| Solid formulations of liquid biologically active agents -> Monitor Keywords |
|
|
 
Solid formulations of liquid biologically active agentsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Preparations Characterized By Special Physical Form, Matrices, Synthetic PolymerSolid formulations of liquid biologically active agents description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060198891, Solid formulations of liquid biologically active agents. Brief Patent Description - Full Patent Description - Patent Application Claims
BACKGROUND OF THE INVENTION [0001] a) Field of the Invention [0002] This invention relates to the preparation of a solid product in the form of a cake, a powder, or the like, by mixing a solvent comprising water, an aqueous solution, at least one non-aqueous organic solvent, or combinations thereof, with at least one stabilizing agent, and subsequently adding at least one liquid biologically active agent to the above mixture; and treating the whole under conditions to give the above solid product which is substantially solvent free. More particularly, the invention relates to the above solid product and a method for rapid reconstitution thereof in an aqueous media, whereby an essentially clear, lipid free, sterile, stable aqueous product is formed containing nano-dispersions or micelles of the aforementioned stabilizing and biologically active agents; and to a method of treating a patient in need of said biologically active agent by administration of said stable aqueous product thereto. In a preferred embodiment, the biologically active agent is water immiscible and may be selected from 2,6-bis-(1-methylethyl)phenol or 2,6-diisopropylphenol commonly known as propofol, 2-phenoxyethanol, quinaldine, methoxyflurane and the like and combinations thereof. The most preferred biologically active agent is propofol. [0003] b) Description of the Prior Art [0004] Propofol (known as 2,6-bis-(1-methylethyl)phenol, also known as 2,6-diisopropylphenol) is currently the most popular anaesthetic in the world. It is used for the induction and maintenance of anaesthesia or sedation upon administrations to humans or animals. Intravenous injection of a therapeutic dose of propofol produces hypnosis rapidly and with minimal excitation, usually within 40 seconds from the start of an administration. Fast onset and short half life (10-15 minutes) allows for a clinically useful profile with prompt recovery. Due to the rising cost of health care, this quick recovery time is especially advantageous for increasingly common outpatient procedures. [0005] At room temperature, propofol is an oil that is immiscible with water (aqueous solubility of approximately, 0.154 mg/mL) and is supplied in a emulsion, at concentrations of 1% or 2% (w/w) (2% is used for longer sedation). Propofol oil-in-water emulsions currently on the market are DIPRIVAN.RTM. (manufactured by AstraZeneca Pharmaceuticals, Inc.), BAXTER.RTM. IPP (manufactured by Gensia Sicor, Inc), and Propofol injectable emulsion (Manuf. Bedford Laboratories). [0006] Extreme care must be taken during manufacture to thoroughly distribute the propofol in the emulsion, as large droplet sizes of propofol in the blood stream have been linked to embolism in humans. These emulsions typically contain: soybean oil (100 mg/mL), glycerol (22.5 mg/mL) and egg lecithin (12 mg/mL). Emulsions are defined by a large particle size, generally of more than 200 nm, thereby creating a milky white opaque formulation. This causes visual inspection for foreign particles in the formulation by the anesthesiologist, to be more difficult. The high lipid content of these emulsions has been linked to hyperlipidaemia. [0007] The presence of the egg lecithin and soybean oil in these emulsions also makes them highly susceptible to microorganism growth and allergic reactions. In order to suppress bacterial growth, manufacturers have added the preservative EDTA (ethylene diamine tetraacetic acid) at 0.05 mg/mL to DIPRIVAN.RTM. and sodium metabisulfite at 0.25 mg/mL, to BAXTER.RTM. PPI propofol, and benzyl alcohol at 1 mg/ml to propofol injectable emulsion of Bedford Laboratories. [0008] Some of these preservatives have been known to cause adverse reactions in humans. Sodium metabisulfite is a sulfite known to cause allergic-type reactions including anaphylactic symptoms and life-threatening or asthmatic episodes in certain sulfite sensitive individuals. Sodium bisulfite has also been shown to catalyze propofol degradation. Similarly, the chelating properties of EDTA are of concern to the FDA due to their unfavorable effects on cardiac and renal function. Moreover, these emulsions cannot be effectively sterilized using standard sterilizing filters, as they are too thermodynamically unstable and tend to separate under the shear force required. Such emulsions are also unstable versus dilution and/or mixing with saline, dextrose or other medication containing solutions. Furthermore, the presence of egg lecithin as an emulsifier and soybean oil as a solubilizer may produce anaphylactic and anaphylactoid reactions in persons allergic to eggs and/or soybeans. [0009] Propofol emulsions are known to be thermodynamically unstable, that is, the oil and water components have a tendency to separate when diluted, sheared, cooled, heated, or mixed with other solutions. Furthermore, this separation is accelerated when the formulation is stored at low temperatures, i.e. below 2.degree. C., or at elevated temperatures, i.e. above 25.degree. C. In addition, these lipid-based emulsions have been associated with pain at the injection site, often causing the concomitant use of a topical anaesthetic upon injection. [0010] A variety of methods and procedures have been described in the prior art for preparing stable formulations for the effective delivery of at least one hydrophobic compound, particularly pharmaceutical drugs, to a desired location in the body. A number of these methods are based on the use of auxiliary solvents; surfactants; soluble forms of the drug, e.g., salts and solvates; chemically modified forms of the drug, e.g., prodrugs; soluble polymer-drug complexes; special drug carriers such as liposomes; and others. [0011] Indeed, the use of surfactant based micelles has attracted a great deal of interest as a potentially effective drug carrier that is capable of solubilizing a hydrophobic drug in an aqueous environment. Typically, micelles and nanodispersions have been shown to alter the pharmacokinetics (and usually the pharmacodynamics) of the biological agent to be delivered. Thus, by sequestering the drug within them, they may prolong the circulation time, may allow more drug to be delivered to a specific location, and/or may allow a different biodistribution when compared to administration of the drug alone. [0012] However, each of the above procedures is associated with certain drawbacks, especially when considering the delivery of "on/off" type anaesthetics, such as propofol. For example, the method based on the use of surfactant micelles to solubilize hydrophobic drugs can be inherently problematic in that some of the surfactants are relatively toxic (e.g. Cremophor EL.RTM.) and that precipitation of hydrophobic drugs may occur when subjected to dilution. Other methods of preparation yield poor entrapment efficiencies (e.g. equilibration methods), relatively large particle sizes (emulsions), or are time-consuming. [0013] Finally, the prolonged circulation time associated with micellar or liposomal delivery can detrimentally affect the "on/off" properties required of an anaesthetic drug such as propofol [0014] Likewise, there have been studies based on the use of cyclodextrin derivates, which are water-soluble cyclic carbohydrate compounds with hydrophobic interior cavities that complex with propofol allowing dissolution of the drug in water to form a clear solution. However, cyclodextrins are expensive and have been associated with hemodynamic adverse events. Also, long-term stability of cyclodextrin formulations has been an issue with formulators. More importantly, cyclodextrins have been linked with renal toxicity at high doses. [0015] There have also been various attempts investigating the use of water-soluble prodrugs comprising a propofol phosphate. However, usually prodrugs require much higher doses (up to ten times and more) for the same response as the instant invention and usually demonstrate a slower onset of action and slower clearance. Moreover, in some propofol prodrugs one of the bi-products is formaldehyde, a probable carcinogen. Prodrugs are also notably unstable resulting in short shelf lives or low storage temperatures to maintain their stability. The beneficial pharmacokinetics are changed due to the use of prodrugs. [0016] Furthermore, when a liquid biologically active agent such as propofol is formulated with the technologies discussed above, a liquid dosage form is produced. However, the stability of such liquid formulations is always a concern with respect to duration and storage conditions. [0017] Thus, what is lacking in the art is a light-weight, dry powder or cake formed from a water immiscible liquid drug, such as propofol, that is stable in several different temperature and dilution conditions for prolonged periods, that is readily reconstituted using aqueous media to produce essentially clear, sterile liquids which do not support bacterial growth, comprising drug-loaded micelles or nanodispersions in an aqueous medium. The micelles or nanodispersions, which are produced directly and spontaneously after addition of the aqueous reconstitution medium, allows high loading levels of propofol or other biologically active liquids to be achieved with substantially no effect on stability. [0018] Many studies, literature articles and patents have been directed toward forming stable anaesthetic compositions suitable for parenteral administration, particularly the administration of propofol and other drugs in liquid form. [0019] For example, WO 02/45709 A1 discloses a stable, clear and sterile aqueous composition comprising propofol, a water-soluble emulsifier (TPGS) and water, suitable for parenteral administration and a process for making the same. However, the final product is a liquid and the process of manufacturing requires both the filtration of the composition through a micron-sized filter and autoclaving the sealed container filled with the filtrate in order to achieve effective sterilization. [0020] WO 03/030862 A2, discloses inhalation anaesthetic compositions and methods comprising a suspension of the anaesthetic in an aqueous solution. The reference teaches the use of surfactant poloxamers, (known as Pluronics.RTM. in the United States and Lutrols.RTM. in Europe) to encapsulate the anaesthetic (i.e. propofol) within the micelles. The preferred embodiments require the presence of propylene glycol in order to achieve adequate solubilization of propofol. However, the product is supplied as a liquid and the presence of water in the inhaled anaesthetic is not always beneficial to patients with pulmonary disorders, such as plural effusion. It will be noted that the composition disclosed in this reference is prepared using a mixture of liquids to constitute a liquid composition. [0021] WO 01/64187 A2 and corresponding U.S. PGPUB No. 2003/0138489 A1, on the other hand, disclose propofol solubilized in aqueous micellar preparations using combinations of poloxamers to form a clear, injectable solution without inclusion of water-miscible co-solvents, such as propylene glycol. According to WO 01/64187 A2, the use of water-miscible co-solvents can have undesirable medical effects, such as superficial thrombophlebitis, intravasal, haemolytic reactions, and possible increase in formation of free propofol. Moreover, WO 01/64187 A2 indicates that autoclaving may be undesirable when the formulation is filtered to sterility since autoclaving has been known to disrupt the micelles, to the extent of requiring re-emulsification. In addition, poloxamers are detergent-like surfactants that are not readily degradable and may open-up tight junctions. Moreover, detergent surfactants may be a source of pain upon injection and require the addition of lidocaine to reduce local pain. The final product is a liquid. [0022] U.S. Pat. No. 6,322,805 discloses a biodegradable polymeric drug carrier micelle composition capable of solubilizing a solid hydrophobic drug in a hydrophilic environment. The patent discloses a biodegradable polymeric drug carrier micelle and a hydrophobic drug wherein the drug is physically trapped within and not covalently bonded to the polymeric drug carrier micelle. The drug carrying micelle is capable of dissolving in water to form a solution thereof, and the drug carrier comprises an amphiphilic block copolymer having a hydrophilic poly(alkylene oxide) component, and a biodegradable hydrophobic polymer component selected from the group consisting of poly(lactic acid), poly(glycolic acid), poly(lactic-co-glycolic acid), poly(.epsilon.-caprolactone), a derivative thereof or a mixture thereof. The disclosed micelle is characterized as a solubilizing agent for a hydrophobic drug. The hydrophobic drug is mixed with the polymeric drug carrier micellar solution and the mixture is either stirred, heated, subjected to ultrasonic treatment, solvent evaporation or dialysis so as to incorporate it into the hydrophobic polymer core, after which it is formed into an aqueous solution. [0023] U.S. Pat. No. 5,543,158 discloses nanoparticles or microparticles formed of a block copolymer consisting essentially of poly(alkylene glycol) and a biodegradable polymer, poly(lactic acid). In the nanoparticle or microparticle, the biodegradable moieties of the copolymer are in the core of the nanoparticle or microparticle and the poly(alkylene glycol) moieties are on the surface of the nanoparticle or microparticle in an amount effective to decrease uptake of the nanoparticle or microparticle by the reticuloendothelial system. Thus, the nanoparticles or microparticles are designed to circulate for prolonged periods within the blood fluids. In this patent, the molecular weight of the block copolymer is too high to be soluble in water, and a nanoparticle can only be prepared by first dissolving the block copolymer and a drug in an organic solvent, forming an o/w emulsion by sonication or stirring, and then collecting the precipitated nanoparticles containing the drug. The patent fails to provide the concept of solubilization of hydrophobic drugs, nor does it teach or suggest the formation of a clear, sterilizable solution containing the polymer/drug blend and subsequent lyophilization thereof, resulting in a readily dispersible micelle or nanodispersion, formed upon reconstitution. Continue reading about Solid formulations of liquid biologically active agents... Full patent description for Solid formulations of liquid biologically active agents Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Solid formulations of liquid biologically active agents patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. Start now! - Receive info on patent apps like Solid formulations of liquid biologically active agents or other areas of interest. ### Previous Patent Application: Polymeric systems for controlled drug therapy Next Patent Application: Aerosol and injectable formulations of nanoparticulate benzodiazepine Industry Class: Drug, bio-affecting and body treating compositions ### FreshPatents.com Support Thank you for viewing the Solid formulations of liquid biologically active agents patent info. IP-related news and info Results in 0.21726 seconds Other interesting Feshpatents.com categories: Software: Finance , AI , Databases , Development , Document , Navigation , Error 174 |
 * Protect your Inventions * US Patent Office filing 
PATENT INFO |
|
