US2642375A - Hemostatic compositions - Google Patents
Hemostatic compositions Download PDFInfo
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- US2642375A US2642375A US242992A US24299251A US2642375A US 2642375 A US2642375 A US 2642375A US 242992 A US242992 A US 242992A US 24299251 A US24299251 A US 24299251A US 2642375 A US2642375 A US 2642375A
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- hemostatic
- oxidized cellulose
- ethylene glycol
- polymerized ethylene
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- 239000000203 mixture Substances 0.000 title claims description 29
- 230000002439 hemostatic effect Effects 0.000 title claims description 27
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 79
- 229920002201 Oxidized cellulose Polymers 0.000 claims description 33
- 229940107304 oxidized cellulose Drugs 0.000 claims description 33
- 208000032843 Hemorrhage Diseases 0.000 claims description 19
- 229940030225 antihemorrhagics Drugs 0.000 claims description 15
- 239000002874 hemostatic agent Substances 0.000 claims description 15
- 210000000988 bone and bone Anatomy 0.000 description 22
- 239000001993 wax Substances 0.000 description 14
- 239000000126 substance Substances 0.000 description 12
- 239000008280 blood Substances 0.000 description 11
- 210000004369 blood Anatomy 0.000 description 11
- 210000001519 tissue Anatomy 0.000 description 10
- 230000000740 bleeding effect Effects 0.000 description 9
- 210000004872 soft tissue Anatomy 0.000 description 9
- 108090000190 Thrombin Proteins 0.000 description 7
- 210000004204 blood vessel Anatomy 0.000 description 7
- 239000002245 particle Substances 0.000 description 7
- 229960004072 thrombin Drugs 0.000 description 7
- 239000004615 ingredient Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 108010010803 Gelatin Proteins 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 108010019393 Fibrin Foam Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000000783 alginic acid Substances 0.000 description 3
- 235000010443 alginic acid Nutrition 0.000 description 3
- 229920000615 alginic acid Polymers 0.000 description 3
- 229960001126 alginic acid Drugs 0.000 description 3
- 150000004781 alginic acids Chemical class 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 239000000470 constituent Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- MGWGWNFMUOTEHG-UHFFFAOYSA-N 4-(3,5-dimethylphenyl)-1,3-thiazol-2-amine Chemical compound CC1=CC(C)=CC(C=2N=C(N)SC=2)=C1 MGWGWNFMUOTEHG-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 206010053567 Coagulopathies Diseases 0.000 description 2
- 229920000742 Cotton Polymers 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000001124 body fluid Anatomy 0.000 description 2
- 239000010839 body fluid Substances 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000035602 clotting Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 230000035876 healing Effects 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- JCXJVPUVTGWSNB-UHFFFAOYSA-N nitrogen dioxide Inorganic materials O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 241000257303 Hymenoptera Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229920002230 Pectic acid Polymers 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 206010051297 Soft tissue haemorrhage Diseases 0.000 description 1
- 239000004902 Softening Agent Substances 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000012790 adhesive layer Substances 0.000 description 1
- -1 aliphatic glycols Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical class CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 150000002605 large molecules Chemical class 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- LCLHHZYHLXDRQG-ZNKJPWOQSA-N pectic acid Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)O[C@H](C(O)=O)[C@@H]1OC1[C@H](O)[C@@H](O)[C@@H](OC2[C@@H]([C@@H](O)[C@@H](O)[C@H](O2)C(O)=O)O)[C@@H](C(O)=O)O1 LCLHHZYHLXDRQG-ZNKJPWOQSA-N 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000006069 physical mixture Substances 0.000 description 1
- 239000010318 polygalacturonic acid Substances 0.000 description 1
- 229920000151 polyglycol Polymers 0.000 description 1
- 239000010695 polyglycol Substances 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000003625 skull Anatomy 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000003699 striated muscle Anatomy 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000004753 textile Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
- A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
- A61L15/26—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
- A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
- A61L15/28—Polysaccharides or their derivatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/04—Materials for stopping bleeding
Definitions
- This invention relates to new and improved hemostatic compositions and specifically relates to such compositions that are absorbable in body fluids by physiologic processes.
- thrombin in a highly potent, purified, water-soluble form has been used as a hemostatic spray as well as in conjunction with human fibrin foam, but thrombin is unstable in aqueous solution and cannot be heat sterilized in an autoclave without destroying its activity as a hemostatic substance. Fi-brinogen in conjunction with thrombin has also been found useful in the formation of an adhesive layer to seal together cut surfaces of soft tissues, notably a skin graft on a prepared bed. More recently an absorbable substance in the form of a sponge has been used and is prepared from a specially prepared gelatin solution which is further processed and sterilized.
- gelatin sponge when dry is a light, off-white
- This absorbable gelatin sponge is normally used in conjunction with a thrombin solution.
- the gelatin sponge mixed with the thrombin solution is used by applying it to a bleeding area where it quicklyimbibes blood which clots as it comes in contact with thrombin. Physiological absorption of the sponge takes place in from 15 to 20 days.
- oxidized cellulose Another recent absorbable substance which has found acceptance by the medical profession as a hemostatic agent is oxidized cellulose. It was found that oxidized cellulose in the form of cotton, paper, gauze, or a non-woven mass had hemostatic properties, and its use as a'hemostatic agent has been widely studied in a variety of animal and human tissues. The material was demonstrated to be non-irritating and to disappear in the tissue leaving a minimum of scar;
- Bone waxes in common use today are, prepared from refined waxes of bees which have been admixed with other non-absorbable and water-insoluble hydrocarbons or vegetable oils.
- Bone Wax has been used for the purpose of controlling hemorrhages from the 'cut surfaces of bones, such as those-of the skull, by forcibly smearing the wax over the cut surface so that the material actsmechanically to occlude and seal the open ends of bleeding osseous vessels and sinuses.
- Such compositions have no specific hemostatic effect per se and quite often result in delayed'healing because of their non-absorbable properties.
- Nonabsorbable bone Waxes since they are left in the wound as a foreign body, frequently constitute a troublesome barrier to subsequent osseous union.
- Another disadvantage of non-absorbable bone wax is the danger of particles of the wax falling ofi the bone edge and lodging in the surrounding tissue Where they provide a foreign body response which retards healing and may result in an inflammatory tissue response.
- hemostatic compositions which have'a specific hemostatic efiect and in which the range of consistency varies from a highly viscous liquid to that of a soft wax and from a soft wax to that ofa semi-solid or solid may be prepared which'include, as ingredients a water-soluble innocuous base and a hemostatic agent.
- the base may be a single substance or a mixture of two or morewatensoluble innocuous substances, and the hemostatic agent is preferably a single substance, but a combination of hemostatic agents may be used.
- Substances found suitable as bases include polymerized low molecular weight aliphatic glycols such as polymerized ethylene glycol, and low molecularweight ethers or esters of polyglycols such as the methyl, ethyl or propyl ethers of polyethylene glycols and the acetic or propionic esters of polyethylene or polypropylene glycols.
- Polymerized ethylene glycol is the preferred water-soluble base, and polymerized ethylene glycols having a molecular weight of from 200 to 4000 and a consistency varying from a liquid of low viscosity to that of a solid wax have been used.
- a combination of two or more polymerized ethylene glycols having molecular weights within this range may also be used, and for the preparation of bone wax it has been found preferable to use a polymerized ethylene glycol having a molecular weight of 1000 to 4000 in combination with a polymerized ethylene glycol having a molecular weight of from 200 to 600.
- Hemostatic agents which have been found valuable for use in combination with a water-soluble innocuous base include oxidized cellulose, pectic acid, alginic acid and its salts including its calcium salts as well as a nitrated calcium salt of alginic acid and other alginic acid derivatives.
- the preferred absorbable hemostatic agent for use in combination with a water-soluble innocuous base is oxidized cellulose.
- the oxidized cellulose which is used is that which results from the oxidation of cellulose with nitrogen dioxide as disclosed in U. S. Patent No. 2,232,990, issued February 25, 1941, and in the Journal of the American Chemical Society, volume 64, page 121, 1942, and whose properties are disclosed in the Journal of the American Chemical Society, volume 64, page 127, 1942.
- Such an oxidized cellulose is described as a homogeneous, alkali-soluble, non-nitrated, undegraded cellulose.
- Oxidized cellulose prepared by this method exhibits a carbon dioxide equivalency of at least 15% and a complete solubility in aqueous sodium hydroxide in 2% concentration. It has been shown that oxidized cellulose having the above physical properties is completely absorbable by body tissues and that tissue slices utilize such oxidized cellulose as a nutrient substrate.
- the preferred hemostatic formulation includes as ingredients polymerized ethylene glycol and oxidized cellulose.
- the oxidized cellulose is in the form of particles in the shape of rods which have an average diameter of 4 to 8 microns and an average length of 10 to 25 microns; the preferred average length is to microns.
- the former is added to the latter at a temperature below 100 C., and the addition is made while the polymerized ethylene glycol is being efliciently stirred.
- the polymerized ethylene glycol base be a mixture of two or more polymerized ethylene glycol compounds of difierent molecular weights; one having a molecular weight between 1000 and 4000 which has a wax-like consistency and one having a molecular weight of less than 200 to 600 which is liquid in consistency.
- the two are mixed and heated and a uniform melt is obtained with the temperature of the melt preferably not above C.
- the melt is allowed to cool to a temperature below 100 C. and pulverized oxidized cellulose is then added while the whole is being stirred efiiciently, and stirring is continued until the mass is in a semi-solid state in order that separation and sedimentation of the oxidized cellulose particles will not occur.
- compositions in which the parts are given by weight, comprising physical mixtures of polymerized ethylene glycol and oxidized cellulose, have been found suitable for use as a bone wax.
- Oxidized cellulose 30 Formulations may be prepared which are satisfactory as hemostatic agents for use in connection with hemorrhages of soft tissues and bone hemorrhages in which the base consists of a single polymerized ethylene glycol which has a molecular weight as high as 1500; but when a polymerized ethylene glycol is used which has a molecular weight higher than 1500, some low molecular weight polymerized ethylene glycol must be added as a softening agent.
- the low molecular weight liquid portion of the polymerized ethylene glycol base may be present in an amount as high as 40% or 50% by weight if a high molecular weight polymerized ethylene lycol is used which has a molecular weight of from three to four thousand.
- the formulations are made softer; and by increasing this ingredient still further, hemostatic compositions having a cream-like consistency are produced.
- a hemostatic formulation specifically. for use on cut bone surfaces is preferred to have a semi-solid consistency such that it can be kneaded between the fingers When at room temperature.
- the hemostatic action of a therapeutic composition prepared according to the preceding examples depends upon the presence of both the polymerized ethylene glycol constituent or constituents and powdered oxidized cellulose, since either of the compounds when used alone is not a satisfactory hemostatic agent, when applied to cut bone surfaces.
- Oxidized cellulose in powdered form when used alone does not adhere to bleeding out surfaces of soft tissue or bone.
- Oxidized cellulose of itself has hemostatic properties, and the polymerized ethylene glycol with which it is intimately admixed and which is absorbable in body fluids enhances the hemostatic action of the oxidized cellulose by enabling it to come in close physical contact and actually to penetrate into severed blood vessels at the surface of cut soft tissues and into severed blood vessels and sinuses present on cut bone surfaces.
- the finely divided particles of oxidized cellulose which are then present at the openings and inside of blood vessels and sinuses exert their hemostatic properties and effectively control bleeding.
- Oxidized cellulose combines chemically with the hemoglobin of the blood and forms a large molecule which agglutinates into a gelatinous mass which in turn acts mechanically to stop the flow of blood in the same way as a true blood clot.
- Oxidized cellulose In order for oxidized cellulose to stop bleeding it must be in firm contact with blood for about two minutes since this amount of time is necessary for the process described above to proceed to a point where the agglutinated substance can act mechanically to stop bleeding.
- the polymerized ethylene glycol of the composition because of its water-soluble properties, enables oxidized cellulose to remain in contact with blood issuing from the vessels of cut soft tissue and bone surfaces long enough for the above chemical reaction to occur.
- a clot In order for a clot to be effective in stemming the flow of blood from a blood vessel or capillary, a clot must be produced inside a severed blood vessel since a clot on the surface of cut soft tissue or bone is readily and quickly removed from the site by the pressure of blood issuing from severed vessels.
- a water-absorbable base such as polymerized ethylene glycol
- a finely divided hemostatic agent such as oxidized cellulose
- A' hemostatic composition for use in the control of tissue and osseous hemorrhage comprising; as a, water-soluble innocuous base, poly,- merized ethylene glycol having an average molecular weight of approximately 1500; and, as a hemostatic agent, finely divided oxidized cellulose intimately admixed therewith.
- a hemostatic composition for use in the control of tissue and osseous hemorrhage comprising; as a water-soluble innocuous base, a mixture of a polymerized ethylene glycol having an average molecular weight of from 200 to 600 and a polymerized ethylene glycol having an average molecular weight of from 1000 to i000; and, as a hemostatic agent, finely divided oxidized cellulose intimately admixed therewith.
- a hemostatic composition for use in the control of tissue, and osseous hemorrhage comprising; as a water-soluble innocuous base, a mixture of approximately parts by weight of a polymerized ethylene glycol having an average molecular weight of approximately 1540 and 10 parts by weight of a polymerized ethylene glycol having an average molecular weight of approximately 300; and, as a hemostatic agent, 30 parts by weight of finely divided oxidized cellulose with particles in the shape of rods having an average diameter of 4 to 8 microns and an average length of 10 to 25 microns intimately admixed therewith.
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- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Hematology (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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Description
Patented June 16, 1953 HEMOSTATIC COMPOSITIONS John Henderson, New Market, and Alfred Bloch and Herbert L. Davis, Highland Park, N. J assignors to Ethicon Suture Laboratories Incorporated, .a corporation of New Jersey N Drawing. Application August 21, 1951, Serial No. 242,992
This invention relates to new and improved hemostatic compositions and specifically relates to such compositions that are absorbable in body fluids by physiologic processes.
Various substances and compositions have been employed by members of the medical profession to control bleeding of soft tissues and cut bone surfaces. Natural clotting agents such as striated muscle have been used, particularly in neurosurgery and in drill holes in bone. Certain plasma fractions have been used, and fibrin from whipped blood has been so prepared that it could be immediately plastered on bleeding surfaces. Human fibrin foam has been used as a' carrier of thrombin, and the fibrin foam has been used in the form of a dry, porous, brittle, creamcolored textile. Another plasma protein, thrombin, in a highly potent, purified, water-soluble form has been used as a hemostatic spray as well as in conjunction with human fibrin foam, but thrombin is unstable in aqueous solution and cannot be heat sterilized in an autoclave without destroying its activity as a hemostatic substance. Fi-brinogen in conjunction with thrombin has also been found useful in the formation of an adhesive layer to seal together cut surfaces of soft tissues, notably a skin graft on a prepared bed. More recently an absorbable substance in the form of a sponge has been used and is prepared from a specially prepared gelatin solution which is further processed and sterilized.
The gelatin sponge when dry is a light, off-white,
reasonably tough, porous substance that may be readily cut by a sharp instrument into any desired shape or size. This absorbable gelatin sponge is normally used in conjunction with a thrombin solution. The gelatin sponge mixed with the thrombin solution is used by applying it to a bleeding area where it quicklyimbibes blood which clots as it comes in contact with thrombin. Physiological absorption of the sponge takes place in from 15 to 20 days.
Another recent absorbable substance which has found acceptance by the medical profession as a hemostatic agent is oxidized cellulose. It was found that oxidized cellulose in the form of cotton, paper, gauze, or a non-woven mass had hemostatic properties, and its use as a'hemostatic agent has been widely studied in a variety of animal and human tissues. The material was demonstrated to be non-irritating and to disappear in the tissue leaving a minimum of scar;
The control of osseous hemorrhage has presented a serious problem to the medical profession because the hemostatic-agents found effective for the control of soft tissue hemorrhages 3 Claims (01.167-65) have not been effective for the control of bleeding from out bone surfaces. One class of materials used for the control of this latter type of hemorrhage is called bone wax. Bone waxes in common use today are, prepared from refined waxes of bees which have been admixed with other non-absorbable and water-insoluble hydrocarbons or vegetable oils. Bone Wax has been used for the purpose of controlling hemorrhages from the 'cut surfaces of bones, such as those-of the skull, by forcibly smearing the wax over the cut surface so that the material actsmechanically to occlude and seal the open ends of bleeding osseous vessels and sinuses. Such compositions have no specific hemostatic effect per se and quite often result in delayed'healing because of their non-absorbable properties. Nonabsorbable bone Waxes, since they are left in the wound as a foreign body, frequently constitute a troublesome barrier to subsequent osseous union. Another disadvantage of non-absorbable bone wax is the danger of particles of the wax falling ofi the bone edge and lodging in the surrounding tissue Where they provide a foreign body response which retards healing and may result in an inflammatory tissue response.
It is an object of this invention to prepare a hemostatic composition which is completely absorbable by body tissues.
It is another object'of this invention to prepare a hemostatic composition which quickly controls hemorrhages from the cut surfaces of soft tissues and more particularly bones.
It is another and further object of this invention to prepare an absorbable hemostatic composition which possesses a specific hemostatic effect and is at the same time absorbable by physiologic processes.
It is still another and further object of this invention to prepare an absorbable hemostatic composition which is readily sterilizable by ordinary autoclaving procedures.
Other objects will be apparent from the following description and examples.
In accordance with the present invention it has been found that hemostatic compositions which have'a specific hemostatic efiect and in which the range of consistency varies from a highly viscous liquid to that of a soft wax and from a soft wax to that ofa semi-solid or solid may be prepared which'include, as ingredients a water-soluble innocuous base and a hemostatic agent. The base may be a single substance or a mixture of two or morewatensoluble innocuous substances, and the hemostatic agent is preferably a single substance, but a combination of hemostatic agents may be used.
Substances found suitable as bases include polymerized low molecular weight aliphatic glycols such as polymerized ethylene glycol, and low molecularweight ethers or esters of polyglycols such as the methyl, ethyl or propyl ethers of polyethylene glycols and the acetic or propionic esters of polyethylene or polypropylene glycols. Polymerized ethylene glycol is the preferred water-soluble base, and polymerized ethylene glycols having a molecular weight of from 200 to 4000 and a consistency varying from a liquid of low viscosity to that of a solid wax have been used. A combination of two or more polymerized ethylene glycols having molecular weights within this range may also be used, and for the preparation of bone wax it has been found preferable to use a polymerized ethylene glycol having a molecular weight of 1000 to 4000 in combination with a polymerized ethylene glycol having a molecular weight of from 200 to 600.
Hemostatic agents which have been found valuable for use in combination with a water-soluble innocuous base include oxidized cellulose, pectic acid, alginic acid and its salts including its calcium salts as well as a nitrated calcium salt of alginic acid and other alginic acid derivatives.
The preferred absorbable hemostatic agent for use in combination with a water-soluble innocuous base is oxidized cellulose. The oxidized cellulose which is used is that which results from the oxidation of cellulose with nitrogen dioxide as disclosed in U. S. Patent No. 2,232,990, issued February 25, 1941, and in the Journal of the American Chemical Society, volume 64, page 121, 1942, and whose properties are disclosed in the Journal of the American Chemical Society, volume 64, page 127, 1942. Such an oxidized cellulose is described as a homogeneous, alkali-soluble, non-nitrated, undegraded cellulose. The oxidation is disclosed as being accomplished by the use of gaseous nitrogen dioxide on cotton which results in the oxidation of the terminal carbon atoms of the glucose units of cellulose with the resultant formation of carboxyl groups at the said terminal carbon atoms. Oxidized cellulose prepared by this method exhibits a carbon dioxide equivalency of at least 15% and a complete solubility in aqueous sodium hydroxide in 2% concentration. It has been shown that oxidized cellulose having the above physical properties is completely absorbable by body tissues and that tissue slices utilize such oxidized cellulose as a nutrient substrate.
The preferred hemostatic formulation includes as ingredients polymerized ethylene glycol and oxidized cellulose. The oxidized cellulose is in the form of particles in the shape of rods which have an average diameter of 4 to 8 microns and an average length of 10 to 25 microns; the preferred average length is to microns.
In compounding oxidized cellulose with polymerized ethylene glycol the former is added to the latter at a temperature below 100 C., and the addition is made while the polymerized ethylene glycol is being efliciently stirred. It i preferred that the polymerized ethylene glycol base be a mixture of two or more polymerized ethylene glycol compounds of difierent molecular weights; one having a molecular weight between 1000 and 4000 which has a wax-like consistency and one having a molecular weight of less than 200 to 600 which is liquid in consistency. In preparing a bone wax in which two polymerized ethylene glycol compounds are used, the two are mixed and heated and a uniform melt is obtained with the temperature of the melt preferably not above C. The melt is allowed to cool to a temperature below 100 C. and pulverized oxidized cellulose is then added while the whole is being stirred efiiciently, and stirring is continued until the mass is in a semi-solid state in order that separation and sedimentation of the oxidized cellulose particles will not occur.
The following examples of compositions, in which the parts are given by weight, comprising physical mixtures of polymerized ethylene glycol and oxidized cellulose, have been found suitable for use as a bone wax.
Oxidized cellulose 30 Formulations may be prepared which are satisfactory as hemostatic agents for use in connection with hemorrhages of soft tissues and bone hemorrhages in which the base consists of a single polymerized ethylene glycol which has a molecular weight as high as 1500; but when a polymerized ethylene glycol is used which has a molecular weight higher than 1500, some low molecular weight polymerized ethylene glycol must be added as a softening agent. The low molecular weight liquid portion of the polymerized ethylene glycol base may be present in an amount as high as 40% or 50% by weight if a high molecular weight polymerized ethylene lycol is used which has a molecular weight of from three to four thousand. By increasin the liquid polymerized ethylene glycol constituent, the formulations are made softer; and by increasing this ingredient still further, hemostatic compositions having a cream-like consistency are produced. A hemostatic formulation specifically. for use on cut bone surfaces is preferred to have a semi-solid consistency such that it can be kneaded between the fingers When at room temperature.
The hemostatic action of a therapeutic composition prepared according to the preceding examples depends upon the presence of both the polymerized ethylene glycol constituent or constituents and powdered oxidized cellulose, since either of the compounds when used alone is not a satisfactory hemostatic agent, when applied to cut bone surfaces. Oxidized cellulose in powdered form when used alone does not adhere to bleeding out surfaces of soft tissue or bone. Oxidized cellulose of itself has hemostatic properties, and the polymerized ethylene glycol with which it is intimately admixed and which is absorbable in body fluids enhances the hemostatic action of the oxidized cellulose by enabling it to come in close physical contact and actually to penetrate into severed blood vessels at the surface of cut soft tissues and into severed blood vessels and sinuses present on cut bone surfaces. The finely divided particles of oxidized cellulose which are then present at the openings and inside of blood vessels and sinuses exert their hemostatic properties and effectively control bleeding.
Chemical reactions of the clotting mechanism of blood are set up when blood contacts oxidized cellulose due to the hemostatic properties of oxidized cellulose. Oxidized cellulose combines chemically with the hemoglobin of the blood and forms a large molecule which agglutinates into a gelatinous mass which in turn acts mechanically to stop the flow of blood in the same way as a true blood clot. In order for oxidized cellulose to stop bleeding it must be in firm contact with blood for about two minutes since this amount of time is necessary for the process described above to proceed to a point where the agglutinated substance can act mechanically to stop bleeding. The polymerized ethylene glycol of the composition, because of its water-soluble properties, enables oxidized cellulose to remain in contact with blood issuing from the vessels of cut soft tissue and bone surfaces long enough for the above chemical reaction to occur.
In order for a clot to be effective in stemming the flow of blood from a blood vessel or capillary, a clot must be produced inside a severed blood vessel since a clot on the surface of cut soft tissue or bone is readily and quickly removed from the site by the pressure of blood issuing from severed vessels. The intimate association of a water-absorbable base such as polymerized ethylene glycol with a finely divided hemostatic agent such as oxidized cellulose enables the particles of oxidized cellulose to enter blood vessels at their severed ends when such a composition is smeared or rubbed over out surfaces of soft tissue and bones because the polymerized ethylene glycol dissolves in blood and penetrates into blood vessels and in doing so carries with it particles of oxidized cellulose.
Since certain changes may be made in the proportions of the ingredients composing the hemostatic therapeutic composition, and since certain ingredients may be varied without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense, but that the invention is to be limited only by the scope of the appended claims.
What is claimed is:
1. A' hemostatic composition for use in the control of tissue and osseous hemorrhage comprising; as a, water-soluble innocuous base, poly,- merized ethylene glycol having an average molecular weight of approximately 1500; and, as a hemostatic agent, finely divided oxidized cellulose intimately admixed therewith.
2.'A hemostatic composition for use in the control of tissue and osseous hemorrhage comprising; as a water-soluble innocuous base, a mixture of a polymerized ethylene glycol having an average molecular weight of from 200 to 600 and a polymerized ethylene glycol having an average molecular weight of from 1000 to i000; and, as a hemostatic agent, finely divided oxidized cellulose intimately admixed therewith.
3; A hemostatic composition for use in the control of tissue, and osseous hemorrhage comprising; as a water-soluble innocuous base, a mixture of approximately parts by weight of a polymerized ethylene glycol having an average molecular weight of approximately 1540 and 10 parts by weight of a polymerized ethylene glycol having an average molecular weight of approximately 300; and, as a hemostatic agent, 30 parts by weight of finely divided oxidized cellulose with particles in the shape of rods having an average diameter of 4 to 8 microns and an average length of 10 to 25 microns intimately admixed therewith.
JOHN HENDERSON. ALFRED BLOC'H. HERBERT L. DAVIS.
References Cited in the file of this patent V UNITED STATES PATENTS OTHER. REFERENCES Seegers et al., Hemostatic Agents, '0. C. Thomas, Springfield, Illinois, 1948, pages 45, 90.
McClelland et al., Chemical News, February 10, 1945, volume 23, Number 3, pages 247, 250.
' Anderson Squibb Abstract Bulletin, volume 18, page 1369 (1945).
and Engineering
Claims (1)
1. A HEMOSTATIC COMPOSITION FOR USE IN THE CONTROL OF TISSUE AND OSSEOUS HEMORRHAGE COMPRISING; AS A WATER-SOLUBLE INNOCUOUS BASE, POLYMERIZED ETHYLENE GLYCOL HAVING AN AVERAGE MOLECULAR WEIGHT OF APPROXIMATELY 1500; AND, AS A HEMOSTATIC AGENT, FINELY DIVIDED OXIDIZED CELLULOSE INTIMATELY ADMIXED THEREWITH.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US242992A US2642375A (en) | 1951-08-21 | 1951-08-21 | Hemostatic compositions |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US242992A US2642375A (en) | 1951-08-21 | 1951-08-21 | Hemostatic compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US2642375A true US2642375A (en) | 1953-06-16 |
Family
ID=22916921
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US242992A Expired - Lifetime US2642375A (en) | 1951-08-21 | 1951-08-21 | Hemostatic compositions |
Country Status (1)
| Country | Link |
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| US (1) | US2642375A (en) |
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3395217A (en) * | 1964-06-19 | 1968-07-30 | Dow Chemical Co | Process for the control of osseous hemorrhage |
| US4191747A (en) * | 1976-12-17 | 1980-03-04 | Hans Scheicher | Corrective agent for the covering and/or filling of bone defects, method for the preparation of same and method of using the same |
| US5696101A (en) * | 1996-04-16 | 1997-12-09 | Eastman Chemical Company | Oxidized cellulose and vitamin E blend for topical hemostatic applications |
| US6162241A (en) * | 1997-08-06 | 2000-12-19 | Focal, Inc. | Hemostatic tissue sealants |
| US20110189304A1 (en) * | 2003-09-23 | 2011-08-04 | Kronenthal Richard L | Absorbable implants and methods for their use in hemostasis and in the treatment of osseous defects |
| US20120027817A1 (en) * | 2003-09-23 | 2012-02-02 | Orthocon, Inc. | Absorbable Implants and Methods for Their Use in Hemostasis |
| EP2773358A4 (en) * | 2011-11-01 | 2015-12-02 | Abyrx Inc | COMPOSITIONS AND METHODS FOR HEMOSTASE |
| EP3072453A2 (en) | 2015-03-25 | 2016-09-28 | Ethicon Endo-Surgery, LLC | Naturally derived bioabsorbable polymer gel adhesive for releasably attaching a staple buttress to a surgical stapler |
| EP3072454A1 (en) | 2015-03-25 | 2016-09-28 | Ethicon Endo-Surgery, LLC | Low glass transition temperature bioabsorbable polymer adhesive for releasably attaching a staple buttress to a surgical stapler |
| EP3072460A2 (en) | 2015-03-25 | 2016-09-28 | Ethicon Endo-Surgery, LLC | Method of applying a buttress to a surgical stapler |
| EP3072457A2 (en) | 2015-03-25 | 2016-09-28 | Ethicon Endo-Surgery, LLC | Biologically derived extracellular matrix with infused viscous absorbable copolymer for releasably attaching a staple buttress to a surgical stapler |
| EP3072458A2 (en) | 2015-03-25 | 2016-09-28 | Ethicon Endo-Surgery, LLC | Surgical staple buttress with integral adhesive for releasably attaching to a surgical stapler |
| EP3072455A2 (en) | 2015-03-25 | 2016-09-28 | Ethicon Endo-Surgery, LLC | Flowable bioabsorbable polymer adhesive for releasably attaching a staple buttress to a surgical stapler |
| WO2016153887A1 (en) | 2015-03-25 | 2016-09-29 | Ethicon Endo-Surgery, Llc | Malleable bioabsorbable polymer adhesive for releasably attaching a staple buttress to a surgical stapler |
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| US2160503A (en) * | 1936-02-14 | 1939-05-30 | Chemische Forschungs Gmbh | Blood stancher |
| US2185255A (en) * | 1937-06-19 | 1940-01-02 | Firm Chem Fab Promonta G M B H | Saponaceous shaving composition |
| DE705450C (en) * | 1939-04-19 | 1941-04-29 | Ig Farbenindustrie Ag | Skin lubricants |
| US2558395A (en) * | 1947-06-03 | 1951-06-26 | Hoffmann La Roche | Undenatured gelatin hemostatic sponge containing thrombin |
Cited By (39)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3395217A (en) * | 1964-06-19 | 1968-07-30 | Dow Chemical Co | Process for the control of osseous hemorrhage |
| US4191747A (en) * | 1976-12-17 | 1980-03-04 | Hans Scheicher | Corrective agent for the covering and/or filling of bone defects, method for the preparation of same and method of using the same |
| US5696101A (en) * | 1996-04-16 | 1997-12-09 | Eastman Chemical Company | Oxidized cellulose and vitamin E blend for topical hemostatic applications |
| US6162241A (en) * | 1997-08-06 | 2000-12-19 | Focal, Inc. | Hemostatic tissue sealants |
| US20110189304A1 (en) * | 2003-09-23 | 2011-08-04 | Kronenthal Richard L | Absorbable implants and methods for their use in hemostasis and in the treatment of osseous defects |
| US20120027817A1 (en) * | 2003-09-23 | 2012-02-02 | Orthocon, Inc. | Absorbable Implants and Methods for Their Use in Hemostasis |
| US20120189671A1 (en) * | 2003-09-23 | 2012-07-26 | Orthocon, Inc. | Absorbable Implants and Methods for their use in Hemostasis |
| US8337879B2 (en) | 2003-09-23 | 2012-12-25 | Orthocon, Inc. | Absorbable implants and methods for their use in hemostasis and in the treatment of osseous defects |
| EP2773358A4 (en) * | 2011-11-01 | 2015-12-02 | Abyrx Inc | COMPOSITIONS AND METHODS FOR HEMOSTASE |
| US11642435B2 (en) | 2011-11-01 | 2023-05-09 | Abyrx, Inc. | Compositions and methods for hemostasis |
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| EP3072460A2 (en) | 2015-03-25 | 2016-09-28 | Ethicon Endo-Surgery, LLC | Method of applying a buttress to a surgical stapler |
| EP3072455A2 (en) | 2015-03-25 | 2016-09-28 | Ethicon Endo-Surgery, LLC | Flowable bioabsorbable polymer adhesive for releasably attaching a staple buttress to a surgical stapler |
| WO2016153887A1 (en) | 2015-03-25 | 2016-09-29 | Ethicon Endo-Surgery, Llc | Malleable bioabsorbable polymer adhesive for releasably attaching a staple buttress to a surgical stapler |
| WO2016153890A1 (en) | 2015-03-25 | 2016-09-29 | Ethicon Endo-Surgery, Llc | Low glass transition temperature bioabsorbable polymer adhesive for releasably attaching a staple buttress to a surgical stapler |
| US20160278775A1 (en) * | 2015-03-25 | 2016-09-29 | Ethicon Endo-Surgery, Llc | Malleable bioabsorbable polymer adhesive for releasably attaching a staple buttress to a surgical stapler |
| EP3072457A2 (en) | 2015-03-25 | 2016-09-28 | Ethicon Endo-Surgery, LLC | Biologically derived extracellular matrix with infused viscous absorbable copolymer for releasably attaching a staple buttress to a surgical stapler |
| WO2016153975A2 (en) | 2015-03-25 | 2016-09-29 | Ethicon Endo-Surgery, Llc | Flowable bioabsorbable polymer adhesive for releasably attaching a staple buttress to a surgical stapler |
| US10136891B2 (en) | 2015-03-25 | 2018-11-27 | Ethicon Llc | Naturally derived bioabsorbable polymer gel adhesive for releasably attaching a staple buttress to a surgical stapler |
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| US10349939B2 (en) | 2015-03-25 | 2019-07-16 | Ethicon Llc | Method of applying a buttress to a surgical stapler |
| US10478187B2 (en) | 2015-03-25 | 2019-11-19 | Ethicon Llc | Biologically derived extracellular matrix with infused viscous absorbable copolymer for releasably attaching a staple buttress to a surgical stapler |
| EP3072458A2 (en) | 2015-03-25 | 2016-09-28 | Ethicon Endo-Surgery, LLC | Surgical staple buttress with integral adhesive for releasably attaching to a surgical stapler |
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