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1.
Pharm Dev Technol ; 19(4): 438-53, 2014 Jun.
Article in English | MEDLINE | ID: mdl-23617261

ABSTRACT

OBJECTIVE: The purpose of this work was to prepare a stable paclitaxel nanosuspension and test it for potential use as a targeted chemotherapeutic. Different particle coatings were employed to assess their impact on cellular uptake in vitro. In vivo work was then performed to demonstrate efficacy in tumor-bearing mouse models. MATERIALS AND METHOD: Paclitaxel nanosuspensions were prepared using a homogenization process and coated with excipients. Surface charge was measured by zeta potential, potency by high-performance liquid chromatography, and solubility using an in-line UV probe. Cellular uptake studies were performed via flow cytometry. In vivo experiments were performed to determine residence time, maximum tolerated dose, and the efficacy of paclitaxel nanosuspensions (Paclitaxel-NS). RESULTS: A stable paclitaxel nanosuspension was prepared and coated with various excipients. Studies in mice showed that the nanosuspension was well-tolerated and at least as effective as the IV Taxol control in prolonging mouse survival in a head and neck cancer model as well as an ovarian cancer model with a lower overall drug dose than the traditional IV administration route. CONCLUSIONS: The paclitaxel nanosuspension is suitable for cellular uptake. The nanosuspension was effective in prolonging life in two separate xenograft orthotopic murine cancer models through two separate routes of administration.


Subject(s)
Antineoplastic Agents/chemistry , Nanoparticles/chemistry , Paclitaxel/chemistry , Suspensions/chemistry , Animals , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cells, Cultured , Excipients/chemistry , Female , Humans , Leukocytes, Mononuclear/drug effects , Mice , NIH 3T3 Cells , Ovarian Neoplasms/drug therapy , Paclitaxel/pharmacology , Suspensions/pharmacology
2.
Nanomedicine (Lond) ; 4(8): 903-17, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19958227

ABSTRACT

BACKGROUND: Factors limiting the efficacy of conventional antiretroviral therapy for HIV-1 infection include treatment adherence, pharmacokinetics and penetration into viral sanctuaries. These affect the rate of viral mutation and drug resistance. In attempts to bypass such limitations, nanoparticles containing ritonavir, indinavir and efavirenz (described as nanoART) were manufactured to assess macrophage-based drug delivery. METHODS: NanoART were made by high-pressure homogenization of crystalline drug with various surfactants. Size, charge and shape of the nanoparticles were assessed. Monocyte-derived macrophage nanoART uptake, drug release, migration and cytotoxicity were determined. Drug levels were measured by reverse-phase high-performance liquid chromatography. RESULTS: Efficient monocyte-derived macrophage cytoplasmic vesicle uptake in less than 30 min based on size, charge and coating was observed. Antiretroviral drugs were released over 14 days and showed dose-dependent reduction in progeny virion production and HIV-1 p24 antigen. Cytotoxicities resulting from nanoART carriage were limited. CONCLUSION: These results support the continued development of macrophage-mediated nanoART carriage for HIV-1 disease.


Subject(s)
Benzoxazines/pharmacokinetics , HIV Protease Inhibitors/pharmacokinetics , Indinavir/pharmacokinetics , Macrophages/drug effects , Macrophages/metabolism , Monocytes/cytology , Ritonavir/pharmacokinetics , Alkynes , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/pharmacokinetics , Anti-HIV Agents/therapeutic use , Benzoxazines/administration & dosage , Benzoxazines/chemical synthesis , Benzoxazines/therapeutic use , Cell Survival/drug effects , Cells, Cultured , Cyclopropanes , HIV Core Protein p24/metabolism , HIV Infections/drug therapy , HIV Protease Inhibitors/administration & dosage , HIV Protease Inhibitors/therapeutic use , Humans , Indinavir/administration & dosage , Indinavir/therapeutic use , Macrophages/virology , Microscopy, Atomic Force , Nanoparticles/administration & dosage , Nanoparticles/adverse effects , Nanoparticles/chemistry , Nanoparticles/ultrastructure , Ritonavir/administration & dosage , Ritonavir/therapeutic use
3.
J Immunol ; 183(1): 661-9, 2009 Jul 01.
Article in English | MEDLINE | ID: mdl-19535632

ABSTRACT

Antiretroviral therapy (ART) shows variable blood-brain barrier penetration. This may affect the development of neurological complications of HIV infection. In attempts to attenuate viral growth for the nervous system, cell-based nanoformulations were developed with the focus on improving drug pharmacokinetics. We reasoned that ART carriage could be facilitated within blood-borne macrophages traveling across the blood-brain barrier. To test this idea, an HIV-1 encephalitis (HIVE) rodent model was used where HIV-1-infected human monocyte-derived macrophages were stereotactically injected into the subcortex of severe combined immunodeficient mice. ART was prepared using indinavir (IDV) nanoparticles (NP, nanoART) loaded into murine bone marrow macrophages (BMM, IDV-NP-BMM) after ex vivo cultivation. IDV-NP-BMM was administered i.v. to mice resulting in continuous IDV release for 14 days. Rhodamine-labeled IDV-NP was readily observed in areas of HIVE and specifically in brain subregions with active astrogliosis, microgliosis, and neuronal loss. IDV-NP-BMM treatment led to robust IDV levels and reduced HIV-1 replication in HIVE brain regions. We conclude that nanoART targeting to diseased brain through macrophage carriage is possible and can be considered in developmental therapeutics for HIV-associated neurological disease.


Subject(s)
Brain/virology , Encephalitis, Viral/drug therapy , HIV-1/drug effects , Indinavir/administration & dosage , Macrophages/transplantation , Macrophages/virology , Nanocapsules/administration & dosage , Severe Combined Immunodeficiency/drug therapy , Animals , Biological Availability , Bone Marrow Cells/pathology , Bone Marrow Cells/virology , Brain/pathology , Cell Movement , Cells, Cultured , Disease Models, Animal , Drug Administration Schedule , Encephalitis, Viral/metabolism , HIV-1/growth & development , Humans , Indinavir/pharmacokinetics , Macrophages/pathology , Male , Mice , Mice, Inbred BALB C , Mice, Knockout , Mice, SCID , Severe Combined Immunodeficiency/virology , Virus Replication/drug effects
4.
Pharm Res ; 25(10): 2302-8, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18509597

ABSTRACT

PURPOSE: Drying of nanosuspensions can cause destabilization of the particles, leading to irreversible aggregation. In order to prepare an effective solid dosage form for a nanosuspension, it is imperative that the spray-dried nanoparticles should go back to their original particle size when reconstituted in an aqueous system. This case study examines impact of various formulation and processing parameters on redispersibility of the spray dried nanoparticles. METHODS: Nanosuspensions were prepared using the microprecipitation-homogenization process. Spray drying of nanosuspensions was achieved using a lab-scale Buchi spray dryer. RESULTS: Formulation components appeared to have the most significant impact on redispersibility of spray dried particles. Absence of surface charge led to particles that could not be redispersed. On the other hand, charged particles stabilized with an appropriate sugar led to spray dried powders that were flowable and easily redispersible. Dissolution testing showed the presence of two phases--a lag phase that represented dispersion of the loose aggregates, and dissolution of the dispersed nanoparticles. CONCLUSIONS: Nanosuspensions of a poorly soluble drug could be spray dried to obtain flowable powders that could be easily redispersed. These optimized powders also showed significantly improved dissolution rates as compared to the micronized drug, or unoptimized nanosuspensions.


Subject(s)
Antifungal Agents/chemistry , Desiccation , Itraconazole/chemistry , Nanoparticles , Technology, Pharmaceutical/methods , Chemical Precipitation , Chemistry, Pharmaceutical , Drug Stability , Models, Chemical , Particle Size , Powders , Rheology , Solubility , Suspensions
5.
Adv Drug Deliv Rev ; 60(8): 939-54, 2008 May 22.
Article in English | MEDLINE | ID: mdl-18343527

ABSTRACT

There has been growing interest in nanoparticles as an approach to formulate poorly soluble drugs. Besides enhanced dissolution rates, and thereby, improved bioavailability, nanoparticles can also provide targeting capabilities when injected intravenously. The latter property has led to increased research and development activities for intravenous suspensions. The first intravenously administered nanoparticulate product, Abraxane (a reformulation of paclitaxel), was approved by the FDA in 2006. Additional clinical trials have been conducted or are ongoing for multiple other indications such as oncology, infective diseases, and restenosis. This article reviews various challenges associated with developing intravenous nanosuspension dosage forms. In addition, various formulation considerations specific to intravenous nanosuspensions as well as reported findings from various clinical studies have been discussed.


Subject(s)
Drug Delivery Systems , Nanoparticles , Pharmaceutical Preparations/administration & dosage , Animals , Biological Availability , Clinical Trials as Topic , Drug Evaluation, Preclinical , Humans , Injections, Intravenous , Pharmaceutical Preparations/chemistry , Solubility , Suspensions
6.
Adv Drug Deliv Rev ; 60(6): 757-67, 2008 Mar 17.
Article in English | MEDLINE | ID: mdl-18096269

ABSTRACT

Parenteral formulations, particularly intravascular ones, offer a unique opportunity for direct access to the bloodstream and rapid onset of drug action as well as targeting to specific organ and tissue sites. Triglyceride emulsions, liposomes and micellar solutions have been traditionally used to accomplish these tasks and there are several products on the market using these lipid formulations. The broader application of these lipid systems in parenteral drug delivery, however, particularly with new chemical entities, has been limited due primarily to the following reasons: a) only a small number of parenteral lipid excipients are approved, b) there is increasing number of drugs that are partially or not soluble in conventional oils and other lipid solvents, and c) the ongoing requirement for site-specific targeting and controlled drug release. Thus, there is growing need to expand the array of targetable lipid-based systems to deliver a wide variety of drugs and produce stable formulations which can be easily manufactured in a sterile form, are cost-effective and at least as safe and efficacious as the earlier developed systems. These advanced parenteral lipid-based systems are at various stages of preclinical and clinical development which include nanoemulsions, nanosuspensions and polymeric phospholipid micelles. This review article will showcase these parenteral lipid nanosystems and discuss advances in relation to formulation development, processing and manufacturing, and stability assessment. Factors controlling drug encapsulation and release and in vivo biodistribution will be emphasized along with in vitro/in vivo toxicity and efficacy case studies. Emerging lipid excipients and increasing applications of injectable lipid nanocarriers in cancer chemotherapy and other disease indications will be highlighted and in vitro/in vivo case studies will be presented. As these new parenteral lipid systems advance through the clinic and product launch, their therapeutic utility and value will certainly expand.


Subject(s)
Drug Delivery Systems , Nanoparticles/administration & dosage , Pharmaceutical Preparations/administration & dosage , Animals , Emulsions/administration & dosage , Emulsions/chemistry , Humans , Injections , Lipids/administration & dosage , Lipids/chemistry , Micelles , Nanoparticles/chemistry , Pharmaceutical Preparations/chemistry , Polymers/administration & dosage , Polymers/chemistry , Solubility , Suspensions/administration & dosage , Suspensions/chemistry
7.
Virology ; 358(1): 148-58, 2007 Feb 05.
Article in English | MEDLINE | ID: mdl-16997345

ABSTRACT

The effectiveness of anti-retroviral therapies (ART) depends on its ultimate ability to clear reservoirs of continuous human immunodeficiency virus (HIV) infection. We reasoned that a principal vehicle for viral dissemination, the mononuclear phagocytes could also serve as an ART transporter and as such improve therapeutic indices. A nanoparticle-indinavir (NP-IDV) formulation was made and taken up into and released from vacuoles of human monocyte-derived macrophages (MDM). Following a single NP-IDV dose, drug levels within and outside MDM remained constant for 6 days without cytotoxicity. Administration of NP-IDV when compared to equal drug levels of free soluble IDV significantly blocked induction of multinucleated giant cells, production of reverse transcriptase activity in culture fluids and cell-associated HIV-1p24 antigens after HIV-1 infection. These data provide "proof of concept" for the use of macrophage-based NP delivery systems for human HIV-1 infections.


Subject(s)
Anti-HIV Agents/pharmacology , Anti-HIV Agents/pharmacokinetics , HIV-1/drug effects , Indinavir/pharmacology , Indinavir/pharmacokinetics , Macrophages/metabolism , Macrophages/virology , Cell Fusion , Cell Survival , Cells, Cultured , Cytoplasm/chemistry , HIV Core Protein p24/biosynthesis , HIV Infections , HIV Reverse Transcriptase/biosynthesis , Humans , Macrophages/chemistry , Macrophages/ultrastructure , Microscopy, Electron, Scanning , Microscopy, Electron, Transmission , Microscopy, Fluorescence , Nanoparticles
8.
Blood ; 108(8): 2827-35, 2006 Oct 15.
Article in English | MEDLINE | ID: mdl-16809617

ABSTRACT

Complex dosing regimens, costs, side effects, biodistribution limitations, and variable drug pharmacokinetic patterns have affected the long-term efficacy of antiretroviral medicines. To address these problems, a nanoparticle indinavir (NP-IDV) formulation packaged into carrier bone marrow-derived macrophages (BMMs) was developed. Drug distribution and disease outcomes were assessed in immune-competent and human immunodeficiency virus type 1 (HIV-1)-infected humanized immune-deficient mice, respectively. In the former, NP-IDV formulation contained within BMMs was adoptively transferred. After a single administration, single-photon emission computed tomography, histology, and reverse-phase-high-performance liquid chromatography (RP-HPLC) demonstrated robust lung, liver, and spleen BMMs and drug distribution. Tissue and sera IDV levels were greater than or equal to 50 microM for 2 weeks. NP-IDV-BMMs administered to HIV-1-challenged humanized mice revealed reduced numbers of virus-infected cells in plasma, lymph nodes, spleen, liver, and lung, as well as, CD4(+) T-cell protection. We conclude that a single dose of NP-IDV, using BMMs as a carrier, is effective and warrants consideration for human testing.


Subject(s)
Drug Delivery Systems , HIV Protease Inhibitors/administration & dosage , Indinavir/administration & dosage , Macrophages/metabolism , Nanostructures , Animals , Chemistry, Pharmaceutical , Disease Models, Animal , HIV Infections/drug therapy , HIV Infections/immunology , HIV Infections/metabolism , HIV Protease Inhibitors/blood , HIV Protease Inhibitors/pharmacokinetics , HIV-1 , Humans , Indinavir/blood , Indinavir/pharmacokinetics , Macrophages/transplantation , Macrophages/ultrastructure , Male , Mice , Mice, Inbred BALB C , Mice, Inbred NOD , Mice, SCID , Microscopy, Electron, Scanning , Nanotechnology , Tissue Distribution
9.
Adv Exp Med Biol ; 566: 389-95, 2005.
Article in English | MEDLINE | ID: mdl-16594177

ABSTRACT

Protein C is an important blood factor protein that regulates the blood coagulation process. Deficiency of protein C can lead to excessive coagulation that results in lack of tissue oxygenation, causing conditions such as deep vein thrombosis, pulmonary embolism, and stroke. Human protein C has been approved as a treatment for congenital protein C deficiency; however, the therapy requires frequent injections, due to the short residence time of the protein. Subcutaneous administration has been examined as an alternative to increase residence time and decrease injection frequency, thereby creating a more patient-friendly dosing regimen. In order to design an efficient injection or infusion protocol for subcutaneously administered proteins, it is important to accurately model the behavior (absorption, distribution, elimination) of these proteins in the body. However, several factors involved in a subcutaneous injection of the protein make modeling this behavior a challenging task. For example, absorption of the drug from the subcutaneous site into the blood stream can be variable depending on the site of injection, physical activity of the patient, etc. Furthermore, degradation of the protein can occur at the site of injection and further modify its absorption. The objective of this work was to demonstrate the utility of frequency response modeling as an alternative method to analyze the behavior of subcutaneously administered protein C. The results of our study indicate that if the dose range yielding the constant clearance of protein C is identified for the patient, models of that type, as presented in our study, can be used to adjust optimal dosing of protein C necessary to reach prescribed levels of the protein in this patient at desired time points, both specified by treatment requirements.


Subject(s)
Models, Biological , Protein C/administration & dosage , Protein C/pharmacokinetics , Half-Life , Humans , Injections, Subcutaneous , Protein C Deficiency/blood , Protein C Deficiency/drug therapy
10.
Drug Discov Today ; 9(14): 603-9, 2004 Jul 15.
Article in English | MEDLINE | ID: mdl-15239979

ABSTRACT

Formulation development during early drug discovery and lead optimization, involves several challenges including limited drug supply, the need for rapid turnaround, and limited development time. It is also desirable to develop initial formulations that will be representative of final commercial formulations. Nanoparticles offer a unique platform for the formulation of poorly soluble drugs - such formulations can be injected (intravenous, subcutaneous, intramuscular), as well as administered through other routes, such as oral, ocular and inhalation. Thus, a single formulation can be used to test and eventually develop multiple dosage forms. Furthermore, nanoparticles offer the opportunity for high drug loading, for low potency compounds, and thus support toxicological evaluation of such compounds.


Subject(s)
Chemistry, Pharmaceutical/methods , Technology, Pharmaceutical , Chemistry, Pharmaceutical/trends , Drug Delivery Systems , Particle Size , Solubility
11.
Crit Rev Ther Drug Carrier Syst ; 20(4): 295-315, 2003.
Article in English | MEDLINE | ID: mdl-14635982

ABSTRACT

Poly(phosphate ester)s, polyphosphonates, and polyphosphazenes are three classes of phosphorus-containing polymers that have received wide attention over the past decade for their utility in biomedicine and tissue engineering. These three families of polymers can lead to a number of subclasses of polymers with varied properties. Significant research in this area has led to niche polymers with morphologies ranging from viscous gels to amorphous microparticles for utility in drug delivery. Furthermore, the pentavalency of phosphorus offers the potential for covalent linking of the drug. The classes of polymers discussed in this review are being explored in human clinical trials for vaccine delivery as well as delivery of oncolytic and CNS therapeutics. More applications in the areas of DNA delivery and tissue engineering are also being explored.


Subject(s)
Organophosphorus Compounds/chemistry , Polymers/chemistry , Delayed-Action Preparations , Drug Carriers , Organophosphates/chemistry
12.
J Biomater Sci Polym Ed ; 14(1): 45-61, 2003.
Article in English | MEDLINE | ID: mdl-12635770

ABSTRACT

Poly(lactide-co-ethylphosphate)s, a new class of linear phosphorus-containing copolymers made by chain-extending low-molecular-weight polylactide prepolymers with ethyl dichlorophosphate, were investigated for their in vitro and in vivo degradation mechanism and kinetics. Microspheres made from poly(lactide-co-ethylphosphate) were studied under both accelerated and normal in vitro degradation conditions. Gel permeation chromatography (GPC), 1H- and 31P-NMR, weight loss measurements, and differential scanning calorimetry (DSC) techniques were used to characterize the change of molecular weight (M(w)), chemical composition, and glass transition temperature (T(g)) of the degrading polymers. The results indicated that the copolymers degraded in a two-stage fashion, with cleavage of the phosphate-lactide linkages contributing mostly to the initial more rapid degradation phase and cleavage of the lactide-lactide bonds being responsible for the slower latter stage degradation. The decrease in the copolymer M(w) was accompanied by a continuous mass loss. Results from the accelerated degradation studies confirmed that the copolymers degraded into various monomers of the copolymers, which were non-toxic and biocompatible. A two-stage hydrolysis pathway was thus proposed to explain the degradation behavior of the copolymers. In vivo degradation studies performed in mice demonstrated a good in vitro and in vivo correlation for the degradation rates. In vivo clearance of the polymer was faster and without any lag phase. These copolymers are potentially advantageous for drug delivery and other biomedical applications where rapid clearance of the polymer carrier and repeated dosing capability are essential to the success of the treatment.


Subject(s)
Biocompatible Materials/chemistry , Lactic Acid/metabolism , Polyesters/metabolism , Polymers/metabolism , Animals , Biodegradation, Environmental , Calorimetry, Differential Scanning , Injections, Subcutaneous , Kinetics , Lactic Acid/administration & dosage , Lactic Acid/chemistry , Magnetic Resonance Spectroscopy , Male , Microscopy, Electron, Scanning , Microspheres , Molecular Weight , Polyesters/administration & dosage , Polyesters/chemistry , Polymers/administration & dosage , Polymers/chemistry , Rats , Rats, Sprague-Dawley
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