Dapoxetine oral soluble film and preparation method thereof

Abstract

The invention discloses a dapoxetine oral soluble film and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. The oral soluble film of dapoxetine is prepared from the following raw materials and auxiliary materials: a dapoxetine resin compound, a film forming material, a plasticizer and a pH regulator, the dapoxetine resin compound is a compound formed by performing ion exchange on dapoxetine hydrochloride and cation exchange resin. Compared with the existing commercially available dapoxetine tablets, the dapoxetine hydrochloride oral soluble film provided by the invention has bioequivalence before meal and after meal and uniform quality, and can realize industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a dapoxetine orally disintegrating film and a preparation method thereof. Background Art

[0002] Dapoxetine hydrochloride is a short-acting serotonin reuptake inhibitor (SSRI). It is the only oral medication approved for the treatment of premature ejaculation in major countries worldwide and is recommended as a first-line medication in international and domestic clinical guidelines. It selectively blocks serotonin reuptake, effectively regulating serotonin levels in the central nervous system, thereby prolonging the ejaculation latency period. Dapoxetine hydrochloride has a rapid onset of action (1-2 hours), can be taken on demand, is effective from the first dose, offers excellent efficacy, and has transient and mild adverse reactions.

[0003] Currently, dapoxetine hydrochloride is marketed in tablet form. The complex preparation process can easily generate dust, hindering worker safety and environmental pollution. Furthermore, standard tablets disintegrate slowly and require water to be swallowed, making them inconvenient for patients with dysphagia and compromising patient privacy. Therefore, a new dosage form that is easier to swallow, requires no water, and disintegrates quickly is needed. Furthermore, to better protect patient privacy, a new dosage form that behaves like a tablet is needed to replace traditional "tablets."

[0004] Orally disintegrating film (ODF) is a solid dosage form for oral administration, roughly the size of a postage stamp. It boasts advantages such as small size, thinness, the absence of water for swallowing, and rapid disintegration. However, dapoxetine hydrochloride has a poor taste, with unpleasant sensations such as bitterness and tongue numbing, a key characteristic of orally disintegrating dosage forms. Oral drug formulations disintegrate in the mouth, and the drug, dissolved in saliva, comes into contact with taste receptors such as taste buds, producing taste. Therefore, blocking drug dissolution in the mouth and preventing contact with taste buds is a fundamental mechanism for taste masking. Ion exchange resins are a commonly used method for taste masking. When drug ions in solution enter the ion pores and exchange charge with the ions of the ion exchange resin, the drug is bound to the resin, forming a new complex. Once the ion exchange resin-drug complex enters the mouth, it takes time for oral saliva to diffuse into the resin pores. Furthermore, the drug is unable to dissolve in the mouth, thus achieving the taste masking effect. In addition, the pores and particles included in the physical structure of the ion resin itself can directly form a physical barrier, block the release of drugs and prevent drugs from contacting taste buds, and can also play a certain role in blocking and masking taste.

[0005] When the complex formed by ion exchange resin and drug is swallowed into the stomach, it stays in the stomach for a long time, 30-60 minutes on an empty stomach and 2-4 hours after a meal. Gastric juice is highly acidic, and its pH is lower than the pKa of the acidic ion exchange resin. Therefore, the drug will be displaced and dissolved in the stomach, and then absorbed and take effect.

[0006] CN114569584A discloses a dapoxetine hydrochloride oral fast-dissolving film and its preparation method. The oral fast-dissolving film has a three-layer structure, including two film-forming layers and a dapoxetine hydrochloride self-microemulsifying layer sandwiched between the two film-forming layers. The preparation method comprises applying a mixed slurry B, allowing it to air dry, then applying a mixed slurry A on the mixed slurry B, then air drying, then applying a mixed slurry B on the mixed slurry A, and then drying the mixed slurry in a forced air drying oven at 10°C to 90°C. The film is then removed from the film and cut to obtain the dapoxetine hydrochloride oral fast-dissolving film. Currently, there is no industrial equipment for preparing three-layer oral fast-dissolving films at home or abroad. This process remains at the laboratory stage, and the formulation process is extremely complex, with low coating and drying efficiency, making it difficult to commercialize. Furthermore, it fails to address the bitter and irritating taste of dapoxetine hydrochloride itself.

[0007] CN116196297A discloses a dapoxetine hydrochloride fast-dissolving orally film and its preparation method. The fast-dissolving orally film comprises the following components: a dapoxetine hydrochloride resin complex and one or more pharmaceutically acceptable oral formulation excipients. The dapoxetine hydrochloride resin complex is a complex of dapoxetine hydrochloride and a taste-masking ion exchange resin, wherein the mass ratio of dapoxetine hydrochloride to taste-masking ion exchange resin is 0.5:1 to 5:1. In this patent application, after formation, the ion exchange resin drug complex is washed with a pH 7.82 buffer solution containing sodium lauryl sulfate, sodium dihydrogen phosphate, and sodium hydrogen phosphate. This process is cumbersome and complex, and sodium lauryl sulfate may remain in the complex. The preparation of the dapoxetine ion exchange resin complex disclosed in this patent application is limited to laboratory-scale production. Furthermore, this patent application discloses in vivo pharmacokinetic testing, but the dosage is 30 mg before a meal. This means that the patent application conducted a pre-meal bioequivalence (BE) study, not a post-meal BE study. When the drug is administered after a meal, the pH value in the stomach usually rises to around 4.5-5.5. The new ion exchange resin complex of dapoxetine has a slow replacement reaction under this pH condition, resulting in lower drug dissolution. Compared with the currently marketed ordinary dapoxetine tablets, the dissolution curve under this pH condition is quite different, resulting in a higher risk of BE after a meal.

[0008] Therefore, providing a dapoxetine hydrochloride orally disintegrating film that uses resin to mask the taste and a preparation method thereof, which is bioequivalent to the existing dapoxetine ordinary tablets on the market before and after meals and can be industrially produced, has become an urgent problem to be solved by those skilled in the art. Summary of the Invention

[0009] A first object of the present invention is to provide a dapoxetine orally disintegrating film having good toughness, suitable demoulding properties, good disintegration properties, a good mouthfeel, a smooth and delicate appearance, a suitable thickness, easy drying, and satisfactory tensile strength and percentage elongation, thereby being easily industrialized for production.

[0010] To achieve the above objectives, the present invention adopts technical solution 1 and technical solution 2:

[0011] Option 1

[0012] A dapoxetine orally dissolving film, comprising the following components: 20 to 55 parts of a dapoxetine resin compound, 15 to 55 parts of a film-forming material, and 3 to 20 parts of a plasticizer;

[0013] The dapoxetine resin complex is a complex formed by ion exchange between dapoxetine acid addition salt and cation exchange resin;

[0014] The film-forming material comprises at least one of polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, and hydroxypropyl cellulose.

[0015] Option 2

[0016] A dapoxetine orally disintegrating film, comprising the following components: 20 to 55 parts of a dapoxetine resin compound, 15 to 55 parts of a film-forming material, and 3 to 20 parts of a plasticizer;

[0017] The dapoxetine resin complex is a complex formed by ion exchange between dapoxetine acid addition salt and cation exchange resin;

[0018] The mass ratio of dapoxetine to cation exchange resin in the dapoxetine resin complex is 1:0.5 to 1:1.5, preferably 1:0.8 to 1:1.2;

[0019] Alternatively, the mass ratio of dapoxetine acid addition salt to cation exchange resin for preparing the dapoxetine resin complex is 1:0.5 to 1:1.5, preferably 1:0.8 to 1:1.2.

[0020] In some embodiments of the present invention, the orally dissolving film further comprises a pH adjuster.

[0021] In some embodiments of the present invention, the orally dissolving film comprises 1 to 12 parts of a pH adjuster, preferably 1.5 to 10 parts, and more preferably 2 to 6 parts.

[0022] A second object of the present invention is to provide a dapoxetine orally disintegrating film that overcomes the prior art's limitation of only being bioequivalent before meals, achieving bioequivalence with tablets before and after meals. Furthermore, the orally disintegrating film exhibits excellent toughness, suitable demolding properties, good disintegration, a pleasant mouthfeel, a smooth and delicate appearance, an appropriate thickness, easy drying, and satisfactory tensile strength and percent elongation, making it easy to commercialize.

[0023] To achieve the above purpose, the present invention adopts technical solution three:

[0024] Option 3

[0025] A dapoxetine orally dissolving film, comprising the following components: 20 to 55 parts of a dapoxetine resin compound, 15 to 55 parts of a film-forming material, 3 to 20 parts of a plasticizer, and 1 to 12 parts of a pH regulator;

[0026] The dapoxetine resin complex is a complex formed by ion exchange between dapoxetine acid addition salt and cation exchange resin.

[0027] The following limitations apply to all technical solutions described above, including Solution 1, Solution 2, and Solution 3.

[0028] In some embodiments of the present invention, the dapoxetine acid addition salt is dapoxetine hydrochloride.

[0029] In some embodiments of the present invention, the cation exchange resin is a weakly acidic cation exchange resin.

[0030] In some embodiments of the present invention, the orally dissolving film comprises the following components in parts by weight: 35-50 parts of dapoxetine resin complex, 20-50 parts of film-forming material, 5-18 parts of plasticizer, and 1.5-10 parts of pH adjuster.

[0031] In some embodiments of the present invention, the orally dissolving film comprises the following components in parts by weight: 40-45 parts of dapoxetine resin complex, 28-47 parts of film-forming material, 7-15 parts of plasticizer, and 2-6 parts of pH adjuster.

[0032] In some embodiments of the present invention, the orally dissolving film comprises the following components in parts by weight: 43 parts of dapoxetine resin complex, 40 parts of film-forming material, 12 parts of plasticizer, and 3.5 parts of pH adjuster.

[0033] In some embodiments of the present invention, the mass ratio of dapoxetine to cation exchange resin in the dapoxetine resin complex is 1:0.5-1:1.5, preferably 1:0.8-1:1.2. Specific values ​​of the mass ratio of dapoxetine to cation exchange resin can be 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, or 1:1.5.

[0034] In some embodiments of the present invention, the mass ratio of dapoxetine acid addition salt to cation exchange resin used to prepare the dapoxetine resin complex is 1:0.5 to 1:1.5, preferably 1:0.8 to 1:1.2. Specific mass ratios of dapoxetine acid addition salt to ion exchange resin may include 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, 1:1.1, 1:1.2, 1:1.3, 1:1.4, or 1:1.5.

[0035] In some embodiments of the present invention, the dapoxetine resin complex is a complex formed by ion exchange between 48.4 parts of dapoxetine hydrochloride and 51.6 parts of a cation exchange resin.

[0036] In some embodiments of the present invention, the cation exchange resin includes polyclinic potassium, Amberlite series resins, and Kyron series resins.

[0037] Preferably, the models of the Amberlite series resins include Amberlite IRP-58, IRP-64, IRP-67, IRP-69, and IRC-50.

[0038] Preferably, the models of the Kyron series resins include Kyron-T-134, T-314, T-104, and T-114.

[0039] In some embodiments of the present invention, the ion exchange resin particle size D90 is 25 to 100 μm, preferably 30 to 90 μm, more preferably 35 to 75 μm, and even more preferably 40 to 60 μm. Preferred ion exchange resin particle sizes D90 are 30, 35, 38, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, and 90 μm.

[0040] Dapoxetine hydrochloride has a positive charge and its aqueous solution is weakly acidic. Considering the adsorption principle and characteristics of weak cation exchange resin, weakly acidic cation exchange resin was selected.

[0041] The present invention selects weakly acidic cation exchange resin, which can quickly release the drug under acidic conditions.

[0042] The ion exchange resin drug complex and orally dissolving film preparation prepared by the invention have excellent quality and smooth process.

[0043] The applicant has found that the particle size and dosage of ion exchange resin affect the drug loading and utilization rate. When the cation exchange resin particle size D90 is 25-100 μm, the drug loading and utilization rate are both good, and the orally dissolving film produced has a smooth and delicate appearance.

[0044] In some embodiments of the present invention, the film-forming material comprises at least one of polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, hydroxypropyl cellulose, polyoxyethylene, hydroxypropyl methylcellulose, povidone, copovidone, and starch;

[0045] In some embodiments of the present invention, the film-forming material includes at least one of polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, and hydroxypropyl cellulose.

[0046] In some embodiments of the present invention, the film-forming material comprises polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, and hydroxypropyl cellulose. In some embodiments of the present invention, the film-forming material comprises 12-27 parts of polyvinyl alcohol, 8-20 parts of polyvinyl alcohol-polyethylene glycol graft copolymer, and 1-8 parts of hydroxypropyl cellulose.

[0047] In some embodiments of the present invention, the mass fraction of the film-forming material polyvinyl alcohol is 12, 13, 15, 17, 19, 21, 23, 25, or 27 parts.

[0048] In some embodiments of the present invention, the mass fraction of the film-forming material polyvinyl alcohol polyethylene glycol graft copolymer is 8, 8.5, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 parts.

[0049] In some embodiments of the present invention, the mass fraction of the film-forming material hydroxypropyl cellulose is 1, 2, 3, 4, 5, 6, 7, or 8 parts.

[0050] In some embodiments of the present invention, the film-forming material includes 13 to 27 parts of polyvinyl alcohol, 8 to 17 parts of polyvinyl alcohol-polyethylene glycol graft copolymer, and 1 to 7 parts of hydroxypropyl cellulose.

[0051] In some embodiments of the present invention, the film-forming material includes 15 to 25 parts of polyvinyl alcohol, 8.5 to 16 parts of polyvinyl alcohol-polyethylene glycol graft copolymer, and 3 to 6 parts of hydroxypropyl cellulose.

[0052] In some embodiments of the present invention, the film-forming material includes 15 to 25 parts of polyvinyl alcohol, 9 to 16 parts of polyvinyl alcohol-polyethylene glycol graft copolymer, and 3 to 6 parts of hydroxypropyl cellulose.

[0053] Preferably, the film-forming material includes 21 parts of polyvinyl alcohol, 15.5 parts of polyvinyl alcohol-polyethylene glycol graft copolymer, and 3.4 parts of hydroxypropyl cellulose.

[0054] Preferably, the film-forming material includes 15 parts of polyvinyl alcohol, 10 parts of polyvinyl alcohol-polyethylene glycol graft copolymer, and 3 parts of hydroxypropyl cellulose.

[0055] Preferably, the film-forming material includes 25 parts of polyvinyl alcohol, 8.9 parts of polyvinyl alcohol-polyethylene glycol graft copolymer, and 6 parts of hydroxypropyl cellulose.

[0056] In some embodiments of the present invention, the polyvinyl alcohol-polyethylene glycol graft copolymer is a graft copolymer of polyvinyl alcohol and polyethylene glycol in a ratio of 30-90:10-45 (w / w); preferably, the polyvinyl alcohol-polyethylene glycol graft copolymer is a graft copolymer of polyvinyl alcohol and polyethylene glycol in a ratio of 75:25 (w / w).

[0057] In some embodiments of the present invention, the molecular weight of the polyvinyl alcohol-polyethylene glycol graft copolymer is 1,000 to 10,000, preferably 2,000 to 8,000, and more preferably 3,000 to 6,000.

[0058] In some embodiments of the present invention, the plasticizer includes at least one of polyethylene glycol, glycerol, sorbitol, propylene glycol, and triacetin.

[0059] In some embodiments of the present invention, the plasticizer includes glycerol and polyethylene glycol.

[0060] In some embodiments of the present invention, the plasticizer includes 5 to 10 parts of glycerol and 2 to 5 parts of polyethylene glycol.

[0061] Preferably, the plasticizer comprises 8.9 parts of glycerol and 2.8 parts of polyethylene glycol; or, the plasticizer comprises 5 parts of glycerol and 2 parts of polyethylene glycol; or, the plasticizer comprises 10 parts of glycerol and 5 parts of polyethylene glycol.

[0062] In some embodiments of the present invention, the molecular weight of polyethylene glycol is 4000-6000.

[0063] In some embodiments of the present invention, the pH adjuster includes an organic acid and an inorganic acid.

[0064] In some embodiments of the present invention, the pH adjuster includes at least one of citric acid, tartaric acid, fumaric acid, ascorbic acid, malic acid, lactic acid, chlorogenic acid, oxalic acid, formic acid, acetic acid and succinic acid.

[0065] In some embodiments of the present invention, the pH adjuster includes at least one of citric acid and tartaric acid.

[0066] In some embodiments of the present invention, the orally dissolving film comprises 1.5 to 10 parts of a pH adjuster, preferably 2 to 6 parts. Preferably, the pH adjuster is 2 parts, 3 parts, 3.5 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, or 10 parts.

[0067] In the present invention, the complex formed by the ion exchange resin and dapoxetine hydrochloride can achieve the purpose of taste masking. In order to have a better taste, in some embodiments of the present invention, the orally dissolving film optionally further comprises 1.2 to 2.7 parts of a flavoring agent.

[0068] In some embodiments of the present invention, the orally dissolving film further comprises 1.2 to 2.7 parts of flavoring agents, or / and 0.5 to 1.0 parts of opacifiers, or / and 0.01 to 0.05 parts of pigments.

[0069] In some embodiments of the present invention, the flavoring agent includes 1.0 to 2.0 parts of sweetener and 0.2 to 0.7 parts of flavor.

[0070] In some embodiments of the present invention, the sweeteners include sucralose, steviol glycosides, acesulfame potassium, aspartame, neotame, and saccharin sodium;

[0071] In some embodiments of the present invention, the orally dissolving film further comprises 0.5 to 1.0 parts of a sunscreen, and / or 0.01 to 0.05 parts of a pigment.

[0072] In some embodiments of the present invention, the sunscreen comprises titanium dioxide;

[0073] In some embodiments of the present invention, the pigment comprises red iron oxide.

[0074] The third object of the present invention is to provide a method for preparing the dapoxetine orally dissolving film, which can be used for industrial production.

[0075] To achieve the above purpose, the present invention adopts technical solution 4:

[0076] Option 4

[0077] The present invention discloses a method for preparing a dapoxetine orally disintegrating film, comprising the following steps:

[0078] S1. Preparation of dapoxetine resin complex: ion exchange adsorption of dapoxetine acid addition salt with a cation exchange resin in water to obtain a dapoxetine resin complex;

[0079] S2. Preparation of slurry: adding a film-forming agent to the solvent, mixing uniformly, adding the remaining excipients, mixing uniformly, then adding dapoxetine resin complex, mixing uniformly, to obtain a slurry to be coated;

[0080] S3. Apply and dry.

[0081] Some embodiments of the present invention further include step S4: cutting and packaging.

[0082] In some embodiments of the present invention, in step S1, a cation exchange resin is dispersed in water, dapoxetine hydrochloride is added, and adsorption is performed to obtain a dapoxetine resin complex; or dapoxetine hydrochloride is dissolved in water, cation exchange resin is added, and adsorption is performed to obtain a dapoxetine resin complex. Preferably, the cation exchange resin is dispersed in water, and dapoxetine hydrochloride is added.

[0083] In some embodiments of the present invention, in step S1, ion exchange adsorption is performed on the cation exchange resin and the dapoxetine acid addition salt in pure water;

[0084] In some embodiments of the present invention, in step S1, the adsorption is followed by filtering, washing the filter cake and then drying the filter cake.

[0085] In some embodiments of the present invention, in step S1, the filter cake is washed with pure water.

[0086] In some embodiments of the present invention, in step S1, the filter cake is washed and then vacuum dried until the moisture content is ≤7 wt%.

[0087] The applicants found that vacuum drying of the dapoxetine resin complex yielded a loose mass that was easily sieved and dried. The resulting orally disintegrating film exhibited suitable demoulding properties, good toughness, and met the required tensile strength and percent elongation. However, drying at atmospheric pressure resulted in a compact filter cake that was difficult to sieve.

[0088] In some embodiments of the present invention, in step S1, the mass ratio of the cation exchange resin to water is 1:8 to 1:20, preferably 1:10 to 1:17, and more preferably 1:10 to 1:15.

[0089] In some embodiments of the present invention, in step S1, the cation exchange resin is stirred and dispersed in water at 50-80°C; the stirring and dispersion temperature is preferably 55-75°C, more preferably 60-70°C.

[0090] In some embodiments of the present invention, in step S1, dapoxetine hydrochloride is added and then adsorbed by stirring at 50-80°C; the adsorption stirring temperature is preferably 55-75°C, more preferably 60-70°C.

[0091] In some embodiments of the present invention, in step S2, the solvent is an ethanol aqueous solution.

[0092] In some embodiments of the present invention, in step S2, after the film-forming agent, the remaining excipients, and the dapoxetine resin complex are added, the mixture is homogenized under vacuum and heating conditions.

[0093] In some embodiments of the present invention, in step S2, the ethanol aqueous solution is an ethanol aqueous solution with a concentration of 10 to 30 wt%, preferably an ethanol aqueous solution with a concentration of 10 to 20 wt%.

[0094] In some embodiments of the present invention, in step S2, the mass of the ethanol aqueous solution is 1.2-2.5 times the total weight of the orally disintegrating film formulation, and preferably the mass of the ethanol aqueous solution is 1.4-1.8 times the total weight of the orally disintegrating film formulation.

[0095] In some embodiments of the present invention, in step S2, polyvinyl alcohol and polyvinyl alcohol-polyethylene glycol graft copolymer are first added to the film-forming agent and homogenized; and then hydroxypropyl cellulose is added and homogenized.

[0096] In some embodiments of the present invention, in step S2, the homogenization intensity is 35-50 Hz, the total homogenization time is greater than or equal to 2 hours, and the vacuum degree is above -0.05 MPa.

[0097] In some embodiments of the present invention, in step S2, the homogenization temperature is 40-60°C.

[0098] In some embodiments of the present invention, in step S3, a continuous coater is used for coating and drying.

[0099] In some embodiments of the present invention, in step S3, a pharmaceutical polyester film is used as a backing and a continuous coating machine is used for coating and drying.

[0100] In some embodiments of the present invention, in step S3, the coating speed is 0.5-1.0 m / min, and the gap between the coating blades is adjusted to 400-800 μm.

[0101] In some embodiments of the present invention, in step S3, the temperature in the front section of the drying area is 60-90° C., and the air volume ranges from 30% to 50%.

[0102] In some embodiments of the present invention, in step S3, the coating drying loss is 6 to 14.5%.

[0103] In some embodiments of the present invention, the method for preparing the dapoxetine orally dissolving film comprises the following steps:

[0104] S1. Preparation of dapoxetine resin complex: Disperse a cation exchange resin in pure water, add dapoxetine hydrochloride, adsorb, filter, wash the filter cake, and dry it. Granulate the dried product to obtain the dapoxetine resin complex;

[0105] S2. Preparation of slurry: Add ethanol aqueous solution to the liquid preparation tank, add the film-forming agent, homogenize under vacuum and heating conditions, then add the remaining excipients, homogenize under vacuum and heating conditions, and finally slowly add the dapoxetine ion exchange resin complex, homogenize under vacuum and heating conditions until the slurry is free of bubbles, stop vacuuming, and discharge the material to be coated;

[0106] S3. Coating and drying

[0107] Using pharmaceutical polyester film as backing, a continuous coating machine is used for coating and drying;

[0108] Preferably, the coating speed is 0.5-1.0 m / min, the coating knife gap is adjusted to 400-800 μm, the temperature of the front section of the drying area is 60-90°C, and the air volume range is 30%-50%; preferably, the coating drying weight loss is 6-14.5%;

[0109] S4. Cutting and packaging

[0110] The coated and dried medicine film is cut by a slitting and packaging machine and packaged using polyester / aluminum medicine composite film.

[0111] A fourth object of the present invention is to provide a method for preparing a dapoxetine resin complex, which has a shorter adsorption equilibrium time, better drug loading and drug utilization, is suitable for industrial production, and the prepared dapoxetine resin complex has a better taste.

[0112] To achieve the above purpose, the present invention adopts technical solution 5:

[0113] Plan 5

[0114] A preparation method of a dapoxetine resin complex comprises the following steps: dispersing a cation exchange resin in water, adding dapoxetine acid addition salt, and adsorbing to obtain the dapoxetine resin complex.

[0115] For further definition of the method for preparing the dapoxetine complex, please refer to the definition of step S1 of the method for preparing the dapoxetine orally dissolving film of the present invention, which will not be repeated here.

[0116] Compared with the prior art, the present invention has the following beneficial effects:

[0117] The invention is scientifically designed and ingeniously conceived. Compared with common tablets, the orally disintegrating film preparation of the invention has the advantages of rapid disintegration, no bitter or numb taste, no need to swallow with water, protection of patient privacy, and convenience in carrying.

[0118] The present invention solves a series of problems in industrialization such as drug loading capacity, drug utilization, taste masking of ion exchange resins, smoothness of orally dissolving film dissolving, coating and drying, cutting and packaging processes, as well as orally dissolving film appearance smoothness, tablet weight variation, demoulding properties, and toughness, thereby ultimately producing a high-quality orally dissolving film preparation of dapoxetine hydrochloride ion exchange resin complex. The production process thereof can be used for large-scale industrial production.

[0119] The orally disintegrating film preparation of the present invention can achieve bioequivalence with a reference preparation of ordinary tablets before and after meals. While improving compliance compared to ordinary tablets, it does not reduce the convenience of clinical use and can still be taken before and after meals, overcoming the problem in the prior art that it is difficult to achieve bioequivalence after meals. BRIEF DESCRIPTION OF THE DRAWINGS

[0120] Attachment Figure 1 This is a physical picture of the dapoxetine hydrochloride orally disintegrating film product of the present invention. DETAILED DESCRIPTION

[0121] To make the purpose, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions in the embodiments of the present invention will be described clearly and completely below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer are followed. Where the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

[0122] The calculation method of drug loading and drug utilization rate described in the embodiment of the present invention is as follows:

[0123]

[0124]

[0125] The dissolution curve determination method described in the embodiment of the present invention is as follows:

[0126] Dissolution medium: pH 1.0 hydrochloric acid solution, pH 4.5 acetate buffer, pH 5.5 acetate buffer, pH 6.8 phosphate buffer.

[0127] Dissolution conditions: paddle method, medium volume 900 ml, rotation speed 50 rpm.

[0128] Detection method: UV-visible spectrophotometry was used with a detection wavelength of 292 nm.

[0129] Samples: The commercially available sample dapoxetine hydrochloride tablets (Priligy) were selected as the reference preparation, and the dapoxetine hydrochloride orally disintegrating film samples prepared in the examples and comparative examples were selected as the experimental samples.

[0130] The content determination method described in the examples of the present invention is as follows:

[0131] Preparation of test solution: Take one tablet of this product, place it in a 100ml volumetric flask, add appropriate amount of mobile phase, sonicate and shake at any time to evenly disperse and dissolve the test product, dilute to the scale with solvent, shake well, take an appropriate amount and centrifuge at an appropriate speed for 5 minutes, and take the supernatant as the test product.

[0132] Reference solution: Take an appropriate amount of dapoxetine hydrochloride reference substance, accurately weigh it, place it in a 50ml volumetric flask, add diluent to dissolve it and dilute it to the scale, shake well, and use it as the reference solution.

[0133] The content was determined by high performance liquid chromatography. The chromatographic column was octadecylsilane bonded silica gel, the mobile phase was a mixed solution of ammonium bicarbonate and diethylamine-acetonitrile (25:75); the detection wavelength was 292 nm.

[0134] The related substance determination method described in the embodiments of the present invention is as follows:

[0135] Test solution: Take one tablet of this product, place it in a 10ml volumetric flask, add an appropriate amount of mobile phase, ultrasonicate and shake at any time to evenly disperse and dissolve the test product, dilute to the scale with solvent, shake well, centrifuge at an appropriate speed for 5 minutes, take the supernatant, place it in a 20ml volumetric flask, and dilute to the scale with solvent.

[0136] Preparation of impurity reference substance stock solution: Weigh an appropriate amount of impurity reference substance and place it in different 10ml volumetric flasks, add solvent to dissolve and dilute to the scale, shake well, and obtain.

[0137] The content was determined by high performance liquid chromatography. The chromatographic column was octadecylsilane bonded silica gel, the mobile phase was a mixed solution of ammonium bicarbonate and diethylamine-acetonitrile (25:75); the detection wavelength was 292 nm.

[0138] Example 1

[0139] This embodiment discloses the industrialized production process of Dapoxetine Hydrochloride Oral Dissolving Film of the present invention, which is as follows:

[0140] (1) Preparation of dapoxetine resin complex

[0141] The formulation of dapoxetine resin complex is shown in Table 1.

[0142] Table 1 Dapoxetine resin complex prescription

[0143] Ingredients Dosage: g Dapoxetine hydrochloride 1500.00 Polyclinic potassium 1600.00 purified water 20000

[0144] The preparation process of the dapoxetine resin complex is as follows: 1600 g of polyclinic potassium (D90: 38 μm) is weighed and dispersed in 20 kg of purified water. The mixture is heated in a water bath at 70°C with stirring at 500 rpm for 1 hour. 1500 g of dapoxetine hydrochloride is then added to the mixture. The mixture is heated in a water bath at 70°C with stirring for another 1 hour to obtain a suspension of dapoxetine hydrochloride and polyclinic potassium. The suspension of dapoxetine hydrochloride and polyclinic potassium is then filtered, and the filter cake is washed three times with purified water and then vacuum dried at 55°C with a moisture content of ≤7% at the drying end point. The dapoxetine resin complex is then sieved through a 60-mesh sieve and collected to obtain the dapoxetine resin complex.

[0145] (2) Slurry preparation

[0146] The batch size of the slurry prescription is 50,000 tablets, as shown in Table 2.

[0147] Table 2 Serum formulation

[0148]

[0149] The polyvinyl alcohol-polyethylene glycol graft copolymer is a graft copolymer of polyvinyl alcohol and polyethylene glycol in a ratio of 75:25 (w / w), and has a molecular weight of about 4500 g / mol.

[0150] The preparation process of the slurry is as follows:

[0151] Add the prescribed amount of 15% ethanol aqueous solution, polyvinyl alcohol, and polyvinyl alcohol-polyethylene glycol graft copolymer into the homogenizing liquid preparation tank and homogenize. Control the homogenization speed to 50 Hz, the vacuum degree ≥-0.05 MPa, the heating temperature to 50°C, and the homogenization time to be not less than 30 minutes to obtain a uniformly dispersed polyvinyl alcohol solution without particles.

[0152] Then slowly add the prescribed amount of hydroxypropyl cellulose, control the same homogenization speed, vacuum degree and heating temperature, and homogenize for no less than 30 minutes;

[0153] Under the same homogenization conditions, slowly add polyethylene glycol 4000, sucralose, citric acid or tartaric acid, titanium dioxide, red iron oxide, glycerin, and mint essence in sequence and homogenize for at least 30 minutes;

[0154] Finally, slowly add dapoxetine hydrochloride ion exchange resin complex and homogenize for no less than 30 minutes under the same homogenization conditions until no bubbles are observed in the slurry. Then stop vacuuming and discharge the material for coating.

[0155] (3) Coating and drying

[0156] The slurry is backed with a medicinal polyester film and is coated and dried using a continuous coater. The coating speed is set at 1.0 m / min, the coating knife gap is adjusted to 550-600 μm, the temperature of the front section of the drying area is 60-90°C, the air volume range is 30%-50%, and the slurry coating thickness is adjusted so that the unit weight of the drug film after drying is controlled within the range of ±5%, and the drying loss is 6-14.5%.

[0157] (4) Cutting and packaging

[0158] After coating and drying, the film is cut using a slitting and packaging machine and packaged in polyester / aluminum composite film. The slitting station cuts the film into rolls with a width of 24±2mm. The cutting station cuts the film into lengths of 30±2mm and widths of 24±2mm. The film weight variation is within ±5%. The packaging specification is 1 piece / bag.

[0159] Example 2-5 Investigation of the Preparation Process of Dapoxetine Resin Complex

[0160] Example 2 Screening of particle size and dosage of polyclinic potassium ion exchange resin

[0161] The effects of different ion exchange resin particle sizes and dosages on the dapoxetine resin complex were investigated using drug loading, drug utilization, and mouthfeel as indicators. The effects of different ion exchange resin particle sizes and dosages on the orally disintegrating film preparation were also investigated using appearance, ease of drying, film release, toughness, tensile strength, and percent elongation as indicators. This approach allowed for the selection of suitable ion exchange resin particle sizes and dosages. The results are shown in Table 3. Dapoxetine resin complexes and orally disintegrating film preparations were prepared according to the method of Example 1. The ion exchange resin particle sizes and dosages used compared to Example 1 are shown in Table 3, with all other conditions remaining the same.

[0162] Table 3 Ion exchange resin particle size and dosage screening results

[0163]

[0164] Note:

[0165] 1) The values ​​in brackets in the drug loading index are theoretical values;

[0166] 2) The tensile strength and percent elongation of orally disintegrating film preparations prepared from cation exchange resins of different particle sizes met the requirements.

[0167] The toughness, demoulding properties, tensile strength and percentage elongation in this embodiment are determined as follows:

[0168] Toughness: Toughness is evaluated by folding resistance, which is divided into A / poor toughness: brittle and breaks after being folded less than 4 times; B / good toughness: can be folded 6 times; C / good toughness: breaks after being folded 8 times.

[0169] Demolding property: Demolding property refers to the difficulty of the orally dissolving film to be separated from the release film (the release film is a carrier film used to coat the orally dissolving film slurry). Easy demolding means that the orally dissolving film is easy to fall off and separate from the release film. As a result, when the orally dissolving film is cut into small rolls and conveyed by the rotating wheel, before it is cut into single pieces, the long small rolls of the orally dissolving film are separated from the release film, making it difficult to roll out the subsequent small rolls and put the pieces into bags. On the other hand, if demolding is difficult, the orally dissolving film and the release film are too tightly adhered. Although the small rolls will not be demolded during transportation, they will be too tightly adhered when cut into single pieces and put into bags, which is not conducive to the separation of the orally dissolving film and the release film. Therefore, appropriate demolding property is required to realize industrial cutting, packaging and bagging.

[0170] Tensile strength: Measured using an AGS-X universal materials testing machine. Hold the film vertically with two clamps and stretch it at a speed of 300 mm / min. Record the applied stress (load) at the time the film breaks. Tensile strength = applied stress (load) / cross-sectional area of ​​the film.

[0171] Percent elongation: Measured using an AGS-X universal testing machine. Hold the film vertically with two clamps. Record the length of the membrane between the two clamps (original length). Stretch the membrane at a rate of 300 mm / min. Record the displacement of the two clamps (increase in length) when the membrane breaks. Percent elongation = increase in length / original length × 100%.

[0172] Screening studies of the ion exchange resin particle size of the present invention showed that ion exchange resins with a D90 of 115 μm had slightly lower drug loading and drug utilization, and the orally dissolving films produced using them had a granular, bumpy, and uneven appearance. Ion exchange resins with D90s of 15 μm and 75 μm, on the other hand, had good drug loading and drug utilization, and the orally dissolving films produced using these two ion exchange resins had a smooth and delicate appearance. However, experiments found that the dapoxetine resin complex with a D90 of 15 μm was more difficult to filter, with screen clogging, requiring greater pressure for filtration, and a longer filtration time of more than 5 hours. Therefore, from an industrial perspective, the ion exchange resin particle size preferably has a D90 of 25 to 100 μm, preferably 30 to 90 μm, more preferably 35 to 75 μm, and even more preferably 40 to 60 μm.

[0173] The screening results of this embodiment also show that the amount of ion exchange resin used will affect the drug loading and drug utilization. If the amount of ion resin used is too low, the drug loading and drug utilization will be low, and the taste masking effect will be poor. In addition, the amount of ion exchange resin used will also affect the thickness of the orally dissolving film. If the amount of ion exchange resin used is too high and the proportion is too high, the amount of space for the film-forming material will be compressed. When the mass ratio of ion exchange resin to drug exceeds 1.5:1, the thickness of the film is thicker and difficult to dry, and the toughness is average, demolding is difficult, and it is difficult to package into bags. The mass ratio of the drug to ion exchange resin of the present invention is 1:0.5 to 1:1.5, preferably 1:0.8 to 1:1.2.

[0174] Example 3 Screening of the amount of water added to prepare dapoxetine resin drug complex

[0175] This example examined the water dosage used in preparing dapoxetine-resin drug complexes, using drug loading, drug utilization, and mouthfeel as indicators. The results of the water dosage investigation are shown in Table 4. In this example, dapoxetine-resin complexes were prepared according to the method of Example 1, with a drug-to-resin ratio of 1:1 and the water dosage shown in the table below. All other conditions remained the same. The results are shown in Table 4.

[0176] Table 4 Results of water addition in the preparation of dapoxetine resin drug complex

[0177]

[0178] Note:

[0179] 1) The values ​​in brackets of drug loading indicators are theoretical values.

[0180] As shown in the table above, a resin-to-purified water mass ratio of 1:10 to 1:17 achieves excellent drug loading and utilization. Considering the volume of industrial equipment, water conservation, and energy consumption, the preferred resin-to-purified water mass ratio in the present invention is 1:10 to 1:15.

[0181] Example 4 Screening of the Feeding Order for Preparing Dapoxetine Resin Drug Complex

[0182] This example investigated the order of adding the resin and drug to prepare a dapoxetine resin-drug complex. The screening results are shown in Table 5. This example prepared a dapoxetine resin complex according to the method of Example 1, with the order of adding the resin and drug as shown in Table 5. All other conditions were the same as in Example 1.

[0183] Table 5 Screening results of the feeding order for preparing dapoxetine resin drug complex

[0184]

[0185] In the prior art, the conventional process for preparing resin-drug complexes involves first dissolving the drug, then adding an ion exchange resin for adsorption, and finally reaching equilibrium to form the ion exchange resin-drug complex. Based on the above investigation, it was found that dispersing the ion exchange resin first before adding dapoxetine hydrochloride resulted in a shorter adsorption equilibrium time, higher drug loading and utilization, and a better taste.

[0186] Example 5 Screening of Polyclerin Potassium Ion Exchange Resin Adsorption and Dispersion Temperature

[0187] This example investigated the effects of the dispersion temperature of the polyclinic potassium resin and the dispersion temperature after adding the drug dapoxetine hydrochloride during the preparation process of the dapoxetine resin complex on adsorption equilibrium time, drug loading, drug utilization, mouthfeel, and related substances. The two temperatures were set to be the same. The results of the dispersion temperature (i.e., purified water temperature) are shown in Table 6. Compared to the method for preparing the dapoxetine resin complex in Example 1, the dispersion temperature in this example is shown in Table 6 below. All other conditions were the same as in Example 1.

[0188] Table 6 Dispersion temperature investigation results

[0189]

[0190]

[0191] Note:

[0192] 1) The values ​​in brackets of drug loading indicators are theoretical values.

[0193] Among them, the chemical name of impurity Z1 is (S)-N,N-dimethyl-3-(naphthalen-2-yloxy)-1-phenylpropan-1-amine hydrochloride, and its structural formula is as follows:

[0194]

[0195] The above test results indicate that higher temperatures facilitate the dissolution of dapoxetine hydrochloride, increase the exchange rate between the resin and dapoxetine, and shorten the equilibrium time. However, excessively high temperatures are detrimental to the stability of dapoxetine's related substances. Applicants have discovered that at low dispersion temperatures, ion exchange resins clump, hindering dispersion. At temperatures exceeding 80°C, the resin turns yellow and the concentration of related substances increases.

[0196] The results of the dispersion temperature investigation show that the dispersion temperature of 50 to 80°C basically meets the requirements, the dispersion temperature is preferably 50 to 75°C, and more preferably 60 to 70°C.

[0197] Examples 6-8 Orally Dissolving Film Preparation Prescription Screening

[0198] Example 6 Screening of film-forming materials

[0199] In this example, different film-forming materials and ratios were used to screen the film-forming materials for the dapoxetine orally dissolving film formulation based on process smoothness and orally dissolving film-related quality indicators.

[0200] Compared to the preparation method of the dapoxetine hydrochloride orally disintegrating film in Example 1, the film-forming materials used in this example are shown in Table 7 below. The amounts and weight percentages of other excipients in Table 7, such as polyethylene glycol 4000, glycerin, sucralose, flavoring, citric acid, titanium dioxide, and red iron oxide, are the same as those in the slurry formulation in Example 1. In Combinations 1 and 2, purified water was added to bring the total weight to 100%.

[0201] Table 7 Film forming material ratio table

[0202]

[0203]

[0204] In the table, % represents mass percentage.

[0205] The results of the film-forming material screening process and quality evaluation are shown in Table 8 below.

[0206] Table 8 Results of film-forming material screening process and quality evaluation

[0207]

[0208] Note:

[0209] 1) The tensile strength and percent elongation of the orally dissolving film preparations of combinations 1 and 6 did not meet the requirements. The tensile strength and percent elongation of the orally dissolving film preparations of combinations 2 to 5 met the requirements.

[0210] 2) The orally disintegrating film preparation of combination 1 disintegrated quickly, the orally disintegrating film preparations of combinations 2 to 5 disintegrated quickly, and the orally disintegrating film preparation of combination 6 disintegrated slowly.

[0211] The results show that the orally dissolving film obtained by selecting a combination of polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, and hydroxypropyl cellulose in a mass ratio of (13-27): (8-17): (1-7) meets the requirements for toughness, demoulding properties, content, related substances, and process smoothness, and can produce a high-quality orally dissolving film preparation. The mass ratio of the film-forming materials polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, and hydroxypropyl cellulose of the present invention is preferably (15-25): (9-16): (3-6).

[0212] When the total proportion of film-forming materials is 18%, polyvinyl alcohol is 10%, polyvinyl alcohol-polyethylene glycol graft copolymer is 8%, and hydroxypropyl cellulose is 0% (combination 1), the film has poor toughness, is fragile, and is easy to demould. When cutting small rolls, it falls off from the release film prematurely before being bagged, which is not conducive to machine packaging and bagging; when the total proportion of film-forming materials is 39.89%, polyvinyl alcohol is 30%, polyvinyl alcohol-polyethylene glycol graft copolymer is 1.89%, and hydroxypropyl cellulose is 8% (combination 5), although the toughness is good, the orally dissolving film and the release film are too tightly attached, making it difficult to demould, and also not conducive to the separation of the orally dissolving film and the release film during machine bagging.

[0213] In the composition of the present invention, the polyethylene-polyethylene glycol graft copolymer is crucial. If its usage is 0% (combination 6), the orally disintegrating film will have poor toughness and poor disintegration properties.

[0214] Example 7 Screening of Plasticizers

[0215] This example uses different plasticizers and ratios, with toughness, demoulding properties, tensile strength, percent elongation, and disintegration as indicators, to screen plasticizers for the formulation of dapoxetine orally disintegrating film. The results of the plasticizer screening are shown in Table 10.

[0216] Compared to the preparation method of the dapoxetine hydrochloride orally disintegrating film in Example 1, the plasticizer combination used in this example is shown in Table 9 below. The amounts and weight percentages of other excipients in the table, such as the polyvinyl alcohol-polyethylene glycol graft copolymer, hydroxypropyl cellulose, sucralose, flavoring, citric acid, titanium dioxide, and red iron oxide, are the same as those in the slurry formulation in Example 1. Purified water was added to both Combinations 1 and 2 to bring the total weight to 100%.

[0217] Table 9 Plasticizer combination ratio

[0218]

[0219] Table 10 Plasticizer screening quality evaluation results

[0220]

[0221] Note:

[0222] 1) The tensile strength and percent elongation of the orally disintegrating films corresponding to combinations 2, 3, 4, and 5 meet the requirements and disintegrate quickly; the tensile strength and percent elongation of the orally disintegrating films corresponding to combinations 1, 6, and 7 do not meet the requirements and disintegrate slowly.

[0223] As shown in Table 10, the combination of glycerol and polyethylene glycol 4000, with a dosage ratio of 5-10% glycerol and 2-5% polyethylene glycol 4000, produced an orally disintegrating film with good toughness and disintegration properties. Replacing polyethylene glycol 4000 with polyethylene glycol 6000 produced equivalent results. When glycerol was combined with sorbitol or polyethylene glycol 4000 with propylene glycol, at the same dosage, the orally disintegrating film had poor toughness and slowed disintegration. Therefore, the preferred plasticizer of the present invention is a combination of glycerol with polyethylene glycol 4000 or polyethylene glycol 6000.

[0224] Example 8 Screening Study of pH Regulators

[0225] Dapoxetine hydrochloride tablets are designed for administration before and after meals. Studies have shown that existing dapoxetine hydrochloride tablets dissolve extremely rapidly in media with pH values ​​of 1.2, 4.5, 5.5, and 6.8, achieving a dissolution rate of 85% in 15 minutes. It is common knowledge in the art that the pH in the stomach before meals is typically <2.0, with a gastric emptying time of 30 to 60 minutes, while the pH in the stomach after meals typically rises to 4.5 to 5.5, with gastric emptying taking 2 to 4 hours. It can be seen that dapoxetine hydrochloride tablets dissolve extremely rapidly under low pH conditions for administration before meals and high pH conditions for administration after meals. The orally dissolving film preparation of the present invention, which does not contain a pH regulator, exhibits a dissolution profile similar to that of the orally dissolving film preparation under low pH conditions before meals, exhibiting rapid dissolution. Therefore, the risk of bioequivalence between the orally dissolving film preparation and the reference preparation (ordinary tablet) before meals is relatively low. However, under the postprandial pH conditions of 4.5-5.5, it is difficult for the dapoxetine ion exchange resin orally dissolving film to achieve rapid dissolution, and the dissolution curve is difficult to achieve a dissolution curve similar to that of the reference preparation. Therefore, the risk of postprandial bioequivalence is relatively high.

[0226] Therefore, it is necessary to improve the dissolution of dapoxetine ion exchange resin orally dissolving film at pH 4.5-5.5 to make it similar to that of ordinary dapoxetine hydrochloride tablets, and to prevent significant dissolution at pH 6.8.

[0227] The applicant has found through extensive testing that by selecting appropriate types and ratios of pH regulators, the dapoxetine ion exchange resin orally dissolving film of the present invention can be bioequivalent to conventional tablets.

[0228] In this example, toughness, demoulding properties, tensile strength, percent elongation, disintegration, and mouthfeel were used as quality evaluation indicators. Furthermore, the dissolution behavior of the dapoxetine orally dissolving film in different dissolution media was used to screen pH adjusters and their formulations. The quality evaluation results of the pH adjuster combination screening are shown in Table 12, and the dissolution curve results of the pH adjuster combination screening are shown in Table 13.

[0229] Compared to the preparation method of the dapoxetine hydrochloride orally disintegrating film in Example 1, the pH adjuster and its formulation used in this example are shown in Table 11 below. The amounts and weight percentages of other excipients in the table, such as hydroxypropyl cellulose, polyethylene glycol 4000, glycerin, sucralose, flavoring, citric acid, titanium dioxide, and red iron oxide, are the same as those in the slurry preparation formula in Example 1. In Combinations 1 and 2, purified water was added to bring the total weight to 100%.

[0230] Table 11 pH regulator combination ratio table

[0231]

[0232]

[0233] Table 12 pH regulator combination screening quality evaluation results

[0234]

[0235] Note:

[0236] 1) The tensile strength and percent elongation of the orally disintegrating films corresponding to combinations 1-7 meet the requirements and disintegrate quickly.

[0237] Table 13 Results of pH regulator combination screening dissolution curve investigation

[0238]

[0239]

[0240] As shown in Tables 12 and 13, adding an appropriate amount of citric acid or tartaric acid (2-6%) to the orally disintegrating film formulation can provide an acidic microenvironment for the dapoxetine ion exchange resin complex to a certain extent, appropriately increasing dissolution at pH 4.5-5.5 by approximately 10-20%, while ensuring that dissolution remains minimal at pH 6.8. This ensures both the mouthfeel of the orally disintegrating film after oral disintegration and bioequivalence to conventional tablets after a meal. However, adding excessive amounts of citric acid or tartaric acid, such as exceeding 10%, can significantly increase the pH at 6.8, increasing oral dissolution and impairing the taste-masking effect of the ion exchange resin. Furthermore, the present invention improved dissolution by 10-20% at pH 5.5. While this did not achieve extremely rapid dissolution and the dissolution profile was still dissimilar to that of the reference preparation, the postprandial BE results indicated that the present invention, with the addition of tartaric acid or citric acid, was bioequivalent to the reference preparation (plain tablets). However, the postprandial Cmax of Comparative Example 1, which lacked a pH adjuster, was not equivalent to that of the reference preparation. Preliminary bioequivalence results obtained using the "MacroFLUX Drug Bioequivalence Prediction System" are shown under "Comparison of In Vitro Dissolution Profile and In Vivo Bioequivalence" in Test Example 1.

[0241] Examples 9-10 Industrial Process Screening for Dapoxetine Hydrochloride Orally Dissolving Film

[0242] Example 9 Investigation of the type and amount of solvent used in preparing slurry

[0243] This example uses viscosity, drying loss, and coating drying smoothness as indicators to examine the type and amount of solvent used in preparing the slurry of the present invention. The results are shown in Table 14. The preparation method of the slurry in this example is the same as that in Example 1.

[0244] Table 14 Slurry preparation solvent type and dosage screening

[0245]

[0246] Note:

[0247] 1) The viscosity of sample 1 slurry is too high, the viscosity of samples 2, 3, and 4 slurries is appropriate, and the viscosity of sample 5 slurry basically meets the requirements.

[0248] As shown in Table 14, adding a certain proportion of ethanol to water can achieve a good effect of removing bubbles. The ethanol content in the solvent can also affect the demoulding properties of the orally dissolving film. Although the ethanol content is too high, it is beneficial to remove bubbles, but it is easy to demould, resulting in the subsequent cutting process. When cutting small rolls, it will break away from the release film and cannot be cut into bags with a single piece. The suitable solvent of the present invention is a 10-30wt% ethanol aqueous solution, and its mass is 1.2 to 2.5 times the total weight of the orally dissolving film formula. Preferably, the solvent of the present invention is a 10-20wt% ethanol aqueous solution, and its mass is 1.4 to 1.8 times the total weight of the orally dissolving film formula.

[0249] Example 10 Coating and Drying Process Screening

[0250] In this example, coating and drying process parameters were evaluated using orally dissolving film thickness, tablet weight variation, content and content uniformity, loss on drying, related substances (individual impurities), and releasability as indicators. The coating and drying process parameters for this example are shown in Table 15 below; all other conditions were the same as in Example 1. The results of the coating and drying process evaluation are shown in Table 16.

[0251] Table 15 Coating and drying process parameters

[0252] serial number Coating knife gap (μm) Coating speed (m / min) Drying temperature (℃) Drying air volume Sample 6 300 0.5 60 30％ Sample 7 400 1.2 60 30％ Sample 8 600 0.8 75 40％ Sample 9 800 0.8 75 40％ Sample 10 1000 0.5 90 50％

[0253] Table 16 Coating and drying process investigation results

[0254]

[0255] Note:

[0256] 1) The orally disintegrating film corresponding to sample 6 was thinner, with larger RSDs for tablet weight variation and content uniformity, and the dapoxetine content was relatively low.

[0257] 2) The RSD of tablet weight variation and content uniformity of samples 7-10 were both good.

[0258] 3) The orally disintegrating films corresponding to samples 7-9 had moderate thickness, were easy to dry, had suitable demoulding properties, and the dapoxetine content met the requirements.

[0259] 4) The orally disintegrating film corresponding to sample 10 was thick, difficult to dry, difficult to demould, and had a relatively high dapoxetine content.

[0260] The results show that when the coating speed is 0.5-1.2 m / min, the coating knife gap is 400-800 μm (to control the wet glue coating thickness), the drying temperature is 60-90°C, and the air volume range is 30%-50%, it is possible to produce an orally disintegrating film semi-finished product with a tablet weight difference within the range of ±5% and a drying loss (moisture) within the range of 6-14.5% that meets the quality requirements.

[0261] Example 11

[0262] Compared with Example 1, this example does not add a pH regulator, and the other conditions are the same.

[0263] Comparative Example

[0264] Comparative Example 1

[0265] In this comparative example, dapoxetine hydrochloride orally disintegrating film was prepared according to the method of CN116196297A.

[0266] (1) Preparation of dapoxetine resin complex

[0267] The formulation of dapoxetine resin complex is shown in Table 17 below.

[0268] Table 17 Dapoxetine resin complex prescription

[0269] Ingredients Action Category Dosage: g Dapoxetine hydrochloride Active ingredient 750 Polyclinic potassium Resin material 250 purified water Fractional solvent 7500

[0270] Process: ① Dissolve the prescribed amount of dapoxetine hydrochloride in 7.5 kg of purified water, stir at 200 rpm, and stir for 5 hours; then add the prescribed amount of ion exchange resin, and stir at the same stirring speed for 5 hours to obtain a suspension of drug and ion exchange resin;

[0271] ② Filter the above suspension through a 60-mesh sieve, wash the filter cake three times with phosphate buffer, and dry it at 40°C overnight to obtain the dapoxetine resin complex for later use.

[0272] (2) Preparation of orally disintegrating film samples

[0273] The formulation of the orally disintegrating film is shown in Table 18 below.

[0274] Table 18 Orally dissolving film formulation

[0275]

[0276] Process:

[0277] ① Add the prescribed amount of plasticizer and flavoring agent to 1.6 times the prescribed amount of purified water, homogenize (40Hz) to dissolve them completely, then add the film-forming material, homogenize (40Hz) and mix evenly to obtain the excipient solution;

[0278] ② Add the dapoxetine resin complex to the excipient solution prepared in step ① and homogenize (40 Hz) to obtain a drug-containing matrix solution;

[0279] ③ The matrix liquid is vacuum defoamed with a vacuum degree of -0.05MPa or above to obtain the intermediate slurry to be coated;

[0280] ④ Use a coating machine to coat, control the tablet weight to about 89 mg, coat and dry (the temperature in the front section of the drying area is 60°C, the air volume range is 50%), and finally cut into small rolls and single pieces and package them into bags to obtain the finished orally dissolving film.

[0281] Test Example 1

[0282] The dapoxetine resin complex and dapoxetine orally disintegrating film prepared in Example 1, Example 11 and Comparative Example 1 were compared.

[0283] 1. Dapoxetine resin complex quality comparison

[0284] The dapoxetine resin complexes prepared in Example 1, Example 11, and Comparative Example 1 were compared based on drug loading, drug utilization, and mouthfeel. The results are shown in Table 19 below.

[0285] Table 19 Dapoxetine resin complex comparison results

[0286] serial number Drug loading Drug utilization Taste Example 1 49.6％(50％) 99.6％ No bitter taste Example 11 49.3％(50％) 99.2％ No bitter taste Comparative Example 1 63.2％(75％) 85.7％ Slightly bitter and numb taste

[0287] Note:

[0288] 1) The values ​​in brackets of drug loading indicators are theoretical values.

[0289] The results show that: the drug loading of Example 1 and Example 11 is close to the theoretical level, the drug utilization rate is high, the taste masking effect is good, and the dapoxetine resin complex has no bitter and numb taste; the absolute value of the drug loading of Comparative Example 1 is higher than that of the present invention, but there is a large difference from the theoretical value, the drug utilization rate is also low, and the taste masking effect is average.

[0290] Applicants have discovered that the adsorption of dapoxetine by ion exchange resins is influenced by factors such as the particle size of the ion exchange resin, the amount of water added, the adsorption temperature (water temperature), and the order of addition. The method of the present invention can produce a dapoxetine resin complex with high drug loading and utilization, as well as good taste-masking properties.

[0291] 2. Orally disintegrating film quality comparison

[0292] 2.1 Comparison of intermediate slurry quality and coating process

[0293] The intermediate slurries prepared in Example 1, Example 11, and Comparative Example 1 were compared in terms of appearance, viscosity, content, content uniformity, coating and drying smoothness, orally dissolving film thickness, tablet weight variation, content and content uniformity, and loss on drying. The results are shown in Table 20 below.

[0294] Table 20 Comparison of intermediate slurry quality and orally disintegrating film quality

[0295]

[0296]

[0297] Note:

[0298] 1) The intermediate products prepared in Example 1, Example 11, and Comparative Example 1 had suitable slurry viscosities and good content uniformity. The orally disintegrating films prepared in Example 1, Example 11, and Comparative Example 1 were easily dried, had good tablet weight variation and content uniformity, and the dapoxetine content met the requirements.

[0299] The results show that the slurries prepared in Example 1 and Example 11 are uniform and fine, with appropriate viscosity, few bubbles, good uniformity, moderate thickness, and are easy to apply and dry. After the orally dissolving film is applied, the wet glue has a fine appearance, no bubbles, and moderate thickness. The quality indicators such as tablet weight difference, content and content uniformity, and loss on drying are all good and meet the requirements.

[0300] Comparative Example 1 uses the existing technology to prepare slurry. According to the description of the prior art, it adopts stirring to prepare the slurry. The applicant found in the preparation process that due to the large viscosity of the slurry, the stirring force is weak in the large-scale production process, which cannot achieve the purpose of dispersing the slurry. It is necessary to adopt high-strength homogenizing equipment to achieve the uniform dispersion and fine slurrying of the slurry. Therefore, in the process of Comparative Example 1, the applicant replaced stirring with homogenization to achieve the preparation of the slurry and the development of subsequent work. The prior art is first stirred (homogenized) and then vacuumed. Due to the large viscosity of the slurry, the bubbles generated during the vigorous stirring process will be wrapped by the matrix. Vacuuming after stirring is not conducive to the escape of bubbles; secondly, the technical solution does not adopt ethanol to assist in removing bubbles. Therefore, the slurry prepared in Comparative Example 1 has many bubbles, and obvious bubbles are still visible in the wet glue after coating.

[0301] 2.2 Comparison of the quality of finished products of dissolving film

[0302] The orally disintegrating films prepared in Example 1, Example 11, and Comparative Example 1 were compared using toughness, demoulding properties, tensile strength, percent elongation, disintegration, and mouthfeel as indices. The results are shown in Table 21 below.

[0303] Table 21 Comparison of the cutting process and finished product quality of the melt-dissolving film

[0304]

[0305] Note:

[0306] 1) The tensile strength and percent elongation of the orally disintegrating films obtained in Example 1, Example 11, and Comparative Example 1 all met the requirements and disintegrated quickly;

[0307] The results showed that the orally disintegrating film prepared in Example 1 of the present invention had good toughness and suitable demoulding properties, making it easy to package the individual pieces into bags. Furthermore, it also had good disintegration and mouthfeel. Example 1 was essentially the same as the technical solution of the present invention, except that it did not contain a pH adjuster. Therefore, the toughness, demoulding properties, disintegration properties, and mouthfeel of the orally disintegrating film still met the requirements.

[0308] Comparative Example 1, using the existing technical solution, exhibited good toughness but was relatively easy to demold. During the machine's process of cutting into small rolls, the orally dissolving film separated from the release film during transport along the rotating shaft, preventing subsequent individual sheet cutting and bagging, resulting in an unsmooth cutting process. Furthermore, the orally dissolving film produced by the industrialized process in Comparative Example 1 still had a slightly bitter and numb taste, likely due to insufficient ion exchange resin, the temperature of the ion exchange process water, and the amount of water added, resulting in a failure to achieve effective taste masking.

[0309] 3. Comparison of in vitro dissolution curve and in vivo bioequivalence

[0310] 3.1 Comparison of in vitro dissolution curves of orally dissolving films

[0311] The orally dissolving films of Example 1, Example 11, Comparative Example 1, and the reference preparation (ordinary tablet) were respectively taken, and their in vitro dissolution curves were measured. The bioequivalence prediction system for drug was used to predict bioequivalence. The results of the in vitro dissolution curve comparison are shown in Table 22, and the results of the bioequivalence prediction test are shown in Table 23 below.

[0312] Table 22 Comparison results of in vitro dissolution curves

[0313]

[0314]

[0315] Table 23 Results of bioequivalence prediction test

[0316]

[0317] As shown in Tables 22 and 23, the in vitro dissolution curves and drug bioequivalence prediction system studies indicate that the technical solution of the present invention, which incorporates a pH adjuster, can achieve bioequivalence before and after a meal. Example 11, which does not incorporate a pH adjuster, failed to achieve BE equivalence after a meal, with Cmax deviating from the lower limit standard (lower limit 80% to upper limit 125%). The in vitro dissolution curve of Comparative Example 1 in a pH 4.5-5.5 medium is significantly lower than that of the reference formulation, and therefore its BE after a meal will not be equivalent.

[0318] The embodiments described above are some, but not all, of the embodiments of the present invention. The detailed description of the embodiments of the present invention is not intended to limit the scope of the invention as claimed, but rather merely represents selected embodiments of the present invention. All other embodiments derived by persons of ordinary skill in the art based on the embodiments of the present invention without inventive effort are also within the scope of protection of the present invention.

Claims

1. A dapoxetine orally disintegrating film, characterized in that: The orally dissolving film comprises the following components in parts by weight: 20 to 55 parts of a dapoxetine resin complex, 15 to 55 parts of a film-forming material, 3 to 20 parts of a plasticizer, and 1 to 12 parts of a pH regulator; The dapoxetine resin complex is a complex formed by ion exchange between dapoxetine acid addition salt and cation exchange resin.

2. The orally dissolving film of dapoxetine according to claim 1, characterized in that: The orally dissolving film comprises the following components in parts by weight: 40 to 45 parts of a dapoxetine resin complex, 28 to 47 parts of a film-forming material, 7 to 15 parts of a plasticizer, and 2 to 6 parts of a pH regulator; And / or, the dapoxetine resin complex is a complex formed by ion exchange between dapoxetine acid addition salt and a cation exchange resin in a mass ratio of 1:0.5 to 1:1.5 (preferably 1:0.8 to 1:1.2); And / or, the cation exchange resin includes polyclinic potassium, Amberlite series resin, Kyron series resin; preferably, the models of the Amberlite series resin include Amberlite IRP-58, IRP-64, IRP-67, IRP-69, IRC-50; preferably, the models of the Kyron series resin include Kyron-T-134, T-314, T-104, T-114; And / or, the particle size D90 of the cation exchange resin is 25 to 100 μm, preferably 30 to 90 μm, more preferably 35 to 75 μm.

3. The dapoxetine orally dissolving film according to claim 1 or 2, characterized in that The orally dissolving film further comprises 1.2 to 2.7 parts of flavoring agent, or / and 0.5 to 1.0 parts of sunscreen, or / and 0.01 to 0.05 parts of pigment.

4. The dapoxetine orally disintegrating film according to any one of claims 1 to 3, characterized in that: The film-forming material comprises at least one of polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, and hydroxypropyl fiber; Preferably, the film-forming material comprises polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer and hydroxypropyl cellulose; Preferably, the film-forming material comprises 13 to 27 parts of polyvinyl alcohol, 8 to 17 parts of polyvinyl alcohol-polyethylene glycol graft copolymer, and 1 to 7 parts of hydroxypropyl cellulose; More preferably, the film-forming material includes 15 to 25 parts of polyvinyl alcohol, 9 to 16 parts of polyvinyl alcohol-polyethylene glycol graft copolymer, and 3 to 6 parts of hydroxypropyl cellulose.

5. The dapoxetine orally disintegrating film according to any one of claims 1 to 4, characterized in that: The plasticizer includes at least one of polyethylene glycol, glycerol, sorbitol, propylene glycol, and triacetin; Preferably, the plasticizer comprises glycerol and polyethylene glycol; Preferably, the plasticizer comprises 5 to 10 parts of glycerol and 2 to 5 parts of polyethylene glycol; Preferably, the molecular weight of the polyethylene glycol is 4000-6000.

6. The dapoxetine orally disintegrating film according to any one of claims 1 to 5, characterized in that: The pH adjuster includes at least one of citric acid, tartaric acid, fumaric acid, ascorbic acid, malic acid, lactic acid, chlorogenic acid, oxalic acid, formic acid, acetic acid and succinic acid; preferably, the pH adjuster includes at least one of citric acid and tartaric acid; And / or, the pH adjuster is 2 to 6 parts.

7. The method for preparing the dapoxetine orally dissolving film according to any one of claims 1 to 6, characterized in that: The steps include: S1. Preparation of dapoxetine resin complex: ion exchange adsorption of dapoxetine acid addition salt with a cation exchange resin in water to obtain a dapoxetine resin complex; S2. Preparation of slurry: adding a film-forming agent to the solvent, mixing uniformly, adding the remaining excipients, mixing uniformly, then adding dapoxetine resin complex, mixing uniformly, to obtain a slurry to be coated; S3. Apply and dry.

8. The preparation method according to claim 7, characterized in that In step S1, the mass ratio of the cation exchange resin to water is 1:8 to 1:20; preferably, the mass ratio of the cation exchange resin to water is 1:10 to 1:17; and / or, the cation exchange resin is dispersed in water with stirring at 50-80° C.; and / or, adding dapoxetine acid addition salt and adsorbing by stirring at 50-80° C.; and / or, dispersing the cation exchange resin in water and then adding the dapoxetine acid addition salt; And / or, after the adsorption in step S1 is completed, the steps of filtering, washing the filter cake and then drying are further included; Preferably, the filter cake is washed with water and then dried; Preferably, the dapoxetine resin complex is vacuum dried to a moisture content of ≤7 wt%.

9. The preparation method according to any one of claims 7-8, characterized in that In step S2, the solvent is an ethanol aqueous solution; Preferably, the ethanol aqueous solution is an ethanol aqueous solution with a concentration of 10-30 wt% (preferably 10-20 wt%); Preferably, the mass of the ethanol aqueous solution is 1.2 to 2.5 times (preferably 1.4 to 1.8 times) the total weight of the orally disintegrating film formulation; And / or, when feeding the film-forming agent, first add polyvinyl alcohol and polyvinyl alcohol-polyethylene glycol graft copolymer and homogenize; then add hydroxypropyl cellulose and homogenize; Preferably, the homogenization intensity is 35-50 Hz, the total homogenization time is greater than or equal to 2 hours, and the vacuum degree is greater than 0.05 MPa; Preferably, the homogenization temperature is 40-60°C.

10. The preparation method according to any one of claims 7 to 9, characterized in that: In the step S3, a continuous coating machine is used for coating and drying; Preferably, in step S3, the coating speed is 0.5-1.0 m / min, and the coating knife gap is 400-800 μm; Preferably, in step S3, the temperature in the front section of the drying area is 60-90°C, and the air volume range is 30%-50%; preferably, in step S3, the coating drying weight loss is 6-14.5%.

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