CN114129528B - Novel sildenafil citrate preparation with clinical advantages and preparation process and application thereof - Google Patents
Novel sildenafil citrate preparation with clinical advantages and preparation process and application thereof Download PDFInfo
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- CN114129528B CN114129528B CN202111475182.4A CN202111475182A CN114129528B CN 114129528 B CN114129528 B CN 114129528B CN 202111475182 A CN202111475182 A CN 202111475182A CN 114129528 B CN114129528 B CN 114129528B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
Abstract
The invention discloses a novel sildenafil citrate preparation with clinical advantages, a preparation process and application thereof, and belongs to the field of pharmaceutical preparations. The novel sildenafil citrate preparation is an orally disintegrating tablet and comprises the following components in percentage by mass: 10-30% of sildenafil citrate and 45-85% of a filler, wherein the filler comprises ethyl cellulose, and the mass of the ethyl cellulose accounts for 3-30% of that of the sildenafil citrate preparation; 3 to 15 percent of disintegrating agent, 0.1 to 5 percent of citric acid and 0.2 to 5 percent of flavoring agent, wherein the percent refers to the mass percentage of each component in the sildenafil citrate preparation. The sildenafil citrate preparation prepared by the invention is not easy to be sticky in the preparation process, is small in tablet weight and convenient to take, can effectively improve the clinical compliance and has clinical advantages. In addition, the tablet has the advantages of high stability, good disintegration effect, excellent dissolution effect and the like, and is beneficial to quick release of the drug effect and quick absorption of gastrointestinal tracts.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a novel sildenafil citrate preparation with clinical advantages and a preparation process and application thereof.
Background
In recent years, the incidence of Erectile Dysfunction (ED) is increasing year by year in China, and the incidence of ED is also obviously increased in middle and young years, which is probably related to great social working pressure, especially under the trend of chronic diseases younger, the incidence of ED accompanied with some diseases is gradually increased, and the physical and psychological health of patients is seriously influenced. Sildenafil is the first choice drug for clinically treating various types of erectile dysfunction at present, is white crystalline powder, is marketed into tablets, namely Wanaike, and is developed into orally disintegrating tablets by original research companies. Sildenafil is not stable, is easy to absorb moisture and stick, is easy to stick and wash when being directly pressed, and has strong bitter taste. Sildenafil citrate is the citrate salt of sildenafil, a selective inhibitor of phosphodiesterase type 5 (PDE 5) specific for cyclic guanosine monophosphate (cGMP), and has the chemical name: 1- { 4-ethoxy-3- (6, 7-dihydro-1-methyl-7-oxo-3-propyl-1 h-pyrazolo [4,3d ] pyrimidin-5-yl) benzenesulfonyl } -4-methylpiperazine citrate. The chemical structural formula is as follows:
the sildenafil citrate preparation developed by the pfizer of the original research company has disintegration time limit of about 100s, which exceeds the requirement of China pharmacopeia 2020 edition (special disintegration apparatus for preparation) within 60s; the tablet weight of the preparation of the original research company is 500mg, which reaches the upper limit of the tablet weight of the preparation and is inconvenient to take; in addition, the bitter taste is obvious, and the used auxiliary materials contain Ludiflash auxiliary materials of BASF company, and have the characteristics of high price and long supply period.
Disclosure of Invention
The technical problem to be solved by the invention is to overcome the defects of long disintegration time limit, easy sticking and obvious bitter taste when the tablet weight is reduced in the prior art, and provide a novel sildenafil citrate preparation with clinical advantages and a preparation process and application thereof. The novel sildenafil citrate preparation has short disintegration time, is convenient for quick release of drug effect, has small tablet weight, is easy to take, can effectively improve clinical compliance and has clinical advantages. The novel sildenafil citrate preparation also has the advantages of unobvious bitter taste, difficult sticking in the preparation process and the like.
The invention solves the technical problems through the following technical scheme:
in the process of research and development, the inventor tries a plurality of auxiliary disintegrating agents, and the disintegrating effect is not ideal. The inventor creatively adds the insoluble auxiliary material ethyl cellulose as one of the fillers into the sildenafil citrate tablet, improves the disintegration effect of the tablet, and solves the problem of short disintegration time limit, but the addition of the ethyl cellulose can cause the increase of the impurity B and cause the stability of the preparation to be poor, so that the citric acid is introduced into the formula, and the inventor finds that the problems of slow disintegration, sticking and the like can be caused when the dosage of the citric acid is too much; meanwhile, when the inventor tries to adjust the tablet weight of the prescription process of the original research company, the inventor finds that the tablet weight is reduced, and the tablet is easy to stick and dash in the tabletting process and cannot be produced, because the raw material medicine has stronger hygroscopicity and viscosity. The inventor further explores the proper content ratio of the ethyl cellulose and the citric acid, and realizes the excellent effects of short disintegration time, difficult sticking and less bitter taste when the tablet weight is reduced by matching with sildenafil citrate, a filling agent, a disintegrating agent and the like.
In order to achieve the purpose, the invention is realized by the following technical scheme:
a novel sildenafil citrate preparation with clinical advantages is an orally disintegrating tablet and comprises the following components in percentage by mass:
10 to 30 percent of sildenafil citrate,
45 to 85 percent of filling agent, wherein the filling agent comprises ethyl cellulose, the mass of the ethyl cellulose accounts for 3 to 30 percent of the mass of the novel sildenafil citrate preparation,
3 to 15 percent of disintegrating agent,
0.1 to 5 percent of citric acid,
0.2 to 5 percent of flavoring agent,
wherein the percentage refers to the percentage of the mass of each component in the novel sildenafil citrate preparation.
In the invention, the main active ingredient of the novel sildenafil citrate preparation is sildenafil citrate.
In the present invention, the sildenafil citrate is preferably 20 to 25% by mass, for example, 22% or 23.4% by mass.
In the present invention, the citric acid is preferably 0.1% to 4.5% by mass, for example, 0.3%, 0.5%, 1% or 2%.
In the present invention, the ethyl cellulose is preferably present in an amount of 13 to 18% by mass, for example 14%, 15% or 17.3%.
In the present invention, it is preferable that the particle size D97 of the ethylcellulose is 100 micrometers, for example, 10 to 80 micrometers.
In the present invention, the mass percentage of the filler is preferably 55% to 75%, for example 57%, 57.6%, 62.1%, 65.4% or 70%;
in the present invention, preferably, the filler further comprises one or more of mannitol, lactose and microcrystalline cellulose.
More preferably, the filler also includes "mannitol and microcrystalline cellulose".
Among them, the mannitol is preferably 23 to 29% by mass, for example, 23.6 or 28.1% by mass, and the microcrystalline cellulose is preferably 19 to 21% by mass, for example, 20% by mass.
For example, the filler further comprises the following components in percentage by mass: 28.1 percent of mannitol and 20 percent of microcrystalline cellulose, wherein the mass percent of each component accounts for the mass percent of the novel sildenafil citrate preparation.
For another example, the filler further comprises the following components in percentage by mass: 23.6 percent of mannitol and 20 percent of microcrystalline cellulose, wherein the mass percent of each component accounts for the mass percent of the novel sildenafil citrate preparation.
In the present invention, the mass percentage of the disintegrant is preferably 6% to 10%, for example 6.7%, 8% or 9%.
In the present invention, preferably, the disintegrant includes one or more of low-substituted hypromellose, croscarmellose, crospovidone, and croscarmellose sodium.
More preferably, the disintegrant is "crospovidone and croscarmellose sodium".
Wherein, the mass percentage of the crospovidone is preferably 1.5-5%, for example 1.7%, and the mass percentage of the croscarmellose sodium is preferably 4-6%, for example 5%, wherein the% means the mass percentage of each component in the novel sildenafil citrate preparation.
In the present invention, the mass percentage of the flavoring agent is preferably 0.8 to 1.2%, for example, 1%.
In the present invention, the flavoring agent may be a conventional flavoring agent in the art. Preferably, the flavoring agent comprises sucralose and/or aspartame, for example, the flavoring agent is sucralose.
In the invention, the novel sildenafil citrate preparation further comprises a glidant.
Wherein, the mass percentage of the glidant is preferably 0.1-2%, more preferably 0.8-1.2%, for example 1%.
The glidant can be a conventional glidant in the art, preferably the glidant comprises colloidal silicon dioxide and/or talc, and more preferably the glidant is colloidal silicon dioxide.
In the present invention, preferably, the novel sildenafil citrate formulation further comprises a lubricant.
Wherein, the mass percentage of the lubricant is preferably 0.2-5%, more preferably 0.8-1.2%, for example 1%;
wherein the lubricant may be a lubricant conventional in the art. Preferably, the lubricant comprises one or more of magnesium stearate, calcium stearate and sodium stearyl fumarate; more preferably, the lubricant is magnesium stearate.
In the invention, preferably, the novel sildenafil citrate preparation further comprises essence, and the mass percentage of the essence is preferably 0.8% -1.2%, for example 1%.
In the invention, preferably, the novel sildenafil citrate preparation comprises the following components in percentage by mass: the sildenafil citrate comprises 20 to 25 percent of sildenafil citrate, 57 to 70 percent of filling agent, 6 to 10 percent of disintegrating agent, 0.1 to 4.5 percent of citric acid, 0.8 to 1.2 percent of flavoring agent, 0.8 to 1.2 percent of glidant, 0.8 to 1.2 percent of lubricant and 0.8 to 1.2 percent of essence by mass percent;
in a preferred embodiment of the invention, the novel sildenafil citrate preparation consists of the following components in percentage by mass: 23.4 percent of sildenafil citrate, 28.1 percent of mannitol, 20 percent of microcrystalline cellulose, 14 percent of ethyl cellulose, 5 percent of crospovidone, 5 percent of croscarmellose sodium, 0.5 percent of citric acid, 1 percent of silicon dioxide, 1 percent of sucralose, 1 percent of essence and 1 percent of magnesium stearate.
In another preferred embodiment of the present invention, the novel sildenafil citrate preparation consists of the following components in percentage by mass: 23.4 percent of sildenafil citrate, 28.1 percent of mannitol, 20 percent of microcrystalline cellulose, 17.3 percent of ethyl cellulose, 1.7 percent of crospovidone, 5 percent of croscarmellose sodium, 0.5 percent of citric acid, 1 percent of silicon dioxide, 1 percent of sucralose, 1 percent of essence and 1 percent of magnesium stearate.
In another preferred embodiment of the present invention, the novel sildenafil citrate preparation consists of the following components in percentage by mass: 23.4 percent of sildenafil citrate, 23.6 percent of mannitol, 20 percent of microcrystalline cellulose, 14 percent of ethyl cellulose, 5 percent of crospovidone, 5 percent of croscarmellose sodium, 5 percent of citric acid, 1 percent of silicon dioxide, 1 percent of sucralose, 1 percent of essence and 1 percent of magnesium stearate.
In the present invention, the novel sildenafil citrate preparation preferably has the following characteristics:
the weight of the tablet is 300g;
the disintegration time can reach 43-60 s;
the total content of impurities after standing for 30 days is less than 1%, for example 0.05-0.07%.
In the invention, the content of impurity B is well controlled by the synergistic effect of citric acid and ethyl cellulose, so that the preparation has better stability. Through the matching of citric acid, ethyl cellulose and other components, the disintegration time limit is mainly solved, and the problems of sticking, taste and the like are assisted to be solved.
Wherein the structural formula of the impurity B is as follows:
in the present invention, the insoluble auxiliary material ethylcellulose can be added by dissolving in ethanol, or ethyl cellulose fine powder is added to wet granulation.
The invention also provides a preparation process of the novel sildenafil citrate preparation, which comprises the following steps: the novel sildenafil citrate preparation is prepared by wet granulating the mixture of the components of the novel sildenafil citrate preparation, drying and tabletting.
In the present invention, the ethylcellulose in the mixture has a particle size D97 of 100 μm, for example from 20 to 80 μm. During the preparation process, the inventor finds that the finer the particle size of the ethyl cellulose is, the better the effect of reducing the sticking is. If the particle size is larger than 100 microns, poor uniformity in the preparation process can be caused, the content of the obtained tablets is inconsistent, and the disintegrating effect and dissolution rate are poor after the disintegrating tablets are disintegrated.
In the present invention, the wet granulation process may be a wet granulation process that is conventional in the art.
In the present invention, preferably, the preparation method of the novel sildenafil citrate preparation comprises the following steps:
(1) Adding ethyl cellulose, part of filler, sildenafil citrate and part of disintegrant into aqueous solution containing citric acid for wet granulation;
or dissolving ethyl cellulose in ethanol, mixing with part of filler, sildenafil citrate and part of disintegrant, granulating, and adding water solution containing citric acid for granulating;
(2) Drying by a fluidized bed to obtain small-particle medicines;
(3) Adding the rest disintegrating agent, the rest filling agent, the flavoring agent and the glidant, and uniformly mixing;
(4) Finally adding a lubricant, mixing and tabletting.
The invention also provides a novel sildenafil citrate preparation prepared by the preparation process.
The invention also provides application of the novel sildenafil citrate preparation in preparing medicaments for treating erectile dysfunction diseases.
The positive progress effects of the invention are as follows:
(1) According to the novel sildenafil citrate preparation, ethyl cellulose with a smaller prescription and lower cost is used for replacing an auxiliary material of ludiflash with a larger prescription, and the preparation obtains better stability and disintegration effect by matching the combination of citric acid and ethyl cellulose with other components in a proper proportion. The disintegration time limit is one time faster than that of the original preparation, meets the technical requirements of the 2020 edition of Chinese pharmacopoeia, is favorable for quick release of the drug effect, and has excellent clinical compliance. Compared with the original preparation, the sildenafil citrate tablet has the advantages of better disintegration effect (within 60s of disintegration time limit), less bitter taste, good stability (almost no increase of impurities after being placed for 30 days), smaller tablet weight, easiness in taking, excellent clinical compliance and the like.
(2) The novel sildenafil citrate preparation is prepared by a wet granulation process, and the process is simple and feasible.
(3) In the preparation process of the novel sildenafil citrate preparation, the problem of no sticking during tabletting can be further solved under the condition of reducing the tablet weight, the production of sildenafil citrate preparation with small tablet weight (300 g) can be realized, and the sildenafil citrate preparation has important application value for preparing medicaments for erectile dysfunction diseases.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.
In the following examples, the ethyl cellulose particles have a particle size D97 of 100. Mu.m.
In the following examples, all the adjuvants used were in accordance with pharmacopoeia requirements. The original preparation was purchased from pfeiri.
Example 1
Prescription:
the preparation method comprises the following steps: adding sildenafil citrate, mannitol, ethyl cellulose and crospovidone into citric acid aqueous solution for wet granulation, then drying by a fluidized bed, adding croscarmellose sodium, microcrystalline cellulose, silicon dioxide, sucralose and essence for mixing, finally adding magnesium stearate for mixing uniformly, and tabletting according to 300 mg.
Example 2
Prescription:
the preparation method comprises the following steps: the sildenafil citrate, the mannitol, the crospovidone and the ethyl cellulose ethanol solution are granulated by a wet method, the citric acid water solution is added for granulation, then fluidized bed drying is carried out, the croscarmellose sodium, the microcrystalline cellulose, the silicon dioxide, the sucralose and the essence are added for mixing, finally the magnesium stearate is added for mixing uniformly, and 300mg tablets are tabletted by weight.
Example 3
Prescription:
the preparation method comprises the following steps: wet granulating sildenafil citrate, mannitol, ethyl cellulose, crospovidone and citric acid aqueous solution, fluidized bed drying, adding croscarmellose sodium, microcrystalline cellulose, silicon dioxide, sucralose and essence, mixing, adding magnesium stearate, mixing, and tabletting at 300 mg.
Comparative example 1
Except essence, other auxiliary materials are prepared according to the original prescription:
prescription:
the preparation method comprises the following steps: mixing sildenafil citrate and 20% ludiflash, silicon dioxide and sucralose in a mixer, transferring to a granulator for granulating, adding croscarmellose sodium, microcrystalline cellulose and the rest ludiflash, mixing by the mixer, granulating by the granulator, adding magnesium stearate, mixing uniformly, and tabletting with 500mg tablets.
Comparative example 2
Prescription:
the preparation method comprises the following steps: mixing sildenafil citrate and 20% ludiflash, silicon dioxide and sucralose in a mixer, transferring to a granulator for granulating, adding croscarmellose sodium, microcrystalline cellulose and the rest ludiflash, mixing by the mixer, granulating by the granulator, adding magnesium stearate, mixing uniformly, and tabletting with 300mg tablets.
Comparative example 3
Prescription:
the preparation method comprises the following steps: the sildenafil citrate, the mannitol, the ethyl cellulose and the crospovidone are added with water solution for wet granulation, then fluidized bed drying is carried out, and then the croscarmellose sodium, the microcrystalline cellulose, the silicon dioxide, the sucralose and the essence are added and mixed, finally the magnesium stearate is added and mixed, and the tablet is prepared according to 300 mg.
Comparative example 4
Prescription:
the preparation method comprises the following steps: adding sildenafil citrate, mannitol and crospovidone into citric acid aqueous solution for wet granulation, drying with fluidized bed, adding croscarmellose sodium, microcrystalline cellulose, silicon dioxide, sucralose and essence, mixing, adding magnesium stearate, mixing, and tabletting at 300 mg.
Comparative example 5
Prescription:
the preparation method comprises the following steps: the sildenafil citrate, the mannitol, the ethyl cellulose and the crospovidone are added into a fumaric acid aqueous solution for wet granulation, then fluidized bed drying is carried out, then the croscarmellose sodium, the microcrystalline cellulose, the silicon dioxide, the sucralose and the essence are added and mixed, finally the magnesium stearate is added and mixed uniformly, and the tablet is prepared according to 300 mg.
Effects of the embodiment
(1) Disintegration time, sticking and taste
The tablets in the above examples and the original preparation produced by feverfew were examined for disintegration time using a special disintegration apparatus for the preparation, and the specific data are shown in the following table. The requirement of the China pharmacopoeia 2020 edition on the disintegration time limit of the preparation is less than or equal to 60S, and the disintegration time limit of the tablet prepared by the technology is far less than that of the original preparation and meets the requirement of the China pharmacopoeia.
And (3) sticking observation: it was observed whether the powder particles adhered to the punch surface during tabletting.
Taste evaluation: adult males of different ages were randomly selected and the evaluation of drug taste after administration was investigated.
TABLE 1 results of different batches
From the above results, it can be seen that, compared with comparative examples 1, 2, 4 and the original formulation, the sildenafil preparations of examples 1 to 3 of the present invention have insignificant bitterness and short disintegration time of less than 60s, which meets the requirement of the 2020 edition of Chinese pharmacopoeia for disintegration time of the preparations, and when the tablet weight is reduced, no sticking occurs during tabletting. When the original prescription process is adopted or no ethyl cellulose is added, the disintegration time is obviously increased, which is not favorable for quick release and absorption of the drug effect. When the original prescription process is adopted and the tablet weight is reduced (comparative example 2), the phenomena of obvious bitter taste and sticking in the tabletting process also occur, and the industrialized production process is not facilitated. Therefore, the adoption of the ethyl cellulose can obviously improve the disintegration effect of the tablet and solve the problem of short disintegration time.
(2) Stability of
We performed stability profiling (60 ℃ C. High humidity RH75% + -5%) for each example and original formulation, and the specific data are shown in Table 3.
TABLE 2 comparison of stability
From the above results, it was found that the stability of the target formulation (examples 1 to 3) of the present invention was higher than that of the original formulation, and the content of impurity B was substantially the same as that of the original formulation after 30 days of the process (comparative example 1). When the weight of the original formulation was reduced to 300g (comparative example 2), the content of impurity B increased slightly after 30 days; when citric acid is not added (comparative example 3) or fumaric acid is used to replace citric acid (comparative example 5), the impurity B is obviously increased and the stability is poor. Therefore, the citric acid can effectively inhibit the increase of the impurity B and improve the stability of the preparation.
While specific embodiments of the invention have been described above, it will be appreciated by those skilled in the art that this is by way of example only, and that the scope of the invention is defined by the appended claims. Various changes and modifications to these embodiments may be made by those skilled in the art without departing from the spirit and scope of the invention, and these changes and modifications are within the scope of the invention.
Claims (30)
1. A novel sildenafil citrate preparation with clinical advantages is characterized in that the novel sildenafil citrate preparation is an orally disintegrating tablet and comprises the following components in percentage by mass:
10 to 30 percent of sildenafil citrate,
45-85% of a filling agent, wherein the filling agent comprises ethyl cellulose, the mass of the ethyl cellulose accounts for 3-30% of the mass of the novel sildenafil citrate preparation, and the particle size D97 of the ethyl cellulose is 100 micrometers; the filler also comprises mannitol and microcrystalline cellulose, wherein the mass percent of the mannitol is 23-29%, and the mass percent of the microcrystalline cellulose is 19-21%;
3% -15% of a disintegrating agent, wherein the disintegrating agent is crospovidone and croscarmellose sodium, the mass percentage of the crospovidone is 1.5% -5%, and the mass percentage of the croscarmellose sodium is 4% -6%;
0.1 to 5 percent of citric acid,
0.2 to 5 percent of flavoring agent,
wherein the percentage refers to the percentage of the mass of each component in the novel sildenafil citrate preparation.
2. The novel sildenafil citrate formulation according to claim 1, wherein said novel sildenafil citrate formulation meets one or more of the following conditions:
(1) the sildenafil citrate accounts for 20 to 25 percent by mass;
(2) the mass percent of the citric acid is 0.1-4.5%;
(3) the mass percent of the ethyl cellulose is 13-18%;
(4) the granularity D97 of the ethyl cellulose is 10-80 microns;
(5) the novel sildenafil citrate preparation also comprises essence.
3. The novel sildenafil citrate formulation according to claim 2, wherein said novel sildenafil citrate formulation meets one or more of the following conditions:
a. the sildenafil citrate accounts for 22% or 23.4% by mass;
b. the mass percent of the citric acid is 0.3%, 0.5%, 1% or 2%;
c. the mass percent of the ethyl cellulose is 14%, 15% or 17.3%;
d. the essence is 0.8-1.2% by mass.
4. The novel sildenafil citrate formulation according to claim 3, wherein the essence is present in an amount of 1% by mass.
5. The novel sildenafil citrate formulation according to claim 1,
the mass percentage of the filler is 55-75%;
and/or the mannitol accounts for 23.6% or 28.1% by mass, and the microcrystalline cellulose accounts for 20% by mass;
wherein the percentage refers to the percentage of the mass of each component in the novel sildenafil citrate preparation.
6. The novel sildenafil citrate formulation of claim 5, wherein the filler is present in an amount of 57%, 57.6%, 62.1%, 65.4% or 70% by weight.
7. The novel sildenafil citrate formulation according to claim 1,
the mass percentage of the disintegrating agent is 6-10%.
8. The novel sildenafil citrate formulation according to claim 7,
the mass percent of the disintegrant is 6.7%, 8% or 9%.
9. The novel sildenafil citrate formulation according to claim 1,
the mass percentage of the crospovidone is 1.7%.
10. The novel sildenafil citrate formulation according to claim 1,
the mass percent of the croscarmellose sodium is 5%.
11. The novel sildenafil citrate formulation according to claim 1,
the mass percent of the flavoring agent is 0.8-1.2%;
and/or, the flavoring agent comprises sucralose and/or aspartame.
12. The novel sildenafil citrate formulation of claim 11, wherein the flavoring agent is present in an amount of 1% by weight;
and/or the flavoring agent is sucralose.
13. The novel sildenafil citrate formulation according to claim 1, wherein,
the novel sildenafil citrate formulation further comprises a glidant.
14. The novel sildenafil citrate formulation of claim 13, wherein the glidant is present in an amount of 0.1 to 2% by weight.
15. The novel sildenafil citrate formulation according to claim 14, wherein the glidant is present in an amount of 0.8 to 1.2% by mass.
16. The novel sildenafil citrate formulation of claim 15, wherein the glidant is present in an amount of 1% by weight.
17. The novel sildenafil citrate formulation of claim 13,
the glidant includes colloidal silicon dioxide and/or talc.
18. The novel sildenafil citrate formulation of claim 17,
the glidant is colloidal silicon dioxide.
19. The novel sildenafil citrate formulation according to claim 1,
the novel sildenafil citrate formulation further comprises a lubricant.
20. The novel sildenafil citrate formulation of claim 19,
the mass percentage of the lubricant is 0.2-5%.
21. The novel sildenafil citrate formulation of claim 20,
the mass percentage of the lubricant is 0.8-1.2%.
22. The novel sildenafil citrate formulation of claim 21,
the mass percent of the lubricant is 1%.
23. The novel sildenafil citrate formulation of claim 19,
the lubricant comprises one or more of magnesium stearate, calcium stearate and sodium stearyl fumarate.
24. The novel sildenafil citrate formulation of claim 23,
the lubricant is magnesium stearate.
25. The novel sildenafil citrate formulation according to claim 1, comprising the following components in percent by mass: the sildenafil citrate consists of sildenafil citrate 20-25 wt%, stuffing 57-70 wt%, disintegrating agent 6-10 wt%, citric acid 0.1-4.5 wt%, corrective 0.8-1.2 wt%, flow aid 0.8-1.2 wt%, lubricant 0.8-1.2 wt% and essence 0.8-1.2 wt%.
26. The novel sildenafil citrate formulation according to claim 25, wherein the novel sildenafil citrate formulation consists of the following components in mass percent:
23.4% of sildenafil citrate, 28.1% of mannitol, 20% of microcrystalline cellulose, 14% of ethyl cellulose, 5% of crospovidone, 5% of croscarmellose sodium, 0.5% of citric acid, 1% of silicon dioxide, 1% of sucralose, 1% of essence and 1% of magnesium stearate;
or the novel sildenafil citrate preparation consists of the following components in percentage by mass: 23.4 percent of sildenafil citrate, 28.1 percent of mannitol, 20 percent of microcrystalline cellulose, 17.3 percent of ethyl cellulose, 1.7 percent of crospovidone, 5 percent of croscarmellose sodium, 0.5 percent of citric acid, 1 percent of silicon dioxide, 1 percent of sucralose, 1 percent of essence and 1 percent of magnesium stearate;
or the novel sildenafil citrate preparation consists of the following components in percentage by mass: 23.4 percent of sildenafil citrate, 23.6 percent of mannitol, 20 percent of microcrystalline cellulose, 14 percent of ethyl cellulose, 5 percent of crospovidone, 5 percent of croscarmellose sodium, 5 percent of citric acid, 1 percent of silicon dioxide, 1 percent of sucralose, 1 percent of essence and 1 percent of magnesium stearate.
27. A preparation process of a novel sildenafil citrate preparation is characterized by comprising the following steps: wet granulating a mixture of the components of the novel sildenafil citrate formulation of any of claims 1 to 26, drying, and tableting;
the ethyl cellulose in the mixture had a particle size D97 of 100 μm.
28. The process for preparing a novel sildenafil citrate formulation as claimed in claim 27, wherein the ethyl cellulose in said mixture has a particle size D97 of 20 to 80 μm.
29. The process for preparing a novel sildenafil citrate formulation according to claim 27, wherein the process for preparing the novel sildenafil citrate formulation comprises the steps of:
(1) Adding ethyl cellulose, part of filler, sildenafil citrate and part of disintegrant into aqueous solution containing citric acid for wet granulation;
or dissolving ethyl cellulose in ethanol, mixing with part of filler, sildenafil citrate and part of disintegrant, granulating, and adding water solution containing citric acid for granulating;
(2) Drying by a fluidized bed to obtain small-particle medicines;
(3) Adding the rest disintegrating agent, the rest filling agent, the flavoring agent and the glidant and mixing uniformly;
(4) Finally adding a lubricant, mixing and tabletting.
30. Use of the novel sildenafil citrate formulation according to any one of claims 1 to 26 or the novel sildenafil citrate formulation prepared by the process for preparing the novel sildenafil citrate formulation according to any one of claims 27 to 29 for the preparation of a medicament for erectile dysfunction.
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