Oral delivery system

The present invention relates to an oral delivery system for the treatment and / or prevention of periodontal, peri and other bacterial and viral diseases and fungal diseases of the mouth and throat and halitosis (hereinafter: pathogen-induced, pathology).

Pathogen-related, pathological changes are very common and are the main reason for tooth loss / implant loss and halitosis in people at an age of about 35 years. A pathogen-related pathological alteration can for example be understood as an infection or inflammation of the periodontal pocket, which, in several steps, can cause the loss of bone, which holds the tooth / implant. There are different forms of the disease severity. Minor cases concern the clinically indicated gingivitis, while more severe cases are clinically known as periodontitis / periimplantitis.

Gingivitis is an inflammation of the gingiva (or gums) that is often caused by poor oral hygiene and / or the hormonal state of the patient. It is believed that the untreated gingivitis develops into periodontitis / periimplantitis. The Periodontitis is a bacterial disease that the gingival tissue, the teeth, implants and the bone surrounding the teeth / implants attacks.

The oral cavity is a substantially aerobic environment, which is traversed by the saliva. In contrast, the periodontal / peri-implant microenvironment is more anaerobic and is traversed by a plasma filtrate, which is called "gingival sulcus fluid". The growth of microorganisms within this microenvironment is considered responsible for the occurrence of a pathogen-related, pathological change. Therefore, the treatment of this change on the monitoring and influencing this growth is directed.

Attempts to treat pathogen-related, pathological changes caused by drugs, z. B. antibacterial agents, which are given in the oral cavity, lined up usually ineffective out because the periodontal / peri-implant pocket is substantially inaccessible. On the other hand, systemic administration of antibiotics results in only a slight success in the treatment of periodontal diseases.

Antibacterial agents such as chlorhexidine and quaternary ammonium salts in the form of mouthwashes have indeed proved to be reasonably effective in the prophylaxis / treatment of pathogen-related, pathological changes. However, these agents have various drawbacks. So often experience side effects such as discoloration of the teeth, tongue, mucous membranes or dentures. Furthermore, these drugs often have unpleasant taste and affect the taste sensation of the patient. Further, it is common in these substances to defects in wound healing. In addition, often also occurs absorption of active ingredients through mucous membranes or through the gastrointestinal tract, which can lead to systemic effects. Furthermore, in the active substances occur frequently toxic degradation products. Another disadvantage is that the active compounds mentioned usually have to be used in very high concentrations in order to achieve a corresponding effect. Furthermore allergogenes potential was observed. In addition, the said substances often act irritative and are not particularly durable. It was also observed that when these substances, the effect is influenced by the blood or protein.

There are pharmaceutical compositions having a release of active ingredients and which are able to be inserted into the periodontal cavity and which slowly release an antimicrobial agent have been developed. For example disclose<patcit id="pcit0001" dnum="US4764377A"><text>US 4,764,377</text></patcit> and <patcit id="pcit0002" dnum="US4892736A"><text>US 4,892,736</text></patcit> introducing tetracycline into nondegradable polymeric fibers which can be wound around the teeth and release the antibiotic into the periodontal cavity for several days. However, the fibers must be fixed with an adhesive in place and be removed at the end of treatment.

<patcit id="pcit0003" dnum="US4569837A"><text>US 4,569,837</text></patcit> discloses the use of water-soluble polymeric substances (eg., methyl cellulose, gelatin, etc.) as a polymeric matrix for a periodontal implant.

<patcit id="pcit0004" dnum="US5002769A"><text>US 5,002,769</text></patcit> discloses a biodegradable system for oral administration with delayed release for the treatment of periodontal diseases. The active substance is in a matrix of hydrolysed gelatin which is crosslinked with glutaraldehyde, embedded.

The compositions described above have varying effectiveness in reducing the bacterial amount of periodontal pocket and in reducing pocket depth. Moreover, these compositions often exhibit the abovementioned disadvantages.

The present invention has for its object to provide an effective delivery system for the treatment and / or prevention of pathogen-related, pathological changes is available, which is easy to use and at the same time effectively.

The object is achieved by an oral delivery system of the type mentioned comprising polyhexanide.

It has been found that polyhexanide is particularly effective when using oral delivery systems in the treatment and / or prevention of periodontal diseases. Polyhexanide can be dropped in particular in such delivery systems, in which a slow release in the field of periodontal pockets is to be achieved, so that prolonged exposure can be achieved.

In a preferred variant of the oral delivery system of this is in a solid dosage form. A solid dosage form has particular advantages in the use of the system.

In a preferred embodiment of the oral delivery system, this is in the form of a chewing gum. Chewing gums have inter alia the advantage that they counteract the observed at Polyhexanid delayed onset of action, since they can be used by the patient without problems over a longer period. This is problematic for example in mouthwashes.

Chewing gums are generally composed of the following commodity groups: Gum base or gum, plasticizers, fillers, lubricants, fats, emulsifiers, flavors, colorants, antioxidants and food acids for flavoring. As gum can either natural products such as chicle, gutta-percha, latex, Benzoeharze or gum arabic, or bodying, synthetic thermoplastics, such as polyvinyl acetate and in amounts of up to 65% of the gum, poly-butadiene-styrene, polyisobutylene, isoprene, polyvinyl polyethylene, can be used.

Typical plasticizers are emulsifiers, resins, waxes or glucitol. Typical fillers are magnesium stearate, chalk, calcium carbonate, silicate or cellulose. The fillers or processing aids preserve the flowability and prevent sticking of the particles at low pressure. As lubricants, fats or emulsifiers typically used mineral oils, microcrystalline waxes or vegetable oils used. These adjuvants prevent sticking of the tools or the tools.

Conventional chewing gums may be highly cariogenic due to their high sugar content, but also massage the gums and salivary glands dry mouth. Through the added flavoring chewing gums also act refreshing, invigorating and / or thirst-quenching.

In order to avoid the above-mentioned cariogenic effects of sugar in chewing gums, chewing gums are brought on the market for a long time sugarless. In these the sugar is replaced with sugar substitutes. These are mainly sorbitol and xylitol.

The inventive chewing gums are used to support dental and oral hygiene and treatment / prevention of pathogen-related, pathological changes. They are particularly suitable for traveling, if there is no possibility for brushing teeth consists. The inventive chewing gums are usually sugar-free and contain similar to toothpaste, traces of minerals for the regeneration of the teeth. The chewing gum according to the invention may also comprise at least one Schleifinittel or at least one abrasive material, in particular calcium carbonate, Calziumphosphate, metaphosphate, silica, aluminum oxides, silicates and / or talc.

Furthermore, the chewing gum according to the invention at least one suspension substance or a humectant, in particular water, glycerol, propylene glycol and / or sorbitol syrup, and at least one thickening, stabilizing and / or binders, in particular gels, starches, alginates, oils and / or Cellulose Gum contain.

To improve the taste properties of the chewing gum, at least one aromatic substance, at least one sweetener and / or at least one sugar substitute, in particular, menthol, peppermint oil, sodium saccharin, aspartame, acesulfame, sorbitol, malitol, xylitol and / or fructose can be added.

In addition, the chewing gum according to the invention may contain further chemical additives, dyes and / or pH regulators, in particular fluorides, astringents, anti-inflammatories, Desensiblisierungsmittel, vitamins, panthenol, white pigments and / or sodium hydroxide.

The inventive oral delivery system in the form of a chewing gum the polyhexanide can be particularly effectively at the sites of action, in particular gain in the gingival pockets. By chewing the gum is pressed into the gingival sulcus, where then the polyhexanide is discharged.

In a further embodiment of the dispensing system of the invention this is in the form of a chip or film comprising a biodegradable or bioerodible pharmaceutically acceptable polymer.

The chip or film of the invention is suitable for implantation in a periodontal pocket and capable of pathogen related to treat pathological changes, in which a delayed release of polyhexanide is desired. The bag may be a natural pocket, can be caused by a disease state, or may be opened intentionally as part of treatment. After their implantation of chip or film softens, swells and changes into a soft paste which adheres to the bag.

Preferably, the chip or film may comprise at least one crosslinking agent which is present in an amount sufficient to render the polymer insoluble in water, while the release is permitted by the polyhexanide from the delivery system.

The film or chip of the invention preferably contains a surface active agent, which is preferably selected from anionic, cationic and nonionic surfactants. The nonionic surfactants may be selected from polyoxyethylene sorbitan fatty acid esters (polysorbate), and sorbitan fatty acid esters.

The chip or film of the invention is preferably adapted for administration to a periodontal pocket having in-vivo release properties, which aim to reduce the depth of a periodontal pocket of a patient.

Advantageously, the chip or film of the invention is in a form such that it biodegrades in the periodontal pocket, whereby it is characterized soft and adhering to the periodontal pocket and in which it, once it has been inserted into a periodontal pocket, gradually the polyhexanide releases over a period of at least about 24 hours, during which the chip or film transforms into a soft material. Thus, the chip serves as a delivery medium of polyhexanide as antimicrobial active ingredient for application into the sulcus or periodontal pocket. The size of a chip / film of the invention is generally in 3x3 - 10x10 mm. In general, the base of the chip / film is a crosslinked gelatin with glutaraldehyde. It certainly has been found that cross-linked gelatin is particularly useful for sustained release of polyhexanide.

Advantageously, the polymer is selected from water-soluble protein, cellulose or cellulose derivative, starch or starch derivative, glyceryl, carbomer, PVP (polyvinylpyrrolidone), gum, acacia gum, guar gum, polyvinyl alcohol, poly-hydroxyethyl, Polyhydroxymethylmethacrylatacrylsäure, polyacrylamide, polyethylene glycols, polylactic acid, polyglycolic acid , copolymers of polylactic and polyglycolic acid, polyanhydrides and polyorthoesters. The water-soluble protein is preferably selected from the group consisting of gelatin, collagen, albumin, an enzyme and fibrinogen.

In a further embodiment of the system according to the invention this is present as a gel or ointment. In this form it is spent usually in the gingival pockets, where it gives Polyhexanid to the environment.

The gel or ointment according to the invention is used for intra-oral application, particularly for application into the sulcus or a periodontal pocket. The polyhexanide acts here again as an antimicrobial agent. The gel / ointment according to the invention may be based on conventional ethanol / glycerol / Macrogol connection.

The gel of the invention or the ointment of the invention can be present both as a finished formulation or as a mixed system. In the presence of a mixing system certain components are mixed only shortly before application and brought to the diseased site. The advantage of this is, inter alia, that a mixed system after mixing is readily processable. Thus, in one embodiment, after mixing first a viscous mass present, which hardens in the mouth after the removal. This facilitates the application considerably. The mixing system can for example be in the form of a mixing capsule.

The inventive oral delivery system has considerable advantages over the known antibacterial agents such as chlorhexidine. So the polyhexanide used in the delivery system according to the invention is not cytotoxic. In addition, no side effects such as discoloration of the teeth, tongue, mucous membranes or dentures are observed. The polyhexanide used is neutral in taste and does not cause taste disturbances. Further, the wound is not disturbed, and the formation of fibrin is reduced. Furthermore, no absorption through mucous membranes or through the gastrointestinal tract is known. Furthermore, do not form toxic degradation products in the application. Another significant advantage is that the effective concentration of polyhexanide is many times lower than, for example, chlorhexidine is. Furthermore Polyhexanid harbors no allergogenes potential is not irritant. Polyhexanide is - if known - non-sensitizing. The durability of polyhexanide is also longer than in the conventional agents. In addition, no development of resistance was observed. Polyhexanide has a broad spectrum of activity and shows a very low protein and blood error (effect is through protein or blood hardly affected).