CN115919867B

CN115919867B - Aidenafil citrate oral sustained-release preparation and preparation method and application thereof

Info

Publication number: CN115919867B
Application number: CN202211600539.1A
Authority: CN
Inventors: 宋更申; 欧阳旭; 史红娟; 蔡银; 闫美玲; 马灿
Original assignee: Beijing Youcare Kechuang Pharmaceutical Technology Co ltd
Current assignee: Beijing Youcare Kechuang Pharmaceutical Technology Co ltd
Priority date: 2022-12-13
Filing date: 2022-12-13
Publication date: 2024-05-24
Anticipated expiration: 2042-12-13
Also published as: CN115919867A

Abstract

The invention relates to an alidenafil citrate oral sustained-release preparation, a preparation method and application thereof. The oral sustained release preparation comprises a pharmaceutical active ingredient, wherein the pharmaceutical active ingredient is alidenafil citrate and/or pharmaceutically acceptable salt thereof. The preparation is a biphasic release preparation with a quick release part and a slow release part combined, the floating time is greatly shortened, the continuous floating time is obviously prolonged, the density is obviously reduced, the tablet is completely released, and the preparation has a good slow release effect; and the time for reaching peak concentration of the blood medicine is obviously prolonged, the stability and bioavailability of the blood medicine concentration are obviously improved, and the medicine can be used for treating Alzheimer disease and erectile dysfunction.

Description

Aidenafil citrate oral sustained-release preparation and preparation method and application thereof

Technical Field

The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to an alidenafil citrate oral sustained-release preparation, a preparation method and application thereof.

Background

Alzheimer's disease (Alzheimer disease, AD), also known as senile dementia, is a central nervous system degenerative disease with hidden onset and chronic progression of the course of the disease, and is one of the most common types of senile dementia. Most of the elderly over 70 years (average male age 73 years, female age 75 years), and a few patients develop rapidly symptoms after physical diseases, fractures, or mental irritation. Women are more male than female (the ratio of men to women is 1:3). The report of the Alzheimer's disease Association in 2018 indicated that AD patients had reached 5000 ten thousand, with an average of 1 new case every 3 seconds of acceleration. By 2030, global patients are expected to be over 8000 ten thousand, and by 2050 may be over 1.5 hundred million.

The main manifestations of Alzheimer's disease are: neuropsychiatric symptoms such as progressive memory impairment, cognitive dysfunction, personality changes, and language impairment severely affect social, work, and life functions.

Currently, the most of the commercial citric acid alidenafil drugs for treating Alzheimer's disease are common quick-release tablets, and take the drugs for 2 times or 3 times 1 day. According to the inquiry, patent CN115054585A describes a pharmaceutical tablet containing alidenafil citrate for treating Alzheimer's disease.

The solubility of the sildenafil citrate bulk drug is pH dependency, the solubility in acid is high (pH 1.2 medium solubility: 4.7 mg/mL), the solubility in alkali is greatly reduced (pH 6.8 medium solubility: 0.04 mg/mL), the gastric emptying time of a human body is about 15-30 min, and then the sildenafil citrate bulk drug is emptied to the duodenum, the small intestine and the ileum for absorption, and most of the retention position of a common 24-hour slow release preparation is in the small intestine or the colon, the pH of the position is about 5.5-7.5, the solubility of the sildenafil citrate in the slightly alkaline intestinal tract is obviously reduced, the absorption effect of the slow release preparation is greatly influenced, and the bioavailability of the slow release preparation is influenced.

By retrieving documents or patents, retrieve:

Patent CN114344270a discloses a PDE5 inhibitor and dapoxetine coated chip and a preparation method thereof, which is characterized in that a tablet core containing the PDE5 inhibitor and a shell layer of dapoxetine are prepared into a coated chip, the tablet core which is independently formed into a tablet replaces direct compression between two active ingredient powders, and independent coating is carried out, so that two active ingredients in the shell layer are separated, the two active ingredients are ensured not to directly react, and the stability is further influenced. However, it does not disclose how to control the time of floating and continuous floating, and thus improve the slow release effect of the preparation, and it is impossible to ensure the long-time stable blood concentration, thereby improving the bioavailability.

Therefore, there is an urgent need to provide an oral sustained release preparation of alidenafil citrate, which can be used for treating Alzheimer's disease, and simultaneously improve the compliance of Alzheimer's disease patients in clinical administration, obviously reduce the time for floating, and prolong the duration of floating, so that the medicine is released continuously in the stomach, the residence time of the medicine in a specific absorption window is prolonged, and the curative effect of the medicine is increased; meanwhile, the slow release preparation can prolong the acting time of the effective concentration of the medicine in the blood plasma after being absorbed, can meet the requirement of taking once a day, and achieves good slow release effect, thereby stabilizing the blood concentration and improving the bioavailability.

Disclosure of Invention

Aiming at the problems, the invention provides an alidenafil citrate oral sustained-release preparation which can be used for treating Alzheimer's disease and improving the clinical administration compliance of Alzheimer's disease patients. The preparation is a biphasic release preparation consisting of a quick release part and a slow release part, can rapidly reach the therapeutic blood concentration level, and can continuously and slowly release and maintain the therapeutic blood concentration level; meanwhile, the slow-release part of the invention is designed into a hydrophilic gel skeleton slow-release preparation, which swells in gastric juice and floats in gastric juice for a long time, thus avoiding the problems of low drug absorption and low bioavailability caused by low solubility in alkaline environment.

The preparation has the advantages that the floating time is greatly shortened (as low as 6 min), the continuous floating time is obviously prolonged (as long as 16 h), the density is obviously reduced (as high as 28 percent), and the tablet is completely released, so that the preparation has a good slow release effect; and the stability of the blood concentration and the bioavailability (up to 95.32%) are obviously improved.

The method comprises the following steps:

an alidenafil citrate oral sustained-release preparation comprises a pharmaceutical active ingredient,

The active pharmaceutical ingredient is alidenafil citrate and/or pharmaceutically acceptable salt thereof.

In some embodiments, the formulation includes a slow release portion.

In some preferred embodiments, the sustained release portion comprises a pharmaceutically active ingredient.

In some more preferred embodiments, the sustained release portion further comprises a matrix material.

In some embodiments, the scaffold material is selected from the group consisting of: any one of a hydrophilic gel skeleton, an insoluble skeleton and a bioerodible skeleton; in some preferred embodiments, the scaffold material is a hydrophilic gel scaffold material.

In some more preferred embodiments, the hydrophilic gel matrix material is a cellulosic material.

In some embodiments, the matrix material further comprises a carbomer-like material and/or a polysaccharide-like material.

In some embodiments, the sustained release portion further comprises any one or more of a surfactant, a lubricant, a disintegrant, a diluent.

In some embodiments, the formulation further comprises an immediate release portion.

In some embodiments, the immediate release portion comprises a pharmaceutically active ingredient.

In some embodiments, the immediate release portion further comprises any one or more of a binder, lubricant, disintegrant, diluent.

In some embodiments, the mass ratio of the pharmaceutically active ingredient in the sustained release portion to the pharmaceutically active ingredient in the immediate release portion is (3-8): 1, preferably 5:1.

In some preferred embodiments, the slow release portion and the quick release portion are used in amounts of, in mass percent, respectively:

in some embodiments, the cellulosic material is selected from the group consisting of: any one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and sodium carboxymethyl cellulose; in some preferred embodiments, the cellulosic material is hydroxypropyl methylcellulose.

In some embodiments, the polysaccharide material is selected from the group consisting of: any one or more of sodium alginate, chitosan and xanthan gum; in some preferred embodiments, the polysaccharide material is sodium alginate.

In some embodiments, the mass ratio of the cellulose material, the carbomer material and the polysaccharide material in the framework material is = (4-1) 1 (1-3); in some preferred embodiments, the mass ratio of cellulosic, carbomer, polysaccharide materials = 2:1:2 in the matrix material.

In some embodiments, the model of hydroxypropyl methylcellulose is selected from the group consisting of: any one or more of K100M, K, M, K, M, K, 100 LV; in some preferred embodiments, the hydroxypropyl methylcellulose is model K100M.

In some embodiments the carbomers are selected from the group consisting of: any one or more of carbomer 934P, carbomer 971P, carbomer 974P; in some preferred embodiments, the carbomers are carbomers 971P.

In some preferred embodiments, the dosage form of the formulation comprises a sustained release tablet or a sustained release capsule.

In some embodiments, the surfactant is selected from the group consisting of: any one or more of glyceryl behenate, glyceryl monooleate, stearyl alcohol, polysorbate, poloxamer, and sodium dodecyl sulfate; in some preferred embodiments, the surfactant is glyceryl behenate.

In some embodiments, the disintegrant is selected from the group consisting of: any one or more of crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethyl cellulose, sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose; in some preferred embodiments, the disintegrant is crosslinked polyvinylpyrrolidone.

In some embodiments, the diluent is selected from the group consisting of: any one or more of lactose, microcrystalline cellulose, calcium hydrogen phosphate, mannitol, and pregelatinized starch; in some preferred embodiments, the diluent is a combination of lactose and microcrystalline cellulose.

In some embodiments, the lubricant is selected from the group consisting of: any one or more of stearic acid, magnesium stearate and sodium stearyl fumarate; in some preferred embodiments, the lubricant is magnesium stearate.

In some embodiments, the binder is selected from: any one or more of polyvinylpyrrolidone K30, hydroxypropyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose and starch slurry; in some preferred embodiments, the binder is polyvinylpyrrolidone K30.

In some preferred embodiments, the oral sustained release formulation is for the treatment of alzheimer's disease.

In some preferred embodiments, the oral sustained release formulation is used to treat erectile dysfunction.

The invention also provides a preparation method of the oral sustained-release preparation, which comprises the following steps:

1) Preparation of the sustained release portion: sieving the active ingredients of the sustained-release part, and mixing the active ingredients with a framework material, a surfactant, a disintegrating agent and a diluent; finally adding a lubricant and mixing to obtain a slow-release part;

2) Preparation of quick release part: uniformly mixing the active pharmaceutical ingredient of the quick-release part, the diluent and the disintegrating agent, adding the adhesive for wet granulation, drying, sieving and mixing with the lubricant to obtain the quick-release part;

3) Combining: the slow release portion and the quick release portion are combined.

In some preferred embodiments, the means of bonding comprises tablet bonding or capsule bonding;

in some embodiments, the tablet bond comprises a two-layer tablet bond or a core-in-tablet bond; in some preferred embodiments, the tablet bond is a bilayer tablet bond;

in some preferred embodiments, the capsule binding comprises biphasic particle binding, biphasic capsule binding, biphasic pellet binding, or biphasic microchip binding.

The invention also provides application of the sildenafil citrate oral sustained-release preparation in preparing a medicament for treating Alzheimer's disease.

The invention also provides an application of the alidenafil citrate oral sustained-release preparation in preparing medicines for treating erectile dysfunction.

The beneficial effects of the invention are as follows:

an oral sustained release preparation of alidenafil citrate can be used for treating Alzheimer's disease and improving the compliance of clinical administration of Alzheimer's disease patients. The preparation prepared by utilizing the specific slow-release framework material has the advantages that the floating time is greatly shortened (as low as 6 min), the continuous floating time is obviously prolonged (as long as 16 h), the density is obviously reduced (as high as 28 percent), the tablet is completely released, and the preparation has a good slow-release effect; and the time for reaching peak concentration of the blood medicine is obviously prolonged (as long as 6.5 h), and the stability and bioavailability of the blood medicine are obviously improved (as high as 95.32%).

The method comprises the following steps:

I) The invention adopts the specific framework materials, especially the combination of cellulose, carbomer and polysaccharide materials, ensures that the floating time is short (as low as 6min and far less than 1 h) and the continuous floating time is long (as long as 16h and far more than 10 h), thereby playing the role of controlling the release rate of the medicine and having good slow release effect.

1. Cellulose material

By adding cellulose materials, the continuous floating time of the tablet can be obviously prolonged, and the release effect of the tablet is improved:

a) When the cellulose material is selected from hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and sodium carboxymethyl cellulose, the sustained-release effect of the tablet is good, and the tablet is expressed as follows:

i. the floating time is obviously shortened (only 6-35 min) which is far lower than the floating time limit of the tablet (1 h);

The continuous floating time is greatly prolonged (up to 12-16 h) and is far longer than the slow release time requirement (more than 10 h) of the slow release preparation, and the slow release preparation can stay in the stomach for a long time to play a role;

Tablet release is complete: the release degree of 1h is 22-32%, the release degree of 4h is 42-56%, the release degree of 12h is 75-95%, the release degree requirement of sildenafil citrate in 24h is satisfied (the release degree of 1h is 15-35%, the release degree of 4h is 40-55%, and the release degree of 12h is 70-100%);

b) Wherein, when K100M is adopted as the model of hydroxypropyl methylcellulose, the sustained release effect of the tablet is best, and the sustained release effect is expressed as follows:

i. The bioadhesion is strong, the viscosity is high, the floating time is the shortest (only 6 min), and is far lower than the floating time limit of the tablet (< 1 h);

The sustained floating time is longest (up to 16 h) and is far longer than the slow release time requirement (> 10 h) of the slow release preparation;

Tablet release is complete: the release degree of 1h is 24%, the release degree of 4h is 45%, the release degree of 12h is 77%, and the release degree requirement of sildenafil citrate in 24h is met (the release degree of 1h is 15% -35%, the release degree of 4h is 40% -55%, and the release degree of 12h is 70% -100%).

2. Polysaccharide material

A) Sodium alginate, chitosan and xanthan gum are added as polysaccharide materials, so that the floating time of the preparation can be reduced, the slow release effect of the tablet is improved, and the preparation is expressed as follows:

i. The time for the tablet to float is obviously shortened (only 6-45 min) and is far lower than the limit of the time for the tablet to float (< 1 h);

The continuous floating time is greatly prolonged (up to 12-16 h) and is far longer than the slow release time requirement (10 h) of the slow release preparation;

Tablet release is complete: the release degree of 1h is 24-30%, the release degree of 4h is 45-54%, the release degree of 12h is 77-96%, the release degree requirement of sildenafil citrate in 24h is met (the release degree of 1h is 15-35%, the release degree of 4h is 40-55%, and the release degree of 12h is 70-100%);

b) Wherein, when the polysaccharide material selects sodium alginate, the slow release effect of the tablet is best, and the slow release effect is expressed as follows:

i. The tablet has the shortest floating time (as low as 6 min) which is far lower than the floating time limit (< 1 h) of the tablet, and as sodium alginate is an alginate extracted and synthesized from seaweed, the sodium alginate is rapidly hydrated into an insoluble alginic acid skeleton in an acidic medium as an anionic compound, and the gel forming speed is high;

3. Carbomers material

By adding carbomer materials, the structural integrity of the tablet can be maintained for a long time, and the sustained release effect of the tablet is improved:

a) The carbomer material is a copolymer of polyalkyl sucrose or polyalkyl pentaerythritol and acrylic acid crosslinked polymer, and due to the characteristic of the crosslinked structure of carbomers (carbomer 934P, carbomer 971P and carbomer 974P), the carbomer material has higher viscosity, the slower the drug release, the stronger the bioadhesion, the longer the continuous floating time, and the better the slow-release effect, which is expressed as:

i. the floating time is obviously shortened (6-25 min) which is far lower than the floating time limit of the tablet (1 h);

The continuous floating time is greatly prolonged (up to 15-16 h) and is far longer than the slow release time requirement (10 h) of the slow release preparation;

Tablet release is complete: the release rate of 1h is 24-34%, the release rate of 4h is 45-55%, the release rate of 12h is 77-98%, the release rate requirement of sildenafil citrate in 24h is met (the release rate of 1h is 15-35%, the release rate of 4h is 40-55%, the release rate of 12h is 70-100%), and the sustained release effect of the tablet is good.

B) Among them, carbomer 971P was used, and the sustained release effect of the tablet was best, and it was shown that:

i. The tablet has the shortest time (as low as 6 min) and is far lower than the time limit of the tablet to float (< 1 h);

4. By controlling the dosage ratio of the hydroxypropyl methylcellulose K100M, carbomer and sodium alginate composition in the framework material, the tablet density (reduced by 28%) and the floating time (much less than 1 h) are obviously reduced, the continuous floating time (10 h) is greatly prolonged, and the tablet is completely released and has good slow release effect.

A) The dosage ratio of the hydroxypropyl methylcellulose K100M, carbomer and sodium alginate is = (4-1): 1 (1-3), and the sustained release effect of the tablet is good, and the tablet is expressed as follows:

i. The floating time is short: the density of the tablet changes rapidly (the density decreases to 17% -28%) within 8 hours after the tablet swells, the floating time is obviously shortened (only 6-15 min), and the floating time limit of the tablet is far lower than (< 1 hour);

The continuous floating time is greatly prolonged (up to 11-16 h) and is far longer than the slow release time requirement (10 h) of the slow release preparation;

Tablet release is complete: the release degree of 1h is 17-28%, the release degree of 4h is 45-55%, the release degree of 12h is 77-85%, and the release degree requirements of sildenafil citrate in 24h are met (the release degree of 1h is 15-35%, the release degree of 4h is 40-55%, and the release degree of 12h is 70-100%);

b) Wherein, when the dosage ratio of the hydroxypropyl methylcellulose K100M, carbomer and sodium alginate is 2:1:2, the sustained release effect of the tablet is best, and the tablet is expressed as follows:

i. The density of the tablet changes fastest (reduced by 28%) within 8 hours after the tablet swells, the float time is shortest (as low as 6 min), and is far lower than the float time limit of the tablet (< 1 h);

II) the biphasic release preparation adopting the combination of quick release and slow release not only can reduce the density of the tablet (obviously reduce 28%) and enhance the slow release effect of the tablet (the floating time can be as low as 6min and is far less than 1h; the continuous floating time is as long as 16 hours, is far longer than 10 hours, and the tablet is completely released), the peak concentration time of the blood medicine can be obviously prolonged, and the stability and bioavailability (up to 95.32%) of the blood medicine concentration can be obviously improved, which is expressed as follows:

i. the quick-release part can be rapidly disintegrated and dissolved out, and can be rapidly disintegrated within 1min, and the quick-release part can be rapidly absorbed within 1 hour to reach the clinically required blood concentration of the therapeutic window;

the sustained release part can be released continuously within 24 hours, the blood concentration is kept at 144.48 +/-35.5 mug/mL, the peak blood concentration time is obviously prolonged (as long as 6.5 hours), the blood concentration is stable, and the bioavailability is obviously improved (as high as 95.32%).

The sildenafil citrate oral sustained-release preparation prepared by the method can be used for treating Alzheimer's disease and erectile dysfunction, and simultaneously improves the compliance of clinical administration of patients, the prepared preparation has the advantages of greatly shortened floating time (as low as 6 min), obviously prolonged continuous floating time (as long as 16 h), obviously reduced density (as high as 28 percent), complete tablet release and good sustained-release effect; and the time for reaching peak concentration of the blood medicine is obviously prolonged (as long as 6.5 h), and the stability and bioavailability of the blood medicine are obviously improved (as high as 95.32%).

Drawings

FIG. 1 is a graph comparing the release profiles of the tablets of examples 1-3 over 24 hours;

FIG. 2 is a graph comparing the release profiles of the tablets of example 3 and example 4 over 24 hours;

FIG. 3 is a graph comparing the release profiles of the tablets of example 3 and example 5 over 24 hours;

FIG. 4 is a graph comparing the release profiles of the tablets of example 3 and example 6 over 24 hours;

FIG. 5 is a graph comparing the release profiles of the tablets of example 3 and example 7 over 24 hours;

FIG. 6 is a graph comparing the release profiles of the tablets of example 3 and example 8 over 24 hours;

FIG. 7 is a graph showing the density change curves of the tablets of example 1 and example 9 after swelling;

FIG. 8 is a graph comparing the release profiles of the tablets of example 3 and example 9 over 24 hours;

FIG. 9 is a graph comparing the release profiles of the tablets of example 3 and example 10 method 1 over 24 hours;

FIG. 10 is a graph comparing the release profiles of the tablets of example 3 and example 10 method 2 over 24 hours;

FIG. 11 is a graph comparing the release profiles of the tablets of example 3 and example 10 method 3 over 24 hours;

Fig. 12 is a graph comparing the release profiles of the tablets of example 3 and example 11 over 24 hours.

Detailed Description

The invention is further illustrated by the following examples. It should be understood that: the embodiments of the present invention are only given for illustrating the present invention, but not for limiting the present invention, and the simple modification of the present invention on the premise of the technical solution of the present invention is all within the protection scope of the present invention.

Example 1:1 material with single component skeleton material

Respectively taking hydroxypropyl methylcellulose K100M, carbomer 971P and sodium alginate as framework materials of the slow-release part,

Wherein,

Method 1: hydroxypropyl methylcellulose K100M in an amount of 150g;

Method 2: carbomer 971P in an amount of 150g;

method 3: sodium alginate, the dosage is 150g;

Other specific ingredients and amounts remained consistent as shown in the following table:

Table 1: example 1 method 1 component Table

Table 2: example 1 method 2 component Table

Table 3: example 1 method 3 component Table

The preparation process comprises the following steps:

1) Preparation of sustained release part of the particles:

Sieving the raw material of alidenafil citrate with a 100-mesh sieve, sequentially adding the auxiliary materials of all other components except magnesium stearate into a hopper mixer, mixing for 20min at the stirring speed of 10rpm, and finally adding magnesium stearate and mixing for 10min to obtain slow-release part particles.

2) Preparation of immediate release partial particles:

Adding sildenafil citrate, lactose, microcrystalline cellulose and crosslinked polyvinylpyrrolidone into a wet granulator, stirring at a speed of 3rps, cutting at a speed of 15rps, premixing for 15min, adding polyvinylpyrrolidone K30 solution, stirring at a speed of 3rps, cutting at a speed of 15rps, granulating for 5min, sieving with a 20-mesh sieve of a swing granulator, performing fluidized bed drying on wet granules, and controlling the moisture content of the granules to be less than 5.0% at a parameter air inlet temperature of 60 ℃ and an air inlet quantity of 60m ³/h; and (3) sieving the dry particles with a 20-mesh sieve by adopting a rapid granulator, adding the dry particles and magnesium stearate into a hopper mixer, mixing for 20min, and stirring at a speed of 10rpm to obtain quick-release partial particles.

3) Combining:

And (2) respectively adding the slow-release part particles 1) and the quick-release part particles 2) into a hopper of a double-layer tablet press, and pressing to obtain the alidenafil citrate oral slow-release double-layer tablet.

Example 2: the skeleton material is a combination of 2 materials

In the embodiment, on the basis of exploring the influence of 1 material as a framework material on the preparation in the embodiment 1, 2 material combinations are selected to explore the influence of the framework material on the preparation, the total addition amount of the framework material is controlled to be unchanged (the framework material accounts for 50wt% of the dry weight of the sustained-release preparation),

The 1 framework material of example 1 was replaced with,

Example 2 method 1 (scaffold = carbomers + polysaccharides):

carbomer 971P: sodium alginate=1:2, wherein the amounts used are respectively: carbomer 971P 50g and sodium alginate 100g;

example 2 method 2 (scaffold = celluloses + polysaccharides):

hydroxypropyl methylcellulose K100M: sodium alginate=1:1, wherein the amounts used are respectively: hydroxypropyl methylcellulose K100M is 75g, and sodium alginate is 75 g;

Example 2 method 3 (scaffold = cellulosics + carbomers):

Hydroxypropyl methylcellulose K100M: carbomer 971 p=2:1, wherein the amounts are respectively: hydroxypropyl methylcellulose K100M was 100g and carbomer 971P was 50g;

Other components of the prescription, prescription dosage and preparation process are the same as in example 1.

Example 3: the framework material is a combination of 3 materials

The framework material is replaced by: framework material = cellulose + carbomers + polysaccharides, combinations of the three.

The combination of the mixture of the hydroxypropyl methylcellulose K100M, the carbomer 971P and the sodium alginate is used as a framework material of a slow-release part, and the dosage ratio of the hydroxypropyl methylcellulose K100M is as follows on the basis of controlling the total addition amount of the framework material to be unchanged (the framework material accounts for 50wt% of the dry weight of the slow-release preparation): carbomer 971P: sodium alginate = 2:1:2. The specific ingredients and amounts are shown in table 4 below:

TABLE 4 Table 4

The preparation process comprises the following steps:

1) Preparation of sustained release part of the particles:

2) Preparation of immediate release partial particles:

3) Combining:

Example 4: selection of the type of cellulosic material in the framework material

In order to explore the influence of cellulose on the sustained-release preparation, a framework material is selected, namely cellulose, carbomers and polysaccharides, and under the combined condition of the three materials, the total addition amount of the framework material is controlled to be unchanged (the framework material accounts for 50 weight percent of the dry weight of the sustained-release preparation),

The cellulose material of example 3 was replaced by hydroxypropyl methylcellulose K100M in its entirety:

method 1: hydroxyethyl cellulose;

Method 2: hydroxypropyl cellulose

Method 3: sodium carboxymethyl cellulose;

Method 4: ethyl cellulose;

the amounts of the prescriptions, other components of the prescriptions and the preparation process are the same as in example 3.

Example 5 selection of the type of polysaccharide Material in the matrix Material

In order to explore the influence of the type of polysaccharide materials on the sustained-release preparation, a framework material is selected, namely cellulose, carbomers and polysaccharides, under the combined condition of the three materials, the total addition amount of the framework material is controlled to be unchanged (the framework material accounts for 50 weight percent of the dry weight of the sustained-release preparation),

The polysaccharide material of example 3 was replaced with sodium alginate:

Method 1: a chitosan;

method 2: xanthan gum;

Method 3: pullulan;

Example 6 selection of carbomer type number in matrix Material

In order to explore the influence of carbomer material types on the sustained-release preparation, a framework material is selected, namely cellulose, carbomer and polysaccharide, and under the combined condition of the three materials, the total addition amount of the framework material is controlled to be unchanged (the framework material accounts for 50 weight percent of the dry weight of the sustained-release preparation),

The model of the carbomer material of example 3 was replaced by carbomer 971P:

method 1: carbomer model number carbomer 934P;

Method 2: the model of carbomer is carbomer 974P;

Example 7: selection of carbomers in the framework material

In order to explore the necessity of adding carbomer materials, in this embodiment, three combination components are used as a skeleton material (skeleton material=hydroxypropyl methylcellulose k100deg.M+carbomer 971P+sodium alginate) in embodiment 3, and the carbomer materials are replaced by polyoxyethylene on the basis of controlling the total addition amount of the skeleton material to be unchanged (skeleton material accounts for 50wt% of dry weight of the sustained release preparation).

That is to say,

Framework material = hydroxypropyl methylcellulose k100deg.M + polyoxyethylene + sodium alginate,

Hydroxypropyl methylcellulose K100M: polyoxyethylene: sodium alginate=2:1:2, the dosage is respectively hydroxypropyl cellulose K100M60g, polyoxyethylene 30g and sodium alginate 60g.

Example 8: model selection of hydroxypropyl methylcellulose

In order to explore the influence of different types of hydroxypropyl methylcellulose on the sustained-release preparation, the best sustained-release effect of the hydroxypropyl methylcellulose is found in the above embodiment, and the influence of the type of cellulose on the sustained-release preparation is explored, and the embodiment refers to embodiment 3, wherein three combined components are taken as framework materials (framework materials = hydroxypropyl methylcellulose + carbomer 971P + sodium alginate), the total addition amount of the framework materials is controlled to be unchanged (the framework materials account for 50wt% of the dry weight of the sustained-release preparation), and the dosage ratio of the hydroxypropyl cellulose, carbomer 971P and sodium alginate is controlled to be consistent with that of embodiment 3.

Model K100M of hydroxypropyl methylcellulose in the recipe of example 3,

The substitution is as follows:

method 1: K15M in an amount of 150g;

Method 2: K4M in an amount of 150g;

method 3: k100LV in an amount of 150g;

method 4: K100M: k100lv=2:1, K100M in 100g, K100LV in 50g;

Example 9 selection of the ratio of hydroxypropyl methylcellulose, carbomer 971P and sodium alginate

In order to explore the influence of the mixture of hydroxypropyl methylcellulose K100M, carbomer 971P and sodium alginate on the sustained-release preparation, the present example refers to example 3, and three combination ingredients are used as the framework materials (framework material=hydroxypropyl methylcellulose k100deg.M+carbomer 971p+sodium alginate), the total addition amount of the framework materials is controlled to be unchanged (the framework materials account for 50wt% of the dry weight of the sustained-release preparation),

The dosage ratio of hydroxypropyl methylcellulose K100M, carbomer 971P and sodium alginate in the prescription of example 3 is calculated by

Hydroxypropyl methylcellulose K100M: carbomer 971P: sodium alginate = 2:1:2,

The replacement is as follows:

Method 1: hydroxypropyl methylcellulose K100M: carbomer 971P: sodium alginate = 1:1:3;

method 2: hydroxypropyl methylcellulose K100M: carbomer 971P: sodium alginate = 4:1:1;

Method 3: hydroxypropyl methylcellulose K100M: carbomer 971P: sodium alginate = 5:1:1;

Method 4: hydroxypropyl methylcellulose K100M: carbomer 971P: sodium alginate = 1:1:4;

Example 10 selection of immediate Release partial Material class

In order to further explore the influence of the type of the quick-release part material of the tablet, on the basis of selecting the framework material of a specific slow-release part, namely, three combined components are used as the framework material (the framework material=hydroxypropyl methylcellulose K100deg.M+carbomer 971P+sodium alginate), the total addition amount of the framework material is controlled to be unchanged (the framework material accounts for 50wt% of the dry weight of the slow-release preparation),

Changing the material type of the quick release part:

TABLE 5

The specific components and the amounts are shown in the following table:

Table 6: example 10 method 1 component Table

Table 7: example 10 method 2 component Table

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Table 8: example 10 method 3 component Table

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The preparation process is the same as in example 3.

EXAMPLE 11 selection of dosage form of sustained release formulation

Based on the prescription of example 3, the dosage form and the combination mode of the oral sustained-release preparation are changed,

From the tablets of example 3, the combination mode is double-layer tablet combination;

change to

Method 1: a capsule, wherein the combination mode is biphasic particle combination;

Method 2: the capsule is combined by biphasic micropills.

The preparation process of the capsule preparation in the method 1 comprises the following steps:

1) Preparation of sustained release part of the particles:

2) Preparation of immediate release partial particles:

3) Combining:

And (2) adding the 1) slow-release part particles and the 2) quick-release part particles into a hopper of a capsule machine in a mode of combining the two-phase particles after the 1) slow-release part particles and the 2) quick-release part particles are mixed uniformly in the mixer, and obtaining the sildenafil citrate oral slow-release capsule after filling.

The preparation process of the capsule preparation of the method 2 comprises the following steps:

1) Preparation of sustained-release partial pellets:

Sieving sildenafil citrate raw material with a 100-mesh sieve, sequentially adding all other auxiliary materials into a wet granulation mixer, mixing for 20min, stirring at 10rpm, adding a proper amount of ethanol water solution to prepare a proper soft material, preparing pellets in an extrusion spheronizer, drying and sieving to obtain sustained-release partial pellets.

2) Preparing quick-release partial pellets:

adding sildenafil citrate, lactose, microcrystalline cellulose and crosslinked polyvinylpyrrolidone into a wet granulation mixing granulator, mixing for 20min at a stirring speed of 10rpm, adding polyvinylpyrrolidone K30 solution to prepare a proper soft material, preparing pellets in an extrusion spheronizer, drying and sieving to obtain quick-release partial pellets.

3) Combining:

and (2) adding the 1) sustained-release part pellets and the 2) quick-release part pellets into a hopper of a capsule machine in a mode of combining the biphasic pellets after the sustained-release part pellets and the quick-release part pellets are mixed uniformly in the mixer, and obtaining the sildenafil citrate oral sustained-release capsule after filling.

Example 12

Patent CN115054585A discloses a tablet of alidenafil citrate, which can be used for treating alzheimer's disease. Therefore, the alidenafil citrate oral sustained-release preparation prepared by the invention can be also used for treating Alzheimer's disease and has good treatment effect.

Experimental example 1: evaluation of Floating time of formulations

The formulations of examples 1 to 11 of the present invention were subjected to a float time study, and the results showed that: the combination of cellulose, carbomer and polysaccharide materials is adopted, the hydroxypropyl methylcellulose K100M, carbomer 971P and sodium alginate composition are selected as slow-release skeleton materials, the dosage ratio of the three is (4-1): 1 (1-3), and the prepared tablet has short floating time, long duration floating time and good floating performance. The method comprises the following steps:

The floating performance was generally evaluated by observing the floating time and the duration of floating of the hydrogel matrix sustained-release preparation, the preparation product prepared in the above example was put into a dissolution cup of 900mL hydrochloric acid solution (ph=1.2), the stirring rate was controlled to 50rpm, the temperature was 37±0.5 ℃, and the time required for floating the preparation product from the bottom to the liquid surface and the duration of floating on the liquid surface were recorded.

TABLE 9

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Experimental example 2: investigation of the Release degree of the formulation

The release degree of the invention in examples 1 to 11 was examined, and the results showed that: the combination of cellulose, carbomer and polysaccharide materials is adopted, the hydroxypropyl methylcellulose K100M, carbomer 971P and sodium alginate composition are selected as slow-release framework materials, the dosage ratio of the three is (4-1): 1 (1-3), and the prepared preparation product is completely released in a medium with pH value of 1.2, and has good slow-release effect. The method comprises the following steps:

The release degree testing method comprises the following steps: according to a release degree measurement method (first method of annex X D of Chinese pharmacopoeia 2020 edition), adopting a device of a dissolution degree measurement method (second method of annex X C of Chinese pharmacopoeia 2010 edition), respectively taking dissolution media with the pH value of 1.2 as solvents, respectively taking 10mL of solution at 1h, 2h, 4h, 6h, 10h, 12h, 16h and 24h, filtering, and immediately supplementing dissolution media with the same temperature and the same volume in an operation container; sampling 10mL at each time point, filtering with PES filter membrane, discarding the previous 2mL of filtrate, collecting the subsequent filtrate 3mL, diluting with 3mL of dissolution medium with pH of 1.2, and measuring the absorbance at 292nm according to spectrophotometry (Chinese pharmacopoeia 2020 edition II appendix IV A);

And taking 12mg (equivalent to 8.5 mg) of the alidenafil citrate reference substance, precisely weighing, putting into a 50mL measuring flask, adding water to dissolve and dilute to a scale, and shaking uniformly to obtain the alidenafil citrate reference substance stock solution. Precisely measuring 5mL of the citric acid alidenafil reference substance stock solution, placing into a 50mL measuring flask, adding medium to dilute to scale, and shaking uniformly.

Release profile of alidenafil citrate requires: the release degree for 1h is 15% -35%, the release degree for 4h is 40% -55%, and the release degree for 12h is 70% -100%. The formulations of the present invention were tested for release under conditions of dissolution medium of dilute hydrochloric acid solution (ph 1.2). Release is shown in the following table:

table 10

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Experimental example 3: investigation of swelling behavior of formulations

The tablet swelling behavior was examined in example 3 and examples 9 and methods 1 to 4 of the present invention, and the results showed that: the hydroxypropyl methylcellulose K100M, carbomer 971P and sodium alginate composition are used as slow-release framework materials, and the swelling behavior of the tablet is obviously influenced by different amounts of the three materials: the dosage ratio of the three is (4-1) 1, and when (1-3), the swelling behavior of the tablet is good, thereby being beneficial to improving the slow release effect. The method comprises the following steps:

The swelling behaviour of the tablet gel material enables the tablet volume to be increased, thereby reducing the density and providing buoyancy. In order to explore the floating mechanism of the tablet, the swelling behavior of the tablet was examined by using the weight and the external dimensions of the tablet as indexes, and the paddle method was used, the medium was hydrochloric acid solution (ph=1.2), the rotation speed was 75rpm, and the temperature was 37±0.5 ℃. The tablets were taken out every other hour, surface moisture was quickly wiped off, the length, width and thickness of the tablets were measured with a digital vernier caliper, and then the tablets were weighed and recorded. The volume of the tablet was measured for the apparent size, and the swollen tablet was then calculated as a cylinder to determine the tablet density.

TABLE 11

Analysis of results:

the results of the above experimental examples 1 to 3 on the density, floating time and release degree after swelling of the obtained preparation were analyzed, and the effect of the matrix material of the sustained-release portion on the sustained-release effect (floating time, sustained floating time and release degree) of the oral sustained-release preparation of alidenafil citrate was as follows:

The invention changes the framework material of the slow-release part:

Selecting a combination of 3 materials (celluloses, carbomers and polysaccharides) as a framework material;

wherein, the cellulose is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and sodium carboxymethyl cellulose;

The polysaccharide is selected from one or more of sodium alginate, chitosan and xanthan gum;

The carbomers select any one or more of carbomers 934P, 971P and 974P;

adjusting the mass ratio of the framework material cellulose material, carbomer material and polysaccharide material (the mass ratio of hydroxypropyl methyl cellulose K100M, carbomer 971P and sodium alginate): in the range of (4-1) 1 (1-3);

the prepared tablet has good slow release effect and is characterized in that:

i. The floating time is obviously shortened (only 6-45 min), and is far lower than the floating time limit of the tablet (1 h);

The sustained floating time is obviously prolonged (up to 11-16 h) and is far longer than the slow release time requirement (10 h) of the slow release preparation; the density is obviously reduced (17% -28%) after swelling;

Tablet release is complete: the release rate of the preparation for 1h is 17-35%, the release rate for 4h is 42-55%, and the release rate for 12h is 75-98%, which all meet the release rate requirements of sildenafil citrate in 24h (the release rate for 1h is 15-35%, the release rate for 4h is 40-55%, and the release rate for 12h is 70-100%).

Conclusion analysis 1:

Examples 1 to 3 each used any 1,2 or 3 of cellulose, carbomer or polysaccharide materials as a matrix material, and the release effects (floating time and release degree) of the tablets prepared therefrom were as follows:

1-1, matrix material distinction of sustained release part of the preparation

Table 12

1-2, Comparison of Release Effect (Floating time and Release degree)

TABLE 13

Examples	Time to float	Duration of floating time
			Example 1 method 1	1.5h±0.08h	14h±0.25h
Example 1 method 2	3.0h±0.14h	12h±0.31h
			Example 1 method 3	10min±1.0min	2h±0.16h
Example 2 method 1	2.5h±0.13h	12h±0.31h
			Example 2 method 2	30min±2.4min	4h±0.15h
Example 2 method 3	2h±0.16h	13h±0.15h
			Example 3	6min±1.5min	16h±0.25h

TABLE 14

Conclusion:

1) The floating time results show that:

in the method 1 of the embodiment 1, only 1 material is adopted, and hydroxypropyl methylcellulose K100M is used as an auxiliary material for a framework material of a slow-release part, so that the hydration speed is low, the bleaching time is 1.5 h+/-0.08 h, which is far higher than the bleaching time limit of a tablet (1 h), the tablet is difficult to stay in stomach, the tablet is unfavorable for the sildenafil citrate to exert curative effect, the slow-release effect is poor, and the tablet cannot be used as a qualified slow-release preparation.

In the method 2 of the embodiment 1, only 1 material is adopted, carbomer, which is the auxiliary material with the largest viscosity, is used as a framework material of a slow-release part, the hydration speed is low, the floating time is 3.0h plus or minus 0.14h, which is higher than the floating time limit of a tablet (1 h), the tablet is extremely difficult to stay in the stomach, the citric acid alidenafil is unfavorable for exerting the curative effect, the slow-release effect is poor, and the tablet cannot be used as a qualified slow-release preparation.

In the method 3 of the embodiment 1, only 1 material is adopted, and the sodium alginate, which is the auxiliary material with the minimum viscosity, is used as the framework material of the slow-release part, so that the hydration speed is high, the bleaching time is 10min plus or minus 1.0min, and is far lower than the bleaching time limit of a tablet (< 1 h); however, the gel erosion speed is high, the continuous floating time is 2 h+/-0.16 h, which is far lower than the slow release time requirement (10 h) of the slow release preparation, the tablet structure is easy to be destroyed, the drug release is fast, the slow release effect is poor, and the sustained release preparation cannot be used as a qualified slow release preparation.

In the method 1 of the embodiment 2, 2 materials are adopted, the combination of carbomer and sodium alginate is used as a framework material of a slow-release part, cellulose (hydroxypropyl methylcellulose K100M) is omitted, the viscosity of a gel framework is enhanced due to high concentration of the carbomer, the hydration speed is low, the floating time is 2.5 h+/-0.13 h and is far higher than the floating time limit (< 1 h) of a tablet, the carbomer and the sodium alginate are not easy to stay in stomach, the citric acid alidenafil is unfavorable for exerting curative effect, the slow-release effect is poor, and the carbomer can not be used as a qualified slow-release preparation.

In the method 2 of the embodiment 2,2 materials are adopted, the combination of the hydroxypropyl methylcellulose K100M and sodium alginate is used as a framework material of a slow-release part, carbomers (carbomer 971P) are omitted, although the hydration speed is high, the bleaching time is 30min plus or minus 2.4min, and is far lower than the bleaching time limit (< 1 h) of a tablet; however, the viscosity of the formed gel skeleton is weakened, the continuous floating time is 4 hours plus or minus 0.15 hours, the sustained release time requirement of the sustained release preparation is far lower than 10 hours, the tablet structure is easy to be destroyed, the drug release is fast, the sustained release effect is poor, and the sustained release preparation cannot be used as a qualified sustained release preparation.

In the method 3 of the embodiment 2, 2 materials are adopted, the combination of the hydroxypropyl methylcellulose K100M and the carbomer 971P is used as a framework material of a slow-release part, polysaccharides (sodium alginate) are omitted, water absorption is difficult, the hydration speed is low, the floating time is 2 hours plus or minus 0.16 hours, which is far higher than the floating time limit of a tablet (less than 1 hour), the tablet is difficult to stay in stomach, the sildenafil citrate is unfavorable for exerting curative effect, the slow-release effect is poor, and the tablet cannot be used as a qualified slow-release preparation.

Example 3 uses 3 materials, the hydroxypropyl methylcellulose K100M, carbomer and sodium alginate composition is used as the framework material of the slow release part, the floating time is 6min plus or minus 1.5min, which is far lower than the floating time limit of the tablet (< 1 h); the sustained floating time is 16h plus or minus 0.25h, which is far longer than the slow release time requirement (10 h) of the slow release preparation, and the drug release is slow and the slow release effect is good.

2) Tablet release results show (fig. 1):

In the method 1-2 of the embodiment 1, only one material is adopted, only one auxiliary material of hydroxypropyl methylcellulose K100M and carbomer is used as a framework material of a slow-release part, the release degree of 4h is 38 percent, 35 percent, the release degree of 12h is 68 percent and 62 percent, the release degree requirement of the sildenafil citrate in 24h is lower (the release degree of 4h is 40-55 percent and the release degree of 12h is 70-100 percent), the tablet release is too slow, the slow-release effect is poor, and the tablet can not be used as a qualified slow-release preparation.

In the method 3 of the embodiment 1, only one material is adopted, the sodium alginate, which is the auxiliary material with the minimum viscosity, is used as the framework material of the slow-release part, the release degree of 1h is 45%, the release degree of 4h is 95%, the release degree is higher than the release degree requirement of the sildenafil citrate in 24h (the release degree of 1h is 15-35%, the release degree of 4h is 40-55%, and the release degree of 12h is 70-100%), the tablet is too fast to release, the slow-release effect is poor, and the tablet cannot be used as a qualified slow-release preparation.

In the method 1 of the embodiment 2, 2 materials are adopted, the combination of carbomer and sodium alginate is used as a framework material of a slow-release part, cellulose (hydroxypropyl methylcellulose K100M) is omitted, the release degree of 4h is 35%, the release degree of 12h is 62%, the release degree requirement of the sildenafil citrate in 24h is lower (the release degree of 4h is 40-55%, the release degree of 12h is 70-100%), the tablet release is too slow, the slow-release effect is poor, and the tablet can not be used as a qualified slow-release preparation.

In the method 2 of the embodiment 2, 2 materials are adopted, the combination of the hydroxypropyl methylcellulose K100M and sodium alginate is used as a framework material of a slow release part, carbomers (carbomer 971P) are omitted, the release degree of the carbomers is 78% in 4 hours, the release degree requirement of the sildenafil citrate in 24 hours is far greater (the release degree of the sildenafil citrate in 4 hours is 40-55%), the tablet structure is easy to be damaged, the tablet is released too fast, the slow release effect is poor, and the tablet cannot be used as a qualified slow release preparation.

In the method 3 of the embodiment 2, 2 materials are adopted, the combination of the hydroxypropyl methylcellulose K100M and the carbomer 971P is used as a framework material of a slow release part, polysaccharides (sodium alginate) are omitted, the release degree of the polysaccharide is 38% in 4h, the release degree of the polysaccharide in 12h is 64%, the release degree of the polysaccharide is lower than the release degree requirement of the sildenafil citrate in 24h (the release degree of the polysaccharide in 4h is 40-55% and the release degree in 12h is 70-100%), the tablet is too slow to release, the slow release effect is poor, and the polysaccharide can not be used as a qualified slow release preparation.

In the embodiment 3, 3 materials are adopted, the hydroxypropyl methylcellulose K100M, carbomer and sodium alginate composition are used as a framework material of a slow-release part, the release degree of 1h is 24%, the release degree of 4h is 45%, the release degree of 12h is 77%, the release degree requirements of sildenafil citrate in 24h (the release degree of 1h is 15% -35%, the release degree of 4h is 40% -55%, the release degree of 12h is 70% -100%), the tablet release is complete, and the tablet slow-release performance is best.

The small knot:

when the framework material of the slow-release part adopts the combination of three materials of cellulose, carbomer and polysaccharide, the tablet has good release effect:

Compared with tablets prepared from any 1 or 2 materials selected from cellulose, carbomer or polysaccharide materials as a framework material of a sustained-release part (for example, examples 1 and 2), the tablets have poor release effect and cannot be used as a qualified sustained-release preparation, and are specifically expressed as follows:

i. The floating time is too long (up to 3 h) and is obviously higher than the floating time limit of the tablet (1 h);

The duration of floating is too short (can be as low as 2 h), which is far lower than the slow release time requirement of slow release preparation (> 10 h);

Tablet release either too fast or too slow: the release rate is too high (the release rate in 1h is up to 45 percent and is 15 to 35 percent higher than the release rate, the release rate in 4h is up to 95 percent and is 40 to 55 percent higher than the release rate, etc.)

Or too low (the release degree of 12h is as low as 62 percent and is lower than the release degree by 70 to 100 percent);

(II) when only a combination of 3 materials (celluloses, carbomers and polysaccharides) was used as the matrix material (e.g., example 3), the tablet release effect was best, and it was specifically expressed as:

i. the floating time is the shortest (can be as low as 6 min) and is far lower than the floating time limit of the tablet (1 h);

Conclusion analysis 2:

from the results in conclusion analysis 1, example 3 was prepared using a combination of 3 materials (celluloses, carbomers and polysaccharides) as a matrix material to obtain a good release effect (floating time and release degree) on the tablet, and therefore, on the basis of example 3, the type of addition of the cellulose materials was changed to investigate its effect on the release effect (floating time and release degree) of the tablet, and the results were as follows:

2-1, matrix material distinction of sustained release part of the preparation

TABLE 15

Examples	Celluloses	Carbomers (carbomers)	Polysaccharides and their use
				Example 3	Hydroxypropyl methylcellulose K100M	Carbomer 971P	Sodium alginate
Example 4 method 1	Hydroxyethyl cellulose	Carbomer 971P	Sodium alginate
				Example 4 method 2	Hydroxypropyl cellulose	Carbomer 971P	Sodium alginate
Example 4 method 3	Sodium carboxymethyl cellulose	Carbomer 971P	Sodium alginate
				Example 4 method 4	Ethylcellulose	Carbomer 971P	Sodium alginate

2-2, Comparison of Release Effect (Floating time and Release degree)

Table 16

Examples	Time to float	Duration of floating time
			Example 3	6min±1.5min	16h±0.25h
Example 4 method 1	25min±2.2min	13h±0.21h
			Example 4 method 2	22min±1.6min	12h±0.45h
Example 4 method 3	35min±3.1min	12h±0.34h
			Example 4 method 4	2h±0.24h	13h±0.12h

TABLE 17

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Conclusion:

1) The floating time results show that:

The matrix material of the sustained-release part in example 3 is a combination of hydroxypropyl methylcellulose K100M, carbomer and sodium alginate, wherein the time for bleaching is 6 min+/-1.5 min which is far lower than the time limit of bleaching of tablets (< 1 h); the sustained floating time is 16h plus or minus 0.25h, which is far longer than the slow release time requirement (10 h) of the slow release preparation, and the drug release is slow and the slow release effect is good.

Example 4 method 1-3 the cellulose type in the matrix material of the slow release part is replaced by hydroxyethyl cellulose, hydroxypropyl cellulose and sodium carboxymethyl cellulose by hydroxypropyl methyl cellulose K100M, the bleaching time is 25 min+/-2.2 min, 22 min+/-1.6 min and 35 min+/-3.1 min respectively, and is far lower than the bleaching time limit (< 1 h) of the tablet; the continuous floating time is 13 h+/-0.21 h, 12 h+/-0.45 h and 12 h+/-0.34 h, which are far longer than the slow release time requirement (10 h) of the slow release preparation, and the slow release effect is good.

In the method 4 of example 4, the cellulose type in the framework material of the slow-release part is replaced by ethyl cellulose by hydroxypropyl methyl cellulose K100M, and because the ethyl cellulose is water-insoluble cellulose, the hydration speed is low, an insoluble film is easy to form, the floating time is 2 h+/-0.24 h, which is far higher than the floating time limit (< 1 h) of a tablet, the tablet is not easy to stay in stomach, the tablet is unfavorable for the curative effect of the sildenafil citrate, the slow-release effect is poor, and the tablet cannot be used as a qualified slow-release preparation.

2) Tablet release results show (fig. 2):

The matrix material of the sustained-release part in example 3 is a combination of hydroxypropyl methylcellulose K100M, carbomer and sodium alginate, the release degree is 24% in 1h, 45% in 4h and 77% in 12h, the release degree requirement of alinafil citrate in 24h is met (the release degree is 15-35% in 1h, 40-55% in 4h and 70-100% in 12 h), the tablet is completely released, and the sustained-release performance is good.

In the method 1-3 of the embodiment 4, the cellulose type in the framework material of the slow-release part is replaced by hydroxyethyl cellulose, hydroxypropyl cellulose and sodium carboxymethyl cellulose by hydroxypropyl methyl cellulose K100M, the release degree of 1h is 22%, 26% and 32%, the release degree of 4h is 42%, 56% and 53%, the release degree of 12h is 75%, 89% and 95%, the release degree requirements of sildenafil citrate in 24h (the release degree of 1h is 15-35%, the release degree of 4h is 40-55%, the release degree of 12h is 70-100%), the tablet release is complete, and the slow-release effect is good;

In the method 4 of example 4, the cellulose type in the framework material of the slow-release part is changed from hydroxypropyl methyl cellulose K100M to ethyl cellulose, the release degree of 12h is 65%, the release degree requirement (70% -100%) of 12h sildenafil citrate is lower, the tablet release is too slow, the slow-release effect is poor, and the tablet cannot be used as a qualified slow-release preparation.

The small knot:

The combination of 3 materials (cellulose, carbomer and polysaccharide materials) is adopted as the framework material of the slow-release part, the cellulose materials are added into the framework material, and the slow-release effect of the tablet is good:

When the cellulose material in the framework material adopts hydroxypropyl methyl cellulose K100M, hydroxyethyl cellulose, hydroxypropyl cellulose and sodium carboxymethyl cellulose, the sustained-release effect of the tablet is good, and the tablet is specifically expressed as follows:

i. The floating time is short (only 6-35 min), which is far lower than the floating time limit of the tablet (1 h);

The continuous floating time is long (up to 12-16 h) and is far longer than the slow release time requirement (10 h) of the slow release preparation;

Tablet release is complete: the release degree of 1h is 22-32%, the release degree of 4h is 42-56%, the release degree of 12h is 75-95%, the release degree requirement of sildenafil citrate in 24h is met (the release degree of 1h is 15-35%, the release degree of 4h is 40-55%, and the release degree of 12h is 70-100%);

(II) when the cellulose material in the matrix material is hydroxypropyl methylcellulose K100M (for example, example 3), the sustained release effect of the tablet is optimal, and the tablet is specifically expressed as follows:

i. The floating time is the lowest (can be as low as 6 min) and is far lower than the floating time limit of the tablet (1 h);

Tablet release is complete: the release degree of 1h is 24%, the release degree of 4h is 45%, the release degree of 12h is 77%, and the release degree requirement of sildenafil citrate in 24h is satisfied (the release degree of 1h is 15% -35%, the release degree of 4h is 40% -55%, and the release degree of 12h is 70% -100%);

(III) when other celluloses (for example, ethyl cellulose in method 4 of example 4) are used as the cellulose-based material in the matrix material, the sustained-release effect of the tablet is poor, and the tablet cannot be used as a qualified sustained-release preparation, and is specifically expressed as follows:

i. the floating time is too long (up to 2 h) and is far higher than the floating time limit of the tablet (1 h);

tablet release is too slow: is lower than the release degree requirement (the release degree for 12h is 65 percent, and the release degree for 12h is 70 to 100 percent).

Conclusion analysis 3:

From the results of conclusion analysis 1 to 2, example 3 uses 3 materials as the matrix material (combination of cellulose, carbomers and polysaccharide materials), and the cellulose uses hydroxypropyl methylcellulose K100M) to prepare tablets with the best release effect (floating time and release degree), so on the basis of example 3, the type of polysaccharide material is changed, and the effect on the release effect (floating time and release degree) of the tablets is investigated, and the result is as follows:

3-1, matrix material distinction of sustained release part of the preparation

TABLE 18

Examples	Celluloses	Carbomers (carbomers)	Polysaccharides and their use
				Example 3	Hydroxypropyl methylcellulose K100M	Carbomer 971P	Sodium alginate
Example 5 method 1	Hydroxypropyl methylcellulose K100M	Carbomer 971P	Chitosan
				Example 5 method 2	Hydroxypropyl methylcellulose K100M	Carbomer 971P	Xanthan gum
Example 5 method 3	Hydroxypropyl methylcellulose K100M	Carbomer 971P	Pullulan polysaccharide

3-2, Comparison of Release Effect (Floating time and Release degree)

TABLE 19

Examples	Time to float	Duration of floating time
			Example 3	6min±1.5min	16h±0.25h
Example 5 method 1	45min±2.5min	13h±0.15h
			Example 5 method 2	42min±2.0min	12h±0.24h
Example 5 method 3	1.6h±0.12h	13h±0.12h

Table 20

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Conclusion:

1) The floating time results show that:

The matrix material of the slow-release part in the embodiment 3 is a combination of hydroxypropyl methylcellulose K100M, carbomer 971P and sodium alginate, and the polysaccharide material adopts sodium alginate, so that the slow-release part can be rapidly hydrated, the bleaching speed is greatly increased, and the bleaching time is reduced; the synergistic effect of the three can reach the floating time of 6min plus or minus 1.5min which is far lower than the floating time limit (< 1 h) of the tablet; the sustained floating time is 16h plus or minus 0.25h, which is far longer than the slow release time requirement (10 h) of the slow release preparation, and the drug release is slow and the slow release effect is good.

In the method of example 5, the skeleton material of the slow-release part 1-2 is a combination of hydroxypropyl methylcellulose K100M, carbomer and polysaccharides, and the polysaccharides are replaced by chitosan and xanthan gum, and the floating time of the chitosan and the xanthan gum is respectively 45 min+/-2.5 min and 42 min+/-2.0 min and is lower than the floating time limit (< 1 h) of the tablet because the hydration speed of the chitosan and the xanthan gum is slightly slower than that of sodium alginate; the sustained floating time is 13h plus or minus 0.15h and 12h plus or minus 0.24h, which are far longer than the slow release time requirement (> 10 h) of the slow release preparation, and the slow release effect is good.

In the method 3 of example 5, the composition of the slow-release part of the skeleton material combined with hydroxypropyl methylcellulose K100M, carbomer and polysaccharide is changed into pullulan, and the hydration speed of the pullulan is obviously slower than that of sodium alginate, the floating time of the pullulan is respectively 1.6 h+/-0.12 h and is far higher than the floating time limit (< 1 h) of a tablet, so that the slow-release effect is poor, and the pullulan cannot be used as a qualified slow-release preparation.

2) Tablet release results show (fig. 3):

The matrix material of the sustained-release part in example 3 is a combination of hydroxypropyl methylcellulose K100M, carbomer 971P and sodium alginate, the release rate is 24% in 1h, 45% in 4h and 77% in 12h, the release rate requirement of sildenafil citrate in 24h is met (15% -35% in 1h, 40% -55% in 4h and 70% -100% in 12 h), the tablet is completely released, and the sustained-release performance is good.

The matrix material of the slow-release part of the method 1-2 in example 5 is a composition of hydroxypropyl methylcellulose K100M, carbomer 971P and polysaccharide, the polysaccharide material is replaced by chitosan and xanthan gum, the release degree of 1h is 25% and 30%, the release degree of 4h is 54% and 52%, the release degree of 12h is 96% and 96%, the release degree requirement of sildenafil citrate in 24h is met (the release degree of 1h is 15% -35%, the release degree of 4h is 40% -55%, the release degree of 12h is 70% -100%), the tablet release is complete, and the slow-release performance is good.

Example 5 method 3 composition of matrix material of slow-release part hydroxypropyl methylcellulose K100M, carbomer 971P and polysaccharide, change polysaccharide material to pullulan, release degree for 4h is 39%, lower than release degree requirement (40% -55%); the release rate of 12 hours is 66 percent, which is lower than the release rate requirement (70-100 percent), the tablet is released too slowly, the slow release effect is poor, and the tablet can not be used as a qualified slow release preparation.

The small knot:

The combination of 3 materials (cellulose, carbomer and polysaccharide materials) is adopted as the framework material of the slow-release part, and when the polysaccharide material is added into the framework material of the slow-release part, the slow-release effect of the tablet is good:

firstly, when sodium alginate, chitosan and xanthan gum (for example, the methods 1-2 of the embodiment 3 and the embodiment 5) are adopted as polysaccharide materials in the framework material, the sustained-release effect of the tablet is good, and the tablet is specifically expressed as follows:

i. the floating time is short (only 6-45 min), and is far lower than the floating time limit of the tablet (1 h);

(II) when sodium alginate (e.g., example 3) is used as the polysaccharide material in the matrix material, the sustained-release effect of the tablet is optimal, and the tablet is specifically expressed as follows:

i. The floating time is the shortest (6 min), which is far lower than the floating time limit of the tablet (< 1 h);

(III) when other materials (for example, pullulan polysaccharide in method 3 of example 5) are adopted as the polysaccharide material in the framework material, the slow release effect is poor, and the polysaccharide material cannot be used as a qualified slow release preparation, and is specifically expressed as follows:

i. the floating time is too long (up to 1.6 h) and is far higher than the floating time limit of the tablet (1 h);

tablet release is too slow: the release degree is too low (the release degrees of 4h and 12h are 39 percent and 66 percent respectively, which are lower than the release degree requirement, the release degree of 4h is 40 to 55 percent, the release degree of 12h is 70 to 100 percent), and the drug release is too slow.

Conclusion analysis 4:

From the results in conclusion analysis 1 to 3, example 3 uses 3 materials as the matrix material (combination of cellulose, carbomers and polysaccharide materials, cellulose uses hydroxypropyl methylcellulose K100M, polysaccharide uses sodium alginate) to prepare tablets with the best release effect (floating time and release), so on the basis of example 3, the model of carbomers material is changed, the influence on the tablet release effect (floating time and release) is explored, and the result is as follows:

4-1, matrix material distinction of sustained release part of the preparation

Table 21

Examples	Celluloses	Carbomers (carbomers)	Polysaccharides and their use
				Example 3	Hydroxypropyl methylcellulose K100M	Carbomer 971P	Sodium alginate
Example 6 method 1	Hydroxypropyl methylcellulose K100M	Carbomer 934P	Sodium alginate
				Example 6 method 2	Hydroxypropyl methylcellulose K100M	Carbomer 974P	Sodium alginate

4-2, Comparison of Release Effect (Floating time and Release degree)

Table 22

Examples	Time to float	Duration of floating time
			Example 3	6min±1.5min	16h±0.25h
Example 6 method 1	25min±3.0min	15h±0.41h
			Example 6 method 2	20min±3.6min	15h±0.35h

Table 23

Conclusion:

1) The floating time results show that:

The matrix material of the sustained-release part in example 3 is a combination of hydroxypropyl methylcellulose K100M, carbomer 971P and sodium alginate, the carbomer material is carbomer 971P, the bleaching time is 6min plus or minus 1.5min, and is far lower than the bleaching time limit (< 1 h) of the tablet; the sustained floating time is 16h plus or minus 0.25h, which is far longer than the slow release time requirement (10 h) of the slow release preparation, and the drug release is slow and the slow release effect is good.

Example 6 the matrix material of the sustained release portion of method 1-2 is also a combination of hydroxypropyl methylcellulose K100M, carbomer and sodium alginate, only the carbomer model is replaced, carbomer 971P is replaced with 934P, 974P, the float time is 25min±3.0min, 20min±3.6min, all well below the float time limit (< 1 h) of the tablet; the continuous floating time is 15 h+/-0.41 h and 15 h+/-0.35 h respectively, which are far longer than the slow release time requirement (> 10 h) of the slow release preparation, and the types (crosslinking degree) of the carbomer can meet the requirements of the tablet on the floating time and the continuous floating time, and the slow release effect is good.

2) Tablet release results show (fig. 4):

The matrix material of the slow release part of the method 1-2 in example 6 is a combination of hydroxypropyl methylcellulose K100M, carbomer and sodium alginate, the carbomer is replaced by 934P or 974P, the release degree of carbomer 971P is 24% and 34% in 1h, the release degree of carbomer in 4h is 50% and 55%, the release degree of carbomer in 12h is 94% and 98%, the requirements of the release degree of sildenafil citrate in 24h (the release degree of 1h is 15% -35%, the release degree of carbomer in 4h is 40% -55%, the release degree of carbomer in 12h is 70% -100%) are met, and the tablet is completely released and has good slow release performance.

The small knot:

the combination of 3 materials (cellulose, carbomers and polysaccharide materials) is adopted as the framework material of the slow-release part, the carbomers are added into the framework material of the slow-release part, and the slow-release effect of the tablet is good:

When carbomers 971P, 934P and 974P are adopted as the types of carbomers in the framework material, the slow release effect of the tablet is good, and the tablet is specifically expressed as follows:

i. the floating time is short (only 6-25 min), and is far lower than the floating time limit of the tablet (1 h);

the continuous floating time is long (15-16 h), which is far longer than the slow release time requirement (10 h) of the slow release preparation;

Tablet release is complete: the release degree of 1h is 24-34%, the release degree of 4h is 45-55%, the release degree of 12h is 77-98%, the release degree requirement of sildenafil citrate in 24h is met (the release degree of 1h is 15-35%, the release degree of 4h is 40-55%, and the release degree of 12h is 70-100%);

(II) when carbomer 971P is adopted as the type of carbomer material in the framework material, the slow release effect of the tablet is best, and the tablet is specifically expressed as follows:

i. the time for bleaching is the shortest (as low as 6 min), which is far lower than the limit of the time for bleaching of the tablet (< 1 h);

Conclusion analysis 5:

From the results in conclusion analysis 4, it was found that the release effect (floating time and release degree) of the tablet prepared in example 3 using 3 materials as the matrix material (combination of cellulose-based, carbomers-based and polysaccharide-based materials, carbomers-based using carbomers 971P) was the best. To verify the importance of carbomers, the carbomers were replaced with polyoxyethylene, and their effect on tablet release (float time and release) was investigated, with the following results:

5-1, matrix material distinction of sustained release part of the preparation

Table 24

Examples	Celluloses	Carbomers (carbomers)	Polysaccharides and their use
				Example 3	Hydroxypropyl methylcellulose K100M	Carbomer 971P	Sodium alginate
Example 7	Hydroxypropyl methylcellulose K100M	Polyoxyethylene	Sodium alginate

5-2, Comparison of Release Effect (Floating time and Release degree)

Table 25

Examples	Time to float	Duration of floating time
			Example 3	6min±1.5min	16h±0.25h
Example 7	20min±1.5min	5h±0.15h

Table 26

Conclusion:

1) The floating time results show that:

the matrix material of the sustained-release part in example 3 is a combination of hydroxypropyl methylcellulose K100M, carbomer 971P and sodium alginate, the carbomer material is selected, the bleaching time is 6min plus or minus 1.5min, and is far lower than the bleaching time limit (< 1 h) of the tablet; the sustained floating time is 16h plus or minus 0.25h, which is far longer than the slow release time requirement (10 h) of the slow release preparation, and the drug release is slow and the slow release effect is good.

In the embodiment 7, the skeleton material of the slow release part is replaced by polyoxyethylene, namely the skeleton material is a composition of hydroxypropyl methylcellulose K100M, polyoxyethylene and sodium alginate, and the gelation speed and the gelation degree of the polyoxyethylene are weaker than those of the carbomer, so that the gelation speed is high, the continuous floating time is 5 h+/-0.15 h, the slow release time requirement (10 h) of the slow release preparation is far lower, the tablet structure is easy to be damaged, the drug release is fast, the slow release effect is poor, and the sustained release preparation cannot be used as a qualified slow release preparation.

2) Tablet release results show (fig. 5):

The matrix material of the sustained-release part in the embodiment 7 is that carbomer is replaced by polyoxyethylene, the gelation speed and degree of the polyoxyethylene are weaker than that of the carbomer, the release degree of the polyoxyethylene is 77% in 4 hours, the release degree is far greater than the release degree requirement (40% -55%), the tablet structure is easy to be damaged, the tablet release is fast, the sustained-release effect is poor, and the sustained-release preparation cannot be used as a qualified sustained-release preparation.

The small knot:

the results show that when the combination of 3 materials is adopted as the framework material of the slow-release part, the carbomer material has importance in the slow-release framework material composition:

When a combination of 3 materials (cellulose, carbomer and polysaccharide materials) is used as a matrix material of the sustained-release portion (for example, example 3), the sustained-release effect of the tablet is good, and the tablet is specifically expressed as follows:

i. the floating time is short (as low as 6 min) and is far lower than the floating time limit of the tablet (1 h);

The sustained floating time is long (up to 16 h) and is far longer than the slow release time requirement (> 10 h) of the slow release preparation;

(II) when other components are used for replacing carbomer materials (such as polyoxyethylene in example 7), the slow release effect is obviously poorer than that of the carbomer materials, and the slow release preparation standard is not met, and the slow release preparation is specifically shown as follows:

i. The continuous floating time is short (5 h plus or minus 0.15 h) and is far lower than the slow release time requirement (10 h) of the slow release preparation;

Tablet release too fast: the release degree is larger than the release requirement (the release degree is 77% in 4 hours and is far larger than the release degree requirement of 40% -55%).

Conclusion analysis 6:

In addition, on the basis of the example 3 with the best tablet slow release effect (floating time and release degree), namely, taking a combination of cellulose, carbomer or polysaccharide materials as a framework material, the influence of different types of hydroxypropyl methyl cellulose in the framework material on the tablet release effect (floating time and release degree) is explored, and the result is as follows:

6-1, matrix material distinction of sustained release part of the preparation

Table 27

Examples	Different types of hydroxypropyl methylcellulose
		Example 3	K100M
Example 8 method 1	K15M
		Example 8 method 2	K4M
Example 8 method 3	K100LV
		Example 8 method 4	K100M:K100LV＝2:1

6-2, Comparison of Release Effect (Floating time and Release degree)

Table 28

Examples	Time to float	Duration of floating time
			Example 3	6min±1.5min	16h±0.25h
Example 8 method 1	20min±1.5min	16h±0.35h
			Example 8 method 2	15min±1.5min	14h±0.75h
Example 8 method 3	10min±2.5min	13h±0.24h
			Example 8 method 4	15min±3.2min	15h±0.14h

Table 29

/>

Conclusion:

1) The floating time results show that:

Example 3 the matrix material of the slow release part is a combination of hydroxypropyl methylcellulose, carbomer and sodium alginate, when the model of hydroxypropyl methylcellulose is K100M, the bleaching time is 6 min+/-1.5 min, which is far lower than the bleaching time limit of the tablet (< 1 h); the sustained floating time is 16h plus or minus 0.25h, which is far longer than the slow release time requirement (10 h) of the slow release preparation, and the drug release is slow and the slow release effect is good.

The matrix material of the slow release part of the method 1-3 of the embodiment 8 is a combination of hydroxypropyl methylcellulose, carbomer and sodium alginate, wherein the model of the hydroxypropyl methylcellulose is K15M, K4M, K LV, the floating time is 20min plus or minus 1.5min, 15min plus or minus 1.5min and 10min plus or minus 2.5min, and the floating time is far lower than the floating time limit (< 1 h) of the tablet; the continuous floating time is 16 h+/-0.35 h, 14 h+/-0.75 h and 13 h+/-0.24 h, which are far longer than the slow release time requirement (10 h) of the slow release preparation, and the slow release effect is good.

Example 8 method 4 the matrix material of the slow release portion is a combination of hydroxypropyl methylcellulose, carbomer and sodium alginate, the hydroxypropyl methylcellulose is adjusted to a combination of two types, the mass ratio is K100M:

k100lv=2:1, float time 15min±3.2min, far below the float time limit of the tablet (< 1 h); the sustained floating time is 15h plus or minus 0.14h, which is far longer than the slow release time requirement (10 h) of the slow release preparation, and the slow release effect is good.

2) Tablet release results show (fig. 6):

The matrix material of the sustained-release part in example 3 is a combination of hydroxypropyl methylcellulose, carbomer and sodium alginate, wherein when the model of the hydroxypropyl methylcellulose is K100M, the release degree of the hydroxypropyl methylcellulose is 24 percent in 1h, 45 percent in 4h and 77 percent in 12h, and the sustained-release tablet has complete release and good sustained-release performance, and meets the release requirements of the sildenafil citrate in 24h (the release degree of the sildenafil citrate in 1h is 15-35 percent, the release degree of the sildenafil citrate in 4h is 40-55 percent and the release degree of the sildenafil citrate in 12h is 70-100 percent).

The matrix materials of the slow release parts of the methods 1-3 of the embodiment 8 are hydroxypropyl methylcellulose, carbomer and sodium alginate compositions, wherein the hydroxypropyl methylcellulose is respectively of the type K15M, K4M, K LV, the release degrees of the hydroxypropyl methylcellulose are respectively 29%, 30% and 35% in 1h, the release degrees of the hydroxypropyl methylcellulose are respectively 50%, 52% and 55% in 4h, the release degrees of the hydroxypropyl methylcellulose are respectively 85%, 89% and 90% in 12h, and the requirements of the release degrees of the sildenafil citrate in 24h (the release degree of the hydroxypropyl methylcellulose is 15-35% in 1h, the release degree of the hydroxypropyl methylcellulose is 40-55% in 4h, the release degree of the hydroxypropyl methylcellulose is 70-100% in 12 h) are met, and the tablet is completely released and has good slow release performance.

Example 8 method 4 the matrix material of the slow release portion is a combination of hydroxypropyl methylcellulose, carbomer and sodium alginate, wherein the hydroxypropyl methylcellulose is a combination of two types, the mass ratio is K100M:

When k100deg.LV=2:1, the release degree is 26% in 1h, 48% in 4h and 88% in 12h, which satisfies the release degree requirement of alinafil citrate in 24h (15-35% in 1h, 40-55% in 4h and 70-100% in 12 h), the tablet is completely released and the slow release performance is good.

The small knot:

The skeleton material of the slow-release part is a composition of hydroxypropyl methylcellulose, carbomer and sodium alginate, and when the hydroxypropyl methylcellulose with different types is adopted, the slow-release effect is good:

Firstly, when the model of hydroxypropyl cellulose in the framework material adopts any one or combination of K100M, K, M, K, M, K and 100LV, the sustained-release effect of the tablet is good, and the tablet is specifically expressed as follows:

i. The floating time is short (only 6-20 min), and is far lower than the floating time limit of the tablet (1 h);

the continuous floating time is long (up to 13-16 h) and is far longer than the slow release time requirement (10 h) of the slow release preparation;

Tablet release is complete: the release degree of 1h is 24-35%, the release degree of 4h is 45-55%, the release degree of 12h is 77-90%, and the release degree requirement of sildenafil citrate in 24h is met (the release degree of 1h is 15-35%, the release degree of 4h is 40-55%, and the release degree of 12h is 70-100%);

(II) when the model of hydroxypropyl cellulose is K100M (e.g., example 3), the sustained release effect of the tablet is best, and is specifically expressed as follows:

Conclusion analysis 7:

In addition, on the basis of the embodiment 3 with the best tablet release effect (floating time and release degree), namely, taking the combination of cellulose, carbomer or polysaccharide materials as a framework material, the influence of different dosages of cellulose (hydroxypropyl methylcellulose), carbomer (carbomer 971P) and polysaccharide material (sodium alginate) in the framework material on the tablet release effect (tablet density, floating time and release degree after swelling) is explored, and the result is as follows:

7-1, matrix material distinction of sustained release part of the preparation

Table 30

Examples	Hydroxypropyl methylcellulose K100M, carbomer 971P and sodium alginate ratio
		Example 3	2:1:2
Example 9 method 1	1:1:3
		Example 9 method 2	4:1:1
Example 9 method 3	5:1:1
		Example 9 method 4	1:1:4

7-2, Comparison of Release effects (tablet Density after swelling, floating time and Release)

Table 31

Table 32

Examples	Time to float	Duration of floating time
			Example 3	6min±1.5min	16h±0.25h
Example 9 method 1	8min±1.0min	11h±0.25h
			Example 9 method 2	15min±2.0min	16h±0.25h
Example 9 method 3	1.5h±0.5h	16h±0.45h
			Example 9 method 4	10min±1.2min	5h±0.28h

Table 33

Conclusion:

1) Tablet density after swelling (fig. 7) and float time results show:

Example 3a hydroxypropyl methylcellulose K100M, carbomer 971P and sodium alginate composition was used in a ratio of 2:1:2, the formulation contained a greater proportion of sodium alginate, the volume increased from 0.75cm ³ to 2.15cm ³ due to rapid expansion of the sodium alginate water absorption capacity, the density decreased rapidly from 1.12g/cm ³ to 0.81g/cm ³ within 8 hours, the density decreased significantly by 28%; greatly quickening the floating speed, reducing the floating time which is 6min plus or minus 1.5min and is far lower than the floating time limit of the tablet (1 h); the sustained floating time is 16h plus or minus 0.25h, which is far longer than the slow release time requirement (10 h) of the slow release preparation, and the slow release effect is good.

Example 9 method 1-2 composition of matrix material hydroxypropyl methylcellulose K100M, carbomer 971P and sodium alginate, the dosage ratio is 1:1:3 and 4:1:1, the prescription contains a large proportion of sodium alginate, the sodium alginate has strong water absorption capacity, the tablet rapidly expands, the volume is increased from 0.75cm ³ to 2.07cm ³、2.12cm³, the density is rapidly reduced from 1.12g/cm ³ to 0.89g/cm ³、0.93g/cm³ within 8 hours, and the density is reduced by 21% and 17%; the floating time is 8min plus or minus 1.0min and 15min plus or minus 2.0min, which are far lower than the floating time limit of the tablet (< 1 h); the continuous floating time is 11h plus or minus 0.25h and 16h plus or minus 0.25h, which is far longer than the slow release time requirement (> 10 h) of the slow release preparation, and the slow release effect is good.

Example 9 method 3 the matrix material is a combination of hydroxypropyl methylcellulose K100M, carbomer 971P and sodium alginate in a 5:1:1 ratio, the sodium alginate ratio in the formulation is too small, the hydration capacity is slow, the density is rapidly reduced from 1.12g/cm ³ to 1.07g/cm ³ within 8 hours, and the density is basically unchanged; the floating time is 1.5h plus or minus 0.5h, which is far longer than the floating time limit of the tablet (< 1 h), is not easy to stay in stomach, is unfavorable for the sildenafil citrate to exert curative effect, has poor slow release effect and cannot be used as a qualified slow release preparation.

In the method of example 9, the framework material 4 is a combination of hydroxypropyl methylcellulose K100M, carbomer 971P and sodium alginate, the dosage ratio is 1:1:4, the proportion of cellulose in the prescription is too small, the continuous floating time is 5 hours plus or minus 0.28 hours, the sustained release time requirement (10 hours) of the sustained release preparation is far lower, the tablet structure is easy to be damaged, the drug release is fast, the sustained release effect is poor, and the sustained release preparation cannot be used as a qualified sustained release preparation.

2) Tablet release results show (fig. 8):

The matrix material of the sustained-release part in the embodiment 3 is a composition of hydroxypropyl methylcellulose, carbomer and sodium alginate, the dosage ratio is 2:1:2, the release degree for 1h is 24%, the release degree for 4h is 45%, the release degree for 12h is 77%, the requirements of the release degree of sildenafil citrate in 24h (the release degree for 1h is 15% -35%, the release degree for 4h is 40% -55%, the release degree for 12h is 70% -100%) are met, and the tablet is completely released and has good sustained-release performance.

The matrix material of the slow release part of the method 1-2 in example 9 is a composition of hydroxypropyl methylcellulose K100M, carbomer 971P and sodium alginate, the dosage ratio is 1:1:3 and 4:1:1, the release degree of 1h is 17%, 28%, the release degree of 4h is 53%, 55%, the release degree of 12h is 85%, 82%, the release degree requirement of sildenafil citrate in 24h is satisfied (the release degree of 1h is 15% -35%, the release degree of 4h is 40% -55%, the release degree of 12h is 70% -100%), the tablet release is complete, and the slow release performance is good.

The matrix material of the slow release part of the method 3 of example 9 is a composition of hydroxypropyl methylcellulose K100M, carbomer 971P and sodium alginate, the dosage ratio is 5:1:1, the release degree of 12h is 65%, the release degree is lower than the requirement (70% -100%), the tablet is slow to release, the slow release effect is poor, and the tablet cannot be used as a qualified slow release preparation.

The matrix material of the slow release part of the method 4 of the embodiment 9 is a composition of hydroxypropyl methylcellulose K100M, carbomer 971P and sodium alginate, the dosage ratio is 75% of the release degree of 1:1:4, the release degree is obviously higher than the release degree requirement (40% -55%), the tablet is fast to release, the slow release effect is poor, and the tablet cannot be used as a qualified slow release preparation.

The small knot:

the matrix material of the slow-release part is a hydroxypropyl methylcellulose K100M, carbomer and sodium alginate composition, and the dosage ratio of the three components significantly influences the slow-release effect (tablet density after swelling, floating time and release degree) of the tablet:

When the dosage ratio of the hydroxypropyl methylcellulose K100M, carbomer and sodium alginate is (4-1): 1 (1-3) (for example, the methods 1-2 of the embodiment 3 and the embodiment 9), the sustained release effect of the tablet is good, and the tablet is specifically expressed as follows:

i. The floating time is short: the density of the tablet is obviously reduced (the density is reduced by 17% -28%) within 8 hours, the floating time is short (only 6-15 min), and the floating time limit of the tablet is far lower than (1 hour);

The continuous floating time is long (up to 11-16 h) and is far longer than the slow release time requirement (more than 10 h) of the slow release preparation;

(II) when the dosage ratio of hydroxypropyl methylcellulose K100M, carbomer and sodium alginate is 2:1:2 (for example, example 3), the sustained release effect of the tablet is best, and the tablet is specifically expressed as follows:

i. The floating time is shortest: the density of the tablets is reduced most (up to 28%) within 8 hours, the time to float is shortest (down to 6 min), well below the time limit of the float of the tablets (< 1 h);

And (III) when the dosage ratio of the hydroxypropyl methylcellulose K100M, carbomer and sodium alginate is (4-1): 1 (1-3) (for example, 5:1:1 and 1:1:4 of the methods 3-4 of the embodiment 9), the sustained release effect of the tablet is poor, and the tablet cannot be used as a qualified sustained release preparation, and is specifically expressed as follows:

i. The floating time is too long: when the proportion of hydroxypropyl methylcellulose is high and the proportion of sodium alginate is low, the density change of the tablet is basically unchanged within 8 hours, the floating time is too long (up to 1.5 hours) and is far longer than the floating time limit of the tablet (< 1 hour);

Too short a duration of floating: the proportion of hydroxypropyl methylcellulose is low, and when the proportion of sodium alginate is high, the continuous floating time is too short (as low as 5 h) and is far lower than the slow release time requirement (> 10 h) of a slow release preparation;

tablet release too fast: the release degree is higher than (77% of release degree in 4h, 40% -55% of release degree is required) or lower than (65% of release degree in 12h, 70% -100% of release degree is required)

Release of alidenafil citrate within 24 h.

Conclusion analysis 8:

From the results in conclusion analyses 1 to 7, it was found that the tablet prepared in example 3 using 3 materials as the matrix material (combination of cellulose-based, carbomers-based and polysaccharide-based materials, carbomers-based using carbomers 971P) had the best release effect (floating time and release rate). Therefore, on the basis of example 3, the influence of the kind of immediate release part material on the sustained release effect of the tablet was further investigated by changing the kinds of diluents and disintegrants of the immediate release part. The results were as follows:

8-1, material distinction of quick release part of preparation

Watch 34

8-2, Comparison of Release Effect (Floating time and Release degree)

Table 35

Table 36

Conclusion:

1) The floating time results show that:

Example 3 diluent of immediate release part adopts lactose and microcrystalline cellulose, disintegrating agent adopts cross-linked polyvinylpyrrolidone, and the time for the tablet to float is 6min + -1.5 min, which is far lower than the time limit of the tablet to float (< 1 h); the sustained floating time is 16h plus or minus 0.25h, which is far longer than the slow release time requirement (10 h) of the slow release preparation, and the slow release effect is good.

Example 10 methods 1-3 vary the type of diluent and/or disintegrant in the immediate release portion, the time to float for a tablet is 8min 1.0min, 8.5min 2.0min, 9min 2.0min, all well below the time limit of the time to float for a tablet (< 1 h); the continuous floating time is 16 h+/-0.31 h, 15.5 h+/-0.21 h and 15.7 h+/-0.35 h, which are far longer than the slow release time requirement (10 h) of the slow release preparation, and the slow release effect is good.

2) Tablet release results are shown (fig. 9-11):

The diluent of the quick release part in example 3 adopts lactose and microcrystalline cellulose, the disintegrating agent adopts cross-linked polyvinylpyrrolidone, the release degree of 1h is 24%, the release degree of 4h is 45%, the release degree of 12h is 77%, the release degree requirement of alinafil citrate in 24h is satisfied (the release degree of 1h is 15% -35%, the release degree of 4h is 40% -55%, the release degree of 12h is 70% -100%), and the tablet has good slow release performance.

The method 1-3 of example 10 changes the types of diluents and/or disintegrants in the immediate release part, the release degree of 1h is 25%, 26%, 25%, the release degree of 4h is 49%, 48%, 49%, and the release degree of 12h is 79%, 80%, and meets the release degree requirements of sildenafil citrate in 24h (the release degree of 1h is 15% -35%, the release degree of 4h is 40% -55%, and the release degree of 12h is 70% -100%), and the tablet has good slow release performance.

The small knot:

the quick-release part of the diluent and/or the type of the disintegrating agent is changed, the floating time and the release degree of the tablet are not significantly different, and when the quick-release part of the diluent and/or the type of the disintegrating agent is replaced (for example, the methods 1-3 of the embodiment 3 and the embodiment 10), the tablet has good slow-release performance, and the specific expression is:

i. the floating time of the tablet is short (only 6-9 min), and is far lower than the floating time limit of the tablet (< 1 h);

The continuous floating time is long (15.5-16 h), which is far longer than the slow release time requirement (10 h) of the slow release preparation;

Tablet release is complete: the release degree of 1h is 24% -26%, the release degree of 4h is 45% -49%, the release degree of 12h is 77% -80%, and the release degree requirements of sildenafil citrate in 24h are met (the release degree of 1h is 15% -35%, the release degree of 4h is 40% -55%, and the release degree of 12h is 70% -100%).

Conclusion analysis 9:

From the results in conclusion analyses 1 to 8, it was found that the oral sustained-release bilayer tablet prepared in example 3 had the best release effect (floating time and release rate). Therefore, on the basis of example 3, the influence of different dosage forms on the sustained release effect was further investigated by changing the dosage form and the biphasic combination mode of the oral sustained release preparation. The results were as follows:

9-1 material differentiation of immediate release part of formulation

Table 37

Examples	Dosage form	Bonding mode
			Example 3	Tablet formulation	Double layer sheet bonding
Example 11 method 1	Capsule preparation	Biphasic particle binding
			EXAMPLE 11 method 2	Capsule preparation	Biphasic pellet combination

9.2 Comparison of Release Effect (float time and Release)

Table 38

Table 39

Conclusion:

1) The floating time results show that:

Example 3 the time to float for a sustained release tablet was 6min ± 1.5min, well below the time limit of the time to float for a tablet (< 1 h); the sustained floating time is 16h plus or minus 0.25h, which is far longer than the slow release time requirement (10 h) of the slow release preparation, and the slow release effect is good.

The preparation forms of the method 1-2 of the embodiment 11 are changed into capsules, the capsules are added into a medium to float rapidly, the floating time is 1min plus or minus 0.5min and 1min plus or minus 0.2min, and the floating time limit of the tablets is far lower than (< 1 h); the continuous floating time is 16.1h plus or minus 0.26h and 15.2h plus or minus 0.31h, which are far longer than the slow release time requirement (> 10 h) of the slow release preparation, and the slow release effect is good.

2) Release results show (fig. 12):

The oral sustained-release bilayer tablet prepared by the method in example 3 has a release rate of 24% in 1h, 45% in 4h and 77% in 12h, meets the release rate requirement of sildenafil citrate in 24h (15% -35% in 1h, 40% -55% in 4h and 70% -100% in 12 h), and has good sustained-release performance.

The dosage forms of the methods 1-2 of example 11 are capsules, the biphasic combination modes are biphasic particle combination and biphasic pellet combination, the release degrees of the capsules are 28% and 24% respectively, the release degrees of the capsules are 52% and 48% respectively, the release degrees of the capsules are 84% and 88% respectively, the release degrees of the capsules are also satisfied with the release degree requirements of the sildenafil citrate in 24 hours (the release degree of the capsules is 15-35% in 1 hour, the release degree of the capsules is 40-55% in 4 hours, and the release degree of the tablets is 70-100% in 12 hours).

The small knot:

the preparation forms and the combination modes of the oral sustained-release preparation (for example, the methods 1-2 of the embodiment 3 and the embodiment 11) are changed, and the prepared sustained-release preparation with different preparation forms has good sustained-release effect; the concrete steps are as follows:

i. the preparation has short bleaching time (only 1-6 min), which is far lower than the bleaching time limit of the tablet (< 1 h);

the continuous floating time is long (15.2-16.1 h), which is far longer than the slow release time requirement (> 10 h) of the slow release preparation;

And iii, complete release: the release degree of 1h is 24-28%, the release degree of 4h is 45-52%, the release degree of 12h is 77-88%, and the release degree requirements of sildenafil citrate in 24h are met (the release degree of 1h is 15-35%, the release degree of 4h is 40-55%, and the release degree of 12h is 70-100%).

Experimental example 4: bioequivalence of

Bioequivalence studies were performed on the best performing example 3 and worse example 9 method 2 of the invention, with example 2 method 1, example 2 method 2, and the slow release formulations of example 11 and method 1 and method 2 of different dosage forms, and on the commercial sildenafil citrate tablets (alishi-30 mg2 tablets), the results showed that: the invention adopts the hydroxypropyl methylcellulose, carbomer and sodium alginate composition as the slow-release framework material, and the prepared slow-release preparation with different dosage forms has the characteristics of high bioavailability and good slow-release effect. The method comprises the following steps:

bioequivalence studies were performed by designing (fasting) double-cycle crossover experiments with the sustained release tablets of example 3, example 2 method 1, example 2 method 2, example 11, method 1 and method 2 with the commercial sildenafil citrate tablets (alishi-30 mg2 tablets) in 32 healthy volunteers. The relevant data are as follows:

Table 40

Remarks:

T _max: the time to peak concentration of the blood drug after administration;

C _max: peak concentration of blood drug occurring after administration;

AUC _last: area under the plasma concentration-time curve in the time from zero to infinity;

AUC _{INF_obs}: area under the plasma concentration-time curve from zero to the last measurable concentration.

Conclusion:

1) The different sustained release effects of the present invention, representative of example 3 (best effect) and example 9, method 2 (less effect), are compared with the commercial equivalents of the sildenafil citrate tablets.

From the analysis of the table, the sustained-release matrix material of the sildenafil citrate oral sustained-release preparation adopts a combination of 3 materials, namely a combination of hydroxypropyl methylcellulose K100M, carbomer 971P and sodium alginate, the dosage ratio of the three materials is 2:1:2 (example 3), and compared with a tablet of Ailisi-30 mg 2, the preparation rapidly disintegrates within 1min and rapidly absorbs the blood concentration of a clinically required therapeutic window within 1 hour; c _max and T _max are not equivalent, C _max is 144.48 +/-35.5 ng/mL, the peak concentration of the blood drug after administration is reduced, T _max is 6.50+/-1.21 hours, and the time of the peak concentration of the blood drug is obviously prolonged by 3.7 times; AUC _last is 1309.12 +/-58.7 ng.h/mL, equivalent to Ailisi-30 mg 2 tablets, and has a relative bioavailability of 95.32%, which indicates that the Aidinafop citrate can achieve the slow release effect, and the bioavailability is obviously improved.

Example 9 method 2 uses a combination of 3 materials, i.e. a combination of hydroxypropyl methylcellulose K100M, carbomer 971P and sodium alginate, the dosage ratio of the three is 4:1:1, the obtained preparation rapidly disintegrates within 1min compared with Ailisi-30 mg 2 tablets, and the blood concentration of the clinically required therapeutic window is rapidly absorbed within 1 hour; c _max is not equivalent to T _max, C _max is 135.26 +/-29.6 ng/mL, the peak concentration of the blood drug after administration is reduced, T _max is 5.82+/-0.52 h, and the time of the peak concentration of the blood drug is obviously prolonged by 3.3 times; AUC _last is 1195.35 + -39.5 ng.h/mL, equivalent to Ailisi-30 mg 2 tablets, and the relative bioavailability is 87.04%, which shows that the Aidinafop citrate can achieve the slow release effect, and the bioavailability is obviously improved.

Example 3 and example 9, method 2, are representative examples of the present invention, and are the best and worse examples of the present invention, both of which can prolong the peak concentration time of blood (up to 5.82-6.5 h) and significantly improve the bioavailability (up to 87.04% -95.32%).

2) The different dosage forms of the present invention and the biphasic combination mode represent example 3 (bilayer tablet) and example 11 methods 1-2 (biphasic granule combined capsule, biphasic pellet capsule) were compared with commercial alidenafil citrate tablet equivalence.

Based on the double-layer tablet sustained release preparation of the embodiment 3, the method 1 and the method 2 of the embodiment 11 change the dosage form and the biphasic combination mode of the oral sustained release preparation, and the prepared sustained release preparation of different dosage forms has good sustained release effect, obviously prolongs the time of reaching peak concentration of blood medicine (reaching 6.0h and 6.2 h), and obviously improves the stability and bioavailability of blood medicine (reaching 90.02 percent and 93.01 percent).

Example 11 method 1 an oral sustained release capsule prepared by combining bi-directional particles disintegrates rapidly within 1min and rapidly absorbs the blood concentration of the clinically required therapeutic window within 1 hour compared with the Ailisi-30 mg 2 tablet; c _max is not equivalent to T _max, C _max is 154.48 +/-31.6 ng/mL, the peak concentration of the blood drug after administration is reduced, T _max is 6.02+/-1.04 h, and the time of the peak concentration of the blood drug is obviously prolonged by 3.4 times; AUC _last is 1236.35 + -43.7 ng.h/mL, equivalent to Ailisi-30 mg 2 tablets, and the relative bioavailability is 90.02%, which indicates that the sildenafil citrate can achieve the slow release effect, and the bioavailability is obviously improved.

Example 11 method 2 an oral sustained release capsule prepared by combining bi-directional pellets, compared with Ailisi-30 mg 2 tablets, disintegrates rapidly within 1min, and rapidly absorbs within 1 hour to reach the clinically required blood concentration in the therapeutic window; c _max is not equivalent to T _max, C _max is 136.28 +/-23.5 ng/mL, the peak concentration of the blood drug after administration is reduced, T _max is 6.21+/-1.21 hours, and the time of the peak concentration of the blood drug is obviously prolonged by 3.6 times; AUC _last is 1277.42 +/-38.5 ng.h/mL, equivalent to Ailisi-30 mg 2 tablets, and has a relative bioavailability of 93.01%, which indicates that the Aidinafop citrate can achieve the slow release effect, and the bioavailability is obviously improved.

3) Other methods example 2 methods 1-2 are equivalent compared to commercial alidenafil citrate tablets.

In the method 1 of the embodiment 2, 2 materials are combined, a composition of carbomer 971P and sodium alginate is used as a slow-release framework material, cellulose is not used, the obtained slow-release tablet is compared with Ailisi, T _max is 3.5+/-1.01 h, the time of reaching the peak concentration of blood is obviously prolonged by 1.57 times, but C _max is 96.82+/-47.7 ng/mL, and the time is obviously reduced by 60%; AUC _last is 915.65 ±57.8ng·h/mL, the relative bioavailability is 66.67%, the analytical reasons may be that the sustained release tablet of the method 1 of example 2 has too long time to float (2.5 h±0.13 h), far longer than the time limit of the tablet to float (< 1 h), the preparation may be emptied to the small intestine and other parts together with gastric emptying without floating, resulting in release of the sildenafil citrate in alkaline environment, low solubility, reduced absorption, and low bioavailability.

In the method 2 of the embodiment 2,2 materials are combined, a composition of hydroxypropyl methylcellulose K100M and sodium alginate is used as a slow-release framework material, carbomers are not used, the obtained slow-release tablet is compared with alishi, T _max is 2.12+/-0.84 h, and the time for reaching peak concentration of blood is prolonged by 56%; c _max is 210.54 +/-36.4 ng/mL, the peak concentration of the blood drug after administration is reduced, and the sustained-release preparation is not realized; AUC _last is 742.36 ±47.8ng·h/mL, the relative bioavailability is 54.05%, the analysis reason may be that the sustained-release tablet of the method 2 of example 2 has too short sustained-floating time (4 h±0.15 h) and is far lower than the sustained-release time requirement (> 10 h) of the sustained-release preparation, the preparation may be emptied to small intestine and other parts along with gastric emptying, so that the sildenafil citrate is released in alkaline environment, the solubility is low, the absorption is reduced, and the bioavailability is low.

The small knot:

The sustained release preparation (for example, example 3, example 9, method 2 and example 11) obtained by adopting the combination of 3 materials (the combination of hydroxypropyl methylcellulose K100M, carbomer 971P and sodium alginate) has obviously improved bioequivalence and good sustained release effect compared with the sustained release preparation obtained by the existing commercial sildenafil citrate tablet (Ailisi-30 mg 2 tablets) and the combination of 2 materials of the invention, and is characterized in that:

i. The time for the peak concentration of the blood medicine to reach is obviously prolonged (up to 6.5 h);

The stability of blood concentration and bioavailability are obviously improved (up to 95.32%).

Claims

1. An oral sustained release formulation of alidenafil citrate, the formulation comprising a sustained release portion and an immediate release portion; the slow release part and the quick release part are respectively used in the following amounts by mass percent:

the active pharmaceutical ingredient is alidenafil citrate;

The framework materials are hydroxypropyl methylcellulose K100M, carbomer 971P and sodium alginate; in the framework material, the mass ratio of the hydroxypropyl methylcellulose K100M, the carbomer 971P and the sodium alginate is = (4-1) 1 (1-3);

The surfactant is glyceryl behenate;

The disintegrating agent of the slow release part is cross-linked polyvinylpyrrolidone; the disintegrating agent of the quick-release part is crosslinked polyvinylpyrrolidone or crosslinked sodium carboxymethyl cellulose;

The lubricant is magnesium stearate;

the adhesive is polyvinylpyrrolidone K30;

The diluent of the slow-release part is microcrystalline cellulose; the diluent of the quick-release part is any one or more of lactose, microcrystalline cellulose, calcium hydrophosphate and pregelatinized starch.

2. The oral sustained release formulation of claim 1, wherein the matrix material is a hydrophilic gel matrix material.

3. The oral sustained-release preparation according to claim 1, wherein a mass ratio of the pharmaceutically active ingredient in the sustained-release portion to the pharmaceutically active ingredient in the immediate-release portion is (3 to 8): 1.

4. The oral sustained release formulation of claim 1, wherein the mass ratio of the pharmaceutically active ingredient in the sustained release portion to the pharmaceutically active ingredient in the immediate release portion is 5:1.

5. The oral sustained-release preparation according to claim 1, wherein the mass ratio of hydroxypropyl methylcellulose K100M, carbomer 971P, sodium alginate in the matrix material is 2:1:2.

6. The oral sustained release formulation of claim 1, wherein the formulation comprises a sustained release tablet or capsule.

7. The oral sustained release formulation of claim 1, wherein the disintegrant of the immediate release portion is cross-linked polyvinylpyrrolidone.

8. The oral sustained release formulation of claim 1, wherein the diluent of the immediate release portion is a combination of lactose and microcrystalline cellulose.

9. The oral sustained-release preparation according to claim 1, which comprises the following specific components and amounts:

。

10. The oral sustained-release preparation according to claim 1, which comprises the following specific components and amounts:

。

11. the oral sustained-release preparation according to claim 1, which comprises the following specific components and amounts:

。

12. the oral sustained-release preparation according to claim 1, which comprises the following specific components and amounts:

。

13. the oral sustained release formulation according to any one of claims 1 to 12, wherein the oral sustained release formulation is for use in the treatment of alzheimer's disease.

14. The oral sustained release formulation according to any one of claims 1 to 12, wherein the oral sustained release formulation is for use in the treatment of erectile dysfunction.

15. A method of preparing the oral sustained release formulation of any one of claims 1 to 14, comprising the steps of:

16. The method of manufacture of claim 15, wherein the means of combination comprises tablet combination or capsule combination;

The tablet bonds include a two-layer tablet bond or a core-in-tablet bond;

the capsule combination comprises a biphasic particle combination, a biphasic capsule combination, a biphasic pellet combination or a biphasic microchip combination.

17. The method of manufacture of claim 16, wherein the tablet bond is a bilayer tablet bond.

18. Use of an oral sustained release preparation according to any one of claims 1 to 14 in the preparation of a medicament for the treatment of alzheimer's disease.

19. Use of an oral sustained release formulation according to any one of claims 1 to 14 in the manufacture of a medicament for the treatment of erectile dysfunction.