Tadalafil self-emulsifying dispersible tablet and preparation method thereof

Abstract

The invention discloses a tadalafil self-emulsifying dispersible tablet and a preparation method thereof. The method comprises the following steps: mixing tadalafil, an oil phase, a surfactant and a cosurfactant according to a certain ratio, carrying out ultrasonic treatment to obtain tadalafil self-emulsion, and adsorbing the tadalafil self-emulsion with a solid adsorbent to obtain a solid adsorption mixture; and adding a filling agent, an adhesive, a disintegrating agent and a lubricating agent into the solid adsorption mixture, and obtaining the tadalafil self-emulsifying dispersible tablet by adopting a direct powder tabletting method. The prepared tadalafil self-emulsifying dispersible tablet is simple in preparation process, the in-vitro dissolution rate of tadalafil is improved, and the defects that tadalafil is poor in oral absorption and low in bioavailability are overcome.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and particularly relates to a tadalafil self-emulsifying dispersible tablet and a preparation method thereof. Background Art

[0002] Tadalafil is a white or off-white solid, and its structure is shown in formula (I). It belongs to a selective phosphodiesterase 5 inhibitor. Due to its advantages such as long action duration, high selectivity, and strong efficacy, it is regarded as the first-choice drug for the treatment of erectile dysfunction. It was first approved by the FDA for erectile dysfunction in 2003 and was approved for the treatment of pulmonary hypertension in 2009.

[0003]

[0004] The mechanism of action of tadalafil is to inhibit the activity of selective phosphodiesterase 5, resulting in an increase in the concentration of cyclic guanosine monophosphate (cGMP), which in turn causes the relaxation of cavernous blood vessels and an increase in blood flow, thereby producing an erection. In the cardio-pulmonary vascular system, it enhances the NO-cGMP signal transduction to promote smooth muscle relaxation, thereby reducing the blood pressure in the pulmonary artery.

[0005] Tadalafil belongs to BCS class II drugs, which are almost insoluble in water and have a slow dissolution rate from tablets, resulting in low bioavailability. In order to achieve the therapeutic concentration, patients need to increase the dosage, which brings the risk of side effects. Therefore, improving the water solubility of the drug and enabling it to quickly exert its efficacy in the body is of great significance for the treatment process using tadalafil.

[0006] Self-emulsifying drug delivery systems (SEDDS) are liquid or solid preparations composed of an oil phase, a surfactant, and a co-surfactant. After gentle stirring in an aqueous medium, this preparation can form an oil-in-water (o / w) emulsion. Such self-emulsifying preparations are easily dispersed in the gastrointestinal tract, and the digestive movements of the stomach and intestines can provide the stirring required for self-emulsification. The droplet size of the emulsion formed by self-emulsification is usually between 100 and 300 nm. Due to the dissolution form of the drug in the preparation and the larger interfacial surface area provided by the small-sized droplets, the release and absorption properties of the drug are improved. For drugs whose absorption is limited by a low dissolution rate, self-emulsifying drug delivery systems can effectively improve the absorption rate and extent of the drug in the human body, improve the drug bioavailability and have good repeatability.

[0007] Traditional self-emulsifying liquid preparations are generally stored in capsules, with poor stability and portability. To overcome such problems, they can be converted into solids by using a suitable adsorbent and prepared into granules by various techniques (such as spray drying, etc.), and further compressed into dispersible tablets. The dispersible tablets produced by this method have the characteristics of fast disintegration, good stability, high bioavailability, and good patient compliance. Summary of the Invention

[0008] In view of the problems of poor solubility and slow dissolution rate of tadalafil, the purpose of the present invention is to provide a self-emulsifying dispersible tablet of tadalafil and its preparation method, so as to improve the problems of low drug bioavailability, poor stability and poor portability.

[0009] Specifically, the present invention is achieved through the following technical solutions:

[0010] In the self-emulsifying liquid of tadalafil of the present invention, the components are in the following weight ratios: tadalafil is 1-30%, the oil phase is 20-50%, the surfactant is 25-40%, and the co-surfactant is 10-15%.

[0011] Preparation method of the self-emulsifying liquid: Accurately weigh the surfactant and co-surfactant according to the component ratio, mix them evenly, add tadalafil and the oil phase, and dissolve them by ultrasonic treatment.

[0012] The oil phase of the present invention is selected from one or more of propylene glycol caprylate, propylene glycol monolaurate, glycerol monooleate, medium-chain triglyceride, and oleic acid polyethylene glycol glycerol ester, preferably glycerol monooleate. The surfactant is selected from one or more of octylphenol polyoxyethylene ether, caprate, Tween 80, polyethylene glycol 400, and oleoyl polyoxyethylene glycerol ester, preferably octylphenol polyoxyethylene ether. The co-surfactant is selected from one or more of diethylene glycol monoethyl ether, polyethylene glycol 200, ethanol, 1,2-propanediol, and butanol, preferably diethylene glycol monoethyl ether.

[0013] Preparation of the self-emulsifying dispersible tablet: Take the above self-emulsifying liquid, adsorb it with a suitable solid material, add a certain proportion of filler, binder, disintegrant to the solid adsorption mixture, and then add a lubricant, and prepare a self-emulsifying dispersible tablet of tadalafil by the powder direct compression process.

[0014] The solid adsorbent of the present invention is selected from microcrystalline silica, microcrystalline cellulose, hydroxypropyl methylcellulose, and calcium carbonate, preferably microcrystalline silica. The filler is selected from one or more of starch, direct compression mannitol, lactose, and microcrystalline cellulose, preferably lactose and microcrystalline cellulose. The binder is selected from hydroxypropyl cellulose and hydroxypropyl methylcellulose, preferably hydroxypropyl methylcellulose. The disintegrant is selected from sodium carboxymethyl starch, cross-linked carboxymethyl cellulose sodium, and cross-linked polyvinylpyrrolidone, preferably sodium carboxymethyl starch. The lubricant is selected from magnesium stearate, sodium stearyl fumarate, and talc powder, preferably magnesium stearate.

[0015] In the self-emulsifying dispersible tablet of tadalafil of the present invention, the components are in the following weight composition: the solid adsorption mixture is 1-30%, the binder is 5-10%, the disintegrant is 5-25%, the lubricant is 1-3%, and the rest is filler.

[0016] The specific preparation steps of the tadalafil self-emulsifying dispersible tablets of the present invention are as follows: Weigh the solid adsorption mixture, filler, binder, and disintegrant according to the prescription amount, mix them, and pass through a 80-mesh sieve. Directly compress the sieved powder, adjust the rotation speed of the tablet press and the hardness of the tablets so that the hardness of the tablets is within 7±2 kg / mm 2 range.

[0017] The tadalafil self-emulsifying liquid of the present invention can also be prepared into pellets, dry suspensions, capsules or other solid preparations.

[0018] Traditional self-emulsifying liquid preparations are generally stored in capsules, with poor stability and portability. The present invention adopts a two-step method of first preparing a self-emulsifying liquid, using a suitable adsorbent to convert it into a solid, and then preparing a dispersible tablet. The produced dispersible tablets have the characteristics of fast disintegration, good stability, high bioavailability, and good patient compliance.

[0019] The present invention will be further described below with reference to specific examples and drawings. It should be understood that the specific examples described herein are only used to explain the present invention and are not used to limit the scope of the present invention. Description of the Drawings

[0020] Figure 1 is the dissolution curves of the preparations of Examples 1-3 and the commercially available preparation at pH 1.2 (0.5% SDS).

[0021] Figure 2 is the dissolution curves of the preparations of Examples 1-3 and the commercially available preparation at pH 4.0 (0.5% SDS). Detailed Description of the Invention

[0022] All reagents are commercially available reagents of analytical purity, and all excipients used are commercially available excipients that meet the pharmaceutical, injectable standards or pharmacopoeia standards. The experimental methods in the following examples are all conventional methods unless otherwise specified.

[0023] Example 1 Preparation of tadalafil self-emulsifying dispersible tablets

[0024] Component I

[0025] Table 1 - Components of tadalafil self-emulsifying dispersible tablets (1000 tablets)

[0026]

[0027]

[0028] II Preparation method

[0029] 1. Weigh the active pharmaceutical ingredient and each excipient according to the component amounts. Mix glyceryl monooleate, medium-chain triglycerides, octylphenol polyoxyethylene ether, and diethylene glycol monoethyl ether evenly, add tadalafil and sonicate until the drug is completely dissolved, and then adsorb the solution with colloidal silicon dioxide.

[0030] 2. Mix the solid adsorption mixture with the filler, binder, and disintegrant, pass through an 80-mesh sieve, and finally add the lubricant and mix evenly. Press the mixed powder into dispersible tablets using the direct powder compression method. Adjust the rotation speed / filling depth and tablet hardness of the tablet press to make the tablet weight 0.4 g and the tablet hardness within the range of 7 ± 2 kg / mm. 2 range.

[0031] Example 2 Preparation of Tadalafil Self-Emulsifying Dispersible Tablets

[0032] Component I

[0033] Table 2 - Components of Tadalafil Self-Emulsifying Dispersible Tablets (1000 tablets)

[0034]

[0035]

[0036] II Preparation Method

[0037] 1. Weigh each active pharmaceutical ingredient and excipient according to the component amounts. Mix propylene glycol caprylate, medium-chain triglycerides, caprate, and 1,2-propanediol evenly, add tadalafil and sonicate until the drug is completely dissolved, and then adsorb the solution with colloidal silicon dioxide.

[0038] 2. Mix the solid adsorption mixture with the filler, binder, and disintegrant, pass through an 80-mesh sieve, and finally add the lubricant and mix evenly. Press the mixed powder into dispersible tablets using the direct powder compression method. Adjust the rotation speed / filling depth and tablet hardness of the tablet press to make the tablet weight 0.5 g and the tablet hardness within the range of 7 ± 2 kg / mm. 2 range.

[0039] Example 3 Preparation of Tadalafil Self-Emulsifying Dispersible Tablets

[0040] Component I

[0041] Table 3 - Components of Tadalafil Self-Emulsifying Dispersible Tablets (1000 tablets)

[0042]

[0043]

[0044] II Preparation Method

[0045] 1. Weigh each active pharmaceutical ingredient and excipient according to the component amounts. Mix propylene glycol octanoate, propylene glycol octanoate, polyethylene glycol 400, and diethylene glycol monoethyl ether uniformly, add tadalafil and sonicate to fully dissolve the drug, and then adsorb the solution with colloidal silica.

[0046] 2. Mix the solid adsorption mixture with fillers, binders, and disintegrants, pass through a 80-mesh sieve, and finally add lubricants and mix uniformly. Press the mixed powder into dispersible tablets by direct powder compression method. Adjust the rotation speed / filling depth and tablet hardness of the tableting machine to make the tablet weight 0.5 g and the tablet hardness within the range of 7 ± 2 kg / mm 2 range.

[0047] Example 4: Examination of dispersion uniformity

[0048] According to the examination method for dispersion uniformity of tablets in the fourth part of the Pharmacopoeia of the People's Republic of China (2020 edition). Take 6 tablets each from Examples 1 to 2, keep the water temperature at 15 - 25 °C, and the tablets should disintegrate completely and pass through the sieve within 3 minutes. In fact, the tablets in Examples 1 to 3 disintegrated completely and passed through the sieve within 1 min 30 s, meeting the requirements of dispersion uniformity

[0049] Example 5: Drug dissolution test

[0050] For the tadalafil self-emulsifying dispersible tablets in Examples 1 to 3, according to the second method (paddle method) for dissolution determination in the fourth part of the Pharmacopoeia of the People's Republic of China (2020 edition), use the solutions with 0.5% SDS at pH 1.2 and pH 4.0 as dissolution media, sample at 5 min, 10 min, 15 min, 30 min, and 45 min, measure the drug concentration at different time points, and plot the cumulative release percentage curve.

[0051] The dissolution results are shown in the attached figure. In the two dissolution media with 0.5% SDS at pH 1.2 and pH 4.0, the cumulative release amounts of the preparations in Examples 1 to 3 can all approach 95% within 15 min. Compared with the commercially available tadalafil tablets, the tadalafil self-emulsifying dispersible tablets have a faster dissolution rate.

Claims

1. A tadalafil self-emulsifying liquid, characterized in that, it is a homogeneous and transparent solution composed of a drug, an oil phase, a surfactant, and a co-surfactant; the components in the tadalafil self-emulsifying liquid are in a weight ratio of: tadalafil is 1-30%, the oil phase is 20-50%, the surfactant is 25-40%, and the co-surfactant is 10-15%.

2. The tadalafil self-emulsifying liquid according to claim 1, characterized in that, the oil phase is selected from one or more of propylene glycol octanoate, propylene glycol monolaurate, glycerol monooleate, medium-chain triglycerides, and polyethylene glycol glycerol oleate; the surfactant is selected from one or more of octylphenol polyoxyethylene ether, decanoate, Tween 80, polyethylene glycol 400, and oleoyl polyoxyethylene glycerol ester; the co-surfactant is selected from one or more of diethylene glycol monoethyl ether, polyethylene glycol 200, ethanol, 1,2-propanediol, and butanol.

3. The tadalafil self-emulsifying liquid according to claim 1 or 2, characterized in that, the oil phase is selected from glycerol monooleate; the surfactant is selected from octylphenol polyoxyethylene ether; the co-surfactant is selected from diethylene glycol monoethyl ether.

4. A tadalafil self-emulsifying dispersible tablet, characterized in that, the tadalafil self-emulsifying solid adsorption mixture is 1-30%, the binder is 5-10%, the disintegrant is 5-25%, the lubricant is 1-3%, and the rest is a filler; the tadalafil self-emulsifying solid adsorption mixture is obtained by adsorbing the tadalafil self-emulsifying liquid described in claim 1 with a solid adsorbent.

5. The tadalafil self-emulsifying dispersible tablet according to claim 4, characterized in that, the solid adsorbent of the solid adsorption mixture is selected from silica micropowder, microcrystalline cellulose, hypromellose, and calcium carbonate; the filler is selected from one or more of starch, direct compression mannitol, lactose, and microcrystalline cellulose; the binder is selected from hydroxypropyl cellulose and hydroxypropyl methyl cellulose; the disintegrant is selected from sodium carboxymethyl starch, cross-linked carboxymethyl cellulose sodium, and cross-linked polyvinylpyrrolidone; the lubricant is selected from magnesium stearate, sodium stearyl fumarate, and talc powder.

6. The tadalafil self-emulsifying dispersible tablet according to claim 5, characterized in that, the solid adsorbent is selected from silica micropowder; the filler is selected from lactose and microcrystalline cellulose; the binder is selected from hydroxypropyl methyl cellulose; the disintegrant is selected from sodium carboxymethyl starch; the lubricant is selected from magnesium stearate.

7. A method for preparing a tadalafil self-emulsifying dispersible tablet according to any one of claims 4-6, comprising the following steps: (1) Preparation of the self-emulsifying liquid: Weigh the surfactant and co-surfactant according to the component amounts, mix them evenly, add the oil phase and tadalafil, and dissolve them by ultrasonic treatment; (2) Preparation of the self-emulsifying dispersible tablet: Take the above self-emulsifying solution, adsorb it with a solid adsorption material to form a solid adsorption mixture; add a filler, a disintegrant, a binder, and a lubricant to the solid adsorption mixture, and prepare the tadalafil self-emulsifying dispersible tablet by direct powder compression.

8. A tadalafil self-emulsifying dispersible tablet, characterized in that, The solid adsorbent used in the tadalafil self-emulsifying solid adsorption mixture is 1-30% of microcrystalline silica gel, the binder is 5-10% of hydroxypropyl methylcellulose, the disintegrant is 5-25% of sodium carboxymethyl starch, the lubricant is 1-3% of magnesium stearate, and the rest are fillers lactose and microcrystalline cellulose; the tadalafil self-emulsifying solid adsorption mixture is obtained by adsorbing the tadalafil self-emulsifying liquid described in claim 3 with a solid adsorbent.

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