WO2007038855A1

WO2007038855A1 - Medical gel

Info

Publication number: WO2007038855A1
Application number: PCT/CA2006/001599
Authority: WO
Inventors: Terence O'reilly; George Botos; Jay Herman
Original assignee: Sigmacon Medical Products Corporation; Germiphene Corporation
Priority date: 2005-10-04
Filing date: 2006-09-28
Publication date: 2007-04-12

Abstract

The present invention provides a medical antimicrobial gel useful as a coupling media and lubricant for light-based or ultrasound cutaneous procedures, comprised of a solvent, a thickener and an antimicrobial agent and preferably a bioadhesive and humectant.

Description

MEDICAL GEL

FIELD OF THE INVENTION

[0001] This invention relates to medical gels and more specifically to medical gels having antimicrobial properties.

BACKGROUND OF THE INVENTION

[0002] Coupling media are often used for light-based cosmetic cutaneous procedures and ultrasound. Conventionally, ointment-like gels have been applied to the body surface as coupling media to ensure such contact. However, materials of this type must be used with care to ensure that there are no air bubbles between the acoustic device and the body surface. They may be impracticable or unsuitable for application in some cases, for example where the body surface is cut or abraded or body organs exposed during surgery are to be visualised and are frequently found to transmit sound or light inefficiently.

[0003] Currently, sterile and/or non-sterile medical gels are being used to lubricate skin during cutaneous light-based procedures to allow for improved mobility of the light device over the skin's surface. Such gels were primarily originally designed for ultrasound applications.

[0004] Most known gels for non-critical applications (non-sterile) are water-base gels containing a cellulose or acrylic thickener. For example, U.S. Patent No. 4,002,221 describes the use of a gel containing a mixture of a cellulose derivate polymer and an acrylic polymer. Other ingredients proposed are propylene glycol as humectants and wetting agents, preservatives (parabens), and a Citric Acid/Potassium Citrate buffer. The recommended pH range is 6.5-7.5 and the recommended viscosity range is 13000 - 60000 cPs.

[0005] Known sterile gels are typically used in invasive ultrasound procedures. Canadian Patent No. 2,312,614 describes an acoustic media for surgical procedures comprising a sterile polyethylene glycol-based media. Further, U.S. Patent No. 5,178,143 teaches an electrically conductive gel, recommended especially for TENS (Transcutaneous Electrical Nerve Stimulation) systems. The gel of U.S. Patent No. 5,178,143 comprises a custom polymer. [0006] One problem facing ultrasound and light-based cutaneous procedures is that the equipment used therewith is often incapable of being autoclaved or effectively sterilized. Therefore, transmission of bacteria from patient to patient via the medical gel can occur. In fact, in a Notice to Hospitals dated October 20, 2004, Health Canada (Health Products and Food Branch) issued a warning to Hospitals regarding the risk of serious infection from ultrasound and medical gels. Health Canada reports several cases of bacteremia and septicaemia whose source was traced to ultrasound and medical gels used during various procedures.

[0007] A need therefore exists for medical gels that decrease the risk of bacterial and microbial infection.

SUMMARY OF THE INVENTION

[0008] According to one broad aspect of the invention, there is provided a medical gel comprising a solvent, a thickener and an antimicrobial agent.

[0009] Preferably, the solvent is water, the thickener is Hydroxyethyl Cellulose and the antimicrobial agent is benzalkonium chloride.

[0010] Preferably the medical gel also comprises glycerine, Polyethylene Glycol with an average molecular weight of 3350 Dalton and menthol.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] In the following description, numerous specific details are set forth to provide a thorough understanding of the invention. However, it is understood that the invention may be practiced without certain specific details.

[0012] A medical gel that has antimicrobial and/or antibacterial properties is provided. The gels of the present invention are useful as coupling and lubricating media for light-based cosmetic cutaneous procedures, including but not limited to hair removal, laser peel for wrinkles, red-nose syndrome, tattoo removal, removal of leg veins and age spots removal. The gels of the present invention are also useful as ultrasound coupling and lubricating media used in the examination of superficial structures of the body, in postoperative or intraoperative ultrasonic examinations as well as preoperative and screening examinations and may be directly applied to the skin. Another use of the gels of the present invention is a general skin cleanser or specifically for wounds, cuts, minor burns and insect bites.

[0013] According to a broad aspect of the invention, the medical gel comprises a solvent, a thickener and an antimicrobial agent. The solvent is preferably water.

[0014] The thickener can be any thickener known in the art used for creating a gel in cooperation with a solvent. Preferably, the thickener is selected from the group consisting of polyacrylate (carbopol), a cellulose derivate such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose or carboxymethyl cellulose, xanthan gum, and mixtures thereof.

[0015] hi one embodiment of the invention, the cellulose derivate is hydroxyethyl cellulose and is present in the gel at 0.1% to 5% w/w, preferably at 2% w/w.

[0016] In another embodiment of the invention, the hydroxyethyl cellulose is preferably a higher molecular weight grade hydroxyethyl cellulose, such as Natrosol™ 250 HHR, and is more preferably present at 1% w/w. In order to compensate for loss in viscosity, a mixture of xanthan gum, such as Rhodigel™, and carboxymethyl cellulose, such as CMC 7H3SXF, may be added. Preferably, the xanthan gum is present at 0.25% w/w and the carboxymethyl cellulose is present at 0.25% w/w.

[0017] The antimicrobial agent is selected from the group consisting of quaternary ammonium compounds, triclosan, hydrogen peroxide and hydrogen peroxide generating compounds. It will be understood, however, by a person skilled in the art that any antimicrobial agent may be used that would be stable and active in a medical gel and is suitable for application to the skin. Preferably, the antimicrobial agent is a quaternary ammonium compounds selected from the group consisting of benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorhexidine acetate and cetyl pyridinum chloride. The antimicrobial agent is chosen, and at a concentration, preferably to not only maintain antibicrobial efficacy of the gel but to actively decrease the risk of transmission of bacteria , fungi and viruses from one patient to another. [0018] Topical antimicrobials are preferable to antibiotics since antibiotics can generate bacterial resistance. Antibiotic-resistant bacteria and viruses are of particular concern generally in the medical field and particularly in hospitals and in operatory settings. Antimicrobials, such as quaternary ammonium compounds, have the advantage of limited toxicity, and a chemical mechanism of action. Without being bound to any theory, it modifies the membrane cell permeability on bacteria and fungi and denatures the protein structure of small enveloped viruses. Therefore, the risk of generating resistance is minimal.

[0019] In one embodiment of the invention, benzalkonium chloride is the antimicrobial agent and is present in the medical gel at 0.04% to 2.0% w/w, preferably at 0.1% w/w.

[0020] In some embodiments of the invention, a bioadhesive is also present in the medical gel. The bioadhesive may be any bioadhesive that increases adherence to the skin and reduces the elasticity of the gel. This may be desirable in some applications since viscoelastic gels are difficult to apply on a vertical surface as they have poor adherence. The bioadhesive is preferably selected from the group consisting of polyvinylpirrolidones of different molecular weight, cellulose derivates and xanthan gum.

[0021] In one embodiment of the invention, the bioadhesive is polyvinylpyrrolidone, such as Plasdone™ C30, and is present in the medical gel at 0.1% to 5% w/w, preferably at 0.3%.

[0022] In another embodiment of the invention, the bioadhesive is a mixture of xanthan gum and carboxymethyl cellulose. Preferably, the xanthan gum is present in the medical gel at 0.25% w/w, and the carboxymethyl cellulose is present at 0.25% w/w. The xanthan gum may be, for example, Rhodigel™, and the carboxymethyl cellulose may be, for example, CMC 7H3SXF or CMC-7MF. This mixture may also serve as a thickener.

[0023] In another embodiment of the invention, the medical gel further comprises at least one of menthol benzocaine, lidocaine and camphor. These compounds may be used to provide any one of a general cooling effect to the skin, some anaesthetic effect and an odour masking effect. In one embodiment, menthol is present in the gel at 0.01% to 10% w/w, preferably, at 0.03% w/w. [0024] In another embodiment of the invention, the gel further comprises at least one of glycerine, propylene glycol, polyethylene oxide with a molecular weight of 200 to 20,000, preferably a molecular weight of 400 to 3500. Glycerin is preferably present at 0.01% to 30% w/w in the gel to prevent the medical gel from freezing when stored in a refrigerator. In some instances, a cold gel is desirable, particularly for some laser procedures to help absorb the heat generated by the procedure. Cold storage may further help preserve the shelf-life of the medical gel. Glycerin also serves as a moisterizer and humectant for the skin.

[0025] PEG is also preferably present as a solvent, bioadhesive, rheology modifier and a humectant. High molecular weight polyethylene glycol (like PEG 3350) have high melting points, being solids at body temperature. PEG solutions exhibit Newtonian rheology (the viscosity is independent of shear) below melting point, thus reducing the drop in viscosity upon application on the skin. Preferably, PEG 3350 is present in the medical gel at 0.1% to 30% w/w.

[0026] In a preferred embodiment of the invention, glycerin and PEG 3350 are each present in the medical gel at 5% w/w.

[0027] hi another embodiment of the invention, PEG 3350 is present in the medical gel at 3% to 5% w/w, and glycerine is not present.

[0028] In a particularly preferred embodiment of the invention, the medical gel comprises (w/w) glycerin USP at 5%, Carbowax™ 3350 PEG at 5%, Natrosol™ 250H USP at 2%, benzalkonium chloride at 0.1%, menthol USP at 0.03%, Plasdone™ C30 at 0.3% and water as the solvent at 87.57%.

[0029] In another preferred embodiment of the invention, the medical gel comprises (w/w) Carbowax™ 3350 PEG at 3% to 5%, Natrosol™ 250 HHR at 1%, benzalkonium chloride at 0.1%, Rhodigel™ at 0.25%, CMC 7H3SXF at 0.25%, methol at 0.03%, and water as the solvent making up the balance.

[0030] The following examples are illustrative of various aspects of the invention, and do not limit the broad aspects of the invention as disclosed herein. EXAMPLE - EX VIVO TESTING OF ONE EMBODIMENT

[0031] The following example relates to one preferred embodiment of the invention.

[0032] This embodiment of the medical gel contains 0.1% Benzalkonium Chloride, which is considered as an efficient skin antiseptic and has a minimal risk of producing allergic reaction. The preferred embodiment also contains a thickener, and a solvent, in accordance with the invention as described above.

[0033] Specifically, the preferred embodiment in the following example is a medical gel comprising (w/w) deionised water at 87.545%, glycerine at 5.0%, Natrosol™ 250H at 2.0%, benzalkonium chloride at 0.1%, methol at 0.03%, Plasdone™ C30 at 0.3%, and Carbowax™ 3350 PEG at 5%.

[0034] The following ex-vivo test method was based on the ASTM method (E 1174-94) for clinical evaluation of a Healthcare Personnel Handwash.

Bacterial Strain:

[0035] A loopful from recently revived stock culture of Serratia marcescens (ATCC 14756) was aseptically inoculated in TSA plate and incubated at 25° C for 24 hrs. After incubation, the purity of the culture was checked by Gram staining.

[0036] The culture was transferred in 10 ml TSB and incubated it at 25° C for 24 hrs. The cells then were harvested by centrifugation (30 minute at approx. 2000 RPM), washed and re- suspended in sterile saline TS. The transferring and harvesting procedure was repeated three times.

[0037] The inoculum was collected in a tube containing 10 ml sterile saline to obtain a count of about 1 x 10⁸ CFU/ml.

Reagents:

[0038] Neutralizing Solution: The neutralizing solution used contained 0.75% Azolectin, 5% Tw een 60, and 0.1 % Sodium Thiosulphate. [0039] Media: Four types of media were used for plating - Tryptic Soy agar (4%), Sabouraud Dextrose agar (6.5%), Mac Conkey agar (5%), and Blood agar (4%).

Test Procedure (Ex- Vivo Procedure):

[0040] Twenty- four samples of 2x2 cm square freshly excised pig skin, preserved overnight in Earle's Balanced Salt Solution (EBSS) at 2-4°C, were prepared. Samples were attached (glued) to individual plastic caps for an easier manipulation and paired (forming 12 pairs).

[0041] 50 μl of inoculum, containing approx. 1 x 10⁸ CFU/ml, were applied onto only one of a skin sample of each pair, then rubbed together with its counterpart for 1 minute and air dried for another 2 minutes.

[0042] Approximately 1 g of the medical gel was applied on one piece of skin of each pair and rubbed with a laser handpiece (Laserscope Recirculating Coolspot) for five minutes.

[0043] Each skin sample and the tip of the laser guide were then swabbed using a sterile swab and buffer solution, and transferred to 100 ml Neutralizing Solution. 1 ml from each sample was then plated on four different media (Tryptic Soy Agar, Sabouraud Dextrose Agar, Blood Agar, Mac Conkey Agar) in duplicate and incubated for seven days at 30⁰C.

[0044] Similarly, each of the untreated pig skin samples (controls) was plated using the same procedure.

[0045] For each sample, the log reduction for red colonies was calculated based on the initial count of inoculum (approx. 44 x 10⁵ CFU/ 25μl).

[0046] The test results are presented in the tables below: Table 1. CFU counts after one day on the four media used

[0047] The average log reduction was between 2.7 and 3.0, with no significant variations. Two samples tested (No 7 and 12) showed minimal growth, the result being consistent throughout the test.

Legend: BA - Blood Agar

SDA - Sabouraud Dextrose Agar

MCA - Mac Conkey Agar

TSA - Tryptic Soy Agar

Statistical analysis: [0048] The average log reduction for each of the four type of media used for plating was analyzed using Two-way ANOVA for 0.05 level of significance for Type I error (Microsoft Excel was used). The difference between the results at one day and seven days were analyzed using T-test for pairs (Microsoft Excel).

[0049] None of the statistical tests performed showed significant difference between media type and incubation time. Table 4. Paired T-test results

Table 5 Two-way ANOVA results

Conclusion:

[0050] Use of 0.1 % Benzalkonium Chloride is classified as Monograph IV product by Health Canada's Therapeutic Products Directorate. It is known that a Minimum Inhibitory Concentration (MIC) for Benzalkonium Chloride is at approximately 450 ppm.

[0051] The ex-vivo evaluation method has been found to be the most appropriate both ethically and practically, as discussed by Gerald McDonnell, Kimberly Haines, Daniel Klein, Mark Rippon, Rob Walmsley, Denise Pretzer, in "Clinical correlation of a skin antisepsis model," J. Microbiol. Methods 1999, 35: 31-35.

[0052] The test results are consistent with known findings that ex-vivo test on pigskin results in a broader range of standard deviation than in- vitro test, with hide-to-hide and other inherent procedure variations; however, overall the test showed clear efficacy in the given testing condition (five-minute contact time) against the test bacteria.

[0053] Hence, the preferred embodiment of the invention has been shown to be effective as described.

[0054] Although preferred embodiments of the invention have been described herein, it will be understood by those skilled in the art that variations may be made thereto and that features of the described embodiments may be combined without departing from the spirit of the invention or the scope of the appended claims.

Claims

CLAIMS:

1. A medical gel comprising a solvent, a thickener and an antimicrobial agent.

2. The medical gel of claim 1, wherein the solvent is water.

3. The medical gel of any one of claims 1-2, wherein the thickener is selected from the group consisting of polyacrylate (carbopol), a cellulose derivate, xanthan gum, and mixtures thereof.

4. The medical gel of claim 3, wherein the cellulose derivate is selected from the group consisting of hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, and carboxymethyl cellulose.

5. The medical gel of claim 4, wherein the cellulose derivate is hydroxyethyl cellulose.

6. The medical gel of claim 5, wherein hydroxyethyl cellulose is present in the gel at 0.1% to 5% w/w.

7. The medical gel of claim 6, wherein hydroxyethyl cellulose is present in the gel at 2% w/w.

8. The medical gel of claim 6, wherein hydroxyethyl cellulose is present in the gel at 1% w/w.

9. The medical gel of any one of claims 3-8, wherein the thickener comprises xanthan gum and carboxymethyl cellulose.

10. The medical gel of claim 9, wherein xanthan gum is present in the medical gel at 0.25% w/w and carboxymethyl cellulose is present in the medical gel at 0.25% w/w.

11. The medical gel of any one of claims 1-10, wherein the antimicrobial agent is selected from the group consisting of quaternary ammonium compounds, triclosan, hydrogen peroxide and hydrogen peroxide generating compounds

12. The medical gel of claim 11, wherein the quaternary ammonium compounds is selected from the group consisting of benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorhexidine Acetate and acetyl pridinum chloride.

13. The medical gel of claim 12, wherein the quaternary ammonium compound is benzalkonium chloride.

14. The medical gel of claim 13, wherein benzalkonium chloride is present in the medical gel at 0.04% to 2.0% w/w.

15. The medical gel of claim 14, wherein benzalkonium chloride is present in the medical gel at 0.1% w/w.

16. The medical gel of any one of claims 1-15, further comprising a bioadhesive.

17. The medical gel of claim of claim 16, wherein the bioadhesive is selected from the group consisting of polyvynil pirrolidones of different molecular weight, cellulose derivates and xanthan gum.

18. The medical gel of claim 17, wherein the bioadhesive is polyvinylpyrrolidone.

19. The medical gel of claim 18, wherein polyvinylpyrrolidone is present in the medical gel at 0.1% to 5% w/w.

20. The medical gel of claim 19, wherein polyvinylpyrrolidone is present in the medical gel at 0.3%.

21. The medical gel of claim 16, wherein the bioadhesive is a mixture of xanthan gum and carboxymethyl cellulose.

22. The medical gel of claim 21, wherein xanthan gum is present in the medical gel at 0.25% w/w and carboxymethyl cellulose is present in the medical gel at 0.25% w/w.

23. The medical gel of any one of claims 1-22, further comprising at least one of menthol benzocaine, lidocaine and camphor.

24. The medical gel of claim 23, wherein menthol is present in the medical gel at 0.1% to 10% w/w.

25. The medical gel of claim 24, wherein menthol is present in the medical gel at 0.03% w/w.

26. The medical gel of any one of claim 1-25, further comprising at least one of propylene Glycol, polyethylene oxide with a molecular weight of 200 to 20,000, glycerine.

27. The medical gel of claim of claim 26, wherein the polyethylene oxide has a molecular weight of 400 to 3500.

28. The medical gel of claim 26, comprising glycerin.

29. The medical gel of claim 28, wherein glycerin is present in the medical gel at 0.01% to 30% w/w.

30. The medical gel of claim 29, wherein glycerin is present in the medical gel at 5% w/w.

31. The medical gel of any one of claims 26-30, comprising PEG 3350.

32. The medical gel of claim 31, wherein PEG 3350 is present in the medical gel at 0.1% to 30% w/w.

33. The medical gel of claim 32, wherein PEG 3350 is present in the medical gel at 3% to

5% w/w.

34. The medical gel of claim 33, wherein PEG 3350 is present in the medical gel at 5% w/w.

35. A medical gel comprising glycerine at 5% w/w, PEG 3350 at 5% w/w, hydroxyethyl cellulose at 2% w/w, benzalkonium chloride at 0.1% w/w, methol at 0.03% w/w, polyvinylpyrrolidone at 0.3% w/w, and water at 87.57% w/w.

36. A medical gel comprising PEG 3350 at 3% to 5% w/w, hydroxyethyl cellulose at 1% w/w, benzalkonium chloride at 0.1% w/w, xanthan gum at 0.25% w/w, carboxymethyl cellulose at 0.25% w/w, methol at 0.03% w/w, and water.

37. Use of the medical gel of any one of claims 1 -36 for an ultrasound procedure.

38. Method of performing an ultrasound procedure comprising applying the medical gel of any one of claims 1-36 on a subject and performing the ultrasound procedure.

39. Use of the medical gel of any one of claims 1-36 for a light-based cutaneous procedure.

40. Method of performing an light-based cutaneous procedure comprising applying the medical gel of any one of claims 1-36 on a subject and performing the light-based cutaneous procedure.

41. Use of the medical gel of any one of claims 1-36 as a skin cleanser.

42. Method of cleaning skin comprising applying the medical gel of any one of claims 1- 36 to the skin.