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1.
Mol Pharm ; 21(7): 3084-3102, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38828798

ABSTRACT

Biopharmaceuticals such as nucleic acids, proteins, and peptides constitute a new array of treatment modalities for chronic ailments. Invasive routes remain the mainstay of administering biopharmaceuticals due to their labile nature in the biological environment. However, it is not preferred for long-term therapy due to the lack of patient adherence and clinical suitability. Therefore, alternative routes of administration are sought to utilize novel biopharmaceutical therapies to their utmost potential. Nanoparticle-mediated pulmonary delivery of biologics can facilitate both local and systemic disorders. Solid lipid nanoparticles (SLNs) afford many opportunities as pulmonary carriers due to their physicochemical stability and ability to incorporate both hydrophilic and hydrophobic moieties, thus allowing novel combinatorial drug/gene therapies. These applications include pulmonary infections, lung cancer, and cystic fibrosis, while systemic delivery of biomolecules, like insulin, is also attractive for the treatment of chronic ailments. This Review explores physiological and particle-associated factors affecting pulmonary delivery of biopharmaceuticals. It compares the advantages and limitations of SLNs as pulmonary nanocarriers along with design improvements underway to overcome these limitations. Current research illustrating various SLN designs to deliver proteins, peptides, plasmids, oligonucleotides, siRNA, and mRNA is also summarized.


Subject(s)
Lipids , Nanoparticles , Nanoparticles/chemistry , Humans , Lipids/chemistry , Drug Delivery Systems/methods , Lung/metabolism , Lung/drug effects , Drug Carriers/chemistry , Animals , Biological Products/administration & dosage , Biological Products/chemistry , Liposomes
2.
J Pharm Pharm Sci ; 27: 12921, 2024.
Article in English | MEDLINE | ID: mdl-39114808

ABSTRACT

Chitosan is an extensively used polymer for drug delivery applications in particulate and non-particulate carriers. Chitosan-based particulate, nano-, and microparticle, carriers have been the most extensively studied for the delivery of therapeutics and vaccines. However, chitosan has also been used in vaccine applications for its adjuvant properties in various hydrogels or as a carrier coating material. The focus of this review will be on the usage of chitosan as a vaccine adjuvant based on its intrinsic immunogenicity; the various forms of chitosan-based non-particulate delivery systems such as thermosensitive hydrogels, microneedles, and conjugates; and the advantages of its role as a coating material for vaccine carriers.


Subject(s)
Chitosan , Drug Delivery Systems , Vaccines , Chitosan/chemistry , Humans , Vaccines/administration & dosage , Vaccines/chemistry , Animals , Hydrogels/chemistry , Hydrogels/administration & dosage , Drug Carriers/chemistry
3.
Mol Pharm ; 19(6): 1814-1824, 2022 06 06.
Article in English | MEDLINE | ID: mdl-35302764

ABSTRACT

Continuous outbreaks of pertussis around the world suggest inadequate immune protection in infants and weakened immune responses induced over time by the acellular pertussis vaccine. Vaccine adjuvants provide a means to improve vaccine immunogenicity and support long-term adaptive immunity against pertussis. An acellular pertussis vaccine was prepared with pertactin, pertussis toxin, and fimbriae 2/3 antigens combined with a triple-adjuvant system consisting of innate defense regulator peptide IDR 1002, a Toll-like receptor-3 agonist poly(I:C), and a polyphosphazene in a fixed combination. The vaccine was delivered intranasally in a cationic lipid nanoparticle formulation fabricated by simple admixture and two schema for addition of antigens (LT-A, antigens associated outside of L-TriAdj, and LAT, antigens associated inside of L-TriAdj) to optimize particle size and cationic surface charge. In the former, antigens were associated with the lipidic formulation of the triple adjuvant by electrostatic attraction. In the latter, the antigens resided in the interior of the lipid nanoparticle. Two dose levels of antigens were used with adjuvant comprised of the triple adjuvant with or without the lipid nanoparticle carrier. Formulation of vaccines with the triple adjuvant stimulated systemic and mucosal immune responses. The lipid nanoparticle vaccines favored a Th1 type of response with higher IgG2a and IgA serum antibody titers particularly for pertussis toxin and pertactin formulated at the 5 µg dose level in the admixed formulation. Additionally, the lipid nanoparticle vaccines resulted in high nasal SIgA antibodies and an early (4 weeks post vaccination) response after a single vaccination dose. The LT-A nanoparticles trended toward higher titers of serum antibodies compared to LAT. The cationic lipid-based vaccine nanoparticles formulated with a triple adjuvant showed encouraging results as a potential formulation for intranasally administered pertussis vaccines.


Subject(s)
Adjuvants, Immunologic , Liposomes , Nanoparticles , Pertussis Vaccine , Whooping Cough , Animals , Antibodies, Bacterial , Bordetella pertussis , Cations , Humans , Liposomes/administration & dosage , Mice , Mice, Inbred BALB C , Nanoparticles/administration & dosage , Pertussis Toxin/administration & dosage , Pertussis Toxin/immunology , Pertussis Vaccine/administration & dosage , Pertussis Vaccine/chemistry , Pertussis Vaccine/immunology , Vaccination , Whooping Cough/prevention & control
4.
Antimicrob Agents Chemother ; 64(11)2020 10 20.
Article in English | MEDLINE | ID: mdl-32816728

ABSTRACT

The purpose of this study was to assess the safety, tolerability, pharmacokinetics (PK), and biodistribution of novel oral amphotericin B (AmpB) formulations following single- and multiple-oral-dose administration to healthy beagle dogs. The liquid formulation of AmpB was administered to three male dogs, and the capsule formulations of AmpB were administered to each of two groups of six male dogs. Blood was collected for pharmacokinetic evaluation on days 1, 2, and 3 (up to 72 h postdosing). Dogs receiving the capsule formulations further received a single oral dose of 100 mg once daily for three more days, and on the 4th day, blood samples were taken at 24 h postdosing and the dogs were humanely sacrificed with the removal of organs, from which tissue samples were taken for analysis of the AmpB content. Multiple-dose studies were completed for 7 or 14 days with daily doses of up to 1,000 mg/day with the capsule formulations. All oral formulations of AmpB following both single- and multiple-dose administration were well tolerated in the dogs, and there were no relevant adverse signs observed, such as changes in hematologic, coagulation, or biochemistry parameters; loss of weight; changes in food or water intake; or signs of gastrointestinal distress. The oral absorption of AmpB from the liquid formulation and the capsule formulations were similar, with no significant differences. The tissue distributions of AmpB were similar following repeated doses of the two capsule formulations to dogs. Following 14 days of treatment with the iCo-010 liquid formulation and the iCo-019 and iCo-022 capsule formulations, the range of values of the maximum observed plasma concentration (Cmax) was 53.2 to 62.3, 24.9 to 66.4, and 36.7 to 85.2 ng/ml, respectively; the range of values of the time to Cmax was 4 to 12, 4 to 24, and 2 to 24 h, respectively; and the range of values of the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration was 2,635 to 3,071, 1,053 to 2,517, and 1,443 to 3,713 ng · h/ml, respectively. We have developed a safe novel oral AmpB formulation suitable for future efficacy studies.


Subject(s)
Amphotericin B , Administration, Oral , Animals , Area Under Curve , Dogs , Male , Tissue Distribution
5.
Antimicrob Agents Chemother ; 64(10)2020 09 21.
Article in English | MEDLINE | ID: mdl-32690643

ABSTRACT

This study evaluated the safety, tolerability, and pharmacokinetics of a novel oral amphotericin B (AmB) formulation (iCo-019) following single doses to healthy humans. The data from this study suggest that iCo-019 has a long circulation time and systemic exposure without the associated gastrointestinal, liver, and kidney toxicity associated with AmB. This novel oral AmB formulation can serve as a new treatment strategy to overcome the limitations of the use of parenterally administered AmB products.


Subject(s)
Amphotericin B , Liver , Administration, Oral , Amphotericin B/adverse effects , Antifungal Agents/adverse effects , Humans , Research Subjects
6.
Can J Anaesth ; 66(7): 803-812, 2019 07.
Article in English | MEDLINE | ID: mdl-30877585

ABSTRACT

PURPOSE: Hyperbaric bupivacaine (0.75% in dextrose) is used for spinal obstetric anesthesia. Occasional clusters of anesthetic failures occur in this setting, not readily attributable to clinical factors. We hypothesized that cold temperature exposure is related to bupivacaine instability. METHODS: An electronic survey was distributed to Canadian anesthesiologists to determine consistencies in spinal anesthesia practice, and to invite submission of failed bupivacaine samples for analysis. Another survey for hospital pharmacists focused on bupivacaine logistics. Ultraviolet (UV) spectrometry, differential scanning calorimetry, and high performance liquid chromatography were used to evaluate the effect of temperature on bupivacaine chemical stability. Mass spectrometry (MS) was used to observe bupivacaine and dextrose degradation in laboratory samples of hyperbaric 0.75% bupivacaine in dextrose. Hyperbaric bupivacaine that failed to produce adequate anesthesia in labour and delivery patients was subject to tandem MS/MS analysis on commonly observed ions to look for ion patterns consistent with bupivacaine degradation products and to compare with laboratory samples subjected to cold temperatures. RESULTS: Canadian obstetric anesthesiologists report similar practices and use hyperbaric bupivacaine for spinal anesthesia. Pharmacists surveyed indicated facility storage at room temperature but variable temperatures during shipping. No standard procedure for failure reporting was identified. Analysis of bupivacaine showed a slight decrease in bupivacaine concentration or UV spectral changes after incubation at temperatures ≤ 4°C. Mass spectrometric analysis of hyperbaric bupivacaine from failed spinal anesthesia cases showed complex and inconsistent patterns of ion formation, and different from the ion patterns observed for cooled vs uncooled bupivacaine solutions. Temperature-related changes were noted for dextrose in cooled samples in which dextrose-related ions were formed. CONCLUSIONS: Canadian clinical practice and handling of hyperbaric bupivacaine is consistent. Most respondents indicated an interest in a formal reporting and collection process. Cold exposure did not degrade bupivacaine. A complex and possibly inconsistent reaction involving dextrose was identified that requires further analysis of a larger sample size to elucidate the mechanisms.


RéSUMé: OBJECTIF: La bupivacaïne hyperbare (0,75 % dans du dextrose) est utilisée pour l'anesthésie obstétricale rachidienne. Il arrive parfois que plusieurs anesthésies rapprochées soient inefficaces dans cette situation, et ces échecs ne sont pas nécessairement attribuables à des facteurs cliniques. Nous avons émis l'hypothèse qu'une exposition de la bupivacaïne au froid expliquerait son instabilité. MéTHODE: Un sondage électronique a été distribué aux anesthésiologistes canadiens afin de déterminer les similitudes dans la pratique de la rachianesthésie, et nous avons invité les médecins à nous envoyer des échantillons de bupivacaïne à des fins d'analyse lorsque leur anesthésie était inefficace. Un autre sondage, envoyé aux pharmaciens hospitaliers, mettait l'emphase sur la logistique entourant la manutention de la bupivacaïne. Nous avons utilisé une spectrométrie de rayons ultraviolets (UV), une analyse calorimétrique différentielle et une chromatographie liquide à haute performance afin d'évaluer l'effet de la température sur la stabilité chimique de la bupivacaïne. Une spectrométrie de masse (SM) a été utilisée pour observer la dégradation de la bupivacaïne et du dextrose dans des échantillons de laboratoire de bupivacaïne hyperbare 0,75 % dans le dextrose. La bupivacaïne hyperbare qui n'a pas procuré une anesthésie adéquate chez des patientes en travail ou en accouchement a été sujette à une analyse de SM/SM en tandem sur les ions fréquemment observés afin d'identifier des modèles ioniques correspondant aux produits de dégradation de la bupivacaïne et les comparer à des échantillons de laboratoire soumis au froid. RéSULTATS: Les anesthésiologistes obstétricaux canadiens font état de pratiques semblables et utilisent de la bupivacaïne hyperbare pour réaliser une rachianesthésie. Les pharmaciens interrogés ont indiqué que la bupivacaïne était entreposée à température ambiante au sein de leur établissement mais qu'elle était exposée à des températures variables pendant l'expédition. Aucune procédure standardisée n'a été identifiée pour rapporter les échecs d'anesthésie. L'analyse de la bupivacaïne a montré une légère réduction dans la concentration de bupivacaïne ou des changements spectraux UV après une période d'incubation à des températures ≤ 4°C. L'analyse par spectrométrie de masse des échantillons de bupivacaïne hyperbare utilisés lors d'échecs de la rachianesthésie a révélé des types de formation des ions complexes et incohérents, lesquels différaient des modèles des ions observés dans les solutions de bupivacaïne refroidies vs non refroidies. Les changements liés à la température ont été notés sur le dextrose dans les échantillons refroidis dans lesquels des ions liés au dextrose se sont formés. CONCLUSION: La pratique clinique canadienne et la manutention de la bupivacaïne hyperbare est homogène. La plupart des répondants ont indiqué être intéressés par un processus formel d'enregistrement et de récolte des données. L'exposition au froid n'a pas dégradé la bupivacaïne. Une réaction complexe et possiblement inconstante ayant un rapport avec le dextrose a été identifiée; elle requiert des analyses approfondies sur un échantillonnage plus important afin d'en élucider les mécanismes.


Subject(s)
Anesthesia, Obstetrical/methods , Anesthesia, Spinal/methods , Anesthetics, Local/administration & dosage , Bupivacaine/administration & dosage , Anesthesiologists/statistics & numerical data , Anesthetics, Local/chemistry , Bupivacaine/chemistry , Cold Temperature , Cross-Sectional Studies , Drug Stability , Drug Storage , Female , Glucose/chemistry , Humans , Pharmacists/statistics & numerical data , Pregnancy , Surveys and Questionnaires
7.
Drug Dev Ind Pharm ; 45(1): 21-26, 2019 Jan.
Article in English | MEDLINE | ID: mdl-30113235

ABSTRACT

PURPOSE: CPX-351 is a liposomal formulation of cytarabine and daunorubicin encapsulated at a 5:1 molar ratio, for the treatment of acute myeloid leukemia. The Scavenger Receptor class B type I (SR-BI) plays an important role in mediating the uptake of high-density lipoproteins. The purpose of this study is to assess the role of the cell surface lipoprotein receptor SR-BI in the uptake of CPX-351 liposomes (Jazz Pharmaceuticals) into K562 leukemia cells. METHODS: K562 cells were pre-treated with 10 nM siRNA for 48 h and then treated with varying amount of CPX-351 for 24, 48 and 72 h. Cells were then collected and analyzed at 480/590 nm on a CytoFLEX Multicolour flow instrument to determine cellular uptake of daunorubicin. Experimental data were analyzed using two-way ANOVA with Bonferroni multiple comparisons. Significance was set at p < .05. RESULTS: K562 cells pre-treated with SR-BI siRNA for 48 h had a reduced SRB1 cell surface concentration (74-85%). Addition of CPX-351 at 10-50 nM followed by measurement of cellular daunorubicin at 48, 48 or 72 h showed a significantly lower percentage of daunorubicin positive population compared with control K562 cells (p < .05). There was significantly less daunorubicin taken up in the SR-BI knock-down cells across all drug concentrations and at all three time points, although there were no concentration-related trends. CONCLUSIONS: These preliminary studies suggest that SR-BI may be one potential mechanism by which CPX-351 is taken up into K562 cells.


Subject(s)
Cell Membrane/metabolism , Cytarabine/metabolism , Daunorubicin/metabolism , Scavenger Receptors, Class B/metabolism , Cell Membrane/drug effects , Cytarabine/pharmacology , Daunorubicin/pharmacology , Humans , K562 Cells , RNA, Small Interfering/pharmacology , Receptors, Scavenger/metabolism
8.
Drug Dev Ind Pharm ; 45(1): 76-87, 2019 Jan.
Article in English | MEDLINE | ID: mdl-30169982

ABSTRACT

OBJECTIVE: To develop an oral sustained release formulation of mycophenolate mofetil (MMF) for once-daily dosing, using chitosan-coated polylactic acid (PLA) or poly(lactic-co-glycolic) acid (PLGA) nanoparticles. The role of polymer molecular weight (MW) and drug to polymer ratio in encapsulation efficiency (EE) and release from the nanoparticles was explored in vitro. METHODS: Nanoparticles were prepared by a single emulsion solvent evaporation method where MMF was encapsulated with PLGA or PLA at various polymer MW and drug: polymer ratios. Subsequently, chitosan was added to create coated cationic particles, also at several chitosan MW grades and drug: polymer ratios. All the formulations were evaluated for mean diameter and polydispersity, EE as well as in vitro drug release. Differential scanning calorimetry (DSC), surface morphology, and in vitro mucin binding of the nanoparticles were performed for further characterization. RESULTS: Two lead formulations comprise MMF: high MW, PLA: medium MW chitosan 1:7:7 (w/w/w), and MMF: high MW, PLGA: high MW chitosan 1:7:7 (w/w/w), which had high EE (94.34% and 75.44%, respectively) and sustained drug release over 12 h with a minimal burst phase. DSC experiments revealed an amorphous form of MMF in the nanoparticle formulations. The surface morphology of the MMF NP showed spherical nanoparticles with minimal visible porosity. The potential for mucoadhesiveness was assessed by changes in zeta potential after incubation of the nanoparticles in mucin. CONCLUSION: Two chitosan-coated nanoparticles formulations of MMF had high EE and a desirable sustained drug release profile in the effort to design a once-daily dosage form for MMF.


Subject(s)
Chitosan/chemical synthesis , Drug Carriers/chemical synthesis , Drug Development/methods , Immunosuppressive Agents/chemical synthesis , Mycophenolic Acid/chemical synthesis , Nanoparticles/chemistry , Administration, Oral , Chitosan/administration & dosage , Chitosan/metabolism , Delayed-Action Preparations/administration & dosage , Delayed-Action Preparations/chemical synthesis , Delayed-Action Preparations/metabolism , Drug Carriers/administration & dosage , Drug Carriers/metabolism , Drug Delivery Systems/methods , Drug Liberation , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/metabolism , Mycophenolic Acid/administration & dosage , Mycophenolic Acid/metabolism , Nanoparticles/administration & dosage , Nanoparticles/metabolism
9.
Drug Dev Ind Pharm ; 43(11): 1743-1758, 2017 Nov.
Article in English | MEDLINE | ID: mdl-28673096

ABSTRACT

Lipid-based drug delivery systems (LBDDS) are one of the most studied bioavailability enhancement technologies and are utilized in a number of U.S. Food and Drug Administration (FDA) approved drugs. While researchers have used several general rules of thumb to predict which compounds are likely to benefit from LBDDS, formulation of lipid systems is primarily an empiric endeavor. One of the challenges is that these rules of thumb focus in different areas and are used independently of each other. The Developability Classification System attempts to link physicochemical characteristics with possible formulation strategies. Although it provides a starting point, the formulator still has to empirically develop the formulation. This article provides a review and quantitative analysis of the molecular properties of these approved drugs formulated as lipid systems and starts to build an approach that provides more directed guidance on which type of lipid system is likely to be the best for a particular drug molecule.


Subject(s)
Drug Delivery Systems/methods , Lipids/analysis , Lipids/chemistry , Biological Availability , Chemistry, Pharmaceutical , Drug Approval , Humans , United States
10.
J Pharm Pharm Sci ; 18(4): 344-67, 2015.
Article in English | MEDLINE | ID: mdl-26626241

ABSTRACT

Consumption of plant sterols/ stanols has long been demonstrated to reduce plasma cholesterol levels. The objective of this review is to demonstrate the lipid-lowering activity and anti-atherogenic effects of natural and semi-synthetic plant sterols/ stanols based on evidence from cell-culture studies, animal studies and clinical trials. Additionally, this review highlights certain molecular mechanisms by which plant sterols/ stanols lower plasma cholesterol levels with a special emphasis on factors that affect the cholesterol-lowering activity of plant sterols/stanols. The crystalline nature and the poor oil solubility of these natural products could be important factors that limit their cholesterol-lowering efficiency. Several attempts have been made to improve the cholesterol-lowering activity by enhancing the bioavailability of crystalline sterols and stanols. Approaches involved reduction of the crystal size and/or esterification with fatty acids from vegetable or fish oils. However, the most promising approach in this context is the chemical modification of plant sterols /stanols into water soluble disodium ascorbyl phytostanyl phosphates analogue by esterification with ascorbic acid. This novel semi-synthetic stanol derivative has improved efficacy over natural plant sterols/ stanols and can provide additional benefits by combining the cholesterol-lowering properties of plant stanols with the antioxidant potential of ascorbic acid. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.


Subject(s)
Anticholesteremic Agents/pharmacology , Cholesterol/blood , Phytosterols/pharmacology , Animals , Anticholesteremic Agents/chemistry , Anticholesteremic Agents/isolation & purification , Ascorbic Acid/administration & dosage , Ascorbic Acid/pharmacology , Atherosclerosis/prevention & control , Humans , Lipids/blood , Phytosterols/chemistry , Phytosterols/isolation & purification , Phytotherapy/methods , Solubility
11.
Drug Dev Ind Pharm ; 41(9): 1425-30, 2015.
Article in English | MEDLINE | ID: mdl-25170660

ABSTRACT

PURPOSE: To evaluate the antifungal activity of amphotericin B (AmB) in a mouse model of systemic candidiasis following administration of a novel oral AmB formulation (iCo-010) that has been pre-exposed to tropical temperatures. METHODS: Amphotericin B (AmB) was prepared as a 5 mg/mL dispersion in a mixture of Peceol, Gelucire 44/14 and VitE-TPGS 2,3 (iCo-010). The formulation was protected from light and incubated in a sealed container at 43 °C for 60 days. Mice infected with Candida albicans were treated with either iCo-010 formulation pre-incubated at 43 °C for 60 days or freshly prepared iCo-010 formulation at doses of 5, 10 and 20 mg/kg once daily for five consecutive days. Single intravenous 5 mg/kg dose of AmBisome® was used as a positive control group. Seven days following the last dose, the kidney, liver, spleen, lung, heart and brain were removed and the number of colony forming units (CFUs) was determined as a measure of tissue fungal load. In addition, the concentration of AmB within each tissue was determined using high performance liquid chromatography (HPLC). RESULTS: There were no significant differences in the reduction of CFUs and the concentration of AmB recovered in all organs at all iCo-010 doses tested between the freshly prepared iCo-010 formulation compared to the formulation that was incubated at 43 °C for 60 days. CONCLUSIONS: A novel oral AmB formulation, iCo-010, incubated at 43 °C for 60 days to simulate the exposure of the formulation to tropical temperatures remained highly effective against murine systemic candidiasis.


Subject(s)
Amphotericin B/administration & dosage , Antifungal Agents/administration & dosage , Candidiasis/drug therapy , Excipients/chemistry , Administration, Oral , Amphotericin B/chemistry , Amphotericin B/pharmacology , Animals , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Candida albicans/drug effects , Chromatography, High Pressure Liquid , Colony Count, Microbial , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Stability , Drug Storage , Female , Mice , Mice, Inbred BALB C , Temperature , Tissue Distribution , Tropical Climate
12.
Lipids Health Dis ; 12: 158, 2013 Oct 29.
Article in English | MEDLINE | ID: mdl-24164705

ABSTRACT

OBJECTIVE: An oral lipid based formulation that exhibits tropical stability (iCo-010) was developed to enhance the absorption of orally administered amphotericin B (AmB). iCo-010 has previously shown high efficacy in an acute model of systemic candidiasis in rats, directing the focus of this study to be its efficacy in a chronic model of systemic candidiasis in mice. METHODS: Mice were infected with 0.6 to 1×108 CFUs of Candida albicans ATCC 18804 strain by tail vein injection and were left for three days to develop the infection after which time treatment was initiated. The infected animals were assigned to the following treatment groups: no treatment (control) or iCo-010 at 5, 10 and 20 mg/kg administered by oral gavage once daily (QD) for 5 consecutive days. The animals were sacrificed 7 days after the last dose and the concentration of AmB and the fungal burden were assessed within the liver, kidneys, heart, lungs, spleen and brain. RESULTS: Although the infection was relatively low (~ 60-100 CFUs/ 1 ml tissue homogenate) in the liver, lungs and heart, the infection level was very high (70 000 CFUs / 1 ml tissue homogenate) in the kidney tissues for the control group. The highest concentrations of AmB were recovered in the kidneys and the spleen. The fungal burden in the tissues was lowered by 69-96% in the treatment groups when compared to the control group. CONCLUSION: Oral iCo-010 is an effective treatment of systemic candidiasis in the mouse model.


Subject(s)
Amphotericin B/pharmacology , Antifungal Agents/pharmacology , Candida albicans/drug effects , Candidiasis/drug therapy , Administration, Oral , Amphotericin B/chemistry , Animals , Candida albicans/growth & development , Candidiasis/microbiology , Colony Count, Microbial , Dose-Response Relationship, Drug , Drug Compounding , Heart/drug effects , Heart/microbiology , Kidney/drug effects , Kidney/microbiology , Liver/drug effects , Liver/microbiology , Lung/drug effects , Lung/microbiology , Mice , Mice, Inbred BALB C , Oleic Acids/chemistry , Organ Specificity , Polyethylene Glycols/chemistry , Spleen/drug effects , Spleen/microbiology , Treatment Outcome
13.
Drug Dev Ind Pharm ; 39(9): 1277-83, 2013 Sep.
Article in English | MEDLINE | ID: mdl-22989082

ABSTRACT

The objective of this study was to assess the pharmacokinetics and tissue distribution of amphotericin B (AmB) in rats following oral administration of three lipid-based formulations (iCo-009, iCo-010 and iCo-011). The lipid-based formulations were administered to rats at a dose of 10 mg/kg and blood samples were withdrawn at predose, 1, 2, 4, 6, 8, 10, 12, 24, 48 and 72 h, after which the animals were sacrificed and the body organs were collected for AmB quantification using a validated HPLC method. Plasma pharmacokinetics parameters were determined using non-compartmental analysis. The disappearance of AmB from plasma was the slowest following the administration of iCo-010 with MRT of 63 h followed by iCo-009 then iCo-011 (36 and 27 h). The AUC(0-24h) of iCo-009 and iCo-010 was 1.5-2-fold higher than that of iCo-011. The kidney exposure was comparable between iCo-009 and iCo-010 and was higher than that of iCo-011. The lung exposure was the highest following iCo-010 administration as compared to that of iCo-009. The distribution of AmB from plasma to tissues resulted in a high accumulation of AmB overtime with slow back-distribution to plasma. The pharmacokinetics profiles varied among the three formulations, despite the similarity in lipid composition between iCo-010 and iCo-011 and the presence of Peceol® as a common component in the formulations. The administration of oral iCo-010 could lead to higher steady state concentrations in the tissues after multiple dosing, which could lead to enhanced eradication of tissue borne fungal and parasitic infections.


Subject(s)
Amphotericin B/administration & dosage , Anti-Infective Agents/administration & dosage , Drug Delivery Systems , Excipients/chemistry , Lipids/chemistry , Administration, Oral , Amphotericin B/chemistry , Amphotericin B/metabolism , Amphotericin B/pharmacokinetics , Animals , Anti-Infective Agents/chemistry , Anti-Infective Agents/metabolism , Anti-Infective Agents/pharmacokinetics , Chromatography, High Pressure Liquid , Drug Compounding , Kidney/metabolism , Lung/metabolism , Male , Oleic Acids/chemistry , Phosphatidylethanolamines/chemistry , Polyethylene Glycols/chemistry , Rats , Rats, Sprague-Dawley , Solubility , Tissue Distribution , Vitamin E/analogs & derivatives , Vitamin E/chemistry
14.
Lipids Health Dis ; 10: 135, 2011 Aug 08.
Article in English | MEDLINE | ID: mdl-21824435

ABSTRACT

BACKGROUND: The purpose of this study was to evaluate the biodistribution and toxicity of amphotericin B (AmB) following multiple oral administrations of a novel tropically stable lipid-based formulation (iCo-010). METHODS: BALB/c mice were allocated into six groups: oral iCo-010 twice daily for 5 days in the dose of 20, 10, 5 and 2.5 mg/kg; vehicle control; and intravenous boluses of Fungizone 2 mg/kg once daily for 5 days. The animals were sacrificed 12 h following the last administration and blood and tissues were collected. RESULTS: The plasma concentrations of AmB were similar to previously reported after administration of iCo-009. Somewhat lower concentrations of AmB were detected in reticulo-endothelial system in the case of iCo-010 when compared with iCo-009. The concentration in kidney was higher with iCo-010 than with iCo-009. The creatinine levels in all oral treatment groups were in a normal range as in the case of iCo-009. Administration of Fungizone resulted in elevated plasma creatinine levels. Histopathology analysis detected no GI, liver or kidney toxicity following multiple dose oral administration of iCo-010. Fungizone treatment induced necrotic changes in hepatic and kidney tissues. CONCLUSIONS: Given the tropical stability of iCo-010, near identical activity against visceral leishmaniasis and significant concentrations in target organs this formulation has a potential to become a treatment of choice in tropical developing countries.


Subject(s)
Amphotericin B/toxicity , Antiprotozoal Agents/toxicity , Administration, Oral , Amphotericin B/administration & dosage , Amphotericin B/pharmacokinetics , Animals , Antiprotozoal Agents/administration & dosage , Antiprotozoal Agents/pharmacokinetics , Chemistry, Pharmaceutical , Creatinine/blood , Drug Evaluation, Preclinical , Drug Stability , Female , Kidney/pathology , Mice , Mice, Inbred BALB C , Tropical Climate
15.
Lipids Health Dis ; 10: 144, 2011 Aug 20.
Article in English | MEDLINE | ID: mdl-21854638

ABSTRACT

BACKGROUND: Invasive fungal infections such as candidiasis constitute an increasingly important medical problem. Drugs currently used for the treatment of candidiasis include polyenes (such as Amphotericin B) and azoles. Amphotericin B (AmpB) presents several limitations such as its nephrotoxicity and limited solubility. We have developed two novel lipid-based AmpB formulations which in vivo show less nephrotoxicity and enhanced solubility compared to Fungizone™ a commercial AmpB formulation. The purpose of this study was to determine the cytotoxicity of Fungizone™, Ambisome™ and two novel AmpB formulations (iCo-009 and iCo-010) against Candida albicans, human kidney (293T) cells and monocytic (THP1) cells. METHODS: Cell cytotoxicity to the AmpB formulations was evaluated by MTS and LDH assays. In vitro anti-Candida albicans activity was assessed after a 48 h drug incubation. RESULTS: None of the AmpB formulations tested showed cytotoxicity against 293T cells. In the case of THP1 cells only Fungizone™ and Ambisome™ showed cytotoxicity at 500 µg/L (n = 4-10, p < 0.05).The calculated EC50 to Candida albicans for the different formulations was as follows: 26.8 ± 2.9 for iCo-010, 74.6 ± 8.9 for iCo-009, 109 ± 31 for Ambisome™ and 87.1 ± 22 for Fungizone™ (µg of AmpB/L, n = 6-12, p < 0.05). CONCLUSIONS: The AmpB formulations analyzed were not cytotoxic to 293T cells. Cytotoxicity in THP1 cells was observed for Fungizone™ and Ambisome™, but not with the novel AmpB formulations. iCo-010 had higher efficacy compared to other three AmpB formulations in the Candida albicans model.The absence of cytotoxicity as well as its higher efficacy for the Candida model compared to Fungizone™ and Ambisome™ suggest that iCo-010 has potential in treating candidiasis.


Subject(s)
Amphotericin B/toxicity , Antifungal Agents/toxicity , Candida albicans/drug effects , Kidney/cytology , Monocytes/drug effects , Amphotericin B/pharmacology , Antifungal Agents/pharmacology , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , HEK293 Cells , Humans , Inhibitory Concentration 50 , Kidney/drug effects
16.
Pharmaceutics ; 13(10)2021 Oct 14.
Article in English | MEDLINE | ID: mdl-34683979

ABSTRACT

The unique properties of chitosan make it a useful choice for various nanoparticulate drug delivery applications. Although chitosan is biocompatible and enables cellular uptake, its interactions at cellular and systemic levels need to be studied in more depth. This review focuses on the various physical and chemical properties of chitosan that affect its performance in biological systems. We aim to analyze recent research studying interactions of chitosan nanoparticles (NPs) upon their cellular uptake and their journey through the various compartments of the cell. The positive charge of chitosan enables it to efficiently attach to cells, increasing the probability of cellular uptake. Chitosan NPs are taken up by cells via different pathways and escape endosomal degradation due to the proton sponge effect. Furthermore, we have reviewed the interaction of chitosan NPs upon in vivo administration. Chitosan NPs are immediately surrounded by a serum protein corona in systemic circulation upon intravenous administration, and their biodistribution is mainly to the liver and spleen indicating RES uptake. However, the evasion of RES system as well as the targeting ability and bioavailability of chitosan NPs can be improved by utilizing specific routes of administration and covalent modifications of surface properties. Ongoing clinical trials of chitosan formulations for therapeutic applications are paving the way for the introduction of chitosan into the pharmaceutical market and for their toxicological evaluation. Chitosan provides specific biophysical properties for effective and tunable cellular uptake and systemic delivery for a wide range of applications.

17.
Bone Rep ; 14: 100753, 2021 Jun.
Article in English | MEDLINE | ID: mdl-33665236

ABSTRACT

PURPOSE: The purpose of this study was to evaluate the efficacy and toxicity of a novel lanthanum compound, La(XT), in an ovariectomized (OVX) rat model of osteoporosis. METHODS: Twenty-four ovariectomized female Sprague Dawley rats were divided into 3 groups receiving a research diet with/without treatment compounds (alendronate: 3 mg/kg; La(XT) 100 mg/kg) for three months. At the time of sacrifice, the kidney, liver, brain, lung and spleen were collected for histological examination. The trabecular bone structure of the tibiae was evaluated using micro-CT and a three-point metaphyseal mechanical test was used to evaluate bone failure load and stiffness. RESULTS: No significant differences were noted in plasma levels of calcium, phosphorus, creatinine, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) between the La(XT) treatment compared to the non-treated OVX group. Alendronate-treated animals (positive control) showed higher BV/TV, Tb.N and lower Tb.Th and Tb.Sp when compared to the non-treated OVX group. Mechanical analysis indicated that stiffness was higher in the alendronate (32.88%, p = 0.04) when compared to the non-treated OVX group. Failure load did not differ among the groups. CONCLUSIONS: No kidney or liver toxicities of La(XT) treatments were found during the three-month study. The absence of liver and kidney toxicity with drug treatment for 3 months, as well as the increased trabecular bone stiffness are encouraging for the pursuit of further studies with La(XT) for a longer duration of time.

18.
J Antimicrob Chemother ; 65(12): 2610-3, 2010 Dec.
Article in English | MEDLINE | ID: mdl-20861140

ABSTRACT

OBJECTIVES: The purpose of this study was to assess the biodistribution and toxicity of amphotericin B (AMB) following multiple dose administration of an oral lipid-based formulation (iCo-009). METHODS: BALB/c female mice were used. ICo-009 was administered twice daily for 5 days at doses of 2.5-20 mg/kg. Untreated animals, oral vehicle or intravenous Fungizone® (1 or 2 mg/kg) served as control groups. The animals were sacrificed 12 h following the last administration of AMB, and blood and multiple tissues were harvested for drug analysis and histopathological evaluation. Plasma or tissue samples were analysed for concentrations of AMB or creatinine by means of HPLC-UV. RESULTS: A dose-dependent accumulation of AMB in liver, spleen, kidney and lung tissues was found. The concentration of the drug in all these organs exceeded the corresponding concentrations in plasma at the same dose. The concentrations of AMB in heart and brain were similar to the corresponding concentrations in plasma. Creatinine concentrations were elevated above normal concentrations in the 2 mg/kg Fungizone® group only. Histopathological analysis of kidney and liver tissues revealed a normal pattern in all treated groups, except the 2 mg/kg Fungizone® group. No gastrointestinal toxicity was found in this study. CONCLUSIONS: A multiple dose treatment regimen with iCo-009 in mice results in a gradual accumulation of AMB in tissues. Despite significant concentrations of AMB, no kidney or liver toxicity of orally administered AMB was detected in this study. Furthermore, multiple oral administration of iCo-009 or of vehicle control did not induce gastrointestinal toxicity.


Subject(s)
Amphotericin B/pharmacokinetics , Amphotericin B/toxicity , Antifungal Agents/pharmacokinetics , Antifungal Agents/toxicity , Kidney/pathology , Liver/pathology , Administration, Oral , Amphotericin B/administration & dosage , Amphotericin B/chemistry , Animals , Antifungal Agents/administration & dosage , Antifungal Agents/chemistry , Biological Availability , Chemistry, Pharmaceutical , Chromatography, High Pressure Liquid , Dose-Response Relationship, Drug , Female , Mice , Mice, Inbred BALB C
19.
J Antimicrob Chemother ; 65(3): 535-7, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20026611

ABSTRACT

OBJECTIVES: To assess the impact of visceral leishmaniasis (VL) on the concentration of amphotericin B (AmB) recovered in the liver and spleen following either intravenous (AmBisome) or oral (iCo-009) AmB administration to mice. METHODS: Livers and spleens previously obtained from VL-infected BALB/c mice (following intravenous AmBisome or oral AmB treatments) were analysed for AmB concentrations. Then, non-infected BALB/c mice were divided into three treatment groups: a single dose of intravenous AmBisome (2 mg/kg, n = 5); and oral AmB every 12 h for 5 days (10 mg/kg, n = 6 and 20 mg/kg, n = 6). The animals were sacrificed 7 days after the initiation of the treatment and the livers and spleens were harvested for drug analysis by HPLC. RESULTS: The single intravenous injection of AmBisome resulted in a 77-fold lower concentration of AmB in infected compared with non-infected liver tissue, while the difference in AmB concentration in the spleen was only 5-fold. The multiple dose oral administration of AmB resulted in a 3-fold lower concentration of AmB in infected compared with non-infected livers for both oral doses, while the differences in AmB concentrations in the spleen were not statistically different for the oral treatment groups. CONCLUSIONS: VL significantly lowered the concentration of AmB in the liver and the spleen when compared with uninfected animals. This effect seems to correlate with the degree of infection of the tissue. In the case of the intravenous liposomal formulation (AmBisome), the differences between the infected and non-infected tissues are of a higher magnitude than in the case of orally administered AmB (iCo-009).


Subject(s)
Amphotericin B/pharmacokinetics , Antiprotozoal Agents/pharmacokinetics , Leishmaniasis, Visceral/drug therapy , Liver/chemistry , Spleen/chemistry , Administration, Oral , Amphotericin B/administration & dosage , Amphotericin B/analysis , Animals , Antiprotozoal Agents/administration & dosage , Antiprotozoal Agents/analysis , Chromatography, High Pressure Liquid , Female , Injections, Intravenous , Mice , Mice, Inbred BALB C
20.
Drug Dev Ind Pharm ; 36(11): 1312-9, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20545513

ABSTRACT

CONTEXT: Visceral leishmaniasis (VL) is a severe and potentially fatal infection caused by the trypanosome parasite Leishmania sp. Over 90% of reported cases occur in India, Bangladesh, Nepal, Sudan, and Brazil, affecting mainly impoverished individuals and creating a significant economic burden through direct and indirect costs of treatment. OBJECTIVES: To identify the direct and indirect costs of VL treatment, compare these costs to household income, and identify the barriers to treatment in each of the five VL-endemic countries. METHODS: Articles obtained through PubMed (US National Library of Medicine), EMBASE, and Cochrane Library were selected for relevance to VL treatment, costs for all forms of amphotericin B, miltefosine, paromomycin, and antimony compounds, and healthcare costs in India, Bangladesh, Nepal, Brazil, and Sudan. Healthcare statistics were obtained from the World Health Organization Statistical Information System, Médecins Sans Frontieres, and each country's national health ministry. RESULTS: Per capita GDP, per capita GNI, cost of drugs, and hospitalization expenses differ by up to 10-fold in each of the five countries where VL is hyperendemic, resulting in unequal barriers to treatment. We found that the cost of specific drugs influences the choice of therapy. CONCLUSIONS: Poverty and VL treatment-related costs cause potential limitations in the provision of full and efficacious treatment, which may result in further dissemination of the disease. Effective nonparenteral antileishmania drugs would provide a significant advantage in reducing the barriers to VL treatment.


Subject(s)
Antiprotozoal Agents/therapeutic use , Cost of Illness , Leishmaniasis, Visceral/drug therapy , Animals , Antiprotozoal Agents/economics , Disease Outbreaks , Drug Costs , Endemic Diseases , Hospital Costs , Humans , Leishmaniasis, Visceral/economics , Leishmaniasis, Visceral/epidemiology , Poverty Areas
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