CN113750069A - Nifedipine sustained release tablet and preparation method thereof - Google Patents
Nifedipine sustained release tablet and preparation method thereof Download PDFInfo
- Publication number
- CN113750069A CN113750069A CN202111316687.6A CN202111316687A CN113750069A CN 113750069 A CN113750069 A CN 113750069A CN 202111316687 A CN202111316687 A CN 202111316687A CN 113750069 A CN113750069 A CN 113750069A
- Authority
- CN
- China
- Prior art keywords
- sustained
- nifedipine
- release
- viscosity
- release material
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Classifications
-
- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Abstract
The invention discloses a nifedipine sustained release tablet and a preparation method thereof, which use a drug release mechanism different from that of a reference preparation, realize the stable release of the drug within 24 hours by compounding high polymer sustained release materials with different viscosities on the premise of reducing the dosage of the sustained release materials, have the biological equivalence with the original drug, are easy for commercial production, reduce the production cost and lighten the drug burden of patients.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations. In particular to a nifedipine sustained-release tablet for treating hypertension and angina and a preparation method thereof.
Background
Nifedipine, a dihydropyridine calcium ion antagonist, is a medicament for treating hypertension and angina pectoris, is developed and marketed by German Bayer company in the 20 th century and the 70 th era, and is fully determined in safety and curative effect after years of clinical use, so that the nifedipine is still one of the first-choice medicaments for clinically treating hypertension and angina pectoris at present.
Pharmacokinetics shows that the biological half-life period of the ordinary nifedipine tablet is relatively short, the fluctuation of the blood concentration is large, compared with the ordinary preparation, the nifedipine sustained-release preparation can slowly release the medicament in vivo, the blood concentration is relatively stable, the peak valley phenomenon is reduced, the side effect is light, and the medicament taking compliance of a patient is also better. Therefore, the common formulation of nifedipine has been gradually replaced internationally by the slow-release agent of nifedipine.
The original research pharmaceutical company Bayer developed a nifedipine sustained-release preparation Adalat based on the nifedipine core-spun tablet technology® CC (30 mg, 60mg, 90 mg), was approved by the US FDA in 1993 at 4 months, and its clinical safety and efficacy have been well verified. Adalat® CC is a pressed core-spun tablet middle tablet, which consists of an external pressed coating layer containing slow-release medicine and an internal tablet core containing rapid-release medicine, and both layers contain nifedipine active ingredients. Adalat® The elimination half-life of CC was approximately 7 hours, whereas that of the conventional immediate release formulation was 2 hours. Compared with the common immediate-release nifedipine, the nifedipine Adalat is taken under the condition of empty stomach® CC can reduce the fluctuation of blood concentration. Originally ground nifedipine sustained release preparation Adalat® CC and its imitation drugs are not on the market at present.
Adalat of original drug® The CC adopts a core-spun sheet technology. The core-spun sheet is a double-layer sheet structure consisting of an inner layer and an outer layer, and is different from the conventional double-layer sheet in that the structure is in the form of the inner layer and the outer layer instead of the upper layer and the lower layer. Usually, the inner core of the core-spun tablet is pre-pressed into a tablet, and then the tablet is filled by a secondary material, and secondary pressing is finished on a special tablet pressAnd (5) preparing. The core-spun tablet has relatively complex pressing process and has the problem of positioning of the tablet core, and a tablet lacking the tablet core can also appear in the tabletting process. Because the production link of the process is long, the core-spun tabletting equipment is expensive, and the manufacturing cost of the final product is relatively high.
Disclosure of Invention
The invention adopts Adalat® CC different drug release mechanisms, two high molecular polymers with different viscosity grades are selected as sustained-release framework materials, and nifedipine sustained-release tablets with stable quality and dosage of 30mg, 60mg and 90mg are prepared. Through the compounding of the two sustained-release materials with different viscosity grades, the viscosity of intermediate degree is realized, the physical property of the skeleton is improved, the strength of the gel layer after the hydration of the polymer is enhanced, the consistency of erosion is obtained, the optimal release effect is achieved, the drug release process is stable, the complete release within 24 hours can be ensured, and the necessary blood drug concentration can be maintained, and the drug can be taken only once a day. Adalat as specified in orange book of America® CC (30 mg, 60mg and 90 mg) is a reference preparation, and the nifedipine sustained-release tablet disclosed by the invention has bioequivalence with the original powder through a preliminary test study on the fasting bioequivalence of a human body.
On one hand, the application provides a nifedipine sustained release tablet, which comprises the following components: 10 to 30 percent of nifedipine, 15 to 60 percent of slow release material composition, 25 to 55 percent of diluent and 0.5 to 1 percent of lubricant, wherein the sum of the dosage of each component is 100 percent. The weight of the sustained release tablet coating is calculated separately and the weight gain of the coating is calculated relative to the total weight of the core.
In some embodiments, nifedipine is preferably used in an amount of 10%, 20% or 30%. The content of the preparation in unit dosage is 30mg, 60mg, 90 mg.
In some embodiments, the amount of the sustained-release material composition is preferably 30 to 45%, and the specific amount may be selected from 30%, 35%, and 40%.
In some embodiments, the high viscosity slow release material has a nominal viscosity in the range of 2700-. The nominal viscosity range of the high-viscosity slow-release material is selected from 2700-5040 mPa.s, 3000-5600 mPa.s, 5000-49000mPa.s, 13000-28000mPa.s, 13500-25200mPa.s, 15000-25000mPa.s or 26250-49000 mPa.s. The nominal viscosity range of the low-viscosity slow-release material is selected from 80-2100mPa.s, 80-120mPa.s, 200-300mPa.s, 150-1500mPa.s, 250-1250mPa.s, 350-1150mPa.s, 450-1100mPa.s or 562-1050 mPa.s.
In some embodiments, the nominal viscosity value after formulation of the high viscosity sustained release material and the low viscosity sustained release material is 1400-3500 mPa.s, preferably 1800-3500 mPa.s.
The post-compounding nominal viscosity value can be used to calculate the viscosity value of two materials after compounding using the phillips of formula: v1/8 = X1*V1 1/8 +X2*V2 1/8 . Wherein V is the viscosity after compounding, X1And X2 Respectively the weight fractions of the two materials, V1And V2The viscosity values of the two materials are respectively.
In some embodiments, the sustained release material composition is composed of two different viscosity grades of polymeric sustained release materials, wherein the amount of the high viscosity sustained release material is 5% to 25%, preferably, 10%, 11%, 12%, 13%, 14% or 15% of the total prescribed amount. The amount of low viscosity sustained release material is 10% to 35%, preferably 20%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35% of the total prescribed amount.
In some embodiments, the high viscosity sustained release material is used in an amount of 10% to 13% of the total prescribed amount. The dosage of the low-viscosity slow release material is 27 to 30 percent of the total prescription amount.
In some embodiments, the particle size D of nifedipine90At 10-25 μm. The nifedipine belongs to low-solubility high-permeability medicines (BCS 2), and the dissolution rate of the nifedipine in the sustained-release tablet is improved by controlling the particle size of the nifedipine and increasing the specific surface area.
In some embodiments, the high viscosity sustained release material is one or more of hydroxyethylcellulose, hydroxypropylmethylcellulose, methylhydroxyethylcellulose.
In some embodiments, the low viscosity sustained release material is one or more of hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose.
In some embodiments, the high viscosity hydroxypropylmethylcellulose is present in an amount of 10% to 13% of the total formula amount. The dosage of the low-viscosity hydroxypropyl methylcellulose accounts for 27-30% of the total prescription amount.
In some embodiments, the high viscosity hydroxypropylmethylcellulose is selected from HPMC K4M, HPMC K15M, or HPMC K35M; the respective nominal viscosity values correspond to 2700 and 5040 mPa.s, 13500 and 25200 and 26250 and 49000mPa.s, respectively. Such as BenecelTM HPMC K15M Pharm XR。
In some embodiments, the low viscosity hydroxypropylmethylcellulose is selected from HPMC K100LV, HPMC K250, or HPMC K750; the respective nominal viscosity values correspond to 80-120mPa.s, 200-300mPa.s and 562-1050mPa.s respectively. Such as BenecelTM HPMC K750 PH PRM。
In some embodiments, the diluent comprises one or more of lactose, dextrin, microcrystalline cellulose, starch. A combination of lactose and microcrystalline cellulose is preferred.
In some embodiments, the diluent is used in an amount of 25% to 55%, preferably 29.5%, 39.5, 49.5%.
In some embodiments, the diluent is 20-35% lactose and 9-20% microcrystalline cellulose. Wherein the lactose is present in an amount selected from 20%, 26.5%, or 33.5% and the microcrystalline cellulose is present in an amount selected from 9.5%, 13%, or 16%.
In some embodiments, the lubricant is one or more of magnesium stearate, stearic acid, talc.
In some embodiments, the nifedipine sustained release tablets are opadry color coated. The light stability research shows that the opadry color coating has the weight gain of not less than 6 percent and has better product protection. The opadry coating is any one of yellow, brown, orange, purple, pink and red in color.
On the other hand, the invention provides a preparation method of the nifedipine sustained-release tablet. The preparation process of the invention is simple and controllable, is easy for commercial production, and overcomes the defects that the original development core-spun tablet has longer production link, needs special tabletting equipment, and possibly has the defects of tablet core shortage in tablet core positioning and tablets.
The preparation method of the nifedipine sustained release tablet comprises the following steps:
step 1: controlling particle diameter D of nifedipine bulk drug90In the range of 10-25 um;
step 2: mixing nifedipine bulk drug, slow release material combination and diluent, and performing wet granulation by using water as a wetting agent;
and step 3: drying the wet granules in a fluidized bed and sieving the dried wet granules with a 18-mesh sieve;
and 4, step 4: finishing the grains;
and 5: mixing the granules with a lubricant and tabletting, wherein the tablet core weight is 300 mg per tablet;
step 6: and carrying out color coating on the tablet core, wherein the weight gain of the coating is not less than 6%.
During the preparation process, for example, an illumination device is used, and the wavelength of an illumination light source is 577-770 nm.
In some embodiments, the drying process described in step 3) employs fluidized bed drying, heating to a material temperature of 55 ℃, and maintaining for 10-20 minutes until the loss on drying is no greater than 3.0%.
In some embodiments, the core hardness produced in step 5) is no more than 1.0% friability at 70-130N.
In some embodiments, the coating of the opadry in step 6) is prepared by coating an aqueous suspension of opadry in any one of yellow, brown, orange, purple, pink and red.
Definition of
The term "%" refers to weight percent relative to the total weight of the uncoated tablet core. Unless specifically defined herein. For example, an opadry color coating weight gain of not less than 6% means a 6% weight gain relative to the total weight of the core after drying of the coating.
The term "total prescribed amount" refers to the prescribed amount of the core of the extended release tablet, excluding the weight of the coating layer. For example, a high viscosity hydroxypropylmethylcellulose amount of 10% to 13% of the total prescribed amount means that the high viscosity hydroxypropylmethylcellulose amount is 10% to 13% of the total tablet core weight.
Numerical values used herein include, in addition to the numerical values themselves, the measurement or operational error ranges acceptable in the art. The error range of the present application may be selected to be ± 10% of a specific numerical value, unless otherwise specifically defined.
Advantageous effects
The invention has the following advantages:
(1) according to the invention, through compounding of the high-molecular sustained-release materials with different viscosities, the viscosity of the intermediate degree is realized, the physical property of the framework is improved, the strength of the gel layer after the hydration of the polymer is enhanced, the erosion consistency is obtained, the stable release of the medicine within 24 hours is realized on the premise of reducing the dosage of the sustained-release materials, and the necessary blood concentration is maintained, and the medicine is only required to be taken once every day.
(2) The nifedipine sustained-release tablet has simple production process, stable product quality and easy commercial production, and overcomes the defects of complex process, longer production link, need of special tabletting equipment, tablet core positioning and possible tablet core shortage of the original tablet.
(3) The nifedipine sustained-release tablet disclosed by the invention is researched on the release degree and related substances, and the detection result shows that the nifedipine sustained-release tablet prepared by the invention has good stability and stable product quality.
(4) The nifedipine sustained-release tablet is prepared by adopting conventional pharmacy, all solvents used in the production process are purified water, PVP (polyvinyl pyrrolidone) containing ethanol as a wetting agent is not used as an adhesive, any organic solvent is not required, and the process is safe and environment-friendly.
(5) The nifedipine sustained-release tablet provided by the invention is preliminarily proved to have biological equivalence with a reference preparation through biological equivalence pre-test research. At present, Adalat is not available in China® The invention provides a nifedipine sustained-release tablet and a preparation method thereof, and fills the blank of the product in the domestic field of simulated pharmacy.
Drawings
FIG. 1 shows the nifedipine sustained release tablets and the reference preparation Adalat in example 1 and comparative examples 1 to 3® A CC release profile;
FIG. 2 shows comparative examples 1-2 and reference formulation Adalat® Time-of-drug profile of CC (90 mg) in fasting condition;
FIG. 3 shows Adalat, a reference formulation, example 1® Time-of-drug profile of CC (90 mg) in fasting condition;
fig. 4 is a graph showing the release rate profiles of example 2 (90 mg nifedipine sustained release tablet), example 3 (60 mg nifedipine sustained release tablet) and example 4 (30 mg nifedipine sustained release tablet).
Detailed Description
The dosage of nifedipine sustained release tablets of 30mg, 60mg and 90mg and the preparation process thereof are further illustrated and described below with reference to the following examples and the accompanying drawings, and it should be noted that the scope of the present invention is not limited by the following examples. Modifications and improvements within the scope of the invention as determined by one skilled in the art without departing from the scope of the invention as set forth in the following claims are intended to be within the full scope of the invention.
The raw materials and auxiliary materials used in the invention are all commercially available.
Hydroxypropyl methylcellulose A, BenecelTMHPMC K750 PH PRM, nominal viscosity value in the range of 562-1050 mPa.s.
Hydroxypropyl methylcellulose B, BenecelTMHPMC K15M Pharm XR, nominal viscosity values in the range of 13500-25200 mPa.s.
Hydroxypropyl methylcellulose BenecelTMHPMC K250 PH PRM, nominal viscosity values in the range of 200-300 mPa.s.
The reference formulation was Adalat CC (90 mg).
For BenecelTMHPMC is described in: https:// www.ashland.com/file _ source/Ashland/Industries/Pharmaceutical/Links/PHA17-1002_ Pharma _ Product _ grades.pdf.
Example 1
A nifedipine sustained-release tablet (90 mg dose) prescription and a preparation method thereof:
the preparation process comprises the following steps:
prescription amounts of lactose, hydroxypropyl methylcellulose, nifedipine (D)90: 10-25um) and microcrystalline cellulose are sequentially added into a high-efficiency wet granulator, and a proper amount of purified water is sprayed for wet granulation. Drying the wet granules in a fluidized bed, and sieving with a 18-mesh sieve for size stabilization; mixing the granules and magnesium stearate in a mixer, and tabletting with a high-speed rotary tabletting machine, wherein the weight of each tablet core is 300 mg theoretically, the tablet hardness is controlled to be 70-130N, and the friability is not more than 1.0%; preparing opadry color coating powder into suspension with purified water, coating in a high-efficiency coating pan, and controlling the air outlet temperature of coating at 38-44 ℃. After spraying, the air outlet temperature is increased to 50 ℃ and drying is carried out for 30 minutes, and finally the weight of the Opadry color coating is increased to be not less than 6.0%.
Example 2
A nifedipine sustained-release tablet (90 mg dose) prescription and a preparation method thereof:
the preparation process of the nifedipine sustained release tablet (90 mg dose) is similar to that of example 1. The difference from the embodiment 1 is that the dosage of the hydroxypropyl methylcellulose A used as the release regulator in the prescription is reduced to 27 percent from 30 percent in the original embodiment 1, and the dosage of the hydroxypropyl methylcellulose B used as the release retardant is improved to 13 percent from 10 percent in the original embodiment 1. Others remain unchanged.
Example 3
A nifedipine sustained-release tablet (60 mg dose) prescription and a preparation method thereof:
the preparation process comprises the following steps:
prescription amounts of lactose, hydroxypropyl methylcellulose, nifedipine (D)90: 10-25um) and then sequentially added into a high-efficiency wet granulator, and a proper amount of purified water is sprayed for wet granulation. Will wetDrying the granules in a fluidized bed, and sieving with a 18-mesh sieve for finishing; mixing the granules and magnesium stearate in a mixer, and tabletting with a high-speed rotary tabletting machine, wherein the weight of each tablet core is 300 mg theoretically, the tablet hardness is controlled to be 70-130N, and the friability is not more than 1.0%; preparing opadry color coating powder into suspension with purified water, coating in a high-efficiency coating pan, and controlling the air outlet temperature of coating at 38-44 ℃. After spraying, the air outlet temperature is increased to 50 ℃ and drying is carried out for 30 minutes, and finally the weight of the Opadry color coating is increased to be not less than 6.0%.
Example 4
A nifedipine sustained-release tablet (30 mg dose) prescription and a preparation method thereof:
the preparation process comprises the following steps:
prescription amounts of lactose, hydroxypropyl methylcellulose, nifedipine (D)90: 10-25um) and then sequentially added into a high-efficiency wet granulator, and a proper amount of purified water is sprayed for wet granulation. Drying the wet granules in a fluidized bed, and sieving with a 18-mesh sieve for size stabilization; mixing the granules and magnesium stearate in a mixer, and tabletting with a high-speed rotary tabletting machine, wherein the weight of each tablet core is 300 mg theoretically, the tablet hardness is controlled to be 70-130N, and the friability is not more than 1.0%; preparing yellow Opadry coating powder into suspension with purified water, coating in a high-efficiency coating pan, and controlling the air outlet temperature of coating at 38-44 deg.C. After spraying, the air outlet temperature is increased to 50 ℃ and drying is carried out for 30 minutes, and finally the weight gain of the coating is not less than 6.0%.
Comparative example 1
A nifedipine sustained-release tablet (90 mg dose) prescription and a preparation method thereof:
prescription amounts of lactose, hydroxypropyl methylcellulose, nifedipine (D)90: 10-25um) are added into a high-efficiency wet granulator in sequence, and a proper amount of pure water is sprayedDissolving water for wet granulation. Drying the wet granules in a fluidized bed, and sieving with a 18-mesh sieve for size stabilization; mixing the granules and magnesium stearate in a mixer, and tabletting with a high-speed rotary tabletting machine, wherein the weight of each tablet core is 300 mg theoretically, the tablet hardness is controlled to be 70-130N, and the friability is not more than 1.0%; preparing the Opadry coating powder into suspension with purified water, coating in a high-efficiency coating pan, and controlling the air outlet temperature of the coating at 38-44 ℃. After spraying, the air outlet temperature is increased to 50 ℃ and drying is carried out for 30 minutes, and finally the weight gain of the coating is not less than 6.0%.
Comparative example 2
A nifedipine sustained-release tablet (90 mg dose) prescription and a preparation method thereof:
the preparation process of the nifedipine sustained release tablet is similar to that of comparative example 1. Compared with the comparative example 1, the difference is that the dosage of the sustained-release material hydroxypropyl methylcellulose in the prescription is increased by 10 percent compared with the comparative example 1. Meanwhile, the dosage of the diluent lactose is correspondingly adjusted, namely reduced by 10 percent.
Comparative example 3
A nifedipine sustained-release tablet (90 mg dose) prescription and a preparation method thereof:
the preparation process of the nifedipine sustained release tablet is similar to that of comparative example 2. The difference from the comparative example 2 is that the diluent consists of 9.5 percent and 20 percent of lactose and microcrystalline cellulose according to the prescription amount respectively, and the sustained-release material consists of hydroxypropyl methyl cellulose A and hydroxypropyl methyl cellulose B which are adjusted into two different viscosity grades in the original comparative example 2 and respectively consist of 35.0 percent and 5.0 percent of the prescription amount.
Example 5
Determination of release rate of nifedipine sustained-release tablets
1. Test materials: the nifedipine sustained release tablets prepared by 90mg dosage of the reference preparation Adalat CC, the comparative examples 1, 2 and 3.
2. The test method comprises the following steps: reference formulation Adalat at a dose of 90mg®The release rate of the nifedipine sustained release tablets prepared by CC (90 mg), example 1, comparative example 2 and comparative example 3 was measured according to the method 15 of the United states Pharmacopeia (USP 43-NF 38).
The release test conditions were as follows:
the method comprises the following steps: paddle method (application settlement basket)
Dissolution medium: 900 mL of pH6.8 phosphate buffer containing 0.5% sodium lauryl sulfate
Rotating speed: 50 rpm
Dissolution medium temperature: 37 +/-0.5 DEG C
Sampling volume: 10 mL
Medium compensation: is free of
Sampling time points are as follows: 2h, 8h, 12h, and 24h
High performance liquid chromatography conditions:
a chromatographic column: 4.6mmx7.5cm,3.5um packaging L60
Flow rate: 1 mL/min
A detector: ultraviolet 380nm
Sample introduction volume: 20 uL
Column temperature: 45 deg.C
Operating time: not less than 2 times of retention time of nifedipine
The dissolution amount of each nifedipine sustained release tablet in different time is respectively calculated, and a release curve is drawn, which is shown in figure 1.
TABLE 1 Release measurement results
As can be seen from the results of table 1, the nifedipine sustained-release tablets prepared in example 1, comparative example 2, and comparative example 3 of the present invention released smoothly, did not show a burst release phenomenon in 2 hours, and were completely released within 24 hours.
After the nifedipine sustained-release tablets were sufficiently studied, the reference preparation, comparative example 1 and comparative example 2 were further studiedPerforming fasting bioequivalence pretest, taking Cmax and AUC as main pharmacokinetic indexes, and investigating whether the Cmax and AUC are similar to Adalat®CC bioequivalence. In vivo experimental data indicate that both Cmax and AUC are higher than the reference formulation under fasting conditions, leading to non-equivalent results.
TABLE 2 pharmacokinetic indices in vivo under fasting conditions
Table 1 the results for the release rates of comparative example 1 and comparative example 2 show that comparative examples 1-2 release faster in vitro than the reference formulation. The fasting bioequivalence pretest further confirms that the drug release of comparative example 1 and comparative example 2 in vivo is faster than that of the reference formulation, resulting in a higher maximum blood concentration that is bioequivalent. Through further optimization and screening of the prescription, the invention designs the prescription of the comparative example 3 and the prescription of the example 1, and finally selects the example (f) with higher content of the release retardant (high-viscosity slow-release material)2= 69). Fasting bioequivalence pretests were again performed. The results of preliminary experiments show that the nifedipine sustained-release tablets of example 1 are bioequivalent to the reference formulation (see table 2 and fig. 3). Based on the bioequivalence results of example 1, the invention further optimized the formulation of the 90mg nifedipine sustained release tablet of example 1 to give example 2. Examples 3 and 4 were developed for nifedipine extended release tablets of low dose 30mg and 60mg, similar to the extended release tablet of 90mg nifedipine. Examples 2-4 the results of the release test and dissolution profile are shown in figure 4.
Stability experiment of nifedipine sustained-release tablet
The stability of example 1 is studied under accelerated conditions, and the accelerated stability test data of 3 months shows that the appearance, related substances, content and release rate of the nifedipine sustained-release tablet are not obviously changed compared with the initial point. This shows that the nifedipine sustained release tablets prepared by the invention have good stability and stable product quality (see table 3).
Table 3 example 1 results of stability study under accelerated conditions
The photostability studies under different color and coating weight gain conditions were performed for examples 2-4, respectively. The experimental data show that the product has good stability when the coating weight of the nifedipine sustained release tablet is increased by more than 6% (see table 4).
Table 4 examples 2-4 photostability test results for different coating weight gains
The content uniformity tests of 90mg, 60mg and 30mg of nifedipine sustained-release tablets prepared in examples 2 to 4 were respectively carried out, and the results show that the nifedipine sustained-release tablets in the invention have good content uniformity, and the product production process is stable, and high-quality nifedipine sustained-release tablets meeting the quality standards can be stably produced (see table 5).
Table 5 measurement results of process content uniformity of nifedipine sustained-release tablets in examples 2 to 4
Claims (17)
1. The nifedipine sustained-release tablet is characterized by comprising the following components in percentage by weight: 10 to 30 percent of nifedipine, 15 to 60 percent of slow release material composition, 25 to 55 percent of diluent and 0.5 to 1 percent of lubricant, wherein the sum of the using amount of each component is 100 percent; the slow release material composition consists of a high-viscosity slow release material and a low-viscosity slow release material, wherein the nominal viscosity range of the high-viscosity slow release material is 2700-49000mPa.s, and the nominal viscosity range of the low-viscosity slow release material is 80-1500 mPa.s.
2. The nifedipine sustained-release tablet of claim 1, wherein the nominal viscosity value of the high-viscosity sustained-release material and the low-viscosity sustained-release material after being compounded is 1400-3500 mPa.s.
3. The nifedipine sustained-release tablet of claim 1, wherein the nominal viscosity value after the high-viscosity sustained-release material and the low-viscosity sustained-release material are compounded is 1800-3500 mPa.s.
4. Nifedipine sustained-release tablets according to any one of claims 1 to 3, characterized in that the nominal viscosity range of the high-viscosity sustained-release material is 5000-49000mPa.s, and the nominal viscosity range of the low-viscosity sustained-release material is 80-1150 mPa.s.
5. Nifedipine sustained-release tablets according to any one of claims 1 to 3, characterized in that the nominal viscosity range of the high-viscosity sustained-release material is 13500-49000mPa.s and the nominal viscosity range of the low-viscosity sustained-release material is 200-1050 mPa.s.
6. The nifedipine sustained-release tablet according to any one of claims 1 to 3, wherein the amount of nifedipine is 10%, 20% or 30%, and the amount of the sustained-release material composition is 30 to 45%.
7. Nifedipine sustained-release tablets according to any one of claims 1 to 3, wherein the amount of the high viscosity sustained-release material is 5% to 25% and the amount of the low viscosity sustained-release material is 10% to 35%.
8. Nifedipine sustained-release tablets according to any one of claims 1 to 3, characterized in that the particle size D of nifedipine90Is 10-25 μm.
9. Nifedipine sustained-release tablets according to any one of claims 1 to 3, wherein the high viscosity sustained-release material is one or more of hydroxyethyl cellulose, hydroxypropyl methylcellulose and methyl hydroxyethyl cellulose, and the low viscosity sustained-release material is one or more of hydroxypropyl cellulose, methylcellulose, hydroxypropyl methylcellulose and sodium carboxymethylcellulose.
10. Nifedipine sustained-release tablets according to any one of claims 1 to 3, wherein the high viscosity sustained-release material is selected from one or more of HPMC K4M, HPMC E4M, HPMC K15M or HPMC K35M, and the low viscosity sustained-release material is selected from one or more of HPMC K100LV, HPMC K250 or HPMC K750.
11. Nifedipine sustained-release tablets according to any one of claims 1 to 3, wherein the diluent is one or more selected from lactose, dextrin, microcrystalline cellulose and starch, and the lubricant is one or more selected from magnesium stearate, stearic acid and talc.
12. Nifedipine sustained release tablets according to any one of claims 1 to 3, characterized in that the diluent is 20-35% lactose and 9-20% microcrystalline cellulose.
13. Nifedipine sustained release tablets according to any one of claims 1 to 3, characterized in that the nifedipine sustained release tablets are color coated, the weight gain of the coating is not less than 6% relative to the total weight of the core.
14. A method for preparing nifedipine sustained release tablets according to any one of claims 1 to 13, characterized by comprising the steps of:
step 1: controlling particle diameter D of nifedipine bulk drug90In the range of 10-25 um;
step 2: mixing nifedipine bulk drug, slow release material combination and diluent, and performing wet granulation by using water as a wetting agent;
and step 3: drying the wet granules in a fluidized bed and sieving the dried wet granules with a 18-mesh sieve;
and 4, step 4: finishing the grains;
and 5: mixing the granules with lubricant, and tabletting to obtain tablet core with weight of 300 mg per tablet.
15. The method for preparing nifedipine sustained release tablets according to claim 14, characterized by further comprising the step 6: and carrying out color coating on the tablet core, wherein the weight gain of the coating is not less than 6%.
16. The method for preparing nifedipine sustained release tablets according to claim 15, wherein the drying process in step 3 is drying by a fluidized bed, heating until the material temperature reaches 55 ℃, and keeping for 10-20 minutes until the loss on drying is not more than 3.0%.
17. The method for preparing nifedipine sustained-release tablets according to claim 16, wherein the hardness of the tablet core prepared in step 5 is 70-130N, and the friability is not more than 1.0%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111316687.6A CN113750069B (en) | 2021-11-09 | 2021-11-09 | Nifedipine sustained release tablet and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111316687.6A CN113750069B (en) | 2021-11-09 | 2021-11-09 | Nifedipine sustained release tablet and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113750069A true CN113750069A (en) | 2021-12-07 |
| CN113750069B CN113750069B (en) | 2022-03-01 |
Family
ID=78784656
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111316687.6A Active CN113750069B (en) | 2021-11-09 | 2021-11-09 | Nifedipine sustained release tablet and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113750069B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114432254A (en) * | 2021-12-30 | 2022-05-06 | 南通联亚药业有限公司 | Nifedipine controlled release tablet |
| CN115192538A (en) * | 2022-08-02 | 2022-10-18 | 沈阳信康药物研究有限公司 | Pressed coated nifedipine sustained release tablet and preparation method thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020114831A1 (en) * | 2000-12-15 | 2002-08-22 | Inger Norden | Pharmaceutical formulation |
| CN1839801A (en) * | 2005-03-31 | 2006-10-04 | 北京德众万全医药科技有限公司 | Insoluble pharmaceutical slow release preparation |
| CN101310712A (en) * | 2007-05-23 | 2008-11-26 | 杭州民生药业集团有限公司 | Nifedipine controlled release preparation and preparation method thereof |
| CN101416965A (en) * | 2007-10-24 | 2009-04-29 | 天津药物研究院 | Oral nifedipine slow-release preparation and preparation method thereof |
| US20090285889A1 (en) * | 2008-05-14 | 2009-11-19 | Capricom Pharma Inc. | Modified release formulations of dihydropyridine compounds and methods of making same |
-
2021
- 2021-11-09 CN CN202111316687.6A patent/CN113750069B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020114831A1 (en) * | 2000-12-15 | 2002-08-22 | Inger Norden | Pharmaceutical formulation |
| CN1839801A (en) * | 2005-03-31 | 2006-10-04 | 北京德众万全医药科技有限公司 | Insoluble pharmaceutical slow release preparation |
| CN101310712A (en) * | 2007-05-23 | 2008-11-26 | 杭州民生药业集团有限公司 | Nifedipine controlled release preparation and preparation method thereof |
| CN101416965A (en) * | 2007-10-24 | 2009-04-29 | 天津药物研究院 | Oral nifedipine slow-release preparation and preparation method thereof |
| US20090285889A1 (en) * | 2008-05-14 | 2009-11-19 | Capricom Pharma Inc. | Modified release formulations of dihydropyridine compounds and methods of making same |
Non-Patent Citations (2)
| Title |
|---|
| YAN ET AL.: "Preparation and Evaluation of a Sustained-Release Formulation of Nifedipine HPMC Tablets", 《DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY》 * |
| 张信中等: "基于粉末直接压片工艺的硝苯地平缓释片:制备、体外释放度及比格犬体内药动学评价", 《国际药学研究杂志》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114432254A (en) * | 2021-12-30 | 2022-05-06 | 南通联亚药业有限公司 | Nifedipine controlled release tablet |
| CN115192538A (en) * | 2022-08-02 | 2022-10-18 | 沈阳信康药物研究有限公司 | Pressed coated nifedipine sustained release tablet and preparation method thereof |
| CN115192538B (en) * | 2022-08-02 | 2023-09-15 | 沈阳信康药物研究有限公司 | Compression-coated nifedipine sustained-release tablet and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113750069B (en) | 2022-03-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP1778201B1 (en) | Extended release pellet formulation containing pramipexole or a pharmaceutically acceptable salt thereof, method for manufacturing the same and use thereof | |
| CN113750069B (en) | Nifedipine sustained release tablet and preparation method thereof | |
| EP1781260B9 (en) | Extended release tablet formulation containing pramipexole or a pharmaceutically acceptable salt thereof, method for manufacturing the same and use thereof | |
| DK2298288T3 (en) | COVERED TABLET FORMULATION AND PROCEDURE | |
| JP6058000B2 (en) | Sustained release formulation of ivabradine or a pharmaceutically acceptable salt thereof | |
| WO2011063732A1 (en) | Paliperidone double-layered osmotic pump controlled release tablet and preparation method thereof | |
| US20130064888A1 (en) | Pharmaceutical formulations | |
| WO2022012172A1 (en) | Oral sustained-release composition for insoluble drug, and preparation method thereof | |
| CN110037994A (en) | A kind of brufen quick-release and slow-release double-layer tablets and preparation method thereof | |
| KR20190000657A (en) | Sustained-release formulation comprising mosapride having a broad molecular weight distribution | |
| WO2021254409A1 (en) | Pharmaceutical composition of complex and preparation method therefor | |
| RU2613192C1 (en) | Tablets of clozapine with sustained release | |
| CN114432254B (en) | Nifedipine controlled release tablet | |
| CN114053237A (en) | Controlled release tablet and preparation method thereof | |
| CN111419812B (en) | Nifedipine-captopril timed osmotic pump controlled release tablet and preparation method thereof | |
| WO2007090595A1 (en) | Solid formulations of valacyclovir hydrochloride | |
| CN109001353B (en) | Quetiapine fumarate tablet pharmaceutical composition and preparation method thereof | |
| CN107744509B (en) | Mosapride citrate tablet and preparation method thereof | |
| TW202143972A (en) | A multiple formulation of ticagrelor | |
| TWI415604B (en) | Controlled release carvediolol formulation | |
| CN110693843A (en) | Lurasidone hydrochloride hydrophilic gel skeleton tablet and preparation method thereof | |
| TW202038918A (en) | Pharmaceutical composition | |
| CN116983274B (en) | Single-layer coated paliperidone sustained release tablet and preparation method thereof | |
| CN105193757A (en) | Metoprolol sustained-release composition and preparation method thereof | |
| CN115624533B (en) | Nifedipine controlled release tablet, preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |