CN109730967B - Nifedipine solid dispersion and preparation method thereof - Google Patents
Nifedipine solid dispersion and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a nifedipine solid dispersion and a preparation method thereof. The nifedipine solid dispersion comprises nifedipine and at least one carrier, wherein the mass fraction of the nifedipine is 10-50%; the nifedipine and the carrier are respectively crushed, sieved and mixed in proportion, and then extruded by a differential asymmetric double-screw extruder to prepare the nifedipine compound. According to the invention, through optimizing the prescription design and the preparation process of hot melt extrusion, nifedipine and povidone are combined through chemical bonds, and nifedipine can be dissolved in water in a large amount after being converted from the original crystalline state to the amorphous state, so that the dissolution rate is greatly improved, and the bioavailability is greatly improved; in addition, the solid dispersion has stable performance, avoids the situation of deterioration after long-time placement, simultaneously realizes the technical advantages of simple preparation, short time consumption and the like of a hot-melt extrusion process, and is beneficial to realizing industrialization.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations. More particularly relates to a nifedipine solid dispersion and a preparation method thereof.
Background
The cardiovascular and cerebrovascular diseases are the general names of cardiovascular and cerebrovascular diseases, and generally refer to ischemic or hemorrhagic diseases of heart, brain and systemic tissues caused by hyperlipidemia, blood viscosity, atherosclerosis, hypertension and the like. The cardiovascular and cerebrovascular diseases are characterized by serious threat to human beings, high disability rate and high death rate, more than 50 percent of survivors of cerebrovascular accidents still can not take care of oneself completely even if the most advanced and perfect treatment means are applied at present, and patients with the cardiovascular and cerebrovascular diseases are numerous and live at the first of various causes of death.
Nifedipine is a 1, 4-dihydropyridine calcium ion antagonist, has very strong effects of dilating coronary arteries and peripheral arteries, has obvious effect of inhibiting vasospasm, is a main medicament for treating cardiovascular and cerebrovascular diseases at present, is a first choice medicament for treating variant angina pectoris, and is widely applied to treating hypertension and preventing and treating angina clinically. In recent years, the clinical application of the medicine is developed rapidly, and the indication range is expanded to a plurality of diseases of digestive system, respiratory system, nervous system and obstetrics and gynecology, such as biliary colic, duodenal ulcer, acute pancreatitis, acute diarrhea, gastrointestinal spastic colic, infantile severe pneumonia with heart failure, bronchial asthma, threatened abortion, threatened premature birth, pregnancy-induced hypertension, dysmenorrhea, vascular headache, ischemic stroke, cerebral infarction and the like. At present, nifedipine is prepared into various dosage forms to be administered in various ways in consideration of the condition and the treatment requirement in clinic. Because nifedipine is insoluble in water, the conventional sugar-coated tablets have slow onset of action, incomplete drug release, low bioavailability and large side effect, and the dosage form is gradually replaced by controlled release tablets, sustained release pellets and sustained release capsules so as to achieve stable and lasting therapeutic action. However, these dosage forms are often slow in onset of action and are not suitable for paroxysmal diseases, such as hypertensive crisis, angina pectoris, biliary colic, acute pancreatitis, acute diarrhea, gastrointestinal spastic colic, premature labor, stroke, etc. The injection administration has quick effect, but needs the assistance of medical staff, and has poor patient compliance.
Chinese patent document (application No. CN200710020096.8) discloses a nifedipine orally disintegrating tablet preparation and a prescription, which comprises nifedipine, a solid dispersion carrier, a filler, a disintegrant, a flavoring agent, a lubricant and the like, wherein the nifedipine orally disintegrating tablet preparation is prepared by firstly preparing a solid dispersion of nifedipine by a melting method or a solvent method with the nifedipine and the solid dispersion carrier, and then granulating by a wet method according to a formula and tabletting. The patent achieves technical requirements through the synergistic effect of the solid dispersion and the disintegrating agent, and utilizes the solid dispersion technology to improve the solubility of the medicine and improve the absorption effect of the medicine, but still has the following defects: 1) in the preparation process, a large amount of pharmaceutic adjuvants such as polyethylene glycol, mannitol and the like are used, and the drug-loading rate is low; 2) because nifedipine has light instability, light shielding must be considered in the wet granulation preparation process; 3) in the invention, the pre-crushed and powdered nifedipine still exists in the auxiliary material in a fine crystalline state, aggregation can occur in the tabletting and placing processes, so that the solubility is reduced (in Achield, Liuyun, Von Lin, the influence of a solid preparation process on the crystal form of a medicament, China journal of the pharmaceutical industry, 2000 year 11), the dissolution amount of 1% sodium dodecyl sulfate solution of the preparation at 37 ℃ is 34.2% -97.87% in 30min, but nifedipine is almost insoluble in water, and the poor solubility and dissolution rate of nifedipine in water are main reasons for the lower oral bioavailability of nifedipine.
Compared with the traditional preparation technology, the hot-melt extrusion technology directly and rapidly mixes and extrudes the mixture of the drug and the carrier material at a certain temperature and pressure to prepare the solid dispersion, does not need to use an organic solvent, has good crystallization inhibition and can ensure that the amorphous drug stably exists in the carrier. However, because of the high temperature used in the hot-melt extrusion process, the drug and the carrier auxiliary materials are required to have certain thermal stability when the solid dispersion is prepared by hot-melt extrusion. Chinese patent document (CN201010594492.3) discloses a method for preparing nifedipine tablets containing solid dispersion by a hot-melt extrusion method, which comprises the following steps: nifedipine, a solid dispersion carrier (hydroxypropyl cellulose) and a release rate regulator (microcrystalline cellulose) are uniformly mixed, placed in hot melt extrusion equipment, melted and extruded at 100-120 ℃ under the conditions of certain hot melt temperature and rotation speed, cooled and crushed. This patent suffers from the following drawbacks: 1) the use of a large amount of carrier materials is required to obtain a solid dispersion with dispersed molecular state, so that the drug loading is low; 2) the patent does not characterize the state of nifedipine in the solid dispersion; 3) the extrusion temperature is 100-120 ℃, the melting point of nifedipine is 171-175 ℃, the nifedipine is difficult to extrude in the temperature range, and the higher extrusion temperature exceeds the maximum tolerance temperature of most carrier materials, so that the problem of stability of the medicine and the carrier cannot be solved.
At present, nifedipine has difficulties in clinical application and preparation development processes: 1) nifedipine is a short-acting antagonist, and the drug effect time is short; the common preparation has unstable drug release, large blood concentration fluctuation and easy occurrence of adverse reaction; 2) nifedipine is insoluble in water, and a release retardant is required to be added in the preparation process of the sustained release preparation, so that the early-stage release of the medicament is slow, and the medicament effect cannot be quickly exerted; 3) the existing preparation of nifedipine solid dispersion also has the defects of complex process, time-consuming spray drying method, high cost, high manufacturing cost of organic solvent residue easily caused by a solvent method, low efficiency and the like, for example, a solvent-culture method is only suitable for preparing small-dose medicines (generally below 50 mg); 4) the continuous processing process needs excellent self-cleaning function, and the narrow distribution and consistency of the residence time are ensured.
Disclosure of Invention
The invention aims to overcome the defects and shortcomings of the prior art and provide a nifedipine solid dispersion dispersed in an amorphous state and a preparation method thereof, which can improve the solubility and dissolution rate of nifedipine in water, thereby improving the in vivo bioavailability of nifedipine and improving the stability of nifedipine.
The above purpose of the invention is realized by the following technical scheme:
the preparation method of the nifedipine solid dispersion comprises the following steps of mixing the nifedipine and at least one carrier, wherein the mass fraction of the nifedipine is 10-50%; the nifedipine and the carrier are respectively crushed, sieved and mixed in proportion, and then extruded by a differential asymmetric double-screw extruder to prepare the nifedipine compound.
According to the invention, the nifedipine and the povidone are combined by optimizing the prescription design and the preparation process of hot melt extrusion, so that the nifedipine solid dispersion is prepared, and the technical advantages of simple preparation, short time and the like of the hot melt extrusion process are realized. In this nifedipine solid dispersion, nifedipine is converted from the original crystalline state to an amorphous state by binding to povidone. Nifedipine is almost insoluble in water originally, and nifedipine can be dissolved in water in a large amount after being combined with povidone and converted into an amorphous state, so that the dissolution rate is greatly improved, and the bioavailability is improved.
The inventor finds that the formula ratio of raw materials, the type of an extruder, the processing temperature, the screw rotating speed and the like in the processing process have great influence on the performance of the nifedipine solid dispersion.
Further, in a preferred embodiment of the present invention, the mass fraction of nifedipine is 20% to 40%.
Further, in a preferred embodiment of the present invention, the nifedipine is 30% by mass, and the carrier is 70% by mass.
Further, in a preferred embodiment of the present invention, the carrier is selected from one or more of povidone, hypromellose acetate succinate (HPMCAS) or polyethylene glycol.
Still further, in a preferred embodiment of the invention, the carrier is selected from one or more of PVP-VA64, PVP-S630, HPMCAS or PEG 6000.
Further, in the preferred embodiment of the present invention, the processing temperature of the extruder is 140 to 190 ℃.
Furthermore, in a preferred embodiment of the present invention, the temperatures of the first to sixth zones of the upper barrel of the extruder are 140 to 150 ℃, 155 to 160 ℃, 161 to 165 ℃, 170 to 185 ℃, 161 to 165 ℃, respectively.
Further, in the preferred embodiment of the present invention, the temperatures of the first to sixth zones of the extruder upper barrel are 150 ℃, 160 ℃, 165 ℃, 175 ℃, 165 ℃, respectively.
Further, in the preferred embodiment of the present invention, the rotation speed of the differential asymmetric twin-screw extruder is 40 to 200 r/min.
Further, in preferred embodiments of the present invention, the single-end rotational speed of the differential asymmetric twin-screw extruder is greater than the double-end rotational speed of the differential asymmetric twin-screw extruder.
Furthermore, in a preferred embodiment of the present invention, the ratio of the single-head rotation speed of the differential asymmetric twin-screw extruder to the double-head rotation speed of the differential asymmetric twin-screw extruder is 2 to 4: 1.
further, in the preferred embodiment of the present invention, the single-end rotation speed of the differential asymmetric twin-screw extruder is 120r/min, and the double-end rotation speed of the differential asymmetric twin-screw extruder is 60 r/min.
Further, in the preferred embodiment of the present invention, the screw diameter of the differential asymmetric twin-screw extruder is 18-26 mm; the length-diameter ratio is 31-36: 1.
further, in the preferred embodiment of the invention, nifedipine is sieved by a sieve of 100-120 meshes before being mixed, and then is dried for 4-8 hours; and (4) mixing, extruding and sieving by a sieve of 60-80 meshes.
Further, in a preferred embodiment of the present invention, nifedipine is pulverized and sieved in a dark place.
Further, in a preferred embodiment of the present invention, the method for preparing the nifedipine solid dispersion comprises the following steps:
s1, screening nifedipine through a 100-mesh sieve in a dark state, and drying;
s2, mechanically and uniformly mixing nifedipine and a carrier in proportion to obtain a physical mixture; the mass percent of the nifedipine is 10-50%;
s3, extruding the physical mixture through a differential asymmetric double-screw extruder, and cooling and crushing to obtain the material; the processing temperature of the extruder is 120-180 ℃, and the rotating speed of the extruder is 40-200 r/min.
The nifedipine solid dispersion prepared by the method is also within the protection scope of the invention
The invention also provides a pharmaceutical preparation containing nifedipine, which comprises the nifedipine solid dispersion and pharmaceutically acceptable auxiliary materials.
Compared with the prior art, the invention has the following beneficial effects:
(1) the dispersion uniformity of the materials in the preparation of the nifedipine solid dispersion has great influence on the stability and the dissolution rate of the nifedipine solid dispersion: compared with the traditional method of introducing asymmetric structure and motion, namely the structure and the rotating speed of the double screws are different, the adopted equipment is the differential asymmetric double screw extruder, so that materials flow in a variable motion space and are subjected to the action of a stretching force field and chaotic mixing, and the melting efficiency and the mixing effect are improved.
(2) The nifedipine solid dispersion prepared by hot-melt extrusion has high drug loading, and the nifedipine can be greatly dissolved in water after being converted into an amorphous state from an original crystalline state by combining with povidone, so that the dissolution rate is greatly improved, and the bioavailability of the nifedipine is greatly improved; in addition, the nifedipine and the povidone are combined by chemical bonds, so that the performance is stable, and the condition of deterioration caused by long-time placement is avoided; in addition, other auxiliary materials can be added in the preparation process to prepare the medicament, and a simple method is provided for the preparation of the nifedipine medicament.
(3) The method disclosed by the invention is simple to operate, does not need a complex preparation process and subsequent treatment steps, and is beneficial to realizing industrialization.
Drawings
Figure 1 is an infrared spectrum of Nifedipine (NEP), the carrier povidone (PVP-VA64), the physical mixture (PM-VA64) and nifedipine solid dispersion (SD-VA 64).
Figure 2 is an XRD pattern of Nifedipine (NEP), the carrier povidone (PVP-VA64), the physical mixture (PM-VA64) and nifedipine solid dispersion (SD-VA 64).
Figure 3 is a dissolution curve of nifedipine solid dispersions in different proportions.
Fig. 4 is a dissolution curve of the solid dispersion obtained by a differential non-bisecting twin-screw extruder and a common twin-screw extruder, wherein NEP is nifedipine, PVP-VA64 is a carrier povidone, SD-common is the common twin-screw extruder, and SD-differential is the differential asymmetric twin-screw extruder.
Detailed Description
The present invention is further illustrated by the following specific examples, which are not intended to limit the invention in any way. Unless otherwise specified, the technical means used in the examples are conventional means well known to those skilled in the art. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.
Unless otherwise indicated, reagents and materials used in the following examples are commercially available.
EXAMPLE 1 preparation of nifedipine solid Dispersion
1. The preparation method of the nifedipine solid dispersion comprises the following steps:
s1, weighing 300g of nifedipine and povidone PVP-VA64700g which are shaded and sieved by a 100-mesh sieve, and drying for 6 hours at the temperature of 60 ℃;
s2, mechanically mixing nifedipine and povidone PVP-VA64 in a closed container for 15min to obtain a physical mixture;
s3, extruding at the single-double screw rotation speed of 120/60r/min on a differential asymmetric double-screw extruder with preset temperatures of 150 ℃, 160 ℃, 165 ℃, 175 ℃ and 165 ℃ in sections from the first zone to the sixth zone of a machine barrel, cooling and crushing the extruded material, and sieving with a 80-mesh sieve to obtain the nifedipine solid dispersion.
2. Results
Figures 1 and 2 are the infrared and XRD spectra of Nifedipine (NEP), the carrier povidone (PVP-VA64), the physical mixture (PM-VA64) and the nifedipine solid dispersion (SD-VA64), respectively.
As shown in figure 1, the C-O characteristic peak of the solid dispersion of the drug nifedipine is from 1679cm-1Red shift to 1681cm-1And the peak shape becomes broad and the strength becomes weak, and furthermore, 3331cm-1The N-H peak at (A) disappears in the nifedipine solid dispersion.
As shown in fig. 2, nifedipine is a typical crystalline compound, and obvious crystal diffraction peaks exist at 8.086 °, 10.392 °, 11.746 °, 14.637, 16.208 °, 17.010 °, 19.550 ° and 24.597 °. In the physical mixture, the crystallization peaks of the drug exist, and in the solid dispersion, the diffraction peaks of the drug almost disappear, and the carrier property is presented, which indicates that the nifedipine is successfully converted into the amorphous state from the original crystallization state through being combined with the povidone by chemical bonds.
Example 2 preparation of nifedipine solid dispersions in different proportions
1. Preparation method
Weighing nifedipine and PVP-VA64 with corresponding mass according to the proportion in Table 1, and mechanically mixing the nifedipine and PVP-VA64 in a closed container for 15min according to the preparation method in example 1 to obtain a physical mixture; extruding the mixture on a differential asymmetric double-screw extruder with preset barrel sections from the first to the sixth at the temperatures of 150 ℃, 160 ℃, 165 ℃, 175 ℃ and 165 ℃ respectively at the rotating speed of a single-double screw at 120/60r/min, cooling and crushing the extruded product, and sieving the cooled and crushed product with a 80-mesh sieve to obtain nifedipine solid dispersoids prepared from raw materials in different proportions.
TABLE 1 mass fractions of nifedipine and PVP-VA64
| Name (R) | 1 | 2 | 3 | 4 | 5 |
| Nifedipine (g) | 100 | 200 | 300 | 400 | 500 |
| PVP-VA64(g) | 900 | 800 | 700 | 600 | 500 |
2. Results
Fig. 3 is a dissolution curve of nifedipine solid dispersion with different proportions. As can be seen from fig. 3, the ratio between nifedipine and the vehicle povidone PVP-VA64 is 3: and 7, the dissolution rate can reach the maximum in the shortest time.
Example 3 preparation of nifedipine solid Dispersion with a common twin screw extruder
1. Referring to the method of example 1, except for replacing the differential asymmetric twin-screw extruder with a general twin-screw extruder, a nifedipine solid dispersion was prepared, including the following steps:
s1, weighing 300g of nifedipine and povidone PVP-VA64700g which are shaded and sieved by a 100-mesh sieve, and drying for 6 hours at the temperature of 60 ℃;
s2, mechanically mixing nifedipine and povidone PVP-VA64 in a closed container for 15min to obtain a physical mixture;
s3, extruding the mixture on a common double-screw extruder with preset barrel sections from one zone to six zones at the temperatures of 150 ℃, 160 ℃, 165 ℃, 175 ℃ and 165 ℃ at the screw rotating speed of 120r/min, cooling and crushing the extruded product, and sieving the crushed product with a 80-mesh sieve to obtain the nifedipine solid dispersion (SD-common).
2. Results
FIG. 4 is a graph showing the solid dispersion release profiles obtained from differential speed non-twin screw and conventional twin screw extruders. The results are shown in FIG. 4: compared with the traditional method of introducing asymmetric structure and motion, namely the double-screw structure and the rotating speed are different, the adopted equipment is the differential asymmetric double-screw extruder, so that materials flow in a variable motion space and are subjected to the action of a stretching force field and chaotic mixing, the melting efficiency and the mixing effect are improved, the dissolution rate of the solid dispersion obtained by the common double-screw extruder reaches 86 percent at most, the differential asymmetric double-screw extruder reaches 97 percent, and the dissolution rate is far higher than that of the common double-screw extruder.
Example 4 stability study of nifedipine solid Dispersion
The products of examples 1, 2 and 3 were examined for stability under accelerated conditions (40 ℃ C., 75% RH), and the properties and active ingredient contents of the products were examined by sampling at 0, 1, 2 and 3 months. See table 2 for results.
Table 2 stability study of nifedipine solid dispersions under accelerated conditions
The nifedipine solid dispersion provided by the invention takes povidone as a carrier, and is prepared by a differential asymmetric double-screw extruder, so that the solubility of nifedipine in water can be improved, and the light stability and the thermal stability of nifedipine can be improved.
EXAMPLE 5 Effect of different Carriers on the Properties of the solid Dispersion of nifedipine
1. Method of producing a composite material
Compatibility between drug and carrier is a key factor affecting hot melt extrusion, with a dramatic effect on the properties of the resulting solid dispersion. Compatibility is an index of the strength of intermolecular interactions between a drug and a carrier without chemical action. The solubility parameter allows for an accurate assessment of the compatibility between compounds. According to the principle of solubility parameter delta2t＝δ2d+δ2p+δ2h，δ2t is the total solubility parameter, δ2d is the dispersion solubility parameter, δ2p is a polar solubility parameter, δ2h is a hydrogen bond solubility parameter. When the difference in solubility parameters between the two compounds is less than 7, good results are shownA compatibility of greater than 10 may be incompatible.
2. Results
The solubility difference between the drug and the carrier was calculated from the solubility parameters and the results are shown in table 3.
TABLE 3 solubility parameter calculation for drugs and polymeric carriers
As can be seen from Table 3, in the present invention, when the carrier is selected from PVP-VA64, PVP-S630, HPMCAS or PEG6000, the drug nifedipine and the polymer carrier show good biocompatibility.
The above detailed description is of the preferred embodiment for the convenience of understanding the present invention, but the present invention is not limited to the above embodiment, that is, it is not intended that the present invention necessarily depends on the above embodiment for implementation. It will be apparent to those skilled in the art that any modification of the present invention, equivalent substitutions of selected materials and additions of auxiliary components, selection of specific modes and the like, which are within the scope and disclosure of the present invention, are contemplated by the present invention.
Claims (11)
1. The preparation method of the nifedipine solid dispersion is characterized in that the nifedipine solid dispersion comprises nifedipine and at least one carrier, and the mass fraction of the nifedipine is 10-50%; respectively crushing and sieving nifedipine and a carrier, mixing the materials in proportion, and extruding the mixture by a differential asymmetric double-screw extruder to prepare the nifedipine-carrier composite material;
the carrier is povidone.
2. The preparation method according to claim 1, wherein the mass fraction of nifedipine is 20-40%.
3. The preparation method according to claim 2, wherein the mass fraction of nifedipine is 30%.
4. The method according to claim 1, wherein the carrier is PVP-VA 64.
5. The method of claim 1, wherein the differential asymmetric twin screw extruder has a processing temperature of 140 to 190 ℃.
6. The method as claimed in claim 1 or 5, wherein the speed of the differential asymmetric twin-screw extruder is 40 to 200 r/min.
7. The preparation method according to claim 1, wherein the screw diameter of the differential asymmetric twin-screw extruder is 18-26 mm; the length-diameter ratio is 31-36: 1.
8. the preparation method of claim 1, wherein the nifedipine is sieved by a 100-120 mesh sieve before being mixed, and then is dried for 4-8 hours; and (4) mixing, extruding and sieving by a sieve of 60-80 meshes.
9. The method according to claim 1, wherein nifedipine is pulverized and sieved in the absence of light.
10. Nifedipine solid dispersion obtainable by the process according to any one of claims 1 to 9.
11. A pharmaceutical preparation containing nifedipine, characterized in that it comprises the nifedipine solid dispersion of claim 10 and pharmaceutically acceptable excipients.
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| US20040115134A1 (en) * | 1999-06-22 | 2004-06-17 | Elan Pharma International Ltd. | Novel nifedipine compositions |
| KR20040079967A (en) * | 2002-02-01 | 2004-09-16 | 화이자 프로덕츠 인크. | Immediate release dosage forms containing solid drug dispersions |
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