Compound preparation for treating erectile dysfunction and premature ejaculation and preparation method thereof

Abstract

The invention provides a compound preparation for treating erectile dysfunction and premature ejaculation and a preparation method thereof.The compound preparation contains a tadalafil inactive part and a fluoxetine hydrochloride active part, and the tadalafil inactive part contains a first stabilizer and a carrier; the tadalafil active part is used for preparing a solid dispersion from an active component tadalafil which is instable in absorption, and the particle size of the solid dispersion needs to be controlled; after the tadalafil active part is prepared into a solid dispersion, the solid dispersion, fluoxetine hydrochloride and auxiliary materials are prepared into a compound preparation, and the auxiliary materials comprise a filler, an adhesive, a disintegrating agent, a second stabilizer and a lubricant. The compound preparation provided by the invention can be used for treating erectile dysfunction and premature ejaculation at the same time. According to the compound preparation prepared by the preparation method provided by the invention, the problem of unstable absorption of tadalafil is reduced, the stability and dissolution rate of tadalafil are improved, the quality of the product is ensured, and the stability and safety of the product are improved.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to a compound preparation for treating erectile dysfunction and premature ejaculation and a preparation method thereof. BACKGROUND

[0002] Erectile dysfunction (ED): is the male in the sexual activity of persistent or repeated unable to achieve and / or maintain adequate penile erection to complete a satisfactory sex life. Simply put, it is "hardness not enough" or "hard not long". The key point is the "start" or "maintain" problem. Occasional erectile difficulty is normal, only persistent (usually more than 3 months) and affect sexual life is clinically significant ED. Severity: can be from mild (occasional failure) to complete inability to erection. Pathogenesis is mainly related to penile cavernosal vascular dysfunction, neural factors, endocrine factors, etc.

[0003] Premature ejaculation (PE): is the male in the sexual activity of persistent or repeated one or both of the following: primary PE: from the first sex life, always in the vagina before or after about 1 minute ejaculation. Secondary PE: past ejaculation time is normal, later significantly shortened, usually within 3 minutes after insertion. The key point is that patients are always or almost always unable to control / delay ejaculation, and therefore feel distressed, frustrated, anxious, and even avoid sex life. The core problem is "controlling ejaculation" and "time is too short". The pathogenesis is caused by a variety of reasons, including psychological factors, physiological factors, environmental factors, etc.

[0004] It should be noted that erectile dysfunction and premature ejaculation, although there are significant differences in symptoms, may actually be related to each other, especially with the increasing life pressure in recent years, many patients have erectile dysfunction (ED) and premature ejaculation (PE), which seriously affects normal life. For example, long-term erectile dysfunction may make patients more nervous and anxious during sex, thereby increasing the risk of premature ejaculation. Therefore, when treating these two diseases, the overall health status of the patient often needs to be considered, and appropriate psychological and physical treatment methods are adopted.

[0005] The treatment methods for erectile dysfunction and premature ejaculation include drug therapy, lifestyle adjustment, and psychological treatment. Drug therapy is one of the important means for erectile dysfunction combined with premature ejaculation. Commonly used drugs include phosphodiesterase-5 inhibitors, 5-hydroxytryptamine reuptake inhibitors, etc. These drugs can improve blood supply and nerve conduction, prolong erection time and delay ejaculation time. Clinically commonly used drugs include sildenafil citrate tablets and dapoxetine hydrochloride tablets. Sildenafil citrate tablets are mainly used for the treatment of erectile dysfunction, while dapoxetine hydrochloride tablets are mainly used for the treatment of premature ejaculation.

[0006] At present, the treatment of ED and PE in clinic is often fragmented. The commercially available tadalafil preparation is tablet, which is poorly absorbed after oral administration and is mainly used for the treatment of erectile dysfunction (ED). There is no good treatment drug for premature ejaculation (PE) at present.

[0007] Therefore, there is an urgent need for a new preparation capable of treating erectile dysfunction and premature ejaculation. SUMMARY

[0008] To solve the above problems, the present application provides a compound preparation for treating erectile dysfunction and premature ejaculation and a preparation method thereof. The compound preparation prepared by the method contains tadalafil and fluoxetine hydrochloride active ingredients, which reduces the problem of unstable absorption of tadalafil.

[0009] In one aspect, the present application discloses a compound preparation for treating erectile dysfunction and premature ejaculation. The compound preparation contains a tadalafil active part and a fluoxetine hydrochloride active part. The tadalafil active part contains a first stabilizer and a carrier. The tadalafil active part is prepared into a solid dispersion of the unstable active ingredient tadalafil, and the particle size of the solid dispersion needs to be controlled. After the tadalafil active part is prepared into a solid dispersion, it is prepared into a compound preparation together with fluoxetine hydrochloride and excipients. The excipients include a filler, a binder, a disintegrant, a second stabilizer and a lubricant.

[0010] Preferably, the first stabilizer is one or more of glyceryl triethylhexadecyl sulfate, sodium dodecyl sulfate, triethyl citrate, and vegetable oil.

[0011] Preferably, the carrier is one or more of PEG, citric acid, sugar, polyvinylpyrrolidone, acrylic resin No. IV, cellulose acetate phthalate, and hydroxypropyl methyl cellulose phthalate.

[0012] Preferably, the lubricant is one or more of magnesium stearate, calcium stearate, stearic acid, talc, silicon dioxide, and polyethylene glycol.

[0013] Preferably, the filler includes one or more of microcrystalline cellulose colloidal silicon dioxide co-treatment, mannitol microcrystalline cellulose co-treatment, lactose, low-iron calcium carbonate, mannitol, sorbitol, starch hydrolysis oligosaccharide, and pregelatinized starch.

[0014] Preferably, the second stabilizer includes one or more of gentisic acid, poloxamer, meglumine, BHT, dodecyl-beta-D-maltoside, betacyclodextrin.

[0015] Preferably, the disintegrant includes one or more of cross-linked sodium carboxymethyl cellulose, cross-linked povidone, and sodium carboxymethyl starch.

[0016] Preferably, the binding agent comprises one or more of hydroxypropyl cellulose, povidone K30, hydroxypropyl methyl cellulose.

[0017] Preferably, the compound preparation is a double-layer tablet, a compound granule, a compound dry suspension or a compound capsule.

[0018] In another aspect, the application also discloses a preparation method of the compound preparation, which comprises the following steps: S1, stirring the carrier, tadalafil and the first stabilizer until they are uniformly mixed, then transferring them to a suitable container and slowly heating or dissolving them, and stirring until a uniform state is formed, and then waiting; S2, quickly pouring the molten semi-solid onto a clean stainless steel plate, spreading it into a thin sheet, and naturally quenching it into a solid; using a pulverizer to pulverize the solid at least once, collecting the material, and controlling the particle size distribution of the material: D90: 300-400 μm; D50: 200-300 μm; D10: 80-150 μm, thereby obtaining a solid dispersion; S3, mixing the solid dispersion with fluoxetine hydrochloride, a filler, a binding agent, a disintegrant, a stabilizer and a lubricant for 10-20 min, and then using a suitable device to prepare a double-layer tablet, a compound granule, a compound dry suspension or a compound capsule.

[0019] Compared with the prior art, the application has the following beneficial effects: The compound preparation provided by the application contains active ingredients of tadalafil and fluoxetine hydrochloride, and can treat erectile dysfunction and premature ejaculation.

[0020] The compound preparation prepared by the preparation method provided by the application reduces the problem of unstable absorption of tadalafil, improves the stability and dissolution of tadalafil, ensures the quality of the product, and improves the stability and safety of the product. DETAILED DESCRIPTION

[0021] The technical solutions of the application will be described clearly and completely below with reference to the embodiments. Obviously, the described embodiments are only part of the embodiments of the application, rather than all the embodiments.

[0022] Embodiment 1 The compound preparation provided by this embodiment is a double-layer tablet, and a preparation method of the double-layer tablet is also provided.

[0023] The prescription of the double-layer tablet is as follows: The preparation method of the double-layer tablet is as follows: S1. Add PEG6000, tadalafil, triethyl glycerol, and sodium lauryl sulfate to a mixer and stir until well mixed. Then transfer to a suitable container and heat slowly while stirring until a homogeneous state is formed. Set aside for use. S2. Quickly pour the molten semi-solid onto a clean stainless steel plate, spread it into a thin sheet, and allow it to cool naturally into a solid. Use a hammer mill to initially crush the solid at a feeding rate of 30% and a rotation speed of 400 rpm. Then, use a hammer mill to further crush the solid (1.3 mm; 0.6 mm screen) at a rotation speed of 4000 rpm. Collect the material and control the particle size distribution as follows: D90: 300 μm - 400 μm; D50: 200 μm - 300 μm; D10: 80 μm - 150 μm, thus obtaining a solid dispersion. S3. Fluoxetine hydrochloride, dodecyl-β-D-maltodextrin, mannitol microcrystalline cellulose co-treatment product, BHT, lactose, and hydroxypropyl methylcellulose phthalate are added to a mixer and mixed for 10-20 minutes. Then, povidone K30 ethanol solution is added, granulated, dried, and sized. Cross-linked povidone is then added and mixed evenly. Finally, magnesium stearate is added and mixed evenly. After mixing the solid dispersion with the aforementioned materials for 10-20 minutes, compound bilayer tablets are prepared using a bilayer tableting machine.

[0024] Example 2 The compound preparation provided in this embodiment is a capsule, and a method for preparing the capsule is also provided.

[0025] The prescription for capsules is as follows: Preparation method of capsules: S1. Add cellulose acetate phthalate, tadalafil, triethyl glycerol and sodium lauryl sulfate to a mixer and stir until well mixed. Then transfer to a suitable container and heat slowly while stirring until a homogeneous state is formed. Set aside for use. S2. Quickly pour the molten semi-solid onto a clean stainless steel plate, spread it into a thin sheet, and allow it to cool naturally into a solid. Use a hammer mill to initially crush the solid at a feeding rate of 30% and a rotation speed of 400 rpm. Then, use a hammer mill to further crush the solid (1.3 mm; 0.6 mm screen) at a rotation speed of 4000 rpm. Collect the material and control the particle size distribution as follows: D90: 300 μm - 400 μm; D50: 200 μm - 300 μm; D10: 80 μm - 150 μm, thus obtaining a solid dispersion. S3, fluoxetine hydrochloride, dodecyl-beta-D-maltoside, microcrystalline cellulose colloidal silicon dioxide co-treatment, poloxamer, lactose, hydroxypropyl methyl cellulose phthalate, into the mixer mixed 10-20 min, then add povidone K30 ethanol solution, granulation, drying, whole grain; then add cross-linked povidone, mix well, then add magnesium stearate, mix well; The solid dispersion is mixed with the foregoing materials to be uniform, and a capsule filling machine is used to prepare the capsules.

[0026] Example 3 The compound preparation provided in this example is a compound granule, and a preparation method of the compound granule is also provided.

[0027] The prescription of the compound granule is as follows: The preparation method of the compound granule is as follows: S1, add cellulose acetate phthalate, tadalafil, glyceryl triethylhexanododecyl sulfate into the mixer and stir until mixed uniformly, then transfer to a suitable container and slowly heat and stir until uniform; S2, quickly pour the molten semi-solid onto a clean stainless steel plate and spread it into a thin sheet, and then naturally quench it into a solid; use a hammer stone crusher to preliminarily crush the solid, feeding speed: 30%, rotating speed: 400 rpm, crushing rate: 30%, then use a hammer crusher for secondary crushing (1.3 mm; 0.6 mm screen), rotating speed: 4000 rpm, collect the material, and control the particle size distribution of the material: D90: 300 μm - 400 μm; D50: 200 μm - 300 μm; D10: 80 μm - 150 μm, to obtain the solid dispersion; S3, fluoxetine hydrochloride, dodecyl-beta-D-maltoside, microcrystalline cellulose colloidal silicon dioxide co-treatment, poloxamer, lactose, hydroxypropyl methyl cellulose phthalate, into the mixer mixed 10-20 min, then add povidone K30 ethanol solution, granulation, drying, whole grain; then add cross-linked povidone, mix well, then add magnesium stearate, mix well; The solid dispersion is mixed with the foregoing materials to be uniform, and a capsule filling machine is used to prepare the capsules.

[0028] Test Example 1: Stability Test - Accelerated Test Example 1 (Example 1), Example 2 (Example 2) and Example 3 (Example 3) are respectively placed at 40℃±2℃, 75%RH±5%RH, and sampled at 3M and 6M to determine the related substances and content, and the results are shown in Table 1.

[0029] Table 1 Test Example 2: Experimental study on the treatment of erectile dysfunction rats Animal grouping and modeling Forty adult Wistar male rats weighing 240-270 g and twenty female rats weighing 210-240 g were used. The male rats were randomly divided into four groups: Example 1 group, Example 2 group, blank group, and model group.

[0030] The female rats were used for pairing to observe the sexual activity of the male rats in a natural state. After the ordinary feed was fed, the ED model was made by the chronic stress restraint method using a restraint cylinder. The restraint cylinder was made of plastic and was tubular with an inner diameter of 5-6 cm at the cylinder opening, a length of about 20 cm, a ventilation opening at the front end of the cylinder, a gate at the rear end, and a medical cotton ball plugged at the rear end to adjust the restraint strength. The model rats were fixed in the above restraint cylinder, and the restraint time was 180 minutes on the first day, and then increased by 10 minutes every day. The amount of cotton ball was increased to increase the restraint strength, and the tolerance of the rats to stress was eliminated by increasing the restraint strength and time. On the 31st day of modeling, the restraint time was 480 minutes, and then the time and strength were maintained, and the modeling time was 8 weeks. The blank group was not treated.

[0031] Example 1 group and Example 2 group were administered with Example 1 and 2 of the present application by gavage on the second day, and the dose was calculated according to the human and animal conversion. The other two groups were administered with water by gavage at the corresponding dose at the same time. The normal group and the model group were fed under the same conditions.

[0032] Detection index and method (1) Sexual activity detection: On the 38th-45th day of modeling, the male rats were caged with different female rats in the group for a total of 3 hours every day to restore their sexual activity. On the 46th-55th day of modeling, each male rat was caged with different female rats in the group for multiple times within 10 days, each time for 30 minutes, and each time with one female rat. The number of sniffing and licking, the number of climbing back, the first climbing back time, and the cumulative climbing back time were observed. The best sexual activity indicators of the rats were selected for recording, and the specific detection table 1 was shown.

[0033] (2) Body weight detection: The body weight at the beginning of modeling on the first day and the body weight at the end of modeling on the 56th day were recorded, and the body weight difference between the two groups before and after the experiment was compared.

[0034] (3) Testicular weight detection: The rat testis was taken out for accurate separation of the associated tissues, and the weight was recorded.

[0035] The activity detection data is shown in Table 2.

[0036] Table 2: Activity detection data statistics ±s ​ Note: compared with the blank group, *P<0.05; compared with the blank group, ##P<0.01; compared with the model group, *P<0.05.

[0037] Sexual activity Sexual activity detection is shown in Table 1. The sniffing and licking times of the treatment group and the model group were significantly different from those of the blank group (P<0.05). The first back climbing time of the Example 1 group and the Example 2 group was extremely significantly different from that of the blank group (P<0.01). The cumulative back climbing time of the Example 1 group and the Example 2 group was significantly different from that of the model group (P<0.05). The cumulative back climbing time of the model group was extremely significantly different from that of the blank group (P<0.01). The cumulative back climbing time of the treatment group was not significantly different from that of the blank group (P>0.05).

[0038] Body weight The body weight difference of the blank group and the Example 1 group, the Example 2 group and the model group was extremely significantly different (P<0.01), and is shown in Table 3 below.

[0039] Table 3: Comparison of body weight difference ±s Note: compared with the blank group, **P<0.01 The testicular weight comparison results are shown in Table 4 below.

[0040] Table 4: Comparison of testicular weight ±s Note: there was no significant difference between the blank group and the example and model groups (P>0.05) Test Example 3: Experimental study on the treatment of premature ejaculation in rats Animal grouping and modeling: 360 Wistar male rats (36 rats screened for premature ejaculation) and 45 female rats were prepared.

[0041] According to the theory of premature ejaculation model preparation, the number of ejaculations conforms to the normal distribution. Based on the law that the number of ejaculations conforms to the normal distribution, a m 10% fast ejaculation group (4-5 times of ejaculation within 30 min) was selected as the premature ejaculation model rats through sexual behavior observation of Wistar rats.

[0042] Female rat preparation: Wistar female rats were selected. Considering that the survival rate of ovariectomized female rats is about 80%, 45 female rats were selected. Under anesthesia, bilateral ovariectomy was performed, and ampicillin sodium was injected intramuscularly after the operation to prevent infection for 3 consecutive days; mating test was performed 2 weeks after ovariectomy. 48 h before the test, estradiol benzoate was injected subcutaneously, and progesterone was injected again 4 h before the test. Vaginal secretion smears were taken with a cotton swab soaked in normal saline, and estrous female rats were selected for standby.

[0043] The female rats are castrated and hormone estrus induced, and the camera definition is adjusted for standby. The screened premature ejaculation model male rats are placed in the behavior observation cage under the illumination of dim red light, and after 5 min of adaptation, the estrus female rats are placed in the cage, and the mating behavior of the rats within 30 min is observed and recorded. The behavioral indexes during mating are observed and recorded: mount latency (ML), intromission latency (IL), ejaculation latency (EL), mount frequency (MF), intromission frequency (IF) and ejaculation frequency (EF).

[0044] Sexual behavior observation, and the indexes during mating are observed and recorded, as shown in Table 5.

[0045] Mount latency (ML): the time from the start of the experiment to the first time of the male rat mounting the female rat (whether or not there is vaginal insertion); Intromission latency (IL): the time from the start of the test to the first time of the male rat inserting the vagina; Ejaculation latency (EL): the time from the first insertion of the male rat to ejaculation; Mount frequency (MF): the number of times of mounting behavior of the male rat before the first ejaculation; Intromission frequency (IF): the number of times of insertion of the male rat before ejaculation; Ejaculation frequency (EF): the total number of ejaculations of the male rat during the 30 min mating experiment.

[0046] Table 5: Comparison of sexual behaviors of rats in each group ±s Note: *P<0.05, **P<0.01 compared with the blank group; &P<0.05, &&P<0.01 compared with the model group.

[0047] In summary, the compound preparation provided by the present application contains the active ingredients of tadalafil and fluoxetine hydrochloride, and can treat erectile dysfunction and premature ejaculation.

[0048] The compound preparation prepared by the preparation method provided by the application reduces the problem of unstable absorption of tadalafil, improves the stability and dissolution of tadalafil, ensures the quality of the product, and improves the stability and safety of the product.

[0049] The above series of detailed descriptions are only specific descriptions of the feasible implementation manners of the application, and are not used to limit the protection scope of the application, and equivalent implementation manners or changes made without departing from the spirit of the application should be included in the protection scope of the application.

[0050] It is obvious for those skilled in the art that the application is not limited to the details of the above exemplary embodiments, and the application can be implemented in other specific forms without departing from the spirit or essential characteristics of the application. Therefore, the embodiments should be regarded as exemplary and non-limiting, the scope of the application is defined by the appended claims rather than the above description, and all changes falling within the meaning and scope of the equivalent elements of the claims are intended to be included in the application.

[0051] In addition, it should be understood that although the present specification is described in terms of embodiments, not every embodiment contains only one independent technical solution, and the description manner of the specification is only for clarity, those skilled in the art should regard the specification as a whole, and the technical solutions in each embodiment can also be properly combined to form other implementation forms which can be understood by those skilled in the art.

Claims

1. A compound preparation for treating erectile dysfunction and premature ejaculation, characterized in that, The compound preparation contains tadalafil active part and fluoxetine hydrochloride active part, the tadalafil active part contains first stabilizer and carrier, the tadalafil active part is prepared into solid dispersion for the active ingredient tadalafil which is unstable in absorption, and the particle size of the solid dispersion needs to be controlled; the tadalafil active part is prepared into solid dispersion, and then is prepared into compound preparation with fluoxetine hydrochloride and auxiliary materials, the auxiliary materials include filling agent, binding agent, disintegrating agent, second stabilizer and lubricant. ​ 2. The complex preparation according to claim 1, characterized in that, The first stabilizer is one or more of glyceryl triethyl citrate, sodium lauryl sulfate, triethyl citrate, vegetable oil.

3. The complex preparation according to claim 2, characterized in that, The carrier is one or more of PEG, citric acid, sugar, polyvinyl pyrrolidone, acrylic resin IV, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate.

4. The complex preparation according to claim 3, characterized in that, The lubricant is one or more of magnesium stearate, calcium stearate, stearic acid, talc, silicon dioxide, polyethylene glycol.

5. The complex preparation according to claim 4, characterized in that, The filling agent includes one or more of microcrystalline cellulose colloidal silicon dioxide co-treatment, mannitol microcrystalline cellulose co-treatment, lactose, low-iron calcium carbonate, mannitol, sorbitol, starch hydrolysis oligosaccharide and pregelatinized starch.

6. The complex preparation according to claim 5, characterized in that, The second stabilizer includes one or more of gentisic acid, poloxamer, meglumine, BHT, dodecyl-β-D-maltoside, betadex.

7. The complex preparation according to claim 6, characterized in that, The disintegrating agent includes one or more of cross-linked sodium carboxymethyl cellulose, cross-linked povidone and sodium carboxymethyl starch.

8. The complex preparation according to claim 7, characterized in that, The binding agent includes one or more of hydroxypropyl cellulose, povidone K30, hydroxypropyl methyl cellulose.

9. The complex preparation according to claim 8, characterized in that, The compound preparation is double-layer tablet, compound granules, compound dry suspension or compound capsule.

10. The method of claim 1-9, wherein the preparation method is characterized in that, The method includes the following steps: S1, stirring the carrier, tadalafil and first stabilizer until they are uniformly mixed, then transferring them into a suitable container and slowly heating or dissolving them, and stirring until a uniform state is formed, and then waiting; S2, quickly pouring the molten semi-solid on a clean stainless steel plate, spreading it into a thin sheet, and naturally quenching it into a solid; using a pulverizer to pulverize the solid at least once, collecting the material, and controlling the particle size distribution of the material: D90: 300-400 μm; D50: 200-300 μm; D10: 80-150 μm, to obtain the solid dispersion; S3, mixing the solid dispersion with fluoxetine hydrochloride, filling agent, binding agent, disintegrating agent, stabilizer and lubricant for 10-20 min, and then using a suitable device to prepare double-layer tablet, compound granules, compound dry suspension or compound capsule.

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