CN116196297A - Dapoxetine hydrochloride oral instant film agent and preparation method thereof - Google Patents
Dapoxetine hydrochloride oral instant film agent and preparation method thereof Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
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- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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Abstract
The invention mainly aims to provide a dapoxetine hydrochloride oral instant membrane and a preparation method thereof, wherein the oral instant membrane comprises the following components: the dapoxetine hydrochloride resin compound is a compound formed by dapoxetine hydrochloride and taste masking ion exchange resin, wherein the mass ratio of the dapoxetine hydrochloride to the taste masking ion exchange resin is 0.5:1 to 5:1, the oral instant film prepared by the method has no pungent taste, high disintegration speed and quick absorption, and improves the medicine privacy and compliance of patients.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a dapoxetine hydrochloride oral instant film agent and a preparation method thereof.
Background
Premature ejaculation (Premature ejaculation, PE) is one of the most common sexual dysfunction diseases in adult males, and the international medical community defines premature ejaculation as a disease that has a short ejaculation latency, poor ejaculation control, and susceptibility to negative physical and psychological effects. The incidence rate of premature ejaculation of adult males reaches 30%, and the physical and psychological health and the quality of life of patients and partners are seriously affected.
The current clinical treatment mode still takes medicine treatment as the main mode, wherein the selective 5-HT reuptake inhibitor dapoxetine hydrochloride is especially suitable for treating premature ejaculation when required due to the characteristics of quick absorption (the peak time is about 1 hour), quick elimination (the half-life period is about 1.5 hours), little accumulation and the like, and is the only drug approved by the national drug administration for treating the indication of premature ejaculation. However, since it needs to be taken with water 1 to 3 hours before sexual life, the concealment is poor and the compliance is still to be improved.
The oral instant film agent is a film-shaped preparation prepared by processing the medicine and a proper film-forming material, and can be rapidly dispersed when being put into the mouth. The oral preparation has the advantages of small volume, convenient carrying, no need of taking with water, dissolution after being placed at the tip of the tongue, strong privacy and the like, and can provide a more private oral preparation choice for patients with premature ejaculation. However, the development of the oral instant film is limited due to the extremely bitter taste and tingling of dapoxetine hydrochloride.
The ion exchange resin is a cross-linked polymer compound with ionizable functional groups, can form a drug resin compound with the ionizable drugs, and can hardly replace the drugs due to lower ion concentration in the oral cavity when the compound enters the oral cavity, thereby achieving the purpose of taste masking. But once the compound enters the gastrointestinal tract, the drug release can be completed under the condition of rich gastrointestinal tract ions, and the drug effect is exerted. Compared with other taste masking technologies, the ion exchange resin has the characteristics of small particle size, small side effect and the like, not only can solve the problem of the bitter taste of dapoxetine hydrochloride, but also can ensure that the oral instant film has no gritty feel, but the problems that the drug release is incomplete, the particle size is too thin to be filtered, the drug loaded originally successfully can be eluted when the outer surface of the composite is washed, the formability of the oral instant film is influenced due to the too large content of the resin and the like can occur in the process of preparing the drug resin composite.
Therefore, the dapoxetine hydrochloride oral instant film agent with good taste, satisfactory drug loading and release and good formability is prepared, and the technical problem to be solved in the field is solved.
Disclosure of Invention
The invention mainly aims to provide a dapoxetine hydrochloride oral instant membrane and a preparation method thereof. The oral instant film prepared by the method has no pungent taste, high disintegration speed and quick absorption, and improves the medicine privacy and compliance of patients.
The invention provides a dapoxetine hydrochloride oral instant film agent, which is characterized by comprising the following components in parts by weight: the dapoxetine hydrochloride resin compound is a compound formed by dapoxetine hydrochloride and taste masking ion exchange resin, wherein the mass ratio of the dapoxetine hydrochloride to the taste masking ion exchange resin is 0.5:1 to 5:1.
in some embodiments, the mass ratio of dapoxetine hydrochloride to taste-masked ion exchange resin is 2:1 to 4:1, in some embodiments, the mass ratio of dapoxetine hydrochloride to taste-masked ion exchange resin is 3:1, the object of the invention can be better realized.
In some embodiments, the pharmaceutically acceptable oral formulation excipients include one or more of a water-soluble polymeric film-forming material, a flavoring agent, a plasticizer.
In some embodiments, the taste-masked ion exchange resin is a polymethacrylic acid-divinylbenzene weakly acidic cation exchange resin.
In some embodiments, the polymethacrylic acid-divinylbenzene weakly acidic cation exchange resin is selected from one or more of Tulsion T-339, amberlite IRP88, ind 234, 234S, kyron-T-134, kyon T-314, amberlite IRP 64, amberlite IRC 50, ind 204, purolite C102DR, kyon-T-104, kyon-T-114, doshion P544 (R), tulsion T-335, ind 343, ind 204, ind 214, ind 264, ind 294, ind 414, ind 464.
In some embodiments, the taste-masked ion exchange resin is selected from Kyon-T-134.
In some embodiments, the water-soluble polymeric film-forming material is selected from one or more of hypromellose, polyoxyethylene, polyvinyl alcohol, povidone, maltodextrin, carbomer, chitosan, trehalose.
In some embodiments, the water-soluble polymeric film-forming material is hypromellose or polyoxyethylene or a mixture of both.
In some embodiments, the plasticizer is selected from one or more of glycerol, propylene glycol, polyethylene glycol, sorbic acid, citric acid, sorbitol, mannitol, triethyl citrate, lactose, sucrose, glycine.
In some embodiments, the plasticizer is selected from one or both of glycerol, polyethylene glycol.
In some embodiments, the flavoring agent is selected from one or more of glucose, sucralose, aspartame, cyclamate, saccharin, aspartame, peppermint oil, orange flavor, tangerine flavor, strawberry flavor.
In some embodiments, the flavoring agent is selected from one or more of sucralose, peppermint oil, aspartame.
In some embodiments, the oral instant film comprises the following components in weight ratio:
in some embodiments, the oral instant film comprises the following components in weight ratio:
in some embodiments, the oral instant film comprises the following components in weight ratio:
in some embodiments, the oral instant film comprises the following components in weight ratio:
in some embodiments, the oral instant film comprises the following components in weight ratio:
in some embodiments, the oral instant film comprises the following components in weight ratio:
the invention also provides a preparation method of the dapoxetine hydrochloride oral instant film, which is characterized by comprising the following steps:
(1) Dissolving dapoxetine hydrochloride in purified water, adding ion exchange resin, and stirring to obtain a suspension of the medicine and the ion exchange resin;
(2) Filtering the ion exchange resin suspension prepared in the step (1) by using a screen, washing and drying for standby;
(3) Adding plasticizer and correctant into purified water, stirring to dissolve completely, adding film forming material, and mixing well;
(5) Stirring the dapoxetine hydrochloride drug resin compound prepared in the step (2) and adding the compound into the mixed solution prepared in the step (3), and uniformly mixing to obtain a drug-containing matrix;
(6) And (3) defoaming the medicine-containing matrix prepared in the step (5) by using vacuum, uniformly coating the medicine-containing matrix on a flat backing material by using a coating machine at the temperature of 25-60 ℃, drying, demolding, cutting, and finally sealing and packaging.
In some embodiments, the wash medium employed in step (2) is a phosphate buffer or a borate buffer.
In some embodiments, the washing medium employed in step (2) is phosphate buffer or boric acid buffer solution having a pH of 7-12.
In some embodiments, the phosphate buffer in the washing medium employed in step (2) is selected from the group consisting of phosphate buffer of sodium dodecyl sulfate, citric acid-disodium hydrogen phosphate buffer, and the like, wherein the phosphate is selected from the group consisting of sodium dihydrogen phosphate and/or disodium hydrogen phosphate and/or potassium dihydrogen phosphate and/or dipotassium hydrogen phosphate.
In some embodiments, the boric acid buffer in the washing medium employed in step (2) is selected from boric acid-potassium chloride buffer.
The invention has the following advantages:
(1) The dapoxetine hydrochloride resin compound prepared by the method can play a good taste masking role by screening the types of the resin, the resin and medicine proportion and the types of the washing medium, and achieves higher resin drug loading and release amount;
(2) The dapoxetine hydrochloride oral instant membrane prepared by the method has good formability by screening the types of the membrane forming materials, the resin and the medicine proportion;
(3) The dapoxetine hydrochloride oral instant film prepared by the preparation method disclosed by the invention has the advantages of no irritating taste, high disintegration speed and good content uniformity, and the medicine privacy and compliance of patients are improved.
Detailed Description
As used in this disclosure, the following words and phrases are generally intended to have the meanings set forth below, unless the context indicates otherwise.
The term "comprising" and grammatical variants thereof, such as "including" and "comprising" are to be construed as open-ended, i.e. "including being selected from". When used to define compositions and methods, "consisting essentially of" or grammatical variations thereof shall mean the exclusion of other elements that have any significance to the composition and method of preparation, but not the exclusion of factors that have no substantial effect on the composition and method of preparation. "consisting of" or grammatical variants thereof shall mean the exclusion of elements not explicitly recited. Embodiments defined by each of these transitional terms are within the scope of this invention. For example, when a formulation is described as comprising components a, B and C, it is within the scope of the invention that the formulation consists essentially of a, B and C and that the formulation consists of a, B and C, independently.
The singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. For example, reference to "an excipient" includes a variety of excipients.
Unless the context clearly indicates otherwise, "multiple" or "multiple" includes plural references to two and more. For example, "multiple excipients" includes two or more excipients.
As used herein, the term "about" in the context of quantitative measurement refers to ± 10%, ±5% or ± 1% of the value. For example, "about 10" means 9-11,9.5-10.5 or 9.9-10.1. The term "about X" also includes "X".
The description of a range of values herein is intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each separate value is incorporated into the specification as if it were individually recited herein.
By "pharmaceutically acceptable" is meant: substances or compounds which are suitable for contact with human and lower animal tissue without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio, within the scope of sound medical judgment.
The term "weight percent" or "percent by weight" or "wt%" is defined as the weight of the individual components in the composition divided by the total weight of all components of the composition and then multiplied by 100%.
The terms "optional," "optional," or "optionally" mean that the subsequently described event or circumstance may, but need not, occur. For example, "optionally other pharmaceutically acceptable excipients" means that other pharmaceutically acceptable excipients may or may not be present.
The term "and/or" is understood to mean any one of the selectable items or a combination of any two or more of the selectable items.
As used herein, the term "treatment" refers to a clinical intervention intended to alter the natural course of a disease in an individual undergoing treatment. Desirable therapeutic effects include those selected from preventing occurrence or recurrence of the disease, alleviating symptoms, reducing any direct or indirect pathological consequences of the disease, preventing metastasis, reducing the rate of disease progression, improving or moderating the disease state, and alleviating or improving prognosis.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. The invention may be embodied in many other forms than described herein and similarly modified by those skilled in the art without departing from the spirit or scope of the invention, which is therefore not limited to the specific embodiments disclosed below.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
The weight of each component mentioned in the description of the embodiments of the present invention may refer not only to the specific content of each component, but also to the proportional relationship of the weight of each component, so long as the content of each component in the orosol film preparation according to the description of the embodiments of the present invention is scaled up or down within the scope of the disclosure of the embodiments of the present invention. Specifically, the parts by weight described in the specification of the embodiment of the present invention may be the weight unit known in the pharmaceutical field such as μ g, mg, g, kg, and may be regarded as weight percentage.
The method for measuring the drug loading rate of the resin comprises the following steps:
control solution: taking about 30mg of dapoxetine hydrochloride bulk drug, precisely weighing, placing into a 50ml measuring flask, adding a diluent for dissolution, diluting to a scale, and shaking uniformly. Precisely weighing 2ml, placing in a 10ml measuring flask, diluting with diluent to scale, and shaking.
Test solution: weighing a proper amount of the sample (corresponding to 60mg of dapoxetine hydrochloride) in a 100ml measuring flask, adding 25ml of 0.1M hydrochloric acid solution, oscillating for 1h in water bath, adding the diluent to the scale, shaking uniformly, filtering, taking 2ml of the subsequent filtrate, placing in a 10ml measuring flask, adding the diluent to the scale, and shaking uniformly to obtain the dapoxetine hydrochloride.
Chromatographic conditions: gradient elution was performed using Xbridge C18 (4.6X105 mm,3 μm) column with 10mmol/L ammonium bicarbonate+6mmol/L diethylamine as mobile phase A and acetonitrile as mobile phase B (Table 1.4-1); the flow rate is 0.6ml per minute; the column temperature is 35 ℃; the detection wavelength is 293nm; the sample volume was 10. Mu.l.
Gradient elution conditions:
| time (min) | Mobile phase a (%) | Mobile phase B (%) |
| 0 | 55 | 45 |
| 20 | 5 | 95 |
| 22 | 55 | 45 |
| 30 | 55 | 45 |
System applicability requirements: the RSD value of the dapoxetine hydrochloride reference substance solution repeatedly injected into the 5-needle should be less than 2.0%.
Assay: precisely measuring 10 μl of each of the sample solution and the reference solution, respectively injecting into a liquid chromatograph, recording the chromatogram, and calculating according to external standard method with peak area.
Content limit: dapoxetine hydrochloride (C) 21 H 23 NO) should be 90.0% -110.0% of the indicated amount.
Resin complex dissolution measurement: 1 detection conditions
The dissolution rate was measured by the ultraviolet-visible spectrophotometry method using the paddle method (second method of European pharmacopoeia 8.0 edition 2.9.3) with reference to the Inlet registration Standard (JX 20150184). The detection method is the same as the content determination method, and an HPLC method is used.
2 preparation of dissolution Medium
0.1M hydrochloric acid medium: weighing 63ml of hydrochloric acid, diluting with water to 7000ml, and mixing.
3 preparation of reference substance solution
Taking about 15mg of dapoxetine hydrochloride raw material medicine, precisely weighing, placing into a 25ml measuring flask, adding methanol for dissolution, diluting to scale, and shaking uniformly to obtain reference substance stock solution. Precisely transferring 1ml of the reference substance stock solution, placing into a 20ml volumetric flask, diluting to scale with 0.1M hydrochloric acid medium, and shaking to obtain the solution of the dissolved reference substance.
4 elution method
Dissolution device: paddle method
Dissolution medium: 0.1M hydrochloric acid medium, 900ml,37 ℃,
dissolution sampling time points: 5min,10min,15min,20min,30min,45min,60min,90min,120min
Rotational speed: 50rpm (n=2)
Fill volume 7ml, sample volume: 1.5ml, fluid infusion volume 1.5ml, sample hold time 10s, pre-action time 45s
Oral instant film dissolution measurement: 1 detection conditions
The dissolution rate was measured by the ultraviolet-visible spectrophotometry method using the paddle method (second method of European pharmacopoeia 8.0 edition 2.9.3) with reference to the Inlet registration Standard (JX 20150184). Since the oral instant film will float on the upper layer of the medium using the paddle method, a basket method (chinese pharmacopoeia 2020 edition, fourth edition, general rule 0931, first method) is used. The detection method uses HPLC method under the same content item (see the chromatographic conditions under item 5.1.1 for details).
2 preparation of dissolution Medium
0.1M hydrochloric acid medium: weighing 63ml of hydrochloric acid, diluting with water to 7000ml, and mixing.
3 preparation of reference substance solution
Taking about 15mg of dapoxetine hydrochloride raw material medicine, precisely weighing, placing into a 25ml measuring flask, adding methanol for dissolution, diluting to scale, and shaking uniformly to obtain reference substance stock solution. Precisely transferring 1ml of the reference substance stock solution, placing into a 20ml volumetric flask, diluting to scale with 0.1M hydrochloric acid medium, and shaking to obtain the solution of the dissolved reference substance.
4 elution method
Dissolution device: rotary basket method
Dissolution medium: 0.1M hydrochloric acid medium, 900ml,37 ℃,
dissolution sampling time points: 5min,10min,15min,20min,30min
Rotational speed: 50rpm (n=2)
Fill volume 7ml, sample volume: 1.5ml, fluid infusion volume 1.5ml, sample hold time 10s, pre-action time 45s
Example 1 class investigation of ion exchange resins
The dapoxetine hydrochloride resin complex was prepared by the following method:
(1) Dissolving 30.0g of dapoxetine hydrochloride in 300.0g of purified water to obtain a medicinal solution, and adding
15.0g of different ion exchange resins are stirred for more than 4 hours to obtain ion exchange resin suspension;
(2) Filtering the ion exchange resin suspension obtained in the step (1) by using a 150-mesh screen, and washing with purified water for three times to obtain a dapoxetine hydrochloride resin composite wet product;
(3) Drying the dapoxetine hydrochloride resin composite wet product obtained in the step (2) at 40 ℃ overnight, and controlling the water content below 7%.
The dapoxetine hydrochloride resin complex was subjected to taste evaluation and drug loading rate detection, and the results are shown in table 1:
TABLE 1 investigation of resin species
As can be seen from the results in Table 1, the different ion exchange resins have substantially uniform taste after drug loading, but have a large difference in drug loading rate, and the strong acid resin of the Ind 224 type has a low drug loading rate, and in order to achieve a high resin drug loading rate on the premise of ensuring taste masking, the resin is preferably of other nine types. The reason for the slight bitter taste of each of the nine drug-resin complexes is presumed to be caused by drug residues of dapoxetine hydrochloride on the surface of the drug-resin complex.
In order to ensure good release of the drug in the drug-resin complex, the nine drug-resin complexes were preferably tested for in vitro dissolution, and the results are shown in table 2.
Table 2 in vitro dissolution test of ion exchange resin drug complexes
The results show that the resin drug compound of Amberlite IRP 69 and Ind 404 can only release less than 10% in 120min, and the dissolution rate of the other seven resin drug compounds is above 85% in 15min, presumably because Amberlite IRP 69 and Ind 404 are strong acid type cationic resins, the drug binding capacity is too strong, and the release is difficult. Thus, the other seven weak acid type cationic resins, in addition, because of the relatively low degree of crosslinking of Kyoon-T-134 and the relatively high expansion rate, may be coarse particles directly prepared into an instant oral film, and it is more preferable to use Kyoon-T-134 resins.
EXAMPLE 2 investigation of the ratio of drug to ion exchange resin
In this example, kyon-T-134 was used as the resin, and 6 kinds of drug-ion exchange resin composites having different ratios were prepared and examined for drug loading rate and taste under the conditions that only the ratio of drug to ion exchange resin was changed and the other preparation steps were the same as in example 1, and the results are shown in Table 3.
TABLE 3 results of drug-resin ratio investigation
Note that: "/" -content detection was not performed due to the presence of bitter tingling or caking.
The results showed that the drug loading rate was in a substantially rising trend with increasing dosing ratio, at a dosing ratio of 0.5:1 to 5:1, the bitter and tingling taste is weaker in the interval, but the higher the medicine-resin ratio is, the larger the film size is, the size (2 cm x 2.5cm x 0.4 mm) of the dapoxetine hydrochloride oral instant film prepared by combining the invention is selected from 2:1 to 4:1, more preferably with a drug-resin ratio of 3:1.
EXAMPLE 3 investigation of the washing Medium species
In the process of preparing the ion exchange resin drug compound, part of the drug can be attached to the surface of the drug-resin compound, so that the taste masking effect is poor, and a proper washing medium is needed to be selected, so that the drug remained on the surface of the drug-resin compound can not be removed, and the drug in the drug-resin compound is not washed and removed, so that the proper washing medium is important. The drug-resin complex prepared in example 2 was washed with different washing media at a drug to resin ratio of 3:1, and the results of the investigation are shown in Table 4.
TABLE 4 washing Medium species investigation results
The results show that the drug-resin complex obtained by using purified water alone as a washing medium still has a tingling sensation; the bitter and tingling sensation of the drug resin compound obtained by using pure ethanol or purified water-95% ethanol as a washing medium also exists, and the drug content of the resin compound can be greatly reduced when the drug resin compound is washed by using ethanol, so that the drug resin compound is not suitable for subsequent development.
Because the drug-resin complex is released mainly by exchange with ions in the medium, washing is generally performed with purified water to ensure a high drug loading, but washing with the medium with ions cannot be performed to avoid eluting the drug, but the purified water has a poor washing effect. The medicine resin compound obtained after washing by adopting the phosphate buffer and the boric acid buffer medium is unexpectedly discovered through a plurality of times of exploration, not only has no reduction of medicine content, but also has no bitter and tingling feeling and good taste, so that the phosphate buffer or the boric acid buffer medium is preferably used as a washing medium.
EXAMPLE 4 investigation of film Forming Material
The effect of different film forming materials on the formability is examined by adding different water-soluble film forming materials to prepare the dapoxetine hydrochloride oral instant film, and the preparation method is as follows:
(1) 10.0ml of purified water is measured and put into a proper container, 0.3g of glycerin, 0.25g of polyethylene glycol 400, 0.22g of sorbitol and 0.025g of aspartame are added, and the mixture is stirred to be completely dissolved;
(2) Adding different kinds of water-soluble film-forming materials into the mixed solution obtained in the step (1), and uniformly mixing;
(3) Stirring and adding 2.25g of the dapoxetine hydrochloride drug resin compound prepared by washing the mixed solution obtained in the step (2) with a phosphoric acid buffer medium in the embodiment 3, and uniformly mixing to obtain a drug-containing matrix;
(4) Defoaming the medicine-containing matrix prepared in the step (3) by vacuum;
(5) And (3) uniformly coating the medicine solution prepared in the step (4) on a flat backing material by using a coating machine, drying at 25-60 ℃ to obtain a film agent, cutting the film agent according to the size of 2cm x 2.5cm x 0.4mm, and finally sealing and packaging to obtain the dapoxetine hydrochloride oral instant film.
TABLE 6 investigation of film-forming Material species
As shown by the results, the oral instant film prepared by using polyoxyethylene N80, polyoxyethylene N10, hydroxypropyl methylcellulose E5 and hydroxypropyl methylcellulose E15 with moderate viscosity as film forming materials has no edge shrinkage and cracking phenomena, and has good formability, and the solution viscosity is too high after the polyvinyl alcohol is used, so that the edge shrinkage phenomenon occurs, and the same formability is poor when the hydroxypropyl cellulose is used, so that the hydroxypropyl methylcellulose and/or the polyoxyethylene are selected to be used as film forming materials together.
EXAMPLE 5 investigation of flavoring Agents
The film forming material was selected from hypromellose E15 and polyoxyethylene, and under the conditions that the types of the flavoring agents were changed and the other preparation steps were the same as in example 4, 4 kinds of oral instant film agents using different flavoring agents were prepared and the mouthfeel thereof was evaluated, and the results are shown in table 7.
TABLE 7 investigation of taste corrigents species
The results show that bitter tingling is still present when sodium chloride is used as a flavouring agent, very slight tingling is still present when peppermint oil or sucralose is used as a flavouring agent, and that aspartame is used as a flavouring agent without bitter tingling in an acceptable range and with a good mouthfeel, so that aspartame is most preferred as a flavouring agent.
EXAMPLE 6 preparation of dapoxetine hydrochloride oral instant film
Table 8 the recipe composition is as follows
| Component (A) | Prescription ratio (%) (45 g) | Action |
| Dapoxetine hydrochloride drug resin compound | 45 | Drug-carrying resin |
| Polyoxyethylene N80 | 34 | Film-forming material |
| Hydroxypropyl methylcellulose E15 | 5 | Film-forming material |
| Glycerol | 8 | Plasticizer(s) |
| Polyethylene glycol 400 | 3 | Plasticizer(s) |
| Sorbitol | 4.5 | Flavoring agent |
| Aspartame | 0.5 | Flavoring agent |
| Purified water | 300 | Solvent(s) |
The preparation method comprises the following steps:
preparation of drug resin composite:
(1) 45.0g of dapoxetine hydrochloride is dissolved in 300.0g of purified water to obtain a medicine solution, 15.0g of Kyon-T-134 resin is added, and the mixture is stirred for more than 4 hours to obtain an ion exchange resin suspension;
(2) Filtering the ion exchange resin suspension obtained in the step (1) by using a 150-mesh screen, and washing with 900ml of buffer solution of sodium dihydrogen phosphate and disodium hydrogen phosphate of sodium dodecyl sulfate with pH of 7.82 for three times to obtain a dapoxetine hydrochloride resin composite wet product;
(3) Drying the dapoxetine hydrochloride resin composite wet product obtained in the step (2) at 40 ℃ overnight, and controlling the water content below 7%.
The preparation of the dapoxetine oral instant film agent comprises the following steps:
(1) Sequentially adding glycerol, polyethylene glycol 400, sorbitol and aspartame into purified water, stirring and dissolving;
(2) Adding hydroxypropyl cellulose E15 and polyoxyethylene N80 into the solution, and stirring to obtain film-forming glue solution; adding the drug resin compound, and uniformly mixing to obtain a drug-containing matrix;
(3) Vacuum defoaming is carried out on the prepared drug-containing matrix to obtain coating liquid;
(4) And uniformly coating the coating liquid on a flat backing material by using a coating machine, drying at 50 ℃, removing the film, cutting the film according to the size of 2cm x 2.5cm x 0.4mm, and finally sealing and packaging to obtain the dapoxetine hydrochloride oral instant film.
The obtained medicinal film preparation has light yellow appearance, smooth and uniform film surface, no gritty feel when subjected to taste evaluation, and no obvious bitter and tingling taste.
EXAMPLE 7 preparation of dapoxetine hydrochloride oral instant film
Table 9 the recipe composition is as follows
| Component (A) | Prescription ratio (%) (45 g) | Action |
| Dapoxetine hydrochloride drug resin compound | 45 | Drug-carrying resin |
| Polyoxyethylene N80 | 32 | Film-forming material |
| Hydroxypropyl methylcellulose E15 | 7 | Film-forming material |
| Glycerol | 6 | Plasticizer(s) |
| Polyethylene glycol 400 | 6 | Plasticizer(s) |
| Sorbitol | 4.4 | Flavoring agent |
| Aspartame | 0.6 | Flavoring agent |
| Purified water | 300 | Solvent(s) |
The preparation method comprises the following steps:
preparation of drug resin composite:
(1) Dissolving 30.0g of dapoxetine hydrochloride in 300.0g of purified water to obtain a medicine solution, adding 20.0g of Kyron-T-134 resin, and stirring for more than 4 hours to obtain an ion exchange resin suspension;
(2) Filtering the ion exchange resin suspension obtained in the step (1) by using a 150-mesh screen, and washing with 900ml of buffer solution of sodium dihydrogen phosphate and disodium hydrogen phosphate of sodium dodecyl sulfate with pH of 7.82 for three times to obtain a dapoxetine hydrochloride resin composite wet product;
(3) Drying the dapoxetine hydrochloride resin composite wet product obtained in the step (2) at 40 ℃ overnight, and controlling the water content below 7%.
The preparation of the dapoxetine oral instant film agent comprises the following steps:
(1) Sequentially adding glycerol, polyethylene glycol 400, sorbitol and aspartame into purified water, stirring and dissolving;
(2) Adding hydroxypropyl cellulose E15 and polyoxyethylene N80 into the solution, and stirring to obtain film-forming glue solution; adding the drug resin compound, and uniformly mixing to obtain a drug-containing matrix;
(3) Vacuum defoaming is carried out on the prepared drug-containing matrix to obtain coating liquid;
(4) And uniformly coating the coating liquid on a flat backing material by using a coating machine, drying at 50 ℃, removing the film, cutting the film according to the size of 2cm x 2.5cm x 0.4mm, and finally sealing and packaging to obtain the dapoxetine hydrochloride oral instant film.
The obtained medicinal film preparation has light yellow appearance, smooth and uniform film surface, no gritty feel when subjected to taste evaluation, and no obvious bitter and tingling taste.
EXAMPLE 8 preparation of dapoxetine hydrochloride oral instant film
Table 10 the recipe composition is as follows
| Component (A) | Prescription ratio (%) (45 g) | Action |
| Dapoxetine hydrochloride drug resin compound | 43 | Drug-carrying resin |
| Polyoxyethylene N80 | 35 | Film-forming material |
| Hydroxypropyl methylcellulose E15 | 5 | Film-forming material |
| Glycerol | 6 | Plasticizer(s) |
| Polyethylene glycol 400 | 5 | Plasticizer(s) |
| Sorbitol | 5.4 | Flavoring agent |
| Sucralose | 0.6 | Flavoring agent |
| Purified water | 300 | Solvent(s) |
The preparation method comprises the following steps:
preparation of drug resin composite:
(1) 24.0g of dapoxetine hydrochloride is dissolved in 300.0g of purified water to obtain a medicine solution, 30.0g of Kyon-T-134 resin is added, and the mixture is stirred for more than 4 hours to obtain an ion exchange resin suspension;
(2) Filtering the ion exchange resin suspension obtained in the step (1) by using a 150-mesh screen, and washing with 900ml of buffer solution of sodium dihydrogen phosphate and disodium hydrogen phosphate of sodium dodecyl sulfate with pH of 7.82 for three times to obtain a dapoxetine hydrochloride resin composite wet product;
(3) Drying the dapoxetine hydrochloride resin composite wet product obtained in the step (2) at 40 ℃ overnight, and controlling the water content below 7%.
The preparation of the dapoxetine oral instant film agent comprises the following steps:
(1) Sequentially adding glycerol, polyethylene glycol 400, sorbitol and aspartame into purified water, stirring and dissolving;
(2) Adding hydroxypropyl cellulose E15 and polyoxyethylene N80 into the solution, and stirring to obtain film-forming glue solution; adding the drug resin compound, and uniformly mixing to obtain a drug-containing matrix;
(3) Vacuum defoaming is carried out on the prepared drug-containing matrix to obtain coating liquid;
(4) And uniformly coating the coating liquid on a flat backing material by using a coating machine, drying at 50 ℃, removing the film, cutting the film according to the size of 2cm x 2.5cm x 0.4mm, and finally sealing and packaging to obtain the dapoxetine hydrochloride oral instant film.
The obtained medicinal film preparation has light yellow appearance, smooth and uniform film surface, no gritty feel when subjected to taste evaluation, and no obvious bitter and tingling taste.
Example 9 in vitro dissolution test of dapoxetine hydrochloride oral fast dissolving film
Taking 6 tablets of the product prepared in example 6, and 6 tablets of commercial dapoxetine hydrochloride tablets
30mg specification) according to the "chinese pharmacopoeia (2020 edition), the dissolution profile of oral fast dissolving film and commercially available tablets was examined by the first method of the general rule 0931. The specific method comprises the following steps: the spin basket method is to use 900ml of 0.1M hydrochloric acid medium as the dissolution medium, and to detect the dissolution sample by high performance liquid chromatography with the detection wavelength of 293nm. The results are shown in Table 11.
Table 11 comparison of dissolution in vitro of dapoxetine hydrochloride oral fast dissolving film
| 5min | 10min | 15min | 20min | 30min | |
| Example 6 sample | 100.5％ | 101.8％ | 102.5％ | 99.7％ | 102.6％ |
| Commercially available tablet | 16.6％ | 71.8％ | 100.4％ | 101.0％ | 101.0％ |
The result shows that the prepared dapoxetine hydrochloride oral instant membrane has a dissolution rate faster than that of a commercially available tablet, and can achieve rapid disintegration.
EXAMPLE 10 content uniformity test of dapoxetine hydrochloride oral instant film
Content uniformity measurement: taking 1 tablet of the oral instant film prepared in example 6, placing in a 100ml measuring flask, adding mobile phase for dissolution, diluting to scale, shaking uniformly, standing, taking supernatant for filtering, taking subsequent filtrate as a sample solution, measuring the content by an HPLC method, and measuring the content uniformity (A+2.2S should be less than or equal to 20.0) according to four parts of Chinese pharmacopoeia 2020, wherein the result is shown in Table 12.
Table 12 results of content uniformity test of dapoxetine hydrochloride oral instant film
| Content uniformity test sample | Content (%) |
| 1 | 100.01 |
| 2 | 101.31 |
| 3 | 100.53 |
| 4 | 99.90 |
| 5 | 101.27 |
| 6 | 100.26 |
| 7 | 100.31 |
| 8 | 100.22 |
| 9 | 101.12 |
| 10 | 100.23 |
| Average value of | 101.42 |
| RSD | 1.2 |
| A+2.2S | 2.8 |
The results show that the prepared dapoxetine hydrochloride oral instant film has better content uniformity.
EXAMPLE 11 in vivo pharmacokinetic testing
The dapoxetine hydrochloride oral instant film agent prepared in comparative example 6 and the commercial dapoxetine hydrochloride tablet
Is a part of the pharmacokinetic data of (a): the test uses a three-cycle crossover test design where subjects were dosed with the oral instant film of example 6 (30 mg pre-meal) first, with an intermittent rinse of 5 days, followed by a 5 day wash-out period followed by a commercially available tablet (30 mg pre-meal). Plasma samples were collected at various time points after dosing during this period and pharmacokinetic parameters were calculated by DAS software with the specific results shown in table 13 below.
Table 13 dapoxetine hydrochloride oral fast dissolving film and commercially available dapoxetine hydrochloride tablet
Pharmacokinetic comparison data of (2)
The result shows that the self-made oral instant film C max Similar to AUC and commercial formulations, indicating that the instant film formulation for oral cavity is notThe effectiveness and safety of the drug can be altered.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (10)
1. The dapoxetine hydrochloride oral instant film is characterized by comprising the following components: the dapoxetine hydrochloride resin compound is a compound formed by dapoxetine hydrochloride and taste masking ion exchange resin, and the mass ratio of the dapoxetine hydrochloride to the taste masking ion exchange resin is 0.5:1 to 5:1.
2. the dapoxetine hydrochloride oral instant film of claim 1, wherein the pharmaceutically acceptable oral formulation excipients comprise one or more of water-soluble polymeric film forming materials, flavoring agents, plasticizers.
3. The dapoxetine hydrochloride oral instant membrane of claim 1, wherein said taste masking ion exchange resin is a polymethacrylic acid-divinylbenzene weak acid cation exchange resin.
4. The dapoxetine hydrochloride oral instant film of claim 2, wherein the water-soluble polymeric film-forming material is selected from one or both of hypromellose and polyoxyethylene.
5. An oral instant film of dapoxetine hydrochloride according to claim 2, wherein said plasticizer is selected from one or more of glycerin, propylene glycol, polyethylene glycol, sorbic acid, citric acid, sorbitol, mannitol, triethyl citrate, lactose, sucrose, glycine.
6. The dapoxetine hydrochloride oral instant film of claims 1-5, wherein the oral instant film comprises the following components in parts by weight:
7. the dapoxetine hydrochloride oral instant film of claim 6, wherein the oral instant film comprises the following components in parts by weight:
8. the dapoxetine hydrochloride oral instant film of claim 7, wherein the oral instant film comprises the following components in parts by weight:
30% -50% of dapoxetine hydrochloride resin compound, 30% -40% of polyoxyethylene and/or hydroxypropyl methylcellulose, 0.5% -10% of sucralose and/or aspartame, and/or 5% -15% of glycerol and/or polyethylene glycol 400 and/or sorbitol.
9. A method for preparing the dapoxetine hydrochloride oral instant film according to claims 1-8, which is characterized by comprising the following steps:
(1) Dissolving dapoxetine hydrochloride in purified water, adding ion exchange resin, and stirring to obtain a suspension of the medicine and the ion exchange resin;
(2) Filtering the ion exchange resin suspension prepared in the step (1) by using a screen, washing and drying for standby;
(3) Adding plasticizer and correctant into purified water, stirring to dissolve completely, adding film forming material, and mixing well;
(5) Stirring the dapoxetine hydrochloride drug resin compound prepared in the step (2) and adding the compound into the mixed solution prepared in the step (3), and uniformly mixing to obtain a drug-containing matrix;
(6) And (3) defoaming the medicine-containing matrix prepared in the step (5) by using vacuum, uniformly coating the medicine-containing matrix on a flat backing material by using a coating machine at the temperature of 25-60 ℃, drying, demolding, cutting, and finally sealing and packaging.
10. The dapoxetine hydrochloride oral instant film of claim 9, wherein the washing medium used in step (2) is selected from phosphate buffer or boric acid buffer with pH of 7-12.
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