WO2014062651A1

WO2014062651A1 - Stabilizer and preservative compositions and methods

Info

Publication number: WO2014062651A1
Application number: PCT/US2013/064998
Authority: WO
Inventors: Douglas D. Cary
Original assignee: Cary Douglas D
Priority date: 2012-10-18
Filing date: 2013-10-15
Publication date: 2014-04-24

Abstract

Methods for preserving and stabilizing whole blood, blood platelets and plasma for transfusion as well as preserving and stabilizing organs for transplant using a composition comprising a carrier, an anticoagulant and a viscosity-increasing agent. The composition may also be used to irrigate and coat devices prior to and during the surgical implantation into the body.

Description

STABILIZER AND PRESERVATIVE COMPOSITIONS AND METHODS

Field of the Invention

The present invention relates to method of preserving and stabilizing whole blood, blood platelets and plasma for transfusion as well as preserving and stabilizing organs for transplant using a composition comprising a carrier, an anticoagulant and a viscosity-increasing agent. The composition may also be used to irrigate and coat devices, such as pacemakers or artificial joints, prior to and during the surgical implantation into the body. Description of the Related Art

Blood transfusions and organ transplants are important and increasingly common medical procedures performed in medical practice. However, as demand for such procedures increase, the supply cannot similarly be increased to meet demand due to long-term storage problems for blood, platelets, plasma and organs. Specifically, long-term storage can result in degradation and damage to red blood cells, platelets, plasma and organs. Moreover, because blood platelets must be stored at room temperature to remain effective, elongated storage periods result in bacteria growth, thus presenting the greatest infection risk in the United States blood supply. The result is that attempts to increase supply have usually been accompanied by increased discard rates due to degradation or bacterial growth.

Accordingly, a continuing and unmet need exists for new and improved preservation and stabilizing compositions for whole blood, blood platelets and plasma for transfusion as well as organs for transplant.

It is an object of the present invention to provide for a method of preserving and stabilizing whole blood for transfusion during storage or transport using a composition comprising a carrier, an anticoagulant and a viscosity-increasing agent.

It is an additional object of the present invention to provide for a method of preserving and stabilizing blood platelets for transfusion during storage or transport using a composition comprising a carrier, an anticoagulant and a viscosity-increasing agent.

It is also an object of the present invention to provide for a method of preserving and stabilizing plasma for transfusion during storage or transport using a composition comprising a carrier, an anticoagulant and a viscosity-increasing agent. It is a further object of the present invention to provide for a method of preserving and stabilizing organs for transplant during storage or transport using a composition comprising a carrier, an anticoagulant and a viscosity-increasing agent.

It is also an object of the present invention to provide a composition for preserving and stabilizing whole blood, blood platelets and plasma for transfusion as well as organs for transplant that exhibits antimicrobial properties.

It is a still further object of the present invention to provide a composition which provides nutritional support to whole blood, blood platelets and plasma for transfusion as well as organs for transplant during storage or transport.

It is additionally an object of the present invention to provide a composition which can be used to coat a device implantable into a mammalian body, such as an artificial joint, catheter, pacemaker and the like, to impart lubricity to the device and prevent contamination and bacterial growth.

It is also an object of the present invention to provide a composition for coating a device implantable into a mammalian body that exhibits antimicrobial properties.

Summary of the Invention

The above objectives and others are obtained by the present invention which is a method for preserving and stabilizing whole blood, blood platelets and plasma for transfusion as well as organs, including heart, eye, lung, kidney, for transplant during storage and transport using a composition comprising a carrier, a viscosity increasing agent and an anticoagulant. The present invention also includes a method of irrigating and coating devices, such as pacemakers or artificial joints, prior to and during the surgical implantation into the body using a composition comprising a carrier, a viscosity increasing agent and an anticoagulant.

In one embodiment of the present invention the composition comprises a carrier, such as water, in an amount of about 25% to about 70%, preferably about 40% to about 60% and most preferably about 45% to about 55%, a viscosity-increasing agent, such as glycerol, in an amount of about 5%) to about 60%, preferably about 15% to about 50% and most preferably about 25% to about 40%, and an anticoagulant in an amount of about 2% to about 20%, preferably about 2% to about 8% and most preferably about 3% to about 6%, wherein the anticoagulant is not heparin and the composition is free of alcohols. The foregoing percentages are given as weight by volume.

In a further embodiment of the present invention the composition comprises an aqueous solution comprising about 2% to about 20%, preferably about 2% to about 8% and most preferably about 3% to about 6%, of a citrate and about 25% to about 70%, preferably about 35%) to about 60%> and most preferably about 40%> to about 55% of glycerol.

In embodiments of the present invention, the composition may further comprise citric acid, dextrose, adenosine and sodium biphosphate.

A further embodiment of the present invention described herein is a blood-compatible, anticoagulant composition consisting essentially of water, about 2% to about 6%, preferably about 3% to about 5%, of a citrate and about 5% to about 60%, preferably about 40% to about 55%, of glycerol. This embodiment is preferably free of heparin and alcoholic compounds, especially CI to C12 alcohols. This embodiment may be prepared by dissolving the sodium citrate and citric acid in water and then adding glycerol. This embodiment may be sterilized after preparation.

A still further embodiment of the present invention includes a method for manufacturing the compositions comprising the steps of combining the viscosity increasing agent with an aqueous mixture of the citrate. The pH of the combination may be adjusted by the addition of pharmaceutically acceptable acids or bases until a range of about 5.8 to about 6.8, preferably about 6.0 to about 6.5, is obtained. A preferred pH adjusting agent is citric acid.

In an embodiment of the present invention, the composition is added to bags for collecting, storing and/or transporting whole blood, blood platelets or plasma before, during or after the whole blood, blood platelets or plasma is collected in the bag. In another embodiment of the present invention the composition is added to a receptacle for storing and/or transporting an organ for transplant, such as coolers, bags, boxes, trays and the like, before, during or after the organ is placed in the receptacle.

In embodiments where the composition is used in bags for collecting whole blood, blood platelets or plasma, the composition is used in a ratio of 1 : 10 to 3 : 10 composition to blood, blood platelets or plasma.

In embodiments where the composition is in receptacles for organs for transplant, 10 ml to 1000 ml of the composition of the present invention should be used. An additional embodiment of the present invention includes a method for imparting lubricity to a device implantable into a mammalian body, such as an artificial joint, catheter or pacemaker, by coating or irrigating the device with the composition of the present invention prior to or during implantation into the body.

A further embodiment of the present invention includes a method for preventing contamination and bacterial growth during and after the implantation of a device, such as an artificial joint, catheter or pacemaker, into a mammalian body by coating or irrigating the device with the composition of the present invention prior to or during implantation into the body.

In another embodiment of the present invention is a method for coating or irrigating a device for implantation into a mammalian body with a composition in accordance with the present invention that exhibits antimicrobial properties.

Additional features may be understood by referring to the following detailed description.

Detailed Description of the Invention

The present invention is a method of preserving, stabilizing and preventing antimicrobial growth in whole blood, blood platelets and plasma for transfusion as well as organs for transplant by adding an amount of a composition comprising a carrier, an anticoagulant and a viscosity- increasing agent to a blood collection bag or organ receptacle. The present invention also includes a method of irrigating and coating devices implantable into a mammalian body prior to and/or during the surgical implantation into the body using a composition comprising a carrier, a viscosity increasing agent and an anticoagulant.

The composition of the present invention may also contain additional agents including citric acid, dextrose, adenosine and sodium biphosphate.

The water that may be used for preparing the compositions of the present invention can be any type of water, such as distilled water commonly used to prepare pharmaceutical preparations (some of which are described in the United States Pharmacopeia) and include, but are not limited to, water for injection, sterile water for inhalation, sterile water for injection, sterile water for irrigation, purified water and sterile purified water.

The viscosity-increasing agents useful in the compositions of the present invention include, but are not limited to, glycerol, protein-based colloidal substances, dextrose, dextran and combinations of the forgoing. The preferred viscosity-increasing agent is glycerol. If glycerol is employed as the viscosity-increasing agent, it is believed that the glycerol will impart antibacterial properties to the compositions and thereby reduce the incidence of microbial growth in the whole blood, blood platelets and organs. The viscosity-increasing agent should be present in the composition in an amount from about 5% to about 60%, preferably about 15% to about 50%) and most preferably about 25% to about 40%>, weight to volume of carrier.

The anticoagulant useful in the compositions of the present invention is any anticoagulant commonly known in the pharmaceutical arts such as riboflavin, citrates,

ethylenediaminetetraacetic acid, warfarin or combinations of the foregoing. It is preferred that the anticoagulant not be heparin or any animal derivative or byproduct. In a preferred embodiment of the composition of the present invention, the anticoagulant is a citrate such as an ester of citric acid, i.e., triethyl citrate, or a citrate salt such as sodium citrate or other

pharmaceutically acceptable salt. The anticoagulant should be present in the composition in an amount from about 2% to about 20%, preferably about 2% to about 8% and most preferably about 3% to about 6%, weight of anticoagulant to volume of carrier.

In one embodiment of the present invention, the viscosity of the composition at room temperature should be about 2 mPa^»s to about 10 mPa^»s, preferably about 3 mPa^»s to about 9 mPa^»s and most preferably about 4 mPa^»s to about 7 mPa^»s. The viscosity can be measured by any means commonly known in the pharmaceutical arts including but not limited to the use of commercially available equipment such as an Ostwald Viscometer, an Hoeppler Viscometer, or a Brookfield Viscometer. A more detailed discussion of methods and apparatus for determining the composition's viscosity can be found in Chapter 17 of Physical Pharmacy, 4th ed., by Alfred Martin.

The density of the composition should be greater than the density of blood. For example, human blood is known to range (depending upon the temperature and age of the patient) from about 1.02 g/ml to about 1.1 g/ml. Therefore, the composition of the present invention should exhibit a density greater than 1.1 g/ml, preferably greater than about 1.12 g/ml and most preferably greater than 1.13 g/ml. The density can be measured by any means commonly known in the pharmaceutical arts. Some acceptable methods for measuring the density of the composition are described in United States Patent No. 4,929,242 and on pages 443-446 of Physical Pharmacy, 4th ed., by Alfred Martin. Embodiments of the present invention employ a composition with a density of 1.1 g/ml to about 3.0 g/ml, preferably 1.1 g/ml to about 2.5 g/ml and most preferably 1.1 g/ml to 2.0 g/ml.

The pH of the composition should be in the range of about 5.5 to about 8, preferably about 5.8 to about 7.5 and most preferably about 6.0 to about 7.0. The pH of the composition may be adjusted to the desired level once the appropriate density and viscosity are obtained. The pH may be adjusted by any means commonly known in the pharmaceutical arts such as the addition of a pharmaceutically acceptable acid or base to the composition. In a preferred embodiment, citric acid is added to the composition to adjust the pH to an appropriate level. The composition may also optionally employ a buffering agent to assist in controlling and

maintaining the desired pH of the composition. The selection of an appropriate buffering agent is within the skill of the ordinary artisan.

The composition should be an isotonic composition, a hypertonic composition or a hyperosmotic composition with respect to the subject's blood. The tonicity may also be referred to as a measurement of the osmolality of the composition. Tonicity or osmolality describes the concentration of solutes in a given solution. An isotonic composition exhibits a tonicity essentially equal to the tonicity of a subject's plasma. When employed in a normally hydrated subject, an isotonic composition does not cause a significant shift of water between the subject's blood vessels and cells. A hypertonic composition exhibits a tonicity higher than the tonicity of a subject's plasma. When employed in a normally hydrated subject, a hypertonic composition causes a shift of water toward the hypertonic composition in an effort to equilibrate the solute concentration. Methods for determining the tonicity or osmolality of the composition are described in United States Patent No. 4,929,242 and on pages 137-140 of Physical Pharmacy, 4th ed., by Alfred Martin. An additional discussion can be found in the paper presented by Marc Stranz at the May 2005 INS Annual Conference entitled "The Implications of Osmolality, Osmolality and pH in Infusion Therapy."

In one embodiment of the present invention, the osmolality of the composition should be greater than the osmolality of human blood. The osmolality of human blood has been reported to range from 275 mOsm/L to 299 mOsm/L. Manuel Zarandona, "Case 422 -Neuropathology Case", http://path.upmc.edu/cases/case422.html. In this embodiment, the osmolality of the composition should be greater than 300 mOsm/L, preferably greater than 320 mOsm/L, and more preferably greater than about 350 mOsm/L. Some embodiments of the composition exhibit an osmolarity between 4,000 mOsm/L and 6,500 mOsm/L, preferably between 4,500 mOsm/L and 6,250 mOsm/L and most preferably between 5,000 mOsm/L and 6,000 mOsm/L.

The composition in accordance with the present invention should be stable to changes in pH and osmolality during long term storage. The composition should also be resistant to bacterial and microbial growth during long term storage. For example, the composition in accordance with the present invention should exhibit less than a 1.0 unit change of pH, preferably less than a 0.5 unit change in the pH, after storage at 25°C and 60% relative humidity for at least six (6) months, preferably one (1) year, when the composition is stored in an appropriate container such as a sterile and sealed syringe or a glass vial. Alternatively, the composition in accordance with the present invention should exhibit less than a 1.0 unit change of pH, preferably less than a 0.5 unit change in the pH, after storage at 40°C and 75% relative humidity for at least one (1) month, preferably three (3) months, when the composition is stored in an appropriate container such as a sterile and sealed syringe or a glass vial.

The composition in accordance with the present invention should also be sterile and thereby prevent the growth of bacteria and microbes upon storage and, more importantly, during use. An appropriate test for determining if the composition is sterile is described in test <71> of the USP 25.

One embodiment of the composition of the present invention incorporates high amounts of glycerol which impart antimicrobial and antibacterial properties to the composition and thereby avoids the need for the use of additional or separate antimicrobial agents such as alcohols. The antimicrobial and antibacterial properties of glycerol also help to reduce the incidence of microbial growth in the blood, blood platelets or organs. Another embodiment of the present invention allows the composition to undergo a sterilization step after it is prepared and, more preferably, after it is packaged for use.

It is also contemplated that devices for implantation into the body can be pre-packaged in an amount of composition of the present invention or coated with the composition of the present invention prior to being packaged.

The present invention, including the proposed citrate-glycerol embodiments, solves longstanding art-recognized problems associated with the long-term storage of whole blood, blood platelets and plasma for transfusion as well as organs for transplant. In particular, the proposed invention will provide a nutritional source, and serve as an anticoagulant in addition to having antimicrobial activity to thereby aid in the preservation and stabilization of whole blood, blood platelets and plasma for transfusion as well as and organs for transplant. In addition, it has been unexpectedly discovered that the combination of a citrate and glycerol results in a synergistic effect that produces compositions with enhanced antimicrobial properties.

Claims

1. A method of preserving or stabilizing whole blood and blood platelets for transfusion during storage or transport comprising the step of adding a composition comprising a) a carrier; b) about 5% to about 60% w/v of a viscosity-increasing agent; and c) 2% to 20% w/v of an anticoagulant to a whole blood or blood platelet collection bag that contains, or will contain, whole blood or blood platelets.

2. The method of claim 1 wherein the carrier is water, the viscosity-increasing agent is glycerol and the anticoagulant is a citrate.

3. The method of claim 2 wherein the anticoagulant is sodium citrate.

4. A method of preserving or stabilizing an organ for transplant during storage or transport comprising the step of adding a composition comprising a) a carrier; b) about 5% to about 60%> w/v of a viscosity-increasing agent; and c) 2% to 20% w/v of an anticoagulant to a receptacle that contains, or will contain, the organ for transplant.

5. The method of claim 4 wherein the carrier is water, the viscosity-increasing agent is glycerol and the anticoagulant is a citrate.

6. The method of claim 5 wherein the anticoagulant is sodium citrate.

7. A method of preventing microbial growth in whole blood, blood platelets or plasma for transfusion during storage or transport comprising the step of adding a composition comprising a) a carrier; b) about 5% to about 60%> w/v of a viscosity-increasing agent; and c) 2% to 20%> w/v of an anticoagulant to a whole blood, blood platelet or plasma collection bag that contains, or will contain, whole blood, blood platelets or plasma.

8. A method of preventing microbial growth in an organ for transplant during storage or transport comprising the step of adding a composition comprising a) a carrier; b) about 5% to about 60% w/v of a viscosity-increasing agent; and c) 2% to 20%> w/v of an anticoagulant to a receptacle that contains, or will contain, the organ for transplant.

9. A method of preventing microbial growth on or in a device implantable into a body comprising the step of coating or irrigating the device with a composition comprising a) a carrier; b) about 5% to about 60%> w/v of a viscosity-increasing agent; and c) 2% to 20%> w/v of an anticoagulant prior to or during surgical implantation of the device into the body.