Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia. (57/735)

PURPOSE: Chronic myelogenous leukemia (CML) results from the breakpoint cluster region-Abl fusion gene product, a tyrosine kinase involved in cell division and apoptosis. Imatinib, an orally administered inhibitor of the breakpoint cluster region-Abl tyrosine kinase, is capable of blocking proliferation and inducing apoptosis in CML cell lines. In this report, we describe the preclinical profile of imatinib and the data submitted in the New Drug Application that led to its marketing approval. EXPERIMENTAL DESIGN: Chemistry manufacturing and controls, animal toxicology, and biopharmaceutical data are described. Results of Phase I and Phase II clinical studies in patients with CML in blast crisis (CML-BC), in accelerated phase (CML-AP), and in chronic phase disease-resistant or intolerant to IFN-alpha (CML-CP) are summarized. The basis for marketing approval and postmarketing commitments by the pharmaceutical company are discussed. RESULTS: Toxicology studies in the rat, dog, and monkey show the hematological, renal, and hepatobiliary toxicity of imatinib. Pharmacokinetic studies in patients with CML demonstrate 98% imatinib bioavailability. The elimination half-lives of the parent drug and the major active metabolite, CGP74588, from plasma are approximately 18 and 40 h, respectively. Approximately 81% of the drug is eliminated in 7 days, 68% in the feces and 13% in the urine. Cytochrome P-450 3A4 is the main enzyme responsible for imatinib metabolism. Phase I and II clinical studies were conducted. The Phase I study, in 83 CML patients, evaluated oral imatinib doses from 25 to 1000 mg/day. Dose-limiting toxicity was not observed. The three Phase II studies, in CML-CP, CML-AP, and CML-BC, enrolled 1027 patients. CML-CP patients received 400 mg/day imatinib, whereas CML-AP and CML-BC patients generally received 600 mg/day imatinib. Primary study endpoints were cytogenetic response rate (CML-CP) and hematological response rate (CML-AP and CML-BC). The cytogenetic response rate for CML-CP patients was 49%. The hematological response rate of CML-AP and CML-BC patients was 63 and 26%, respectively. The most common imatinib adverse events were nausea, vomiting, myalgia, edema, and diarrhea. Elevated liver enzymes and/or bilirubin were reported in 27 patients (2.6%). CONCLUSIONS: On May 10, 2001, imatinib mesylate (Gleevec, formerly known as STI-571 and Glivec), manufactured and distributed by Novartis Pharmaceuticals, East Hanover, NJ, was approved by the United States Food and Drug Administration for the treatment of CML in three clinical settings: CML-BC, CML-AP, and CML-CP. This report summarizes the Food and Drug Administration's review of the New Drug Application.  (+info)

Mechanism of in vitro release kinetics of flurbiprofen loaded ethylcellulose micropellets. (58/735)

Flurbiprofen loaded ethylcellulose micropellets with different drug loading were prepared by a quasi-emulsion solvent diffusion technique. Encapsulation parameters of micropellets such as actual drug loading, drug encapsulation efficiency (DEE) and loss of coating polymer (LCP) were determined. Actual drug loading was increased with the increased initial drug loading whereas encapsulation efficiency decreased with the increase of actual drug loading. In vitro drug release profiles of these micropellets were evaluated in distilled water (DW) and also in phosphate buffer solution (PBS) to indicate pH dependency release rates. All the batches of micropellets released about 35-59% in DW and 89-97% in PBS during the period of 8 h and the burst effect of about 50-75% in the first 1.5 h was seen only in PBS. The mechanism of release kinetics was evaluated by fitting the release data to the zero order, first order, Higuchi, Baker-Lonsdale and Peppas equations and also to the differential forms of zero order, first order and Higuchi model. Adequate fitting of release data was found with first order, Higuchi and Peppas models and hence these models were selected for F-test statistics for ascertaining the mechanism of drug release. Higuchi model of drug release in DW and PBS of all the formulations was ruled out due to its significantly different F-value with other models. Thus, mechanism of release of flurbiprofen from ethylcellulose micropellets may be explained by the diffusional exponent model of Peppas et al. as ascertained by F-test statistics rather than the same, based on some other diffusional models even though they have shown good correlation.  (+info)

Delivery of erythropoietin by encapsulated myoblasts in a genetic model of severe anemia. (59/735)

BACKGROUND: Existing animal models of anemia inadequately reflect the hematocrit usually present in chronic renal failure (CRF) patients and do not permit long-term treatment studies. The transgenic mouse strain 134.3LC (Epo-TAg(H)) displays a severe chronic anemia resembling that observed clinically during CRF, while displaying an active, normal life span. This phenotype makes it a particularly interesting mouse model for testing erythropoietin (Epo)-based gene transfer strategies. METHODS: Ex vivo gene therapy was employed to administer mouse Epo to homozygous anemic Epo-TAg(H) mice. Encapsulated C(2)C(12) myoblasts genetically engineered to secrete 163 IU mouse Epo/10(6) cells/day were subcutaneously transplanted on the dorsal flank of the mice. Efficacy of delivered Epo was monitored by weekly measurements of animal hematocrit. RESULTS: Most treated homozygous Epo-TAg(H) mice displayed only a transient rise in hematocrit before eventually decreasing to levels as low as 3%. Administering the immunosuppressor anti-CD4+ monoclonal antibody (mAb) to homozygous Epo-TAg(H) mice, beginning at the time of implantation, permitted a rise in hematocrit that remained stable at elevated levels in cases of continued immunosuppression. CONCLUSIONS: Mice having the T antigen insertion in both Epo alleles appeared to develop an immune response to the natural mouse Epo delivered by encapsulated cells. By preventing this reaction using immunosuppression, we demonstrate that encapsulated myoblasts can deliver therapeutic doses of mouse Epo systemically and restore hemopoiesis in a genetic model of severe anemia.  (+info)

Mass variation tests for coating tablets and hard capsules: rational application of mass variation tests. (60/735)

The mass variation test is a simplified alternative test version of the content uniformity test. In the case of coating tablets and capsules, the mass variation test is principally applied to test the inner cores or fillings containing the active ingredient. However, some exceptions exist in pharmacopoeias. The effects of tablet coating and capsule shell on the results of the mass variation test were studied. The mass variation of outer crusts (coatings, capsule shells) and inner cores (core tablets, fillings) was measured separately in several products. The effects of coating on weight variability were very large for sugar-coated tablets. Relative standard deviation (RSD) of the formulation weight (RSD(W)) of sugar-coated tablets (2.73%) was larger than that of plain tablets (0.77%). The cause of the large RSD(W) is the large variation the weight of sugar-coating accounting for 44% of formulation weight. In the case of film-coated tablets, the effect of coating weight on the mass variation test was very small because the rate of coating in comparison to the whole weight was small. In the case of hard capsules, the usage of whole formulation weight resulted in underestimation of variations of filling weight. The differences between dosage forms in the applicability of the mass variation test are caused by differing weight proportions and variability of the outer coatings or shells. To avoid the underestimation of mass variation for hard capsules, a corrected acceptance value is useful. For all the dosage units, the mass variation test can principally be applied to determine which mass is expected to be proportional to the content of the active ingredient. However, some modification of acceptance values enables application of the mass variation tests to inapplicable cases, such as when the RSD of drug concentration (RSD(C)) is larger than 2%.  (+info)

Colonic delivery of 4-aminosalicylic acid using amylose-ethylcellulose-coated hydroxypropylmethylcellulose capsules. (61/735)

BACKGROUND: 4-Aminosalicylic acid has the potential for use in the treatment of diseases of the colon. AIM: To assess the feasibility of delivering 4-aminosalicylic acid directly to the colon using a hydroxypropylmethylcellulose capsule coated with a mixture of amylose, a polysaccharide metabolized by bacterial enzymes in the colon, and ethylcellulose. METHODS: Seven healthy male volunteers received, on three separate occasions, an uncoated or amylose-ethylcellulose-coated hydroxypropylmethylcellulose capsule containing 4-aminosalicylic acid Na (550 mg), or an intravenous injection of 4-aminosalicylic acid Na (135 mg). The capsules were radiolabelled with 99mTc to allow their positions in the gastrointestinal tract to be followed using a gamma camera. Plasma and urine samples were collected and assayed for 4-aminosalicylic acid and metabolite concentrations. RESULTS: The uncoated capsules broke down within 10 min in the stomach, allowing rapid and complete absorption of the drug. The coated capsules remained intact in the upper gastrointestinal tract, and had a median gastric emptying time of 61 min (interquartile range, 77 min) and a median colon arrival time of 363 min (interquartile range, 185 min). For the coated capsules, only the metabolite was detected in the plasma and/or urine after the capsules had reached the colon. CONCLUSIONS: The specific coating protected the drug until the capsule reached the colon, where 4-aminosalicylic acid was slowly released and absorbed. Thus, such a formulation has the potential for use in the treatment of inflammatory bowel disease.  (+info)

Oxidation of linoleic acid encapsulated with soluble soybean polysaccharide by spray-drying. (62/735)

Linoleic acid was encapsulated with a soluble soybean polysaccharide, gum arabic, or a mixture of both together with maltodextrin, and the oxidation process of the encapsulated acid was measured at 37 degrees C and at a relative humidity of 12%. The soybean polysaccharide was more effective for encapsulating the acid and suppressing the oxidation of the encapsulated acid than gum arabic. A mixture of the soybean polysaccharide and maltodextrin was also effective for this purpose when the weight fraction of the polysaccharide was equal to or greater than 0.75.  (+info)

Antibacterial activities of nisin Z encapsulated in liposomes or produced in situ by mixed culture during cheddar cheese ripening. (63/735)

This study investigated both the activity of nisin Z, either encapsulated in liposomes or produced in situ by a mixed starter, against Listeria innocua, Lactococcus spp., and Lactobacillus casei subsp. casei and the distribution of nisin Z in a Cheddar cheese matrix. Nisin Z molecules were visualized using gold-labeled anti-nisin Z monoclonal antibodies and transmission electron microscopy (immune-TEM). Experimental Cheddar cheeses were made using a nisinogenic mixed starter culture, containing Lactococcus lactis subsp. lactis biovar diacetylactis UL 719 as the nisin producer and two nisin-tolerant lactococcal strains and L. casei subsp. casei as secondary flora, and ripened at 7 degrees C for 6 months. In some trials, L. innocua was added to cheese milk at 10(5) to 10(6) CFU/ml. In 6-month-old cheeses, 90% of the initial activity of encapsulated nisin (280 +/- 14 IU/g) was recovered, in contrast to only 12% for initial nisin activity produced in situ by the nisinogenic starter (300 +/- 15 IU/g). During ripening, immune-TEM observations showed that encapsulated nisin was located mainly at the fat/casein interface and/or embedded in whey pockets while nisin produced by biovar diacetylactis UL 719 was uniformly distributed in the fresh cheese matrix but concentrated in the fat area as the cheeses aged. Cell membrane in lactococci appeared to be the main nisin target, while in L. casei subsp. casei and L. innocua, nisin was more commonly observed in the cytoplasm. Cell wall disruption and digestion and lysis vesicle formation were common observations among strains exposed to nisin. Immune-TEM observations suggest several modes of action for nisin Z, which may be genus and/or species specific and may include intracellular target-specific activity. It was concluded that nisin-containing liposomes can provide a powerful tool to improve nisin stability and availability in the cheese matrix.  (+info)

Colloidosomes: selectively permeable capsules composed of colloidal particles. (64/735)

We present an approach to fabricate solid capsules with precise control of size, permeability, mechanical strength, and compatibility. The capsules are fabricated by the self-assembly of colloidal particles onto the interface of emulsion droplets. After the particles are locked together to form elastic shells, the emulsion droplets are transferred to a fresh continuous-phase fluid that is the same as that inside the droplets. The resultant structures, which we call "colloidosomes," are hollow, elastic shells whose permeability and elasticity can be precisely controlled. The generality and robustness of these structures and their potential for cellular immunoisolation are demonstrated by the use of a variety of solvents, particles, and contents.  (+info)