CN114224834B - Albendazole nano suspension with high bioavailability and preparation method thereof - Google Patents
Albendazole nano suspension with high bioavailability and preparation method thereof Download PDFInfo
- Publication number
- CN114224834B CN114224834B CN202111598896.4A CN202111598896A CN114224834B CN 114224834 B CN114224834 B CN 114224834B CN 202111598896 A CN202111598896 A CN 202111598896A CN 114224834 B CN114224834 B CN 114224834B
- Authority
- CN
- China
- Prior art keywords
- albendazole
- suspension
- stabilizer
- cosolvent
- homogenization
- 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.)
- Active
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
- A61K9/10—Dispersions; Emulsions
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y40/00—Manufacture or treatment of nanostructures
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
Abstract
The invention belongs to the field of veterinary drug pharmaceutical preparations, and provides an albendazole nanosuspension and a preparation method thereof k30 ) And tween-80. The albendazole nanosuspension prepared by the anti-solvent method-high pressure homogenization method has the advantages of simple preparation process and high onset speed. The experimental result shows that compared with albendazole ivermectin powder and albendazole suspensions of other brands on the market, the particle size of the nano suspension is reduced, so that the nano suspension is more easily, quickly and uniformly dispersed in gastrointestinal fluid, the nano suspension is easily transferred to an absorption part through a hydration layer of a gastrointestinal wall under the action of a stabilizer, the dissolution rate and the permeability of a medicament are improved, the medicament can be continuously dissolved from a matrix and permeate to the absorption part, the absorption rate of the medicament in the gastrointestinal tract is increased, the bioavailability of the medicament is improved, and the insect expelling effect is enhanced.
Description
Technical Field
The invention belongs to the field of veterinary drug preparations. In particular to an albendazole nano suspension with higher bioavailability and a preparation method thereof.
Background
Albendazole (Albendazole, ABZ), also known as Albendazole, chemically as methyl 5-propylthio-1H-benzimidazole-2-carbamate, is a benzimidazole class of broad-spectrum antiparasitic agents that has been recommended by the World Health Organization (WHO) as one of the major anti-echinococcosis drugs. In recent years, the traditional Chinese medicine composition is widely used in clinic, and the curative effect of the traditional Chinese medicine composition is widely accepted. Albendazole has a strong killing effect on nematodes, cestodes and trematodes in animals, and the action mechanism of albendazole is mainly that albendazole is combined with microtubulin of polypide to destroy the basic structure of polypide, and block cell propagation processes such as mitosis, protein assembly, energy metabolism and the like. The albendazole not only has strong effect on adults, but also has strong effect on killing immature insect bodies, larvae and eggs.
However, albendazole is a poorly soluble drug, has strong first pass effect, extremely low gastrointestinal absorption rate, low concentration in plasma and liver tissues, and only 30% of cure rate for non-intestinal parasites such as echinococcosis granulosa and the like. The albendazole in the current market is mainly prepared into tablets, powder and suspension. The inventor of shenyang weijia animal husbandry limited has mainly worked on the development of albendazole suspensions and powders suitable for piglets. For various veterinary drug forms of albendazole, after the tablets enter a body, the tablets are moistened and disintegrated to slowly release and absorb the drug, so that the peak time is long, the effect is slow and the bioavailability is low. The powder is mixed with feed for administration, but the effect of expelling insects is not reliable due to uneven mixing and intake because of the influence of feed type, granularity, feed intake and the like. Suspensions are superior to tablets and powders in the route of administration, but the bioavailability of conventional suspensions remains low due to the poor solubility of albendazole. The low solubility and bioavailability of albendazole severely restrict the application of albendazole in veterinary clinic, so that the improvement of the bioavailability by using a novel preparation technology is very necessary.
A suspension is a heterogeneous liquid formulation formed by dispersing a poorly soluble solid drug in a dispersion medium in a particulate state. The drug particles in the suspension are generally between 0.5-10 μm, small can be 0.1 μm and large can be 50 μm or larger. The Nano Crystals (NC), also called nano suspension, is a dispersion of poorly water soluble drugs or drug compounds in a medium, usually water, under the action of a stabilizer, and the size of the drug particles is reduced to below 1 μm by using nano technologies such as mechanical grinding, high pressure homogenization or controlled crystallization, etc., to form a drug nano colloid dispersion system, which can significantly improve the solubility and bioavailability of poorly water soluble drugs. Compared with other methods for solving the problem of difficult solubility, the method does not need to add any carrier matrix, only adds the stabilizing agent in the preparation process to stabilize the prepared nanocrystal, has simple production process, and the prepared drug nanosuspension has the advantages of good solubility and high bioavailability, so the method can effectively solve the problem of clinical application of the difficult solubility drug, is beneficial to the absorption of the drug in intestinal tracts and prolongs the in-vivo action time of the drug, thereby improving the bioavailability of the difficult solubility drug.
The inventor changes the traditional suspension preparation process, utilizes a nanocrystal technology, and prepares the albendazole nano suspension with higher bioavailability by an anti-solvent method-high pressure homogenization method, provides a new strategy for improving the clinical curative effect of the albendazole, and has better market prospect and higher economic benefit and social benefit.
Disclosure of Invention
In order to overcome the defects of poor solubility and low bioavailability of the existing albendazole nanosuspension generally, the invention mainly aims to provide the veterinary albendazole nanosuspension which is simple in preparation method, obvious in drug effect and particularly high in bioavailability.
Specifically, the invention is realized by the following technical schemes:
in a first aspect, the present invention provides an albendazole nanosuspension comprising albendazole, a cosolvent and a stabilizing agent, and optionally a preservative,
the albendazole nanosuspension is prepared by an anti-solvent method-high pressure homogenization method, the average particle size of the albendazole in the nanosuspension is less than 400nm, and the albendazole is in a quasi-circular shape under an electron microscope.
Alternatively, in the albendazole nanosuspension described above, the cosolvent is selected from one or more of the following: l-tartaric acid, citric acid, L-malic acid, DL-malic acid; the stabilizer is selected from one or more of the following: tween, polyethylene glycol, polyvinylpyrrolidone (PVP), poloxamer 188; and the preservative is selected from one or more of: sodium benzoate, potassium sorbate, ethylparaben, methylparaben and dimethyl fumarate.
Alternatively, in the albendazole nanosuspension described above, the cosolvent is preferably L-malic acid; the stabilizer is preferably a mixture of polyvinylpyrrolidone (PVP) and tween at a certain ratio, and more preferably, PVP k30 And tween-80 in a weight ratio of 5:1-1:1, most preferably, PVP k30 And tween-80 in a weight ratio of 3: 1; the preservative is preferably sodium benzoate.
Alternatively, in the albendazole nanosuspension, the albendazole nanosuspension comprises 5-15 parts by weight of albendazole, 5-30 parts by weight of cosolvent and 2-10 parts by weight of stabilizer, and optionally comprises 0.0005-0.005 part by weight of preservative.
Alternatively, in the albendazole nanosuspension, the albendazole nanosuspension comprises 10 parts of albendazole, 20 parts of cosolvent and 4 parts of stabilizing agent by weight, and optionally comprises 0.002 part of preservative.
In a second aspect, the present invention provides a method for preparing the albendazole nanosuspension described in the first aspect, which comprises the following steps:
(1) According to the formula proportion of the first aspect, firstly, dissolving a cosolvent by using a small amount of distilled water, heating to 80-90 ℃, adding the albendazole raw material into the cosolvent, and keeping the heating temperature to completely dissolve the albendazole raw material in the cosolvent solution;
(2) Weighing a stabilizer, dissolving the stabilizer in a proper amount of distilled water, slowly adding the dissolved albendazole solution into the stabilizer solution by using a high-speed disperser under a shearing condition, recrystallizing and separating out the albendazole, and shearing to obtain a smaller particle size to obtain a primary mixed solution;
(3) Placing the primary mixed solution in a high-pressure homogenizer, and homogenizing for certain times at a set temperature and pressure to obtain a nanocrystal suspension;
(4) Adding dissolved antiseptic into the homogenized nanocrystal suspension, stirring, mixing, adjusting pH, adding distilled water to full volume, and stirring.
Alternatively, in the above production method, in the step (2), the shearing condition is 5000 to 10000rpm,10 to 25min, preferably, the shearing condition is 8000rpm,20min.
Alternatively, in the above production method, in the step (3), the homogenization temperature is 20 to 50 ℃, the homogenization pressure is 30 to 150MPa, and the number of times of homogenization is 10 to 30.
Alternatively, in the above production method, in the step (3), the preferred homogenization process parameters are a homogenization temperature of 30 ℃ and 25 cycles each at a homogenization pressure of 100MPa and 50 MPa.
Alternatively, in the above preparation method, in the step (4), the pH adjusting agent used is selected from one or more of: sodium hydroxide, sodium bicarbonate and ethanolamine, preferably, the pH regulator is sodium hydroxide, and the pH is regulated to 5-7.
Compared with the prior art, the invention has the following beneficial effects:
the invention adopts the nanometer suspension prepared by the albendazole through an anti-solvent method-high pressure homogenization method, can obtain smaller medicine particle size, compared with albendazole ivermectin powder and Foshan Zhengdian albendazole suspension, the reduction of the medicine particle size enables the medicine preparation to be more easily, quickly and uniformly dispersed in gastrointestinal fluid, under the action of a stabilizing agent, the medicine overcomes the obstacle when macromolecules pass through epithelial cell membranes of gastrointestinal tracts, is easy to be transferred to absorption sites through hydration layers of the gastrointestinal tracts, is beneficial to improving the medicine dissolution rate and permeability, can be continuously dissolved out from a matrix and permeate to the absorption sites, enables the medicine to be quickly absorbed and the absorption amount to be increased in the gastrointestinal tracts, improves the medicine bioavailability and enhances the parasite expelling effect.
The albendazole nano suspension provides a new strategy for improving the clinical curative effect of albendazole, and has better market prospect and higher economic benefit and social benefit.
Drawings
FIG. 1: the albendazole nano suspension has a form under a scanning electron microscope.
FIG. 2: blank plasma chromatogram.
FIG. 3: ABZSX, MBZ and ABZ chromatograms are added into blank plasma.
FIG. 4: ABZSX, MBZ, ABZ chromatograms in plasma after dosing.
FIG. 5: plasma concentration-time profile of ABZSX after oral administration of albendazole ivermectin powder and 2 suspensions (45 mg/kg. Bw) in rats.
Detailed Description
The invention is further illustrated with reference to specific examples. It should be understood that the specific embodiments described herein are merely illustrative of the invention and do not limit the scope of the invention.
The examples do not show the specific techniques or conditions, according to the technical or conditions described in the literature in the field, or according to the product specifications. The reagents or instruments used are conventional products which are not indicated by manufacturers and are available from normal sources.
The experimental procedures in the following examples are all conventional ones unless otherwise specified. The test materials used in the following examples are all commercially available products unless otherwise specified.
Example (b):
1. material
1.1 drugs and reagents
Albendazole raw material, purchased from medicine limited of hogpo pot ahi, lot No. 9011806059;
albendazole reference, purchased from the institute of veterinary drugs and medicine, lot number 100373-201103;
albendazole sulfoxide control, available from dr. Ehrenstorfer GmbH, germany, under lot number G119446;
mebendazole control, available from the chinese institute for veterinary medicine, lot No. H1032011;
malic acid, purchased from sienna tianzheng pharmaceutic adjuvant ltd, lot number 20181229;
heparin sodium, purchased from shenyang ltd, national drug group chemical reagent, lot No. 20180426;
albendazole ivermectin powder (10%), shenyang weijia biotechnology limited, lot number 2019040101;
albendazole suspension (10%), zhengdian biotechnology limited, foshan city, lot No. 2019101701.
Methanol, acetonitrile and the like are all chromatographically pure; sodium hydroxide, ethyl acetate, glacial acetic acid, 95% ethanol and the like are analytically pure.
1.2 Main test Instrument
LC-1260 high performance liquid chromatograph, agilent, USA;
XHF-DY high speed disperser, ningbo Xinzhi Biotech GmbH;
ZETASIZERNano-ZS90 particle size analyzer, malvern instruments ltd, UK;
high pressure homogenizer APV2000, APV, germany.
1.3 test animals
30 clean SD rats with male body weight of 200 +/-20 g provided by Liaoning Biotechnology GmbH, and subject animal qualification number SCXK (Liao) 2015-0001. The animals were normally kept for 1 week before the test, and were drunk freely and eaten.
2. Main test method
2.1 prescription screening of Albendazole nanosuspensions
The veterinary drug quality standard (2017 edition) is recorded, and the specification of albendazole suspension is 100mL:10g, the study takes albendazole as a main drug, and screens a cosolvent, a stabilizer and a preservative in the nano suspension through a single-factor test according to the preparation requirement of the suspension. Selection of L 9 (3 4 ) The table design and orthogonal test are carried out, and the concentrations of the cosolvent, the stabilizer and the preservative are screened to screen the optimal prescription.
2.2 preparation Process
According to the formula proportion, firstly dissolving a cosolvent by using a small amount of distilled water, heating to 80-90 ℃, adding the albendazole raw material into the cosolvent, and keeping the heating temperature to completely dissolve the albendazole raw material in the cosolvent solution; and weighing a stabilizer, dissolving the stabilizer in a proper amount of distilled water, slowly adding the dissolved albendazole solution into the stabilizer solution by using a high-speed disperser under a shearing condition, recrystallizing and separating out the albendazole, and shearing to obtain a smaller particle size to obtain a primary mixed solution. And (3) placing the initial mixed solution into a high-pressure homogenizer, and homogenizing for certain times at a set temperature and pressure to obtain the nano suspension. Adding appropriate amount of dissolved antiseptic into the homogenized nanocrystal suspension, stirring, adjusting pH, adding water to full volume, and stirring.
2.3 quality evaluation of nanosuspensions
2.3.1 color and pH Change
The appearance, color, clarity and pH of the suspension were observed and recorded.
2.3.2 determination of sedimentation volume ratio
The examination is carried out by referring to a detection method of the sedimentation volume ratio of the oral suspension in the pharmacopoeia of the people's republic of China (2015 edition, appendix 0111): 50mL of the product is taken and placed in a measuring cylinder with a plug, the measuring cylinder is sealed, the product is vigorously shaken for 1min, and the height H of the beginning of the suspension is recorded 0 After 3H of standing, the final height H of the suspension is recorded.
Calculated as follows: sedimentation volume ratio = H/H 0 。
2.3.3 weight Dispersion test
The examination was carried out with reference to the "redispersion" test method for suspensions in pharmacy (seventh edition): the suspension was placed in a 100mL stoppered graduated cylinder, the cylinder was inverted at 20 times/min and the disappearance of the sediment at the bottom of the cylinder was observed after a certain period of rotation.
2.3.4 nanoparticle morphology and particle size distribution
And (4) detecting the nano suspension by using a scanning electron microscope, and observing the nano form. And (3) measuring the particle size distribution of the nano suspension by using a Malvern laser particle size analyzer, fully shaking the nano suspension before measurement, and diluting the nano suspension with deionized water to a proper concentration.
2.3.5 nanosuspension content determination
The examination was carried out with reference to the quality standard of "albendazole suspension" in "veterinary drug quality standards" (2017 edition): taking the product, shaking, precisely weighing appropriate amount (about 20mg equivalent to albendazole), placing in 100mL measuring flask, adding glacial acetic acid 10mL, shaking to dissolve, diluting with ethanol to scale, shaking, filtering, precisely weighing secondary filtrate 5mL, placing in 100mL measuring flask, diluting with ethanol to scale, shaking, measuring absorbance at 295nm wavelength by ultraviolet-visible spectrophotometry, and determining absorption coefficient (E) 1cm 1％ ) And (4) calculating to obtain the product 444. Taking the product, measuring relative density, and converting the sample amount into mL.
2.3.6 formulation stability Studies
According to the ' preparation stability test guiding principle ' in the pharmacopoeia of the people's republic of China (2015 edition), the nanosuspension is subjected to a normal-temperature and accelerated investigation test for 6 months at regular intervals; meanwhile, the content, the properties, the pH value, the sedimentation volume ratio, the weight dispersity and the like of the nano suspension are considered, and the stability of the nano suspension under the conditions of high temperature, high humidity and the like is researched.
2.4 pharmacokinetic testing
2.4.1 design of pharmacokinetic experiments
Rats were randomly divided into three groups, one group was administered albendazole ivermectin powder, one group was administered albendazole nanosuspension prepared in this study, and one group was administered albendazole suspension of Buddha Zhengdian, fasted for 12h before administration, had free water, and had food returned for 6h after administration. According to the clinical use of albendazole pigsThe recommended dosage of the bed is converted to obtain the dosage of rats, namely the dosage of 45mg/kg.bw is used for gastric lavage administration, the three groups are diluted by proper amount of water before administration to prepare stock solution for standby, each rat is weighed and marked, and the gastric lavage is carried out according to the weight of 2mL/0.2kg rat. And taking about 0.5mL of blood from tail vein before administration, 0.5, 1.5, 3, 4, 5, 6, 7, 8, 12 and 24h after administration, placing in a heparin anticoagulation centrifuge tube, and collecting blood at 4000 r.min -1 Centrifuging, separating plasma, storing at-20 deg.C, and determining.
2.4.2 chromatographic conditions for Albendazole sulfoxide (ABZSX) in murine blood
And (3) chromatographic column:
XB-C18,3 μm, 4.6X 250mm; the mobile phase (methanol: acetonitrile =1: 1) is subjected to gradient elution with water according to an initial ratio of 70; in 34-40min, the proportion is from 30% → 70%; the detection wavelength is 292nm; the flow rate is 1.0 mL/min -1 (ii) a The column temperature was 35. + -. 1 ℃.
2.4.3 plasma sample treatment
Accurately sucking 200 μ L rat plasma, placing in 2mL centrifuge tube, sequentially adding 0.4mol/L NaOH50 μ L,0.01mg/mL Mebendazole (MBZ) internal standard solution 100 μ L and ethyl acetate 1.0mL, vortex oscillating for 3min, and then 12000 r.min -1 Centrifuge for 10min. The supernatant was aspirated into another centrifuge tube, 0.5mL of ethyl acetate was added to the first tube, the above procedure was repeated to perform vortex oscillation and centrifugation, the two supernatants were combined, the nitrogen stream was dried at 40 ℃, the residue was dissolved in 200 μ L of a methanol acetonitrile mixture (methanol: acetonitrile = 1), 12000r · min -1 Centrifuging for 10min, and collecting supernatant as sample to be tested, wherein the sample volume is 50 μ L.
2.4.4 establishment of plasma Standard Curve
Precisely measuring 9 parts of blank plasma of 200 mu L, respectively placing the blank plasma into 2mL centrifuge tubes, respectively taking one blank reference, respectively adding equivalent Mebendazole (MBZ) internal standard solution, respectively adding different amounts of standard stock solution albendazole sulfoxide (ABZSX) into the 2mL centrifuge tubes, and obtaining standard plasma samples with the liquid medicine concentrations of 0.01, 0.02, 0.05, 0.2, 1, 3.5, 7 and 10 mu g/mL in sequence. The plasma samples were processed according to the plasma sample processing method, analyzed by HPLC, and chromatograms were recorded. And (3) establishing a plasma standard curve by taking the ratio of the measured ABZSX peak area to the peak area of the internal standard as a horizontal coordinate (x) and the concentration (y) as a vertical coordinate, and fitting a regression equation to calculate a correlation coefficient (r).
2.4.5 methodological validation
Putting 200L of blank plasma into a 2mL centrifuge tube, then sequentially adding three concentrations of diluted ABZSX standard working solution, namely high concentration, medium concentration and low concentration, fully and uniformly mixing to prepare plasma samples containing 0.2, 3.5 and 10 mu g/mL ABZSX concentrations respectively, processing according to a plasma processing method, carrying out HPLC detection and analysis, and setting 5 parallel detection in each concentration one day to examine the variation coefficient in the day; the test was repeated continuously for 5 days to determine the daytime coefficient of variation. And calculating the recovery rate, accuracy, precision and sensitivity of the method.
2.4.6 determination of drug concentration in rat plasma
And (3) completing plasma samples of the same mouse in the same analysis batch, processing and detecting according to a plasma sample processing method, substituting the obtained peak areas of the ABZSX into a standard curve regression equation, and calculating the concentration of the ABZSX in the plasma at each time point.
2.5 data analysis
Analyzing and processing methodology data and a plasma standard working curve by adopting an ExceL software and drawing a pharmaceutical-time curve graph; pharmacokinetic parameters were obtained by processing plasma concentration-time data in a non-compartmental model using pharmacokinetic analysis software Winnonlin 5.2, data expressed as mean ± standard deviation (x ± s).
3. Test results
3.1 prescription screening of Albendazole nanosuspensions
3.1.1 screening of Co-solvents
In the test, L-tartaric acid, citric acid, L-malic acid and DL-malic acid are respectively selected as cosolvents, 10g of the cosolvents are respectively weighed, dissolved by a small amount of distilled water, heated to 80-90 ℃,10 g of albendazole raw material is added into the cosolvents, the heating temperature is kept, and the time and the state after the albendazole is completely dissolved in the cosolvent solution are recorded. The experimental result shows that the L-malic acid is dissolved at the fastest speed, the liquid medicine is clear and transparent after being dissolved, citric acid is added, and the L-tartaric acid and the DL-malic acid are dissolved for a longer time.
3.1.2 screening of stabilizers
Selecting Tween 80, polyethylene glycol 400, polyethylene glycol 300, and polyvinylpyrrolidone (PVP) K-30 ) And poloxamer 188 is used as a stabilizer, several stabilizers are respectively prepared into a suspension under the same shearing condition by using a high-speed disperser according to the preparation process, and the stability of each prescription is compared by taking the physical properties, the sedimentation volume ratio and the median particle size of the suspension as investigation indexes to determine the optimal stabilizer. See table 1 and table 2.
Table 1: formulation for screening stabilizers
Table 2: test results of stabilizer screening
The test results show that the five stabilizers used in the preliminary screening are Tween 80 and PVP K-30 The prepared suspension has good properties, the median particle size is smaller, but the sedimentation volume ratio is slightly lower; the suspension prepared from polyethylene glycol 400 and polyethylene glycol 300 has unqualified properties; the suspension prepared from poloxamer 188 has unqualified sedimentation volume ratio and larger particle size. Comparison of Tween 80 and PVP K-30 More advantageously, it is possible to attempt to combine the two as stabilizers.
3.1.3 screening of preservatives
On the basis of a stabilizer screening test, a sample is prepared by using a dominant stabilizer, and sodium benzoate, potassium sorbate, ethylparaben, methylparaben and dimethyl fumarate are respectively added according to 0.5 percent, and detection is carried out according to the microbial limit detection standard of Chinese veterinary pharmacopoeia.
The results show that the bacteriostatic effect of the sodium benzoate, the ethylparaben and the dimethyl fumarate is good, but the ethylparaben has low solubility in water, and ethanol is required to be added as a cosolvent; the dimethyl fumarate has low solubility in water and needs to be heated for dissolution; therefore, sodium benzoate which is easily dissolved in water is selected as the preservative.
3.1.4 screening of prescriptions
Taking albendazole as a main drug, determining that L-malic acid is a cosolvent, tween 80 and PVP (polyvinyl pyrrolidone) through a one-factor test K-30 Is used as a stabilizer, and sodium benzoate is used as a preservative. Selection of L 9 (3 4 ) Designing a table and carrying out an orthogonal test on L-malic acid, tween 80 and PVP K-30 And the concentration of sodium benzoate is screened, and the stability of each prescription is compared by taking the physical properties, sedimentation volume ratio, median particle size, weight dispersity and other pharmaceutical characteristics of the suspension as indexes to determine the optimal prescription. The levels of the factors and the results are shown in tables 3, 4 and 5.
Table 3: formula of each component and dosage level meter thereof
Table 4: orthogonal design table
Table 5: results of testing pharmacological characteristics of each group of suspensions
The results in table 5 show that the albendazole suspension is kept still for 3d after preparation, and the formulas 2, 6 and 7 have good stability and are not easy to settle; the redispersion is good, no sediment is left at the bottom of the measuring cylinder, and the measuring cylinder can be uniformly dispersed; the median particle size is superior to other compositions. The three groups of formula preparations are subjected to microbial limit detection, and the result accords with the pharmacopoeia regulation.
By performing single-factor test and orthogonal design test on the formulation composition, the formulation for preparing the suspension is preferably 7 th group, namely 10g of albendazole, 20g of L-malic acid, 1g of Tween 80 and 3g of PVP (polyvinyl pyrrolidone) in each 100mL of suspension K-30 0.002g of sodium benzoate. The suspension sample initially has the characteristics of stable storage at room temperature, no caking and easy redispersion.
According to the existing suspension formulation, the screening of the cosolvent and the stabilizer in the nano suspension is carried out through a single-factor test. Finally determining that the L-malic acid is cosolvent, the Tween 80 and the PVP through particle size measurement K-30 Is used as a stabilizer and sodium benzoate is used as a preservative.
3.2 preparation Process screening of Albendazole nanosuspension
Selecting L according to the results of the previous formula screening test by using the particle size of the nano suspension as an evaluation index 9 (3 4 ) And (3) designing a table and carrying out an orthogonal test to further optimize the technological conditions of the homogenization pressure combination (A), the homogenization times (B) and the homogenization temperature (C). The factors and levels of the orthogonal tests and the test results are shown in tables 6 and 7.
Table 6: factors and levels of orthogonal design experiments
Note: a refers to homogeneous pressure combination; b refers to the number of homogenization times; c means the homogenization temperature.
Table 7: orthogonal design table
The primary and secondary relationship that the grain size of the nano-crystal is influenced by various factors is A > B > C, which indicates that the homogeneous pressure has the greatest influence on the preparation of the nano-crystal. According to the results of the orthogonal tests, the preferred process parameters are a temperature of 30 ℃,100MPa and 50MPa, each for 25 cycles.
Meanwhile, in order to ensure the feasibility of the preparation process, 3 times of repeated tests of different batches are carried out according to the optimal process conditions, and the average particle size of the obtained result is (365.43 +/-1.68) nm, which indicates that the preferred preparation process is stable and feasible.
The following experiments of the invention are all carried out by adopting the albendazole nanosuspension prepared by the preferable prescription and the preferable preparation method.
3.3 quality evaluation of Albendazole nanosuspensions
3.3.1 color and pH
The nano suspension prepared according to the optimal formula process is white-like in appearance, obvious layering is not observed during standing, and the properties are not obviously changed after the nano suspension is placed for a long time. During the standing process, the pH of the suspension has no obvious change, and the change range is +/-0.1 compared with the initial value.
3.3.2 sedimentation volume ratio
Placing 50mL of the nano suspension in a measuring cylinder with a plug, standing for 30min without layering, standing for 3h until the sedimentation volume ratio is 0.99, which meets the requirements of veterinary drug code of the people's republic of China, and standing for a period of time until the sedimentation surface is not changed any more, and measuring that the sedimentation volume ratio is 0.98.
3.3.3 weight Dispersion
And (3) placing the prepared albendazole nano suspension in a 100mL measuring cylinder with a plug under a room temperature environment, sealing the plug, placing and settling for 7d, turning over the measuring cylinder at the speed of 20 times/min, and eliminating sediments at the bottom, so that the redispersibility is better.
3.3.4 morphological observations and particle size distributions
The nanometer suspension is in a quasi-circular shape under an electron microscope, the shape and the size of the medicine are uniform, and the median particle size is 358.1nm. See fig. 1, table 8 for details.
Table 8: particle size distribution of Albendazole nanosuspension (n = 3)
3.3.5 nanosuspension content
Through determination, the albendazole nanometer suspension content is 99.6%, accord with the pharmacopoeia regulation.
3.4 stability of Albendazole nanosuspensions
The preparation is subjected to an accelerated test under the conditions that the temperature is 30 +/-2 ℃ and the relative humidity is 65 +/-5%, the sample is sampled and detected for 6 months at regular intervals and 1 month, 2 months, 3 months and 6 months respectively, and no obvious difference exists in key investigation items such as sample content, properties, pH value, sedimentation volume ratio, redispersion and the like. Meanwhile, the particle size of a sample which is subjected to accelerated investigation for 6 months is detected, the particle size of the sample is increased when the sample is stored for 6 months under the conditions of room temperature and accelerated sample, but the difference is not obvious, and specific results are shown in tables 9 and 10.
Table 9: results of accelerated albendazole nanosuspension test
Table 10: physical stability of Albendazole nanosuspensions (n = 3)
3.5 kinetic characterization of Albendazole nanosuspensions in rats
3.5.1 method specificity
Under the chromatographic condition established in the test, the albendazole sulfoxide ABZSX has the retention time of 9.7min, stable baseline, good drug peak shape, good separation from impurity peaks and high detection efficiency. The retention time of the internal standard mebendazole is 22min, and the retention time of the albendazole is 28min. Blank plasma chromatogram is shown in figure 2, blank plasma chromatogram with ABZSX (2 ug/mL), internal standard MBZ (10 μ g/mL), albendazole ABZ (3 μ g/mL) is shown in figure 3, and sample plasma chromatogram is shown in figure 4.
3.5.2 plasma Standard working Curve
According to the method for establishing the standard curve, the standard curve is established by taking the measured ratio of the albendazole sulfoxide (ABZSX) peak area to the peak area of an internal standard as an abscissa (x) and the concentration (y) as an ordinate, the ABZSX is in the concentration range of 0.02-10 mu g/mL, the peak area ratio and the concentration form a good linear relation, the regression equation is y = 0.250x +0.0147, and the correlation coefficient r is 0.9992.
3.5.3 methodological validation results
Adding ABZSX standard working solution into blank plasma to make the concentrations of the working solution respectively 0.2, 3.5 and 10 mug/mL, processing according to plasma samples, detecting by HPLC, setting each concentration to be 5 parallels, and determining the variation coefficient in the day to be within 10%; repeating the detection for 5 days, and determining that the day variation coefficient is within 10%; the recovery rate is 83.39% -95.41%; the limit of detection (LOD) and the limit of quantitation (LOQ) are respectively 0.01 and 0.02 mu g/mL, and specific data are shown in Table 11.
Table 11: results of ABZSX addition recovery and intra-day/inter-day variation coefficient test (n = 5) to blank plasma
3.5.4 pharmacokinetic data
The administration and sample treatment were carried out according to the experimental setup protocol, and the mean plasma concentrations at each time point of the three formulations orally administered to rats were shown in table 12 and the mean plasma concentration-time curve was shown in fig. 5 by hplc analysis, detection and calculation. Pharmacokinetic parameters and relative bioavailability of each formulation were estimated using non-compartmental analysis methods and the pharmacokinetic parameters are shown in table 13.
The albendazole nano-suspension developed by the research, albendazole ivermectin powder and the albendazole suspension have the blood drug peak concentration C max 5.895, 2.804 and 2.053 mu g/mL respectively, and the drug peak reaching time T max The time periods are respectively 4.0 h, 4.667 h and 4.40h, which shows that the peak concentration of the albendazole nano suspension is obviously higher than that of albendazole ivermectin powder and albendazole suspension of Foshan Zhengdian, and the absorption rate is obviously higher than that of other two preparations.
The relative bioavailability of the albendazole nano suspension to albendazole ivermectin powder and albendazole suspension in Buddha is 214% and 299.74% respectively, and the albendazole nano suspension in the research can obviously improve the bioavailability of albendazole.
Table 12: plasma concentrations of metabolite ABZSX (n = 10) at various time points after oral administration of albendazole ivermectin powder and 2 suspensions (45 mg/kg. Bw) in rats
Table 13: major pharmacokinetic parameters of ABZSX after oral administration of albendazole ivermectin powder and 2 suspensions (45 mg/kg. Bw) to rats (n = 10)
4. Conclusion and discussion
The preparation process of the nano suspension mainly combines the precipitation technology in the Bottom-up technology and the high-pressure homogenization technology in the Top-down technology for use, namely an anti-solvent method-high-pressure homogenization method. In the precipitation process, crystalline-state particles of the nanocrystals can be generated when the drug is separated out, amorphous-state nanocrystals can also be generated, and on the basis of the two forms of the nanocrystals, the nanocrystals with smaller polydispersity index and smaller particle size can be easily obtained by further performing a high-pressure homogenization process. According to the invention, in the process of drug precipitation, the high-speed disperser is used for shearing, so that the precipitated nanocrystals can obtain smaller particle sizes through primary shearing, the primary mixed liquid is obtained, the primary mixed liquid is subjected to high-pressure homogenization, the particle size reduction which needs more homogenization circulation and more circulation pressure is avoided, the production time is reduced, and the machine abrasion is reduced.
The nano suspension of the invention changes the traditional precipitation method that the medicine is dissolved in an organic solvent and the stabilizing agent is dissolved in an anti-solvent (usually water) for crystallization and precipitation in terms of the formula. The method has the disadvantages that the medicine needs to be dissolved in an organic solvent, and the obtained nano suspension has the defects of existence of the organic solvent, poor physical stability, easy generation of sedimentation and aggregation and low medicine loading capacity. In the research, an organic solvent is not adopted, but the medicine is dissolved in a cosolvent malic acid solution, and the dissolved medicine is added into an aqueous solution of a stabilizer for crystallization and precipitation under the heating condition of ensuring the stability of the medicine. Malic acid can be used in pharmaceutical preparation, and is beneficial for absorption and diffusion of medicine in vivo and beneficial to organism.
The quality evaluation and preparation stability research results of the nano-suspension in the research show that the nano-suspension meets the quality requirements of suspensions in Chinese animal pharmacopoeia, an accelerated test is carried out for 6 months under specified conditions, the appearance color, the content, the pH value, the sedimentation volume ratio and the redispersion of the preparation all meet the requirements, and the particle size after the nano-suspension is placed for 6 months does not change significantly, which shows that the albendazole nano-suspension prepared by the preparation process in the research has high physical stability.
After oral administration of albendazole, the albendazole is metabolized into albendazole sulfoxide ABZSX, albendazole sulfone ABZSN and ABZSO 2 －NH 2 The most important metabolite is ABZSX, which is also the active ingredient against echinococcosis. The results of pharmacokinetic and relative bioavailability experiments in rats show that when the albendazole nano-suspension of the research is orally taken, compared with albendazole ivermectin powder and albendazole suspension in the Yangshan, the main pharmacokinetic parameter T in vivo is max 、C max 、AUC 0-∞ 、Vz_F、Cl_F、MRT、t 1/2 All have significant differences; the bioavailability of the preparation is remarkably higher than that of powder (relative bioavailability F = 214%) and a Foshan Zhengdian product (relative bioavailability F = 299.74%). Albendazole belongs to a concentration-dependent drug, and the improvement of the drug concentration can obviously improve the clinical treatment effect.
Wherein, the nano preparation of the research has smaller T than powder and Buddha mountain Zhengdian products max Higher C max Indicating that it is rapidly absorbed in the body and the drug absorption amount is increased; the nano preparation of the research also has longer in-vivo average retention time (MRT), higher area under the curve of drug time AUC and lower clearance rate Cl _ F, which proves that the preparation has longer retention time in the gastrointestinal tract and increased absorption, thereby improving the life of the drugHas high bioavailability and improved therapeutic effect.
In conclusion, the nanometer suspension prepared from albendazole by an anti-solvent method-high pressure homogenization method can obtain smaller drug particle size, compared with albendazole ivermectin powder and Foshan Zhengdian albendazole suspension, the drug preparation is easier to rapidly and uniformly disperse in gastrointestinal fluid due to the reduction of the particle size, and under the action of a stabilizer, the drug overcomes the obstacle when macromolecules pass through the epithelial cell membrane of the gastrointestinal tract, is easy to transfer to an absorption part through a hydration layer of the gastrointestinal wall, is favorable for improving the dissolution rate and the permeability of the drug, can be continuously dissolved out of a matrix and permeate to the absorption part, ensures that the absorption rate is rapid and the absorption amount is increased in the gastrointestinal tract, improves the bioavailability of the drug, and enhances the insect expelling effect.
It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.
Claims (2)
1. An albendazole nanosuspension, which is characterized in that: the albendazole nano suspension is prepared from 10 parts by weight of albendazole, 20 parts by weight of cosolvent, 4 parts by weight of stabilizer and 0.002 part by weight of preservative, wherein the albendazole nano suspension is prepared by an anti-solvent method-high pressure homogenization method, the average particle size of the albendazole in the nano suspension is less than 400nm, the albendazole is in a quasi-circular shape under an electron microscope, the cosolvent is L-malic acid, and the stabilizer is PVP k30 And tween-80 in a weight ratio of 3:1, the preservative is sodium benzoate, and the preparation method of the albendazole nanosuspension comprises the following steps:
(1) According to the formula proportion, firstly dissolving a cosolvent by using a small amount of distilled water, heating to 80-90 ℃, adding the albendazole raw material into the cosolvent, and keeping the heating temperature to completely dissolve the albendazole raw material in the cosolvent solution;
(2) Weighing a stabilizer, dissolving the stabilizer in a proper amount of distilled water, slowly adding the dissolved albendazole solution into the stabilizer solution by using a high-speed disperser under a shearing condition, recrystallizing and separating out the albendazole, and obtaining a smaller particle size by shearing to obtain a primary mixed solution, wherein the shearing condition is 8000rpm and 20min;
(3) Placing the primary mixed solution in a high-pressure homogenizer, homogenizing for certain times at a set temperature and pressure to obtain a nanocrystal suspension, wherein the homogenization process parameter is a homogenization temperature of 30 ℃, and each circulation is carried out for 25 times under the homogenization pressures of 100MPa and 50 MPa;
(4) Adding dissolved antiseptic into the homogenized nanocrystal suspension, stirring, adjusting pH, adding distilled water to full volume, and stirring to obtain the final product, wherein the pH regulator is sodium hydroxide and the adjusted pH is 5-7.
2. A process for the preparation of the albendazole nanosuspension of claim 1, characterized in that: the method comprises the following steps:
(1) According to the formula proportion of claim 1, firstly dissolving a cosolvent by using a small amount of distilled water, heating to 80-90 ℃, adding albendazole raw material into the cosolvent, and keeping the heating temperature to completely dissolve the albendazole raw material in the cosolvent solution;
(2) Weighing a stabilizer, dissolving the stabilizer in a proper amount of distilled water, slowly adding the dissolved albendazole solution into the stabilizer solution by using a high-speed disperser under a shearing condition, recrystallizing and separating out the albendazole, and obtaining a smaller particle size by shearing to obtain a primary mixed solution, wherein the shearing condition is 8000rpm and 20min;
(3) Placing the primary mixed solution in a high-pressure homogenizer, homogenizing for certain times at a set temperature and pressure to obtain a nanocrystal suspension, wherein the homogenization process parameter is a homogenization temperature of 30 ℃, and the homogenization process parameters are respectively circulated for 25 times under the homogenization pressures of 100MPa and 50 MPa;
(4) Adding dissolved antiseptic into the homogenized nanocrystal suspension, stirring, adjusting pH, adding distilled water to full volume, and stirring to obtain the final product, wherein the pH regulator is sodium hydroxide and the adjusted pH is 5-7.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111598896.4A CN114224834B (en) | 2021-12-24 | 2021-12-24 | Albendazole nano suspension with high bioavailability and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111598896.4A CN114224834B (en) | 2021-12-24 | 2021-12-24 | Albendazole nano suspension with high bioavailability and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114224834A CN114224834A (en) | 2022-03-25 |
| CN114224834B true CN114224834B (en) | 2022-11-11 |
Family
ID=80762627
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111598896.4A Active CN114224834B (en) | 2021-12-24 | 2021-12-24 | Albendazole nano suspension with high bioavailability and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114224834B (en) |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010011289A2 (en) * | 2008-07-24 | 2010-01-28 | University Of Houston | Parenteral and oral formulations of benzimidazoles |
| WO2010080754A2 (en) * | 2009-01-06 | 2010-07-15 | Pharmanova, Inc. | Nanoparticle pharmaceutical formulations |
| CN101947201A (en) * | 2010-09-08 | 2011-01-19 | 洛阳惠中兽药有限公司 | Veterinary nanometer suspension, preparation method thereof and application thereof |
| CN101984958A (en) * | 2010-11-01 | 2011-03-16 | 新疆医科大学第一附属医院 | Nanoscale albendazole micropowder and preparation method thereof |
| CN102440996A (en) * | 2011-12-29 | 2012-05-09 | 郑国祥 | Compound albendazole suspension containing ivermectin nanoemulsion and preparation method thereof |
| TW201323013A (en) * | 2011-10-19 | 2013-06-16 | Univ Gent | Pharmaceutical nanosuspension |
| CN108403646A (en) * | 2018-04-08 | 2018-08-17 | 新疆医科大学第附属医院 | Albendazole nano powder and preparation method thereof |
| CN110693830A (en) * | 2019-10-10 | 2020-01-17 | 华中农业大学 | Veterinary oxfendazole nano suspension and preparation method thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2669815A1 (en) * | 2006-11-28 | 2008-06-05 | Marinus Pharmaceuticals | Nanoparticulate formulations and methods for the making and use thereof |
| GB0909154D0 (en) * | 2008-09-25 | 2009-07-08 | Nanomaterials Tech Pte Ltd | A process for making particles for delivery of drug nanoparticles |
| US20180344645A1 (en) * | 2017-06-06 | 2018-12-06 | Purdue Research Foundation | Prepartion of nanocrystals and nanaoparticles of narrow distribution and uses thereof |
| EP3616688A1 (en) * | 2018-08-27 | 2020-03-04 | Centre National de la Recherche Scientifique - CNRS | Preparation of nanosuspension comprising nanocrystals of active pharmaceutical ingredients with little or no stabilizing agents |
-
2021
- 2021-12-24 CN CN202111598896.4A patent/CN114224834B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010011289A2 (en) * | 2008-07-24 | 2010-01-28 | University Of Houston | Parenteral and oral formulations of benzimidazoles |
| WO2010080754A2 (en) * | 2009-01-06 | 2010-07-15 | Pharmanova, Inc. | Nanoparticle pharmaceutical formulations |
| CN101947201A (en) * | 2010-09-08 | 2011-01-19 | 洛阳惠中兽药有限公司 | Veterinary nanometer suspension, preparation method thereof and application thereof |
| CN101984958A (en) * | 2010-11-01 | 2011-03-16 | 新疆医科大学第一附属医院 | Nanoscale albendazole micropowder and preparation method thereof |
| TW201323013A (en) * | 2011-10-19 | 2013-06-16 | Univ Gent | Pharmaceutical nanosuspension |
| CN102440996A (en) * | 2011-12-29 | 2012-05-09 | 郑国祥 | Compound albendazole suspension containing ivermectin nanoemulsion and preparation method thereof |
| CN108403646A (en) * | 2018-04-08 | 2018-08-17 | 新疆医科大学第附属医院 | Albendazole nano powder and preparation method thereof |
| CN110693830A (en) * | 2019-10-10 | 2020-01-17 | 华中农业大学 | Veterinary oxfendazole nano suspension and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 《难溶性药物理化性质对其纳米混悬剂生物利用度的影响》;李炜;《中国优秀博硕士学位论文全文数据库(博士)》;20141015;第医药卫生科技辑卷(第10期);E079-4 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114224834A (en) | 2022-03-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Wang et al. | Bioavailability and pharmacokinetics of sorafenib suspension, nanoparticles and nanomatrix for oral administration to rat | |
| EP2802314B1 (en) | A method for producing stable, amorphous hybrid nanoparticles comprising at least one protein kinase inhibitor and at least one polymeric stabilizing and matrix- forming component. | |
| EP2932978A1 (en) | Application of silicon dioxide aerogel in pharmacy | |
| JP2004534811A (en) | Pharmaceutical composition comprising a polymer and drug assembly | |
| Priotti et al. | Albendazole microcrystal formulations based on chitosan and cellulose derivatives: physicochemical characterization and in vitro parasiticidal activity in Trichinella spiralis adult worms | |
| KR20190005183A (en) | Full Best Land formulation and its use | |
| Wagh et al. | Formulation and evaluation of glimepiride solid dispersion tablets for their solubility enhancement | |
| WO2014003677A1 (en) | Pharmaceutical compositions comprising solid dispersion particles containing tadalafil | |
| CN114224834B (en) | Albendazole nano suspension with high bioavailability and preparation method thereof | |
| CN103494820B (en) | Two medicine carrying PLGA nanoparticle of a kind of nimodipine/ligustrazine and preparation method thereof | |
| CN112336692A (en) | Folic acid tablet and preparation method thereof | |
| Palani et al. | Enhancement of rosuvastatin calcium bioavailability applying nanocrystal technology and in-vitro, in-vivo evaluations | |
| US11344496B2 (en) | Methods for preparing stabilized amorphous drug formulations using acoustic fusion | |
| CN107137349B (en) | Gambogic acid nanosuspension and preparation method thereof | |
| CN111148513A (en) | Sustained-release suspension containing dezocine analogue ester and preparation method thereof | |
| CN106902357B (en) | Pharmaceutical composition and application thereof, pharmaceutical clathrate, intravenous preparation and preparation method | |
| Zai et al. | Solid lipid nanoparticle improves oral bioavailability of famotidine | |
| CN114042046B (en) | Ibrutinib albumin nano preparation for soluble injection and preparation method and application thereof | |
| Koli et al. | Development of albendazole nanosuspension by various techniques | |
| Tamboli et al. | Immediate release solid dispersion tablet of azilsartan: Formulation strategy to enhance oral bioavailability | |
| CN110787125A (en) | Aprepitant nano preparation and preparation method thereof | |
| CN113952298B (en) | Cefquinome sulfate nano suspension and preparation method thereof | |
| Khader et al. | Enhancement of Solubility And Dissolution Profile of Clopidogrel By Various Solid Dispersion Formulations | |
| Chen et al. | Determination of deferasirox particle size distribution via laser diflraction and its application in establishing a correlation between particle size and drug dissolution in vitro. | |
| Geetha et al. | Formulation And Evaluation of Ibrutinib Nanosuspension |
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 |