CN113413388B - Sildenafil citrate-containing pharmaceutical composition, preparation method and application thereof - Google Patents
Sildenafil citrate-containing pharmaceutical composition, preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a sildenafil citrate-containing pharmaceutical composition, which is prepared by a wet granulation process and comprises 3-45 wt% of sildenafil citrate, 0.5-5 wt% of an adhesive, 2-20 wt% of a sweetening agent, 3-20 wt% of a disintegrating agent, 0.5-3 wt% of a glidant, 0.5-5 wt% of a lubricant and the balance of a filler, wherein the filler is selected from a mixture of microcrystalline cellulose and mannitol; the adhesive is one or a mixture of more than one of povidone, hydroxypropyl methylcellulose and hydroxypropyl cellulose; the disintegrant is selected from one or more of crospovidone, croscarmellose sodium and low-substituted hydroxypropyl cellulose, the pharmaceutical composition is a low-dose dispersible tablet of sildenafil citrate, and has the advantages of low cost, easy preparation, quick dissolution and short disintegration time.
Description
Technical Field
The invention relates to a sildenafil citrate-containing pharmaceutical composition, a preparation method and application thereof
Background
Sildenafil citrate was the earliest drug developed by U.S. feverfew and is a highly colorful drug in the treatment of male Erectile Dysfunction (ED), was marketed in the us in 1998 and entered china in 2002, while sildenafil citrate is also approved in the european union and japan for the treatment of pulmonary hypertension in children, applicable to children.
At present, sildenafil citrate preparations on the market are mostly ordinary tablets, the disintegration speed is not fast, the treatment of old, young and patients with swallowing dysfunction is difficult, orally disintegrating tablets can help to disintegrate and dissolve quickly, but the phenomenon of difficult dose division exists, for people such as children, the dosage is greatly reduced compared with healthy adults, 20mg, 25mg or 50mg tablets are difficult to be accurately divided into 10mg doses for the treatment of children, and the dosage is especially the same for children taking 5mg every time, so that the corresponding children indications and the dosage recommendation of children less than 20 mg/time exist, but the current situation that the accurate administration cannot be carried out exists in the clinical practical application.
The dispersible tablet is a solid preparation, belongs to one type of tablets, can be rapidly and uniformly dispersed in water, has the advantages that the common tablets cannot realize, and is convenient for patients to take. Because the dispersible tablet can be completely disintegrated within 3 minutes, the dissolution of the medicine can be greatly improved, the peak reaching time of oral administration can be shortened, and even the bioavailability of certain medicine indications can be improved. The developed sildenafil citrate dispersible tablets are particularly suitable for patients with dysphagia to take, have superior clinical advantages for accurate administration of children including children to treat, and fill up the blank of current clinical application.
Sildenafil citrate tablet on the market
Is a medicament for treating pulmonary hypertension, and has the problems of slow disintegration, difficult dose division and the like. Sildenafil citrate orally disintegrating tablet on the market
Is a medicine for treating erectile dysfunction, has higher dosage specification (50 mg) and difficult divided dosage, and cannot be used for treating pulmonary hypertension of children. The sildenafil citrate orally disintegrating tablet contains auxiliary materials such as essence of an antioxidant, a binding agent polyvinyl acetate and the like, the purchase price of the imported auxiliary materials is very high, the manufacturing cost is increased even if the sildenafil citrate orally disintegrating tablet is applied, meanwhile, the sildenafil citrate orally disintegrating tablet is not enough in hardness and needs to be packaged by double aluminum, the production cost is greatly increased (the double aluminum cost is at least 5 times of that of a plastic bottle), and the existing 20mg sildenafil citrate tablets
Is priced as 47 yuan per tablet (4198 yuan per box, china market pricing 2021 years). For the disease of pulmonary hypertension which is life-threatening and needs to be taken for a long time, the high cost is an important factor for influencing the medication.
Patent CN103040835 discloses a pharmaceutical composition of sildenafil citrate and PD-1 type pregelatinized starch and a preparation method thereof, which uses auxiliary materials containing adhesive and flavoring agent, and is prepared into orally disintegrating tablets by fluidized bed granulation and tabletting, and the taste and disintegration are better; patent CN1254246 discloses a preparation method of orally disintegrating tablet of sildenafil and its salt, active ingredients are masked by powder coating technology, and then mixed and directly tabletted to prepare orally disintegrating tablet, the two patents have the disadvantages of difficult production control, easy moisture absorption, low hardness, and incapability of being packaged by plastic bottles, so the cost is high, and the effect of taking in divided dose is difficult to achieve for patients with low dose; patent CN104706606 discloses a tablet and its preparation method, which adopts methylcellulose to wrap main drug for pretreatment, then directly mixes with auxiliary material for tabletting, and has poor disintegration and dispersion properties, and is not suitable for children or elderly patients with dysphagia to take. Patent CN108392639 discloses a sildenafil citrate pharmaceutical composition, which adopts sildenafil citrate-mesoporous molecular sieve composite to mask taste, has complex process and is difficult to industrialize.
In view of the reasons, the invention develops the sildenafil citrate dispersible tablet with small dose, which has good taste and stability, can be quickly disintegrated and dispersed uniformly in water, has hardness suitable for being packaged by a medicinal plastic bottle, is easy to industrialize and convenient for children to take, overcomes the defects of the existing products and technologies and can simultaneously meet all the advantages described above; the production cost of the dispersible tablet is greatly reduced, so that the medication cost of patients is reduced, and the long-term medication of the patients is facilitated.
Disclosure of Invention
In order to solve the technical problems, the invention provides a sildenafil citrate-containing pharmaceutical composition, wherein the sildenafil citrate is 3-45 wt%, the adhesive is 0.5-5 wt%, the sweetener is 2-20 wt%, the disintegrant is 3-30 wt%, the colloidal silicon dioxide is 0.1-5 wt%, the lubricant is 0.1-5 wt%, and the rest is filler selected from one or more of microcrystalline cellulose, mannitol, sorbitol, lactose and calcium hydrogen phosphate; the adhesive is one or a mixture of more than one of povidone, hydroxypropyl methylcellulose and hydroxypropyl cellulose; the disintegrant is selected from one or more of crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and pregelatinized starch; the lubricant is one or a mixture of more than one of magnesium stearate and sodium stearyl fumarate. The sweetener is one or more of sucralose, aspartame and essence.
The existing imported drug of sildenafil citrate does not disclose the dosage of the prescription, but the cost of the used adhesive is too high according to the product specification, so the inventor selects the adhesive povidone with lower cost through drug screening. Meanwhile, the imported medicines are packaged by double aluminum or aluminum plastic, in order to reduce the industrial cost, the inventor adopts a low-price medicinal plastic bottle for packaging, so that the indexes such as the hardness and the friability of the product need to be increased to meet the requirements of bottling, and the microcrystalline cellulose is a plastic filler and has the effect of increasing the hardness of the preparation, so that the filler is a mixture of the microcrystalline cellulose and mannitol. According to experimental research, the stability of the effective substances of the product is influenced by the single use of the crospovidone, and if the crospovidone is not used, the disintegration effect cannot reach the effect specified by pharmacopoeia, so the crospovidone and other disintegrants are mixed for use, and the disintegrant is a mixture of the crospovidone and croscarmellose sodium. The glidant is colloidal silicon dioxide, so that the wall sticking phenomenon in the wet granulation process is effectively prevented, and the flow assisting effect is realized. The lubricant and the sweetener respectively adjust the lubricating dispersivity and the taste masking property of the material.
According to the above explanation, the present invention provides a sildenafil-containing pharmaceutical composition, which comprises, by weight: 3 to 45 percent of sildenafil citrate, 0.5 to 5 percent of polyvidone serving as an adhesive, 2 to 20 percent of a sweetening agent, 3 to 20 percent of crospovidone and croscarmellose sodium serving as a disintegrating agent, 0.5 to 4 percent of colloidal silicon dioxide, 0.5 to 5 percent of a lubricant, and microcrystalline cellulose and mannitol serving as the rest filling agents.
Preferably, the composite material comprises 3-40% of sildenafil citrate, 0.5-3% of povidone, 2-10% of sweetening agent, 5-20% of crospovidone and croscarmellose sodium, 0.5-3% of colloidal silicon dioxide, 1-5% of lubricant and the balance of microcrystalline cellulose and mannitol by weight percentage.
Further, the pharmaceutical composition comprises the following components in percentage by weight: 3-40% of sildenafil citrate, 1-2% of povidone, 3-7% of sweetening agent, 3-8% of crospovidone, 3-10% of croscarmellose sodium, 1.0-3.0% of colloidal silicon dioxide, 1-4% of lubricant and the balance of microcrystalline cellulose and mannitol.
Furthermore, the pharmaceutical composition comprises the following components in percentage by weight: 15% -16% of sildenafil citrate, 1% -2% of povidone, 3% -7% of sweetening agent, 3% -8% of crospovidone, 3% -10% of croscarmellose sodium, 1.0% -3.0% of colloidal silicon dioxide, 1% -3% of lubricant, and the balance microcrystalline cellulose and mannitol.
Wherein the weight ratio of the microcrystalline cellulose to the mannitol is 1:0.5 to 1:3, preferably 1:2.
the weight ratio of the crospovidone to the croscarmellose sodium is 1:0.5-1:2, preferably 1.
The disintegrant needs to meet a special content and a special proportion, excessive crospovidone (more than 8 percent) can increase related substances of a product and further cause a stability problem, and the lower content cannot achieve the effect of internally controlled 90s internal disintegration (according to the characteristics of the dispersible tablet, the compliance of patients in use and the convenience of clinical application, the internal control screening index of an inventor is 90s internal disintegration, the disintegration time is easily accepted by patients and meets the industrialized requirement), so that auxiliary croscarmellose sodium is needed to be matched to achieve the stable and easily disintegrated function, the disintegration time of the product is prolonged on the contrary if the content of the croscarmellose sodium is too much, other disintegrants such as sodium carboxymethyl starch and the like can also cause the same problem, and therefore, a balanced proportion needs to be found to achieve the required standard.
In order to package a product by a medicinal plastic bottle, higher requirements are put forward on the hardness of a dispersion tablet, the hardness of the product can be improved by microcrystalline cellulose, but the disintegration and dispersion time of the product can be prolonged under the condition of improving the hardness by using too much microcrystalline cellulose, and the hardness and the compressibility of the product are adversely affected by using a little microcrystalline cellulose; conventional binders such as hypromellose, pregelatinized starch, etc. are used in slightly larger amounts which are detrimental to tablet strength and dissolution, while slightly smaller amounts may result in a lower hardness and lower content of the product. How to rapidly disintegrate and disperse the product without affecting the hardness of the product is an internationally recognized high-difficulty technical problem.
The filler, the adhesive and the disintegrant all affect the hardness and disintegration of the product, and the inventor screens and researches the filler, the adhesive and the disintegrant to find out the optimal proportion and screen out the optimal balance proportion which can meet the requirement, so that the product has higher hardness while ensuring the rapid disintegration, and the technical problem is perfectly solved.
In the pharmaceutical composition, the inventor selects the adhesive 'povidone' used, the specification model is k15 to k50, different k values respectively represent corresponding average molecular weight ranges, the higher the k value is, the higher the relative viscosity of the aqueous solution is, and the preferred model is k30;2.5mg-20mg tablet studies found that povidone is 1.0% to 3.0% by total weight, and preferably 1.5% when 10 mg/tablet.
The dosage of the sildenafil of the pharmaceutical composition is 2.5-50 mg/tablet, preferably 2.5-20 mg/tablet, and particularly preferably 10 mg/tablet.
In the above pharmaceutical composition, because of the reasons of the disintegrant and the characteristics of wet granulation, the pharmaceutical composition is divided into an internal addition component and an external addition component, wherein the internal addition component comprises sildenafil citrate, internal addition colloidal silicon dioxide, mannitol and povidone, and the rest is the external addition component, the internal addition colloidal silicon dioxide is preferably 0.5-2%, the external addition colloidal silicon dioxide is preferably 0.5-2%, further preferably 0.5-1.5%, particularly preferably 1-1.5% and 1-1.5%.
Further provided is a method for preparing the pharmaceutical composition, which comprises the following steps:
1) Sildenafil citrate, polyvidone, mannitol, and internal colloidal silicon dioxide, sieving, and mixing;
2) Adding purified water, granulating, sieving with soft material, and wet granulating;
3) Drying the wet granules to obtain dry granules, and performing dry granulation;
4) Adding the rest colloidal silicon dioxide, crospovidone, croscarmellose sodium, microcrystalline cellulose and a sweetening agent into the dried and granulated material, uniformly mixing, adding a lubricant, uniformly mixing, and tabletting to obtain the sildenafil citrate-containing pharmaceutical composition.
Further specifically, it is preferable that:
1) Sieving sildenafil citrate, polyvidone, mannitol and colloidal silicon dioxide, and mixing, wherein the sieve mesh range is 300-2000 um;
2) Adding purified water for granulation, sieving the prepared soft material for wet granulation, and sieving the granules in a sieve mesh range: 1000um to 9000um;
3) Wet granulating and drying, and dry granulating the prepared dry granules, wherein the sieve mesh range is as follows: 600um to 2000um;
4) Adding colloidal silicon dioxide, crospovidone, croscarmellose sodium, microcrystalline cellulose and a sweetening agent into the dry and granulated material, uniformly mixing, adding a lubricating agent, uniformly mixing, and tabletting to obtain the sildenafil citrate-containing pharmaceutical composition.
The preparation method adopts oven drying or fluidized bed drying for drying until the moisture is less than 5 percent, preferably less than 3 percent.
The invention further discloses application of the pharmaceutical composition in medicines for treating pulmonary hypertension.
The inventor carries out screening investigation on auxiliary materials such as an adhesive, a filling agent, a disintegrating agent and the like in order to break the barrier of import and reduce the cost of the medicine, finds that the content, disintegration, stability and hardness of the product are all caused by simply replacing the imported expensive auxiliary materials, and the quality requirement of the medicine is difficult to meet.
Meanwhile, the pharmaceutical composition is a tablet, and the content of sildenafil citrate in the tablet is 2.5-50 mg/tablet, preferably 2.5-20 mg/tablet, 5mg,10mg and 20mg according to sildenafil, so that the clinical requirements of patients in all ages can be met.
Detailed study screening the study procedure was as follows:
1. screening of adhesives
The tablet of the invention is a sildenafil citrate orally disintegrating tablet which is a product on the market with rapid disintegration
The inventor tries to remove the auxiliary material and replace the auxiliary material with a Chinese domestic adhesive auxiliary material to reduce the cost because polyvinyl acetate contained in the original medicine has no domestic pharmaceutic adjuvant and the price of the imported composite auxiliary material containing the polyvinyl acetate is high (650 yuan/kg). The conventional binding agents such as hypromellose, pregelatinized starch and the like are unfavorable for the strength and dissolution rate of tablets in slightly larger dosage, and the hardness and content of the product are reduced in slightly smaller dosage, so the conventional binding agents are not suitable for being used as ideal binding agents of tablets, therefore, the inventor selects povidone as an auxiliary material, draws up a formula 1 according to the conventional dosage of the auxiliary material, and selects povidone k30 (120 yuan/kg) with different proportions on the basis, and the formula is shown in table 1:
table 1: adhesive screening (20 mg/tablet)
By adopting a wet granulation process and fluidized bed drying, through tests, the inventor finds that the disintegration of the binder with the dosage of 3% is obviously slower than 1.5%, while the raw material medicine cannot be effectively bonded in the wet granulation process of the prescription with the dosage of 0.75%, so that the material loss in the drying process is more, the yield is reduced, the product content is reduced, the prescription without the binder (0%) has lower yield, and the prescription 2 with the proportion of 1.5% can effectively bond the povidone without influencing the disintegration time, so that the povidone with the dosage of 1.5% is finally selected as the binder to replace polyvinyl acetate, and the povidone with the model number of k15-k50 can meet the requirements, and particularly, the povidone with the model number of k30 is preferably selected.
However, in the process of stability investigation, the related substances of the product are greatly increased, and through the discovery of compatibility screening of raw and auxiliary materials (see the result of compatibility investigation of raw and auxiliary materials in table 2 for details), the crospovidone serving as the auxiliary material can promote the degradation of the product and make the product unstable.
Table 2: raw material and auxiliary material compatibility investigation result
2. Optimization and screening of disintegrants
TABLE 3 study of disintegrant formulations
In the early stage screening of the disintegrating agent, different types and different dosages of the disintegrating agent are inspected, the disintegrating agent has obvious influence on the disintegration time of a product, the more the croscarmellose sodium is used alone, the slower the disintegration is, and the requirement that the disintegration time is less than 90s cannot be met, although the disintegration performance of the product can be obviously improved by using only crospovidone, the stability of the product becomes poor when the dosage exceeds 8%, the quick disintegration effect cannot be achieved when the dosage is too low, and the combined application effect of the disintegrating agents is good; the compatibility research of raw materials and auxiliary materials shows that the crospovidone can promote the degradation of sildenafil citrate, in order to avoid the degradation of main drugs in the stability investigation process, the inventor places a disintegrant outside to be mixed, reduces the contact and interaction with the raw materials, can improve the stability of tablets on the premise of not influencing the disintegration performance, investigates the stability for 3 months under the acceleration condition (40 ℃, 75 percent RH), the oxidation impurity is less than LOQ, and the stability is good, so the disintegration performance is improved and the stability is improved through the process adjustment, the ratio of the croscarmellose sodium to the crospovidone is 1:1 and 1: at 1.5, the disintegration time is satisfactory, but the increase of crospovidone causes risks to the stability of the product, and formula 8 (7.5% crospovidone) has risks related to the increase of substances, so that the optimal formula further prefers formula 7, and finally the weight ratio of the disintegrant is determined as follows: 5% croscarmellose sodium and 5% crospovidone were combined.
Table 4 stability test results
The seventh formulation compressed tablets of different hardness and the corresponding disintegration time as shown, the higher the hardness, the longer the disintegration time, resulting in a slower disintegration dispersion. See figure 1.
In practical research, the disintegrant has an optimal dosage range which needs to be adjusted according to the specification of the tablet, the dosage of the 10mg specification tablet is preferably 3-8% of crospovidone, the dosage of the croscarmellose sodium is preferably 3-10%, and the dosage ratio is preferably 1:1, for 20 mg/tablet and even higher tablet, the total amount of disintegrant is preferably 5% -20%, within this range, the disintegration is fast (less than 90 seconds) even if the hardness reaches 40N-55N, which not only meets the requirement of hardness, but also has fast disintegration and dispersion effect.
3. Screening of the Filler proportions
The orally disintegrating tablet on the market is packaged by double aluminum, the cost is high, in order to reduce the industrialization cost, the inventor adopts a medicinal plastic bottle with lower price for packaging, which puts higher requirements on the hardness and friability of the tablet, so the inventor needs to further improve the hardness under the condition of not influencing the quality indexes such as the disintegration time, the stability and the like of the product, and through deep research, the inventor finds that the use amount of microcrystalline cellulose is increased, which is beneficial to improving the hardness of the tablet, but the disintegration time is prolonged, so the proportion of the microcrystalline cellulose and the mannitol needs to be screened to find the optimal proportion.
TABLE 5 screening of fillers
The microcrystalline cellulose in the prescription 10 has poor granulation effect when being added into the internal phase and longer disintegration time, so that the microcrystalline cellulose is completely added into the external phase, and the internal phase is only added with the mannitol filling agent for granulation. The proportion of microcrystalline cellulose to mannitol in formula 11, formula 12 and formula 13 is 1:0.5, 1:1.1, 1:0.5, formula 11 has a small proportion of mannitol as an inner phase filler, the granulation effect is poor, and the disintegration speed is slightly slow after the mannitol in formula 13 is increased, so formula 12 is preferred, and the disintegration is rapid on the premise of ensuring that the tablet has enough hardness to support the plastic bottle packaging and transportation stability, and the inventor selects the optimal proportion of 1:0.5 to 1:3, preferably 1:0.5 to 1:2, the hardness can reach 40N-55N, and finally the cost of the product is further reduced, and when the filler is screened, the phenomenon that the material is stuck to the wall is easily caused because no flow aid is added into the inner phase, so that the inventor carries out addition screening on the colloidal silicon dioxide.
4. Screening of glidants
The sildenafil citrate bulk drug has the characteristic of being sticky, the phenomenon of material wall sticking can often occur in the process of preparation, the product yield is reduced, and the content is reduced. Based on the formula 12, the detection results of the silicon dioxide samples with different proportions are as follows: (the measuring cylinder is sticky, which means that the blended materials are sticky, and the wall is sticky in a granulating pan, so that the risk of reducing the yield and the content of the product is caused, and the risk needs to be avoided as much as possible, which is also a requirement for industrialization.)
TABLE 6 screening of internal phase glidants
The internal phase 1% colloidal silica works well from a flow point of view, the final amount of internal phase colloidal silica being 0.5-1.5%, preferably 1.0%; the added colloidal silica is 0.5 to 1.5%, preferably 1.0%.
5. Screening of lubricant type and amount
In the process of process amplification, the phenomenon of sticking during tabletting is found, in order to realize smooth industrialization, the inventor screens the lubricant, and based on the formula 15, the investigation results of the lubricants with different types and dosage are as follows:
TABLE 7 screening of Lubricants
And (4) analyzing results: upon compression by a rotary tablet press, it was found that 3.0% sodium stearyl fumarate and 1.0% magnesium stearate had a slight sticking phenomenon, and that 1.5% magnesium stearate did not stick and disintegrated faster, so that magnesium stearate was selected as the lubricant in a proportion of 1.0% to 3.0%, preferably in a proportion of 1-1.5%.
6. Screening of sweeteners
The imported medicine is added with essence for covering the bitterness of sildenafil citrate and increasing the taste, the prices of the imported essence and the compound essence are expensive, 6 ten thousand yuan per bag is minimum, different essences and sweeteners are screened by the inventor, and through taste evaluation and stability investigation, the inventor finally adopts high-quality and low-price common sweeteners for taste correction, such as aspartame and sucralose, the price is less than 1 ten thousand yuan per bag, namely the bitterness of the main medicine is covered to make the taste better, the stability of the product is also increased (particularly the sucralose has less influence on the main medicine), and the cost of the product is reduced.
The existing published data have studied on the industrialization of sildenafil citrate tablets, but the disintegration property, the stability, the compressibility and the like can not be considered at the same time, so that the quality of the product in the industrialization process can not be ensured, and the consistency between batches and in batches is poor.
Therefore, the tablet and the preparation method thereof disclosed by the invention have the advantages that through experimental screening, the expensive imported auxiliary materials are successfully replaced by the auxiliary materials with low price in China, so that the cost of the product is greatly reduced, the quality of the product is not influenced, and through the prescription and process research, the hardness of the product is greatly improved while the product can be rapidly disintegrated and dispersed; through systematic and deep experimental study, the stability of the product is obviously improved through the improvement of the process; the method has the characteristics of high industrialization degree, simple process, stable quality, rapid disintegration and good taste, solves the defects of the existing product, greatly reduces the cost of the product, ensures that patients can achieve the same treatment effect without taking high-price imported medicines, and reduces the medication burden.
Drawings
FIG. 1 is a graph of hardness versus disintegration time.
Detailed Description
Example 1 (10 mg/tablet)
The preparation method comprises the following steps:
1. sildenafil citrate, povidone k30, mannitol and colloidal silicon dioxide are sieved by a 600um sieve and then added into a wet mixing granulator for premixing.
2. After the premixing is finished, adding water into a wet mixing granulator for granulation, and performing wet granulation on the prepared soft material by using a sieve pore with 8000 mu m.
3. And (3) drying: fluidized bed drying is adopted, and the water content of the material is controlled to be less than or equal to 3 percent.
4. And (4) carrying out dry granulation on the dried dry particles, and screening the particles with the mesh size of 1000 mu m.
5. Adding colloidal silicon dioxide, sucralose, crospovidone, croscarmellose sodium and microcrystalline cellulose into the dry and granulated material, and mixing uniformly by using a mixer.
6. Adding the materials into magnesium stearate, and mixing uniformly.
7. And (5) tabletting.
8. And (6) packaging.
The tablets with different hardness are pressed on a rotary tablet press by adopting different rotating speeds, and the detection results of the obtained product are as follows:
and (4) analyzing results: the disintegration time was slightly slower with increasing hardness, but when the hardness was in the range of 30N to 65N, the tablets were completely disintegrated within 90s and the friability was acceptable. The high-speed tabletting condition is almost unchanged compared with the low-speed tabletting condition, and the efficiency of tabletting in large-scale production is improved.
The tablet product has satisfactory product stability, as measured under the conditions of stability of 25 ℃/60% RH and 40 ℃/75% RH, as detailed below:
note: m is month, ND is not detected, and LOQ is the lowest detection limit.
The manufacturer information of the auxiliary materials used in the examples is as follows
Example 2 (5 mg/tablet)
The preparation method comprises the following steps:
1. sildenafil citrate, povidone k15, mannitol and colloidal silicon dioxide are sieved by a 850um sieve and then added into a wet mixing granulator for premixing.
2. After the premixing is finished, adding water into a wet mixing granulator for granulation, and carrying out wet granulation on the prepared soft material by using a 6000-micron sieve mesh.
3. And (3) drying: fluidized bed drying is adopted, and the moisture of the material is controlled to be less than or equal to 3 percent.
4. And (4) carrying out dry granulation on the dried dry particles, and screening the particles with the screen mesh aperture of 1200 mu m.
5. Adding colloidal silicon dioxide, essence, polyvinylpolypyrrolidone, croscarmellose sodium and microcrystalline cellulose into the dry whole grain material, and uniformly mixing by using a mixer.
6. Adding the materials into magnesium stearate, and mixing uniformly.
7. Tabletting, wherein the tablet range is 25-55N.
8. And (6) packaging.
Example 3 (20 mg/tablet)
The embodiment is prepared by increasing the proportion of the components on the basis of the embodiment 1, and the specification is as follows: 20 mg/tablet (calculated as sildenafil). The preparation method is the same as example 1.
Example 4 (20 mg/tablet)
The preparation method comprises the following steps:
1. sildenafil citrate, povidone k30, mannitol and colloidal silicon dioxide are sieved by a 1000um sieve and then added into a wet mixing granulator for premixing.
2. After the premixing, adding water into a wet granulator for granulation, and carrying out wet granulation on the prepared soft material by using a sieve pore with the size of 4000 mu m.
3. And (3) drying: fluidized bed drying is adopted, and the water content of the material is controlled to be less than or equal to 3 percent.
4. And (4) carrying out dry granulation on the dried dry particles, and screening the particles with the mesh aperture of 1500 mu m.
5. Adding colloidal silicon dioxide, crospovidone, aspartame, croscarmellose sodium and microcrystalline cellulose into the dry whole granule material, and mixing with a mixer.
6. Adding the materials into magnesium stearate, and mixing uniformly.
7. Tabletting, wherein the tablet range is 25-55N.
8. And (6) packaging.
Example 5 (15 mg/tablet)
The preparation method comprises the following steps:
1. sildenafil citrate, povidone k50, mannitol and colloidal silicon dioxide are sieved by a 400um sieve and then mixed.
2. Adding purified water, granulating, and wet-granulating with 6350 μm sieve.
3. And (3) drying: fluidized bed drying is adopted, and the moisture of the material is controlled to be less than or equal to 3 percent.
4. And (4) carrying out dry granulation on the dried dry particles, wherein the aperture of a sieve is 1575 mu m.
5. Adding colloidal silicon dioxide, sucralose, crospovidone, microcrystalline cellulose and croscarmellose sodium into the dried and granulated material, and uniformly mixing.
6. Adding the materials into magnesium stearate, and mixing uniformly.
7. Tabletting, wherein the tablet range is 25-55N.
8. And (6) packaging.
Example 6 (10 mg/tablet)
The preparation method is the same as example 1.
Claims (4)
1. A sildenafil citrate-containing pharmaceutical composition is characterized by comprising the following components in percentage by weight: 3-40% of sildenafil citrate, 1-2% of povidone, 3-7% of sweetening agent, 3-8% of crospovidone, 3-10% of croscarmellose sodium, 1-3% of colloidal silicon dioxide, 1-4% of lubricating agent and the balance of microcrystalline cellulose and mannitol, wherein the weight ratio of the microcrystalline cellulose to the mannitol is 1:0.5 to 1:3; the weight ratio of the crospovidone to the croscarmellose sodium is 1-1.5, and the lubricant is one or a mixture of more than one of magnesium stearate and sodium stearyl fumarate; the pharmaceutical composition comprises internal and external components, wherein the internal component comprises sildenafil citrate, internal colloidal silicon dioxide, mannitol and polyvidone, and the rest is the external component, wherein the internal colloidal silicon dioxide is 0.5-1.5%, and the external colloidal silicon dioxide is 0.5-1.5%;
the pharmaceutical composition is prepared by the following method:
1) Sildenafil citrate, polyvidone, mannitol, and internal colloidal silicon dioxide, sieving, and mixing;
2) Adding purified water for granulation, and sieving the prepared soft material for wet granulation;
3) Drying the wet granules to obtain dry granules, and performing dry granulation;
4) Adding the rest colloidal silicon dioxide, crospovidone, croscarmellose sodium, microcrystalline cellulose and sweetening agent into the dry and granulated material, uniformly mixing, adding a lubricant, uniformly mixing, and tabletting to obtain the sildenafil citrate-containing pharmaceutical composition.
2. The pharmaceutical composition of claim 1, wherein the weight ratio of microcrystalline cellulose to mannitol is 1:0.5 to 1:2.
3. the pharmaceutical composition according to any one of claims 1-2, wherein the pharmaceutical composition is a dispersible tablet having a dosage ranging from 2.5mg to 50mg per tablet, calculated as sildenafil.
4. The pharmaceutical composition according to claim 3, wherein the pharmaceutical composition is a dispersible tablet having a dosage range of 2.5mg to 20mg on a sildenafil basis per tablet.
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| CN114129528B (en) * | 2021-12-03 | 2023-03-24 | 上海金城素智药业有限公司 | Novel sildenafil citrate preparation with clinical advantages and preparation process and application thereof |
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| US20160213673A1 (en) * | 2015-01-27 | 2016-07-28 | Glanbia Nutritionals (Ireland) Limited | Endurance formulation and use |
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