WO1993009770A1 - Composition pharmaceutique bactericide contenant de la chlorhexidine et de l'eugenol - Google Patents
Composition pharmaceutique bactericide contenant de la chlorhexidine et de l'eugenol Download PDFInfo
- Publication number
- WO1993009770A1 WO1993009770A1 PCT/FR1992/001047 FR9201047W WO9309770A1 WO 1993009770 A1 WO1993009770 A1 WO 1993009770A1 FR 9201047 W FR9201047 W FR 9201047W WO 9309770 A1 WO9309770 A1 WO 9309770A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- eugenol
- chlorhexidine
- pharmaceutical composition
- composition according
- present
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Definitions
- the present invention relates to bactericidal pharmaceutical compositions, active on most of the bacterial species usually encountered in humans, the tolerance of these compositions being further improved.
- antiseptic drugs which can be defined as chemical agents which oppose the proliferation of bacteria and destroy them, have been proposed in therapy. Mention may in particular be made of halogens, heavy metal salts, quaternary ammoniums, salicylic acid and its derivatives.
- antiseptics are administered prophylactically or curatively.
- the present invention relates to a bactericidal pharmaceutical composition, characterized in that it comprises a synergistic association of ch lorhexidine and eugenol.
- Chlorhexidine, or l -hexamethylenebis [5- (p-chloroDhenyI) biguanide] is a local antiseptic described in US Pat. No. 2,684,924, and widely used in topical application, especially in ENT or uterine, and disinfectant.
- This compound can be put in the form of different salts; ! s) sei (s) used in the pharmaceutical composition will be chosen in function: ⁇ c _e its solubility in excipients and its non-toxicity.
- ⁇ * e chlorhexidine it is understood, throughout the description, as well based as one of its pharmaceutically acceptable salts, such as digluconate, diglucoheptonate, di-isethionate, diacetate or dichlorhy e of chlorhexidine.
- chlorhexidine can pre " ⁇ r a certain number of drawbacks like i'idiosyncrasy, the risk of systemic d 3 by skin penetration during repeated applications and, in the case of administration in the form of mouthwash, blackening * . teeth.
- Eugenol is a molecule used in perfumery, for clove aroma and in dentistry for its analgesic properties associated with a slight antiseptic action.
- CMB maximum bactericidal concentrations
- chlorhexidine-eugenol association which is the subject of the present invention, manifests however a cytotoxic activity much lower than that which can be observed for other combinations of antiseptics.
- This characteristic is of major interest in vivo, where the cells involved in the immune defense system are in contact with the administered antiseptic. This is especially true in the case of periodontal and dental conditions where these cells are called to the site of infection.
- a composition with reduced cytotoxicity (expressed by a relatively high FCC index) will be less traumatic for the subject and will therefore cause fewer side effects.
- composition containing a chlorhexidine / eugenol association differs from the other compositions that can be envisaged, in that it exhibits both a strong synergy of bactericidal effects, and a weak cytotoxic sy nergy, which results in a difference between FCC and high BCF, on average 0.194.
- a pharmaceutical composition according to the invention will comprise chlorhexidine, present at a concentration between 0.01% w / v and 0.5% w / v, and eugenol, present at a concentration between 0 , 05% w / v and 1% w / v.
- the chlorhexidine concentration may be between 0.02% w / v and 0.2% w / v.
- the concentration of eugenol in the composition is between 0.08% w / v and 0.64% w / v.
- compositions comprising a combination of chlorhexidine and eugenol within the indicated concentration limits, will exhibit good bactericidal activity, without the need to increase the doses of each of these products.
- too high a concentration of eugenol leads to a pronounced clove taste which is not satisfactory for the patient.
- concentrations of eugenol used in a preferred manner in the present invention overcome this drawback while ensuring synergistic bactericidal activity making it possible to considerably reduce the chlorhexidine concentrations.
- the chlorhexidine / eugenol ratio will preferably be between 2/1 and 1/32. which makes it possible to observe good BCF indexes (much lower than 0.75). This for chlorhexidine concentrations between 200 and 2000 ⁇ g / ml, and eugenol concentrations between 800 and 6400 ⁇ g / ml.
- this chlorhexidine / eugenol ratio will be less than 1.
- compositions according to the invention in which the chlorhexidine / eugenol ratio is preferably equal to approximately 1/4.
- the subject of the present invention is therefore a composition containing a synergistic association of chlorhexidine and eugenol, the chlorhexidine concentration being between 200 and 1000 ⁇ g / ml, and the eugenol concentration being between 800 and 4000 ⁇ g / ml, with a chlorhexidine / eugenol ratio equal to approximately 1/4.
- a pharmaceutical composition as defined in the present invention may more particularly have an activity which is exerted on the bacterial strains responsible for affections of the oral cavity such as caries, periodontal diseases and mycoses.
- the microenvironment of subgingival bacteria is a complex medium, mainly composed of crevicular fluid, rich in proteins, reducing the bactericidal activity of chlorhexidine.
- Candida albicans is most often responsible for oral yeast infections, and also sensitive to the compositions according to the invention.
- the pharmaceutical composition is characterized in that it is a stomatological composition intended to be administered locally in the oral cavity, in particular in the form of a mouthwash.
- a nipple a sucking tablet, a gingival balm or a solution for irrigating the periodontal pockets. It obviously includes all the excipients necessary for its formulation as well as preservatives, dyes, etc.
- All these administrations may be carried out for preventive or curative purposes, in a single or repeated manner.
- the present invention relates to a pharmaceutical composition containing a synergistic bactericidal association such as has been defined, and characterized in that its activity is exerted on the strains of skin bacteria.
- the present invention therefore relates to a dermatological composition, intended to be applied locally, in particular in the form of a lotion, cream or ointment.
- compositions may also contain other active principles such as, for example, inflammatory agents whose action will be advantageously complementary to the activ I was bactericidal.
- Figure 1 Representation in logarithmic and decimal coordinates of the activity of chlorhexidine / eugenol associations on a strain of Capnocytophaga ochracea.
- Figure 2 Representation in logarithmic and decimal coordinates of the activity of chlorhexidine / eugenol associations on a strain of Streptococus mutans.
- strain '2 and 3 Three bacterial strains of each species have been tested, two are of periodontal origin (strain '2 and 3), the third strains carry the following references:
- Capnocytophaga ochracea IPP 8210 (Capnocytophaga 1)
- Candida albicans 3 one strain is of oral origin (C. albicans 3), the other two are referenced:
- Candida albicans ATCC 2091 (C. albicans 1)
- Candida albicans ATCC 10231 (C. albicans 2).
- the method used is a dilution-neutralization micromethod (according to the AFNOR NF T 72-150 standard), adapted to the chessboard technique.
- this method consists in carrying out a complete association of two serial dilution ranges of two antimicrobials, so that each concentration of an antimicrobial is in the presence of all the concentrations of the other antimicrobial range, and vice versa.
- the results can be expressed by calculating the BCF index.
- the FBC index accounts for the type of interaction between two products A and B, it is defined as follows:
- Table 1 reports, for each strain tested, the minimum index BCF values as well as the CMB of associated products corresponding to it, and the CMB of non-associated products.
- the chlorhex idine / eugenol associations were found to be synergistic on all of the strains tested.
- the BCF indexes determined are all much lower than the BCF index corresponding to the synergy limit (0.75) since the maximum obtained is 0.53 1.
- the CMBs of the associated products are divided:
- results can also be expressed in the form of a graphical representation:
- the first is a representation in logarithmic coordinates and "simulates" the association microplate. For each coordinate, the concentrations of each associated product or only l are reported (intersection with the axes). The bold lines link the limit points for bactericidal disease. For each association, the theoretical limits of synergy were represented at the same time as the experimental curve.
- the second is the association's isobologram, represented in decimal coordinates.
- Chlorhexidine digluconate (CHX), cetylpyridini um chloride (CCP), polyvinylpyrrolidone iodine (PVPI), hexetidine, eugenol, and hexamidine were combined in pairs.
- Table 2 shows the average of the minimum BCF index obtained on all the strains. We note that certain combinations lead to simply additive or even antagonistic associations (BCF> 2); the best BCF index is obtained with the chlorhexidine / eugenol combination.
- Example 2 The toxic activity of the synergistic associations defined in Example 2 was tested on the main cellular elements involved in the immune defense mechanisms (polynuclear and macrophages), as well as on the epithelial cells of the mouth. Table 3 shows that the associations more synergistic in bactenidia are also shown to be synergistic towards polynuclear cells. This characteristic is defined by the calculation of an FCC index.
- the FCCs obtained do not, however, follow the values of the index BCFs since the chiorhexidine-eugenol association, very synergistic in bactenidia, present in cytotoxicity, a much more moderate synergy.
- chlorhexidine-eugenoi association presents the largest difference between FCC and FBC (ideally, we seek FCC - FBC as large as possible).
- the DB 8453 solution has the same activity for a lower chlorhexidine concentration 4 times, therefore fewer side effects (such as blackening of the teeth).
- the DB 8454 solution shows a marked increase in bactericidal activity for an identical chlorhexidine concentration.
- Formulation 2 (DB 8453) - Chlorhexidine digluconate 0.025 g - Eugenol 0.1 g - Chlorobutanol 0.5 g - Poloxamer 188 1 g - Ethyl alcohol at 95 ° 35 ml - Sorbitol 44 g - Menthol nature 0.150 g - Methyl parahydrobenzoate 0.090 g - Propyl parahydrobenzoate 0.045 g - Mint essence 1/200 1.5 ml - Coccine red dye 0.003 g - Sterilized water qs 100 ml
- Formulation 3 (DB 8454) - Chlorhexidine digluconate 0.1 g - Eugenol 0.4 g - Chlorobutanol 0.5 g - Poloxamer 188 1 g - Ethyl alcohol at 95 ° 35 ml - Sorbitol 44 g - Menthol nature 0.150 g - Methyl parahydrobenzoate 0.090 g - Propyl parahydrobenzoate 0.045 g - Mint essence 1/200 1.5 ml - Coccine red dye 0.003 g - Sterilized water qs 100 ml Formulation 4 - Chlorhexidine digluconate 0.2 g - Eugenol 0.4 g - Chlorobutanol 0.5 g - Poloxamer 188 1 g - Ethyl alcohol at 95 ° 35 ml - Sorbitol 44 g - Plain menthol 0.150 g - Methyl para
Abstract
Description
Claims
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP93900241A EP0612243A1 (fr) | 1991-11-13 | 1992-11-12 | Composition pharmaceutique bactericide contenant de la chlorhexidine et de l'eugenol |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9113919A FR2683454B1 (fr) | 1991-11-13 | 1991-11-13 | Composition pharmaceutique bactericide. |
FR91/13919 | 1991-11-13 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1993009770A1 true WO1993009770A1 (fr) | 1993-05-27 |
Family
ID=9418837
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FR1992/001047 WO1993009770A1 (fr) | 1991-11-13 | 1992-11-12 | Composition pharmaceutique bactericide contenant de la chlorhexidine et de l'eugenol |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP0612243A1 (fr) |
FR (1) | FR2683454B1 (fr) |
WO (1) | WO1993009770A1 (fr) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005058364A2 (fr) * | 2003-12-12 | 2005-06-30 | Reckitt Benckiser Healthcare (Uk) Limited | Systeme de preservation |
US7008649B2 (en) | 1998-12-07 | 2006-03-07 | Ecosmart Techonlogies, Inc. | Cancer treatment composition and method using natural plant essential oils with signal transduction modulators |
JP2013067570A (ja) * | 2011-09-21 | 2013-04-18 | Sunstar Inc | 口腔用組成物 |
WO2019083397A1 (fr) | 2017-10-23 | 2019-05-02 | Общество С Ограниченной Ответственностью "Сан Системз" | Solubilisation de la base de chlorhexidine, compositions antiseptique et désinfectante |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2972347B1 (fr) * | 2011-03-11 | 2013-04-12 | Pf Medicament | Composition de soin et/ou d'hygiene bucco-dentaire |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS57179108A (en) * | 1981-04-25 | 1982-11-04 | Sunstar Inc | Cement composition for filling of dental root canal |
JPH0629177B2 (ja) * | 1984-06-01 | 1994-04-20 | ライオン株式会社 | 口腔用組成物 |
-
1991
- 1991-11-13 FR FR9113919A patent/FR2683454B1/fr not_active Expired - Fee Related
-
1992
- 1992-11-12 EP EP93900241A patent/EP0612243A1/fr not_active Withdrawn
- 1992-11-12 WO PCT/FR1992/001047 patent/WO1993009770A1/fr not_active Application Discontinuation
Non-Patent Citations (2)
Title |
---|
PATENT ABSTRACTS OF JAPAN vol. 10, no. 131 (C-346)(2188) 15 Mai 1986 * |
PATENT ABSTRACTS OF JAPAN vol. 7, no. 22 (C-148)(1167) 28 Janvier 1983 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7008649B2 (en) | 1998-12-07 | 2006-03-07 | Ecosmart Techonlogies, Inc. | Cancer treatment composition and method using natural plant essential oils with signal transduction modulators |
US7291650B2 (en) | 1998-12-07 | 2007-11-06 | Ecosmart Technologies, Inc. | Cancer treatment composition and method using natural plant essential oils |
WO2005058364A2 (fr) * | 2003-12-12 | 2005-06-30 | Reckitt Benckiser Healthcare (Uk) Limited | Systeme de preservation |
WO2005058364A3 (fr) * | 2003-12-12 | 2006-02-23 | Reckitt Benckiser Healthcare | Systeme de preservation |
JP2013067570A (ja) * | 2011-09-21 | 2013-04-18 | Sunstar Inc | 口腔用組成物 |
WO2019083397A1 (fr) | 2017-10-23 | 2019-05-02 | Общество С Ограниченной Ответственностью "Сан Системз" | Solubilisation de la base de chlorhexidine, compositions antiseptique et désinfectante |
Also Published As
Publication number | Publication date |
---|---|
EP0612243A1 (fr) | 1994-08-31 |
FR2683454B1 (fr) | 1995-06-09 |
FR2683454A1 (fr) | 1993-05-14 |
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