CN109925293B - Eplerenone oral solid preparation and preparation method thereof - Google Patents
Eplerenone oral solid preparation and preparation method thereof Download PDFInfo
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- CN109925293B CN109925293B CN201910211403.3A CN201910211403A CN109925293B CN 109925293 B CN109925293 B CN 109925293B CN 201910211403 A CN201910211403 A CN 201910211403A CN 109925293 B CN109925293 B CN 109925293B
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Abstract
The invention discloses an eplerenone oral solid preparation which comprises the following components in percentage by weight: 10 to 35 percent of eplerenone, 0.5 to 5 percent of lauryl sodium sulfate, 50 to 80 percent of filling agent, 3 to 10 percent of disintegrating agent and 0.1 to 1.8 percent of lubricating agent. In addition, a preparation method is also disclosed. The oral solid preparation overcomes the problem of poor dissolution rate of the eplerenone oral solid preparation, and has excellent bioavailability.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an eplerenone oral solid preparation and a preparation method thereof.
Background
Eplerenone (Eplerenone) with the chemical name of (7 alpha, 11 alpha, 17 alpha) -9, 11-epoxy-17-hydroxy-3-oxo-pregn-4-ene-7, 21-dicarboxylic acid, gamma-lactone, 7-methyl ester and the chemical structural formula is shown as the formula (1):
eplerenone is an oral highly selective aldosterone receptor antagonist (SAB) that blocks the action of the renin-angiotensin-aldosterone system (RAAS) by competitively inhibiting aldosterone binding to mineralocorticoid receptors and antagonizing aldosterone binding to mineralocorticoid receptors in epithelial (e.g., kidney) and non-epithelial (e.g., heart, blood vessels, and brain) tissues plays an important role in regulating the function of the human cardiovascular system. Therefore, eplerenone can effectively control hypertension, relieve the damage of target organs such as heart, brain, kidney and the like, improve microalbuminuria of patients with type II diabetes, has similar side effect incidence rate to placebo and has good tolerance. Has important significance for controlling hypertension of hypertension patients, preventing cardiovascular diseases related to target organ damage, improving prognosis of hypertension patients and the like.
Eplerenone molecules contain no ionized structures and are almost insoluble in water, and eplerenone biopharmaceuticals is classified as BCS class III. Eplerenone has the characteristics of difficult water solubility and high permeability. Solid preparation prepared by conventional preparation process has low dissolution rate and low oral bioavailability (the eplerenone tablet reported by FDA and PMDA publications has in vivo bioavailability of only 69%), and CN1230179C and US20030215518A1 disclose micronized eplerenone pharmaceutical composition and EP1527782A1 disclose micronized nano eplerenone microparticle (D)90Less than 0.8 μm) into tablet, capsule, etc.
The technical means of micronization belongs to a general conventional method for improving the difficult-soluble drugs, and the bioavailability of the tablet prepared by adopting the technical means in a human body is up to 69 percent according to the PMDA public report. Although the in vitro dissolution rate and in vivo bioavailability of the slightly soluble drug can be improved to a certain extent by adopting a micronization technical means, the requirement on achieving excellent content uniformity required by mixing in a preparation process is higher due to the fact that the powder characteristics of the micronized material are greatly changed, the complexity of material control is increased, the difficulty is increased, the production convenience is reduced, and the cost is higher.
US2003236236a1 and CN101152187A disclose methods for increasing the dissolution of poorly soluble drugs by including a nonionic surfactant such as polysorbate or poloxamer, but the addition of a nonionic surfactant unnecessarily lowers the surface tension of the liquid relative to the drug which is readily wetted by water, and is detrimental to water penetration and tablet disintegration.
Disclosure of Invention
The inventor develops an eplerenone oral solid preparation, avoids using a hydrophilic adhesive and a nonionic surfactant, and overcomes the problem of poor dissolution rate of the eplerenone oral solid preparation.
The invention aims to provide an eplerenone oral solid preparation.
Another object of the present invention is to provide a method for preparing the above oral solid preparation.
Specifically, the invention provides an eplerenone oral solid preparation which comprises the following components in percentage by weight: 10 to 35 percent of eplerenone, 0.5 to 5 percent of lauryl sodium sulfate, 50 to 80 percent of filling agent, 3 to 10 percent of disintegrating agent and 0.1 to 1.8 percent of lubricating agent.
In an embodiment of the present invention, the eplerenone oral solid preparation provided by the present invention, wherein the filler may be one or more selected from lactose, microcrystalline cellulose, pregelatinized starch, mannitol, xylitol, and calcium hydrogen phosphate, preferably lactose and microcrystalline cellulose.
In an embodiment of the present invention, the eplerenone oral solid preparation provided by the present invention, wherein the disintegrant is one or more selected from the group consisting of croscarmellose sodium, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, and crospovidone, preferably croscarmellose sodium or low substituted hydroxypropyl cellulose.
In an embodiment of the present invention, the eplerenone oral solid preparation provided by the present invention, wherein the lubricant is selected from magnesium stearate, calcium stearate, sodium fumarate stearate, or stearic acid, preferably magnesium stearate or sodium fumarate stearate.
In an embodiment of the present invention, there is provided an oral solid formulation of eplerenone wherein eplerenone is formulated with sodium lauryl sulfate and water as a suspension, and the suspension is then added to a pre-blend of a filler and a disintegrant.
In the embodiment of the invention, the eplerenone oral solid preparation provided by the invention is prepared by mixing the lauryl sodium sulfate and water in a weight ratio of 1: 4-1: 150; preferably 1:7 to 1: 50.
In some embodiments, the eplerenone oral solid preparation provided by the present invention comprises the following components by weight: 10% -35% eplerenone, 0.5% -5% sodium lauryl sulfate, 50% -80% filler, 3% -10% croscarmellose sodium, and 0.1% -1.8% magnesium stearate, where the filler is microcrystalline cellulose and lactose: wherein the weight ratio of the microcrystalline cellulose to the lactose is 1:0.1-1: 10.
In some embodiments, the lactose can be lactose monohydrate or lactose anhydrous.
On the other hand, the invention provides a preparation method of the eplerenone oral solid preparation, which comprises the following steps:
(1) preparing a suspension
Dissolving sodium dodecyl sulfate in water, suspending eplerenone in the water, heating and stirring at 30-50 ℃, and carrying out ultrasonic treatment;
(2) premixing
Uniformly mixing the filler and the disintegrant to obtain a premix;
(3) granulating and straightening
Adding the suspension obtained in the step (1) into the premix obtained in the step (2) to prepare a soft material, and sieving the soft material to granulate; drying and granulating to obtain dry granules;
(4) total mixing
And (4) adding a lubricant into the dry particles obtained in the step (3), and uniformly mixing.
In an embodiment of the present invention, the present invention provides a preparation method, further comprising the steps of tabletting and coating, or further comprising the step of filling and making into capsules.
The eplerenone oral solid preparation does not need to be subjected to special micronization treatment on raw material medicines so that the particle size of API is reduced to D90Under the condition of less than 120 mu m and without using water-soluble polymer auxiliary materials, the eplerenone oral solid preparation with high dissolution and excellent bioavailability is obtained.
Detailed Description
The invention is further described below by way of examples. It will be apparent to those skilled in the art that equivalent modifications of the following examples using prior art teachings are within the scope of the present invention.
Dissolution apparatus: paddle method
Rotating speed: 50rpm
Dissolution medium: 0.1mol/L hydrochloric acid
Volume of dissolution medium: 1000ml
Sampling time points are as follows: 5. 10, 15, 20, 30, 45 and 60min
Sampling volume: 7ml (Filter membrane filtration, discarding the initial filtrate, taking the subsequent filtrate as the test solution)
UV method, measurement wavelength: 245nm
Example 1
Eplerenone tablet
(1) Suspension prescription and preparation method (API + SDS)
The prescribed amount of sodium dodecyl sulfate is dissolved in the prescribed amount of purified water, after complete dissolution, the prescribed amount of eplerenone is added and suspended in the solution, stirred at 40 ℃ for 1h, and the suspension is again sonicated for 1 h.
(2) Premixing
Uniformly mixing the microcrystalline cellulose, the anhydrous lactose and the croscarmellose sodium according to the prescription amount to obtain the premix.
(3) Granulating, drying and grading
Slowly and uniformly adding the suspension obtained in the step (1) into the premix to prepare a soft material, and granulating through a 40-mesh screen. Drying in a forced air drying oven at 55 +/-5 ℃ until the moisture is within the range of 2-3 percent. Taking out the granules, and sieving with 80 mesh sieve to obtain dry granules.
(4) Total mixing
Adding additional auxiliary material magnesium stearate 1.5 mg/tablet, and mixing uniformly.
(5) Tabletting
The tablet hardness is 4-9 kg.
(6) Coating film
Dispersing Opadry (Y-1-7000) in water, stirring, and sieving with 80 mesh sieve to obtain coating solution. Putting the tablet core into a coating pan, controlling the rotation speed of the coating pan at 3-14rpm, the temperature of the tablet bed at 35-55 deg.C, the air intake temperature at 50-85 deg.C, the spray rotation speed at 20-60rpm, increasing the weight of the coating by about 4%, cooling the temperature in the coating pan to below 40 deg.C after coating, and taking out the tablet.
Example 2
Eplerenone tablet
(1) Suspension prescription and preparation method (API + SDS)
The prescribed amount of sodium dodecyl sulfate is dissolved in the prescribed amount of purified water, after complete dissolution, the prescribed amount of eplerenone is added and suspended in the solution, stirred at 40 ℃ for 1h, and the suspension is again sonicated for 1.5 h.
(2) Premixing
Uniformly mixing the microcrystalline cellulose, the lactose monohydrate and the croscarmellose sodium according to the prescription amount to obtain the premix.
(3) Granulating, drying and grading
Slowly and uniformly adding the suspension obtained in the step (1) into the premix to prepare a soft material, and granulating through a 40-mesh screen. Drying the mixture in a fluidized bed at 50-70 ℃ until the water content is within the range of 2% -3%. Taking out the granules, and sieving with 80 mesh sieve to obtain dry granules.
(4) Total mixing
Adding additional auxiliary material magnesium stearate 1.0 mg/tablet, and mixing uniformly.
(5) Tabletting
The tablet hardness is 5-10 kg.
(6) Coating film
Dispersing Opadry (14F1200) in water, stirring uniformly, and sieving with 80 mesh sieve to obtain coating solution. Putting the tablet core into a coating pan, controlling the rotation speed of the coating pan at 3-14rpm, the temperature of the tablet bed at 35-55 deg.C, the air intake temperature at 50-85 deg.C, the spray rotation speed at 20-60rpm, increasing the weight of the coating by about 4%, cooling the temperature in the coating pan to below 40 deg.C after coating, and taking out the tablet.
Example 3
Eplerenone tablet
(1) Suspension prescription and preparation method (API + SDS)
The prescribed amount of sodium dodecyl sulfate is dissolved in the prescribed amount of purified water, after complete dissolution, the prescribed amount of eplerenone is added and suspended in the solution, stirred at 40 ℃ for 1h, and the suspension is again sonicated for 1.5 h.
(2) Premixing
Uniformly mixing the microcrystalline cellulose, the lactose monohydrate and the croscarmellose sodium according to the prescription amount to obtain the premix.
(3) Granulating, drying and grading
Slowly and uniformly adding the suspension obtained in the step (1) into the premix to prepare a soft material, and granulating through a 40-mesh screen. Drying the mixture in a fluidized bed at 50-70 ℃ until the water content is within the range of 2% -3%. Taking out the granules, and sieving with 80 mesh sieve to obtain dry granules.
(4) Total mixing
Adding additional adjuvant magnesium stearate 0.5 mg/tablet, and mixing well.
(5) Tabletting
The tablet hardness is 2-7 kg.
(6) Coating film
Dispersing Opadry (15B130004) in water, stirring uniformly, and sieving with 80 mesh sieve to obtain coating solution. Putting the tablet core into a coating pan, controlling the rotation speed of the coating pan at 3-14rpm, the temperature of the tablet bed at 35-55 deg.C, the air intake temperature at 50-85 deg.C, the spray rotation speed at 20-60rpm, increasing the weight of the coating by about 4%, cooling the temperature in the coating pan to below 40 deg.C after coating, and taking out the tablet.
Comparative example 1:
the eplerenone tablets were prepared using the preparation method of "micronized eplerenone compositions" disclosed in CN 1230179C.
Prescription:
the preparation method comprises the following steps:
1. micronizing eplerenone (D)90About 60 mu m) and lactose monohydrate, microcrystalline cellulose, hydroxypropyl methylcellulose and lauryl sodium sulfate are evenly mixed, water is added to prepare soft materials, and the soft materials are screened by a 40-mesh screen to prepare wet particles;
2. and (3) placing the wet granules in a 55 ℃ oven to be dried until the drying weight loss is less than 2%, taking out the granules, and sieving the granules by a 40-mesh sieve to complete the granules.
3. Adding croscarmellose sodium, pulvis Talci, and magnesium stearate into the dry granules, mixing, and tabletting to obtain tablet with hardness of 5-10kg and weight of 170 mg.
Comparative example 2:
the eplerenone tablet is prepared by adopting the preparation method of the eplerenone pharmaceutical composition disclosed in CN 101152187A.
Prescription:
the preparation method comprises the following steps:
1. respectively crushing the auxiliary materials and sieving the crushed auxiliary materials with a 100-mesh sieve;
2. fully and uniformly mixing eplerenone, mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose and poloxamer 338, adding a proper amount of polyvinylpyrrolidone aqueous solution to prepare a soft material, and granulating with a 20-mesh sieve;
3. placing the wet granules in a 55 ℃ oven to be dried until the drying weight loss is less than 2%, taking out the granules, and finishing the granules by using a 20-mesh sieve;
4. adding crosslinked polyvinylpyrrolidone and magnesium stearate into the dry granules, mixing, and tabletting to obtain tablet with hardness of 8-15kg and weight of 250 mg.
Comparison of dissolution results
The invention overcomes the defect that the particle size of the raw material medicine must be controlled before the preparation process of the solid preparation, and the particle size of the raw material medicine is controlled to be less than 60 mu m by micronization to achieve good dissolution effect, thereby realizing the requirement of good bioavailability in vivo.
According to the invention, the eplerenone raw material medicine is not required to be subjected to special micronization treatment to be controlled to a very fine particle size, a complex process for preparing hydrophilic active substance particles is not required, an API + SDS suspension is prepared by heating, stirring and ultrasonic dispersion methods of SDS and API, the suspension is added into other auxiliary material mixtures for wet granulation and drying, and is sieved by an 80-mesh screen, granulated, tabletted and coated. The method can greatly improve the dissolution speed of the solid preparation, and the dissolution speed reaches more than 85% in 5min and more than 90% in 10 min; the bioavailability of the solid preparation in beagle dogs is more than 80%.
Claims (12)
1. An eplerenone oral solid preparation, which consists of the following components in percentage by weight: 10 to 35 percent of eplerenone, 0.5 to 5 percent of sodium dodecyl sulfate, 50 to 80 percent of filling agent, 3 to 10 percent of disintegrating agent and 0.1 to 1.8 percent of lubricating agent; wherein, the preparation method of the oral solid preparation comprises the steps of preparing a suspension of eplerenone, sodium dodecyl sulfate and water, and adding the suspension into a pre-mixture of a filling agent and a disintegrating agent to prepare a soft material.
2. The oral solid preparation of claim 1, wherein the filler is one or more selected from lactose, microcrystalline cellulose, pregelatinized starch, mannitol, xylitol, and calcium hydrogen phosphate.
3. The oral solid preparation of claim 2, wherein the filler is lactose and microcrystalline cellulose.
4. The oral solid preparation of claim 1, wherein the disintegrant is one or more selected from the group consisting of croscarmellose sodium, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, and crospovidone.
5. The oral solid preparation of claim 4, wherein the disintegrant is croscarmellose sodium or low substituted hydroxypropylcellulose.
6. The oral solid preparation of claim 1, wherein the lubricant is selected from magnesium stearate, calcium stearate, sodium fumarate stearate, or stearic acid.
7. The oral solid preparation of claim 6, wherein the lubricant is magnesium stearate or sodium fumarate stearate.
8. The oral solid preparation according to any one of claims 1 to 7, wherein the weight ratio of the sodium lauryl sulfate to water is 1:4 to 1: 150.
9. The oral solid preparation of claim 8, wherein the weight ratio of the sodium lauryl sulfate to the water is 1:7 to 1: 50.
10. The oral solid preparation of claim 1, which consists of the following components in percentage by weight: 10% -35% eplerenone, 0.5% -5% sodium lauryl sulfate, 50% -80% filler, 3% -10% croscarmellose sodium, and 0.1% -1.8% magnesium stearate, where the filler is microcrystalline cellulose and lactose: optionally, the microcrystalline cellulose to lactose weight ratio is from 1:0.1 to 1: 10.
11. A method for producing the oral solid preparation according to any one of claims 1 to 10, comprising the steps of:
(1) preparing a suspension
Dissolving sodium dodecyl sulfate in water, suspending eplerenone therein, heating and stirring at 30-50 ℃, and carrying out ultrasonic treatment;
(2) premixing
Uniformly mixing the filler and the disintegrant to obtain a premix;
(3) granulating and straightening
Adding the suspension obtained in the step (1) into the premix obtained in the step (2) to prepare a soft material, and sieving the soft material to granulate; drying and granulating to obtain dry granules;
(4) total mixing
And (4) adding the disintegrating agent into the dry granules obtained in the step (3), and uniformly mixing.
12. The method of claim 11, further comprising tableting and coating, or further comprising filling and making into capsules.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| PT1175220E (en) * | 1999-12-08 | 2005-07-29 | Pharmacia Corp | EPLERENONE COMPOSITIONS IN NANOPARTICLES |
| US20020132001A1 (en) * | 2000-05-11 | 2002-09-19 | Garthwaite Susan M. | Aldosterone antagonist composition for release during aldosterone acrophase |
| TR201007653A2 (en) * | 2010-09-20 | 2012-04-24 | Bi̇lgi̇ç Mahmut | Pharmaceutical composition containing eplerenone |
| CN105362242B (en) * | 2015-12-10 | 2019-04-26 | 合肥久诺医药科技有限公司 | A kind of eplerenone dispersible tablet |
| CN107019679A (en) * | 2017-03-27 | 2017-08-08 | 北京万全德众医药生物技术有限公司 | A kind of eplerenone tablet and preparation method thereof |
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