CN114344270A

CN114344270A - PDE5 inhibitor and dapoxetine core-spun tablet and preparation method thereof

Info

Publication number: CN114344270A
Application number: CN202210093231.6A
Authority: CN
Inventors: 高保安; 褚襄萍; 王刚; 许洁; 刘金丹; 陈仕魁; 姚建堤; 毛昌元
Original assignee: Fujian Ruitailai Pharmaceutical Technology Co ltd; Fujian Cosunter Pharmaceutical Co Ltd
Current assignee: Fujian Ruitailai Pharmaceutical Technology Co ltd; Fujian Cosunter Pharmaceutical Co Ltd
Priority date: 2022-01-26
Filing date: 2022-01-26
Publication date: 2022-04-15

Abstract

The invention relates to the technical field of medicines, in particular to a compound preparation for treating male erectile dysfunction and premature ejaculation and a preparation method thereof. A PDE5 inhibitor and dapoxetine core-coated tablet comprises a tablet core and a shell layer; the PDE5 inhibitor is disposed within the chip core, and the dapoxetine is disposed within the shell layer; or dapoxetine disposed in the core and a PDE5 inhibitor disposed in the shell; the weight ratio of the dapoxetine to the PDE5 inhibitor is 4-70: 2.5-100; the core-spun tablet can realize that the PDE5 inhibitor and the dapoxetine are respectively placed in the shell layer and the tablet core, so that the tablet core is independently tabletted, and shell layer materials are prepared into the shell layer, thereby avoiding the problems of compatibility reaction, influence on drug effect and more impurities caused by the direct powder pressing of common double-layer tablets.

Description

PDE5 inhibitor and dapoxetine core-spun tablet and preparation method thereof

Technical Field

The invention relates to the technical field of medicines, in particular to a compound preparation for treating male erectile dysfunction and premature ejaculation and a preparation method thereof.

Background

Erectile Dysfunction (ED) refers to the inability to achieve or sustain an erection for satisfactory sexual life, and is the most common disease of male sexual dysfunction. ED treatment three of the most widely used oral drugs currently include Sildenafil (Sildenafil), vardenafil (Varden afil) and Tadalafil (Tadalafil). Sildenafil is a phosphodiesterase5 (PDE 5) inhibitor developed by Pfizer, U.S. and marketed in the united states under the trade name wanigra (Viagra) 4 months in 1998. Vardenafil is another PDE5 inhibitor co-developed by bayer and glatiramer, germany, under the trade name lida (Levitra), first marketed in germany in 9 months 2003 and approved for marketing in china in 9 months 2004. Tadalafil is another PDE5 inhibitor developed by the cooperation of the american world wide company (Lily) and lcosils in the united states, with the trade name of loving (Cialis), first marketed in the european union at 10 months in 2002, and approved by the FDA at 11 months in 2003.

Premature Ejaculation (PE) is the most common disorder of ejaculation, with a prevalence of over 1/3 in adult men and a serious impact on the quality of sexual life. Dapoxetine hydrochloride (dapoxetine) is a selective 5-hydroxytryptamine reuptake inhibitor (SSRIs), developed by American sally under the trade name "BILITHI (PRILIBY)", marketed in China in 2013, and is the only drug approved by the State drug administration for the treatment of premature ejaculation. Evidence-based medical evidence at home and abroad proves that dapoxetine hydrochloride has definite effectiveness and dosage safety in the treatment of all types of premature ejaculation patients, and is widely applied to clinic.

The literature reports (the Chinese experts group for diagnosis and treatment of premature ejaculation and erectile dysfunction common diseases, J, Chinese journal of Male science, 2021, 27(5), 461-doped region 466), the Premature Ejaculation (PE) and the Erectile Dysfunction (ED) are the most common sexual dysfunction of men, and a plurality of epidemiological studies prove that the PE and the ED commonly exist and mutually influence each other. Since ED has been reported in up to 50% of premature ejaculation men in the past 10 years of data, the concept of erectile and loss of ejaculation control (LCEE) has recently been proposed by foreign scholars, sharing PE with ED as a categorical entity. A survey of 4997 men from the asia-pacific region with a stable sex relationship found that 30% of PE men reported ED. In conclusion, the research and development of a compound preparation capable of treating ED and PE diseases simultaneously has great clinical significance.

The compound preparation contains two or more active ingredients in the same preparation unit, has the advantages of good drug compliance, high curative effect, reduced medication cost and the like, but the risk of compatibility reaction exists when a plurality of active ingredients coexist, which is the biggest problem faced by the stability of the compound preparation. The tadalafil and dapoxetine mixed tablet produced and marketed by sanuri pharmaceutical company (sunrise) in India is mainly characterized in that the time-delay effect is added on the premise of erection assistance, and the mixed tablet is very popular with wide ED and PE patients. The mixed tablet is prepared by mixing tadalafil and dapoxetine, and the two active ingredients are in direct contact, so that the problem of compatibility reaction exists, and the safety cannot be guaranteed.

Compatibility research finds that obvious compatibility reaction exists between dapoxetine for treating PE and tadalafil for treating ED, particularly under the high-temperature high-humidity and illumination environments, the impurity content is obviously increased, a large amount of unknown impurities are generated, and long-term stability has great challenge. Chinese patent CN112263581A discloses a double-layer tablet compound preparation for treating PE and ED and a preparation method thereof, the compound preparation is composed of dapoxetine for treating PE and tadalafil for treating ED, two active ingredients are respectively pressed in an upper layer and a lower layer by a double-layer tablet press, although the two active ingredients are not directly mixed, the upper layer and the lower layer are still in close contact, and the risk of compatibility reaction of the two active ingredients is not fundamentally solved. Therefore, it will be a great challenge to develop a more stable compound preparation for treating PE and ED simultaneously.

Disclosure of Invention

Technical problem to be solved

In view of the defects and shortcomings of the prior art, the invention provides a dapoxetine core-coated tablet serving as a PDE5 inhibitor, which can enable the product to be more stable, better in safety and better in compliance of clinical medication.

Correspondingly, the invention also provides a preparation method of the dapoxetine core-spun tablet serving as the PDE5 inhibitor.

(II) technical scheme

In order to achieve the purpose, the invention adopts the main technical scheme that:

in a first aspect, the embodiment of the present invention provides a PDE5 inhibitor and dapoxetine core-coated tablet, which includes a tablet core and a shell layer; the PDE5 inhibitor is disposed within the chip core, and the dapoxetine is disposed within the shell layer;

or

Dapoxetine is disposed in the core and the PDE5 inhibitor is disposed in the shell;

the weight ratio of the dapoxetine to the PDE5 inhibitor is 4-70: 2.5-100;

optionally, the PDE5 inhibitor is one or a combination of two or more of tadalafil, sildenafil, vardenafil.

Optionally, each core-spun tablet contains 5-60mg of dapoxetine and 2.5-100mg of PDE5 inhibitor.

Optionally, it comprises 5-30mg of dapoxetine and 5-50mg of a PDE5 inhibitor.

Optionally, the tablet core comprises the following components in parts by weight: 10-70 parts of dapoxetine, 0-70 parts of sustained-release material, 10-85 parts of filler, 0-10 parts of solubilizer, 0-10 parts of disintegrant, 0-20 parts of adhesive, 0.1-5 parts of lubricant and 0-1 part of colorant.

Optionally, the shell layer comprises the following components in parts by weight: 1-50 parts of PDE5 inhibitor, 0-90 parts of sustained-release material, 5-95 parts of filler, 0-20 parts of solubilizer, 0-10 parts of disintegrant, 0-20 parts of adhesive and 0.1-5 parts of lubricant.

Optionally, the tablet core comprises the following components in parts by weight: 5-80 parts of PDE5 inhibitor, 0-85 parts of sustained-release material, 10-90 parts of filler, 0-20 parts of solubilizer, 0-10 parts of disintegrant, 0-20 parts of adhesive, 0.1-5 parts of lubricant and 0-1 part of colorant.

Optionally, the shell layer comprises the following components of 4-30 parts of dapoxetine, 0-80 parts of sustained-release material, 5-90 parts of filler, 0-10 parts of solubilizer, 0-10 parts of disintegrant, 0-20 parts of adhesive and 0.1-5 parts of lubricant by weight.

Optionally, the sustained-release material comprises one or a combination of more than two of ethyl methyl cellulose, hydroxypropyl cellulose, eucalyptus, methyl cellulose, ethyl cellulose, carnauba wax, carbomer, polyvinyl chloride, stearyl alcohol, stearic acid, povidone, and polyoxyethylene;

or/and

the filler comprises one or more of lactose, microcrystalline cellulose, sucrose, pregelatinized starch, calcium carbonate, calcium sulfate, calcium hydrogen phosphate, calcium phosphate, magnesium oxide, diatomite, mannitol, sodium chloride, dextrin, and calcium hydrogen phosphate;

or/and

the solubilizer comprises one or the combination of more than two of sodium dodecyl sulfate, tween 80 and docusate sodium;

or/and

the disintegrating agent comprises one or more of sodium carboxymethyl starch, croscarmellose sodium, low-substituted hydroxypropyl cellulose, starch, crospovidone and microcrystalline cellulose;

or/and

the adhesive comprises one or more of hydroxypropyl cellulose, polyvidone, sodium carboxymethylcellulose, hydroxypropyl methylcellulose and starch slurry;

or/and

the lubricant comprises one or more of magnesium stearate, stearic acid, talcum powder, superfine silica powder, polyethylene glycol and sodium stearyl fumarate;

or/and

the colorant comprises one or more of red iron oxide, yellow iron oxide, lemon yellow, carmine, indigo blue and brilliant blue.

In a second aspect, the present invention also provides a method for preparing a PDE5 inhibitor and dapoxetine core-coated tablet as described in any of the above embodiments, comprising the steps of: the tablet core or the shell layer is prepared by a powder direct compression method, wet granulation or dry granulation, and then the PDE5 inhibitor and dapoxetine core-spun tablets are prepared.

Optionally, it comprises the steps of: and preparing the core-coated tablet by the core-coated material, and pressing a shell layer on the core-coated tablet to obtain the PDE5 inhibitor and dapoxetine core-coated tablet.

Optionally, it comprises the steps of: pressing the tablet core material into tablets by a powder direct compression method to obtain tablet cores; filling shell layer materials on the tablet core layer, and pressing the core-spun tablets into core-spun tablets by a core-spun tablet pressing machine.

Optionally, when the core tablet comprises dapoxetine and the shell layer comprises a PDE5 inhibitor, the method for preparing the core-spun tablet comprises the following steps:

preparation of S1 tablet core

Mixing dapoxetine with adjuvants, and tabletting by powder direct compression method to obtain tablet core;

more specifically, it may be: the preparation of the tablet core further comprises: the dapoxetine and auxiliary materials are premixed, then are prepared into granules by a wet granulation method or a dry granulation method, and are subjected to total mixing, and finally, the tablets are pressed to obtain the tablet core.

Preparation of S2 shell material

Mixing a PDE5 inhibitor and auxiliary materials to obtain a shell material;

more specifically, it may be: the preparation method comprises the steps of premixing a PDE5 inhibitor and auxiliary materials, granulating the mixture by a wet granulation method or a dry granulation method, and mixing the granules to obtain a shell material.

Preparation of S3 core-spun tablets

And placing the shell material and the core tablet into a core-spun tablet tabletting machine, filling the shell material for the first time, then filling the core tablet, filling the shell material for the second time, and finally pressing into the core-spun tablet.

Optionally, when the tablet core comprises the PDE5 inhibitor and the shell comprises dapoxetine, the preparation method of the core-spun tablet comprises the following steps:

preparation of S1 tablet core

Mixing PDE5 inhibitor and adjuvants, and making tablet by powder direct compression method to obtain tablet core;

more specifically, it may be: the preparation of the tablet core further comprises: the preparation method comprises the steps of premixing the PDE5 inhibitor and auxiliary materials, then preparing the mixture into granules by a wet granulation method or a dry granulation method, carrying out total mixing, and finally pressing the mixture into tablets to obtain the tablet core.

Preparation of S2 shell material

Mixing dapoxetine with auxiliary materials to obtain a shell material;

more specifically, it may be: the dapoxetine and auxiliary materials are premixed, then are prepared into granules by a wet granulation method or a dry granulation method, and are subjected to total mixing to obtain a shell layer material.

Preparation of S3 core-spun tablets

The auxiliary materials refer to one or a combination of more than two of sustained-release materials, fillers, solubilizers, disintegrants, binders, lubricants and coloring agents.

Optionally, the tablet core has a weight of 30-150 mg.

Optionally, the tablet core has a weight of 40-60 mg.

Optionally, the weight of the shell layer is 200-400 mg.

Optionally, the weight of the shell layer is 200-300 mg.

Optionally, the tablet core is a plain tablet.

Optionally, the tablet core is a coated tablet, and the coating is hydroxypropyl methylcellulose coating, polyvinyl alcohol coating, acrylic resin coating, and Ewing coating.

Optionally, the core-spun sheet is a plain sheet;

optionally, the core-spun tablet is a coated tablet, and the coating is hydroxypropyl methylcellulose coating, polyvinyl alcohol coating, acrylic resin coating, and Ewing coating.

(III) advantageous effects

The invention has the beneficial effects that:

according to the PDE5 inhibitor and dapoxetine core-spun tablet disclosed by the invention, the dosage form of the core-spun tablet can realize that the PDE5 inhibitor and dapoxetine are respectively placed in the shell layer and the tablet core, so that the tablet core is independently formed, and the shell layer material is prepared into the shell layer, so that the problems of compatibility reaction, influence on drug effect and more impurities caused by direct powder pressing of common double-layer tablets are solved.

The preparation of the invention has better compliance and safety in clinical medication. Compared with the core-spun tablets in the prior art in which the core tablet containing the pharmacodynamic ingredients is coated by the non-drug filler serving as the shell, the core-spun tablets are different in that the two pharmacodynamic ingredients are respectively arranged in the shell and the core tablet, and the difference of the in-vivo release sequence of the two pharmacodynamic ingredients is realized by utilizing the structural particularity of the core-spun tablets, so that the in-vivo pharmacodynamic action of the drug is further improved. Specifically, the preparation with two active ingredients in different release sequences can be prepared according to the requirements of different patients, the treatment effect is better, and the compliance of clinical medication is greatly improved.

The core-spun tablet disclosed by the invention is small in impurity number, low in impurity content and good in safety.

Among them, the stability is better: the tablet core is independently tabletted, and is not directly pressed between two kinds of powder, and meanwhile, independent coating can be carried out, so that the tablet core is effectively isolated from active ingredients in the shell layer, and the stability of the product is further ensured.

The invention skillfully develops a compound preparation of a PDE5 inhibitor and dapoxetine by utilizing a core-spun tablet technology. The core-spun sheet is a double-layer sheet structure consisting of an inner layer and an outer layer, and is different from a common double-layer sheet, and the core-spun sheet is in a form of the inner layer, the outer layer and the upper layer instead of the lower layer.

Drawings

FIG. 1 is a diagram: the core-spun sheet is in a structural schematic diagram;

reference numerals: 1-tablet core; 2-shell layer.

Detailed Description

For a better understanding of the present invention, reference will now be made in detail to the present invention by way of specific embodiments thereof.

The invention adopts the core-coated tablet technology, provides the PDE5 inhibitor and dapoxetine core-coated tablet, can ensure that the existing product has better stability and safety, can control the release sequence and the release speed of the active ingredients in a targeted manner according to clinical requirements, and can be more effective in treating patients sharing different ED and PE.

In addition, the half-life period and the onset time of the PDE5 inhibitor and the dapoxetine are different, the preparation of the core-spun tablet is improved, the two medicines are respectively placed in a tablet core layer or a shell layer, and the treatment requirements of patients sharing PE and ED with different degrees can be met by utilizing the preparation form of the tablet with the time difference release effect in the gastrointestinal tract, so that the clinical effect is better.

Generally, the core tablet core of the core tablet is a compressed tablet, and then the second compression is completed on a special tablet machine by filling the second material, as shown in figure 1. The core-spun sheet is a special double-layer sheet form. The core tablet can be coated independently, and then the shell material is used for pressing the core tablet, so that the core tablet and the shell can be completely isolated from two different active ingredient particles, which cannot be prepared by other tablet forms. And a thick shell layer is added to further protect the tablet core, so that the stability of the tablet core is better. According to the invention, the PDE5 inhibitor and dapoxetine are respectively placed in the tablet core and the shell layer, so that the compatibility reaction of the two active ingredients is effectively avoided, and the stability is ensured. In addition, due to the particularity of the core-spun tablet structure and the combination of preparation technology, the release sequence and time difference of active ingredients can be regulated and controlled, and the effectiveness of the medicine can be further ensured.

In order to better understand the above technical solutions, exemplary embodiments of the present invention will be described in more detail below. While the following shows exemplary embodiments of the invention, it should be understood that the invention may be embodied in various forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.

Example 1: tadalafidopoxetine core-spun tablet

Preparation of tablet core

Weighing 560g of dapoxetine hydrochloride, 13g of silicon dioxide, 407g of lactose and 10g of croscarmellose sodium, placing the weighed materials in a hopper mixer, rotating at 10 r/min, mixing for 15 min, adding 10g of magnesium stearate, and continuously mixing for 5 min to obtain a total core mixture; and (3) putting the total mixed material of the tablet core into a tabletting machine, and tabletting by using a 5mm circular flat-inclined punch to ensure that the weight of the tablet is about 60mg and the hardness is 20-40N, thus obtaining the dapoxetine tablet core plain tablet. And (3) putting the tablets into a coating pan, and coating with stomach-soluble hydroxypropyl methylcellulose coating powder to increase the weight by about 3% to obtain the dapoxetine tablet core.

Preparation of shell material

Weighing 7g of hydroxypropyl cellulose and 2.8g of sodium dodecyl sulfate, placing the hydroxypropyl cellulose and the sodium dodecyl sulfate in 175ml of purified water, and stirring the mixture to dissolve the hydroxypropyl cellulose and the sodium dodecyl sulfate to be used as an adhesive; weighing 40g of tadalafil, 715.2g of lactose, 36g of croscarmellose sodium and 16g of hydroxypropyl cellulose, placing the weighed materials in a wet granulation pot, stirring the materials with a stirring paddle at 300 revolutions per minute and a cutting knife at 1500 revolutions per minute, mixing the materials for 10 minutes, slowly adding a binder, granulating the materials for 5 minutes to obtain wet granules, drying the wet granules at 60 ℃ until the moisture content is less than 3%, and discharging the materials to obtain dried materials; drying and granulating the dried material by using a 1.5mm net to obtain dry particles; and (3) putting the dry granules into a hopper mixer, adding 28g of croscarmellose sodium and 150g of microcrystalline cellulose at a speed of 10 rpm, mixing for 15 minutes, adding 5g of magnesium stearate, and mixing for 5 minutes to obtain a shell layer material.

Making of core-spun sheet

And (3) placing the tablet core and the shell layer material into a tablet machine for core-spun tablets, and punching the tablets by using a 9mm circular arc to ensure that the weight of the tablets is about 312mg, and the hardness of the tablets is 70-80N, so that the tadalafil-paroxetine core-spun tablets are obtained. And (3) putting the tablets into a coating pan, and coating with stomach-soluble hydroxypropyl methylcellulose coating powder to increase the weight by about 3% to obtain the tadalafiloxetine core-coated tablets.

Example 2: tadalafidopoxetine core-spun tablet

Preparation of tablet core

Weighing 448g of dapoxetine hydrochloride, 13g of silicon dioxide, 30g of croscarmellose sodium and 1g of red ferric oxide, placing the weighed materials in a material bag for premixing, and sieving the materials by a 40-mesh sieve to obtain a premixed material; placing the premixed material into a hopper mixer, adding 498g of lactose at 10 revolutions per minute, mixing for 15 minutes, adding 10g of magnesium stearate, and continuously mixing for 5 minutes to obtain a total core mixed material; and (3) putting the total mixed material of the tablet core into a tabletting machine, and tabletting by using a 5mm circular flat and inclined punch to ensure that the weight of the tablet is about 50mg and the hardness is 20-40N, thus obtaining the dapoxetine tablet core.

Preparation of shell material

Making of core-spun sheet

And (3) placing the tablet core and the shell layer material into a tablet machine for core-spun tablets, and punching the tablets by using a 9mm circular arc to ensure that the weight of the tablets is about 300mg, and the hardness of the tablets is 70-80N, so that the tadalafil-Poxetine core-spun tablets are obtained.

Example 3: tadalafidopoxetine core-spun tablet

Preparation of tablet core

Weighing 224g of dapoxetine hydrochloride, 10g of silicon dioxide, 30g of croscarmellose sodium and 1g of red ferric oxide, placing the weighed materials in a material bag for premixing, and sieving the materials by a 40-mesh sieve to obtain a premixed material; placing the premixed material into a hopper mixer, adding 730g of lactose and 10 r/min, mixing for 15 minutes, adding 5g of magnesium stearate, and continuously mixing for 5 minutes to obtain a total mixed material of the tablet core; and (3) putting the total mixed material of the tablet core into a tabletting machine, and tabletting by using a 5mm circular flat and inclined punch to ensure that the weight of the tablet is about 50mg and the hardness is 20-40N, thus obtaining the dapoxetine tablet core.

Preparation of shell material

Making of core-spun sheet

And (3) placing the tablet core and the shell layer material into a tablet machine for core-spun tablets, and punching the tablets by using a 9mm circular arc to ensure that the weight of the tablets is about 300mg, and the hardness of the tablets is 80-100N, so that the tadalafil-paroxetine core-spun tablets are obtained. And (3) putting the tablets into a coating pan, and coating with stomach-soluble hydroxypropyl methylcellulose coating powder to increase the weight by about 3% to obtain the tadalafiloxetine core-coated tablets.

Example 4: tadalafidopoxetine core-spun tablet

Preparation of tablet core

Weighing 112g of dapoxetine hydrochloride, 13g of silicon dioxide, 30g of croscarmellose sodium, 336g of microcrystalline cellulose and 499g of lactose, placing the weighed materials in a hopper mixer, mixing for 15 minutes at 10 revolutions per minute, adding 10g of magnesium stearate, and continuously mixing for 5 minutes to obtain a total core mixed material; putting the total mixed material of the tablet core into a tabletting machine, and carrying out flat and inclined punching on the tablet with the diameter of 5mm to ensure that the weight of the tablet is about 50mg and the hardness is 20-40N, thus obtaining a dapoxetine tablet core plain tablet; and (3) putting the tablets into a coating pan, and coating with gastric-soluble coating powder to increase the weight by about 3% to obtain the dapoxetine coated tablet core.

Preparation of shell material

Weighing 5g of povidone and 803 g of tween, putting into 200ml of purified water, and stirring to dissolve the povidone and tween to obtain an adhesive; weighing 40g of tadalafil, 707g of lactose, 36g of sodium carboxymethyl starch and 26g of hydroxypropyl methyl cellulose, putting the weighed materials into a wet granulation pot, stirring the materials with a stirring paddle at 400 revolutions per minute and a cutting knife at 1200 revolutions per minute, mixing the materials for 10 minutes, slowly adding a binder, granulating the materials for 7 minutes to obtain wet granules, drying the wet granules at 60 ℃ until the moisture content is less than 3%, and discharging the materials to obtain dried materials; drying and granulating the dried material by using a 1.2mm net to obtain dry particles; and (3) putting the dry granules into a hopper mixer, adding 30g of sodium carboxymethyl starch and 148g of microcrystalline cellulose for 10 r/min, mixing for 15 min, adding 5g of magnesium stearate, and mixing for 5 min to obtain a shell layer material.

Making of core-spun sheet

And (3) placing the coated tablet core and shell layer materials in a tablet machine for core-spun tablets, and punching the tablets by using a 9mm circular arc to ensure that the tablets have the weight of about 300mg and the hardness of 80-100N, thus obtaining the tadalafilpodoxetine core-spun tablets.

Example 5: tadalafidopoxetine core-spun tablet

Preparation of tablet core

Weighing 50g of tadalafil, 30g of silicon dioxide and 1g of red ferric oxide, placing the weighed materials in a material bag for premixing, and sieving the materials by a 40-mesh sieve to obtain a premixed material; placing the premixed material into a hopper mixer, adding 764g of cellulose-lactose, 50g of croscarmellose sodium and 100g of sodium lauryl sulfate at 10 revolutions per minute, mixing for 15 minutes, adding 5g of magnesium stearate, and continuously mixing for 5 minutes to obtain a total core mixed material; and (3) putting the total mixed material of the tablet core into a tabletting machine, and tabletting by using a 5mm circular flat and inclined punch to ensure that the weight of the tablet is about 50mg and the hardness is 30-40N, thus obtaining the dapoxetine tablet core.

Preparation of shell material

268.7g of dapoxetine hydrochloride, 285.6g of microcrystalline cellulose, 634.3g of lactose, 40g of croscarmellose sodium and 30g of silicon dioxide are weighed and placed in a hopper mixer, 10 revolutions per minute are carried out, mixing is carried out for 15 minutes, 10g of magnesium stearate is added, and mixing is continued for 5 minutes, so as to obtain a shell layer material.

Making of core-spun sheet

Example 6: sildenafil-dapoxetine core-spun tablet

Preparation of tablet core

Weighing 448g of dapoxetine hydrochloride, 10g of silicon dioxide, 17g of corn starch, 13g of sodium carboxymethyl starch and 2g of carmine, placing the weighed materials in a material bag for premixing, and sieving the materials by a 40-mesh sieve to obtain a premixed material; placing the premixed material into a hopper mixer, adding 500g of lactose at 10 revolutions per minute, mixing for 15 minutes, adding 10g of magnesium stearate, and continuously mixing for 5 minutes to obtain a total core mixed material; putting the total mixed material of the tablet core into a tabletting machine, and carrying out flat and inclined punching on the tablet with the diameter of 5mm to ensure that the weight of the tablet is about 50mg and the hardness is 20-40N, thus obtaining a dapoxetine tablet core plain tablet; and (3) putting the tablets into a coating pan, and coating with gastric-soluble polyvinyl alcohol coating powder to increase the weight by about 5% to obtain the dapoxetine coated tablet cores.

Preparation of shell material

Weighing 140.4g of sildenafil citrate, 600g of microcrystalline cellulose and 250g of lactose, placing the materials in a wet granulation pot, stirring 300 revolutions per minute by a stirring paddle and 1500 revolutions per minute by a cutting knife, mixing for 8 minutes, slowly adding 400g of purified water, granulating for 4 minutes to obtain wet granules, drying at 70 ℃ until the water content is less than 3%, and discharging to obtain a dried material; drying and granulating the dried material by using a 1.5mm net to obtain dry particles; and (3) putting the dry granules into a hopper mixer, adding 35.6g of croscarmellose sodium at 10 rpm, mixing for 15 minutes, adding 10g of magnesium stearate, and mixing for 5 minutes to obtain a shell material.

Making of core-spun sheet

Placing the core tablet and the shell layer material in a core tablet machine, punching the tablet by using a 9mm circular arc to ensure that the tablet weight is about 302.5mg, and the tablet hardness is 100 plus 120N, thus obtaining the sildenafil-Pooxetine core-spun tablet plain tablet; and (3) putting the plain tablets into a coating pan, and coating with gastric-soluble polyvinyl alcohol coating powder to increase the weight by about 5% to obtain the sildenafil-dapoxetine core-coated tablets.

Example 7: sildenafil-dapoxetine core-spun tablet

Preparation of tablet core

Weighing 224g of dapoxetine hydrochloride, 30g of croscarmellose sodium and 1g of red ferric oxide, placing the weighed materials in a material bag for premixing, and sieving the materials by a 40-mesh sieve to obtain a premixed material; placing the premixed material into a hopper mixer, adding 740g of cellulose-lactose at 10 r/min, mixing for 15 minutes, adding 5g of magnesium stearate, and continuously mixing for 5 minutes to obtain a total mixed material of the tablet core; and putting the total mixed material of the tablet core into a tabletting machine, and tabletting by using a 5mm round flat inclined punch to ensure that the weight of the tablet is about 50mg and the hardness is 20-40N, thus obtaining the sildenafil tablet core.

Preparation of shell material

Weighing 281g of sildenafil citrate, 500g of microcrystalline cellulose and 200g of pregelatinized starch, placing the materials in a hopper mixer at the rotating speed of 10 r/min, mixing for 20 min, adding 9g of magnesium stearate, and mixing for 5 min to obtain the premixed material. Placing the premixed material into a dry granulating machine, setting the hydraulic pressure at 70-100bar, setting the pressure wheel gap at 1-3mm, rotating the compression roller at 15 r/min, horizontally feeding at 30 r/min, vertically feeding at 20 r/min, initially moving at 0.5mm, and granulating with a mesh aperture of 1.0mm, and performing dry granulation to obtain dry granules; and (3) putting the dry granules into a hopper mixer, adding 10g of magnesium stearate at 10 rpm, and mixing for 10 minutes to obtain a shell layer material.

Making of core-spun sheet

And (3) placing the tablet core and the shell layer material into a core-spun tablet tabletting machine, and punching the tablet by using a 9mm circular arc to ensure that the tablet weight is about 300mg and the tablet hardness is 60-90N, thus obtaining the sildenafil and dapoxetine core-spun tablet.

Example 8: sildenafil-dapoxetine core-spun tablet

Preparation of tablet core

Weighing 560g of dapoxetine hydrochloride, 100g of microcrystalline cellulose and 330g of lactose, placing the weighed materials in a hopper mixer at the rotating speed of 15 revolutions per minute, mixing for 30 minutes, adding 5g of magnesium stearate, and mixing for 5 minutes to obtain the premixed material. Placing the premixed material in a dry granulating machine, setting the hydraulic pressure to be 90-120bar, setting the pressure wheel gap to be 1-3mm, setting the rotation speed of a compression roller to be 10 r/min, setting the horizontal feeding speed to be 25 r/min, setting the vertical feeding speed to be 10 r/min, setting the initial displacement to be 0.5mm and setting the aperture of a whole grain screen to be 1.5mm, and carrying out dry granulation to obtain dry granules; putting the dry-process granules into a hopper mixer, adding 5g of magnesium stearate at 15 rpm, and mixing for 10 minutes to obtain a total core mixture; and putting the total mixed material of the tablet core into a tabletting machine, and tabletting by using a 7mm round flat inclined punch to ensure that the weight of the tablet is about 60mg and the hardness is 25-40N, thus obtaining the sildenafil tablet core.

Preparation of shell material

Weighing 562g of sildenafil citrate, 290g of hydroxypropyl cellulose, 100g of Uttqi RLPO and 38g of sodium chloride, putting the weighed materials into a wet granulation pot, stirring 200 revolutions per minute by a stirring paddle and 1100 revolutions per minute by a cutting knife, mixing for 5 minutes, slowly adding 180g of purified water, granulating for 6 minutes to obtain wet granules, drying at 70 ℃ until the moisture content is less than 3%, and discharging to obtain a dried material; drying and granulating the dried material by using a 1.0mm net to obtain dry particles; and (3) putting the dry granules into a hopper mixer, adding 10g of magnesium stearate, and mixing for 5 minutes to obtain a shell material.

Making of core-spun sheet

And (3) placing the core tablet and the shell layer material in a core tablet machine, and punching the tablet by using a 9mm circular arc to ensure that the tablet weight is about 310mg and the tablet hardness is 130-150N, thus obtaining the sildenafil-dapoxetine core-spun tablet.

Example 9: vardenaftidapoxetine core-coated tablet

Preparation of tablet core

Weighing 89.6g of vardenafil hydrochloride, 20g of silicon dioxide, 60g of sodium carboxymethyl starch and 1g of red ferric oxide, placing the materials in a material bag for premixing, and sieving the materials by a 60-mesh sieve to obtain a premixed material; placing the premixed material into a hopper mixer, adding 729.4g of cellulose-lactose and 100g of pregelatinized starch for 15 r/min, mixing for 15 min, adding 10g of magnesium stearate, and continuously mixing for 5 min to obtain a total core mixed material; and putting the total mixed material of the tablet core into a tabletting machine, and tabletting by using a 7mm round flat and inclined punch to ensure that the weight of the tablet is about 120mg and the hardness is 50-60N, thus obtaining the vardenafil tablet core.

Preparation of shell material

Weighing 84g of dapoxetine hydrochloride, 10g of silicon dioxide, 500g of microcrystalline cellulose, 400g of lactose and 6g of magnesium stearate, placing the weighed materials in a hopper mixer, and mixing for 30 minutes at 15 revolutions per minute to obtain a premixed material; placing the premixed material in a dry granulating machine, setting the hydraulic pressure to be 90-120bar, setting the pressure wheel gap to be 1-3mm, rotating the compression roller at 8 r/min, horizontally feeding at 16 r/min, vertically feeding at 12 r/min, initially moving at 0.5mm, and granulating with a granulating mesh diameter of 1.0mm, and performing dry granulation to obtain dry granules; and (3) placing the dry granules into a hopper mixer, adding 10g of magnesium stearate at 15 rpm, and mixing for 5 minutes to obtain a shell layer material.

Making of core-spun sheet

And (3) placing the tablet core and the shell layer material into a core-spun tablet tabletting machine, and punching the tablet by using an arc of 11mm to ensure that the tablet weight is about 520mg and the hardness is 70-90N, thus obtaining the vardenafil and dapoxetine core-spun tablet.

Example 10: vardenaftidapoxetine core-coated tablet

Preparation of tablet core

Weighing 179g of vardenafil hydrochloride, 30g of silicon dioxide, 150g of sodium carboxymethyl starch and 3g of red ferric oxide, placing the materials in a material bag for premixing, and sieving the materials by a 60-mesh sieve to obtain a premixed material; placing the premixed material into a hopper mixer, adding 508g of lactose and 120g of mannitol at 15 rpm, mixing for 15 minutes, adding 10g of magnesium stearate, and continuously mixing for 5 minutes to obtain a total mixed material of the tablet core; and putting the total mixed material of the tablet core into a tabletting machine, and tabletting by using a 5mm round flat and inclined punch to ensure that the weight of the tablet is about 30mg and the hardness is 30-40N, thus obtaining the vardenafil tablet core.

Preparation of shell material

Weighing 84g of dapoxetine hydrochloride, 216g of dextrin, 100g of calcium carbonate, 110g of starch, 400g of lactose and 70g of sodium carboxymethyl starch, placing the components in a hopper mixer, mixing for 30 minutes at 15 revolutions per minute, adding 20g of magnesium stearate, and continuously mixing for 5 minutes to obtain a premixed material; placing the premixed material in a dry granulating machine, setting hydraulic pressure of 70-90bar, setting a pressure wheel gap of 1-2mm, rotating speed of a compression roller of 8 revolutions per minute, horizontal feeding speed of 10 revolutions per minute, vertical feeding speed of 8 revolutions per minute, initial displacement of 0.5mm and mesh aperture of 1.2mm, and performing dry granulation to obtain dry granules; and (3) placing the dry-method particles in a hopper mixer, and mixing for 5 minutes to obtain a shell layer material.

Making of core-spun sheet

Placing the tablet core and the shell layer material in a tablet machine for core-spun tablets, and punching the tablets by using a 9mm circular arc to ensure that the tablets have the weight of about 230mg and the hardness of 75-90N, thus obtaining vardenafil-dapoxetine core-spun tablets; and (3) putting the plain tablets into a coating pan, and coating with enteric-coated Eudragit coating powder to increase the weight by about 15% to obtain the tadalafilpodoxetine enteric coated core-spun tablets.

Comparative example 1

The other points are different from those of example 5 in that: directly pressing into double-layer tablet. The method specifically comprises the following steps: the core material prepared under the item 5 of example was taken as the first layer material of the double-layer tablet, and the shell material under the item 5 of example was taken as the second layer material of the double-layer tablet. And (3) placing the core material and the shell material in a double-layer tablet making machine, and punching the tablet by using a 9mm circular arc, wherein the first layer is filled with 50mg and the second layer is filled with 300mg to prepare a double-layer tablet, namely the common double-layer tablet.

Experimental example 1: compatibility study of PDE5 inhibitor with dapoxetine

The PDE5 inhibitor exemplifies tadalafil and demonstrates the advantages of the present invention. Weighing tadalafil and dapoxetine hydrochloride, sieving and mixing according to the ratio of 2: 3 to obtain a mixture of tadalafil and dapoxetine hydrochloride. The tadalafil, the dapoxetine hydrochloride, the tadalafil and the dapoxetine hydrochloride are placed under the conditions of high temperature (60 ℃), high humidity (92.5% RH), high temperature and high humidity (50 DEG/82% RH) and illumination of 5000lx +/-500 lx respectively for 30 days, impurities are measured according to a method, the compatibility condition of the tadalafil and the dapoxetine is inspected by taking the maximum single impurity content, the total impurity content and the number of the impurities as evaluation indexes, and the experimental results are shown in the following table.

Compatibility investigation result of tadalafil and dapoxetine for 0 day and 30 days

And (4) analyzing results:

the tadalafil and the dapoxetine are separately and independently inspected, the total impurity content in 0 day is 0.008 percent and 0.020 percent respectively, the impurity content is very low, the safety is good, and the number of the impurities is only 1; when tadalafil was mixed with dapoxetine, the impurity levels were much greater than those of the separately placed samples under the same examination conditions. Particularly, under the conditions of high temperature, high humidity and illumination, 14 impurities are generated, although certain protective measures can be taken in the production and storage processes, the problem of photolysis cannot be fundamentally avoided, and hidden dangers are brought to the safety of clinical medication. In the core-spun tablet, the two active ingredients are separately and respectively isolated in the tablet core and the shell layer, and the tablet core can be coated with a film, so that the contact between the tablet core and the shell layer is further avoided, and the defect of compatibility reaction is overcome.

Experimental example 2: quality comparison of commercially available single preparation and compound preparation

The quality of commercially available single tadalafil tablets (sieliei), commercially available dapoxetine hydrochloride tablets (brix) and commercially available tadalafil tablets (Sunrize) was compared with each other by using the impurity content as an index. The impurity content was measured by the method, and the experimental results are shown in the following table.

Quality comparison of commercially available single preparation and compound preparation

Sample name	Maximum individual impurity content (%)	Total impurity content (%)	Number of impurities
				The commercial single component: tadalafil tablet	0.032	0.032	1
The commercial single component: dapoxetine hydrochloride tablet	0.019	0.035	4
				The commercial compound is as follows: tadalafidopoxetine tablets	0.084	0.254	10

And (4) analyzing results:

compared with the impurity content of the commercially available single preparation and the compound preparation, the impurity content of the compound preparation is far greater than that of each single preparation, the impurity number is as high as 10, and the safety is worthy of thinking. The core technical characteristic of the invention is to design a core-spun tablet, which can separate the active ingredients of the tadalafil and the dapoxetine hydrochloride in the same preparation unit, thereby solving the problem of compatibility reaction.

Experimental example 3: the stability of the compound preparation of the invention is compared with that of the compound preparation on the market

The inventor inspects the quality and the stability of the compound preparation from various angles, takes the impurity content as an index, and compares the quality with the compound preparation on the market. The commercially available compound preparation tadalafilpodxetine tablet, the sample of comparative example 1, the sample of the invention of example 1, the sample of example 2, the sample of example 3, the sample of example 4 and the sample of example 5 were placed under accelerated conditions (40 ℃, 75% RH) for 3 months, and then sampled to detect the impurity content, and the results were as follows:

the comparison result of the impurity content of the compound of the invention and the compound sold in the market

And (4) analyzing results:

accelerated stability tests show that the impurity number and the impurity content of the tadalafilpodoxetine core-spun tablet are far smaller than those of a compound preparation and a common double-layer tablet sold in the market, and the safety of clinical medication is improved. Further supporting the advantages of the present invention.

Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A PDE5 inhibitor and dapoxetine core-coated tablet, which is characterized in that: it comprises a tablet core and a shell layer; the PDE5 inhibitor is disposed within the chip core, and the dapoxetine is disposed within the shell layer;

or

The dapoxetine is disposed within a chip core, and the PDE5 inhibitor is disposed within a shell layer;

the weight ratio of the dapoxetine to the PDE5 inhibitor is 4-70: 2.5-100.

2. The PDE5 inhibitor and dapoxetine core-coated tablet of claim 1, wherein: the PDE5 inhibitor is one or more of tadalafil, sildenafil and vardenafil.

3. The PDE5 inhibitor and dapoxetine core-coated tablet according to claim 2, comprising 5-30mg of dapoxetine and 5-50mg of PDE5 inhibitor.

4. The PDE5 inhibitor and dapoxetine core-coated tablet according to claim 1, wherein the core comprises the following components in parts by weight: 10-70 parts of dapoxetine, 0-70 parts of sustained-release material, 10-85 parts of filler, 0-10 parts of solubilizer, 0-10 parts of disintegrant, 0-20 parts of adhesive, 0.1-5 parts of lubricant and 0-1 part of colorant.

5. The PDE5 inhibitor and dapoxetine core-coated tablet according to claim 4, wherein the shell layer comprises the following components in parts by weight: 1-50 parts of PDE5 inhibitor, 0-90 parts of sustained-release material, 5-95 parts of filler, 0-20 parts of solubilizer, 0-10 parts of disintegrant, 0-20 parts of adhesive and 0.1-5 parts of lubricant.

6. The PDE5 inhibitor and dapoxetine core-coated tablet according to claim 1, wherein the core comprises the following components in parts by weight: 5-80 parts of PDE5 inhibitor, 0-85 parts of sustained-release material, 10-90 parts of filler, 0-20 parts of solubilizer, 0-10 parts of disintegrant, 0-20 parts of adhesive, 0.1-5 parts of lubricant and 0-1 part of colorant.

7. The PDE5 inhibitor and dapoxetine core-spun tablet of claim 6, wherein the shell layer comprises the following components, by weight, 4-30 parts of dapoxetine, 0-80 parts of slow release material, 5-90 parts of filler, 0-10 parts of solubilizer, 0-10 parts of disintegrant, 0-20 parts of adhesive and 0.1-5 parts of lubricant.

8. The PDE5 inhibitor and dapoxetine coated tablet of any one of claims 4 to 7, wherein: the slow release material comprises one or more of ethyl methyl cellulose, hydroxypropyl cellulose, Ewing, methyl cellulose, ethyl cellulose, carnauba wax, carbomer, polyvinyl chloride, octadecanol, stearic acid, polyvidone and polyoxyethylene;

or/and

9. A process for the preparation of a PDE5 inhibitor and dapoxetine core-coated tablet according to any one of claims 1 to 7, comprising the steps of: the tablet core or the shell layer is prepared by a powder direct compression method, wet granulation or dry granulation, and then the PDE5 inhibitor and dapoxetine core-spun tablets are prepared.

10. A process for the preparation of a PDE5 inhibitor and dapoxetine core-coated tablet according to any one of claims 1 to 7, comprising the steps of: and preparing the core-coated tablet by the core-coated material, and pressing a shell layer on the core-coated tablet to obtain the PDE5 inhibitor and dapoxetine core-coated tablet.