ITFI20140116A1 - COMPOSITION FOR DENTAL USE FOR THE TREATMENT OF PARADONTAL POCKETS - Google Patents

Description

TITLE

COMPOSITION FOR DENTAL USE FOR THE

TREATMENT OF PERIODONTAL POCKETS

DESCRIPTION

Scope of the invention

The present invention relates to a composition for dental use for the treatment of pathologies of the oral cavity, in particular of periodontal pockets, i.e. those inflammatory processes of bacterial origin that occur in the bone tissue surrounding the collar and the dental root.

Description of the prior art

The inflammatory phenomena that occur in correspondence of the gingival sulcus involve the deep soft tissues and the periodontal bone, with a loss of supporting alveolar bone.

In the etiology of inflammation of periodontal tissues, the accumulation of bacteria in the gingival sulcus plays an important role and tends to deepen becoming a periodontal pocket. This microbial ecology, which is found in the deep areas inside a periodontal pocket? very different from that present in the oral cavity in that? characterized by obligate and facultative Gram negative anaerobic bacteria such as Bacteroidaceae, Actinobacillus Actninomycetemcomitans and Spirochete. Consequently, the suppression of these bacteria? essential to obtain the resolution of the pathology.

The elimination of these bacterial deposits on the root surface does not? in any case easy. Normally, these deposits can be removed mechanically (debritement), albeit to increase the effect of debritement? the additional use of antimicrobial substances is advisable, in particular local antimicrobial products that release high doses of antibiotic in the site affected by the disease for several days.

Attempts at therapy include the use of antibiotic and anti-inflammatory drugs, as well as the possible revision of surgical curettage of the affected area. Furthermore, sterilizing therapy can be successfully used through the use of lasers possibly associated with the use of Chlorhexidine.

These treatments involve the use of suitable instruments (curettes) possibly associated with the application of local antiseptics such as chlorhexidine digluconate for 3 or 4 weeks, systemic antibiotic therapy with ornidazole (2 x 500 mg / day for ten days) or amoxicillin clavulanic acid (2 gr / day for ten days), topical antibiotic therapy with Slow Release Devices systems such as tetracycline fibers or metronidazole gel. In the most cases? serious can you? arrive at the use of regenerative techniques of the lost bone tissue with the use of membrane with or without grafts.

Several factors prevent therapeutic agents from spreading when applied to superficial periodontal tissues. Anatomically, the gingival tissue adheres to the collar of the teeth, mechanically limiting the path of diffusion of the substances present in the mouth. Furthermore, a gingival fluid, which has a plasma-like composition, permeates the periodontal environment and is continuously produced by diseased periodontal tissues at a rate of 10 to 100 microliters per hour. This fluid, coming from the lining of the pocket, creates a net outward flow, which further hinders the introduction of drugs from substances applied superficially from the outside.

These factors are sufficient to isolate the pouch environment to the point where saliva fails to penetrate, and locally applied medicinal agents have been largely ineffective in the treatment of advanced periodontitis. Although mouthwashes may be effective in reducing superficial gingivitis due to poor oral hygiene, the effective range of these agents does not extend to the periodontal pocket.

Introduction of antibacterial agents into the periodontal pocket? result ineffective due to their rapid removal due to the rapid flow of crevicular liquid from the same, thus reducing? to a minimum the duration of contact in the area where it must act.

Conventional therapy for periodontal disease involves the mechanical removal of bacterial plaque at periodic intervals. This operation normally involves intervening through periodontal surgery to directly access the pocket and to remodel the damaged tissues. These procedures require a high degree of technical expertise from art professionals, are expensive, and often result in pain, extensive bleeding, and local discomfort in general. Since? these procedures provide, at best, only a temporary reduction of bacterial populations, they must be repeated at regular intervals to be effective.

Methods of drug administration for periodontal therapy have hitherto been largely directed towards superficial application. For example: - Long-acting tablets to keep in the mouth (US 3,911,099);

- Buccal implants for delivering drugs into saliva (US 4,020,558);

- Topically applied gels (US 3,679,360);

- Topical use of bandages containing topically applied drugs (US 3,339,546);

- A hardening plastic mass containing drugs (US 3,964,164);

- A periodontal dressing (US 3,219,527);

- A topical dressing composed of a finely divided particulate vector and suspended medicinal agents (US 3,698,392);

- A bandage to cover mucous surfaces (US 3,339,546); - A microencapsulated liquid for topical applications in animals (US 4,329,333);

- Drug-containing film forming foam devices (US 3,844,286).

In addition, various fibrous forms for superficial drugs have been described, including: - Impregnated dental floss for drug delivery (US Pat numbers 3.417.179, 2.667.443,

2,748,781, 3,942,539. );

- Resorbable solid fibers of polyglycolic acid with incorporated medicaments (US 3,991,766);

- And hollow cellulose acetate fibers (US 4,175,326).

Systemic antibiotic therapies have also been used for periodontal infections. In this case, the goal was to eliminate or suppress any growth of specific pathogenic species. Systemic administration of antibiotics begins with the selection of the appropriate antibiotic for the antibacterial spectrum. Thus, for example, penicillin could be administered to eliminate anaerobic gram-positive infections, metranidazole to eliminate gram-negative anaerobic infections, and tetracycline to eliminate actinobacillus infections. Actually, they come like this. eliminated specific organisms sensitive to relatively low concentrations of antibiotic reached by these types of therapy (approx. 2-10 ug / ml).

Due to the low antibiotic concentrations achieved with systemic administration and the relatively high levels of bacterial resistance associated with periodontal pathogens, the clinical success of this therapy? was scarce, as discussed by Genco in "Antibiotics in the treatment of human periodontal diseases", in G. Periodontology, vol. 52, pages 545-558 (1981). Therefore, it appears that none of the previously described procedures have led to an acceptable system for the optimal delivery of effective levels of antibacterial substances at the site where one? established periodontal disease.

EP0404558 discloses the use of a device for administering a therapeutic agent to be positioned inside the periodontal pocket in such a way that the diseased pocket regions come into intimate contact with it. The active agent is then released into the diseased site, eliminating the variability. which was linked to the long diffusion path associated with superficial or systemic treatments. The composition features a liquid methacrylic polymer, a therapeutic agent and a release regulating agent. The polymer retains the therapeutic agent, and the release regulating agent progressively dissolves the polymer so that the therapeutic agent is released slowly. However, due to the presence of the release of the regulating agent, the biocompatibility? can be reduced, especially in the presence of bone wounds, so? how allergic problems can arise. Also, the addition of an adhesive agent? suggested, since? the polymer film can not? adhere to the surface to be treated. Polyethylene glycols or dibutyl phthalate are the preferred plasticizers; such agents play a role in improving the speed? of degradation of the film and to improve adhesion.

A further limitation? that the release of the therapeutic agent can? last no more? a few hours. Furthermore, the release of optimal concentrations of any medicinal agent within the periodontal pocket appears not to have been anticipated. The liquid methacrylic polymer used?: Alcoholic solution of Eudragit RL with Eudispert as a release regulating agent; Eudragit RS RL in 1/1 ratio with Eudispert as a release regulating agent. Other release regulating agents are cross-liking agents (such as glutaraldehyde, citric acid, lysine, aspartic acid, glutaric acid), polysaccharides (such as dextran), lipids (such as docusate sodium), polyhydroxycompound (such as PEG, glycerol, propylene glycol ), proteins (such as Byco E or Byco C).

A similar approach? described in DE4125048, where Eudragit forms a water-soluble polymer film. In this way, a controlled release of a therapeutic agent? obtained by dissolution of the film in saliva. However, this mechanism does not allow for a release of the therapeutic agent in short periods such as a couple of hours. Other solutions similar to this problem are described in:

- EP 140.766, wherein a polymeric matrix, such as ethylene-vinyl acetate copolymer and other copolymers or fibers, which is semi-permeable to a therapeutic agent. The copolymer is placed in the periodontal pocket and then removed after a certain time, during which time the therapeutic agent? been released. This system has the drawback that the polymer matrix? semi permeable and not completely permeable. Furthermore, the polymer matrix must be removed after a certain time, and what about it? requires further intervention by the dentist;

- US A3925895 discloses a methacrylate polymer used to fill root canals in which a drug can be used. be incorporated; - A US 3956480 describes a treatment to be applied on the surface of the teeth in combination of a cationic germicide and an anionic polymer; - A US 3846542 refers to an acrylic composition for filling cavities. dental containing a boric acid releasing compound; - EP 0264660 A2 describes the use of a dental material to combat caries and periodontitis

- EP 1392364 describes the use of a device for administering therapeutic agents such as antibiotics, disinfectants, antivirals, desensitizers to be positioned inside the periodontal pocket in such a way that the diseased pocket regions come into intimate contact with it. The composition features two Eudragit RS RL methacrylic polymers in a ratio of 1.5-3 / 1 dissolved in a hydroalcoholic solution. After evaporation of the alcoholic component, the polymers form a film that keeps the therapeutic agent (soluble in both alcohol and water) inside, releasing it progressively for about a week. The release mechanism? linked to the characteristics of the film that? permeable but insoluble in oral liquids. The therapeutic agent being water-soluble is taken out of the film during permeation by oral liquids However, this composition presents a Eudragit RS / RL ratio in clear favor of the RS polymer which has characteristics of a low hydrophilicity unlike the RL polymer which is very pi? hydrophilic, it shows a low and protracted release profile with therefore a poor bioavailability. There? forces high concentrations of the therapeutic agent (eg piperacillin sodium see 10%) and high concentrations of alcohol to solubilize the RS component: not less than 80%. There? implies a level of low biocompatibility? towards the cell lines of the oral mucosa both for the high local concentrations of alcohol but also for the high concentrations of piperacillin. Another aspect? the difficult and long solubilization of the piperacillin powder in the preparation with the hydroalcoholic solution due to the high alcohol content (greater than 80%). These characteristics of the aforesaid composition involve high industrial costs due to the high concentrations of the therapeutic agent used (eg: piperacillin) and the high quantity? of alcohol to 95 ?. Finally, the formation of the film inside the pocket can? leave residues of non-water-soluble polymeric material for a much longer time? a week long, being able to trigger problems of tolerability? local.

- IT 0001389310 (piperacillin tazobactam Eudragit RS + RL: describes the use of an administration device based on an antibiotic, piperacillin sodium associated with the beta-lactamase inhibitor tazobactam sodium to be positioned inside the peri-implant pocket so that the diseased regions of the pocket and the infected surface of the implant come into intimate contact with them. The composition has two Eudragit RS RL methacrylic polymers in a ratio of 1.5-3 / 1 dissolved in a hydroalcoholic solution. The polymers after evaporation of the alcoholic component form a film that preserves piperacillin and tazobactam (both soluble in alcohol and in water) inside releasing them progressively for about a week. The release mechanism is linked to the characteristics of the film which is permeable but insoluble in oral liquids. composition presenting a Eudragit RS / RL ratio in clear favor of the RS polymer which has characteristics of a bas sa hydrophilicity unlike the RL polymer which is much more? hydrophilic, it shows a low and protracted release profile with therefore a poor bioavailability. There? forces high concentrations of the therapeutic agent (eg piperacillin sodium see 10%) and high concentrations of alcohol to solubilize the RS component: not less than 80%. There? implies a level of low biocompatibility? towards the cell lines of the oral mucosa both for the high local concentrations of alcohol but also for the high concentrations of piperacillin and tazobactam. Another aspect? the difficult and long solubilization of the piperacillin and tazobactam powder in the preparation with the hydroalcoholic solution due to the high alcohol content (greater than 80%). These characteristics of the aforesaid composition involve high industrial costs due to the high concentrations of the therapeutic agent used (eg: piperacillin) and the high quantity? of alcohol to 95 ?. Finally, the formation of the film inside the pocket can? leave residues of non-water-soluble polymeric material for a much longer time? a week long, being able to trigger problems of tolerability? local.

Summary of the invention? therefore it is an object of the present invention to provide a new composition for the treatment of periodontal disease, by means of a release system of a therapeutic agent placed inside the periodontal pocket, without a release regulating agent or adhesive agent being present and therefore cannot arise problems of biocompatibility? or allergic problems.

Another object of the present invention to provide a new composition for the treatment of periodontal diseases by means of a device for the administration of a therapeutic agent, in which a slow release of a therapeutic agent is obtained through a new pharmaceutical form: a gel that is insoluble in water but a this permeable.

Another object of the present invention is to provide a new composition for the treatment of periodontal diseases by means of a device for the administration of a therapeutic agent, in which a slow release of a therapeutic agent is obtained thanks to the new pharmaceutical form in adhesive gel, which? characterized by a high release profile and therefore by a high bioavailability. There? allows you to use low quantities? of the therapeutic agent

Another object of the present invention to provide a novel composition for the treatment of periodontal pockets by means of a delivery system for a therapeutic agent, in which high doses of such agent last on average 6 days.

These objects are achieved by a composition as defined in claim 1

These objects are achieved by a composition according to the invention for the treatment of periodontal pockets, comprising a therapeutic agent characterized by a mixture of antibiotics which comprises piperacillin sodium and tazobactam sodium in a given weight ratio. Preferably the weight ratio of tazobactam sodium to piperacillin sodium? 1: 8 realizing so? the best synergy between the two antibiotics. These are characterized by the fact that they are soluble both in water and in alcohol, joining a biocompatible polymeric material and that said biocompatible polymeric material? a liquid methacrylate copolymer chosen from: Eudragit RL, Eudragit RS, a mixture thereof. Preferably, said liquid methacrylate copolymer? a mixture of EUDRAGIT RS 100 and EUDRAGIT RL 100. Preferably the polymers are supplied in the liquid state in a hydroalcoholic solution, preferably using 95? alcohol. When the polymers in a particular ratio between them and with a particular water-alcohol ratio of the solution are introduced into a periodontal pocket, there is the formation of an adhesive gel with unique characteristics as it is not soluble in oral liquids but permeable to these, which allows completely occupy the volume of the pocket thanks to an expansion during the formation in the pocket, thus releasing? high quantities? of the active agent according to the invention in a controlled manner for a desired period of time.

The hydroalcoholic solution? characterized by a mixture of ethanol and water in a range of 20-40% w / w of water. The presence of this high quantity? of water ? advantageous for improving the solubilization of the therapeutic agent when the latter does not have high solubility? in alcohol, and on the other hand it has a good solubility? in water. In this way the preparation of the composition by mixing the polymer solution and the therapeutic agent (i.e. powder)? pi? rapid. Up to 40% of water for the polymer solution and the final liquid composition remain as a clear solution, i.e. without polymer precipitation. A further advantage over EP 1392364? that the lower alcohol content allows a greater biocompatibility? of the adhesive gel to the oral cell lines. Chemically, Eudragit RS and RL are copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups. Ammonium groups are present as salts and make polymers permeable. The polymers are described in USP / NF as "ammonium methacrylate copolymer, type A" (EUDRAGIT RL) and "type B" (Eudragit RS).

A first advantage of the composition according to the invention? that if you use a therapeutic agent which? soluble in both water and alcohol, in the biocompatible polymer comprising EUDRAGIT RL and EUDRAGIT RS, the gel formed surprisingly adheres to the pocket surfaces and no adhesive additives are required. This substantially increases the biocompatibility? compared to the known art, in that. not only not? the release regulating agent was used but not the material adhesive material, as instead provided in EP0404558

Pi? precisely, the adhesive gel of biocompatible polymeric material, not being soluble in water, is then resistant up to a normal erosion consumption within the pocket environment for up to about one week. This erosion of the gel results more? constant and regular than that observed in the film of EP 1392364. In fact, a non-constant erosion can? lead to residues of materials present in the pocket observed even after 15 days which may not be tolerated. The formation of an adhesive gel, instead of the film of EP 1392364, allows a complete erosion of this material which is never found in the application site after 10 days.

If a therapeutic agent soluble in alcohol but not in water were present in the gel, when the water present in the pouch liquids permeates through the gel, the therapeutic agent would not be released. On the other hand, if a therapeutic agent were not soluble in alcohol, it could not be accommodated within the polymer alcohol solution.

Therefore, according to claim 1, if in the adhesive gel of biocompatible polymeric material? present a therapeutic agent that? soluble in both alcohol and water, when the water present in the pocket permeates through the polymeric material, the therapeutic agent is released. The speed? and the entity? release depends on the physical nature of the polymeric material in this case in the form of a gel, and on its permeability? to water. Mixtures can be obtained from which the therapeutic agent will spread? at speed? controlled for selected time periods. Pi? precisely, from a correct weight ratio of the two polymeric materials Eudragit RS and RL, the formation of an adhesive gel is obtained, unlike what obtained in EP 1392364 where the formation of a film was obtained, and a higher release profile? always high compared to EP 1392364. In fact, by varying the RS / RL ratio, the property? hydrophilic varies accordingly but above all the formation of an adhesive gel is obtained. In particular, if RL? increased, the release profile of the therapeutic agent not only? pi? fast but surprisingly? quantitatively more? high. There? it allows to use concentrations of the therapeutic agent up to five times lower than EP 1392364. This entails further advantages such as a significant reduced industrial cost of the product.

The formation of the gel inside the pocket, unlike the formation of the film obtained from the composition of EP 1392364, allows a better dimensional stabilization in the volume of the pocket with therefore a better contact surface and therefore a better bioavailability. towards the soft tissues of the pocket. In fact surprisingly in a comparative study three groups of 6 patients with 6 mm periodontal pockets were treated with a) IMPLACID Simit Pharma (composition of IT 0001389310 based on piperacillin sodium tazobatam sodium), b) PERIOCID Simit Pharma (composition of EP 1392364 based on sodium piperacillin, c) adhesive gel composition as per claim 1. After 3 months at the clinical control surprisingly yes? had a reduction in the depth? of pockets greater in group c than in groups a and b. In particular, the group at depth? average 4.9 mm, group b depth? 5.3 mm, group c depth? 3.6 mm

Preferably, the RS / RL ratio? between 1 / 1.5 / and 1/3, so that the release of the therapeutic agent lasts up to 7 days. Favorite RS / RL ratio? of 1/2.

The therapeutic agent who? soluble in both water and alcohol? preferably selected from: Piperacillin sodium, Tazobactam sodium and their mixture;

This invention is not? limited to the use of only the agents mentioned above. A wide variety? of therapeutic agents can be used in the invention, which can? be provided in this way and are potentially effective for periodontal therapy. It is recognized that in certain forms of therapy, combinations of these agents in the same delivery system can? be useful for obtaining an optimal effect. What? , for example, an antibacterial agent and an anti-inflammatory agent can be combined in a single delivery system to provide combined efficacy. Non-limiting examples of the present invention are the following:

EXAMPLE 1

solution

Eudragit RL 100 9% (w / w) Eudragit RS 100 3% (w / w)

Purified water 40%

Ethanol 96% q.s. 100 g

dust

Piperacillin sodium 2% (w / w) Tazobactam sodium 0.25% (w / w)

EXAMPLE 2

solution

Eudragit RL 100 8% (w / w) Eudragit RS 100 4% (w / w)

Purified water 30%

Ethanol 96% q.s. 100 g

dust

Piperacillin sodium 2% (w / w) Tazobactam sodium 0.25% (w / w)

EXAMPLE 3

solution

Eudragit RL 100 7.5% (w / w) Eudragit RS 100 4.5% (w / w) Purified water 25%

Ethanol 96% q.s. 100 g

dust

Piperacillin sodium 2% (w / w) Tazobactam sodium 0.25% (w / w)

EXAMPLE 4

solution

Eudragit RL 100 6.5% (w / w) Eudragit RS 100 3% (w / w)

Purified water 30%

Ethanol 96% q.s. 100 g

dust

Piperacillin sodium 2% (w / w) Tazobactam sodium 0.25% (w / w)

EXAMPLE 5

solution

Eudragit RL 100 7% (w / w) Eudragit RS 100 4.5% (w / w) Purified water 25%

Ethanol 96% q.s. 100 g

dust

Piperacillin sodium 2% (w / w) Tazobactam sodium 0.25% (w / w)

EXAMPLE 6

solution

Eudragit RL 100 7% (w / w) Eudragit RS 100 4.5% (w / w) Purified water 25%

Ethanol 96% q.s. 100 g

dust

Piperacillin sodium at 4% (w / w) Tazobactam sodium at 0.5% (w / w)

EXAMPLE 7

solution

Eudragit RL 100 7.5% (w / w) Eudragit RS 100 3.5% (w / w) Purified water 25%

Ethanol 96% q.s. 100 g

dust

Piperacillin sodium 5% (w / w)

0.625% (w / w) sodium tazobactam

Advantageously, the above compositions are associated with application means in the region of the periodontal pocket, in particular? a dental kit is provided including a disposable syringe equipped with a piercing needle (to be used to reconstitute the solution with the powder) and a blunt tip needle (to replace the piercing one and used to place the solution in the pocket. be applied advantageously in the periodontal pocket by bending the blunt tip needle, mimicking a periodontal probe, and positioning the blunt needle tip near the base of the pocket and then injecting the solution until it reaches the upper edge of the gum. point you can extract the needle as the solution rehydrating with the crevicular liquid present in the pocket is instantly transformed into the adhesive gel described above

The above description in the form of examples? able to show the invention from a conceptual point of view so that others, using the known technique, will be able to modify and / or adapt these examples in various applications without further research and without departing from the inventive concept, and, therefore, it is intended that such adaptations and modifications will be considered as equivalent to these examples. The means and materials for carrying out the various functions described may be of various nature without thereby departing from the scope of the invention. It is understood that the expressions or terminology used have a purely descriptive purpose and therefore not limited.

Claims (16)

CLAIMS 1. A composition for the treatment of periodontal pockets, comprising two therapeutic agents in a biocompatible polymeric material, characterized in that said therapeutic agents are soluble in both water and alcohol and that said biocompatible polymeric material? a liquid methacrylate copolymer chosen from EUDRAGIT RS or Eudragit RL or a mixture thereof, so that? an adhesive gel is formed and said therapeutic agents are released progressively by permeation of water through said polymeric material. 2 . Composition according to claim 1, wherein said liquid methacrylate copolymer? a mixture of EUDRAGIT RS 100 and EUDRAGIT RL 100. 3. Composition according to claim 1, wherein the ratio RS / RL? between 1 / 1.5 and 1/3. 4. Composition according to claim 1, wherein the solvent of said liquid methacrylate copolymer? a hydro-alcoholic solvent comprising 20-40% water 5 Composition for the treatment of periodontal pockets according to claim 1 wherein said organic solvent? ethyl alcohol 95? 6. Composition according to claim 1, wherein said therapeutic agents are preferably selected from: sodium piperacillin, sodium tazobactam 7. A composition for the treatment of periodontal pockets, according to claim 1, wherein said ratio by weight between said sodium tazobactam and said sodium piperacillin? preferably 1? 8. 8. Composition according to claim 1, wherein said biocompatible polymeric material and said therapeutic agent are mixed in the following weight ratio Eudragit RL 100 7-9% (w / w) Eudragit RS 100 0.2-4.5% (w / w) Therapeutic agent 0.5-5% (w / w) Purified water 20-40% (w / w) Ethanol 96% q.s. 100 g 9. A composition for the treatment of periodontal pockets, according to claim 1, in which said acrylic resin? such that said adhesive gel has physical characteristics which are maintained for 6-7 days after which, upon eroding, it disappears from the application site. 10. A composition for the treatment of periodontal pockets, according to claim 1, characterized in that it is applied topically in the region of the pocket affected by the inflammatory process. 11. Composition for the treatment of periodontal pockets, according to claim 1, in which the aforesaid composition? associated with application means in the dental region affected by the inflammatory process, in particular a dental kit comprising a flexible needle with a blunt tip. 12.kit for dental use, in particular for the treatment of periodontal pockets characterized by the fact of including: ? a first bottle containing a hydroalcoholic solution comprising: ? an organic solvent; ? at least one biocompatible acrylic resin, called, or each acrylic resin being permeable, but insoluble to water; ? a second bottle containing a powdered mixture of antibiotics, said powdered mixture comprising piperacillin sodium and tazobactam sodium in a given weight ratio. 13. Kit for dental use, in particular for the treatment of periodontal pockets, according to claim 12, in which said first bottle contains 1-5 ml of hydroalcoholic solution. 14. Kit for dental use, in particular for the treatment of periodontal pockets, according to claim 12, wherein said second bottle contains 100 mg of piperacillin sodium and 12.5 mg of tazobactam sodium. 15.Kit for dental use, in particular for the treatment of periodontal pockets, according to claim 11, in which? furthermore, at least one syringe equipped with a piercing needle is provided with which the hydroalcoholic solution is withdrawn from the first bottle and introduced into the second bottle to make a resulting composition. 16.Kit for dental use, in particular for the treatment of periodontal pockets, according to claim 11, in which? at least one blunt-tipped flexible applicator needle is also provided for applying said resulting composition to an application site.