WO2000078760A1 - Process for preparing sildenafil, and troche which comprises sildenafil and apomorphine - Google Patents

Abstract

The invention relates to a process for the preparation of sildenafil, a troche which comprises sildenafil and apomorphine and its production. The process according the invention comprises the reaction of an acylchloride and an ammonium salt, neutralize, wash etc. The troche according to the invention comprises apomorphine hydrochloride and sildenafil citrate. The troche is produced by inclusion with cyclodextrin, lipoid or cellulase, and mixing with auxiliary.

Description

 FIELD OF THE INVENTION The present invention relates to a method for preparing sildenafil, a bulk drug for treating sexual dysfunction, and sildenafil and hydrochloric acid. Apomorphine compound oral tablet preparation (hereinafter referred to as apoxidi) and a preparation method thereof, and more specifically, the present invention relates to the preparation of sildenafil by reacting a compound containing a sulfonyl chloride group with piperazine ammonium salt. Sildenafil citrate (also known as sildenafil citrate) and apomorphine hydrochloride are used to form a compound oral tablet preparation and a method for preparing such a compound oral tablet preparation belongs to the field of medicine. Background technique

The chemical name of Sildenafil (SILD): 5- [2-ethoxy-5- (4-methylpiperazine-1-sulfonyl) phenyl] -1-methyl-3 -N-propyl-1, 6-dihydro-7H-pyrazolo [4, 3-d] pyrimidin-7-one, the chemical structure is shown in the structural formula (I), the compound can selectively inhibit cGMP PDE without inhibiting cM! P PDE, an early drug for the treatment of cardiovascular diseases, was previously disclosed in EP-A-0463756. In recent years, studies have found that sildenafil citrate (CSILD) has a clinical effect in treating male erectile dysfunction, see WO-A- 94/28902 and CN1124926A; its mechanism of action is through the type 5 phosphodiesterase ( Highly selective inhibition of PDE ₅ ), increase the level of cyclic guanylic acid (cGMP), enhance the effect of NO released by the penis, relax the smooth muscle of the cavernous body, increase blood flow to the penis and erect, and its preparation is called hiebone or Viagra .

盐酸阿扑吗啡 (简写为 AP0)是一个临床上使用了多年的老药。 它是一种多巴胺受体兴 奋剂， 由于它兴奋延髓呕吐中枢的作用， 长期以来以皮下注射途径给药， 用来催吐、 抢救 中毒病人。 60 年代开始发现它能诱发阴茎勃起， 在性刺激时能刺激多巴胺受体， 增加大脑 到勃起组织的神经电脉冲， 经脊髓传递， 通过阴部神经， 使阴茎释放 NO, 增加阴茎的血流 量， 引发男性阴茎勃起， 改善糖尿病， 帕金森氏症以及心理障碍所致的性功能障碍症， 然陆续进行了一些研究， 但因其存在： A) 化学性质极不稳定、 遇光、 湿和仝'气极易分解： B ) 胃肠给药因肝脏 "首过"代谢， 口服基本无效； C ) 由于其激活大脑多巴胺受体， 兴奋 呕吐中枢， 引起恶心、 呕吐； D) 味道极苦等问题， 限制了其口服药用。 Structural formula (I)

Apomorphine hydrochloride (AP0 for short) is an old medicine that has been used clinically for many years. It is a dopamine receptor stimulant. Because of its excitatory role in the medulla oblongata center, it has been administered by subcutaneous injection for a long time to induce vomiting and rescue poisoned patients. It was found in the 1960s that it can induce penile erections, stimulate dopamine receptors during sexual stimulation, increase the electrical nerve impulses from the brain to the erectile tissues, and transmit through the spinal cord through the genital nerves to release NO from the penis and increase blood flow to the penis. Male penile erections, improvement of diabetes, Parkinson's disease and sexual dysfunction caused by psychological disorders, some studies have been carried out, but because of their existence: A) extremely unstable chemical properties, exposure to light, humidity and the same Qi Easily broken down: B) Gastrointestinal administration is basically ineffective due to "first pass" metabolism of the liver; C) Because it activates the brain's dopamine receptors, excites the vomiting center and causes nausea and vomiting; D) Extremely bitter taste and other problems, restrictions Has its oral medicinal properties.

The physical and chemical properties of sildenafil citrate are relatively stable. The oral bioavailability is about 40%. The dosage of oral tablets is 25-100mg / person (70kg) based on the amount of sildenafil, which is equivalent to that of sildenafil citrate. When the calculated dose of dinafil is 34.5 to 138 mg / person (70kg), it has the advantages of accurate curative effect and convenient oral administration, but there are also some problems, such as slow onset, usually only after 1-2 hours, and Taking ffl with nitrate drugs together will severely lower blood pressure; ffl with head hernia, flushing, and indigestion; ffl may also have visual disturbances such as diplopia, blue vision, amblyopia, and spot edema. CN1057464A and CN1168376A disclose methods for preparing sildenafil and its derivatives. Among them, the sildenafil derivative (IV) is prepared by reacting a compound having the general formula (II) with an excess of (III) in CN1057464A; by using this method, a series of derivatives of the compound (IV) can be obtained in a yield 21—88%, see reaction formula 1, when compound (IV) is specifically reaction 1

The yield of Compound (I) was 88%.

 In CN1168376A, the following reaction formula 2 is used to prepare the compound (I).

 Reaction 2

上述反应的关键步骤是结构式（V )化合物的关环反应。 环化反应的收率可以达到 95 %， 总收率可以达到 51. 7%或 47. 8%,在适当的条件下，得到的产物不需要进一步的纯化处理。 发明目的 本发明的目的在于公开一种新的合成西地那非的方法，该方法较现有的方法更为简单， 且反应后无需后处理可以直接得到符合药 ffl产品。

The key step of the above reaction is the ring-closure reaction of the compound of structural formula (V). The yield of the cyclization reaction can reach 95%, and the total yield can reach 51.7% or 47.8%. Under appropriate conditions, the product obtained does not require further purification treatment. OBJECTS OF THE INVENTION The object of the present invention is to disclose a new method for synthesizing sildenafil. The method is simpler than the existing methods, and after the reaction, the product can be directly obtained without the need for post-treatment.

 Another object of the present invention is to provide a buccal tablet containing didenafil citrate and apomorphine hydrochloride, which is hereinafter referred to as apsidil (APSD) by oral mucosal route, avoiding liver The "first pass" metabolism of morphine, and by controlling the content time of buccal tablets, it can be absorbed in a balanced manner, reducing or eliminating the feeling of nausea, vomiting and lowering blood pressure; and even in the case of less dosage, Compared with the two places of phenafil alone, W has stronger drug efficacy and better treatment effect, and enables patients with sexual dysfunction to obtain more effective and satisfactory treatment.

 According to yet another S of the present invention, a method for preparing a buccal tablet of a combination preparation of two dinafil citrate and apomorphine hydrochloride is provided in the T. The method adopts a cyclodextrin, liposome or cellulose process, Including apomorphine hydrochloride and denafil citrate separately or in combination with apomorphine hydrochloride and denafil, the formed inclusion compound can be made into buccal tablets, which can improve the apomorphine hydrochloride. Stability, anti-oxidation, anti-decomposition, eliminate the mutual interference between the two main drugs, can hide the bitter taste of the drug, and reduce side effects. Joke

 In the prior art, compounds containing acyl halide groups can be reacted with amines to form sulfonamide-containing compounds. However, it is generally considered that it is very difficult to react compounds containing acyl halides to form sulfonamide compounds. The reaction to form sulfonamide has not been reported so far.

 The inventors of this patent have unexpectedly discovered that the acyl halide can be reacted with a hinge salt to obtain a sulfonamide compound. Under appropriate conditions, the reaction is easier to perform. The obtained product can be purified to obtain a pure sulfonamide compound after neutralization and water washing treatment. . Specifically, the compound of the formula (VI) is reacted with various salts of 1-methylpiperazine, that is, the compound of the formula (VB), and the salt obtained after the reaction! I. Structure with VI, you only need to be neutralized and washed, and you can get Sildenafil that meets the pharmaceutical standards. The purity is 98%. In some cases, you need to recrystallize without With other post-treatments, the reaction yield is high.

Apomorphine hydrochloride mainly acts on the human brain and nerve center, stimulates dopamine receptors, and passes through the genital nerves to congest penile blood vessels; sildenafil citrate acts as a peripheral blood vessel to congest the cavernous body to achieve Yin erection. According to the pharmacodynamic characteristics of the two, in theory, when the two are combined, apomorphine hydrochloride plays a role in the human brain and nerve center. The drug has a fast acting tablet, a fast acting effect, and citrate. Dinafil is mainly used in peripheral blood vessels and has a long-lasting effect, so it can enhance the efficacy after compounding. However, if the combination of sildenafil citrate and apomorphine hydrochloride is only two kinds, Knowing the simple superposition of drugs, the present invention has no great significance. The researchers of the present invention mainly explored a compound preparation made of a mixture of sildenafil citrate and apomorphine hydrochloride in adults to reduce siliceous citrate In the case of phenafil, it can reduce by-products, overcome the slow onset of sildenafil citrate (the negative psychological effects of slow onset are obvious in sexual behavior), and improve the drug at the same time. In terms of effectiveness, the process for preparing compound buccal tablets according to the present invention can overcome the unpleasant taste of apomorphine hydrochloride; the researchers of the present invention determined the amount of the human body that can be accepted and its effect through the fire test. And found that sildenafil citrate compound preparation and mixing apomorphine hydrochloride formed, its efficacy is much higher than both the superposition effect. BRIEF DESCRIPTION OF THE DRAWINGS

 The present invention is described in more detail below with reference to the drawings and specific embodiments, and the description of the drawings is as follows:

 FIG. 1 is a 1H-NMR spectrum of sildenafil of the present invention;

 2 is a 13C-NMR spectrum chart of sildenafil citrate according to the present invention;

 3 is a mass spectrum of sildenafil citrate of the present invention;

 4 is an HPLC spectrum of sildenafil citrate according to the present invention;

 Figure 5 is the DTA spectrum of β-cyclodextrin;

 Figure 6 is the DTA spectrum of apomorphine hydrochloride;

 Figure 7 is a DTA spectrum of stearic acid;

 8 is the DTA spectrum of a mixture of apomorphine hydrochloride and stearic acid;

 M 9 is the DTA spectrum of apomorphine hydrochloride after cyclodextrin inclusion;

 10 is an optical microscope photograph of apomorphine hydrochloride;

 m 11 is an optical microscope photograph of e-cyclodextrin;

 m 12 is a photomicrograph of stearic acid;

 13 is an optical microscope photograph of apomorphine hydrochloride, β-cyclodextrin and stearic acid mixture; detailed description

The following is a detailed description of the sildenafil preparation process. In one embodiment of the present invention, a compound of formula (VI) can be reacted with a 1-methylpiperazine hinge salt compound of formula (W) to form sildenafil Non-salt compound 01); and the reaction is easy to proceed at room temperature. The reaction takes 1 to 8 hours to generate a salt of the two dinafin compound with the structure 1. The mixture is diluted with water, and the pH value is adjusted with an alkaline solution to make the structural formula (I). Sildenafil compounds exist in free form, and the purity can reach or exceed 98%, and the yield is about 79-95%. In short, the above reaction products only need to be neutralized and washed, and no longer need to be separated by chromatography. Other post-treatments can obtain pure products that meet clinical quality standards. The reaction is shown in reaction 3, where Υ and Φ are reverse ionization Υ, Υ can be F―, CI--, Br―, Γ; Φ can be M ² -to M―, that is, a single salt or a double salt.

 The 1-methylpiperazine salt compound may be selected from the group consisting of 1-methylpiperazine hydrochloride, hydrobromide, hydrofluorate, hydroiodate, sulfate, sulfite, nitrate, phosphate Other inorganic salts, C1- 8 acid organic salts, double salts or double salts, and the preferred 1-methylpiperazine salts are selected from the hydrochloride hydrochloride.

 Suitable solvents in reaction 3 may be selected from C1-C6 alcohols, 1,2-dimethoxyacetamidine, 1,2-monoethoxyethane, dimethylsulfoxide, dimethylformamide, dimethyl Acetylacetamide, N-methylpyrrolidone, preferred solvents are ethanol, 2-propanol and dimethylformamide.

 The alkali solution in the neutralization reaction is selected from inorganic bases such as potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, and sodium bicarbonate, or organic bases such as methylamine, ammonia, and pyridine. The preferred alkali solutions are sodium hydroxide and carbonic acid. Sodium, ammonia and pyridine, most preferred are sodium hydroxide and sodium carbonate.

 It is particularly preferred that the 1-methylpiperazine salt compound is 1-methylpiperazine monohydrochloride, the solvent is ethanol, and the alkaline solution is a sodium hydroxide solution.

 It is obvious to those skilled in the art that sildenafil citrate prepared by the method of the present invention can be obtained by any method in the prior art.

Obviously, compared with the preparation method of sildenafil disclosed in the prior art, the present invention uses an acid chloride to directly react with a hinge salt, and the reaction is performed in a shorter time, the reaction is easy, the product does not need to be purified, and the yield is high; and Can be obtained for direct medicinal use

Reaction 3

For sildenafil, the method of the present invention is more convenient and effective than the prior art.

 Since apomorphine hydrochloride is easily oxidized to green in the air or sunlight, the oral bioavailability is less than 4%. In order to improve the stability of apomorphine hydrochloride, overcome the first-pass effect of the liver, improve bioavailability, reduce bitterness, To reduce side effects, the present invention firstly encapsulates apomorphine hydrochloride with cyclodextrin, liposomes, or cellulose to form an oral tablet. By inclusion, the stability of apomorphine hydrochloride can be improved, and the apomorphine hydrochloride can be masked. Very strong bitterness, and the drug is evenly absorbed in the oral mucosa, which can reduce the side effects of nausea and blood pressure.

 Accordingly, in one embodiment of the present invention, cyclodextrin is selected as the inclusion agent, because cyclodextrin has the characteristics of molecular micro-reward, and the three-dimensional structure is a ring-shaped hollow cylindrical shape with narrow upper and lower ends, The exterior and entrance are hydrophilic and the interior is hydrophobic. It can accommodate molecules or groups of other hydrophobic substances of suitable shape and size to be embedded in their voids to form clathrates. Apomorphine hydrochloride and sildenafil citrate are guest molecules, and the respective organic parts can enter the cyclodextrin molecule or be connected by hydrogen bonds to protect the guest molecules. Therefore, light and air can reduce apomorphine hydrochloride. The effect of morphine increases its stability and can mask the bitterness of the two main drugs. At the same time, because the main medicine is contained in a cylinder of cyclodextrin, under the action of oral saliva and enzymes, the tablets are gradually contained, which can make the main medicine absorbed through the oral mucosa in a balanced manner, which reduces apoxidi nausea and lowers blood pressure. Side effects, avoid first-pass effects of the liver, and improve the bioavailability of the drug.

The above cyclopaste is selected from one or more combinations of the following groups:. _Cyclodextrin (. ^^), β-cyclodextrin (β-CD), Y-cyclodextrin (γ-CD), hydroxypropyl-β_cyclodextrin (HP-β-CD), B Cyclodextrin (E-β-CD), dimethyl-β-cyclodextrin (DM-β-CD), trimethyl-β-cyclodextrin (TM-β-CD), monoglycosyl- β-cyclodextrin (Gi. P-CD), diglycosyl-β-cyclodextrin (G _2. β- CD), maltotriosyl-β-cyclodextrin (G _{: i} . β-CD) , Dimonoglycosyl-β-cyclodextrin (2G ,. β- CD), dibisglycosyl- β-cyclodextrin (2G ,. β- CD).

 The cyclodextrin-encapsulated apoxidi oral preparation of the present invention further contains a wetting and thickening agent, an acidic medium, a lubricant, a flavoring agent, a filler, a coloring agent, and a preservative.

Wherein the wetting tackifier is selected from hypromellose, ethyl methyl cellulose, ethyl cellulose, poly alpha-hydroxyethyl methacrylate, povidone, polyvinyl acetate, cellulose acetate, gelatin , Dextrin, white dextrin, microcrystalline cellulose, formazan Cellulose, methyl acrylate, acrylic resins I-IV, hydroxyethyl methyl cellulose, hydroxy ethyl cellulose, carbomer, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose More than one combination.

 The acidic medium may be selected from one or a combination of stearic acid, palmitic acid, palmitic acid, ascorbic acid, and the like.

 The lubricant may be one or more combinations of organic and inorganic salts such as magnesium stearate and calcium stearate.

 In this embodiment, on the basis of using sucrose as a bulking agent and flavoring agent, two or more kinds of mannitol, IS A sugar to other synthetic sugars, menthol, and flavor are added as the flavoring agent.

 Saturated solution method, ultra Lubo method, freeze-drying method, and grinding method can be used to encapsulate the above drugs. In this embodiment, when the saturated solution method is used for encapsulation, the apomorphine hydrochloride is unstable in aqueous solution, light, and air. It is easy to be oxidized to green, and the inclusion yield is low; other methods such as ultrasonic method and freeze-drying method are relatively expensive, while the grinding method has no similar problems, and the method is simple, so the grinding method is preferred.

 In the ffl grinding method, one or more of the above wetting and thickening agents are selected, and stearic acid is used as an acidic medium to ensure the stability of apomorphine hydrochloride. During the inclusion, only apomorphine hydrochloride may be included, or sildenafil citrate and apomorphine hydrochloride may be separately included, and then mixed and granulated to reduce mutual interference between the two components and ensure that each For stability, it is also possible to encapsulate both dinafil citrate and apomorphine hydrochloride simultaneously with cyclodextrin.

 In this embodiment, taking the unstable apomorphine hydrochloride as an example, the inclusion of cyclodextrin (β-CD) to apomorphine hydrochloride is discussed, and it is experimentally determined that: cyclodextrin and apomorphine hydrochloride The ratio is 3: 1-7: 1, the inclusion time is 30-180 minutes, and the HPMC concentration is 3%, the inclusion effect is better. The cyclodextrin apomorphine hydrochloride ratio is preferably 4: 1 -6: 1 The inclusion time is 40-50 minutes and the HPMC concentration is 3%; the most preferred ratio of cyclodextrin apomorphine hydrochloride is 5: 1, the inclusion time is 45 minutes and the HPMC concentration is 3%.

 Observing the crystal form of the particles with a microscope, it was found that before the inclusion, β-CD and apomorphine hydrochloride were both regular crystals observed in the microscope, and after inclusion, substances with different D. crystalline forms appeared in the microscope field. Differential thermal analysis (DTA analysis) showed that the peak shape was completely changed after inclusion of apomorphine hydrochloride with β-cyclodextrin, indicating that a new structure was formed. These changes may be due to the fact that the organic part of apomorphine hydrochloride entered the cyclodextrin and was internally divided, which not only masked the bitter taste of apomorphine hydrochloride, but also changed the crystal structure of cyclodextrin.

 A similar situation was obtained with cyclodextrin-containing sildenafil citrate. Experiments showed that the optimal ratio of cyclodextrin-containing sildenafil citrate was 2: 1-7: 1, and the HPMC concentration was 3 %; Preferably 3: 1-5: 1.

 The present invention also determines the use of sweeteners and other excipients according to the requirements of the formulation science and the characteristics of the drug. The best formula for obtaining apoxidi oral buccal tablets is as follows:

Apomorphine hydrochloride (with C ₁₇ H _l7 N0 ^ · HC1) 2-10g

Sildenafil citrate ((^ ΛΛΟ ^ · C ₆ H _H 0 ₇ )

 β-cyclodextrin 60- 670g

 Wetting adhesive 60-600g

 Acid medium 2- 10g

 Mannitol 26-30g

 Preservatives 0. 03-0. 05g

 Sweetener 600-850g

 Spice 4-10g

Menthol 2g Pigmented

 Lubricant 5-15R

 Made into 1000 tablets

 Preparation of apoxidi in the present invention: ": art is:

 1. Disperse the wetting adhesive with ethanol, then soak it with distilled water to completely dissolve, stir well, and pass through a 80-mesh sieve for later use.

 2. Put β-cyclodextrin (β-CD) into the mortar, add the wetting binder solution, grind it evenly, then add the acidic medium and apomorphine hydrochloride and continue to grind until it is fully contained, and set aside (as raw material 1) .

 3. Put (β-CD) into the mortar and add the wetting adhesive solution. After grinding evenly, add the two citrate citrate and continue to grind until it is completely enclosed, and set aside (as raw material 11).

 4. Mix the sweetener and pigment mother powder thoroughly, sieved, then add Raw Material I and Raw Material II to mix evenly, pass through a 16 mesh sieve and a 20 mesh sieve once, and finally add a preservative-containing binder solution Soft wood.

 5. Sieve the 16-mesh soft material into granules. Bake in a thin plate, dry with ventilation, and dry the granules with 16-mesh whole grains.

6. After the granulation, ffl—quantify the fine powder, mix the flavor and flavoring agent and sieve it once, then mix with the whole batch of granules, and finally add magnesium stearate to mix and tablet.

 Preparation I: The art further includes:

 Steps 1 to 2 ij is the same as above 1 to 2;

 3. Mix the sweetener and the pigment masterbatch thoroughly, sifter, and then add the raw material I and dicenafil citrate, once through a 16-mesh sieve and a 20-mesh sieve, and finally add a preservative-containing binder The solution is made into a soft material, and then the above is used: ": Yi prepares buccal tablets.

 The preparation process of the present invention further includes:

 1 is the same as 1 above,

 2 Put some ¾-cyclodextrin (β-CD) into the mortar and add a suitable ¾ binder solution, grind evenly, then add stearic acid, apomorphine hydrochloride, and sildenafil citrate, and continue to grind until Completely inclusive, prepare Sichuan (as raw material III), and then use the above process to prepare buccal tablets.

 In another embodiment of the present invention, apomorphine hydrochloride and sildenafil citrate are separately or simultaneously encapsulated with lecithin, and the resulting liposome Λ has a stable structure and can cover the bitterness of both drugs . The formula for preparing liposomes is as follows: Sildenafil citrate 20-120g

 Egg Yolk Lecithin 20-120g

 Wetting tackifier 4- 24g

 Tween -80 2— 12g

 Phosphate pH 7.2 buffer 25-130ml

 Apomorphine hydrochloride 2-10g

 Egg Yolk Lecithin 2-10g

 Cholesterol l-6g

 Wetting thickener 0. 5-2g

 Phosphate buffer pH 6. 8 5— 15ml

The method of encapsulating the two main drugs is as follows: Put sildenafil in a pH 7.2 phosphate buffer solution and stir well, then add egg yolk lecithin, polyethylene glycol, and Tween-80, mix thoroughly and dry. Pass through 30 mesh sieve and set aside. Add apomorphine to a pH 6.8 phosphate buffer solution and stir well, then add egg yolk lecithin, cholesterol, and polyethylene glycol 2000. Mix well, ventilate and dry at 50 ° C.

 In another embodiment of the present invention, two drugs are directly encapsulated with cellulose, and the formula is as follows:

 Sildenafil citrate 20-120g

 Mannitol

 Wetting tackifier 2-4% (EtoH80%, 0 20%)

 Dispersant 1-3%

 Apomorphine hydrochloride 2-10g

 Stearic acid 2-10g

 Wetting tackifier 2- 5% (EtoH80%, H, 0 20%)

 Polyethylene glycol 6000 0.5-3%

 The preparation process is as follows: first disperse HPMC ffl EtoH, dissolve polyethylene glycol W distilled water, and then combine the two, and the concentration of PEG 6000 is 1.5% for future use. Mix sildenafil citrate and mannitol evenly, add some of the above preparations to make a soft material; mix apomorphine hydrochloride with an acidic medium, add the above preparations and mix well; Maternal law

1

Gradually expand the population. The “daughter-in-law” method mentioned here refers to: when the use of the main component is small, in order to make the main component evenly dispersed in all the auxiliary materials, the main material and the small auxiliary materials are mixed and dispersed ob, Then the uniformly mixed materials are uniformly mixed with the remaining auxiliary materials. As for the number of auxiliary materials used and the number of premixing, those skilled in the art will determine the properties of the auxiliary materials and then combine the two into all the auxiliary materials. Mix evenly, add Sichuan liquid to make soft material, granulate with 16 mesh, blast dry, whole grain, add spices, slippery material to tablet.

In order to investigate the interaction between apomorphine hydrochloride and sildenafil citrate, a series of animal experiments were performed in the present invention. SD rats sexual behavior experiments have proven that apomorphine hydrochloride and dicenafil citrate have Strong interaction W, the amount of sildenafil citrate is 1. 8-10. 80 mg / k _g , the use of apomorphine hydrochloride ¾ is 0. 18-0.9 mg / kg, according to human and The equivalent dose of body surface area between rats is: when sildenafil citrate 20-120mg / person (70kg) and apomorphine hydrochloride 2-10mg / person (70kg), it will promote the pursuit of female rats Sex in rats has some effect.

 When the amount of sildenafil citrate is 2.70- 10.8mg / kg, the M of apomorphine hydrochloride is 0.18- 0.72mg / kg, which is an effective agent based on the body surface area between humans and humans. ¾ is: when sildenafil citrate 30-120mg / person (70kg), apomorphine hydrochloride 2-8mg / person (70kg) has a better effect on promoting the sexual behavior of male and female rats hunting female human rats.

 When the amount of sildenafil citrate is 3.6-6. 5mg / kg, the use of apomorphine hydrochloride is 0.27-0. 54mg / kg, which is calculated based on the body surface area between humans and rats, etc. The effective dose is: · When sildenafil citrate 40-50mg / person (70kg), apomorphine hydrochloride 3- 6mg / person (70kg), it is better to promote male rats to hunt for sexual behavior of female rats Effect.

 In order to study the pharmacology and toxicology of sildenafil citrate and apomorphine hydrochloride when used together, the present invention conducted a series of animal tests.

 I. General pharmacological experiments:

 1. Psycho-nervous system: Ordinary NIH mice were given subcutaneously two high, medium and low doses of the test drug. The test results showed that there were no significant abnormalities in the psychiatric and nervous system indicators of the mice in each test group. No significant difference was found between the vehicle group and the pre-dose comparison. It can be judged that the drug has no significant effect on the mental nervous system.

 2. Circulation and Respiratory System: Using ordinary SD rats, three doses of the test drug were administered sublingually at one time, and the blood pressure, electrocardiogram, respiration and other relevant indicators of the animals were measured before and after administration. The test results showed that when the proposed clinical dose was 3 times, there was no significant change in blood pressure, ECG QRS, ST, T wave, rhythm, and respiratory rate of the animals.

2. Toxicity Studies 1. Acute toxicity: LD _{50 in} mice by intragastric administration: 960.96mg / kg _; LD _{50 in} mice by intraperitoneal injection _: 150. 48mg / kg _; in accordance with the acute toxicity classification standard for chemicals formulated in 1997, this product is classified as low toxicity level.

 2. Long-term toxicity test:

When the rats were administered for two months, when the dose was 25 times the clinical dose (mg / m ² was 4 times), no toxicity to the rats was observed, and no significant abnormalities were seen in important organs. No impact on biochemical indicators.

When the rhesus monkey was administered for a month, the clinical dose was 5 times (mg / m ² was 1.8 times). No toxicity to the rhesus monkey was observed, and no significant abnormality was observed in important organs. All examinations, including anatomy / blood biochemistry, blood routine, urine routine, cardiovascular, and organ coefficients, did not show significant abnormal changes.

 It was administered sublingually to rats once or for seven consecutive days to test the irritation of the product to the oral mucosa. The test showed that the product was non-irritating to the mucosa.

 2. Pharmacodynamic Research

 The results of animal experiments prove that when the dosage of apoxidi is lower than that of sildenafil M, it can also greatly improve and improve the sexual behavior of male animals. The specific results are as follows:

 1. The effects of apoxidi on sexual function of male human rats suggest that the effects of apoxidi and tadpole on improving sexual function in rats. This product can significantly shorten the capture and climbing latency of rats and increase the number of times of capture and climb. Compared with the positive control Viagra group, each agent group ¾ shortens the capture and climb latency and increases the number of times of capture and climb.成 Significantly significant difference, in which the low-dose group (presented by clinical agents) ffl 4. 2 mg / kg is much lower than Viagra's M 12. 6 mg / kg, but the efficacy is better than Viagra group; and The drug effect increases with increasing dose. The above results are summarized in Table 1:

 Effects of apoxidi and sildenafil citrate (12.6 mg / kg) on sexual function in male rats

 2. The effects of apocedi on the sexual function of castrated male rats suggest that when the androgen effect is weakened or lacking, apodidi can still shorten the penile erection latency of castrated rats and increase the yin of castrated rats ^ Length, sex control Viagra group, the onset of apocydil in various doses is earlier. The specific results are shown in Table 2. The agents in the table are the same as those in Table 1.

 CSILD in the table is sildenafil citrate

3. The effect of apoxidi on penile length and diameter of rhesus monkeys suggests that: apoxidi can rapidly increase the penis length and diameter of male rhesus monkeys. The increase in diameter is of statistical significance, and the drug effect increases with dose. And the enhancement, compared with the positive control Viagra group, its onset time is earlier, the effect of the low-dose group is slightly stronger than Viagra, and the effect of the medium-dose group close to the Viagra group, the effect is significantly enhanced; the specific results are shown in Table 3 and Table 4, In Tables 3 and 4, The doses in the high and low dose groups were 16. 2, 5. 4, and 1.8 mg / kg, and the doses in the Viagra group were 5.6 mg / kg with sildenafil citrate.

 Table 3.Effects of apoxidi and sildenafil citrate on penile length

4. Apraxidil increases the intracorporeal pressure of the corpus cavernosum of the macaque monkey and decreases the smooth muscle tubules of the cavernous sinus, suggesting that apocelidi makes the erection of the penile corpus cavernosum of the rhesus monkey related to its ability to increase the intracorporeal pressure of the corpus cavernosum of the rhesus monkey and reduce smooth muscle electricity Its drug effect increases with increasing dose, and it increases the intracorporeal pressure of the corpus cavernosum of the cynomolgus monkey and decreases the yin and smooth muscle function, and it has a significant effect at 15 minutes; compared with the positive control Viagra, each agent At ¾ group, the effect was stronger than Viagra at 15min. The results are shown in Tables 5 and 6. In Tables 5 and 6, the medicaments for each group are the same as the corresponding values in Tables 3 and 4.

 Table 5 Comparison of apoxidi and sildenafil citrate in reducing cavernous sinus smooth muscle cells

By comparing the efficacy of apoxidi and sildenafil citrate at the same dose, the efficacy of aposilidi in each trial was better than that of sildenafil citrate in each dose group, only In the test for reducing the penile smooth muscle of the rhesus monkey, the decrease of aposilidi in the low-dose group was lower than that of sildenafil citrate, mainly due to the small EMG base number of the four animals in the apocydi group before administration. Therefore, the range of variation is narrow; it is particularly important to emphasize that in the above-mentioned animal experiments, the dosage of apoxidi and sildenafil citrate in the middle-dose group is slightly lower but close to that in the low-dose group. The dosage is lower than that of didenafil citrate, but even low-dose apocylide is more effective than sildenafil citrate alone. The specific results are shown in Table 7.

 Table 7 Comparison of pharmacodynamic strength of apoxidi low-dose group and Viagra group

 According to the results of the pharmacodynamics test of apocetil, the efficacy of the apocedi low-dose ¾ group is better than that of the T Viagra group or equivalent.

 The above-mentioned tests suggest that the strength of the apocedi low-dose ¾ group is basically similar to that of the positive control Viagra group. In all experiments, according to animal body surface conversions, the apocedi low-dose ¾ group is equivalent to 46 mg of human agent. / Time / person (28.47mg based on two-denafil), the Viagra group is equivalent to a human agent ¾ lOOmg / time / person (based on two-denafil), indicating that sildenafil citrate Combined with apomorphine hydrochloride, the two play a synergistic role, which can reduce the use of fenamic acid and dinafil and improve the efficacy.

 By analyzing the ffl and its intensity at various time points and comparing with the sexual control drug Viagra, it was found that the drug started faster than Viagra, and the effect was significant at 15 minutes after administration, and continued to increase at 30 minutes, maintaining By 45min, Sakugawa began to weaken by 60min. It shows that the drug will be effective in 15 minutes, 15 minutes and 15-45 minutes as an intensity person, and it will start to weaken at 60 minutes. It may have the characteristics of quick onset and rapid weakening. The maintenance time is about 1 hour. It is more suitable for the physiological characteristics of animals and humans, and has practical application significance.

 In summary, the compound preparation of the present invention affects the animal's sexual function in humans and unilaterals (Viagra), which is characterized by fast onset, low dosage, and appropriate maintenance time, which is convenient for patients to master and use; and the treatment in the prior art The drug for erectile dysfunction is used as a single agent in the central nervous system, and it is used as a single agent in different peripheral blood vessels. The apocylide developed by the present invention will act on the nerve center pyramidal dopamine receptor agonist apochloride hydrochloride. Morphine and sildenafil citrate, a PD inhibitor that acts on peripheral blood vessels, combine the two characteristics of rapid drug action of the nervous system and long-lasting effect of peripheral vascular enzyme inhibitors, enabling the two to exert synergistic effects. It can reduce the dosage of sildenafil citrate even if the onset time of the drug is earlier (effective at 15min), without reducing the drug effect, and can maintain a proper time.

The following are specific examples of sildenafil according to the present invention. The examples are only used to illustrate the present invention, but not to limit the present invention. In the example of the sildenafil preparation method, a Merck silica gel 60F254 chromatography plate was used for purity check, and a high performance liquid chromatography (HPLC O 4. 6 * 250mmC18 column, phosphate buffer pH 7.0. Methanol as mobile phase) was used. Determine the content. The 1H NMR spectrum was measured with a Varian INOVA-400; elemental analysis was performed with a Heraeus Rapid-CHNO elemental analyzer.

 Example 1

 This example relates to 5- [2-ethoxy-5- (4-methylpiperidinylsulfonyl) phenyl] 1-methyl-3-n-propyl-1, 6-dihydro- The method for preparing 7H-pyrazolo [4. 3-d] pyrimidin-7-one (compound I) is as follows: Compound (VI) is selected from 5- (5-chlorosulfonyl-2-ethoxyphenyl) )-1-methyl-3 -n-propyl-1, 6-dihydro-7H-pyrazolo [4. 3-d] pyrimidine-7-one 7. 5g (0. 018mol) was added to 125ml ethanol, With stirring, 2.95 g (0.022 mol) of 1-methylpiperidine monohydrochloride was added at room temperature, and the reaction was carried out for 3 hours, 75 ml of water was added, and then the reactant was neutralized to pH 7.0 with 4N sodium hydroxide solution The title compound was in a free state, stirred at 5-1 (TC for 2 hours, suction filtered, the filter cake was washed with water and dried under vacuum in the presence of phosphorus pentoxide, to give the title compound 7.85 g, yield 92%, mpl89-190 ° C o δ (DMSO-d6) 0.926 (3Η, triplet), 1. 323 (3H, triplet), 1. 721 (2H, six; £ peak), 2. 142 (3H, singlet), 2 367 (4H, singlet, width), 2. 768 (2H, doublet). 2. 898 (4H, singlet, width), 4. 156 (3H, singlet), 4. 205 (2H, Quadruple peak 7. 372 (1H, doublet), 7. 815 (2H, multiplet), 12. 229 (1H, singlet, broad), see ¾ 1.

 The elemental analysis values of dinafil citrate were obtained by reacting the two dinafil compounds with citric acid: C49. 70%, H5. 68%, N12. 40%, S5. 00%; Theoretical value: C50. 37%, H5. 85%, N12. 59%, S4. 80%. 13C—MNR spectrum is shown in Figure 2, and mass spectrum is shown in Figure 3.

 Hi 99. 8% sildenafil citrate was used as a reference, and high-performance liquid chromatography (HPLC) analysis showed that the above reaction did not require purification steps such as crystallization and chromatographic separation, and the purity of the compound directly obtained was 98.4 %, As shown in Figure 4, meets pharmaceutical standards. Thin layer chromatography (TLC) analysis also confirmed the above results.

 Examples 2-7

 The title compound was prepared according to the method of Example 1 with 1-methylpiperazine as a suitable mono-salt, as shown in Table 8:

 Table 8 Preparation of Compound I using 1-methylpiperazine monosalt

 Analysis of the products by thin layer chromatography (TLC) and high performance liquid chromatography (HPLC) showed that the substances that met the quality standards were directly obtained.

 Examples 8-12

 The title compound was prepared according to the method of Example 1 with a suitable double salt of 1-methylpiperazine, as shown in Table 9:

 Table 9 Preparation of Compound I with 1-methylpiperazine double salt

 Example 1 Monomethylpiperazine double salt% yield

8 Double Hydrochloride 91 9 Dihydrobromide 89

 10 Dinitrate 86

11 Diformate 84

12 Diacetate 85 Analysis of the product by thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC) showed that substances that met the quality standards were obtained directly.

 Examples 13-19

 Examples 13-19 relate to the yields obtained by using other double salts, and the method is the same as that of Example 1.

 Table 10 Preparation of Compound I with 1-methylpiperazine double salt

 Analysis of the products by thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC) showed that sildenafil met the quality standards directly.

 In order to explore the interaction between apomorphine hydrochloride and sildenafil citrate, a series of animal experiments were performed in the present invention. The following experimental examples can be seen in body A. Unless otherwise specified, the "apo two places" in the present invention "Refers to a compound preparation.

 Experimental example 1

 8%。 In this experimental example and the following examples, the purity of the sildenafil citrate was 98.4%, and the purity of apomorphine hydrochloride was 98.8%. The solvent was physiological saline; the selected animals were sexually mature female and male SD fire rats, body M 200-280g, male and female, two days before the experiment, female rats were injected with estradiol benzoate, and the male and female were fed in separate cages.

 Experimental method: Two drugs, sildenafil citrate and apomorphine hydrochloride, were deduced to rats based on clinical HJ agents in adults. Hydroxypropyl methylcellulose (HPMC) was formulated into a paste with physiological saline. Two males ¾ apply a paste of hydroxypropyl methylcellulose and physiological saline to the oral mucosa, put the male rats back into the cage after application, and then inject two females to the estrous phase two days after estradiol benzoate injection. The rats were placed in a cage, and the number of times that male and female mice were captured by female rats was observed and calculated.

 Drug M: sildenafil citrate 3.60mg / kg body weight, apomorphine hydrochloride 0.45 mg / kg body weight, the aforementioned drug was formulated with 5% hydroxypropyl methylcellulose 3ml in a paste .

 Results: In this experimental example, the average number of captures by male rats in 60 minutes was 16 times.

 Experimental Examples 2-20

 In this experimental example, the test drugs, animals, and experimental methods are the same as those in Experimental Example 1. Table 11 shows the average number of times that male rats capture female rats when the test drug doses and ratios in Experimental Examples 2-20 are different.

 Table 11: Cedi citrate 33 and apomorphine hydrochloride π-1; effects of different dosage ratios on male rats' sexual behavior

 CSILD (mg / human equivalent dose APO (mg / kg human equivalent HPMC arrest experimental example)

kg weight) (mg / person. 70kg) * weight) (mg /. 70kg) (%) times 2 2. 70 30 0. 72 8 2 13

3 5. 40 60 0. 54 6 1 26

4 10. 80 120 0. 36 4 2 30

5 2. 70 30 0. 18 2 1 9

6 3. 60 40 0. 54 6 5 25

7 3. 60 40 0. 36 4 5 13

8 4. 50 50 0. 27 3 2 18

9 9. 00 100 0. 18 2 2 28

10 4. 50 50 0. 45 5 1 12

11 6. 30 70 0. 72 8 1 11

12 7. 20 80 0. 27 3 1 15

13 3. 60 40 0. 72 8 5 8

14 2. 70 30 0. 45 5 5 16

15 4. 50 50 0. 18 2 1 9

16 1. 80 20 0. 90 10 2 7

17 2. 70 30 0. 90 10 1 9

18 8. 10 90 0. 27 3 5 26

19 3. 60 40 0 0 2 7

20 0 0 0. 54 6 2 5

* Equivalent agent S (mg / person. 70kg) converted to body surface area

 The above sexual behavior experiments of SD rats have proven that apomorphine hydrochloride and denafil citrate have a strong interaction. Experiments have shown that the use of sildenafil citrate is less than 2.7 mg / kg, a hydrochloride When the ¾ of morphine is less than 0.18 mg / kg, the efficacy of any combination of the two drugs is lower than the single dose of sildenafil flavin 3.6 mg / kg into a single dose of apomorphine hydrochloride 18mg / kg for 0.54mg / kg; Sildenafil citrate for 1. 8-10. 80 mg / kg, apomorphine hydrochloride for 0. 18-0. 9mg / kg, according to the body surface area between humans and humans, the effective agent M is: Sildenafil citrate 20-120mg / person (70kg), apomorphine hydrochloride 2-10mg / person (70kg), promote male Rats have a certain effect in hunting female rats for sexual behavior.

 When the amount of sildenafil citrate is 2.70-10. 8rag / kg, the use of apomorphine hydrochloride is 0.18-0.72mg / kg, which is calculated based on the body surface area between humans and rats, etc. The effective dose is: 30-120mg / person (70kg) of dinafil citrate, 2-8mg / person (70kg) of apomorphine hydrochloride have good effects on promoting the sexual behavior of male rats in pursuit of female rats.

 When the amount of sildenafil citrate is 3.6-6. 5mg / kg, the amount of apomorphine hydrochloride is 0.27-0. 54mg / kg, which is equivalent to the body surface area between humans and rats. The dosage is: when sildenafil citrate 40-50mg / person (70kg) and apomorphine hydrochloride 3-6mg / person (70kg), it has a better effect on promoting male rats to pursue the sexual behavior of female rats .

 Example 20

1. Disperse 3g of hypromellose (HPMC) with 20ral ethanol (EtOH), then add 80'C distilled water 80ral to completely dissolve it, stir to obtain 3% HPMC solution, and pass through 80 mesh sieve for later use. 2. Put 5gp-cyclodextrin (β-CD) into the mortar and add 7.0 ml of HPMC solution, grind evenly, then add lg stearic acid and lg apomorphine hydrochloride and continue grinding for 45 minutes.

 Observe the crystal form of the particles with a microscope. P-CD and apomorphine hydrochloride are regular crystals observed in the microscope before inclusion. After inclusion, the regular crystals in the microscope field are reduced and appear different from the original. Substance of crystalline form; inspected and evaluated according to the following criteria, with a score of 13, as shown in Table 12:

 Table 12

 Examples 21-43

 Change the concentration and amount of HPMC and the type and use of cyclodextrin, and use different grinding times. Other conditions are the same as in Example 20, and the amount of stearic acid is lg. The specific results are shown in Table 13:

 Table 13

 Example Cyclodextrin AP0 HPMC Grinding time Included evaluation Name Dosage g (g)%, ml (minutes) Price

21 β-CD 3 1 2, 4.2 45 8

 〃

 22 3 1 3, 4.2 15 7

23 〃 3 1 1, 4.2 30 5

24 5 1 2, 7.0 30 12

25 〃 5 1 1, 7.0 15 9

26 7 1 3, 9.8 30 12

 ,,

 27 7 1 1, 9.8 45 13

28 〃 7 1 2, 9.8 15 8

29 7 1 3, 9.8 60 13

 〃

 30 4 1 3, 5.6 45 12

31 〃 5 1 3, 7.0 60 13

32 〃 5 1 3, 7.0 120 13

33 5 1 3, 7.0 180 13

34 〃 4 1 3, 5.6 30 11

35 4 1 3, 5.6 60 13

36 〃 6 1 3, 8.4 35 13

37 〃 6 1 3, 8.4 45 13 38 4 1 3, 5.6 60 13

39 5 1 2, 7.0 50 13

40 6 1 3, 8.4 50 13

41 6 1 3, 8.4 40 13

42 4 1 3, 5.6 60 13

43 β- CD 5 1 water 5ml 45 12 The inclusion complex of cyclodextrin and apomorphine hydrochloride was analyzed by METLER FP90 Central Processor and METLER FP84 TA Microscop 1y Q Cell differential thermal analyzer (DTA analysis), according to 5 ° C / min heat up for analysis, ac

It was found that the DTA spectra of β-cyclodextrin, apomorphine hydrochloride and stearic acid were single peaks. Before inclusion, the DTA spectra of β-cyclodextrin, apomorphine hydrochloride and stearic acid were corresponding. The peaks were added, and the peak shape completely changed after the inclusion of β-cyclodextrin, indicating that a new structure was formed. The spectra are shown in Figure 5-9.

 Optical microscope (NIKON, eyepiece CFWN 010X / 20, objective lens 4 / 0.13) photos show that β-cyclodextrin, apomorphine hydrochloride and stearic acid all have regular crystal forms under the optical microscope, β-cyclodextrin The mixture of apomorphine hydrochloride and stearic acid is a mixture of three crystal forms under an optical microscope. After β-cyclodextrin is incorporated into apomorphine hydrochloride, the original compounds of the compounds are included under the optical microscope. The crystalline material was quenched, and a new structure with different original crystals appeared. The photos are shown in Figure 10-13.

 Example 44

1. Disperse 3g of HPMC, disperse ^ 20 ml of ethanol first, and dip in 80 ml of 80 ^H C distilled water to completely dissolve, stir well, prepare MJ (3% HPMC solution) through 80 mesh sieve .

 2. Put 3 g of cyclodextrin into the mortar, add 4.2 ml of HPMC solution, grind evenly, and then add sildenafil citrate lg for 45 minutes to obtain sildenafil citrate inclusion compound. The bitterness of the inclusion compound is basically fire extinguishing and the taste is good.

 Examples 45-58

 A similar method as described in Example 44 was used to change the type of cyclodextrin and the ratio of tilinafil citrate, the concentration of HPMC with Wtt, and the milling time to prepare the inclusion compound of tilenafil citrate, as shown in the table. As shown in Figure 14, the taste of the drug is improved.

 Table 14

 Cyclodextrin (g) CSILD HPMC% When grinding

 Examples

 M (g) and ml (minutes)

 45 β-CD 3 1 3, 4. 2 30 slightly bitter, acceptable

 46 β-CD 5 1 1, 7. 0 45 The bitterness is basically extinguished and the taste is good

47 β-CD 5 1 3, 4. 2 30 slightly bitter, acceptable

 48 β-CD 7 1 3, 9. 8 45 The bitterness is basically extinguished and the taste is good

49 β-CD 7 1 2, 9, 8 30 Slightly bitter, acceptable

 50 β-CD 5 1 3, 7. 0 45 The bitterness is basically extinguished and the taste is good

51 β-CD 3 1 3, 4. 2 60 The bitterness is basically extinguished and the taste is good

52 β-CD 2 1 3, 2. 8 45 Slightly bitter, acceptable

 53 β-CD 2 1 3, 2.8 60 Slightly bitter, acceptable

 54 4 1 3, 5.6 55 Bitterness basically disappeared

 55 TM β -CD 3 1 3, 4.2 40 The bitterness has almost disappeared

56 5 1 2, 7. 0 50 The bitterness basically disappeared 57 2G2 β-CD 7 1 3, 9. 8 30 The bitterness basically disappeared

 58 β-CD, 3 1 water 5ml 60 slightly bitter, acceptable

 Example 59

 The preferred embodiment of the present invention uses the following formulation and preparation process:

Apomorphine hydrochloride (with C ₁₇ H ₁₇ N0 ₂ · HC1) 6g

Sildenafil citrate (C ₂₂ H _{: 1} .N ₆ 0 ₄ S 40g

 β-Cyclodextrin 150g

 Hypromellose 6g

 6g stearic acid

 Mannitol 28g

 Methyl parahydroxybenzoate 0.04g

 Sucrose 780g

 o

 15g

 Grass Grape Spice 5g

 Menthol 2g

 .ίί'ιΐ ^> 素 0. 05g

 Calcium stearate R

 Made into 1000 tablets

 1. Disperse 6g of hypromellose (HPMC) in 40ml of ethanol, and then dip in 200ml of 80 ° C distilled water to dissolve it completely.

 2. Put 30 g of cyclodextrin (β-CD) into the mortar, add 42 ml of 3% HPMC solution, grind it evenly, then add 6 g of stearic acid and 6 g of apomorphine hydrochloride and continue grinding for 45 min. ).

 3. Put 120g (β-CD) into the mortar and add 170ml 3% HPMC solution. After grinding, add 40g sildenafil acetate and continue grinding for 45 minutes. Prepare J (as raw material 11).

 4. Thoroughly mix sucrose, mannitol, and pigment masterbatch, sifter, and then add Raw Material I and Raw Material II to mix evenly, pass through a 16 mesh sieve and a 20 mesh sieve once, and finally add a preservative-containing HPMC solution to make it soft. material.

 5. The soft material is sieved with 16 mesh sieve, and the thin pan is baked. Baking temperature is controlled below 6CTC, ventilated and dried, after drying, the granules are W 16 mesh whole granules.

 6. After the granulation, the 40-mesh sieve must be sieved. Fine powder, flavor and flavoring agent are mixed and sieved once through the 32-mesh sieve, and then the whole batch of granules are mixed. The obtained tablets were accelerated in a humidity environment of 4CTC 75% for 6 months. The results showed that the tablet content changed little and the tablets were stable. The specific results are shown in Table 15: Table 15

实施例 60-85

Examples 60-85

 The following three tables are mainly to change the proportion of the main ingredients or the types and uses of the auxiliary materials. The method of Example 59 above is used to prepare apoxidi compound oral buccal tablets. Each formulation is used to prepare 1000 apo surface, see Λ body results. Table] 6, Table 17, Table 1 σ8:

 Table 16 a c

 8

 Table 17

 (g) Examples

 70 71 72 73 74 75 Apomorphine hydrochloride 6 6 6 6 6 6 Sildenafil citrate 40 40 40 40 40 40 γ-CD 150

 E- β -CD 150

 150

 150

 150

150 Hypromellose 6 6 6 6 6 6 / NOO / 00145

表 18

Table 18

 Example 86

This embodiment is a compound preparation, and the two main drugs are grouped and combined. 1. Put 40g of sildenafil citrate in 50ml of pH 7.2 phosphate buffer solution and stir well, then add 40g of egg yolk lecithin, 8g of polyethylene glycol 2000, 4g of Tween-80 to mix thoroughly and dry, Pass 30 mesh sieve and set aside.

 2. Put 6 g of apomorphine hydrochloride into 10 ml of pH 6.8 phosphate buffer solution and stir well, then add 8 g of egg yolk lecithin, 3 g of cholesterol, and 2 g of polyethylene glycol 2000, mix thoroughly and ventilate and dry at 50 ° C. Get it through a 30 mesh screen.

 Example 87

 First disperse 3g of HPMC with 20ml of EtoH, dissolve 1.5g of polyethylene glycol with 20ml of 80 ° C distilled water, then combine the two, add 0 60ral to make the concentration of HPMC 3%, and the concentration of PEG 6000 1. 5%, prepare Sichuan; 40g of sildenafil citrate and 40g of mannitol are mixed uniformly, and the above part of the W solution is added to make a soft material.

 Mix 6g apomorphine hydrochloride and 6g stearic acid, add the above prepared Sichuan liquid and mix well to make a soft material.

 The two are gradually expanded to a certain extent with the auxiliary method using the auxiliary method, and then the two are combined into all the auxiliary materials, mixed thoroughly and mixed, and the spare liquid is added to make a soft material, granulated at 16 mesh, and blow dried under 60 ° C. Whole granules, flavored, slippery, can be compressed into tablets.

 Examples 88-97

 The method of Example 1 was used to prepare the two dinafils, and the reaction time was changed to the solvent. The results are shown in Table 19:

 Table 19

 Example 99

 Sildenafil was prepared by the method of Example 1, except that the compound (VI) was selected from W 5- (5-mosulfonyl-2-ethoxyphenyl) -1-methyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo [4. 3-d] pyrimidin_7_one yielded a 78% yield of dinafinil. Example 100

 Sildenafil was prepared by the method of Example 1, except that the compound (VI) was selected from W 5- (5-fluorosulfonyl-2-ethoxyphenyl) -1-methyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo [4. 3-d] pyrimidin-7-one, yielding a sildenafil yield of 95%. The following is an animal experiment of the pharmacodynamics of the compound preparation of the present invention, as follows:

 Experimental example 21

 The purpose of this experimental example is to observe the effects of apoxidi on male rats' sexual behavior.

This experimental example and the following experimental examples refer to apocylide as 98.4% sildenafil citrate and 98.8% apochloride A mixture of morphine drug substance 40: 6; the positive control drug is Viagra, 100 (sildenafil) mg / tablet (based on sildenafil base, such as sildenafil citrate) produced by Pfizer Inc. It is 140 (sildenafil citrate) mg / tablet) and the batch number is 79R008E.

 The animals used in this experimental example are clean Sprague-Dawlay rats, 200-280g in body size, half male and half female, a total of 100 animals. The high, middle, and low doses of apoxidi, described in this experiment and the following experiments: Group ¾ and the negative control vehicle (ie, excipients) were administered in the same way as the clinical one oral mucosa; Viagra group Oral administration.

 The pharmacodynamic test of this experimental example consists of three groups of high, medium, and low doses. The high dose ¾ group is 37.8 mg / kg, the medium dose M group is 12. 6 mg / kg, and the low dose ¾ group is 4. 2itig. / kg.

 The positive control group used Viagra at 9mg / kg as sildenafil, and 12.6mg / kg as sildenafil citrate; formulated with distilled water; the negative control group was 5% hydroxypropyl methylcellulose; apo Formulated with 5% hydroxypropyl methylcellulose; Table 20 Test drug doses

 Test method Female rats were intramuscularly administered with estradiol benzoate, 0.1 mg / head two days before the test, to promote their entry into estrus; male rats were randomly divided into apocedidiol (37.8 mg / kg) ), Medium (12.6 mg / kg), low (4.2 mg / kg) three dose groups; 5% hydroxypropyl methylcellulose negative control group and positive control-Viagra group (9.0 mg / kg), a total of Five groups of 10 animals.

 Experimental observation indicators: Each group of animals were given the corresponding test drugs according to body S. After the administration, the test animals were placed in observation cages (31 X 24 X 20cm) in a 1: 1 ratio of males and females. Keep the room quiet and observe the male rats' sexual behavior. The indicators are:

 1. Capture incubation period; it means the time from when the male and female animals catch the cage to the first time the male mouse catches the female rat;

2. Capture times: Observe the number of times the male rats capture the female rats within 60 minutes;

 3. Climbing incubation period: It refers to the time from when the male and female animals are closed to the first climb of the male rat after the cage is closed;

 4. Number of climbs: Observe the number of times the male rats climbed within 60 minutes;

 The experimental results are shown in Table 21 (X soil SD):

 Table 21

Comparison between groups, ** P <0. 01, * P <0. The conclusion of this experimental example is that: after oral administration of apoxidi 37.8 mg / kg, 12.6 mg / kg, and 4.2 mg / kg to rat oral mucosa, cages with female rats can significantly shorten the rat's capture latency and The climbing incubation period increases the number of captures and climbs in rats, and the conclusion indicates that apocedi has the effect of improving sexual performance in animals.

 The high, medium, and low doses of apocylide described in this experimental example are all effects of Viagra 9. Omg / kg. The conclusion shows that low dose sildenafil (4.2 mg / kg of apoxidi Equivalent to sildenafil base 2.85mg / kg and apomorphine hydrochloride (0.2mg / kg) and apomorphine compound preparation has a stronger drug effect ffl than that of monodenafil (9.0mg / kg), The above conclusion also shows that the effect of apoxidi on the sexual behavior of humans and mice described in this experimental example, the intensity of its pharmacological effect increases with the increase of the dosage.

 Experimental Example 22

 In this experimental example, the effects of the test drug on animal sexual function were examined by observing the changes in yin ¾ length, S diameter, and the length of the erectile latency period after electrical stimulation of κyin after administration of castrated male rats.

 The test drug, agent M setting, animal model, and route of administration are equivalent to Experimental Example 21.

 Test method: Castration surgery of animals: Male rats of S-200-260g were taken and adapted in the test environment for 1-2 days, and then castration surgery was performed, that is, anesthetized animals were administered with sodium pentobarbital femoral cavity ( Anesthesia; ¾ is 45mg / kg), the animals are lying on their backs, and a 1 cm incision is made in the depression in the middle of the bilateral testes, the testes are squeezed out, the wound is ligated, and the outer skin is sutured. Use iodine to eliminate ¾ suture, and then intramuscularly inject limamycin (4 I. U./kg) to prevent infection.

 Grouped administration test: The animals with successful operation were ranked 10th and randomly divided into five groups, 12 in each group, namely the PI I drug group (Viagra group), three high, medium, and low doses of the test drug ¾ group, Hypromellose control group; each group was given the corresponding drug once, and the control group was given the corresponding formulation solvent (5% hypromellose), and 15min, 30min, and 60rain were given before administration. Measure the penis diameter and length of the animal, and observe the latency of the penis to the penis erection (seconds).

 Test data processing: The comparison of the test results before and after the administration, the paired test and the comparison test between the groups were used for statistical processing. Based on this, the efficacy was evaluated. The results are as follows:

 1. The effect of apocedi on penile erection latency of castrated male rats is shown in the table below. It can be seen from the table that the high, medium and low doses of apocedi are in the group (37.8, 12.6, 4.2mg). / kg) can significantly shorten the erection period of human yin and yin under stimulus. It takes 15 minutes after taking the drug, and the effect is the strongest at 30 minutes (P <0.01), and the effect is enhanced with the increase of M; PII sex control-Viagra Group, the penile erection latency of rats was significantly shortened after 60 min of administration; the high and medium dose groups of apodia 15 min after administration were more effective than Viagra to shorten the penile erection latency, 30 min in the high, medium and low 3 Each agent ¾ group shortened the penile erection incubation time more significantly than Viagra (P <0.01) (X ± SD). The A body is shown in Table 22:

 Table 22

Note: The Viagra group is 12.6rag / kg based on sildenafil citrate. Compared with before administration, ** P <0.01, * P <0.05; APSD each agent ^: Compared with Viagra group, U P <0.05, S # P <0.01.

 2.Effect of apoxidi on penile diameter and length

The high-, medium-, and low-dose groups of apoxidi (37.8, 12.6, 4.2 mg / kg) had no significant effect on the change of the diameter of the penis in humans and rats, and had an effect on the length of the yin. Significantly increased length (P <0.05); 30 minutes after administration in the Viagra group, the length of yin ¾ could be significantly increased (P <0.05); 15 minutes after administration in the apodigal high, medium, and low dose groups, human and rat penis length Compared with Viagra, the increase was obvious, especially with high and low doses; the group showed ^: (P <0.05). In this experimental example, the Viagra group is 12.6nig / kg based on sildenafil citrate. The effect of Apo on the diameter (mm) and length (mm) of castrated rats (X ± SD) See Table 23:

Note: Viagra group is 12.6mg / kg based on dicralnafil citrate.

 Experimental Example 23

 This experimental example describes the effect of apoffidi on the length and length of male cynomolgus monkeys. The drugs and preparation methods used in this experiment are the same as those in Experimental Example 21; aposidedichuan is formulated with 5% hydroxypropyl methylcellulose; Viagra Prepared with distilled water, see Table 24 for A.

 Note: Viagra group is 5.6mg / kg based on sildenafil citrate.

 Animals: 5-11kg male macaques (FJLA-103) provided by the Fujian Non-Human Primate Experimental Animal Center, 4 animals in each group, a total of 20; apoxidi was administered via the buccal capsule mucosa, and Viagra was orally administered medicine. The test drug apoxidi was divided into two dose groups, respectively 16.2rag / kg, 5.4mg / kg, and 1.8mg / kg; [5 | The sex drug control group Viagra set a dose tt group as: 4. Omg / kg. Negative drug control group 5% hydroxypropyl cellulose solution.

 Test procedure: The animals were randomly divided into five groups, namely the PII drug group (Viagra group), the test drug high, medium and low three doses of the M group, the solvent control group, 4 animals in each group, each group corresponding to a single administration The control group was given the corresponding formulation solvent (5% light propyl methylcellulose), and the penis diameter and length of the animals were measured 15min, 30min, 45min, and 60min before the administration, respectively. Test data processing: The test results were statistically processed by paired t test before and after administration. The results are shown in Tables 25 and 26.

 The results of this experiment showed that: after the administration of apocedi 16.2 mg / kg, 5.½ g / kg ^ in the buccal pouch for 15-60min, the penile diameter of the macaque can be increased significantly (P <0.01); 1.8 mg / The low-kg ¾ group had a significant increase in diameter at 15 minutes after taking the drug (P <0.05), and a significant increase in penile diameter at 30-60 minutes had a significant ¾ (P <0.01); the PII sex control Viagra group (4.0 mg / kg) in 45min increased the penile diameter of rhesus monkeys significantly; apocydi medium and low doses ¾ increased penis length at 15-45min and 30-45min respectively.

 Experimental example 24

In this experimental example, the test drug, dose setting, animal model, administration route, and test data processing are the same as in Experimental Example 23. The test method is to randomly divide the animals into five groups, namely the positive drug group (Viagra group), Test the high, medium and low dose groups, the solvent control group. 4 animals per group. Animals in each group were anaesthetized with a dose of 10 mg / kg of ketamine. The anesthetized animals were placed on the operating table supine, lying on their backs, and their limbs were selected. One side of the male monkey's penis was selected as the cavernous body. / 00145 The cavernous cavity internal pressure (ICP) and smooth muscle electricity test side, the cavernous sinus smooth muscle electromyogram (EMG) reference electrode was fixed on the inside of the male monkey's thigh, and the penis and scrotal skin were routinely disinfected. The concentric needle electrode is inserted into the cavernous body of the penis on one side, and the angle of the needle is 45 ", the depth is 0.5 to 0.8 cm, and the signal is amplified by the DC preamplifier and recorded by the automatic balance recorder. Keep away from the electrode 1. 1.5 cm An 8-gauge needle was inserted into the sponge, and a pressure transducer was connected. The pressure signal was input to the automatic balance recorder to dynamically and simultaneously record the EMG and ICP before the administration. Then, the corresponding drugs were given in groups of dose M. The changes in EMG and II ICP values were observed at 30, 45, and 60 minutes. The results are shown in Tables 27 and 28.

Note: The Viagra group is 5.6 mg / kg based on sildenafil citrate; the comparison of each group before and after administration, ** P <0. 01, * P <0. 05 ,; between groups Compare ft P <0.05.

CONCLUSION: Apocelid excites the erection of cynomolgus monkey erection, it can increase the pressure of corpus cavernosum ^ and the reduction of penile smooth muscle electricity, in the dose of 1. 8-16. 2mg / kg ¾: the range can be obvious Increased Yin significantly: Cavernous cavity pressure, lowering yin-smooth muscle potential; Low-dose group increased macula monkey penile cavernous cavity pressure, and lowering yin: The effect of smooth muscle was similar to that of Viagra group; but at 15 minutes, Apo The effect of Xidi Dian Viagra, suggest that Apo and Onpa have a faster effect than Viagra, and the effect of increasing the internal pressure of the cavernous cavity of the penis is most obvious 15-45min after administration. The effect of lowering yin_smooth muscle potential is most obvious at 30-45rnin. The effect of apoxidi in reducing penile smooth muscle potential and increasing the pressure in the cavernous cavity of the penis increased with increasing dose.

GdAOONC / ssoo

Table 23

 Note: Viagra group is calculated as 12.6mg / kg based on dicralnafil; ** P <0.01, * P <0.05 compared with pre-dose; compared with Viagra group, each dose of APSD group, SP <0.05, <0.01 Table 25 Comparison of changes in yin ^ ^ (degree) of cynomolgus monkeys before and after administration

 Number of cases

 min 30 min after dosing 45 min after dosing 60 min after dosing

 Group before administration 15 after administration

 (n) (mg / kg)

 Solvent control group 4 60.75 ± 5.12 65.00 ± 10.80 60.00 ± 4.08 62.50 ± 5.07 60.50 ± 7.94

 APSD high dose group 4 16.2 71.75 ± 15.13 80.50 ± 7.72 86.00 ± 6.27 86.25 ± 4.79 84.25 ± 6.08

 APSD medium; ¾ group 4 5.4 80.25 ± 6.18 91.75 ± 7.41 * 92.75 ± 7.80 * 90.50 ± 7.72 * 87.75 ± 7.18

 APSD low dose group 4 1.8 78.25 ± 5.68 87.25 ± 8.62 90.00 ± 4.55 * 89.75 ± 5.91 * 84.75 ± 7.76

Viagra group 4 4.0 62.75 ± 4.57 68.00 ± 8.83 68.25 ± 4.72 68.00 ± 6.73 65.75 ± 8.50

OM 09 09] d / I00 / 0 S2

Table 26 Comparison table of penile diameter (band) changes before and after administration in each group of rhesus monkeys (X ± SD):

Note: The Viagra group in Tables 25 and 26 is 12.6 mg / k _g based on sildenafil citrate _; comparison before and after administration, P <0.01, * P <0.05c

 Table 27 Comparison table of changes in EMG (unit UV) of each group of animals before and after administration (X ± SD):

 Note: The Viagra group is calculated as 5.6mg / kg based on dicralnafil citrate. The comparison of each group before and after administration is ** P <0.01, * P <0.05, and the comparison between the groups # P <0.05 .

Claims

Claim 1. A method for preparing sildenafil, specifically a 5- [2-ethoxy-5- (4-methylpiperazinylsulfonyl) phenyl] -1-methyl-3 -A method for preparing n-propyl-1, 6-dihydro-7H-pyrazolo [4. 3-d] pyrimidin-7-one, characterized in that 5- (5-halosulfonyl-2-ethoxyl Phenyl) -1-methyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo [4. 3-d] pyrimidin-7-one with 1-methylpiperazine salt, After being neutralized and washed with water, sildenafil has a purity of more than 98%.  2. The preparation method according to claim 1, characterized in that 5- (5-thio · sulfonyl-2-ethoxyphenyl) -1-methyl-3-n-propyl-1, 6 -Dihydro-7Η-pyrazolo [4. 3-d] pyrimidin-7-one 7.5 g (0.018 mol) was added to 125 ml of ethanol, stirred, and 1-methylpiperazine monohydrochloride 2 was added at room temperature 2 95 g (0.022 mol), react for 1 hour, add 75 ml of water, and then neutralize the reactant to pH 7.0 with 4N sodium hydroxide solution, make the title compound free, stir at 5-10 ° C for 2 hours, and suction filter , The filter cake was washed with water and dried in the presence of phosphorus pentoxide to obtain the title compound 7.85 g, yield 92%, mpl89-190'C, with 99.8% sildenafil acetate as reference 4%。 Material, high performance liquid chromatography (HPLC) analysis showed that the above reaction does not require crystallization, chromatographic separation and other purification steps, the purity of the compound directly obtained was 98.4%.  3. The method according to claim 1, wherein the 5- (5-halosulfonyl-2-ethoxyphenyl)-1-methyl-3-n-propyl- The halosulfonyl halide in 1, 6-dihydro-7H-pyrazolo [4. 3-d] pyrimidin-7-one is F-, CL-, Br- or I-, preferably CL-.  4. The preparation method according to claim 1, wherein the 1-methylpiperazine salt is a single salt, comprising 1-methylpiperazine hydrobromide, sulfate, nitrate, phosphate, Acetate was propionate and the title compound was prepared in a yield of 87-93%.  5. The preparation method according to claim 1, wherein the 1-methylpiperazine salt is a double salt, comprising 1-methylpiperazine dihydrochloride, dihydrobromide, and dinitrate , Diformate, diacetate, the yield of the title compound was 84-91%.  6. The preparation method according to claim 1, wherein the 1-methylpiperazine salt is a double salt, including 1-methylpiperazine hydrochloride monohydrobromide double salt, and hydrochloric acid mononitrate , Hydrochloride monoformate double salt, hydrochloride monoacetate double salt, monohydrobromide nitrate double salt, nitrate monoacetate double salt, formic acid monoacetate double salt, the yield of the title compound was 78-82%.  7. The preparation method according to claim 1, wherein the 1-methylpiperazine salt is preferably a hydrochloride salt. 8. The preparation method according to claim 1, characterized in that the solvent can be selected from tl C1-C6 alcohol, 1, 2-dimethoxyacetamidine, 1, 2-diethoxyethane, di Methyl sulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, and preferred solvents are ethanol, 2-propanol, and dimethylformamide.  9. The preparation method according to claim 1, wherein the alkaline solution is selected from inorganic bases such as potassium hydroxide, sodium hydroxide, sodium carbonate, and sodium bicarbonate, or organic bases such as methylamine, ammonia, and pyridine. The preferred alkaline solutions are sodium hydroxide, sodium carbonate, ammonia and pyridine, and sodium hydroxide and sodium carbonate are most preferred.  10. The preparation method according to claim 1, wherein the 1-methylpiperazine salt compound is preferably 1-methylpiperazine monohydrochloride, the solvent is ethanol, and the alkaline solution is a sodium hydroxide solution. .  11. The preparation method according to claim 1, wherein the sildenafil compound of structural formula (I) is generated in the form of a salt, and the product is collected by neutralizing a pre-diluted reaction mixture, followed by filtering and washing, Sildenafil can also be isolated and purified by conventional techniques such as recrystallization. 12. An apoxidi compound buccal tablet, containing auxiliary materials such as a wetting adhesive, an acidic medium, a lubricant, a preservative, a flavoring agent, and a pigment, characterized in that the compound buccal tablet contains citrus Sildenafil gallate and apomorphine hydrochloride and inclusion agents. 13. The aposilidi compound oral tablet according to claim 12, characterized in that the dosage of sildenafil citrate in the compound oral tablet is 20-120mg / person (70kg), a hydrochloride The dosage of promorphine is 2-10mg / person (70k _g ).  14. The aposilidi compound oral buccal tablet according to claim 13, characterized in that the amount of sildenafil citrate in the compound oral buccal tablet is preferably 30-120 mg / person (70 kg), hydrochloric acid The amount of apomorphine is preferably 2-8 mg / person (70 kg).  15. The aposilidi compound oral tablet according to claim 14, characterized in that the dosage of sildenafil citrate in the compound oral tablet is most preferably 40-50 mg / person (70 kg), W ^ of apomorphine hydrochloride: preferably 3-6 / mg human (70kg).  16. The apoxidi compound oral buccal tablet according to claim 12, wherein the wetting and thickening agent in T is selected from hypromellose, ethyl methyl cellulose, ethyl cellulose, Poly alpha-hydroxyethyl methacrylate, povidone, polyvinyl acetate, cellulose acetate, gelatin, dextrin, white dextrin, microcrystalline cellulose, methyl cellulose, methyl acrylate, acrylic resin I- No. IV, one or more combinations of hydroxyethyl methyl cellulose, hydroxyethyl cellulose, carbomer, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose.  17. The apoxidi compound oral buccal tablet according to claim 12, wherein the compound in the compound oral buccal tablet described in T. is cyclodextrin. 18. The compound oral buccal tablet of Apu according to claim 17, characterized in that the cyclodextrin is selected from one or more combinations of the following groups: α-cyclodextrin ( a- CD), β-cyclodextrin (β-CD), y-cyclodextrin (Y-CD), hydroxypropyl-β-cyclodextrin (HP-β-CD), ethylcyclodextrin ( Ee-CD), dimethyl-β-cyclodextrin (DM-e-CD), trimethyl-β-cyclodextrin (TM-β-CD), monoglycosyl-β-cyclodextrin (G ,. e-CD), diglycosyl-β-cyclodextrin (G β-CD), maltotriosyl-β-cyclodextrin (G _{: t} . β- CD), dimonoglycosyl — β- Cyclodextrin (2G, .β-CD), dibis-glycosyl-e-cyclodextrin (2G ₂ .β-CD).  19. The apoxidi compound oral buccal tablet according to claim 12, wherein the dosage of apomorphine hydrochloride and cyclodextrin in the compound oral buccal tablet is 7: 1-3: 1.  20. The apoxidi compound buccal tablet according to claim 19, wherein the dosage of apomorphine hydrochloride and cyclodextrin in the compound buccal tablet is preferably 6: 1-4: 1.  21. According to claim 18, the apoxidi compound oral buccal tablet is characterized in that the dosage of apomorphine hydrochloride and cyclodextrin in the compound oral tablet is most preferably 5: 1. 22. The apoxidi compound buccal tablet according to claim 12, characterized in that the compound buccal tablet described in D is: apomorphine hydrochloride (containing C ₁₇ H ₁₇ N0 ₂ · HC1) 2 -10g Sildenafil citrate (C ₂₂ H, ₀ NASC ₆ H ₈ 0 ₇ ) 20-120g  β-cyclodextrin 60-670g  Wetting adhesive 60-600g  Acid medium 2—10g  Mannitol 26- 30g  Preservative 0.03— 0.05g  Sweetener 600-850g  Spice 4- 10g  Menthol 2g  Pigment amount  Lubricant 5-15R Made into 1000 tablets 23. The apoxidi compound oral buccal tablet according to claim 22, wherein the formula of the compound oral buccal tablet is preferably: Apomorphine hydrochloride (with C ₁₇ H, ₇ N0 ₂ · HC1) 6g Sildenafil citrate _{(2 .Ν 6 0 ^ · C} 6 H 8 0 7) 40g  β-Cyclodextrin 150g  Hypromellose 6g  6g stearic acid  Mannitol 28g  Methyl parahydroxybenzoate 0.04g  Sucrose 780g  15g  Strawberry Spice 5g  Menthol 2g  Bright blue pigment 0. 05g  Calcium stearate  1000 tablets  24. The method for preparing apoxidi compound buccal tablet according to claim 12, characterized in that in the preparation method, at least one of apomorphine hydrochloride and apoxidi is contained in the preparation method, It is then mixed with other ingredients and ground and pressed.  25. The method for preparing apoxidi compound oral buccal tablets according to claim 24, wherein in the method described in D, cyclodextrin is used to contain at least one of apomorphine hydrochloride and apoxidi One kind, then mixed with other ingredients, grinded and compressed.  26. The method for preparing apoxidi compound oral blob according to claim 25, wherein the method for preparing is:  (1) Disperse the wetting adhesive with ethanol first, and then soak it with distilled water to completely dissolve, stir well, and pass through a 80 mesh sieve for later use.  (2) Put {¾-cyclodextrin into the mortar, add the wetting binder solution, grind it evenly, and then add the acidic medium and apomorphine hydrochloride to continue grinding until it is fully contained, and use it as the raw material I.  (3) Put β-cyclodextrin into the mortar and add the wetting binder solution. After grinding uniformly, add dinafil citrate and continue to grind until it is completely contained, and use it as the raw material II.  (4) Mix the sweetener and pigment mother powder thoroughly, sifter, and then add Raw Material I and Raw Material II to mix evenly, pass through a 16-mesh sieve and a 20-mesh sieve once, and finally add a preservative-containing HPMC solution to make it soft. material.  (6) Sieve the soft material Chuan 16 Θ to sieve the granules and thinly pan the pans to bake. Baking temperature is controlled below 6 ° C, ventilated and dried. After drying, the granules are whole with 16 mesh.  (7) After granulation, mix a certain amount of fine powder with spices and flavoring agents and sifter once, mix with the whole batch of granules, and finally add magnesium stearate to mix and press.  27. The method for preparing apoxidi compound oral blob according to claim 25, characterized in that the method for preparing Ding is as follows:  (1) Disperse the wetting adhesive with ethanol first, then dip it in distilled water to completely dissolve, stir well, and pass through 80 0 sieve for later use; (2) Put P-cyclodextrin into the mortar, add the wetting binder solution, grind it evenly, then add the acidic medium and apomorphine hydrochloride and continue to grind until it is fully contained, and use it as the raw material I; (3) Mix the sweetener and the pigment mother powder thoroughly and sieved, then add the raw material I and sildenafil citrate, pass each of the 16 mesh sieve and the 20 mesh sieve once, and finally add the preservative-containing adhesive Agent solution made of soft wood;  (4) Dry and tablet.  28. The method for preparing apoxidi compound oral buccal tablet according to claim 25, wherein the method is:  (1) Disperse the wetting adhesive with ethanol, then dip it in distilled water to completely dissolve it, stir well and pass it through an 80 mesh sieve for later use;  (2) Put a certain amount of β-cyclodextrin (β-CD) into the mortar and add a suitable HPMC solution, grind evenly, and then add stearic acid, apomorphine hydrochloride and sildenafil citrate to continue grinding Until fully enclosed, ready for use (for raw material III);  (3) Mix the sweetener and pigment mother powder thoroughly, sifter, and then add raw material III, pass through 16 Θ sieve and 20 B sieve once, and finally add a preservative-containing binder solution to make a soft material;  (4) Dry and tablet.  29. The method for preparing apoxidi compound oral buccal tablets according to claim 24, wherein the method further comprises: using a lecithin to separate apomorphine hydrochloride or sildenafil citrate. At the same time, the liposome is encapsulated. The formula for preparing liposomes is as follows:  Sildenafil citrate 20-120g  Egg Yolk Lecithin 20-120g  Wetting tackifier 4-24g  Tween-80 2- 12g  Phosphate pH 7.2 buffer 25-130ml  Apomorphine hydrochloride 2-10g  Egg Yolk Lecithin 2-10g  Cholesterol l-6g  Wetting thickener 0. 5-2g  Phosphate buffer pH 6. 8 5-15ml  Preparation:  (1) Put sildenafil in a pH 7.2 phosphate buffer solution and stir well, then add egg yolk lecithin, polyethylene glycol, Tween -80, mix thoroughly and dry, pass through a 30 mesh sieve, and set aside.  (2) Put apomorphine into a pH 6.8 phosphate buffer solution and stir well, then add egg yolk lecithin, bile I alcohol, and polyethylene glycol 200 to mix thoroughly, ventilate and dry at 50 ° C, and pass through a 30 mesh sieve , That is.  30. The method for preparing apoxidi compound oral buccal tablet according to claim 24, wherein the method further comprises: separately or directly encapsulating two drugs with cellulose, and the formula is as follows:  Sildenafil citrate 20-120g  Mannitol  Wetting tackifier 2-4% (EtoH80%, ¾0 20%)  Dispersant 1-3%  Apomorphine hydrochloride 2-10g  Stearic acid 2-10g Wetting tackifier 2-5% (EtoH80%, H ₂ 0 20%) Polyethylene glycol 6000 0.5-3% The preparation process is as follows: HPMC is first dispersed with EtoH, polyethylene glycol is dissolved with distilled water, and then the two are combined, and EtoH and H ₂ 0 are added respectively to an appropriate HPMC concentration, and the PEG 6000 concentration is 1.5%, which is reserved. Mix dinafil and mannitol evenly, add some of the above-mentioned stock solution to make a soft material; mix apomorphine with an acidic medium, add the above-mentioned stock solution to mix well; the two are gradually expanded by the auxiliary method with the auxiliary method. Then, the two are combined into all auxiliary materials, fully mixed and homogenized, and added with a reserve liquid to make a soft material, granulated with 16 mesh, dried under aeration of 60 ° C, whole granulated, flavored and slippery to tablet.  31. The method according to claim 24, wherein the acidic medium can be selected from β, stearic acid, palmitic acid, palmitic acid, and ascorbic acid, or a combination thereof.  32. The method according to claim 24, wherein the lubricant is one or more combinations of polyelectrolyte, organic and inorganic salts such as magnesium stearate, calcium stearate, and the like.  33. The method according to claim 24, wherein the filler and flavoring agent further include two or more kinds of mannitol, protein or other synthetic sugars, menthol, and spices.  34. The method according to claim 24, characterized in that the grinding can use a saturated solution method, an ultrasonic method, a freeze-drying method, and a grinding method to encapsulate the drug,  35. The method according to claim 24 or 33, characterized in that T · preferred Sichuan grinding method is included.  36. The method according to claim 24, characterized in that, in the case of inclusion by grinding, one or more of the wetting and thickening agents are selected, and stearic acid is used as an acidic medium to enclose It can only contain apomorphine hydrochloride; it can also include sildenafil citrate and apomorphine hydrochloride separately, and then mix and granulate; it can also use acyclic morphine and apomorphine hydrochloride simultaneously. Dextrin inclusion.  37. The method according to claim 24, wherein the inclusion ratio of β-cyclodextrin (β-CD) to apomorphine hydrochloride is 3: 1-7: 1, and the inclusion time is 30-180. Minutes, HPMC concentration is 3%, preferably cyclodextrin apomorphine hydrochloride ratio is 4: 1 -6: 1, inclusion time is 40-50 minutes, HPMC concentration is 3%; most preferred is cyclodextrin and ahydrochloride The promorphine ratio was 5: 1, the inclusion time was 45 minutes, and the HPMC concentration was 3%.  37. The method according to claim 24, characterized in that the optimal ratio of the cyclodextrin-containing citrate I «j-denafil is 2: 1-7: 1 and the HPMC concentration is 3 %; Preferably 3: 1 to 5: 1.