CA1260488A - Absorbable bone wax formulation - Google Patents
Absorbable bone wax formulationInfo
- Publication number
- CA1260488A CA1260488A CA000513258A CA513258A CA1260488A CA 1260488 A CA1260488 A CA 1260488A CA 000513258 A CA000513258 A CA 000513258A CA 513258 A CA513258 A CA 513258A CA 1260488 A CA1260488 A CA 1260488A
- Authority
- CA
- Canada
- Prior art keywords
- glycolide
- castor oil
- process according
- fatty acid
- catalyst
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/78—Preparation processes
- C08G63/82—Preparation processes characterised by the catalyst used
- C08G63/823—Preparation processes characterised by the catalyst used for the preparation of polylactones or polylactides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
- A61K31/765—Polymers containing oxygen
-
- 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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/046—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/02—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds
- C08G63/06—Polyesters derived from hydroxycarboxylic acids or from polycarboxylic acids and polyhydroxy compounds derived from hydroxycarboxylic acids
- C08G63/08—Lactones or lactides
Abstract
ABSTRACT
The triglyceride castor oil is reacted with the lactones glycolide and/or lactide in such a manner as to pro-duce resins with properties which range from oils to waxes at room temperature. The waxes may be used directly as syn-thetic absorbable haemostatic agents for the control of osseous haemorrhage. A biocompatible powder such as calcium stearate may also be mixed with the copolyester resins to produce a wax useful in the stated role. Water soluble bio-compatible components such as dextran may also be added. The preferred haemostatic agent is a 50/50 w/w mixture of calcium stearate powder and resin with a glycolide:castor oil molar ratio of 6:1 with approximately 80% of the glycolide present as a polymeric solid which melts above room temperature.
The triglyceride castor oil is reacted with the lactones glycolide and/or lactide in such a manner as to pro-duce resins with properties which range from oils to waxes at room temperature. The waxes may be used directly as syn-thetic absorbable haemostatic agents for the control of osseous haemorrhage. A biocompatible powder such as calcium stearate may also be mixed with the copolyester resins to produce a wax useful in the stated role. Water soluble bio-compatible components such as dextran may also be added. The preferred haemostatic agent is a 50/50 w/w mixture of calcium stearate powder and resin with a glycolide:castor oil molar ratio of 6:1 with approximately 80% of the glycolide present as a polymeric solid which melts above room temperature.
Description
lZ60488 This invention relates to the preparation of copo-lyester resin from castor oil, glycolide and/or lactide and their use as sealants to control osseous haemorrhage. (The term ~copolyester resin" as used herein is intended to refer to the reaction product of castor oil with glycolide and/or lactide). This invention also relates to mixtures of the copolyester resin with a biocompatible fatty acid salt such as calcium stearate and optionally with water soluble biocompatible components such as dextran.
Various means of haemostasis have been employed by members of the medical profession. These include: ligation, application of pressure, application of absorbant pads,and use of haemostatic agents such as thrombin and cyanoacrylate adhesives. For control of bleeding from cut bone surfaces in particular a class of materials called bone waxes is often used. The waxes are smeared over the bleeding surface of the bone to plug the osseous vessells and sinuses allowing clotting to occur. Haemostasis is achieved by this tamponade action.
Bone waxes used in surgery are generally prepared from refined beeswax and are not absorbed by the body. The wax remains at the site of application for long periods and could act as a source of inflammatory reaction and could interfere with bone~regrowth (cf. S.J. Sorrenti, et al, Clin.
Orthop., (182), 293-296, (1984).
Any material which is going to be used by surgeons as a bone wax has to have certain suitable handling properties.
The wax must be soft enough to be malleable when kneaded ,between the fingers, it must stick to bone, preferably it ,~30 must not stick to surgeon's gloves, and it must not lose its 'properties when used in the wet bloody field found during :~j surgical operations. That is, the ~wa~x must not absorb sig--,nificant amounts of water and lose its texture. The more , ~- :
12~0488 hydrophobic the wax the less likely this would happen. How-ever, the more hydrophobic the wax the less likely the wax will be infiltrated by body fluids and absorbed by cellular acti-vity. A suitable lipophilic-hydrophilic balance of proper-ties is required to produce a bone wax which absorbs in vivo.
U.S. Pat. 4439420 discloses mixtures for use in control of osseous haemorrhage formed from a base of castor oil and/or other body absorbable naturally occuring oils, synthetic polyols, or water wlth fatty acid salts and bio-compatible water soluble solids such as dextran. The watersoluble solids act as hydrophilic fillers in the base to enhance absorption. Castor oil and the fatty acid salts are too low in molecular size to exhibit significant plastic behavior as defined for example in G. Odian, "Principles of Polymerization", McGraw Hill, New York, (1970), pp. 33-38.
That is, these mixtures are more paste like than plastic, exhibiting little ductility or ~ohesive flow under elongation.
U.S. Pat. 4443430 discloses low molecular weight copolymers of glycolide and lactide, prepared using dodecanol to limit the molecular weight, for use in control of osseous haemorrhage (The use of hydroxyl containing compounds in conjunction with a stannous salt catalyst to produce polylactones has been described in detail by Schindler et al, J. Polym. Sci., (20), 319-326, (1982). Also, high molecular weight polylactones prepared from dihydroxy polyoxyethylenes and low molecular weight glycols have been described by Casey, et al, U.S. Pat.
4452973, U.S. Pat. 4429080, and U.S. Pat. 4438253, and Shalaby, et al, German Pat. DE 3335588Al). In these patents the polymers are formed using dihydroxy water soluble compounds which dissolve in molten glycolide. Because dodecanol, which is a solid at room temperature is used to synthesize the copolymers described in U.S. Pat. 4443430, copolymers with high lactide content (~ 30~) are required to produce soft waxes in the preferred molecular weight range for plastic behavior.
lt is known from experience that lactide/glycolide copolymers in the stated molecular weight range with such high lactide content (~30~) are very tacky and gum-like.
U.S. Pat. 4440789 discloses a low molecular weight polydioxanone polymer for use in control of osseous haemorrhage.
The present invention provides a new synthetic absorbable bone wax which is based on novel polyesters from the reaction of glycolide and/or lactide with castor oil.
Use of the higher molecular weight polyesters from castor oil in the bone wax formulations produces waxes with improved plastic behavior, that is, mouldibility and cohesiveness, compared to the formulations described in U.S. Pat. 4439420.
The waxes have more ductility and elongation compared to for-mulations based on castor oil. The preferred formulations exhibit a combination of properlties that result in superior handling characteristics. The preferred formulations can be spread on an adhere to the cut surface of bone. They do not stick to surgeon's gloves and the handling properties do not change in a wet environment.
It is surprising that glycolide, which is not miscible with castor oil, can~be reacted with it to produce a homogeneous product under the appropriate conditions. The use of castor oil, a high molecular weight coreactant with flexible pendant groups emanating from its glycerol nucleus, provides the ability to use high glycolide:oil mole ratios such as 9:1 and still produce soft malleable waxes that do not readily absorb moisture. The high glycolide content produces a wax which is less sticky and gum-like than copolyesters containing hlgh percentages of lactide. The waxes produced absorb in v~vo .
~.26~488 The copolyesters of the instant invention are pro-duced from reacting glycolide and/or lactide with castor oil and catalyst at elevated -temperatures so that the lactones melt. The preferred catalyst is stannous octoate and is used in the lactone:catalyst mole ratio of 1100:1 to 13000:1. The preferred temperature ran~e i~ 105-125 C. When glycolide is reacted with the castor oil the glycolide is preferentially added to the heated castor oil and catalyst in a gradual manner to produce a more homogeneous product. These copolyesters can be used in bone wax formulations to control osseous hae-morrhage from cut bone.
The bone wax composition of the present invention comprises: i) a polyester resin prepared from glycolide reacted with castor oil and catalyst where the glycolide:oil molar ratio varies from 3:1 to 9:1, preferentially 6:1, which comprises between 40% and 100% by weight of the total compo-sition; and ii) a fatty acid salt which comprises between 0% and 60%
by weight of the total composition; and iii) a water soluble biocompatible solid which comprises between 0% and 10~ by weight of the total composition.
The cation of the fatty acid salt is preferably calcium, the fatty acid anion being saturated or unsaturated and containing from 10 to 22 carbon atoms in the chain. The water soluble solid is selected from any biocompatible material, preferentially polymeric solids such as dextran.
The composition has a wax-like consistency which adheres preferentially to the cut surface of bone rather than to itself or to surgeon's gloves or utensils. The wax can be sterilized by high energy radiation and is effective in the control of osseous haemorrhage from cut bone. The wax absorbs in vivo and does not interfere with subsequent healing and regrowth of bone.
The polyesters of the present invention are prepared from glycolide and/or lactide reacted with castor oil at elevated temperatures using a polymerization catalyst, pre-ferably a stannous salt of a fatty acid.
The polymerization is conducted with pure and dry reactants under vacuum or an atmosphere of dry nitrogen at a temperature sufficient to melt the lactone but not degrade the castor oil, usually between 105-125C. The desired consistency of the final product depends on the glycolide/lactide mole ratio, the lactone/oil mole ratio, and in some cases the amount of catalyst. When glycolide is reacted with the castor oil it is preferred to add the glycolide in a gradual manner to the oil-catalyst mixture. This is because a solid forms when under certain circumstances. Gradual addition of gly-colide ensures a more homogeneous- product. An explanation of this phenomenon which is not meant to limit the scope of the invention is that this solid, which melts above the reaction temperature, is polyester which solidifies because the poly-glycolide component produces high melting polymer chains with the capability of forming crystalline domains. It is also possible that some or all of the glycolide in the solid polymer has been initiated by residual water or other hydroxy component rather than the castor oil. When low levels of stannous octoate catalyst are used (glycolide:catalyst mole ratio 9000:1) the solids does not form immediately but tends to form large particles which settle out of the product. When high calalyst levels are used (e.g. glycolide:catalyst mole ratio 1100:1) the solid forms immediately and the particles are small enough to remain suspended in the product as in a colloid.
This product when cooled is waxy with no grittiness or hardness associated with the solid. No solid forms when the glycolide is added gradually to the castor oil - catalyst mixture when ~260488 the glycolide:oil ratio is 3:1 an~ the glycolide:c~talyst ratio is 4500:1 (Example 7). To verify that glycolide has reacted with the castor oil, liquid chromatography of this 3:1 glycolide:oil mole ratio product was carried out. Also, the solid was fractionated from the polyesters with higher glyco-lide:catalyst mole ratios using dichloromethane, a good solvent for castor oil, and the DCM soluble portion analyzed by liquid chromatography for evidence of unreacted castor oil. The results of the analyse~ are ~iven in Table I. The results show that glycolide does react with castor oil. Inherent viscosity results in Table I show that the solid isolated by fractionating by dichloromethane is a higher molecular weight material. Infrared analysis of the solid revealed it to be a polymer of glycolide.
Specific details concerning the preparation of copolyesters of glycolide and/or lactide with castor oil are set forth in the followingexamples.
The following example~ are provided to further illustrate preferred embodiments of the present invention.
The results of analysis of the synthesized polyesters are provided in Table 1. All liquid chromatography was carried out in tetrahydrofuran solvent at 1 ml/min flow rate using samples of concentration of O.lg/lOml. The samples were analyzed using two 30 cm x 1 cm Dupont ZorbaxTM 60S size exclusion columns calibrated with monodisperse anionically polymerized polystyrene. All inherent viscosity measurements were carried out in either hexafluoroisopropanol or dichloromethane solvent at a concentration of lg/25ml and a temperature of 25C.
The bone wax composition of the present invention consists preferably of a polyester based on glycolide and castor oil with a glycolide:oil mole ratio of 6:1 mixed with calcium stearate. The composition optionally includes an agent for enhancing in vivo absorption, a preferred agent in .
~z6~4a~
this connection being dextran. The inherent viscosity of the preferred polyester is about 0.101 dl/g. This polyester is workable and softenable by hand and has a wax-like consistency.
Approximately 80% of the glycolide is present as a polymeric solid which melts above room temperature.
To prepare the bone wax formulation the components are mixed together in a mo.tar and pestle to produce a homogeneous product. On an industrial scale the components may be mixed using a dough mixer, mill, extruder, or some other means of providing mechanical shear and mixing.
Table II sets forth the consistency and tactile properties of the instant composition. A comparison with a composition claimed in U.S. Pat. 4439420 is made. It will be noted from Table II that the polyester with 6:1 glycolide:
castor oil mole ratio mixed with calcium stearate on an equal weight basis provides the most desirable properties of those compositions listed in the Tabl,e. Applicant has also found that sterilization with Co60 gamma radiation has no adverse effect on the consistency and tactile properties of any of the instant compositions of Table II.
The in vivo tissue reaction and absorption of the preferred composition in rats is described in Table III. Rods of the bone wax composition were injected into the gluteal muscles of rats from pre-loaded 16 gauge needles. Adult female Woodlyn Wistar albino rats were used. All rats were held in the animal colony for at least one week prior to being employed in the study. They were maintained according to the guidelines set down by the Canadian Association for Laboratory Animal Sciences and had food and water ad libitum.
All implantation procedures were carried out with the test animals under general anaesthesia (MetofaneTM). The skin of the rat was shaved, washed with GAMOPHENTM leaves and painted lZ~i0488 with IOPREP
Two rats were used for each time period studied for a total of four muscles per time period. The implants only elicited slight to moderate tissue reaction with no evidence of necrosis. Absorbable sutures of polyglycolide generally absorb in vivo between 90 to 100 days in vivo. After 140 days in vivo the bone wax formulation was on average 90% absorbed.
It is surmised that absorption would have been completed after 200 days. The hydrophobic castor oil nucleous of the poly-ester serves to repel tissue fluid absorption and decreasescellular infiltration.
The following examples are provided to further illustrate the preferred embodiments of the present invention.
21.2 grams of L-lactide was charged into a round bottom ampoule, the lactide was heated at 105-110C for one hour at 4mm Hg, then 51.6 gramslof castor oil was added and the mixture stirred at 105-110C at 4mm Hg for one hour. The lactide was miscible in the oil. After this mixture was cooled to solidification and subjected to 500 microns Hg vacuum at room temperature for one hour. After breaking the vacuum, 10 microlitres of stannous octoate was added and the ampoule flame sealed under 4mm Hg. The contents of the ampoule were stirred and reacted eight hours at 120-125C. A fluid yellow oil similar in consistency to castor oil was obtained. This was characterized by liquid chromatography as shown in Table 1.
The reaction described in example 1 was repeated using 24.1 grams of L-lactide and 26.2 grams of castor oil with 10 microlitres of catalyst. A more viscous oil was obtained.
Its LC was measured (Table I).
~)4Ba The reaction described in example 1 was repeated using 24 grams of L-lactide and l9.S grams of castor oil with microlitresof catalyst. A very viscous clear sticky resin was obtained. Its LC was measured (Table I).
EXAMPI.E 4 The reaction described in example 1 was repeated using 24 grams of L-lactide and 13 grams of castor oil with 10 microlitres of catalyst. A verysticky gum-like semisolid with the consistency of solid honey was obtained. The product was opaque off white in colour. Its LC was measured (Table I).
5.5 grams of the product of example 4 and 2.5 grams of calcium stearate were kneaded into a homogeneous wax like material in a mortar and pestle. The product had a chewing gum like consistency and when spread on a surface would stick only with difficulty, preferring to come away with itself.
The handling properties on bone are described in Table II.
11.6 grams of glycolide and 1.6 g L-lactide were weighed into a round bottom glass ampoule and heated for 1 hour at 105-110C at 4mm Hg. Then 34.5 grams of castor oil were added and the mixture stirred for 1 hour at 105-110C
at 4mm Hg. The glycolide was not miscible in the castor oil and vigorous stirring was required to disperse the glycolide in the oil. The mixture was cooled to solidification with stirring to maintain dispersion and kept 1 hour at 500 microns Hg. Then 10 microlitres of stannous octoate catalyst was added and the contents flame seales in the ampoule at 4mm Hg. The mixture was stirred and reacted eight hours at 120-125C. The glycolide was not miscible in the oil, after g ~2~;0488 approximately twelve minutes a white solid appeared, some large particles stuck to the sides of the ampoule. The remainder of the solid remained dispersed as if a colloid producing an offwhite liquid. After cooling to room temperature a stiff nonflowing resin formed which has the appearance similar to the product of example 4 except that it was not sticky or resinous. It could be spread with a spatula much like soft butter which it resembled in colour. The product was smooth and not lumpy butthe large particles which first formed and stuck to the glass were hard and brittle.
The reaciion of example 6 was repeated except that the glycolide was added gradually to castor oil from a powder addition funnel. 17.25 grams of castor oil containing 10 microlitres of stannous octoate was heated at 120-125C with stirring and 6.45 grams of glycolide added at lS minute intervals over an eight hour pe~iod under 4mm Hg. After all the glycolide had been added the reaction was reacted for another two hours. During this reaction only a trace amount of white solid formed, the product was a clear yellow liquid at reaction temperature. Before cooling the stirring was stopped and the small amount of solid allowed to settle.
The product was decanted from the solid and when it had cooled to room temperature an offwhite opaque resin formed.
This product was more fluid than the product of example 6 and had an opalescent appearance. The LC and inherent viscosity of the product were measured (Table I).
The reaction described in examle 6 was repeated using a greater amount of catalyst, 100 microlitres of stannous octoate. Glycolide (11.6 g) and 1.6 grams of L-lactide were heated for 1 hour at 105-110C and 4mm Hg. Then 12~0488 34.5 grams of castor oil were added and mixed for 1 hour at 105-110C at 4mm Hg. The mixture was cooled to solidification with stirring and held at 500 microns Hg for 1 hour at room temperature. Then the 100 microlitres of catalyst was added and the ampoule flame sealed under 4mm Hg. A fine white solid appeared immediately after the lactones had melted and an opaque colloid formed. After the reaction the product cooled into a stiff nonflowing solid identical to example 6 except there was no evidence of hard solid particles on the glass.
10 Analysis of this material by fractionation by dichloromethane is described in Table I.
The reaction of example 6 was repeated except that half the quantity of castor oil (increased lactone:oil ratio) was used and the reaction was carried out under a blanket of dry nitrogen in a 250 ml erlenmeyer flask with a large stirbar to ensure efficient mixing and dispersion of the immiscible glycolide in the oil. 12.9 grams of glycolide was reacted with 17.25 grams of castor oil with 10 microlitres of stannous octoate. As in example 6 a large quantity of white solid particles stuck to the side of the flask. The product resembled that of example 6 with a greater amount of hard white solid formed on the reaction vessel walls.
The reaction of example 9 was repeated using a greater amount of catalyst, 100 microlitres of stannous octoate catalyst. Glycolide (12.9 g) was heated at 105-110C
for 1 hour at 4mm Hg in a 250 ml erlenmeyer flask. Then 17.25 grams of castor oil was added and the mixture stirred and heated at 105-110C for 1 hour at 4mm Hg. The mixture was cooled to solidification with stirring to ensure dispersion of glycolide in the oil and held at 500 microns Hg at room ~Z6048~
temperature for 1 hour. Then the 100 microlitres of catalyst was added and the mixture reacted under a dry nitrogen blanket at 120-125C for eight hours. A fine white solid appeared dispersed in the oil as soon as the lactone melted. The mixtu-e has a colloidal appearance and became whiter with time. After approximately 15 minutes the stir bar slowed and ceased to stir as an offwhite wax forme~. The reaction mixture appeared to be a nonflowing wax-li~:e solid. After the reaction mixture was cooled to room temperature the product was an offwhite waxy solid with the appearance and consistency of white chocolate. The product was smooth and homogeneous with no evidence of hard solid stuck to the glass. The viscosity of the product and analysis of the product after fractionation by dichloromethane are shown in Table I.
Handling of the product on wet bone is described in Table II.
The reaction of example 10 was repeated except that 50 microlitres of stannous oct~oate was used. The product formed was identical. The only difference noted was that the stir bar stirred for approximately 60 minutes before the wax formed stopping its motion.
The reaction of example 10 was repeated except that the glycolide was added gradually to the castor oil - catalyst mixture in the same manner described in example 7. 17.25 grams of castor oil and 100 microlitres of stannous octoate catalyst in a round bottom ampoule were heated at 120-125C.
The glycolide (12.9 grams) was added gradually to the oil-catalyst with stirring over a 10 hour period at 15 minute intervals. The system was kept under 4mm Hg. A finely dispersed white solid formed immediately after the first glycolide was addedand an opaque dispersion formed. The stir l~t;~l!~B
bar kept stirring throughout the reaction but when the mixturecooled to room temperature the same stiff offwhite wax resembling white chocolate that formed in examples 10 and 11 was produced.
The reaction of example 8 was repeated except using half the amount of castor oil (increased lactone:oil ratio).
An offwhite stiff wax resembling the product of example 10 was produced. 11.6 grams of glycolide, 1.6 grams of lactide, 17.25 grams of castor oil, and 100 microlitres of stannous octoate catalyst were reacted. Analysis of the product by fractionation by dichloromethane is described in Table I.
The reaction of example 13 was repeated using less castor oil (increased lactone:oil ratio). 11.6 grams of glycolide and 1.6 grams of L-lactide were reacted with 13 grams of castor oil with 100 mi~rolitres of stannous octoate catalyst. The reaction proceeded as in example 13. An off-white wax resembling white chocolate was formed except that the wax was harder than that produced in examples 10, 11, 12 and 13. Pieces of the wax could be snapped in two rather than bending as with the previously prepared materials. A
description of the handling properties of this material on wet bone is given in Table II.
.9 grams of the product of example 10 and 10 grams ,, of calcium stearate were mixed into a homogenous wax in a mortar and pestle. The handling properties of this material on wet bone are described in Table II. The in vivo absorption and tissue reaction of this material are summarized in Table III.
. ~ .
~0488 The product of example 2 was further reacted with 9.6 grams of glycolide. The glycolide was added gradually to the starting material. 49.5 grams of the product of example 2 was heated at 120-125 C with stirring in a round bottom ampoule. The glycolide was added gradually over an 8 hour period at 15 minute intervals under 4mm Hg. A
homogenous slightly opaque liquid formed which formed a gel upon cooling to room temperature. The product was-,analyzed by LC (Table I).
An absorbable bone wax formulation was prepared for comparison to example 15 by combining 10 g of the wax prepared in example 14 with 5 g of calcium stearate by mixing in a mortar and pestle. The handling properties of this material on wet bone are described in Table II.
As a comparison to the copolyesters prepared from castor oil a polyester was prepared by reacting 52.2 g glycolide, 7.2 g lactide, 22.2 g 1,4-butanediol and 100 20 microlitres of stannous octoate catalyst under partial vacuum for 8 h at 120-125C. This produced a water white clear liquid which became on opalescent resin at room temperature.
To prepare a bone wax, 17.5g of this resin was mixed with 32.5 calcium stearate in a mortar and pestle. A white paste formed. The ~handling properties of this material on wet bone are described in Table II. It is noteworthy that this ; material had poor handling in a wet environment.
':
TABLE I
Characterization of Polyesters of Glycolide and Lactide Prepared by Reaction with Cast~r Oil wt% Peak INHERENT VISCOSI'~fES (dl/g)*
Sample DCM Insoluble Elution Volume DCM DCM
Solid Liquid Chromatograph Soluble Insoluble (DCM Soluble Portions) Sample Fraction Solid -Castor Oil 0 15.48 0.0615 (HFIP) - -0.0353 (DCM) Example 1 0 15.30 0.0389 (DCM) -Example 2 0 14.80 0.0779 (HFIP) - -0.0401 (DCM) Example 3 0 14.6 0.0505 (DCM) Example 4 0 14.0 0.0548 (DCM) example 7 0 15.26 0.0640 (HFIP) -- -- -- -Example 8 12% 15.24 - 0.0681 (HFIP) 0.125 (HFIP) _,_ _ ._ . _ . _ .. .. .
Example 13 25% 15.21 ~ 0.0758 ~HFIP) 0.147 (HFIP) Example 10 35% 15.27 0.1010 (HFIP) Example 16 0 14.26 0.0949 (HFIP) . . . ~
~Solvent used for viscosity measurement shown in brackets.
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Various means of haemostasis have been employed by members of the medical profession. These include: ligation, application of pressure, application of absorbant pads,and use of haemostatic agents such as thrombin and cyanoacrylate adhesives. For control of bleeding from cut bone surfaces in particular a class of materials called bone waxes is often used. The waxes are smeared over the bleeding surface of the bone to plug the osseous vessells and sinuses allowing clotting to occur. Haemostasis is achieved by this tamponade action.
Bone waxes used in surgery are generally prepared from refined beeswax and are not absorbed by the body. The wax remains at the site of application for long periods and could act as a source of inflammatory reaction and could interfere with bone~regrowth (cf. S.J. Sorrenti, et al, Clin.
Orthop., (182), 293-296, (1984).
Any material which is going to be used by surgeons as a bone wax has to have certain suitable handling properties.
The wax must be soft enough to be malleable when kneaded ,between the fingers, it must stick to bone, preferably it ,~30 must not stick to surgeon's gloves, and it must not lose its 'properties when used in the wet bloody field found during :~j surgical operations. That is, the ~wa~x must not absorb sig--,nificant amounts of water and lose its texture. The more , ~- :
12~0488 hydrophobic the wax the less likely this would happen. How-ever, the more hydrophobic the wax the less likely the wax will be infiltrated by body fluids and absorbed by cellular acti-vity. A suitable lipophilic-hydrophilic balance of proper-ties is required to produce a bone wax which absorbs in vivo.
U.S. Pat. 4439420 discloses mixtures for use in control of osseous haemorrhage formed from a base of castor oil and/or other body absorbable naturally occuring oils, synthetic polyols, or water wlth fatty acid salts and bio-compatible water soluble solids such as dextran. The watersoluble solids act as hydrophilic fillers in the base to enhance absorption. Castor oil and the fatty acid salts are too low in molecular size to exhibit significant plastic behavior as defined for example in G. Odian, "Principles of Polymerization", McGraw Hill, New York, (1970), pp. 33-38.
That is, these mixtures are more paste like than plastic, exhibiting little ductility or ~ohesive flow under elongation.
U.S. Pat. 4443430 discloses low molecular weight copolymers of glycolide and lactide, prepared using dodecanol to limit the molecular weight, for use in control of osseous haemorrhage (The use of hydroxyl containing compounds in conjunction with a stannous salt catalyst to produce polylactones has been described in detail by Schindler et al, J. Polym. Sci., (20), 319-326, (1982). Also, high molecular weight polylactones prepared from dihydroxy polyoxyethylenes and low molecular weight glycols have been described by Casey, et al, U.S. Pat.
4452973, U.S. Pat. 4429080, and U.S. Pat. 4438253, and Shalaby, et al, German Pat. DE 3335588Al). In these patents the polymers are formed using dihydroxy water soluble compounds which dissolve in molten glycolide. Because dodecanol, which is a solid at room temperature is used to synthesize the copolymers described in U.S. Pat. 4443430, copolymers with high lactide content (~ 30~) are required to produce soft waxes in the preferred molecular weight range for plastic behavior.
lt is known from experience that lactide/glycolide copolymers in the stated molecular weight range with such high lactide content (~30~) are very tacky and gum-like.
U.S. Pat. 4440789 discloses a low molecular weight polydioxanone polymer for use in control of osseous haemorrhage.
The present invention provides a new synthetic absorbable bone wax which is based on novel polyesters from the reaction of glycolide and/or lactide with castor oil.
Use of the higher molecular weight polyesters from castor oil in the bone wax formulations produces waxes with improved plastic behavior, that is, mouldibility and cohesiveness, compared to the formulations described in U.S. Pat. 4439420.
The waxes have more ductility and elongation compared to for-mulations based on castor oil. The preferred formulations exhibit a combination of properlties that result in superior handling characteristics. The preferred formulations can be spread on an adhere to the cut surface of bone. They do not stick to surgeon's gloves and the handling properties do not change in a wet environment.
It is surprising that glycolide, which is not miscible with castor oil, can~be reacted with it to produce a homogeneous product under the appropriate conditions. The use of castor oil, a high molecular weight coreactant with flexible pendant groups emanating from its glycerol nucleus, provides the ability to use high glycolide:oil mole ratios such as 9:1 and still produce soft malleable waxes that do not readily absorb moisture. The high glycolide content produces a wax which is less sticky and gum-like than copolyesters containing hlgh percentages of lactide. The waxes produced absorb in v~vo .
~.26~488 The copolyesters of the instant invention are pro-duced from reacting glycolide and/or lactide with castor oil and catalyst at elevated -temperatures so that the lactones melt. The preferred catalyst is stannous octoate and is used in the lactone:catalyst mole ratio of 1100:1 to 13000:1. The preferred temperature ran~e i~ 105-125 C. When glycolide is reacted with the castor oil the glycolide is preferentially added to the heated castor oil and catalyst in a gradual manner to produce a more homogeneous product. These copolyesters can be used in bone wax formulations to control osseous hae-morrhage from cut bone.
The bone wax composition of the present invention comprises: i) a polyester resin prepared from glycolide reacted with castor oil and catalyst where the glycolide:oil molar ratio varies from 3:1 to 9:1, preferentially 6:1, which comprises between 40% and 100% by weight of the total compo-sition; and ii) a fatty acid salt which comprises between 0% and 60%
by weight of the total composition; and iii) a water soluble biocompatible solid which comprises between 0% and 10~ by weight of the total composition.
The cation of the fatty acid salt is preferably calcium, the fatty acid anion being saturated or unsaturated and containing from 10 to 22 carbon atoms in the chain. The water soluble solid is selected from any biocompatible material, preferentially polymeric solids such as dextran.
The composition has a wax-like consistency which adheres preferentially to the cut surface of bone rather than to itself or to surgeon's gloves or utensils. The wax can be sterilized by high energy radiation and is effective in the control of osseous haemorrhage from cut bone. The wax absorbs in vivo and does not interfere with subsequent healing and regrowth of bone.
The polyesters of the present invention are prepared from glycolide and/or lactide reacted with castor oil at elevated temperatures using a polymerization catalyst, pre-ferably a stannous salt of a fatty acid.
The polymerization is conducted with pure and dry reactants under vacuum or an atmosphere of dry nitrogen at a temperature sufficient to melt the lactone but not degrade the castor oil, usually between 105-125C. The desired consistency of the final product depends on the glycolide/lactide mole ratio, the lactone/oil mole ratio, and in some cases the amount of catalyst. When glycolide is reacted with the castor oil it is preferred to add the glycolide in a gradual manner to the oil-catalyst mixture. This is because a solid forms when under certain circumstances. Gradual addition of gly-colide ensures a more homogeneous- product. An explanation of this phenomenon which is not meant to limit the scope of the invention is that this solid, which melts above the reaction temperature, is polyester which solidifies because the poly-glycolide component produces high melting polymer chains with the capability of forming crystalline domains. It is also possible that some or all of the glycolide in the solid polymer has been initiated by residual water or other hydroxy component rather than the castor oil. When low levels of stannous octoate catalyst are used (glycolide:catalyst mole ratio 9000:1) the solids does not form immediately but tends to form large particles which settle out of the product. When high calalyst levels are used (e.g. glycolide:catalyst mole ratio 1100:1) the solid forms immediately and the particles are small enough to remain suspended in the product as in a colloid.
This product when cooled is waxy with no grittiness or hardness associated with the solid. No solid forms when the glycolide is added gradually to the castor oil - catalyst mixture when ~260488 the glycolide:oil ratio is 3:1 an~ the glycolide:c~talyst ratio is 4500:1 (Example 7). To verify that glycolide has reacted with the castor oil, liquid chromatography of this 3:1 glycolide:oil mole ratio product was carried out. Also, the solid was fractionated from the polyesters with higher glyco-lide:catalyst mole ratios using dichloromethane, a good solvent for castor oil, and the DCM soluble portion analyzed by liquid chromatography for evidence of unreacted castor oil. The results of the analyse~ are ~iven in Table I. The results show that glycolide does react with castor oil. Inherent viscosity results in Table I show that the solid isolated by fractionating by dichloromethane is a higher molecular weight material. Infrared analysis of the solid revealed it to be a polymer of glycolide.
Specific details concerning the preparation of copolyesters of glycolide and/or lactide with castor oil are set forth in the followingexamples.
The following example~ are provided to further illustrate preferred embodiments of the present invention.
The results of analysis of the synthesized polyesters are provided in Table 1. All liquid chromatography was carried out in tetrahydrofuran solvent at 1 ml/min flow rate using samples of concentration of O.lg/lOml. The samples were analyzed using two 30 cm x 1 cm Dupont ZorbaxTM 60S size exclusion columns calibrated with monodisperse anionically polymerized polystyrene. All inherent viscosity measurements were carried out in either hexafluoroisopropanol or dichloromethane solvent at a concentration of lg/25ml and a temperature of 25C.
The bone wax composition of the present invention consists preferably of a polyester based on glycolide and castor oil with a glycolide:oil mole ratio of 6:1 mixed with calcium stearate. The composition optionally includes an agent for enhancing in vivo absorption, a preferred agent in .
~z6~4a~
this connection being dextran. The inherent viscosity of the preferred polyester is about 0.101 dl/g. This polyester is workable and softenable by hand and has a wax-like consistency.
Approximately 80% of the glycolide is present as a polymeric solid which melts above room temperature.
To prepare the bone wax formulation the components are mixed together in a mo.tar and pestle to produce a homogeneous product. On an industrial scale the components may be mixed using a dough mixer, mill, extruder, or some other means of providing mechanical shear and mixing.
Table II sets forth the consistency and tactile properties of the instant composition. A comparison with a composition claimed in U.S. Pat. 4439420 is made. It will be noted from Table II that the polyester with 6:1 glycolide:
castor oil mole ratio mixed with calcium stearate on an equal weight basis provides the most desirable properties of those compositions listed in the Tabl,e. Applicant has also found that sterilization with Co60 gamma radiation has no adverse effect on the consistency and tactile properties of any of the instant compositions of Table II.
The in vivo tissue reaction and absorption of the preferred composition in rats is described in Table III. Rods of the bone wax composition were injected into the gluteal muscles of rats from pre-loaded 16 gauge needles. Adult female Woodlyn Wistar albino rats were used. All rats were held in the animal colony for at least one week prior to being employed in the study. They were maintained according to the guidelines set down by the Canadian Association for Laboratory Animal Sciences and had food and water ad libitum.
All implantation procedures were carried out with the test animals under general anaesthesia (MetofaneTM). The skin of the rat was shaved, washed with GAMOPHENTM leaves and painted lZ~i0488 with IOPREP
Two rats were used for each time period studied for a total of four muscles per time period. The implants only elicited slight to moderate tissue reaction with no evidence of necrosis. Absorbable sutures of polyglycolide generally absorb in vivo between 90 to 100 days in vivo. After 140 days in vivo the bone wax formulation was on average 90% absorbed.
It is surmised that absorption would have been completed after 200 days. The hydrophobic castor oil nucleous of the poly-ester serves to repel tissue fluid absorption and decreasescellular infiltration.
The following examples are provided to further illustrate the preferred embodiments of the present invention.
21.2 grams of L-lactide was charged into a round bottom ampoule, the lactide was heated at 105-110C for one hour at 4mm Hg, then 51.6 gramslof castor oil was added and the mixture stirred at 105-110C at 4mm Hg for one hour. The lactide was miscible in the oil. After this mixture was cooled to solidification and subjected to 500 microns Hg vacuum at room temperature for one hour. After breaking the vacuum, 10 microlitres of stannous octoate was added and the ampoule flame sealed under 4mm Hg. The contents of the ampoule were stirred and reacted eight hours at 120-125C. A fluid yellow oil similar in consistency to castor oil was obtained. This was characterized by liquid chromatography as shown in Table 1.
The reaction described in example 1 was repeated using 24.1 grams of L-lactide and 26.2 grams of castor oil with 10 microlitres of catalyst. A more viscous oil was obtained.
Its LC was measured (Table I).
~)4Ba The reaction described in example 1 was repeated using 24 grams of L-lactide and l9.S grams of castor oil with microlitresof catalyst. A very viscous clear sticky resin was obtained. Its LC was measured (Table I).
EXAMPI.E 4 The reaction described in example 1 was repeated using 24 grams of L-lactide and 13 grams of castor oil with 10 microlitres of catalyst. A verysticky gum-like semisolid with the consistency of solid honey was obtained. The product was opaque off white in colour. Its LC was measured (Table I).
5.5 grams of the product of example 4 and 2.5 grams of calcium stearate were kneaded into a homogeneous wax like material in a mortar and pestle. The product had a chewing gum like consistency and when spread on a surface would stick only with difficulty, preferring to come away with itself.
The handling properties on bone are described in Table II.
11.6 grams of glycolide and 1.6 g L-lactide were weighed into a round bottom glass ampoule and heated for 1 hour at 105-110C at 4mm Hg. Then 34.5 grams of castor oil were added and the mixture stirred for 1 hour at 105-110C
at 4mm Hg. The glycolide was not miscible in the castor oil and vigorous stirring was required to disperse the glycolide in the oil. The mixture was cooled to solidification with stirring to maintain dispersion and kept 1 hour at 500 microns Hg. Then 10 microlitres of stannous octoate catalyst was added and the contents flame seales in the ampoule at 4mm Hg. The mixture was stirred and reacted eight hours at 120-125C. The glycolide was not miscible in the oil, after g ~2~;0488 approximately twelve minutes a white solid appeared, some large particles stuck to the sides of the ampoule. The remainder of the solid remained dispersed as if a colloid producing an offwhite liquid. After cooling to room temperature a stiff nonflowing resin formed which has the appearance similar to the product of example 4 except that it was not sticky or resinous. It could be spread with a spatula much like soft butter which it resembled in colour. The product was smooth and not lumpy butthe large particles which first formed and stuck to the glass were hard and brittle.
The reaciion of example 6 was repeated except that the glycolide was added gradually to castor oil from a powder addition funnel. 17.25 grams of castor oil containing 10 microlitres of stannous octoate was heated at 120-125C with stirring and 6.45 grams of glycolide added at lS minute intervals over an eight hour pe~iod under 4mm Hg. After all the glycolide had been added the reaction was reacted for another two hours. During this reaction only a trace amount of white solid formed, the product was a clear yellow liquid at reaction temperature. Before cooling the stirring was stopped and the small amount of solid allowed to settle.
The product was decanted from the solid and when it had cooled to room temperature an offwhite opaque resin formed.
This product was more fluid than the product of example 6 and had an opalescent appearance. The LC and inherent viscosity of the product were measured (Table I).
The reaction described in examle 6 was repeated using a greater amount of catalyst, 100 microlitres of stannous octoate. Glycolide (11.6 g) and 1.6 grams of L-lactide were heated for 1 hour at 105-110C and 4mm Hg. Then 12~0488 34.5 grams of castor oil were added and mixed for 1 hour at 105-110C at 4mm Hg. The mixture was cooled to solidification with stirring and held at 500 microns Hg for 1 hour at room temperature. Then the 100 microlitres of catalyst was added and the ampoule flame sealed under 4mm Hg. A fine white solid appeared immediately after the lactones had melted and an opaque colloid formed. After the reaction the product cooled into a stiff nonflowing solid identical to example 6 except there was no evidence of hard solid particles on the glass.
10 Analysis of this material by fractionation by dichloromethane is described in Table I.
The reaction of example 6 was repeated except that half the quantity of castor oil (increased lactone:oil ratio) was used and the reaction was carried out under a blanket of dry nitrogen in a 250 ml erlenmeyer flask with a large stirbar to ensure efficient mixing and dispersion of the immiscible glycolide in the oil. 12.9 grams of glycolide was reacted with 17.25 grams of castor oil with 10 microlitres of stannous octoate. As in example 6 a large quantity of white solid particles stuck to the side of the flask. The product resembled that of example 6 with a greater amount of hard white solid formed on the reaction vessel walls.
The reaction of example 9 was repeated using a greater amount of catalyst, 100 microlitres of stannous octoate catalyst. Glycolide (12.9 g) was heated at 105-110C
for 1 hour at 4mm Hg in a 250 ml erlenmeyer flask. Then 17.25 grams of castor oil was added and the mixture stirred and heated at 105-110C for 1 hour at 4mm Hg. The mixture was cooled to solidification with stirring to ensure dispersion of glycolide in the oil and held at 500 microns Hg at room ~Z6048~
temperature for 1 hour. Then the 100 microlitres of catalyst was added and the mixture reacted under a dry nitrogen blanket at 120-125C for eight hours. A fine white solid appeared dispersed in the oil as soon as the lactone melted. The mixtu-e has a colloidal appearance and became whiter with time. After approximately 15 minutes the stir bar slowed and ceased to stir as an offwhite wax forme~. The reaction mixture appeared to be a nonflowing wax-li~:e solid. After the reaction mixture was cooled to room temperature the product was an offwhite waxy solid with the appearance and consistency of white chocolate. The product was smooth and homogeneous with no evidence of hard solid stuck to the glass. The viscosity of the product and analysis of the product after fractionation by dichloromethane are shown in Table I.
Handling of the product on wet bone is described in Table II.
The reaction of example 10 was repeated except that 50 microlitres of stannous oct~oate was used. The product formed was identical. The only difference noted was that the stir bar stirred for approximately 60 minutes before the wax formed stopping its motion.
The reaction of example 10 was repeated except that the glycolide was added gradually to the castor oil - catalyst mixture in the same manner described in example 7. 17.25 grams of castor oil and 100 microlitres of stannous octoate catalyst in a round bottom ampoule were heated at 120-125C.
The glycolide (12.9 grams) was added gradually to the oil-catalyst with stirring over a 10 hour period at 15 minute intervals. The system was kept under 4mm Hg. A finely dispersed white solid formed immediately after the first glycolide was addedand an opaque dispersion formed. The stir l~t;~l!~B
bar kept stirring throughout the reaction but when the mixturecooled to room temperature the same stiff offwhite wax resembling white chocolate that formed in examples 10 and 11 was produced.
The reaction of example 8 was repeated except using half the amount of castor oil (increased lactone:oil ratio).
An offwhite stiff wax resembling the product of example 10 was produced. 11.6 grams of glycolide, 1.6 grams of lactide, 17.25 grams of castor oil, and 100 microlitres of stannous octoate catalyst were reacted. Analysis of the product by fractionation by dichloromethane is described in Table I.
The reaction of example 13 was repeated using less castor oil (increased lactone:oil ratio). 11.6 grams of glycolide and 1.6 grams of L-lactide were reacted with 13 grams of castor oil with 100 mi~rolitres of stannous octoate catalyst. The reaction proceeded as in example 13. An off-white wax resembling white chocolate was formed except that the wax was harder than that produced in examples 10, 11, 12 and 13. Pieces of the wax could be snapped in two rather than bending as with the previously prepared materials. A
description of the handling properties of this material on wet bone is given in Table II.
.9 grams of the product of example 10 and 10 grams ,, of calcium stearate were mixed into a homogenous wax in a mortar and pestle. The handling properties of this material on wet bone are described in Table II. The in vivo absorption and tissue reaction of this material are summarized in Table III.
. ~ .
~0488 The product of example 2 was further reacted with 9.6 grams of glycolide. The glycolide was added gradually to the starting material. 49.5 grams of the product of example 2 was heated at 120-125 C with stirring in a round bottom ampoule. The glycolide was added gradually over an 8 hour period at 15 minute intervals under 4mm Hg. A
homogenous slightly opaque liquid formed which formed a gel upon cooling to room temperature. The product was-,analyzed by LC (Table I).
An absorbable bone wax formulation was prepared for comparison to example 15 by combining 10 g of the wax prepared in example 14 with 5 g of calcium stearate by mixing in a mortar and pestle. The handling properties of this material on wet bone are described in Table II.
As a comparison to the copolyesters prepared from castor oil a polyester was prepared by reacting 52.2 g glycolide, 7.2 g lactide, 22.2 g 1,4-butanediol and 100 20 microlitres of stannous octoate catalyst under partial vacuum for 8 h at 120-125C. This produced a water white clear liquid which became on opalescent resin at room temperature.
To prepare a bone wax, 17.5g of this resin was mixed with 32.5 calcium stearate in a mortar and pestle. A white paste formed. The ~handling properties of this material on wet bone are described in Table II. It is noteworthy that this ; material had poor handling in a wet environment.
':
TABLE I
Characterization of Polyesters of Glycolide and Lactide Prepared by Reaction with Cast~r Oil wt% Peak INHERENT VISCOSI'~fES (dl/g)*
Sample DCM Insoluble Elution Volume DCM DCM
Solid Liquid Chromatograph Soluble Insoluble (DCM Soluble Portions) Sample Fraction Solid -Castor Oil 0 15.48 0.0615 (HFIP) - -0.0353 (DCM) Example 1 0 15.30 0.0389 (DCM) -Example 2 0 14.80 0.0779 (HFIP) - -0.0401 (DCM) Example 3 0 14.6 0.0505 (DCM) Example 4 0 14.0 0.0548 (DCM) example 7 0 15.26 0.0640 (HFIP) -- -- -- -Example 8 12% 15.24 - 0.0681 (HFIP) 0.125 (HFIP) _,_ _ ._ . _ . _ .. .. .
Example 13 25% 15.21 ~ 0.0758 ~HFIP) 0.147 (HFIP) Example 10 35% 15.27 0.1010 (HFIP) Example 16 0 14.26 0.0949 (HFIP) . . . ~
~Solvent used for viscosity measurement shown in brackets.
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Claims (20)
1. Process for the preparation of copolyester resins for use as sealants to control osseous haemorrhage which comprises reacting glycolide, lactide or mixtures thereof with castor oil in the presence of a catalyst at a temper-ature high enough to melt the lactones.
2. Process according to claim 1, wherein said catalyst comprises stannous octoate.
3. Process according to claim 2, wherein the lactone:
catalyst mole ratio is between about 1100:1 and 13000:1.
catalyst mole ratio is between about 1100:1 and 13000:1.
4. Process according to claims 1,2 or 3, wherein the reaction temperature is between about 105 and 125°C.
5. Process according to claim 1, wherein glycolide is reacted with castor oil.
6. Process according to claim 5, wherein said glycolide is gradually added to heated castor oil, to produce homogeneous copolyester resins.
7. Process according to claim 5, wherein the glycolide:
castor oil molar ratio varies from 3:1 to 9:1.
castor oil molar ratio varies from 3:1 to 9:1.
8. Process according to claim 7, wherein the glycolide:
castor oil molar ratio is about 6:1.
castor oil molar ratio is about 6:1.
9. Process according to claim 7, which comprises adding a fatty acid salt and a water soluble biocompatible solid to said copolyester resin to produce a bone wax composition wherein said copolyester resin comprises between 40% and 100% by weight of the total composition, said fatty acid salt comprises between 0% and 60% by weight of the total composition; and said water soluble biocompatible solid comprises between 0% and 10% by weight of the total compo-sition.
10. Process according to claim 9, wherein the cation of said fatty acid salt is calcium; the fatty acid anion being saturated or unsaturated and containing from 10 to 22 carbon atoms in the chain.
11. Process according to claim 9, wherein said water soluble biocompatible solid is dextran.
12. Process according to claims 1, 2 or 3, wherein the polymerization is conducted with pure and dry reactants under vacuum.
13. Process according to claims 1, 2 or 3, wherein the polymerization is conducted in an atmosphere of dry nitrogen.
14. Copolyesters of castor oil with glycolide, lactide or mixtures thereof.
15. Copolyesters of castor oil with glycolide.
16. Copolyesters of castor oil with glycolide, wherein the glycolide:castor oil molar ratio varies from 3:1 to 9:1.
17. Copolyesters of castor oil with glycolide wherein the glycolide:castor oil molar ratio is about 6:1.
18. A composition comprising a 40% to 100% by weight of a copolyester of castor oil with glycolide wherein the glycolide:castor oil molar ratio varies from 3:1 to 9:1, 0 to 60% by weight of a fatty acid salt and 0 to 10% by weight of a water soluble biocompatible solid.
19. A composition as defined in claim 18, wherein the cation of said fatty acid salt is calcium, the fatty acid anion being saturated or unsaturated and containing from 10 to 22 carbon atoms in the chain.
20. A composition as defined in claim 18, wherein the water soluble biocompatible solid is dextran.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000513258A CA1260488A (en) | 1986-07-07 | 1986-07-07 | Absorbable bone wax formulation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000513258A CA1260488A (en) | 1986-07-07 | 1986-07-07 | Absorbable bone wax formulation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1260488A true CA1260488A (en) | 1989-09-26 |
Family
ID=4133512
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000513258A Expired CA1260488A (en) | 1986-07-07 | 1986-07-07 | Absorbable bone wax formulation |
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| Country | Link |
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| CA (1) | CA1260488A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0610086A2 (en) * | 1993-02-05 | 1994-08-10 | Ethicon, Inc. | Castor oil polymers for needle coatings |
| US5681873A (en) * | 1993-10-14 | 1997-10-28 | Atrix Laboratories, Inc. | Biodegradable polymeric composition |
| US6261583B1 (en) | 1998-07-28 | 2001-07-17 | Atrix Laboratories, Inc. | Moldable solid delivery system |
| WO2005095378A3 (en) * | 2004-03-24 | 2006-03-16 | Archer Daniels Midland Co | Vegetable based dioxanone derivatives, synthesis and uses thereof |
| WO2008029527A1 (en) | 2006-09-04 | 2008-03-13 | Bio-Energy Corporation | Polyester polyol |
-
1986
- 1986-07-07 CA CA000513258A patent/CA1260488A/en not_active Expired
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0610086A2 (en) * | 1993-02-05 | 1994-08-10 | Ethicon, Inc. | Castor oil polymers for needle coatings |
| US5371176A (en) * | 1993-02-05 | 1994-12-06 | Ethicon, Inc. | Castor oil polymers |
| EP0610086A3 (en) * | 1993-02-05 | 1994-12-21 | Ethicon Inc | Castor oil polymers for needle coatings. |
| US5681873A (en) * | 1993-10-14 | 1997-10-28 | Atrix Laboratories, Inc. | Biodegradable polymeric composition |
| US6261583B1 (en) | 1998-07-28 | 2001-07-17 | Atrix Laboratories, Inc. | Moldable solid delivery system |
| WO2005095378A3 (en) * | 2004-03-24 | 2006-03-16 | Archer Daniels Midland Co | Vegetable based dioxanone derivatives, synthesis and uses thereof |
| US7754823B2 (en) | 2004-03-24 | 2010-07-13 | Archer-Daniels-Midland Company | Vegetable based dioxanone derivatives, synthesis and uses thereof |
| WO2008029527A1 (en) | 2006-09-04 | 2008-03-13 | Bio-Energy Corporation | Polyester polyol |
| EP2065421A1 (en) * | 2006-09-04 | 2009-06-03 | Bio-Energy Corporation | Polyester polyol |
| EP2065421A4 (en) * | 2006-09-04 | 2010-12-15 | Bio Energy Corp | Polyester polyol |
| US8058470B2 (en) | 2006-09-04 | 2011-11-15 | Bio-Energy Corporation | Polyester polyol |
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