Patent Grant
9700051
This application is a 371 of PCT/FR2013/050021, filed on Jan. 4, 2013, which claims priority to French Application No. 1250312, filed Jan. 12, 2012.
The present invention concerns a disinfecting agent composition useful in particular for the disinfection of inert (or inanimate) material objects.
By “inert material object” is meant herein an object in inert materials i.e. non-living or non-biological material or not originating from living or biological material.
At the current time, this type of disinfection is performed either by sterilising heat treatment in an autoclave, or by washing or soaking with or in solutions of agents qualified as disinfectants.
A disinfecting agent is a chemical product which kills or inactivates microorganisms such as bacteria, viruses and protozoa. However, unlike an antiseptic agent which is intended to be applied to a human or animal body, or an antibiotic agent which is intended to be administered inside a human or animal body, a disinfectant agent is used to disinfect inert objects. There is a major difference between first an antibiotic activity (direct action on microorganisms and used in man inside the body) or antiseptic activity (destruction of microorganisms on the outer surfaces of the body, in particular living tissue, skin, mucosa), and secondly a disinfecting activity (destruction of microorganisms on inert objects). In practice the antibiotic or antiseptic activity of a chemical substance concerns the action on relatively reduced concentrations of bacteria which can be used in or on man inside or outside the body and must therefore have acceptable toxicity. Some of these antibiotics can be formulated for use as antiseptics. On the other hand, antiseptic or antibiotic agents cannot be used as disinfectants since the antibacterial and antifungal properties required for a disinfecting agent are much more drastic, the concentrations of bacteria to be killed being much higher, meaning that they cannot be used as medicinal products in particular on account of their toxicity.
In everyday language the term “disinfectant” often includes both disinfectants in the strict sense and antiseptics which may lead to confusion. In addition the term “antibacterial” is often misused as a synonym of antiseptic or disinfectant for commercial purposes to highlight the sterilising property of a product, without however heeding the medical specifications for a disinfectant or antiseptic in their strict sense.
Disinfecting agents in their strict sense form one of the four groups (disinfectants, protective products, anti-parasitic products, other products) of Biocides in the meaning of Directive 98/8/CE of the European Parliament and Council of 16 Feb. 1998 concerning the placing of biocidal products on the market. The disinfectants according to the present invention therefore have a precise denomination and a specific European legal status: they are neither antibiotics in the strict sense nor antiseptics.
There are European standards, EN 1040 (for bacteria) and EN 1275 (for yeasts) to qualify a chemical compound as chemical disinfecting agent for use in the pharmaceutical, medical, dental, veterinary, agri-food and industrial sectors, and for domestic or community use. According to the standards in force a disinfecting agent must kill 99.999% of targeted germs i.e. a 5-log reduction using an inoculum of 108 cfu/ml gram+ and gram− bacteria S. Aureus and P. aeruginosa, and 99.99% of fungi i.e. a 4-log reduction using an inoculum of 108 cfu/ml yeast (A. niger and C. albicans).
At the current time in the medical sector, and in particular for cleaning and pre-disinfecting medical instruments, use is made of solutions of disinfecting agents such as alcohol, acid or oxidizing compounds in particular acid glutaraldehyde, ethyl or isopropyl alcohol, sodium hypochlorite.
More particularly, in the case of cystic fibrosis which is a genetic disease characterized by recurrent lung infection, the treatment of this disease requires aerosol antibiotic therapy using nebulizers (1-4). However, on account of the repeated use of these devices, potentially pathogenic germs are frequently found in the nebulizer equipment and this microbial contamination may be the cause of patient re-infection and treatment failure (5-7). Therefore at the present time the cleaning and disinfection of nebulizing equipment are recommended (8). Disinfection can be obtained for example by soaking in solutions containing acetic acid (2%) or in boiling water (9-10). Other methods include soaking in ethanol (70%) or isopropyl alcohol (90%) for 5 minutes, rinsing with tap water followed by air drying (18-19). Sodium hypochlorite has also been recommended but with standards varying from one country to another (11-12). For example, the French association for combating cystic fibrosis recommends the use of sodium hypochlorite solution with 0.08% active chlorine for 15 to 30 minutes, whilst the American foundation recommends soaking of infected equipment in a solution with 0.13% active chlorine for 3 minutes. In 2001, Rosenfield et al. (18) were the first to study nebulizer contamination with a mixture of strains of S. aureus and P. aeruginosa, by using tap water for cleaning at 35° C. for 30 s followed by drying at ambient temperature. In 2006, a study (20) on the cleaning of ultrasonic nebulizers performed by patients indicated that those who carried out disinfection of the nebulizer with sodium hypochlorite (100 ppm) for 1 hour once a day after use, were less infected than the nebulizers disinfected after a waiting time of 24 hours. More recently Reychler et al. (12,18) compared the in vitro efficacy of numerous commercial disinfectants against numerous Gram positive and Gram negative bacteria, including sodium hypochlorite, 3.5% acetic acid, 0.5% Hexanios, washing-up detergent (0.5%) for 20 minutes and washer (dishwasher) with marked variations regarding the efficacy of these methodologies depending on the bacterial strains under consideration. Also, Monforte et al. (7) have shown that proper disinfection could entail washing of the nebulizer in soapy water after use of the equipment and soaking of this equipment in 1% solution of sodium hypochlorite up until the following use. By following this protocol only 12.5% of patient nebulizers were contaminated whilst 60% were contaminated after following other disinfecting routes. Additionally, the type and quality of water sources used for rinsing nebulizers are variable (demineralised water, tap water, sterile water) possibly leading to results of greater or lesser success. The cumbersome nature of these methods soon becomes apparent since patients use this equipment daily. Also these patients are very largely dependent on their families, in particular their children for everything related to care and maintenance of the equipment; the time to be devoted to mere cleaning of nebulizers for example amounts to a major drawback.
Also, these disinfecting agents are not satisfactory for the following additional reasons.
Some agents such as acid glutaraldehyde are not devoid of effects on equipment in plastic or treated metal material since they may lead to corrosion or degradation.
Also from an ecological viewpoint, one of the major problems is that these disinfecting agents after use are poured into urban wastewater networks even though they represent high quantities of corrosive and/or toxic products that are discharged into wastewater networks degrading piping and increasing the difficulty of controlling biological treatment in downstream treatment stations. Another problem related to toxicity is the relative hazardous nature of the handling of these products by users.
A further problem with disinfecting agents is that they may induce microorganism resistance or a relatively limited spectrum of antibacterial or antifungal action, in the same way as is known in therapy with antibiotic medications or antiseptics.
Finally, A. Niger is a filamentous fungus which forms spores that are difficult to eliminate. At the current time, treatment by disinfection with acid glutaraldehyde (0.5%) or alkaline glutaraldehyde can only obtain a 1-log reduction in the number of spores of A. Niger and within a time of 100 minutes (23,24).
It is the objective of the present invention to provide a disinfecting agent that is simple, effective, quick-acting, non-hazardous and practical to use for patient comfort and the comfort of patients' families.
More particularly one objective of the present invention is therefore to produce a novel less toxic disinfecting agent that can be recycled after use in wastewater networks without causing any ecological problem and which has a broad spectrum of action without inducing resistance.
A further objective is to provide a disinfecting agent which also kills fungus spores.
A further objective of the invention is to provide a disinfecting agent which has the fastest possible destructive action, in particular within less than 8H and in the form of an aqueous composition.
For this purpose the subject of the present invention is the use of a compound selected from among squalamine and a squalamine-analogue aminosteroid compound as agent to disinfect an inert material object, the said compound being formulated in the form of an aqueous or water-soluble composition.
The present invention also provides an aqueous or water-soluble disinfecting composition useful for a use of the invention, characterized in that as active disinfecting compound it comprises a said compound selected from among squalamine and a said antibacterial and antifungal squalamine-analogue aminosteroid compound with suitable excipients for a water-soluble or aqueous formulation.
By “squalamine-analogue aminosteroid compound” is meant herein an antibacterial and antifungal compound of formula I below.
Squalamine has been described (13-15, 22) as an antibacterial and antifungal agent for therapeutic use whose mode of action is original in that it acts as a detergent, hence it has a resulting broad spectrum of activity and especially action against multi-resistant bacteria and does not induce bacterial resistance. It has been described in WO 20011/067501 that squalamine and its aminosteroid analogues have antibiotic, antibacterial activity in topical application in the form of a lipophilic formulation, in particular an ointment, without cutaneous toxicity and without induced resistance on account of a mechanism of action differing from that of antibiotics, at concentrations of 0.5 to 5 mg/ml and allowing a 4-log reduction of a 106 cfu/ml concentration of S. aureus within 24 hours and a 5-log reduction within 48 hours. In addition an in vitro antifungal action has been described at squalamine concentrations of 4-16 ring/l allowing a 4-log reduction of a 106 concentration of A. niger within 24 hours.
Such results do not qualify squalamine and its aminosteroid analogues as disinfecting agent in accordance with the objectives of the invention, namely to eradicate much higher quantities of microorganisms while being in the form of an aqueous solution and at concentrations which do not induce cutaneous toxicity.
As mentioned above, in standardised in vitro tests the following reductions must be obtained with a disinfecting agent:
In addition, according to the invention, it was sought to produce a disinfecting agent in formulations in an aqueous medium at concentrations not inducing cutaneous toxicity in an aqueous medium.
The inventors have found that squalamine and its aminosteroid analogues meet these criteria at concentrations in an aqueous solution of 2 000 ring/l and that at these concentrations they do not cause cutaneous toxicity and in addition they allow a 4-log reduction of spores.
Finally it was observed that squalamine and its said analogues do not induce any degradation of the equipment treated and/or in contact with the product.
Although squalamine and its aminosteroid analogues were capable in topical application in the form of a lipophilic composition to reduce a concentration of 106 S aureus by 4-log in 24 hours without inducing resistance, it was not at all obvious that these compounds could obtain a 5-log reduction in less than 1 hour of a 108 concentration of S. aureus or P. aeruginosa, or 4-log reduction in less than 8 hours of a 108 concentration of C. albicans or A. niger (including eradication of spores with regard to A. niger). The microorganism concentrations involved for disinfection are higher (100 times) and the disinfectant effect must be obtained more rapidly. The other antibiotics used in man do not have this capability, nor do most of the antiseptics.
In addition, it was not obvious either that it would be possible to produce aqueous or water-soluble compositions such as water-soluble tablets able to have this desired efficacy in order to qualify as disinfectant.
More particularly, the present invention concerns compositions of disinfecting agents useful in particular for the disinfection of objects used in the food, home, transport sectors and in medical sectors in particular pharmaceutical, diagnostic, dental or surgical.
Particular mention can be of:
The objects concerned are more particularly rigid objects in plastic polymer material, inorganic or mineral material, in particular in steel or metal, or in composite material.
The transport sector can also be cited, in particular stretchers and inner claddings of vehicles, ambulances in particular, or the home or transport sectors for domestic or communal use in particular home objects such as furniture and fixtures such as floors, walls, water pipes, seating, door handles, stretchers.
The method of the invention is more particularly advantageous for equipment in plastic materials which cannot be sterilised by heat treatment in an autoclave and/or metal materials which corrode in an acid or oxidizing medium.
More particularly a said compound and a said composition of the invention are capable of killing in vitro:
a) at least 99.999% of pathogenic bacteria S. aureus and P. aeruginosa in a suspension containing a 108 cfu/ml concentration of said bacteria at 20° C., in particular in less than 60 minutes; and
b) at least 99.990% of pathogenic yeasts C. albicans and A. niger in a suspension containing a concentration of at least 107 cfu/ml of said yeasts at 20° C., in particular in less than 60 minutes.
Characteristics a) and b) correspond to the criteria required by European standards EN 1040 (for bacteria) and respectively EN 1275 (for yeasts) for a chemical disinfecting agent used in the pharmaceutical, medical, veterinary, agri-food, industrial sectors and for domestic or communal use.
Herein the characteristics a) and b) are obtained with concentrations of the said compound of squalamine an aminosteroid analogue of at least 0.3 mM (0.2 g/l) for characteristic a), and at least 3.2 mM (2 g/l) for characteristic b).
More particularly for use according to the invention the said object is placed in contact with an aqueous composition of the said compound of squalamine and aminosteroid analogue.
Further particularly the said object is soaked in the said aqueous solution or a said aqueous composition is applied to the said object.
The said aqueous composition may be contained in a substrate, particularly a gel or wipe capable of releasing the said composition onto the said object when the said substrate is contacted therewith and in particular is moved over the said object.
Still further particularly the said compound is used in the form of an aqueous solution at a concentration of at least 3 mM, preferably at 3 to 8 mM (about 2 to 5 g/l).
Aqueous solutions of said compounds at the above concentrations allow the disinfecting of a said object infected with pathogenic bacteria and/or pathogenic yeasts by killing on the said object:
i) at least 99.999% of pathogenic bacteria S. aureus and P. aeruginosa on a said object in less than 20 minutes at 20° C.; and
ii) at least 99.990% of pathogenic yeasts C. albicans and A. niger, including spores, in less than 6 hours at 20° C.
Further particularly a solid water-soluble composition is diluted in an aqueous solution, the composition preferably being in powder or tablet form containing a said compound at a concentration of at least 2.5% by weight, the said composition being soluble in an aqueous solution.
Still further particularly the said compound is squalamine of following formula Ia:
Yet further particularly, the said squalamine-analogue aminosteroid compound meets a general formula comprising a backbone of formula (I) below on which at least 1 polyamine chain —NHR is grafted, R being an optionally substituted hydrocarbon chain comprising at least one —NH2 group: (I)
where:
Furthermore particularly, the said compound meets a general formula comprising a said backbone of formula (I) comprising:
where:
preferably with:
b) the other carbons of the said backbone comprising a radical R0 the same or different selected from among H, OH, NH2, SH, and R1, preferably R0 being H or OH but only a single R0 represents OH.
Still further particularly, the said aminosteroid compound meets one of the following general formulas IIa, IIb, IIc or IId wherein R represents —[(CH2)n—(NR1)k—(CH2)m]p—NH2, n, m, p, k and R1 having the denotations given above, and preferably R is selected from among: —(CH2)n1-NH2 wherein n1=2 to 14, and —(CH2)3—NH—(CH2)3—NH—(CH2)3—NH2:
Still further particularly the said compound is an aminosteril called ASD 2 meeting the following general formula II-1:
Other said suitable compounds meet the general formula formed by a said backbone of formula (I) having:
a) 2 identical —NHR chains on the carbons at positions 3 and 20 respectively, and R is —[(CH2)n-(NR1)k—(CH2)m]p—NH2
where:
wherein preferably if k=0, then p=1, or if k=1, then p=2; and
b) the other carbons of the said backbone of formula (I) comprise a radical R0 the same or different selected from among H, NH2, SH or R1, preferably R0 being H or OH but with only a single R0 being OH.
Still further particularly, the said compound meets the following general formulas IIIc or IIIb, wherein R represents —[(CH2)n—(NR1)k—(CH2)m]p—NH2, and preferably R is selected from among —(CH2)n—NH2 where n=2 to 14, and —(CH2)3—NH—(CH2)3—NH—(CH2)3—NH2:
Still further particularly, the said aminosteroid compound meets following formula III-1:
Still further particularly, a composition of the invention has a concentration of 0.5 to 5%, preferably at least 2.5% by weight of said squalamine compound or said squalamine-analogue aminosteroid compound in the form of a water-soluble salt.
Still further particularly a composition of the invention is in the form of an aqueous solution or solid water-soluble tablet or water-soluble powder, the said excipients preferably being selected from among microcrystalline cellulose, lactose, starch, croscarmellose sodium, colloidal silica and magnesium stearate.
Still further particularly the said antibacterial squalamine compound or said squalamine-analogue aminosteroid compound is in the form of a water-soluble salt, preferably in the form of a hydrochloride, hydrobromide, triflate, phosphate, lactate or succinate salt.
Still further particularly the said material object is equipment for food, medical, dental, pharmaceutical, diagnostic or surgical use.
Other characteristics and advantages of the present invention will become better apparent on reading the following description given as a non-limiting illustration with reference to the appended drawings in which:
In the different tests below the strains used were Pseudomonas aeruginosa DSM 939 (ATCC 15442), Staphylococcus aureus DSM 799 (ATCC 6538), Candida albicans DSM 1386 (ATCC 10231) and Aspergillus niger ATCC 16404.
1) Test on disinfecting antibacterial action as per standard FR-EN 1040.
1.1) Protocol.
The microbial contamination of nebulizers was obtained in vitro by soaking the inner part of nebulizers (Pari LC, SPRINT SP, Pari, Germany) in a bacterial suspension prepared in Mueller Hinton broth containing 1·108 to 5·108 cfu/mL of bacteria. Disinfection was performed by soaking this same part in a solution of sterile water containing squalamine for 1 h at a determined concentration of 0.5 g/L for the bacteria under consideration (S. aureus or P. aeruginosa). The nebulizer was then rinsed with two successive sterile water solutions. The bacterial count was performed on the second wash bath on Tryptone Soya Agar (24 h).
1.2) Result.
It was found that the aqueous solution of squalamine or ASD 2 used at 0.5 g/l obtains an 8-log reduction of viable cells of S. aureus, P. aeruginosa within 1 hour which is more efficient than recommended by the standard which specifies a 5-log reduction in 1 hour (Figure).
2) Test on Disinfecting Antifungal Activity as Per Standard FR-EN 1275.
2.1) Protocol.
Nebulizer contamination with fungi was obtained in vitro by soaking the inner part of nebulizers (Pari LC, SPRINT SP, Pari, Germany) in 1·107 fungi suspension at 5·107 cfu/mL prepared in Sabouraud broth. After incubation the nebulizer was soaked in sterile water containing squalamine at the determined concentrations in relation to the fungal strains under consideration (i.e. 0.5 g/L for C. albicans (1 hour soaking) and 2 g/l for A. niger (6 h soaking). The nebulizer was then rinsed with two successive solutions of sterile water. The fungal count was performed on the second wash bath. The count of fungal colonies was performed on malt extract agar-agar (48 h).
2.2) Result.
It was ascertained that the aqueous solution of squalamine or ASD 2 used 0.5 g/l allowed a 6-log reduction in viable cells of C. albicans and A. niger in 1 h, which fully tallies with the recommendations set by the standard (minimum 4-log [Figure]). However for A. Niger, on account of the presence of spores, a concentration of 2 g/l was needed to obtain a 4-log reduction of viable spore cells in 6 hours. A higher concentration would allow this time of fungicidal action to be further reduced if desired.
3) Water-Soluble Composition of Squalamine and ASD 2.
A formulation of squalamine in the form of water-soluble tablets was prepared as follows. A batch of 20 g was prepared; the mixture was mixed in a Turbula Tapent T 20 mixer, Switzerland. The tablets were formed in a press of type Korsch Erwika Tape EKO, Germany. The raw materials were initially sieved. The squalamine (0.5 g) was mixed with microcrystalline cellulose (7.2 g), lactose (10 g), starch (1.4 g), croscarmellose sodium (0.6 g) and colloidal silica (0.04 g). Sieved magnesium stearate was subsequently added and mixed. The final mixture was compressed on an alternating press equipped with 8.0 mm pistons. The excipients used had a specifically adapted particle size (50.0 μm) to obtain compression. The water-soluble tablets obtained containing 2.5% of compound were then stored in a low density polyethylene bottle.
The disinfection experiments were conducted less than 10 days after manufacture of the squalamine tablets. We were nevertheless able to demonstrate the stability of these tablets since more than one year after their manufacture their activity remained unchanged.
4) Disinfectant Treatment of a Nebulizer with an Aqueous Solution of Water-Soluble Composition of Squalamine and ASD 2.
The bacterial contamination of nebulizers is a major problem for patients suffering from cystic fibrosis leading to reduced performance of nebulizers and an increased risk of patient re-infection with polluting bacteria.
The inventors validated the use of squalamine and ASD 2 in the following in vitro model of nebulizer disinfection.
4.1) Material and Method.
Nebulizers of Pari LC type were infected with bacteria (S. aureus and P. aeruginosa) via a suspension calibrated at 108 cfu/ml, and with fungi (C. albicans and A. niger) via a suspension calibrated at 107 cfu/ml. These nebulizers were then disinfected by soaking in a squalamine solution for 20 min, Glutaraldehyde and korsolex (peracetic acid) being used as inhibition control.
The microbial contamination of the nebulizer was obtained in vitro by soaking the inner part of the nebulizer (Pari LC, SPRINT SP, Pari, Germany) in a bacterial suspension prepared in Mueller Hinton broth containing 1·108 to 5·108 cfu/ml of bacteria (NF EN 1040, 1997) for 20 minutes. Disinfection was obtained by soaking this same part in a sterile water solution containing squalamine or ASD 2 for 2 minutes at the determined concentration in relation to the bacteria under consideration. For the fungi, suspensions of 1·107 to 5·107 cfu/ml (NF EN 1275, 1997) were prepared in Sabouraud broth and after incubation the nebulizer was soaked in sterile water containing squalamine or ASD 2. The nebulizer was then rinsed with two successive solutions of sterile water. The bacterial or fungal count was performed on the second wash bath. The counting of bacterial or fungal colonies was conducted on Tryptone Soya Agar for 24 hours for bacterial growth and on malt extract agar-agar for fungi at 37° C. for 48 hours.
The bactericidal and fungicidal test was performed three times in independent experiments and each bacterium and mould was evaluated separately. The concentration of squalamine and ASD 2 was increased until the required bactericidal and fungicidal activity was obtained. The disinfection time was set at 20 minutes for the first case and subsequently extended to 6 hours for A. Niger.
4.2) Result.
It was found that the aqueous solution of squalamine or ASD 2 used at 0.5 g/l obtains a 5-log reduction in viable cells of S. aureus, P. aeruginosa and a 4-log reduction for C. albicans in 20 minutes, whilst a concentration of 2 g/l was needed to obtain a 4-log reduction in viable cells of A. Niger within 6 hours.
4.2.1) The nebulizers used were infected with different bacterial suspensions (S. aureus and P. aeruginosa) calibrated at 108 cfu/ml or fungal suspensions (C. albicans and A. niger) calibrated at 107 cfu/ml. In a preliminary set of experiments, values of Minimum Inhibitory Concentration (MIC) and Time Kill of squalamine and ASD 2 were determined against chosen reference bacteria and fungi (MIC only). The MIC values were 2, 4, 16 and 16 mg/l against S. aureus, P. aeruginosa, C. albicans and A. Niger, respectively (Table 1 and
The squalamine tablets therefore exhibited their capability of reducing by 5-log the number of viable bacterial cells after a contact time of 20 minutes, similar to the results obtained under homogenous experimental conditions. It is also noteworthy that these tablets disintegrate in less than 5 minutes in water, indicating easy, non-hazardous handling thereof. An improvement on this tablet model can be obtained by preparing effervescent tablets which ensure faster, homogeneous dispersion of squalamine in the medium.
To conclude, squalamine or an analogue of squalamine appears to be a simple, quick and efficient solution for disinfecting any material which be contaminated.
Within this context, a 5-log reduction of viable bacterial cells and 4-log reduction of viable fungal cells is observed, thereby demonstrating the disinfecting activity of squalamine. A 4-log reduction in the fungal growth of A. Niger requires a longer treatment period (6 hours) than for bacteria, conforming to the MIC value of squalamine which was higher for fungi compared with bacteria. However, A. Niger is a filamentous fungus which forms spores that are difficult to eliminate and the tested compounds allowed a 4-log reduction also to be obtained in the number of A. Niger spores.
S. aureus DSM 799
P. aeruginosa DSM 939
C. albicans DSM 1386
A. niger ATCC 16404
5) Toxicity and Corrosion:
Cutaneous toxicity was examined over a period of 15 days by applying a squalamine ointment onto the backs of shaven mice (batch of 10 mice). No skin lesion, redness or inflammation of any kind was able to be observed. Also the mice did not lose weight and continued to feed and drink in comparable manner to non-treated mice.
Concerning a potential effect on plastic or metallic material, a nebulizer was left for 8 days in a squalamine solution having a concentration of 2 g/L and no deterioration of the metal or plastic (in particular regarding colour and flexibility) was observed.
No cutaneous toxicity was observed and the compounds had no effect on plastic or metal material and did not cause any degradation thereof.
| Number | Date | Country | Kind |
|---|---|---|---|
| 12 50312 | Jan 2012 | FR | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/FR2013/050021 | 1/4/2013 | WO | 00 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2013/104849 | 7/18/2013 | WO | A |
| Number | Name | Date | Kind |
|---|---|---|---|
| 6350738 | Savage et al. | Feb 2002 | B1 |
| 20110123624 | Zasloff | May 2011 | A1 |
| Number | Date | Country |
|---|---|---|
| 2011067501 | Jun 2011 | WO |
| WO 2011066260 | Jun 2011 | WO |
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| Number | Date | Country | |
|---|---|---|---|
| 20150005274 A1 | Jan 2015 | US |
