CA2561728A1 - Bifunctional bioadhesive compositions for oral implantology - Google Patents
Bifunctional bioadhesive compositions for oral implantology Download PDFInfo
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- CA2561728A1 CA2561728A1 CA002561728A CA2561728A CA2561728A1 CA 2561728 A1 CA2561728 A1 CA 2561728A1 CA 002561728 A CA002561728 A CA 002561728A CA 2561728 A CA2561728 A CA 2561728A CA 2561728 A1 CA2561728 A1 CA 2561728A1
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- Canada
- Prior art keywords
- solution
- similar
- polyoxyethylene sorbitan
- drug
- sorbitan monolaurate
- Prior art date
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- Abandoned
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- 239000000227 bioadhesive Substances 0.000 title claims abstract description 14
- 239000000203 mixture Substances 0.000 title abstract description 26
- 230000001588 bifunctional effect Effects 0.000 title description 3
- 239000007943 implant Substances 0.000 claims abstract description 40
- 229940079593 drug Drugs 0.000 claims abstract description 39
- 239000003814 drug Substances 0.000 claims abstract description 39
- 229920001213 Polysorbate 20 Polymers 0.000 claims abstract description 25
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims abstract description 25
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims abstract description 25
- 229940122361 Bisphosphonate Drugs 0.000 claims abstract description 24
- 150000004663 bisphosphonates Chemical class 0.000 claims abstract description 24
- 230000011164 ossification Effects 0.000 claims abstract description 6
- 238000011065 in-situ storage Methods 0.000 claims abstract description 5
- ACSIXWWBWUQEHA-UHFFFAOYSA-N clodronic acid Chemical compound OP(O)(=O)C(Cl)(Cl)P(O)(O)=O ACSIXWWBWUQEHA-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 229960002286 clodronic acid Drugs 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 10
- 230000000694 effects Effects 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 238000002560 therapeutic procedure Methods 0.000 claims description 4
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 claims description 3
- DBVJJBKOTRCVKF-UHFFFAOYSA-N Etidronic acid Chemical compound OP(=O)(O)C(O)(C)P(O)(O)=O DBVJJBKOTRCVKF-UHFFFAOYSA-N 0.000 claims description 3
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-N 0.000 claims description 3
- IIDJRNMFWXDHID-UHFFFAOYSA-N Risedronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CC1=CC=CN=C1 IIDJRNMFWXDHID-UHFFFAOYSA-N 0.000 claims description 3
- UGEPSJNLORCRBO-UHFFFAOYSA-N [3-(dimethylamino)-1-hydroxy-1-phosphonopropyl]phosphonic acid Chemical compound CN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O UGEPSJNLORCRBO-UHFFFAOYSA-N 0.000 claims description 3
- 229940062527 alendronate Drugs 0.000 claims description 3
- 229960004585 etidronic acid Drugs 0.000 claims description 3
- 229940015872 ibandronate Drugs 0.000 claims description 3
- PUUSSSIBPPTKTP-UHFFFAOYSA-N neridronic acid Chemical compound NCCCCCC(O)(P(O)(O)=O)P(O)(O)=O PUUSSSIBPPTKTP-UHFFFAOYSA-N 0.000 claims description 3
- 229950010733 neridronic acid Drugs 0.000 claims description 3
- WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 claims description 3
- 229940046231 pamidronate Drugs 0.000 claims description 3
- 229940089617 risedronate Drugs 0.000 claims description 3
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 claims description 3
- 229960004276 zoledronic acid Drugs 0.000 claims description 3
- 238000007596 consolidation process Methods 0.000 claims description 2
- 239000004053 dental implant Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 230000008468 bone growth Effects 0.000 claims 1
- 230000001737 promoting effect Effects 0.000 claims 1
- 230000004936 stimulating effect Effects 0.000 claims 1
- 230000009471 action Effects 0.000 abstract description 12
- 230000002035 prolonged effect Effects 0.000 abstract description 7
- 230000008901 benefit Effects 0.000 abstract description 4
- 239000000243 solution Substances 0.000 description 31
- 238000009472 formulation Methods 0.000 description 8
- 239000007788 liquid Substances 0.000 description 6
- 230000035587 bioadhesion Effects 0.000 description 5
- 230000000699 topical effect Effects 0.000 description 5
- 239000012049 topical pharmaceutical composition Substances 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 239000000853 adhesive Substances 0.000 description 3
- 230000001070 adhesive effect Effects 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- 208000001132 Osteoporosis Diseases 0.000 description 2
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000000645 desinfectant Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 238000002513 implantation Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229910052719 titanium Inorganic materials 0.000 description 2
- 239000010936 titanium Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 241000707825 Argyrosomus regius Species 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 201000002980 Hyperparathyroidism Diseases 0.000 description 1
- 208000003076 Osteolysis Diseases 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 241000404883 Pisa Species 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000956 alloy Substances 0.000 description 1
- 229910045601 alloy Inorganic materials 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000019568 aromas Nutrition 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000000560 biocompatible material Substances 0.000 description 1
- 125000005340 bisphosphate group Chemical group 0.000 description 1
- 230000010478 bone regeneration Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- HJKBJIYDJLVSAO-UHFFFAOYSA-L clodronic acid disodium salt Chemical compound [Na+].[Na+].OP([O-])(=O)C(Cl)(Cl)P(O)([O-])=O HJKBJIYDJLVSAO-UHFFFAOYSA-L 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000012835 hanging drop method Methods 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 229940124589 immunosuppressive drug Drugs 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 208000029791 lytic metastatic bone lesion Diseases 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 238000012148 non-surgical treatment Methods 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 230000000278 osteoconductive effect Effects 0.000 description 1
- 230000002138 osteoinductive effect Effects 0.000 description 1
- 239000006174 pH buffer Substances 0.000 description 1
- 239000003973 paint Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000001966 tensiometry Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000001173 tumoral effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Neurosurgery (AREA)
- Dermatology (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
Bioadhesive solutions of bisphosphonates and Tween 20 are described, with an action that promotes ossification, useful for applications in oral implantology. With respect to the compositions currently in use, these solutions have the advantage of a greater permanence in-situ, before, during and after application of the implant, they present a more intense action of the drug, prolonged over time, and favour complete ossification around the implant.
Description
BIFUNCTIONAL BIOADHESIVE COMPOSITIONS FOR ORAL
IMPLANTOLOGY
FIELD OF THE INVENTION
The present invention falls within the field of topical pharmaceutical compositions for applications in oral implantology.
PRIOR ART
Pharmaceutical compositions for topical use are composed of a pharmaceutical carrier associated with an active principle; the aim is to release the drug on the surface where it can act directly, or where it can be absorbed by the derma and exert systemic efFects.
The first requirement in the preparation of topical formulations is that the substance used as a pharmaceutical carrier must have sufficient capacity to incorporate the necessary quantities of drug and that, once applied on the patient, it is able to release the drug in a predetermined interval of time. However, even in the presence of optimal carriers, the release and absorption of the drug may be insufficient: a possible cause of this problem is the low bioadhesivity of the formula. In fact, bioadhesion conditions and regulates the process of permeation and absorption of an active principle: there is a bioadhesive efFect when the adhesive forces of a substratum prevail over the adhesive forces of the formulative system with which they come in contact. In practice, the two surfaces that come in contact (the medicating composition and the biological substratum on which it is applied) must be as far as possible similar to each other from the paint of view of their surface characteristics.
The surFace characteristics of a body are conventionally expressed through three parameters called the polar component (CP), dispersed component (CD) and surFace free energy (ELS), equal to the sum of CD and CP; the set of these three values determines the so-called tensiometric profile, which is typical and difFerent for each surFace; the integrated expression of the tensiometric profile (tensiometric imprint) may be graphically represented by means of a system of three Cartesian axes in space. How these parameters are measured and the definition of the tensiometric profile are carried out by means of known techniques (A. Bettero, M. Gregorio, M.
Lovrecich, M. Marcazzan, A. Semenzato (1999) "In vivo and in vifro evaluafion of bioadhesive effect (TVS index of bioadhesivity)': Proc. Drug delivery for the third millennium. CRS Int. Congress. Pisa, 10-12 October; N. Realdon, M. Battan, M.
Marcazzan, E. Ragazzi and A. Bettero (1998) "A tensiomefric approach fo evaluate sfability and compatibility of maferials for biomedical and pharmaceutical use" Proc. 2nd World Meeting APGI/APV, Paris. 25-28 May. (pp. 1-3); A.
Bettero, A. Castegnaro, M. Gregorio, L. Marcati, M. Marcazzan (2002) "Tensiometricprint as evaluation marker for topical formulafions stability': Proc. 4th World Meeting on Pharmaceutical, Biopharmaceutic, Pharmaceutical Technology. Florence, 8-11 April.) When the topical composition and the substratum to be treated present comparable surface characteristics, they adhere to each other in an optimal way, thus ensuring the best affinity and maximising the useful surface for the release of the drug; at the same time, intense interaction forces are developed between the two surfaces which ensure a strong and lasting adhesion. Instead, when the two surfaces present unbalanced tensiometric profiles, the bioadhesive effect is reduced.
In these cases, to improve bioadhesion it is common practice to reduce aspecifically the surface tension on the interface between topical composition and patient, using agents with surface activity. This simple system works when there is only one interface involved, that is the one between the pharmaceutical composition and the patient: that is what normally happens for topical formulations.
There is a different situation when several interfaces are involved in the action dynamics of the drug, and the various surfaces involved present significantly different tensiometric profles. The topical formulations used in implantology are an example of this: examples of formulations used in implantology are those which are applied in the dental socket before applying a prosthesis. These compositions (for example antibiotic pastes) are administered prior to the application of the implant on the surface of the patient that is to be in contact with the implant; their role is to remain in the cavity between implant and patient, and to perform the pharmacological action there for a prolonged interval of time; the drug used is generally a product belonging to the group of bisphosphonates, as bone formation promoters; during its permanence in-situ, the formulation promotes the increase of bone tissue around the implant, consolidating it and ensuring its stability in time.
IMPLANTOLOGY
FIELD OF THE INVENTION
The present invention falls within the field of topical pharmaceutical compositions for applications in oral implantology.
PRIOR ART
Pharmaceutical compositions for topical use are composed of a pharmaceutical carrier associated with an active principle; the aim is to release the drug on the surface where it can act directly, or where it can be absorbed by the derma and exert systemic efFects.
The first requirement in the preparation of topical formulations is that the substance used as a pharmaceutical carrier must have sufficient capacity to incorporate the necessary quantities of drug and that, once applied on the patient, it is able to release the drug in a predetermined interval of time. However, even in the presence of optimal carriers, the release and absorption of the drug may be insufficient: a possible cause of this problem is the low bioadhesivity of the formula. In fact, bioadhesion conditions and regulates the process of permeation and absorption of an active principle: there is a bioadhesive efFect when the adhesive forces of a substratum prevail over the adhesive forces of the formulative system with which they come in contact. In practice, the two surfaces that come in contact (the medicating composition and the biological substratum on which it is applied) must be as far as possible similar to each other from the paint of view of their surface characteristics.
The surFace characteristics of a body are conventionally expressed through three parameters called the polar component (CP), dispersed component (CD) and surFace free energy (ELS), equal to the sum of CD and CP; the set of these three values determines the so-called tensiometric profile, which is typical and difFerent for each surFace; the integrated expression of the tensiometric profile (tensiometric imprint) may be graphically represented by means of a system of three Cartesian axes in space. How these parameters are measured and the definition of the tensiometric profile are carried out by means of known techniques (A. Bettero, M. Gregorio, M.
Lovrecich, M. Marcazzan, A. Semenzato (1999) "In vivo and in vifro evaluafion of bioadhesive effect (TVS index of bioadhesivity)': Proc. Drug delivery for the third millennium. CRS Int. Congress. Pisa, 10-12 October; N. Realdon, M. Battan, M.
Marcazzan, E. Ragazzi and A. Bettero (1998) "A tensiomefric approach fo evaluate sfability and compatibility of maferials for biomedical and pharmaceutical use" Proc. 2nd World Meeting APGI/APV, Paris. 25-28 May. (pp. 1-3); A.
Bettero, A. Castegnaro, M. Gregorio, L. Marcati, M. Marcazzan (2002) "Tensiometricprint as evaluation marker for topical formulafions stability': Proc. 4th World Meeting on Pharmaceutical, Biopharmaceutic, Pharmaceutical Technology. Florence, 8-11 April.) When the topical composition and the substratum to be treated present comparable surface characteristics, they adhere to each other in an optimal way, thus ensuring the best affinity and maximising the useful surface for the release of the drug; at the same time, intense interaction forces are developed between the two surfaces which ensure a strong and lasting adhesion. Instead, when the two surfaces present unbalanced tensiometric profiles, the bioadhesive effect is reduced.
In these cases, to improve bioadhesion it is common practice to reduce aspecifically the surface tension on the interface between topical composition and patient, using agents with surface activity. This simple system works when there is only one interface involved, that is the one between the pharmaceutical composition and the patient: that is what normally happens for topical formulations.
There is a different situation when several interfaces are involved in the action dynamics of the drug, and the various surfaces involved present significantly different tensiometric profles. The topical formulations used in implantology are an example of this: examples of formulations used in implantology are those which are applied in the dental socket before applying a prosthesis. These compositions (for example antibiotic pastes) are administered prior to the application of the implant on the surface of the patient that is to be in contact with the implant; their role is to remain in the cavity between implant and patient, and to perform the pharmacological action there for a prolonged interval of time; the drug used is generally a product belonging to the group of bisphosphonates, as bone formation promoters; during its permanence in-situ, the formulation promotes the increase of bone tissue around the implant, consolidating it and ensuring its stability in time.
In the topical compositions for implantology the drug interFaces with two surfaces (that of the patient and that of the implant) that have notably difFerent characteristics, in particular in the ratio between the dispersed component and the polar component. In these cases it is particularly difFicult to obtain a good degree of bioadhesivity and therefore an intense and prolonged action of the drug over time; it also happens that the medicating solution is dispersed quickly from the place of application, before and during application of the implant, so that at the end only a fraction of the desired dose of drug remains frmly in the cavity between patient and implant.
The present invention solves these problems by means of new topical formulations of bisphosphonates, with optimum characteristics of bioadhesivity and a more intense and prolonged action in time in comparison with the current formulations.
SUMMARY
It has now been discovered that pharmaceutical compositions with a degree of bioadhesion equally shared between the two surfaces, that is on orre side towards the patient and on the other towards the implant, allow a real increase in the efFcacy of the drug. -fhe present inventors have therefore identified compositions of bisphosphonates having the above-mentioned particular surface characteristics:
these compositions, obtained by mixing the bisphosphonate solutions with very low quantities of '1-ween 20 or similar, have the advantage of a greater permanence in-situ, before, during and after application of the implant, they present a more intense and prolonged action in time of the drug in comparison with the compositions currently in use, and they favour complete ossification around the implant.
DESCRIPTION OF FIGURES
Figures 1 a, 1 b, 1 c: action mechanism proposed for the present invention Figure 2a: tensiometric imprints of clodronate Figure 2b: tensiornetric imprint of implant Figure 2c: superimposition of imprints Figure 3a and 3b: su rFace free energies (ELS) of the modified clodronate and of clodronate .
The present invention solves these problems by means of new topical formulations of bisphosphonates, with optimum characteristics of bioadhesivity and a more intense and prolonged action in time in comparison with the current formulations.
SUMMARY
It has now been discovered that pharmaceutical compositions with a degree of bioadhesion equally shared between the two surfaces, that is on orre side towards the patient and on the other towards the implant, allow a real increase in the efFcacy of the drug. -fhe present inventors have therefore identified compositions of bisphosphonates having the above-mentioned particular surface characteristics:
these compositions, obtained by mixing the bisphosphonate solutions with very low quantities of '1-ween 20 or similar, have the advantage of a greater permanence in-situ, before, during and after application of the implant, they present a more intense and prolonged action in time of the drug in comparison with the compositions currently in use, and they favour complete ossification around the implant.
DESCRIPTION OF FIGURES
Figures 1 a, 1 b, 1 c: action mechanism proposed for the present invention Figure 2a: tensiometric imprints of clodronate Figure 2b: tensiornetric imprint of implant Figure 2c: superimposition of imprints Figure 3a and 3b: su rFace free energies (ELS) of the modified clodronate and of clodronate .
DETAILED DESCRIPTION OF THE INVENTION
The present invention coneems a bioadhesive medicated formulation, useful for applications in oral implantology, comprising one or more drugs belonging to the class of bisphosphonates, in association with one or more compounds chosen among polyoxyethylene sorbitan monolaurate and similar.
By the term "bioadhesive system" it is meant liquid a system in which the drug is uniformly distributed, dissolved in a solution, in the entire volume of the liquid present. Therefore in the present invention the drug does not form a distinct phase from the liquid carrier, as occurs for example in the case of suspensions, emulsions, microemulsions, mycellar or colloidal systems, liposomes, etc. Any bisphosphonate, that is a compound containing one or more free phosphoric groups, salified, esterified or complexed, and possessing pro-ossifying properties, can be advantageously used in the present invention. These drugs are known per se and are widely used in therapy; some examples are alendronate, ethydronate, clodronate, risedronate, pamidronate, neridronate, zoledronate, ibandronate, olpadronate. Among the bisphosphonates the diphosphonates are preferred, in particular clodronate and its disodic salt, currently used in therapy as a pro-ossifying agent, for example in the treatment of osteoporosis, tumoral osteolysis, etc.
In the solutions to which the invention refers, the bisphosphonate is contained in a concentration preferably between 1 and 20 mg/ml, or, more preferably, between and 15 mg/ml; however, the concentration may be increased or reduced beyond these limits if the condition of the patient require it.
Polyoxyethylene sorbitan monolaurate (commercially known by the name T'ween 20) is a non ionic surfactant; in the present invention it is used in a concentration of up to 0.5% by weight, with respect to the weight of the solution.
Preferably the concentration varies between 0.025% and 0.250%, more preferably between 0.05% and 0.125%; concentrations higher than 0.5% are not desired, because the system may exceed the critical mycellar concentration and form multiphasic structures: these structures considerably reduce the superFicial afFinity of the composition and are therefore not desired.
As an alternative to Tween 20, compounds of a similar class may be used. As well as bisphosphonates and Tween 20, the corr-~position to which the present invention refers may contain suitable quantities of other excipients such as preserving, viscosifying, anti-oxidising or stabilising agents, pH buffers, etc. Moreover, in the case of formulations intended for the oral cavity, taste correctors may be used 5 such as sweeteners, aromas, etc.
In addition to phosphonates, other adjuvant drugs for implantology may be present, for example disinfectants, immunosuppressive drugs, antibiotics, anti-inflammatory agents, analgesics, etc.
The solvent used is generally water or another biocompatible fluid that can be mixed with water. The solvent must be compatible with the site of application and must be able to dissolve the phosphonate a nd the Tween 20 present.
The invention also concerns a Process for preparing the above-mentioned bioadhesive solutions comprising the mixinrg in a suitable solvent of at least one bisphosphonate and of one or more compounds chosen between Tween 20 and similar. The compositions thus realised may be used advantageously in any circumstance where the topical administration of bisphosphonates is necessary, in particular in implantology. Application is made directly on the site that is to host the implant and/or in the area around it. 1-he compositions described herein are applied in oral osseointegrated implantology: they may be applied, for example, in the surgical and non surgical treatment of p~arodontopathies and of dermatological pathologies; they are useful in surgical operation in cervico-facial area in which the grafting of biocompatible materials is contemplated (such as prostheses o r implants, for example dental implants), and in surgical operations where osteosynthesis devices of any nature, type and material are to be used; the invention is particularly useful in the case of implants made of titanium and its alloys, osteoinductive and osteoconductive materials, biocompatible barriers for bone regeneration, suture threads of any type and material. Generally, the treatment contemplates the prior administration of suitable quantities of the medicated solution on the site where the implant is to be applied (e.g. dental socket); the implant too may even be wetted with the solution before application ;
the application of the implant is carried out according to the normal known surgica I
/ orthodontic techniques. It is also possible to administer or inject the solution after implantation, in the area of tissue corresponding to er next to the prosthesis; or a part of the solution may be applied before and a part after implantation.
An action mechanism proposed for the present invention is illustrated in figures 1 a, 1 b, 1 c; the figures schematically represents a dental socket already filled with the medicated solution (hatched area), into which the implant is inserted. Without wishing to be restrained by theory, it is believed that a high adhesivity of the solution with regard to both the patient and the implant is useful for increasing the efficacy ~ of the formulation: in fact, if there is a lack of affinity between the medicating solution and any one of the two systems (patient and/or implant), when the implant is introduced into the cavity, air pockets are created between the implant and the drug (fig. 1 b) or between the drug and the patient (fig. 1 a) which push part of the medicating solution towards the outside, expelling it from the site of action; the air pockets remain even once the implant is applied, limiting the contact surface between patient/drug/implant, and thus reducing the pro-ossifying activity of the drug around the implant, and in the end the stability of the implant itself. Instead, if the solution adheres in a balanced way to both surfaces (fig. 1 c), no air pockets are formed, and the entire cavity between the patient and the implant remains occupied by the medicating solution _ The invention therefore includes the use of a solution containing one or more bisphosphates and one or more compounds chosen from Tween 20 and similar, in the preparation of a medication useful in implantology to favour the good course of the implant operation, as well as the consolidation of the implant and ossification around it. Although preferably used in implantology, the present solution may also be advantageously used for all treatments that require the application of bisphosphonates, for superficial or transdermic action: examples of these conditions are osteoporosis, bone tumour, osteolysisr, hyperparathyroidism, etc.
A further object of the present invention is a kit of parts, comprising: (i) one or more dosage units of a solution of bisphosphonates and/or salts thereof, and (ii) one or more dosage units of polyoxyethylene sorbitan monolaurate and/or similar.
The dosage units (i) and (ii) are usually, but not exclusively, phials. Upon use, preferably, the solution of bisphosphonate is removed from the dosage unit (i) by means of e.g. a syringe, and is transferred into the dosage unit (ii) containing the polyoxyethylene sorbitan monolaurate. The bisphosphonates and the polyoxyethylene sorbitan monolaurate of the kit are dosed in such a way that, when mixed together, they obtain the medicated solution object of the invention, previously described. The thus integrated unit (ii), suitably shaken, is ready for application onto the patient.
The kit may optionally include further tools for assisting in the operation of implant, such as a suitable source of disinfectant / antiseptic agent, adhesive substances for fixing the implant, sterilised items, etc. The kit is usefu I for oral implantology, and for any other conditions requiring the application of the medicated solution according to the present invention.
The solutions realised according to the present invention sh ~w various advantages with respect to the compositions currently in use: the medicating solution is interiorised in the site of action in greater quantities and with less dispersion; the high contact surface between the solution and the tissue of the patient guarantees an increased transfer of the drug and a prolonged permanence in-situ of the composition: a more intense and protracted effect of the drug over time is thus obtained. While having the same therapeutic effect, this also allows the reduction of the dose of drug, reducing the risks of accumulation, of local irritations, or of systematic diffusion, and it also reduces the cast of the product. A further advantage is that in the compositions to which the invention refers, Tween 20 exerts its bioadhesive effect in sub-clinical doses, that is it does not itself produce any pharmacological effect on the patient; so from a pharmacological-toxicological point of view, these formulations are equivalent to the phosphonate solutions already approved and used in therapy.
The present invention is now illustrated by means of the following examples, the function of which is not limiting.
EXPERIMENTAL PART
The high bioadhesivity of the solutions to which the present invention refers was demonstrated by means of the TVS (Tensiometric Versus Skin) technique, which is based on the principle of permutability of tensiometry according to which, by using liquids with a known tensiometric value, unknown solids (substrata) may be characterised, and vice versa (cf. Bettero).
It is known that a system is by nature composed of a set of volume elements which coexist in conditions of thermodynamic stability. This stability depends on the microstructural lattice and on the surface free energy of the system. The surface free energy is a reflection of the inter- and intramolecular forces v~hich are generated inside the system itself. The extent of the imbalance of these forces depends on the nature, the number and the concentration of the volume elements, and on the microstructural arrangement that has been determined freely or on a technological basis. The surface free energy (ELS), its polar component (CP) and its dispersed component (CD) regulate the afFnity of a system for another system/substratum and the work of adhesion/bioadhesion.
Mefhodological approach The TVS methodological approach is based on the hanging drop and angle of contact methods, using test liquids and solids with a known tensiometric value. The hanging drop method allows measurement of the surface tension of a fluid system. The angle of contact method allows measurement of the polar and dispersed components of the system examined. When the surface tension and the angle of contact of the system examined are known, the tensiometric profile and the polar energy component of the system examined are determined with the Owens calculation method. Each system is characterised by a well defined tensiometric imprint (TVS index). The TVS
index expresses the surface characteristics of a system in an integrated way. The TVS
bioadhesivity index expresses the tensiometric affinity of a system for a substratum.
Resulfs The following tensiometric imprints were therefore determined:
(i) a commercially available bisphosphonate solution (phial: 100 mg of disodium clodronate in an aqueous solution of benzyl alcohol);
(ii) a dedicated titanium lamina, representative of the surface of an implant;
(iii) a representative biological test substratum (mean weighted value relative to skin in vivo, to explanted cutaneous tissue, to oral mucosa, and to femoral bone).
Figures 2a and 2b show the tensiometric imprints of clodronate and of the implant respectively; in figure 2c, the two imprints are shown superimposed on the imprint of the substratum (shown in grey).
The imbalance of the polar energy component (CP) and the meagre common overlapping area between the three imprints is indicative of a considerabt a difference of surFace properties (affinities) among the three systems.
There was then realised:
(iv) a solution according to the present invention, in which clodronate was modified by adding 0.125% of Tween 20 (clodronate-T20) Figures 3a and 3b compare the surFace free energies (ELS) of the modified clodronate (clodronate-T20) with those of clodronate available on the market.
With respect to figure 2c, the ELSICD/CP levels of clodronate were significanrtly reduced, increasing its tensiometric affinity for the substratum and for the implant (b ioadhesivity index).
These data show that the solution of clodronate-T20, produced according to the invention, is a balanced bifunctional system, having a substantially equivalent bioadhesion capacity with regard to two tissues (patient and implant) that are profoundly difFerent from each other from the point of view of their surFace characteristics. Thanks to its surface characteristics, the solution to which the invention refers is able to form a kind of uniform and stable "liquid bridge"
that is firmly and lastingly interposed between patient and implant. In further release tests, the invention compositions showed a greater intensity of efFect and a more prolonged release over time, with respect to the commercial formulations of bisphosphonate in the same dose.
The present invention coneems a bioadhesive medicated formulation, useful for applications in oral implantology, comprising one or more drugs belonging to the class of bisphosphonates, in association with one or more compounds chosen among polyoxyethylene sorbitan monolaurate and similar.
By the term "bioadhesive system" it is meant liquid a system in which the drug is uniformly distributed, dissolved in a solution, in the entire volume of the liquid present. Therefore in the present invention the drug does not form a distinct phase from the liquid carrier, as occurs for example in the case of suspensions, emulsions, microemulsions, mycellar or colloidal systems, liposomes, etc. Any bisphosphonate, that is a compound containing one or more free phosphoric groups, salified, esterified or complexed, and possessing pro-ossifying properties, can be advantageously used in the present invention. These drugs are known per se and are widely used in therapy; some examples are alendronate, ethydronate, clodronate, risedronate, pamidronate, neridronate, zoledronate, ibandronate, olpadronate. Among the bisphosphonates the diphosphonates are preferred, in particular clodronate and its disodic salt, currently used in therapy as a pro-ossifying agent, for example in the treatment of osteoporosis, tumoral osteolysis, etc.
In the solutions to which the invention refers, the bisphosphonate is contained in a concentration preferably between 1 and 20 mg/ml, or, more preferably, between and 15 mg/ml; however, the concentration may be increased or reduced beyond these limits if the condition of the patient require it.
Polyoxyethylene sorbitan monolaurate (commercially known by the name T'ween 20) is a non ionic surfactant; in the present invention it is used in a concentration of up to 0.5% by weight, with respect to the weight of the solution.
Preferably the concentration varies between 0.025% and 0.250%, more preferably between 0.05% and 0.125%; concentrations higher than 0.5% are not desired, because the system may exceed the critical mycellar concentration and form multiphasic structures: these structures considerably reduce the superFicial afFinity of the composition and are therefore not desired.
As an alternative to Tween 20, compounds of a similar class may be used. As well as bisphosphonates and Tween 20, the corr-~position to which the present invention refers may contain suitable quantities of other excipients such as preserving, viscosifying, anti-oxidising or stabilising agents, pH buffers, etc. Moreover, in the case of formulations intended for the oral cavity, taste correctors may be used 5 such as sweeteners, aromas, etc.
In addition to phosphonates, other adjuvant drugs for implantology may be present, for example disinfectants, immunosuppressive drugs, antibiotics, anti-inflammatory agents, analgesics, etc.
The solvent used is generally water or another biocompatible fluid that can be mixed with water. The solvent must be compatible with the site of application and must be able to dissolve the phosphonate a nd the Tween 20 present.
The invention also concerns a Process for preparing the above-mentioned bioadhesive solutions comprising the mixinrg in a suitable solvent of at least one bisphosphonate and of one or more compounds chosen between Tween 20 and similar. The compositions thus realised may be used advantageously in any circumstance where the topical administration of bisphosphonates is necessary, in particular in implantology. Application is made directly on the site that is to host the implant and/or in the area around it. 1-he compositions described herein are applied in oral osseointegrated implantology: they may be applied, for example, in the surgical and non surgical treatment of p~arodontopathies and of dermatological pathologies; they are useful in surgical operation in cervico-facial area in which the grafting of biocompatible materials is contemplated (such as prostheses o r implants, for example dental implants), and in surgical operations where osteosynthesis devices of any nature, type and material are to be used; the invention is particularly useful in the case of implants made of titanium and its alloys, osteoinductive and osteoconductive materials, biocompatible barriers for bone regeneration, suture threads of any type and material. Generally, the treatment contemplates the prior administration of suitable quantities of the medicated solution on the site where the implant is to be applied (e.g. dental socket); the implant too may even be wetted with the solution before application ;
the application of the implant is carried out according to the normal known surgica I
/ orthodontic techniques. It is also possible to administer or inject the solution after implantation, in the area of tissue corresponding to er next to the prosthesis; or a part of the solution may be applied before and a part after implantation.
An action mechanism proposed for the present invention is illustrated in figures 1 a, 1 b, 1 c; the figures schematically represents a dental socket already filled with the medicated solution (hatched area), into which the implant is inserted. Without wishing to be restrained by theory, it is believed that a high adhesivity of the solution with regard to both the patient and the implant is useful for increasing the efficacy ~ of the formulation: in fact, if there is a lack of affinity between the medicating solution and any one of the two systems (patient and/or implant), when the implant is introduced into the cavity, air pockets are created between the implant and the drug (fig. 1 b) or between the drug and the patient (fig. 1 a) which push part of the medicating solution towards the outside, expelling it from the site of action; the air pockets remain even once the implant is applied, limiting the contact surface between patient/drug/implant, and thus reducing the pro-ossifying activity of the drug around the implant, and in the end the stability of the implant itself. Instead, if the solution adheres in a balanced way to both surfaces (fig. 1 c), no air pockets are formed, and the entire cavity between the patient and the implant remains occupied by the medicating solution _ The invention therefore includes the use of a solution containing one or more bisphosphates and one or more compounds chosen from Tween 20 and similar, in the preparation of a medication useful in implantology to favour the good course of the implant operation, as well as the consolidation of the implant and ossification around it. Although preferably used in implantology, the present solution may also be advantageously used for all treatments that require the application of bisphosphonates, for superficial or transdermic action: examples of these conditions are osteoporosis, bone tumour, osteolysisr, hyperparathyroidism, etc.
A further object of the present invention is a kit of parts, comprising: (i) one or more dosage units of a solution of bisphosphonates and/or salts thereof, and (ii) one or more dosage units of polyoxyethylene sorbitan monolaurate and/or similar.
The dosage units (i) and (ii) are usually, but not exclusively, phials. Upon use, preferably, the solution of bisphosphonate is removed from the dosage unit (i) by means of e.g. a syringe, and is transferred into the dosage unit (ii) containing the polyoxyethylene sorbitan monolaurate. The bisphosphonates and the polyoxyethylene sorbitan monolaurate of the kit are dosed in such a way that, when mixed together, they obtain the medicated solution object of the invention, previously described. The thus integrated unit (ii), suitably shaken, is ready for application onto the patient.
The kit may optionally include further tools for assisting in the operation of implant, such as a suitable source of disinfectant / antiseptic agent, adhesive substances for fixing the implant, sterilised items, etc. The kit is usefu I for oral implantology, and for any other conditions requiring the application of the medicated solution according to the present invention.
The solutions realised according to the present invention sh ~w various advantages with respect to the compositions currently in use: the medicating solution is interiorised in the site of action in greater quantities and with less dispersion; the high contact surface between the solution and the tissue of the patient guarantees an increased transfer of the drug and a prolonged permanence in-situ of the composition: a more intense and protracted effect of the drug over time is thus obtained. While having the same therapeutic effect, this also allows the reduction of the dose of drug, reducing the risks of accumulation, of local irritations, or of systematic diffusion, and it also reduces the cast of the product. A further advantage is that in the compositions to which the invention refers, Tween 20 exerts its bioadhesive effect in sub-clinical doses, that is it does not itself produce any pharmacological effect on the patient; so from a pharmacological-toxicological point of view, these formulations are equivalent to the phosphonate solutions already approved and used in therapy.
The present invention is now illustrated by means of the following examples, the function of which is not limiting.
EXPERIMENTAL PART
The high bioadhesivity of the solutions to which the present invention refers was demonstrated by means of the TVS (Tensiometric Versus Skin) technique, which is based on the principle of permutability of tensiometry according to which, by using liquids with a known tensiometric value, unknown solids (substrata) may be characterised, and vice versa (cf. Bettero).
It is known that a system is by nature composed of a set of volume elements which coexist in conditions of thermodynamic stability. This stability depends on the microstructural lattice and on the surface free energy of the system. The surface free energy is a reflection of the inter- and intramolecular forces v~hich are generated inside the system itself. The extent of the imbalance of these forces depends on the nature, the number and the concentration of the volume elements, and on the microstructural arrangement that has been determined freely or on a technological basis. The surface free energy (ELS), its polar component (CP) and its dispersed component (CD) regulate the afFnity of a system for another system/substratum and the work of adhesion/bioadhesion.
Mefhodological approach The TVS methodological approach is based on the hanging drop and angle of contact methods, using test liquids and solids with a known tensiometric value. The hanging drop method allows measurement of the surface tension of a fluid system. The angle of contact method allows measurement of the polar and dispersed components of the system examined. When the surface tension and the angle of contact of the system examined are known, the tensiometric profile and the polar energy component of the system examined are determined with the Owens calculation method. Each system is characterised by a well defined tensiometric imprint (TVS index). The TVS
index expresses the surface characteristics of a system in an integrated way. The TVS
bioadhesivity index expresses the tensiometric affinity of a system for a substratum.
Resulfs The following tensiometric imprints were therefore determined:
(i) a commercially available bisphosphonate solution (phial: 100 mg of disodium clodronate in an aqueous solution of benzyl alcohol);
(ii) a dedicated titanium lamina, representative of the surface of an implant;
(iii) a representative biological test substratum (mean weighted value relative to skin in vivo, to explanted cutaneous tissue, to oral mucosa, and to femoral bone).
Figures 2a and 2b show the tensiometric imprints of clodronate and of the implant respectively; in figure 2c, the two imprints are shown superimposed on the imprint of the substratum (shown in grey).
The imbalance of the polar energy component (CP) and the meagre common overlapping area between the three imprints is indicative of a considerabt a difference of surFace properties (affinities) among the three systems.
There was then realised:
(iv) a solution according to the present invention, in which clodronate was modified by adding 0.125% of Tween 20 (clodronate-T20) Figures 3a and 3b compare the surFace free energies (ELS) of the modified clodronate (clodronate-T20) with those of clodronate available on the market.
With respect to figure 2c, the ELSICD/CP levels of clodronate were significanrtly reduced, increasing its tensiometric affinity for the substratum and for the implant (b ioadhesivity index).
These data show that the solution of clodronate-T20, produced according to the invention, is a balanced bifunctional system, having a substantially equivalent bioadhesion capacity with regard to two tissues (patient and implant) that are profoundly difFerent from each other from the point of view of their surFace characteristics. Thanks to its surface characteristics, the solution to which the invention refers is able to form a kind of uniform and stable "liquid bridge"
that is firmly and lastingly interposed between patient and implant. In further release tests, the invention compositions showed a greater intensity of efFect and a more prolonged release over time, with respect to the commercial formulations of bisphosphonate in the same dose.
Claims (20)
1. Bioadhesive medicated solution, comprising one or more drugs belonging to the class of bisphosphonates and/or salts thereof, in association with one or more compounds chosen among polyoxyethylene sorbitan monolaurate and similar.
2. Solution according to claim 1, wherein the polyoxyethylene sorbitan monolaurate or similar is present in concentrations by weight of up to 0.5%.
3. Solution according to claims 1-2, wherein the polyoxyethylene sorbitan monolaurate or similar is present in concentrations by weight between 0.025%
and 0.250%.
and 0.250%.
4. Solution according to claims 1-3, wherein the polyoxyethylene sorbitan monolaurate or similar is present in concentrations by weight between 0.05%
and 0.125%.
and 0.125%.
5. Solution according to claims 1-4, wherein the drug is chosen among alendronate, ethydronate, clodronate, risedronate, pamidronate, neridronate, zoledronate, ibandronate, olpadronate and salts thereof.
6. Solution according to claim 1-5, wherein the drug is present in a concentration between 1 and 20 mg/ml.
7. Solution according to claims 1-6, wherein the drug is present in a concentration between 5 and 15 mg/ml.
8. Process for preparing the solutions described in claim 1, characterised by mixing one or more drugs belonging to the class of bisphosphonates and/or salts thereof, one or more compounds chosen among polyoxyethylene sorbitan monolaurate and similar, with a solvent able to dissolve completely said bisphosphonates, and polyoxyethylene sorbitan monolaurate or similar.
9. Process according to claim 8, wherein the final solution obtained has a concentration of polyoxyethylene sorbitan monolaurate or similar up to 0.5% by weight with respect to the weight of the solution.
10. Process according to claims 8-9, wherein the final solution obtained has a concentration of polyoxyethylene sorbitan monolaurate or similar between 0.025 and 0.250% by weight with respect to the weight of the solution.
11. Process according to claims 8-10, wherein the final solution obtained has a concentration of polyoxyethylene sorbitan monolaurate or similar between 0.05 %
and 0.125% by weight with respect to the weight of the solution.
and 0.125% by weight with respect to the weight of the solution.
12. Process according to claims 8-11, wherein the drug is chosen among alendronate, ethydronate, clodronate, risedronate, pamidronate, neridronate, zoledronate, ibandronate, olpadronate and salts thereof.
13. Process according to claims 8-12, wherein the drug is used in a concentration between 1 mg/ml and 20 mg/ml
14. Process according to claims 8-13, wherein the drug is used in a concentration between 5mg/ml and 15 mg/ml.
15. Bioadhesive medicated solution, comprising one or more drugs belonging to the class of bisphosphonates and/or salts thereof, in association with one or more compounds chosen among polyoxyethylene sorbitan monolaurate and similar, for use in therapy.
16. Use of a bioadhesive medicated solution, comprising one or more drugs belonging to the class of bisphosphonates and/or salts thereof, in association with one or more compounds chosen among polyoxyethylene sorbitan monolaurate and similar, in the preparation of a drug useful for applications in oral implantology.
17. Use according to claim 16, for promoting ossification in the areas between the surface of the patient and the surface of the implant.
18. Use according to claim 16, for increasing the stability in-situ of an implant applied on the patient.
19. Use according to claim 16, for the consolidation of dental implants and dental prostheses.
20. Use of a bioadhesive medicated solution, comprising one or more drugs belonging to the class of bisphosphonates, in association with one or more compounds chosen among polyoxyethylene sorbitan monolaurate and similar, in the preparation of a drug having an activity of stimulating bone growth in oral districts of the body.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ITMI2004A000641 | 2004-03-31 | ||
ITMI20040641 ITMI20040641A1 (en) | 2004-03-31 | 2004-03-31 | BIFUNCTIONAL BIOADHESIVE COMPOSITIONS FOR ORAL IMPLANTOLOGY |
PCT/EP2005/051440 WO2005094784A2 (en) | 2004-03-31 | 2005-03-30 | Bifunctional bioadhesive compositions for oral implantology |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2561728A1 true CA2561728A1 (en) | 2005-10-13 |
Family
ID=35064438
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002561728A Abandoned CA2561728A1 (en) | 2004-03-31 | 2005-03-30 | Bifunctional bioadhesive compositions for oral implantology |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1773291A2 (en) |
BR (1) | BRPI0508805A (en) |
CA (1) | CA2561728A1 (en) |
IT (1) | ITMI20040641A1 (en) |
WO (1) | WO2005094784A2 (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8940320B2 (en) | 2005-10-27 | 2015-01-27 | Thommen Medical Ag | Dental implant and production method for said implant |
JP5424642B2 (en) * | 2005-10-27 | 2014-02-26 | ニクリス アーゲー | Implant and manufacturing method thereof |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5403829A (en) * | 1993-03-24 | 1995-04-04 | Leiras Oy | Use of bisphosphonates in endo-osteal bone surgery |
US6572874B1 (en) * | 1998-05-15 | 2003-06-03 | Umd, Inc. | Vaginal delivery of bisphosphonates |
AUPQ232599A0 (en) * | 1999-08-19 | 1999-09-09 | Royal Alexandra Hospital For Children, The | Drug for treating fractures |
-
2004
- 2004-03-31 IT ITMI20040641 patent/ITMI20040641A1/en unknown
-
2005
- 2005-03-30 BR BRPI0508805-4A patent/BRPI0508805A/en not_active IP Right Cessation
- 2005-03-30 WO PCT/EP2005/051440 patent/WO2005094784A2/en not_active Application Discontinuation
- 2005-03-30 CA CA002561728A patent/CA2561728A1/en not_active Abandoned
- 2005-03-30 EP EP05729467A patent/EP1773291A2/en not_active Withdrawn
Also Published As
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BRPI0508805A (en) | 2007-08-07 |
WO2005094784A3 (en) | 2006-05-11 |
EP1773291A2 (en) | 2007-04-18 |
WO2005094784A2 (en) | 2005-10-13 |
ITMI20040641A1 (en) | 2004-06-30 |
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