WO2006006054A1

WO2006006054A1 - Method for preparing a polymeric biocompatible system for the pharmacological release by topic use and use of said system

Info

Publication number: WO2006006054A1
Application number: PCT/IB2005/001918
Authority: WO
Inventors: Marcella Trombetta; Paola Romagnoli; Silvia Licoccia
Original assignee: Universita' Degli Studi Di Roma 'tor Vergata'; Universita' Campus Bio-Medico Di Roma
Priority date: 2004-07-09
Filing date: 2005-07-06
Publication date: 2006-01-19
Also published as: ITMI20041376A1

Abstract

The present invention relates to the preparation of composite hydrogels comprising one or more pharmacologically active substances, and their use through topical administration for the focussed release of said substances. In particular, said composite hydrogels can be used for topical use, for the release of drugs characterised by complex morphologies and by being an interface between different tissues.

Description

METHOD FOR PREPARING A POLYMERIC BIOCOMPATIBLE SYSTEM FOR THE PHARMACOLOGICAL RELEASE BY TOPIC USE AND USE OF SAID SYSTEM

s DESCRIPTION

The object of this invention is the preparation of composite hydrogels comprising one or more pharmacologically active substances, and the topically administered use of pharmacologically active substances for the controlled release of said pharmacologically active substances o In particular, these composite hydrogels could be used for drug delivery in morphologically complex targets, which require the use of materials able to fit them perfectly.

Therefore, these hydrogels can be applied in soft tissues, in bone/tissue, bone/prosthetic implants, soft tissue/prosthetic implant interfaces, bone locks, in s sinus- filling, and on damaged, painful fibrous tissues, thus ranging over several fields of clinical and surgical medicine.

Recent developments of medical science are increasingly focused on target therapy, i.e. tending as far as possible, to make the drug reach directly the district (organ, tissue, and so on) that is affected by the pathology to be treated. 0 Li other words, the systematic absorption of the drug is avoided as far as possible as such a form of administration fairly aspecific. When it is absorbed systemically, often a very low percentage of the active principle reaches the target; in order to be effective it therefore has to be administered in high doses with the result of overloading the work of other 5 organs (e.g. the liver) often causing undesired and harmful side effects. Through in situ drug delivery, it is instead possible to treat the pathology on/in the affected organ directly, largely avoiding the drawbacks disclosed above. Starting from these considerations, in recent years, different drug delivery systems have been developed for oral, injectable and topical types of administration.

Polymeric materials are the materials most widely used as drug-delivery devices. These polymers mainly fall into two classes:

- non-biodegradable matrices; biodegradable matrices. The following currently commercially available systems can be cited by way of example: bone cements - they are mainly intended to stabilise a prosthesis system, membranes - which are dividable into: removable devices intended for exocutaneous applications (for example patches) or internal applications (for the treatment of brain tumours, or as implantable contraceptives) for example, or

- permanent devices, intended for internal applications (for example, coronary stents releasing restenosis inhibitors).

The following systems belonging to the latter class that are currently on the market can be illustrated as examples:

- microspheres - they are intended for taking drugs through inhalation (for example in the treatment of persistent asthma, of rhinitis, of diabetes' therapy) or for in situ delivery (e.g. the treatment of tumours of the prostrate). Many of these systems have the drawback of not being perfectly adapted to the morphology of the guest site or, if this is possible, of staying there permanently

(as, for example in the case of bone cement).

An example of a cavity that is particularly delicate is the dental socket inasmuch as it consists of hard and soft highly vascularised tissue, the morphology of which is characteristic of each patient.

Since 1995, several biodegradable polymeric systems have been developed, with the purpose of providing not only temporary drug delivery systems, but systems that are universally adaptable to the human body.

The main polymers, or polymeric systems that have been used commercially are: polyesters: polylactic acid (PLA), polyglycol acid (PGA) and their copolymers, for example polylactic-co-glycolic acid (PLGA);

- polyanhydrides: 1,3 -bis-(p- carboxyphenol)propane, sebacic acid;

- pseudo-polyamino acids: aminocarbonate, urethane, carbonates; - polyphosphoresters : a recent class of polymers that have a single main chain consisting of phosphorus atoms bonded to each carbon or hydrogen atom in the chain;

- polysaccharides: hydroxypropyl methylcellulose (HPMC);

- polysiloxane and other polymers. Although many of them have had a certain success in the surgical field, their biodegradability has proved to be a drawback in some ways. The main drawbacks that occurred during their clinical application were, for example, the following:

- uneven distribution of the drug in the polymer; - an excess of unloaded polymer. An example is the PLA or PLA-PLGA-based carrier system for the intake of insulin through inhalation.

The hormone is released in the lungs following the erosion of the microspheres of said polymers containing the drug. It has been shown that only 20% of the inhaled microspheres contain the active principle. A large quantity of empty polymer is thus deposited on the respiratory organ with the inevitable occurrence of restrictive pathologies harming the lungs.

The search for biocompatible polymeric substances that are able to absorb a drug and then release it in a controlled and focussed manner has also involved the study of ceramic products such as hydrotalcites, and more recently, the study of polymeric hydrogels belonging to the class of polysaccharides such as the aforementioned hydroxypropylmethylcellulose (HPMC).

These products have nevertheless mainly been used in the preparation of pharmaceutical formulas for oral use, i.e. for systemic non-topical use. These systems have been formulated for oral use and are able to release the active principle only if there is very acid pH in the stomach.

The unresolved problem remains of being able to have a system that is suitable for releasing a drug topically, in which said system is completely biocompatible, able to release the active principle at physiological pH values (about 7,4) and is above all morphologically versatile, i.e. fully adaptable to the place of application.

This latter aspect is of fundamental importance when the release system has to be applied internally.

The applicants have adequately addressed this problem by devising a series of composite polymeric hydrogels comprising suitable pharmacologically active substances reversibly entangled in a hydrophilic polymeric matrix. The hydrogels of the present invention are polymeric materials that are able to absorb water that is more than 20% of their own weight, whilst maintaining their own 3D (three-dimensional) structure. Water absorption results in swelling of the system.

This property has proved to be extraordinarily useful for the controlled release of pharmacologically active substances that are preferably soluble in water contained in the cross-linked matrix. The starting product used to synthesise said hydrophilic cross-linked polymeric matrix specified above can be chosen from hydrophilic oxygenated polymers that can gel in water.

Of these, polyethylene oxide (commonly referred to as PEO, which is the abbreviation which will be used from now on, also in the claims) is particularly preferred. The term PEO indicates a family of hydrosoluble, oxygenated, linear resin polymers characterised by the repetition unit CH₂-CH₂-O- and having a variable molecular weight. For example, PEOs are known commercially that are characterised by average molecular weight comprised between 600 and 10⁷. PEO has also been approved by different public health authorities and by the U.S. Food and Drug Administration for food and clinical use. Its absolute biocompatibility and biodegradability have thus been recognised and certified. Solid matrices (pills) for oral administration and also intraocular solid PEO- based inserts are known (i.e. in the form of a simple .polymer, not in the form of a hydrogel cross-linked with water) for the controlled release of drugs. Normally, said matrices/inserts are prepared by mixing suitable quantities of PEO and drug in a suitable solid phase (if necessary by diluting powders with alcohol and then evaporating the solvent) and then subjecting the mixture of powders to compression to obtain the desired oral solid or intraocular formulation. The PEO matrix is biodegraded upon contact with the fluids of the organism, thereby releasing the drug.

At present, however, no topical applications of composite polymeric hydrogels of the class of oxygenated hydrophilic polymers able to gel in water, such as those belonging to the PEO family, are known. In particular, the use of these PEO hydrogels for topical drug delivery in soft tissues, in bone/tissue, bone/prosthetic implant, soft tissue/prosthetic implant interfaces, bone locks, in sinus-filling and on damaged, painful fibrous tissues is not known. The present invention now enables the preparation of composite PEO-based hydrogels containing one or more pharmacologically active substances to be employed for the topical release of said drugs in the situations disclosed above. In this invention the synthesis of PEO-based composite hydrogels is mostly achieved using apyrogenous water, without the need to use any other organic or inorganic solvent. Moreover, PEOs with different molecular weight can be used, depending on the consistency, appearance and application use of the desired final product. Depending on the molecular weight of the specific PEO used, it is possible to synthesise gelled systems with different consistency, density and viscosity (density d varying from 1.100 to 1.140 g/cm³), with various and controlled stiffness, stability and/or biodegradibility, softness, flexibility, transparency, and so on..

For the purposes of this invention, a wide range of PEOs with a various molecular weight can be used depending on the desired final application of the produced composite hydrogel. For example, PEOs with average molecular weight M_v from 600 to 5 000 000 can be used.

Preferably, PEOs having an M_v between 1 000 000 and 3 000 000 are used and even more preferably PEOs having an M_v between of approximately 2 000 000 are used, The drug is added during the phase of hydrogel synthesis preferably in a water solution (or possibly in a water suspension). If it is available in powder it is first dissolved or suspended in apyrogenous water and is then added during the phase of synthesis of the hydrogel by continuous stirring in order to ensure maximum dispersal. The quantity of water used to solubilise or suspend the drug is calculated in the total calculation of the solvent used as it is the ratio of polymer to the total quantity of water used that gives the desired product its final density and consistency.

The entire preparation of the composite hydrogels of the present invention comprising at least a pharmacologically active substance is preferably conducted in conditions of absolute sterility so as to supply a completely sterile final product that is ready to be packaged, preserved or used.

Before synthesis, both the oxygenated hydrophilic polymer and the instruments to be used are sterilised in an autoclave following the standard protocol used in molecular biology (water steam; T=121 °C; P=I Arm; t^O min). Everything is then dried in a dry oven at 60 °C for 12h, taking the appropriate care and using the markers required to maintain and check the sterility thereof. In a sterile environment and through stirring, apyrogenous sterile water is added to the sterilised polymer (possibly DNA-fi-ee, i.e. also free from traces of DNA of polluting organisms, according to the site for which it intended), in various PEO : H₂O ratios in weight, depending on the desired consistency for the final product.

Normally, the PEO_. : H₂O ratio can vary from 1:1 to 1:10 in weight, more preferably from 1 :2 to 1 :5 in weight. As indicated previously, the quantity of water used to solubilise or suspend the drug or drugs has to be calculated in the total calculation of the aforementioned polymer: solvent ratio.

Therefore, depending on the type of hydrogel, the water solvent is added to the PEO in aliquots that vary according to the quantity of water used to dissolve or suspend the drug or drugs to be incorporated in the gel.

The preparation procedure of the composite hydrogels for topical application of the present invention (comprising at least a pharmacologically active substance incorporated in a hydrophilic cross-linked polymeric matrix based on an oxygenated hydrosoluble polymer) is preferably conducted at ambient temperature and substantially comprises the following phases: a) mixing said oxygenated hydrosoluble polymer that has preferably been previously sterilised as disclosed above with water until a semi-solid, i.e. fluid-dense paste is obtained; b) adding by stirring the drug, or of the drugs in a water solution or suspension; c) further adding of water until cross-linking of the polymeric matrix is completed and the desired consistency is obtained.

In one of the preferred applications, said oxygenated hydrosoluble polymer is selected from the PEOs, as disclosed above. To ensure optimal dispersion of the drug(s) inside the polymeric matrix the addition specified in b) is preferably made in portions preferably through continuous stirring.

According to the second type of drug(s) to be incorporated in the PEO after the addition of each aliquot the mixture is stirred for a suitable period of time. Normally, after each addition, the mixture is stirred mechanically for a period of time comprised between Ih and 5h, or even more depending on the quantity and the concentration of the drug to be dispersed.

Step c) is also carried out by stirring: the addition of water is used to complete cross-linking between the linear molecules of the original polymer and to reach the desired consistency.

After adding the last aliquot of solvent, the system is stirred for a further 24h -

48h, even up to 72 h, according to the degree of cross-linking (and therefore of gel features) that it is desired to obtain.

When oxygenated hydrophilic linear polymers such as, preferably, PEOs come into contact with the water, forces of attraction between the polymer and the water come into play with the formation of intra- and inter- hydrogen bridge bonds.

Said bonds give rise to a structure that is stable according to the molecular weight of the polymer and the number of hydrogen bonds that form with water, i.e. the quantity of water that bonds with the polymer. The cross-linked matrix that is formed swells and can incorporate or coordinate within itself other water and/or pharmacologically active molecules. In particular, the polarity of the PEO ensures coordination with a wide series of polar pharmacologically active molecules through the formation of weak intermolecular bonds, substantially of the electrostatic and therefore reversible type.

The quantity of water required to complete cross-linking is determined on a case-by-case basis, according to the type of PEO used (i.e. according to its molecular weight) and according to the consistency of the finished product that it is wished to prepare.

As a general rule, PEOs having higher molecular weight display greater swelling in water than the corresponding PEOs having lighter molecular weight, thus enabling the synthesis of denser and more viscous hydrogels that are more slowly biodegradable and therefore more resistant. At the end of the gelling phase specified in phase c) above, the sterile cross- linked composite hydrogel containing the desired drug(s) is ready for topical application.

It is then transferred to a sterile vacutainer or to another suitable sealed sterile package or kit to be stored before use or delivery to the place of application. As mentioned previously, the process of the present invention is preferably conducted at ambient temperature; nevertheless, the possibility of also using temperatures above 25 ⁰C is not absolutely excluded (preferably between 25 and 60⁰C), according to the thermal stability of the drug to be inserted into the polymeric matrix. In such a case, the elimination of the excess water integrated into the matrix but not chemically bonded by hydrogen-bridge bonds to the polymer chains is promoted.

The PEO is shown to be particularly stable in conditions of preliminary sterilisation in adopted autoclaves. By means of Fourier transform infrared spectroscopy (FT-IR), with the use of an attenuated total reflection cell (ATR/FTIR cell) it has been, in fact, possible to evaluate the integrity of the polymer after the aforementioned sterilisation process.

Attached Figure 1 shows the ATR/FTIR spectra recorded on a sample of pure PEO, with Mv 2 000 000 before (Fig. Ia) and after (Fig. Ib) sterilisation.

The spectra are virtually identical, and are virtually superimposable.

Both have the same number of bands at the same frequencies and have perfectly comparable intensity.

In the 1700-1600 cm^'1 region, absorption due to stretching of the carbonyl group is completely absent, which group typically forms following oxidation of the

PEO.

It is thus shown how this sterilisation process does not alter the structure of the polymer matrix in any way.

It can also be observed how drying at 60 °C of the sterilised matrix enables physiologically absorbed water to be completely eliminated, thus ensuring that it is possible to control the polymer: solvent ratio exactly and constantly in the subsequent cross-linking phase.

Analyses of the ATR/FT-IR characterisation conducted on samples of composite gel comprising the drug have enabled the formation of the coordination link between the functional groups of the drug and the polymer chain to be identified.

In fact, attached figure 2 shows the signals of the ATR/FT-IR spectra obtained by removing the spectrum of the hydrogel system without drugs (i.e. PEO + H₂O) from those containing respectively the active principles neridronate (Fig. 2a) and mesna (Fig. 2b), both synthesised according to the method of the present invention, in which the PEO used has the molecular weight M_v 2 000 000. The spectra in Figure 2 thus show the characteristic bands of the pharmacologically active molecule interacting with the polymer-solvent system. From these spectra it is evident that the polar bonds in the drug functional groups are perturbed by the interaction with the PEO chains.

In fact, in the region of the stretching of the OH oxydryl groups (i.e. in the 4000- 2600 cm^'1 region), in both cases positive and negative peaks can be observed. The first correspond to the formation of new hydrogen bonds between the polymer and the drug, the second correspond to the disappearance of the preceding PEO-water bonds inasmuch as they are replaced by the new PEO- drug interactions.

The position of the new oxydryl differs according to the elements involved in the formation of said bonds and therefore in their chemical formula. Moreover, in the 1800-900 cm^"1 region, absorption characteristic both of the perturbation of the PEO chains due to interaction with the drugs, and absorption typical of the IR (infrared) active bonds present in the drug molecules, are evident, for example at 1185 cm^"1 the mesna functional group -SO₃ ^" is shown). Figure 2 thus represents the confirmation of direct coordination of the drug with the PEO polymer and not with its hydration envelope. The polymeric composite hydrogels of the present invention are particularly advantageous for both internal and external topical applications.

In this invention, internal use is particularly favoured.

The composite PEO-based hydrogels of the present invention have numerous advantages. For example, the original PEO polymers are commercial products that are therefore characterised by their easy availability and low price.

They are, moreover, well-known for being completely atoxic and are approved by the main international health administrations for food and/or drug applications. The mechanical features of ductility and elasticity of the products of the invention, unlike the pharmacological release systems that are currently commercially available, enable them to adapt perfectly to any cavity regardless of its morphology, even if open blood vessels are present (for example in the case of gum cavities that are open after an extraction), Other substantial advantages of the controlled-release composite polymeric matrix of the present invention can be identified in the atoxicity and sterility of the product and in the fact that the compound is supplied already ready for use in a sealed sterile package.

In this context, one of the preferred aspects of the present invention relates to a kit comprising a number of sterile, sealed ready-to-use containers possibly containing different quantities of at least composite polymeric hydrogel and possibly comprising different doses of a drug or a mixture of drugs to be administered topically in such a way as to be able to respond appropriately to the different needs of the patients. The composite hydrogels of the present invention thus have the peculiarity of being directly applicable as such by the user without any need, as on the other hand occurs with many other pharmacological release polymeric systems currently in use in clinical practice, to have to make it up in situ, simultaneously with the intervention. All the problems arising from the variability of the mixture/solvent ratio and from the wait time between preparation and use are thus avoided that for many heat-hardening products is lethal.

An explicative comparison can, for example, be made with the so-called bone cements (polymethylacrilate-based polymers PMMA) that are prepared in the operating theatre at the moment of use. The preparation reaction of the bone cement is strongly exothermal, so if the surgeon applies the product too soon the bone may develop necrosis. On the other hand, if too much time elapses before the application, bubbles form and the prosthesis does not set in a stable manner. Above all, also the sterility of the implant risks being compromised. With the products of the present invention, the health worker finds himself or herself using a gel that has already been cross-linked and polymerised upstream without the need to carry out any manipulation. As the product is in a sterile, sealed and disposable package it will be sufficient to simply open the package and apply the product directly to the application site, adapting it to the morphology thereof.

In particular, owing to the use of a multidose multipurpose kit it will be possible to respond in a safe and versatile manner to various therapeutical and/or surgical needs.

The controlled release device of the present invention can be implemented using any molecule that is pharmacologically active in water or in the structure of which there are polar groups that are able to interact with the chosen matrix thereby giving a series of weak and eversible bonds.

Said bonds are easily broken when the polymeric matrix containing the drug, in contact with the humidity of the physiological environment in which it is applied, exchanges the drug with water and in this way releases the active molecule in situ.

Of the classes of drugs that are usable for preparing the PEO-based composite hydrogels of the present invention the following can be mentioned by way of non-limitative example of the invention and of its applicational potential: - chemotherapeutical osteoinductors: for example,^' biphosphonates such as pamidronate, alendronate, neridronate, zoledronic acid and ibadronate :

- mucolyctic sulphonamides: for example, mesna, ambroxol;

- other antibiotics: for example, amoxicillin, ampicillin, clavulonate;

- epithelialising proteins; - analgesics: for example lidocaine or ibuprofen.

As previously reported, the internal application of the composite hydrogels of the present invention, is preferred.

A particularly preferred example relates to the use of the composite hydrogels of the invention is in the field of dental implants. In fact, after tooth extraction, it is necessary to fill the dental sockets that have formed with anti-inflammatory drugs but also with drugs that inhibit bone reabsorption with the relative consequent thinning of the jaw. This process could compromise the possibility or the success of the subsequent implant.

In this case, the use of a PEO-based hydrogel having Mv 2 000 000 and comprising the mesna mucolyctic drug and bisphosphonate such as neridronate enables the occurrence of phenomena of reabsorption of the jawbone to be prevented in the part subjected to tooth extraction without any inflammatory phenomenon occurring.

Furthermore, the presence of neridronate after the implant had taken place enabled good adhesion and the corresponding bone take.

In another particularly preferred example the application of a PEO-based pharmacological release system having Mv 2 000 000 and containing the mesna mucolyctic agent in the treatment of post-surgical fibrosis on the vertebral column has provided positive results of optimal biocompatibility and a diminution of the phenomenon of cicatricial fibrosis in the tissue-bone interface. Another particularly interesting application relates to the treatment of corneal ulcers with epithethialising proteins in which a PEO-based semifluid hydrogel having M_v 2 000 000 and containing said epithelialising proteins has enabled the regenerating principles of the ulcer to be conveyed for 72h as opposed to the 12h of the effect obtained by direct installation, with high patient acceptability without any inflammatory event and without the known harmful side effects occurring that are typically connected with the prolonged use of eyewashes and PEO-based solid ocular inserts. Promising results were also obtained in ear, nose and throat applications by devising a PEO-based system having Mv 2000 000 and containing lidocaine anaesthetic analgesic.

Said system is applied locally to the site following a tonsillectomy in order to diminish the great pain that constitutes the main undesired effect if the operation is carried out on adult patients. Patients experienced a decrease in the degree and persistence of the pain. Other further favourable or at least promising results were also obtained in the following cases:

- hydrogel with neridronate: (PEO Mv 2 000 000) in dental implants in the jaw: high biocompatibility, no inflammatory and side effects, better bone take and take of the screw titanium implant in the bone;

- hydrogel with neridronate (PEO Mv 2 000 000) in bone locks: high biocompatibility, bone reabsorption inhibition, no inflammatory and side effects; hydrogel with neridronate (PEO Mv 2 000 000) in dental socket after dental extraction: drastic decrease of jawbone reabsorption;

- hydrogels containing mesna (PEO Mv 2 000 000) in vertebrectomy: high biocompatibility, no inflammatory and side effects; drastic decrease of fibroses in the cicatricial/vertebrae interface, decrease of pain due to the contraction of such fibroses that cause vertebral compression. ^" - hydrogel with epithelialising proteins (PEO Mv 2 000 000) for the treatment of corneal ulcers: high patient acceptability, without any inflammatory event and without the known harmful side effects occurring that are typically connected with the use of the systems commonly used in clinical practice. - hydrogels containing lidocaine (PEO Mv 2 000 000) after tonsillectomy: good biocompatibility, no inflammatory or side effects, drastic pain decrease.

Merely by way of non-limitative example the preparation of a composite hydrogel according to the present invention is disclosed below that contains about 0.5% neridronate by weight (compared with the weight of the final product).

3 g of PEO (having M_v 2 000 000) and the instrument to be used are sterilised in an autoclave, in accordance with the standard protocol used in molecular biology (water steam; T=121 °C; P=I Atm; t=20 min). Drying in a thermostatic oven at 60 ⁰C for 12h then occurs, using proper care and the markers required for monitoring and checking sterility.

2.0 ml of sterile, apyrogenous DNA-free water are added to 2000 mg of sterilized PEO₅ stirring for 5h to obtain a dense paste.

Then, stirring continuously, and at 5h intervals, two aliquots of 1.6 ml of water solution containing 21.6 mg of neridronate, are added (total drug amount 43.2 mg).

Finally, 0.8 ml of sterile apyrogenous water is added.

The system is mechanically stirred for a further 48h.

The composite sterile hydrogel, containing neridronate, is immediately packaged in a plastic sterile container, covered with aluminium and sealed to keep it sterile.

Claims

1. A method for preparing hydrogels for topical applications, comprising at least a pharmacologically active substance incorporated in a cross-linked hydrophilic polymeric matrix based on an oxygenated hydrosoluble polymer comprising the folio-wing steps: a) mixing said oxygenated hydrosoluble polymer with water until a dense paste is obtained; b) adding, whilst stirring, a water solution or suspension of said at least a pharmacologically active substance; c) further adding, whilst stirring, of water until complete cross-linking of the polymeric matrix and obtaining of the desired consistency.

2. Method according to claim 1, wherein oxygenated hydrosoluble polymer is selected from PEOs.

3. Method according to claim 2, wherein said PEO has a molecular weight varying between 600 and 5 000 000, preferably between 1 000 000 and 3

000 000, more preferably about 2 000 000.

4. Method according to claim 2, wherein the weighted ratio PEO : H₂O varies between 1:1 and 1:10 in weight, preferably from 1:2 to 1:5 in weight.

5. Method according to any one of claims 2 to 4, wherein said PEO is sterilised before use.

6. Method according to claim 1, wherein said water is sterile and apyrogenous.

7. Method according to claim 6, wherein said water is DNA-free.

8. Method according to claim 1, wherein said at least one pharmacologically active substance is a polar substance that is able to be coordinated with said cross-linked matrix by means of reversible, weak intermolecular bonds.

9. Method according to claim 8, wherein said pharmacologically active substance is hydrosoluble.

10. Method according to claims 8 and 9, wherein said pharmacologically active substance is selected from: chemotherapeutical osteoinductors such as the bisphosphonates pamidronate, alendronate, neridronate, zoledronic acid and ibadronate; other mucolvctic substances: for example mesna, ambroxol; antibiotics: for example amoxicillin, ampicillin, clavulonate; epithelialising proteins; analgesics: for example lidocaine or ibuprofen.

11. Method according to claim 1, wherein said cross-linking of said polymeric matrix occurs by the formation of intra and inter-chain hydrogen bridge bonds between said oxygenated hydrosoluble polymer and the water molecules.

12. Method according to any one of claims 1 to 11, wherein the device is sterilised before use and the entire product is placed in conditions of absolute sterility to make a final product that is perfectly sterile and ready for use.

13. Method according to claim 1, wherein addition specified in step b) is carried out in portions; after the addition of each portion, the mixture is stirred for a period comprised between Ih and 5h.

14. Method according to claim 1 , wherein, at the end of said adding of water specified in step c), the mixture is stirred for a further 24-48h.

15. Method according to claim 14, wherein said stirring is continued for up to 72h.

16. Use of a composite hydrogel according to any one of claims 1 to 15, for prepararing a pharmaceutical composition for the focussed release of pharmacologically active substances to be administered topically.

17. Use according to claim 16, for external use.

18. Use according to claim 16, for internal administration.

19. Use according to claim 16, for topical application on morphologically complex target that require the use of materials that are able to adapt to the shape of application site.

20. Use according to claim 19, for topical application to the soft tissues in bone/tissue, bone/prosthetic implants, soft tissue/prosthetic implant, bone locks, in sinus-filling, and on damaged, painful fibrous tissues.

21. Use according to claim 19, for topical application to any cavity, even in the presence of open blood tissues.

22. Use according to claim 21, for topical application to dental sockets in the jaw after tooth extraction.

23. Use according to claim 21, for topical application in the field of jaw dental implants.

24. Use according to claim 19, for topical application in vertebrectomy.

25. Use according to claim 20, for topical application in the field of bone locks.

26. Use according to claim 20, for topical application in the field of fibrous tissues.

27. Use according to claim 20, for topical application in the field of corneal ulcers.

28. Use according to claim 16, for topical application in the field of ear, nose and throat medicine.

29. Use according to claim 16, wherein said pharmacologically active substances are selected from between:

- chemotherapeutical osetoinductors such as the biphosphonates such as pamidronate, alendronate, neridronate, zoledronic acid, ibadronate - mucolyctic sulphonamides: for example mesna, ambroxol; antibiotics: for example amoxicillin, ampicillin, clavulonate; epithelialising proteins;

- analgesics: for example lidocaine or ibuprofen.

30. Kit comprising a number of sterile, sealed ready-to-use packages containing at least a composite hydrogel according to any one of claims

1 to 15.

31. Kit according to claim 30, wherein said sealed sterile packages contain different quantities of at least said one composite hydrogel.

32. Kit according to claim 30-31, wherein said composite hydrogel comprises various quantities and concentrations of pharmacologically active substance.

33. Use of the kit according to claims 30-32, for the topical administration of said composite hydrogel.