CN115531405A

CN115531405A - Compound pharmaceutical composition for treating male diseases and preparation method and application thereof

Info

Publication number: CN115531405A
Application number: CN202211092817.7A
Authority: CN
Inventors: 全丹毅; 米多龙
Original assignee: Jiangsu Jicui New Pharmaceutical Preparation Technology Research Institute Co ltd
Current assignee: Jiangsu Jicui New Pharmaceutical Preparation Technology Research Institute Co ltd
Priority date: 2022-09-08
Filing date: 2022-09-08
Publication date: 2022-12-30

Abstract

The invention provides a compound pharmaceutical composition for treating male diseases, which comprises the following components in percentage by mass: 47 to 73 percent of icariin, 4 to 11 percent of main drug containing dapoxetine and 19 to 42 percent of auxiliary materials. The compound pharmaceutical composition can treat premature ejaculation and erectile dysfunction at the same time, can further improve the treatment effect on premature ejaculation, and can also reduce the incidence rate of adverse reactions of organisms.

Description

Compound pharmaceutical composition for treating male diseases and preparation method and application thereof

Technical Field

The invention relates to the field of medicine research, in particular to a compound medicine composition for treating male diseases and a preparation method and application thereof.

Background

Premature Ejaculation (PE) is the ejaculation disorder disease with the highest incidence in the family of andrology, and the incidence rate of the PE is second to the penile Erectile Dysfunction (ED) in the diagnosis and treatment of the common sexual dysfunction diseases in the family of andrology. The premature ejaculation symptom is mainly characterized in that the penis is involuntary ejaculation after being stimulated in the vagina with minimum stimulation, namely, the latent time of the ejaculation in the vagina is shortened and the automatic control capability of the ejaculation is reduced, thereby generating negative influence on the self-respect and confidence of a patient, further causing the satisfaction of both parties to sexual life to be reduced, generating vicious circle and finally seriously influencing the life quality of couples.

The definition of PE in recent years mainly includes three elements: intravaginal Ejaculation Latency (IELT) is short, sexual satisfaction is poor and ejaculatory control is poor. PE has affected the quality of life of patients and has also plagued or annoyed spouses or sexual partners, eventually leading to even a number of household or social problems. Recent research guidelines classify PEs into 4 major categories: primary, secondary, natural variant and PE-like ejaculatory dysfunction. According to statistics, the incidence rate of PE in middle-aged and young men in China is up to 35%, but the PE is influenced by the traditional concept of people, the actual incidence rate is higher than the ratio, and the clinical diagnosis ratio is lower.

The current clinical treatments for PE mainly include psychobehavioral therapy, drug therapy and surgical treatment. The psychobehavioral therapy belongs to a common clinical intervention method, the main action mechanism is to improve the control ability of ejaculation by guiding a patient to learn and control the ejaculation skill and adjusting the psychological state of the patient, thereby further improving the satisfaction of the patient and the sexual partner thereof to the sexual life. The clinical operation treatment is mainly circumcision, although the sexual intercourse time can be prolonged, the operation can affect sensory nerves of the penis, cause sensory dysfunction and even induce erectile dysfunction and the like, and the sexual life satisfaction of a patient cannot be effectively improved, so that the drug therapy is the main treatment means of PE at present.

The dapoxetine is the first specific medicine for PE treatment in the world at present, clinical tests show that the ejaculation time of the dapoxetine group is prolonged to 2-3 minutes from about 1.5 minutes compared with that of a placebo group, the actual prolonged time is only 0.5-1.5 min, the medicine needs to be taken 1 hour before sexual life, and a plurality of adverse reactions such as headache, dizziness, diarrhea, insomnia, somnolence, orthostatic hypotension and the like occur to most patients in the clinical use process.

In addition, clinically, more patients suffer from the symptoms of PE and ED sexual dysfunction, and the traditional method adopts the matching of two single medicines, which can cause inconvenience in taking the medicine for the patients, and the body adverse reaction generated by dapoxetine is still obvious. There are no drugs and treatments available for treating the above two disorders simultaneously.

Disclosure of Invention

Based on the above, the invention provides a compound pharmaceutical composition for treating male diseases, which can treat premature ejaculation and penile erectile dysfunction simultaneously, further improve the treatment effect on premature ejaculation, and reduce the incidence rate of adverse reactions of organisms.

The invention is realized by the following technical scheme.

A compound pharmaceutical composition for treating male diseases comprises the following components in percentage by mass: 47 to 73 percent of icariin, 4 to 11 percent of main drug containing dapoxetine and 19 to 42 percent of auxiliary materials.

In one embodiment, the icariin has a purity of 80% or more.

In one embodiment, the dapoxetine-containing main drug is one or more selected from dapoxetine, dapoxetine hydrochloride and dapoxetine sulfate.

In one embodiment, the excipient comprises one or more of a slow release material and a lubricant.

In one embodiment, the slow release material is selected from one or more of polyacrylic resin, carbomer resin, hypromellose and hypromellose acetate succinate.

In one embodiment, the lubricant is selected from one or more of magnesium stearate, sodium fumarate stearate, glyceryl behenate and talc.

In one embodiment, the compound pharmaceutical composition is in the form of capsules, tablets or granules.

The invention also provides application of the compound pharmaceutical composition in preparing a medicine for treating male dysfunction.

In one embodiment, the male dysfunction includes male erectile dysfunction and premature ejaculation.

The invention also provides a preparation method of the compound pharmaceutical composition for treating male diseases, which comprises the following steps:

mixing the components with a solvent, and granulating; wherein the solvent is selected from one or more of water and alcohol.

Compared with the prior art, the compound pharmaceutical composition for treating male diseases has the following beneficial effects:

the icariin in the composition has the effects of tonifying kidney yang and strengthening bones and muscles, and has a synergistic effect with the main medicine containing the dapoxetine, the icariin can promote the prolongation of the ejaculation latency period by the dapoxetine, reduce the incidence of adverse reaction of the dapoxetine on organisms, and obviously enhance the treatment effect on the male premature ejaculation symptoms. Meanwhile, the compound medicine composition can also effectively treat male erectile dysfunction.

Drawings

FIG. 1 is a graph of in vitro cumulative release provided in example 1 of the present invention;

FIG. 2 is a graph of in vitro cumulative release provided in example 2 of the present invention;

FIG. 3 is a graph of in vitro cumulative release provided in example 3 of the present invention;

FIG. 4 is a graph of in vitro cumulative release provided in example 4 of the present invention;

FIG. 5 is a graph of in vitro cumulative release provided in example 5 of the present invention;

FIG. 6 is a graph of in vitro cumulative release provided in example 6 of the present invention;

FIG. 7 is a graph of in vitro cumulative release provided in example 7 of the present invention;

FIG. 8 is a graph of the in vitro cumulative release profile provided by comparative example 1 of the present invention;

FIG. 9 is a graph of the in vitro cumulative release profile provided by comparative example 2 of the present invention;

FIG. 10 is a graph of the in vitro cumulative release profile provided by comparative example 3 of the present invention;

FIG. 11 is a graph of plasma concentration in rats provided in example 4 of the present invention;

FIG. 12 is a graph showing the plasma concentration in rats according to comparative example 1 of the present invention;

FIG. 13 is a graph showing the plasma concentration in rats according to comparative example 2 of the present invention;

fig. 14 is a graph showing the plasma concentration in rats according to comparative example 3 of the present invention.

Detailed Description

To facilitate an understanding of the invention, the invention will now be described more fully with reference to the accompanying drawings. Preferred embodiments of the present invention are shown in the drawings. This invention may, however, be embodied in many different 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.

Furthermore, the terms "first", "second" and "first" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include at least one such feature. In the description of the invention, "a plurality" means at least two, e.g., two, three, etc., unless explicitly specified otherwise. In the description of the present invention, "a plurality" means at least one, e.g., one, two, etc., unless explicitly specified otherwise.

The words "preferably," "more preferably," and the like, in the present disclosure mean embodiments of the disclosure that may, in some instances, provide certain benefits. However, other embodiments may be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, nor is it intended to exclude other embodiments from the scope of the invention.

When a range of values is disclosed herein, the range is considered to be continuous and includes both the minimum and maximum values of the range, as well as each value between such minimum and maximum values. Further, when a range refers to an integer, each integer between the minimum and maximum values of the range is included. Further, when multiple range describing features or characteristics are provided, the ranges may be combined. In other words, unless otherwise indicated, all ranges disclosed herein are to be understood to encompass any and all subranges subsumed therein.

All percentages, parts and ratios are by weight of the total composition of the invention, unless otherwise specified. All mass references to listed ingredients are given as active levels unless otherwise indicated and therefore do not include solvents or by-products that may be included in commercially available materials. The term "mass percent content" herein may be represented by the symbol "%". All molecular weights herein are weight average molecular weights expressed in daltons, unless otherwise indicated. All formulations and tests herein occur at 25 ℃ environment, unless otherwise indicated. The use of "including," "comprising," "containing," "having," or other variations thereof herein, is meant to encompass the non-exclusive inclusion, as such terms are not to be construed. The term "comprising" means that other steps and ingredients can be added which do not affect the end result. The compositions and methods/processes of the present invention comprise, consist of, and consist essentially of the essential elements and limitations described herein, as well as any of the additional or optional ingredients, components, steps, or limitations described herein. The terms "potency", "performance", "effect" and "efficacy" are not distinguished from one another herein.

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 herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.

The invention provides a compound pharmaceutical composition for treating male diseases, which comprises the following components in percentage by mass: 47 to 73 percent of icariin, 4 to 11 percent of main drug containing dapoxetine and 19 to 42 percent of auxiliary material.

It is understood that, in the present invention, the chemical structure of icariin is as follows:

in one specific example, icariin is obtained by extracting dried stems and leaves of Chinese herbal medicine. More specifically, the Chinese herbal medicine is selected from Epimedium sagittatum, epimedium pubescens, epimedium wushanense, or Epimedium koreanum.

In a specific example, icariin is produced by a chemical or enzymatic artificial synthesis method.

In a specific example, the purity of icariin is 80% or more.

It is understood that in the present invention, the purity of icariin includes, but is not limited to, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98.1%, 98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%.

Preferably, icariin has a purity of 98% or more. More than 98 percent of icariin has large drug-loading rate and smaller preparation weight of unit dose, thereby being beneficial to swallowing.

In a specific example, the dapoxetine-containing principal agent is selected from one or more of dapoxetine, dapoxetine hydrochloride, and dapoxetine sulfate.

Preferably, the main drug containing dapoxetine is dapoxetine hydrochloride, namely, dapoxetine hydrochloride, and the structure of the dapoxetine hydrochloride is as follows:

it can be understood that the high-purity icariin in the invention can be directly purchased from the market, or extracted from dried stems and leaves of crude drugs such as epimedium sagittifolia, epimedium dauricum, epimedium wushanense or epimedium koreanum, or artificially synthesized by methods such as chemistry, enzyme catalysis and the like, and dapoxetine hydrochloride is an artificially synthesized chemical drug. The inventor unexpectedly finds that the icariin and the dapoxetine hydrochloride are combined to produce a synergistic effect after being used, can produce a more obvious curative effect than the icariin and the dapoxetine hydrochloride when being used alone at a lower dose, and has more stable blood concentration and better curative effect.

In one particular example, the excipient includes one or more of a slow release material and a lubricant.

The inventor finds that the icariin and dapoxetine compound composition prepared by adding the sustained-release material in the formula has better curative effect and lower adverse reaction incidence compared with the common quick-release formulation. The concrete embodiment is as follows: the dapoxetine and icariin maintain effective drug concentration in vivo for a longer time, the drug concentration is more stable than that of a common quick-release preparation, and the rapid change of the blood drug concentration in vivo of the drug is avoided, so that the incidence rate of adverse reactions and side effects is reduced.

In a specific example, the slow release material is selected from one or more of polyacrylic resin, carbomer resin, hypromellose, hyprolose and hypromellose acetate succinate.

Preferably, the slow release material is a combination of polyacrylic resin and carbomer resin; more preferably, the slow release material is a combination of polyacrylic resin and carbomer resin in a weight ratio of 2 to 1 to 5.

More specifically, the polyacrylic resin is selected from one or more of methacrylic acid-ethyl acrylate copolymer and ethyl acrylate-methyl methacrylate copolymer. Preferably, the polypropylene resin is an ethyl acrylate-methyl methacrylate (1.

More specifically, the carbomer resin is Carbopol 971P or Carbopol 974P. Preferably, the carbomer resin is Carbopol 974P.

In a particular example, the lubricant is selected from one or more of magnesium stearate, sodium stearyl fumarate, glyceryl behenate, and talc. Preferably, the lubricant is a combination of talc and glyceryl behenate, more preferably, the lubricant is glyceryl behenate.

In a specific example, the compound pharmaceutical composition is in the form of capsules, tablets or granules.

The sustained-release oral solid preparation provided by the invention is convenient to take, long in curative effect maintaining time, and taken once a day, does not need to consider when sexual behaviors occur, is more private and convenient to take, and can greatly improve the medication compliance of patients.

In a specific example, the compound pharmaceutical composition comprises the following components in percentage by mass: 47 to 73 percent of icariin, 4 to 11 percent of main drug containing dapoxetine, 18 to 41 percent of sustained release agent and 1 to 4 percent of lubricant.

The invention also provides application of the compound medicine composition in preparing a medicine for treating male dysfunction.

In one particular example, male dysfunction includes male erectile dysfunction and premature ejaculation.

More specifically, the preparation method of the compound pharmaceutical composition for treating male diseases comprises the following steps:

mixing icariin, a main drug containing dapoxetine and a sustained-release material;

adding water or ethanol water solution, and granulating by wet method;

drying the prepared wet granules at 40-60 ℃ until the moisture content is lower than 5%;

finally adding lubricant, and preparing into tablet, capsule or granule.

The compound pharmaceutical composition for treating male diseases and the preparation method thereof according to the present invention will be further described in detail with reference to the following specific examples. The starting materials used in the following examples are all commercially available products unless otherwise specified.

Example 1

The present embodiment provides a compound pharmaceutical composition, which is specifically as follows:

sieving 500g of icariin (with the purity of 98.3%) and 33.6g of dapoxetine hydrochloride with a 60-mesh sieve to remove agglomeration, placing the icariin and the dapoxetine hydrochloride into a high-shear wet granulation machine, uniformly mixing the icariin and the hydroxypropyl methylcellulose K4M, atomizing and spraying a proper amount of purified water at the stirring rotating speed of about 250rpm for granulation, starting a cutter after the granulation is finished, keeping the stirring rotating speed unchanged, continuing the granulation for 5min at the rotating speed of about 2500rpm of the cutter, transferring wet granules into a fluidized drying machine after the granulation is finished, drying the granules in hot air at the temperature of about 60 ℃ of an air inlet, and finishing the drying after the moisture of the granules is less than or equal to 5.0%. Granulating through a conical screen mesh with the size of about 1.0mm, adding 6.4g of glyceryl behenate after granulating, mixing uniformly, adopting an oval punch die with the size of 16mm multiplied by 8mm to press a tablet with the size of 0.69g, controlling the hardness to be 120-200N, and adopting a gastric-soluble film coating premix to carry out film coating.

Example 2

The embodiment provides a compound pharmaceutical composition, which comprises the following components:

300g of icariin (with the purity of 98.3%) and 33.6g of dapoxetine hydrochloride are sieved by a 60-mesh sieve to remove agglomeration, the mixture is placed in a high-shear wet granulation machine, is uniformly mixed with 100g of hydroxypropyl cellulose (with the molecular weight of about 10 ten thousand), purified water with a proper amount is atomized and sprayed at the stirring rotating speed of about 250rpm for granulation, a cutter is opened after the granulation is finished, the stirring rotating speed is kept unchanged, the granulation is continued for 5min at the rotating speed of about 2500rpm of the cutter, wet granules are transferred into a fluidized drying machine after the granulation is finished, the granules are dried in hot air at the temperature of about 60 ℃ of an air inlet, and the drying is finished after the granule moisture is less than or equal to 5.0%. Granulating through a conical screen with the diameter of about 1.0mm, adding 12g of magnesium stearate and 6g of talcum powder after granulating, uniformly mixing, adopting an oval punch die with the diameter of 16mm multiplied by 8mm to restrain 0.45g of tablets, controlling the hardness to be 120-200N, and adopting a gastric-soluble film coating premix to carry out film coating.

Example 3

625g of icariin (with the purity of 80%) and 67.2g of dapoxetine hydrochloride are sieved by a 60-mesh sieve to remove agglomeration, the mixture is placed in a high-shear wet granulation machine and uniformly mixed with 180g of carbomer 971P, an appropriate amount of purified water is atomized and sprayed at the stirring speed of about 250rpm for granulation, after the granulation is finished, a cutter is opened, the stirring speed is kept unchanged, the granulation is continued for 5min at the rotation speed of about 2500rpm of the cutter, after the granulation is finished, wet granules are transferred into a fluidized drying machine, the granules are dried in hot air at the temperature of about 60 ℃ of an air inlet, and the drying is finished after the moisture of the granules is less than or equal to 5.0%. Granulating with conical screen of about 1.0mm, adding 20g of glyceryl behenate and 10g of pulvis Talci, mixing, molding with 20mm × 10mm oval punch press to obtain 0.92g tablet, controlling hardness at 180-250N, and film coating with gastric-soluble film coating premix.

Example 4

sieving 500g of icariin (with the purity of 99.5%) and 67.2g of dapoxetine hydrochloride through a 60-mesh sieve to remove agglomeration, placing the mixture in a high-shear wet-method granulator, uniformly mixing with 150g of ethyl acrylate, methyl methacrylate (1) copolymer and 75g of carbomer 974P, atomizing and spraying a proper amount of 30% ethanol purified water solution at the stirring speed of about 250rpm to granulate, starting a cutter after the granulation is finished, keeping the stirring speed unchanged, continuing the granulation for 7min at the rotation speed of about 2500rpm of the cutter, transferring the wet granules into a fluidized drying machine after the granulation is finished, drying in hot air at the temperature of about 60 ℃ at an air inlet, and finishing the drying after the moisture of the granules is less than or equal to 5.0%. Granulating with conical screen of about 1.0mm, adding 9.8g glyceryl behenate, mixing, molding into tablet with 20mm × 10mm ellipse punch press with hardness controlled at 180-250N, and film coating with gastric-soluble film coating premix.

Example 5

sieving 500g of icariin (with the purity of 80%) and 67.2g of dapoxetine hydrochloride through a 60-mesh sieve to remove agglomeration, placing the mixture in a high-shear wet granulation machine, uniformly mixing the mixture with 300g of ethyl acrylate, methyl methacrylate (1) copolymer and 50g of carbomer 974P, atomizing and spraying a proper amount of 30% ethanol purified water solution at the stirring speed of about 250rpm to granulate, starting a cutter after the granulation is finished, keeping the stirring speed unchanged, continuing the granulation for 7min at the rotation speed of about 2500rpm of the cutter, transferring wet granules into a fluidized drying machine after the granulation is finished, drying the granules in hot air at the temperature of about 60 ℃ of an air inlet, and finishing the drying after the water content of the granules is less than or equal to 5.0%. Sieving with 1.0mm conical sieve, adding 9.8g glyceryl behenate, mixing, and packaging into aluminum plastic aluminum composite film bag (about 1.05g per bag).

Example 6

150g of icariin (with the purity of 98.3%) and 33.6g of dapoxetine hydrochloride are sieved by a 60-mesh sieve to remove agglomeration, the mixture is placed in a high-shear wet-method granulator, is uniformly mixed with 90g of ethyl acrylate, methyl methacrylate (1) copolymer and 30g of carbomer 974P, an appropriate amount of purified water is sprayed by atomization at a stirring speed of about 250rpm for granulation, a cutter is opened after the granulation is finished, the stirring speed is kept unchanged, the granulation is continued for 5min at the rotation speed of about 2500rpm of the cutter, the wet granules are transferred into a fluidized drying machine after the granulation is finished, and are dried in hot air at the temperature of about 60 ℃ in an air inlet, and the drying is finished after the moisture of the granules is less than or equal to 5.0%. And (3) finishing the granules by a conical screen with the diameter of about 1.0mm, adding 3.4g of glyceryl behenate after finishing the granules, uniformly mixing, and filling 1# hydroxypropyl methylcellulose hollow capsules, wherein each capsule is filled with about 0.3g of granules.

Example 7

sieving 500g of icariin (with the purity of 99.5%) and 33.6g of dapoxetine hydrochloride through a 60-mesh sieve to remove agglomeration, placing the mixture in a high-shear wet-method granulator, uniformly mixing with 100g of methacrylic acid, ethyl acrylate (1) copolymer and 40g of carbomer 971P, atomizing and spraying a proper amount of 30% ethanol purified water solution at the stirring speed of about 250rpm to granulate, starting a cutter after the granulation is finished, keeping the stirring speed unchanged, continuing to granulate for 7min at the rotation speed of about 2500rpm of the cutter, transferring wet granules into a fluidized drying machine after the granulation is finished, drying in hot air at the temperature of about 60 ℃ at an air inlet, and finishing the drying after the moisture of the granules is less than or equal to 5.0%. Granulating through a conical screen mesh with the size of about 1.0mm, adding 12.4g of glyceryl behenate after granulating, mixing uniformly, adopting an oval punch die with the size of 16mm multiplied by 8mm to press a tablet with the size of 0.69g, controlling the hardness to be 150-00N, and adopting a gastric-soluble film coating premix to carry out film coating.

Comparative example 1

The comparative example provides a compound pharmaceutical composition, which comprises the following components in percentage by weight:

sieving 500g of icariin (purity of 99.5%) with a 60-mesh sieve to remove agglomeration, placing the icariin in a high-shear wet-process granulator, uniformly mixing with 150g of ethyl acrylate, methyl methacrylate (1) copolymer and 75g of carbomer 974P, atomizing and spraying a proper amount of 30% ethanol purified water solution at the stirring speed of about 250rpm to granulate, starting a cutter after the granulation is finished, keeping the stirring speed unchanged, continuing granulating for 7min at the rotation speed of about 2500rpm of the cutter, transferring wet granules into a fluidized-bed dryer after the granulation is finished, drying in hot air at the temperature of about 60 ℃ of an air inlet, and finishing the drying after the moisture of the granules is less than or equal to 5.0%. Granulating through a conical screen mesh with the diameter of about 1.0mm, adding 9.8g of glyceryl behenate after granulating, mixing uniformly, adopting an oval punch die with the diameter of 20mm multiplied by 10mm to press a tablet with the diameter of 0.73g, controlling the hardness to be 180-250N, and adopting a gastric-soluble film coating premix to carry out film coating.

Comparative example 2

sieving 500g of icariin (with the purity of 99.5%) and 67.2g of dapoxetine hydrochloride with a 60-mesh sieve to remove agglomeration, placing the mixture in a high-shear wet granulation machine, uniformly mixing with 150g of microcrystalline cellulose, 75g of lactose monohydrate, 30g of povidone K30 and 35g of crospovidone XL10, atomizing and spraying a proper amount of 30% ethanol purified water solution at the stirring speed of about 250rpm to granulate, starting a cutter after the granulation is finished, keeping the stirring speed unchanged, continuing the granulation for 7min at the rotation speed of about 2500rpm of the cutter, transferring wet granules into a fluidized drying machine after the granulation is finished, drying in hot air at the temperature of about 60 ℃ of an air inlet, and finishing the drying after the moisture of the granules is less than or equal to 5.0%. Granulating through a conical screen mesh with the diameter of about 1.0mm, adding 9.8g of glyceryl behenate after granulating, mixing uniformly, adopting an oval punch die with the diameter of 20mm multiplied by 10mm to restrain 0.87g of tablets, controlling the hardness to be 180-250N, and adopting a gastric-soluble film coating premix to carry out film coating.

Comparative example 3

671.7g of dapoxetine hydrochloride was sieved through a 60 mesh sieve to remove aggregates, and mixed with 877.5g of lactose T80 monohydrate, 292.5g of microcrystalline cellulose PH102, 80g of croscarmellose sodium, 50g of colloidal silicon dioxide and 28g of magnesium stearate in a conical mixer, and subjected to film coating by using a circular punch mold with a diameter of 6.5mm and a restriction of 0.1g of tablets, the hardness of which was controlled at 60-120N, and a gastric-soluble film coating premix.

The formulations and process parameter settings for examples 1-7 and comparative examples 1-3 are shown in Table 1.

TABLE 1

Effect test

The above examples 1 to 7 and comparative examples 1 to 3 were subjected to effect verification experiments, including measurement of the release/dissolution rate and evaluation of the therapeutic effect.

(1) Method for testing release/dissolution:

a second method-paddle method which accords with the general rule of Chinese pharmacopoeia 0931 is adopted as a test device, 1000ml of phosphate buffer salt with pH6.8 and containing 1.0 percent of Tween 80 is used as a dissolution medium, and the dissolution speed is 100rpm.

And (3) chromatographic column: agilent Poroshell 120EC-C ₁₈ (4.6×150mm，4μm)，

Mobile phase: 10mM ammonium acetate (ph 5.5) -acetonitrile =50

Column temperature: 35 ℃;

sample introduction volume: 10 mu L of the solution;

flow rate: 1.0mL/min;

detection wavelength: 270nm;

operating time: 15min;

elution procedure: water phase: organic phase =50 isocratic elution.

The results of the icariin cumulative release test are shown in table 2, and the results of the dapoxetine cumulative release test are shown in table 3. The in vitro cumulative release profiles of icariin and dapoxetine determined in examples 1-7 and comparative examples 1-3 are shown in FIGS. 1-10, respectively.

Table 2 icariin cumulative release (%)

TABLE 3 cumulative Release of dapoxetine (%)

(2) SD male rats with ED and PE models weighing 300g +/-20 g are adopted, the experimental group is administrated by intragastric administration according to the icariin dosage of 52.5mg/kg and the dapoxetine dosage of 6.3mg/kg, and the treatment effect and adverse reaction incidence rate of experimental animals in the examples and the comparative examples are respectively evaluated by taking the placebo group as a control. The results of the observation of the therapeutic effect are shown in Table 4.

TABLE 4 Observation of efficacy of Single and repeated administrations

(3) In vivo blood concentration measurement

Randomly selecting 24 adult healthy male rats with the body weight of 260-320 g, carrying out single intragastric administration according to the icariin dose of 52.5mg/kg and the dapoxetine dose of 6.3mg/kg after fasting for 12 hours, and carrying out venous blood collection for 0h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 6h, 8h, 10h, 12h, 14h, 16h, 18h, 20h, 24h, 36h, 48h and 72h after administration, and after fresh blood centrifugation, taking supernate and injecting the supernate into LC/MS/MS for analysis to determine the blood concentration.

Example 4 and comparative examples 1-3 were measured for plasma drug concentration in rats, and the results are shown in FIGS. 11 to 14.

All possible combinations of the technical features of the above embodiments may not be described for the sake of brevity, but should be considered as within the scope of the present disclosure as long as there is no contradiction between the combinations of the technical features.

The above-mentioned embodiments only express several embodiments of the present invention, so as to understand the technical solutions of the present invention specifically and in detail, but not to be understood as the limitation of the protection scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. It should be understood that the technical solutions provided by the present invention, which are obtained by logical analysis, reasoning or limited experiments, are within the scope of the appended claims. Therefore, the protection scope of the present invention should be subject to the content of the appended claims, and the description and the drawings can be used for explaining the content of the claims.

Claims

1. The compound pharmaceutical composition for treating male diseases is characterized by comprising the following components in percentage by mass: 47 to 73 percent of icariin, 4 to 11 percent of main drug containing dapoxetine and 19 to 42 percent of auxiliary material.

2. The compound pharmaceutical composition for treating male diseases according to claim 1, wherein the purity of icariin is 80% or more.

3. The compound pharmaceutical composition for treating male diseases according to claim 1, wherein the main drug containing dapoxetine is one or more selected from dapoxetine, dapoxetine hydrochloride and dapoxetine sulfate.

4. The compound pharmaceutical composition for treating male diseases according to claim 1, wherein the auxiliary materials comprise one or more of sustained-release materials and lubricants.

5. The combination pharmaceutical composition for treating male diseases according to claim 4, wherein the sustained-release material is selected from one or more of polyacrylic resin, carbomer resin, hypromellose and hypromellose acetate succinate.

6. The compound pharmaceutical composition for treating male diseases according to claim 4, wherein the lubricant is one or more selected from magnesium stearate, sodium fumarate stearate, glyceryl behenate and talc.

7. The compound pharmaceutical composition for treating male diseases according to any one of claims 1 to 6, wherein the dosage form of the compound pharmaceutical composition is capsules, tablets or granules.

8. Use of a combination pharmaceutical composition according to any one of claims 1 to 7 in the manufacture of a medicament for the treatment of male sexual dysfunction.

9. The use of the combination pharmaceutical composition of claim 8 in the preparation of a medicament for the treatment of male sexual dysfunction, wherein the male sexual dysfunction comprises male erectile dysfunction and premature ejaculation.

10. A method for preparing a compound pharmaceutical composition for treating male diseases according to any one of claims 1 to 7, which comprises the following steps: