CA1338980C - Bone cement for sustained release of substances - Google Patents
Bone cement for sustained release of substancesInfo
- Publication number
- CA1338980C CA1338980C CA000573388A CA573388A CA1338980C CA 1338980 C CA1338980 C CA 1338980C CA 000573388 A CA000573388 A CA 000573388A CA 573388 A CA573388 A CA 573388A CA 1338980 C CA1338980 C CA 1338980C
- Authority
- CA
- Canada
- Prior art keywords
- component
- bone cement
- emulsifying agent
- therapeutic substance
- diagnostic
- 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 - Fee Related
Links
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
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/001—Use of materials characterised by their function or physical properties
- A61L24/0015—Medicaments; Biocides
-
- 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
- A61L24/001—Use of materials characterised by their function or physical properties
-
- 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
- A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
-
- 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
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
- A61L2300/406—Antibiotics
-
- 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
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
Abstract
A bone cement is disclosed wherein the liquid component contains a therapeutic or diagnostic sub-stance in combination with an emulsifying agent for said substance.
Description
P.C. 7241 BONE CEMENT FOR SUSTAINED RELEASE OF SUBSTANCES
The present invention relates to a bone cement.
More particularly, the present invention relates to a bone cement wherein a diagnostic or therapeutic agent is incorporated in the liquid component with the agent being incorporated by the use of an emulsifying agent.
Bone cements find wide usage in a variety of applications. For instance, they are used for cementing implants in place, for the anchoring of endoprostheses of the joints, in the treatment of skull defects, and for the performance of spinal fusion.
Typically, these bone cements are made by mixing together a powdered homopolymer or copolymer of methyl-methacrylate and a suitable liquid monomer, usually methylmethacrylate in the presence of a catalyst system. Additionally, the bone cement may also contain x-ray contrast agents, such as barium sulfate or zirconium dioxide, or dyes for the identification of the bone cement in the body.
In usage, a doughy mixture is prepared from the two components which is then placed in the body and allowed to set in situ due to polymerization of the monomer. Polymerization of the monomer can be accel-erated by the presence of a redox catalyst system, usually an organic peroxy compound, such as dibenzoyl peroxide, plus a reducing component, such as p-toluidine.
The placement of a foreign object, such as the bone cement or cemented prosthesis, requires that ~ prophylactic measures be taken to guard against infec-~ tion at the boundary surfaces found between the bone cement and bone, and/or between the bone, bone cement, and prosthesis. Such prophylactic measures have generally involved the addition of antibiotics to the one cement.
For instance, in United States Patent No. 4,059, 684, the antibiotics which are added to the bone cement are the hydrohalides or sulfates of gentamicin in combination with sodium chloride, potassium chloride, sodium bromide or potassium bromide. In this patent, the antibiotic can be incorporated into either the powdered polymer or copolymer or the liquid monomer.
No mention is made of the addition of an emulsifying agent to incorporate the antibiotic into the liquid monomer.
Other antibiotics which have been added to bone cement include penicillin and tetracycline, which in most instances, are added to the powdered polymer or copolymer.
In United Kingdom Patent No. 1,532,318, the methylmethacrylate liquid monomer is present as an emulsion in water. No mention is made of the incorporation of antibiotics into this monomer.^
In all situations wherein an antibiotic is added to a bone cement, the initial release is in a relative-ly high concentration to assure its bactericidal and bacteriostatic action. After this initial release, a diminution o~ the concentration takes place with the release rate, which is now lower, remaining relatively constant over a longer period of time. The net result is that even though the antibiotic release is sus-tained, the active concentration of the antibiotic is low. Thus, early infections may be prevented but later infections may not be reliably prevented or combatted.
As is known, increasing the concentration of antibiotic may impair the mechanical strength of the bone cement so there remains a need for a bone cement from which the antibiotic will be released at both a sustained rate and at a high concentration.
Fig. 1 is a graph showing the concentration of released erythromycin over a sustained time period from a bone cement of the present invention.
The present invention is directed to a bone cement comprising the combination of components A and B
wherein:
Component A comprises a powdered polymer or copolymer of an acrylic ester and, Component B comprises a liquid monomer of an acrylic ester containing (a) a diagnostic or thera-peutic substance, and (b) an emulsifying agent for said diagnostic or therapeut-c substance, whereby the incorporation of said diagnostic or therapeutic sub-stance in the bone cement composition is substantially in component B.
Preferred powdered polymers or copolymers of acrylic esters include methacrvlates, methylmethacry-lates and copolymers of methylmethacrylate and styrene.
Preferred liquid monomers of acrylic esters include methylmethacrylates.
Prepared substances include therapeutic substances such as erythromycin, gentamicin, or colistin, combina-tions thereof, or pharmaceutically acceptable salts thereof. Most preferred are pharmaceutically accept-able salts of erythromycin.
Preferred emulsifying agents include sorbitan mono oleate polyoxyethylene and sodium dihexyl sulfo-succinate.
Another aspect of the present invention is the liquid monomer of an acrylic ester containing the diagnostic or therapeutic substance and an emulsifying agent for said substance.
The present invention provides a composition for the preparation of a bone cement from which, e.g., an antibiotic will be released in a sustained high concentration.
The first component of the composition comprises a powdered polymer or copolymer of an acrylic ester.
By the term "polymer or copolymer of an acrylic ester"
is meant a polymer of an acrylate, e.g. a methacrylate, - polymethylmethacrylate etc., as well as copolymers of the above compounds with non-acrylates, for example, such as methyl methacrylate-styrene copolymers. In addition, the powder component may contain an x-ray contrast agent such as barium sulfate or zirconium dioxide. If present, these x-ray contrast agents, especially barium sulfate, are added in the amount of about 5 to 15 weight percent with respect to the powdered polymer or copolymer. A catalyst, typically benzoyl peroxide, may also be incorporated in the powdered polymer or copolymer, in which case a reducing agent, for example, dimethyl p-toluidine, would be incorporated in the liquid monomer. Alternatively, the powdered polymer or copolymer may contain a reducing agent, in which case a peroxide catalyst would be incorporated in the liquid monomer.
The second component of the bone cement composition comprises a liquid monomer of an acrylic ester containing (a) a diagnostic or therapeutic substance and (b) an emulsifying agent for said diag-nostic or therapeutic substance. This results in the incorporation of the diagnostic or therapeutic sub-stance present in the bone cement composition being substantially in component B. By "substantially" is meant that at least 75% of the diagnostic or thera-peutic substance in the composition is in component B.
Higher ranges can also be used with as much as 80-90%
-5- l 33898~
of the diagnostic or therapeutic substance being incor-porated in component B. In a preferred case, 100 percent of the diagnostic or therapeutic agent in the bone cement composition can be incorporated in component B. A preferred liquid monomer of an acrylic ester is methylmethacrylate. In the present invention, it has surprisingly been found that incorporation of the diagnostic or therapeutic agent into the liquid monomer by means of the emulsifying agent leads to a high sustained concentration of the diagnostic or therapeutic substance over time. The remainder of ~the specification will discuss the increased concentration of therapeutic substances, especially antibiotics, but is is to be understood that the discussion applies equally well to diagnostic substances, such as radio-active tracers, etc., as well as other classes of therapeutic substances such as anti-cancer drugs, anti-inflammatory drugs, immunostimulants, immunosup-pressants, osteogenesis promotors, etc.
In the present invention, a major proportion of the antibiotic is preferably incorporated in the liquid monomer by means of an emulsifying agent. This results in a number of advantages over the previously known methods in which the antibiotics were compounded with the powder component of the cement. One problem associated with this method was the requirement that there be proper mixing of the therapeutic agent with the powder component with homogeneous dispersion of the antibiotic and elimination of aggregates. Such results were not always achieved. Other requirements for the effective release of the therapeutic substance into the liquid monomer; namely the requirement of a large surface area for the diffusion of water from the surrounding tissues into the cement mantle and the requirement that the substance contained in the cement 1 338980 .
mantle be soluble in the liquid containing the sub-stance, are eliminated. The liquid which does get transported out of the cement mantle into the sur-rounding tissue contains the desired substance. Thus, a number of advantages are apparent.
Examples of antibiotics which can be incorporated into the liquid monomer are erythromycin, gentamicin, colistin, penicillin, Terramycin, Aureomycin, Vibra-mycin, etc. Especially preferred anitbiotics are erythromycin, gentamycin and colistin. The concen-tration of antibiotic which may be incorporated into the liquid monomer ranges from about 0.03 to about 8.0 weight percent, based on the liquid monomer. Of course, those skilled in the art to which this inven-tion applies will recognize that, depending upon theactivity of the antibiotic, higher or lower ranges can also be used.
In the present invention, the antibiotic, or other diagnostic or therapeutic agent, is incorporated into the liquid monomer by means of a emulsifying agent. An especially preferred emulsifying agent is sorbitan mono-oleate polyoxyethylene, also known as Tween 80.
Another preferred emulsifying agent is sodium dihexyl sulfosuccinate. Other emulsifying agents which can be used in the present invention are polyoxyethylensor-bitanmonopalmitate, polyoxyethylensorbitanmonostearate and polyoxyethylenesorbitanmonooleate. In addition to stabilizing the therapeutic substance in the liquid monomer, the emulsifying agent also possibly serves to dissipate the heat formed during the exothermic poly-merization of the monomer. In the present invention, the emulsifying agent is present in an amount ranging from about 0.1 to about 10.0 weight percent, based on the liquid monomer.
* Trademark ,~
In formulating the liquid monomer/therapeutic - substance component of the present invention, the order of mixing of the ingredients is not critical. For instance, the antibiotic, for example, may be dissolved in water, if it is water soluble, and the emulsifying agent can be added to the dissolved antibiotic. The emulsified antibiotic can then be added to the liquid monomer. If the antibiotic is soluble in the liquid monomer, the antibiotic may be added to the monomer containing the emulsifying agent or the antibiotic mixed with the emulsifying agent may be added to the liquid monomer.
While the invention has been described with relation to a bone cement comprising the combination of the powdered polymer or copolymer and the liquid monomer containing the diagnostic or therapeutic substance plus the emulsifying agent, it will be apparent that the liquid monomer itself containing the emulsifier and diagnostic or therapeutic substance is also contemplated as being another aspect of the present invention. This liquid monomer/therapeutic or diagnostic substance/emulsifying agent composition can be used as a foreproduct for bone cement. Accordingly, such composition also orms a part of the present invention.
The present invention is illustrated by the following examples, which are not to be construed as limiting the invention, the scope of which is to be determined by the appended claims.
Bone cements of the invention are made by adding the following indicated liquid components to a powder component containing a radiopacifier. The cement is hand-mixed in a conventional manner for known bone cement. The following examples give the method of preparing the liquid component to be mixed with the powdered component.
Example 1 The liquid component was prepared by mixing the following ingredients in the order given. The com-ponents were mixed in a resealable polyethylene container until all were evenly dispersed.
1. 3.655 g erythromycin gluceptate 2. 17.8 g water 3. 1.8 ml Tween 80 4. 100 ml of Methyl methacrylate monomer (97.4% v/v), (containing also 2.5 ml N, N-dimethyl-para-toluidine (2.6% v/v) and 75 ' 15 ppm hydroquinone).
One fifth of this mixture was added per dose of the powder component, 40 g, (containing 6.0 g Poly-methyl methacrylate (15%w/w), 30.0 g of Methyl methacrylate-styrene-copolymer (75% w/w) and 4.0 g Barium Sulfate U.S.P. (lOZ w/w)) and hand-mixed to form the bone cement.
Example 2 Another liquid component was prepared by adding ~ the following ingredients in the order given in the same way as Example l.
1. 1.5 g erythromycin gluceptate 2. 7.08 g water 3. 0.7 ml Tween-80 4. 40.0 ml Methyl methacrylate (97.4% v/v Methyl methacrylate, 2.6% v/v N, N-dimethyl-para-toluidine, 75 ~ 15 ppm hydroquinone).
Two doses of the powder component (80 g) con-taining 12.0 g Polymethyl methacrylate (15% w/w), 60.0 g Methyl methacrylate-styrene-copolymer (75% w/w), 8 g Barium Sulfate U.S.P. (10% w/w)) were hand-mixed with the liquid to form the cement.
Example 3 Another liquid component was prepared by adding the following ingredients in the order given.
1. 0.731 g erythromycin gluceptate 2. 2.07 g water 3. 3.2 g Aerosol ~-80~
4. 40.0 ml Methyl methacrylate (containing 97.4% v/v Methyl methacrylate, 2.6% v/v N, N-dimethyl-para-toluidine(2.6Z) and 75 ~ 15 ppm of hydroquinone).
The present invention relates to a bone cement.
More particularly, the present invention relates to a bone cement wherein a diagnostic or therapeutic agent is incorporated in the liquid component with the agent being incorporated by the use of an emulsifying agent.
Bone cements find wide usage in a variety of applications. For instance, they are used for cementing implants in place, for the anchoring of endoprostheses of the joints, in the treatment of skull defects, and for the performance of spinal fusion.
Typically, these bone cements are made by mixing together a powdered homopolymer or copolymer of methyl-methacrylate and a suitable liquid monomer, usually methylmethacrylate in the presence of a catalyst system. Additionally, the bone cement may also contain x-ray contrast agents, such as barium sulfate or zirconium dioxide, or dyes for the identification of the bone cement in the body.
In usage, a doughy mixture is prepared from the two components which is then placed in the body and allowed to set in situ due to polymerization of the monomer. Polymerization of the monomer can be accel-erated by the presence of a redox catalyst system, usually an organic peroxy compound, such as dibenzoyl peroxide, plus a reducing component, such as p-toluidine.
The placement of a foreign object, such as the bone cement or cemented prosthesis, requires that ~ prophylactic measures be taken to guard against infec-~ tion at the boundary surfaces found between the bone cement and bone, and/or between the bone, bone cement, and prosthesis. Such prophylactic measures have generally involved the addition of antibiotics to the one cement.
For instance, in United States Patent No. 4,059, 684, the antibiotics which are added to the bone cement are the hydrohalides or sulfates of gentamicin in combination with sodium chloride, potassium chloride, sodium bromide or potassium bromide. In this patent, the antibiotic can be incorporated into either the powdered polymer or copolymer or the liquid monomer.
No mention is made of the addition of an emulsifying agent to incorporate the antibiotic into the liquid monomer.
Other antibiotics which have been added to bone cement include penicillin and tetracycline, which in most instances, are added to the powdered polymer or copolymer.
In United Kingdom Patent No. 1,532,318, the methylmethacrylate liquid monomer is present as an emulsion in water. No mention is made of the incorporation of antibiotics into this monomer.^
In all situations wherein an antibiotic is added to a bone cement, the initial release is in a relative-ly high concentration to assure its bactericidal and bacteriostatic action. After this initial release, a diminution o~ the concentration takes place with the release rate, which is now lower, remaining relatively constant over a longer period of time. The net result is that even though the antibiotic release is sus-tained, the active concentration of the antibiotic is low. Thus, early infections may be prevented but later infections may not be reliably prevented or combatted.
As is known, increasing the concentration of antibiotic may impair the mechanical strength of the bone cement so there remains a need for a bone cement from which the antibiotic will be released at both a sustained rate and at a high concentration.
Fig. 1 is a graph showing the concentration of released erythromycin over a sustained time period from a bone cement of the present invention.
The present invention is directed to a bone cement comprising the combination of components A and B
wherein:
Component A comprises a powdered polymer or copolymer of an acrylic ester and, Component B comprises a liquid monomer of an acrylic ester containing (a) a diagnostic or thera-peutic substance, and (b) an emulsifying agent for said diagnostic or therapeut-c substance, whereby the incorporation of said diagnostic or therapeutic sub-stance in the bone cement composition is substantially in component B.
Preferred powdered polymers or copolymers of acrylic esters include methacrvlates, methylmethacry-lates and copolymers of methylmethacrylate and styrene.
Preferred liquid monomers of acrylic esters include methylmethacrylates.
Prepared substances include therapeutic substances such as erythromycin, gentamicin, or colistin, combina-tions thereof, or pharmaceutically acceptable salts thereof. Most preferred are pharmaceutically accept-able salts of erythromycin.
Preferred emulsifying agents include sorbitan mono oleate polyoxyethylene and sodium dihexyl sulfo-succinate.
Another aspect of the present invention is the liquid monomer of an acrylic ester containing the diagnostic or therapeutic substance and an emulsifying agent for said substance.
The present invention provides a composition for the preparation of a bone cement from which, e.g., an antibiotic will be released in a sustained high concentration.
The first component of the composition comprises a powdered polymer or copolymer of an acrylic ester.
By the term "polymer or copolymer of an acrylic ester"
is meant a polymer of an acrylate, e.g. a methacrylate, - polymethylmethacrylate etc., as well as copolymers of the above compounds with non-acrylates, for example, such as methyl methacrylate-styrene copolymers. In addition, the powder component may contain an x-ray contrast agent such as barium sulfate or zirconium dioxide. If present, these x-ray contrast agents, especially barium sulfate, are added in the amount of about 5 to 15 weight percent with respect to the powdered polymer or copolymer. A catalyst, typically benzoyl peroxide, may also be incorporated in the powdered polymer or copolymer, in which case a reducing agent, for example, dimethyl p-toluidine, would be incorporated in the liquid monomer. Alternatively, the powdered polymer or copolymer may contain a reducing agent, in which case a peroxide catalyst would be incorporated in the liquid monomer.
The second component of the bone cement composition comprises a liquid monomer of an acrylic ester containing (a) a diagnostic or therapeutic substance and (b) an emulsifying agent for said diag-nostic or therapeutic substance. This results in the incorporation of the diagnostic or therapeutic sub-stance present in the bone cement composition being substantially in component B. By "substantially" is meant that at least 75% of the diagnostic or thera-peutic substance in the composition is in component B.
Higher ranges can also be used with as much as 80-90%
-5- l 33898~
of the diagnostic or therapeutic substance being incor-porated in component B. In a preferred case, 100 percent of the diagnostic or therapeutic agent in the bone cement composition can be incorporated in component B. A preferred liquid monomer of an acrylic ester is methylmethacrylate. In the present invention, it has surprisingly been found that incorporation of the diagnostic or therapeutic agent into the liquid monomer by means of the emulsifying agent leads to a high sustained concentration of the diagnostic or therapeutic substance over time. The remainder of ~the specification will discuss the increased concentration of therapeutic substances, especially antibiotics, but is is to be understood that the discussion applies equally well to diagnostic substances, such as radio-active tracers, etc., as well as other classes of therapeutic substances such as anti-cancer drugs, anti-inflammatory drugs, immunostimulants, immunosup-pressants, osteogenesis promotors, etc.
In the present invention, a major proportion of the antibiotic is preferably incorporated in the liquid monomer by means of an emulsifying agent. This results in a number of advantages over the previously known methods in which the antibiotics were compounded with the powder component of the cement. One problem associated with this method was the requirement that there be proper mixing of the therapeutic agent with the powder component with homogeneous dispersion of the antibiotic and elimination of aggregates. Such results were not always achieved. Other requirements for the effective release of the therapeutic substance into the liquid monomer; namely the requirement of a large surface area for the diffusion of water from the surrounding tissues into the cement mantle and the requirement that the substance contained in the cement 1 338980 .
mantle be soluble in the liquid containing the sub-stance, are eliminated. The liquid which does get transported out of the cement mantle into the sur-rounding tissue contains the desired substance. Thus, a number of advantages are apparent.
Examples of antibiotics which can be incorporated into the liquid monomer are erythromycin, gentamicin, colistin, penicillin, Terramycin, Aureomycin, Vibra-mycin, etc. Especially preferred anitbiotics are erythromycin, gentamycin and colistin. The concen-tration of antibiotic which may be incorporated into the liquid monomer ranges from about 0.03 to about 8.0 weight percent, based on the liquid monomer. Of course, those skilled in the art to which this inven-tion applies will recognize that, depending upon theactivity of the antibiotic, higher or lower ranges can also be used.
In the present invention, the antibiotic, or other diagnostic or therapeutic agent, is incorporated into the liquid monomer by means of a emulsifying agent. An especially preferred emulsifying agent is sorbitan mono-oleate polyoxyethylene, also known as Tween 80.
Another preferred emulsifying agent is sodium dihexyl sulfosuccinate. Other emulsifying agents which can be used in the present invention are polyoxyethylensor-bitanmonopalmitate, polyoxyethylensorbitanmonostearate and polyoxyethylenesorbitanmonooleate. In addition to stabilizing the therapeutic substance in the liquid monomer, the emulsifying agent also possibly serves to dissipate the heat formed during the exothermic poly-merization of the monomer. In the present invention, the emulsifying agent is present in an amount ranging from about 0.1 to about 10.0 weight percent, based on the liquid monomer.
* Trademark ,~
In formulating the liquid monomer/therapeutic - substance component of the present invention, the order of mixing of the ingredients is not critical. For instance, the antibiotic, for example, may be dissolved in water, if it is water soluble, and the emulsifying agent can be added to the dissolved antibiotic. The emulsified antibiotic can then be added to the liquid monomer. If the antibiotic is soluble in the liquid monomer, the antibiotic may be added to the monomer containing the emulsifying agent or the antibiotic mixed with the emulsifying agent may be added to the liquid monomer.
While the invention has been described with relation to a bone cement comprising the combination of the powdered polymer or copolymer and the liquid monomer containing the diagnostic or therapeutic substance plus the emulsifying agent, it will be apparent that the liquid monomer itself containing the emulsifier and diagnostic or therapeutic substance is also contemplated as being another aspect of the present invention. This liquid monomer/therapeutic or diagnostic substance/emulsifying agent composition can be used as a foreproduct for bone cement. Accordingly, such composition also orms a part of the present invention.
The present invention is illustrated by the following examples, which are not to be construed as limiting the invention, the scope of which is to be determined by the appended claims.
Bone cements of the invention are made by adding the following indicated liquid components to a powder component containing a radiopacifier. The cement is hand-mixed in a conventional manner for known bone cement. The following examples give the method of preparing the liquid component to be mixed with the powdered component.
Example 1 The liquid component was prepared by mixing the following ingredients in the order given. The com-ponents were mixed in a resealable polyethylene container until all were evenly dispersed.
1. 3.655 g erythromycin gluceptate 2. 17.8 g water 3. 1.8 ml Tween 80 4. 100 ml of Methyl methacrylate monomer (97.4% v/v), (containing also 2.5 ml N, N-dimethyl-para-toluidine (2.6% v/v) and 75 ' 15 ppm hydroquinone).
One fifth of this mixture was added per dose of the powder component, 40 g, (containing 6.0 g Poly-methyl methacrylate (15%w/w), 30.0 g of Methyl methacrylate-styrene-copolymer (75% w/w) and 4.0 g Barium Sulfate U.S.P. (lOZ w/w)) and hand-mixed to form the bone cement.
Example 2 Another liquid component was prepared by adding ~ the following ingredients in the order given in the same way as Example l.
1. 1.5 g erythromycin gluceptate 2. 7.08 g water 3. 0.7 ml Tween-80 4. 40.0 ml Methyl methacrylate (97.4% v/v Methyl methacrylate, 2.6% v/v N, N-dimethyl-para-toluidine, 75 ~ 15 ppm hydroquinone).
Two doses of the powder component (80 g) con-taining 12.0 g Polymethyl methacrylate (15% w/w), 60.0 g Methyl methacrylate-styrene-copolymer (75% w/w), 8 g Barium Sulfate U.S.P. (10% w/w)) were hand-mixed with the liquid to form the cement.
Example 3 Another liquid component was prepared by adding the following ingredients in the order given.
1. 0.731 g erythromycin gluceptate 2. 2.07 g water 3. 3.2 g Aerosol ~-80~
4. 40.0 ml Methyl methacrylate (containing 97.4% v/v Methyl methacrylate, 2.6% v/v N, N-dimethyl-para-toluidine(2.6Z) and 75 ~ 15 ppm of hydroquinone).
5. 0.731 g erythromycin gluceptate Two doses (80 g) of powder component containing 15% w/w Polymethyl methacrylate w/w,-75% w/w Methyl methacrylate-Styrene-copolymer and lOZ Barium Sulfate U.S.P.) were hand-mixed with the above liquid component to form the cement.
Example 4 The following ingredients were mixed in the order given.
1. 1.670 g gentamicin sulfate 2. 7.440 g water 3. 0.753 g Tween-80 4. 40.0 ml Methyl methacrylate (containing 97.4 v~v Methyl methacrylate, 2.6% v/v N, N-dimethyl-para-toluidine, and 75 1 15 ppm hydroquinone) 5. 2.11 g liquid component in Example 1 The liquid component was added to the powder component, 80 g, (containing 15% w/w PoLymethyl methacrylate, 75%
w!w Methyl methacrylate-Styrene-copolymer and 10% w/w Barium Sulfate, U.S.P.) and hand-mixed to form the cement.
*Trademark - lo - 1 3 3 8 9 8 0 SUPPLEMENTARY DISCLOSURE
This supplementary disclosure includes an additional example of a bone cement composition .
In accordance with this supplementary disclosure a bone cement composition is provided comprising the combination of components A and B wherein:
Component A comprises a powdered polymer or copolymer of an acrylic ester and, Component B comprises a liquid monomer of an acrylic ester containing (a) cefoperazone or pharmaceutically acceptable salts thereof, an emulsifying agent for the cefoperazone, or pharmaceutically acceptable salts thereof, whereby the incorporation of cefoperazone or pharmaceutically acceptable salts thereof is substantially in component B.
In the drawings:
Figure 2 is a graph showing the concentration of released active cefoperazone over a sustained period of time from a bone cement of the present invention.
The principal disclosure has described the preferred ingredients of components A and B. This supplementary disclosure adds cefoperazone to the list of preferred therapeutic substances. The cefoperazone may be incorporated in the same manner and in the same range as described in the principal disclosure.
The following example gives the method of preparing a liquid component to be mixed with a powder component, as described in the principal disclosure.
Example 5 Another liquid component was prepared by adding the following ingredients in the order given in the same way as Example 1.
1. 0.500 g of Cefoperazone sodium 2. 4.0 g water 3. 0.4 g Tween 80 .. 4. 10.0 ml of Methyl Methacrylate monomer (97.4~ v/v) containing also 2.5 ml N, N-dimethyl-paratoluidine (2.6%
v/v) and 75 + 15 ppm hydroquinone.
One dose of the powder component (40 g) containing 6.0 g Polymethyl methacrylate (15% w/w) 30 g of Methyl Methacrylate-styrene-Polymer (75% w/w) and 4.0 g Barium Sulphate USP (10% w/w) and hand mix to form cement.
: ~n
Example 4 The following ingredients were mixed in the order given.
1. 1.670 g gentamicin sulfate 2. 7.440 g water 3. 0.753 g Tween-80 4. 40.0 ml Methyl methacrylate (containing 97.4 v~v Methyl methacrylate, 2.6% v/v N, N-dimethyl-para-toluidine, and 75 1 15 ppm hydroquinone) 5. 2.11 g liquid component in Example 1 The liquid component was added to the powder component, 80 g, (containing 15% w/w PoLymethyl methacrylate, 75%
w!w Methyl methacrylate-Styrene-copolymer and 10% w/w Barium Sulfate, U.S.P.) and hand-mixed to form the cement.
*Trademark - lo - 1 3 3 8 9 8 0 SUPPLEMENTARY DISCLOSURE
This supplementary disclosure includes an additional example of a bone cement composition .
In accordance with this supplementary disclosure a bone cement composition is provided comprising the combination of components A and B wherein:
Component A comprises a powdered polymer or copolymer of an acrylic ester and, Component B comprises a liquid monomer of an acrylic ester containing (a) cefoperazone or pharmaceutically acceptable salts thereof, an emulsifying agent for the cefoperazone, or pharmaceutically acceptable salts thereof, whereby the incorporation of cefoperazone or pharmaceutically acceptable salts thereof is substantially in component B.
In the drawings:
Figure 2 is a graph showing the concentration of released active cefoperazone over a sustained period of time from a bone cement of the present invention.
The principal disclosure has described the preferred ingredients of components A and B. This supplementary disclosure adds cefoperazone to the list of preferred therapeutic substances. The cefoperazone may be incorporated in the same manner and in the same range as described in the principal disclosure.
The following example gives the method of preparing a liquid component to be mixed with a powder component, as described in the principal disclosure.
Example 5 Another liquid component was prepared by adding the following ingredients in the order given in the same way as Example 1.
1. 0.500 g of Cefoperazone sodium 2. 4.0 g water 3. 0.4 g Tween 80 .. 4. 10.0 ml of Methyl Methacrylate monomer (97.4~ v/v) containing also 2.5 ml N, N-dimethyl-paratoluidine (2.6%
v/v) and 75 + 15 ppm hydroquinone.
One dose of the powder component (40 g) containing 6.0 g Polymethyl methacrylate (15% w/w) 30 g of Methyl Methacrylate-styrene-Polymer (75% w/w) and 4.0 g Barium Sulphate USP (10% w/w) and hand mix to form cement.
: ~n
Claims (29)
1. A process for the production of a bone cement composition comprising combining components A and B
wherein:
component A comprises a powdered polymer or copolymer of an acrylic ester; and component B comprises a liquid monomer of an acrylic ester, said liquid monomer containing a diagnostic or therapeutic substance and an emulsifying agent for said diagnostic or therapeutic substance, whereby the incorporation of said diagnostic or therapeutic substance in the bone cement composition is substantially in component B.
wherein:
component A comprises a powdered polymer or copolymer of an acrylic ester; and component B comprises a liquid monomer of an acrylic ester, said liquid monomer containing a diagnostic or therapeutic substance and an emulsifying agent for said diagnostic or therapeutic substance, whereby the incorporation of said diagnostic or therapeutic substance in the bone cement composition is substantially in component B.
2. The process of claim 1 wherein component A is polymethyl methacrylate.
3. The process of claim 1 wherein component A is a copolymer of methylmethacrylate and styrene.
4. The process of claim 1 wherein component B
contains a therapeutic substance.
contains a therapeutic substance.
5. The process of claim 4 wherein said therapeutic substance is an antibiotic.
6. The process of claim 5 wherein said antibiotic is erythromycin, or a pharmaceutically acceptable salt thereof.
7. The process of claim 1 wherein said emulsifying agent is sorbitan mono-oleate polyoxyethylene.
8. A process for the incorporation of a diagnostic or therapeutic substance into a liquid monomer of an acrylic ester comprising incorporating said diagnostic or therapeutic agent into said liquid monomer by means of an emulsifying agent.
9. The process of claim 8 wherein said therapeutic substance is erythromycin, or a pharmaceutically acceptable salt thereof.
10. A bone cement composition comprising the combination of components A and B wherein:
Component A comprises a powdered polymer or copolymer of an acrylic ester and, Component B comprises a liquid monomer of an acrylic ester containing (a) a diagnostic or therapeutic substance and (b) an emulsifying agent for said diagnostic or therapeutic substance, whereby the incorporation of said diagnostic or therapeutic substance in the bone cement composition is substantially in component B.
Component A comprises a powdered polymer or copolymer of an acrylic ester and, Component B comprises a liquid monomer of an acrylic ester containing (a) a diagnostic or therapeutic substance and (b) an emulsifying agent for said diagnostic or therapeutic substance, whereby the incorporation of said diagnostic or therapeutic substance in the bone cement composition is substantially in component B.
11. A liquid monomer of an acrylic ester containing (a) a diagnostic or therapeutic substance and (b) an emulsifying agent for said substance.
12. The bone cement of claim 10 wherein component A is polymethyl methacrylate.
13. The bone cement of claim 10 wherein component A is a copolymer of methylmethacrylate and styrene.
14. The bone cement of claim 10 wherein component B is methylmethacrylate.
15. The bone cement of claim 10 wherein component B contains a therapeutic substance.
16. The bone cement of claim 15 wherein said therapeutic substance is an antibiotic.
17. The bone cement of claim 16 wherein said antibiotic is selected from the group consisting of erythromycin, gentamicin, and colistin, or pharmaceutically acceptable salts thereof.
18. The bone cement of claim 17 wherein said antibiotic is erythromycin.
19. The bone cement of claim 10 wherein said emulsifying agent is sorbitan mono-oleate polyoxyethylene.
20. The bone cement of claim 17 wherein said emulsifying agent is sodium dihexyl sulfosuccinate.
21. The monomer of claim 11 wherein said therapeutic substance is erythromycin, or a pharmaceutically acceptable salt thereof.
CLAIMS SUPPORTED BY THE SUPPLEMENTARY DISCLOSURE
CLAIMS SUPPORTED BY THE SUPPLEMENTARY DISCLOSURE
22. A bone cement composition comprising the combination of components A and B wherein:
Component A comprises a powdered polymer or copolymer of an acrylic ester and, component B comprises a liquid monomer of an acrylic ester containing (a) cefoperazone or pharmaceutically acceptable salts thereof, an emulsifying agent for the cefoperazone or pharmaceutically acceptable salts thereof, whereby the incorporation of cefoperazone or pharmaceutically acceptable salts thereof, is substantially in component B.
Component A comprises a powdered polymer or copolymer of an acrylic ester and, component B comprises a liquid monomer of an acrylic ester containing (a) cefoperazone or pharmaceutically acceptable salts thereof, an emulsifying agent for the cefoperazone or pharmaceutically acceptable salts thereof, whereby the incorporation of cefoperazone or pharmaceutically acceptable salts thereof, is substantially in component B.
23. The bone cement of claim 22 wherein component A
is polymethyl methacrylate.
is polymethyl methacrylate.
24. The bone cement of claim 22 wherein component A
is a copolymer of methylmethacrylate and styrene.
is a copolymer of methylmethacrylate and styrene.
25. The bone cement of claim 22 wherein component B
is methylmethacrylate.
is methylmethacrylate.
26. The bone cement of claim 22 wherein said emulsifying agent is sorbitan mono-oleate polyoxyethylene.
27. The bone cement of claim 22 wherein said emulsifying agent is sodium dihexyl sulfosuccinate.
28. A liquid monomer of an acrylic ester containing (a) cefoperazone, or pharmaceutically acceptable salts thereof and (b) an emulsifying agent for the cefoperazone or pharmaceutically acceptable salts thereof.
29. A process for the production of a bone cement composition comprising combining components A and B
wherein:
component A comprises a powdered polymer or copolymer of an acrylic ester; and component B comprises a liquid monomer of an acrylic ester, said liquid monomer containing cefoperazone or pharmaceutically acceptable salts thereof and an emulsifying agent for the cefoperazone or pharmaceutically acceptable salts thereof, whereby the incorporation of cefoperazone or pharmaceutically acceptable salts thereof is substantially in component B.
wherein:
component A comprises a powdered polymer or copolymer of an acrylic ester; and component B comprises a liquid monomer of an acrylic ester, said liquid monomer containing cefoperazone or pharmaceutically acceptable salts thereof and an emulsifying agent for the cefoperazone or pharmaceutically acceptable salts thereof, whereby the incorporation of cefoperazone or pharmaceutically acceptable salts thereof is substantially in component B.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US79,627 | 1987-07-30 | ||
US07/079,627 US4900546A (en) | 1987-07-30 | 1987-07-30 | Bone cement for sustained release of substances |
Publications (1)
Publication Number | Publication Date |
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CA1338980C true CA1338980C (en) | 1997-03-11 |
Family
ID=22151754
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA000573388A Expired - Fee Related CA1338980C (en) | 1987-07-30 | 1988-07-29 | Bone cement for sustained release of substances |
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US (1) | US4900546A (en) |
EP (1) | EP0301759B1 (en) |
JP (1) | JPH0638849B2 (en) |
AT (1) | ATE70191T1 (en) |
AU (2) | AU596905B2 (en) |
CA (1) | CA1338980C (en) |
DE (1) | DE3866817D1 (en) |
ES (1) | ES2027763T3 (en) |
GR (1) | GR3003348T3 (en) |
IE (1) | IE61038B1 (en) |
ZA (1) | ZA885525B (en) |
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-
1987
- 1987-07-30 US US07/079,627 patent/US4900546A/en not_active Expired - Lifetime
-
1988
- 1988-07-20 AT AT88306666T patent/ATE70191T1/en not_active IP Right Cessation
- 1988-07-20 EP EP88306666A patent/EP0301759B1/en not_active Expired - Lifetime
- 1988-07-20 DE DE8888306666T patent/DE3866817D1/en not_active Expired - Lifetime
- 1988-07-20 ES ES198888306666T patent/ES2027763T3/en not_active Expired - Lifetime
- 1988-07-28 ZA ZA885525A patent/ZA885525B/en unknown
- 1988-07-28 JP JP63189556A patent/JPH0638849B2/en not_active Expired - Fee Related
- 1988-07-29 CA CA000573388A patent/CA1338980C/en not_active Expired - Fee Related
- 1988-07-29 AU AU20197/88A patent/AU596905B2/en not_active Ceased
- 1988-07-29 IE IE234088A patent/IE61038B1/en not_active IP Right Cessation
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1990
- 1990-08-17 AU AU61105/90A patent/AU624017B2/en not_active Ceased
-
1991
- 1991-12-16 GR GR91401982T patent/GR3003348T3/en unknown
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ATE70191T1 (en) | 1991-12-15 |
AU596905B2 (en) | 1990-05-17 |
DE3866817D1 (en) | 1992-01-23 |
AU6110590A (en) | 1990-11-22 |
JPS6443261A (en) | 1989-02-15 |
ES2027763T3 (en) | 1992-06-16 |
IE882340L (en) | 1989-01-30 |
EP0301759A3 (en) | 1989-08-02 |
AU2019788A (en) | 1989-04-20 |
EP0301759A2 (en) | 1989-02-01 |
GR3003348T3 (en) | 1993-02-17 |
JPH0638849B2 (en) | 1994-05-25 |
IE61038B1 (en) | 1994-09-07 |
AU624017B2 (en) | 1992-05-28 |
ZA885525B (en) | 1990-04-25 |
EP0301759B1 (en) | 1991-12-11 |
US4900546A (en) | 1990-02-13 |
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