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Lura V, Lura A, Breitkreutz J, Klingmann V. The revival of the mini-tablets: Recent advancements, classifications and expectations for the future. Eur J Pharm Biopharm 2025; 210:114655. [PMID: 39922507 DOI: 10.1016/j.ejpb.2025.114655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 12/16/2024] [Accepted: 02/02/2025] [Indexed: 02/10/2025]
Abstract
Mini-tablets have recently raised huge interest in pharmaceutical industry. The present review aims to identify the rational, the opportunities and challenges of this emerging small solid drug dosage form by a structured literature review following the PRISMA algorithm. In total, more than 5,000 literature and patent sources have been found starting with the very first in the 60s of the past century, followed by the first multiparticular products using mini-tablets with pancreatin (Panzytrat® by the former BASF subsidiary Knoll/Nordmark) authorized in 1985. There seems to be a second boost of common interest in the 2000s when clinical studies demonstrated that one or more mini-tablets could enable superior drug administration even in very young patients including neonates over the former gold standard, a liquid drug preparation. Several pharmaceutical companies immediately started clinical development programs using the mini-tablet concept and the first products have been recently authorized by the competent authorities. Superiority was given as the mini-tablets ease the swallowing procedure compared to conventional tablets, enable various modified drug release opportunities including taste-masking by film-coating technology and provide excellent drug stability compared to liquid oral dosage forms. Due to these product attributes they are particularly beneficial to children and their caregivers. Furthermore, there is potential for precise individual drug dosing by counting adequate amounts of the multiple drug carriers. Most recently, two novel products with different concepts were authorized by the EMA and entered the market which are highlighted in this review: the first orodispersible mini-tablet with enalapril maleate for congenital heart failure (Aqumeldi® from Proveca Pharma) and the first single unit mini-tablet with matrix-type controlled melatonin release for insomnia (Slenyto® from Neurim Pharmaceuticals). Our review reveals, that the majority of the published scientific papers use co-processed, ready-to-use excipients for the orodispersible mini-tablet formulations. However, traditional fillers such as microcrystalline cellulose or lactose have also been used for immediate release mini-tablets after adding a (super)disintegrant and a lubricant. The manufacturing of mini-tablets is conducted on conventional rotary tablet presses, predominantly equipped with multi-tip toolings to improve the yield or production speed. Scaling-up has been successfully realized from compaction simulators to pilot and production scale. Film-coatings enabling gastric resistance, taste masking or sustained-release properties have been realized in both fluid-bed and drum coaters using the same polymers as for conventional tablets. There is still a significant lack in regulatory guidance despite the recent success of the mini-tablet concept, starting from suitable characterization methods in the pharmacopoeias up to the design and conduct of clinical studies on mini-tablets.
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Affiliation(s)
- Valentinë Lura
- Institute of Pharmaceutics and Biopharmaceutics, Heinrich-Heine-University Düsseldorf, Universitätsstrasse 140225 Düsseldorf, Germany
| | - Ard Lura
- Institute of Pharmaceutics and Biopharmaceutics, Heinrich-Heine-University Düsseldorf, Universitätsstrasse 140225 Düsseldorf, Germany
| | - Jörg Breitkreutz
- Institute of Pharmaceutics and Biopharmaceutics, Heinrich-Heine-University Düsseldorf, Universitätsstrasse 140225 Düsseldorf, Germany
| | - Viviane Klingmann
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Moorenstrasse 540225 Düsseldorf, Germany.
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2
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Tang X, Yang M, Gu Y, Jiang L, Du Y, Liu J. Orally Deliverable Dual-Targeted Pellets for the Synergistic Treatment of Ulcerative Colitis. DRUG DESIGN DEVELOPMENT AND THERAPY 2021; 15:4105-4123. [PMID: 34616144 PMCID: PMC8489837 DOI: 10.2147/dddt.s322702] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 08/23/2021] [Indexed: 12/15/2022]
Abstract
Purpose The effective treatment of ulcerative colitis (UC) poses substantial challenges, and the aetiopathogenesis of UC is closely related to infectious, immunological and environmental factors. Currently, there is a considerable need for the development of orally bioavailable dosage forms that enable the effective delivery of therapeutic drugs to local diseased lesions in the gastrointestinal tract. Methods Berberine (BBR) and Atractylodes macrocephala Koidz (AM) volatile oil, derived from the Chinese herbs Coptis chinensis Franch and Atractylodes macrocephala Koidz, have anti-inflammatory and immunomodulatory activities. In this study, we prepared colon-targeted pellets loaded with BBR and stomach-targeted pellets loaded with AM volatile oil for the synergistic treatment of UC. The Box-Behnken design and β-cyclodextrin inclusion technique were used to optimize the enteric coating formula and prepare volatile oil inclusion compounds. Results The two types of pellets were spherical and had satisfactory physical properties. The pharmacokinetic results showed that the AUC and MRT values of the dual-targeted (DPs) pellets were higher than those of the control pellets. In addition, in vivo animal imaging confirmed that the DPs could effectively deliver BBR to the colon. Moreover, compared with sulfasalazine and monotherapy, DPs exerted a more significant anti-inflammatory effect by inhibiting the expression of inflammatory factors including IL-1β, IL-4, IL-6, TNF-α and MPO both in serum and tissues and enhancing immunity by decreasing the production of IgA and IgG. Conclusion The DPs play a synergistic anti-UC effect by exerting systemic and local anti-inflammatory and provide an effective oral targeted preparation for the treatment of UC.
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Affiliation(s)
- Xiaomeng Tang
- Department of Pharmacy, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, People's Republic of China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China.,Department of Pharmacy, Changhai Hospital, Naval Medical University, Shanghai, 200433, People's Republic of China
| | - Meng Yang
- Department of Pharmacy, Shanghai Ninth People Hospital, Shanghai Jiao Tong University, Shanghai, 200011, People's Republic of China
| | - Yongwei Gu
- Department of Pharmacy, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, People's Republic of China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China
| | - Liangdi Jiang
- Department of Pharmacy, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, People's Republic of China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China.,College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, 250355, People's Republic of China
| | - Yue Du
- Department of Pharmacy, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, People's Republic of China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China.,College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, 250355, People's Republic of China
| | - Jiyong Liu
- Department of Pharmacy, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032, People's Republic of China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China.,Department of Pharmacy, Changhai Hospital, Naval Medical University, Shanghai, 200433, People's Republic of China
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Koehl NJ, Henze LJ, Bennett-Lenane H, Faisal W, Price DJ, Holm R, Kuentz M, Griffin BT. In Silico, In Vitro, and In Vivo Evaluation of Precipitation Inhibitors in Supersaturated Lipid-Based Formulations of Venetoclax. Mol Pharm 2021; 18:2174-2188. [PMID: 33890794 PMCID: PMC8289286 DOI: 10.1021/acs.molpharmaceut.0c00645] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
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The concept of using
precipitation inhibitors (PIs) to sustain
supersaturation is well established for amorphous formulations but
less in the case of lipid-based formulations (LBF). This study applied
a systematic in silico–in vitro–in vivo approach to assess the merits of
incorporating PIs in supersaturated LBFs (sLBF) using the model drug
venetoclax. sLBFs containing hydroxypropyl methylcellulose (HPMC),
hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinylpyrrolidone
(PVP), PVP-co-vinyl acetate (PVP/VA), Pluronic F108,
and Eudragit EPO were assessed in silico calculating
a drug–excipient mixing enthalpy, in vitro using a PI solvent shift test, and finally, bioavailability was
assessed in vivo in landrace pigs. The estimation
of pure interaction enthalpies of the drug and the excipient was deemed
useful in determining the most promising PIs for venetoclax. The sLBF
alone (i.e., no PI present) displayed a high initial drug concentration
in the aqueous phase during in vitro screening. sLBF
with Pluronic F108 displayed the highest venetoclax concentration
in the aqueous phase and sLBF with Eudragit EPO the lowest. In vivo, the sLBF alone showed the highest bioavailability
of 26.3 ± 14.2%. Interestingly, a trend toward a decreasing bioavailability
was observed for sLBF containing PIs, with PVP/VA being significantly
lower compared to sLBF alone. In conclusion, the ability of a sLBF
to generate supersaturated concentrations of venetoclax in
vitro was translated into increased absorption in
vivo. While in silico and in vitro PI screening suggested benefits in terms of prolonged supersaturation,
the addition of a PI did not increase in vivo bioavailability.
The findings of this study are of particular relevance to pre-clinical
drug development, where the high in vivo exposure
of venetoclax was achieved using a sLBF approach, and despite the
perceived risk of drug precipitation from a sLBF, including a PI may
not be merited in all cases.
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Affiliation(s)
- Niklas J Koehl
- School of Pharmacy, University College Cork, College Road, T12 YN60 Cork, Ireland.,Drug Product Development, Janssen Research and Development, Johnson & Johnson, Turnhoutseweg 30, 2340 Beerse, Belgium
| | - Laura J Henze
- School of Pharmacy, University College Cork, College Road, T12 YN60 Cork, Ireland.,Analytical Development, Janssen Research and Development, Johnson & Johnson, Turnhoutseweg 30, 2340 Beerse, Belgium
| | | | - Waleed Faisal
- School of Pharmacy, University College Cork, College Road, T12 YN60 Cork, Ireland.,Faculty of Pharmacy, Minia University, Minia, Egypt
| | - Daniel J Price
- Merck KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany.,Institution of Pharmaceutical Technology, Goethe University Frankfurt, Max-von-Laue-Strasse 9, 60439 Frankfurt am Main, Germany
| | - René Holm
- Drug Product Development, Janssen Research and Development, Johnson & Johnson, Turnhoutseweg 30, 2340 Beerse, Belgium.,Department of Science and Environment, Roskilde University, 4000 Roskilde, Denmark.,Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense, Denmark
| | - Martin Kuentz
- Institute of Pharma Technology, University of Applied Sciences and Arts Northwestern Switzerland, Hofackerstrasse 30, 4132 Muttenz, Switzerland
| | - Brendan T Griffin
- School of Pharmacy, University College Cork, College Road, T12 YN60 Cork, Ireland
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Fine-Shamir N, Dahan A. Methacrylate-Copolymer Eudragit EPO as a Solubility-Enabling Excipient for Anionic Drugs: Investigation of Drug Solubility, Intestinal Permeability, and Their Interplay. Mol Pharm 2019; 16:2884-2891. [PMID: 31120762 DOI: 10.1021/acs.molpharmaceut.9b00057] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
The purpose of this work was to investigate the use of the dimethylaminoethyl methacrylate-copolymer Eudragit EPO (EPO) in oral solubility-enabling formulations for anionic lipophilic drugs, aiming to guide optional formulation design and maximize oral bioavailability. We have studied the solubility, the permeability, and their interplay, using the low-solubility nonsteroidal anti-inflammatory drug mefenamic acid as a model drug. Then, we studied the biorelevant solubility enhancement of mefenamic acid from EPO-based formulations throughout the gastrointestinal tract (GIT), using the pH-dilution dissolution method. EPO allowed a profound and linear solubility increase of mefenamic acid, from 10 μg/mL without EPO to 9.41 mg/mL in the presence of 7.5% EPO (∼940-fold; 37 °C); however, a concomitant decrease of the drug permeability was obtained, both in vitro and in vivo in rats, indicating a solubility-permeability trade-off. In the absence of an excipient, the unstirred water layer (UWL) adjacent to the GI membrane was found to hinder the permeability of the drug, accounting for this UWL effect and revealing that the true membrane permeability allowed good prediction of the solubility-permeability trade-off as a function of EPO level using a direct relationship between the increased solubility afforded by a given EPO level and the consequent decreased permeability. Biorelevant dissolution studies revealed that EPO levels of 0.05 and 0.1% were insufficient to dissolve mefenamic acid dose during the entire dissolution time course, whereas 0.5 and 1% EPO allowed complete solubility with no drug precipitation. In conclusion, EPO may serve as a potent solubility-enabling excipient for BCS class II/IV acidic drugs; however, it should be used carefully. It is prudent to use the minimal EPO amounts just sufficient to dissolve the drug dose throughout the GIT and not more than that. Excess amounts of EPO provide no solubility gain and cause further permeability loss, jeopardizing the overall success of the formulation. This work may help the formulator to hit the optimal solubility-permeability balance, maximizing the oral bioavailability afforded by the formulation.
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Affiliation(s)
- Noa Fine-Shamir
- Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences , Ben-Gurion University of the Negev , Beer-Sheva 84105 , Israel
| | - Arik Dahan
- Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences , Ben-Gurion University of the Negev , Beer-Sheva 84105 , Israel
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5
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Gómez B, Míguez B, Yáñez R, Alonso JL. Manufacture and Properties of Glucomannans and Glucomannooligosaccharides Derived from Konjac and Other Sources. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2017; 65:2019-2031. [PMID: 28248105 DOI: 10.1021/acs.jafc.6b05409] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Glucomannans (GM) are polymers that can be found in natural resources, such as tubers, bulbs, roots, and both hard- and softwoods. In fact, mannan-based polysaccharides represent the largest hemicellulose fraction in softwoods. In addition to their structural functions and their role as energy reserve, they have been assessed for their healthy applications, including their role as new source of prebiotics. This paper summarizes the scientific literature regarding the manufacture and functional properties of GM and their hydrolysis products with a special focus on their prebiotic activity.
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Affiliation(s)
- Belén Gómez
- Chemical Engineering Department, Polytechnic Building, University of Vigo (Campus Ourense) , 32004 Ourense, Spain
- CITI , Avenida Galicia 2, Tecnopole, San Cibrao das Viñas, 32900 Ourense, Spain
- CINBIO , University Campus, 36310 Vigo, Pontevedra, Spain
| | - Beatriz Míguez
- Chemical Engineering Department, Polytechnic Building, University of Vigo (Campus Ourense) , 32004 Ourense, Spain
- CITI , Avenida Galicia 2, Tecnopole, San Cibrao das Viñas, 32900 Ourense, Spain
- CINBIO , University Campus, 36310 Vigo, Pontevedra, Spain
| | - Remedios Yáñez
- Chemical Engineering Department, Polytechnic Building, University of Vigo (Campus Ourense) , 32004 Ourense, Spain
- CITI , Avenida Galicia 2, Tecnopole, San Cibrao das Viñas, 32900 Ourense, Spain
- CINBIO , University Campus, 36310 Vigo, Pontevedra, Spain
| | - José L Alonso
- Chemical Engineering Department, Polytechnic Building, University of Vigo (Campus Ourense) , 32004 Ourense, Spain
- CITI , Avenida Galicia 2, Tecnopole, San Cibrao das Viñas, 32900 Ourense, Spain
- CINBIO , University Campus, 36310 Vigo, Pontevedra, Spain
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6
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Debotton N, Dahan A. Applications of Polymers as Pharmaceutical Excipients in Solid Oral Dosage Forms. Med Res Rev 2016; 37:52-97. [DOI: 10.1002/med.21403] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2015] [Revised: 06/07/2016] [Accepted: 06/24/2016] [Indexed: 01/10/2023]
Affiliation(s)
- Nir Debotton
- Department of Chemical Engineering; Shenkar College of Engineering and Design; Ramat-Gan Israel
| | - Arik Dahan
- Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences; Ben-Gurion University of the Negev; Beer-Sheva Israel
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7
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Hautala J, Heinämäki J, Hietala S, Juppo AM. Development of novel flavored Eudragit® E films for feline minitablet coatings. J Drug Deliv Sci Technol 2016. [DOI: 10.1016/j.jddst.2016.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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8
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Feuser PE, Gaspar PC, Jacques AV, Tedesco AC, Santos Silva MCD, Ricci-Júnior E, Sayer C, de Araújo PHH. Synthesis of ZnPc loaded poly(methyl methacrylate) nanoparticles via miniemulsion polymerization for photodynamic therapy in leukemic cells. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2016; 60:458-466. [DOI: 10.1016/j.msec.2015.11.063] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Revised: 11/09/2015] [Accepted: 11/23/2015] [Indexed: 12/20/2022]
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9
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Palugan L, Cerea M, Zema L, Gazzaniga A, Maroni A. Coated pellets for oral colon delivery. J Drug Deliv Sci Technol 2015. [DOI: 10.1016/j.jddst.2014.12.003] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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10
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Film coatings for oral colon delivery. Int J Pharm 2013; 457:372-94. [DOI: 10.1016/j.ijpharm.2013.05.043] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2013] [Revised: 05/14/2013] [Accepted: 05/16/2013] [Indexed: 01/07/2023]
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11
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Kharb V, Saharan VA, Dev K, Jadhav H, Purohit S. Formulation, evaluation and 32full factorial design-based optimization of ondansetron hydrochloride incorporated taste masked microspheres. Pharm Dev Technol 2013; 19:839-52. [DOI: 10.3109/10837450.2013.836220] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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12
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Overcoming therapeutic obstacles in inflammatory bowel diseases: A comprehensive review on novel drug delivery strategies. Eur J Pharm Sci 2013; 49:712-22. [DOI: 10.1016/j.ejps.2013.04.031] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2013] [Revised: 04/14/2013] [Accepted: 04/29/2013] [Indexed: 02/07/2023]
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13
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Pereira AGB, Fajardo AR, Nocchi S, Nakamura CV, Rubira AF, Muniz EC. Starch-based microspheres for sustained-release of curcumin: preparation and cytotoxic effect on tumor cells. Carbohydr Polym 2013; 98:711-20. [PMID: 23987403 DOI: 10.1016/j.carbpol.2013.06.013] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2013] [Revised: 06/12/2013] [Accepted: 06/13/2013] [Indexed: 11/19/2022]
Abstract
Curcumin (CUR) has been proved to be highly cytotoxic against different tumor cell lines. However, its poor solubility in aqueous medium and fast degradation in physiological pH are the common drawbacks preventing its efficient practical use. Herein, we report the development of original microspheres based on the biopolymer starch crosslinked with N,N-methylenebisacrylamide (MBA) to be applied as an efficient delivering system for CUR. The starch-based microspheres showed high loading efficiency even in loading solution with different CUR concentrations. In vitro release assays data showed that the CUR release is governed by anomalous transport (n=0.73) and it is pH-dependent. Cytotoxicity assays showed that starch microspheres could improve the cytotoxicity of CUR toward Caco-2 and HCT-116 tumor cell lines up to 40 times than that found for pure CUR. This behavior was attributed to the slowly and sustained release of CUR from the microspheres.
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Affiliation(s)
- Antonio G B Pereira
- Grupo de Materiais Poliméricos e Compósitos (GMPC) - Chemistry Departament, Maringa State University, Av. Colombo 5790, 87020-900 Maringá, Paraná, Brazil.
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Krishnaiah YSR, Khan MA. Strategies of targeting oral drug delivery systems to the colon and their potential use for the treatment of colorectal cancer. Pharm Dev Technol 2012; 17:521-40. [PMID: 22681390 DOI: 10.3109/10837450.2012.696268] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Colorectal cancer (CRC) is the third most common cause of cancer-related death in both men and women. Often, surgical intervention remains the choice in treating CRC. Traditional dosage forms used for treating CRC deliver drug to wanted as well as unwanted sites of drug action resulting in several adverse side effects. Targeted oral drug delivery systems are being investigated to target and deliver chemotherapeutic and chemopreventive agents directly to colon and rectum. Site-specific delivery of a drug to colon increases its concentration at the target site, and thus requires a lower dose with reduced incidence of side effects. The major obstacle to be overcome for successful targeting of drug to colon through oral route is that drug absorption/degradation must be avoided in stomach and small intestine before the dosage form reaches colon. The review includes discussion of physiological factors that must be considered when targeting drugs directly to colorectal region, an outline on drugs used for treatment and prevention of CRC, and a brief description of various types of colon-targeted oral drug delivery systems. The focus is on the assessment of various formulation approaches being investigated for oral colon-specific delivery of drugs used in the treatment and prevention of CRC.
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Affiliation(s)
- Yellela S R Krishnaiah
- Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Science, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Springs, MD 20993, USA.
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15
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Maroni A, Zema L, Del Curto MD, Foppoli A, Gazzaniga A. Oral colon delivery of insulin with the aid of functional adjuvants. Adv Drug Deliv Rev 2012; 64:540-56. [PMID: 22086142 DOI: 10.1016/j.addr.2011.10.006] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2011] [Revised: 09/30/2011] [Accepted: 10/27/2011] [Indexed: 12/11/2022]
Abstract
Oral colon delivery is currently considered of importance not only for the treatment of local pathologies, such as primarily inflammatory bowel disease (IBD), but also as a means of accomplishing systemic therapeutic goals. Although the large bowel fails to be ideally suited for absorption processes, it may indeed offer a number of advantages over the small intestine, including a long transit time, lower levels of peptidases and higher responsiveness to permeation enhancers. Accordingly, it has been under extensive investigation as a possible strategy to improve the oral bioavailability of peptide and protein drugs. Because of a strong underlying rationale, most of these studies have focused on insulin. In the present review, the impact of key anatomical and physiological characteristics of the colon on its viability as a protein release site is discussed. Moreover, the main formulation approaches to oral colon targeting are outlined along with the design features and performance of insulin-based devices.
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16
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Patel MM, Amin AF. Development of a novel tablet-in-capsule formulation of mesalamine for inflammatory bowel disease. Pharm Dev Technol 2012; 18:390-400. [DOI: 10.3109/10837450.2011.653819] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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17
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Electrolyte-Stimulated Biphasic Dissolution Profile and Stability Enhancement for Tablets Containing Drug-Polyelectrolyte Complexes. Pharm Res 2012; 29:2710-21. [DOI: 10.1007/s11095-011-0656-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2011] [Accepted: 12/13/2011] [Indexed: 10/14/2022]
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18
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Mustafin RI, Bukhovets AV, Sitenkov AY, Garipova VR, Kemenova VA, Rombaut P, Van den Mooter G. Synthesis and characterization of a new carrier based on Eudragit® EPO/S100 interpolyelectrolyte complex for controlled colon-specific drug delivery. Pharm Chem J 2011. [DOI: 10.1007/s11094-011-0681-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Tailoring of drug delivery of 5-fluorouracil to the colon via a mixed film coated unit system. ACTA PHARMACEUTICA 2011; 61:343-51. [PMID: 21945913 DOI: 10.2478/v10007-011-0023-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The study was carried out to establish the effectiveness of a mixed film composed of ethylcellulose/Eudragit S100 for colonic delivery of 5-flourouracil (5-FU). Tablets cores containing 5-FU were prepared by direct compression method by coating at different levels (2-9%, m/m) with a non-aqueous solution containing ethylcellulose/Eudragit S100. Coated tablets were studied for the in vitro release of 5-FU and the samples were analyzed spectrophotometrically at 266 nm. Drug release from coated systems depended on the thickness of the mixed film and the composition of the core. Channel formation was initiated in the coat by dissolution of the Eudragit S100 fraction at higher pH in the colonic region. The release was found to be higher in tablets containing Avicel as filler owing to its wicking action compared to that from lactose containing cores. Furthermore, batches containing superdisintegrant (1%, m/m Cross-PVP) along with Avicel in the core released approximately 81.1% drug during the colonic transit time. Kinetic studies indicated that all the formulations followed first-order release kinetics. The developed delivery system will expectedly deliver the drug to the colon.
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20
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Kindermann C, Matthée K, Strohmeyer J, Sievert F, Breitkreutz J. Tailor-made release triggering from hot-melt extruded complexes of basic polyelectrolyte and poorly water-soluble drugs. Eur J Pharm Biopharm 2011; 79:372-81. [PMID: 21596136 DOI: 10.1016/j.ejpb.2011.05.001] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2011] [Revised: 04/15/2011] [Accepted: 05/02/2011] [Indexed: 11/28/2022]
Abstract
The aim of the study was the formulation of polyelectrolyte complexes composed of poorly water-soluble acid drugs and basic polymethacrylates by hot-melt extrusion enabling a tailor-made release pattern by the addition of inorganic salts. The influence of different electrolytes was analyzed at varying conditions in order to control drug delivery from the complexes. Poorly water-soluble model drugs naproxen and furosemide were applied in their non-ionic form. After hot-melt extrusion of the naproxen-polymethacrylate powder blend, XRPD and DSC measurements indicated the formation of a single-phase amorphous system. Milled extrudates were stable under storage at long-term and intermediate conditions. Polyelectrolyte complex formation by an acid-base reaction during hot-melt extrusion could be proven by the lack of vibrations of dimethylamino and carboxylic groups by FT-IR and Raman spectroscopy. The complexes did not dissolve in demineralized water. Drug release could be immediately induced by addition of neutral electrolytes. Tailor-made dissolution profiles were realized by controlled electrolyte triggering. Maximal effects were achieved by concentrations of 0.05-0.15 M NaCl. Different anions of alkali halogenides revealed variant magnitudes of the effect depending on the anion radius. Polyelectrolyte complex formation and dissolution principles were also confirmed for furosemide.
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Affiliation(s)
- Christoph Kindermann
- Institute of Pharmaceutics and Biopharmaceutics, Heinrich-Heine-University, Duesseldorf, Germany
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21
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Krenzlin S, Siepmann F, Wils D, Guerin-Deremaux L, Flament MP, Siepmann J. Non-coated multiparticulate matrix systems for colon targeting. Drug Dev Ind Pharm 2011; 37:1150-9. [PMID: 21417601 DOI: 10.3109/03639045.2011.562214] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND Colon specific drug delivery can significantly improve the efficacy of local treatments of inflammatory bowel diseases. Film coatings containing the starch derivative Nutriose have recently been reported to minimize 5-ASA release in media simulating the upper gastro intestinal tract (GIT), while releasing the drug in a time-controlled manner upon contact with feces from Crohn's Disease and Ulcerative Colitis patients. It was the aim of this study to prepare Nutriose-containing matrix pellets and mini tablets in order to avoid a film coating step. METHODS Highly dosed matrix pellets were prepared by extrusion-spheronization, highly dosed mini tablets by compression. Various types of lipids were added and drug release measured in 0.1 N HCl and phosphate buffer pH 6.8, optionally containing pepsin and pancreatin. RESULTS The type of added lipid and the preparation technique, in particular the curing conditions, significantly affected the resulting drug release kinetics. Glyceryl palmitostearate containing pellets and mini tablets showed the most promising results upon appropriate curing, minimizing premature drug release in media simulating the upper GIT. CONCLUSION The proposed novel multiparticulates do not require a film coating step and show an interesting potential for site-specific drug delivery to the colon of inflammatory bowel disease patients.
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Affiliation(s)
- S Krenzlin
- Université Lille Nord de France, College of Pharmacy, France
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22
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Bharaniraja B, Jayaram Kumar K, Prasad CM, Sen AK. Modified katira gum for colon targeted drug delivery. J Appl Polym Sci 2010. [DOI: 10.1002/app.32829] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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23
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Siddique S, Khanam J, Bigoniya P. Development of sustained release capsules containing "coated matrix granules of metoprolol tartrate". AAPS PharmSciTech 2010; 11:1306-14. [PMID: 20721649 DOI: 10.1208/s12249-010-9501-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2009] [Accepted: 07/23/2010] [Indexed: 11/30/2022] Open
Abstract
The objective of this investigation was to prepare sustained release capsule containing coated matrix granules of metoprolol tartrate and to study its in vitro release and in vivo absorption. The design of dosage form was performed by choosing hydrophilic hydroxypropyl methyl cellulose (HPMC K100M) and hydrophobic ethyl cellulose (EC) polymers as matrix builders and Eudragit® RL/RS as coating polymers. Granules were prepared by composing drug with HPMC K100M, EC, dicalcium phosphate by wet granulation method with subsequent coating. Optimized formulation of metoprolol tartrate was formed by using 30% HPMC K100M, 20% EC, and ratio of Eudragit® RS/RL as 97.5:2.5 at 25% coating level. Capsules were filled with free flowing optimized granules of uniform drug content. This extended the release period upto 12 h in vitro study. Similarity factor and mean dissolution time were also reported to compare various dissolution profiles. The network formed by HPMC and EC had been coupled satisfactorily with the controlled resistance offered by Eudragit® RS. The release mechanism of capsules followed Korsemeyer-Peppas model that indicated significant contribution of erosion effect of hydrophilic polymer. Biopharmaceutical study of this optimized dosage form in rabbit model showed 10 h prolonged drug release in vivo. A close correlation (R(2) = 0.9434) was established between the in vitro release and the in vivo absorption of drug. The results suggested that wet granulation with subsequent coating by fluidized bed technique, is a suitable method to formulate sustained release capsules of metoprolol tartrate and it can perform therapeutically better than conventional immediate release dosage form.
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24
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Ross GR, Gusils C, Oliszewski R, Colombo de Holgado S, González SN. Effects of probiotic administration in swine. J Biosci Bioeng 2010; 109:545-9. [DOI: 10.1016/j.jbiosc.2009.11.007] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2009] [Revised: 08/11/2009] [Accepted: 11/09/2009] [Indexed: 11/25/2022]
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25
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Moustafine RI, Salachova AR, Frolova ES, Kemenova VA, Van den Mooter G. Interpolyelectrolyte complexes of Eudragit® E PO with sodium alginate as potential carriers for colonic drug delivery: monitoring of structural transformation and composition changes during swellability and release evaluating. Drug Dev Ind Pharm 2009; 35:1439-51. [DOI: 10.3109/03639040902988574] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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26
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Rane AB, Gattani SG, Kadam VD, Tekade AR. Formulation and evaluation of press coated tablets for pulsatile drug delivery using hydrophilic and hydrophobic polymers. Chem Pharm Bull (Tokyo) 2009; 57:1213-7. [PMID: 19881269 DOI: 10.1248/cpb.57.1213] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2023]
Abstract
The aim of present investigation was to develop press coated tablet for pulsatile drug delivery of ketoprofen using hydrophilic and hydrophobic polymers. The drug delivery system was designed to deliver the drug at such a time when it could be most needful to patient of rheumatoid arthritis. The press coated tablets containing ketoprofen in the inner core was formulated with an outer shell by different weight ratio of hydrophobic polymer (micronized ethyl cellulose powder) and hydrophilic polymers (glycinemax husk or sodium alginate). The release profile of press coated tablet exhibited a lag time followed by burst release, in which outer shell ruptured into two halves. Authors also investigated factors influencing on lag time such as particle size and viscosity of ethyl cellulose, outer coating weight and paddle rpm. The surface morphology of the tablet was examined by a scanning electron microscopy. Differential scanning calorimeter and Fourier transformed infrared spectroscopy study showed compatibility between ketoprofen and coating material.
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Affiliation(s)
- Ashish Babulal Rane
- Department of Pharmaceutics and Quality Assurance, R. C. Patel Institute of Pharmaceutical Education & Research, Shirpur 425 405, Maharashtra, India
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27
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Gohel M, Parikh R, Nagori S, Dabhi M. Design of a Potential Colonic Drug Delivery System of Mesalamine. Pharm Dev Technol 2008; 13:447-56. [DOI: 10.1080/10837450802088679] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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28
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Law D, Zhang Z. Stabilization and Target Delivery of Nattokinase Using Compression Coating. Drug Dev Ind Pharm 2008; 33:495-503. [PMID: 17520440 DOI: 10.1080/03639040601050247] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
The aim of the work is to develop a new formulation in order to stabilize a nutraceutical enzyme Nattokinase (NKCP) in powders and to control its release rate when it passes through the gastrointestinal tract of human. NKCP powders were first compacted into a tablet, which was then coated with a mixture of an enteric material Eudragit L100-55 (EL100-55) and Hydroxypropylcellulose (HPC) by direct compression. The activity of the enzyme was determined using amidolytic assay and its release rates in artificial gastric juice and an intestinal fluid were quantified using bicinchoninic acid assay. Results have shown that the activity of NKCP was pressure independent and the coated tablets protected NKCP from being denatured in the gastric juice, and realized its controlled release to the intestine based on in vitro experiments.
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Affiliation(s)
- D Law
- Centre for Formulation Engineering, Department of Chemical Engineering, School of Engineering, University of Birmingham, Edgbaston, Birmingham, UK
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29
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Zilberman M, Shifrovitch Y, Aviv M, Hershkovitz M. Structured Drug-eluting Bioresorbable Films: Microstructure and Release Profile. J Biomater Appl 2008; 23:385-406. [DOI: 10.1177/0885328207088261] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Bioresorbable drug-eluting films can be used in many biomedical applications. Examples for such applications include biodegradable medical support devices which combine mechanical support with drug release and antibiotic-eluting film coatings for prevention of bacterial infections associated with orthopedic implants or during gingival healing. In the current study, bioresorbable drug-loaded polymer films are prepared by solution processing. Two film structures are studied: A polymer film with large drug crystals located on its surface (A-type) and a polymer film with small drug particles and crystals distributed within the bulk (B-type). The basic mode of drug dispersion/location in the film (A or B-type) is found to be determined mainly by the process of film formation and depends mainly on the solvent evaporation rate, whereas the drug's hydrophilicity has a minor effect on this structuring process. Most release profiles from A-type films exhibit a burst effect of ~30% and a second release stage that occurs at an approximately constant rate and is determined mainly by the polymer weight loss rate. An extremely high burst release is exhibited only by a very hydrophilic drug. The matrix (monolithic) nature of the B-type film enables release profiles that are determined mainly by the host polymer's degradation profile, with a very low burst effect in most of the studied systems. In addition to the drug location/ dispersion in the film, the host polymer and drug type also strongly affect the drug's release profile from the film. It has been demonstrated that appropriate selection of the process parameters and film components (polymer and drug) can yield film structures with desirable drug release behaviors. This can lead to the engineering of new bioresorbable drug-eluting film-based implants for various applications.
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Affiliation(s)
- M. Zilberman
- Department of Biomedical Engineering, Faculty of Engineering Tel Aviv University, Tel Aviv 69978, Israel,
| | - Y. Shifrovitch
- Department of Biomedical Engineering, Faculty of Engineering Tel Aviv University, Tel Aviv 69978, Israel
| | - M. Aviv
- Department of Biomedical Engineering, Faculty of Engineering Tel Aviv University, Tel Aviv 69978, Israel
| | - M. Hershkovitz
- Department of Biomedical Engineering, Faculty of Engineering Tel Aviv University, Tel Aviv 69978, Israel
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30
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Wei H, Qing D, De-Ying C, Bai X, Li-Fang F. In-vitro and in-vivo studies of pectin/ethylcellulosefilm-coated pellets of 5-fluorouracil for colonic targeting. J Pharm Pharmacol 2008; 60:35-44. [PMID: 18088503 DOI: 10.1211/jpp.60.1.0005] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The aim of the present study was to define in-vitro and in-vivo characteristics of pectin/ethylcellulose-film-coated pellets of 5-fluorouracil (5-FU) for colonic targeting. The pellet cores were coated to different film thicknesses with three different pectin/ethylcellulose formulations using a fluidized bed coater. The gastrointestinal (GI) transit of coated pellets was determined by counting the percentage of coated pellets in the GI lumen by celiotomy at certain times after oral administration. 5FU was administered to rats at a dose of 15 mg kg(-1). The toxicity of 5-FU in the GI tract was evaluated using histological examination. The 1:2 ratio pectin:ethylcellulose-coated pellets with 30% total weight gain (TWG-30%) produced more satisfactory drug-release profiles in the simulated gastric, intestinal and colonic fluids. Most of the coated pellets were eliminated from the stomach in 2 h, moved into the small intestine after 2-4 h, and reached the large intestine after 4 h. After oral administration of coated pellets, 5-FU started appearing in the plasma at 7 h, and reached peak plasma concentration (Cmax) of 3.21+/-2.01 microg mL(-1) at 16 h (Tmax); the Cmax for uncoated pellets was 22.21+/-2.60 microg mL(-1) at Tmax 0.75 h. The TWG-30% formulation showed delayed Tmax, decreased Cmax and prolonged mean residence time compared with uncoated pellets. Marked pathological features in the colon were seen in rats given coated pellets, but no injuries were observed in the upper GI tract. The formulation of TWG-30% could deliver 5-FU to the colon for local action.
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Affiliation(s)
- He Wei
- Department of Pharmaceutics, School of Pharmaceutical Science, Hebei Medical University, 361, ZhongShan East Road, ShiJiaZhuang, 050017, P. R. China
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31
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Shah PP, Mashru RC, Rane YM, Thakkar A. Design and optimization of mefloquine hydrochloride microparticles for bitter taste masking. AAPS PharmSciTech 2008; 9:377-89. [PMID: 18431670 PMCID: PMC2976944 DOI: 10.1208/s12249-008-9052-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2007] [Accepted: 01/19/2008] [Indexed: 11/30/2022] Open
Abstract
The objective of the present investigation was to reduce the bitterness with improved dissolution, in acidic medium (pH 1.2), of mefloquine hydrochloride (MFL). Microparticles were prepared by coacervation method using Eudragit E (EE) as polymer and sodium hydroxide as precipitant. A 3(2) full factorial design was used for optimization wherein the drug concentration (A) and polymer concentration (B) were selected as independent variables and the bitterness score, particle size and dissolution at various pH were selected as the dependent variables. The desirability function approach has been employed in order to find the best compromise between the different experimental responses. The model is further cross validated for bias. The optimized microparticles were characterized by FT-IR, DSC, XRPD and SEM. Bitterness score was evaluated by human gustatory sensation test. Multiple linear regression analysis revealed that the reduced bitterness of MFL can be obtained by controlling the dissolution of microparticles at pH 6.8 and increasing the EE concentration. The increase in polymer concentration leads to reduction in dissolution of microparticles at pH > 5 due to its insolubility. However the dissolution studies at pH 1.2 demonstrated enhanced dissolution of MFL from microparticles might be due to the high porosity of the microparticles, hydrophilic nature of the EE, and improved wettability, provided by the dissolved EE. The bitterness score of microparticles was decreased to zero compared to 3+ of pure ARM. In conclusion the bitterness of MFL was reduced with improved dissolution at acidic pH.
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Affiliation(s)
- Punit P Shah
- Center of Relevance and Excellence in NDDS, Pharmacy Department, The M. S. University of Baroda, G H Patel building, Donor's Plaza, Fatehgunj, Vadodara, Gujarat, India.
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32
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Siepmann F, Wahle C, Leclercq B, Carlin B, Siepmann J. pH-sensitive film coatings: towards a better understanding and facilitated optimization. Eur J Pharm Biopharm 2007; 68:2-10. [PMID: 17881197 DOI: 10.1016/j.ejpb.2007.03.025] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2006] [Revised: 03/22/2007] [Accepted: 03/22/2007] [Indexed: 11/28/2022]
Abstract
The major aims of this study were: (i) to prepare and characterize polymeric film coatings with pH-dependent properties for oral administration; and (ii) to better understand the underlying mass transport mechanisms upon exposure to simulated gastric and intestinal fluids. Propylene glycol alginate (containing free carboxylic groups) was chosen as a pH-sensitive film former, which was blended with different amounts of ethylcellulose (being water-insoluble throughout the gastro-intestinal tract). The water uptake kinetics of thin free films in 0.1M HCl and phosphate buffer pH 7.4 were monitored gravimetrically and quantitatively described using an appropriate analytical solution of Fick's law of diffusion. Interestingly, the addition of only a low percentage (2.5-10%) of propylene glycol alginate to ethylcellulose significantly increased both, the rate and extent of the films' water uptake, irrespective of the pH of the release medium. Importantly, diffusion was found to be the pre-dominant mass transport mechanism for all system compositions and types of release media. The apparent water diffusivity in the polymeric films could quantitatively be determined as a function of the polymer blend ratio. It significantly increased with increasing pH of the release medium, due to the presence of the free carboxylic groups in propylene glycol alginate. Also the dry mass loss of the polymer networks was much more pronounced at high compared to low pH. The differences in both water uptake as well as dry mass loss resulted in a clear pH-dependence of the drug release kinetics from coated pellets. Importantly, desired pH-sensitive release rates can easily be adjusted by varying the propylene glycol alginate content.
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Affiliation(s)
- F Siepmann
- College of Pharmacy, University of Lille, 3 Rue du Professeur Laguesse, Lille, France
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33
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Siepmann F, Hoffmann A, Leclercq B, Carlin B, Siepmann J. How to adjust desired drug release patterns from ethylcellulose-coated dosage forms. J Control Release 2007; 119:182-9. [PMID: 17391796 DOI: 10.1016/j.jconrel.2007.02.003] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2006] [Revised: 02/02/2007] [Accepted: 02/06/2007] [Indexed: 11/28/2022]
Abstract
The aim of this study was to provide an easy and efficient tool to adjust desired drug release kinetics from (aqueous) ethylcellulose-coated solid dosage forms and to better understand the underlying mass transport mechanisms. Pure ethylcellulose films are poorly permeable for many substances and can result in very low release rates for certain drugs from coated dosage forms, if the film coatings are completely formed and remain intact upon exposure to the release media. To increase the permeability of the polymeric membranes, different amounts of a water-soluble poly(vinyl alcohol)-poly(ethylene glycol) graft copolymer (PVA-PEG graft copolymer) were added to an aqueous ethylcellulose dispersion (Aquacoat ECD). Importantly, the presence of only a low percentage of this hydrophilic copolymer significantly increased the resulting water uptake rate and extent, dry weight loss and drug permeability of the films. In contrast to hydroxypropyl methylcellulose (HPMC), the PVA-PEG graft copolymer does not cause flocculation of the colloidal coating dispersion (leading to potentially variable release rates). Interestingly, the transport of water as well as of the model drug theophylline through the polymeric networks was primarily controlled by pure diffusion. The penetration kinetics could be quantitatively described by Fick's law of diffusion, irrespective of the type of release medium and PVA-PEG graft copolymer content. Most important from a practical point of view, a broad spectrum of pH-independent drug release rates can easily be obtained from drug-loaded pellets by simply varying the PVA-PEG graft copolymer content. An appropriate curing step after coating is required, but interestingly the investigated curing conditions (differing in time and relative humidity) resulted in very similar drug release patterns, indicating that stable film structures are likely to be achieved.
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Affiliation(s)
- F Siepmann
- College of Pharmacy, JE 2491, University of Lille, 3 Rue du Professeur Laguesse, 59006 Lille, France
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34
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Li S, Yang Y, Yang X, Xu H. In vitro degradation and protein release of semi-IPN hydrogels consisted of poly(acrylic acid-acrylamide-methacrylate) and amylose. J Appl Polym Sci 2007. [DOI: 10.1002/app.26389] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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35
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Parvez S, Malik KA, Ah Kang S, Kim HY. Probiotics and their fermented food products are beneficial for health. J Appl Microbiol 2006; 100:1171-85. [PMID: 16696665 DOI: 10.1111/j.1365-2672.2006.02963.x] [Citation(s) in RCA: 727] [Impact Index Per Article: 38.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Probiotics are usually defined as microbial food supplements with beneficial effects on the consumers. Most probiotics fall into the group of organisms' known as lactic acid-producing bacteria and are normally consumed in the form of yogurt, fermented milks or other fermented foods. Some of the beneficial effect of lactic acid bacteria consumption include: (i) improving intestinal tract health; (ii) enhancing the immune system, synthesizing and enhancing the bioavailability of nutrients; (iii) reducing symptoms of lactose intolerance, decreasing the prevalence of allergy in susceptible individuals; and (iv) reducing risk of certain cancers. The mechanisms by which probiotics exert their effects are largely unknown, but may involve modifying gut pH, antagonizing pathogens through production of antimicrobial compounds, competing for pathogen binding and receptor sites as well as for available nutrients and growth factors, stimulating immunomodulatory cells, and producing lactase. Selection criteria, efficacy, food and supplement sources and safety issues around probiotics are reviewed. Recent scientific investigation has supported the important role of probiotics as a part of a healthy diet for human as well as for animals and may be an avenue to provide a safe, cost effective, and 'natural' approach that adds a barrier against microbial infection. This paper presents a review of probiotics in health maintenance and disease prevention.
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Affiliation(s)
- S Parvez
- Helix Pharms Co. Ltd, Kyung-Hee University, and Department of Biological Sciences of Oriental Medicine, Graduate School of Interdepartmental Studies, Institute of Oriental Medicines, Kyung-Hee University, Dongdaemoon-gu, Seoul, Korea
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36
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Gazzaniga A, Maroni A, Sangalli ME, Zema L. Time-controlled oral delivery systems for colon targeting. Expert Opin Drug Deliv 2006; 3:583-97. [PMID: 16948555 DOI: 10.1517/17425247.3.5.583] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
In recent years, many research efforts have been spent in the achievement of selective delivery of drugs into the colon following oral administration. Indeed, colonic release is regarded as a beneficial approach to the pharmacological treatment or prevention of widespread large bowel pathologies, such as inflammatory bowel disease and adenocarcinoma. In addition, it is extensively explored as a potential means of enhancing the oral bioavailability of peptides, proteins and other biotechnological molecules, which are known to be less prone to enzymatic degradation in the large, rather than in the small, intestine. Based on these premises, several formulation strategies have been attempted in pursuit of colonic release, chiefly including microflora-, pH-, pressure- and time-dependent delivery technologies. In particular, this review is focused on the main design features and release performances of time-controlled devices, which rely on the relative constancy that is observed in the small intestinal transit time of dosage forms.
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Affiliation(s)
- Andrea Gazzaniga
- Istituto di Chimica Farmaceutica e Tossicologica P. Pratesi, Università di Milano, V.le Abruzzi 42, 20131 Milan, Italy.
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Zilberman M. Dexamethasone loaded bioresorbable films used in medical support devices: structure, degradation, crystallinity and drug release. Acta Biomater 2005; 1:615-24. [PMID: 16701842 DOI: 10.1016/j.actbio.2005.06.007] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2005] [Revised: 05/20/2005] [Accepted: 06/30/2005] [Indexed: 11/24/2022]
Abstract
Bioresorbable polymer films containing dexamethasone (DM) were prepared using a solution processing technique. Investigation of the films focused on cumulative DM release as affected by film morphology (drug location/dispersion in the film) and degradation processes. Two film structures were studied: A-type, a polymer film with large drug crystals located on the film's surface, and B-type, a polymer film with small drug particles and crystals distributed within the bulk. The effect of the polymer's degree of crystallinity on the drug release profile was also studied. Prototypical applications of these films are biodegradable medical support devices which combine mechanical support with drug release. In most of our studied systems the drug release profile from the film is determined mainly by both drug location/dispersion in the film and the polymer's weight loss rate. All release profiles from A-type films exhibited a burst effect of approximately 30%, accompanied by a second release phase at a constant rate, whereas the release profiles from B-type films were determined mainly by the degradation profile of the host polymer, and did not exhibit any burst effect. A high degree of crystallinity is important for the current application, since good mechanical properties are required. This contributes to slower drug release rates, mainly at relatively low weight losses, whereas at high weight losses, where a porous structure is created, the crystallinity almost does not affect the rate of drug release. The shape of the porous structure that develops with degradation also affects the drug release profile from the B-type films.
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Affiliation(s)
- M Zilberman
- Department of Biomedical Engineering, Faculty of Engineering, Tel Aviv University, Tel Aviv 69978, Israel.
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38
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Kesisoglou F, Zimmermann EM. Novel drug delivery strategies for the treatment of inflammatory bowel disease. Expert Opin Drug Deliv 2005; 2:451-63. [PMID: 16296767 DOI: 10.1517/17425247.2.3.451] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Inflammatory bowel disease (IBD) encompasses two idiopathic inflammatory diseases of the intestinal tract: Crohn's disease and ulcerative colitis. Existing therapy for IBD consists mainly of orally or rectally administered small drug molecules, such as 5-aminosalicylates and corticosteroids, or potent systemic immune suppressants. IBD presents a challenging target for drug delivery, particularly by the oral route, as, contrary to most therapeutic regimens, minimal systemic absorption and maximal intestinal wall drug levels are desired. Several delivery strategies are employed to achieve this goal, including the chemical modification of the drug molecules, the use of controlled- and delayed-release formulations and the use of bioadhesive particles. The goal of this review is to summarise existing IBD therapy and examine novel approaches in intestinal drug delivery.
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Affiliation(s)
- Filippos Kesisoglou
- University of Michigan Department of Pharmaceutical Sciences, College of Pharmacy, Ann Arbor, MI 48109-1065, USA
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Abstract
Fifteen years of research in the area of colon-specific drug delivery has left us with a slim choice of viable techniques, not because of the lack of proofs of concept but because of the ambiguity regarding the therapeutic necessity of targeting the colon with drugs. Critical analysis of existing technologies as well as medically based novel ideas could lead to interesting prospects.:
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Affiliation(s)
- Abraham Rubinstein
- The Hebrew University of Jerusalem, Faculty of Medicine, School of Pharmacy, P.O. Box 12065, Jerusalem 91120, Israel.
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40
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Abstract
Increasing acceptance of protein- and peptide-based drugs necessitates an investigation into the suitability of various sites for their administration. Colon is being investigated for delivery of such molecules. Colon-specific drug delivery is designed to target drug molecules specifically to this area. Development of site-specific delivery systems may exploit a specific property of the target site for drug activation/release. The gastrointestinal tract is inhabited by over 400 bacterial species, each having a specific niche in the tract. Colon, the distal part of the intestine is inhabited by a large variety of gram negative microflora. This flora produces a vast number of enzymes which are being exploited for formulation of colon-specific drug delivery systems. A number of microbially activated systems for colon-specific drug delivery are being evaluated. These include prodrugs and synthetic or natural polymer-based delivery systems. This article aims at reviewing the various microbially activated drug delivery systems for colon-specific drug delivery with specific reference to the microflora of the various segments of the gastrointestinal tract and their role in targeting drug delivery to the colon.
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Affiliation(s)
- V R Sinha
- University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160 014, India.
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Abstract
The aim of the present study was to develop a single unit, site-specific drug formulation allowing targeted drug release in the colon. Tablets were prepared using polysaccharides or synthetic polymer as binders. These included xanthan gum, guar gum, chitosan and Eudragit E. Indomethacin was used as a model drug. The prepared tablets were enteric coated with Eudragit-L 100 to give protection in the stomach. The coated tablets were tested in-vitro for their suitability as colon specific drug delivery systems. The drug release studies were carried out in simulated stomach environment (pH 1.2) for 2 h followed by small intestinal environment at pH 6.8. The dissolution data obtained from tablets demonstrates that the dissolution rate of the tablet is dependent upon the type and concentration of polysaccharide/polymer used as binder. The results demonstrate that enteric coated tablets containing 3% chitosan as a binder, showed only 12.5% drug release in the first 5 h, which is the usual upper gastrointestinal transit time, whereas, tablets prepared using guar gum as binder, were unable to protect drug release under similar conditions. Preparations with xanthan gum as a binder formed time-dependent release formulations. When used in a concentration of 5.92% in the tablets, 28% drug release was observed in the usual upper gastrointestinal tract conditions. It was also found that enteric coated preparation formulated with 8.88% of Eudragit E as binder could be used to carry water insoluble drug molecules to the colon especially in IBD. The above study shows that chitosan could be successfully used as a binder, for colon targeting of water insoluble drugs in preference to guar gum when used in the same concentration. Additionally, formulations developed with chitosan and Eudragit E would be highly site specific since drug release would be at a retarded rate till microbial degradation or polymer solubilization takes place in the colon.
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Affiliation(s)
- V R Sinha
- University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160 014, India.
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Pang YN, Zhang Y, Zhang ZR. Synthesis of an enzyme-dependent prodrug and evaluation of its potential for colon targeting. World J Gastroenterol 2002; 8:913-7. [PMID: 12378641 PMCID: PMC4656586 DOI: 10.3748/wjg.v8.i5.913] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To synthesize dexamethasone-succinate-dextran (DSD) conjugate and to evaluate the potentiality of DSD for the treatment of inflammatory bowel diseases.
METHODS: Dexamethasone was attached to dextran (average molecular weight = 70400 Dalton) using succinate anhydride in an anhydrous environment catalyzed by 4-dimethylaminopyridine and 1,1’-carbonyldiimidazole. The chemical structure of DSD was identified by UV, IR and NMR, and the in vivo drug release behavior of this prodrug was investigated after oral administration of DSD suspension.
RESULTS: The DSD conjugate was obtained in two steps and the content of dexamethasone in DSD was 11.28%. The dextran prodrug was stable in rat stomach and small intestine and negligibly absorbed from these tracts. Four to nine hours after the oral administration, most of the prodrug (> 95%) had moved to the cecum and colon, and was easily hydrolyzed by an endodextranase. Recover of dexamethasone from colon and cecum after administration of DSD conjugate was 6-12 folds higher than the recovery after administration of unmodified dexamethasone (t = 2.74, P < 0.05). The preferential release of free dexamethasone in cecum and colon over that in the small intestine was statistically significant (t = 2.27, P < 0.05).
CONCLUSION: The results of this study indicate that dextran conjugates may be useful in selectively delivering glucocorticoids to the colon.
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Affiliation(s)
- Yi-Nuo Pang
- West China School of Pharmacy, Sichuan University, Chengdu, 610041, Sichuan Province, China
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