WO2008090440A1

WO2008090440A1 - Lipid-based gynaecologic suppository

Info

Publication number: WO2008090440A1
Application number: PCT/IB2008/000135
Authority: WO
Inventors: Carlo Ghisalberti
Original assignee: Carlo Ghisalberti
Priority date: 2007-01-22
Filing date: 2008-01-22
Publication date: 2008-07-31
Also published as: ITMI20070084A1

Abstract

Vaginal suppository essentially formed by C 10-C12 lipids, namely medium chain fatty acid (MCFA) and monoglycerides thereof, with melting point from 32° to 36°C, optionally comprising additional ingredients to enhance the overall biocidal effect.

Description

LIPID-BASED GYNAECOLOGIC SUPPOSITORY

FIELD OF THE INVENTION

The invention refers to vaginal suppositories to treat infective vaginitis. BACKGROUND OF THE INVENTION

Gynaecologic infections, also named infective vaginitis or "vaginosis", are caused by the over-proliferation of a variety of opportunistic microbes.

The causative agents of the greyish smelling discharge are bacteria of the strain Gardnerella vaginalis, or anaerobic bacteria such as Bacteroides, Peptococcus, Mobiluncus, and Bacteroides spp. The itching or burning yellowish discharge are a clear indication of Trichomonas vaginalis, a sexually transmitted protozoa. The more common therapy is metronidazole, preferably extended to the partner. The itching, whitish discharge are mostly candidosis, i.e. infection by C. albicans, although also C. tropicalis and C. glabrata are spreading out and, unfortunately, more resistant to antifungal agents. The pharmacologic therapy use topical ciclopirox olamine and azoles; or systemic ketoconazole, fluconazole and itraconazole. Many women are often reluctant to undergo pharmacologic treatments in recurrent vaginitis due to a phsycologic or cultural resistance to the use of drugs. Untreated cases may increase the incidence of pelvic inflammatory disease (PID), endometritis, cervicitis, pregnancy complications, and HIV infections among other conditions. On the other side, the biocidal action of certain lipid and their monoglycerides was disclosed in the early 70s by Kabara et all.: U.S. 4,002,775; and Antimicrob. Agents Chemother., 1972; 2(1), 23- 28, 1973; 4(5),501-6. Monolaurin actually carry out a biocidal activity on a number of pathogen, e.g. Staphylococcus epidermis and S. aureus, Streptococcus agalactiae, Listeria m., and on gram negatives such as Vibrio par ahaemolyticus and H. pylori, on protozoa and on mycetes such as C. albicans. Capric acid were studied by Bergsson et all., Antimicrob Agent Chemother. 1998; 42(9):2290-4, e.g. in a virucidal cream (Pharmazie. 2005; 60(12):897-9).

Despites these and other researches about the biocidal activity of capric and lauric acid and monoglycerides, little if any follow-up is available on the marketplace.

Seemingly, the water-containing formulations studied by these authors may supply sub-inhibitory biocidal gradients, hence being ineffective in the clinical practice.

It would be therefore of interest to introduce a "low impact" gynaecologic therapy, both physiological and psychological, still having an effective antibiotic effect. SUMMARY OF THE INVENTION

We have developed methods and compositions for vaginal disinfection essentially using endogenous C 10-Cl 2 lipids, i.e. the so-called "medium chain fatty acids" (MCFA), and monoglycerides thereof, with optional minor amount of biocidal compounds to improve the action of said endogenous lipids.

The particular efficiency of the inventive device may be explained from the fact that it can overcome the biofilms resistance to water-containing formulations. In fact microbes can be up to 4,000 times more resistant than the same organism in a free-floating state. Comparisons of MIC (minimum inhibitory concentration) tests with MBEC (minimum biofϊlm eradication concentration) tests vividly display the differences in susceptibility from the planktonic to the biofϊlm state. In fact, classic other formulations can inadvertently expose the biofilm to a sub-lethal concentration of antibiotics, thereby also increasing the chances of development of resistance.

The methods and compositions are based upon a vaginal suppository substantially comprising said C 10-Cl 2 lipids in concentration not less than 95% w/w and having a melting point ranging from 32° to 36°C, preferably, but not necessarily, in the presence and one or more complementary ingredient.

The inventive method comprise the manufacturing of a suppository comprising at least 95% w/w of endogenous C 10-Cl 2 lipids and the local administration of said suppository so to release at least 6 mmol of MCFA-equivalents per unit dose. An increased biocidal effectiveness is produced in comparison to that produced by analogous water-containing compositions, either emulsified or gel-based.

The composition and methods also involve an increased biocidal activity of the ClO- C 12 lipids forming the vaginal suppository by minor amount of complementary ingredients in a homogenous system having melting point between 31.5 and 37.5°C.

It is an object of the present invention a gynaecologic suppository according to claim 1.

It is another object of the present invention the use of a composition comprising medium-chain fatty acids (MCFA) and monoglycerides thereof, according to claim 10.

It is a further object of the present invention a method for manufacturing a medicament intended for the treatment of infective vaginitis, characterized according to claim 11. BRIEF DESCRIPTION OF THE DRAWINGS Figures 1-4 illustrate the phase diagrams of the binary mixture of the C 10-Cl 2 lipids, i.e. the major components of the suppository of invention.

LEGEND Diagram phases: L = liquid state; M = melting phase; S = solid state.

Components of the binary blends: LA = lauric acid; CA = capric acid; MLA = monolaurin; MCA = monocaprin; UA = Undecylenic acid. The desired melting point - in the range of 32° to 36°C - is achieved within (inside) the horizontal white lines. DETAILED DESCRIPTION OF THE INVENTION

The invention provides a gynaecologic composition for topical administration to treat infective vaginitis which is substantially formed by endogenous C 10-Cl 2 lipids, namely medium chain fatty acid (MCFA) and monoglycerides thereof, with optional minor amount of biocidal compounds to improve the action of said lipids.

In a first embodiment, the present invention is a vaginal suppository comprising MCFA and monoglycerides thereof in amount not less than 95% w/w characterized in that the melting point ranges from 32° to 36°C.

In a other embodiment, the vaginal suppository of the present invention is further characterised by the ability to release at least 6 mmol of MCFA-equivalents per unit dose, preferably about 12 mmol of MCFA-equivalents per unit dose, or even up to 24 mmol of MCFA-equivalents per unit dose.

The expression "C 10-Cl 2 lipids" as used herein means "medium chain fatty acids (MCFA) and monoglycerides thereof, hence including:

Capric (decanoic) acid: CAS 334-48-5 ; m.p. 31-33°C; MW 172.1

Undecanoic acid: CAS 112-37-8; m.p. 28-31°C; MW 186.29

Lauric (dodecanoic) acid: CAS 143-07-7; m.p. 43-45°C ; MW 200.3

Glyceril caprate (monocaprin) CAS 26402-22-2 ; m.p. 17.8°C ; MW 246.34

Glyceril laurate (monolaurin) CAS 27215-38-4 ; m.p. 56-60°C; MW 274.21

The suppository of the present invention comprises one or more MCFA selected among capric acid and lauric acid.

MCFA are commercially available, e.g.. from: Universal Preserv-A-Chem, Inc.; A&E Connock; Aceto Corp; Akzo Nobel; Alfa Pharmachem; Berje; Cognis; DeWoIf Chemical; Fleurchem; Penta Manufacturing; Spectrum Chemical Mfg.; Uniqema; Beckman Chemikalien; CasChem; Merck Schuchard; Protameen Chemicals; Stearinerie Dubois FiIs. The suppository of the present invention comprises one or more MCFA, and/or a MCFA-monoglyceride selected among monocaprin and monolaurin.

Monocaprin and monolaurin are commercially available, e.g. from: A&E Connock; Abitec Corp; Dr. Straetmans; Inolex Chemical; Stearinerie Dubois; Taiyo Kagaku; Cognis; Croda Chemicals; DeWoIf Chemical; Fitz Chem Corp; Jeen International; Med-Chem Labs; Protameen Chemicals; Sasol; Stepan Company; Ultra Chemical; Uniqema; Universal Preserv-A-Chem.

In another embodiment, the vaginal suppository of invention will comprise a) Cl 0-C 12 lipids in an amount not less than 95% w/w of the composition; b) omplementary ingredients account for the remaining 5% w/w of the composition; provided that such complementary ingredients do not alter the melting point range of the inventive suppository, i.e. ranging from 32° to 36°C.

Such complementary ingredients are selected from the group consisting of : bl) other MCFA-derivatives such as MCFA ester of polyols e.g. ethylen glycol laurate/caprate, propylene glycol caprate/laurate, 1,2-butylen glycol caprate/laurate, 1,2- pentylen glycol caprate/ laurate, 1,2-hexylen glycol caprate/laurate, and analogs; b2) other MCFA-derivatives such as MCFA-hydroxamic derivatives such as: decanoic acid hydroxamide ("DHA"), and dodecanoic hydroxamide. b3) gallic acid ester such as C6-C12 n-alkyl ester of gallic acid, e.g. octyl gallate, nonyl gallate, decyl gallate, and dodecyl gallate; or terpene alcohol ester of gallic acid as those cited in co-pending application PCT/IB07/003804, e.g. geranyl gallate, neryl gallate, farnesyl gallate, α-terpenyl gallate, fenchyl gallate, and bornyl gallate. b5) a terpene compound, or a natural oil comprising thereof, e.g. lavander oil, eucalyptus oil, thyme oil, origanum majorana oil, sage oil, and satureja oil. b6) antiobiotics including: azoles such as miconazole, clotrimazole, econazole, oxiconazole,; aralkylamines such as terbinafine, natrifme, morpholines, amorpholine; polyenes such as amphoteracin B, nystatin and natamaycin; hydroxypyridones such as ciclopirox olamine, octopirox, and rilopirox.

Infectious organisms often grow in biofilm systems that are commonly referred to as "slime". Such biofϊlms have a mechanical structure in addition to a chemical or biochemical structure. The effects of these biofϊlms on disinfectant agents, systems, and methods have not been well understood. The Applicant believes that the inventive suppository have a particular efficacy against biofilms that function to protect at least some of the infectious microbe in tha vaginal mucosa. In fact, the biofilm can establish a protective "matrix" of glycocalyx inducing a "biofilm resistance phenotype", that protects the colonizing organisms within the biofilm by multiple up- and down-regulation of specific genes.

The Applicant has discovered that the vaginal suppository of the invention in solid- massive form are effective in treating biofilms because they help to destroy the structure of the biofilm and allow the blend of C 10-Cl 2 lipids, with the further help of complementary ingredients, to kill or inhibit the growth of microbes within the vaginal biofilm. From the common experience, the same effect could not be achieved by, e.g., an ovule comprising MCFA in emulsion and/or in other diluted forms.

The present invention is illustrated by the following examples that should not be considered limiting.

EXAMPLES Examples 1-4 - Binary blends for suppositories

This study serves to establish the proper melting range of binary mixtures of capric acid (CA), undecyulenic acid (UA)₅ lauric acid (LA) and their monoglycerides thereof, monocarin (MCA) and monolaurin (MLA). The preferred mix is found slightly above and below the corresponding lines of 31.5 and 37.5°C. Examples 5-16 - Vaginal suppositories

The ingredient in proportion indicated in Tables I and II are mixed and melted at a temperature slightly exceeding 40°C, poured in a previously cooled, suppository forging die, then manually separated to afford suppositories of different weight size, from 1 to 3 g each, i.e. according to the die used.

The material are sourced from the following vendors: capric and lauric acid are distilled fraction (98%) from the Kortacid™ serie from Akzo Nobel, Sweden; monolaurin as Monomuls™ 90 L from Cognis Corp. or "Laurate de glycerol" from Stearinerie Dubiois, F; monocaprin as Capmul™ MCM (ClO) from Abitec Corp, USA.

Other materials are generally of reagent grade (Sigma- Aldrich). TABLE I

Ingredient (w/w) Ex. 5 Ex. 6 Ex. 7 Ex. 8 Ex. 9 Ex. 10 Ex. 11 Ex. 12

Capric acid 80 76 - - - - 10

Undecylenic acid - - - - - - - 25

Laurie acid 20 19 50 40 - 10 -

Monolaurin - 4499 6600 5555 4400 7755 75

Monocaprin _ 43 48 10

Lavander oil - 4

Thyme oil 1

Melting range (°C) 36-37 33-34 32-36 32-35 34-36 32-36 33-37 34-37

TABLE II

Ingredient (w/w) Ex. 13 Ex. 14 Ex. 15 Ex. 16 Ex. 17 Ex. 18 Ex. 19 Ex. 20

Capπc acid - - 5 - 5 - 19 19

Undecylenic acid - - - - - 5 - -

Laurie acid - - 10 - 10 10 39 39

Monolaurin 60 60 50 60 50 50 39 39

Monocaprin 38 39 34 38 34 34 - -

Dodecyl gallate 0.5 0.5 0.5 - - - 0.5 0.5

DHA - - - 0.5 - 0.5 - -

EDTA - - - - - - 0.5 -

Ciclopirox olamine - - - - - - 0.5 -

Clotrimazole - - - - 0.5 - - -

Lavander oil 1.5 0.5 0.5 1.5 0.5 0.5 1.5 2.5

Melting range (°C) 32-35 33-36 32-36 32-35 33-36 32-36 33-34 32-35

In vitro efficacy test

The enhanced antibiotic activity of MCFA and monoglycerides thereof by complementary ingredients has been evaluated in Applicant co-pending application PCT/IB07/00557, Examples 1-12 of Table I. Case study - In vivo efficacy test

A rapid agglutination test "Candida Bichro-Latex Albicans" (Technogenetics; Sesto SG, Italy) with specific monoclonal anti-body for C. albicans membrane antigens was applied to evaluate the activity of the suppository of the Example 20. A female volunteer (36 years old) affected by recurrent candidosis and positive upon a control of cervical swabs was treated with 2 suppositories in one day provided full clearance.

Claims

1. Gynaecologic suppository essentially comprising medium-chain fatty acids (MCFA) and/or monoglycerides thereof, characterized in that the melting point is in between 32 and 36°C, and further characterized in that a single dose will release from about 6 to about 24 mmoles of MCFA-equivalents.

2. The suppository of claim 1 wherein the MCFA and monoglycerides thereof are capric acid, lauric acid, monolaurin, and monocaprin, said lipids accounting from 90% to (preferably) 95% w/w of the suppository.

3. The suppository of claims 1 and 2 further comprising a MCFA-hydroxamic derivative such as decanoic acid hydroxamide or dodecanoic hydroxamide.

4. The suppository of claims 1 and 2 further comprising a gallic acid ester selected from the group consisting of octyl gallate, dodecyl gallate; geranyl gallate, neryl gallate, farnesyl gallate, α-terpenyl gallate, and bornyl gallate.

5. The suppository of claims 1 and 2 further comprising one or more terpene oil selected from lavander, eucalyptus, thyme, marjoram, sage, and satureja oil.

6. The suppository of claims 1 and 2 further comprising an antiobiotic selected from the group consisting of clotrimazole, econazole, miconazole, terbinafine, naftrifine, amorpholine, ciclopirox olamine, octopirox, and rilopirox.

7. Method for inhibiting a microorganism in infective vaginitis comprising admistration of a suppository that comprises MCFA and/or their monoglycerides thereof in amount from about 6 to about 24 mmoles of MCFA-equivalents in single dose, for a period of time effective to inhibit the microorganism.

8. The method of claim 7, wherein the microorganism is one or more of fungi, bacteria, yeasts, molds.

9. The method of claim 7, wherein the microorganisms are one or more from the group consisting of Gardner xlla vaginalis, C. albicans, and Trichomonas vaginalis.

10. Use of a composition comprising medium-chain fatty acids (MCFA) and/or monoglycerides thereof, said composition having melting point is in between 32 and 36°C, for the manufacture of a medicament for the treatment of infective vaginitis.

11. A method for manufacturing a medicament intended for the treatment of infective vaginitis, characterized in using one or more medium-chain fatty acids (MCFA) and/or monoglycerides thereof.