Oral delivery system

Translation of description of equivalent WO 2015162070 A2

0001description

0002An oral delivery system

0003The 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 HaHtosis (hereinafter: pathogen-induced, pathology).

0004Pathogen-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.

0005Gingivitis 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, which the gum tissue, the teeth, implants and the bone surrounding the teeth / implants, engages.

0006The oral cavity is a substantially aerobic environment, which is flowed through by the saliva. In contrast, the periodontal / peri-implant Mikroumge- is advertising more anaerobic and is flowed through 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 changes. Therefore, the treatment of these

0007Change directed to the monitoring and influencing this growth.

0008Attempts 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, the systemic

0009Administration of antibiotics only to a limited success in the treatment of periodontal diseases.

0010Antibacterial 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 Geschmacksemp- making 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 Träkt, 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. Further has been observed that at these substances, the effect is influenced by the blood or protein.

0011There are pharmaceutical compositions which comprise a release of active substances and which are capable, in the pe to be used riodontale avität and which slowly release an antimicrobial agent developed. For example, US 4,764,377 and US 4,892,736 the incorporation of 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.

0012US 4,569,837 discloses the use of water-soluble polymeric substances (eg., Methyl cellulose, gelatin, etc.) as a polymeric matrix for a periodontal implant.

0013US 5,002,769 discloses a biodegradable system for oral administration with delayed release for the treatment of periodontal diseases. Of the

0014Active agent is in a matrix of hydrolysed gelatin which is crosslinked with glutaraldehyde, embedded.

0015The 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.

0016The present invention has for its object to provide an effective delivery system for the treatment and / or prevention of pathogen-related, pathological

0017to make 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.

0018It 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.

0019In 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.

0020Chewing 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.

0021As 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.

0022Typical 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 for use. These adjuvants prevent sticking of the tools or the tools.

0023Conventional chewing gum can be strong kariesför- horror because of 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.

0024To achieve the above cariogenic effect of sugar in chewing gums avoid timeouts, have long been sugar-free chewing gum brought to the market. In these the sugar is replaced with sugar substitutes. These are mainly sorbitol and xylitol.

0025The inventive chewing gums are used to support dental and oral hygiene and treatment / V orbeugung of pathogen-related, pathological

0026Changes. 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 an abrasive, or at least one abrasive material, in particular calcium carbonate, Calziumphosphate, metaphosphate, silica, aluminum oxides, silicates and / or talc.

0027Furthermore, the chewing gum according to the invention may comprise at least material a suspension 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 included. 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 are added.

0028In 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.

0029The 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 GE pressed into the gingival sulcus, where then the polyhexanide is discharged.

0030In 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.

0031The 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.

0032Preferably, 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.

0033The film or chip of the invention preferably contains a surface active agent, which is preferably selected from anionic, and non katiönischen ionic surface active agents. 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.

0034Advantageously, 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.

0035Advantageously, 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 , polyglycolic acid, copolymers of polyester sigsäure 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 of the invention can on conventional ethanol / glycerol / macrogol based compound.

0036The 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.

0037The 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 formed during the application no toxic degradation products. Another significant advantage is that the Wirkkonzenträtion 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 formation of resistance would be 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).