CN115969781A

CN115969781A - Aidenafil citrate injection and preparation method and application thereof

Info

Publication number: CN115969781A
Application number: CN202310037723.8A
Authority: CN
Inventors: 宋更申; 欧阳旭; 王瑞强
Original assignee: Beijing Youcare Kechuang Pharmaceutical Technology Co ltd
Current assignee: Beijing Youcare Kechuang Pharmaceutical Technology Co ltd
Priority date: 2023-01-09
Filing date: 2023-01-09
Publication date: 2023-04-18

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an Aidenafil citrate injection, and a preparation method and application thereof. The injection has good solubilization effect, remarkably improves the solubility of the citric acid alidenafil, and remarkably reduces the level of insoluble particles; meanwhile, the freeze-drying key temperature is obviously improved, the water content is low, the impurity content is low, and the stability is greatly improved; and the cosolvent dosage is obviously reduced, the isotonic effect is good, the safety and the clinical compliance are obviously improved, and the composition can be used for treating the Alzheimer disease.

Description

Aidenafil citrate injection and preparation method and application thereof

Technical Field

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to an Aidinafei citrate injection, and a preparation method and application thereof.

Background

Alzheimer's Disease (AD), also called senile dementia, is a degenerative disease of the central nervous system, with an insidious onset and a chronic progressive course, and is one of the most common types of senile dementia. It is mainly manifested as progressive dysmnesia, cognitive dysfunction, personality change and language disorder, etc., and seriously affects social, work and life functions. Most of the elderly are over 70 years old (average 73 years old in men and 75 years old in women), and few patients have rapid and distinct symptoms after physical illness, bone fracture or mental stimulation. Women are more than men (the proportion of men and women is 1:3). The report of the alzheimer's disease association 2018 indicates that AD patients have reached 5000 ten thousand, and 1 new case is found every 3 seconds on average. Worldwide patients are expected to exceed 8000 million by 2030 and may exceed 1.5 million by 2050.

Alzheimer's disease, which is mainly manifested by a decline in cognitive function, psychiatric symptoms and behavioral disorders, a gradual decline in the ability to self-care in daily life. In the late stage of Alzheimer's disease, patients may have symptoms of dysphagia, and the symptoms may be related to factors such as increased muscle tone, cognitive dysfunction, myasthenia gravis and the like of the patients in the late stage of Alzheimer's disease. At this time, the chewing and swallowing functions of the patient are affected, so that the swallowing difficulty occurs, and the symptoms generally continue for the entire onset period due to the increased muscle tone and myasthenia gravis of the patient, which are generally irreversible.

At present, the marketed form of the citric acid alidenafil is a tablet, the administration mode is that water is required to be used for taking, most of Alzheimer patients are old people, situations of swallowing inconvenience, swallowing difficulty or other cognitive dysfunction and the like can exist, the tablet with a large size is not suitable for the old Alzheimer patients, the clinical compliance is poor, and parenteral administration is possibly required.

Therefore, it is necessary to develop an parenteral injection, and simultaneously, because the solubility of the active ingredient sildenafil citrate in water is 4.08mg/mL, the solubility is low, the therapeutic dose for treating the Alzheimer disease is 42-126 mg, the required volume of water for injection is at least 10.3-27.5 mL and is more than 10mL, the injection volume is large, and the Alzheimer disease patients can be administrated at home due to special conditions, such as intramuscular injection or subcutaneous injection therapy, the possibility is provided for the home administration, the treatment compliance of the patients can be greatly improved, and intramuscular injection: the dosage is 1-5 mL generally; subcutaneous injection: the injection dosage is generally 1-2 mL, and the dosage requirement is lower.

At present, the injection is commonly used in various manners such as organic cosolvent, surfactant solubilizer and cyclodextrin inclusion.

The adoption of organic cosolvent is one of the oldest means for solving the problem of low solubility of the injection. The organic cosolvent can improve the solubility of the insoluble drug in an aqueous solution, the dosage is less than 20 percent, and the organic cosolvent is widely applied to preparations on the market. For highly lipophilic compounds, the addition of a suitable organic solvent to the aqueous solution can reduce the ability of the aqueous system to expel non-polar molecules through the carbon-hydrogen bond regions of the organic solvent molecules; it can also be understood from the perspective of polarity that organic solvents can reduce the polarity of aqueous solutions, and if the polarity of the drug is similar to the polarity of the added organic solvent, the drug may obtain higher solubility, which is the so-called "similar phase dissolution" principle. The existing injection needs high-concentration organic solvent to maintain the dissolution state of the medicine, does not need to reach high solubility during administration, and can reduce the side effect generated by the high-concentration organic solvent after dilution, thereby meeting the clinical administration requirement. By searching for documents or patents, we found:

patent CN100344624C discloses an argininamide pharmaceutical preparation, which increases the solubility of argatroban injection by adding cosolvent-diol or triol and glycerin.

Patent CN103006554B discloses an ornidazole injection and a preparation method thereof, wherein anhydrous ethanol plays a role of a cosolvent and a stabilizer, and the solubility of the ornidazole injection is increased.

The products on the market are dissolved in a large amount of organic solvents, such as ethanol, and comprise: deacetyl hairy flower glycoside injection (containing 10% ethanol), digitoxin injection (containing 10% (V/V) ethanol), nimodipine injection (containing 20% (V/V) ethanol), glycerol nitrate injection, diazepam injection, pyritinol hydrochloride injection, shuxuening injection (adjuvant containing 95% ethanol), folium Ginkgo extract injection, and XUESAITONG injection; azithromycin injection (solvent containing ethanol), azithromycin sodium chloride injection (solvent containing ethanol), amphotericin B liposome for injection (adjuvant containing anhydrous ethanol), and chloramphenicol injection; tacrolimus injection (containing 638mg of ethanol per milliliter) and cyclosporine injection (containing ethanol as an auxiliary material); docetaxel injection (adjuvant containing anhydrous ethanol), docetaxel for injection (special solvent is ethanol sterilized water solution), paclitaxel injection (containing anhydrous ethanol), etoposide injection, and docetaxel injection, and ethanol is added to increase solubility of the injection.

The surfactant is used as a solubilizer and is a common solubilizing mode of the injection. The solubility is increased by dissolving the poorly soluble drug in the micelle formed by the surfactant, and the amount of the poorly soluble drug added is small (0.5% to 1.0%). The injection is widely applied to a plurality of known commercially available injections, such as intravenous anesthetic (Fowley), antineoplastic drugs of etoposide (etoposide) and docetaxel (Everdin/Etoridin) and vitamin K1 injection which are all solubilized by adding polysorbate; such as paclitaxel injection

The solubilisation is carried out by adding polyoxyethylated castor oil.

The two solubilization methods are not applicable to all drugs, and their useful amounts are limited. The dosage of the organic solvent is as follows: not more than 20%; the dosage of the surfactant is as follows: 0.5 to 1 percent.

In addition, cyclodextrin inclusion is also a dissolution-aiding means. Cyclodextrin is one of basic substances in supramolecular chemistry, and because both ends of a ring of cyclodextrin are hydrophilic and an inner cavity of the cyclodextrin is hydrophobic, drug molecules with proper molecular size and form can be wrapped in the hydrophobic cavity through hydrogen bonds and van der Waals force to form an inclusion compound, and the cyclodextrin is applied to preparations on the market such as voriconazole for injection, posaconazole injection, ziprasidone injection and the like. The cyclodextrin is administered in an amount (maximum amount for intraperitoneal and intravenous routes of administration is 10 g-kg) ^-1 ). Cyclodextrin inclusion requires cyclodextrin to be included with the guestMolecules form inclusion compounds, and a lower inclusion ratio may greatly increase the amount of cyclodextrin used, which may cause a decrease in medication safety, and thus, there is a need to increase the inclusion ratio, decrease the amount of cyclodextrin used, and increase medication safety.

Therefore, there is an urgent need to provide an injection of Aidenafil citrate and a preparation method thereof. The injection has good solubilization effect, remarkably improves the solubility of the citric acid alidenafil, and remarkably reduces the level of insoluble particles; meanwhile, the freeze-drying key temperature is obviously increased, the water content is low, the impurity content is low, and the stability is greatly improved; and the cosolvent dosage is obviously reduced, the isotonic effect is good, the safety and the clinical compliance are obviously improved, and the composition can be used for treating the Alzheimer disease.

Disclosure of Invention

Aiming at the problems, the invention provides an Aidenafil citrate injection and a preparation method thereof. The injection improves the solubility of the citric acid alidenafil by adding the cyclodextrin derivative, and obviously reduces the level of insoluble particles (the content of particles larger than or equal to 10 mu m is as low as 25.4 particles, and the content of particles larger than or equal to 25 mu m is as low as 1.4 particles);

meanwhile, by adding a saccharide substance or a sugar alcohol substance: in one aspect, in the injection: (1) the consumption of the cosolvent cyclodextrin derivative can be obviously reduced, the biological safety is improved, (2) the solubility is further improved, and the synergistic solubilization effect is enhanced; on the other hand, when the injection is prepared into a freeze-dried preparation, the properties (inclusion ratio, quality, key temperature and stability) of the freeze-dried preparation can be also obviously improved: (1) the inclusion ratio is remarkably improved (up to 1:2), the synergistic solubilization effect is good, (2) the isotonic effect is good, the administration safety is high, (3) the freeze-drying key temperature is high, the water content is low (as low as 0.6%), the impurity content is low (as low as 0.002%), the stability is greatly improved, and (4) the freeze-drying preparation is good in forming and good in appearance property; (5) the re-dissolving time is short (23-96 s), and is less than 120s; remarkably improves the safety and clinical compliance of the medicine, and can be used for treating Alzheimer disease. The method comprises the following specific steps:

the invention provides an injection of citric acid alidenafil, which comprises active ingredients of medicaments,

the active pharmaceutical ingredient comprises citric acid alidenafil and/or pharmaceutically acceptable salt thereof.

In some embodiments, wherein the injection further comprises a pH adjusting agent and/or an injection solvent.

In some embodiments, wherein the injection comprises a co-solvent and/or a solubilizing agent.

In some embodiments, the cosolvent and the solubilizer are selected from any one of cyclodextrin derivatives, organic cosolvents and surfactants, and are preferably cyclodextrin derivatives.

In some embodiments, wherein the cyclodextrin derivative comprises beta-cyclodextrin and/or gamma-cyclodextrin.

In some preferred embodiments, wherein the cyclodextrin derivative is selected from the group consisting of: any one or more of hydroxyethyl-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, methyl-beta-cyclodextrin, maltose-beta-cyclodextrin, carboxymethyl-beta-cyclodextrin, sulfoethyl-beta-cyclodextrin, sulfopropyl-beta-cyclodextrin, sulfobutyl-beta-cyclodextrin sodium, methyl-beta-cyclodextrin and hydroxypropyl-gamma-cyclodextrin; more preferably hydroxypropyl-beta-cyclodextrin and/or sodium sulfobutyl-beta-cyclodextrin.

In some embodiments, wherein the molar ratio of the pharmaceutically active ingredient to the cyclodextrin derivative is 1: (2-20); preferably, the molar ratio is 1 (5-10).

In some embodiments, wherein the injection further comprises a saccharide or a sugar alcohol.

In some embodiments, wherein the carbohydrate is selected from the group consisting of: any one or more of glucose, trehalose, sucrose and dextran; the sugar alcohol substance comprises sorbitol and/or mannitol, preferably sorbitol.

In some embodiments, wherein the injection comprises a pharmaceutically active ingredient, a pH adjuster, an injection solvent, a cyclodextrin derivative, and optionally a saccharide or sugar alcohol.

In some embodiments, wherein the pH adjusting agent is selected from: any one or more of hydrochloric acid, sulfuric acid, tartaric acid, citric acid, sodium hydroxide, potassium hydroxide, sodium bicarbonate, disodium hydrogen phosphate and sodium dihydrogen phosphate.

In some embodiments, wherein the solvent for injection is selected from: one or more of ethanol, propylene glycol, glycerol, sorbitol and water for injection, preferably water for injection.

In some embodiments, wherein the injection is for the treatment of alzheimer's disease.

In some embodiments, wherein the injection is for the treatment of erectile dysfunction.

A preparation method of citric acid alidenafil injection comprises the following steps:

1) Solution preparation: formulating the pharmaceutically active ingredient and/or optionally other ingredients into an injection;

2) Filtering;

3) Filling;

4) Sterilizing;

5) And (6) leak detection and packaging.

In some embodiments, wherein a lyophilization process is used in place of sterilization in step 4), a lyophilized formulation of citric acid alidenafil injection is obtained.

In some embodiments, wherein the lyophilization process comprises the steps of:

a. pre-freezing;

b. primary drying;

c. resolving and drying;

d. pressing and plugging;

e. and (6) rolling a cover.

An application of citric acid alidenafil injection in preparing medicine for treating Alzheimer disease is provided.

An application of citric acid alidenafil injection in preparing the medicines for treating erectile disfunction is disclosed. The invention has the advantages that:

an Aidenafil citrate injection, which has the following advantages:

by adding the cyclodextrin derivative, the solubility of the citric acid alidenafil is greatly improved, and the level of insoluble particles (the content of particles larger than or equal to 10 mu m is as low as 25.4 particles, and the content of particles larger than or equal to 25 mu m is as low as 1.4 particles) is obviously reduced;

meanwhile, by adding a saccharide substance or a sugar alcohol substance: in one aspect, in the injection: (1) the consumption of the cosolvent cyclodextrin derivative can be obviously reduced, the biological safety is improved, (2) the solubility is further improved, and the synergistic solubilization effect is enhanced; on the other hand, when the injection is prepared into a freeze-dried preparation, the properties (inclusion ratio, quality, key temperature and stability) of the freeze-dried preparation can be also obviously improved: (1) the inclusion ratio is remarkably improved (as high as 1:2), the synergistic solubilization effect is good, (2) the isotonic effect is good, the administration safety is high, (3) the freeze-drying key temperature is high, the water content is low (as low as 0.6%), the impurity content is low (as low as 0.002%), the stability is greatly improved, and (4) the freeze-drying preparation is good in forming and good in appearance property; (5) the re-dissolving time is short (23-96 s) and is less than 120s; the method comprises the following specific steps:

(one) injection solubility influence:

1. when other solubilizing methods (organic cosolvent/surfactant solubilizer) are adopted or no cosolvent/solubilizer is adopted, the prepared injection solution is turbid, has low solubility and cannot be used as a qualified injection; only by adopting the dissolving-assisting mode of the cyclodextrin derivative inclusion, the prepared injection solution is clear and has good solubility, and the specific expression is as follows:

i. the citric acid alidenafil raw material medicine is completely dissolved, and the solubilization effect is good;

ii, the number of insoluble particles is small (25.4 particles with the particle size of not less than 10 μm, and 1.4 particles with the particle size of not less than 25 μm), and both are far smaller than the number limit of 6000 particles and 600 particles;

and iii, the injection is clear in a low-temperature freeze-thawing process, and the solubility is good.

2. When different types of cyclodextrin derivatives (any one or more of hydroxyethyl-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, methyl-beta-cyclodextrin, maltose-beta-cyclodextrin, carboxymethyl-beta-cyclodextrin, sulfoethyl-beta-cyclodextrin, sulfopropyl-beta-cyclodextrin, sulfobutyl-beta-cyclodextrin, methyl-beta-cyclodextrin and hydroxypropyl-gamma-cyclodextrin) are adopted, the obtained injection solution is clear and has good solubility, and the specific expression is as follows:

i. in the preparation process, the raw material medicine citric acid alidenafil is completely dissolved, and the solubilization effect is good;

ii, the number of insoluble particles is small (25.4-113 particles with a particle size of 10 μm or more, and 1.4-59 particles with a particle size of 25 μm or more, respectively), and both are far smaller than the number limit of 6000 particles and 600 particles of the insoluble particles;

and iii, the solution is clear and has good solubility in the freeze-thaw process of the injection.

Wherein, when the cyclodextrin derivative adopts sulfobutyl-beta-cyclodextrin sodium, the obtained injection solution is clear and has the best solubility, and the expression is as follows:

i. the citric acid alidenafil raw material medicine is completely dissolved, and the solubilizing effect is best;

the number of insoluble particles is minimum (25.4 particles with the particle size of 10 μm or more and 1.4 particles with the particle size of 25 μm or more), and both are far smaller than the number limit of 6000 particles and 600 particles;

and iii, clarifying the solution of the injection in a low-temperature freeze-thawing process, wherein the solubility is the best.

3. By controlling the molar ratio of the citric acid alidenafil to the cyclodextrin derivative (sulfobutyl-beta-cyclodextrin sodium) to be 1: (2-20), the obtained injection solution is clear and has good solubility, and the specific expression is as follows:

i. in the preparation process, the citric acid alidenafil raw material medicine is completely dissolved, and the solubilization effect is good;

the number of insoluble fine particles is small (18 to 1167 particles at 10 μm or more and 1.3 to 325 particles at 25 μm or more), and is far smaller than 6000 and 600 particles at the limit of the number of insoluble fine particles: as the molar ratio of the citric acid alidenafil to the cyclodextrin derivative increases (from 1:2 to 1 to 20), the dosage of the cyclodextrin derivative in the formula increases, and the number of insoluble particles is remarkably reduced; when the molar ratio of the citric acid alidenafil to the cyclodextrin derivative is increased from 1:5 to 1;

the injection keeps clear and colorless in the low-temperature freeze-thawing process and has good solubility.

Wherein, when the molar ratio of the citric acid alidenafil to the cyclodextrin derivative (sulfobutyl-beta-cyclodextrin sodium) is 1:5, the dosage of the cyclodextrin derivative is less, the biosecurity is high, and the obtained injection solution is clear and has the best solubility, which is specifically represented as:

i. in the preparation process, the citric acid alidenafil raw material medicine is completely dissolved, and the solubilization effect is best;

ii, the number of insoluble particles is small (25.4 particles with a particle size of 10 μm or more, and 1.4 particles with a particle size of 25 μm or more, respectively), and both are far smaller than the number limits of 6000 particles and 600 particles of the insoluble particles;

the injection keeps clear and colorless in the low-temperature freezing and thawing process, and has the best solubility.

4. On the basis of adding cyclodextrin derivatives, when a prescription of further adding saccharides or sugar alcohol substances (sorbitol), the prepared injection solution is clear, the solubility is further improved, and the synergistic solubilization effect is enhanced, which is specifically represented as follows:

i. in the preparation process, the citric acid alidenafil raw material medicine is completely dissolved, and the synergistic solubilization effect of the cyclodextrin derivative and the saccharide substance or the sugar alcohol substance is good;

ii, the number of insoluble particles is small (18.6-1167 particles with the particle size of 10 mu m or more and 0.9-325 particles with the particle size of 25 mu m or more), and both are far smaller than the number limit of 6000 particles and 600 particles of the insoluble particles;

iv, the injection keeps clear and colorless solution and has good solubility in the low-temperature freeze-thawing process.

Wherein, on the basis that the molar ratio of the citric acid alidenafil to the cyclodextrin derivative (sulfobutyl-beta-cyclodextrin sodium) is 1:5, when a prescription of a carbohydrate substance or a sugar alcohol substance (sorbitol) is added, the prepared injection solution is clear, has the best solubility and the best synergistic solubilization effect, and is specifically represented as follows:

i. in the preparation process, the citric acid alidenafil raw material medicine is completely dissolved, and the synergistic solubilization effect of the cyclodextrin derivative and the sugar substance or sugar alcohol substance is the best;

the number of insoluble particles is the least (18.6 particles with a particle size of 10 μm or more and 0.9 particle with a particle size of 25 μm or more), and both are far smaller than the number limit of 6000 particles and 600 particles of the respective insoluble particles;

5. When the prescription refers to the same substance, sildenafil citrate injection on the market of the US FDA

The prepared injection solution is turbid, has poor solubility and cannot be used as a qualified injection; only when the prescription combination (the combination of the cyclodextrin derivative and the sugar substance or the sugar alcohol substance or only the addition of the cyclodextrin derivative) is adopted, the obtained injection solution is clear and has good solubility, and the specific expression is as follows:

the number of insoluble fine particles is small (18.6 to 1167 particles at 10 μm or more and 0.9 to 325 particles at 25 μm or more), and both are far smaller than 6000 and 600 particles, respectively;

(II) Effect of lyophilized formulation Properties (inclusion ratio, quality, critical temperature and stability)

a) When the prescription is not added with sugar substances or sugar alcohol substances, the prepared freeze-dried preparation has good properties (inclusion ratio, quality, key temperature and stability) and can be used as a qualified freeze-dried preparation; by adopting a prescription of adding sugar substances or sugar alcohol substances, the obtained freeze-dried preparation has better properties (inclusion ratio, quality, key temperature and stability):

when the saccharide substance or the sugar alcohol substance adopts sorbitol, trehalose, glucose and dextran, the prepared freeze-dried preparation has better properties (inclusion ratio, quality, key temperature and stability), and the specific expression is as follows:

i. the inclusion ratio of the citric acid alidenafil and the cyclodextrin derivative is high (1:2-1:4), and the cyclodextrin derivative and the carbohydrate or the sugar alcohol have good synergistic solubilization effect;

ii, the molar ratio of osmotic pressure is within the range of 1.0-1.2, so that an isotonic effect can be achieved, and the administration safety is high;

the freeze-dried preparation is well formed and has good appearance;

good stability: the freeze-drying critical temperature is high (the collapse temperature Tc is-27 to-21 ℃, and the glass transition temperature Tg of a dried sample is 65-84 ℃); low impurity content (all below the impurity limit); the water content is low (0.6-1.4%);

v. the re-dissolving time is short (23-96 s), and is less than 120s;

b) Wherein, when the glucide or sugar alcohol substance adopts sorbitol, the obtained freeze-dried preparation has the best properties (inclusion ratio, quality, key temperature and stability), and the properties are represented as follows:

i. the inclusion ratio of the citric acid alidenafil and the cyclodextrin derivative is high (1:2), and the cyclodextrin derivative and the carbohydrate or sugar alcohol substance have the best synergistic solubilization effect;

the osmotic pressure molar ratio is 1.0, the isotonic effect is best, and the administration safety is high;

the freeze-dried preparation is well formed and has good appearance;

the stability is best: the highest critical temperature for freeze-drying (the collapse temperature Tc reaches-21 ℃, and the glass transition temperature Tg of a dried sample reaches 77 ℃); low impurity content (as low as 0.002%); the lowest moisture content (as low as 0.6%);

v. short reconstitution times (as low as 23 s), well below 120s;

Detailed Description

The invention is further illustrated by the following examples. It should be understood that: the embodiments of the present invention are given for illustration only, and not for limitation, and the simple modifications of the present invention based on the technical solutions of the present invention belong to the protection scope of the present invention.

Example 1

1-1, prescription:

the molar ratio of the citric acid alidenafil to the sulfobutyl-beta-cyclodextrin sodium is controlled to be 1:5, and the specific formula comprises the following components:

table 1: composition table of example 1

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1-2. Preparation process:

1) Solution preparation:

taking 20-80% of the total amount of the water for injection to be placed in a liquid preparation tank, controlling the temperature to be 30-80 ℃, adding sulfobutyl-beta-cyclodextrin sodium into the water for injection, stirring to dissolve the sulfobutyl-beta-cyclodextrin sodium, adding sildenafil citrate into the cyclodextrin derivative solution, and stirring to ensure that the liquid medicine is uniform and clear; slowly adding a small amount of pH regulator solution into the liquid preparation tank, and regulating the pH range of the liquid medicine to 3.0-8.0; the water for injection is used for fixing or weighting to the full amount.

2) And (3) filtering: the liquid medicine is finely filtered to a buffer tank through a 0.45 mu m polyethersulfone filter core and a 0.22 mu m polyethersulfone filter core.

3) Filling: filling the liquid medicine into an ampoule bottle, wherein the filling volume is 5 mL/ampoule bottle.

4) And (3) sterilization: moist heat sterilization at 121 ℃ and F0 is more than 12.

5) And (3) leak detection and packaging: and packaging after the leakage detection is qualified.

Example 2: non-cyclodextrin derivatives

Referring to the formulation and the preparation process of example 1, the difference from example 1 is that the cyclodextrin derivative is not added to the formulation, and the amount of the formulation, other components in the formulation and the preparation process are the same as those of example 1.

Example 3: replacement of cyclodextrin derivatives with other substances (organic co-solvent/surfactant solubilizers)

Referring to the formulation and preparation process of example 1, the difference from example 1 is that the sodium sulfobutyl- β -cyclodextrin in the formulation is replaced by an organic co-solvent or surfactant solubilizer:

1) Organic cosolvent (proportion is 20%)

Referring to the formulation and the preparation process of example 1, the difference from example 1 is that the sulfobutyl-beta-cyclodextrin sodium in the formulation is replaced by an organic cosolvent with the maximum dosage of 20%:

table 2: example 3 compositional tables for method 1-method 4

Organic co-solvent for method 1: ethanol;

organic co-solvent for method 2: propylene glycol;

organic co-solvent for method 3: glycerol;

organic co-solvent for method 4: polyethylene glycol 300.

The usage of the cosolvent by weight portion is 20 weight portions;

the amount of the formulation, other components in the formulation and the preparation process were the same as in example 1.

2) Surfactant solubilizer (ratio is 2%)

Referring to the formulation and the preparation process of example 1, the difference from example 1 is that sulfobutyl-beta-cyclodextrin sodium in the formulation is replaced by surfactant solubilizer, and the dosage is 2% of the maximum dosage:

table 3: example 1 compositional tables for method 5-method 10

Surfactant of method 5: tween 80;

surfactant of method 6: a poloxamer;

surfactant of method 7: sodium lauryl sulfate;

surfactant of method 8: 15-hydroxy stearic acid polyethylene glycol ester;

surfactant of method 9: polyoxyethylene hydrogenated castor oil;

surfactant of method 10: lecithin;

the dosage of the solubilizer is 2 weight portions;

Example 4: selection of the type of cyclodextrin derivative

Referring to the formulation and preparation process of example 1, the difference from example 1 is that the kind of cyclodextrin derivative is changed, the cyclodextrin derivative of example 1 is replaced with sodium sulfobutyl-beta-cyclodextrin,

the method comprises the following steps: hydroxypropyl-beta-cyclodextrin;

the method 2 comprises the following steps: hydroxyethyl-beta-cyclodextrin;

the method 3 comprises the following steps: sulfopropyl-beta-cyclodextrin;

the method 4 comprises the following steps: alpha-cyclodextrin;

Example 5: molar ratio of the pharmaceutically active ingredient to the cyclodextrin derivative

Referring to the formulation and preparation process of example 1, the difference from example 1 is that the molar ratio of the pharmaceutical active ingredient to the cyclodextrin derivative is changed, the molar ratio of citric acid alidenafil to sulfobutyl-beta-cyclodextrin sodium of example 1 is 1:5,

instead of this, the user can,

the method comprises the following steps: the molar ratio is 1:2;

the method 2 comprises the following steps: the molar ratio is 1:10;

the method 3 comprises the following steps: the molar ratio is 1:20;

The above examples show the importance of cyclodextrin derivatives, and the higher the molar ratio of pharmaceutically active ingredient to cyclodextrin derivative, the more significantly the solubilization effect. Example 6 was designed by reducing the molar ratio of the pharmaceutically active ingredient to the cyclodextrin derivative to 1:2 (to avoid the problem that the solubilizing effect of the saccharide or sugar alcohol cannot be exhibited due to the excessive amount of the cyclodextrin derivative) and investigating the effect of the solubility of the saccharide or sugar alcohol on the injection.

Example 6: sugar or sugar alcohol

In order to investigate the effect of saccharides or sugar alcohols on the effect of injections, this example refers to the formulation and preparation process of method 1 of example 5, i.e., the effect of saccharides or sugar alcohols on the solubility of injections was examined by adding saccharides or sugar alcohols sorbitol to 1:2, which is the minimum molar ratio of the pharmaceutically active ingredient to the cyclodextrin derivative.

6-1, prescription:

table 4: composition table of example 6

6-2, a preparation process:

1) Solution preparation:

taking 20-80% of the total amount of the water for injection to be placed in a liquid preparation tank, controlling the temperature to be 30-80 ℃, adding sulfobutyl-beta-cyclodextrin sodium into the water for injection, stirring to dissolve the sulfobutyl-beta-cyclodextrin sodium, sequentially adding citric acid alidenafil and sorbitol into the cyclodextrin derivative solution, and stirring to ensure that the liquid medicine is uniform and clear; slowly adding a small amount of pH regulator solution into the liquid preparation tank, and regulating the pH range of the liquid medicine to 3.0-8.0; the water for injection is used for fixing or weighting to the full amount.

4) And (3) sterilization: sterilizing at 121 deg.C with wet heat, and F0 is greater than 12.

The above examples show that when the molar ratio of the pharmaceutically active ingredient to the cyclodextrin derivative is 1:2, which is the lowest, the injection prepared by adding the saccharide or sugar alcohol can significantly improve the synergistic solubilization effect. Example 7 was designed by studying the influence of the solubility effect of a saccharide or sugar alcohol on an injection by setting the molar ratio of the pharmaceutically active ingredient having the best dissolution effect to the cyclodextrin derivative to 1:5.

Example 7:

referring to the prescription and the preparation process of example 1, on the basis of controlling the molar dosage ratio of the pharmaceutical active ingredient to the cyclodextrin derivative to be 1:5, the sugar substance or the sugar alcohol substance sorbitol is added, and the specific prescription is as follows:

7-1, prescription:

referring to the formula of example 1, the sugar or sugar alcohol is added, and the specific formula composition is as follows:

table 5: composition table for example 7

7-2, a preparation process:

1) Solution preparation:

3) Filling: and filling the liquid medicine into an ampoule bottle, wherein the filling volume is 5 mL/ampoule.

5) And (4) leak detection and packaging: and packaging after the leakage detection is qualified.

Example 8: freeze-dried preparation

Referring to the formulation and preparation process of example 7, the difference from example 7 is that the sterilization of step 4) is replaced by a lyophilization process, which comprises the following steps:

a. pre-freezing: the freeze dryer is started to pre-freeze the product, and the pre-freezing is divided into two stages:

in the first stage, the theoretical set temperature of the heat conducting oil is-10 ℃, the set time is 30min, and the heat is preserved for 120min;

the theoretical set temperature of the heat conducting oil in the second stage is-45 ℃, the set time is 120min, and the heat preservation time is 240min. And after the product is kept completely frozen, starting to refrigerate the water catcher, keeping the temperature of the water catcher at minus 50 ℃ for 1min, pre-vacuumizing the water catcher, wherein the set value of the pre-vacuumizing is 0.2mbar, and performing a primary drying process after the vacuum of the box body is below the set value.

b. Primary drying: the process is divided into two stages, namely the theoretical set temperature of the heat conducting oil is-12 ℃, the set time is 120min, and the heat preservation time is 1200min. The theoretical temperature of the heat conducting oil is set to be-5 ℃, the set time is 120min, and the vacuum degree is controlled to be below 0.2mbar in the whole process of heat preservation for 1200min.

c. And (3) resolving and drying: the process is divided into a stage, namely the theoretical set temperature of the heat conducting oil is 45 ℃, the set time is 120min, and the heat preservation time is 360min. The vacuum degree should be controlled below 0.11mbar during the whole process.

d. And (3) plug pressing: filling nitrogen to 730-750 mbar, and pressing.

e. And (3) rolling a cover: setting the capping speed of a capping machine: 300 pieces/min. The residual oxygen is controlled to be less than or equal to 2 percent.

The amount of the formulation, other components in the formulation and the preparation process were the same as in example 7.

Example 9: freeze-dried preparation without adding sugar or sugar alcohol

Referring to the prescription of example 1, namely, sugar substances or sugar alcohols are not added in the prescription, and the dosage and other components in the prescription are consistent with those in example 1; the preparation process was identical to example 8.

Example 10: selection of sugar or sugar alcohols

Referring to the formulation and the preparation process of example 8, the difference from example 8 is that the kinds of saccharides or sugar alcohols are changed, sorbitol of example 8,

instead of this, the user can,

the method comprises the following steps: trehalose;

the method 2 comprises the following steps: glucose;

the method 3 comprises the following steps: dextran;

the method 4 comprises the following steps: xylitol;

the amount of the formulation, other components in the formulation and the preparation process were the same as in example 8.

Example 11

Patent CN115054585A discloses an Aidenafil citrate drug tablet which can be used for treating Alzheimer's disease. Therefore, the citric acid alidenafil injection prepared by the invention can be used for treating Alzheimer disease and has good treatment effect.

Comparative example 1: reference to the prescription of sildenafil citrate injection

Reference to the same substance, sildenafil citrate injection marketed by FDA of America

The preparation process of the prescription is the same as that of example 1. The method comprises the following specific steps:

1. prescription:

table 6: composition table of comparative example 1

2. The preparation process comprises the following steps:

1) Solution preparation:

taking 20-80% of the total amount of the water for injection to be placed in a liquid preparation tank, controlling the temperature to be 30-80 ℃, adding glucose into a solvent, stirring to dissolve the glucose, adding the raw material medicines into the solution, and stirring to ensure that the liquid medicine is uniform and clear; slowly adding a small amount of pH regulator solution into the liquid preparation tank, and regulating the pH range of the liquid medicine to 3.0-8.0; the water for injection is used for fixing or weighting to the full amount.

Experimental example 1: investigation of solubility behavior

Solubility during preparation of comparative examples 1 to 7 and comparative example 1: the injection samples were placed at low temperature and tested by freeze-thaw testing: respectively standing at the low temperature of minus 10 ℃ to minus 20 ℃ for 2 days and at the temperature of 40 +/-2 ℃ for 2 days, and circulating for 3 times; freeze thawing at-2-8 deg.c for 2 days and at 40 deg.c +/-2 deg.c for 2 days, circulating for 3 times and inspecting its solubility:

table 7: solubility of examples 1-7, comparative example 1

/>

Note:

"solution clear" indicates that the clarity of the solution does not exceed the standard solution with a turbidity number of 0.5;

"/" indicates that precipitates were visible to the naked eye in the solution, and thus insoluble particles were not detected.

Table 8: solubility of examples 1-7, comparative example 1

Note:

"/" indicates that the solution is turbid 0 days after preparation, the injection is not qualified, and a low-temperature freeze-thaw test is not required.

Analysis of results (one):

the results of examples 1 to 7 and comparative example 1 of the present invention were analyzed to investigate the effect of different solubilizers/solubilizers, the types of cyclodextrin derivatives, the different amounts of sildenafil citrate and cyclodextrin derivatives, and the solubility effect of saccharides or sugar alcohols on injections, as follows:

1. to investigate the effect of cyclodextrin derivatives on the solubility effect of injections, the co-solvent cyclodextrin derivative (sulfobutyl- β -cyclodextrin sodium) in the formulation of example 1 was omitted as follows:

1-1, prescription differences

Table 9: recipe differences between example 1 and example 2

Examples	Cosolvent
		Example 1	Sulfobutyl-beta-cyclodextrin sodium
Example 2	/

1-2, solubility results for injections

Table 10: solubility of examples 1 to 2

Note:

Table 11: solubility of examples 1 and 2

Note:

"/" indicates that the solution was turbid 0 days after preparation and the injection failed, and no low temperature freeze-thaw test was required.

And (4) conclusion:

in the embodiment 1, the cyclodextrin derivative sulfobutyl-beta-cyclodextrin sodium is adopted to realize inclusion, the citric acid alidenafil raw material medicine is completely dissolved in 0 day of the obtained injection, and the solubilization effect is good; the number of insoluble particles is more than or equal to 10 mu m and is 25.4 particles, the number of insoluble particles is more than or equal to 25 mu m and is 1.4 particles, and the insoluble particles are far less than the respective limits of 6000 particles and 600 particles; the injection can keep the solution clear and colorless in the processes of 3 times of low-temperature circulation and freeze-thaw circulation, and has good solubility.

Example 2 prescription without any solubilizer, in the preparation process of the injection, the citric acid alidenafil is not completely dissolved, the solution is turbid, a large amount of the citric acid alidenafil as a raw material is separated out, the precipitates can be seen by naked eyes, insoluble particles do not need to be detected, the solubility is low, and the injection cannot be used as a qualified injection.

And (3) knotting:

a) Compared with the prescription without any solubilizer, the prescription with the cyclodextrin derivative (for example, the example 1) is clear, and the injection solution prepared by the prescription has good solubility, which is represented by the following specific expression:

the number of insoluble fine particles is at least (25.4 particles at. Gtoreq.10 μm, 1.4 particles at. Gtoreq.25 μm), and both are far smaller than the number limits of 6000 particles and 600 particles, respectively;

b) On the contrary, when a prescription without any solubilizer is adopted, the prepared injection solution is turbid, has low solubility and cannot be used as a qualified injection, and the specific expression is as follows:

the raw material solution of the citric acid alidenafil is turbid, and the citric acid alidenafil as the raw material is precipitated in a large amount, and precipitates can be seen by naked eyes, so that the solubility is low.

2. In order to explore the influence of the solubilizing mode of cyclodextrin derivative inclusion and other solubilizing modes (organic cosolvent and surfactant solubilizer) on the solubility of the citric acid alidenafil injection, the cosolvent cyclodextrin derivative (sulfobutyl-beta-cyclodextrin sodium) in the formula components is replaced by the organic cosolvent (example 3, method 1-4) or the surfactant solubilizer (example 3, method 5-10), which is specifically as follows:

2-1, prescription differentiation

Table 12: recipe differences between example 1 and example 3

2-2, solubility results

Table 13: solubility of examples 1 and 3

Note:

"/" indicates that precipitates were visible to the naked eye in the solution, and thus insoluble fine particles were not detected.

Table 14: solubility of examples 1 and 3

Note:

And (4) conclusion:

in the embodiment 1, the cyclodextrin derivative sulfobutyl-beta-cyclodextrin sodium is adopted for inclusion, so that the citric acid alidenafil bulk drug is completely dissolved in 0 day of the obtained injection, and the solubilization effect is good; the number of insoluble particles is small (25.4 particles with the particle size of not less than 10 mu m and 1.4 particles with the particle size of not less than 25 mu m), and the number of the insoluble particles is far less than the number limit of 6000 particles and 600 particles; the injection can keep the solution clear and colorless in the processes of 3 times of low-temperature circulation and freeze-thaw circulation, and has good solubility.

In the methods 1 to 4 of the embodiment 3, the maximum amount of 20% of organic cosolvents, namely ethanol, propylene glycol, glycerol and polyethylene glycol 300, are respectively added, so that the requirement of complete dissolution of the citric acid aildenafil raw material cannot be met, the solution is turbid, the synergistic solubilization effect is avoided, and precipitates can be seen by naked eyes, so that insoluble particles are not detected, the solubility is poor, and the injection cannot be used as a qualified injection.

In the method 5-10 of example 3, the surfactant with 2% of the maximum amount is added to solubilize the citric acid and the edenafil respectively, namely tween 80, poloxamer, sodium lauryl sulfate, 15-hydroxystearic acid polyethylene glycol ester, polyoxyethylene hydrogenated castor oil and lecithin, which cannot meet the requirement of completely dissolving the citric acid and the edenafil raw material medicine, the solution is turbid, the synergistic solubilization effect is not realized, and precipitates can be seen by naked eyes, so that insoluble particles do not need to be detected, the solubility is poor, and the citric acid and the edenafil raw material medicine cannot be used as a qualified injection.

And (3) knotting:

a) Compared with other solubilizing methods (organic cosolvent/surfactant solubilizer), the solubilizing method (such as sulfobutyl-beta-cyclodextrin sodium in example 1) only adopting the cyclodextrin derivative inclusion compound of the invention has the advantages that the prepared injection solution is clear and has good solubility, and the specific expression is as follows:

the number of insoluble particles is the smallest (25.4 particles with a particle size of 10 μm or more and 1.4 particles with a particle size of 25 μm or more), and both are far smaller than the number limit of 6000 particles and 600 particles of the respective insoluble particles;

b) On the contrary, other solubilizing methods (organic cosolvent/surfactant solubilizer, for example, example 3) resulted in turbid injection solution and low solubility, which can not be used as qualified injection, specifically:

the citric acid alidenafil bulk drug solution has turbidity phenomenon, precipitates can be seen by naked eyes, and the solubility is low.

3. The above results of analyses 1-2 show that the cosolvent in the prescription of the citric acid alidenafil injection has the best solubilization effect and the best solubility by inclusion of the cyclodextrin derivative (sulfobutyl-beta-cyclodextrin sodium) in example 1. To further investigate the effect of cyclodextrin derivative species on the solubility of injections, the following results were analyzed to replace the co-solvent cyclodextrin derivative (sulfobutyl- β -cyclodextrin sodium) in the formulation components of example 1 with other cyclodextrin derivatives and to investigate the effect of different cyclodextrin derivative species on the solubility of injections, as follows:

3-1, differentiation of prescription

Table 15: recipe differences between example 1 and example 4

Examples	Class of cyclodextrin derivatives
		Example 1	Sulfobutyl-beta-cyclodextrin sodium
Example 4 method 1	Hydroxypropyl-beta-cyclodextrin
		Example 4 method 2	Hydroxyethyl-beta-cyclodextrin
Example 4 method 3	Sulfopropyl-beta-cyclodextrin
		Example 4 method 4	alpha-Cyclodextrin

3-2, solubility results for injection

Table 16: solubility of examples 1 and 4

Note:

Table 17: solubility of examples 1 and 4

Note:

"solution clear" means that the clarity of the solution does not exceed the standard solution of No. 0.5 turbidity;

and (4) conclusion:

the cyclodextrin derivatives of the methods 1 to 3 of the embodiments 1 and 4 respectively adopt sulfobutyl-beta-cyclodextrin sodium, hydroxypropyl-beta-cyclodextrin sodium, hydroxyethyl-beta-cyclodextrin sodium and sulfopropyl-beta-cyclodextrin sodium, and the obtained injection has complete dissolution of the citric acid alidenafil raw material in 0 day and good solubilization effect; the number of insoluble microparticles is small (25.4, 104, 113 and 89 microparticles with the particle size of not less than 10 μm, and 1.4, 12, 59 and 27 microparticles with the particle size of not less than 25 μm), and the number of insoluble microparticles is far less than the number limit of 6000 and 600; the injection can keep the solution clear and colorless in the processes of 3 times of low-temperature circulation and freeze-thaw circulation, and has good solubility.

In the embodiment 4, the cyclodextrin derivative of the method 4 adopts alpha-cyclodextrin sodium, and the citric acid alidenafil raw material medicine is separated out in a small amount in 0 day of the injection, and precipitates can be seen by naked eyes; a small amount of raw material medicines are separated out in the processes of 3 times of low-temperature circulation and freeze-thaw circulation, so the solubilizing effect is not good; the solubility is low, and the injection cannot be used as a qualified injection.

And (3) knotting:

a) Compared with other cyclodextrin derivative types, only by using the cyclodextrin derivative type (any one or more of hydroxyethyl-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, methyl-beta-cyclodextrin, maltose-beta-cyclodextrin, carboxymethyl-beta-cyclodextrin, sulfoethyl-beta-cyclodextrin, sulfopropyl-beta-cyclodextrin, sulfobutyl-beta-cyclodextrin, methyl-beta-cyclodextrin and hydroxypropyl-gamma-cyclodextrin) of the present invention, the obtained injection solution is clear and has good solubility:

for example, the injection solution prepared by using sulfobutyl-beta-cyclodextrin sodium in example 1, hydroxypropyl-beta-cyclodextrin in method 1 in example 4, hydroxyethyl-beta-cyclodextrin in method 2 in example 4 and sulfopropyl-beta-cyclodextrin in method 3 in example 4 is clear and has good solubility, which is shown in the following concrete steps:

i. the citric acid alidenafil as the raw material medicine is completely dissolved, and the solubilization effect is good;

b) When sulfobutyl-beta-cyclodextrin sodium is used as the cyclodextrin derivative (for example, in example 1), the obtained injection solution is clear and has the best solubility, which is represented by the following specific expression:

i. the citric acid alidenafil as the raw material medicine is completely dissolved, and the solubilization effect is best;

the solution is clear and has the best solubility in the freeze-thawing process of the injection;

c) On the other hand, when other cyclodextrin derivative species (for example, α -cyclodextrin of method 4 of example 4) are used, the resulting injection solution is turbid, has poor solubility, and cannot be used as a qualified injection, which is expressed as follows:

i. little citric acid alidenafil raw material medicine is separated out, the precipitate can be seen by naked eyes, and the solubilizing effect is poor;

and ii, a small amount of raw material medicines are separated out in the low-temperature freeze thawing process, and the solubility is low.

4. The above results of analysis 1-4 show that the solubility of the cosolvent in the prescription of the citric acid alidenafil injection is the best when the cyclodextrin derivative sulfobutyl-beta-cyclodextrin sodium in example 1 is used for inclusion.

In order to further explore the influence of different dosages of the active pharmaceutical ingredients and the cyclodextrin derivatives on the solubility of the injection, the dosage molar ratio of the citric acid alidenafil to the sulfobutyl-beta-cyclodextrin sodium is changed, and the specific formula is as follows:

4-1, prescription differentiation

Table 18: recipe differences between example 1 and example 5

4-2, solubility results for injections

Table 19: solubility of examples 1 and 5

Note:

table 20: solubility of examples 1 and 5

Note:

and (4) conclusion:

in the embodiment 1, when the molar ratio of the citric acid alidenafil to the cyclodextrin derivative is 1:5, the dosage of the cyclodextrin derivative is less, and the biological safety is high; the citric acid alidenafil raw material medicine is completely dissolved in 0 day, and the solubilization effect is good; the number of insoluble particles is small (25.4 particles with the particle size of more than or equal to 10 mu m and 1.4 particles with the particle size of more than or equal to 25 mu m), and the number of the insoluble particles is far less than the number limit of 6000 particles and 600 particles; the injection keeps clear and colorless solution and has good solubility in the processes of 3 times of low-temperature circulation and freeze-thaw circulation;

in the embodiment 5, when the molar ratio of the citric acid aildenafil to the cyclodextrin derivative in the methods 1 to 3 is 1:2, 1; the number of insoluble particles is small (1167 particles, 25 particles and 18 particles with the particle size of not less than 10 mu m, 325 particles, 2.1 particles and 1.3 particles with the particle size of not less than 25 mu m) and is far less than the number limit of 6000 particles and 600 particles of insoluble particles; the injection can keep the solution clear and colorless in the processes of 3 times of low-temperature circulation and freeze-thaw circulation, and has good solubility.

And (3) knotting:

a) By controlling the molar ratio of the active pharmaceutical ingredient to the cyclodextrin derivative to be 1 (2-20), the obtained injection solution is clear and has good solubility:

for example, injection solutions prepared in example 1 (mole ratio = 1:5), example 5, method 1 (mole ratio = 1:2), example 5, method 2 (mole ratio =1 10) and example 5, method 3 (mole ratio =1 = 20) were clear and have good solubility, as shown in:

i. the citric acid alidenafil raw material medicine is completely dissolved in 0 day, and the solubilization effect is good;

ii, the number of insoluble fine particles is small (18 to 1167 particles of not less than 10 μm and 1.3 to 325 particles of not less than 25 μm), and both are far smaller than the number limit of 6000 and 600 particles of the insoluble fine particles: as the molar ratio of the citric acid alidenafil to the cyclodextrin derivative increases (from 1:2 to 1 to 20), the dosage of the cyclodextrin derivative in the formula increases, and the number of insoluble particles is remarkably reduced; when the molar ratio of the citric acid alidenafil to the cyclodextrin derivative is increased from 1:5 to 1;

and iii, the injection keeps clear and colorless solution and has good solubility in the low-temperature freeze-thawing process.

b) Among them, when the molar ratio of the pharmaceutically active ingredient to the cyclodextrin derivative is 1:5 (e.g., example 1), the cyclodextrin derivative is used in a minimum amount, the biosafety is high, and the solubility of the resulting injection is the best, which is represented by:

i. the citric acid alidenafil raw material medicine is completely dissolved at 0 day, and the solubilization effect is best;

ii, the number of insoluble particles is small (25.4 particles with a particle size of 10 μm or more, and 1.4 particles with a particle size of 25 μm or more, respectively), and both are far smaller than the number limit of 6000 particles and 600 particles of the insoluble particles;

5. The above results of analyses 1 to 4 show that the solubility of the injection prepared by including the citric acid alidenafil with a cyclodextrin derivative (for example, sulfobutyl- β -cyclodextrin sodium of example 1) is most effective. Wherein, the higher the molar ratio of the pharmaceutical active ingredient to the cyclodextrin derivative, the more the solubilization effect can be significantly improved, but the lower the molar ratio of the pharmaceutical active ingredient to the cyclodextrin derivative, the less the amount of the cyclodextrin derivative, and the higher the safety of the administration.

In order to further improve the safety, on the basis of a prescription with a small dosage of cyclodextrin derivatives, namely, on the basis of a prescription with a low dosage of cyclodextrin derivatives (example 5, 1 molar ratio =1:2 and example 1 molar ratio = 1:5), the situation that the synergistic solubilization effect of saccharides or sugar alcohols cannot be embodied due to the excessive dosage of cyclodextrin derivatives is avoided, and the influence of the saccharides or sugar alcohols on the solubility effect of the injection is researched by adding sorbitol. The method comprises the following specific steps:

5-1, prescription differences

Table 21: example 5 recipe differences for method 1, example 6, example 1, example 7

Examples	Molar ratio of citric acid alidenafil to sulfobutyl-beta-cyclodextrin sodium	Sugar or sugar alcohol
			EXAMPLE 5 method 1	1:2	/
Example 6	1:2	Sorbitol
			Example 1	1:5	/
Example 7	1:5	Sorbitol

5-2, solubility results for injection

Table 22: example 5 solubility of method 1, example 6, example 1, example 7

Note:

table 23: example 5 solubility of method 1, example 6, example 1, example 7

/>

Note:

and (4) conclusion:

on the basis that the molar ratio of the citric acid alidenafil to the sulfobutyl-beta-cyclodextrin sodium is 1:2 in the method 1 of the embodiment 5, when no sugar substance or sugar alcohol substance is added, the citric acid alidenafil raw material medicine is completely dissolved in 0 day of the injection, and the solubilization effect is good; the number of insoluble particles is small (1167 particles at not less than 10 mu m and 325 particles at not less than 25 mu m), and both are far less than 6000 particles and 600 particles of the number limit of the insoluble particles; the injection can keep the solution clear and colorless in the processes of 3 times of low-temperature circulation and freeze-thaw circulation, and has good solubility.

On the basis that the molar ratio of the citric acid alidenafil to the sulfobutyl-beta-cyclodextrin sodium is 1:2 in the embodiment 6, when the glucide or sugar alcohol substance is sorbitol, the citric acid alidenafil raw material medicine is completely dissolved in 0 day of the injection, and the synergistic solubilization effect of the cyclodextrin derivative and the glucide or sugar alcohol substance is good; the number of insoluble particles is reduced significantly compared with the method 1 in the embodiment 5 (542 particles with the size of more than or equal to 10 mu m and 164 particles with the size of more than or equal to 25 mu m), and both are far less than the number limits of 6000 particles and 600 particles of the respective insoluble particles; the injection can keep the solution clear and colorless in the processes of 3 times of low-temperature circulation and freeze-thaw circulation, and has good solubility.

On the basis of controlling the molar ratio of the citric acid alidenafil to the sulfobutyl-beta-cyclodextrin sodium to be 1:5 in the embodiment 1, when no sugar substance or sugar alcohol substance is added, the citric acid alidenafil raw material medicine is completely dissolved in 0 day of the injection, and the solubilization effect is good; the number of insoluble particles is small (25.4 particles with the particle size of not less than 10 mu m and 1.4 particles with the particle size of not less than 25 mu m), and the number of the insoluble particles is far less than the number limit of 6000 particles and 600 particles; the injection can keep the solution clear and colorless in the processes of 3 times of low-temperature circulation and freeze-thaw circulation, and has good solubility.

On the basis of controlling the molar ratio of the citric acid alidenafil to the sulfobutyl-beta-cyclodextrin sodium to be 1:5 in the embodiment 7, when the glucide or sugar alcohol substance is sorbitol, the citric acid alidenafil raw material medicine is completely dissolved in 0 day of the injection, and the synergistic solubilization effect of the cyclodextrin derivative and the glucide or sugar alcohol substance is good; the number of insoluble particles is reduced compared with that of the particles in the embodiment 1 (18.6 particles with the particle size of 10 μm or more and 0.9 particle with the particle size of 25 μm or more), and the number of the insoluble particles is far less than the number limit of 6000 particles and 600 particles; the injection can keep the solution clear and colorless in the processes of 3 times of low-temperature circulation and freeze-thaw circulation, and has good solubility.

And (4) summarizing:

a) When a formulation containing a sugar or sugar alcohol (e.g., sorbitol in examples 6 and 7) is further added in addition to the cyclodextrin derivative, the injection solution prepared is clear, the solubility is further improved, and the synergistic solubilization effect is enhanced, which is specifically represented by:

i. the citric acid alidenafil raw material medicine is completely dissolved in 0 day, and the synergistic solubilization effect of the cyclodextrin derivative and the sugar substance or sugar alcohol substance is good;

b) Wherein, when the molar ratio of the pharmaceutical active ingredient to the cyclodextrin derivative is 1:5 and a prescription of a carbohydrate or a sugar alcohol (for example, example 7) is added, the prepared injection solution is clear, has the best solubility and the best synergistic solubilization effect, and is characterized in that:

i. the citric acid alidenafil raw material medicine is completely dissolved in 0 day, and the synergistic solubilization effect of the cyclodextrin derivative and the sugar substance or sugar alcohol substance is the best;

6. The above results of analysis 1 to 5 show that the cosolvent in the prescription of the citric acid alidenafil injection is included by the cyclodextrin derivative (sulfobutyl-beta-cyclodextrin sodium) used in example 7, and when the molar ratio of the active pharmaceutical ingredient to the cyclodextrin derivative is 1:5, the injection prepared by adding the saccharide or sorbitol which is a sugar alcohol substance has the best solubility.

To further investigate the effect of the formulation combination of the present invention (adding cyclodextrin derivatives only or using a combination of cyclodextrin derivatives and both saccharides or sugar alcohols) on the solubility of the injections, refer to the same class of substance, sildenafil citrate injection marketed by FDA in usa

The injection prepared by the prescription of (1) is compared with the injection prepared by the prescription of the best embodiment and the next two embodiments of the invention (embodiment 7, embodiment 1 and embodiment 5, method 1), and the influence of different prescription combinations on the solubility of the injection is researched, and the specific steps are as follows:

6-1, prescription differentiation

Example 7:

table 24: composition table for example 7

Example 1:

table 25: composition table of example 1

Example 5 method 1:

table 26: EXAMPLE 5 compositional Table for method 1

Comparative example 1:

table 27: composition table of comparative example 1

6-2, solubility results for injection

Table 28: solubility of example 7, example 1, example 5, method 1, comparative example 1

Note:

Table 29: solubility of example 7, example 1, example 5, method 1, comparative example 1

Note:

And (4) conclusion:

example 7 as the best example of the present invention, the formulation adopts the combination of cyclodextrin derivatives and sugar substances or sugar alcohols, and the molar ratio of the citric acid alidenafil to the sulfobutyl-beta-cyclodextrin sodium is 1:5, by adopting the combination of the formulation, the citric acid alidenafil raw material medicine is completely dissolved in 0 day of the injection, and the synergistic solubilization effect of the cyclodextrin derivatives and the sugar substances or sugar alcohols is good; the number of insoluble particles is small (18.6 particles with the particle size of more than or equal to 10 mu m and 0.9 particle with the particle size of more than or equal to 25 mu m), and the number of the insoluble particles is far less than the number limit of 6000 particles and 600 particles; the injection can keep the solution clear and colorless in the processes of 3 times of low-temperature circulation and freeze-thaw circulation, and has the best solubility.

Example 1 as the next best example of the invention, the formula adopts cyclodextrin derivatives, no saccharides or sugar alcohols are added, the molar ratio of the citric acid alidenafil to the sulfobutyl-beta-cyclodextrin sodium is 1:5, the formula combination is adopted, the citric acid alidenafil raw material medicine is completely dissolved in 0 day of the injection, and the synergistic solubilization effect of the cyclodextrin derivatives and the saccharides or sugar alcohols is good; the number of insoluble particles is small (25.4 particles with the particle size of not less than 10 mu m and 1.4 particles with the particle size of not less than 25 mu m), and the number of the insoluble particles is far less than the number limit of 6000 particles and 600 particles; the injection can keep the solution clear and colorless in the processes of 3 times of low-temperature circulation and freeze-thaw circulation, and has good solubility.

Example 5 method 1 as the next best example of the present invention, cyclodextrin derivatives are adopted in the formula, no saccharides or sugar alcohols are added, and the molar ratio of the citric acid alidenafil to the sulfobutyl-beta-cyclodextrin sodium is 1:2, by adopting the formula combination, the citric acid alidenafil raw material drug is completely dissolved in 0 day of the injection, and the synergistic solubilization effect of the cyclodextrin derivatives and the saccharides or sugar alcohols is good; the number of insoluble particles is small (1167 particles with the particle size of not less than 10 mu m and 325 particles with the particle size of not less than 25 mu m), and both are far smaller than the number limit of 6000 particles and 600 particles of the insoluble particles; the injection can keep the solution clear and colorless in the processes of 3 times of low-temperature circulation and freeze-thaw circulation, and has good solubility.

Comparative example 1 reference analogous substance sildenafil citrate injection marketed by FDA of America

The citric acid alidenafil is incompletely dissolved, the solution is turbid, a large amount of citric acid alidenafil is separated out, part of raw material medicine crystals can be seen by naked eyes, and no synergistic solubilization effect exists; precipitates are visible to the naked eye, the solubility is poor, and the injection cannot be used as a qualified injection.

And (3) knotting:

a) Compared with other existing formulas, only when the formula combination (the combination of the cyclodextrin derivative and the sugar substance or the sugar alcohol substance or only the cyclodextrin derivative is added) is adopted, the obtained injection solution is clear, and the solubility is good:

for example, example 7 employs a prescribed combination of cyclodextrin derivatives and sugar or sugar alcohols; examples 1 and 5 method 1 employed a formulation combination with addition of only cyclodextrin derivatives, as detailed below:

b) On the contrary, refer to the same substance-sildenafil citrate injection on the market of the US FDA

The prepared injection solution is turbid, has poor solubility, cannot be used as a qualified injection, and hasThe body expression is:

the solution was turbid, precipitates were visible to the naked eye, and the solubility was low.

The above analysis of the results (one) shows that the cyclodextrin derivative and the saccharide or sugar alcohol improve the synergistic solubilization effect of the injection and further affect the solubility, and the following evaluations were performed in order to further explore the influence of the saccharide or sugar alcohol and different kinds of saccharide or sugar alcohol on the properties (inclusion ratio, quality, critical temperature and stability) of the lyophilized preparation.

Experimental example 2: evaluation of inclusion ratio of lyophilized preparation

The inclusion ratio of the active molecules of the medicine and the cyclodextrin derivatives is detected by adopting a phase equilibrium solubility method, the inclusion ratio results of the citric acid alidenafil and the cyclodextrin derivatives in the embodiments 8-10 of the invention are analyzed, and the influence of the sugar substances or sugar alcohol substances on the inclusion ratio of the freeze-dried preparation is researched. On the basis of adding cyclodextrin derivatives as cosolvent, the influence of saccharide or sugar alcohol and different kinds of saccharide or sugar alcohol on the inclusion ratio of the lyophilized preparation is researched. The results are as follows:

table 30: example 8, example 9, example 10 recipe differentiation of methods 1-4

Experimental example 3: evaluation of lyophilized preparation quality

In order to investigate the influence of saccharides or sugar alcohols and different kinds of saccharides or sugar alcohols on the quality of lyophilized preparations, reconstitution time, molding condition, osmotic pressure, pH of solution, appearance properties, clarity of solution, and the like of the lyophilized preparations prepared in examples 8 to 10 of the present invention were compared. The results are as follows:

table 31: quality evaluation of lyophilized formulations of examples 8, 9, and 10, methods 1 to 4

Experimental example 4: evaluation of Key temperature of lyophilized preparation

The critical temperature results of examples 8 to 10 of the present invention were analyzed to investigate the influence of the saccharide substance on the critical temperature of the injection. On the basis of adding cyclodextrin derivatives as cosolvent, the influence of saccharides or sugar alcohols and different saccharides on the critical temperature of the lyophilized preparation is researched.

The freeze-drying preparation has different prescriptions and different key temperatures, the higher the freeze-drying key temperature is, the easier the freeze-drying is, the shorter the freeze-drying period is, and the better the stability is correspondingly. 2 key temperatures for the lyophilized product: tc (collapse temperature), tg (glass transition temperature of dried sample), collapse temperature of each prescription measured using a freeze-drying microscope, glass transition temperature of the concentrated solution and dried sample of each prescription measured using DSC, and the results were as follows:

table 32: example 8, example 9, example 10 methods 1-4 Freeze-dried formulations Critical temperature

Experimental example 5: evaluation of stability of lyophilized preparation

The stability results of examples 8 to 10 of the present invention were analyzed to investigate the influence of saccharides or sugar alcohols on the stability of lyophilized preparations. On the basis of adding cyclodextrin derivatives as cosolvent, the influence of saccharides or sugar alcohols and different kinds of saccharides or sugar alcohols on the stability of lyophilized preparation is examined.

The accelerated 6-month condition examination was performed under the temperature condition of 40 ℃ and the relative humidity condition of 75%, and the key quality attribute impurity contents of the freeze-dried preparation prepared freshly and the freeze-dried preparation after 6 months of the accelerated test were measured, and the results are as follows.

Wherein, the impurity PM4: the process and the degraded impurities are also an intermediate PM4, and the chemical name is as follows: 4- (5- (((3s, 5r) -3,5-dimethylpiperazin-1-yl) sulfonyl) -2-ethoxybenzamido) -1-methyl-3-propyl-1H-pyrazole-5-carboxamide, formula:

impurity 19: the process and the degradation impurities have the chemical name: 4-ethoxy-3- (1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo [4,3-d ] pyrimidin-5-yl) benzenesulfonic acid having the formula:

table 33: example 8, example 9, example 10 methods 1-4 Freeze-dried formulation stability

Analysis of results (ii):

the results of examples 8 to 10 of the present invention were analyzed to investigate the influence of saccharides or sugar alcohols and different kinds of saccharides or sugar alcohols on the properties (inclusion ratio, quality, critical temperature and stability) of the lyophilized preparation, as follows:

1. in order to investigate the influence of the addition of sugar or sugar alcohol on the properties (inclusion ratio, quality, critical temperature and stability) of the lyophilized preparation, the use of sorbitol, which is a sugar or sugar alcohol, was omitted on the basis of the addition of cyclodextrin derivatives, and the comparison with injections, to which sugar or sugar alcohol was added, was carried out, specifically as follows:

1-1, difference

Table 34: recipe differences of example 8 and example 9

Examples	Molar ratio of citric acid alidenafil to sulfobutyl-beta-cyclodextrin sodium	Sugar or sugar alcohol
			Example 8	1:5	Sorbitol
Example 9	1:5	/

1-2, effect of lyophilized preparation

Table 35: inclusion ratios of examples 8 and 9

Examples	Inclusion ratio of Aidenafil citrate to a cyclodextrin derivative
		Example 8	1:2
Example 9	1:4

Table 36: quality of example 8 and example 9

Table 37: critical temperatures for examples 8 and 9

Key temperature/. Degree.C	Example 8	Example 9
			Tc (collapse temperature)	-21	-28
Tg (glass transition temperature of dried sample)	77	70

Table 38: example 8 stability of example 9

And (4) conclusion:

adding a saccharide substance or a sugar alcohol substance sorbitol on the basis of adding the cyclodextrin derivative in the embodiment 8, wherein the inclusion ratio of the Aidinafil citrate to the cyclodextrin derivative is 1:2, the inclusion ratio is high, and the synergistic solubilization effect of the cyclodextrin derivative and the saccharide substance or the sugar alcohol substance is good; the freeze-dried preparation is well formed, the osmotic pressure molar ratio is 1.0, the isotonic effect can be achieved, and the administration safety is high; white cake-like, loose and fine block-shaped materials with good appearance; tc (collapse temperature) is-21 ℃, tg (glass transition temperature of a dried sample) is 77 ℃, the freeze-drying key temperature is high, the freeze-drying is easy, the freeze-drying period is short, and the stability is good; under the conditions of acceleration for 6 months at the temperature of 40 ℃ and the relative humidity of 75 percent, the content of each impurity is low and is obviously lower than the limit of each impurity, and the stability is good; the moisture content in 0 month and 6 months is 0.6% and 0.7%, and the moisture content is low; the redissolution time of 0 month and 6 months is 23s and 35s, the redissolution time is short, and the obtained freeze-dried preparation has good property;

on the basis of adding the cyclodextrin derivative in the embodiment 9, the sugar substance or the sugar alcohol substance is not added, the inclusion ratio of the citric acid aildenafil to the cyclodextrin derivative is 1:4, the inclusion ratio is high, and the solubilization effect is good; the freeze-dried preparation is well formed, the osmotic pressure molar ratio is 1.1, the isotonic effect can be achieved, and the administration safety is high; white cake-like, loose and fine block-shaped materials with good appearance; tc (collapse temperature) is-28 ℃, tg (glass transition temperature of a dried sample) is 70 ℃, the freeze-drying key temperature is high, the freeze-drying is easy, the freeze-drying period is short, and the stability is good; under the condition of accelerating for 6 months at the temperature of 40 ℃ and the relative humidity of 75 percent, the content of each impurity is low and is obviously lower than the limit of each impurity, and the stability is good; the water content in 0 month and 6 months is 0.9% and 1.3%, and the water content is low; the re-dissolving time of 0 month and 6 months is 100s and 110s, the re-dissolving time is short, and the obtained freeze-dried preparation has good property;

and (3) knotting:

a) In the prescription of adding cyclodextrin derivatives, the prescription of adding or not adding saccharides or sugar alcohols (for example, sorbitol is added in example 8, and saccharides or sugar alcohols are not added in example 9) has good properties (inclusion ratio, quality, key temperature and stability) of the prepared freeze-dried preparation, and the preparation is specifically represented as follows:

i. the inclusion ratio of the citric acid alidenafil and the cyclodextrin derivative is high (1:2-1:4), and the solubilization effect is good; ii, the molar ratio of osmotic pressure is 1.0-1.1, the isotonic effect is good, and the administration safety is high;

the freeze-dried preparation is well formed and has good appearance;

good stability: the freeze-drying key temperature is higher (the collapse temperature Tc is-28 to-21 ℃, and the glass transition temperature Tg of a dried sample is 70 to 77 ℃); low impurity content (as low as 0.002%); the lowest moisture content (as low as 0.6%);

v. short reconstitution time (23-110 s), much less than 120s.

b) Based on the addition of cyclodextrin derivatives, the formulation with saccharide or sugar alcohol (e.g., sorbitol in example 8) is added, and the prepared lyophilized preparation has better properties (inclusion ratio, quality, critical temperature and stability) as follows:

i. the inclusion ratio of the citric acid alidenafil and the cyclodextrin derivative is higher (1:2), and the synergistic solubilization effect of the cyclodextrin derivative and the carbohydrate or sugar alcohol is better;

the osmotic pressure molar ratio is 1.0, the isotonic effect is better, and the administration safety is higher;

the freeze-dried preparation is well formed and has good appearance;

better stability: the freeze-drying key temperature is higher (the collapse temperature Tc is-21 ℃, and the glass transition temperature Tg of a dried sample is 77 ℃); low impurity content (as low as 0.002%); lower moisture content (as low as 0.6%); v. reconstitution times are much shorter (down to 23 s), well below 120s.

On the basis of adding cyclodextrin derivatives, the influence of adding sugar substances or sugar alcohol substances on the properties (inclusion ratio, quality, key temperature and stability) of the freeze-dried preparation is shown in the following specific expression:

table 39: comparison of the Effect of the lyophilized formulations of example 8 and example 9

2. In order to investigate the influence of different kinds of saccharides or sugar alcohols on the properties (inclusion ratio, quality, critical temperature and stability) of the lyophilized preparation, injections prepared from different kinds of saccharides or sugar alcohols were subjected to comparative analysis based on the addition of cyclodextrin derivatives, as follows:

2-1, prescription differentiation

Table 40: example 8 recipe differences from methods 1-4 of example 10

2-2, freeze-dried formulation Properties (inclusion ratio, quality, critical temperature and stability)

Table 41: inclusion ratios of examples 8 to methods 1-4 of example 10

Examples	Inclusion ratio of Aidenafil citrate to a cyclodextrin derivative
		Example 8	1:2
EXAMPLE 10 method 1	1:4
		EXAMPLE 10 method 2	1:3
Example 10 method 3	1:4
		EXAMPLE 10 method 4	1:5

Table 42: quality of methods 1 to 4 of examples 8 and 10

Table 43: critical temperatures for methods 1-4 of examples 8 and 10

Table 44: example 8 and example 10 stabilization of methods 1-4

And (4) conclusion:

sorbitol is adopted as the saccharide substance or the sugar alcohol substance in the embodiment 8, the inclusion ratio of the citric acid alidenafil and the cyclodextrin derivative is 1:2, the inclusion ratio is high, and the synergistic solubilization effect of the cyclodextrin derivative and the saccharide substance or the sugar alcohol substance is good; the osmotic pressure molar ratio is 1.0, so that an isotonic effect can be achieved; the freeze-dried preparation is well formed, is in a white cake shape, is loose and fine blocks, and has good appearance property; tc (collapse temperature) is-21 ℃, tg (glass transition temperature of a dried sample) is 77 ℃, the freeze-drying key temperature is high, the freeze-drying is easy, the freeze-drying period is short, and the stability is good; under the condition of accelerating for 6 months at the temperature of 40 ℃ and the relative humidity of 75 percent, the content of each impurity is low and is obviously lower than the limit of each impurity, and the stability is good; the water content in 0 month and 6 months is 0.6% and 0.7%, and the water content is low; the re-dissolving time of 0 month and 6 months is 23s and 35s, which is far less than 120s, the re-dissolving time is short, and the obtained freeze-dried preparation has good property;

example 10 methods 1 to 3, the types of the saccharides or sugar alcohols are changed to trehalose, glucose and dextran, respectively, the inclusion ratio of the obtained lyophilized preparation, namely the citric acid aildenafil and the cyclodextrin derivatives is 1:4, 1:3 and 1:4, is reduced, but the solubilization effect is still satisfied, and the synergistic solubilization effect of the cyclodextrin derivatives and the saccharides or sugar alcohols is good; the freeze-dried preparation is well formed, is in a white cake shape, is loose and fine blocks, and has good appearance property; tc (collapse temperature) is-25 ℃, 27 ℃ and 23 ℃, tg (glass transition temperature of a dried sample) is 74 ℃, 65 ℃ and 84 ℃, the freeze-drying key temperature is high, the freeze-drying is easy, the freeze-drying period is short, and the stability is good; under the conditions of acceleration for 6 months at the temperature of 40 ℃ and the relative humidity of 75 percent, the content of each impurity is low and is obviously lower than the limit of each impurity, and the stability is good; moisture content at 0 month is 1.0%, 1.0% and 0.8%, moisture content at 6 month is 1.4%, 1.3% and 1.4% low; the redissolution time of 0 month is 54s, 90s and 34s, the redissolution time of 6 months is 52s, 96s and 45s, the redissolution time is less than 120s, the redissolution time is short, and the obtained freeze-dried preparation has good property;

in the embodiment 10, xylitol is adopted as the saccharide or sugar alcohol substance in the method 4, the inclusion ratio of the citric acid alidenafil and the cyclodextrin derivative is 1:5, the inclusion ratio is low, and the synergistic solubilization effect of the cyclodextrin derivative and the saccharide or sugar alcohol substance is poor; the freeze-dried preparation is slightly atrophied in molding, and is a white freeze-dried block with poor appearance property; tc (collapse temperature) is-36 ℃, tg (glass transition temperature of a dried sample) is 55 ℃, the freeze-drying key temperature is obviously reduced, freeze-drying is difficult, the freeze-drying period is long, and the stability is poor; the moisture content in 0 month is 1.8%, the moisture content in 6 months is 2.8%, and the moisture content is obviously increased; the redissolution time of 0 month is 205s, the redissolution time of 6 months is 235s, the redissolution time is far longer than 120s, the redissolution time is overlong, and the obtained freeze-dried preparation has poor property.

And (3) knotting:

a) Compared with the prescription added with cyclodextrin derivatives, the freeze-dried preparation prepared by adopting different types of sugar substances or sugar alcohol substances (any one or more of glucose, trehalose, sucrose, dextran, sorbitol and mannitol) has better properties (inclusion ratio, quality, key temperature and stability):

for example, the lyophilized formulation prepared using sorbitol in example 8, trehalose in example 10, glucose in example 10, method 2 and dextran in example 10, method 3, had good properties (inclusion ratio, quality, critical temperature and stability) as shown in:

i. the inclusion ratio of the citric acid alidenafil and the cyclodextrin derivative is high (1:2-1:4), and the cyclodextrin derivative and the carbohydrate or sugar alcohol substance have good synergistic solubilization effect;

the freeze-dried preparation is well formed and has good appearance;

v. the re-dissolving time is short (23-96 s), and is less than 120s;

b) Among them, when sorbitol is used as the saccharide or sugar alcohol based on the cyclodextrin derivative (for example, example 8), the obtained lyophilized preparation has the best properties (inclusion ratio, quality, critical temperature and stability), which are represented as follows:

the freeze-dried preparation is well formed and has good appearance;

the stability is best: the freeze-drying critical temperature is highest (the collapse temperature Tc is-21 ℃, and the glass transition temperature Tg of a dried sample is 77 ℃); low impurity content (as low as 0.002%); the moisture content was lowest (as low as 0.6%;

v. short reconstitution times (as low as 23 s), well below 120s;

c) On the contrary, when other sugar substances or sugar alcohol substances (for example, xylitol of the method 4 of the embodiment 10) are adopted on the basis of adding the cyclodextrin derivative, the obtained freeze-dried preparation has poor properties (inclusion ratio, quality, key temperature and stability) and cannot be used as a qualified freeze-dried preparation, and the specific expression is as follows:

i. the inclusion ratio of the citric acid alidenafil and the cyclodextrin derivative is low (1:5), and the cyclodextrin derivative and the carbohydrate or sugar alcohol substance have no synergistic solubilization effect;

ii, the freeze-dried preparation is slightly atrophied in molding and has poor appearance and properties;

poor stability: the freeze-drying key temperature is obviously reduced (the collapse temperature Tc is minus 36 ℃, and the glass transition temperature Tg of a dried sample is 55 ℃); high moisture content (up to 2.8%);

reconstitution times were too long (up to 235s, much greater than 120 s).

On the basis of adding cyclodextrin derivatives, the influence of different kinds of saccharides or sugar alcohols on the properties (inclusion ratio, quality, critical temperature and stability) of the freeze-dried preparation is shown in the following concrete expression:

table 45: comparison of the Properties of the lyophilized formulations of example 8 and methods 1-4 of example 10

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Claims

1. An Aidenafil citrate injection comprises a pharmaceutical active ingredient, wherein the pharmaceutical active ingredient is Aidenafil citrate and/or pharmaceutically acceptable salts thereof.

2. The injection according to claim 1, further comprising a pH adjusting agent and/or an injection solvent.

3. The injection according to claim 1 or 2, further comprising a co-solvent and/or a solubilizer.

4. The injection according to claim 3, wherein the cosolvent and the solubilizer are selected from any one of cyclodextrin derivatives, organic cosolvents and surfactants, and are preferably cyclodextrin derivatives.

5. The injection according to claim 4, wherein the cyclodextrin derivative comprises β -cyclodextrin and/or γ -cyclodextrin; preferably, the cyclodextrin derivative is selected from: any one or more of hydroxyethyl-beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, methyl-beta-cyclodextrin, maltose-beta-cyclodextrin, carboxymethyl-beta-cyclodextrin, sulfoethyl-beta-cyclodextrin, sulfopropyl-beta-cyclodextrin, sulfobutyl-beta-cyclodextrin sodium, methyl-beta-cyclodextrin and hydroxypropyl-gamma-cyclodextrin; more preferably hydroxypropyl-beta-cyclodextrin and/or sodium sulfobutyl-beta-cyclodextrin.

6. An injection according to claim 4 or 5, wherein the molar ratio of the pharmaceutically active ingredient to the cyclodextrin derivative is 1: (2-20); preferably, the molar ratio is 1 (5-10).

7. The injection according to any one of claims 1 to 4, further comprising a sugar substance or a sugar alcohol substance.

8. The injection according to claim 7, wherein the saccharide is selected from the group consisting of: any one or more of glucose, trehalose, sucrose and dextran;

the sugar alcohol substance comprises sorbitol and/or mannitol, preferably sorbitol.

9. The injection according to claim 7, wherein the injection comprises a pharmaceutically active ingredient, a pH adjusting agent, an injection solvent, a cyclodextrin derivative, and optionally a saccharide or sugar alcohol.

10. The injection according to claim 2, wherein the pH adjusting agent is selected from the group consisting of: any one or more of hydrochloric acid, sulfuric acid, tartaric acid, citric acid, sodium hydroxide, potassium hydroxide, sodium bicarbonate, disodium hydrogen phosphate and sodium dihydrogen phosphate.

11. The injection according to claim 2, wherein the solvent for injection is selected from the group consisting of: one or more of ethanol, propylene glycol, glycerol, sorbitol and water for injection, preferably water for injection.

12. The injection according to any one of claims 1 to 11, wherein the injection is for the treatment of alzheimer's disease.

13. An injection according to any one of claims 1 to 11 for use in the treatment of erectile dysfunction.

14. A method for preparing an injection according to any one of claims 1 to 13, comprising the steps of:

2) Filtering;

3) Filling;

4) Sterilizing;

5) And (6) detecting leakage and packaging.

15. The preparation method according to claim 14, wherein a lyophilization process is used instead of sterilization in step 4) to obtain a lyophilized preparation of the citric acid alidenafil injection.

16. The preparation method according to claim 15, wherein the lyophilization process comprises the steps of:

a. pre-freezing;

b. primary drying;

c. resolving and drying;

d. pressing and plugging;

e. and (6) rolling a cover.

17. Use of an injection according to any one of claims 1 to 13 in the manufacture of a medicament for the treatment of alzheimer's disease.

18. Use of the injection according to any one of claims 1 to 13 for the manufacture of a medicament for the treatment of erectile dysfunction.