Starch Microspheres Research Articles

In vitro fecal fermentation of alginate‐starch microspheres shows slow fermentation rate and increased production of butyrate

The development of dietary fibers with slow fermentation profiles that deliver desirable fermentation products, such as butyrate, to distal regions of the colon may be beneficial for colonic health. The purpose of this study was to determine whether alginate-entrapped starch might be used for such a designed dietary fiber. Alginate-starch microspheres were prepared from 1, 2, or 3% alginate and 10% starch. A blank was also prepared using only alginate. Samples were subjected to in vitro digestion and fermentation. A sample of normal corn starch was included as a control. During fermentation, total gas volume was measured using a graduated syringe, and short chain fatty acids (SCFAs) were quantified by gas chromatography. Alginate entrapment significantly reduced starch digestion to less than 20%. During fermentation, higher alginate concentrations significantly reduced both the total and rate of gas production. This implies that the starch microspheres would not contribute to the uncomfortable bloating experienced with many dietary fibers. Increasing alginate concentration changed the rate of SCFA production from a parabolic to more linear profile, while simultaneously and substantially increasing the proportion of butyrate (of total SCFAs) produced. This suggests than starch entrapment may allow for a significant and constant, slow delivery of butyrate throughout the colon.

Formulation and Characterization of Formaldehyde Cross-linked Degradable Starch Microspheres Containing Terbutaline Sulfate

ABSTRACTPreparation of starch microspheres using epichlorohydrin is a time consuming method and requires around 18 hr for cross-linking reaction. To reduce reaction time, terbutaline sulfate (TBS) loaded degradable starch microspheres (DSM) were prepared using formaldehyde as the cross-linking agent. All microspheres were spherical in shape and had a porous, rough surface with a mean particle size of 18–24 μm. Whatever the cross-linking time, it was seen that the release of the TBS was not complete during the release experiments. The influence of enzyme on the degradation of microspheres was moderate. Following intravenous administration, initial uptake of microspheres by the lung was higher than those of other organs.

Recrystallization of waxy maize starch during manufacturing of starch microspheres for drug delivery: Optimization by experimental design

Gelatinized starch/water dispersions with a water content of 70% w/w were studied in order to evaluate the influence of the incubation time at two fixed temperatures (6 and 37 °C) on the recrystallization behavior. The starch material was produced from waxy maize starch by acid hydrolysis followed by a mechanical treatment, i.e. a high pressure homogenization. Empirical models for the recrystallization of the model starch dispersions were investigated by using a central composite circumscribed (CCC) design in two factors involving 11 trials. The rebuilt crystalline structure was estimated by measuring the melting transition parameters with differential scanning calorimetry (DSC). The designed models for the melting enthalpy, the melting transition temperatures, and the melting interval as the responses were reproducible and predictable and the results were analyzed by using a response surface modeling. Operative conditions for the formation of the most thermally stable crystalline structure with the highest possible crystallinity were determined. It was also concluded that the decisive factor for the crystallinity of the given starch material was a prolonged storage at 6 °C, while thermal characteristics of the crystallites could be controlled by storage at 37 °C. An interaction effect was observed between the incubation time at these two experimental temperatures regarding enthalpy values and the melting interval of the samples.

Cross-linked starch microspheres: Effect of cross-linking condition on the microsphere characteristics

Cross-linked starch microspheres were prepared using different kinds of cross-linking agents. The influence of several parameters on morphology, size, swelling ratio and drug release rate from these microspheres were evaluated. These parameters included cross-linker type, concentration and the duration of cross-linking reaction. Microspheres cross-linked with glutaraldehyde had smooth surface compared with those prepared with epichlorhydrine or formaldehyde. The particle size increased with increasing the cross-linking time and increasing the drug loading. Swelling ratio of the particles was a function of cross-linker type but not the concentration or time of cross-linking. Drug release from starch microspheres was measured in phosphate buffer and also in phosphate buffer containing alpha-amylase. Results showed that microspheres cross-linked with epichlorhydrine released all their drug content in the first 30 minutes. However, cross-linking of the starch microspheres with glutaraldehyde or formaldehyde decreased drug release rate. SEM and drug release studies showed that cross-linked starch microspheres were susceptible to the enzymatic degradation under the influence of alpha-amylase. Changing the enzyme concentration from 5000 to 10,000 IU/L, increased drug release rate but higher concentration of enzyme (20,000 IU/L) caused no more acceleration.

Radiofrequency Ablation of Normal Lungs after Pulmonary Artery Embolization with Use of Degradable Starch Microspheres: Results in a Porcine Model

The present study was performed to evaluate the effect of pulmonary artery embolization on radiofrequency (RF) ablation of normal porcine lungs. RF ablation zones (n=34) were created in the normal lungs of five domestic pigs (five zones in each of the first two pigs and eight zones in each of the remaining three pigs) with an expandable multitined electrode with use of bilateral thoracotomy. RF ablation was performed without pulmonary artery embolization (group 1, n=8), immediately after embolization (group 2, n=11), 15 minutes after embolization (group 3, n=7), and 30 minutes after embolization (group 4, n=8) with degradable starch microspheres. Among them, 12 ablation zones were excluded from this study because they were considerably limited by the presence of the pleura or large bronchi. The remaining 22 zones were included (n=7, n=5, n=4, and n=6 in groups 1, 2, 3, and 4, respectively). Coagulation necrosis volumes in the ablation zones were measured and compared among the groups. Coagulation necrosis volumes were 0.9+/-0.5 cm3, 2.1+/-0.4 cm3, 2.1+/-1.0 cm3, and 1.9+/-0.6 cm3 in groups 1, 2, 3, and 4, respectively. Groups 2-4 showed significantly larger coagulation volumes than group 1 (P=.012, P=.023, and P=.010 in groups 2, 3, and 4, respectively). Pulmonary artery embolization contributed to larger volumes of coagulation necrosis after RF ablation of normal lungs.

Transarterial Therapy for Hepatocellular Carcinoma: Which Technique Is More Effective? A Systematic Review of Cohort and Randomized Studies

Chemoembolization (TACE) improves survival in cirrhotic patients with hepatocellular carcinoma (HCC). The optimal schedule, or whether embolization (TAE) alone gives the same survival advantage, is not known. To evaluate whether specific patient characteristics and/or radiological transarterial techniques result in better outcomes. A PubMed search was carried out for cohort and randomized trials (n = 175) testing transarterial therapies; meta-analysis was performed where appropriate. Anticancer drugs were used as sole agent in 75% of cases (double 15% and triple 6%): doxorubicin (36%), cisplatin (31%), epirubicin (12%), mitoxantrone (8%), mitomycin (8%), and SMANCS (5%). Embolizing agents used were: gelatin sponge particles (71%), polyvinyl alcohol (PVA) particles (8%), degradable starch microspheres (DSM) (4%), and embospheres (4%). Sessions per patient were 2.5 +/- 1.5 (interval: 2 months). Objective response was 40 +/- 20%; survival rates at 1, 2, 3, and 5 years were: 62 +/- 20%, 42 +/- 17%, 30 +/- 15%, and 19 +/- 16%, respectively, and survival time was 18 +/- 9.5 months. The post-TACE complications were: acute liver failure, 7.5% (range 0-49%); acute renal failure, 1.8% (0-13%); encephalopathy, 1.8% (0-16%); ascites, 8.3% (0-52%); upper gastrointestinal bleeding; 3% (0-22%); and hepatic or splenic abscess, 1.3% (0-2.5%). Treatment-related mortality was 2.4% (0-9.5%), mainly due to acute liver failure. Our meta-analysis of nine randomized controlled trials (RCTs) confirmed that TACE improves survival; but a meta-analysis of TACE versus TAE alone (3 RCTs, 412 patients) demonstrated no survival difference. No chemotherapeutic agent appears better than any other. There is no evidence for benefit with lipiodol. Gelatin sponge is the most used embolic agent, but PVA particles may be better. TAE appears as effective as TACE. New strategies to reduce the risk of post-TACE complications are required.

From Starch to Starch Microspheres: Factors Controlling the Microspheres Quality

AbstractStarch microparticle is a dosage form suitable for encapsulation of protein drugs. The microparticle characteristics can be influential factors for consecutive sustained drug release from the starch matrix and impact its ability to be coated by poly(D,L‐lactide‐co‐glycolide). In this study, six types of starch microparticles were investigated and characterized. Desired qualities of the microspheres such as spherical form of the particles, well‐defined and sharp particle contours were coincident with coarse surface morphology, sharp and distinct peaks in DSC and X‐ray graphs. It was concluded that the quality of the starch microparticles was influenced by molecular properties of the starch material as well as type of buffer, and these factors were related to recrystallization kinetics, amount and quality of ordered/crystalline structure of final starch microspheres and their microscopic appearance.

Hepatic intraarterial chemotherapy with gemcitabine in patients with unresectable cholangiocarcinomas and liver metastases of pancreatic cancer: a clinical study on maximum tolerable dose and treatment efficacy

To define the maximum tolerated dose (MTD) of hepatic intraarterial chemotherapy with gemcitabine, administered with and without starch microspheres, in patients with inoperable intrahepatic cholangiocarcinomas and liver metastases of pancreatic carcinomas. Gemcitabine was administered on days 1 and 8 with intervals of 2 weeks between the cycles. In group A the initial gemcitabine dose of 1,000 mg/m(2) (without microspheres) was increased in 200-mg/m(2) steps up to a maximum dose of 2,000 mg/m(2). In group B the MTD with microspheres was assessed by giving an additional microsphere dose according to tumor extent and body weight, increasing gemcitabine starting from a dose-step below the MTD with microspheres. The MTD was evaluated via clinical and laboratory findings. Twenty-four patients were enrolled (12 males, 12 females, mean age 59.17 years; intrahepatic cholangiocarcinoma: n = 17, liver metastases of pancreatic carcinoma: n = 7). The MTD of gemcitabine without microspheres was reached at 1,400 mg/m(2), and of gemcitabine with microspheres at 1,800 mg/m(2). The comparative evaluation revealed statistically significant better data for the time to progression (p < 0.01) and survival for the group with microspheres (6.8 and 20.2 months) in comparison to the group without microspheres (4.2 and 13.5 months). This clinical study indicates that the intraarterial application of gemcitabine with doses higher than the recommended 1,000 mg/m(2) is well tolerated if combined with microspheres, and yields respectable results in patients who do not respond to systemic chemotherapy.

Adenovirus Vector-Mediated Gene Transfer Using Degradable Starch Microspheres for Hepatocellular Carcinoma in Rats

When gene therapy is performed for malignant tumors, gene transfer efficiency and selectivity are extremely important. The delivery of anticancer agents and embolic agents through tumor feeding artery is known as transarterial embolization. We speculated that genes might be efficiently and selectively transferred to hepatocellular carcinomas (HCCs) by degradable starch microspheres (DSM) as the embolic agent, which could be trapped within the tumor and release a gene vector. Therefore, we studied the use of DSM for adenovirus vector-mediated gene transfer to HCC in vivo. HCC was induced in rats with diethylnitrosamine and phenobarbital, after which either AxCALacZ and DSM or AxCALacZ alone was injected through the hepatic artery. Histological examination revealed that beta-galactosidase expression was greater (P < 0.001), and more selective (P < 0.001) in tumors after injection of AxCALacZ and DSM, than after injection of the vector alone. Injection of DSM together with an adenovirus vector through the hepatic artery can result in efficient and cancer-selective transfer of genes to HCC.

Starch-based microspheres produced by emulsion crosslinking with a potential media dependent responsive behavior to be used as drug delivery carriers

This paper describes the development and characterization of starch microspheres for being used as drug delivery carriers in tissue engineering applications. The developed starch microspheres can be further loaded with specific growth factors and immobilized in scaffolds, or administrated separately with scaffolds. Furthermore and due to the processing conditions used, it is expected that these microspheres can be also used to encapsulate living cells. The aim of this study was to evaluate the efficacy of this methodology for further studies with biologically active agents or living cells. The starch microspheres were prepared using an emulsion crosslinking technique at room temperature to allow for the loading of biologically active agents. A preliminary study was performed to evaluate the incorporation of a model drug (nonsteroidal anti-inflammatory drug-NSAID) and investigate its release profile as function of changes in the medium parameters, such as ionic strength and pH. The developed starch-based drug delivery system has shown to be dependent on the ionic strength of the release medium. From preliminary results, the release seems to be pH-dependent due to the drug solubility. It was found that the developed microspheres and the respective processing route are appropriate for further studies. In fact, and based in the processing conditions and characterization, the developed system present a potential for the loading of different growth factors or even living cells on future studies with these systems for improving bone regeneration in tissue engineering, especially because the crosslinking reaction of the microspheres takes place at room temperature.

Transarterial Chemoembolization With Degradable Starch Microspheres, Irinotecan, and Mitomycin-C in Patients With Liver Metastases

Degradable starch microspheres (DSMs) provide transient occlusion of small arteries and are thought to improve the therapeutic effect of anticancer drugs. Irinotecan (CPT-11) is one of the most effective anticancer agents. We herein report cases with liver metastases treated with transarterial chemoembolization with DSM, CPT-11, and mitomycin-C (DSM-CPT therapy). Five patients underwent DSM-CPT therapy for liver metastases that originated from colorectal cancer for four and gastric cancer for one. They all lack indication for surgery. They were all male with an age range of 42-78 years (mean, 55.2 years). Three of them had pretreatment histories with 5-fluorouracil or related agents, and four of them had combined systemic or local chemotherapy at the period. Required doses for stasis of whole blood flow of hepatic artery of DSMs were used with CPT-11 and mitomycin-C. After one to six injections, four patients had a partial response and the disease progressed in one patient with gastric cancer origin. Two of the partial response patients underwent surgery after 2 months of the partial response period. Carcinoembryonic antigen and CA19-9 levels in partial response patients decreased to 16.1% and 19.3% of the level before treatment, respectively. DSM-CPT therapy can be a potential therapy for liver metastases.

The Stability of Insulin in Solid Formulations Containing Melezitose and Starch. Effects of Processing and Excipients

ABSTRACTSolid insulin formulations obtained by different methods of preparation were compared with respect to chemical stability and morphology. Spray- and freeze-drying, solution enhanced dispersion by supercritical fluids (SEDS) and precipitation into starch microspheres were the methods used for preparation of solid powders. The excipients applied were melezitose, starch, and sodium taurocholate. The stability of the samples was evaluated after storage in open containers at 25°C and 30% RH for 6 months.All samples were amorphous after processing and storage as detected by XRD, except for the starch microspheres which were semi-crystalline. The spray- and freeze-dried samples containing melezitose and sodium taurocholate experienced a significant water uptake during storage, resulting in changes in morphology and disappearance of Tg. However, the chemical stability of these samples did not seem to be affected by the water uptake. Changes in morphology were not observed for the SEDS powders and the starch microspheres.The chemical stability of the samples was assessed by HPLC. In general, conventional spray- and freeze drying resulted in samples with higher chemical stability compared to SEDS powders and starch microspheres. Nevertheless, the excipients applied were observed to be of major importance, and further optimization of the formulation as well as processing conditions may lead to slightly different conclusions.

Optimization of cross-linked high amylose starch microspheres containing 5-fluorouracil

The objective of the present investigation was the preparation of microspheres consisting of high amylose starch cross-linked in situ by means of sodium trimetaphosphate. 5-fluorouracil was chosen as a model drug. Since this preparation entailed several process and formulation variables, a preliminary screening design was applied to identify the most important factors and thereby simplify the system under study. This was performed with regard to the spherical shape and the capacity of drug encapsulation of the obtainable microparticles. An eight-factor 12-run Plackett-Burman design enabled the factor number to be reduced so that a three-factor face-centered central composite design could subsequently be applied in order to optimize the formulation by response surface methodology. The factors involved in the optimization process were the concentrations of the following components: 5-fluorouracil, starch and cross-linker. The responses evaluated were the morphology of the microspheres (a qualitative response) and the drug encapsulation efficiency. An optimal formulation yielded microparticles that were spherical in shape, with a volume diameter of 25.5±0.6pm and a narrow particle size distribution. Particle yield ranged from 85 to 98%, the encapsulation efficiency reached about 30% and the drug loading was in the range of 0.8-1.5%. Due to polymer swelling properties, 5-fluorouracil was released in vitro in a sustained manner by an anomalous release mechanism. Microparticles also showed good mucoadhesion properties that would make them suitable for peroral drug administration.

Liver microcirculation after hepatic artery embolization with degradable starch microspheresin vivo

To observe the dynamic changes of liver microcirculation in vivo after arterial embolization with degradable starch microspheres (DSM). DSM were injected into the proper hepatic artery through a silastic tube inserted retrogradely in gastroduodenal artery (GDA) of SD rats. Fluorescent microscopy was used to evaluate the dynamic changes of blood flow through the terminal portal venules (TPVs), sinusoids and terminal hepatic venules (THVs). The movements of DSM debris were also recorded. Six hours after injection of DSM, percentages of THVs with completely stagnant blood flow were recorded. Two phases of blood flow change were recorded. In phase one: after intra-arterial injection of DSM, slow or stagnant blood flow was immediately recorded in TPVs, sinusoids and THVs. This change was reversible, and blood flow resumed completely. In phase two: after phase one, blood flow in TPVs changed again and three patterns of blood flow were recorded. Six hours after DSM injection, 36.9% +/- 9.2% of THVs were found with completely stagnant blood flow. DSM can stop the microcirculatory blood flow in some areas of liver parenchyma. Liver parenchyma supplied by arteries with larger A-P shunt is considered at a higher risk of total microcirculatory blood stagnation after injection of DSM through hepatic artery.

Chemoocclusion vs chemoperfusion for treatment of advanced hepatocellular carcinoma: A randomised trial

AimsTransarterial chemoembolization (TACE) can be associated with considerable toxicity and treatment-associated mortality. Transient transarterial chemoocclusion (TACO) using degradable starch microspheres (DSM) has been proposed as a potentially safer alternative while maintaining anti-tumour efficiency. In a randomised phase II trial TACO was compared to transarterial chemoperfusion without DSM (TACP). MethodsSeventy-four patients with advanced HCC were randomised to two treatment arms: (i) TACO (600–1200mg DSM) and (ii) TACP. In both arms regional chemotherapy consisted of cisplatin (100mg/m2) and doxorubicin (60mg/m2). Both arms were corresponding in terms of age, gender, liver performance state, and tumour-stage. A maximum of six treatment cycles was applied in monthly intervals. Follow-up was performed in terms of tumour response, time to progression, survival and quality of life. ResultsTumour response rates did not differ significantly between the two treatment arms, however, there was a tendency towards higher response rates in the TACO arm (TACO vs TACP): partial response: 26 vs 9%, stable disease: 41 vs 55%, progressive disease: 33 vs 36%. Time to tumour progression (32 vs 27 weeks), and overall survival (60 vs 69 weeks) were not significantly different. Grade 4 adverse events were rare in both arms and treatment-associated mortality was not observed. In addition, there was no significant difference in terms of quality of life under therapy (EORTC). ConclusionTACO with DSM did not improve response or survival significantly compared to TACP in advanced non-resectable HCC.

Prospective randomized controlled trial of hepatic arterial embolization or infusion chemotherapy with 5-fluorouracil and degradable starch microspheres for colorectal liver metastases

Survival benefit from hepatic artery embolization (HAE) or hepatic arterial infusion chemotherapy (HAI) in patients with unresectable colorectal liver metastases has not previously been assessed in a randomized controlled trial. Sixty-one patients were randomized, 20 to receive no treatment, 22 to receive HAE, and 19 to receive HAI with 5-fluorouracil and degradable starch microspheres. Both treatments were acceptable to the patients in terms of low treatment morbidity rate. Median survival from diagnosis of metastases was 9.6 months for controls, 8.7 months for the HAE group and 13.0 months in the HAI group. There was no apparent survival benefit for the HAE group. The increased survival in the HAI group was observed in all the subgroups analysed but failed to reach statistical significance. The greatest observed benefit was achieved in the subgroup with less than 50 per cent hepatic replacement with tumour at presentation (median survival from diagnosis 10.0 months for controls, 10.2 months for HAE and 23.6 months for HAI); 36 per cent of patients developed extrahepatic disease recurrence. No significant benefit has been shown from either HAE or HAI, but a more carefully selected group of patients with only low volume hepatic disease may benefit from HAI therapy.

Changes in vascularity of liver tumours after hepatic arterial embolization with degradable starch microspheres.

The role of vascularity as a prognostic factor was investigated in 35 patients undergoing arterial chemotherapy for liver tumours. Compared with parenchyma, tumour vascularity was classified as hot (18 cases), cold (12 cases), and mixed (12 cases) using 99mTc-macroaggregated albumin (MAA) hepatic arterial scans. The proportion of patients showing complete and partial responses to treatment was higher in the hot group (56 per cent) than in the combined cold and mixed group (12 per cent). In 15 cases (six hot, six cold and three mixed lesions), additional MAA scans were performed immediately after arterial embolization with degradable starch microspheres (DSMs). Either complete or partial reversal of tumour vascularity was observed after DSM-embolization in five and seven cases respectively, two and two of them respectively showing native cold lesions. As tumour vascularity appears to be a prominent prognostic factor, DSM-embolization should improve the efficacy of treatment by improving liver extraction of drugs and causing flow redistribution towards hypovascular areas.

Treatment of patients with irresectable liver metastases from colorectal cancer by chemo-occlusion with degradable starch microspheres.

Chemo-occlusion of the liver increases the tumour concentration of drugs. Thirty-nine patients with colorectal liver metastases received a monthly bolus administration of mitomycin C (10 mg/m2 on day 1) plus a continuous infusion of 5-fluorouracil (500 mg/m2 daily from days 1 to 5). Drugs were given via both portal (one-third of the dose) and arterial (two-thirds) routes to control large and small metastases. Arterially administered mitomycin C was mixed with individualized doses of degradable starch microspheres. In 16 patients treatment was not started or was interrupted early because of arterial or portal catheter problems. In 23 patients who received two or more cycles of treatment the mean(s.d.) microsphere dose was 835(399) mg. Toxicity was mild, consisting mainly of pain. Five complete and five partial responses were seen, and six patients had stable disease. The median time to progression and length of survival were 6 and 16 months respectively. The relatively high rates of complete and overall response in hypovascular tumours (six of 12 lesions) may support the rationale of chemo-occlusion.

Liver Metastases in Rats: Chemoembolization Combined with Interstitial Laser Ablation for Treatment

To assess the effect of transcatheter arterial chemoembolization (TACE) combined with laser-induced thermotherapy (LITT) for treatment of liver metastases in an animal model. All experiments were approved by the German government and the institutional animal research review board. After subcapsular liver implantation of colorectal cancer cells in 30 WAG rats (on day 0), the animals were randomly assigned to three interventional treatment groups. In the 10 rats in group A, TACE was performed: Fourteen days after cancer cell implantation and within 20 minutes after laparotomy and retrograde placement of a microcatheter into the gastroduodenal artery, these rats were injected with mitomycin (0.1 mg), iodized oil (0.1 mL), and degradable starch microspheres (5.0 mg). In the 10 rats in group B, LITT was performed: Also on day 14, the tumors in these animals were exposed to Nd:YAG laser light of 1064 nm at 2 W for 5 minutes. In the 10 rats in group C, combined treatment was administered: TACE was performed on day 14, and LITT was performed on day 21. Tumor volumes were measured before (on day 13) and after (on day 28) treatment with magnetic resonance (MR) imaging, and the mean tumor growth ratio (day 13 tumor volume divided by day 28 tumor volume) was calculated. The mean tumor volumes measured before and after the treatments were, respectively, 0.11 and 0.60 cm(3) in group A, 0.11 and 0.68 cm(3) in group B, and 0.11 and 0.35 cm(3) in group C. The mean tumor growth ratio was 5.42 in group A, 6.14 in group B, and 3.15 in group C. According to Bonferroni test results, compared with the rats in groups A and B (controls), the group C rats had significantly inhibited tumor growth (P < .01 for both comparisons). Use of combined TACE-LITT treatment, compared with the use of TACE or LITT alone, significantly inhibits tumor growth.

744 POSTER Hepatic arterial infusion of carboplatin mixed with degradable starch microspheres by using implanted reservoir in patients with advanced hepatocellular carcinoma

744 POSTER Hepatic arterial infusion of carboplatin mixed with degradable starch microspheres by using implanted reservoir in patients with advanced hepatocellular carcinoma