Use of octenidine dihydrochloride in semi-solid preparations

Abstract

Use of octenidine dihydrochloride for the preparation of a semi-solid pharmaceutical composition for the treatment of wounds, wherein the composition contains 0.005 to 5 wt.% octenidine dihydrochloride, characterized in that the composition is an emulsifier-free aqueous-alcoholic gel.

Description

[0001] The present invention relates to the use of octenidine dihydrochloride for the preparation of a semi-solid pharmaceutical composition for the treatment of wounds, atopic dermatitis, infected eczema, dermatomycoses, vaginal infections, acne, herpes and / or for combating multi-resistant pathogens.

[0002] The use of semi-solid pharmaceutical compositions for the treatment of wounds, infected eczema, dermatomycoses, vaginal infections, acne, herpes, and / or for combating multidrug-resistant pathogens is well known. The state of the art in the treatment of atopic dermatitis or infected eczema, for example, is the use of antibiotics such as bufexamac, which are known to lead to the development of resistance. The development of resistance is exacerbated by frequent use of antibiotics, leading to the well-known MRSA problems. Imidazoles (e.g., clotrimazole) are used to treat dermatomycoses, which are highly recurrent. For the treatment of vaginal infections, preparations specifically designed for vaginal mycoses are used (again, the aforementioned imidazoles with the disadvantages described above) or preparations specifically designed for bacterial infections (e.g., poly(propylene glycol)-iodine, which has the disadvantage of soiling underwear).State-of-the-art treatments for acne include antibiotics (e.g., erythromycin, neomycin, tetracyclines; disadvantage: risk of resistance development), benzoyl peroxide (disadvantage: skin irritation, drying of the skin), tretinoin (vitamin A acid; disadvantage: skin irritation), and other active ingredients such as salicylic acid, sulfur, or resorcinol, which have disadvantages due to poor tolerability. Antiviral drugs (e.g., acyclovir) are currently primarily used to treat herpes, which cause skin intolerance in the form of redness and scaling. Antibiotics are currently used to treat multidrug-resistant pathogens (e.g., MRSA), which, as described above, lead to the development of resistance.

[0003] Known semi-solid products with antimicrobial agents are therefore associated with numerous disadvantages, including: - Development of resistance (e.g. antibiotics), - strong inherent coloration of the preparation, which is often not accepted by users (PVP-iodine, antimicrobial dyes such as gentian violet and brilliant green), - toxicological concerns - limited spectrum of activity (e.g. Triclosan).

[0004] WO 02 / 02128 relates to the promotion of whole body health in humans and animals through the use of topical oral compositions containing a safe and effective amount of an antimicrobial agent in admixture with a pharmaceutically acceptable carrier, the compositions being effective in controlling bacterially mediated diseases and conditions in the oral cavity and preventing the spread of pathogenic oral bacteria, associated bacterial toxins and endotoxins, and resulting inflammatory cytokines and mediators into the bloodstream.

[0005] DE 3925540 C1 relates to an aqueous antiseptic composition for mucous membrane and wound treatment, characterized by a content of a) N,N min -(1,10 decanediyldi-1[4H]pyridinyl-4-ylidene)bis-(1-octanamine) dihydrochloride (octenidine) and b) phenoxyethanol (POE) and / or phenoxypropanol (POP) in a weight ratio of octenidine to POE or POP of 1:20 to 1:1 at an octenidine concentration of 0.05 to 0.5 wt% and a POE or POP concentration of 5 to 0.5 wt%.

[0006] The object of the invention was therefore to provide pharmaceutical compositions that do not have these disadvantages, are effective against a wide variety of germs, can be formulated with a variety of formulation bases for pharmaceutical compositions, and are suitable for the treatment of wounds, atopic dermatitis, infected eczema, dermatomycoses, vaginal infections, acne, herpes, and / or for combating multidrug-resistant pathogens. In particular, the compositions should be toxicologically safe and not prone to the development of resistance.

[0007] It has now been surprisingly found that this object is achieved by the use of octenidine dihydrochloride for the preparation of a semi-solid pharmaceutical composition for the treatment of wounds, wherein the composition contains 0.005 to 5 wt.% octenidine dihydrochloride, characterized in that the composition is an emulsifier-free aqueous-alcoholic gel. The invention further relates to semi-solid pharmaceutical compositions which are an emulsifier-free aqueous-alcoholic gel containing 0.005 to 5 wt.% octenidine dihydrochloride for the treatment of wounds. The term "semi-solid" refers to all dosage forms that are neither solid (tablets, capsules) nor liquid (drops, syrups). Semi-solid dosage forms

[0008] Ointments (Latin: unguenta) are spreadable preparations intended for application by applying or rubbing onto the skin. They consist of one or more ointment bases (such as petrolatum, wool fat, lanolin, etc.) into which the active ingredient is incorporated. The active ingredient should be dissolved or finely dispersed. To increase solubility, ointments often contain water or oils. However, in an ointment, the fat / oil content is higher than the water content.

[0009] Creams are very similar to ointments, but they contain more water than fat / oil.

[0010] CreSa is an abbreviation for a combination of cream and ointment.

[0011] In the case of ointments and creams according to the invention, the viscosity is generally 500 to 15,000 mPa s, preferably 1,000 to 10,000 mPa s, measured with a rotational viscometer at 95 s -1 and 20 °C.

[0012] Paste is the name given to ointments containing large amounts of powdered ingredients (e.g., zinc oxide, talc, etc.). Pastes contain no water and, due to their high powder content, are considerably firmer than ointments.

[0013] Aqueous-alcoholic gels (hydrogels) are valued for their transparency and non-greasy nature. Lipophilic gels (oleogels) are also used for their aesthetic appearance and consistency-giving properties. Gels are primarily intended for external use and should be applied thinly.

[0014] A hydrogel is a mostly translucent substance made from gelatin, tragacanth, carbopol, or similar swelling agents with the addition of water and glycerin. When the water evaporates, they have a cooling effect.

[0015] The lipophilic gels comprise a lipophilic phase. Besides higher molecular weight homologues of the lipid phase, organo-modified bentonites (Benton ® ) and highly dispersed silicon dioxide are used.

[0016] An emulsion is a preparation consisting of immiscible liquids, such as oil and water. A distinction is made between W / O (water in oil) or O / W (oil in water) and ambiphilic emulsions. These must be shaken vigorously before use. The addition of an emulsifier enables the finest dispersion of the liquids, making the emulsions stable, meaning the oil and water do not separate again. Depending on the application, emulsions are intended for internal or external use. Emulsions for external use are often referred to as lotions. This is an oil-in-water emulsion.

[0017] CreLo is a combination of cream and lotion.

[0018] Suppositories (Latin: suppositoria) are variously shaped, single-dose medicinal preparations intended for insertion into the rectum, where they release their active ingredient after melting or dissolving. They consist of a hard fat (e.g., Stadimol) or polyethylene glycol, into which the active ingredient is incorporated under heat. This heated mass is then poured into molds. Hard fat suppositories are heat-sensitive and should therefore never be stored above 25°C. A typical suppository size for adults is about 2 g and for children about 1 g. Suppositories are best inserted after a bowel movement and in the supine position. To make insertion easier, the suppositories can be immersed in water beforehand. Rubbing them in with creams or ointments should be avoided, as this can impair the effectiveness of the suppositories.

[0019] Suppositories for vaginal insertion are divided into vaginal suppositories and vaginal spheres (Latin: ovulum). Vaginal suppositories are similar in their manufacturing and composition to "regular" suppositories. Vaginal spheres are usually made of gelatin, water, and glycerin and have a spherical shape. Both dosage forms weigh approximately 3 g. They should be used in the evening, if possible, while lying on your back. Creams should also be avoided during insertion. The manufacturer provides an insertion aid with various suppositories. It is also important to store them below 25°C.

[0020] Octenidine dihydrochloride corresponds to the following formula:

[0021] The active ingredient has been used for many years in a mucous membrane and wound antiseptic in the form of an aqueous solution (see the preparation Octenisept ®Schülke & Mayr GmbH, Norderstedt, Germany). However, this application form limits its use in some indications. If the product is to remain on the surface to be treated (e.g., skin or mucous membranes) for a longer period of time for therapeutic reasons, the preparation must be spreadable. However, it was surprising that a wide variety of semi-solid pharmaceutical compositions can be formulated using octenidine dihydrochloride as the active ingredient, with the selection of ingredients ensuring good tolerability in accordance with the respective indication.

[0022] In a preferred embodiment, the composition contains 0.01 to 2 wt% octenidine dihydrochloride, preferably 0.02 to 1 wt%, more preferably 0.03 to 0.8 wt%, in particular 0.05 to 0.5 wt%.

[0023] The composition is in the form of a gel. A preferred embodiment is one in which the composition is formulated for topical (external) or rectal or vaginal application.

[0024] According to the invention, the composition can contain additional active ingredients that complement the effectiveness of octenidine dihydrochloride and can optionally be used in a significantly lower concentration than in known commercial products when combined with octenidine dihydrochloride. This can significantly reduce some of the existing disadvantages. These additional active ingredients include: clotrimazole and other locally effective antifungals, cortisones, tretinoin, benzoyl peroxide, acyclovir, local anesthetics (e.g., benzocaine, lidocaine, polidocanol, etc.), antibiotics, bufexamac, etc. 1. Wound treatment

[0025] According to one embodiment, the composition according to the invention is used for the treatment of wounds. An emulsifier-free formulation containing a high level of moisturizing factors (namely, a gel) is selected. 2. Atopic dermatitis or infected eczema

[0026] When using the composition containing octenidine dihydrochloride to treat infected eczema, it is preferably formulated as an oil-in-water (O / W), water-in-oil (W / O) or ambiphilic emulsion (creams), depending on the skin type. 3. Dermatomycoses

[0027] Gels and creams are preferred as semi-solid formulations for the treatment of mycoses. 4. Vaginal infections

[0028] Creams and suppositories are preferred dosage forms for the treatment of vaginal infections. In such formulations, octenidine dihydrochloride exhibits a particularly beneficial effect because it is effective against both fungi and bacteria, eliminating the need for two different preparations.

[0029] The advantages of the invention will become apparent in particular from the following examples. Example Example 1 Fucidin Cream (Comparison)

[0030] 1 ml contains: Fusidic acid (antibiotic) 19.72 mg, other ingredients: cetyl alcohol, butylhydroxyanisole, glycerol, potassium sorbate, polysorbate 60, hydrochloric acid, petrolatum, water.

[0031] The following formulations according to the invention were prepared: 1. Gel 0,05 g Octenidine dihydrochloride 9,90 g Propylene glycol 2,50 g Hydroxyethylcellulose Water ad 100.00 g

[0032] In such gels, the viscosity is generally about 4500 to 5 500 mPa s (rotational viscometer RS600, sensor Z40 DIN Ti, Thermo Haake, at 34 s -1 , 20 °C). 2. Ointment (comparison) 0,2 g Octenidine dihydrochloride 6,0 g Wool wax alcohols (mixture of sterols and higher aliphatic alcohols from wool wax, 33.5 wt% cholesterol) 0,5 g Cetylstearyl alcohol 3,0 g Paraffinum liquidum

[0033] Vaselinum album ad 100,00 g 3. O / W cream (comparison) 0,1 g Octenidine dihydrochloride 4,0 g Glycerol monostearate 40-50 6,0 g Cetyl alcohol 7,5 g Medium-chain triglycerides (at least 95% by weight saturated fatty acids with 8 to 10 carbon atoms) 25,5 g White petrolatum 7,0 g Macrogol 1000 glycerol monostearate

[0034] The viscosity of such creams is in the range of approximately 5,000 to 6,500 mPa·s (rotational viscometer RV20, system M5, measuring device SV1, Thermo Haake, at 95 s -1 , 20 °C). 4. W / O cream (comparison) 0,50 g Octenidine dihydrochloride 4,00 g Lameform TGI (triglycerol diisostearate) 2,00 g Monomuls 90-018 (glycerol oleate) 3,00 g Beeswax, white 2,00 g Zinc stearate 10,00 g Eutanol G (2-octyldodecanol) 10,00 g Isopropyl myristate 5,00 g Glycerol 85% w / w 1,00 g Mg sulfate water ad 100.00 g 5. W / O cream (comparison) 0,30 g Octenidine dihydrochloride 2,63 g Monomuls 90-018 2,11 g Beeswax, white 2,11 g Zinc stearate 3,16 g Glycerol 85% w / w 0,74 g Mg sulfate 5,26 g Paraffin thin liquid 10,53 g Cetiol V (decyl oleate) water ad 100.00 g 6. A. Antifungal Gel (Comparison) 0,1 g Octenidine dihydrochloride 0,5 g Clotrimazole 30,6 g 1-Propanol 10,0 g Dehyton K (cocoamidopropyl betaine) 2,5 g Natrosol 250 HHX Pharm, Tylose H 100,000 p (hydroxyethyl cellulose) Water ad 100.00

[0035] The viscosity of such antifungal gels is usually around 250,000 to 400,000 mPa s (rotational viscometer RV20, system M5, measuring device SV2, Thermo Haake, at 0.45 s -1 , 20 °C).

[0036] Formulation 6B is equivalent to Formulation 6A but does not contain octenidine dihydrochloride. 7. Antifungal Cream (Comparison) 0,1 g Octenidine dihydrochloride 0,5 g Clotrimazole 0,6 g Cremophor A 25 (Ceteareth-25) 5,0 g Cutina GMS (Glycerol Stearate) 10,0 g Eutanol G (Octyldodecanol) 8,0 g Lanette O (cetostearyl alcohol) 0,5 g Silicone oil 1,0 g Phenoxyethanol 4,0 g Sorbitol water ad 100.00 g

[0037] For such creams, the viscosity is typically about 1,000 to 2,000 mPa s (rotational viscometer RV20, system M5, measuring device SV2, Thermo Haake, 160 s -1 , 20 °C). 8. Vaginal suppositories (comparison) 0,2 g Octenidine dihydrochloride

[0038] Macrogol 1000 ad 100 g Example 2Method

[0039] The bactericidal and fungicidal efficacy was determined in a quantitative suspension test with high protein load ("dirty conditions") according to the standard methods of the German Society for Hygiene and Microbiology (DGHM) for testing chemical disinfection processes (as of September 1, 2001). For methodological reasons, ready-to-use preparations can only be tested at concentrations ≤ 80 wt.%. Test organisms Staphylococcus aureus ATCC 6538 Pseudomonas aeruginosa ATCC 15422 Escherichia coli ATCC 10538 Enterococcus hirae ATCC 10541 Candida albicans ATCC 10231

[0040] 2.1 Quantitative suspension test with high protein load (RF values) with formulation 1 (gel) 1 minute 5 minutes 15 minutes S. aureus 80% by weight ≥6,32 ≥6,31 ≥6,27 50 wt.% ≥6,32 ≥6,31 ≥6,27 P. aeruginosa 80% by weight ≥6,1 ≥6,15 ≥6,12 50 wt.% 0 2,10 5,52 E. coli 80% by weight ≥6,03 ≥6,12 ≥6,08 50 wt.% ≥6,03 ≥6,12 ≥6,08 E. hirae 80% by weight ≥6,12 ≥6,12 ≥6,08 50 wt.% 5,82 ≥6,12 ≥6,08 C. albicans 80% by weight ≥5,67 ≥5,46 ≥5,43 50 wt.% 2,17 3,94 ≥5,43

[0041] This formulation is a wound gel for wound treatment with rapid efficacy and a high proportion of moisturizing factors, which is required for moist wound treatment. The results show that the ready-to-use gel is sufficiently effective against all test organisms after just 1 minute of contact time, even with high protein load. 2.2 Quantitative suspension tests with formulation 3 (O / W cream)

[0042] 10 g of Formulation 3 were weighed and mixed with 0.1 ml of Staph. aur. and Staph. epidermidis germ suspensions. The germ suspension was thoroughly worked into the cream using a glass rod to ensure good and even distribution. After 6 hours, 1 g of cream was removed and thoroughly mixed with 9 ml of decongestant solution. After a 20-minute exposure time, 0.1 ml was removed and spread onto an agar plate containing casein, soy peptone agar. Result: germ Formulation 3 Placebo formulation 3 Sample 1 Sample 2 Sample 1 Sample 2 Staph. aur. 0 CFU 0 CFU Lawn growth Lawn growth Staph. epid. 0 CFU 0 CFU Lawn growth Lawn growth

[0043] Formulation 3 shows complete efficacy, meaning no colony-forming units (CFU) are detected, whereas the placebo, due to the absence of octenidine (placebo), showed a lawn growth. CFUs could no longer be counted. 2.3 Skin tests with formulation 3

[0044] For this purpose, 5 cm 20.1 ml of a Staph. epidermidis bacterial suspension (skin testing is not permitted with Staph. aur.) was applied to the forearm and allowed to dry. Subsequently, 0.1 g of Formulation 3 was applied to one forearm and 0.1 g of Fucidin cream to the other. The cream was spread evenly with a finger cot and allowed to absorb. The treated areas were then covered with a swab and secured with a transparent bandage (Tegaderm, 3M). After 2 or 6 hours, any remaining germs were removed with a decongestant solution using the ring method (d = 3 cm). Another skin area was treated with water and served as a control. A mixture of Tween 80, saponin, histidine, and cysteine ​​was used as the eluent. Exposure time RF values Formulation 3 2 hours 2,72 Formulation 3 6 hours 2,91 Fucidin cream 2 hours 1,63 Fucidin cream 6 hours 2,09

[0045] Formulation 3 shows better efficacy than Fucidin cream after both 2 hours and 6 hours. on formulation 6 Method: Plate diffusion test 1. Agar hole test solutions and culture media: CSA (casein peptone-soy flour peptone agar) SA (Sabouraud Dextrose Agar) CSL (casein peptone-soy flour peptone solution) NaCl (physiological saline solution, 0.85 wt%) Malt (wort peptone agar) Test germs: Staphylococcus aureus ATCC 6538 Pseudomonas aeruginosa ATCC 15442 Escherichia coli ATCC 11229 Candida albicans ATCC 10231 Aspergillus niger ATCC 6275 Cultivation and preparation of the inoculation solutions:

[0046] Bacteria: 24-hour 10 ml CSL cultures are prepared from 24-hour CS slants. The titer of the bacterial suspensions is ~10 9 CFU / ml. Yeasts: 72-hour 10 ml CSL cultures are prepared from 72-hour malt plate cultures. The titer of the yeast suspension is ~10 8 CFU / ml. Molds: A 7- to 14-day-old A. niger culture on Sabouraud agar is washed with 5 ml of sterile NaCl solution, filtered through a sterile glass funnel with glass wool, and made up to 100 ml. This is diluted 1:100 with sterile NaCl solution before use. The titer of the mold suspension is ~10 6 CFU / ml. Implementation:

[0047] 0.1 ml of the bacterial suspension is spread onto CSA.

[0048] 0.1 ml of the C. albicans suspension is spread onto SA.

[0049] 0.2 ml of the A. niger suspension is spread onto SA.

[0050] A 9 mm diameter hole is punched in the center of the agar plates using a flame-treated cork borer. This hole is filled to the brim with the sample to be tested. The plates are allowed to stand at room temperature for 2 hours to pre-diffusion.

[0051] Bacteria and yeasts are incubated at 36 °C for 24 to 48 hours. Molds are incubated at 25 °C for 3 days. Evaluation:

[0052] The zone of inhibition is measured from the edge of the hole to the beginning of germ growth. It is given in mm. If the germ has grown to the edge of the hole, the zone of inhibition is 0 mm. Results 0.1 ml of germ suspension was spatulated out 0.15 g of gel per hole 6A 6B Staph. aureus 5 5 E. coli 2 0 Pseud. aerug. 3 2,5 Miraculous Proteus 2,5 0 Streptococcus faecium 6 6 Candida albicans 5 6 Trichophyton mentagrophytes 20,7 20,0 Three-rue 15,0 7,3 Microsporum gypseum 22,7 17,3 Epidermophyton floccosum 35,0 34,7 Aspergillus niger 11,7 10,0 Penicillium fumigatus 10,3 10,0

Claims

[1] Use of octenidine dihydrochloride for the preparation of a semi-solid pharmaceutical composition for the treatment of wounds, wherein the composition contains 0.005 to 5% by weight of octenidine dihydrochloride, characterized by that the composition is an emulsifier-free aqueous-alcoholic gel. [2] Use according to claim 1, characterized by that the composition contains 0.01 to 2 wt% octenidine dihydrochloride, preferably 0.02 to 1 wt%, more preferably 0.03 to 0.8 wt%, in particular 0.05 to 0.5 wt%. [3] Use according to claim 1 or 2, characterized by that the aqueous-alcoholic gel is made from a swelling agent with the addition of water and glycerin. [4] Use according to claim 1, characterized by that the composition is a topical composition. [5] Semi-solid pharmaceutical composition which is an emulsifier-free aqueous-alcoholic gel and contains 0.005 to 5% by weight of octenidine dihydrochloride for the treatment of wounds. [6] Semi-solid pharmaceutical composition according to claim 5, characterized by that the composition contains 0.01 to 2 wt% octenidine dihydrochloride, preferably 0.02 to 1.5 wt%, more preferably 0.03 to 0.8 wt%, in particular 0.05 to 0.5 wt%. [7] Semi-solid pharmaceutical composition according to claim 5 or 6, characterized by that the aqueous-alcoholic gel is made from a swelling agent with the addition of water and glycerin. [8] Semi-solid pharmaceutical composition according to claim 5, characterized by that the composition is a topical composition.