EP4058038A1

EP4058038A1 - New formulation of lactobacillus strains for the treatment and prevention of heli-cobacter pylori colonisation in the upper airways and the digestive system

Info

Publication number: EP4058038A1
Application number: EP20845672.3A
Authority: EP
Inventors: Alexander REIPRICH
Original assignee: Belano Medical Ag
Current assignee: Belano Medical Ag
Priority date: 2019-11-14
Filing date: 2020-11-16
Publication date: 2022-09-21
Also published as: WO2021093912A1; US20220409680A1; DE102019007892A1

Abstract

The invention relates to new compositions for the treatment and prevention of Helicobacter pylori colonisation in the oral cavity, the upper airways, the oesophagus and the digestive system, wherein the composition is composed preferably in the form of a chewing gum.

Description

New formulation of Lactobacillus strains for the therapy and prophylaxis of the colonization with Helicobacter pylori in the upper respiratory tract and the

Digestive system

Field of the invention

The invention relates to new formulations for the therapy of Helicobacter pylori infections of the upper respiratory tract, the esophagus and the digestive system, the formulation preferably being composed in the manner of a chewing gum.

Prior art and background of the invention

It is known that Helicobacter pylori infections of the stomach can lead to chronic inflammation and gastric ulcers. It is also known that H. pylori can also settle outside the stomach, e.g. in plaque and gingival pockets, in canker sores, the tonsils and tonsils and in nasal polyps. H. pylori colonization can be associated with indigestion, nausea, chronic mucosal ulcers, hives, anemia, coronary circulatory disorders, insulin resistance, type 2 diabetes and gingivitis. Various preparations for the therapy of Helicobacter pylori infections are known, in particular antibiotics.

It is also known that certain Lactobacillus strains are replaceable against H. pylori infections. Some of such strains include: mentioned in EP 1963483 B1. Nevertheless, it was found that in individual cases, despite initial therapeutic success, the infection flares up again due to reinfections. There is therefore a need for improved formulations of known Lactobacillus strains in order to better combat H. pylori sources of spread outside the gastrointestinal tract and new infections due to oronasal uptake of H. pylori.

It has now been found that, surprisingly, compositions in which Lactobacillus strains are known in principle, in particular Lactobacillus reuteri, especially Lactobacillus reuteri cells deposited as DSM 17648, can be formulated in the form of chewing gum, and that the application of chewing gum formulated in this way previous therapeutic successes outside of the digestive system surpasses.

Confirmation copy The term "Lactobacillus cells" in the sense of the invention (hereinafter also lactic acid bacteria or lactobacilli) includes those microorganisms that require carbohydrates, in particular glucose and lactose, for lactic acid fermentation and mostly use the Embden-Meyerhof biosynthetic pathway. The Lactobacillus cells can be alive, viable or dead, fragmented as

Cell wall components or in the form of isolated cell wall molecules can be used.

The Lactobacillus cells are grouped together taxonomically in the Lactobacteriaceae family. They are gram-positive, non-spore forming, and generally immobile. The Lactobacillus cells live anaerobically, but are aerotolerant, although they do not contain any haemins (cytochrome, catalase) (Schleifer et al., System. Appl. Microb .: 18, 461-467 (1995) or Ludwiq et al., System. Appl Microb 15: 487-501 (1992).

According to the invention, particularly those species are included which are suitable for homofermentative lactic acid fermentation or heterofermentative lactic acid fermentation.

Such Lactobacillus Also preferred are cells selected from the group Lactobacillus crispatus, Lactobacillus gasseri, Lactobacillus lactis, Lactobacillus helveticus, Lactobacillus acidophilus, Lactobacillus bulgaricus, Lactobacillus delbrueckii, Lactobacillus casei, Lactobacillus paracasei, Lactobacillus pentosus, Lactobacillus rhamnosus and Lactobacillus plantarum (all homofermentativ) furthermore Lactobacillus reuteri, Lactobacillus brevis, Lactobacillus fermentum, Lactobacillus viridescens and Bifidobacterium bifidum (all heterofermentative).

Lactobacillus reuteri are preferred according to the invention. Lactobacillus reuteri cells, as deposited under DSM 17648, are very particularly preferred. For the application according to the invention, the Lactobacillus cells can be used living, viable, dead, fragmented as cell wall components or in the form of isolated cell wall molecules. The compositions can be in the form of pharmaceutical and / or dietetic formulations and / or medical products and / or cosmetic products.

The invention therefore relates to compositions containing an effective dose of Lactobacillus cells in the form of chewing gum for the therapy and prophylaxis of H. pylori infections of the upper respiratory tract, esophagus and digestive system.

The invention relates in particular to compositions according to claim 1, containing an effective dose, for example between 1 × 10 ³ to ^{1 × 10 13} Lactobacillus reuteri cells living, viable, dead or fragmented. Furthermore can also

Cell wall components or isolated cell wall molecules each from 1 × 10 ³ to ^{1 × 10 13} cells can be used per application. The preferred dose contains ^{1 × 10 9} to 1 × 10 ¹¹ Lactobacillus reuteri cells per application. The preferred forms of application are viable or dead cells. The invention specifically relates to compositions according to claim 1, containing an effective dose, for example between 1 × 10 ³ to ^{1 × 10 13} Lactobacillus reuteri DSM 17648 cells living, viable, dead or fragmented. Furthermore, cell wall components or isolated cell wall molecules, each made up of 1 × 10 ³ to ^{1 × 10 13} Lactobacillus reuteri DSM 17648 cells, can be used per application. The particularly preferred application form are viable or dead Lactobacillus reuteri DSM 17648 cells.

The preferred dose contains ^{1 × 10 9} to 1 × 10 ¹¹ Lactobacillus reuteri cells per application.

It appears to be decisive for the application that the compositions according to the invention remain in the mouth and throat for a prolonged period and continuously release the lactobacilli during this time. As an alternative to the chewing gum formulation, compositions are therefore suitable which usually have a longer residence time in the upper respiratory tract. The dwell time in the mouth should typically be at least 30 seconds, preferably longer than 2 minutes, particularly preferably more than 5 minutes, very particularly preferably more than 10 minutes.

In particular, the following dosage forms are used:

1. Buccal tablets (also muco-adhesive buccal tablets) or orodispersible orodispersible tablets,

2. Oral active ingredient films

3. Gargle solutions or concentrates (including powder / tablets for preparation)

4. Mouthwash or concentrates (including powder / tablets for preparation), gum cleaning solutions

5. Oromucosal preparations such as drops, gels, liquids, pastes, solutions, sprays and / or suspensions

6. Sublingual preparations such as sprays, tablets, films

7. Lozenges or candies

8. Oral powder or granules

9. Preparations for nasal use, such as nasal drops, liquid nasal sprays, nasal powders, semi-solid preparations for nasal use, nasal rinses or nasal sticks

The chewing gums according to the invention can be produced, for example, on the basis of a "gum base", as offered by various companies, for example by Cafosa under the name PWD 01, PWD 03 or PWD 04. Such compositions initially contain the actual gum compound, usually consisting of a or more elastomers, preferably selected from the group comprising polyisobutylene, isobutylene / isoprene copolymer and vinyl acetate / vinyl laurate copolymer, polyvinyl acetate. In addition, resins, preferably to be selected from the group comprising vegetable rosin esters, synthetic resins and / or terpene resins, hydrogenated or partially hydrogenated vegetable oils and / or waxes selected from the group comprising vegetable waxes, waxes derived from petroleum and / or synthetic waxes can be an ingredient be of composition. In addition, emulsifiers and technical aids, more precisely, but not exclusively, glycerol monostearate, acetylated monoglycerides, Lecithin, sugar esters and triacetin, inert fillers like maltodextrin, vegetable starch, silicon dioxide (E551), aerosil, magnesium stearate and antioxidants are used. It usually contains sweeteners such as glucose, sucrose or fructose. However, the sweeteners are preferably sugar-free and contain, for example, acesulfame, aspartame, cyclamate, saccharin, sucralose, thaumatin, neohesperidin, neotame, xylitol, mannitol, erythritol, isomalt, steviol glycoside and / or sorbitol.

To improve the taste, aromas (e.g. strawberry aroma, vanilla aroma, raspberry aroma, banana aroma, chocolate aroma, mint aroma, thyme aroma or sage aroma) and acidulants such as citric acid or lactic acid can be added.

The lactobacilli according to the invention (e.g. DSM 17648) are added to this basic chewing gum mixture and mixed with one another by vigorous stirring. DSM 17648 can be added in the form of the product Pylopass (Novozymes A / S), in which DSM 17648 is commercially available. The chewing gum base, including the lactobacilli, of the present invention is in the form of a free flowing particulate material or granules capable of being compressed at high speed by a standard tableting machine directly into chewing gum tablets of various shapes, shapes and weights. Finally, the chewing gum is usually made up and packaged. The chewing gums typically contain an effective dose per chewing gum

Lactobacilli, eg Lactobacillus reuteri DSM 17648, which can be between 1 × 10 ³ to ^{1 × 10 13} cells living, viable, dead or fragmented as cell wall components. The preferred dose contains 1 x 10 ⁹ to 1 x 10 ¹¹ lactobacilli per application.

Further information on the composition of corresponding chewing gum can be found in the specialist literature, e.g. Biswal et al. International Journal of Advances in Pharmacy, Biology and Chemistry, Vol. 2 (2), pp.351 ff.

The chewing gums according to the invention can also contain other active ingredients, such as emulsifiers, wetting agents, antibiotics, acid regulators, gastric acid blockers or anti-inflammatory agents. However, they preferably only contain Lactobacillus cells, preferably DSM 17648, as an effective component. It has been shown that the H. pylori therapy is significantly improved through regular use of such chewing gum and / or other preparations according to the invention. In particular, the colonization of the upper respiratory tract and the esophagus with H. pylori is reduced, and the repopulation of the gastrointestinal tract is significantly reduced.

Without wishing to be bound by this theory, it is assumed that plaque and gingival pockets or biofilms contained in the upper airways and the esophagus, especially in the presence of chronic inflammatory inflammation of the oral epithelia, such as chronic periodontal disease or chronically recurrent aphids, possibly H. pylori- Contain cells that cannot be adequately controlled by conventional forms of therapy. By using the chewing gum according to the invention and / or other preparations according to the invention, these hidden sources of infection can also be better combated.

The chewing gums according to the invention and / or other preparations according to the invention are typically taken over a period of six days to six months. It can be used several times a day. Typically, four to six chewing gums about every two hours a day for a period of 28 days are sufficient for effective therapy. Such chewing gums can also be used prophylactically, e.g. B. when traveling to risk areas or in close contact with H. pylori infected people. The prophylactic use of such chewing gum is particularly advantageous since the use of classic antibiotics for prophylaxis is out of the question because of the risk of resistance building up.

Examples

1) Composition of the gum base

Gum Base. 22-26%

Xylitol. 8 - 12% plasticizer. max. 2%

Anticaking agent (E-551). max. 2%

Antioxidant (BHT). max. 260 ppm

Sorbitol. up to 100%

2) Composition of the chewing gum according to the invention Lactobacillus cells e.g. L reuteri DSM 17648 50mg / gum

Gum base Hig PWD-01 90%

Rubber (in gum base) 21.6%

Sorbitol (in gum base) 57.6%

Xylitol (in gum base) 10.5% flavor (mint)

Div additives ad 100%

Typically 50 mg L. reuteri contains 5 x 10 ⁹ cells

3) Use of the chewing gums according to the invention a) Subjects with chronic periodontal disease and H. pylori colonization in

Dental plaques in deep gingival pockets are given 4-6 chewing gums per day according to Example 2, which are preferably chewed in the morning, at noon, in the afternoon and in the evening for 20-40 minutes after meals. After chewing four to six chewing gum, there was an average decrease in H. pylori density in plaque samples and mouthwash samples by 20%. b) Subjects with chronic periodontal disease and evidence of H. pylori in plaque in deep gum pockets and simultaneous dyspepsia receive 4 to 6 chewing gum per day according to Example 2, which is preferably chewed in the morning, noon, afternoon and evening for 20-40 minutes after meals become. After 28 days it can be significantly less

Detect H. pylori in plaque, clinical signs of periodontal disease have improved in more than half of the patients, dyspeptic symptoms have improved significantly in 80% of the patients. 4) Making Buccal Films a) The films are made by the modified casting solvent evaporation method (Angela Abruzzo et al., Pharmaceutics 2020, 12 (3), 241). HPMC (2.5% by weight) is dissolved in water containing PG (1% by weight) and the solution is stirred for 8 hours until a viscous, gel-like solution forms (viscosity 9100 mPa s, pH 6.3 ). Optionally, biodegradable and at the same time physiologically compatible polymers can be added to the solution to delay the dissolution (e.g. polylactic acid, polyvinyl alcohol, xanthan gum). The viscous solution is then left at room temperature for at least 8 hours to ensure a clear, bubble-free gel. The bubble-free gel (6.7 g) is poured onto a Petri dish (5 cm diameter) and dried in the oven at 50 ° C. for 5 hours. After this time, the dried Lactobacillus preparation is applied to one side of the film (loaded side). Glass rings of suitable size (height, 1 cm; diameter, 1 cm) are used to enclose a sufficient amount (10 mg, corresponding to 9.21 ± 0.25 log CFU) of LactobacilluszeWen and to cut the film into the final dosage forms. Finally, the Petri dish is placed in a desiccator at 20 ° C. for at least one day in order to complete the film formation (until the weight is constant).

The buccal films are further characterized according to Angela Abruzzo et al., Pharmaceutics 2020, 12 (3), 241. b) Subjects with chronic periodontal disease and evidence of H. pylori in plaque in deep gingival pockets and simultaneous dyspepsia receive 5 of the buccal films described above, which are preferably placed in the oral cavity (inside of the cheek) in the morning, at noon, in the afternoon and in the evening over a period of 2 - 30

Dissolve minutes.

Here, too, significantly less H. pylori can be detected in plaque after 28 days, clinical signs of periodontal disease have improved in more than half of the patients, and dyspeptic symptoms have improved significantly in more than 75% of the patients.

Claims

Patent claims:

1. Composition containing a physiologically effective dose of Lactobacillus cells in the form of a) a chewing gum, b) another preparation with an extended residence time in the mouth or c) a preparation with an area of application in the upper respiratory tract, for the treatment of H. pylori colonization of the upper respiratory tract , esophagus and / or digestive system.

2. Composition according to claim 1, wherein the Lactobacillus cells are selected from the group Lactobacillus crispatus, Lactobacillus gasseri, Lactobacillus lactis, Lactobacillus helveticus, Lactobacillus acidophilus, Lactobacillus bulgaricus,

Lactobacillus delbrueckii, Lactobacillus casei, Lactobacillus paracasei, Lactobacillus pentosus, Lactobacillus rhamnosus and Lactobacillus plantarum, Lactobacillus reuteri, Lactobacillus brevis, Lactobacillus brevis, Lactobacillus fermentum and / or virides bifidacillus, Bifidacillus.

3. Composition according to claim 1, containing an effective dose

Lactobacillus cells per application between 10 ³ and 10 ¹³ cells living, viable, dead or fragmented or cell wall components or isolated cell wall molecules each from 1 x10 ³ to 1x10 ¹³ cells per application.

4. Composition according to claim 3, containing an effective dose of Lactobacillus cells per application between 10 ⁹ and 10 ¹¹ cells living, viable, dead or fragmented or cell wall components or isolated cell wall molecules each from 10 ⁹ to 10 ¹¹ cells per application.

5. Composition according to claim 1, containing Lactobacillus reuteri as deposited under DSM 17648 in the form of chewing gum for the therapy of H. pylori colonization of the oral cavity, the upper respiratory tract, the esophagus, the stomach and the intestine.

6. Composition according to at least one of claims 1-5, containing Lactobacillus cells in viable or dead form.

7. Composition according to claim 1 in a dosage form selected from

Buccal tablets (also muco-adhesive buccal tablets) or orodispersible orodispersible tablets,

Oral active ingredient films

Gargle solutions or concentrates (incl. Powder / tablets for preparation) Mouthwash or concentrates (incl. Powder / tablets for preparation) Gum cleaning solutions

Oromucosal preparations, such as drops, gels, liquids, pastes, solutions, sprays and / or suspensions. Sublingual preparations, such as sprays, tablets, films, lozenges or candies Powders or granules for oral use - preparations for nasal use, such as nasal drops, liquid

Nasal sprays, nasal powders, semi-solid preparations for nasal use, nasal washes or nasal sticks.