Patent Application
20080015480
The following definitions of agents and other terms apply herein. Those of skill in the art will appreciate that the definitions are intended to illustrate the use of the terms, but not to limit the invention. In general, the agent definitions embrace the agent's primary purpose, although it will be appreciated that the agent may produce secondary effects.
Hemostasis: stoppage of bleeding or hemorrhage.
Hemostat or hemostatic agent: a substance that substantially stops bleeding or hemorrhage.
Topical: placement on an exterior body surface.
Antiseptic or antiseptic agent: inhibits growth or reproduction of bacteria.
Sanitizer or sanitizing agent: cleans but does not necessarily sterilize.
Disinfectant or disinfecting agent: destroys, neutralizes or inhibits growth of disease-carrying organisms such as microbes.
Antibacterial or antibacterial agent: inhibits bacterial growth.
Antibiotic or antibiotic agent: a microorganism that destroys or inhibits the growth of other microorganisms.
Bactericide or bactericidal agent: kills some or all bacteria.
Astringent or astringent agent: causes non-selective tissue shrinkage.
Sterilizer or sterilizing agent: kills a very high proportion of or all bacteria.
Microbicide or microbicidal agent: kills some or all microbes.
Solid: a phase or condition that is neither gas nor liquid nor semi-liquid; characterized as being of a fixed morphology or shape incapable of flowing despite outside action; can assume a dry powder form.
Liquid or semi-liquid: a phase or condition between solid and gas; characterized as being capable at least of very slowly changing shape and being capable at most of freely flowing without outside action; amorphous.
Gel: a jelly-like substance which can be formed as a viscoelastic substance formed from coagulation of a colloidal liquid. A semi-liquid.
Evaporative gel: a gel that substantially evaporates, leaving behind some or no residue, within a defined and relatively short, period of time.
Gelling agent: assists in forming a gel.
Evaporative gelling agent: a gelling agent that assists in forming an evaporative gel.
Evaporative agent: an agent that substantially evaporates within a relatively short period of time.
Skin penetration enhancer or transdermal migration-enhancing agent: substance that enables or facilitates other substances to move through the skin.
Defined ratio: a ratio involving non-zero, i.e. at least trace, amounts of each of two or more combined constituents. A ratio that is not arbitrary.
Thus, alcohol is an example of a sanitizer with bactericidal properties; vasoconstrictors and procoagulants are examples of hemostats or hemostatic agents; betadine and chlorhexidine are examples of microbicides; Purell™ is an example of an evaporative gel. Water, isopropyl myristate, glycols and solvents including alcohols are examples of a skin penetration enhancer or transdermal migration-enhancing agent. Carbomer™ 940, an acrylic acid polymer, is an example of a gelling agent, as are members of the Carbopol™ family of rheology modifiers.
Catecholamines include epinephrine and norepinephrine. Drugs having sympathomimetic properties, including that of vasoconstriction, include phenylephrine, oxymetazoline and pseudoephedrine, and may be referred to herein as vasoconstrictors. Hematologic substances that trigger or are a part of the clotting cascade (described above) that leads to formation of a clot include fibrinogen, prothrombin, clotting “factors” (e.g. factor VIII), platelets, fibrin and thrombin. Other substances that can initiate or assist in the clotting cascade include cotton, collagen and tannic acid, as well as chitosan and acetylglucosamines (specifically including poly-.beta.-1.fwdarw.4-N-acetylglucosamine polysaccharide species—see U.S. Pat. No. 6,630,459), and, finally, minerals including zeolite, and starches derived from potato. For purposes of the present invention, such foregoing substances may include compounds thereof, in solid, liquid or semi-liquid form.
Hematologic substances and other substances that can initiate or assist in the clotting cascade may be referred to herein as procoagulants.
The invention in accordance with various preferred embodiments involves providing a liquid or semi-liquid topically-applicable compound containing a vasoconstrictor and/or a procoagulant, an evaporative gel or transdermal migration-enhancer and, optionally, one or more additional components. A vasoconstrictor or procoagulant applied at the external skin surface migrates transdermally by action of the migration-enhancer, to a subdermal wound site where it promotes blood clotting therein through vasoconstrictive and/or procoagulative action around traumatized (e.g. pierced, torn, vivisected, ruptured or otherwise opened or ulcerated) blood vessels.
A preferred embodiment of the present invention may include its formulation as an evaporative gel, whereby on application, by rubbing onto a body surface, much or substantially all of the volume of the gel evaporates within a short period of time from onset of application, leaving behind either some or no residue. The gel is a delivery mechanism for the active agent, whether vasoconstrictor, procoagulant or both; once the evaporative agent has substantially evaporated the active agents remain either on the skin surface or migrate through the surface and/or injury to the subdermal injury site. In a test series of embodiments of the present invention a one milliliter amount of the invented compound evaporated when rubbed onto skin in less than 60 seconds from commencement of application. Generally, the preferred embodiments have an evaporation time of between 10 seconds and 300 seconds in one milliliter amounts.
Depending upon the constituents of a specific embodiment it may be expected that some proportion of the volume of the compound might remain following evaporation. For example, where a generally non-soluble solid is included in the formulation, it is expected that the volume of the post-evaporation residue will be approximately equal to the volume of such non-soluble solids.
Examples of gelling agents used in an evaporative gel include high molecular weight cross-linked polymers of acrylic acid, such as members of the family of rheology modifiers known under the trade name Carbopol™. More particularly, a substance commercially known as Carbomer™ 940, can be used. For purposes specific to this embodiment of the present invention, Carbomer™ 940 would be mixed directly into an evaporative agent, for example, an alcohol, more particularly ethanol at a strength of 195 proof, instead of into water, to create the evaporative gel. The other substances required or desired for the compound also can be mixed into the gel formulation. The rapid evaporation of the gel is caused by the large volume proportion of an alcohol or other evaporative agent contained therein.
Tests of an early version of the present invention indicated a need for a viscosity, or resistance to flow, greater than experienced with most liquids and gels, specifically those gels having sanitizer properties, for example the gel sold under the PURELL® brand. A common metric of viscosity is the centipoise (equal to one millipascal second), where, at room temperature, i.e. approximately 70 degrees Fahrenheit (70° F.), water has a viscosity of one centipoise, blood might have a viscosity of approximately 10 centipoise, molasses might have a viscosity of approximately 5,000 centipoise, tomato paste might have a value of approximately 150,000 centipoise, and so on.
A problem identified with a compound having a low viscosity, for example generally between one and 100 centipoise, is that the components in the compound will quickly spread over an area larger than the target area of application because of its tendency to flow freely, resulting in a lower-than-desired density of the compound remaining on the target area for a shorter-than-desired period of time. As viscosity increases, the compound flows less freely, thereby permitting the compound to remain on the target area in sufficient density for a longer period of time. Subsequent testing of an embodiment has shown a compound having a viscosity of greater than approximately 25,000 centipoise but less than approximately 250,000 centipoise to have desirable viscosity characteristics. The viscosity of the compound can be adjusted by varying the proportion of gelling agent and/or liquids or semi-liquids used.
These viscosity parameters, as well as other parameters set forth herein, are illustrative and are not intended to limit the claims unless the claims themselves are expressly so limited.
The following examples of preferred embodiments are generally for topical application to a patient following a cannulation procedure, more particularly a femoral catheterization procedure at the time the cannula is withdrawn from the patient's femoral artery. The amount of the hemostatic compound, including an evaporative gel or migration-enhancing agent (and other optionally added components), to be applied is between approximately 0.1 milliliters and approximately 10 milliliters, more particularly in the range of approximately 0.25 milliliters and approximately 3.0 milliliters.
A hemostatic compound includes the following substances: a vasoconstrictor, a sanitizer, a gelling agent, and a transdermal-enhancing agent. More particularly, this compound includes: epinephrine in a concentration by volume of between approximately 0.1% and approximately 40%, or more particularly between approximately 5% and approximately 20%; ethanol in a concentration by volume of between approximately 20% and approximately 90%, or more particularly between approximately 40% and approximately 80%; Carbomer™ 940 in a concentration by volume of between approximately 0.1% and approximately 5%, or more particularly between approximately 0.25% and approximately 1.0%; isopropyl myristate in a concentration by volume of between approximately 1% and approximately 15%, or more particularly between approximately 3% and approximately 10%.
A hemostatic compound includes the following substances: a vasoconstrictor, a sanitizer, a gelling agent, and a transdermal-enhancing agent. This compound further includes, in addition to those substances described in Example 1 herein, a disinfectant having a microbicidal property which persists as a microbicidally effective residue following its application. More particularly, the compound of Example 1 further includes chlorhexidine gluconate in a concentration of between approximately 0.5% and approximately 20%, or more particularly between approximately 1% and approximately 5%.
A hemostatic compound includes the following substances: a procoagulant, a sanitizer, a gelling agent, and a transdermal-enhancing agent. More particularly, this compound includes: chitosan in a concentration by volume of between approximately 2% and approximately 50%, or more particularly between approximately 10% and approximately 40%; ethanol in a concentration by volume of between approximately 20% and approximately 90%, or more particularly between approximately 40% and approximately 80%; Carbomer™ 940 in a concentration by volume of between approximately 0.1% and approximately 5%, or more particularly between approximately 0.25% and approximately 1.0%; isopropyl myristate in a concentration by volume of between approximately 1% and approximately 15%, or more particularly between approximately 3% and approximately 10%.
Other examples and embodiments of the invention are contemplated and are within the spirit and scope of the invention. For example, phenylephrine or oxymetazoline can be selected as alternative vasoconstrictors in Examples 1 and 2. Thrombin can be selected as an alternative procoagulant in the compound of Example 3, as can an acetylglucosamine polysaccharide or a starch derived from potato. The foregoing examples and embodiments thus are not intended to be exhaustive, rather they are meant to be illustrative.
A series of tests of several versions of the present invention were conducted to determine safety, composition, and hemostatic efficacy. All tests were performed with informed consent on healthy males between the ages of 50 and 60, who were also anti-coagulated using aspirin, herbal preparations, Plavix or a combination of these anti-coagulants. (Those of skill in the art will appreciate that the anti-coagulants were used to promote bleeding to facilitate observation and recordation of the bleeding inhibition effect, if any, of the invented compound.)
Because systemic application of epinephrine can potentially have profound effects including bronchial smooth muscle relaxation, cardiac stimulation, vasodilation in skeletal muscle, stimulation of glycogenolysis in the liver and so on, the first safety test involved topical application of one-half milliliter of a 10% epinephrine solution to the subject's unbroken skin to determine if any respiratory or hemodynamic symptoms followed. No symptoms were detected. A second safety test was conducted using an alcohol-epinephrine solution, wherein two milliliters were topically applied to each of two subjects' unbroken skin, while monitoring electrocardiogram and blood pressure. No abnormal signs or symptoms were detected. It was during this series of tests that a requirement for a higher viscosity was detected.
Subsequent series of tests were performed to determine hemostatic efficacy of an alcohol gel in which various concentrations of epinephrine were applied to the volar aspects of the test subjects' forearms in the areas of small bleeding punctures and comparing the bleeding times with similar applications of an alcohol gel without epinephrine. Presence or absence of bleeding was determined at 30-second intervals following the puncture by blotting the puncture with white tissue and visually observing whether blood was present. The gels were applied 30 seconds after each puncture. A first series showed that epinephrine concentrations of substantially less than 4% were inadequate to conclusively demonstrate a significant decrease in bleeding time.
A second series of similar tests of the invented compound was conducted, but with a version having an epinephrine concentration of approximately 5%, where the first application to a puncture used a gel without epinephrine; this was followed by a second application to a separate puncture using a gel containing an approximately 5% epinephrine concentration. Bleeding times for the gel without epinephrine averaged approximately 270 seconds. Bleeding times for the gel containing epinephrine averaged approximately 120 seconds for a bleeding time reduction of approximately 56%. Subsequent observations of the puncture sites revealed no unusual sequelae or re-bleeds.
Similar clotting time improvements were observed in a test series employing granulated chitosan suspended in an alcohol gel, wherein the chitosan comprised approximately 30% by volume of the gel formulation.
In accordance with one embodiment of the invention, the compression steps are manual and are unassisted by a compression device. In accordance with another embodiment of the invention, compression is manual and is assisted by use of a compression device such as that shown in
Assisted manual compression can be enhanced by the use of the patented and/or patent-pending Compressar® or Compass™ products mentioned above. Such are available from Advanced Vascular Dynamics of Portland, Oreg., USA.
Other steps not shown can also be performed, in accordance with the invented method, or the same steps can be performed somewhat differently or with somewhat different timing, so long as they accomplish the intended purpose, which is to inhibit bleeding at a wound site produced by cannulation.
The modality of the bleeding inhibition thus involves enabling a hemostatic agent that is applied topically to the exterior surface of a mammal's skin nevertheless to migrate effectively inwardly therefrom across the substantial barriers produced by the stratum corneum to underlying tissue.
After application of the invented compound illustrated in
Those of skill will appreciate that use of the invented compound is not limited to hospital or clinical settings, or to any particular medical procedure, e.g. cannulation. Indeed, the invented compound finds broad utility in field and home uses such as so-called ‘first aid’ treatment following minor or serious accidental injury such as puncture, incision or abrasion that might occur at home, in the workplace or anywhere. Such first aid or emergency uses and their efficacy in bleeding stoppage are illustrated above in relation to the described experimental test results. Thus, many uses of the invented compound, as well as alternative methods of its use, are contemplated as being within the spirit and scope of the invention.
It will be understood that the present invention is not limited to the method or detail of construction, fabrication, material, application or use described and illustrated herein. Indeed, any suitable variation of fabrication, use, or application is contemplated as an alternative embodiment, and thus is within the spirit and scope, of the invention.
From the foregoing, those of skill in the art will appreciate that several advantages of the present invention include the following.
The present invention provides an inexpensive, non-invasive, quick and relatively clean mechanism to stop bleeding at a puncture, incision, abrasion or other wound site. The invented compound is applied topically, i.e. to the external surface of the skin, but because of its unique components it is effective to promote hemostasis where needed beneath the skin's surface by delivering a hemostatic agent to the tissue underlying the stratum corneum. The delivery is enabled and/or facilitated by a transdermal migration-enhancing agent and via migration down the cannulation track.
The compound can have any or all added agents, including an astringent agent, a sanitizing agent, a sterilizing agent, an analgesic agent, a skin permeability agent, an antibiotic agent, a skin adhesive agent, an evaporative agent, an aloe agent, a tocopherol agent, a fragrance agent and a cosmetic agent. The compound can be applied with any suitable applicator, e.g. a swab or tissue, or without such applicator, for example, by using a squeeze tube or bottle. The compound finds particular utility in connection with catheterizations that are performed in hospital settings or in the event of accidental punctures, incisions and abrasions that can occur anywhere.
Analgesic agents reduce pain. Skin adhesive agents, e.g. liquid suture materials or other gluey substances, promote skin adherence and wound closure. Aloe agents promote healing. Tocopherol agents such as vitamin E promote skin regeneration. Fragrance agents provide more pleasing bouquets. Cosmetic agents such as foundations, bronzers, blot powders, blushers, cover-ups, etc. cover bruises, blemishes or other visible skin trauma.
Advantages of the invention include the ability to easily and non-invasively apply a hemostatic and evaporative gel or transdermal migration-enhancing or sanitizing agent, optionally with a microbicidal and other agents as described herein, to help stop bleeding and prevent infection at a wound site. The ability to apply an otherwise liquid, hard-to-control substance, in the form of an easy-to-control substance which substantially evaporates after application, results in a convenience benefit and targeted-site-application benefit. The ability to apply all of said substances at once, to save time, is a great advantage. Unintended and/or undesirable systemic effects nevertheless are avoided, thus rendering the compound's use safe even for vulnerable patients, i.e. patients with pre-existing conditions such as dysrhythmias.
It is further intended that any other embodiments of the present invention that result from any changes in application or method of use or operation, method of manufacture, shape, size, or material which are not specified within the detailed written description or illustrations contained herein yet are considered apparent or obvious to one skilled in the art are within the scope of the present invention.
Accordingly, while the present invention has been shown and described with reference to the foregoing embodiments of the invented compound and its use, it will be apparent to those skilled in the art that other changes in form and detail may be made therein without departing from the spirit and scope of the invention as defined in the appended claims.
This application is a Divisional of U.S. patent application Ser. No. 11/486,780, entitled HEMOSTATIC COMPOUND AND ITS USE, filed 14 Jul. 2006, the disclosure of which is herein incorporated by reference in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| Parent | 11486780 | Jul 2006 | US |
| Child | 11704453 | US |
