Tadalafil supramolecular nanoparticles and preparation method thereof

Abstract

The invention provides tadalafil supramolecular nanoparticles and a preparation method thereof, and relates to the technical field of medical treatment. The tadalafil supramolecular nanoparticle comprises a particle composed of a microfiber skeleton, in-situ molecular glue and a drug carrier component, the drug loading rate of the particle needs to be larger than 58%, the particle has a hexagonal pore channel arrangement structure, the microfiber skeleton is ginkgo leaf cell walls with the delignification rate of 40-60%, and the cell walls contain natural channels with the diameter of 20-100 nm. According to the technology, natural channels of ginkgo leaf cell walls are utilized to form ordered pore channels to improve the drug loading capacity, abietic acid-tartaric acid molecular glue realizes intestinal targeted release and avoids gastric acid damage and a first pass effect, sericin protein films enable particles to be rapidly disintegrated in an oral cavity and take effect conveniently, natural plant carriers are fully degraded and free of toxicity, and rolling forming ensures the mechanical strength of the particles; long-term storage is facilitated, and efficient, safe and convenient medication experience is brought to patients.

Description

TECHNICAL FIELD

[0001] The present application relates to the medical technology field, specifically to a tadalafil supramolecular nanoparticle and a preparation method thereof. BACKGROUND

[0002] Tadalafil particles are a kind of drug dosage forms with tadalafil as the main component. Tadalafil is a selective and reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). The drug particles can relax the smooth muscle in the corpus cavernosum of the penis under sexual stimulation, allowing blood to flow into the penile tissue, thereby helping men to achieve and maintain an erection, and are mainly used for the treatment of male erectile dysfunction. When used, it needs to be guided by a doctor. It may have some adverse reactions, such as headache, indigestion, back pain, myalgia, nasal congestion, etc. At the same time, there are some contraindications and precautions, such as patients taking nitrate drugs are prohibited from using it.

[0003] The tadalafil particles produced by the prior art generally have three defects: first, the conventional carrier depends on synthetic high molecular materials (such as hydroxypropyl cellulose), which degrades slowly in the human body and is prone to residual metabolic by-products; second, to improve the dissolution rate, micronization treatment is used, which causes the surface energy of the drug particles to surge, and the particles are prone to moisture absorption and caking during storage; finally, the immediate-release particles disintegrate too early in the gastric acid environment, not only stimulating the gastric mucosa, but also being inactivated by the liver first-pass effect, with an actual bioavailability of less than 40%. SUMMARY

[0004] In view of the deficiencies of the prior art, the present application provides a tadalafil supramolecular nanoparticle and a preparation method thereof, which solves the problem of low drug utilization efficiency of the prior art.

[0005] To achieve the above purpose, the present application realizes the following technical scheme: a tadalafil supramolecular nanoparticle, comprising particles composed of a microfiber skeleton, an in-situ molecular glue, and a drug carrier component:

[0006] The drug loading rate of the particles is greater than 58%, and the particles have a hexagonal pore arrangement structure. The microfiber skeleton is a cell wall of Ginkgo biloba leaves with a delignification rate of 40% to 60%. The cell wall contains natural channels with a diameter of 20 nm to 100 nm.

[0007] The in-situ molecular glue is a hydrogen-bonded complex formed by self-assembly of matairesinol and ammonium tartrate in a molar ratio of 1:0.5 to 1:2 in the natural channels. The drug carrier is a tadalafil crystal bonded to the carboxyl sites of the in-situ molecular glue.

[0008] Preferably, the number of natural channels is greater than 30, and the outer surface of the particles is coated with a silk glue protein film with a thickness of 0.5 μm to 2 μm.

[0009] Preferably, the hydrogen bond complex has a molecular structure of abietic acid-COOH···HO-tartaric acid, and the long axis of the hexagonal channel has an angle of less than 10° with the main vein direction of the ginkgo leaf.

[0010] A preparation method of tadalafil supramolecular nanoparticles, comprising the following steps:

[0011] S1. Carrier activation

[0012] 80-120 mesh ginkgo leaf powder is treated in a 0.5 mol / L NaOH-ethanol mixture (volume ratio 1:3) at 50°C for 30 minutes, and then washed with water until neutral;

[0013] S2. Vacuum drug loading

[0014] The activated carrier is immersed in an ethanol aqueous solution containing 5% to 15% tadalafil, abietic acid and tartaric acid, the ethanol concentration is ≤30%, and the vacuum is maintained at -0.09 MPa for 10 minutes, the normal pressure is restored within 5 seconds, and the cycle is repeated 3 times;

[0015] S3. Roll forming

[0016] The roll is rolled 3 times by opening V-shaped grooves on the roll surface, and the roll gap is 50 μm;

[0017] S4. Low-temperature curing

[0018] Cut into 2 mm x 3 mm particles at -20°C, and then spray 5% silk glue protein solution and dry at room temperature to form

[0019] Preferably, the molar concentration ratio of abietic acid to tartaric acid in step S2 is 1:1.2, and the depth of the V-shaped groove in step S3 is 20 μm, and the center distance between adjacent grooves is 100 μm.

[0020] Preferably, the roll speed in step S3 is 2 rpm to 4 rpm, and the cutting direction in step S4 is parallel to the main vein direction of the ginkgo leaf.

[0021] Preferably, the production equipment comprises a vacuum drug loading unit, a roll forming unit, and a low-temperature cutting unit, the vacuum drug loading unit is provided with a laser bubble breaking sensor with a wavelength of 650 nm, the roll forming unit is provided with a V-shaped groove array with a depth of 20 μm and a spacing of 100 μm on the roll surface, and the low-temperature cutting unit is provided with a liquid nitrogen temperature control system to maintain the working cavity at -20±2°C.

[0022] Preferably, the tadalafil supramolecular particles after forming in step S4 have a disintegration rate of more than 95% in artificial saliva within 30 seconds.

[0023] Preferably, the tadalafil supramolecular particle has a particle size distribution polydispersity index less than 0.15, a 2-hour cumulative release rate less than 15% in a pH 1.2 medium, and a 45-minute release rate greater than 90% in a pH 6.8 medium.

[0024] The present application provides a tadalafil supramolecular nanoparticle and a preparation method thereof. The present application has the following beneficial effects:

[0025] The present application provides a tadalafil supramolecular nanoparticle and a preparation method thereof. The present application has the following beneficial effects: BRIEF DESCRIPTION OF DRAWINGS

[0026] Figure 1 The present application provides a tadalafil supramolecular nanoparticle and a preparation method thereof. The present application has the following beneficial effects: DETAILED DESCRIPTION

[0027] The technical solutions in the embodiments of the present application will be clearly and completely described with reference to the drawings in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative work fall within the scope of the present application.

[0028] As shown in Figure 1 The present application provides a tadalafil supramolecular nanoparticle, which comprises a particle composed of a microfiber skeleton, an in-situ molecular glue, and a drug carrier component:

[0029] The drug loading rate of the particle is greater than 58%, and the particle has a hexagonal pore arrangement structure. The microfiber skeleton is a cell wall of ginkgo leaves with a delignification rate of 40% to 60%. The cell wall contains natural channels with a diameter of 20 nm to 100 nm.

[0030] The in-situ molecular glue is a hydrogen bond complex formed by self-assembly of abietic acid and ammonium tartrate in a molar ratio of 1:0.5 to 1:2 in the natural channel. The drug carrier is a tadalafil crystal bonded to the carboxyl site of the in-situ molecular glue.

[0031] The natural channels are more than 30, and the grain external surface is coated with a silk fibroin film with a thickness of 0.5-2 μm. The molecular structure of the hydrogen bond complex is rosin acid-COOH···HO-tartaric acid, and the angle between the long axis of the hexagonal channel and the main vein direction of the ginkgo leaf is less than 10°.

[0032] A preparation method of tadalafil supramolecular nanoparticles, comprising the following steps:

[0033] S1. Carrier activation

[0034] 80-120 mesh ginkgo leaf powder is treated in a 0.5 mol / L NaOH-ethanol mixture with a volume ratio of 1:3 at 50°C for 30 minutes, and then washed with water until neutral;

[0035] S2. Vacuum drug loading

[0036] The activated carrier is immersed in an ethanol aqueous solution containing 5%-15% tadalafil, rosin acid and tartaric acid, the ethanol concentration is ≤30%, and the vacuum is maintained at -0.09 MPa for 10 minutes, the normal pressure is restored within 5 seconds, and the cycle is repeated for 3 times;

[0037] S3. Roll forming

[0038] The roll is rolled for 3 times by opening V-shaped grooves on the roll surface, and the roll gap is 50 μm;

[0039] S4. Low-temperature curing

[0040] The particles are cut into 2 mm×3 mm at -20°C, and then dried and formed into a shape at room temperature after spraying a 5% silk fibroin solution.

[0041] In step S2, the molar concentration ratio of rosin acid to tartaric acid is 1:1.2, the depth of the V-shaped groove in step S3 is 20 μm, and the center distance between adjacent grooves is 100 μm. The roll speed in step S3 is 2-4 rpm, and the cutting direction in step S4 is parallel to the main vein direction of the ginkgo leaf. The production equipment includes a vacuum drug loading unit, a roll forming unit and a low-temperature cutting unit. The vacuum drug loading unit is provided with a laser bubble breaking sensor with a wavelength of 650 nm, the roll forming unit is provided with a V-shaped groove array with a depth of 20 μm and a spacing of 100 μm on the roll surface, and the low-temperature cutting unit is provided with a liquid nitrogen temperature control system to maintain the working cavity at -20±2°C. The tadalafil supramolecular particles after forming in step S4 have a disintegration rate of more than 95% in artificial saliva within 30 seconds. The particle size distribution polydispersity index of the tadalafil supramolecular particles is less than 0.15, the 2-hour cumulative release rate in a pH 1.2 medium is less than 15%, and the 45-minute release rate in a pH 6.8 medium is more than 90%.

[0042] The present technology forms a hexagonal ordered pore structure through the natural nanochannel of ginkgo biloba leaf cell wall, significantly improves the drug loading capacity, and uses the pH response characteristics of the self-assembled molecular gel of abietic acid and tartaric acid to remain stable in the gastric acid environment and precisely disintegrate and release in the intestinal neutral environment, avoiding the destruction of the drug by gastric acid and preventing the loss of liver first-pass effect. The innovation adopts the silk sericin coating and mechanical rolling forming process to realize the dual advantages of second-level disintegration rate for oral saliva and high mechanical strength for moisture-proof storage and transportation. The full degradation characteristics of the natural plant carrier completely eliminate the risk of synthetic polymer residue toxicity, and the whole process does not require organic solvents to ensure production safety, providing a new drug solution with high efficiency, fast dissolution, targeted release and long-term stability for patients with erectile dysfunction.

[0043] Although embodiments of the present application have been shown and described, it is to be understood that various modifications, substitutions, replacements and changes can be made to these embodiments without departing from the principles and spirit of the present application, and the scope of the present application is defined by the appended claims and their equivalents.

Claims

1. A tadalafil supramolecular nanoparticle, characterized in that: The particles include microfiber skeleton, in-situ molecular glue and drug carrier components: The drug loading rate of the particles must be greater than 58% and have a hexagonal pore arrangement structure. The microfibril skeleton is a ginkgo leaf cell wall with a delignification rate of 40% to 60%, and the cell wall contains natural channels with a diameter of 20nm to 100nm; The in-situ molecular glue is a hydrogen bond complex formed by self-assembly of rosinic acid and ammonium tartrate in a molar ratio of 1:0.5 to 1:2 in the natural channel, and the drug carrier is a tadalafil crystal bonded to the carboxyl site of the in-situ molecular glue.

2. The tadalafil supramolecular nanoparticle according to claim 1, characterized in that: The number of the natural channels is greater than 30, and the outer surface of the particle is covered with a sericin film with a thickness of 0.5 μm to 2 μm.

3. The tadalafil supramolecular nanoparticles and the preparation method thereof according to claim 1, characterized in that: The molecular structure of the hydrogen bond complex is arosinic acid-COOH···HO-tartaric acid, and the angle between the major axis of the hexagonal pore and the direction of the main vein of the ginkgo leaf is less than 10°.

4. The method for preparing tadalafil supramolecular nanoparticles according to any one of claims 1 to 3, characterized in that: The following steps are involved: S1. Vector Activation 80-120 mesh ginkgo leaf powder was treated in 0.5 mol / L NaOH-ethanol mixture (volume ratio 1:3) at 50°C for 30 minutes and washed with water until neutral; S2. Vacuum drug loading The activated carrier is immersed in an ethanol aqueous solution containing 5% to 15% tadalafil, rosinic acid and tartaric acid, with an ethanol concentration of ≤30%, maintained at -0.09 MPa vacuum for 10 minutes, and restored to normal pressure within 5 seconds, and the cycle is repeated 3 times; S3. Roll forming Roll the rollers three times with V-grooves on the roller surface, with a roller distance of 50 μm; S4. Low temperature curing The pellets were cut into 2mm×3mm particles at -20℃, sprayed with 5% sericin solution and dried at room temperature to form pellets.

5. The method for preparing tadalafil supramolecular nanoparticles according to claim 4, wherein: The molar concentration ratio of rosinic acid to tartaric acid in step S2 is 1:1.

2. The depth of the V-shaped groove in step S3 is 20 μm, and the center distance between adjacent grooves is 100 μm.

6. The method for preparing tadalafil supramolecular nanoparticles according to claim 4, wherein: The roller speed in step S3 is 2 rpm to 4 rpm, and the cutting direction in step S4 is parallel to the main vein direction of the ginkgo leaf.

7. The method for preparing tadalafil supramolecular nanoparticles according to claim 4, wherein: The production equipment includes: a vacuum drug loading unit, a roller forming unit, and a low-temperature cutting unit. The vacuum drug loading unit is equipped with a laser bubble breaking sensor with a wavelength of 650nm. The roller forming unit has a V-groove array with a depth of 20μm and a spacing of 100μm on the roller surface. The low-temperature cutting unit has a built-in liquid nitrogen temperature control system to maintain the working chamber at -20±2°C.

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