The assignee for this patent application is
Reporters obtained the following quote from the background information supplied by the inventors: "A wound is an injury to the body, as from violence, accident, or surgery, that typically involves laceration or breaking of a membrane and usually damages to underlying tissues, and/or bones.
"The treatment of a wound depends on the type, cause, location and depth of the wound as well as which other structures beyond the skin are involved. But, generally the treatment involves cleaning, treating with an antibiotic, protecting the wound by covering it with a gauze dressing pad to absorb fluids and prevent further contamination and/or closing the wound to prevent further contamination. Wound closure typically involves using a suture, metal clips, staples and adhesive strips.
"Generally, the risk of infection in a wound is reduced by adequate wound cleansing and/or debridement by removing any foreign material and non-viable tissue before application of an antibiotic at the wound.
"Vacuum-assisted wound closure systems, which are wound closure systems that continuously or intermittently apply sub-atmospheric pressure to the surface of a wound, may be used to remove wound fluid and non-viable tissue, to decrease the level of bacteria in the wound, to improve blood flow in the wound bed and surrounding tissue and/or pull the wound edges together and stimulate cell growth. Such vacuum-assisted wound closure systems are described in, for example, U.S. Pat. Nos. 4,949,880, 5,100,396, 5,261,893, 5,527,293, 6,071,267, 7,799,004, and Gestring, Negative Pressure Wound Therapy,
"A depot is a way of administering an active ingredient, such as an antibiotic, into the body of a patient for systemic or local action. It is generally administered by subcutaneous or intramuscular injection or instillation into other body tissues, vessels or cavities. A depot can also be applied to a wound before it is staunched, stitched, bandaged or otherwise closed. Unlike removable depots, biodegradable depots disintegrate or degrade within a pre-defined time, typically after the entrapped active pharmaceutical ingredient has been delivered. In other constructs, the biodegradable injectable depot releases its active pharmaceutical ingredient roughly simultaneously with, or as a function of, its gradual degradation. A key advantage of certain biodegradable delivery depots is their ability to deliver medication directly to the intended site of action providing elevated local concentrations of medication when compared to systemic levels.
"Depots can also modulate delivery of medication to enable various release profiles. The release profile could be immediate release (burst) followed by a steady state, could be, among others, 'zero order' or constant rate of delivery, could provide a slow rise to steady state, or could even provide for a delayed release. In addition, depots have the advantage of allowing release over an extended period of time, with a single administration. Blood levels are not compromised by, for example, patient compliance issues.
"Depots can be comprised of particulate systems such as microsphere-based depots and nanosphere-based depots, or can also be comprised of a biodegradable gel, typically made from soluble matrix formers (polymers, lipids, carbohydrates) and either an organic solvent or a mixture of water miscible and non-miscible solvents.
"Phospholipids have been used to prepare depots comprising a lipophilic pharmacological active agent. Phospholipids are soluble in oils or organic solvents but insoluble in water. To form a depot, a high concentration of depot-forming phospholipids is often required. This can impact the volume and viscosity of the resulting depot and, accordingly, currently available phospholipid depots can be very difficult to inject through a conventional needle or a syringe. References describing phospholipids-based formulations include WO 89/00077, WO 02/32395, EP 0282405 and U.S. Pat. Nos. 5,863,549, 4,252,793, 5,660,854, 5,693,337, and Wang et al., Lyophilization Of Water-In-Oil Emulsions To Prepare Phospholipid-Based Anhydrous Reverse Micelles For Oral Peptide Delivery, 39
"Vancomycin is a glycopeptide antibiotic used in the prophylaxis and treatment of infections caused by Gram-positive bacteria. It is generally the drug of choice for serious infection and endocarditis caused by S. aureus, coagulase-negative staphylococci, streptococcus pneumoniase, .beta.-hemolytic streptococci, corynebacterium group JK, viridans streptococci, or enterococci when .beta.-lactams cannot be used because of drug allergy or resistance. Vancomycin can be combined with other antimicrobials when treating, inter alia, methicillin-resistant coagulase-negative staphylococcal prosthetic valve endocarditis, and enterococcal endocarditis. It has also been used as an alternative agent for pneumococcal meningitis caused by strains with reduced penicillin sensitivity. Vancomycin has been used in cardiac and vascular surgery to prevent post surgical infection.
"Gentamicin is an aminoglycoside antibiotic used to treat many types of bacterial infections particularly those caused by Gram-negative bacteria. It has been used in a surgical setting because it acts against pathogens such as anaerobes and enterococci. Gentamicin has been used in other surgical applications (e.g. orthopedic settings) and is currently being used in a biodegradable collagen implant.
"Both vancomycin and gentamicin in their currently available and commonly used salt forms, e.g. vancomycin hydrochloride and gentamicin sulfate are very hydrophilic antibiotics. These antibiotics, particularly in their salt forms are also difficult to formulate into injectable depots based on phospholipids or other high oil phase content formulations, as they are not freely soluble in phospholipid or oil.
"In addition, by conducting a series of stability tests, it has now been found that vancomycin and gentamicin degrade by different mechanisms. Vancomycin loses its stability through hydrolysis and gentamicin degrades due to oxidation or adduct formation. Thus, formulations containing either one of the actives are generally sensitive to these conditions. Moreover, both vancomycin and gentamicin are heat-sensitive and cannot be sterilized by using heat, such as autoclaving or gamma-radiation.
"Accordingly, attempting to formulate a depot comprising a vancomycin salt, gentamicin salt or both along with a phospholipid and oil provide many practical challenges. One such attribute includes the formulation should not feature high viscosity since the formulation has to be sterilized by filtering through a sterilizing membrane, such as one having pores of about 0.22 micron or less. There also remains certain dichotomous problems. For instance, these actives also have compatibility problems with phospholipids which, like viscosity, suggests a need to keep phospholipid content low. However, the need for coherent and cohesive gel formation and proper release characteristics suggest just the opposite.
"Accordingly, there remains an unmet need for storage stable viscous phospholipid depots containing a vancomycin, gentamicin, a pharmaceutical salt thereof or a mixture thereof that can be administered by subcutaneous or intramuscular injection or by injection or instillation into a wound or other body tissues, vessels or cavities to treat and/or prevent wound infection."
In addition to obtaining background information on this patent application, NewsRx editors also obtained the inventors' summary information for this patent application: "One aspect of the present invention provides a process for making a depot comprising a hydrophilic water-soluble pharmaceutically active agent(s) comprising: (1) dissolving, a hydrophilic form of vancomycin, gentamicin or a mixture thereof in water; (2) forming an oil-in-water emulsion comprising a phospholipid, an oil, and an aqueous solution comprising the vancomycin, gentamicin, or the mixture thereof (an 'emulsion'); (3) homogenizing the emulsion using a high-pressure homogenizer, such as a MICROFLUIDIZER to obtain a 'monophasic solution,' (4) ensuring that the pH of the emulsion and/or the monophasic solution is between about 3 to about 6, a range of from about 3 to about 5, or a range of from about 3 to about 4 by adjusting the pH as necessary, (5) lyophilizing the pH adjusted solution, (6) adding a viscosity modifying agent in an amount sufficient to obtain a desired viscosity, (7) pre-filtering of the viscosity modified solution to obtain a clear solution, (8) removing some amount of the viscosity modifying agent from the clear solution to obtain a depot having from about 5.5 wt % to about 7.5 wt % of the viscosity modifying agent relative to the total weight of the depot, (9) sterilizing the depot without heating the depot. In another embodiment, pre-filtering and removing the viscosity modifying agent are optional steps. Any form of vancomycin and/or gentamicin, which is or which can be made hydrophilic may be used. In some embodiments, the pharmaceutically active agent(s) is a pharmaceutically acceptable salt of vancomycin or gentamicin. In some embodiments, the pharmaceutically active agent(s) is a mixture of a pharmaceutically acceptable salt of vancomycin and gentamicin. Depots comprising the hydrophilic form of vancomycin, gentamicin or a mixture thereof are also contemplated, whether made by this process or by some other.
"In an embodiment, the method further comprises a step of aseptically filling the viscous depot in a syringe, a vial or any other appropriate device capable of storing and/or delivering the depot to the treatment site or wound.
"In accordance with another aspect of the invention, a stabilizing agent is optionally dissolved in water along with the pharmaceutically acceptable ingredient(s). Examples of the stabilizing agent includes, but not limited to EDTA disodium, glycine, L-histidine, citric acid, mithionine, ascorbic acid, L-cysteine, alpha-tocopherol, and mixtures thereof. In yet another aspect of the invention, the depot does not include a stabilizing agent.
"In yet another embodiment, the step of homogenizing the emulsion is performed, which results in a primary emulsion, wherein the lipid/oil discontinuous phase has an average diameter of less than about 200 nm, less than about 100 nm, or less than about 80 nm.
"The reduction of average diameter of the lipid droplets is believed, without limitation, to reduce the viscosity of the resulting monophasic solution, allowing sterilization through a filter, rather than by using a heat-based sterilization system, such as by autoclaving or gamma-radiation sterilization, which can affect stability of vancomycin and/or gentamicin.
"Before the step of homogenization, the emulsion is generally a white, opaque, thick yogurt-like mass. After homogenization, the resulting monophasic solution is generally clear, translucent, and water-like in viscosity and flow properties.
"Although the present invention is not limited by any particular theory of operation, it is believed that a very hydrophilic form of vancomycin, gentamicin, or a mixture thereof, can be formulated with phospholipids to form a monophasic solution as defined herein resulting in storage stable viscous depots with desirable properties. It is believed that the extremely small lipid droplets provided during homogenization may be instrumental in the eventual properties of the depots produced, among other factors that may be involved.
"In accordance with another embodiment of the present invention, the pH of the monophasic solution is from about 3 to about 6, a range of about 3 to about 5, or a range of from about 3 to about 4 in other embodiments of the invention.
"In accordance with yet another embodiment of the present invention, the pH of the viscous depot, the final product, is from about 3 to about 6, a range of about 3 to about 5, or a range of from about 3 to about 4.
"Another aspect of the present invention provides a depot comprising at least one hydrophilic water-soluble pharmaceutically active agent(s) selected from the group consisting of a pharmaceutically acceptable salt of vancomycin, gentamicin, and a mixture thereof, water, a phospholipid, and one or more of an oil, a pH adjusting agent, and a viscosity modifying agent, wherein the water present in the depot is no more than about 4 wt %, no more than about 2 wt %, no more than at least 1 wt %, or no more than about 0.5 wt % of water relative to the total weight of the depot. In another embodiment, the depot is syringeable.
"In one embodiment of the present invention, the depot comprises a hydrophilic form of one or both vancomycin and gentamicin. In another embodiment, the depot comprises pharmaceutical salts of one or both vancomycin and gentamicin. In another embodiment, the depot comprises pharmaceutically acceptable salts of either vancomycin or gentamicin. In yet another embodiment, the depot comprises a pharmaceutical salt of either vancomycin or gentamicin.
"The depots in accordance with the present invention are, in one embodiment, 'clear.' This offers advantages in being able to see entrapped air, foreign bodies, and the like to prevent the unintended introduction of same into the body. Interestingly, it has also been discovered that when pharmaceutically acceptable salts of both vancomycin and gentamicin are present in the depot, the depot of the invention is clearer than when the depot contains a pharmaceutically acceptable salts of either vancomycin or gentamicin alone. In such embodiment where pharmaceutically acceptable salts of both vancomycin and gentamicin are present in the depot, the clarity of such depot is 'ultra clear' as defined herein. In an embodiment where the depot comprises pharmaceutically acceptable salts of either vancomycin or gentamicin, the clarity of such depot is 'translucent' or 'clear' as defined herein.
"In another embodiment, the viscosity modifying agent is ethanol, wherein the amount of ethanol present in the depot is from about 3 wt % to about 25.0 wt %, about 4 wt % to about 10 wt %, or about 5 wt % to about 6.5 wt % relative to the total weight of the composition.
"In yet another embodiment, the amount of phospholipid present in the depot is from about 5 wt % to about 95 wt %, about 25 wt % to about 75 wt %, or about 35 wt % to about 60 wt % relative to the total weight of the composition.
"In accordance with another embodiment of the present invention, the amount of oil present in the depot is from about 5 wt % to about 95 wt %, from about 25 wt % to about 75 wt %, or from about 35 wt % to about 60 wt % relative to the total weight of the composition.
"In accordance with an embodiment of the present invention, no more than about 80%, no more than about 50%, or no more than about 20% of vancomycin and/or gentamicin is released at two hours when measured in accordance with a USP method I using 500 ml of deionized water as a medium.
"In accordance with another aspect of the invention, the depot optionally comprises a stabilizing agent to improve the stability of vancomycin, gentamicin or both. Examples of the stabilizing agent include, but not limited to EDTA (ethylenediaminetetraacetic acid), disodium edetate, glycine, L-histidine, citric acid, methionine, ascorbic acid, L-cysteine, alpha-tocopherol, and mixtures thereof. In accordance with yet another aspect of the invention, the viscous depot does not contain a stabilizing agent. In still another embodiment, the amount of stabilizing agent used, if any, will not negatively impact the stability of each active, vancomycin or gentamicin, in the depot.
"In another aspect of the invention, a viscous depot is provided in an applicator, syringe, vial or any other device capable of storing and/or delivering the depot to the treatment site, depot site or wound.
"Another aspect of the present invention is a method of administering, via intradermal, intramuscular, subcutaneous, instillation or topically, the viscous depot of the invention comprising a pharmaceutically acceptable salt of vancomycin, gentamicin or a mixture thereof, water, phospholipid, an oil, a pH adjusting agent and a viscosity modifying agent
"Yet another aspect of the present invention is a method of preventing and/or treating post surgical infection by introducing a depot of the present invention.
"An aspect of the present invention is a method of preventing and/or treating a wound infection by introducing a depot of the present invention to a wound. In an embodiment of the present invention, the wound is selected from the group consisting of a surgical wound, orthopedic wound, traumatic wound, a combat wound and any combination thereof.
"In accordance with an aspect of the present invention, the surgical wound includes, but not limited, an incised wound, which is clean cut by a sharp instrument.
"In another aspect of the present invention, the orthopedic wounds include, but not limited to, injuries to the musculoskeletal system, extremities including pelvis, spine and associated structures, and any combination thereof.
"In yet another aspect of the present invention, the traumatic wounds include, but not limited to, open wounds to head, face, chest, abdomen, extremities (including pelvis), and/or external and/or injuries with torn and irregular edge with presence of foreign matter and/or non-viable tissue fragments, such as laceration, abrasions, puncture wounds, penetration wounds, and any combination thereof.
"In another aspect of the present invention, the combat wounds include, but not limited to, injuries inflicted by an explosive device and/or a weapon, gunshot wounds, any of the traumatic wounds mentioned above, and any combination thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
"FIG. 1 is a process flow diagram of an embodiment of the method of making an inventive composition in accordance with an aspect of the invention.
"FIG. 2 shows the assay recovery of vancomycin and gentamicin of the formulation of EXAMPLE 1 after the autoclave treatment.
"FIG. 3 is an in vitro release profile of gentamicin and vancomycin of the formulation of EXAMPLE 6 using USP method I.
"FIG. 4 illustrates plasma concentrations of vancomycin of the formulation of EXAMPLE 1 in rabbits.
"FIG. 5 illustrates tissue concentrations of vancomycin of the formulation of EXAMPLE 1 in rabbits.
"FIG. 6 illustrates plasma concentrations of gentamicin of the formulation of EXAMPLE 1 in rabbits.
"FIG. 7 illustrates tissue concentrations of gentamicin of the formulation of EXAMPLE 1 in rabbits.
"FIG. 8 illustrates mean vancomycin plasma concentrations in rabbits after single SC wound instillation of the formulation of EXAMPLE 6.
"FIG. 9 illustrates mean total plasma concentration of gentamicin of the formulation of EXAMPLE 6 in rabbits."
For more information, see this patent application: Chen,
Keywords for this news article include: Vancomycin, Glycopeptides, Sterilization, Infection Control,
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