WO2014033368A1 - Composition pour la réparation et la régénération de tissus - Google Patents

Composition pour la réparation et la régénération de tissus Download PDF

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Publication number
WO2014033368A1
WO2014033368A1 PCT/FI2013/050835 FI2013050835W WO2014033368A1 WO 2014033368 A1 WO2014033368 A1 WO 2014033368A1 FI 2013050835 W FI2013050835 W FI 2013050835W WO 2014033368 A1 WO2014033368 A1 WO 2014033368A1
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Prior art keywords
bioactive glass
composition
bisphosphonate
composition according
aqueous
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PCT/FI2013/050835
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English (en)
Inventor
Kirsi ROSENQVIST
Mia SIVÉN
Anne Juppo
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Rosenqvist Kirsi
Siven Mia
Anne Juppo
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Publication of WO2014033368A1 publication Critical patent/WO2014033368A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/02—Inorganic materials
    • A61L27/10—Ceramics or glasses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
    • A61L2300/112—Phosphorus-containing compounds, e.g. phosphates, phosphonates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/412—Tissue-regenerating or healing or proliferative agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/06—Materials or treatment for tissue regeneration for cartilage reconstruction, e.g. meniscus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/10—Materials or treatment for tissue regeneration for reconstruction of tendons or ligaments
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/12—Materials or treatment for tissue regeneration for dental implants or prostheses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/34—Materials or treatment for tissue regeneration for soft tissue reconstruction

Definitions

  • the invention relates to new compositions and dosage forms in the field of tissue repair and regeneration, utilizing local drug delivery.
  • compositions and dosage forms comprising bioactive glass and bisphosphonate, said compositions being suitable for example for tissue repair, improving bone formation and regeneration of tissue.
  • the invention also relates to the method for the manufacture of said compositions and dosage forms, and to the use of said compositions for local delivery of a complex formed of bioactive glass and bisphosphonate, particularly in dental applications, medical devices, combination products, implants and the like.
  • Bioactive glasses are a family of biologically active synthetic materials which, when implanted into living tissue, induce formation of an interracial bond between the material and the surrounding tissue.
  • Bioactive glasses are surface-reactive glass- ceramics designed to induce biological activity that results in the formation of a strong bond between the bioactive glass and living tissue, such as bone.
  • Bioactive glasses have found medical applications in the preparation of synthetic bone graft materials for general orthopedic, craniofacial, maxillofacial and periodontal repair, as well as bone tissue engineering scaffolds. Bioactive glass can interact with living tissue including hard tissue such as bone, and soft connective tissue.
  • Bioactive glasses are regarded as promising non-toxic materials for tissue regeneration based on for example their distinctive properties of bone bonding, controlled biodegradability and ability to stimulate new bone growth even three times more than hydroxyapatite, when implanted in bone.
  • Bone bonding properties appear to be due to the formation of an apatite layer on the glass surface.
  • the relatively low silicon content and high alkaline content lead to a rapid ion exchange in an aqueous environment. This exchange generally leads to an increase in pH of solution.
  • the initially rapid release of sodium is accompanied by a somewhat slower release of other ion species, mostly calcium and silica. Under certain conditions in solution, these ion species will precipitate onto the glass and onto other nearby surfaces, to form calcium-containing mineral layers.
  • the outer glass surface itself can transform to apatite layer.
  • the ability to build such a surface is referred to as a measure of the "bioactivity" of the glass.
  • This phenomenon can be described briefly as leaching, dissolution, and precipitation, even though apatite formation is a complex process involving different stages.
  • the surface of glass is dealkalized by exchange of cations (Na + K + or Ca + with H + or H 3 0 + ).
  • This is followed by break-up of the silicate to form silanols; as a result of breaking of Si-O-Si bonds loss of soluble silica in the form of Si(OH) 4 to solution takes place and formation of silanols happens.
  • silicate glasses were first observed in soda-calcia-phospho-silica glasses in 1969, resulting in the development of a bioactive glass comprising calcium salts, phosphorous, sodium salts and silicon.
  • These silica glasses comprised Si0 2 (40-52%) as the network former, and CaO (10-50%), Na 2 0 (10-35%), P 2 0 5 (2-8%), CaF 2 (0-25%) and B 2 0 3 (0-10%).
  • the inclusion of components, such as boron oxide (B 2 0 3 ) and calcium fluoride (CaF 2 ) has allowed modification of the properties of the bioactive glass, including the rate of dissolution and the level of bioactivity.
  • Bisphosphonates are pyrophosphate analogues, which have potent inhibitory effect on bone resorption. They have high affinity for bone minerals and they are selectively uptaken by osteoclasts and strongly inhibit bone resorption by inducing apoptosis in osteoclasts. They are typically used in the treatment of bone disorders, particularly in such as hypercalcemia of cancer, osteoporosis, metastic bone disease, multiple myeloma, fibrous dysplasia and Paget disease.
  • Each bisphosphonate has its own profile of activity, defined by its unique side chains.
  • the chemical structure of bisphosphonates is presented in the general formula I below. ( I )
  • R 1 is typically OH, H or CI.
  • Bisphosphonates can be divided in the following groups: First generation bisphosphonates not presenting nitrogen atoms in R 2 side chain; second generation having a nitrogen atom in said alkyl chain; and third generation having a nitrogen atom included within a heterocyclic ring in said side chain. Nitrogen-containing bisphosphonates exhibit more powerful inhibition of bone resorption, and they strongly induce apoptosis of osteoclasts, however they also have increased risk for osteonecrosis.
  • Second generation bisphosphonates such as pamidronate and alendronate containing a primary nitrogen atom in an alkyl chain have up to hundred times increased anti-resorptive potency when compared with the first generation ones, etidronate and clodronate. Further modifications of the chain, to produce compounds containing tertiary nitrogen groups, such as ibandronate and olpadronate, increase the activity.
  • the most potent bisphosphonates to date are risendronate and zolendronate, containing a nitrogen atom within a heterocyclic group and having activity up to 10 000 times higher than etidronate.
  • Bisphosphonates have very poor intestinal absorption (1-10%) and low bioavailability (1-3%) through oral or intravenous administration. Inflammation and ulceration of the upper gastrointestinal tract have been reported as adverse effects.
  • Solutions containing 0.064, 0.32, 8 and 16 mg/ml of sodium clodronate were made and 50 ⁇ aliquots of said solutions were added to the discs, followed by drying. Accordingly, earlier coating techniques based on plasma-spraying or sol-gel could thus be avoided. It was also found that the concentration of 0.32 mg/ml alendronate was ideal for enhancing cell viability and osteoblastic profile, making it suitable for improving implant-bone integration and in applications where regeneration of the tissue is required.
  • Microspheric scaffolds of poly(L-lactide-co-£— caprolactone) were manufactured by mixing the polymer melt with bioactive glass-ceramic granules and alendronate and the mixture was dissolved in dicloromethane. This solution was then added to an aqueous medium containing 5% of polyvinyl chloride and stirred to obtain microspheres, which were washed and dried. Said microspheres are suggested for local delivery of the drug alendronate, for the treatment of osteoporosis like bone defects. Spherical mesoporous microspheres are presented in Zhu M. et al.
  • microspheres were manufactured by combining emulsification and evaporation induced self-assembly process, whereby high storage capacity and sustained release of the drug (alendronate sodium) were obtained.
  • bioglass powder was obtained with the emulsion-evaporation procedure. The powder was then immersed in buffered alendronate sodium solution, and the drug loaded particles were dried. The obtained powdery mesoporous miscrospheres were suggested for the use in implants.
  • the bone graft substitute of bioactive glass (Biogran ® composed of 45% silicon dioxide, 24.5% calcium oxide, 24.5% sodium oxide and 6% phosphorus pentoxide) was soaked with alendronate (Fosamax ® ) solution dissolved in saline and it was placed in the bone defect, flaps of the bone defect were repositioned and sutured. Biogran ® solution in saline without alendronate was used as control.
  • US 2009/0208428 relates to bioactive glass comprising strontium and silicon dioxide, and to the use of it in the prevention and/or treatment of damage to tissue, optionally in combination with additional materials.
  • compositions known in the art comprising bioactive glass, typically in the form of dry powders, microspheres, cements, pastes etc and they usually contain other components acting as carriers, such as polymers, or active ingredients.
  • bioactive glass typically in the form of dry powders, microspheres, cements, pastes etc
  • they usually contain other components acting as carriers, such as polymers, or active ingredients there is still a need for new improved compositions and dosage forms, particularly for local delivery, comprising bioactive glass and bisphosphonate, and to a method for the manufacture of said compositions and dosage forms, where the apatite formation can be accelerated and the adverse effects of bisphosphonates can be avoided.
  • Another aim of the present invention is to provide a method for the manufacture of said compositions and dosage forms.
  • composition and dosage form for the treatment and/or prevention of tissue damage comprises a dry component(s) comprising at least one bioactive glass and an aqueous component(s) comprising at least one aqueous medium, and said dry component comprises at least bisphosphonate or said aqueous component comprises at least one bisphosphonate or both comprise at least one bisphosphonate.
  • composition and dosage according to the present invention comprising a complex formed of at least one bioactive glass and at least one bisphosphonate, and an aqueous medium, is particularly suitable for local delivery, for tissue repair and regeneration, for example for improving bone formation and regeneration of bone tissue, cartilage tissue, soft tissues, including connective tissues and dental tissues.
  • the composition of the present invention provides a surprisingly high rate of apatite deposition and leads to rapid repair and reconstruction of diseased and damaged tissues, including bone tissue, cartilage tissue and soft tissues, as well as wound healing.
  • compositions and dosage form are particularly useful in the local treatment and/or prevention of bone tissue, cartilage tissue and soft connective tissue damage, and for the prevention of resorption of bone tissue, particularly in the field of dental applications, such as in the treatment and prevention of periodontitis.
  • the ease of manufacture of the composition the applicability of the composition to various sites of use, suitability for delivering locally the complex formed of at least one bioactive glass and at least one bisphosphonate in the presence of an aqueous medium, and avoiding challenges relating to other administration forms are some examples of the desired benefits achieved by the present invention.
  • Figure 1 depicts changes in pH over the time (hours) for clodronate (clod), bioactive glass (BG) and combination product (BG+clod 200mg).
  • Figure 2 illustrates a SEM micrograph of some apatite formation on the surface of pure bioactive glass (with saline for 72 hours) in pH 9.45.
  • the bar represents 40 ⁇ .
  • Figure 3 illustrates a SEM micrograph of apatite formation on the top of the bioactive glass in combination of clodronate (with saline for 72 hours) in pH 9.45.
  • the bar represents 40 ⁇ .
  • Figure 4 illustrates a XRPD diffractogram of the combination product (BG+clod 200mg) and pure clodronate with saline for 15 days.
  • Figure 5 illustrates FTIR absorption spectra of clodronate, bioactive glass and combination product with saline for 72 hours (* phosphate groups).
  • Figure 6 illustrates DSC thermograms of clodronate, combination product and bioactive glass with saline for 72 hours.
  • Figure 7 presents changes in pH over the time for clodronate, bioactive glass (and combination product with 900 ⁇ saline.
  • Figure 8 presents changes in pH over the time for clodronate, bioactive glass and combination product with 1350 ⁇ saline.
  • Figure 9 illustrates a XRPD diffractogram of pure clodronate (Clod), combination product (BGl+clod) containing bioactive glass having particle size ⁇ 0.5 mm and 200 mg of clodronate in saline, allowed to stand for 15 days, combination product (BG2+clod) containing bioactive glass having particle size of 0.5-0.8 mm and 200 mg of clodronate in saline, allowed to stand for 15 days, calcium clodronate (CaClod) and hydroxyapatite (Hydapa).
  • the formation of hydroxyapatite and calcium clodronate can be clearly seen in the combination product containing bioactive glass having a bigger particle size, whereas in the combination product containing bioactive glass having particle size below 0.5 mm this was not shown.
  • complex refers here to a combination product formed of bioactive glass and bisphosphonate in an aqueous environment, when bioactive glass is brought into contact with bisphosphonate in an aqueous medium.
  • a rapid change of pH from acidic (even pH around 4) to basic (even pH close to 12) can be observed during formation of said product.
  • compositions and dosage forms for local delivery, for the treatment and/or prevention of tissue damage, where for example the problems and adverse events relating to systemic administration of bisphosphonates can be avoided and the apatite formation in connection with bioactive glass can be improved and/or accelerated.
  • a pharmaceutical composition or dosage form suitable particularly for local administration, can be obtained from at least one bioactive glass and at least one bisphosphonate in the presence of an aqueous medium.
  • Said pharmaceutical composition or dosage form for the treatment and/or prevention of tissue damage, comprises a dry component (s) comprising at least one bioactive glass, and an aqueous component comprising at least one aqueous medium, and said dry component comprises at least bisphosphonate or said aqueous component comprises at least one bisphosphonate or both comprise at least one bisphosphonate.
  • a dry component comprising at least one bioactive glass
  • an aqueous component comprising at least one aqueous medium
  • said dry component comprises at least bisphosphonate or said aqueous component comprises at least one bisphosphonate or both comprise at least one bisphosphonate.
  • Said pharmaceutical composition or dosage form can be manufactured with a simple and economic method without the need to use complicated techniques.
  • Surprisingly high and rapid apatite formation was observed with the composition or dosage form, resulting from the complex formed of bisphosphonate and bioactive glass in the presence of an aqueous medium.
  • the bisphosphonate reacts rapidly in an aqueous medium with the bioactive glass to form the active complex.
  • This can be seen as a very clear and rapid change of pH, from acidic to basic.
  • the actual pH values depend on the bisphosphonate and on the bioactive glass.
  • the rate of pH change is also dependent on the particle size of the components, such as the bioactive glass.
  • the complex (combination product) formed of bisphosphonate and bioactive glass has the ability to enhance and accelerate apatite formation of bioactive glass, and simultaneously bisphosphonate is brought directly to the site where tissue, such as bone repair/regeneration is needed. Accordingly, a highly active complex or combination product is formed of the bioactive glass and bisphosphonate, when brought into contact with the aqueous medium.
  • the surprisingly high enhancing effect on the formation of apatite can particularly be seen already very shortly after the complex is formed, i.e. when the aqueous medium is brought into contact with the bioactive glass and bisphosphonate.
  • a pharmaceutical composition or dosage form comprising a dry component (s) comprising at least one bioactive glass, and an aqueous component comprising at least one aqueous medium, and said dry component comprises at least bisphosphonate or said aqueous component comprises at least one bisphosphonate or both comprise at least one bisphosphonate, optionally in admixture with known excipients, diluents, flavoring agents, aromatizing agents, stabilizers, formulation providing additives, formulation promoting agents commonly used in the pharmaceutical practice.
  • a dry component (s) comprising at least one bioactive glass, and an aqueous component(s) comprising at least one aqueous medium, and said dry component comprising at least one bisphosphonate or said aqueous component comprising at least one bisphosphonate may be used for the preparation of a pharmaceutical composition or dosage form for local treatment and/or prevention of tissue damage.
  • the composition or dosage form is administered 0 days - 6 months after combining the dry component(s) and the aqueous component(s).
  • the composition is administered 50 hours - 6 months after combining the components.
  • the composition is administered after 50 hours, preferably after 80 hours and before 6 months, preferably before 3 months.
  • Said composition is particularly useful in the treatment of damage to a tissue, for the repair, regeneration, reconstruction of damaged or diseased tissue and/or prevention of damage to the tissue.
  • the tissue may be bone tissue, cartilage tissue, soft tissues including connective tissues and dental tissues.
  • Said dental tissue may include such as but not limited to calcified dental tissues such as enamel and dentin.
  • the tissues may be animal tissues, preferably mammalian or human tissues.
  • the composition is suitably provided for humans or animals, such as dogs, cats, horses, sheep, cows, pigs etc.
  • Hydroxyapatite apatite
  • apatite is in its most active state when it is formed, i.e. when it is formed or deposited on the surface of bioactive glass. This takes place for example when bioactive glass is brought into contact with body fluids like saliva etc.
  • at least one bioactive glass is combined with at least one bisphosphonate to provide a composition, suitable for local delivery.
  • the composition is applied locally at the site where treatment is desired, for example in the dental region.
  • the formed complex in said composition enhances and accelerates the formation of hydroxyapatite. Additionally said composition and bisphosphonate are brought directly to the site where needed, in desired amounts to provide the desired effect.
  • the pharmaceutical composition or dosage form is a pharmaceutical composition or dosage form
  • Said composition comprises a dry component (s) comprising at least one bioactive glass and an aqueous component comprising at least one aqueous medium, and said dry component(s) comprises at least one bisphosphonate or said aqueous component(s) comprises at least one bisphosphonate or both comprise at least one bisphosphonate, and said aqueous component is brought into contact with the dry component(s) prior to use.
  • the composition comprises a complex formed of at least one bioactive glass or a combination of bioactive glasses, and at least one bisphosphonate or a combination of bisphosphonates, and at least one aqueous medium.
  • the dry component refers here to the bioactive glass(es), as such or combined with the bisphosphonate(s) in dry (solid) form
  • the aqueous component refers here to the aqueous medium in liquid form, or alternatively, to the aqueous medium comprising the bisphosphonate(s) dissolved therein.
  • the dry component is suitably reconstituted with the aqueous component prior to use.
  • the bioactive glass is selected from any available bioactive glasses, such as but not limited to silica glasses (glasses based on silicon dioxide) where the content of silicon dioxide is no more than 60 wt %.
  • Said silica glasses additionally comprise a source of calcium, such as calcium oxide (CaO), calcium fluoride (CaF 2 ), calcium carbonate (CaC0 3 ), calcium nitrate (Ca(N0 3 )2), calcium sulphate (CaS0 4 ), calcium silicates, and a source of phosphorus, such as P 2 0 5 .
  • the glasses may have a variation in the ratio of these components.
  • the silica glasses may optionally comprise one or more other components such as boron oxide (B 2 0 3 ), sodium oxide (Na 2 0), sodium carbonate (Na 2 C0 3 ), sodium nitrate (NaN0 3 ), sodium sulphate (Na 2 S0 4 ), sodium silicates, potassium oxide (K 2 0), potassium carbonate (K 2 C0 3 ), potassium nitrate (KN0 3 ), potassium sulphate (K 2 S0 4 ), potassium silicates, strontium oxide (SrO), strontium carbonate (SrC0 3 ), strontium nitrate (SrN0 3 ), strontium acetate (Sr(CH 3 C0 2 ) 2 ), strontium sulphate (SrS0 4 ), strontium fluoride (SrF 2 ), strontium phosphate (Sr 3 (P0 4 ) 2 ), strontium silicates, magnesium oxide (MgO), magnesium carbonate (Mg
  • the bioactive glass may optionally comprise silver, suitably provided as silver oxide in a molar percentage of from 0 up to 1%, 0.75%, 0.5% or 0.25%.
  • the incorporation of silver may provide antibacterial properties to the bioactive glass.
  • suitable bioactive glasses are commercially available silica glasses, such as but not limited to S53P4 containing Si0 2 53%, Na 2 0 23%, CaO 20% and P 2 0 4 4% w/w, and 45S5, containing silicon dioxide Si0 2 45% w/w and a 5 : 1 molar ratio of calcium (source of calcium) to phosphorus (source of phosphorus).
  • silica glasses such as but not limited to S53P4 containing Si0 2 53%, Na 2 0 23%, CaO 20% and P 2 0 4 4% w/w, and 45S5, containing silicon dioxide Si0 2 45% w/w and a 5 : 1 molar ratio of calcium (source of calcium) to phosphorus (source of phosphorus).
  • the bioactive glass is selected from silica glasses comprising from 30 to 60% w/w silicon dioxide, at least one source of calcium, at least one source of phosphorus and optionally at least one source of sodium.
  • the bioactive glass may be obtained using any techniques known in the art. Typically bioactive glasses are manufactured using methods such as but not limited to melt- derived techniques and sol-gel techniques known in the art. Preferably bioactive glass obtained using melt-derived techniques (referred to as melt-derived bioactive glass) is used in the present invention, whereby impurities originating from the sol- gel technique can be avoided.
  • the bioactive glass may have an average particle size from 0.1 to 2000 ⁇ .
  • an average particle size from 500 to 800 ⁇ is suitable.
  • the bioactive glass may comprise fractions having different particle size distributions, whereby for example the rate of bone formation may be controlled and adjusted according to the need.
  • the composition may comprise 40 to 98% w/w, preferably 45 to 95% w/w of bioactive glass or a combination of bioactive glasses, calculated from the dry matter.
  • Suitable bisphosphonates are selected from known bisphosphonates, such as but not limited to etidronate, clodronate, tiludronate, pamidronate, alendronate, risedronate, ibandronate, zoledronate, incadronate, olpadronate, neridronate, YH529 (minondronate) and EB-1053.
  • the bisphosphonate is selected from etidronate and clodronate, particularly preferably it is clodronate.
  • the composition may comprise 2 to 60% w/w of bisphosphonate or a combination of bisphosphonates, preferably 5 to 55% w/w of bisphosphonate, calculated from the dry matter.
  • the composition may comprise 5 to 95% w/w of the aqueous medium, preferably 20 to 75% w/w and particularly preferably 30 to 70% w/w, when reconstituted or mixed with the dry component(s).
  • composition may optionally comprise an additive or a combination of additives, excipients, diluents, flavoring agents, aromatizing agents, stabilizers, formulation providing agents and formulation promoting agents, such as but not limited to flavors, sweeteners, aromes, scents, colorants, viscosity increasing agents, surfactants, pH-indicators, antioxidants, preservatives, anti-foaming agents, pH adjusting agents, antimicrobial agents, and antibiotics in amounts well known in the art.
  • additives such as but not limited to flavors, sweeteners, aromes, scents, colorants, viscosity increasing agents, surfactants, pH-indicators, antioxidants, preservatives, anti-foaming agents, pH adjusting agents, antimicrobial agents, and antibiotics in amounts well known in the art.
  • the pharmaceutical dosage form for the treatment and/or prevention of tissue damage comprises the composition, wherein the dry component(s) is provided in a first compartment or vessel and the aqueous component(s) is provided in a second compartment or vessel, the dry component and the aqueous component are brought into contact with each other prior to the administration.
  • the bioactive glass or glasses may be mixed or blended, with the bisphosphonate or bisphosphonates using any suitable mixing method. Any method, such as but not limited to spray drying, lyophillization, dry powder mixing, wet granulation, granulation, mixing with turbula, pelleting, extrusion with spheronization may be utilized to obtain the dry component comprising the bioactive glass(es) and bisphosphonate.
  • the aqueous medium contains the bisphosphonate(s) the bisphosphonate is dissolved in the aqueous medium using mixing and a temperature between 5 to 80°C. Bisphosphonates are typically readily soluble in water.
  • the optional additives and excipients may be incorporated in the dry component or in the aqueous medium, depending on the properties of the additive/excipient.
  • the composition may suitably be formulated as a dosage form or a kit or package, which comprises the dry component in a separate compartment of an application device or in a vessel, and the aqueous component in another separate compartment of the application device or in another vessel. Prior to use the dry component and the aqueous component are brought into contact with each other, whereby they are mixed to form the final composition.
  • the final composition may be used as such or alternatively it may be allowed to stand for 50 to 80 hours after mixing in order to allow the pH change to take place, such as but not limited to from strongly acidic to strongly basic.
  • the composition is intended for use in close proximity of tissue sensitive to pH changes or acidic pH, it is preferable to use the composition from 50 to 80 hours after mixing the dry component and the aqueous component.
  • the composition should preferably be used within 6 months after mixing, preferable within 30 days after mixing and particularly preferably within 15 days after mixing in order to achieve the desired effect without adverse effects.
  • a pH indicator may be incorporated in the composition, mixed in the dry component or in the aqueous component, for providing indication when the pH of the (final) composition after mixing the components has reached a desired range for administration or stabilized to a suitable level. This depends for example of the site of treatment.
  • the components are suitably packed in containers, such as but not limited to 2-part containers which are as such well known in the art, vessels, syringes or the like, which enable easy and rapid mixing of the components prior to the use.
  • containers such as but not limited to 2-part containers which are as such well known in the art, vessels, syringes or the like, which enable easy and rapid mixing of the components prior to the use.
  • Mixing of the components may result in a suspension or lacquer or gel (mouthwash, varnish etc) or paste (such as toothpaste, filler for cavities, chewing gum etc.) or foam or aerosol, to be applied locally on the desired site in need for the treatment.
  • the pharmaceutical composition according to the invention may suitably be used locally in the treatment and/or prevention of damage to a tissue.
  • the composition may be used in medical applications in the field of synthetic bone graft materials for general orthopedic, craniofacial, maxillofacial and periodontal repair, as well as bone tissue engineering scaffolds.
  • the application of the composition provides increased rate of apatite deposition, leading to more rapid repair and reconstitution of diseased and damaged tissue.
  • the composition may also be formulated into toothpaste, dentrifice, chewing gum and mouth wash, as well as filler to treat root cavities and/or to prevent further deterioration of the teeth.
  • the composition may be used of fixation of devices, such as implant, for repairing of bone defects, for remodelling of soft underlining tissue, for promoting new bone formation, for rebuilding of cartilage tissue, reconstruction of cartilage tissue, such as nose and ear repair etc.
  • the tissue may be animal tissue, suitably mammalian or human tissue, animals being such as but not limited to dogs, cats, horses, sheep, cows and pigs.
  • the tissue may be bone tissue, cartilage tissue, soft tissues including connective tissues and dental tissues including calcified dental tissues such as but not limited to enamel and dentin.
  • the composition may suitably be used for the treatment of bone fractures, dental cavities, and for the treatment and prevention of periodontal disease, or hypersensitivity in the teeth. Particularly the composition is suitable for use on the dental region, for example as local treatment of periodontitis, for repairing tissue damage, which have not been possible using methods and compositions of the state of the art. When the composition is intended for use in close proximity of tissues sensitive to acidic pH or pH change, it is preferable to use the composition after 50 hours from mixing the aqueous component with the dry components.
  • the dry component of the composition is brought into contact with the aqueous component prior to the use, such as from 0 to 80 d before the use, suitably 0 - 50 d before the use, for obtaining the final composition.
  • the maximum activity of the formed complex is maintained for at least 6 months, suitably for at least 4 weeks.
  • the final composition may be applied one single time locally or the application may be carried out repeatedly, for example for the treatment and/or prevention of periodontal disease etc.
  • the composition has several advantages.
  • the bisphosphonate, particularly the clodronate shown in the examples has a clear synergistic effect with the bioactive glass on the formation of apatite, where the bisphosphonate enhances the desired apatite formation on the bioactive glass significantly.
  • the bisphosphonate can be delivered locally to the desired site of action and the adverse effects relating to the oral administration of bisphosphonates can be avoided.
  • the dosage of bisphosphonate is very low compared to that in oral administration and thus also local adverse effects, such as irritation of mucous membranes can be avoided.
  • composition of the invention enhances and activates the metabolism in the tissue significantly more than bioactive glass and provides for more effective bone formation.
  • the pH increase with the combination product is greater and can be maintained for longer periods of time than that with bioactive glass alone, whereas with the bisphosphonate (clodronate) no pH increase could be noticed at all.
  • a combination product comprising the bisphosphonate and bioactive glass having the particle size in the range of 0.5 - 0.8 mm is used the pH increase took place in a controlled manner, which is a clear advantage with tissues sensitive to pH changes, such as dental tissues.
  • composition comprising bioactive glass and clodronate
  • the combination product (complex) of bioactive glass (BG) and clodronate was characterized and the effect of clodronate to the bioactivity of BG was studied.
  • the physical and chemical characteristics of the samples were identified by e.g. Scanning electron microscopy (SEM), X-ray powder diffraction (XRPD) and Fourier transform infrared spectroscopy (FTIR) .
  • Bioactive glass Bioactive glass (S53P4), BonAliveTM (BonAlive Biomaterials Ltd, former Vivoxid Ltd) contains four oxides (Si0 2 53%, Na 2 0 23%, CaO 20% and P 2 0 5 4% w/w). It is amorphous, having density of 2.66 g/cm 3 and is odourless white granule in particle size: 0.5-0.8 mm. Bioactive glass was used as dry granules or 1 g bioactive glass moisturized with 900 ⁇ of 0.9% saline.
  • Ciodronate (PharmaZell GmbH, Ph. Eur.) in the form of disodium salt (CH 2 CI 2 0 6 P 2 Na 2 4H 2 0 360.9 g/mole) was used.
  • BG The bioactivity process of BG starts when BG is immersed into biological fluids in vivo, simulated body fluids, or other buffered solutions in vitro. Ion leaching and exchange with surrounding solution results bone-like apatite layer formation onto the BG surface. Also the slight alkalinisation is thereby induced. These two phenomena form the basis for the osteoproductive properties of BG.
  • the liquid medium chosen was 0.9% saline, which alone induced only slightly the apatite formation of BG.
  • PSD particle size distribution
  • the X-ray diffraction patterns of the dry and wetted samples were measured using an X-ray powder diffraction (XRPD) 2theta diffracto meter (Bruker axs D8).
  • XRPD X-ray powder diffraction
  • the XRPD experiments were performed in symmetrical reflection mode with CuK a radiation (1.54 A) using Gobel Mirror bent gradient multilayer optics.
  • the scattered intensities were measured with a scintillation counter.
  • the angular range was from 5 to 40° (2 ⁇ ) with steps of 0.05° and the measuring time was 6 s/step. All of the samples were measured at room temperature.
  • FTIR spectroscopy was used to analyze dry and wetted samples.
  • the samples were analyzed using Vertex 70 (Bruker Optics Inc.) attenuated total reflectance (ATR) accessory (MIRacle TM ATR, PIKE Technologies, Inc.) by measuring the spectra 20 times with 4 cm "1 resolution between 4000-650 cm “1 under dry air flow.
  • the spectra were further treated using OPUS 4.0 program (Bruker Optics Inc.).
  • the resulting spectra were baseline corrected to minimize the effect of differing baselines on further data analysis.
  • DSC measurements were performed on DSC analyser (model 821 e , Mettler Toledo Ag) using STAR software (STAR 5.1, Sun Soft Inc.).
  • the temperature axis of the equipment was calibrated with zinc and indium.
  • the runs were performed under nitrogen gas flow (50 mL/min) in aluminium pans, and the weights of the samples were 5-7 mg.
  • the heating rate was 10°C/min over the temperature range 15-450°C.
  • the apatite formation on the top of the bioactive glass is related to the ion exchange causing pH increase.
  • the increase of pH was higher in the combination of BG and clodronate than BG alone indicating that the activity of the bioactive glass is stronger in the combination product as can be seen in Fig. 1 representing changes in pH over the time (hours) for clodronate (clod), bioactive glass (BG) and combination product (BG + clod 200mg).
  • the apatite formation is also surprisingly extensive already after 3 days, as can be seen in Fig. 3, showing SEM micrograph of apatite formation on the top of the bioactive glass in combination of clodronate (with saline for 72 hours) in pH 9.45. This has not been reported previously.
  • the apatite formation in the combination product was detected also with the XRPD, as can been in Fig. 4, showing a XRPD diffractogram of combination product
  • Fig. 5 illustrates the different IR absorption spectra of bioactive glass, clodronate and combination product of bioactive glass and clodronate with saline for 72 hours. As shown at the time of 72 hours in SEM micrographs (Figs. 2 and 3) there is clear evidence of apatite formation. Clear apatite formation can be seen in Fig. 5, showing FTIR absorption spectra of clodronate, bioactive glass and combination product with saline for 72 hours (* phosphate groups).
  • the FTIR spectrum of the combination product illustrates well-defined phosphate bending vibrational band at 1200-900 cm “1 , conforming the formation of a Ca-P-rich layer on the top of the BG, which indicates the apatite formation.
  • IR spectrum shows the characteristic bands of O-H and P-0 reflecting the vibrations of the OH and P0 4 groups in the hydroxyapatite. For example, one of the bands for phosphate groups is shown at 1090 cm "1 . As expected this phenomena can also be seen in the pure BG spectrum, even not as intense. Additionally, Si-O-Si stretch (1200-1000 cm “1 ) can be seen in the combination product and bioactive glass indicating apatite formation.
  • Fig. 6 shows the thermal analysis of the studied samples and particularly the DSC thermograms of clodronate, combination product and bioactive glass with saline for 72 hours.
  • the initial endothermic process around 100°C can be attributed to loss of residual water.
  • the peak seen for clodronate at 136°C seems to disappear in the combination product indicating that there is molecular interaction between BG and clodronate, which has been confirmed already with FTIR spectra (Fig. 5).
  • Bioactivity of the BG and combination product has been proved with pH change, SEM micrograph, XRPD and FTIR spectra.
  • the SEM micrograph and FTIR and XRPD diffraction clearly showed that there is apatite formation in the combination product.
  • this apatite formation is more extensive in the combination product than BG alone.
  • clodronate enhances the activity of the BG.
  • the bioactivity property remains longer in the combination product than BG alone, thus suggesting that combination of clodronate and BG creates a favourable environment for the apatite formation.
  • clodronate has remarkable ability to enhance the apatite formation of BG and thus promotes the process.
  • Bioactive glass (S53P4), BonAliveTM was used in this example. It is amorphous, having density of 2.66 g/cm 3 and is odourless white granule in particle size: 0.5-0.8 mm and ⁇ 0.5 mm. Bioactive glass was used as dry granules or 1 g bioactive glass moisturized with 900 ⁇ or 1350 ⁇ of 0.9% saline.
  • PSD particle size distribution
  • SEM Scanning electron micrographs
  • the X-ray diffraction patterns of the dry and wetted samples were measured using an X-ray powder diffraction (XRPD) 2theta diffracto meter (Brukeraxs D8).
  • XRPD X-ray powder diffraction
  • the XRPD experiments were performed in symmetrical reflection mode with CuK a radiation
  • FTIR Fourier transformed infrared
  • DSC Differential scanning calorimetric
  • the distribution of the particle size (volume size) of the different BG fractions and clodronate are shown in Table 2.
  • the particle size distributions of both starting material is basic informative data for the characterization of the used material.
  • Fig. 7 changes in pH over the time (hours) for clodronate (clod), bioactive glass (BG) and combination product (BG+clod 100 mg or 200mg) with 900 ⁇ saline added are presented.
  • Fig 8 changes in pH over the time (hours) for clodronate (clod), bioactive glass (BG) 0.5-0.8 mm or ⁇ 0.5 mm and combination product (BG (0.5-0.8 mm or ⁇ 0.5mm) + clod (100 mg, 200mg or 300mg)) with 1350 ⁇ saline added are presented.

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Abstract

La présente invention concerne une composition ou une forme galénique destinée à une administration locale, pour le traitement et/ou la prévention de lésions tissulaires, ladite composition comprenant un (des) composant(s) sec(s) comprenant au moins un verre bioactif, et un (des) composant(s) aqueux comprenant au moins un milieu aqueux, et ledit composant sec comprend au moins un bisphosphonate ou ledit composant aqueux comprend au moins un bisphosphonate, ou les composants comprennent tous les deux au moins un bisphosphonate.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001066044A2 (fr) * 2000-03-03 2001-09-13 Smith & Nephew, Inc. Particule façonnee et composition pour carence osseuse, et procede de fabrication de ladite particule
WO2008077257A1 (fr) * 2006-12-22 2008-07-03 Mathys Ag Bettlach Précurseur pour la préparation d'un matériau pâteux de remplacement d'os par adjonction d'un liquide
US20090208428A1 (en) * 2006-06-16 2009-08-20 Imperial Innovations Limited Bioactive Glass
US20120231057A1 (en) * 2011-03-11 2012-09-13 Hack Gary D Treatment and prevention of dental pathology in humans and non-human animals

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001066044A2 (fr) * 2000-03-03 2001-09-13 Smith & Nephew, Inc. Particule façonnee et composition pour carence osseuse, et procede de fabrication de ladite particule
US20090208428A1 (en) * 2006-06-16 2009-08-20 Imperial Innovations Limited Bioactive Glass
WO2008077257A1 (fr) * 2006-12-22 2008-07-03 Mathys Ag Bettlach Précurseur pour la préparation d'un matériau pâteux de remplacement d'os par adjonction d'un liquide
US20120231057A1 (en) * 2011-03-11 2012-09-13 Hack Gary D Treatment and prevention of dental pathology in humans and non-human animals

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
BUI, X.V. ET AL.: "Chemical Reactivity of Biocomposite Glass-Zoledronate.", JOURNAL OF THE AUSTRALIAN CERAMIC SOCIETY, vol. 46, no. 2, 2010, pages 24 - 28 *
ROSENQVIST, K. ET AL.: "Bone tissue engineering is a rapidly growing area of research involving the use of bioactive glass (BG) alone and in combination with different materials.", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 452, no. 1-2, 2013, pages 102 - 107 *
SRISUBUT, S. ET AL.: "Effect of local delivery of alendronate on bone formation in bioactive glass grafting in rats.", ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY AND ENDODONTOLOGY., vol. 104, no. 4, October 2007 (2007-10-01), pages E11 - E16 *

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