Oral delivery of macromolecules using intestinal patches: applications for insulin delivery

Whitehead, Kathryn A.; Shen, Zancong; Mitragotri, Samir

doi:10.1016/j.jconrel.2004.04.013

Cited by 115 publications

(65 citation statements)

References 32 publications

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“…Our technique is readily applicable to investigating the therapeutic benefit of prolonged local delivery of NAW therapeutics (e.g., acyclovir, bisphosphonates, furosemide, levodopa, and metformin) at their sites of greatest absorption (1, 3). Additionally, localized oral delivery of polymer nanoencapsulated proteins within specific regions of the GI, genes, and antibodies within the small intestines demonstrated tremendous potential to enable conversion to oral delivery of biologic therapies currently delivered by injection (5,(15)(16)(17)(18)(19). Similarly, localized oral delivery to the ileum would expose vaccines to GALT increasing their contact with the immune system (1,14).…”

Section: Discussionmentioning

confidence: 99%

“…Early GI magnetic retentive efforts for oral administration focused on creating the maximal attractive force between a dosage and an external magnet to either retain a large dosage form at the site of interest (1,3) or to increase the uptake of magnetic nanoparticle formulations (6,(14)(15)(16)(17)(18)(19). We institute a computercontrolled material testing device equipped with a load-cell that has a programmed feedback loop, constantly adjusting the position of the external magnet between upper and lower intermagnetic force bounds defined by the user.…”

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confidence: 99%

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Localization of magnetic pills

Laulicht¹,

Gidmark²,

Tripathi

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Numerous therapeutics demonstrate optimal absorption or activity at specific sites in the gastrointestinal (GI) tract. Yet, safe, effective pill retention within a desired region of the GI remains an elusive goal. We report a safe, effective method for localizing magnetic pills. To ensure safety and efficacy, we monitor and regulate attractive forces between a magnetic pill and an external magnet, while visualizing internal dose motion in real time using biplanar videofluoroscopy. Real-time monitoring yields direct visual confirmation of localization completely noninvasively, providing a platform for investigating the therapeutic benefits imparted by localized oral delivery of new and existing drugs. Additionally, we report the in vitro measurements and calculations that enabled prediction of successful magnetic localization in the rat small intestines for 12 h. The designed system for predicting and achieving successful magnetic localization can readily be applied to any area of the GI tract within any species, including humans. The described system represents a significant step forward in the ability to localize magnetic pills safely and effectively anywhere within the GI tract. What our magnetic pill localization strategy adds to the state of the art, if used as an oral drug delivery system, is the ability to monitor the force exerted by the pill on the tissue and to locate the magnetic pill within the test subject all in real time. This advance ensures both safety and efficacy of magnetic localization during the potential oral administration of any magnetic pill-based delivery system. magnetic pills | retention | localization | drug delivery F or many orally administered pharmaceuticals, increased residence time in a particular region of the gastrointestinal (GI) tract would greatly improve their therapeutic benefit (1-3). Typically, physiological digestive processes govern the GI residence of standard pills. We have developed a magnet-based delivery system visualized by biplanar videofluoroscopy in vivo that yields real-time monitoring and control over the duration of GI residence of model magnetic pills in the small intestines of rats both as a tool for investigating the GI site-specific absorption and action of therapeutics and as a critical step towards enabling clinical localization of magnetic pills. Our system can safely and reliably retain drugs for a user-defined duration in any region of the GI with the ability to monitor and control the force applied by the orally ingested magnet to the intestinal wall.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Localization of magnetic pills

Laulicht¹,

Gidmark²,

Tripathi

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…The polymeric microparticles degrade over time, releasing insulin into the lumen of the intestine. The insulin directly released in the lumen of the small intestine then can be absorbed and regulate blood glucose levels [19]. The microparticles first serve to protect the insulin during transit to the small intestine and then allow the insulin to be anchored in the small intestine and be slowly released over time.…”

Section: Discussionmentioning

confidence: 99%

The use of charge-coupled polymeric microparticles and micromagnets for modulating the bioavailability of orally delivered macromolecules

et al. 2008

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Protein drugs have low bioavailability after oral administration, which is due in part to fast transit of the drugs or drug delivery vehicles through the gastrointestinal tract. Increasing the time that the drugs spend in the intestine after dosing would allow for greater absorption and increased bioavailability. We developed a formulation strategy that can be used to prolong intestinal retention of drug delivery vehicles without substantial alterations to current polymeric encapsulation strategies. A model drug, insulin, was encapsulated in negatively-charged poly(lactic-co-glycolic acid) (PLGA) microparticles, and the microparticles were subsequently mixed with positively-charged micromagnets, whose size will prevent them from being absorbed. Stable complexes formed through electrostatic interaction. The complexes were effectively immobilized in vitro in a model of the mouse small intestine by application of an external magnetic field. Mice that were gavaged with radio-labeled complexes and fitted with a magnetic belt retained 32.5% of the 125 I-insulin in the small intestine compared with 5.4% for the control group 6 hours after administration (p=0.005). Furthermore, mice similarly gavaged with complexes encapsulating insulin (120 Units/kg) exhibited long-term glucose reduction in the groups with magnetic belts. The corresponding bioavailability of insulin was 5.11% compared with 0.87% for the control group (p=0.007).• Correspondence to Robert Langer (Office

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“…The rats were all kept in standard and conditioned animal cages and left for one week to acclimatize to the new laboratory environment while being fed with standard laboratory diet. Diabetes was induced by intravenous injection of alloxan dissolved in normal saline through the marginal ear vein at a dose of 120 mg/kg (Whitehead et al, 2004;Sarmento et al, 2007). After 3-5 days of the alloxan treatment, rats with frequent urination, loss of weight, and blood glucose levels higher than 120 mg/dL were considered diabetic and selected for the study.…”

Section: Induction Of Diabetesmentioning

confidence: 99%

“…Insulin is administered parenterally by subcutaneous injection (Beals & Kovach, 1997), which results in low level of compliance due to pain as well as complications due to multiple jabs, hence the need for an alternative less invasive but effective method of insulin administration (Gowthamarajan & Kulkarni, 2003). The oral route is considered to be the most convenient, acceptable and desired route of drug delivery which will help eliminate the pain caused by injection, psychological barrier associated with multiple daily injection and possible infections (Kisel et al, 2001;Kim & Peppas, 2003;Whitehead et al, 2004;Cui et al, 2006;Sarmento et al, 2007). Oral delivery of insulin as a non-invasive therapy for diabetes mellitus is still a challenge to the drug delivery technology, due to low oral bioavailability, lack of lipophility, poor permeability across intestinal epithelium because of insulin high molecular weight as well as digestion by proteolytic enzymes in the luminal cavity (Tozaki, 2001; Gowthamarajan & Kulkarni, 2003;Tiyaboonchai, 2003;Krauland et al, 2004;Li & Deng, 2004;Nakamura et al, 2004;Toorisaka et al, 2005;Sajeesh & Sharma, 2006;Sarmento, 2006;Tuesca & Lowman, 2006;Lin, 2007;Simon, 2007).…”

Section: Introductionmentioning

confidence: 99%

Influence of magnesium stearate on the physicochemical and pharmacodynamic characteristics of insulin-loaded Eudragit entrapped mucoadhesive microspheres

et al. 2014

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Effective oral insulin delivery has remained a challenge to the pharmaceutical industry. This study was designed to evaluate the effect of magnesium stearate on the properties of insulin-loaded Eudragit Õ RL 100 entrapped mucoadhesive microspheres. Microspheres containing Eudragit Õ RL 100, insulin, and varying concentrations of magnesium stearate (agglomeration-preventing agent) were prepared by emulsification-coacervation method and characterized with respect to differential scanning calorimetry (DSC), morphology, particle size, loading efficiency, mucoadhesive and micromeritics properties. The in vitro release of insulin from the microspheres was performed in simulated intestinal fluid (SIF, pH 7.2) while the in vivo hypoglycemic effect was investigated by monitoring the plasma glucose level of the alloxaninduced diabetic rats after oral administration. Stable, spherical, brownish, mucoadhesive, discrete and free flowing insulin-loaded microspheres were formed. While the average particle size and mucoadhesiveness of the microspheres increased with an increase in the proportion of magnesium stearate, loading efficiency generally decreased. After 12 h, microspheres prepared with Eudragit Õ RL 100: magnesium stearate ratios of 15:1, 15:2, 15:3 and 15:4 released 68.20 ± 1.57, 79.40 ± 1.52, 76.60 ± 1.93 and 70.00 ± 1.00 (%) of insulin, respectively. Reduction in the blood glucose level for the subcutaneously (sc) administered insulin was significantly (p 0.05) higher than for most of the formulations. However, the blood glucose reduction effect produced by the orally administered insulin-loaded microspheres prepared with four parts of magnesium stearate and fifteen parts of Eudragit Õ RL 100 after 12 h was equal to that produced by subcutaneously administered insulin solution. The results of this study can suggest that this carrier system could be an alternative for the delivery of insulin.

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Oral delivery of macromolecules using intestinal patches: applications for insulin delivery

Cited by 115 publications

References 32 publications

Localization of magnetic pills

Localization of magnetic pills

The use of charge-coupled polymeric microparticles and micromagnets for modulating the bioavailability of orally delivered macromolecules

Influence of magnesium stearate on the physicochemical and pharmacodynamic characteristics of insulin-loaded Eudragit entrapped mucoadhesive microspheres

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