CN111759816A - Oral solid nano crystal slow-release composition and preparation method thereof - Google Patents
Oral solid nano crystal slow-release composition and preparation method thereof Download PDFInfo
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Abstract
The invention discloses an oral solid nano-crystal sustained-release composition and a preparation method thereof. The invention combines the nanocrystal technology with the framework material, and adopts the process of uniformly mixing the solidified nanocrystals with the framework material and directly tabletting to prepare the solid nanocrystal sustained-release composition. The sustained-release composition utilizes the characteristics of large specific surface area, high saturation solubility, large surface energy and the like of the nano crystal, overcomes the defects of large difficulty in industrial production and easy influence of various factors on the dissolution of a skeleton tablet of the existing osmotic pump, improves the bioavailability and the release stability of insoluble drugs, and realizes the long-acting sustained-release effect similar to that of the osmotic pump.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to an oral solid nanocrystal sustained-release composition, and specifically relates to a novel oral solid nanocrystal sustained-release system prepared by preparing a BCS class II medicament into solid nanocrystals and mixing the solid nanocrystals with a solid framework material and then directly tabletting, and medical application of the novel oral solid nanocrystal sustained-release system.
Background
The Biopharmaceutical Classification System (BCS) classifies drugs into four categories based on their intestinal permeability and solubility in water. BCS class, which is a high solubility-high permeability drug; BCS class two, low solubility-high permeability drugs; BCS, class three, high solubility-low permeability drugs; BCS, four classes, are low solubility-low permeability drugs.
Among them, the BCS class ii drugs and the BCS class iv drugs are poorly soluble drugs, which have low solubility in intestinal tract and slow dissolution rate, and further cause poor bioavailability, poor safety, poor curative effect, poor patient compliance, and the like, and the low solubility of the drugs is one of the main reasons for failure in research and development.
Bioavailability refers to the degree and rate of absorption of the active ingredient into the blood, often in positive correlation with biological effects, and can improve the therapeutic effect of the active ingredient.
Increasing the solubility of poorly soluble drugs has been an important scientific problem in the pharmaceutical industry, and there are several delivery strategies for poorly soluble drugs. The traditional solubilization strategy needs to introduce a large amount of inactive ingredients such as organic solvents, and the like, so that the effect of increasing the solubility can be achieved, but toxic and side effects are often caused, the compliance of patients is poor, and the treatment effect is influenced. The novel delivery strategy mostly utilizes the carrier to isolate the insoluble substances, less inactive ingredients are introduced, the solubility and bioavailability of the active substances in vivo can be increased, and the introduced carrier can be modified to further increase the therapeutic effect. However, the new delivery strategy is difficult to industrialize, has more uncontrollable factors and immature process, and limits further application.
The nanocrystal technology refers to a technology by controlling the growth of active ingredient crystals or pulverizing the active ingredient crystals into crystals of which any one dimension is less than 1000 nm. Nanocrystals generally include an active ingredient and an inactive ingredient that prevents crystal growth. After the insoluble active ingredients are prepared into the nano-crystals, the specific surface area is greatly increased, and the saturated vapor pressure on the surfaces of the crystals is changed, so that the solubility and the dissolution speed are increased, and further, the bioavailability is improved, and the treatment effect is improved.
The nano crystal does not need a special carrier, and the introduced inactive substances with the stabilizing effect are few, and are mostly inactive substances with good safety, so that the nano crystal is not easy to cause toxic or side effect. Industrial production techniques of nanocrystals are mature, and there are a large number of examples of industrial production and widespread use.
The preparation technology of the nano-crystal mainly comprises Bottom-up and Top-down and the combination technology of the Bottom-up and the Top-down. The Bottom-up refers to a method of injecting a good solvent containing a drug into a poor solvent, precipitating crystals from the drug due to a sharp drop in solubility, and controlling the particle size during the precipitation of the crystals. The Bottom-up has low energy consumption and simple equipment, can control the particle size in a narrow range, and mainly comprises a trace precipitation method, a supercritical fluid method and an acid-base vaporization effervescence auxiliary precipitation method. Top-down refers to a method for reducing the particle size of a drug by using mechanical external force, and mainly comprises a medium grinding method and a high-pressure homogenizing method. Top-down is easier to be produced industrially than Bottom-up, has better process reproducibility, and is invented by Welan corporation
The technology is widely used in industrial production, and most of the commercially available nanocrystalline preparations adopt the technology. In recent years, nanocrystal technology has been widely used to improve bioavailability, enhance delivery efficiency of poorly soluble drugs, and improve patient compliance, and since 2000, there have been many nanonasThe rice crystal product is approved by the FDA.
The current commercial oral nanocrystal preparation has different degrees of improvement on bioavailability and solubility, and can reduce the influence of food on the bioavailability. However, the existing oral nanocrystal products are quick-release preparations, and varieties needing to maintain the in-vivo drug concentration for a long time are still in blank states, and the oral nanocrystal sustained-release preparations are lacked.
Nifedipine, chemically named 1, 4-dihydro-2, 6-dimethyl-4- (2-nitrophenyl) -3, 5-pyridinedicarboxylic acid dimethyl ester, is a dihydropyridine calcium channel blocker, selectively acts on an L-type calcium channel, can relax vascular smooth muscle, has a remarkable dilating effect on coronary arteries and peripheral blood vessels of the heart, and is widely used for clinically treating hypertension, preventing and treating angina pectoris caused by coronary heart disease, particularly angina pectoris caused by variant angina pectoris and coronary artery spasm.
Nifedipine is a BCS two-class drug, is almost insoluble in water, is dissolved out to be a main factor for limiting the absorption of nifedipine, has strong liver and intestine first pass effect, is influenced by P-gp efflux in intestinal tracts, is metabolized by PY450 in livers, and has low oral bioavailability. Most BCS classes, except nifedipine, are affected by low solubility, which leads to reduced bioavailability and increased delivery difficulty of the drug, and to lower pharmacological effects, which has become one of the major challenges in the development of new drugs. The pharmacological action of the nifedipine is related to the concentration of the nifedipine, so that the improvement of the bioavailability of the nifedipine has important significance for stably reducing the blood pressure of patients and reducing adverse reactions. Meanwhile, the invention discloses a novel preparation which is widely applied to BCS class II drugs and can improve the solubility and the dissolution rate, and the problem to be solved by the pharmaceutical industry is always solved.
Compared with the common preparation, the nifedipine sustained-release preparation has the advantages of slow release, reduced peak valley phenomenon, stable blood concentration, reduced occurrence probability and occurrence time of adverse reactions and better blood pressure control, so the nifedipine sustained-release preparation becomes the mainstream of the variety.
Most representative is nifedipine controlled release tablet
GITS (Germany Bayer) and nifedipine sustained-release tablets
CC (buffy, usa).
Nifedipine controlled release tablet
GITS (Germany Bayer) belongs to a push-pull osmotic pump, is a drug release system which is driven by osmotic pressure to release drugs, can achieve zero-order release in vitro, can release the drugs for 24 hours continuously, and is not easily influenced by factors such as food, gastrointestinal motility, pH, ionic strength and the like. However, the industrial production of osmotic pumps has high requirements on equipment and technology, such as high-speed laser drilling equipment, high-speed double-layer tablet presses and the like, which increases the production cost and limits the production costUse of an osmotic pump.
Nifedipine sustained release tablet
CC (American pfeiffer) belongs to a skeleton sustained-release tablet and consists of an inner quick-release medicine-containing layer and an outer sustained-release medicine-containing layer. The product can also realize long-acting release in vitro, but two high blood concentration points can appear in vivo. The drug release behavior of the matrix sustained-release tablet is easily influenced by ionic strength, pH value of release environment, gastrointestinal peristalsis and the like, and is easily influenced by the change of release conditions (ionic strength of release medium, pH value and rotating speed of a dissolution instrument) in an in-vitro release experiment, and the drug release speed is easily changed.
In order to solve the problems of low bioavailability of nifedipine, long-term stable release of nifedipine and the like, various attempts have been made in the pharmaceutical industry. US patent No. US5871776 discloses a method for preparing nifedipine sustained release tablets, which consist of two drug release layers and an outer coating, and can achieve long-lasting release for 22 hours, but have a release delay of 2 hours. US patent No. US5871775 discloses a nifedipine sustained release formulation comprising an amorphous coprecipitate of nifedipine and polyvinylpyrrolidone and excipients, the release time being controlled between 8 and 24 hours by adjusting the ratio of cellulose derivative, condensed ethylene and lactose. The US patent with the patent number US5861173 discloses a nifedipine sustained-release tablet, wherein the inner core and the outer shell of the tablet both contain nifedipine, so that the nifedipine sustained release can be realized, and at least 55% of nifedipine can be released in 6 hours.
The release behavior of the matrix tablet is easily influenced by various factors such as ionic strength, and after the ionic strength is changed by adjusting the proportion of sodium chloride in a release medium, the matrix tablets made of different materials have the phenomenon of slow release speed along with the increase of the ionic strength. (Ali Nokhodchi, Kofi Assire-Addo. (2014.) Drug release from matrix matrices and the effect of food Expert Option on Drug delivery 11:9,1401-
Disclosure of Invention
The invention aims to provide an oral solid sustained-release composition and a preparation method thereof, wherein the active ingredient is nanocrystal, the bioavailability of insoluble drugs is improved, and the in-vitro long-acting sustained-release effect similar to an osmotic pump can be achieved. Compared with an osmotic pump process, the preparation method is simple, has low requirements on equipment, and can overcome the defects that the traditional matrix tablet is easily influenced by food, intestinal peristalsis and pH.
The oral solid sustained-release composition provided by the invention is a nanocrystal sustained-release composition, and after the nanocrystal of the active ingredient and the framework material are combined together, the obtained nanocrystal sustained-release composition has unexpected effects, and can overcome the influence of factors such as ionic strength, the rotating speed of a dissolution instrument and the like on the in-vitro release of a framework tablet.
The oral solid nanocrystal sustained-release composition provided by the invention comprises an active ingredient nanocrystal and a solid framework material, wherein the active ingredient nanocrystal comprises a pharmaceutical active ingredient, a stabilizer and a freeze-drying protective agent.
The particle size of the active ingredient nanocrystals is preferably in the range of 50-900 nm.
In order to ensure that the active ingredient is the nano crystal in the preparation process, the oral solid sustained-release composition adopts a method of firstly grinding the nano crystal into nano particles and then freeze-drying the nano crystal to obtain the active ingredient, and the freeze-drying process well ensures that the particle size of the crystal is maintained at a nano level. The preparation method comprises the following steps: uniformly mixing the active ingredients of the medicine and the stabilizing agent in water, adding the mixture into a grinder to be ground into nano-scale particles, adding a freeze-drying protective agent, uniformly mixing and freeze-drying to obtain active ingredient nanocrystals; and then sieving the freeze-dried powder of the active ingredient nanocrystal, and mixing the freeze-dried powder with a solid framework material to obtain the solid nanocrystal sustained-release composition.
In the oral solid nanocrystal sustained-release composition, the active pharmaceutical ingredients are insoluble drugs, including but not limited to: nifedipine, felodipine, glipizide, gliclazide, nimodipine, fenofibrate, gemfibrozil, glimepiride, ibuprofen, indomethacin, irbesartan, lamotrigine, loratadine, lovastatin, and the like. In the embodiment provided by the invention, nifedipine, felodipine and glipizide are used as active ingredients to prepare the solid nanocrystal sustained-release composition.
The oral solid nanocrystal sustained-release composition provided by the invention comprises 2-30% of pharmaceutical active ingredients by mass. Preferably 3% -20%.
The addition of at least one stabilizer can reduce aggregation of the nanocrystals, reducing particle size. The stabilizer is preferably selected from one or more of the following: hypromellose, sodium dodecyl sulfate, poloxamer (polyoxyethylene polyoxypropylene ether block copolymer), ethyl cellulose, polyvidone, tween, span, polyethylene glycol, etc. The tween can be tween 20, tween 60, tween 80, etc.; the poloxamer can be poloxamer 407, poloxamer 188 or the like; the polyvidone can be PVP K12PF, PVPK17PF, PVP K25, PVP K30, PVP K90, etc.; the hypromellose may be HPMC E5, HPMC E15, HPMC E50, HPMC K4M, HPMC K100M, etc. In the examples provided by the present invention, hypromellose, povidone, tween and/or sodium dodecyl sulfate are used as stabilizers.
In the oral solid nanocrystal sustained-release composition provided by the invention, the proportion of the stabilizer to the pharmaceutical active ingredient is preferably 0.2: 1-50: 1 (mass ratio), more preferably 0.2: 1-20: 1, and most preferably 0.5: 1-5: 1.
In the oral solid nanocrystal sustained-release composition provided by the invention, the freeze-drying protective agent can be selected from one or more of the following substances: glucose, maltose, lactose, sucrose, levan, sodium dihydrogen phosphate, potassium dihydrogen phosphate, mannitol, glycine, etc. Preferably one or more of lactose, sucrose, mannitol, and sodium dihydrogen phosphate.
In the oral solid nanocrystal sustained-release composition provided by the invention, the proportion of the freeze-drying protective agent to the pharmaceutical active ingredient is preferably 0.1: 1-40: 1 (mass ratio), more preferably 0.2: 1-20: 1, and most preferably 0.5: 1-5: 1.
In the oral solid nanocrystal sustained-release composition provided by the invention, the solid matrix material can be selected from one or more of the following substances: acacia, acrylic resin, sodium alginate, povidone, xanthan gum, methylcellulose, hydroxypropyl cellulose, hypromellose, ethylcellulose and the like. In the embodiment provided by the invention, hypromellose, povidone and acrylic resin are used as solid framework materials.
In the oral solid nanocrystal sustained-release composition provided by the invention, the solid matrix material accounts for 10-90% (mass ratio), and preferably 20-70%. The mass ratio of the solid framework material to the pharmaceutical active ingredient is preferably 1: 9-9: 1.
The invention also provides a preparation method of the oral solid nanocrystal sustained-release composition, which comprises the following steps:
1) uniformly mixing the active ingredients and the stabilizer in water, and preferably stirring for 10-40 min;
2) adding the suspension obtained in the step 1) into a grinder to be ground into nano-scale particles, wherein the grinding time is preferably 5-50 min;
3) adding a freeze-drying protective agent into the suspension ground in the step 2), uniformly mixing, and freeze-drying;
4) sieving the freeze-dried powder obtained in the step 3), and uniformly mixing the freeze-dried powder with a solid framework material.
The invention creatively combines the nanocrystal technology with the framework material, and adopts the process of uniformly mixing the solidified nanocrystals with the framework material and directly tabletting to prepare the novel nanocrystal sustained-release composition. The sustained-release composition simultaneously utilizes the characteristics of large specific surface area, high saturation solubility, large surface energy and the like of the nano-crystal, overcomes the defects of large industrial production difficulty of the existing osmotic pump and easy influence of various factors on the dissolution of the matrix tablet, improves the bioavailability and the release stability of the indissolvable drug, and realizes the long-acting sustained-release effect similar to the osmotic pump. Compared with the prior art, the invention has the following technical advantages:
1. compared with an osmotic pump preparation, the preparation method has the advantages of simple process, low equipment requirement, contribution to large-scale production and capability of realizing 24-hour in-vitro sustained release. Meanwhile, the delayed release phenomenon of the osmotic pump can not occur.
2. Compared with the common hydrophilic gel sustained-release tablet, the sustained-release composition has the advantages that the release behavior is not easily influenced by factors such as the rotating speed of a dissolution instrument, the ionic strength and the like.
3. Compared with osmotic pump preparations and common hydrophilic gel sustained-release tablets, the invention improves the bioavailability and Cmax.
4. Compared with nifedipine and other bulk drugs, the sustained-release composition provided by the invention can improve the inherent dissolution rate of the drug.
Drawings
Hereinafter, the experimental protocol of the present invention will be described in detail with reference to the accompanying drawings.
Fig. 1 is an XRD powder diffraction pattern of the nifedipine solid crystals obtained in example 3 and comparative example 2.
FIG. 2 is a particle size distribution diagram of nifedipine nanocrystals obtained in example 3, with particle size 281.2 and PDI (polydispersity index) of 0.208.
Fig. 3 is an in vitro release profile of a commercially available formulation (nifedipine osmotic pump, the same applies below), the nifedipine nanocrystal sustained release composition prepared in example 3, and the nifedipine sustained release composition prepared in comparative example 2.
FIG. 4 is a graph showing the effect of the rotational speed of the dissolution apparatus on the in vitro dissolution of the oral solid nifedipine nanocrystal sustained release composition and the conventional sustained release composition, wherein A is the in vitro release curve of the oral solid nifedipine nanocrystal sustained release composition prepared in example 1 at three rotational speeds of 50r/min, 75r/min and 100 r/min; b is the in vitro release curve of the ordinary nifedipine sustained-release composition prepared in the comparative example 1 at three rotating speeds of 50r/min, 75r/min and 100 r/min.
Fig. 5 is a graph of the effect of ionic strength on the in vitro dissolution of oral solid nifedipine nanocrystal sustained release compositions and conventional sustained release compositions, wherein a is the dissolution curve of the nifedipine nanocrystal sustained release composition prepared in example 2 in dissolution media containing 0.4% sodium chloride, 0.8% sodium chloride by mass and no sodium chloride; and B is the dissolution curve of the nifedipine sustained-release composition prepared in the comparative example 2 in a dissolution medium containing 0.4 percent of sodium chloride and 0.8 percent of sodium chloride by mass and not containing sodium chloride.
Fig. 6 is a graph showing the effect of pH of a release medium on the in vitro release of an oral solid nifedipine nanocrystal sustained release composition prepared in example 3 and a conventional sustained release composition, wherein a is the oral solid nifedipine nanocrystal sustained release composition prepared in comparative example 1, and B is the nifedipine sustained release composition prepared in comparative example 1.
FIG. 7 is a result of a beagle pharmacokinetic study of a commercially available formulation (nifedipine osmotic pump), the nifedipine nanocrystal sustained release composition prepared in example 4, and the nifedipine sustained release composition prepared in comparative example 2, in which the commercially available formulation, the nifedipine nanocrystal sustained release composition prepared in example 3, and the nifedipine sustained release composition AUC prepared in comparative example 2 were separately performed∞The concentration of the drug in the blood (area under the curve of the blood concentration) is 700.7ng/mL, 277.8ng/mL and 257.1ng/mL respectively, and the Cmax is 98.10ng/mL, 39.76ng/mL and 43.80ng/mL respectively.
Detailed Description
The invention is further illustrated and explained by the following specific examples, which are not to be construed as limiting the invention.
Example 1 preparation of nifedipine oral solid nanocrystal sustained release System
Uniformly mixing 12g of nifedipine and 24g of polyoxyethylene polyoxypropylene ether block copolymer in 100mL of water, adding the obtained suspension into a grinder, grinding for 15min at 2500r/min, diluting the grinding liquid to 500mL, adding 15g of cane sugar, uniformly mixing, and freeze-drying for 24h to obtain the solid nanocrystal. The solid nanocrystals were sieved through a 80 mesh sieve, mixed with 60g xanthan gum and 10g povidone, and directly compressed to give tablets with the following composition:
example 2. nifedipine oral solid nanocrystal sustained release System preparation
Uniformly mixing 10g of nifedipine, 11g of tween and 6.6g of sodium dodecyl sulfate in 100mL of water, adding the obtained suspension into a grinding machine, grinding at 2000r/min for 10min, diluting the grinding liquid to 500mL, adding 18g of mannitol, uniformly mixing, and freeze-drying for 24h to obtain the solid nanocrystal. Sieving the solid nanocrystals through a 80 mesh sieve, mixing with 120g hypromellose and 10g povidone, and directly tabletting to obtain tablets having the following composition:
example 3 preparation of nifedipine oral solid nanocrystal sustained release System
Uniformly mixing 10g of nifedipine and 10g of hydroxypropyl methylcellulose in 100mL of water, adding the obtained suspension into a grinding machine, grinding for 10min at a speed of 2500r/min, diluting the grinding liquid to 500mL, adding 12g of cane sugar, uniformly mixing, and freeze-drying for 24h to obtain the solid nanocrystal. Sieving the solid nanocrystals through a 80 mesh sieve, mixing with 120g hypromellose and 10g povidone, and directly tabletting to obtain tablets having the following composition:
example 4. nifedipine oral solid nanocrystal sustained release System preparation
Uniformly mixing 10g of nifedipine, 15g of povidone and 5g of SDS into 100mL of water, adding the obtained suspension into a grinder, grinding for 10min at 3000r/min, diluting the grinding liquid to 500mL, adding 15g of mannitol, uniformly mixing, and freeze-drying for 24h to obtain the solid nanocrystal. Sieving the freeze-dried powder with a 80-mesh sieve, mixing with 50g of hydroxypropyl methylcellulose, and directly tabletting to obtain tablets with the following compositions:
example 5 preparation of oral solid nanocrystal sustained release System for felodipine
Uniformly mixing 5g of felodipine and 5g of poloxamer in 100mL of water, adding the obtained suspension into a grinding machine, grinding at 3500r/min for 20min, diluting the grinding liquid to 500mL, adding 25g of cane sugar and 10g of sodium dihydrogen phosphate, uniformly mixing, and freeze-drying for 36h to obtain the solid nanocrystal. Sieving the solid nanocrystals through a 80 mesh sieve, mixing with 80g hypromellose and 15g ethylcellulose, and directly tabletting to obtain tablets having the following composition:
example 6 preparation of oral solid nanocrystal sustained release System for felodipine
Uniformly mixing 5g of felodipine and 3g of povidone in 100mL of water, adding the obtained suspension into a grinding machine, grinding at 3500r/min for 20min, diluting the grinding liquid to 500mL, adding 25g of cane sugar, uniformly mixing, and freeze-drying for 24 h. Sieving the freeze-dried powder with a 80-mesh sieve, mixing with 100g of hydroxypropyl methylcellulose and 15g of ethyl cellulose, and directly tabletting to obtain the tablet with the following composition:
example 7 glipizide oral nanocrystal sustained release System preparation
Mixing 5g of glipizide, 11g of tween and 5g of hydroxypropyl methylcellulose in 100mL of water, adding the obtained suspension into a grinder, grinding for 10min at the speed of 2500r/min, diluting the grinding liquid to 500mL, adding 20g of mannitol, uniformly mixing, and freeze-drying for 24h to obtain the solid nanocrystal. Sieving the solid nanocrystals through a 80 mesh sieve, mixing with 80g hypromellose and 15g ethylcellulose, and directly tabletting to obtain tablets having the following composition:
example 8 glipizide nanocrystal sustained release System preparation
Mixing 5g of glipizide, 11g of tween and 5g of hydroxypropyl methylcellulose in 100mL of water, adding the obtained suspension into a grinder, grinding for 10min at the speed of 2500r/min, diluting the grinding liquid to 500mL, adding 20g of mannitol, uniformly mixing, and freeze-drying for 24h to obtain the solid nanocrystal. Sieving the solid nanocrystal with a 80-mesh sieve, mixing with 150g of hypromellose, 10g of sodium alginate and 15g of ethyl cellulose, and directly tabletting to obtain a tablet with the following composition:
comparative example 1 nifedipine oral solid sustained-release composition
3g of nifedipine, 3.4g of SDS and 10g of mannitol are uniformly mixed to obtain solid micron crystals. Sieving solid micrometer crystal with 80 mesh sieve, mixing with hydroxypropyl methylcellulose 40g and polyvidone 3.3g, and tabletting directly. Tablets having the following composition were obtained:
comparative example 2 nifedipine oral solid sustained-release composition
And 3g of nifedipine and 6.6g of cane sugar are uniformly mixed to obtain solid micron crystals. Sieving the solid micron crystal with a 80-mesh sieve, uniformly mixing with 43g of hydroxypropyl methylcellulose and 3.3g of povidone, and directly tabletting to obtain a tablet with the following composition:
EXPERIMENTAL EXAMPLE 1 characterization of solid crystals of nifedipine
The nifedipine solid crystals obtained in example 3 and comparative example 2 were subjected to XRD (X-ray diffraction) powder diffraction.
The experimental results showed that the nifedipine crystals in experimental example 3 and comparative example 2 had similar crystal structures, see fig. 1.
EXAMPLE 2 measurement of particle diameter of nifedipine nanocrystal
The nifedipine solid nanocrystals obtained in example 3 were dissolved in water, and the particle size was measured using a laser particle sizer (Malvern, germany), and the experimental results are shown in fig. 2.
Experimental example 3 inherent dissolution of nifedipine
The inherent dissolution conditions of the nifedipine nanocrystals prepared in example 3 and the nifedipine nanocrystals in comparative example 2 were as follows:
dissolution medium: 1% SDS (sodium dodecyl sulfate), pH6.8 phosphate buffer
Dissolution volume: 700mL
The determination method comprises the following steps: measurement by ultraviolet method
Detection wavelength: 238nm
TABLE 1 inherent dissolution rates of nifedipine nanocrystals and nifedipine nanocrystals
| Sample name | 3-10 min dissolution amount (μ g/mL) | Dissolution Rate (μ g/min) |
| Nifedipine nanocrystals | 128.8 | 18.40 |
| Nifedipine micron crystal | 32.6 | 4.66 |
EXAMPLE 4 commercially available preparation (nifedipine osmotic pump), nifedipine nanocrystal sustained release composition, and in vitro dissolution of nifedipine sustained release composition
Adalat GITS, the nifedipine nanocrystal sustained release composition prepared in example 3, and the nifedipine sustained release composition prepared in comparative example 2 were released in vitro under the following conditions:
dissolution medium: phosphate buffer of 1% SDS, pH6.8
Dissolution volume: 900mL
The dissolution method comprises the following steps: referring to the first method (rotary basket method) of the dissolution method in Chinese pharmacopoeia 2015 edition, the rotating speed is 100r/min
The determination method comprises the following steps: ultraviolet spectrophotometer measurement
Detection wavelength: 238nm
Measuring temperature: 37 deg.C
The experimental results are shown in fig. 3, and it can be seen that the in vitro release curves of the three are close and the release behaviors are similar.
Experimental example 5 Effect of rotational speed on the in vitro Release of nifedipine nanocrystal sustained Release compositions and nifedipine sustained Release compositions
The in vitro release conditions of the nifedipine nanocrystal sustained release composition prepared in example 1 and the nifedipine sustained release composition prepared in comparative example 1 were as follows:
dissolution medium: phosphate buffer of 1% SDS, pH6.8
Dissolution volume: 900mL
The dissolution method comprises the following steps: referring to the first method (rotary basket method) of the dissolution method in Chinese pharmacopoeia 2015 edition, the rotating speeds are 100r/min, 75r/min and 50r/min respectively
The determination method comprises the following steps: ultraviolet spectrophotometer measurement
Measuring wavelength: 238nm
Measuring temperature: 37 deg.C
The experimental results are shown in figure 4, and it can be seen that the in vitro drug release behavior of example 1 is less affected by the rotational speed.
EXAMPLE 6 Effect of Ionic Strength on the in vitro Release of nifedipine nanocrystal sustained Release compositions and nifedipine sustained Release compositions
The in vitro release conditions of the nifedipine nanocrystal sustained release composition prepared in example 2 and the nifedipine sustained release composition prepared in comparative example 2 were as follows:
dissolution medium: 1% SDS, 0.8% NaCl, pH6.8 phosphate buffer; 1% SDS, 0.4% NaCl, pH6.8 phosphate buffer; phosphate buffer of 1% SDS, pH6.8
Dissolution volume: 900mL
The dissolution method comprises the following steps: referring to the first method (rotary basket method) of the dissolution method in Chinese pharmacopoeia 2015 edition, the rotating speed is 100r/min
The determination method comprises the following steps: ultraviolet spectrophotometer measurement
Measuring wavelength: 238nm
Measuring temperature: 37 deg.C
The experimental results are shown in fig. 5, and it can be seen that the in vitro drug release behavior of example 2 is not easily affected by the ionic strength.
Experimental example 7 Effect of pH on the in vitro Release of nifedipine nanocrystal sustained Release compositions and nifedipine sustained Release compositions
The in vitro release conditions of the nifedipine nanocrystal sustained release composition prepared in example 3 and the nifedipine sustained release composition prepared in comparative example 1 were as follows:
dissolution medium: 1% SDS, pH6.8 phosphate buffer; 1% SDS, phosphate buffer pH 4.5; 1% SDS, pH1.2 buffer; 1% SDS in water.
Dissolution volume: 900mL
The dissolution method comprises the following steps: referring to the first method (rotary basket method) of the dissolution method in Chinese pharmacopoeia 2015 edition, the rotating speed is 100r/min
The determination method comprises the following steps: ultraviolet spectrophotometer measurement
Measuring wavelength: 238nm
Dissolution temperature: 37 deg.C
The experimental results are shown in fig. 6, and it can be seen that the in vitro drug release behaviors of example 3 and comparative example 1 are not easily affected by pH.
Experimental example 8
A commercially available formulation nifedipine osmotic pump, the nifedipine nanocrystal sustained release composition prepared in example 4, and the nifedipine sustained release composition prepared in comparative example 2 were subjected to a beagle pharmacokinetic study, respectively. Three groups of 6 beagle dogs are crossly administered in male and female halves, blood is taken at 1h, 3h, 5h, 6h, 7h, 10h, 14h, 18h and 24h after fasting administration, and blood concentration is determined by using a liquid mass spectrometry technology.
The experimental results are shown in fig. 7, and it can be seen that example 4 improves the blood concentration of the active ingredient in the body as compared to the commercially available formulation and comparative example 2.
In the above experiments, the sustained-release composition prepared in the present invention was only selected from some examples, and it should be noted that other sustained-release compositions of the present invention also have similar release effects.
Claims (11)
1. An oral solid sustained-release composition is a nanocrystal sustained-release composition and comprises an active ingredient nanocrystal and a solid framework material, wherein the active ingredient nanocrystal comprises a pharmaceutical active ingredient, a stabilizer and a freeze-drying protective agent.
2. The oral solid sustained-release composition of claim 1, wherein the nanocrystals of the active ingredient have a particle size ranging from 50 to 900 nm.
3. The oral solid sustained-release composition according to claim 1, wherein the pharmaceutically active ingredient is a poorly soluble drug selected from the group consisting of: nifedipine, felodipine, glipizide, gliclazide, nimodipine, fenofibrate, gemfibrozil, glimepiride, ibuprofen, indomethacin, irbesartan, lamotrigine, loratadine, and lovastatin.
4. The oral solid sustained-release composition according to claim 1, wherein the pharmaceutical active ingredient is present in the sustained-release composition at a mass ratio of 2% to 30%.
5. The oral solid sustained release composition of claim 1, wherein the stabilizer is selected from one or more of the following: hydroxypropyl methylcellulose, sodium dodecyl sulfate, poloxamer, ethyl cellulose, povidone, tween, span and polyethylene glycol.
6. The oral solid sustained-release composition according to claim 1, wherein the mass ratio of the stabilizer to the pharmaceutically active ingredient is 0.2:1 to 50:1, preferably 0.2:1 to 20:1, and more preferably 0.5:1 to 5: 1.
7. The oral solid sustained release composition of claim 1, wherein the lyoprotectant is selected from one or more of the following: glucose, maltose, lactose, sucrose, levan, sodium dihydrogen phosphate, potassium dihydrogen phosphate, mannitol and glycine.
8. The oral solid sustained-release composition according to claim 1, wherein the mass ratio of the freeze-drying protective agent to the pharmaceutical active ingredient is 0.1: 1-40: 1, preferably 0.2: 1-20: 1, and more preferably 0.5: 1-5: 1.
9. The oral solid sustained release composition of claim 1, wherein the solid matrix material is selected from one or more of the following: acacia, acrylic resin, sodium alginate, povidone, xanthan gum, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose and ethyl cellulose.
10. The oral solid sustained-release composition of claim 1, wherein the solid matrix material is present in the sustained-release composition in an amount of 10% to 90% by mass; the mass ratio of the solid framework material to the pharmaceutical active ingredient is 1: 9-9: 1.
11. A process for the preparation of an oral solid sustained release composition according to any one of claims 1 to 10, comprising the steps of:
1) uniformly mixing the active ingredients of the medicine and the stabilizing agent in water;
2) adding the suspension obtained in the step 1) into a grinder to be ground into nano-scale particles;
3) adding a freeze-drying protective agent into the ground suspension, uniformly mixing, and freeze-drying to obtain an active ingredient nanocrystal;
4) sieving the active ingredient nanocrystal obtained in the step 3), and uniformly mixing the active ingredient nanocrystal with the solid framework material.
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| CN111249239A (en) * | 2020-01-17 | 2020-06-09 | 中国药科大学 | Loratadine nanocrystal and preparation method thereof |
| CN112816596A (en) * | 2021-02-05 | 2021-05-18 | 湖南慧泽生物医药科技有限公司 | Method for measuring external dissolution degree of nifedipine controlled release tablet |
| CN113842460A (en) * | 2021-11-12 | 2021-12-28 | 上海楷替生物医药科技有限公司 | Statin medicine nanocrystal and preparation method and application thereof |
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| CN113842460A (en) * | 2021-11-12 | 2021-12-28 | 上海楷替生物医药科技有限公司 | Statin medicine nanocrystal and preparation method and application thereof |
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