WO2008032054A2 - Composite material comprising a tissue matrix compound and a bioactive glass - Google Patents

Composite material comprising a tissue matrix compound and a bioactive glass Download PDF

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Publication number
WO2008032054A2
WO2008032054A2 PCT/GB2007/003445 GB2007003445W WO2008032054A2 WO 2008032054 A2 WO2008032054 A2 WO 2008032054A2 GB 2007003445 W GB2007003445 W GB 2007003445W WO 2008032054 A2 WO2008032054 A2 WO 2008032054A2
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WIPO (PCT)
Prior art keywords
composite material
material according
bioactive glass
composition
collagen
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PCT/GB2007/003445
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French (fr)
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WO2008032054A3 (en
Inventor
Gareth Roberts
Xiaobin Zhao
Ian Thomson
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Novathera Limited
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Publication of WO2008032054A2 publication Critical patent/WO2008032054A2/en
Publication of WO2008032054A3 publication Critical patent/WO2008032054A3/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00Medicinal preparations containing inorganic active ingredients
    • A61K33/24Heavy metals; Compounds thereof
    • A61K33/38Silver; Compounds thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00Medicinal preparations containing inorganic active ingredients
    • A61K33/42Phosphorus; Compounds thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/446Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with other specific inorganic fillers other than those covered by A61L27/443 or A61L27/46
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders

Definitions

  • the present invention relates to a composite material which has applications in the field of soft tissue augmentation including cosmetic applications, plastic surgery and wound repair.
  • Cosmetic and plastic surgery procedures require materials and procedures to enable the filling of tissue voids, for example, to remove or fill wrinkles or skin blemishes.
  • the optimal characteristics for a material to be used in soft tissue augmentation include: safety; long term effectiveness in situ (preferably over 6 months, a year or longer); biologically active to stimulate tissue regeneration; simple to use with minimally invasive procedures; and, - ease of availability.
  • collagen is the most popular material for the correction of facial wrinkles, with products derived from both animal and human sources currently used by cosmetic and plastic surgeons.
  • bovine derived collagen when bovine derived collagen is used, about 1% of patients will not be eligible for treatment due to an allergic sensitivity to the material, and a further 1% will develop an allergy during treatment.
  • the drawback of collagen treatment is that the effect is only temporary and the collagen will be totally reabsorbed within 3-6 months.
  • HA hyaluronic acid
  • cadaveric sources of material are expensive, complicated, require careful selection and are often an unattractive proposition for the patient.
  • a first aspect of the invention relates to a composite material comprising a tissue matrix compound and a bioactive glass.
  • a second aspect of the invention relates to a pharmaceutical or cosmetic composition
  • a pharmaceutical or cosmetic composition comprising a composite material as described herein and a biocompatible carrier, excipient or diluent.
  • a third aspect of the invention relates to an injectable formulation suitable for administration to a human, said composition comprising a composite material as described herein and a biocompatible carrier, excipient or diluent.
  • a fourth aspect of the invention relates to a syringe prefilled with an injectable formulation according to the invention.
  • FIG. 1 Further aspects of the invention relate to the use of a composite material as described herein in the preparation of a medicament for treating a skin blemish, for augmenting soft tissue, and/or for treating urinary incontinence.
  • Another aspect of the invention relates to the use of a composite material as described herein as a cosmetic product.
  • Yet further aspects relate to methods of treating skin blemishes, reducing or treating wrinkles, augmenting soft tissue and/or stimulating fibroblast growth using the composite material as described herein.
  • Another aspect of the invention relates to a method of filling a void in a patient, said method comprising injecting a composite material or composition as described herein into said void.
  • Another aspect of the invention relates to a method of cosmetically altering the appearance of a portion of a patient's face or body, said method comprising injecting a composite material or composition as described herein into said portion.
  • a further aspect of the invention relates to a method of prophylactic, therapeutic or cosmetic treatment of a subject, said method comprising administering to said subject a composite material or a composition as described herein.
  • a further aspect of the invention relates to a method of treating urinary incontinence, said method comprising injecting a composite material or composition as described herein into the submucusal tissues of the urethra or bladder neck or into the tissues adjacent to the urethra.
  • the invention further provides processes for preparing the composite material and compositions as described herein.
  • a first aspect of the invention relates to a composite material comprising a tissue matrix compound and a bioactive glass.
  • Bioactive glasses have been used for a number of years as bone void fillers and in the reconstruction of dental or facial bone lesions in maxillofacial surgery. Bioactive glasses have been demonstrated to be reabsorbed, non-toxic in vivo and excreted through the body's natural metabolic pathways. The dissolution products of bioactive glasses have also been demonstrated to stimulate osteoblast cell growth in vitro [Christodoulou et al 2006; J Biomed Mater Res B Appl Biomater. 77(2):431-46]. Bioactive glasses can also be formulated to enable the controlled delivery of antibacterial products at the site of application [Bellantone et al 2002; Antimicrobial Agents and Chemotherapy: 46(6): 1940-1945].
  • bioactive glasses can be formulated into an injectable composite material with a tissue matrix compound, e.g. collagen.
  • the material demonstrates an ability to stimulate fibroblast growth, and is able to support the augmentation of soft tissue defects through the presence of collagen. It is therefore envisaged that the novel composite material of the invention will provide an optimal material for use in soft tissue augmentation, providing both short and long- term augmentation of the target site.
  • the collagen is mammalian, more preferably, human.
  • the collagen is recombinant, more preferably human recombinant.
  • bioactive glass refers to an inorganic glass material having an oxide of silicon as its major component and which is capable of bonding with growing tissue when reacted with physiological fluids.
  • Bioactive glasses are well known to those skilled in the art and are disclosed, for example, in "An Introduction to Bioceramics", L. Hench and J. Wilson, Eds. World Scientific, New Jersey (1993).
  • the bioactive glass is melt derived.
  • the bioactive glass comprises by approximate weight percent of about 42 to about 52 % by weight of silicon dioxide (SiO 2 ), about 15 to about 25 % by weight of sodium oxide (Na 2 O), about 15 to about 25 % by weight calcium oxide (CaO), and about 1 to about 9 % by weight phosphorus oxide (P 2 O 5 ).
  • the bioactive glass is sol-gel derived.
  • the bioactive glass comprises by approximate weight percent of about 40 to about 90% % by weight of silicon dioxide (SiO 2 ), about 6 to about 50 % by weight calcium oxide (CaO), and from 0 to about 12 % by weight phosphorus oxide (P 2 O 5 ).
  • the bioactive glasses used in the present invention are derived using the sol- gel method, essentially as described in US 5,074,916.
  • the bioactive glass further comprises a silver salt.
  • a silver salt imparts antibacterial properties into the composite of the invention which helps prevent infection in the area undergoing treatment.
  • the silver salt is silver oxide. Further details of silver-containing bioglasses are described in US 6,482,444 (Bellatone et al; assigned to Imperial College
  • the bioactive glass further comprises about 0.1 to about 12% by weight silver oxide (Ag 2 O).
  • the bioactive glass comprises by approximate weight percent of about 45 to about 86 % by weight of silicon dioxide (SiO 2 ), about 10 to about 36 % by weight calcium oxide (CaO), about 3 to about 12 % by weight phosphorus oxide (P 2 O 5 ) and about 3 to about 12 % by weight silver oxide (Ag 2 O).
  • the oxides can be present as solid solutions or mixed oxides, or as mixtures of oxides.
  • CaF 2 , B 2 O 3 , Al 2 O 3 , MgO, Na 2 O, ZnO and K 2 O may also be included in the composition in addition to silicon, phosphorus and calcium oxides.
  • the preferred range for B 2 O 3 is from O to about 10 % by weight.
  • the preferred range for K 2 O is from O to about 8 % by weight.
  • the preferred range for MgO is from O to about 5 % by weight.
  • the preferred range for Al 2 O 3 is from O to about 3 % by weight.
  • the preferred range for CaF 2 is from O to about 12.5 % by weight.
  • the preferred range for ZnO is from O to about 3 % by weight.
  • the preferred range for Na 2 O is from O to about 20% by weight.
  • sol-gel derived bioactive glasses are shown below:
  • the glass is 45S5 Bioglass, which has a composition by weight percentage of approximately 45 % SiO 2 , 24.5 % CaO, 24.5 % Na 2 O and 6 % P 2 O 5 .
  • the bioglass is 70S sol-gel bioglass, i.e. the bioglass contains about 70 % SiO 2 , and about 30 % CaO.
  • Particulate, non-interlinked bioactive glass is preferred. That is, the glass is preferably in the form of small, discrete particles. Note that under some conditions the discrete particles of the present invention can tend to cling together because of electrostatic or other forces but are still considered to be non-interlinked.
  • Useful ranges of particle sizes are less than about 1200 microns, typically about 1 to about 1000 microns as measured by SEM or laser light scattering techniques.
  • the size range of the particles is about 100 to about 800 microns. In a more preferred embodiment of the invention, the size range of the particles is about 300 to about 700 microns. In an alternative preferred embodiment, the size range of the particles is less than about 90 microns.
  • the particle size of the bioactive glass is about 10 to about 150 micons, more preferably about 20 to about 100 microns, even more preferably about 15 to about 25 microns.
  • the particle size of the bioactive glass is less than about 50 microns, more preferably less than about 25 microns.
  • the bioactive glass is preferably prepared using a sol-gel method.
  • a sol-gel method When compared with conventional glass production techniques, there are a number of advantages associated with the sol-gel process: lower processing temperatures, purer and more homogenous materials, good control over the final composition, and tailoring of the surface and pore characteristics of the product.
  • Sol-gel derived glass is generally prepared by synthesizing an inorganic network by mixing metal alkoxides in solution, followed by hydrolysis, gelation, and low temperature firing (around 200-900 0 C) to produce a glass.
  • Sol-gel-derived glasses produced in this way are known to have an initial high specific surface area compared with either melt-derived glass or porous melt-derived glass. The process and types of reactions which typically occur in sol-gel formation are described in more detail in US 6,482,444 [Bellatone et al; assigned to Imperial College Innovations].
  • the bioactive glass used in the present invention is preferably a porous sol-gel glass. Highly porous bioactive glass has a relatively fast degradation rate and high surface area in comparison to non-porous bioactive glass compositions.
  • the pore size is from 0 to about 50 ⁇ m, more preferably about 0.0001 to about 25 ⁇ m, even more preferably about 0.001 to about 10 ⁇ m.
  • the degree of porosity of the glass is from 0 to about 85 %, more preferably about 30 to about 80 %, and even more preferably about 40 to about 60 %.
  • Porous bioactive glass can be prepared, for example, by incorporating a leachable substance into the bioactive glass composition, and leaching the substance out of the glass.
  • a leachable substance for example, minute particles of a material capable of being dissolved in a suitable solvent, acid, or base can be mixed with or incorporated into the glass, and subsequently leached out.
  • Suitable leachable substances are well known to those of skill in the art and include, for example, sodium chloride and other water-soluble salts. The particle size of the leachable substance is roughly the size of the resulting pore.
  • porosity can be achieved using sintering and/or foaming or by controlling the treatment cycle of glass gels to control the pores and interpores of the material.
  • the composite materials of the invention further comprise a tissue matrix compound.
  • tissue matrix compound is used to describe a compound normally found in the tissue matrix which can be used as a bulking agent in combination with bioactive glasses.
  • Tissue matrix compounds include, but are not limited to collagen, elastin, hyaluronic acid and hydroxyapatites.
  • the tissue matrix compound is collegen or elastin.
  • the tissue matrix compound is collagen. In another highly preferred aspect of the current invention the tissue matrix compound is elastin.
  • Collagen is the major protein component of bone, cartilage, ligament, tendon, skin and connective tissue in animals.
  • the term "collagen” is often used as a generic term to cover a wide range of protein molecules which share a common triple helical structure.
  • Type I collagen is the major collagen of skin, tendon and ligament, whereas Type III collagen is important in blood vessels.
  • the collagen molecule is composed of three collagen polypeptides which form a tight triple helix. The majority of each polypeptide is characterised by repeating amino acid sequence GIy-X-Y-, where X and Y can be any amino acid but are most usually proline and hydroxyproline.
  • GIy-X-Y- amino acid sequence
  • X and Y can be any amino acid but are most usually proline and hydroxyproline.
  • At each end of the collagen polypeptide there is a non triple helical telopeptide region. The telopeptide regions of the collagen chains are responsible for the crosslinking between the chains.
  • Collagen is synthesised within the cell as precursor collagen chains. During further cellular processing the telopeptide regions at each end of the collagen molecule are formed. These regions play an essential role in the maturation of the collagen matrix by intramolecular crosslinking formation which is a crucial step in the formation of strong collagenous tissues. In the extracellular matrix, the collagen is incorporated into fibrils, which then further associate in tissue to form fibre bundles.
  • collagen Because of its vital role in all connective tissues, collagen has increasingly become the basis of biomaterials, including native, unmodified tissue grafts, manufactured medical products including replacement components for the cardiovascular system, as well as injectable collagen for soft tissue augmentation.
  • the present invention typically utilises injectable or soluble collagen.
  • a range of commercially available collagenous biomaterials and soluble collagen implants are available including ZYDERM and ZYPLAST (injectable collagen implants, Collagen
  • ATELOCOLLAGEN injectable collagen implants, Koken Company, Tokyo
  • GELFOAM gelatin haemostat foams, Upjohn Co., Michigan
  • COLLASTAT collagen haemostat sponges, Kendall Co., Boston.
  • collagen is derived from recombinant human sources.
  • the ratio of collagen to bioactive glass is from 20-99.99:0.01-80 more preferably from 80-99:1-20
  • a second aspect of the invention relates to a pharmaceutical or cosmetic composition
  • a pharmaceutical or cosmetic composition comprising a composite material as described above and a biocompatible carrier, excipient or diluent.
  • the compositions may be for human or animal usage in human and veterinary medicine.
  • Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985).
  • suitable carriers include lactose, starch, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol and the like.
  • suitable diluents include ethanol, glycerol and water.
  • the choice of pharmaceutical carrier, excipient or diluent can be selected with regard to the intended route of administration and standard pharmaceutical practice.
  • the pharmaceutical compositions may comprise as, or in addition to, the carrier, excipient or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s).
  • suitable binders include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flow lactose, beta-lactose, corn sweeteners, natural and synthetic gums, such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose and polyethylene glycol.
  • Suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Preservatives, stabilizers, dyes and even flavoring agents may be provided in the pharmaceutical composition.
  • preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid.
  • Antioxidants and suspending agents may be also used.
  • the composition is a pharmaceutical composition which comprises at least one additional pharmaceutical agent.
  • additional pharmaceutical agents include anti-inflammatory agents, analgesics, such as xylocaine and lidocaine, and antibiotics, such as gentimycin, vanomycin, ciprofloxacin, cefotetan and penicillins.
  • the composition is in the form of an injectable composition.
  • the composition is in the form of liquid.
  • the composition is in the form of a suspension, cream, gel or paste.
  • the composition is in the form of a moldable composition.
  • an injectable formulation suitable for administration to a human comprising a composite material as described herein and a biocompatible carrier, excipient or diluent.
  • Another aspect of the invention relates to a syringe pref ⁇ lled with an injectable formulation as described above.
  • the syringe may be a conventional syringe suitable for administering compositions to humans.
  • Another aspect of the invention relates to the use of a composite material as described herein in the preparation of a medicament for treating a skin blemish.
  • the augmentation includes the repair or correction of defects in soft tissue.
  • the defects include frown lines, nasolabial creases, wrinkles and other superficial sclerodermal lines.
  • a further aspect of the invention relates to a method of treating urinary incontinence, said method comprising injecting a composite material or composition as described herein into the submucusal tissues of the urethra or bladder neck or into the tissues adjacent to the urethra.
  • the injections provide tissue bulk and increase resistance to urinary flow.
  • the composition of the current invention is advantageous over compositions based on a tissue matrix compounds alone, as the bioactive glasses of the present invention increase the bulking nature of the material and remain in situ for a longer period requiring less frequent treatments.
  • a further aspect of the invention relates to the use of a composite material as described herein as a cosmetic product.
  • the cosmetic product is a dermal filler.
  • a further aspect of the invention relates to a method of treating a skin blemish, said method comprising contacting a composite material as described herein with said skin blemish.
  • Yet another aspect of the invention relates to a method of augmenting soft tissue, said method comprising contacting a composite material according as defined herein with said soft tissue.
  • Another aspect of the invention relates to a method of augmenting soft tissue which comprises injecting a composite material or composition as defined herein into a subject in need thereof.
  • the augmentation includes the repair or correction of defects in soft tissue. More preferably, the defects include frown lines, nasolabial creases, wrinkles and other superficial sclerodermal lines.
  • a further aspect of the invention relates to a method of filling a void in a patient, said method comprising injecting a composite material or composition as described herein into said void.
  • the composition is retained in said void for a time period sufficient to increase healing of said void.
  • Yet another aspect of the invention relates to a method of cosmetically altering the appearance of a portion of a patient's face or body, said method comprising injecting a composite material or composition as described herein into said portion.
  • the composite material of the invention can be used in cosmetic or plastic surgery.
  • a further aspect of the invention relates to a method of prophylactic, therapeutic or cosmetic treatment of a subject, said method comprising administering to said subject a composite material or composition as described herein.
  • Another aspect of the invention relates to a method of stimulating fibroblast growth in a subject, said method comprising contacting a composite material as described herein with the subject.
  • Another aspect of the invention relates to a method of stimulating fibroblast growth in a biological sample, said method comprising contacting a composite material as described herein with the biological sample.
  • the sample is an in vitro or ex vivo sample.
  • PROCESS Another aspect of the invention relates to a process for preparing a composite material as described herein, said process comprising contacting the bioactive glass with a tissue matrix compound.
  • the bioactive glass is in the form of a powder.
  • the tissue matrix compound is collagen or elastin, more preferably collagen.
  • the composite material of the invention is prepared by contacting the bioactive glass with a liquid collagen or collagen matrix.
  • the bioactive glass is contacted with the liquid collagen or collagen matrix for at least thirty (30) minutes.
  • the ratio of tissue matrix compound to bioactive glass is from 20-99.99:0.01-80, more preferably from 80-99:1-20
  • a further aspect relates to a process for preparing a pharmaceutical or cosmetic composition according to the invention, said process comprising contacting a composite material as described herein with a biocompatible diluent, excipient or carrier.
  • Figure 1 shows an image of bioactive glass particles of sizes 125- 106 microns at 2.5X magnification.
  • Figure 2 shows an image of bioactive glass particles of ⁇ 25 microns at 2OX magnification.
  • the images in Figures 1 and 2 are standard light microscope images obtained using an Olympus Inverted Light Microscope, Olympus Ltd, London UK.
  • Figure 3 shows the change in optical density between Day 1 and Day 7 (fibroblast count relative to thermanox) for (i) toxic control; (ii) Thermanox; (iii) TheraGlass; and (iv) TheraGlass + collagen (10 %, 20 %, 40 %, 60 %, 80 %) and (v) 100 % collagen.
  • TheraGlass/Collagen Formulating an Injectable Composite.
  • TheraGlass particle sizes were tested; ⁇ 25 microns and 125-106 microns as described in US 5,074,916 followed by particle size specific sieving.
  • the test specimens were ejected from a 5 ml syringe to evaluate the ease of injecting each ratio.
  • Test materials were prepared and tested immediately. The ease of flow, using index above, and amount of material ejected before blocking were recorded.
  • Particles with a mean diameter of 110 ⁇ m and any morphology can be ejected through a 23 gauge needle at low concentrations (preferably ⁇ 20%).
  • Particles with a mean diameter of 15 microns and any morphology can be ejected through a 23 gauge needle with considerable ease.
  • TheraGlass particles when suspended in collagen, can be ejected from a 23 gauge endoscope needle (25cm long).
  • TheraGlass/Collagen (rat tail, Type 1) materials were tested to determine fibroblastic response, plus controls (+ve and -ve).
  • Thermanox (Nalge Nunc International, 75 Panorama Creek Drive Rochester, NY 14625-2385) and PVC (Organo-tin stabilized (vinylchloride), Smiths Medical International Ltd, Hythe , Kent, CT21 5BN) materials were in accordance with controls as described with ISO 10993-5 Biological Evaluation of Medical Devices (Tests for in vitro cytotoxicity).
  • TheraGlass has a positive stimulatory effect on fibroblast cell growth.
  • the presence of collagen on TheraGlass has little effect on the fibroblast proliferation.
  • Neither the TheraGlass nor the Collagen proteins cause any toxic effect.

Abstract

The present invention provides a composite material comprising a tissue matrix compound and a bioactive glass. The invention also relates to pharmaceutical and cosmetic compositions containing the composite material. Further aspects of the invention relate to the use of the composite material for treating a skin blemish or augmenting soft tissue.

Description

COMPOSITE MATERIAL
The present invention relates to a composite material which has applications in the field of soft tissue augmentation including cosmetic applications, plastic surgery and wound repair.
BACKGROUND
Cosmetic and plastic surgery procedures require materials and procedures to enable the filling of tissue voids, for example, to remove or fill wrinkles or skin blemishes. The optimal characteristics for a material to be used in soft tissue augmentation include: safety; long term effectiveness in situ (preferably over 6 months, a year or longer); biologically active to stimulate tissue regeneration; simple to use with minimally invasive procedures; and, - ease of availability.
The treatments currently in use are associated with a range of limitations. By way of example, synthetic implants (e.g. silicone injections, hydrogels, polyacrylamide gel and plastic microspheres) carry risks of infection, inflammation, migration and extrusion. Materials found naturally in the body or found inorganically are therefore more attractive.
To date, collagen is the most popular material for the correction of facial wrinkles, with products derived from both animal and human sources currently used by cosmetic and plastic surgeons. However, when bovine derived collagen is used, about 1% of patients will not be eligible for treatment due to an allergic sensitivity to the material, and a further 1% will develop an allergy during treatment. Moreover, the drawback of collagen treatment is that the effect is only temporary and the collagen will be totally reabsorbed within 3-6 months.
Additional materials, such as hyaluronic acid (HA), have been approved for use in wrinkle augmentation. HA is a glycosoaminoglycan which occurs naturally in the skin as a structural element and can be injected as a 'filler' into soft tissue voids or wrinkles. However, as with collagen, HA is typically reabsorbed within a year and has no known regenerative characteristics on tissue in vivo.
Composites of animal and human derived (cadaveric) materials have also been pursued. However, cadaveric sources of material are expensive, complicated, require careful selection and are often an unattractive proposition for the patient.
More recently, autologous cell therapies have been pursued using the patient's own cell sources to treat soft tissue voids. Whilst these procedures are proving increasingly successful, the process requires both the isolation of cells from the patient, expansion in vitro and then a further surgical procedure to deliver the cells back to the patient at the site of interest.
Accordingly, it is an object of the present invention to provide an improved material for use in soft tissue augmentation surgery and other cosmetic and therapeutic applications.
Aspects of the invention are set forth below and in the accompanying claims. For the avoidance of doubt, preferred embodiments apply to all aspects of the invention.
STATEMENT OF INVENTION
A first aspect of the invention relates to a composite material comprising a tissue matrix compound and a bioactive glass.
A second aspect of the invention relates to a pharmaceutical or cosmetic composition comprising a composite material as described herein and a biocompatible carrier, excipient or diluent.
A third aspect of the invention relates to an injectable formulation suitable for administration to a human, said composition comprising a composite material as described herein and a biocompatible carrier, excipient or diluent. A fourth aspect of the invention relates to a syringe prefilled with an injectable formulation according to the invention.
Further aspects of the invention relate to the use of a composite material as described herein in the preparation of a medicament for treating a skin blemish, for augmenting soft tissue, and/or for treating urinary incontinence.
Another aspect of the invention relates to the use of a composite material as described herein as a cosmetic product.
Yet further aspects relate to methods of treating skin blemishes, reducing or treating wrinkles, augmenting soft tissue and/or stimulating fibroblast growth using the composite material as described herein.
Another aspect of the invention relates to a method of filling a void in a patient, said method comprising injecting a composite material or composition as described herein into said void.
Another aspect of the invention relates to a method of cosmetically altering the appearance of a portion of a patient's face or body, said method comprising injecting a composite material or composition as described herein into said portion.
A further aspect of the invention relates to a method of prophylactic, therapeutic or cosmetic treatment of a subject, said method comprising administering to said subject a composite material or a composition as described herein.
A further aspect of the invention relates to a method of treating urinary incontinence, said method comprising injecting a composite material or composition as described herein into the submucusal tissues of the urethra or bladder neck or into the tissues adjacent to the urethra. The invention further provides processes for preparing the composite material and compositions as described herein.
DETAILED DESCRIPTION As mentioned above, a first aspect of the invention relates to a composite material comprising a tissue matrix compound and a bioactive glass.
Bioactive glasses have been used for a number of years as bone void fillers and in the reconstruction of dental or facial bone lesions in maxillofacial surgery. Bioactive glasses have been demonstrated to be reabsorbed, non-toxic in vivo and excreted through the body's natural metabolic pathways. The dissolution products of bioactive glasses have also been demonstrated to stimulate osteoblast cell growth in vitro [Christodoulou et al 2006; J Biomed Mater Res B Appl Biomater. 77(2):431-46]. Bioactive glasses can also be formulated to enable the controlled delivery of antibacterial products at the site of application [Bellantone et al 2002; Antimicrobial Agents and Chemotherapy: 46(6): 1940-1945].
Surprisingly, the present applicant has demonstrated that bioactive glasses can be formulated into an injectable composite material with a tissue matrix compound, e.g. collagen. The material demonstrates an ability to stimulate fibroblast growth, and is able to support the augmentation of soft tissue defects through the presence of collagen. It is therefore envisaged that the novel composite material of the invention will provide an optimal material for use in soft tissue augmentation, providing both short and long- term augmentation of the target site.
Preferably, the collagen is mammalian, more preferably, human. In one highly preferred embodiment, the collagen is recombinant, more preferably human recombinant.
As used herein, the term "bioactive glass" refers to an inorganic glass material having an oxide of silicon as its major component and which is capable of bonding with growing tissue when reacted with physiological fluids. Bioactive glasses are well known to those skilled in the art and are disclosed, for example, in "An Introduction to Bioceramics", L. Hench and J. Wilson, Eds. World Scientific, New Jersey (1993).
In one preferred embodiment, the bioactive glass is melt derived. Preferably, for this embodiment, the bioactive glass comprises by approximate weight percent of about 42 to about 52 % by weight of silicon dioxide (SiO2), about 15 to about 25 % by weight of sodium oxide (Na2O), about 15 to about 25 % by weight calcium oxide (CaO), and about 1 to about 9 % by weight phosphorus oxide (P2O5).
In another preferred embodiment, the bioactive glass is sol-gel derived. Preferably, for this embodiment, the bioactive glass comprises by approximate weight percent of about 40 to about 90% % by weight of silicon dioxide (SiO2), about 6 to about 50 % by weight calcium oxide (CaO), and from 0 to about 12 % by weight phosphorus oxide (P2O5).
Preferably, the bioactive glasses used in the present invention are derived using the sol- gel method, essentially as described in US 5,074,916.
In one highly preferred embodiment, the bioactive glass further comprises a silver salt. Advantageously, the inclusion of a silver salt imparts antibacterial properties into the composite of the invention which helps prevent infection in the area undergoing treatment. Preferably, the silver salt is silver oxide. Further details of silver-containing bioglasses are described in US 6,482,444 (Bellatone et al; assigned to Imperial College
Innovations).
More preferably, the bioactive glass further comprises about 0.1 to about 12% by weight silver oxide (Ag2O).
In one preferred embodiment, the bioactive glass comprises by approximate weight percent of about 45 to about 86 % by weight of silicon dioxide (SiO2), about 10 to about 36 % by weight calcium oxide (CaO), about 3 to about 12 % by weight phosphorus oxide (P2O5) and about 3 to about 12 % by weight silver oxide (Ag2O). The oxides can be present as solid solutions or mixed oxides, or as mixtures of oxides. Preferably, CaF2, B2O3, Al2O3, MgO, Na2O, ZnO and K2O may also be included in the composition in addition to silicon, phosphorus and calcium oxides. The preferred range for B2O3 is from O to about 10 % by weight. The preferred range for K2O is from O to about 8 % by weight. The preferred range for MgO is from O to about 5 % by weight. The preferred range for Al2O3 is from O to about 3 % by weight. The preferred range for CaF2 is from O to about 12.5 % by weight. The preferred range for ZnO is from O to about 3 % by weight. The preferred range for Na2O is from O to about 20% by weight.
In the context of the present invention, particularly preferred sol-gel derived bioactive glasses are shown below:
Figure imgf000007_0001
In one especially preferred embodiment, the glass is 45S5 Bioglass, which has a composition by weight percentage of approximately 45 % SiO2, 24.5 % CaO, 24.5 % Na2O and 6 % P2O5.
In one highly preferred embodiment of the invention, the bioglass is 70S sol-gel bioglass, i.e. the bioglass contains about 70 % SiO2, and about 30 % CaO. Particulate, non-interlinked bioactive glass is preferred. That is, the glass is preferably in the form of small, discrete particles. Note that under some conditions the discrete particles of the present invention can tend to cling together because of electrostatic or other forces but are still considered to be non-interlinked. Useful ranges of particle sizes are less than about 1200 microns, typically about 1 to about 1000 microns as measured by SEM or laser light scattering techniques. In one preferred embodiment, the size range of the particles is about 100 to about 800 microns. In a more preferred embodiment of the invention, the size range of the particles is about 300 to about 700 microns. In an alternative preferred embodiment, the size range of the particles is less than about 90 microns.
In one especially preferred embodiment, the particle size of the bioactive glass is about 10 to about 150 micons, more preferably about 20 to about 100 microns, even more preferably about 15 to about 25 microns.
In another especially preferred embodiment, the particle size of the bioactive glass is less than about 50 microns, more preferably less than about 25 microns.
The bioactive glass is preferably prepared using a sol-gel method. When compared with conventional glass production techniques, there are a number of advantages associated with the sol-gel process: lower processing temperatures, purer and more homogenous materials, good control over the final composition, and tailoring of the surface and pore characteristics of the product.
Sol-gel derived glass is generally prepared by synthesizing an inorganic network by mixing metal alkoxides in solution, followed by hydrolysis, gelation, and low temperature firing (around 200-9000C) to produce a glass. Sol-gel-derived glasses produced in this way are known to have an initial high specific surface area compared with either melt-derived glass or porous melt-derived glass. The process and types of reactions which typically occur in sol-gel formation are described in more detail in US 6,482,444 [Bellatone et al; assigned to Imperial College Innovations]. The bioactive glass used in the present invention is preferably a porous sol-gel glass. Highly porous bioactive glass has a relatively fast degradation rate and high surface area in comparison to non-porous bioactive glass compositions. Preferably, the pore size is from 0 to about 50 μm, more preferably about 0.0001 to about 25 μm, even more preferably about 0.001 to about 10 μm. Preferably, the degree of porosity of the glass is from 0 to about 85 %, more preferably about 30 to about 80 %, and even more preferably about 40 to about 60 %.
Porous bioactive glass can be prepared, for example, by incorporating a leachable substance into the bioactive glass composition, and leaching the substance out of the glass. For example, minute particles of a material capable of being dissolved in a suitable solvent, acid, or base can be mixed with or incorporated into the glass, and subsequently leached out. Suitable leachable substances are well known to those of skill in the art and include, for example, sodium chloride and other water-soluble salts. The particle size of the leachable substance is roughly the size of the resulting pore.
The relative amount and size of the leachable substance gives rise to the degree of porosity. Alternatively, porosity can be achieved using sintering and/or foaming or by controlling the treatment cycle of glass gels to control the pores and interpores of the material.
In addition to containing bioactive glass, the composite materials of the invention further comprise a tissue matrix compound.
For the purposes of the current invention, a tissue matrix compound is used to describe a compound normally found in the tissue matrix which can be used as a bulking agent in combination with bioactive glasses. Tissue matrix compounds include, but are not limited to collagen, elastin, hyaluronic acid and hydroxyapatites. Preferably, the tissue matrix compound is collegen or elastin.
In one highly preferred aspect of the current invention the tissue matrix compound is collagen. In another highly preferred aspect of the current invention the tissue matrix compound is elastin.
Collagen is the major protein component of bone, cartilage, ligament, tendon, skin and connective tissue in animals. The term "collagen" is often used as a generic term to cover a wide range of protein molecules which share a common triple helical structure. However, the most common types of collagen present in connective tissue are Types I- III. Type I collagen is the major collagen of skin, tendon and ligament, whereas Type III collagen is important in blood vessels. The collagen molecule is composed of three collagen polypeptides which form a tight triple helix. The majority of each polypeptide is characterised by repeating amino acid sequence GIy-X-Y-, where X and Y can be any amino acid but are most usually proline and hydroxyproline. At each end of the collagen polypeptide there is a non triple helical telopeptide region. The telopeptide regions of the collagen chains are responsible for the crosslinking between the chains.
Collagen is synthesised within the cell as precursor collagen chains. During further cellular processing the telopeptide regions at each end of the collagen molecule are formed. These regions play an essential role in the maturation of the collagen matrix by intramolecular crosslinking formation which is a crucial step in the formation of strong collagenous tissues. In the extracellular matrix, the collagen is incorporated into fibrils, which then further associate in tissue to form fibre bundles.
Because of its vital role in all connective tissues, collagen has increasingly become the basis of biomaterials, including native, unmodified tissue grafts, manufactured medical products including replacement components for the cardiovascular system, as well as injectable collagen for soft tissue augmentation.
The present invention typically utilises injectable or soluble collagen. A range of commercially available collagenous biomaterials and soluble collagen implants are available including ZYDERM and ZYPLAST (injectable collagen implants, Collagen
Corporation, Palo Alto), ATELOCOLLAGEN (injectable collagen implants, Koken Company, Tokyo), GELFOAM (gelatin haemostat foams, Upjohn Co., Michigan) and COLLASTAT (collagen haemostat sponges, Kendall Co., Boston).
In a preferred embodiment of the current invention, collagen is derived from recombinant human sources.
Preferably, the ratio of collagen to bioactive glass is from 20-99.99:0.01-80 more preferably from 80-99:1-20
PHARMACEUTICAL COMPOSITIONS
A second aspect of the invention relates to a pharmaceutical or cosmetic composition comprising a composite material as described above and a biocompatible carrier, excipient or diluent. The compositions may be for human or animal usage in human and veterinary medicine.
Examples of such suitable excipients for the various different forms of pharmaceutical compositions described herein may be found in the "Handbook of Pharmaceutical Excipients, 2nd Edition, (1994), Edited by A Wade and PJ Welter.
Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985).
Examples of suitable carriers include lactose, starch, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol and the like. Examples of suitable diluents include ethanol, glycerol and water.
The choice of pharmaceutical carrier, excipient or diluent can be selected with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical compositions may comprise as, or in addition to, the carrier, excipient or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s). Examples of suitable binders include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flow lactose, beta-lactose, corn sweeteners, natural and synthetic gums, such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose and polyethylene glycol.
Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
Preservatives, stabilizers, dyes and even flavoring agents may be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may be also used.
In one preferred embodiment, the composition is a pharmaceutical composition which comprises at least one additional pharmaceutical agent. Suitable additional pharmaceutical agents include anti-inflammatory agents, analgesics, such as xylocaine and lidocaine, and antibiotics, such as gentimycin, vanomycin, ciprofloxacin, cefotetan and penicillins.
In one preferred embodiment of the invention, the composition is in the form of an injectable composition.
In one preferred embodiment of the invention, the composition is in the form of liquid.
In another preferred embodiment of the invention, the composition is in the form of a suspension, cream, gel or paste.
In another preferred embodiment of the invention, the composition is in the form of a moldable composition. Another aspect of the invention relates to an injectable formulation suitable for administration to a human, said composition comprising a composite material as described herein and a biocompatible carrier, excipient or diluent. Another aspect of the invention relates to a syringe prefϊlled with an injectable formulation as described above. The syringe may be a conventional syringe suitable for administering compositions to humans.
THERAPEUTIC APPLICATIONS
Another aspect of the invention relates to the use of a composite material as described herein in the preparation of a medicament for treating a skin blemish.
Another aspect of the invention relates to the use of a composite material as described herein in the preparation of a medicament for soft tissue augmentation. Preferably, the augmentation includes the repair or correction of defects in soft tissue. Preferably, the defects include frown lines, nasolabial creases, wrinkles and other superficial sclerodermal lines.
A further aspect of the invention relates to a method of treating urinary incontinence, said method comprising injecting a composite material or composition as described herein into the submucusal tissues of the urethra or bladder neck or into the tissues adjacent to the urethra. The injections provide tissue bulk and increase resistance to urinary flow. The composition of the current invention is advantageous over compositions based on a tissue matrix compounds alone, as the bioactive glasses of the present invention increase the bulking nature of the material and remain in situ for a longer period requiring less frequent treatments.
A further aspect of the invention relates to the use of a composite material as described herein as a cosmetic product. Preferably, the cosmetic product is a dermal filler.
A further aspect of the invention relates to a method of treating a skin blemish, said method comprising contacting a composite material as described herein with said skin blemish. Yet another aspect of the invention relates to a method of augmenting soft tissue, said method comprising contacting a composite material according as defined herein with said soft tissue.
Another aspect of the invention relates to a method of augmenting soft tissue which comprises injecting a composite material or composition as defined herein into a subject in need thereof. As mentioned above, preferably, the augmentation includes the repair or correction of defects in soft tissue. More preferably, the defects include frown lines, nasolabial creases, wrinkles and other superficial sclerodermal lines.
A further aspect of the invention relates to a method of filling a void in a patient, said method comprising injecting a composite material or composition as described herein into said void. Preferably, the composition is retained in said void for a time period sufficient to increase healing of said void.
Yet another aspect of the invention relates to a method of cosmetically altering the appearance of a portion of a patient's face or body, said method comprising injecting a composite material or composition as described herein into said portion. By way of example, the composite material of the invention can be used in cosmetic or plastic surgery.
A further aspect of the invention relates to a method of prophylactic, therapeutic or cosmetic treatment of a subject, said method comprising administering to said subject a composite material or composition as described herein.
Another aspect of the invention relates to a method of stimulating fibroblast growth in a subject, said method comprising contacting a composite material as described herein with the subject.
Another aspect of the invention relates to a method of stimulating fibroblast growth in a biological sample, said method comprising contacting a composite material as described herein with the biological sample. Preferably, the sample is an in vitro or ex vivo sample.
PROCESS Another aspect of the invention relates to a process for preparing a composite material as described herein, said process comprising contacting the bioactive glass with a tissue matrix compound.
In one preferred embodiment, the bioactive glass is in the form of a powder.
Preferably, the tissue matrix compound is collagen or elastin, more preferably collagen.
Preferably, the composite material of the invention is prepared by contacting the bioactive glass with a liquid collagen or collagen matrix.
Preferably, the bioactive glass is contacted with the liquid collagen or collagen matrix for at least thirty (30) minutes.
Preferably, the ratio of tissue matrix compound to bioactive glass (by weight %) is from 20-99.99:0.01-80, more preferably from 80-99:1-20
A further aspect relates to a process for preparing a pharmaceutical or cosmetic composition according to the invention, said process comprising contacting a composite material as described herein with a biocompatible diluent, excipient or carrier.
The present invention is further described by way of non-limiting example and with reference to the following figures, wherein:
Figure 1 shows an image of bioactive glass particles of sizes 125- 106 microns at 2.5X magnification. Figure 2 shows an image of bioactive glass particles of <25 microns at 2OX magnification.
The images in Figures 1 and 2 are standard light microscope images obtained using an Olympus Inverted Light Microscope, Olympus Ltd, London UK.
Figure 3 shows the change in optical density between Day 1 and Day 7 (fibroblast count relative to thermanox) for (i) toxic control; (ii) Thermanox; (iii) TheraGlass; and (iv) TheraGlass + collagen (10 %, 20 %, 40 %, 60 %, 80 %) and (v) 100 % collagen.
EXAMPLES
1. TheraGlass/Collagen: Formulating an Injectable Composite.
Samples of collagen (Type 1, rat tail collagen, Sigma Aldrich) matrix with 70/30 sol gel (70 wt % silica, 30 wt % calcium) glass powder were mixed in the following ratios; 10, 20, 40, 60 and 80 wt % glass powder with the remaining comprising of collagen. TheraGlass (Bioactive glasses) were prepared essentially as described in US 5,074,916. [Note all the bioactive glasses used in the present examples are 58S sol-gel glasses].
Two ranges of TheraGlass particle sizes were tested; <25 microns and 125-106 microns as described in US 5,074,916 followed by particle size specific sieving. The test specimens were ejected from a 5 ml syringe to evaluate the ease of injecting each ratio.
Using a simple scoring system, data was obtained to determine force (Ease of Flow Index) required to eject syringe contents through a 23 gauge, BARD Collagen endoscope needle (25cm long).
Figure imgf000016_0001
Results
Samples of bioactive sol gel glass, 125-106 and <25 microns were mixed with a liquid collagen in the following ratios:
Figure imgf000017_0001
Test materials were prepared and tested immediately. The ease of flow, using index above, and amount of material ejected before blocking were recorded.
125- 106 microns
Figure imgf000017_0002
Conclusions
Particles with a mean diameter of 110 μm and any morphology can be ejected through a 23 gauge needle at low concentrations (preferably <20%).
Particles with a mean diameter of 15 microns and any morphology can be ejected through a 23 gauge needle with considerable ease.
TheraGlass particles, when suspended in collagen, can be ejected from a 23 gauge endoscope needle (25cm long).
2. Effect of TheraGlass/Collagen Composite on Fibroblast growth
Seven TheraGlass/Collagen (rat tail, Type 1) materials were tested to determine fibroblastic response, plus controls (+ve and -ve).
Figure imgf000018_0001
Sample 8) Thermanox plastic (positive control) Sample 9) PVC (toxic control)
Thermanox (Nalge Nunc International, 75 Panorama Creek Drive Rochester, NY 14625-2385) and PVC (Organo-tin stabilized (vinylchloride), Smiths Medical International Ltd, Hythe , Kent, CT21 5BN) materials were in accordance with controls as described with ISO 10993-5 Biological Evaluation of Medical Devices (Tests for in vitro cytotoxicity).
Primary Human Fibroblasts (Passage number 14) were seeded onto the test materials, discs of 14 mm diameter, at a density of 1.6 x 104 cell per well. Adherent cells were examined microscopically (Inverted microscope) for morphology and cell density on the test materials at 1 and 7 days. Cell metabolic activity was determined by alamar blue direct contact testing following the manufacturers instructions (Serotec, 22 Bankside, station approach Kidlington, Oxford, OX5 IJE, UK), to determine an associated density of metabolically active cells. This process was repeated for three regions of interest (random) on all test materials.
Results
1) Microscopic observation showed no morphological changes consistent with a cytotoxic event, except for the toxic control.
2) An increase of cell number was observed on all materials, except toxic control, implying no cytotoxic response to test materials.
Figure 3 indicates how optical density increased between 1 and 7 days. Conclusions
TheraGlass has a positive stimulatory effect on fibroblast cell growth. The presence of collagen on TheraGlass has little effect on the fibroblast proliferation. Neither the TheraGlass nor the Collagen proteins cause any toxic effect.
Various modifications and variations of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in the relevant fields are intended to be covered by the present invention.

Claims

1. A composite material comprising a tissue matrix compound and a bioactive glass.
2. A composite material according to claim 1 wherein the tissue matrix compound is collagen.
3. A composite material according to claim 1 wherein the tissue matrix compound is elastin.
4. A composite material according any preceding claim wherein the bioactive glass is a sol-gel derived bioactive glass.
5. A composite material according to any preceding claim wherein the bioactive glass comprises by approximate weight percent of about 40 to about 90 % by weight of silicon dioxide (SiO2), about 6 to about 50 % by weight calcium oxide (CaO), and from 0 to about 12 % by weight phosphorus oxide (P2O5).
6. A composite material according to any preceding claim wherein the bioactive glass further comprises a silver salt.
7. A composite material according to claim 6 wherein the bioactive glass further comprises about 0.1 to about 12% by weight silver oxide (Ag2O).
8. A composite material according to claim 7 wherein the bioactive glass comprises by approximate weight percent of about 45 to about 86 % by weight of silicon dioxide (SiO2), about 10 to about 36 % by weight calcium oxide (CaO), about 3 to about 12 % by weight phosphorus oxide (P2O5) and about 3 to about 12 % by weight silver oxide (Ag2O).
9. A composite material according to any preceding claim wherein the bioactive glass further comprises one or more of the following: CaF2, B2C<3, Al2O3, MgO, K2O and Na2O.
10. A composite material according to any preceding claim wherein the bioactive glass contains about 70% SiO2 and about 30 % CaO.
11. A composite material according to any preceding claim wherein the collagen is recombinant.
12. A composite material according to any preceding claim wherein the collagen is human.
13. A pharmaceutical or cosmetic composition comprising a composite material according to any one of claims 1 to 12 and a biocompatible carrier, excipient or diluent.
14. A composition according to claim 13 which is in the form of an injectable composition.
15. A composition according to claim 14 which is in the form of liquid.
16. A composition according to claim 14 which is in the form of a suspension, gel, cream or paste.
17. A composition according to claim 13 which is in the form of a moldable composition.
18. An injectable formulation suitable for administration to a human, said composition comprising a composite material according to any one of claims 1 to 12 and a biocompatible carrier, excipient or diluent.
19. A syringe prefilled with an injectable formulation according to claim 18.
20. Use of a composite material according to any one of claims 1 to 12 in the preparation of a medicament for treating a skin blemish.
21. Use of a composite material according to any one of claims 1 to 12 in the preparation of a medicament for soft tissue augmentation.
22. Use according to claim 21 wherein the augmentation includes the repair or correction of defects in soft tissue.
23. Use according to claim 22 wherein the defects include frown lines, nasolabial creases, wrinkles and other superficial sclerodermal lines.
24. Use of a composite material according to any one of claims 1 to 12 in the preparation of a medicament for treating urinary incontinence.
25. Use of a composite material according to any one of claims 1 to 12 as a cosmetic product.
26. Use according to claim 25 wherein the cosmetic product is a dermal filler.
27. A method of treating a skin blemish, said method comprising contacting a composite material according to any one of claims 1 to 12 with said skin blemish.
28. A method of augmenting soft tissue, said method comprising contacting a composite material according to any one of claims 1 to 12 with said soft tissue.
29. A method of augmenting soft tissue which comprises injecting a composite material according to any one of claims 1 to 12, or a composition according to any one of claims 11 to 17, into a subject in need thereof.
30. A method according to claim 28 or claim 29 wherein the augmentation includes the repair or correction of defects in soft tissue.
31. A method according to claim 30 wherein the defects include frown lines, nasolabial creases, wrinkles and other superficial sclerodermal lines.
32. A method of filling a void in a patient, said method comprising injecting a composite material according to any one of claims 1 to 12, or a composition according to any one of claims 13 to 17, into said void.
33. A method according to claim 32 wherein said composition is retained in said void for a time period sufficient to increase healing of said void.
34. A method of cosmetically altering the appearance of a portion of a patient's face or body, said method comprising injecting a composite material according to any one of claims 1 to 12, or a composition according to any one of claims 13 to 17, into said portion.
35. A method of stimulating fibroblast growth in a subject, said method comprising contacting a composite material according to any one of claims 1 to 12, or a composition according to any one of claims 13 to 17, with the subject.
36. A method of prophylactic, therapeutic or cosmetic treatment of a subject, said method comprising administering to said subject a composite material according to any one of claims 1 to 12, or a composition according to any one of claims 13 to 17.
37. A process for preparing a composite material according to any one of claims 1 to 12, said process comprising contacting the bioactive glass with a matrix tissue compound.
38. A process according to claim 37 wherein the bioactive glass is in the form of a powder.
39. A process according to claim 37 or claim 38 wherein the matrix tissue compound is collagen or elastin.
40. A process according to claim 39 wherein the collagen is in the form of liquid collagen or a collagen matrix.
41. A process according to any one of claims 38 to 40 wherein the ratio of bioactive glass to tissue matrix compound is 20-99.99:0.01-80 more preferably from 80-99:1-20.
42. A process for preparing a composition according to any one of claims 13 to 17, said process comprising contacting a composite material according to any one of claims 1 to 12 with a biocompatible diluent, excipient or carrier.
43. A composite material comprising a tissue matrix compound and a bioactive glass, for use in medicine.
44. A composite material comprising a tissue matrix compound and a bioactive glass, for use as a cosmetic preparation.
45. A composite material, pharmaceutical composition, use, method or process substantially as described herein.
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