A tadalafil-polyglutamic acid amorphous composition and its preparation method and application

Abstract

The present invention relates to the field of medical technology. The present invention provides a tadalafil-polyglutamic acid amorphous composition and a preparation method and application thereof, wherein the composition is obtained by mixing tadalafil and polyglutamic acid. The drug loading of the tadalafil-polyglutamic acid amorphous composition of the present invention can be as high as 75%, overcoming the disadvantage of low drug loading of traditional solid dispersions. At the same time, due to the high T g The value greatly improves the physical stability of the tadalafil-polyglutamic acid amorphous composition. In addition, the tadalafil-polyglutamic acid amorphous composition also significantly improves the water solubility of tadalafil. More importantly, tadalafil-polyglutamic acid amorphous compositions with different mass ratios can obtain different solubilization curves, thereby providing a variety of options for the design of tadalafil preparations with different drug release curves, and also laying the foundation for meeting different clinical needs of tadalafil.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a tadalafil-polyglutamic acid amorphous composition and a preparation method and application thereof. Background Art

[0002] Tadalafil (TAD) is a selective, reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase 5 (PDE5). It can enhance male erectile function by inhibiting PDE5 and increasing the content of cGMP. TAD was launched in China in 2005 and is a widely used andrological drug for the treatment of erectile dysfunction. According to the Biopharmaceutics Classification System (BCS), TAD has the characteristics of low solubility and high permeability and belongs to BCS Class II drugs. Therefore, it has low solubility in water and slow dissolution rate, which leads to low oral bioavailability and slow onset of action in clinical use, which limits the clinical application of TAD to a certain extent.

[0003] Preparing poorly soluble drugs into amorphous solid dispersions is one of the common methods to improve their solubility and dissolution rate, but the traditional solid dispersions have low drug loading, which leads to excessive volume of the final dosage form. Co-amorphous systems are new single-phase amorphous systems composed of two or more small molecules. Amino acids are the most important type of carriers, with many types, low cost, easy availability, and rich options. However, a considerable number of amino acids are difficult to form co-amorphous systems with drugs, or the co-amorphous systems formed have poor physical stability, which limits further application.

[0004] Therefore, how to combine the advantages of traditional solid dispersions and new co-amorphous systems, overcome their shortcomings, and construct a new type of tadalafil amorphous composition is of great significance for meeting the diverse formulation development needs and further improving the clinical therapeutic effect of tadalafil. Summary of the invention

[0005] The purpose of the present invention is to provide a preparation method and application of a tadalafil-polyglutamic acid amorphous composition to meet the diverse formulation development needs and improve the clinical therapeutic effect of tadalafil.

[0006] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0007] The invention provides a tadalafil-polyglutamic acid amorphous composition, wherein the composition is obtained by mixing tadalafil and polyglutamic acid.

[0008] Preferably, the X-ray powder diffraction pattern of the composition has no sharp diffraction peaks.

[0009] Preferably, the mass ratio of tadalafil to polyglutamic acid during mixing is 1:3 to 3:1.

[0010] The present invention also provides a method for preparing the composition, comprising the following steps: mixing tadalafil with polyglutamic acid, and grinding to obtain the composition.

[0011] Preferably, the grinding method is intermittent: tadalafil and polyglutamic acid are mixed and then frozen for 18 to 22 minutes, then ground for 18 to 22 minutes, and the freezing-ball milling operation is repeated. The total ball milling time is 54 to 66 minutes.

[0012] Preferably, the freezing temperature is -70 to -90°C.

[0013] Preferably, mechanical ball milling is used during the grinding.

[0014] The present invention also provides application of the composition in preparing medicine for treating male erectile dysfunction.

[0015] The present invention also provides a medicine, which contains the tadalafil-polyglutamic acid amorphous composition and one or more pharmaceutically acceptable excipients.

[0016] The invention provides a tadalafil-polyglutamic acid amorphous composition and a preparation method and application thereof. The composition is obtained by mixing tadalafil and polyglutamic acid.

[0017] The inventors of the present invention creatively used polyamino acids as carriers of tadalafil amorphous compositions, which significantly increased the water solubility of tadalafil. The present invention uses polyamino acids as carriers and prepares tadalafil amorphous compositions according to different mass ratios. Different from traditional solid dispersions and co-amorphous systems, it combines the advantages of both and can not only improve the water solubility of tadalafil: compared with crystalline tadalafil, the C ratio of polyamino acids to tadalafil (3:1) is 1:1. max Improved by 2.5 times, T max It is 8 times smaller and still has good physical stability.

[0018] The drug loading of the tadalafil-polyglutamic acid amorphous composition of the present invention can be as high as 75%, overcoming the disadvantage of low drug loading of traditional solid dispersions. g The value greatly improves the physical stability of the tadalafil-polyglutamic acid amorphous composition. In addition, the tadalafil-polyglutamic acid amorphous composition also significantly improves the water solubility of tadalafil. More importantly, the tadalafil-polyglutamic acid amorphous composition with different mass ratios can obtain different solubilization curves, thereby providing a variety of options for the design of tadalafil preparations with different drug release curves, and also laying the foundation for meeting different clinical needs of tadalafil. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 The X-ray powder diffraction patterns of crystalline TAD and PGA measured in Example 5;

[0020] Figure 2 X-ray powder diffraction patterns of the amorphous PGA-TAD composition and pure amorphous TAD measured in Example 5;

[0021] Figure 3 The mDSC heat flow curve of the sample measured in Example 6;

[0022] Figure 4 The dissolution curve of the sample powder measured in Example 7;

[0023] Figure 5 This is the X-ray powder diffraction pattern of the stability sample of Example 8 measured at 25°C;

[0024] Figure 6 This is the X-ray powder diffraction pattern of the stability sample of Example 8 placed at 40°C;

[0025] Figure 7 It is the chemical structure of polyglutamic acid. DETAILED DESCRIPTION

[0026] The invention provides a tadalafil-polyglutamic acid amorphous composition, wherein the composition is obtained by mixing tadalafil and polyglutamic acid.

[0027] In the present invention, the polyglutamic acid (γ-poly-glutamic acid, PGA) is a water-soluble, biocompatible, biodegradable, edible high molecular polymer that is non-toxic to the human body and the environment. g ) is as high as 190.7°C, which is conducive to constructing a tadalafil amorphous composition with high physical stability. The chemical structure of polyglutamic acid is as follows Figure 7 shown.

[0028] In the present invention, the X-ray powder diffraction pattern of the composition has no sharp diffraction peak.

[0029] In the present invention, the mass ratio of tadalafil to polyglutamic acid during the mixing is preferably 1:3 to 3:1, more preferably 1:2 to 2:1, and even more preferably 1:1.

[0030] The present invention also provides a method for preparing the composition, comprising the following steps: mixing tadalafil with polyglutamic acid, and grinding to obtain the composition.

[0031] In the present invention, the grinding method is intermittent: tadalafil and polyglutamic acid are mixed and then frozen for 18 to 22 minutes, then ground for 18 to 22 minutes, and the freezing-ball milling operation is repeated, and the total ball milling time is 54 to 66 minutes; more preferably, tadalafil and polyglutamic acid are mixed and then frozen for 20 minutes, then ground for 20 minutes, and the freezing-ball milling operation is repeated, and the total ball milling time is 60 minutes.

[0032] In the present invention, the temperature during the grinding process is preferably not higher than 40°C, and more preferably not higher than 30°C.

[0033] In the present invention, the freezing temperature is preferably -70 to -90°C, more preferably -80°C.

[0034] In the present invention, the grinding is preferably performed by mechanical ball milling.

[0035] In the present invention, the frequency of the mechanical ball milling during the grinding is preferably 20 to 30 Hz, and more preferably 25 Hz.

[0036] The present invention also provides application of the composition in preparing medicine for treating male erectile dysfunction.

[0037] The present invention also provides a medicine, which contains the tadalafil-polyglutamic acid amorphous composition and one or more pharmaceutically acceptable excipients.

[0038] The technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0039] In the following examples, tadalafil is abbreviated as TAD, and polyglutamic acid is abbreviated as PGA.

[0040] Example 1 Preparation of PGA-TAD amorphous composition with a drug loading rate of 25%

[0041] 187.5 mg TAD and 562.5 mg PGA were added to a 50 mL ball mill containing a stainless steel ball with a diameter of 25 mm and ball milled at a frequency of 25 Hz. The model of the ball mill is Cryomill, Retsch, Germany. In order to avoid the heat generated during the ball milling process affecting the sample preparation, the ball mill containing the sample was first frozen at -80 ° C for 20 minutes, and then the ball milling operation was performed. After ball milling for 20 minutes, the sample was frozen for another 20 minutes, and the total ball milling time was 60 minutes. The sample was collected to obtain the PGA-TAD (3:1) amorphous composition.

[0042] Example 2 Preparation of PGA-TAD amorphous composition with a drug loading rate of 50%

[0043] 375 mg of TAD and 375 mg of PGA were ball-milled according to the method in Example 1 to obtain a PGA-TAD (1:1) amorphous composition.

[0044] Example 3 Preparation of PGA-TAD amorphous composition with a drug loading rate of 75%

[0045] 562.5 mg of TAD and 187.5 mg of PGA were ball-milled according to the method in Example 1 to obtain a PGA-TAD (1:3) amorphous composition.

[0046] Example 4 Preparation of amorphous sample of pure TAD

[0047] 750 mg of TAD was ball-milled according to the method in Example 1 to obtain amorphous TAD (Amo TAD).

[0048] X-ray powder diffraction (XRPD) determination of the sample of Example 5

[0049] Measuring instrument: X-ray diffractometer (D8ADVANCE, BRUKER), Bruker, Germany.

[0050] Determination conditions:

[0051]

[0052] A small amount of each sample prepared in Examples 1 to 4 was placed on an XRPD sample tray with a zero background plate to flatten the sample surface, and then the sample tray was placed in an eight-position automatic sampler of the XRPD for sample injection, and the original data was saved after the test was completed.

[0053] The results are as follows Figure 1 As shown in Figure 2, the API TAD has a sharp diffraction peak, indicating that the API is in a crystalline state; the carrier PGA and the TAD after ball milling do not have sharp diffraction peaks, indicating that they are in an amorphous state. After ball milling of PGA-TAD mixed with different ratios, there is no sharp diffraction peak in its XRPD spectrum, indicating that the PGA-TAD composite is transformed into an amorphous state after ball milling.

[0054] Determination of the sample by modulated differential scanning calorimetry (mDSC) of Example 6

[0055] Measuring instrument: Discovery DSC (TA Instruments, New Castle, USA).

[0056] Measurement conditions: 4.2 mg, 4.5 mg, 4.7 mg, and 4.3 mg of sample powder were taken from the samples prepared in Examples 1 to 4 and filled into Tzero pans, which were sealed with Tzero aluminum lids. The samples were heated from 100°C to 250°C at a rate of 2°C / min for analysis. The temperature amplitude after modulation was 0.212°C, and the cycle was 40s. The glass transition temperature was calculated using TA Instruments Trios software (version 3.3.1). Each sample was determined in three independent measurements and reported as the mean ± standard deviation. The measured mDSC heat flow curve is shown in the figure below. Figure 3 shown.

[0057] The results are shown in Table 1. Although PGA-TAD (3:1 and 1:1) has two separate glass transition temperatures (T g ), no homogeneous system is formed, but the second T g T is significantly higher than TAD g This may be due to the PGA's own T g higher (190.7°C), so that the T g This may contribute to improving the physical stability of the amorphous composition.

[0058] Table 1 Amorphous sample T g The results of the measurement

[0059]

[0060]

[0061] Example 7 Powder Solubility Test of Crystalline TAD, Amorphous TAD and PGA-TAD Amorphous Composition

[0062] Determination instruments: RC806D dissolution apparatus (TianDa TianFa Technology Co., Ltd., Tianjin), HPLC (Agilent 1260, USA).

[0063] Determination method: According to the 2020 edition of the "Chinese Pharmacopoeia (Part 4)" 0931 dissolution and release determination method, the samples prepared in Examples 1 to 4 were subjected to in vitro dissolution experiments, and crystalline TAD was used as a comparison. The dissolution medium is 200mL of pH 6.8 phosphate buffered saline solution, the speed is 100 rpm, the medium temperature is 37±0.5°C, and 3mL of solution is taken at 2, 5, 10, 20, 30, 60, 120, 180, 240, 360, and 1440min, respectively, and the same volume of preheated dissolution medium is added. The taken out solution is filtered through a 0.45μm microporous filter membrane to take 1mL of the subsequent filtrate. In order to prevent the drug in the subsequent filtrate from being oversaturated and precipitated, an equal volume of acetonitrile is added to the subsequent filtrate and mixed evenly, and the drug concentration in the sample is determined by HPLC.

[0064] HPLC chromatographic conditions are as follows:

[0065] Chromatographic column: Reverse C18 column (Agilent, 5μm, 4.6*150mm)

[0066] Mobile phase: 0.02M pH 6.8 phosphate buffered saline: acetonitrile = 55%: 45% (v:v)

[0067] Flow rate: 1mL / min

[0068] Injection volume: 20 μL

[0069] Detection wavelength: 285nm

[0070] The results are as follows Figure 4 As shown in Figure 2, the concentration of TAD in the amorphous PGA-TAD (3:1) composition reached 6.86 μg / mL after 180 min of dissolution, while the concentrations of crystalline TAD and amorphous TAD were only 1.96 μg / mL and 2.48 μg / mL, respectively. max After that, the drug concentration slowly decreases until it reaches saturation concentration, which is beneficial to prolong the action time of TAD. max Only 1.1 times higher, both T max It is particularly important to point out that the dissolution curves of PGA-TAD amorphous compositions with different ratios are different, which provides options for diversified TAD release curves: we can obtain different TAD release curves by changing the ratio of PGA and TAD and constructing different PGA-TAD amorphous compositions to meet diverse clinical needs.

[0071] Example 8 Physical Stability Test of Amorphous TAD and PGA-TAD Amorphous Composition

[0072] A certain amount of amorphous samples prepared in Examples 1 to 4 were weighed into EP tubes and placed in two desiccators. The two desiccators were placed in a 40°C oven and room temperature environment, respectively, and XRPD was used to determine whether the samples were transformed into crystals after 2 weeks, 2 months, 3 months, and 9 months. The measurement results are shown in Figure 2. Figure 5 , 6 As shown in Table 2 (√ represents stability; × represents that the sample has undergone crystal transformation), amorphous TAD underwent crystal transformation after being placed at 40°C for 9 months, while all PGA-TAD amorphous compositions still maintained an amorphous state, confirming that the PGA-TAD amorphous composition can effectively improve the physical stability of amorphous TAD.

[0073] Table 2 Amorphous sample stability placement results

[0074]

[0075] Example 9 Preparation of PGA-TAD Amorphous Composition Capsules

[0076] Pass lactose monohydrate through a 200-mesh sieve and the PGA-TAD amorphous composition prepared in Example 2 through a 100-mesh sieve for later use. Weigh 400.0 g of 200-mesh lactose monohydrate, 450.0 g of microcrystalline cellulose (SH102), 4.0 g of magnesium stearate, and 100 g of PGA-TAD amorphous composition in sequence. Place all the raw materials and auxiliary materials in a square cone mixer and mix them evenly for 5 minutes. Take out the materials and add them to the hopper of the fully automatic capsule filling machine. Use 2 # The gelatin empty capsule shells were filled with a theoretical loading of 190.8 mg / capsule. The filling process was smooth, the capsule weight difference was within 3%, the main drug TAD content was within ±3% of the predetermined dosage specification (10 mg), and the filling accuracy met the quality requirements.

[0077] As can be seen from the above examples, the present invention provides a tadalafil-polyglutamic acid amorphous composition and its preparation method and application, wherein the composition is obtained by mixing tadalafil and polyglutamic acid. The drug loading of the tadalafil-polyglutamic acid amorphous composition of the present invention can be as high as 75%, overcoming the disadvantage of low drug loading of traditional solid dispersions. At the same time, due to the high T g The value greatly improves the physical stability of the tadalafil-polyglutamic acid amorphous composition. In addition, the tadalafil-polyglutamic acid amorphous composition also significantly improves the water solubility of tadalafil. More importantly, the tadalafil-polyglutamic acid amorphous composition with different mass ratios can obtain different solubilization curves, thereby providing a variety of options for the design of tadalafil preparations with different drug release curves, and also laying the foundation for meeting different clinical needs of tadalafil.

[0078] The above 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 tadalafil-polyglutamic acid amorphous composition, characterized in that: The composition is obtained by mixing tadalafil and polyglutamic acid; The X-ray powder diffraction pattern of the composition has no sharp diffraction peaks, which are PGA-TAD 1:3, PGA-TAD 1:1 or PGA-TAD 3:1 in FIG2 ; The mass ratio of tadalafil to polyglutamic acid during mixing is 1:3, 3:1 or 1:

1.

2. The method for preparing the composition according to claim 1, characterized in that: The method comprises the following steps: mixing tadalafil with polyglutamic acid, and grinding to obtain the composition.

3. The preparation method according to claim 2, characterized in that: The grinding method is intermittent: tadalafil and polyglutamic acid are mixed and then frozen for 18 to 22 minutes, then ground for 18 to 22 minutes, and the freezing-ball milling operation is repeated, and the total ball milling time is 54 to 66 minutes.

4. The preparation method according to claim 3, characterized in that: The freezing temperature is -70 to -90°C.

5. The preparation method according to any one of claims 2 to 4, characterized in that The grinding is performed by mechanical ball milling.

6. Use of the composition according to claim 1 or the composition prepared by the preparation method according to any one of claims 2 to 5 in the preparation of a medicament for treating male erectile dysfunction.

7. A medicine containing the composition according to claim 1 or the composition prepared by the preparation method according to any one of claims 2 to 5, characterized in that: The medicine contains a tadalafil-polyglutamic acid amorphous composition and one or more pharmaceutically acceptable auxiliary materials.

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