the various elements disclosed herein fall within the scope of the present invention. In addition, the scope of the present invention is not considered as being limited by the specific descriptions described below.

[0024] Expressions such as "comprising," used in the Specification of the present application, should be understood as open-ended terms that include the possibility of including other embodiments, unless mentioned particularly differently in a phrase or sentence in which the expression is included.

[0025] The inventors of the present invention have adopted tenofovir alafenamide succinate as an active ingredient among various tenofovir alafenamide compounds having acid addition salts to develop a treatment for chronic hepatitis B. However, it was confirmed that tenofovir alafenamide succinate has a problem of generating a related substance due to its unstable carboxyl-ester bond, leading to hydrolysis. To address this issue, screening of various pharmaceutical additives was carried out to discover that the use of a specific additive provides a pharmaceutical composition capable of holding stable under severe and accelerated open conditions, thereby completing the present invention.

[0026] Hereinafter, the present invention will be described in detail.

[0027] Unless otherwise specified in this specification, the term "wt.%" refers to the mass ratio of a specific component to the entire pharmaceutical composition in which it is incorporated.

[0028] Pharmaceutical Composition

[0029] To solve the technical problem above, the present invention provides the technical solution described below.

[0030] In one aspect, the present invention provides a pharmaceutical composition comprising tenofovir alafenamide succinate.

[0031] Specifically, the tenofovir alafenamide succinate acts as an active ingredient in the pharmaceutical composition.

[0032] The term "active ingredient" as used herein means including a main component as a substances or a substance group (including herb medicine, etc., of which a pharmacologically active component, etc., has not been identified yet) expected to directly or indirectly exhibit the efficacy and effect of the pharmaceutical composition by an intrinsic pharmacological action.

[0033] In the present invention, the pharmaceutical composition may comprise stabilizers, which specifically comprise succinic acid but is not limited thereto.

[0034] In the present invention, the content of the stabilizer may be 0.5 to 5.0 wt.% based on the total weight of the pharmaceutical composition, specifically 0.8 to 3.0 wt.%, but is not limited thereto.

[0035] In the present invention, the pharmaceutical composition may comprise at least one pharmaceutical additive consisting of an excipient, a disintegrant, a binder, and a lubricant, but is not limited thereto.

[0036] In the present invention, the excipient may include at least one or more of lactose hydrate and microcrystalline cellulose, but is not limited thereto.

[0037] In the present invention, the disintegrant may be sodium croscarmellose, but is not limited thereto.

[0038] In the present invention, the binder may be povidone, but is not limited thereto.

[0039] In the present invention, the lubricant may include at least one or more of colloidal silicon dioxide and magnesium stearate, but is not limited thereto.

[0040] In the present invention, the pharmaceutical composition may be a solid oral dosage preparation, but is not limited thereto.

[0041] In the present invention, the solid oral dosage preparation may include at least one of film-coated tablets, capsules, powders, granules, pills, troches, oral jelly, and orally disintegrating films, but is not limited thereto.

[0042] In the present invention, the pharmaceutical composition may be used for the prevention or treatment of chronic hepatitis B, and is not limited thereto.

[0043] In the present invention, the term "prevention" refers to the delay in the onset of a disease, disorder, or condition. Prevention may be considered complete if the onset of the disease, disorder, or condition is delayed for the expected period.

[0044] In the present invention, the term "treatment" refers to the partial or complete reduction, improvement, alleviation, inhibition, or delay of the onset of a specific disease, disorder, and / or condition, reducing severity, or reducing the occurrence of one or more symptoms or characteristics.

[0045] Examples and Comparative Examples

[0046] Hereinafter, the present invention will be described in details based on examples and comparative examples. However, the examples and comparative examples described below are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

[0047] Comparative Example 1 and Examples 1 to 13: Preparation of Film-Coated Tablets

[0048] The following preparation methods were adopted using the compositions and contents (unit: mg / tablet) as listed in Tables 1, 2 and 3 to prepare film-coated tablets containing tenofovir alafenamide succinate as an active ingredient according to Comparative Example 1 and Examples 1 to 13.

[0049] Preparation Methods:

[0050] (1)Preparation of Inner Granules

[0051] The stabilizer was first dissolved in purified water, and povidone K30 as a binder was added, followed by stirring to prepare a binding solution. Then, tenofovir alafenamide succinate as an active ingredient, lactose hydrate and microcrystalline cellulose as excipients, and sodium croscarmellose as a disintegrant were mixed in the binding solution to prepare granules using a high speed mixer (HSM). The granules were then wet milled, dried and dry milled to obtain inner granules.

[0052] (2)Preparation of plain tablets

[0053] The inner granules were mixed with microcrystalline cellulose as an excipient, sodium croscarmellose as a disintegrant, and colloidal silicon dioxide and magnesium stearate as lubricants, followed by compressing to produce plain tablets.

[0054] (3)Preparation of Film-Coated Tablets

[0055] Opadry was dissolved in purified water to prepare a film-coating solution, which was then applied to the plain tablets produced according to the above-described method to produce film-coated tablets.

[0056] Purpose of mixingName of ingredientsComparative Example 1Example 1Example 2Example 3Example 4Example 5Active ingredientTenofovir alafenamide succinate(as tenofovir alafenamide)31.200(25.000)31.200(25.000)31.200(25.000)31.200(25.000)31.200(25.000)31.200(25.000)ExcipientLactose hydrate27.67526.67526.67526.67526.67526.675ExcipientMicrocrystalline cellulose24.10024.10024.10024.10024.10024.100DisintegrantSodium croscarmellose1.0001.0001.0001.0001.0001.000StabilizerTocopherol acetate-1.000----Tocopherol--1.000---Butyl hydroxyanisole---1.000--Butyl hydroxytoluene----1.000-Propylene glycol-----1.000BinderPovidone K303.0003.0003.0003.0003.0003.000SolventPurified water32.00032.00032.00032.00032.00032.000Weight of inner granules86.97586.97586.97586.97586.97586.975ExcipientMicrocrystalline cellulose24.00024.00024.00024.00024.00024.000DisintegrantSodium croscarmellose1.0001.0001.0001.0001.0001.000LubricantColloidal silicon dioxide1.0001.0001.0001.0001.0001.000LubricantMagnesium stearate2.0252.0252.0252.0252.0252.025Final mixture weight115.000115.000115.000115.000115.000115.000Coating agentOpadry5.0005.0005.0005.0005.0005.000SolventPurified water45.00045.00045.00045.00045.00045.000Total weight120.000120.000120.000120.000120.000120.000

[0057] Purpose of mixingName of ingredientsExample 6Example 7Example 8Example 9Example 10Example 11Active ingredientsTenofovir alafenamide succinate(as tenofovir alafenamide)31.200(25.000)31.200(25.000)31.200(25.000)31.200(25.000)31.200(25.000)31.200(25.000)ExcipientLactose hydrate24.67524.67524.67524.67524.67524.675ExcipientMicrocrystalline cellulose24.10024.10024.10024.10024.10024.100DisintegrantSodium croscarmellose1.0001.0001.0001.0001.0001.000StabilizersCitric acid3.000-----Succinic acid-3.000----Disodium edetate hydrate--3.000---Ascorbic acid---3.000--Anhydrous sodium sulfite----3.000-Sodium pyrosulfate-----3.000BinderPovidone K303.0003.0003.0003.0003.0003.000SolventPurified water32.00032.00032.00032.00032.00032.000Weight of inner granules86.97586.97586.97586.97586.97586.975ExcipientMicrocrystalline cellulose24.00024.00024.00024.00024.00024.000DisintegrantSodium croscarmellose1.0001.0001.0001.0001.0001.000LubricantColloidal silicon dioxide1.0001.0001.0001.0001.0001.000LubricantMagnesium stearate2.0252.0252.0252.0252.0252.025Final mixture weight115.000115.000115.000115.000115.000115.000Coating agentOpadry5.0005.0005.0005.0005.0005.000SolventPurified water45.00045.00045.00045.00045.00045.000Total weight120.000120.000120.000120.000120.000120.000

[0058] Purpose of mixingName of ingredientsComparative Example 1Example 7Example 12Example 13Active ingredientTenofovir alafenamide succinate(as tenofovir alafenamide)31.200(25.000)31.200(25.000)31.200(25.000)31.200(25.000)ExcipientLactose hydrate27.67524.67525.67526.675ExcipientMicrocrystalline cellulose24.10024.10024.10024.100DisintegrantSodium croscarmellose1.0001.0001.0001.000StabilizerSuccinic acid-3.0002.0001.000BinderPovidone K303.0003.0003.0003.000SolventPurified water32.00032.00032.00032.000Weight of inner granules86.97586.97586.97586.975ExcipientMicrocrystalline cellulose24.00024.00024.00024.000DisintegrantSodium croscarmellose1.0001.0001.0001.000LubricantColloidal silicon dioxide1.0001.0001.0001.000LubricantMagnesium stearate2.0252.0252.0252.025Final mixture weight115.000115.000115.000115.000Coating agentOpadry5.0005.0005.0005.000SolventPurified water45.00045.00045.00045.000Total weight120.000120.000120.000120.000

[0059] Hereinafter, the present invention will be described in details based on experimental examples. However, the experimental examples described below are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

[0060] Experimental Examples

[0061] Experimental Example 1: (Related Substance) Stability Test Method

[0062] 1. Test Method

[0063] The active ingredient tenofovir alafenamide succinate is susceptible to hydrolysis due to the unstable carbonyl-ester linkage, leading to the generation of related substances during the hydrolysis process. Therefore, to ensure the stability of the pharmaceutical composition containing tenofovir alafenamide succinate, appropriate stabilizers were screened as follows.

[0064] Tests for related substances (%) were conducted with different stabilizer types and contents. The results are presented in Tables 4, 5 and 6 (Comparative Example 1 containing no stabilizer).

[0065] In this regard, the operating conditions of the equipment were given as follows, and the storage conditions were maintained under accelerated conditions and accelerated open conditions (40°C, 75% relative humidity).

[0066] <Operating Conditions of the equipment>

[0067] (1) Detector: UV-Vis spectrophotometer (measurement wavelength: 260 nm)

[0068] (2) Column: Inertsil ODS-3 (4.6 × 250 mm, 3 μm) or an equivalent column

[0069] (3) Injection volume: 10 μL

[0070] (4) Flow rate: 0.8 mL / min

[0071] (5) Column temperature: constant temperature around 40°C

[0072] (6) Sample temperature: constant temperature around 4°C

[0073] (7) Mobile phase:

[0074] - A - Mixture of methanol, t-butyl alcohol, and pH 5.5 buffer solution (75:25:900)

[0075] - B - Mixture of methanol, t-butyl alcohol, and pH 5.5 buffer solution (675:25:300)

[0076] Note: The buffer solution was prepared by dissolving 1.42 g of disodium hydrogen phosphate in 1 L of purified water and adjusting the pH to 5.5 with phosphoric acid.

[0077]

[0078] 2. Selection of Optimal Stabilizer

[0079] Referring to Tables 4 and 5, upon accelerated open for 2 weeks, the Example 7 that contained succinic acid as a stabilizer formed 0.96% of related substances, 0.39% less than the Comparative Example 1 containing no stabilizer (the total content of related substances: 1.35%).

[0080] It was therefore confirmed that the formulation including succinic acid (Example 7) was improved in stability.

[0081] Accelerated* (Open)PeriodComparative Example 1Example 1Example 2Example 3Example 4Example 5TenofovirInitial0.070.070.070.070.080.063 days0.340.400.380.410.430.371 week0.570.770.730.780.810.682 weeks1.101.481.401.481.531.25Total content of related substancesInitial0.130.160.160.170.180.153 days0.500.570.550.590.620.901 week0.731.051.001.101.131.462 weeks1.351.931.822.052.062.37Increment from initial (total content of related substances)3 weeks0.370.410.390.420.440.751 week0.600.890.840.930.951.312 weeks1.221.771.661.881.882.22

[0082] Accelerated* (Open)PeriodExample 6Example 7Example 8Example 9Example 10Example 11Tenofovir00.120.070.070.080.080.083 days0.610.240.410.270.390.401 week1.070.390.780.400.650.702 weeks1.880.631.480.591.081.23Total content of related substances00.250.140.180.340.180.193 days1.470.400.612.120.540.561 week2.510.621.162.990.830.902 weeks4.290.962.214.221.281.45Increment from initial (total content of related substances)3 days1.220.260.431.780.360.371 week2.260.480.982.650.650.712 weeks4.040.822.033.881.101.26

[0083] (In Tables 4 and 5, * accelerated conditions refer to open at 40°C and 75% RH.)

[0084] 3. Optimal Content of Stabilizer

[0085] Through the experiments, the succinic acid proved to have a stabilizing effect when used as a stabilizer. The formulations with different weights of succinic acid (Examples 7, 12 and 13) were evaluated in regards to the stability. The results are presented in Table 6.

[0086] The stability tests for the formulations of Examples 7, 12, and 13 (related substances) were conducted as described above.

[0087] Referring to Table 6, the total content of related substances was 0.39% to 0.66% lower in the formulation of Example 7 containing 3 mg of succinic acid per tablet (the total content of related substances after 2 weeks of accelerated open: 0.96%), the formulation of Example 12 containing 2 mg of succinic acid per tablet (the total content of related substances after 2 weeks of accelerated open: 0.84%) and the formulation of Example 13 containing 1 mg of succinic acid per tablet (the total content of related substances after 2 weeks of accelerated open: 0.69%) than in the formulation of Comparative Example 1 not containing a stabilizer (the total content of related substances after 2 weeks of accelerated open: 1.35%).

[0088] In conclusion, all the formulations containing succinic acid at different contents of 1, 2 and 3 mg / tablet (Examples 7, 12 and 13) were improved in stability, suggesting that the desirable content of succinic acid was 1 mg per tablet in consideration of the total content of related substances in the formulation of Example 13, the content of succinic acid is preferably 1 mg per tablet.

[0089] Accelerated* (Open)PeriodComparative Example 1Example 7Example 12Example 13TenofovirInitial0.070.070.070.073 days0.340.240.220.191 week0.570.390.390.322 weeks1.100.630.700.55Total content of related substancesInitial0.130.140.100.123 days0.500.400.350.301 week0.730.620.500.412 weeks1.350.960.840.69Increment from initial (total content of related substances)3 days0.370.260.250.181 week0.600.480.400.292 weeks1.220.820.740.57

[0090] (In Table 6, * accelerated conditions refer to open at 40°C and 75% RH.)

[0091] As described above, a specific part of the present invention was described in details. The specific description is only a preferred embodiment for those of ordinary skill in the related art, and it is clear that the scope of the present invention is not limited thereto. Therefore, the substantial scope of the invention will be defined by the attached claims and their equivalents.

Claims

1.A pharmaceutical composition comprising tenofovir alafenamide succinate.2.The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises a stabilizer.3.The pharmaceutical composition according to claim 2, wherein the stabilizer is succinic acid.4.The pharmaceutical composition according to claim 2, wherein the content of the stabilizer is 0.5 to 5.0 wt.% based on the total weight of the pharmaceutical composition.5.The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is a solid oral dosage preparation.6.The pharmaceutical composition according to claim 5, wherein the solid oral dosage preparation includes at least one of film-coated tablets, capsules, powder, granules, pills, troches, oral jelly, and orally disintegrating films.7.The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is used for prevention or treatment of chronic hepatitis B.