CN116672330A - Dapoxetine hydrochloride compound and oral dissolving film thereof - Google Patents

Dapoxetine hydrochloride compound and oral dissolving film thereof Download PDF

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Publication number
CN116672330A
CN116672330A CN202310775917.8A CN202310775917A CN116672330A CN 116672330 A CN116672330 A CN 116672330A CN 202310775917 A CN202310775917 A CN 202310775917A CN 116672330 A CN116672330 A CN 116672330A
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dapoxetine hydrochloride
film
dapoxetine
oral
hydrochloride
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张云
李敏营
李春香
张兴爽
张佳美
刘海丽
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Zhengzhou Antu Industrial Group Co ltd
Zhengzhou Demai Pharmaceutical Co ltd
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Zhengzhou Antu Industrial Group Co ltd
Zhengzhou Demai Pharmaceutical Co ltd
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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Abstract

The application discloses a dapoxetine hydrochloride compound and an oral dissolving film thereof, belonging to the technical field of chemical pharmaceutical preparations. The dapoxetine hydrochloride oral solution membrane takes a compound prepared by the reaction of the dapoxetine hydrochloride and the cationic resin as a medicinal active ingredient, and other auxiliary materials are added, so that the prepared dapoxetine hydrochloride oral solution membrane has excellent tensile property, film forming property, disintegration property, good taste and higher stability. In addition, when the dapoxetine hydrochloride oral dissolved film contains the 5-type phosphodiesterase inhibitor, the stability of the compound medicament of the dapoxetine hydrochloride and the 5-type phosphodiesterase inhibitor can be improved, and the mouthfeel of the medicament can be improved.

Description

Dapoxetine hydrochloride compound and oral dissolving film thereof
Technical Field
The application relates to the technical field of chemical pharmaceutical preparations, in particular to a dapoxetine hydrochloride compound and an oral dissolving film thereof.
Background
Dapoxetine hydrochloride (Dapoxetine) under the chemical name (+) - (S) -N, N-dimethyl-alpha- [2- (1-naphthyloxy) ethyl]Benzamide hydrochloride of formula C 21 H 23 ON & HCl, structural formula:
dapoxetine hydrochloride, which is a selective 5-hydroxytryptamine reuptake inhibitor (SSRI), is clinically used mainly for the treatment of 18-64 year old male Premature Ejaculation (PE) patients meeting all the following conditions.
Tadalafil (tadalafil), a cyclic guanosine monophosphate specific phosphodiesterase 5 (PDE 5) inhibitor. Clinically used for the treatment of male Erectile Dysfunction (ED), and erectile dysfunction combined with symptoms and signs of benign prostatic hyperplasia.
According to clinical studies, patients with PE are often accompanied by mild or moderate ED, and clinically PE and ED combined patients are common, for which tadalafil and dapoxetine compound can be administered. The prior art discovers that when tadalafil, dapoxetine and auxiliary materials are directly mixed to prepare a preparation, the impurity content is obviously increased under the high-temperature high-humidity and illumination environment, a large amount of unknown impurities are generated, and the long-term stability of the two compound medicines has a huge challenge (CN 202011366450.4, publication number is CN 112263581A).
The oral dissolving film is called as oral dissolving film (oral fastdissolving films OFDF), also called as oral dispersing film, oral dissolving film, oral quick dissolving film, sublingual film, lingual film, is a new drug delivery system, the preparation is that the effective components of a certain dosage of chemicals or traditional Chinese medicine extract are fixed on a film made of modified starch and colloid, the size, shape and thickness are similar to those of a stamp, and the film can be placed on the tongue, so that the drug can be quickly dissolved and released in saliva without drinking water.
Dapoxetine hydrochloride, bitter and astringent taste, and can generate unacceptable pungency after contacting with taste buds, and how to eliminate the bitter and spicy feel is a difficult problem in the development of dapoxetine hydrochloride oral film-dissolving agent.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present application is to provide a dapoxetine hydrochloride complex and an oral membrane thereof. The dapoxetine hydrochloride oral solution film has the advantages of excellent film property, good taste, short disintegration time and high stability.
In order to achieve the above purpose, the application adopts the following technical scheme:
the application provides a dapoxetine hydrochloride compound which is prepared by ion exchange reaction of dapoxetine hydrochloride and cationic resin.
Preferably, the molar ratio of the dapoxetine hydrochloride to the cationic resin is (25-40): (10-25); more preferably (30 to 35): (15-20).
Preferably, the cationic resin is selected from the group consisting of
Amberlite IRP-88。
The dapoxetine hydrochloride compound is prepared by the reaction of dapoxetine hydrochloride and cationic resin. The preparation method specifically comprises the following steps:
dissolving dapoxetine hydrochloride and cationic resin in water, stirring, reacting, and drying to obtain the dapoxetine hydrochloride compound.
The temperature of the reaction is preferably 60℃to 80 ℃.
The drying temperature is preferably 50 to 70 ℃.
The application also provides a dapoxetine hydrochloride oral dissolved film, which comprises the dapoxetine hydrochloride compound, a film forming material, a plasticizer and pharmaceutically acceptable auxiliary agents.
The weight ratio of the film forming material to the dapoxetine hydrochloride compound is preferably (35-65): (40-65); more preferably (40 to 60): (50-60); further preferably (45 to 55): (52-58).
The weight ratio of the plasticizer to the dapoxetine hydrochloride compound is preferably (9-24): (40-65); more preferably (12 to 20): (50-60); further preferably (14 to 18): (52-58).
Preferably, the auxiliary agents are fillers and flavoring agents.
The weight ratio of the filler to the dapoxetine hydrochloride compound is preferably (6-12): (40-65); more preferably (7 to 11): (50-60); further preferably (8 to 10): (52-58).
The weight ratio of the flavoring agent to the dapoxetine hydrochloride compound is preferably (3-23): (40-65); more preferably (8 to 18): (50 to 60), more preferably (12 to 18): (52-58).
The dapoxetine hydrochloride oral solution film takes the cationic resin as a framework, masks the taste of the dapoxetine hydrochloride, and is supplemented with other auxiliary materials, so that the special taste of the dapoxetine hydrochloride is masked, and the contents of film forming materials and flavoring agents in a prescription are obviously reduced.
The application discloses a dapoxetine hydrochloride oral dissolving film, which comprises the following components in parts by weight:
40-65 parts of dapoxetine hydrochloride compound;
35-65 parts of film forming materials;
9-24 parts of plasticizer;
6-12 parts of filler;
3-23 parts of flavoring agent.
More preferably, the dapoxetine hydrochloride oral dissolved film comprises the following components in parts by weight:
50-60 parts of dapoxetine hydrochloride compound;
40-60 parts of film forming material;
12-20 parts of plasticizer;
7-11 parts of filler;
8-18 parts of flavoring agent.
Further preferably, the dapoxetine hydrochloride oral dissolved film comprises the following components in parts by weight:
52-58 parts of dapoxetine hydrochloride compound;
45-55 parts of film forming material;
14-18 parts of plasticizer;
8-10 parts of filler;
12-18 parts of flavoring agent.
In the dapoxetine hydrochloride orosol film, the filler is preferably microcrystalline cellulose or lactose, and more preferably microcrystalline cellulose (pH 101).
The flavoring agent is preferably one or more of aspartame, neotame, sucralose and peppermint powder essence; more preferably one or more of aspartame, peppermint powder flavor and sucralose.
In addition, the dapoxetine hydrochloride orosol film can also contain a light shielding agent.
The opacifier preferably adopts FD & C blue No. 2 aluminum lake or FD & C yellow No. 6 aluminum lake.
Compared with Amberlite IRP-69, amberlite IRP-88 is selected as cationic resin, and the drug component (dapoxetine hydrochloride) of the oral solution film is more easily dissociated from the dapoxetine hydrochloride compound.
Therefore, the dapoxetine hydrochloride complex in the dapoxetine hydrochloride oral membrane preferably adopts Amberlite IRP-88 as cationic resin.
Preferably, the film forming material is selected from one or more of polyvinyl alcohol, hydroxypropyl cellulose and hypromellose; more preferably, the film-forming material is selected from hydroxypropyl cellulose and/or hypromellose.
Preferably, the hypromellose is selected from hypromellose E5 or hypromellose E15. In some embodiments of the application, the film-forming material is selected from the group consisting of hypromellose E5 and hypromellose E15.
Preferably, the weight ratio of the hypromellose E5 to the hypromellose E15 is (10 to 50): (10-20); more preferably (30 to 40): (10-20); further preferably 35: (10-20).
In some embodiments of the application, the weight ratio of hypromellose E5 to hypromellose E15 is 35:10 or 35:15 or 35:20.
Preferably, the plasticizer is selected from one or more of polyethylene glycol, glycerol and polysorbate. More preferably, the plasticizer is selected from polyethylene glycol and glycerol.
Preferably, the polyethylene glycol is selected from one or more of PEG200, PEG400, PEG600, and PEG 1000.
Preferably, the weight ratio of the polyethylene glycol to the glycerol is (5-15): (3-9); more preferably (8 to 12): (4-6); in some embodiments of the application, the polyethylene glycol is selected from polyethylene glycol 400 (PEG 400). The weight ratio of PEG400 to glycerol was 10:6.
The preparation method of the dapoxetine hydrochloride oral membrane comprises the following steps:
uniformly mixing and dispersing the dapoxetine hydrochloride compound and an alcohol solution of lecithin, adding a film forming material, a plasticizer, pharmaceutically acceptable auxiliary agents and water, and mixing to obtain slurry; coating, film making, drying and cutting to obtain the dapoxetine hydrochloride oral solution film.
The present application is not particularly limited to the above-mentioned all drying methods, and may be a drying method known to those skilled in the art such as vacuum drying and normal pressure drying.
Preferably, the dapoxetine hydrochloride orosol membrane further comprises a 5-type phosphodiesterase inhibitor.
The stability of the 5-type phosphodiesterase inhibitor is obviously improved by combining the dapoxetine hydrochloride and the 5-type phosphodiesterase inhibitor, and the dapoxetine hydrochloride can be used for treating the combined patient with Premature Ejaculation (PE) and male Erectile Dysfunction (ED).
Preferably, the weight ratio of the 5-type phosphodiesterase inhibitor to the dapoxetine hydrochloride complex is (15-20): (50-60); more preferably (18 to 22): (54-56). In some embodiments of the application, the weight ratio of the 5-phosphodiesterase inhibitor to dapoxetine hydrochloride complex is preferably 10:27.
preferably, the 5-phosphodiesterase inhibitor is selected from one or more of tadalafil, sildenafil or vardenafil; more preferably, the 5-phosphodiesterase inhibitor is selected from tadalafil.
The dapoxetine hydrochloride oral solution film has the advantages of smooth appearance, smooth surface and good film property, most of bitterness and pungency are covered, and oral dissolution can be accepted by people. And the disintegration time period, the dissolution in vitro is faster, and the stability is high.
Compared with the prior art, the dapoxetine hydrochloride oral solution film provided by the application takes the compound prepared by the reaction of the dapoxetine hydrochloride and the cationic resin as the drug active ingredient, and other auxiliary materials are added, so that the prepared dapoxetine hydrochloride oral solution film has excellent tensile property, film forming property, disintegration property, good taste and higher stability. In addition, when the dapoxetine hydrochloride oral dissolved film contains the 5-type phosphodiesterase inhibitor, the stability of the compound medicament of the dapoxetine hydrochloride and the 5-type phosphodiesterase inhibitor can be improved, and the mouthfeel of the medicament can be improved.
Detailed Description
To further illustrate the present application, the dapoxetine hydrochloride complex and the orosity thereof provided by the present application are described in detail below with reference to examples.
The following hydroxypropyl cellulose and hypromellose refer to different types of hydroxypropyl cellulose and hypromellose commercially available.
Preparation of dapoxetine hydrochloride Complex
Example 1
1. The composition is as follows: 33.60g of dapoxetine hydrochloride, 22.18g of Amberlite IRP-88 resin (example 1-1); or dapoxetine hydrochloride 33.60g, amberlite IRP-88 resin 33.60g (examples 1-2).
2. The preparation method comprises the following steps: adding dapoxetine hydrochloride (API) and Amberlite IRP-88 resin into 10mL of purified water, placing in a 70 ℃ constant temperature water bath kettle, stirring for 6 hours, suction filtering to obtain a filter cake, then placing in a 60 ℃ constant temperature drying oven for drying, controlling the water content to be 2-7wt%, crushing, sieving with a 60-mesh sieve, performing air current crushing and sieving, and controlling the final particle size to be X 90 ＜10μm。
Comparative examples 1 to 1
Dapoxetine hydrochloride complex
The procedure is as in example 1-1, except that Amberlite IRP-69 is used for the resin.
Comparative examples 1 to 2
Dapoxetine hydrochloride complex
The same as in comparative example 1-1, except that Amberlite IRP-69 was used for the resin and the amount was 1.06 times that of dapoxetine hydrochloride. The composition is as follows: 33.60g of dapoxetine hydrochloride and 35.62g of Amberlite IRP-69 resin.
(II) investigating drug binding Rate of dapoxetine hydrochloride Complex of different resins
1. Sample:
the composites prepared in examples 1-1 and comparative examples 1-2.
2. Experimental method
The method is measured according to high performance liquid chromatography (China pharmacopoeia 2020 edition four general rules 0512).
Preparation of test solution: 37mg (about 20mg equivalent to dapoxetine) of the sample is precisely weighed, placed in a 200mL measuring flask, 160mL of 0.1mol/L hydrochloric acid methanol solution is added, placed in a water bath at 60 ℃ for heating for 15 minutes, then subjected to ultrasonic treatment for 20 minutes, cooled, diluted to a scale with 1.4wt% sodium hydroxide solution, shaken uniformly, filtered, and 4mL of primary filtrate is removed, and a subsequent filtrate is taken;
preparation of a control solution: the dapoxetine hydrochloride reference substance 22mg is taken, precisely weighed, placed in a 200mL measuring flask, added with 160mL of 0.1mol/L hydrochloric acid for dissolution, diluted to scale by 1.4wt% sodium hydroxide solution and shaken well.
Chromatographic conditions: octadecylsilane chemically bonded silica is used as filler (Xtime C18, 4.6mm.times.150mm, 5 μm or column with equivalent performance); taking a mixed solution of ammonium bicarbonate and diethylamine (containing 10mmol/L ammonium bicarbonate and 6mmol/L diethylamine) -acetonitrile (35:65) as a mobile phase; the flow rate is 1.5mL per minute; the column temperature is 35 ℃; the detection wavelength was 293nm.
System applicability requirements: in the reference solution chromatogram, the theoretical plate number is not lower than 2500 calculated according to the dapoxetine peak.
Assay: precisely measuring 20 mu L of the sample solution and 20 mu L of the reference solution, respectively injecting into a liquid chromatograph, recording the chromatograms, calculating according to an external standard method and dividing the result by 1.119.
( Explanation: the mixed solution of ammonium bicarbonate and diethylamine contains 10mmol/L ammonium bicarbonate and 6mmol/L diethylamine, after conversion, the content of ammonium bicarbonate in 1L mixed solution is 790mg, the content of diethylamine is 438.84mg, and the rest is water )
2) The calculation formula is as follows:
drug binding% = (initial concentration of dapoxetine hydrochloride-concentration of dapoxetine hydrochloride in supernatant)/initial concentration of dapoxetine hydrochloride ×100%
3. Experimental results: see Table 1
Table 1 comparison of binding rates
Lot number Conditions (conditions) Peak area Content (mg/mL) Binding Rate (%)
Example 1-1 Supernatant (1:0.66) 141668 0.0507 99.94
Comparative examples 1 to 2 Supernatant (1:1.06) 352511 0.788 99.12
Note that: taking example 1-1 as an example, the drug binding rate% = (100-0.0507×1.12)/100×100=99.94%; for the reasons of multiplying by 1.12, the liquid phase detection is mainly of the concentration of dapoxetine, which needs to be folded back to dapoxetine hydrochloride, molecular weight of dapoxetine hydrochloride 341.15, molecular weight of dapoxetine 305.41, 341.15/305.41 =1.117, so the content after detection is multiplied by 1.12.
The results in Table 1 show that the binding rates of comparative examples 1-2 and examples 1-1 are close, demonstrating that both the strong acid type cationic resin IRP-69 and the weak acid type cationic resin IRP-88 can be almost completely bound to dapoxetine hydrochloride. But the excellent combination rate can be achieved only by using a large amount of AmberLite IRP-69 resin.
Preparation of dapoxetine hydrochloride oral membrane
Example 2
1. The composition is as follows: see Table 2
TABLE 2 formulation of example 2 (dosage unit: mg)
2. The preparation method comprises the following steps:
1) Taking purified water, sequentially adding PEG400, glycerol, microcrystalline cellulose pH101, sucralose, peppermint powder essence and FD & C blue No. 2 aluminum lake, stirring and dissolving until no macroscopic particles exist, adding hydroxypropyl methylcellulose E5 and hydroxypropyl methylcellulose E15, stirring until no dry powder and no caking exist in a glue solution system, taking a homogeneous state, adding a dapoxetine hydrochloride compound, stirring for 10min, shearing and dispersing for 10min, and then stirring and dispersing for 10min at the same speed; (stirring speed: 1000rpm; shearing speed: 3.0 x 1000 rpm)
2) Defoaming: placing the prepared liquid medicine in a vacuum environment, and carrying out negative pressure standing to remove bubbles;
3) Coating: the coating parameters of the coating machine are that the peristaltic pump rotating speed is 1.5rpm, the gear pump speed is 18rpm, the roller rotating speed is 370rpm, the temperature of the front plate is 45 ℃, the temperature of the rear plate is 55 ℃, the film thickness is 0.15mm, and the dapoxetine hydrochloride oral dissolved film is obtained.
Comparative example 2
The formulation was as in example 2-2, see Table 3. The difference is that the dapoxetine hydrochloride compound is prepared by adopting the method of comparative examples 1-2, and the resin is Amberlite IRP-69 resin.
Comparative examples 3 to 6
1. The preparation method is the same as that of example 2-2, the dapoxetine hydrochloride compound is prepared in example 1-1, and the specific component formula is shown in Table 3:
table 3 comparative examples 2 to 6 compositions of dapoxetine hydrochloride oral films (unit: mg)
2. The preparation method comprises the following steps: as in example 2-2.
(IV) dapoxetine hydrochloride oral dissolved film stretching detection
The plasticizer affects the film agent characteristics of the orosol film, and the tensile property of the orosol film is examined in the experiment.
1. Sample: oral films prepared in examples 2-2, comparative example 5, and comparative example 6.
2. The detection method comprises the following steps: the tensile strength, the elongation and the like are the performances of the film agent characteristics, and are the indexes for measuring the mechanical properties of the film agent. The film agent is sheared into the size of 20mm multiplied by 30mm, 6 film agents are selected for each group, no obvious scratches, particles and bubbles are required to be formed on the surface of the film agent, and the edges of the film agent are smooth and have no gaps or burrs. Each film was longitudinally stretched using a tensile tester (stretching speed 25 mm/min) until the film broke, and the readings were recorded to calculate the tensile strength and elongation.
2.1 breaking force:
the breaking force refers to the maximum force used to break the oral film.
2.2 tensile Strength
Refers to the ability of the film to be broken when pulled.
2.3 tensile Strength
Refers to the maximum load bearing capacity of the film agent under stretching conditions.
2.4 elongation at break: the elongation at break is the ratio of the elongation to the original length in the process of elastic deformation of the film.
3. Detection result: see Table 4
TABLE 4 tensile test results
Table 4 the results show that: the tensile strength, tensile strength and elongation were higher for example 2-2 than for comparative examples 5, 6.
The results show that: the combined effect of the two plasticizers of polyethylene glycol and glycerol is better than that of the polyethylene glycol or glycerol singly. In addition, as the amount of plasticizer added decreases within certain limits, the film tends to decrease in tensile strength, stretch-break strength, tensile strength and elongation.
(V) investigation of film Forming Property of dapoxetine hydrochloride orosol film
The film forming performance is inspected by 1) whether the glue solution can be formed into a film after being dried; 2) Whether film release is easy after film formation; 3) And (3) whether a mucous membrane exists after film formation.
1. Sample: examples 2-2, comparative example 3, comparative example 4.
2. The experimental method comprises the following steps: observing the film forming speed of the glue solution, and observing whether the glue solution is easy to demould, whether the glue film phenomenon exists or not and how brittle after film forming.
3. Experimental results:
example 2-2: the glue solution can be quickly formed into a film after being dried, is easy to take off the film, has no mucous membrane phenomenon and has good brittleness;
comparative example 3: the glue solution is dried and forms a film slowly, and a mucous membrane phenomenon exists;
comparative example 4: the glue solution can be quickly formed into a film after being dried, is easy to take off the film, has no mucous membrane phenomenon, but the film agent is fragile and is easy to break.
The results show that the combined effect of the hypromellose E5 and the hypromellose E15 in the application is better than that of the hypromellose E5 or the hypromellose E15 used alone.
Release degree of dapoxetine hydrochloride orosol film
The oral film is disintegrable in the oral cavity, and is absorbed in the gastrointestinal tract along with swallowing of saliva, and the dissolution curve is simulated in vivo, so that the curve examination of 4 dissolution mediums is adopted.
1. Sample:
the sample provided in example 2-2; comparative example 2 provides a sample.
2. Experimental method
According to the dissolution and release rate measurement method of 0931 edition 2020 of Chinese pharmacopoeia, the release rate of the drug is checked by adopting an HPLC method.
2.1 test sample solution: taking 12 pieces of the product from each medium, referring to method 2 of the fourth method (Pao Ding method) of the fourth section rule 0931 of the year 2020 edition of Chinese pharmacopoeia, taking 900mL of each medium (0.1 mol/L hydrochloric acid, sodium acetate-glacial acetic acid buffer (pH 4.5), sodium dihydrogen phosphate-sodium hydroxide buffer salt (pH 6.8) and water) as dissolution medium, sampling 10mL (10 mL with the same medium and no liquid) at the rotation speed of 50rad/min at the temperature of 37 ℃ for 5min, 10min, 15min, 30min, 45min and 60min, filtering, and taking the subsequent filtrate of the discarded 4mL of primary filtrate as each test solution.
2.2 chromatographic conditions: octadecylsilane chemically bonded silica is used as filler (Xtime C18, 4.6mm.times.150mm, 5 μm or column with equivalent performance); taking acetonitrile (35:65) which is a mixed solution of ammonium bicarbonate and diethylamine as a mobile phase; the flow rate is 1.5mL per minute; the column temperature is 35 ℃; the detection wavelength is 293nm;
assay: the subsequent filtrate was measured at a precision of 20. Mu.L, separately injected into a liquid chromatograph, the chromatogram was recorded, calculated as peak area by external standard method, and the result was divided by 1.119.
2.3 melting time limit: the time period for dissolution of the sample in the pH6.8 medium was observed. ( Explanation: dissolving oral film in oral cavity with pH of 6.6 to 7.1, and examining dissolution time limit with pH6.8 medium )
3. Experimental results:
3.1 melting time in pH6.8 medium: see Table 5
TABLE 5 melting time limit of examples 2-2, comparative example 2
Table 5 the results show that: examples 2-2 and comparative example 2 had an average melting time period of 46s and 43s, respectively, in a medium at pH6.8, and were all melted and passed through the screen within 300 s.
The results demonstrate that the products of examples 2-2 and comparative example 2 meet the formulation requirements when dissolved in the oral cavity.
3.2 release results: see Table 6-1, 6-2
TABLE 6-1 drug Release degree (unit:%)
Time (min) 0.1M hydrochloric acid medium Aqueous medium pH4.5 Medium pH6.8 Medium
5min 96.1 5.6 56.6 20.9
10min 97.1 4.5 66 31.9
15min 97.6 4.9 67 34.7
30min 98.9 / / /
45min 98.9 / / /
60min 99.1 / / /
TABLE 6-2 comparative example 2 drug Release (unit:%)
Time (min) 0.1M hydrochloric acid medium Aqueous medium pH4.5 Medium pH6.8 Medium
5min 7.2 / / 2.9
10min 10.6 / / 5.2
15min 11.9 / / 6.7
30min 14.3 / / 9.7
45min 15.8 / / 11.5
60min 17.1 / / /
The results in tables 6-1, 6-2 show that: the dissolution behavior of the formulation product of example 2-2 in each medium is pH dependent and it is completely soluble in 0.1M hydrochloric acid medium, indicating that dapoxetine hydrochloride is completely dissociated by gastric acid; whereas comparative example 2 was difficult to dissociate in 0.1M hydrochloric acid medium.
The results show that: compared with Amberlite IRP-69 resin, the dapoxetine hydrochloride compound prepared by using Amberlite IRP-88 resin can be well dissociated in the stomach.
Compound oral soluble film of dapoxetine hydrochloride and tadalafil
Example 3
1. The formula comprises the following components: see Table 7. Dapoxetine hydrochloride complexes were prepared according to the formulation and method of example 1-1.
Table 7 Compound oral solution formulation (dosage unit: mg)
2. The preparation method comprises the following steps:
1) Taking purified water, sequentially adding PEG400, glycerol, microcrystalline cellulose pH101, sucralose, peppermint powder essence and FD & C blue No. 2 aluminum lake, stirring and dissolving until no macroscopic particles exist, adding hydroxypropyl methylcellulose E5 and hydroxypropyl methylcellulose E15, stirring until no dry powder and no caking exist in a glue solution system, taking a homogeneous state, adding a dapoxetine hydrochloride compound and tadalafil, stirring for 10min, shearing and dispersing for 10min, and stirring and dispersing for 10min at the same speed; (stirring speed: 1000rpm; shearing speed: 3.0 x 1000 rpm)
2) Defoaming: placing the prepared medicinal liquid in a vacuum environment, and exhausting and soaking overnight;
3) Coating: the coating parameters of the coating machine are that the peristaltic pump rotating speed is 1.5rpm, the gear pump speed is 18rpm, the roller rotating speed is 370rpm, the temperature of the front plate is 45 ℃, the temperature of the rear plate is 55 ℃, the film thickness is 0.15mm, and the compound oral-dissolving film of dapoxetine hydrochloride and tadalafil is obtained.
Stability investigation of (eight) Compound orolytic Membrane
1. Test materials:
1.1 detection of samples: example 3-2.
1.2 control:
tadalafil impurity E, (6 r,12ar,12 br) -6- (benzo [ d ] [1,3] dioxazol-5-yl) -6 a-hydroxy-2-methyl-2, 3,6a,7,12a,12 b-hexahydropyrazino [1',2' -1,5] pyrrolo [3,4-b ] quinolin-1, 4,12 (6H) -trione.
Tadalafil impurity G, (12 bR) -6- (benzo [ d ] [1,3] dioxazol-5-yl) -12-hydroxy-2-methyl-2, 3,6,12 b-tetrahydropyrazino [1,2' -1,5] pyrrolo [3,4-b ] quinoline-1, 4-dione.
Tadalafil impurity I, (8 a ' r) -6' - (benzo [ d ] [1,3 dioxa-5-yl) -2' -methyl-2 ',3',8',8a ' -tetrahydro-6'H-spiro [ indoline-3, 7' -pyrrolo [1,2-a ] pyrazine ] -1',2,4' -trione.
Dapoxetine impurity A, 1-naphthol.
Dapoxetine impurity E, dimethyl [ (1S) -3- (1-naphthoxy) -1-phenylpropyl ] -amine oxy hydrochloride.
Dapoxetine impurity F, N-methyl-3- (1-naphthoxy) -1-phenyl-1-propanamine hydrochloride.
Dapoxetine impurity B, (R) -3- (naphthyl-1-oxy) -phenylpropanol.
Dapoxetine impurity G,3- [4- [3- (dimethylamino) -3-phenylpropoxy ] -1-naphthyl ] -1-phenyl-1-propanone hydrochloride.
Dapoxetine impurity H, N, N-dimethyl- (. Alpha.) - [2- [ [4- [ (2E) -3-phenyl-2-propenyl ] -1-naphthyl ] oxy ] ethyl ] benzamide hydrochloride.
2. The experimental method comprises the following steps:
2.1 conditions for acceleration experiments:
the temperature is 40+/-2 ℃ and the relative humidity is 75+/-5 percent.
2.2 experimental conditions for long term experiments:
the temperature is 25+/-2 ℃ and the relative humidity is 60+/-5 percent)
2.3 specific detection index
Preparation of test solution: cutting 1 piece of the product into films with the size of 1cm multiplied by 1cm, placing the films into a 100mL measuring flask, adding 80mL of 0.1mol/L hydrochloric acid methanol solution, carrying out cold water ultrasonic treatment for 20 minutes, diluting to a scale with 1.4wt% sodium hydroxide solution, shaking uniformly, filtering (adopting a glass injector), discarding 4mL of primary filtrate, and taking the subsequent filtrate;
chromatographic column, waters XTerra RP18 (3.0 mm x 150mm,3.5 μm), mobile phase, phase a: mixed solution of ammonium bicarbonate and diethylamine (containing 10mmol/L ammonium bicarbonate and 6mmol/L diethylamine), phase B: acetonitrile; the gradient elution conditions are shown in Table 8, the detection wavelength is 293nm, the column temperature is 35 ℃, and the flow rate is 0.6mL/min.
TABLE 8 gradient elution TABLE
Time (minutes) Phase A (%) Phase B (%)
0 75 25
15 75 25
40 5 95
45 5 95
50 75 25
60 75 25
3. Experimental results: see Table 9
TABLE 9 stability results for example 3-2
Table 9 the results show that: under accelerated conditions, dapoxetine impurity F increased slightly, without exceeding the standard (1%), and otherwise without significant change.
The results show that: the dapoxetine hydrochloride and tadalafil compound oral film provided by the application has good stability.
Taste investigation of mouth-soluble film
1. Sample:
the orosity films provided in example 2-2, comparative example 2 and example 3-2.
2. Experimental method
2.1 subjects: the clinical main administration subjects of dapoxetine hydrochloride are male adult patients, and the evaluation is carried out again to recruit healthy adult male volunteers 20-50 years old and 27 people altogether.
2.2 experimental method: taking a piece of dapoxetine hydrochloride oral film agent, placing the dapoxetine hydrochloride oral film agent on a tongue surface, and containing the dapoxetine hydrochloride oral film agent in the mouth, and scoring the mouth feel of the film agent at 5min, 30min and 60min respectively by taking the time of placing the oral film agent on the tongue surface as a base line.
2.3 evaluation index: bitter, spicy, sweet and fragrant, wherein:
bitter taste scoring criteria: 5 minutes, no bitter taste; 4 minutes, almost no bitter taste; 3 minutes, slightly bitter; 2 minutes, the bitter taste is obvious; 1 min, unacceptable bitter;
spicy scoring criteria: 5 minutes, no spicy flavor exists; 4 minutes, almost no spicy taste; 3 minutes, slightly spicy; 2 minutes, the spicy flavor is obvious; 1 min, unacceptable peppery;
sweetness scoring criteria: 5 minutes, very much liked; 4, liking; 3 minutes, acceptable; 2 points, dislike; 1 minute, unacceptable.
3. Experimental results: table 10-1, table 10-2 and Table 10-3
Table 10-1 results of taste experiments of example 2-2
( And (3) injection: the number represents the number of people giving the score, and the percentage is the percentage of each scored number to the total number of people )
TABLE 10-2 mouthfeel test results of comparative example 2
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TABLE 10-3 results of taste experiments for example 3-2
The results in tables 10-1, 10-2, and 10-3 show that:
the tastes of the examples 2-2 and 3-2 are similar, and the bitter and spicy tastes of the effective components are covered.
The taste evaluation of comparative example 2 was superior to that of examples 2-2 because the API in comparative example 1 was not easily dissociated from the complex. But is not easy to dissociate and reduces the drug effect, so the drug effect and the taste masking effect of the dapoxetine hydrochloride oral dissolved film prepared by the embodiment 2-2 or the embodiment 3-2 are better.
The results show that: the dapoxetine hydrochloride oral membrane provided by the application has the advantages that the bitter taste and the pungency of the compound oral membrane of dapoxetine hydrochloride and tadalafil are mostly covered, and the oral dissolution can be accepted by people.
The above description of the embodiments is only for aiding in the understanding of the method of the present application and its core ideas. It should be noted that it will be apparent to those skilled in the art that various modifications and adaptations of the application can be made without departing from the principles of the application and these modifications and adaptations are intended to be within the scope of the application as defined in the following claims.

Claims (10)

1. The dapoxetine hydrochloride compound is characterized by being prepared from dapoxetine hydrochloride and cationic resin through an ion exchange reaction.
2. The dapoxetine hydrochloride complex of claim 1, wherein the molar ratio of dapoxetine hydrochloride to cationic resin is (25-40): (10-25).
3. The dapoxetine hydrochloride complex of claim 1, wherein said cationic resin is selected from Amberlite IRP-88.
4. A dapoxetine hydrochloride orosol film comprising a dapoxetine hydrochloride complex according to any of claims 1 to 3, a film forming material, a plasticizer and a pharmaceutically acceptable adjuvant.
5. The dapoxetine hydrochloride orosol film of claim 4, wherein said adjuvants are fillers and flavoring agents.
6. The dapoxetine hydrochloride orosol film of claim 5, wherein the components are as follows in parts by weight:
40-65 parts of dapoxetine hydrochloride compound;
35-65 parts of film forming materials;
9-24 parts of plasticizer;
6-12 parts of filler;
3-23 parts of flavoring agent.
7. The dapoxetine hydrochloride orosol film of claim 4, wherein said film forming material is selected from one or more of polyvinyl alcohol, hydroxypropyl cellulose, hypromellose;
the plasticizer is selected from one or more of polyethylene glycol, glycerol and polysorbate;
the polyethylene glycol is one or more selected from PEG200, PEG400, PEG600 and PEG 1000.
8. The orosol film according to claim 4, wherein the plasticizer is selected from polyethylene glycol and glycerol;
the weight ratio of the polyethylene glycol to the glycerol is (5-15): (3-9).
9. The dapoxetine hydrochloride oromembrane of claim 4, wherein said oromembrane further comprises a phosphodiesterase type 5 inhibitor.
10. The dapoxetine hydrochloride orosol film of claim 9, wherein the weight ratio of the 5-type phosphodiesterase inhibitor to the dapoxetine hydrochloride complex is (15-20): (50-60);
the 5-type phosphodiesterase inhibitor is selected from one or more of tadalafil, sildenafil or vardenafil.
CN202310775917.8A 2023-06-28 2023-06-28 Dapoxetine hydrochloride compound and oral dissolving film thereof Pending CN116672330A (en)

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