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

Definitions

• the present invention falls within the field of topical pharmaceutical compositions for applications in oral implantology.
• 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.
• the release and absorption of the drug may be insufficient: a possible cause of this problem is the low bioadhesivity of the formula.
• 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.
• the two surfaces that come in contact must be as far as possible similar to each other from the point 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.
• 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.
• compositions for example antibiotic pastes
• 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.
• 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.
• 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.
• compositions with a degree of bioadhesion equally shared between the two surfaces, that is on one side towards the patient and on the other towards the implant allow a real increase in the efficacy of the drug.
• the 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 Tween 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 1a, 1b, 1c action mechanism proposed for the present invention
• Figure 2a tensiometric imprints of clodronate
• Figure 2b tensiometric imprint of implant
• Figure 2c superimposition of imprints
• Figure 3a and 3b surface free energies (ELS) of the modified clodronate and of clodronate .
• ELS surface free energies
• the present invention concerns 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.
• bioadhesive system 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 phosphonic 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, olpadro ⁇ ate.
• 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.
• the bisphosphonate is contained in a concentration preferably between 1 and 20 mg/ml, or, more preferably, between 5 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 Tween 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.
• 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.
• Tween 20 compounds of a similar class may be used.
• the composition 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.
• taste correctors may be used such as sweeteners, aromas, etc.
• phosphonates In addition to phosphonates, other adjirvant drugs for implantology may be present, for example disinfectants, immunosuppressive drugs, antibiotics, ant ⁇ - 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 mixing 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.
• 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 or 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.
• 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 surgical / orthodontic techniques. It is also possible to administer or inject the solution after implantation, in the area of tissue corresponding to or 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 1a, 1b, 1c; the figures schematically represents a dental socket already filled with the medicated solution (hatched area), into which the implant is inserted.
• 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 poclcets are created between the implant and the drug (fig. 1b) or between the drug and the patient (fig.
• 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.
• a solution containing one or more bisphosphates and one or more compounds chosen from Tween 20 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.
• 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, osteolysis, 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.
• 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 show 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 cost of the product.
• 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.
• 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 affinity of a system for another system/substratum and the work of adhesion/bioadhesion.
• 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.
• 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 considerabl e difference of surface properties (affinities) among the three systems.
• FIGs 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 ELS/CD/CP levels of clodronate were significantly reduced, increasing its tensiometric affinity for the substratum and for the implant (b ioadhesivity index).
• ELS surface free energies

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• 2004
  • 2004-03-31 IT ITMI20040641 patent/ITMI20040641A1/it unknown
• 2005
  • 2005-03-30 BR BRPI0508805-4A patent/BRPI0508805A/pt 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

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