Fast-dissolving tablets of glyburide based on ternary solid dispersions with PEG 6000 and surfactants

Marketed glyburide tablets present unsatisfying dissolution profiles that give rise to variable bioavailability. With the purpose of developing a fast-dissolving tablet formulation able to assure a complete drug dissolution, we investigated the effect of the addition to a reference tablet formulation of different types (anionic and nonionic) and amounts of hydrophilic surfactants, as well as the use of a new technique, based on ternary solid dispersions of the drug with an hydrophilic carrier (polyethylene glycol [PEG] 6000) and a surfactant. Tablets were prepared by direct compression or previous wet granulation of suitable formulations containing the drug with each surfactant or drug:PEG:surfactant ternary dispersions at different PEG:surfactant w/w ratios. The presence of surfactants significantly increased (p<0.01) the drug dissolution rate, but complete drug dissolution was never achieved. On the contrary, in all cases tablets containing ternary solid dispersions achieved 100% dissolved drug within 60 min. The best product was the 10:80:10 w/w ternary dispersion with PEG 6000 and sodium laurylsulphate, showing a dissolution efficiency 5.5-fold greater than the reference tablet formulation and 100% drug dissolution after only 20 min.     

Mechanism of increased dissolution of diazepam and temazepam from polyethylene glycol 6000 solid dispersions

Solid dispersion literature, describing the mechanism of dissolution of drug-polyethylene glycol dispersions, still shows some gaps; (A). only few studies include experiments evaluating solid solution formation and the particle size of the drug in the dispersion particles, two factors that can have a profound effect on the dissolution. (B). Solid dispersion preparation involves a recrystallisation process (which is known to be highly sensitive to the recrystallisation conditions) of polyethylene glycol and possibly also of the drug. Therefore, it is of extreme importance that all experiments are performed on dispersion aliquots, which can be believed to be physico-chemical identical. This is not always the case. (C). Polyethylene glycol 6000 (PEG6000) crystallises forming lamellae with chains either fully extended or folded once or twice depending on the crystallisation conditions. Recently, a high resolution differential scanning calorimetry (DSC)-method, capable of evaluating qualitatively and quantitatively the polymorphic behaviour of PEG6000, has been reported. Unraveling the relationship between the polymorphic behavior of PEG6000 in a solid dispersion and the dissolution characteristics of that dispersion, is a real gain to our knowledge of solid dispersions, since this has never been thoroughly investigated. The aim of the present study was to fill up the three above mentioned gaps in solid dispersion literature. Therefore, physical mixtures and solid dispersions were prepared and in order to unravel the relationship between their physico-chemical properties and dissolution characteristics, pure drugs (diazepam, temazepam), polymer (PEG6000), solid dispersions and physical mixtures were characterised by DSC, X-ray powder diffraction (Guinier and Bragg-Brentano method), FT-IR spectroscopy, dissolution and solubility experiments and the particle size of the drug in the dispersion particles was estimated using a newly developed method. Addition of PEG6000 improves the dissolution rate of both drugs. Mechanisms involved are solubilisation and improved wetting of the drug in the polyethylene glycol rich micro-environment formed at the surface of drug crystals after dissolution of the polymer. Formulation of solid dispersions did not further improve the dissolution rate compared with physical mixtures. X-ray spectra show that both drugs are in a highly crystalline state in the solid dispersions, while no significant changes in the lattice spacings of PEG6000 indicate the absence of solid solution formation. IR spectra show the absence of a hydrogen bonding interaction between the benzodiazepines and PEG6000. Furthermore, it was concluded that the reduction of the mean drug particle size by preparing solid dispersions with PEG6000 is limited and that the influence of the polymorphic behavior of PEG6000 (as observed by DSC) on the dissolution was negligible.     

Characterization of ternary solid dispersions of itraconazole, PEG 6000, and HPMC 2910 E5

In order to reduce the crystallinity of PEG 6000, blends were prepared by spray drying and extrusion with the following polymers; PVP K25, PVPVA 64, and HPMC 2910 E5. The maximal reduction of crystallinity in PEG 6000 was obtained by co-spray drying with HPMC 2910 E5. In the next step the model drug Itraconazole was added to the blend and the resulting ternary solid dispersions were characterized. The results of this study show that the addition of PEG 6000 to the Itraconazole/HPMC 2910 E5 system leads to phase separation that in most cases gives rise to recrystallization of either PEG 6000 or Itraconazole. For all ternary dispersions containing 20% of Itraconazole the drug was highly amorphous and the dissolution was improved compared to the binary 20/80 w/w Itraconazole/HPMC 2910 E5 solid dispersion. For all ternary dispersions containing 40% of Itraconazole, the drug was partially crystalline and the dissolution was lower than the dissolution of the binary 40/60 w/w Itraconazole/HPMC 2910 E5 dispersion. These results show that provided Itraconazole is highly amorphous the addition of PEG 6000 to HPMC 2910 E5 leads to an increase in drug release.     

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。     

Improvement of the dissolution kinetics of SR 33557 by means of solid dispersions containing PEG 6000

Solid dispersions of SR 33557 in preparations containing from 30 to 80% w/w polyethylene glycol 6000 (PEG 6000) were prepared by the fusion method. The solubility of the drug substance either alone or in solid dispersions was determined in pH 1.2 and 4.5 media (extraction fluid NFXII, without enzyme). A large increase in the solubility was noted from the 80% w/w PEG preparation. A wettability study performed by measuring the contact angle on tablets of either drug substance or PEG 6000, or solid dispersions, revealed a minimal contact angle for the 80% w/w PEG 6000 solid dispersion (eutectic composition of SR 33557/PEG 6000 phase diagram). Dissolution kinetic analysis performed at pH 1.2 on all solid dispersions, on the physical mixtures containing 70 and 80% w/w PEG 6000, and on SR 33557 alone, showed a maximum release rate (100%) for the solid dispersions containing 70 and 80% w/w PEG 6000. The dissolution rate of the physical mixtures was faster than that of the drug substance alone but remained, however, lower than that of the solid dispersions, at the same composition. It was also observed that the dissolution rate, at pH 1.2 and 4.5, of the 70% w/w PEG 6000 solid dispersion was practically pH independent, which was not the case for the drug substance alone. The latter solid dispersion showed a slowing down of the dissolution kinetics after 3 months storage at 50°C whereas no change in the dissolution rate was observed following storage for 12 months at 25°C.     

Physicochemical characterization and in vivo properties of Zolpidem in solid dispersions with polyethylene glycol 4000 and 6000.

Solid dispersions and physical mixtures of Zolpidem in polyethylene glycol 4000 (PEG 4000) and 6000 (PEG 6000) were prepared with the aim to increase its aqueous solubility. These PEG based formulations of the drug were characterized in solid state by FT-IR spectroscopy, X-ray powder diffraction, and differential scanning calorimetry. By these physical determinations no drug-polymer interactions were evidenced. Both solubility and dissolution rate of the drug in these formulations were increased. Each individual dissolution profile of PEG based formulation fitted Baker-Lonsdale and first order kinetic models. Finally, significant differences in ataxic induction time were observed between Zolpidem orally administered as suspension of drug alone and as solid dispersion or physical mixture. These formulations, indeed, showed almost two- to three-fold longer ataxic induction times suggesting that, in the presence of PEG, the intestinal membrane permeability is probably the rate-limiting factor of the absorption process. Copyright     

通心舒滴丸成型工艺研究

目的　通过试验选择通心舒滴丸最佳的成型工艺。方法　以滴丸的溶散时间、丸重差异变异系数及外观质量作为综合评定指标,对药物清膏与基质的比例、基质配比(PEG4 0 0 0与PEG6 0 0 0的比例)、滴速、药液温度以正交试验法实验,优选出滴丸最佳成型工艺。结果　以清膏∶基质 =1∶2 5,PEG4 0 0 0∶PFG6 0 0 0 =1∶1,滴速为 4 5滴·min-1,药液温度为 85℃进行滴制,为最佳成型工艺。结论　本试验筛选出滴丸的最佳成型工艺,滴丸外观性状好、溶散度较好,丸重差异小,符合滴丸剂的质量标准。     

Studies on dissolution enhancement and mathematical modeling of drug release of a poorly water-soluble drug using water-soluble carriers.

Role of various water-soluble carriers was studied for dissolution enhancement of a poorly soluble model drug, rofecoxib, using solid dispersion approach. Diverse carriers viz. polyethylene glycols (PEG 4000 and 6000), polyglycolized fatty acid ester (Gelucire 44/14), polyvinylpyrollidone K25 (PVP), poloxamers (Lutrol F127 and F68), polyols (mannitol, sorbitol), organic acid (citric acid) and hydrotropes (urea, nicotinamide) were investigated for the purpose. Phase-solubility studies revealed AL type of curves for each carrier, indicating linear increase in drug solubility with carrier concentration. The sign and magnitude of the thermodynamic parameter, Gibbs free energy of transfer, indicated spontaneity of solubilization process. All the solid dispersions showed dissolution improvement vis-à-vis pure drug to varying degrees, with citric acid, PVP and poloxamers as the most promising carriers. Mathematical modeling of in vitro dissolution data indicated the best fitting with Korsemeyer-Peppas model and the drug release kinetics primarily as Fickian diffusion. Solid state characterization of the drug-poloxamer binary system using XRD, FTIR, DSC and SEM techniques revealed distinct loss of drug crystallinity in the formulation, ostensibly accounting for enhancement in dissolution rate.     

Enhanced solubility and permeability of exemestane solid dispersion powders for improved oral delivery

The aim of the present investigation was to enhance the solubility of exemestane (EXM), by solid dispersion (SD) technique using PEG 6000 as a carrier. Phase solubility studies were conducted with PEG 6000 and PEG 20000 to evaluate the effect of carriers on aqueous solubility of EXM. The aqueous solubility of EXM was favoured with PEG 6000 compared to PEG 20000. SDs of EXM using polyethylene glycol 6000 (PEG 6000) as carrier were prepared in different drug to carrier ratios. Solid-state characterization indicated decrease in crystallinity of the drug. The in vitro dissolution rate of EXM was enhanced from both SDs and tablet formulations prepared using SD compared to pure EXM. The in situ permeability studies investigated using single-pass intestinal perfusion technique in rats revealed increase in effective intestinal permeability (P_eff, cm/s) by 4.45 folds with SDs. Thus, EXM-PEG 6000 SDs showed improved solubility and permeability.     

Similarities in the release rates of different drugs from polyethylene glycol 6000 solid dispersions

The dissolution rates (mg min-1) of 10 drugs, solid dispersed by fusion in polyethylene glycol 6000 (PEG 6000) have been examined by rotating disc methodology. The dispersions generally displayed release rates which were linearly dependent upon the drug concentration (% drug) at high polymer content. However the range over which this linearity was encountered varied unduly, e.g. 0-2% for phenylbutazone and 0-15% for paracetamol. The slope of this line (mean value: 0.451 mg min-1 % -1) was statistically the same for nine of the drugs studied, the exception being griseofulvin which did not form a true solid dispersion but was a microcrystalline dispersion of the drug within the PEG. During fusion, chain scission of the PEG 6000 occurred in the presence of several drugs. PEG 6000 was incompatible with disulfiram, frusemide, chlorothiazide and chlorpropamide.     

Dissolution rates of hydrocortisone and prednisone utilizing sugar solid dispersion systems in tablet form

The utilization of ternary sugar solid dispersion systems and the incorporation of these systems into tablet dosage forms were investigated. The dispersion systems were prepared by the fusion method using 50% sucrose-50% mannitol and 50% sorbitol-50% mannitol. Other systems investigated utilized sorbitol, mannitol, and polyethylene glycol 6000 for comparison. The drug component was hydrocortisone or prednisone. The results from a modified NF XIII dissolution rate determination revealed that the mannitol system had the fastest dissolution rate, followed by sorbitol-mannitol, sucrose-mannitol, sorbitol, and finally, polyethylene gylcol 6000. The corticosteroids were stable and did not decompose during preparation of the dispersion systems or direct compression of the tablets. A short-term stability study revealed that the tablets retained their fast dissolution rates and that the tablet characteristic tests, i.e., tablet hardness, remained unchanged. The use of sugar combinations overcame some difficulties previously reported with single sugar systems.     

尼莫地平固体分散物的制备及其片剂溶出度的研究

目的：提高难溶性药物尼莫地平的溶出速率。方法：选用PVP－k30和PEG6000为载体制备了不同晶型尼莫地平固体分散物和机械混合物，比较了它们片剂体外的溶出速率。结果：尼莫地平固体分散物的片剂溶出度高于机械混合物的，低熔点机械混合物片剂溶出度高于高熔点的，不同晶型尼莫地平PEG6000固体分散物片剂体外的溶出速率无显著性差异，低熔点尼莫地平PVK－k30固体分散物的片剂的90min累积溶出量比高熔点的高。结论：不同晶型尼莫地平制备成PVP-k30和PEG6000固体分散物都可以提高其片剂体外的溶出度。     

Enhanced dissolution and systemic availability of albendazole formulated as solid dispersions

Solid dispersions (SDs) containing the anthelmintic compound albendazole (ABZ) and either Pluronic 188 (P 188) or polyethylene glycol 6000 (PEG 6000) as hydrophilic carriers were formulated. Drug–polymers interactions in solid state were investigated using different techniques.

Only a 4% of total ABZ was dissolved at 5 min post-incubation, reaching dissolution rates of 32.8% (PEG 6000) and 69.4% (P 188) in SDs. In this way, P 188 was substantially more efficient as ABZ dissolution promoter in comparison to PEG 6000, especially at the initial stages of the dissolution processes (<30 min).

An increased systemic availability (p < 0.001) was obtained when ABZ was administered as ABZ-P 188 SDs, with a 50% enhancement in systemic exposure (AUC values) compared to treatment with an ABZ suspension. Consistently, the Cmax increased 130% (p < 0.001) following treatment with P 188 based SD ABZ formulation. For the ABZ-PEG 6000 SD formulation, the favorable effect on ABZ systemic availability did not reached statistical significance compared to the control group.

The study reported here showed the utility of pharmacokinetic assays performed on mice as a model for preliminary drug formulation screening studies.     

Solid dispersion adsorbates for enhancement of dissolution rates of drugs

Amalgamation of solid dispersion and melt adsorption technologies was utilized for enhancing the dissolution rate of poorly soluble drugs. Glibenclamide was employed as a model drug. PEG6000 and Gelucire44/14 were used as hydrophilic carriers for the preparation of solid dispersions, and lactose was utilized as an adsorbent for the preparation of solid dispersion adsorbates. A high dissolution rate of solid dispersion adsorbates was observed when compared to solid dispersions alone and one of the marketed products.     

Enhancement of solubility and permeability of Candesartan cilexetil by using different pharmaceutical interventions

The poor solubility and wettability of Candesartan cilexetil (CAN) leads to poor dissolution and hence, low bioavailability after oral administration. The aim of the present study was to improve the solubility and dissolution rate and hence the permeability of CAN by preparing solid dispersions/inclusion complexes. Solid dispersions were prepared using PEG 6000 [hydrophilic polymer] and Gelucire 50/13 [amphiphilic surfactant] by melt agglomeration (MA) and solvent evaporation (SE) methods in different drug-to-carrier ratios, while inclusion complexes were made with hydroxypropyl-β-cyclodextrin (HP-β-CD) [complexing agent] by grinding and spray drying method. Saturation solubility method was used to evaluate the effect of various carriers on aqueous solubility of CAN. Based on the saturation solubility data, two drug-carrier combinations, PEG 6000 (MA 1:5) and HP-β-CD (1:1 M grinding) were selected as optimized formulations. FTIR, DSC, and XRD studies indicated no interaction of the drug with the carriers and provided valuable insight on the possible reasons for enhanced solubility. Dissolution studies showed an increase in drug dissolution of about 22 fold over the pure drug for PEG 6000 (MA 1:5) and 12 fold for HP-β-CD (1:1 M grinding). Ex-vivo permeability studies revealed that the formulation having the greatest dissolution also had the best absorption through the chick ileum. Capsules containing solid dispersion/ complex exhibited better dissolution profile than the marketed product. Thus, the solid dispersion/inclusion complexation technique can be successfully used for enhancement of solubility and permeability of CAN.     

光照对尼群地平固体分散体微丸体外溶出度的影响

目的:考察光照对尼群地平固体分散体微丸体外溶出行为的影响。方法:将以PEG6000、PVPk30、F68和PVPk30/F68为载体的微丸4种尼群地平固体分散体微丸,分别置于日光灯3000Lx、自然光下照射,于0,5,10d取样,通过体外溶出度试验考察微丸中药物的溶出行为变化。结果:在日光灯3000Lx和自然光照射下,4种尼群地平固体分散体微丸的体外溶出速度均有下降,自然光的影响更为显著。几种微丸中,以F68微丸对光的稳定性最好,自然光照10d后药物的60min累积溶出百分率仍在80%以上。结论:可采用F68作为可溶性载体材料制备尼群地平固体分散体微丸,稳定性较好。     

格列喹酮固体分散体的制备及溶出度测定

目的:制备格列喹酮固体分散体并考察其体外溶出性。方法:以聚乙烯吡咯烷酮K30(PVP)、聚乙二醇6000(PEG)为载体,溶剂熔融法和溶剂法制备格列喹酮固体分散体,并与原料药比较体外溶出度。结果:载体比例越大,药物溶出愈快。载体为PVP所制固体分散体的体外溶出行为总体优于载体为PEG者。格列喹酮-PVP固体分散体(1∶7)10min内体外溶出度达到70%以上,优于格列喹酮原料药。结论:成功制备了格列喹酮固体分散体。     

依托泊苷固体分散体的制备及体外研究

目的 制备依托泊苷固体分散体，改善依托泊苷的溶出度。方法 应用聚乙烯吡咯烷酮（PVPK30）和聚乙二醇（PEG6000）为载体，以溶剂法制备固体分散体。采用正交实验设计考察制备固体分散体的最佳工艺条件，并对所得样品进行体外溶出度研究，以X线衍射、DSC-量热分析进行物相鉴定。结果 依托泊苷在载体PVPK30和PEG6000中结晶消失。药物的溶出速度随载体比例增加而增加。结论 采用PVPK30和PEG6000所制依托泊苷固体分散体能显著提高药物的体外溶出度，药物以无定形状态或分子态存在于载体中。     

Influence of water uptake,gel network,and disintegration time on prednisone release from encapsulated solid dispersions

Prednisone is considered the glucocorticoid of choice for anti-inflammatory and immunosuppressant effects. However, its very low aqueous solubility can compromise oral bioavailability. Changes in the dissolution of a prednisone-PEG 6000 solid dispersion into capsule were investigated by addition of pregelatinized starch. Physical state of prednisone:PEG 6000 was analyzed by X-ray diffractometry, and scanning electron microscopy. Capsule formulations containing prednisone-PEG 6000 and pregelatinized starch showed superior dissolution properties (>?95% in 60?min) when compared with reference capsules without disintegrant (<?45% in 60?min). Water uptake and disintegration time were directly correlated with pregelatinized starch amount. The morphology of prednisone-PEG 6000 particles with disintegrant was analyzed by SEM, showing a novel surface structure. Thus, solid dispersions of a poorly water soluble drug combined with a disintegrant were confirmed as a valid approach to the improvement of drug dissolution.     

热熔挤出技术制备吡罗昔康固体分散体

目的采用热熔挤出技术制备难溶性药物吡罗昔康固体分散体,来提高其溶出速率。方法以共聚维酮(PVP-VA64)为亲水性载体材料,聚乙二醇6000为增塑剂,采用热熔挤出技术制备吡罗昔康固体分散体。通过比较差示扫描量热图谱和累积溶出曲线,来表征和评价所制备的固体分散体。结果所制备的固体分散体溶出速率较物理混合物均显著提高。结论热熔挤出技术适用于制备吡罗昔康固体分散体,药物是以无定型分散在载体中,溶出度得到显著提高。