环孢素-泊洛沙姆188固体分散体的体外评价

目的以泊洛沙姆188（F68）为载体制备环孢素（CsA）固体分散体并考察其体外溶出。方法以溶剂一熔融法制备固体分散体，以差示扫描量热法（DSC）和X．射线衍射法鉴定CsA在体系中的存在状态，以FTIR表征药物与载体的相互作用，以摇瓶法测定CsA的溶解度，按《中国药典》溶出度第三法测定CsA从物理混合物和固体分散体中的溶出。结果X-射线衍射图谱显示CsA结晶衍射峰消失，提示药物以无定形或分子状态存在于固体分散体中。FTIR结果表明药物与载体间无相互作用。药物溶解度和溶出度均随着F68比例的增加而增大，固体分散体和物理混合物60min的累积溶出百分率分别为99．32％和75．41％，两者具显著性差异（P〈0．01）。结论F68能提高CsA的溶解度和溶出度，可用来制备CsA的固体剂型。     

Effect of drug-carrier interaction on the dissolution behavior of solid dispersion tablets

The objective of this study was to compare the dissolution behavior of tablets prepared from solid dispersions with and without drug-carrier interactions. Diazepam and nifedipine were used as model drugs. Two types of carriers were used; polyvinylpyrrolidone (PVP K12, K30 and K60) and saccharides (inulin 1.8?kDa, 4?kDa and 6.5?kDa). Solid dispersions with various drug loads were prepared by lyophilization. It was found that the drug solubility in aqueous PVP solutions was significantly increased indicating the presence of drug-carrier interaction while the drug solubility was not affected by the saccharides indicating absence of drug-carrier interaction. X-ray powder diffraction and modulated differential scanning calorimetry revealed that all solid dispersions were fully amorphous. Dissolution behavior of solid dispersion tablets based on either the PVPs or saccharides was governed by both dissolution of the carrier and drug load. It was shown that a fast drug dissolution of solid dispersions with a high drug load could be obtained with carrier that showed interaction with the drug.     

Physicochemical characterization of tacrolimus-loaded solid dispersion with sodium carboxylmethyl cellulose and sodium lauryl sulfate

To develop a novel tacrolimus-loaded solid dispersion with improved solubility, various solid dispersions were prepared with various ratios of water, sodium lauryl sulfate, citric acid and carboxylmethylcellulose-Na using spray drying technique. The physicochemical properties of solid dispersions were investigated using scanning electron microscopy, differential scanning calorimetery and powder X-ray diffraction. Furthermore, their solubility and dissolution were evaluated compared to drug powder. The solid dispersion at the tacrolimus/CMC-Na/sodium lauryl sulfate/citric acid ratio of 3/24/3/0.2 significantly improved the drug solubility and dissolution compared to powder. The scanning electron microscopy result suggested that carriers might be attached to the surface of drug in this solid dispersion. Unlike traditional solid dispersion systems, the crystal form of drug in this solid dispersion could not be converted to amorphous form, which was confirmed by the analysis of DSC and powder X-ray diffraction. Thus, the solid dispersion system with water, sodium lauryl sulfate, citric acid and CMC-Na should be a potential candidate for delivering a poorly water-soluble tacrolimus with enhanced solubility and no convertible crystalline.     

Surface-active derivative of inulin (Inutec® SP1) is a superior carrier for solid dispersions with a high drug load

The aim of this study was to compare the applicability of inulin, its surface-active derivative (Inutec? SP1), and polyvinylpyrrolidone (PVP) as carriers in high drug load solid dispersions (SDs) for improving the dissolution rate of a range of lipophilic drugs (diazepam, fenofibrate, ritonavir, and efavirenz). The SDs were prepared by spray freeze-drying. Scanning electron microscopy showed that the obtained samples were highly porous spherical particles. Modulated differential scanning calorimetry showed that the drugs incorporated in these carriers were fully or partially amorphous. The solubility of the drugs in solutions of the different carriers was increased in an order: inulin 2.3 kDa < PVP K30 ? Inutec? SP1. The dissolution behavior of SD tablets was evaluated. Inutec? SP1-based SD tablets showed the best performance followed by PVP- and inulin-based SD tablets. The superior dissolution behavior of the drugs from Inutec? SP1-based SDs could be ascribed to its surface-active nature. In addition, Inutec? SP1-based SD tablets gave good physical stability at 20 °C/45% relative humidity (RH) and 40 °C/75% RH for 3 months.     

Solid dispersions based on inulin for the stabilisation and formulation of delta 9-tetrahydrocannabinol.

The aim of this study was to develop a dry powder formulation that stabilises the chemically labile lipophilic Delta(9)-tetrahydrocannabinol (THC), that rapidly dissolves in water in order to increase the bioavailability and that opens new routes of administration. It was investigated whether these aims can be achieved with solid dispersions consisting of a matrix of inulin, an oligo-fructose, in which THC is incorporated. These solid dispersions were prepared by lyophilisation of a solution of THC and inulin in a mixture of water and tertiary butyl alcohol (TBA). Both 4 and 8 wt.% of THC could be incorporated in a glassy matrix of inulin. In the solid dispersions only 0.4-0.5 wt.% of residual TBA was present after storage at 20 degrees C/45% relative humidity (RH) for 7 days. Unprotected THC was completely degraded after 40 days of exposure to 20 degrees C and 45% RH. However, solid dispersions exposed to the same conditions still contained about 80% non-degraded THC after 300 days. Dissolution experiments with tablets compressed from inulin glass dispersion material showed that THC and inulin dissolved at the same rate. Tablets weighing 125 mg and containing 2mg THC were prepared from a mixture of THC containing solid dispersion, polyvinylpolypyrrolidone (PVPP) and mannitol. Dissolution tests revealed that from these tablets 80% of the THC was dissolved within 3 min, which makes them promising for sublingual administration. It was concluded that THC can be strongly stabilized by incorporating it in a matrix of inulin. The aqueous dissolution rate was high which may improve bioavailability.     

Comparison of HPMC based polymers performance as carriers for manufacture of solid dispersions using the melt extruder

Preparation of amorphous solid dispersions using hot-melt extrusion process for poorly water soluble compounds which degrade on melting remains a challenge due to exposure to high temperatures. The aim of this study was to develop a physically and chemically stable amorphous solid dispersion of a poorly water-soluble compound, NVS981, which is highly thermal sensitive and degrades upon melting at 165 °C. Hydroxypropyl Methyl Cellulose (HPMC) based polymers; HPMC 3cps, HPMC phthalate (HPMCP) and HPMC acetyl succinate (HPMCAS) were selected as carriers to prepare solid dispersions using hot melt extrusion because of their relatively low glass transition temperatures. The solid dispersions were compared for their ease of manufacturing, physical stability such as recrystallization potential, phase separation, molecular mobility and enhancement of drug dissolution. Two different drug loads of 20 and 50% (w/w) were studied in each polymer system. It was interesting to note that solid dispersions with 50% (w/w) drug load were easier to process in the melt extruder compared to 20% (w/w) drug load in all three carriers, which was attributed to the plasticizing behavior of the drug substance. Upon storage at accelerated stability conditions, no phase separation was observed in HPMC 3cps and HPMCAS solid dispersions at the lower and higher drug load, whereas for HPMCP, phase separation was observed at higher drug load after 3 months. The pharmaceutical performance of these solid dispersions was evaluated by studying drug dissolution in pH 6.8 phosphate buffer. Drug release from solid dispersion prepared from polymers used for enteric coating, i.e. HPMCP and HPMCAS was faster compared with the water soluble polymer HPMC 3cps. In conclusion, of the 3 polymers studied for preparing solid dispersions of thermally sensitive compound using hot melt extrusion, HPMCAS was found to be the most promising as it was easily processible and provided stable solid dispersions with enhanced dissolution.     

Spray freeze drying to produce a stable Delta(9)-tetrahydrocannabinol containing inulin-based solid dispersion powder suitable for inhalation.

The purpose of this study is to investigate whether spray freeze drying produces an inhalable solid dispersion powder in which Delta(9)-tetrahydrocannabinol (THC) is stabilised. Solutions of THC and inulin in a mixture of tertiary butanol (TBA) and water were spray freeze dried. Drug loads varied from 4 to 30 wt.%. Various powder characteristics of the materials were determined. Stability of THC was determined and compared with freeze dried material. The powders, dispersed with an inhaler based on air classifier technology, were subjected to laser diffraction analysis and cascade impactor analysis. Highly porous particles having large specific surface areas (about 90 m(2)/g) were produced. At high drug loads, THC was more effectively stabilised by spray freeze drying than by freeze drying. Higher cooling rates during spray freeze drying result in improved incorporation. Fine particle fractions of up to 50% were generated indicating suitability for inhalation. It was concluded that spray freeze drying from a water-TBA mixture is a suitable process to include lipophilic drugs (THC) in inulin glass matrices. High cooling rates during the freezing process result in effective stabilisation of THC. The powders can be dispersed into aerosols with a particle size appropriate for inhalation.     

Application of novel chitosan derivatives in dissolution enhancement of a poorly water soluble drug

Solid dispersions of the poorly water soluble drug dexamethasone and newly synthesized chitosan derivatives (chitosan succinate, CS, and chitosan phthalate, CP) were prepared by spray drying. The resulting microspheres were evaluated in terms of their drug loading or encapsulation efficiency as well as drug release profile. Differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and infrared spectroscopy (IR) were used to evaluate the solid dispersion for possible interactions between drug and polymers. The pure drug was evaluated in the same manner for comparison purposes. High loading levels (>74%) were achieved using CP and CS as polymer matrices. Drug release rate was accelerated significantly upon the formation of the solid dispersions; the drug release rate was increased with increasing percentage of the chitosan derivatives in the microspheres. IR studies showed no chemical interaction while the X-ray studies showed a significant change in the crystallinity of the drug upon formation of solid dispersions.     

An Investigation into the Effect of Spray Drying Temperature and Atomizing Conditions on Miscibility,Physical Stability,and Performance of Naproxen–PVP K 25 Solid Dispersions

The present study investigates the effect of changing spray drying temperature (40°C–120°C) and/or atomizing airflow rate (AR; 5–15 L/min) on the phase structure, physical stability, and performance of spray-dried naproxen–polyvinylpyrrolidone (PVP) K25 amorphous solid dispersions. The modulated differential scanning calorimetry, attenuated total internal reflectance-Fourier transform infrared, and powder X-ray diffractometry (pXRD) studies revealed that higher inlet temperature (IT) or atomization airflow leads to the formation of amorphous-phase-separated dispersions with higher strongly H-bonded and free PVP fractions, whereas that prepared with the lowest IT was more homogeneous. The dispersion prepared with the lowest atomization AR showed trace crystallinity. Upon exposure to 75% relative humidity (RH) for 3 weeks, the phase-separated dispersions generated by spray drying at higher temperature or higher atomization airflow retained relatively higher amorphous drug fraction compared with those prepared at slow evaporation conditions. The humidity-controlled pXRD analysis at 98% RH showed that the dispersion prepared with highest atomization AR displayed the slowest kinetics of recrystallization. The molecular-level changes occurring during recrystallization at 98% RH was elucidated by spectroscopic monitoring at the same humidity. The rate and extent of the drug dissolution was the highest for dispersions prepared at the highest atomizing AR and the lowest for that prepared with the slowest atomizing condition.     

An in-vitro assessment of a NanoCrystal beclomethasone dipropionate colloidal dispersion via ultrasonic nebulization.

Short duration ultrasonic nebulization of a concentrated NanoCrystal colloidal dispersion of beclomethasone dipropionate demonstrated an increased respirable fraction and decreased throat deposition when evaluated in an Andersen 8-stage cascade impactor in comparison to the commercially available propellant-based product Vanceril. An aqueous-based 1.25% w/w colloidal dispersion of beclomethasone dipropionate when aerosolized via an Omron NE-U03 ultrasonic nebulizer generated a respirable drug dose from 22.6 to 39.4 micrograms per 2 s actuation period, compared to 12.8 micrograms for a single actuation of Vanceril. When viewed as a percentage of the emitted dose (through the actuator or mouthpiece), the respirable fraction ranged from 56 to 72% for the nanocrystalline formulation versus 36% for the propellant system. In addition, the throat deposition as seen in the induction port was 9-10% of the emitted dose for the novel suspension, as compared to 53% for the commercial product. Thus, when used with the device outlined herein, a nanocrystalline colloidal suspension of beclomethasone dipropionate affords greater potential drug delivery to the conductive airways of the lung in both quantity and as a percent of emitted dose. Additionally, lower potential throat deposition values were observed which may retard the development of undesirable side effects, such as candidiasis, when compared to a propellant based delivery system. Lastly, the ability to atomize aqueous-based nanocrystalline colloidal dispersions represents an environmentally sound alternative to the current chlorofluorocarbon (CFC)-based products and may avoid the technical difficulties of reformulating with chlorine-free propellants.     

尼莫地平固体分散物的研究

尼莫地平临床上主要用于防治缺血性脑血管疾病．该药为难溶性药物，生物利用度低，本文采用了固体分散技术制备了尼莫地平两种固体分散物，其体外溶出速率１０分钟以内达８０％以上，较市售片有显著提高．两种固体分散物中，固体分散物Ⅰ为本实验室研制，固体分散物Ⅱ参照国内、外文献用ＰＶＰ为载体制备．两种固体分散物均能明显提高尼莫地平的体外溶出速率，但固体分散物Ⅱ易于老化，经相对湿度ＲＨ７５％４０℃贮藏３个月溶出速率明显下降，同样条件下，固体分散物Ⅰ则无明显变化．二种固体分散物Ｘ－射线衍射图谱表明尼莫地平以非晶体状态存在，而在ＲＨ７５％４０℃条件下放置３个月后，固体分散物ⅡＸ－射线衍射图谱出现了尼莫地平结晶峰．     

Preparation, characterization and in vitro dissolution of aceclofenac-loaded PVP solid dispersions prepared by spray drying or rotary evaporation method

This study was conducted to enhance dissolution rate of aceclofenac (ACF) with extremely low solubility and high permeability (BCS class II) in water using poly vinyl pyrrolidone (PVP) and sodium lauryl sulfate as carriers. Solid dispersions were prepared by spray drying method and rotary evaporation method using different ratios of ACF and polymers. The characterization of solid dispersions was evaluated by scanning electron microscopy, Fourier transformation infrared spectroscopy, differential scanning calorimetry and powder X-ray diffractometer. The dissolution behavior of solid dispersions was compared with pure ACF (API) and Airtal^® (Deawoong, Co, Korea) as control groups in simulated phosphate buffer at pH 6.8. The dissolution rate of the drug was affected by nature and amount of polymer used. The prepared solid dispersion of ACF/PVP (1:5) appeared to have the highest dissolution rate. Therefore, solid dispersion techniques of spray drying and rotary evaporation method can be successfully used for the enhancement of the dissolution rate of ACF.     

他达那非固体分散体的制备和性质研究

目的制备他达那非(tadalafil,TD)固体分散体并进行性质研究。方法利用喷雾干燥法制备固体分散体,以表观溶解度和溶出度为指标筛选处方,采用差示扫描量热(DSC)、粉末X-射线衍射(PXRD)和接触角测定等技术研究药物的存在状态和润湿性等理化性质。结果固体分散体将他达那非的表观溶解度提高22.6倍;20min内药物的累积溶出超过90%;固体分散体药物以分子或无定形状态存在;接触角减小,润湿性增大。结论采用十二烷基硫酸钠(SDS)和介孔硅为载体制备的他达那非固体分散体,能明显提高药物的表观溶解度和溶出度。     

Free flowing solid dispersions of the anti-HIV drug UC 781 with Poloxamer 407 and a maximum amount of TPGS 1000: Investigating the relationship between physicochemical characteristics and dissolution behaviour

Solid dispersions and physical mixtures made up of the poorly water-soluble drug UC 781, a polymer and a surfactant were prepared to contribute to the understanding of the relationship between physicochemical characteristics and dissolution behaviour. In addition, to facilitate downstream processing while still favouring drug dissolution to a maximum extent, formulation conditions were investigated to obtain a free flowing powder which contains a maximum amount of surfactant. Poloxamer 407, a polyethylene-polypropylene glycol block copolymer, was selected as a suitable polymer based on UC 781 supersaturation results. d-Alpha-tocopheryl polyethyleneglycol succinate 1000 (TPGS 1000) was preferred as a surfactant since it increased UC 781 dissolution when formulated in a self-micro emulsifying drug delivery system (SMEDDS), as compared to TPGS 400, TPGS 4000 and TPGS 6000. Based on flow properties, a TPGS 1000/Poloxamer 407 ratio of 80/20 was used to prepare solid dispersions by spray drying. Pure drugs, physical mixtures and solid dispersions were characterized by differential scanning calorimetry and X-ray powder diffraction. Eutectic phase behaviour was obtained in which the relative distribution of the polyethylene glycol folding was dependent on UC 781 concentration. Drug release was markedly increased when formulated as a solid dispersion with Poloxamer 407 and TPGS 1000. Formulation of solid dispersions did however not further improve the drug dissolution rate compared to that of physical mixtures. Nonetheless, variability of dissolution results was considerably reduced upon solid dispersion formulation.     

Physicochemical characterization and dissolution properties of meloxicam-gelucire 50/13 binary systems

A solid dispersion of Meloxicam (MX), a poorly soluble, non steroidal anti-inflammatory drug, and Gelucire 50/13 was prepared by spray drying. Spherical microparticles were yielded with smooth surfaces as observed by scanning electron microscopy. According to differential scanning calorimetry and powder X-ray diffractometry analysis, MX was transformed from the crystalline state to the amorphous state as confirmed by the disappearance of its melting peak and the crystalline peaks. The dissolution tests at pH 7.4 revealed that the dissolution rate of encapsulated MX was 2.5-fold higher than that of the corresponding physical mixture and fourfold higher than the drug alone, respectively. The microparticles prepared at a ratio of 1:4 (drug/Gelucire) exhibited a 4-fold higher anti-inflammatory activity on the paw edema of rats in comparison to the drug alone. All in all, this work reveals that spray drying is a suitable technique for preparation of solid dispersions with improved biopharmaceutical and pharmacological characteristics of MX.     

Preparation of high solubilizable microemulsion of naproxen and its solubilization mechanism

With the aim of developing a novel valsartan-loaded solid dispersion with enhanced bioavailability and no crystalline changes, various valsartan-loaded solid dispersions were prepared with water, hydroxypropyl methylcellulose (HPMC) and sodium lauryl sulphate (SLS). Effects of the weight ratios of SLS/HPMC and carrier/drug on both the aqueous solubility of valsartan and the drug-release profiles of solid dispersions were investigated. The physicochemical properties of solid dispersions were characterized using scanning electron microscope (SEM), differential scanning calorimetry (DSC) and X-ray diffraction (XRD). The bioavailability of the solid dispersions in rats was evaluated compared to valsartan powder and a commercial product (Diovan). Unlike the conventional solid dispersion system, the valsartan-loaded solid dispersion had a relatively rough surface and did not change the crystalline form of the drug. It was suggested that the solid dispersions were formed by attaching hydrophilic carriers to the surface of the drug, thus changing from a hydrophobic to a hydrophilic form without changing the crystalline form. The drug-loaded solid dispersion composed of valsartan/HPMC/SLS at a weight ratio of 3/1.5/0.75 improved the drug solubility by about 43-fold. It gave a higher AUC, C(max) and shorter T(max) compared to valsartan powder and the commercial product. The solid dispersion improved the bioavailability of the drug in rats by about 2.2 and 1.7-fold in comparison with valsartan powder and the commercial product, respectively. Thus, the valsartan-loaded solid dispersion would be useful for delivering poorly water-soluble valsartan with enhanced bioavailability and no crystalline changes.     

缬沙坦固体分散体的制备及体外溶出度研究

目的采用冷冻干燥法制备缬沙坦（Valsartan）速释固体分散体（SD）来提高其体外溶出度。方法分别以羟丙甲基纤维素（HPMC）、聚乙二醇6000（PEG6000）、聚乙烯吡咯烷酮k30（PVPk30）为载体,十二烷基硫酸钠（SDS）为表面活性剂来制备不同比例的缬沙坦固体分散体,通过测定体外溶出度,来选择最优辅料及比例,结果当以PEG6000载体,SDS为表面活性剂时,且药物：PEG6000：SDS=1：5：1％时药物呈现了很好的水溶性。结论在5min时即可溶出90％以上,很大程度上提高了缬沙坦的体外溶出度。     

Strongly enhanced dissolution rate of fenofibrate solid dispersion tablets by incorporation of superdisintegrants

In this study, it was shown that the incorporation of superdisintegrants in solid dispersion tablets containing a high drug load can strongly enhance the dissolution rate of the highly lipophilic drug fenofibrate. In addition, the dissolution rate was more increased when the superdisintegrant was incorporated in the drug containing solid dispersions than when it was physically mixed with the solid dispersions. The dissolution rate enhancement strongly depended on the type of superdisintegrants and increased in the order Polyplasdone^® XL-10 < Polyplasdone^® XL  Ac-Di-Sol^® ≈ Primojel^®. The dissolution behavior also depended on the type of hydrophilic carriers. Solid dispersion tablets based on inulin 4 kDa, polyethylene glycol 20 K and polyvinylpyrrolidone K30 showed a much faster dissolution than those based on mannitol and hydroxypropyl-β-cyclodextrin. Finally, inulin 4 kDa-based solid dispersion tablets showed excellent storage stability, while polyethylene glycol 20 K-and polyvinylpyrrolidone K30-based solid dispersion tablets did not.     

Silymarin-solid dispersions: characterization and influence of preparation methods on dissolution

The influence of preparation methodology of silymarin solid dispersions using a hydrophilic polymer on the dissolution performance of silymarin was investigated. Silymarin solid dispersions were prepared using HPMC E 15LV by kneading, spray drying and co-precipitation methods and characterized by FTIR, DSC, XRPD and SEM. Dissolution profiles were compared by statistical and model independent methods. The FTIR and DSC studies revealed weak hydrogen bond formation between the drug and polymer, while XRPD and SEM confirmed the amorphous nature of the drug in co-precipitated solid dispersion. Enhanced dissolution compared to pure drug was found in the following order: co-precipitation > spray drying > kneading methodology (p < 0.05). All preparation methods enhanced silymarin dissolution from solid dispersions of different characteristics. The co-precipitation method proved to be best and provided a stable amorphous solid dispersion with 2.5 improved dissolution compared to the pure drug.     

Cefuroxime axetil solid dispersion with polyglycolized glycerides for improved stability and bioavailability

Objectives Cefuroxime axetil (CA), a poorly soluble, broad spectrum cephalosporin ester prodrug, is hydrolysed by intestinal esterase prior to absorption, leading to poor and variable bioavailability. The objective was therefore to formulate a stable amorphous solid dispersion of the drug with enhanced solubility and stability against enzymatic degradation. Methods Spray drying was used to obtain a solid dispersion of CA with Gelucire 50/13 and Aerosil 200 (SDCAGA), and a solid dispersion of CA with polyvinyl pyrrolidone (SDCAP); amorphous CA (ACA) was obtained by spray drying CA alone. The formulations were characterized by differential scanning calorimetry, X‐ray powder diffraction, scanning electron microscopy and Fourier transform infrared spectroscopy studies, and compared for solubility, dissolution and bioavailability in rats. Key findings SDCAP and SDCAGA showed improved solubility and dissolution profiles owing to amorphization and formation of solid dispersions with hydrophilic carriers. The improved stability of amorphous CA in solid dispersions compared to ACA alone was attributed to hydrogen bonding interactions involving the amide of CA with the carbonyl of polyvinyl pyrrolidone in SDCAP, whereas in SDCAGA the interactions were at multiple sites involving the amide and carbonyl of CA with the carbonyl and hydroxyl of Gelucire 50/13. However, SDCAGA showed superior bioavailability compared to SDCAP, ACA and CA. Conclusions Improvement in physical stability of solid dispersions was attributed to hydrogen bonding, while improvement in bioavailability of SDCAGA compared to SDCAP, in spite of comparable solubility and dissolution profile, may be attributed to Gelucire, which utilizes intestinal esterase for lipolysis, protecting the prodrug from enzymatic degradation to its non‐absorbable base form.