The present invention provides compositions comprising an anti-angiogenic factor, and a polymeric carrier. Representative examples of anti-angiogenic factors include Anti-Invasive Factor, Retinoic acids and derivatives thereof, and paclitaxel. Also provided are methods for embolizing blood vessels, and eliminating biliary, urethral, esophageal, and tracheal/bronchial obstructions.

Anti-angiogenic compositions and methods of use

Implantable devices and methods for delivering drugs and other substances to locations within the body of a human or animal subject to treat or diagnose sinusitis and a variety of other disorders. The invention includes implantable substance delivery devices that comprise reservoirs and barriers that control the rate at which substances pass out of the reservoirs. The delivery devices may be advanced into the body using guidewires, catheters, ports, introducers and other access apparatus. In some embodiments the delivery devices may be loaded with one or more desired substance before their introduction into the body. In other embodiments the delivery devices are loaded and/or reloaded with a desired substance after the delivery device has been introduced into the body.

Implantable devices and methods for delivering drugs and other substances to treat sinusitis and other disorders

Drugs, especially low aqueous solubility drugs, are provided in a porous matrix form, preferably microparticles, which enhances dissolution of the drug in aqueous media. The drug matrices preferably are made using a process that includes (i) dissolving a drug, preferably a drug having low aqueous solubility, in a volatile solvent to form a drug solution, (ii) combining at least one pore forming agent with the drug solution to form an emulsion, suspension, or second solution and hydrophilic or hydrophobic excipients that stabilize the drug and inhibit crystallization, and (iii) removing the volatile solvent and pore forming agent from the emulsion, suspension, or second solution to yield the porous matrix of drug. Hydrophobic or hydrophilic excipients may be selected to stabilize the drug in crystalline form by inhibiting crystal growth or to stabilize the drug in amorphous form by preventing crystallization. The pore forming agent can be either a volatile liquid that is immiscible with the drug solvent or a volatile solid compound, preferably a volatile salt. In a preferred embodiment, spray drying is used to remove the solvents and the pore forming agent. The resulting porous matrix has a faster rate of dissolution following administration to a patient, as compared to non-porous matrix forms of the drug. In a preferred embodiment, microparticles of the porous drug matrix are reconstituted with an aqueous medium and administered parenterally, or processed using standard techniques into tablets or capsules for oral administration.

Porous drug matrices and methods of manufacture thereof

The invention relates to the discovery of novel soluble neutral active Hyaluronidase Glycoproteins (sHASEGPs), methods of manufacture, and their use to facilitate administration of other molecules or to alleviate glycosaminoglycan associated pathologies. Minimally active polypeptide domains of the soluble, neutral active sHASEGP domains are described that include asparagine-linked sugar moieties required for a functional neutral active hyaluronidase domain. Included are modified amino-terminal leader peptides that enhance secretion of sHASEGP. The invention further comprises sialated and pegylated form of a recombinant sHASEGP to enhance stability and serum pharmacokinetics over naturally occurring slaughterhouse enzymes. Further described are suitable formulations of a substantially purified recombinant sHASEGP glycoprotein derived from a eukaryotic cell that generate the proper glycosylation required for its optimal activity.

Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases

Hypercholesterolaemia plays a crucial role in the development of atherosclerotic diseases in general and coronary heart disease in particular. The risk of progression of the atherosclerotic process to coronary heart disease increases progressively with increasing levels of total serum cholesterol or low density lipoprotein (LDL) cholesterol at both the individual and the population level. The statins are reversible inhibitors of the microsomal enzyme HMG-CoA reductase, which converts HMG-CoAto mevalonate. This is an early rate-limiting step in cholesterol biosynthesis. Inhibition of HMG-CoA reductase by statins decreases intracellular cholesterol biosynthesis, which then leads to transcriptionally upregulated production of microsomal HMG-CoA reductase and cell surface LDL receptors. Subsequently, additional cholesterol is provided to the cell by de novo synthesis and by receptor-mediated uptake of LDL-cholesterol from the blood. This resets intracellular cholesterol homeostasis in extrahepatic tissues, but has little effect on the overall cholesterol balance. There are no simple methods to investigate the concentration-dependent inhibition of HMG-CoA reductase in human pharmacodynamic studies. The main clinical variable is plasma LDL-cholesterol, which takes 4 to 6 weeks to show a reduction after the start of statin treatment. Consequently, a dose-effect rather than a concentration-effect relationship is more appropriate to use in describing the pharmacodynamics. Fluvastatin, lovastatin, pravastatin and simvastatin have similar pharmacodynamic properties; all can reduce LDL-cholesterol by 20 to 35%, a reduction which has been shown to achieve decreases of 30 to 35% in major cardiovascular outcomes. Simvastatin has this effect at doses of about half those of the other 3 statins. The liver is the target organ for the statins, since it is the major site of cholesterol biosynthesis, lipoprotein production and LDLcatabolism. However, cholesterol biosynthesis in extrahepatic tissues is necessary for normal cell function. The adverse effects of HMG-reductase inhibitors during long term treatment may depend in part upon the degree to which they act in extrahepatic tissues. Therefore, pharmacokinetic factors such as hepatic extraction and systemic exposure to active compound(s) may be clinically important when comparing the statins. Different degrees of liver selectivity have been claimed for the HMG-CoA reductase inhibitors. However, the literature contains confusing data concerning the degree of liver versus tissue selectivity. Human pharmacokinetic data are poor and incomplete, especially for lovastatin and simvastatin, and it is clear that any conclusion on tissue selectivity is dependent upon the choice of experimental model. However, the drugs do differ in some important aspects concerning the degree of metabolism and the number of active and inactive metabolites. The rather extensive metabolism by different cytochrome P450 isoforms also makes it difficult to characterise these drugs regarding tissue selectivity unless all metabolites are well characterised. The effective elimination half-lives of the hydroxy acid forms of the 4 statins are 0.7 to 3.0 hours. Protein binding is similar (>90%) for fluvastatin, lovastatin and simvastatin, but it is only 50% for pravastatin. The best characterised statins from a clinical pharmacokinetic standpoint are fluvastatin and pravastatin. The major difference between these 2 compounds is the higher liver extraction of fluvastatin during the absorption phase compared with pravastatin (67 versus 45%, respectively, in the same dose range). Estimates of liver extraction in humans for lovastatin and simvastatin are poorly reported, which makes a direct comparison difficult.

Pharmacodynamics and pharmacokinetics of the HMG-CoA reductase inhibitors. Similarities and differences.

A controlled release drug delivery device, comprised of swellable polymers, whose degree of swelling in an environment of use is controlled by swelling modulators blended within the polymers, is disclosed. The swelling modulators can include buffers, osmagents, surfactants or combinations thereof surrounded by a microporous coating or interspersed within individual matrices. The combination of controlled release swelling modulators with swellable polymers may be applied to regulate patterns of beneficial agent (typically a drug) release.

Swelling modulated polymeric drug delivery device

The instant invention is directed to an osmotic pump, for the controlled release of diltiazem L-malate to an environment of use, said pump comprising: (A) a core which comprises a therapeutically effective amount of diltiazem L-malate and an effective buffering amount of sodium bitartrate surrounded by (B) a rate controlling water insoluble wall, having a fluid permeability of 6.96×10 -18 to 6.96×10 -14 cm 3 sec/g and a reflection coefficient of less than 0.5, prepared from: (i) a polymer permeable to water but impermeable to solute and (ii) 0.1 to 60% by weight, based on the total weight of (i) and (ii), of at least one pH insensitive pore forming additive dispersed throughout said wall.

Controlled porosity osmotic pump

The controlled porosity osmotic pump

The instant invention is directed to a multiparticulate osmotic pump, for the controlled release of a pharmaceutically active agent to an environment of use, said pump comprising: (I) a carrier medium which does not maintain its integrity in the environment of use; (II) a multiple of tiny osmotic pump elements each consisting essentially of: (A) a core comprises at least one pharmacologically active agent soluble in an external fluid, or a mixture of an agent having a limited solubility in the external fluid with an osmotically effective solute that is soluble in the fluid, which exhibit an osmotic pressure gradient across the wall against the external fluid surrounded by (B) a rate controlling water insoluble wall, having a fluid permeability of 6.96×10 -18 to 6.96×10 14 cm 3 sec/g and a reflection coefficient of less than 0.5, prepared from: (i) a polymer permeable to water but impermeable to solute and (ii) 0.1 to 60% by weight, based on the total weight of (i) and (ii), of at least one pH insensitive pore forming additive dispersed throughout said wall.

Gaylen M. Zentner

Papers

Swelling modulated polymeric drug delivery device

Controlled porosity osmotic pump

The controlled porosity osmotic pump

Multiparticulate controlled porosity osmotic

Osmotic flow through controlled porosity films: An approach to delivery of water soluble compounds