HK1116388B - Absorbable implants and methods for their use in hemostasis and in the treatment of osseous defects - Google Patents

Description

Resorbable implants and methods for their use in hemostasis and treatment of bone defects

Cross Reference to Related Applications

This application claims priority to U.S. provisional application 60/504,978 filed on 23/9/2003.

Statement regarding jointly initiated research or development (not applicable)

Reference to the appendix of sequence listings, tables or computer program listings submitted on compact disks

(see 37CFR 1.52(e) (5)) (not applicable)

Background

Technical Field

The present invention relates to the management, treatment and beneficial control of bone conditions such as bleeding and defects through the use of materials having different viscosities, cohesive strengths and consistencies, most particularly putty-like materials and creams, pastes, ointments, lotions and gels. Most particularly, a variety of new, surgically implantable, absorbable formulations that may contain absorption accelerators, bone growth inducing materials, anti-infective or anti-neoplastic agents for reducing the risk of infection or tumor growth, respectively, analgesics, anti-inflammatory agents, clot inducing agents such as vasoconstrictors and hemostatic materials may be used as bone hemostatic devices and/or as bone healing or therapeutic aids. The composition may also include a radiopaque material and a colorant.

Description of the related Art

Cancellous and cortical bone relatively contains vascular tissue that bleeds when its vasculature is damaged. There are therefore at least two major problems that must be medically addressed when a bone is surgically cut or traumatically fractured, such as in open or compound fractures. The first of these is the occurrence of bone haemorrhages. When bone bleeding occurs, it must be stopped or effectively controlled (hemostasis) to prevent adverse surgical consequences. The second problem is the bone growth problem that promotes healing (bone growth) of the injured bone. Conventional surgical osteotomy procedures include open-heart surgery involving sternal separation, orthopedic and spinal surgery including hip implants, neurosurgery involving spinal or cerebral incisions, amputation, trauma treatment, and many other procedures.

Currently, bone hemostasis is achieved by one or more of the following methods: (i) artificially impregnating the bleeding surface with a commercially available non-absorbable "bone wax" (ii) the use of various hemostatic agents, such as oxidized cellulose or microcrystalline collagen, and (iii) electrocautery. None of these techniques promote bone growth to any significant extent. In addition to the unmet need for an effective, rapidly absorbable bone hemostatic material, there is a surgical need for materials that fill bone defect voids and promote healing of these cavities. Many pasty materials are currently available to surgeons for this purpose, most commonly based on coarse powdered, demineralized allograft bone suspended in suitable biocompatible excipients. These compositions are designed to induce osteogenesis and healing of defects, but due to their consistency, non-adhesiveness and other physical properties of their compositions, they do not reliably adhere to damaged bone and are not effective hemostatic agents.

There are two prior art subjects related to bone hemostasis and bone healing, respectively. As discussed below, until now, substantially only products based on plasticized nonabsorbable waxes have been available to surgeons for bone hemostasis. The disadvantages of using substitutes such as oxidized cellulose and tissue destructive application electrocautery (discussed below) are unsatisfactory alternatives.

The first body of the prior art is specific to bone wax, which is manually pressed into the hole in the surface of the bleeding bone, acts as an effective mechanical tamponade, and prevents the escape of blood. Currently available bone waxes consist of a mixture of non-absorbable components such as beeswax, paraffin, petrolatum, fatty ester plasticizers and the like. These products must be heated prior to use and become soft, kneadable and dispersible by the surgeon onto or into the surface of the fractured bone. Since the available bone waxes are not absorbable and stay indefinitely where they are placed by the surgeon, they act as permanent physical barriers to inhibit bone growth, thereby preventing or slowing bone healing. Furthermore, such sites act as permanent post-operative lesions of infection. If this infection does not occur, it is often chronic and difficult to treat with conventional anti-infective therapy and re-surgery, and surgical removal of these affected sites often becomes necessary. For these reasons, commercially available bone wax is not widely used in orthopedic surgery.

Other products or techniques for use in this application include oxidized cellulose products, which are indicated for use in soft groupsTissue haemostasis, e.g. SurgicelIt is absorbable and is not expected to induce the complications described above with respect to bone wax. However, they are not effective hemostatic products for bone due to their unsuitable physical form (knit), and they are difficult to be effectively used for broken bone due to lack of adhesion within the bone hole.

Chemical cauterization of sealed extravasated blood vessels using electrocautery is time consuming and produces extensive tissue damage, can delay bone growth, and allows soft tissue in-growth, thereby interfering with normal bone cells, often presenting difficult problems for orthopedic surgeons, particularly spinal surgeons.

Various forms of collagen, alone or in combination with fibrin and suspended in various delivery vehicles, have been proposed as bone hemostatic agents, but problems such as storage instability, cohesiveness and biocompatibility have prevented practical implementation.

The reason why adapting synthetic absorbable polymers for such applications has not been successful is clearly the difficulty in properly formulating hydrolytically unstable synthetic absorbable polymers into practical products with reasonable package shelf life, useful handling properties, and acceptable biocompatibility and absorption rates.

The second body of the prior art is primarily concerned with bone healing and treatment of bone defects. The bone healing prior art compilation primarily describes the formation of biocompatible, resorbable excipients to deliver and support processed particulate allogeneic bone when applied to defects, such as incised cavities. These liquid or paste-like excipients consist of various polyalkyl compounds, ester derivatives of polyols, hydrogels, etc., sometimes containing additives for increasing the viscosity of the excipient (to delay excipient dissipation, thereby extending the cohesiveness of the implant) or factors that induce new bone growth. Anti-infective, anti-tumor and other additives are also described for use in these products. These compositions have never been indicated, acting or described in the prior art as bone hemostatic agents and are claimed.

A. Bone hemostasis

Attempts to provide absorbable bone hemostatic agents have not been entirely successful. An absorbable bone sealant containing fibrin and collagen (british patent 1,584,080) requires mixing in the operating room. One reported hemostatic dispersion of microfibrillar collagen in polyethylene glycol loses cohesiveness too quickly as the glycol dissipates. Microcrystalline collagen lyophilized sponges designed for soft tissue hemostasis (U.S.6,454,787) are also not suitable for bone bleeding control. Hemostatic agents using polylactide (U.S.4,186,448), lactide/glycolide oligomers (U.S.5,143,730, 6,420,454), plasticized polymer mixtures (U.S.5,641,502), absorbable hydrogel-forming composites (U.S.6,413,539) are not readily suitable for bone hemostasis. Polydioxanone (U.S.4,443,430) synthesized absorbable polymeric materials are difficult to use due to their relative instability in biocompatible, proton-delivering excipients. Another absorbable polyester, such as caprolactone polymer (u.s.6,485,749), has been described as a replacement for bone wax.

A system having a putty-like consistency at room temperature preferably in combination with a fatty acid salt such as calcium stearate, an absorption enhancer such as dextran and an excipient such as castor oil was developed (u.s.4,568,536) as an absorbable biocompatible matrix for the delivery of antibiotics such as meclocycline sulfosalicylate and other pharmaceutically active agents for the treatment of periodontal disease. However, this technique, along with similar absorbable compositions described in U.S.4,439,420 and U.S.4,650,665, is deficient in that they are designed for drug delivery during prolonged absorption, but are not optimal for rapid bone healing, and in that they contain dextran, polysaccharides, which are currently considered toxicologically unacceptable implant materials.

B. Bone defect healing

Materials designed for bone defect healing (but not hemostasis) are based on ground cortical and/or cancellous bone allogenic, demineralized, osteogenic bone powder, typically 1-12mm in particle size, in a biocompatible carrier selected from polyols such as glycerol and polyol derivatives such as glycerol monoacetate (U.S.5,073,373, U.S.5,484,601). Many additions are cited for this composition, such as anti-infective and anti-tumor agents, surfactants, vitamins, endocrine tissues, and the like. A variant of this technique (u.s.5,284,655) requires an increase in volume of the demineralized bone component of at least 10% after contact with a swelling agent. Biocompatible suspending agents for swollen demineralized bone particles are selected from polyols and their esters, sucrose, polysaccharides, alginic acid, amylose, agar, and the like. Another aspect of the 5,073,373 patent (U.S.5,290,558) provides a flowable powder and claims a large number of natural and synthetic polyhydroxy materials and their ester derivatives as vehicles for demineralized bone powder containing various additives such as BMP, IGF-1, anti-infective agents, hydroxyapatite, surfactants, bioerodible polymers and various thickeners such as PVA, PVP, CMC, gelatin, dextran, collagen, polyacrylates, and the like. To improve the handling properties of bone defect fillers, (U.S.5,314,476), particularly implant adhesion after the suspended excipient dissipates, a high ratio (10: 1) of medium length to medium thickness demineralized bone particles are suspended in the excipient cited in the' 558 patent. In a completely different approach (U.S. Pat. No. 6,030,635), demineralized bone carrier powders based on aqueous solutions of polyelectrolytes such as sodium hyaluronate, chitosan and N, O-carboxymethyl chitosan are required. These viscous, high molecular weight hydrogels may contain anti-infective and other additives. A variation of U.S. patent 6,030,635(U.S.6,437,018) includes the addition of a sodium phosphate buffer to form a more viscous hydrogel carrier for smaller particle size mineralized or demineralized bone.

Recently issued patent (U.S.6,565,884) describes a composition based on lecithin suspended in or containing unsaturated triglycerides, such as corn oil. The product is said to be useful for inducing bone growth. However, such surface active compositions may be easily washed away after implantation. In another attempt to provide useful materials to stimulate new bone formation (U.S.6,576,249), a method of dissolving demineralized bone matrix in water added to mineralized or demineralized bone matrix particles forming a water-soluble gelatinous suspension to form a viscous solution is described.

As recently noted, in the search for a matrix for controlled release of a variety of drugs primarily used in the treatment of periodontal disease, workers have developed absorbable, biocompatible, putty-like compositions that adhere to bone (teeth), are compliant at room temperature, and are easily applied (u.s.4,568,536). While the primary purpose of such compositions is for delayed drug delivery, the systems are based primarily on previously disclosed putty-like compositions specifically developed as bone hemostatic agents (U.S.4,439,420).

The composition described in U.S.4,439,420 is essentially based on a combination of three types of substances, a fatty acid salt, preferably calcium stearate, a fluid base, preferably castor oil, and an absorption accelerator, preferably dextran. This preferred composition, when tested for absorbability as an intramuscular implant, is described as requiring approximately 4 weeks of absorption. No information or data is provided regarding the efficacy as a hemostatic device and clearly no experiments have been conducted to determine the rate of absorption of the substance when actually used as a bone hemostatic device. Resorption from the closed trabecular space is expected to be significantly slower than that of the more anatomically "open" intramuscular site used as a model.

The 4,439,420 patent discloses alternatives to the three preferred ingredients. Alternatives to calcium stearate are magnesium, zinc, aluminum, lithium and barium salts of saturated and unsaturated fatty acids containing 10 to 22 carbon atoms (collectively referred to as fatty acid salts). Alternatives to castor oil are ethylene oxide/propylene oxide block copolymers, polyethylene glycol, methoxypolyethylene glycol, triglycerides, fatty acid esters, sesame oil, almond oil, cottonseed oil, corn oil, olive oil, cod liver oil, safflower oil and soybean oil (generally mixed with fatty acid salts)Molecules that form slowly absorbed putty-like substances). An alternative to dextran is Carbowax、PluronicsGlycerol and propylene glycol, which act as absorption accelerators by post-operative absorption of liquids and/or dissipation, thereby physically destroying the implant remaining in the tissue.

4,439,420 the main reason why putty-like compositions are not suitable for bone hemostasis is that the materials, although biodegradable, absorb too slowly and thus inhibit new bone ingrowth and healing by acting as a physical barrier like a non-absorbable, paraffin-based bone wax. Furthermore, the preferred compositions described in said patents contain one component, namely dextran, which is not toxicologically acceptable. Finally, the 4,439,420 composition is "completely free of fibrous materials," which may be significantly detrimental to optimal osteogenesis, a desirable feature of a bone hemostatic device. 4,439,420 does not disclose the addition of agents such as demineralized bone, bone growth factors, and fibrocollagen to enhance osteogenesis and healing and the addition of anti-infective agents to inhibit infection.

Brief description of the invention

The formulations of the present invention are compositions of varying viscosity and cohesive strength, including both putty-like and non-putty-like formulation consistencies.

The term "putty" as used herein is as it is used in the prior art and is generally known to those skilled in the art. Pastes of different viscosities (e.g. biscuit pastes), moulding clays and enameling putties, depending on the indication and the end application, are examples of consistencies of suitable products. Putties of different viscosities that may be used in the present invention include those that are capable of adhering to bone. Generally, a soft, moldable, preferably inelastic, cohesive mixture prepared by intimately mixing micronized material with liquid dispersing excipients and having the ability to deform in any direction is a suitable consistency for the putty-like compositions of the present invention.

However, as will be described later, compositions having lower adhesive strength than the putties described above are within the scope of the present invention and may be used in specific applications where a more tacky, more cohesive putty is less desirable. For the purposes of this invention, the primary difference between the putties of the present invention and materials that are not considered putties (i.e., non-putties) but are still within the scope of the present invention is that the putties have lower adhesive strength than the putty formulations.

The various non-putties of the present invention are characterized by having the cohesive strength of creams, pastes, ointments, lotions, foams, gels, foamed proteins, foamed creams, and the like. Preferably, the non-putty-like has only a portion of the cohesive strength of the putty of the present invention and tends to crack or tear easily under small pressures, thus generally having the same effect on the putty. The following description will give the subject putty primarily but it will be understood that if a less cohesive strength material is desired, one skilled in the art will simply change the proportions of the components or add other materials as appropriate to accomplish the same purpose.

The present invention relates to the formation of medically acceptable putty-like and non-putty-like compositions using dispersing excipients that are intimately mixed with micronized fillers, some of which have previously been used but not with the dispersing excipients of the present invention, and some of which have therefore not been used to prepare these putty-like and non-putty-like compositions, which have not previously been reported for use in the preparation of such materials.

A sterile, absorbable bone hemostatic agent, i.e., a material that provides virtually immediate surgical hemostasis and yet will be absorbed in the body after a relatively short period of time without compromising hemostatic efficacy, would have significant medical advantages over currently available materials. It minimally inhibits osteogenesis and subsequent bone healing. Furthermore, bone healing aids, such as growth factors, in particular, for example, platelet-derived growth factor (PDGF) and/or Bone Morphogenic Protein (BMP) and the like, may be added to the formulation to stimulate the bone healing process. Moreover, the addition of agents such as collagen, Demineralized Bone Matrix (DBM) and/or hydroxyapatite will allow the hemostatic material to advantageously undergo osteoconduction and osteoinduction. Suitable anti-infective agents, such as antibiotics represented by tobramycin and gentamicin, or bacteriostatic and bactericidal materials, such as iodine, silver salts, colloidal silver, and the like, are added to reduce the potential for infection, particularly in contaminated open wounds, such as complex fractures. The addition of colorant will aid visibility during processing. The addition of radiopaque substances allows post-operative sequelae to be observed by radiographic methods. The addition of chemotherapeutic agents or radionuclides is useful when the putty is used, for example, to create a bone cavity from a tumor resection. Analgesic compounds for pain relief and vasoconstrictors and clot inducers for reducing bleeding are useful additives.

The new and inventive concept described below with respect to the preparation of the product of the invention comprises at least two components, component 1 being a filler and component 2 being a dispersant, which when intimately mixed with the filler in suitable proportions result in a matrix for the product of the invention. Selection of the appropriate component 2 will result in a composition that is absorbed by the body over an acceptable period of time. In this case, component 2 will act as its own absorption accelerator, while the formulation does not require a separate absorption accelerator. However, if desired, the compositions of the present invention may also be provided with optional ingredients for accelerating the absorption of the putty by the body.

The present invention provides implantable, resorbable, biocompatible, putty-like compositions for use as mechanical hemostatic tamponades (temponades) for the control of bone bleeding due to surgery or trauma, and for providing osteoinductive matrices that promote improved bone healing.

Accordingly, in one aspect, the present invention provides compositions of sterilizable putty-like materials and methods for their use, comprising the steps of: the putty-like composition is physically squeezed into the bleeding area of the bone, thereby mechanically arresting bleeding, and then the composition is absorbed and harmlessly eliminated from the body.

In another aspect, particularly but not necessarily limited to traumatic open wounds, an anti-infective agent is added to the putty-like composition and then released from the composition post-operatively to inhibit the occurrence of post-operative infection.

In another aspect, the present invention adds one or more of mineralized or demineralized bone particles, collagen, hydroxyapatite, bone morphogenic protein, and/or other bone growth factors to the non-absorbable or slowly absorbed bone hemostatic materials known in the art to form a new putty-like for the dual purpose of initial hemostasis and then stimulation of new bone formation.

In another aspect, the present invention adds an anti-infective agent to a putty-like composition containing a bone growth stimulating additive to inhibit the development of post-operative infections.

Anti-infective agents that are antibacterial, bacteriostatic or bacteriocidal materials may be added to the putty-like substance or may be reversibly incorporated into additives to be incorporated into the putty, such as gelatin or collagen. For example, iodine is used as an anti-infective agent, and a complex of iodine with gelatin, collagen or PVP may be used. In addition, colloidal silver, silver salts or salt complexes containing gelatin or other polymers may be used. Furthermore, antibiotics can be added in addition to the putties described above as part of the delivery system, preferably as part of the putty component. In particular, gentamicin in combination with powdered collagen is an example of a useful antibiotic delivery system. Similarly, an anti-tumor agent can be added to the putty-like composition in the same manner, preferably as a free agent, to provide a material that is effective against tumorigenesis. Pain-reducing analgesics, clot-inducing agents used as chemical hemostatic agents and anti-inflammatory agents may also be added. Also, radiopaque components may be added to allow radiographic visualization, and colorants added to improve intra-operative performance.

Other objects, features and advantages will be apparent in the written description that follows.

Detailed Description

The compositions of the present invention include compositions comprising at least two, preferably three, four or more components. They are most preferably body absorbable. In many embodiments, they have a putty-like consistency. In one embodiment, the composition is a mechanical hemostatic packing that prevents bone bleeding by applying a putty-like composition to the affected area. By "mechanical hemostatic packing" is meant that the composition functions to stop bleeding by mechanically compressing the bleeding area of the bone, rather than by chemical hemostasis, i.e., by chemically stopping bleeding in whole or in part. In another embodiment, the compositions are used for osteogenesis in addition to mechanical hemostatic agents, as they contain an added ingredient, bone growth inducing material, to help induce bone growth. Of the at least two components described in the first sentence of this paragraph, component 1 is a micronized filler material having an average particle size sufficient to form a putty-like consistency when intimately mixed with the second component, i.e., the dispersing excipient component 2 of the present invention. Examples of component 1 are hydroxyapatite, carboxylates, preferably fatty acid salts, such as calcium stearate or homologues thereof, such as calcium laurate or other micronising agents, such as synthetic absorbable polymers, such as polyglycolide, polylactide, copolymers of lactide and glycolide, polydioxanone, polycaprolactone, and absorbable glass, (such as those based on phosphorus pentoxide, etc.). Component 2 the dispersing vehicle is a liquid which when intimately mixed with component 1 forms a putty-like implant. While the two-component compositions of the present invention provide the essential features of suitable hemostatic materials described herein, they may also, but need not, comprise optional components 3-12 as may be desired, as shown below. For example, optional component 3 is an absorption accelerator and optional component 4 is a bone growth inducing material. Other components may be added to provide additional characteristics to the putty-like and non-putty-like compositions of the present invention, as will be explained in more detail below.

The following is a detailed description of the different components.

Component 1

Component 1 comprises a finely divided, preferably micronized, biocompatible, body-absorbable material which, when mixed with a liquid dispersing excipient, component 2, forms the composition of the present invention. Suitable compositions are obtained when the average particle size of the component 1 material is about 50 microns or less, but preferred average particle sizes range from about 3 to about 25 microns, most preferably from about 6 to about 15 microns, especially when a putty-like composition is desired. The particle size range of the non-putty composition can be greater than the particle size of the putty composition, if desired.

One group of examples of materials suitable for use in the present invention are one or more salts having a carboxylate anion and a metal cation, some of which are known in the art and described in U.S. Pat. Nos. 4,439,420 and 4,568,536.

Suitably, the salt may be a salt of a saturated or unsaturated carboxylic acid containing from about 6 to 22 carbon atoms in the chain, preferably calcium, magnesium, zinc, aluminium, lithium or barium having from 8 to 20 carbon atoms. Preferred saturated carboxylic acids providing carboxylate anions may be selected from aliphatic acids such as caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid and its intervening homologs, but the most preferred acids are higher fatty acids such as lauric acid, myristic acid, palmitic acid and stearic acid, most preferably stearic acid. Calcium and aluminum palmitates and stearates are preferred salts, with calcium stearate being most preferred because of its good safety and putty-forming characteristics. However, aluminum stearate, aluminum palmitate or aluminum laurate are also suitable.

Examples of suitable unsaturated aliphatic acids that can be used to provide the carboxylate cation are oleic acid and linoleic acid, since they use the same cations described above.

It has been found that finely divided materials, e.g., about 50 microns or less, other than the carboxylate may beEffective component 1 material. For example, it has been surprisingly found that micronized hydroxyapatite (calcium phosphate), especially at average particle sizes of less than about 25 microns, forms an excellent putty, especially with tocopherol acetate as the liquid dispersant (component 2). Moreover, some of the other materials discussed in component 4 may be used as component 1 provided in micronized form. Examples of these are Demineralized Bone Matrix (DBM), Mineralized Bone Matrix (MBM), insoluble absorbable collagen, gelatin derived from collagen, monosaccharides and polysaccharides. It is believed that any biocompatible material will form a medical composition when converted to a very small particle size. In the production of the composition according to the invention it is not uncommon, for example, to use hydroxyapatite particles of 6 to 12 microns as component 1 and suitable component 2, with or without suitable component 3 such as gelatin and bone chips such as demineralized bone matrix or mineralized bone matrix having a particle size of about 0.5 to about 1mm or more, as component 4. Other examples are finely ground synthetic absorbable homopolymers and copolymers, such as polyglycolide, polylactide, copolymers of lactide and glycolide, polydioxanone, polycaprolactone, copolymers of dioxanone and caprolactone and trimethylene carbonate, gelatin, monosaccharides such as glucose and mannose and polysaccharides such as carboxymethylcellulose and oxidized cellulose, represented by SurgicoleStarch, sucrose, suitably in the form of fructose, alginic acid, hyaluronic acid, chitosan and its acetyl derivatives, and the like, as well as absorbable glass, and the like. Furthermore, certain bioactive materials, such as bioglass (discussed in more detail below with respect to component 4), which may be considered non-absorbable in the conventional sense, may be used in micronized form as component 1. For example, absorbable polymers having an average particle size of less than about 25 microns will form useful, stably absorbable hemostatic putties when mixed with, for example, tocopheryl acetate or triglyceride oils, particularly castor oil of U.S. patent 4,439,420. Thus, any natural or synthetic absorbable polymer that can be reduced to a sufficiently small particle size if combined with a suitable phaseThe excipients, when mixed, will form a stable absorbable putty.

It has also been found that absorbable glasses based on phosphorus pentoxide (instead of silica) and containing alkali or alkaline earth metal oxides, such as sodium oxide, potassium oxide, calcium oxide and magnesium oxide, dissolve slowly in aqueous media as network polymers and can be used as component 1. Furthermore, such compounds may be used as absorption accelerators, i.e. as component 3, in which case they may be used, but need not be, in micronized form when used as component 1. U.S. patent 4,612,923 mentions the prior art regarding the preparation of these glasses and their use as strength-enhancing and hardness-enhancing additives for synthetic absorbable surgical devices. When the 325 mesh glass described in us patent 4,612,923 is further crushed to an average particle size of less than 50 microns, the resulting fine powder forms a medically acceptable putty when mixed with the excipients described in us patent 4,439,420 and this specification. The rate of water dissolution (absorption) of such glasses can be increased by increasing the proportion of alkali metal oxides and decreased by increasing the proportion of alkaline earth metal oxides.

The above-described novel process of forming a useful resorbable putty by substantially reducing the particle size of the filler excipient component 1 overcomes many of the difficulties of the prior art, particularly the difficulties of synthetic resorbable polymers as bone hemostatic agents.

Component 2

As the second component, i.e. the material which is mixed with component 1 to obtain the composition of the invention, there may be mentioned several classes of materials which have not hitherto been used as dispersants for the preparation of medicinal putties. At the outset, it should be noted that component 2 is biocompatible and is preferably a liquid, as the liquid form facilitates mixing with component 1 to form a putty or non-putty substance. However, it should be recognized that component 2 may also be a solid if a liquid excipient (a liquefying agent, described more fully below) is used as the medium for components 1 and 2.

To aid in understanding the terms used herein, and to help distinguish this aspect of the invention from that of the prior art, it may be useful at this point to emphasize the nature of the chemical entities referred to in the specification by a brief review of the relevant classical chemical terms to ensure an understanding of the appropriate chemical distinctions.

The carboxylic acid defined by the attachment of an OH group to a carbonyl group functions through a covalent bond. As a result, carboxylic acids have physical and chemical properties that are quite different from materials containing carbonyl functional groups (e.g., aldehydes, ketones) or hydroxyl functional groups (alcohols). Species that contain both a carbonyl group and a hydroxyl group that are not directly linked by a covalent bond, such as hydroxyacetone, also differ similarly in that they exhibit ketone and alcohol properties, but not carboxylic acid characteristics. Carboxylic acids always combine a carbonyl group and an OH group and have an acidic character, but the OH group does not have an alcoholic hydroxyl character. Thus, monocarboxylic acids are not described as monohydroxy compounds. To illustrate this, consider acetic acid and ethanol, both of which are dicarbonic compounds containing OH groups. In acetic acid, hydrogen atoms of OH groups are released as ions in water, while hydrogen atoms in hydroxyl groups in ethanol are not so released. Thus, the carboxylic acid dissociates and forms a carboxylate with the base, such as calcium stearate, a property that distinguishes the OH group of the carboxylic acid from the alcoholic hydroxyl group that does not dissociate to form a salt with the base. Thus, the characterization of a carboxylic acid as an alcohol, a monohydric alcohol, or some such terms is entirely incorrect, as it is not an alcohol in a chemical sense. Polycarboxylic acids are also not called polyols or polyhydrocarbyl compounds or polyols (polyols) simply because they contain carboxylic OH groups. These groups are not characterized as alcohols. Examples of these differences are illustrated by considering the known molecule, citric acid. This material has three carboxyl groups and one hydroxyl group on the same molecule. Citric acid is a monohydric (monohydric) alcohol and a polycarboxylic acid. Citric acid contains three carboxyoh groups and does not classify this monohydroxy compound as a polyhydrocarbyl compound. Due to major differences in activity, synthesis and reaction, the chemistry of alcohols in each organic chemistry textbook is always considered in a separate section than the carboxylic acid chemistry.

The alcohol may be considered a hydroxy derivative of a hydrocarbon orAlkyl derivatives of water. They are represented by the structure R-OH, where R is an alkyl group. Unlike the hydrogen atoms of the hydroxyl groups of carboxylic acids, which are easily ionized, the R — OH hydrogen atoms are not substantially ionized in water. On this basis, fatty alcohols are considered neutral rather than acidic. One or more hydroxyl groups may be added to the hydrocarbon moiety such that, for example, propane has one hydroxyl group (propanol), two hydroxyl groups (propylene glycol) or propylene glycol (propylene glycol)), or three hydroxyl groups (glycerol or glycerin). Propylene glycol and glycerol are simple examples of polyols. Polysaccharides, such as hyaluronic acid, contain many hydroxyl groups on each monomer unit and are correctly referred to as polyols. The alcohols may have short alkyl chains, such as methanol, ethanol, propanol, etc., or they may have longer alkyl chains, such as lauryl alcohol, myristyl alcohol, etc. It is very important to note lauric acid (C)₁₁H₂₃COOH, a fatty acid) and lauryl alcohol (C)₁₂H₂₅OH, a fatty alcohol) are completely different molecules in oxidation state and functionality, although they all contain 12 carbon atoms.

Esters generally originate from the reaction of a carboxylic acid with an alcohol and can be converted back to the original carboxylic acid and alcohol by hydrolysis. Thus, acetic acid and ethanol are combined during esterification to form ethyl acetate and water. The term fat (or vegetable or animal oil) is limited to esters of various long-chain saturated or unsaturated fatty acids with glycerol (glycerides). Oils cited in the prior art as vehicles for preparing putty-like materials refer exclusively to glycerides, such as castor oil, sesame oil, olive oil and the like, as well as simple fatty acid esters, such as lauric alcohol. The prior art has never suggested free liquid fatty carboxylic acids, such as saturated octanoic acid and unsaturated oleic acid, as excipients for the preparation of putty-like materials. Most importantly, the use of esters of fatty alcohols with low molecular weight mono-or polycarboxylic acids, such as lauryl acetate (esters of lauryl alcohol and acetic acid) is entirely new for the preparation of putty-like materials and is chemically different from the ethyl laurate cited in the prior art (esters of lauric acid with ethanol).

Returning now to the description of the components of the present invention, more specifically component 2, these components are described more specifically below:

as a first type of component 2, there are one or more absorbable C' s₈-C₁₈Monohydric alcohol and C₂-C₆Esters of aliphatic monocarboxylic acids. The monohydric alcohol may be selected from C₈-C₁₈Alcohols, such as octanol, decanol, lauryl alcohol, myristyl alcohol, stearyl alcohol and the intervening homologs thereof. Preferred alcohols are higher aliphatic compounds, such as lauryl alcohol, myristyl alcohol and stearyl alcohol. And C₂-C₆Examples of useful esters of monocarboxylic acids are lauryl acetate and myristyl propionate.

As a second type of component 2, there are one or more absorbable C' s₂-C₁₈Esters of monohydric alcohols with polycarboxylic acids. C₂-C₁₈Monohydroxy alcohols other than C as described in the first class of esters₈-C₁₈The alcohol may also include lower fat C₂-C₈Alcohols such as ethanol, propanol, butanol, pentanol, heptanol, hexanol, and octanol, produce the corresponding ethyl, propyl, butyl, pentyl, heptyl, hexyl, and octyl moieties. The polycarboxylic acid may be chosen from malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, maleic acid, fumaric acid, glutaconic acid, citric acid, malic acid and, if present, esters of the hydroxyl functions of esterified polycarboxylic acids, in particular of acetylcitric acid and acetylmalic acid. It will be apparent to those skilled in the art that many combinations of alcohols/acid esters may be selected from the above, but the monohydroxy alcohols/polyacids preferred for use in the present invention are diethyl succinate, dioctyl succinate, triethyl citrate, tributyl citrate and their higher and lower homologues, acetyl triethyl citrate, acetyl tributyl citrate and their higher and lower homologues, butyryl triethyl citrate, diethyl malate, di-amyl malate and acetyl diethyl malate and their higher and lower homologues.

Another class of materials suitable as component 2 is higher C₈-C₁₂Up to about C₃₀And is preferably a liquid or liquefiable oneAnd hydroxyl alcohols such as octanol and decanol. Particularly surprisingly, suitable embodiments in this case are the aromatic alcohol tocopherols (vitamin E), in their optically active or racemic form and in any of the alpha, beta, gamma and delta forms, and C₂-C₁₀Liquid tocopheryl esters of aliphatic monocarboxylic acids, polycarboxylic acids, or mixtures thereof (sometimes referred to herein as tocopheryl esters). Tocopheryl esters, such as acetates, butyrates, caproates, caprylates, caprates, and intervening homologs thereof and polycarboxylates, such as those described in the preceding paragraph, particularly the esters of succinic acid, citric acid, and malic acid, are useful, with succinate being preferred.

Another class of materials that may be used as component 2 are absorbable hydrocarbons having from about 10 to about 14 carbon atoms. For example decane and dodecane are suitable.

Another class of materials useful as component 2 are liquid or liquefiable saturated or unsaturated, free carboxylic acids, such as non-esterified fatty acids, oleic acid, linoleic acid, caprylic acid, capric acid, and lauric acid. In this case, liquid, saturated fatty acids are generally suitable, but may not be desirable because of their unpleasant odor. Certain low melting saturated free fatty acids that form lower melting low melting mixtures that are liquid at room temperature are also suitable. One advantage of saturated free fatty acids is that they have improved radiation sterilization stability, while unsaturated acids, such as oleic acid, may require radiation sterilization in oxygen-free containers. The higher homologues of solid acids may also be used in admixture with component 1 in the presence of a liquefaction medium or other suitable component. Any compatible liquid may be used as long as it ensures that component 2 is liquefied and biocompatible.

Another class of materials useful as component 2 are simple dialkyl and alkylaryl ethers and ethers of cyclic polymers of alkylene glycols such as ethylene glycol, known as crown ethers, all of which have boiling points above about 80 ℃, e.g., di-n-butyl ether, di-n-hexyl ether, di-n-octyl ether and asymmetric ethers, e.g., ethylhexyl ether, ethylphenyl ether, and the like, or different ethylene oxide to propylene oxide ratios and different molecular weights, preferably 1000-10,000 Block copolymers of ethylene oxide and propylene oxide (Pluronics)). They are available in liquid or solid form. Examples of suitable materials are those known below in examples 42, 56 and 57. In addition to their suitability as component 2, they can also be used as absorption accelerators (component 3). They may be used according to the trade name PluronicsObtained from BASF corp.mt.olive, new jersey 07828.

Another class of materials that may be used as component 2 are symmetrical and asymmetrical dialkyl and alkylaryl ketones having boiling points above about 80℃, such as methyl propyl ketone, diethyl ketone, methyl butyl ketone, ethyl propyl ketone, methyl amyl ketone, and 2-octanone, 2-nonanone, 2-decanone, and methylphenyl ketone.

Another class of materials useful as component 2 is selected from the group consisting of polyalkyl compounds, polyalkyl compound esters, solutions of polyalkyl compounds and mixtures thereof, and fatty acid esters.

Preferred liquid polyalkyl compounds are selected from acyclic polyhydric alcohols, polyalkylene glycols, and mixtures thereof.

Specific examples of the foregoing are liquid solutions of ethylene glycol, diethylene glycol, triethylene glycol, 1, 2-propanediol, trimethylolethane, trimethylolpropane, erythritol, pentaerythritol, polyethylene glycol, fatty acid monoesters, such as glycerol monolaurate. The foregoing solids may be dissolved or dispersed in a suitable solvent medium such as propylene glycol, glycerol, monoacetin, diacetin, liquid polyethylene glycol, and mixtures thereof. As the glyceride, there may be mentioned monoglycerides such as glyceryl acetate, glyceryl stearate, their analogs and the like, diglycerides such as glyceryl diacetate, glyceryl didecanoate, glyceryl dibutyrate, glyceryl dilaurate and the like, and triglycerides such as olive oil, castor oil, almond oil, sesame oil, cottonseed oil, corn oil, cod liver oil, safflower oil and soybean oil. It should be noted that the foregoing polyhydrocarbyl compounds may also be used as component 3 absorption accelerators, if desired. If DBM powder is present in the formulation (e.g., component 1), the polyol may not be an acyclic polyhydroxy alcohol, a non-reducing sugar, a sugar alcohol, a sugar acid, a monosaccharide, a disaccharide, a water-soluble or water-dispersible oligosaccharide, a polysaccharide, a polyalkylene glycol, or a mixture thereof.

As a statement of general applicability, it should be noted that component 2 materials that are liquid at room temperature are preferred materials for component 2, and that no liquefier is required because they are liquids. However, substances useful as component 2 are compounds which are solid at room temperature. In these cases, particularly where a putty is desired, solid component 2 is converted to a liquid form before, during, or after mixing with component 1 by using an absorbable biocompatible liquefying agent capable of liquefying, or solubilizing, the solid of component 2. As used herein, "liquefying agent" refers to an agent, such as a suitable solvent, that can dissolve a solid or any other agent, even though the agent may not be considered a solvent in the conventional meaning of the term, or an agent that can liquefy the solid, such as by heating, or an agent that can disperse a solid in a liquid into a dispersion to help form a uniform putty, cream, or paste-like mixture. The particular agent used will, of course, depend on the nature of component 2 in the particular formulation. Suitable reagents are materials similar to component 2, although it is not described herein precisely as component 2.

The aforementioned novel concepts and compositions utilizing esters of monohydric alcohols with the aforementioned mono-or polycarboxylic acids provide a resorbable bone hemostatic implant. It has been found that the novel use of simple esters of lower molecular weight, non-toxic and rapidly degradable, such as diethyl succinate, triethyl citrate and lauryl acetate, provides an excellent alternative to higher molecular weight fatty acid triglycerides, such as castor oil, with respect to component 2. This aspect of the invention therefore allows the elimination, where required, of the forms of component 2 known in the art, namely hydrophobic, slowly absorbed esters such as triglycerides represented by ricinoleic acid triglyceride, castor oil and fatty acid esters such as isopropyl myristate, and the need to use absorption accelerators.

However, these prior known putty compositions containing the component 2 materials known in the art, such as those in U.S. patent 4,439,420, may be used to obtain an osteogenic bone hemostatic material according to another aspect of the present invention. It has been found that the compositions known in the art can be improved by the addition of osteogenic materials such as Demineralized Bone Matrix (DBM), Mineralized Bone Matrix (MBM), hydroxyapatite or growth factors such as Bone Morphogenetic Protein (BMP) and Platelet Derived Growth Factor (PDGF) when it is desired to have a bone hemostatic composition with osteogenic properties and slower absorption characteristics.

Component 3-optional

A third component, typically a hydrophilic material, is optionally included as an absorption accelerator and may even be used to control absorption kinetics by physically assisting in the breakdown of the implant material. Accelerators used in the prior art can be used if they are non-toxic or biocompatible. Such as Carbowax、Pluronics(see discussion above and discussion below regarding component 2), one or a combination of glycerol, propylene glycol, lecithin, betaine, and polyhydroxy compounds such as hyaluronic acid, carboxymethylcellulose, and chitosan, and acetyl derivatives thereof, may be used as absorption enhancers in the compositions of the present invention, and the above conditions are followed. However, other materials which are swellable or soluble and absorbable, such as soluble or insoluble, natural or synthetic polypeptides, examples of which are purified, soluble fiber-in-powder, are preferably used for this purposeComminuted, but swollen collagen, more rapidly absorbable soluble procollagen, e.g. VitrogenAnd more rapidly absorbable cold and hot water soluble polypeptides such as gelatin. Lecithin and octylphenyl ethoxylates, e.g. TritonX100 may be used as a biocompatible surfactant to aid in swelling. Polyvinylpyrrolidone and other soluble, absorbable polymers, such as block copolymers of ethylene oxide and propylene oxide, such as polyaspartic acid, polyglutamic acid, and salts thereof, discussed with respect to component 2 and the relatively hydrophilic polypeptide, also function within this range. Most preferably, the composition of the invention comprises as a third component an insoluble, fibrillar collagen, soluble collagen, gelatin, octylphenyl ethoxylate (e.g. Triton X100), a block copolymer of ethylene oxide and propylene oxide, polyvinylpyrrolidone or an absorbable phosphorus pentoxide based glass or a stable mixture of the foregoing. Particle size ranges of about 200-500 microns produce suitable results, although larger or smaller particle sizes may be used depending on the needs of the end user. Gelatin, PVP and other polymers are used as thickening additives in bone demineralization techniques, but not as absorption accelerators. The thickening properties of gelatin are directly a function of the Bloom number of the gelatin. Gelatin having a Bloom number in the range of 100-300 is suitable for the compositions of the present invention, although the above values and those below may be used if the resulting product is acceptable to the end user.

Examples of some suitable proportions of components to produce a composition having the above properties are as follows:

component 1. is about 5-80 wt%, preferably about 20-50 wt% of the final composition.

Component 2. is about 10-70 wt%, preferably about 20-50 wt% of the final composition.

Component 3. is about 0-80 wt%, preferably about 10-70 wt% of the final composition.

Although the foregoing discussion has been provided primarily in the context of materials having a putty consistency, compositions having less tackiness or less adhesiveness may be desirable in certain applications. For example, it may be desirable to place the composition of the invention in the void (filled or formed, e.g., hairline crack) of a bone and only have difficulty filling a high viscosity putty therein. The less viscous form of the putty compositions of the present invention is a desirable alternative. All that is required is to change the ratios shown therein to allow for higher liquid concentrations, or to add compatible liquid diluents to achieve this. Using this method, acceptable forms of the material can also be obtained. Other non-putty compositions of lesser cohesive strength, such as creams, ointments, gelatins, lotions, and the like, as previously described, may be prepared in the same manner.

Component 4-optional

The above products are suitable hemostatic products which also allow bone growth at the site of bone wounds. Thus, they are osteoconductive. One desirable aspect of the invention also renders the hemostatic product osteoinductive, i.e., provides a product comprising component 4, an amount of bone growth inducing material (osteogenic material) sufficient to induce bone growth. Thus, incorporation of osteogenic materials, e.g., growth factors such as Platelet Derived Growth Factor (PDGF), transforming growth factor beta (TGF- β), insulin-related growth factor-I (IGF-I), insulin-related growth factor-II (IGF-II), Fibroblast Growth Factor (FGF), beta-2-microglobulin (BDGF II), Bone Morphogenic Protein (BMP), and combinations thereof, have been found to stimulate osteogenesis to various degrees. Other bone growth inducing materials, such as Demineralized Bone Matrix (DBM), osteonectin, osteocalcin, osteogenin and combinations thereof, Mineralized Bone Matrix (MBM) and/or hydroxyapatite, a component of normal bone and bioactive glass, allow the hemostatic product to properly form bone.

Hydroxyapatite is an inorganic calcium phosphate mineral, which can be, among other thingsPrepared synthetically or from sarcandra glabra (in which all organic material has been removed) has been shown to support rapid ingrowth of new bone tissue. The bioactive glass is biocompatible micronized glass particles. They are used as bone implant materials. A batch of bioglass can be expressed as vitryxxx^TMCommercially available from Schott, GmbH, Mainz, Germany. According to the manufacturer, when implanted into the body, resurfacing forms "hydroxycarbo-apatite", thereby allowing bone repair cells to deposit and form new bone tissue.

In use, an appropriate amount of osteogenic material is added to the compositions of the present invention, and depending on the material, the amount ranges from about 0.001 to about 60 weight percent, preferably from about 0.001 to about 40 weight percent.

When used as component 4, i.e. as an osteogenic material, it is preferred to use certain agents, such as DBM in the form of a larger average particle size or mineralized bone. Suitable larger average particle sizes range from about 0.05 to 10mm, preferably from about 0.1 to 5mm, and most preferably from about 0.5 to 1 mm. However, it may also be suitable to use smaller or larger particle sizes or higher or lower amounts of component 4 if the end user needs to be met.

With respect to the relative amounts of osteogenic material used in the compositions of the present invention, an effective bone growth inducing amount can be used, which means that the material has a sufficient amount and average particle size to be osteoinduced in the composition. The amount used may vary depending on the effectiveness of the osteogenic agent and the average particle size of the material. For example, growth factors such as BMP, Platelet Derived Growth Factor (PDGF), and the like are effective at partial weight percent concentrations, while effective amounts of DBM, mineralized bone matrix, and hydroxyapatite are generally at higher weight percent concentrations, e.g., about 10% to about 50% or higher, with a preferred average particle size slightly larger than the average particle size used in component 1.

The addition of bone growth inducing material not only improves the composition of the present invention, but also improves the hemostatic formulations of the prior art to obtain a new composition thereof. These additions also enable these hemostatic formulations to be osteogenic. It is believed that the presence of osteogenic material also improves osteoinductive properties, as the relatively large particles tend to "open up" the putty structure, thereby providing space into which induced bone may proliferate.

Types of prior art hemostatic formulations that are particularly improved by such additions are disclosed in U.S. patent nos. 4,439,420 and 4,568,536, each of which is incorporated herein by reference for all purposes. Accordingly, the specification and claims of this application are to be read as if the specification and claims were individually read into the text. For convenience, the formulations of those patents may be generally characterized as comprising an absorbable hemostatic composition for controlling bone bleeding, comprising: a component comprising a biocompatible fatty acid salt having a cation selected from the group consisting of calcium, magnesium, zinc, aluminum, lithium and barium and a component comprising a body absorbable biocompatible base selected from the group consisting of ethylene oxide/propylene oxide block copolymers, polyols, polyethylene glycols and methoxypolyethylene glycols, triglycerides and fatty acid esters, and optionally an absorption enhancer. Thus, in this aspect of the invention, a bone growth inducing material is added to the above prior art formulation to produce an osteogenic hemostatic material and an osteoinductive bone defect filling material.

Other optional ingredients

A pharmaceutically effective amount of an anti-infective agent alone or in combination with a substrate may be added to any of the compositions described above to slow its release. Examples of such anti-infective substances are tetracycline, vancomycin, cephalosporins and aminoglycosides, such as tobramycin and gentamicin, alone or in combination with collagen, as well as combinations of the foregoing, iodine, colloidal silver, silver salts, alone or as PVP complexes, alone or in combination with carriers, such as gelatin, collagen and the like.

Other materials, for example clot inducers such as epinephrine, tannic acid, ferrous sulfate, and sulfate double salts of trivalent and monovalent metals (double-sulfates), e.g., aluminum potassium sulfate and aluminum ammonium sulfate; antineoplastic agents, e.g. methotrexate, cisplatin, doxorubicin and combinations thereof, radiationNuclides such as strontium 89 and the like; analgesics, such as benzocaine, lidocaine, tetracaine, fentanyl (a potent non-steroidal compound), and the like, anti-inflammatory substances, such as non-specific ibuprofen and aspirin, or COX-2 specific inhibitors, such as rofecoxib and celecoxib; radiopaque substances, e.g. iodine compounds, e.g. as EthiodolEthyl monoiodo stearate, available from Savage Laboratories, and barium salts such as barium stearate may be added to the formulations in amounts effective to achieve their therapeutic or diagnostic purpose. According to the characteristics of the colorant chosen, colorants, e.g. gentian violet, D&C Violet #2 and D&C Green #6 is suitable.

In certain embodiments of the present invention, it may be desirable to intimately mix water with the compositions of the present invention. The presence of small amounts of water, on the order of up to 10% or more, is assisted in a number of ways in which the tactile properties of the composition are altered. In this regard, the resulting compositions are generally imparted with a reduced roughness sensation as compared to compositions without added water. In some instances, it is desirable to provide putty-like formulations or less viscous non-putty formulations having a cohesive strength less than that of a putty, such as creams, pastes, or the materials described herein, based on water or other aqueous liquids rather than the more hydrophobic excipients. Fillers such as metal fatty acid salts, e.g., calcium stearate, and other non-wettable fillers described herein are not wetted by water and do not provide an aqueous putty-like (less thick) composition. However, we have found that small amounts of surface active materials, such as lecithin, Pluronics are usedFor example Pluronic L-35Treating the bulking agent to sufficiently wet the non-wettable bulking agent to enable preparation of a suitable fatty acid salt-water formulation when component 2 is an aqueous vehicle. Suitable aqueous excipients are water, saline, various biocompatible buffers, various body fluids, such as blood, serum, blood component concentrates, and the like.

Although the above putties are less resistant to washing than putties prepared using more hydrophobic materials, they are applied to bone defect repair where more rapid decomposition of the implant is desired. Nonionic, cationic and anionic surfactants are suitable, although virtually any biocompatible surfactant may be used, for example, dodecyltrimethylammonium chloride, sodium lauryl sulfate, nonoxynol-9, tweens such as polyoxyethylene sorbitan monolaurate, Tergitol-7, i.e., sodium heptadecyl sulfate, and antimicrobial surfactants, 1-lauryl-3-ethylbenzotriazolium (triazolium) bromide, and the like. Non-putty-like compositions, such as creams, pastes, and the like, may be prepared by using additional amounts of water. This is particularly useful in surgical procedures where it is desired to use blood rather than water to form a putty or cream-like composition.

The above discussion relating to the use of clot inducing agents in the present invention exemplifies embodiments where the compositions can be used for chemical hemostasis. That is, whether or not these compositions are mechanical hemostatic, the addition of synthetic materials to the compositions of the present invention results in compositions that can be used as chemical hemostatic materials. Thus, putties that have been mechanically hemostatic can be more effectively hemostatic by the addition of clot-inducing materials. Similarly, lower cohesive strength creams or pastes that may lack significant mechanical hemostatic properties can be made hemostatic by the addition of a blood clotting material. An example of the latter is a bleeding acetabulum to which a thin layer of the vasoconstrictor-modifying paste of the invention is applied in hip surgery.

The above components, when added together in suitable proportions, give rise to desirable, putty-like and non-putty-like agents having various advantageous characteristics to varying degrees. Different combinations of components may require different times and temperatures of the preparation process to obtain the putty-like characteristics. For example, certain materials such as finely divided hydroxyapatite may require a longer time to achieve a putty-like state than other components. Generally, the putty-like compositions of the present invention are absorbable within a reasonable period of time, typically within 30 days, although for some applications the absorption time may extend to months or more. They are usually moldable or shapeable by hand at room temperature, can be handled well in the presence of blood, and can be washed with saline. They are sometimes tacky to the touch, but not so tacky as to stick to wet or dry surgical gloves. They are radiation sterilizable in the absence of radiation sensitive materials such as DBM or certain antibiotics.

The actual proportions of materials selected will depend on the materials themselves, the amounts of components used and the intended application of the final putty composition. The user will initially be directed to the need to achieve the target viscosity, cohesive strength and consistency, i.e., the consistency of the composition ranges from a flowable liquid consistency to a cream, paste, ointment, gel, etc., and to a more viscous putty-like consistency, while maintaining other target characteristics in the end-use components.

When used in surgery, the compositions described in the specification must be sterile. All compositions except those described below were radiation sterilized using, for example, a standard cobalt-60 radiation source and a nominal dose of 25 kGy. The exceptions are formulations containing radiation sensitive additives such as demineralized bone matrix, bone morphogenic proteins, certain antibiotics, unsaturated molecules such as oleic acid, and the like. When these materials are used, sterility can be achieved by radiation sterilization of the filled putty-like material and the sterile addition of pre-sterile radiation-sensitive additives followed by aseptic packaging.

The compositions described in the specification can be packaged in a variety of forms and can be sterile or sterilizable. The packaging itself may be sterile or sterilizable. The composition may be packaged as an amorphous (i.e. unshaped or not shaped) material, such as a paste, cream or putty, or in the shape of its container. They may be generally shaped as parallelepipeds, examples of which are small brick shapes or slabs (gum sticks), or as conventional circles, examples of which are cylindrical, ovoid or spherical products. Alternatively, the product may be packaged in a syringe-like or piston-assisted dispenser that can be pressed or extruded through a hole of suitable cross-section and shape, as the application allows and the viscosity is appropriate. A mechanical assist device similar to that used for caulking may be included. Another package includes a product in a squeezable, deformable tube, such as a toothpaste-type tube or a collapsible tube, such as a tube for caulking applications, with an aperture shaped and sized to dispense any suitable shape to a surface to be treated. The package may contain an outer barrier as an outer packaging, such as peelable water vesicles, to deliver the package aseptically to a sterile site.

The invention also contemplates methods of using the compositions of the invention. For example, one embodiment is a method of mechanically controlling bone bleeding by administering to the bleeding bone an effective amount of any of the compositions of the present invention, wherein the composition has a sufficiently thick consistency, such as in a putty composition of the present invention. In this case, the composition is a mechanical hemostatic plug.

Another embodiment of the method of use of the present invention is a method of chemically controlling bone bleeding by administering an effective amount of a composition of the present invention, wherein the composition comprises a clot inducing agent as described above. In the case of putty, the composition is a mechanical hemostatic plug. Mechanical hemostatic tamponades of the invention that also contain a clot inducing agent will serve as both a mechanical hemostatic agent and a chemical hemostatic agent.

Another method of the invention is a method of inducing bone growth in a bone defect by applying an effective amount of any of the compositions of the invention comprising a bone growth inducing agent to the affected bone area, particularly when the composition comprises a bone growth inducing material such as DBM, mineralized bone matrix, bone morphogenic protein, hydroxyapatite, and the like.

Another method is a method of treating infection in or around the bone by administering an effective amount of any of the compositions of the present invention comprising an anti-infective agent to the affected bone area to be treated.

Another method is to destroy cancer cells in or around the bone by administering an effective amount of any of the compositions of the invention containing an anti-tumor agent to the affected bone area containing such cells.

Another method is to reduce pain in or around the bone by administering an effective amount of a composition of the invention containing an analgesic to the affected area.

Another method is a method of controlling inflammation in or around the bone by administering to the affected area an effective amount of any of the compositions of the present invention containing an anti-inflammatory agent.

Another method is a method for evaluating the status of an intraosseous region to which an implant has been administered by: an effective amount of a composition of the invention containing a radioopaque agent is administered to the affected area, the area is then radiographed, and the status of the area is determined.

Another method is to wet any of the bulking agents used in the present invention which can be made into a water-based putty from the treated bulking agent by rendering the bulking agent hydrophobic with a cationic, anionic or nonionic surfactant and then using any source of liquid, such as water itself, saline or body fluids such as blood, serum, etc.

The skilled person will know the manner of using the composition and its amount. In some applications, a large amount of padding may be used, while in other applications only a small amount is needed or required.

The methods and examples provided below are intended to more fully describe preferred embodiments of the invention and to demonstrate the advantages and utility thereof.

The following examples illustrate specific embodiments of the present invention.

Example 1

In this and the following examples, compositions were prepared by the following methods, unless otherwise indicated: all dry reagents were first mixed mechanically and then any liquid reagents were added gradually. The composition is "worked" with a spatula (spatula) at room temperature until the desired consistency is obtained. In some cases, if the material requires additional ingredients to improve consistency, the material is added and continuously kneaded or "worked" until the desired putty-like consistency is achieved. The components are expressed in parts by weight.

Component 1 calcium stearate 4g

Component 2 tocopheryl acetate 3g

Component 3 gelatin 3g

The sample produces a putty-like substance with excellent water resistance, physical and hemostatic characteristics, and water resistance, i.e., it strongly resists attempts to wash it off under the force of flowing tap water.

Example 1a)

By varying the proportions of the liquid components, the compositions of the present invention can be brought into a state of lower (i.e., more liquid) or higher (i.e., more rigid) viscosity. Examples of low viscosity formulations are as follows: to the putty formulation of example 1 was added 3g of acetyl triethyl citrate. The resulting product has a cream-like consistency and can be applied to bone under appropriate circumstances as a hemostatic agent or as a delivery agent for various additives such as drugs.

Example 2

Partial replacement of stearic acid with bone growth inducing material

a) Component 1 calcium stearate 3g

Component 2 tocopheryl acetate 3g

Component 3 gelatin 3g

Component 4 hydroxyapatite (6-12 micron particle size) 1g

The resulting product was a putty-like material comparable to the product in example 1. When a small amount of gentian violet sufficient to impart a visibly light violet colour to the above formulation, a coloured product having the characteristics of the product of example 1 is obtained.

b) Calcium stearate is completely replaced by hydroxyapatite

Component 1 hydroxyapatite (6-12 micron particle size) 2g

Component 2 tocopheryl acetate 2.5g

Ingredient 3 gelatin 2g

The composition was allowed to stand at room temperature for 72 hours, yielding a product having the characteristics of the product of example 1.

Example 3

Component 1 aluminum palmitate 5g

Component 2 tocopheryl acetate 3g

Component 3 gelatin 3g

The resulting product was an oil-ash-like material having properties similar to those described for the product of example 1.

Examples 3a), 3b), 3c)

The putty-like formulation of example 3 was converted to a less viscous composition by modifying the formulation of example 3 as follows:

formulation 3a had the consistency of a soft putty.

Formulation 3b had a thick cream consistency much like a cake icing.

Formulation 3c had a consistency of a slow flowing composition much like cold honey.

Each of them can be applied to bone as a hemostatic agent.

Example 4

Component 1 calcium stearate 5g

Component 2 tocopheryl acetate 3g

Component 3 gelatin 3g

Fraction 4DBM 3g

The resulting product has osteoconductive additional properties beyond the hemostatic properties of the product of example 1.

Example 5

The product 5a obtained is an oilGrey, and have physical characteristics similar to those of example 1. Product 5b is also putty-like and absorbs more rapidly than 5 a. Triton (R) sX100 is available from Dow Chemical Co., Midland, Michigan.

Example 6

Component 1 calcium stearate 4g

Component 2 triethyl citrate 3g

Component 3 gelatin 3g

The resulting product is putty-like and has the physical characteristics of being used as a hemostatic agent, but is not preferred when compared to the product of example 5.

Example 7

Component 1 calcium stearate 2g

Component 2 acetyl triethyl citrate 2g

The resulting product had excellent putty-like and physical characteristics compared to the product of example 1.

Example 8

Component 1 calcium stearate 0.5g

Component 2 triethyl citrate 1g

Component 4 hydroxyapatite 2g

A low viscosity injectable composition having hemostatic properties is obtained.

Example 9

Component 1 calcium stearate 5g

Component 2 tocopheryl acetate 2g

Component 4 hydroxyapatite 2g

A composition having excellent putty-like characteristics and water resistance is obtained.

Example 10

Component 1 hydroxyapatite 2g

Component 2 triethyl citrate 2.5g

A composition is obtained which is easy to apply to the surface of thick bones and has good adhesion and filling characteristics.

Example 11

Component 1 calcium stearate 3g

Component 2 tocopheryl acetate 1.0g

Component 2 triethyl citrate 1.5g

Ingredient 3 gelatin 2g

The resulting product is a good material with putty-like physical characteristics similar to example 1 and slightly more tacky than the product of example 1.

Example 12

Component 1 calcium stearate 4g

Ingredient 2 lauric acid 4g

Component 2 tocopheryl acetate 5g

Calcium stearate was mixed with molten lauric acid and formed a good putty that solidified upon cooling. The solids were then crushed and mixed with tocopherol to give a good putty.

The resulting product had a putty-like consistency at body temperature and a slightly harder consistency at room temperature.

Example 13

Component 1 calcium stearate 4g

Component 2 triethyl citrate 4g

Ingredient 2 lauric acid 4g

The resulting product was putty-like and had physical characteristics similar to example 1 and was slightly less cohesive.

Example 14

Component 1 calcium stearate 2g

Component 2 dodecane 1g

The resulting product has good water resistance, low viscosity, and good comparability to the other physical characteristics of example 1.

Example 15

Component 1 calcium stearate 2g

Component 2 octanol-11 g

The resulting product was of lower viscosity and had physical characteristics similar to the product of example 14, but with slightly less stickiness.

Example 16

Component 1 calcium stearate 2g

Component 2 diethyl succinate 2g

Ingredient 3 gelatin 2g

The product obtained is a good putty similar to example 1.

Example 17

Component 1 calcium stearate 4g

Component 2 diethyl succinate 3g

The resulting product was a good putty of improved consistency compared to the product of example 16.

Example 18

Component 1 calcium stearate 4g

Component 2 acetyl triethyl citrate 3g

Component 3 gelatin 3g

The product obtained corresponds to the product obtained in example 1.

Example 19

Component 1 aluminum palmitate 4g

Component 2 tocopheryl acetate 3g

Component 2 triethyl citrate 3g

The resulting product is a soft, slightly translucent putty with good water resistance and good hemostatic characteristics.

Example 20

Component 1 calcium stearate 3g

Component 2 tocopheryl acetate 3g

Component 3 gelatin 3g

Fraction 4 demineralized bone matrix 1g

The product obtained is a putty-like substance with properties equivalent to those of the product of example 1 and with osteogenic properties.

Example 21

Component 1 hydroxyapatite 3g

Component 2 tocopheryl acetate 3.5g

Component 3 gelatin 3g

In this example, the material was initially soft and oily and lacked cohesiveness. However, when left to stand at room temperature for 72 hours, an excellent putty with good water resistance was formed. Increasing the amount of tocopheryl acetate by adding 3g resulted in a paste of roughness attributable to gelatin.

Example 22

Component 1 calcium stearate 3g

Component 2 di-n-hexyl ether 2.5g

Ingredient 3 gelatin 2g

The resulting product was putty-like and had good water resistance and physical characteristics similar to example 1.

Example 23

Component 1 calcium stearate 3g

Component 2 di-n-amyl ketone 2.5g

Ingredient 3 gelatin 2g

The resulting product was putty-like and had good water resistance and physical characteristics similar to example 22.

Example 24

Component 1 calcium stearate 3g

Component 2 tocopheryl acetate 3g

Component 3 bovine collagen (powdered) 3g

The resulting product was putty-like with good water resistance and physical characteristics similar to example 23. Furthermore, the putty had a fibrous texture as a result of the fibrous powdered collagen sponge additive being present as absorption accelerator (component 3).

Example 25

Component 1 calcium stearate 3g

Component 2 tocopheryl acetate 3g

Component 3 bovine collagen (powdered) 3g

Containing gentamicin sulphate

ColllatampG, obtainable from Europe

Continent

Obtaining the hemostatic putty with anti-infectious performance.

Example 26

Component 1 calcium stearate 4g

Component 2 tocopheryl acetate 3g

Component 3 gelatin 3g

Anti-infective gentamicin sulfate 120mg

Example 1 was repeated except that 120mg of gentamicin sulfate was combined with the dry components and then tocopheryl acetate was added to prepare putty. This example shows the preparation of a putty having anti-infective properties.

Example 27

Component 1 calcium stearate 4g

Component 2 tocopheryl acetate 3g

Component 3 gelatin 3g

Example 1 was repeated except that the gelatin was soaked in 2% aqueous silver nitrate solution at room temperature for 2 hours, washed with twice distilled water and once acetone, and then dried overnight. Such formulations have anti-infective properties due to the presence of the silver/gelatin complex.

Example 28

Component 1 calcium stearate 4g

Component 2 tocopheryl acetate 3g

Component 3 gelatin 3g

Example 1 was repeated except that 10mg of gelatin was incubated overnight in 1ml of an aqueous solution containing 10 micrograms of lyophilized human bone morphogenetic protein (BMP-2, Sigma-Aldrich) and then air dried overnight. The wet gelatin is washed with acetone to remove residual moisture and combined with the residual gelatin to produce a putty having osteogenic and hemostatic properties.

Example 29

Component 1 calcium stearate 4g

Component 2 tocopheryl acetate 3g

Component 3 gelatin 3g

Example 1 was repeated except that 0.5ml of Betadine was added(povidone-iodine, 10%; equal to 1% may be used)The iodine obtained) was mixed into 10g of the putty of example 1. The material turns brown and has anti-infective properties.

Example 30

Component 1 micronized polylactic acid 3g

Component 2 tocopheryl acetate 1.5g

The mixture formed an excellent putty with good water resistance and properties equivalent to the product of example 1.

Example 31

The following composition is described in U.S. patent 4,439,420 as a preferred composition containing approximately 40% calcium stearate, 30% dextran, and 30% castor oil. If water is added, the preferred composition is 38% calcium stearate, 28% dextran, 27% castor oil, and 7% water (all weights are weight percentages). The composition is prepared by mechanical mixing at room temperature to avoid possible degradation of heat sensitive components.

Calcium stearate 4g

Castor oil 3g

Dextran 3g

The calcium stearate and dextran were dry mixed in a 50ml glass beaker, castor oil was added and stirred with a spatula. After "treatment" of the mixture with a spatula for several minutes at room temperature, the consistency changes gradually. The mixture becomes brittle and turns a putty-like after further processing. Addition of a small amount of water (about 1g) reduced the gritty nature of the dextran.

Example 32

The formulation in example 31 was modified as described below to prepare a new putty-like composition of the present invention. The substance is an effective hemostatic agent and an effective osteogenic bone defect filler.

Calcium stearate 2g

Castor oil 1.5g

Dextran 1.5g

DBM (demineralized bone matrix) 1.5g

The purpose of this example is to show that DBM can be added to the composition described in US patent 4,439,420 to obtain an putty-like substance with osteogenic properties.

Example 33

Component 1 aluminum palmitate 5g

Component 2 tocopheryl acetate 3g

Component 3 gelatin 3g

Methotrexate (2 g) as additive

This new chemotherapeutic putty was filled into bone defects after surgical removal of the bone tumor.

Example 34

Component 1 aluminum palmitate 5g

Component 2 tocopheryl acetate 3g

Component 3 gelatin 3g

Additive strontium 89 (as a salt)

The above formulation when provided with a radioactive effective amount of strontium 89 results in the radiotherapeutic putty described in example 33.

Example 35

Component 1 crushed absorbable phosphate glass 3g

Component 2 tocopheryl acetate 1g

The crucible containing sodium dihydrogen phosphate hydrate was heated at about 800 degrees celsius for 4 hours, and then rapidly cooled. The resulting absorbable phosphorus glass mass was then broken up with a hammer and the fragments were ground to a fine powder while being processed in a rotary ball mill for about 72 hours. Finely ground glass (3g) was stirred with tocopheryl acetate (1.0g) until a putty-like material was formed with good physical and water resistance.

Example 36

Component 1 calcium stearate 3g

Component 2 Ethyl laurate 3g

Fraction 4 demineralized bone matrix 1g

The purpose of this example is to show that DBM can be added to the composition described in U.S. Pat. No. 4,439,420 to obtain a putty-like substance with osteogenic properties.

Example 37

Component 1 hydroxyapatite 3g

Component 2 Isopalmitate 3.5g

Component 3 gelatin 3g

After stirring at room temperature for 72 hours, an excellent putty having good water resistance equivalent to that of example 2 was obtained.

Example 38

Component 1 calcium stearate 5g

Component 2 Glycerol (USP) 15g

3 grams of calcium stearate was mixed with 3 grams increments of glycerin until the mixture assumed a creamy consistency (15 grams of glycerin total). At this stage, an additional 2 grams of calcium stearate was mixed into the mixture to give a composition with good flapped protein consistency and appearance.

Example 39

Component 1 calcium stearate 1g

Component 2 tocopheryl acetate 1g

Component 3 Glycerol 25g

A softer putty is obtained with excellent water resistance.

Example 40

Component 1 sucrose (fructose) 3g

Component 2 Olive oil 2g

This results in a relatively hard putty that is very easy to wash and useful when low water resistance is required.

EXAMPLE 41

3 grams of the product from example 38 above was mixed with 0.75ml of deionized water containing 30ppm of colloidal silver (Source natrals, inc., scots Valley, CA 98006). The resulting hemostatic cream turned off-white due to the presence of the antimicrobial silver and it was slightly less viscous than the original cream.

Example 42

Component 1 calcium stearate 4g

Component 2 PluronicL-35* 0.2g

(molecular weight 1900)

Component 12 Water 2g

*Pluronic 588310，Lot WPAW-502B，BASF，Corp.Mt.Olive，NJ 07828-1234

The ingredients were combined and stirred until a putty-like material was produced. The material readily disperses in excess water.

Example 43

Component 1 calcium stearate 12.0g

Component 2 d, 1-alpha tocopheryl acetate 7.5g

Component 3 Soybean lecithin granule 1.3g

The calcium stearate and lecithin (Archer-Daniels-Midland Ultralec P) were dry mixed, tocopherol acetate was added and vigorously stirred. A putty was formed that had good water resistance and processability but was slightly more viscous than the corresponding formulation containing gelatin rather than lecithin.

Example 44

Component 1 calcium stearate 0.6g

Component 1 Potato starch 3.8g

Component 2 d, 1-alpha tocopheryl acetate 1.6g

*-Razin International，Inc.

6527 Route 9

Howell，New Jersey 07731

Tocopherol acetate and calcium stearate were mixed together and then starch was added. The mixture formed a soft white putty with good water resistance. To prevent post-treatment adhesions from forming, the putty may need to be sterilized with 25kGy of ionizing gamma radiation from a cobalt 60 source to degrade the starch. Alternatively, the starch may be subjected to radiation degradation prior to formulation into the putty.

Examples 45-51 below show that example 1 produces putty compositions having good water resistance and increased absorption with increasing increments from slow absorption to faster absorption as the amount of gelatin increases relative to the amount of calcium salt.

Ca salt fraction 2 parts-gelatin%

Example 4512 Ca stearate 7.5 tocopheryl acetate 00

Example 4612 Ca stearate 7.5 tocopheryl acetate 2.010

Example 4712 Ca 7.5 stearic acid tocopheryl acetate 3.515

Example 4812 Ca stearate 7.5 tocopheryl acetate 5.020

Example 4912 Ca laurate 7.5 tocopheryl acetate 4.520

Example 5012 Ca 7.5 triethyl citrate 4.520 Ca stearate

Example 510.6 Ca stearate 1.6 tocopheryl acetate 5.070

a) Fraction-% b) fraction%

EXAMPLE 52 component 1 Ca stearate 3.4312.3521

Component 2 tocopheryl acetate 3.2292.2120

Component 3 gelatin (150Bloom) 4.4403.0428

Component 4DBM 03.4031

Total 11.011.0

The resulting product has characteristics similar to example 53 putty.

The gelatin in formulation a) is present at 40 wt% and the composition has a good putty consistency as well as good water resistance and absorption.

If it is desired to obtain a more dense excipient which can be used in an anchoring nail or screw, such as a pedicle screw, for use in bone in orthopedic procedures, the foregoing formulation can be modified by including large particle size bone fragments therein and applying it to the appropriate bone site. Thus, when 31 parts DBM, particle size 1-5mm, are added to 69 parts of formulation a) a formulation b) is produced comprising 31% DBM and 28% gelatin. The consistency is that of a thick, thick putty in which a locking pin or screw can be placed and anchored to the adjacent bone. The osteogenic nature of the formulation allows bone growth around the nail or screw, permanently anchoring them to the adjacent bony structures, early or late.

Example 53

Component 1 Ca stearate 3.0g

Component 2 tocopheryl acetate 0.4g

Component 2 tributyl citrate 2.3g

Component 3 gelatin 2.0g

A putty with very good hemostatic and absorption characteristics was obtained.

Example 54

Component 1 Ca stearate 3.0

Component 2 tocopheryl acetate 0.4

Component 2 acetyl tributyl citrate 2.3

Component 3 gelatin 2.0

The resulting product has characteristics similar to example 53 putty.

Example 55

Component 1 calcium stearate 2.0g

Component 2 tocopheryl acetate 1.5g

Component 3 PluronicF-38* 2.0g

(molecular weight 4700)

Product 583095, Lot WP1W-515B, BASF Corp., Mt. Olive, NJ07828-1234

Pluronic is provided as a "lozenge" and ground into a powder and then mixed. The mixture formed an excellent putty.

Example 56

Component 1 calcium stearate 4.0g

Component 2 PluronicL-35 3.0g

(molecular weight 1900)

Pluronic in this exampleIs a viscous liquid and forms excellent putty. Because this Pluronic is water soluble, it is not necessary to add an absorption accelerator.

The above examples illustrate specific embodiments of the present invention. Other embodiments within the scope of the invention may be made by those skilled in the art as described in the foregoing specification.

Claims (39)

1. A composition comprising in intimate admixture components 1 and 2 wherein,

component 1 is a finely divided carboxylate salt having a carboxylate anion and a metal cation, intimately mixed with component 2, wherein,

component 2 is a composition comprising a first member and a second member, wherein the first member is selected from the group consisting of substantially pure tocopherol, C of tocopherol₂-C₁₀Aliphatic monocarboxylic acid esters, polycarboxylic acid esters of tocopherol and mixtures thereof, and the second member is ethylene oxide and propylene oxideOptionally further comprising an analgesic and/or a liquid Pluronic,

wherein component 2 comprises 10-70% by weight of the composition.

2. The composition of claim 1, wherein the composition is body absorbable.

3. The composition of claim 1 wherein component 2 comprises a member selected from the group consisting of tocopherols, their acetates, butyrates, caproates, caprylates, caprates and intervening homolog esters, and their succinates, citrates or malates.

4. The composition of claim 1 wherein component 2 comprises tocopherol, tocopheryl acetate or tocopheryl succinate.

5. The composition of claim 4 wherein component 2 comprises tocopheryl acetate.

6. The composition of claim 1 wherein the carboxylate anion of component 1 is selected from the group consisting of saturated or unsaturated carboxylic acids containing from about 6 to about 22 carbon atoms.

7. The composition of claim 1 wherein the carboxylate salt cation of component 1 is calcium, magnesium, zinc, aluminum or barium or mixtures thereof.

8. The composition of claim 1 wherein the carboxylate anion of component 1 is an aliphatic acid selected from the group consisting of caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, and intervening homologs thereof.

9. The composition of claim 8 wherein the carboxylate anion of component 1 is stearic acid.

10. The composition of claim 8 wherein the carboxylate anion of component 1 is palmitic acid.

11. The composition of claim 7 wherein the carboxylate salt cation of component 1 is calcium.

12. The composition of claim 7 wherein the carboxylate salt cation of component 1 is magnesium or zinc.

13. The composition of claim 1 wherein component 2 is selected from the group consisting of tocopherols, their acetates, butyrates, caproates, caprylates, caprates and intervening homolog esters, and their succinates, citrates or malates.

14. The composition of claim 13 wherein component 2 comprises tocopheryl acetate.

15. The composition of claim 1 further comprising component 3, said component 3 selected from the group consisting of absorbable, soluble or insoluble, natural or synthetic polypeptides, insoluble, fibrillar collagen, soluble procollagen, gelatin, lecithin, betaine, calcium phosphate, octylphenyl ethoxylate, polyvinylpyrrolidone, and block copolymers of ethylene oxide and propylene oxide.

16. The composition of claim 15 wherein component 3 comprises a member of the group consisting of: gelatin, octylphenyl ethoxylate, and block copolymers of ethylene oxide and propylene oxide.

17. The composition of claim 1, further comprising an bone growth inducing effective amount of component 4, said component 4 selected from the group consisting of growth factors, demineralized bone matrix, mineralized bone matrix, calcium phosphate, and bone morphogenic protein.

18. The composition of claim 17 wherein component 4 is selected from the group consisting of calcium phosphate and demineralized bone matrix.

19. The composition of claim 1 comprising at least one additional ingredient selected from the group consisting of colorants and anti-infective agents.

20. The composition of claim 1 comprising at least one additional ingredient selected from the group consisting of absorbable clot inducing agents, absorbable antineoplastic agents, absorbable analgesics, and absorbable radiopacifiers.

21. The composition of claim 1, further comprising an analgesic.

22. The composition of claim 21, wherein the analgesic is selected from the group consisting of benzocaine, lidocaine, and tetracaine.

23. The composition of claim 21, wherein the analgesic is lidocaine.

24. The composition of claim 1, wherein the composition is sterile.

25. The composition of claim 1, wherein the composition further comprises a bone growth inducing agent.

26. The composition of claim 1, wherein the composition further comprises an anti-infective agent.

27. The composition of claim 1, wherein the composition further comprises an antineoplastic agent.

28. The composition of claim 1, wherein the composition further comprises a clot inducing agent.

29. The composition of claim 1, wherein the composition further comprises an anti-inflammatory agent.

30. The composition of claim 1, wherein the composition further comprises a radiopacifier.

31. A package comprising the composition of claim 1, wherein the composition is in the form of an amorphous or conventional round or conventional parallelepiped shape or cream or paste or container holding it, wherein the composition is sealed in a sterile barrier package and is sterile or sterilizable.

32. The package of claim 31, wherein the package comprises a plunger or applicator, whereby the composition can be expelled from the package by applying mechanical pressure to the plunger or applicator.

33. The package of claim 31, wherein the package comprises a squeezable, deformable tube having an openable outlet, whereby the composition can be expelled from the tube by applying mechanical pressure thereto.

34. Use of a composition according to any one of claims 1 to 30 in the manufacture of a medicament for mechanically controlling bone bleeding.

35. Use of a composition according to claim 26 in the manufacture of a medicament for the treatment of infection in or around bone.

36. Use of a composition according to claim 27 in the manufacture of a medicament for the destruction of cancer cells in or around bone.

37. Use of a composition according to any one of claims 1 to 30 in the manufacture of a medicament for reducing pain at an intraosseous or periosseous site.

38. Use of a composition according to claim 28 in the manufacture of a medicament for chemically controlling bone bleeding.

39. Use of a composition according to claim 29 in the manufacture of a medicament for controlling inflammation in or around bone.