BR112012007111B1 - Microbicidal composition for coating a medical device, medical device and method for manufacturing a coating for a medical device - Google Patents

Description

(54) Title: MICROBICIDE COMPOSITION FOR COATING A MEDICAL DEVICE, MEDICAL DEVICE AND METHOD FOR MANUFACTURING A COATING FOR A MEDICAL DEVICE (51) lnt.CI .: A61L 27/34; A61L 27/54; A61L 17/00; A61L 17/14; A61L 24/00; A61L 29/08; A61L 29/16; A61L 31/10; A61L 31/16 (30) Unionist Priority: 29/09/2009 US 12 / 569,571 (73) Holder (s): ETHICON, INC.

(72) Inventor (s): HENRY POKROPINSKI; JEROME A. FISHER; JERRY JOHN; HUIMIN WANG; STEPHEN ROTHENBURGER; ΧΙΝΤΙΑΝ MING (85) National Phase Start Date: 29/03/2012

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Invention Patent Report for MICROBICIDE COMPOSITION FOR COATING A MEDICAL DEVICE, MEDICAL DEVICE AND METHOD FOR MANUFACTURING A COATING FOR A MEDICAL DEVICE.

The present description relates to microbicidal / bactericidal compositions and their use for coating articles such as medical devices. More specifically, microbicidal / bactericidal compositions are described, which can be derived from traditional Chinese medicines.

Each year, patients undergo a vast number of surgical procedures in the United States. Current data shows that about twenty-seven million procedures are performed each year. Post-surgical and surgical site infections (SSIs) occur in approximately two to three percent of all cases. This amounts to more than 675,000 SSIs each year.

In a surgical setting, when a medical device is used, a risk of infection can be created. The risk of infection increases dramatically with the use of implantable or invasive medical devices such as intravenous catheters, arterial grafts, intrathecal or intracerebral bypass and prosthetic devices, which create a gateway for pathogens while in close contact with body tissues and fluids. The occurrence of infections at the surgical site can often be associated with bacteria that colonize the medical device. For example, during a surgical procedure, bacteria from the atmospheric environment may enter the surgical site and adhere to the medical device. The bacteria can use the implanted medical device as a pathway to the surrounding tissue. This bacterial colonization in the medical device can cause infection, morbidity and mortality to the patient. Another adverse aspect concerns the formation of biofilms. Bacteria that live in a biofilm generally have significantly different properties from free-floating bacteria of the same species, due to the dense and protected environment of the film. This environment can provide increased resistance to antibiotics, since the dense extracellular matrix and the outer layer of cells protect the interior of the bacterial community. In some cases the resistance to antibiotics can be increased up to 1,000 times.

Numerous methods have been developed that incorporate microbicidal agents into medical devices to reduce the risk of infection associated with invasive or implantable medical devices. Such devices desirably provide effective levels of microbicidal agent while the device is being used.

Traditional Chinese Medicine, also known as TCM, includes a set of traditional medical practices originating in China. TCM practices include treatments such as herbal medicine, acupuncture, dietary therapy, Tui na massage and Shiatsu massage. Qigong and Taijiquan are also closely associated with TCM. Despite the fact that it is well accepted in the current medical care trend across East Asia, in general, TCM is often considered to be an alternative medical system in much of the western world.

Houttuynia cordata, also known as herba houttuyniae and, in Japan, as dokudami, is a perennial plant widely distributed in Asia, including Japan, Taiwan, China, Himalayas and Java. Houttuynia cordata is a flowering plant that grows in humid and dark places, and is the only species in the genus Houttuynia. In Chinese, it is literally known as fish-smelling herb. Houttuynia is also used in Traditional Chinese Medicine (TCM). The dokudami cha drink, in Japanese, literally Houttuynia cordata tea, is an infusion produced from Houttuynia cordata leaves, oolong tea leaves, and Tear of Our Lady.

Patent publication No. 2002/0031559 proposes a suppository for the treatment of human illnesses comprising at least one herb and a suppository vehicle. A method for treating unwanted symptoms of allergic rhinitis, sinusitis, nasal congestion, nasal drip, nasal polyps, infections, fevers, coughs, spasms, dizziness, and seizures in a human is also proposed, which uses a suppository that have herbs . Methods for the production, administration and formulation of herbal medicines in the form of suppositories for the treatment of human diseases and diseases are also proposed. A suppository that may include Houttuynia cordata as an ingredient is proposed.

Patent publication No. 2006/0264347 discloses a microbicidal composition comprising a cationic surfactant derived from the condensation of fatty acids and esterified dibasic amino acids, such as lauric arginate, and an iodinated sulfone compound such as diiodomethyl-ptolylsulfone. The composition can be used as a microbicidal formulation alone, or in combination with medical articles or medical devices.

Patent 7,485,327 proposes a composition comprising Melissa leaf extract, which is known to inhibit angiogenesis and the activity of matrix metalloproteinases. Melissa leaf extract is known to inhibit angiogenesis and matrix metalloproteinase activity, so it can be applied to the treatment or prevention of diseases related to angiogenesis and matrix metalloproteinase. The composition comprising Melissa leaf extract may also comprise more than one component of other anti-angiogenic, anti-cancer, anti-inflammatory and anti-aging components. This particular composition comprising Melissa leaf extract can be used for pharmaceutical, dietary and / or cosmetic purposes. U.S. patent 7,485,327 proposes the use of Houttuynia cordata extract as an ingredient with the Melissa leaf, which is a bactericide. The composition can be administered via an implant.

Chinese Publication No. 2005-10046735 allegedly proposes an eye preparation containing new sodium houttuyfonate and a preparation process, the preparation comprising new sodium houttuyfonate as the active constituent and pharmaceutically acceptable auxiliary materials, and can be prepared in various preparations eyedrops, including eye drops, gels, cloudy solutions, microspheres, microemulsions, implants and effervescent tablets.

Document W09850087 proposes coated medical devices adapted to be passed through narrow openings in the body such as catheters. The coatings provided give durability to the

4/30 catheter without appreciably adding to the thickness of the catheter and without decreasing the tensile strength of the catheter.

WO0126708 proposes polymeric valves, valve devices, machines and instruments. The proposed devices include implantable devices with a sufficiently long life span, which are responsive to the patient's therapeutic needs and which release a certain amount of a drug in response to a biological stimulus.

Despite these advances in the technique, it would be beneficial to incorporate a microbicidal / bactericidal composition into an invasive or implantable medical device to reduce the risk of infection. In addition, it would be desirable to provide a microbicidal / bactericidal composition derived from one or more traditional Chinese medicines, which exhibit activity upon contact with fluids in the human body.

In one aspect, a microbicidal composition is provided for coating a medical device. The microbicidal composition includes a polymeric film-forming material and a traditional Chinese medicine, with the microbicidal agent comprising a material selected from the group comprising Houttuynia cordata extract, sodium houttuyfonate and new sodium houttuyfonate, and mixtures thereof.

In one form, the microbicidal composition comprises sodium houttuyfonate or new sodium houttuyfonate, with an average particle size less than about 100 pm.

In another form, the microbicidal composition comprises sodium houttuyfonate or new sodium houttuyfonate, with an average particle size of less than about 50 pm.

In yet another form, the microbicidal composition comprises sodium houttuyfonate or new sodium houttuyfonate, with an average particle size of less than about 40 pm.

In yet another form, the microbicidal composition comprises sodium houttuyfonate or new sodium houttuyfonate, with an average particle size less than about 40 pm and a standard deviation

5/30 of the particle size less than about 30 pm.

In a further form, the polymeric film-forming material comprises a biodegradable and biocompatible polymer, copolymeric hydrogel or mixtures thereof.

In yet another additional form, the polymeric film-forming material is selected from aliphatic polyesters, poly (amino acids), copoly (ether-esters), polyalkylene oxalates, polyamides, poly (ethylene glycol), poly (iminocarbonates), polyesters , polyoxaesters, polyamidoesters, polyoxaesters containing amine groups, poly (anhydrides), polyphenols 10, polysaccharide gels and copolymers and mixtures thereof.

In yet another additional form, the polymeric film-forming material is selected from homopolymers and copolymers of lactide, glycolide, epsilon-caprolactone, para-dioxanone, trimethylene carbonate, alkyl derivatives of trimethylene carbonate, monoglyceride polyesters, hi15 carboxyl methyl drogels cellulose and mixtures thereof.

In one form, the polymeric film-forming material is selected from lactide homopolymers (APL) and glycolide homopolymers (PGA).

In another form, the polymeric film-forming material is selected from APL and PGA copolymers.

In yet another form, the microbicidal composition includes calcium stearate.

In another aspect, a medical device is provided. The medical device includes a microbicidal composition that comprises a material selected from the group consisting of Houttuynia cordata extract, sodium houttuyfonate, new sodium houttuyfonate and mixtures thereof.

In one form, the medical device is in the form of an implantable medical device.

In another form, the medical device is in the form of a fiber, fiber, mesh, powder, microspheres, flakes, sponge, foam, fabric, non-woven, fabric mat, a film, suture anchor device, sutuík ; ¹ W. ¹ i '; jjí,

6/30 ra, catheter, clamp, stent, surgical adhesive, clips, plate and thread, medication delivery device, barrier to prevent adhesion, and adhesive tissue.

In yet another aspect, a method is provided for manufacturing a coating for a medical device. The method includes the step of forming a suspension comprising a polymeric film-forming material, and a microbicidal agent comprising a material selected from the group consisting of Houttuynia cordata extract, sodium houttuyfonate and new sodium houttuyfonate, and mixtures thereof.

In yet another aspect, a method for making a microbicidal medical device is provided, the method comprising the step of applying a microbicidal coating to the medical device, the microbicidal coating including a polymeric film-forming material, and a microbicidal agent , with the microbicidal agent including a material selected from the group consisting of Houttuynia cordata extract, sodium houttuyfonate and new sodium houttuyfonate, and mixtures thereof.

In one form, the microbicidal medical device is packaged and sterilized.

Various advantages and benefits of one or more aspects presented here include: excellent in vitro microbicidal efficacy against SSI pathogens, ability to distribute evenly presented coating formulations, controlled release of microbicidal properties, and increased effectiveness and stability of microbicidal coating formulations presented. In addition, medical devices coated with the microbicidal coating formulations shown have excellent stability after sterilization. In addition, potential side effects are limited or non-existent due to the nature of the microbicidal agents and coating formulations presented here.

Figure 1 presents a graphical representation of the effect of

7/30 particle size in the concentration of sodium houttuyfonate for a suture coated with sodium houttuyfonate, and

Figure 2 presents a graphical representation of the effect of particle size in the zone of inhibition for a suture coated with sodium houttuyfonate.

Except where otherwise stated, all technical and scientific terms used herein are designed to have the same meaning as is commonly understood by one versed in a relevant technique. The phraseology, terminology and notation used here, throughout this description, are intended to be descriptive only, and should not be considered as limiting.

In addition, all technical and scientific words, terms, and / or phrases introduced, defined, described, and / or exemplified in the sections above are equally or similarly applicable in the illustrative description, examples and claims in the appendix.

For use in the present invention, the singular forms one, one and o include the reference in the plural, unless the context clearly determines otherwise.

By biodegradable, it is meant that a polymer can be degraded or otherwise decomposed in the body in such a way that the components of the degraded polymer can be absorbed by or otherwise passed into the body.

Each of the following terms: includes, includes, has, 'has, understands, and comprises, and its linguistic or grammatical variants, derivatives, and / or conjugates, for use in the present invention, mean including, but not limited to.

Throughout the illustrative description, the examples, and the appended claims, a numerical value of a parameter, characteristic, object, or dimension, can be determined or described in terms of a numeric range format. It should be fully understood that the numeric range format is provided to illustrate the implementation of forms presented here, and should not be understood or considered as a limitation

8/30 inflexible of the scope of the forms presented here.

Consequently, a numeric range mentioned or described also refers to, and encompasses, all sub-ranges and individual numeric values (where a numeric value can be expressed as an integer, integral, or fractional numeral) within the mentioned numeric range or described. For example, a numeric range mentioned or described from 1 to 6 also refers to, and covers, all of its possible sub-ranges, such as 1 to 3, 1 to 4, 1 to 5, 2 to 4 , 2 to 6, 3 to 6, etc., and individual numerical values, such as 1, 1.3, 2, 2.8, 3, 3.5, 4, 4.6, 5, 5.2, and 6, within the numeric range mentioned or described from 1 to 6. This applies regardless of the width, extent, or numerical size of the numeric range mentioned or described.

Additionally, to mention or describe a numeric range, the phrase in the range between about a first numeric value and about a second numeric value, is considered equivalent to, and means the same as, the phrase in the range of about a first value numeric about a second numeric value, and therefore these two phrases of equivalent meaning can be used interchangeably. For example, to mention or describe the numerical range of room temperature, the phrase room temperature refers to a temperature in the range between about 20 ° C and about 25 ° C, is considered equivalent to, and means the same as, the phrase room temperature refers to a temperature in the range of about 20 ° C to about 25 ° C.

It should be understood that the various forms presented here are not limiting in their application to details of the order or sequence, and number, of steps or procedures, and sub-steps or sub-procedures, of the operation or implementation of the forms of the method or for details of the type, composition, construction, arrangement, order and number of compositions, devices, assemblies, sub-assemblies, mechanisms, structures, components, elements, and configurations, and peripheral equipment, utilities, accessories, and materials, presented in the following illustrative description and examples, except where otherwise specified in the present invention. THE

9/30 composition, devices and methods presented here can be practiced or implemented according to several other alternative forms and in several other ways.

A microbicidal composition for coating a medical device is shown here. The microbicidal composition includes a polymeric film-forming material and a traditional Chinese medicine (MCT), with the microbicidal agent comprising a material selected from the group comprising Houttuynia cordata extract, sodium houttuyfonate and new sodium houttuyfonate, and mixtures thereof. .

As indicated above, Houttuynia cordata is widely distributed in Asia, including Japan, Taiwan, China, Himalayas and Java. Houttuynia cordata is a flowering plant that grows in humid and dark places, and is the only species in the genus Houttuynia. Houttuynia is also used in TCM. The dokudami cha drink, in Japanese, literally Houttuynia cordata tea, is an infusion produced from Houttuynia cordata leaves, oolong tea leaves, and Tear of Our Lady. Like striped bamboo extract, Houttuynia cordata extract is obtained by a low temperature / high pressure extraction method.

Herba houttuyniae is the whole fresh herb, or the dry part of Houttuynia cordata. The key microbicidal component is Houttuynin, or decanoyl acetaldehyde, which is unstable and prone to polymerization. Current synthesized sodium sulfite derivatives, known as sodium houttuyfonate or new sodium houttuyfonate, are more stable and thus useful in medical applications.

Houttuynin has been shown to have a marked suppressive effect on various bacteria and viruses. The dual anti-infectious activity in terms of preventing and treating secondary infections and against viral infections has been found to be in addition to that of common antibiotics. In vitro tests have shown that Houttuynin has a marked inhibitory effect on Micrococcus catarrhalis, Staphylococcus Aureus, Bacillus influenzae, pneumococci, Escherichia coli, Bacillus dysenteria, Bacillus proteus, Bacillus diphtheriae, and mycobacteria, and also has a strong effect on Bacillus Lep10 / 30 topira.

Houttuynin apozem was found to have an inhibitory action on influenza viruses (of Asian-Chinese origin) and on epidemic hemorrhagic fevers virus (EHFV) in vitro, and may delay the cytopathogenic effect of an orphan strain strain 11 (ECHO11). The fixed oil component of houttuynin via peritoneal injection has been shown to have a prophylactic effect in rats that have been infected with the FM1 flu virus, and the drug via the oral or nasal routes also offered a degree of protection.

The clinical application of Houttuynia cordata dates from the times of the Tang Dynasty, when the herb was documented in the book Chinese Matéria Medica.

Currently available Houttuynia cordata preparations include apozem water, houttuynin tablets, houttuynin injections, acute bronchitis syrup, capsules for phlegm elimination, Huang powder preparation for infusion for the treatment of long cough with asthma, and mango antitussive and others.

Sodium houttuyfonate, or Ci2H ₂ 3O ₅ SNa, also known as sodium decanoyl acetaldehyde sulfide, has a molecular weight of 302.36 and is a white or almost white needle-like crystalline powder that has a subtle odor. Suitable sources of sodium houttuyfonate include Hubei Yuanhe Organic Foodstuffs Co., Ltd, located in the Jinkou Industrial Area, Zhifang Street, Wuhan, Zhejiang, China 430074, and Second Pharma Co., Ltd., located in the Fine Chemicals Zone Gulf of Hangzhou, Shangyu, Zhejiang, China 312369.

The new sodium houttuyfonate, or Ci ₄ H27NaO ₅ S, is available in needle-shaped crystals or a crystalline powder, and is white in color. It is available from Hangzhou HETD Pharmaceutical & Chemical Co., Ltd., located at No. 8 Yi Road, at Xi Yuan Xi Hu Industrial Park, Sandun Hangzhou, Zhejiang, China 310030, and from Linyi Furui Fine Chemical Co ., Ltd, located in shandong china, linyi, Shandong, China 251500. The new sodium houttuyfonate is a scale-like or crystalline powder that has a relatively unpleasant odor. He's easily

11/30 soluble in hot water, slightly soluble in water and ethanol, and almost insoluble in chloroform and benzene. It is easily soluble in a sodium hydroxide solution.

It has been found that the beneficial microbicidal effect of TCM's, such as sodium houttuyfonate, can be enhanced through a grinding operation that aims to reduce the average particle size of the crystalline material.

Commercial grade sodium houttuyfonate has a particle size distribution in the range of approximately 1,000 pm to 4 pm, with an average of approximately 145 pm. This highly variable distribution in particle size results from longitudinal and axial measurement of needle-like crystals. The particle size and geometry of sodium houttuyfonate produces aggregates, resulting in an uneven coating distribution when applied to a substrate. Thus, it was discovered that the geometry of the raw material and its particle size and distribution needs modification and refinement to produce an acceptable coating. Particle size reduction can be achieved through several well-known processing techniques, such as a ball mill or a jet mill. A ball mill reduces particle size by mechanically crushing the material through collision with a hardened medium (i.e., spheres). A jet mill operates on the principle of particle acceleration through a stream of air, gas or water vapor, where the resulting collisions cause fractures. These processing techniques fracture the crystals of sodium houttuyfonate and produce particles with improved symmetry and a significantly narrower particle size distribution. The particle size distribution can additionally be selectively narrowed further through classification.

Thus, in one form, the microbicidal composition with 30 comprises sodium houttuyfonate or new sodium houttuyfonate, or mixtures thereof, which have an average particle size of less than about 100 pm. In another form, the microbicidal composition comprises hout

12/30 sodium tuyphonate or new sodium houttuyfonate, with an average particle size less than about 50 pm. In yet another form, the microbicidal composition comprises sodium houttuyfonate or new sodium houttuyfonate, with an average particle size of less than about 40 pm. In yet another form, the microbicidal composition comprises sodium houttuyfonate or new sodium houttuyfonate, with an average particle size less than about 40 pm and a standard deviation of particle size less than about 30 pm.

The microbicidal compositions shown here can advantageously serve as coating compositions, providing a vehicle for delivering the microbicidal agent to the surface of the medical device. As those skilled in the art will recognize, coatings are conventionally used in the manufacture of certain medical devices, such as, for example, absorbable and non-absorbable multifilament sutures. Examples of medical devices, as well as coatings that can be applied to this, can be found in U.S. Patents 4,201,216, 4,027,676, 4,105,034, 4,126,221, 4,185,637, 3,839,297, 6,260,699,

5,230,424, 5,555,976, 5,868,244, and 5,972,008, each of which is incorporated here in its entirety. As disclosed in US Patent No. 4,201,216, the coating composition can include a film-forming polymer and a substantially water-insoluble salt of a C6 or higher fatty acid. As another example, an absorbable coating composition that can be used for an absorbable medical device can include poly (alkylene oxylates) with the alkylene moieties being derived from C ₆ or mixtures of C4 to C12 diols, which is applied to a medical device from a solvent solution, as disclosed in US Patent No. 4,105,034. The compositions shown can include a polymer or copolymer, which can include lactide and glycolide, as a binding agent. The compositions can also include calcium stearate, as a lubricant. Medical devices do not conventionally employ a coating in the manufacturing process, however, they can also be coated with a microbicidal composition comprising an MTC microbial agent.

Examples of suitable biocompatible and biodegradable polymers that can be used in accordance with the present invention include, but are not limited to, polymers selected from the group consisting of aliphatic polyesters, poly (amino acids), copoly (ether esters), polyalkyl oxalates, polyamides , poly (ethylene glycol), poly (iminocarbonates), polyorthoesters, polyoxaesters, polyamidoesters, polyoxaesters containing amine groups, poly (anhydrides), polyphosphazenes, biopolymers, and copolymers, and mixtures thereof.

Useful aliphatic polyesters include, but are not limited to, lactide homopolymers and copolymers (which includes lactic acid, D-, L- and meso-lactide), glycolide (including glycolic acid), epsiloncaprolactone, para-dioxanone (1,4 -dioxan-2-one), trimethylene carbonate (1,3dioxan-2-one), alkyl derivatives of trimethylene carbonate, polyester monoglycerides, and polymer mixtures thereof.

Preferred polymers used in the invention comprise lactide homopolymers (APL) and glycolide homopolymers (PGA). Most preferred are APL and PGA (PLGA) copolymers, as copolymers comprising from about 80 to about 99 mol percent APL.

In one form, the polymeric film-forming material comprises a biodegradable and biocompatible polymer, copolymer, or mixtures thereof. The polymeric film-forming material can be selected from aliphatic polyesters, poly (amino acids), copoly (ether-esters), polyalkylene oxalates, polyamides, poly (ethylene glycol), poly (iminocarbonates), polyioresters, polyoxaesters, polyamidoesters, polyoxyesters containing amine, poly (anhydride), polyphosphazene groups, polysaccharide gels and copolymers and mixtures thereof.

In another form, the polymeric film-forming material can be selected from homopolymers and copolymers of lactide, glycolide, epsilon-caprolactone, para-dioxanone, trimethylene carbonate, alkyl derivatives of trimethylene carbonate, monoglyceride polyesters, carboxy methyl hydrogels cellulose, and mixtures thereof. The film forming material

Polymeric 14/30 can be selected from lactide homopolymers (APL) and glycolide homopolymers (PGA). In one form, the polymeric film-forming material is selected from APL and PGA copolymers.

In another aspect, the microbicidal composition may optionally contain other components that optimize the microbicidal effectiveness of the composition, or that otherwise serve as active agents for other benefits. These components include, but are not limited to, additional microbicides, additional salts, and any other excipients or active ingredients that provide the compositions with beneficial properties or improve the microbicidal activity of the compositions. Such components include, but are not limited to, microbicidal agents such as triclosan, trichlorocarban, 2-phenoxyethanol, chlorhexidine salts, hexetidine and cetylpyridinium salts, antibiotics, and other active ingredients.

The microbicidal compositions described herein can be used to coat substrate materials. In addition, they can be part of the coating containing the microbicidal composition described herein. These coatings may comprise either a single layer or multiple layers. In another form, the microbicidal composition can also be applied to a preformed article or part of a manufacturing article as a coating. The coated article can be produced, for example, by immersing the article in the composition, coextruding the article, cable coating the article, or spraying the article with the composition and then drying the coated article.

The microbicidal compositions described herein are used alone or in combination with other polymer coatings to provide advantageous properties on the substrate surface. These compositions can also be used to release pharmaceutical agents that, for example, are anti-infectives, anticoagulants, optimize the curing process, are antiviral, fungicidal, antithrombogenic, or impart other properties to the coated substrates.

Microbicidal compositions can also be used to inhibit the growth of algae, fungi, mollusks, or microbes on surfaces.

15/30 cies. The microbicidal compositions described herein can also be used as herbicides, insecticides, anti-fog agents, diagnostic agents, sunscreens, and scaling agents.

The coating dispersions can be preferably prepared by initially solubilizing all soluble compounds in an organic solvent or solvent mixture and then adding the insoluble components to the solution. The dispersion is created by combining the aforementioned compounds in a vessel that minimizes solvent evaporation and then mixes with a mechanical mixer. The mixer must provide sufficient energy to create a homogeneous dispersion or suspension, without allowing the aggregation of insoluble compounds. Suitable devices are high speed paddle mixers, homogenizers, sonicators, vortex mixers and other commonly used mixing devices that produce, dispersions, suspensions or emulsions.

The microbicidal agents of the MTC shown here can be present in the coating composition in a concentration of about 1 to about 15% by weight, or from about 1.5 to about 7.5% by weight, or about 2.0 to about 5.0% by weight. In one form, the MTC microbicidal agents shown here are present at a concentration of about 2.5% by weight. In another form, the MTC microbicidal agents shown here are present at a concentration of about 5% by weight.

The coating of medical devices with MTC microbicidal agent dispersions, such as sodium houttuyfonate dispersions, must be carried out in a manner that precisely controls the amount and distribution of the coating applied to the medical device. The coating operation can be performed by a traditional method of diving and drying, as described in US patent 5,817,129, the contents of which are fully incorporated here, where the substrate is passed through a vessel containing the suspension or dispersion , and then passed over a set of wheels to remove the excess coating and sent through a drying system to remove the

16/30 te vehicle. Coatings can also be applied to medical devices through spray, dip coating, tank immersion, mat coating, and other coating methodologies well known in the industry.

In another aspect, a manufacturing article is presented here which is a medical device comprising the microbicidal compositions described herein. In one form, the medical device can be selected from a fiber, mesh, powder, microspheres, flakes, sponge, foam, fabric, non-woven, fabric mat, a film, suture anchor device, suture, staple , surgical adhesive, clips, plate and thread, medication delivery device, barrier to prevent adhesion, and adhesive fabric. The medical device can be coated with one or more of the microbicidal compositions shown here. In one form, the medical device can be coated or impregnated with the microbicidal composition by dipping, soaking, spraying or coating the medical device with the microbicidal composition, as mentioned above and shown in the examples below.

In another form, the microbicidal agents described herein can be mixed with the polymer or polymer mixture used to form the medical device and then subsequently molded or extruded to form the medical device. The microbicidal agents described herein can be present in the polymer or polymer mixture in a concentration of about 1 to about 15% by weight, or from about 1.5 to about 7.5% by weight, or from about 2.0 to about 5.0% by weight. In one form, the MTC microbicidal agents shown here are present at a concentration of about 2.5% by weight. In another form, the MTC microbicidal agents shown here are present at a concentration of about 5% by weight. As will be understood by those skilled in the art, a master batch of microbicidal agent and polymer can first be formed and then mixed with the balance of polymer or polymer mixture to achieve the desired concentration of MTC microbicidal agent.

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In yet another aspect, a method for making a coating for a medical device is provided. The method includes the step of forming a suspension that comprises a polymeric film-forming material, and a microbicidal agent that comprises a material selected from the group consisting of Houttuynia cordata extract, sodium houttuyfonate and new sodium houttuyfonate, and mixtures thereof.

In yet another aspect, a method for making a microbicidal medical device is provided, the method comprising the step of applying a microbicidal coating to the medical device, the microbicidal coating including a polymeric film-forming material, and a microbicidal agent, with the microbicidal agent including a material selected from the group consisting of Houttuynia cordata extract, sodium houttuyfonate and new sodium houttuyfonate, and mixtures of the same.

As will be understood, medical devices are typically sterilized to make the microorganisms located therein substantially non-viable. In particular, 'sterile' means in the technical field a minimum sterility safety level of 10 ' ⁶ . Examples of sterilization processes are described in US Patents 3,815,315, 3,068,864, 3,767,362, 5,464,580, 5,128,101 and 5,868,244, each of which is incorporated herein in its entirety. Specifically, absorbable medical devices can be sensitive to radiation and heat. Consequently, it may be desirable to sterilize these devices with the use of conventional sterilizing gases or agents such as, for example, ethylene oxide gas.

Absorbable medical devices are sensitive to moisture and are therefore often packaged in hermetically sealed packaging, such as sealed foil packaging. However, the 30 sealed foil packages are also impermeable to sterilizing gas. In order to compensate for this and use foil packaging in ethylene oxide gas sterilization processes, processes have ΐ'ΒΓΛ ¹ 'f

18/30 been developed using foil packaging that has gas-permeable or permeable air vents (for example, Tyvek® non-woven material, produced by EI du Pont, from Nemours and Company, Wilmington, Delaware, USA ). The gas-permeable vents are mounted to an open end of the package and allow air, water vapor and ethylene oxide to pass into the package. After the sterilization process is complete, the package is sealed adjacent to the breather, so the breather is effectively excluded from the sealed breather, and the breather is eliminated or otherwise removed, thus producing a hermetically sealed gas-tight package. Another type of foil package that has a vent is a containment bag type package that has a vent mounted adjacent to one end of the package, the vent being sealed on one side of the package creating a ventilated section. After the sterilization process is complete, the packaging is sealed adjacent to the ventilated section, and the sealed packaging is eliminated from the ventilated section.

Specific forms will now be described further, by way of example. While the following examples demonstrate certain forms presented here, they should not be construed as limiting the scope of the invention, but rather as contributing to a complete description.

Examples

Test Method Used to Measure Sodium Houttuyfonate Content

As indicated above, microbicidal compositions for coating a medical device as shown here, may include a polymeric film-forming material, and a microbicidal agent comprising a material selected from a group consisting of Houttuynia cordata, houttuyfonate extract sodium, and new sodium houttuyfonate, and mixtures thereof. In one form, the composition may also include calcium stearate, or a copolymer of lactide and glycolide. In order to precisely determine the sodium houttuyfonate (SH) content for a medical device coated as an absorbable suture

19/30 speed, the following test method was developed.

The test methods previously available for determinations of SH content include iodine titration and UV methods. When such methods are used to determine the SH content in an absorbable suture, they tend to interfere with the suture matrix and are therefore ineffective for product quality control tests. For example, a basic solution is used when conducting the iodine titration method, which reacts with the suture polymer. In addition, tens of grams of suture samples are required for each test in order to achieve the sensitivity of the titration method. The UV spectroscopy method is more sensitive, however the coating materials can interfere with the detection of UV spectrometry.

Consequently, a test method for determining sodium houttuyfonate was developed, which uses high performance liquid chromatography (HPLC). This method can be applied to both non-sterile and sterile absorbable medical devices, including sutures.

The developed method includes two steps: (1) removal of sodium houttuyfonate from the matrix of the absorbable medical device in a suitable solvent system and (2) detection and quantification of sodium houttuyfonate using HPLC with UV detection.

The solubility properties of sodium houttuyfonate indicate that it is only slightly soluble in cold water and in most organic solvents, such as acetonitrile and methanol. The sodium houttuyfonate must be completely removed from the coating of the medical device, which, as indicated, may also contain calcium stearate and lactide / glycolide copolymer, and be dissolved in the extraction solution for quantification. A mixed solvent system containing solvents with different polarity indices and suitable pH has been discovered to achieve the desired extraction efficiency. The solvent system consists of 70% phosphate buffer pH 10.8 in aqueous solution and 30% acetonitrile. The extraction procedure involves placing a sample of the medical device in the solvent and stirring the sample for 30 minutes

20/30 at room temperature. The results of the extraction efficiency analysis indicate a recovery of sodium houttuyfonate greater than 99%.

The HPLC determinations, performed in the tests below, used an Agilent 1100 series model, with a 250 x 4.6 mm Phenomenex, Gemini-NX C18, column of 250 x 4.6 mm, 5 pm. A mixed solution of 70% phosphate buffer pH 10.8 and 30% acetonitrile was used as the mobile phase. The sodium houttuyfonate compound is detected by a UV detector at a wavelength of λ = 283 nm. The HPLC conditions were as follows:

Column: Gemini-NX, 5 pm, 110A °, 4.6x250 mm, Phenomenex Mobile Phase: CH ₃ CN: Buffer * 300: 700 * 0.017MK ₂ HPO ₄ , pH = 10.8 Aqueous solution Flow: 2.0 ml / min

Column Temperature: 55 ° C

Injection Volume: 10 pl

Processing Time: 8 min

Example 1: The Production of a Suture with an MCT

A L (-) lactide / glycolide copolymer containing 65 mol% of lactide and 35 mol% of glycolide was dissolved in 4.5% by weight ethyl acetate. To the solution was added sodium houttuyfonate (Second Pharm Co LTD Lot # 071213) at 2.5% and 5% by weight. Calcium stearate was added to the solution at 4.5% by weight. The solution was vortexed at room temperature until a uniform suspension was formed. A 2/0 polyglactin 910 dyed braid suture was coated by dipping the suture into the suspension. The suture was subjected to drying at room temperature. The suture coated with the MCT was cut into pieces 68.9 cm (27 inches) long and sterilized with EO.

The suture coated with the MCT produced was evaluated for its physical properties. The MCT suture went through the suture performance test routine, which indicated a normal physical property of the suture produced. The suture coated with sodium houttuyfonate, as discussed above, was designated as the suture prototype with an MCT-1.

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Example 2: Sterilization Stability with Ethylene Oxide

The suture with an MCT-1, prepared in Example 1, was analyzed by HPLC and in vitro efficacy tests before and after sterilization with ethylene oxide (OE). The results presented in Tables 3 and 4, below, indicate that the suture coated with the MCT has an acceptable stability for sterilization with OE.

Example 3:

Microbicidal efficacy was assessed in vitro by an inhibition zone test and a log reduction test. The data in Table 1 and Table

2 indicate that suture with an MCT-1 showed efficacy in vitro against methicillin-resistant Staphylococcus Aureus (MRSA) and methicillin-resistant Staphylococcus Epidermidis (MRSE) through zone inhibition and log reduction tests.

The results of the in vitro efficacy tests of the suture with a

MCT-1 indicate that while it is less effective than a commercially available polyglactin 910 bactericidal suture for an inhibition zone test, it is more effective than a commercially available polyglactin 910 bactericidal suture for a reduction test log, suggesting a different mode of action. MCT-1 activity appears to be rapidly microbicidal for susceptible strains. This differs from the predominantly bacteriostatic activity of triclosan, which is used in commercially available polyglactin 910 bactericidal sutures.

Table 1: In vitro Efficiency by Zone of Inhibition (ZOI)

Suture - Inhibition Zone (mm) MRSA MRSE Suture with a 2.5% MCT-1 1.6 1.8 Suture with a 5% MCT-1 2.4 3.0 Table 2: In vitro efficacy or Loq reduction Suture Logarithmic Reduction MRSA MRSE E. coli

Suture with an MCT-1 2.5% Suture with an MCT-1 5%

4.0

4.0

4.0

4.0

0.7

1.0

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Suture Logarithmic Reduction MRSA MRSE E. coli Bactericidal polyglactin suture 910 * 1.7 2.0 0 Control suture (Polyglactin 910 * non-bacterial suture) 0 0 0

* Commercially available

Table 3: Stability for EO Sterilization

MRSA

Suture Inhibition zone (mm) Logarithmic Reduction Suture with a 2.5% MCT-1 1.6 4.0 Suture with an MCT-1 2.5% EO 1.3 4.0 Suture with a 5% MCT-1 2.4 4.0 Suture with a MCT-1 5% EO 2.0 4.0

Table 4: Effect of EO Sterilization and Storage on Houttuyfonate-Na Content in the Suture with an MCT-1

Sodium Houttuyfonate content

Suture sample (PPm) *% loss 2.5% Suture with a MCT-1 baseline Non-EO 1,968 N / D 2.5% suture with an MCT-1 EO 1,685 14.4 5% suture with a non-EO baseline MCT-1 4,282 N / D 5% suture with an MCT-1 EO 3,307 22.8

% Loss = (ppm of non-EO suture - ppm of EO suture / ppm of non-EO suture 100%)

Absorbable sutures were coated by immersion in a mixture of a selected MTC, absorbable coating polymers and other additives in ethyl acetate. The coated sutures were dried, sterilized and packaged. The products were found to have the desired physical and mechanical properties and bactericidal / microbicidal properties.

Example 4: Effect of Particle Size and Particle Size Distribution on Coating Stability and Microbicidal Effectiveness

Studies have been done using sutures coated with the sodium 23-30 houttuyfonate microbicidal dressings shown here, with the sodium houttuyfonate coatings prepared using crushed or un-ground sodium houttuyfonate. The sutures were coated at two coating levels, using the coating method described above.

Particle size analysis was performed using a Beckman Coulter model LS 320 laser diffraction particle size analyzer. The results of these studies are shown below in Tables 5-7 and graphically shown in figures 1 and 2.

As indicated below, coated sutures employing 10 crushed sodium houttuyfonate produced greater efficiency during coating, more sodium houttuyfonate over a suture for the same amount of sodium houttuyfonate in the coating dispersion, a much more consistent level of sodium houttuyfonate on the suture and a significant reduction in the percentage of RSD. In addition, crushed sodium houttuyfo15 does not show significant loss of concentration (PPM) or reduction in the zone of inhibition (ZOI), when stored at 25 and 50 ° C for four weeks. The crushed sodium houttuyfonate provided greater zones of inhibition of Staph aureus after sterilization with ethylene oxide (EO). The crushed sodium houttuyfonate produced a greater reduction in the Staph aureus log after sterilization with EO and did not show a significant reduction in the Log Reduction when stored at 25 and 50 ° C for four weeks.

Table 5

Effect of Particle Size and Coating Level on

Performance for sodium Houttuyfonate (SH)

description

SH Non-crushed (As received from the supplier)

Crushed SH (Small particle size)

Benefits of Reduced Particle Size Sodium Houttuyfonate

Average Particle Size (pm)

144.7

37.4

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Effect of Particle Size and Coating Level on

Performance for sodium Houttuyfonate (SH)

description

Particle Size Standard Deviation (pm)% of Particles Below 100 pm% of Particles Below 10 pm

SH Non-crushed (As received from the supplier)

Crushed SH (Small particle size)

25.8

99.4

1.8 18.2

Benefits of Reduced Particle Size Sodium Houttuyfonate

SH PPM content for a 2.084 5% Sterile Baseline Coating

PPM content of SH for a Coating with a. 7.5% Sterile Baseline

The crushed SH produces

6.407 greater efficiency during coating - more SH in the suture for the same

9,436 amount of coating dispersion

% Of RSD in PPM in the SH for a coating with a 5% sterile baseline

% Of RSD in PPM in the SH for a coating with a 7.5% sterile baseline q 9 The crushed SH produces much more consistent levels in the suture - the% of RSD is significantly reduced θ> 2

SH content in PPM after 4 weeks at 50 ° C for 113% 5% coating

SH content in PPM after 4 weeks at 50 ° C for a 905 7.5% coating

The crushed SH not 7-470 shows significant loss of PPM when stored

10,469 at 50 ° C for four weeks

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Effect of Particle Size and Coating Level on

description Non-crushed SH (As received at from the supplier) Crushed SH (Small particle size) Staph aureus ZOI for a 5% Sterile Baseline Coating 1.3 2.5 Staph aureus ZOI for a 7.5% Sterile Baseline Coating 2.0 3.5 Staph aureus ZOI after 4 weeks at 50 ° C for a 5% Coating 0.2 2.8 Staph aureus ZOI after 4 weeks at 50 ° C for a 7.5% Coating 1.0 3.9 Staph aureus Log Reduction for a 5% Sterile Baseline Coating 1.1 3.8 Staph aureus Log Reduction for a 7.5% Sterile Baseline Coating 3.6 3.8 Log reduction of Staph aureus after 4 weeks at 50 ° C for a 5% coating 0.2 3.6 Log reduction of Staph aureus after 4 weeks at 50 ° C for a 7.5% coating 1.0 3.6

Performance for sodium Houttuyfonate (SH)

Benefits of Reduced Particle Size Sodium Houttuyfonate

The crushed SH showed zones of greater Staph aureus inhibition after sterilization with EO

The crushed SH shows no significant reduction in ZOI when stored at 50 ° C for four weeks

The crushed SH presents a greater reduction in Staph aureus Log after sterilization with EO

The crushed SH shows no significant reduction in Log reduction when stored at 50 ° C for four weeks

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Effect of Particle Size, Coating Level and Storage Conditions

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27/30

Effect of Particle Size, Coating Level and Storage Conditions

Non-crushed SH Microbiological data EC LR 1 1 SA LR T ~ 3.6 CO C0 CO ~ 0.2 O Zone Inhibition SD 1 1 Average Inhibition Zone (O V 2.0 <O_ CM C \ í 0.0 0.9 SA3 SA2 SA 1 SH Shredded in Laboratory Microbiological data EC LR ε'ο 0.3 1 1 l I SA LR 3.8 3.8 3.6 CD co 3.6 3.6 SD Inhibition Zone 0.2 v ~ O θ ' CO θ ' O τ- ο Average Inhibition Zone LO cm 3.5 3.6 co co 2.8 3.9 SA3 2.5 3.5 __1 3.5 co co 2.8 3.9 SA2 Γ'- CM 3.6 3.6 T ~ 2.9 ’Μ’ SA1 CM 3.5 3.6 CD co 2.8 3.9 Storage condition Sterile Baseline Sterile Baseline _i 4 Weeks @ 25 ° C O O LO CM @ ω ass ç ass AND Φ ω 4 Weeks @ 50 ° C 4 Weeks @ 50 ° C Level Coating (%) 0 'S 7.5 O LO LO O LO LO

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An additional aspect of the present invention includes a medical device that has a microbicidal composition comprising a microbicidal agent selected from the group consisting of Houttuynia cordata extract, sodium houttuyfonate, new sodium houttuyfonate, and mixtures thereof. In one form, the microbicidal agent comprises new sodium houttuyfonate. In another form, the microbicidal agent comprises sodium houttuyfonate. In another form, the sodium houttuyfonate or the new sodium houttuyfonate has an average particle size of less than about 100 pm. In another form, the microbicidal agent has an average particle size of less than about 50 pm. In another form, the microbicidal agent has an average particle size of less than about 40 pm. In another form, the microbicidal agent has an average particle size of less than about 40 pm and a standard deviation of particle size of less than about 30 pm. In another form, the microbicidal composition is coated on at least one surface of the medical device and further comprises a polymeric film-forming material. In one form, the polymeric film-forming material comprises a biodegradable and biocompatible polymer, or a mixture thereof. In another form, the microbicidal agent is present at a concentration of about 1 to about 15% by weight. In another form, the microbicidal agent is present at a concentration of about 1.5 to about 7.5%, by weight. In another form, the microbicidal agent is present at a concentration of about 2.0 to about 5.0%, by weight. In one form, the microbicidal agent has an average effective particle size to enhance the microbicidal effectiveness of the microbicidal agent. In another form, the medical device is in the form of a fiber, fiber, mesh, powder, microspheres, flakes, sponge, foam, fabric, non-woven, fabric mat, a film, suture anchor device, suture , catheter, clamp, stent, surgical adhesive, clips, plate and thread, medication delivery device, barrier to prevent adhesion, and adhesive tissue.

In a further aspect, a method for manufacturing a coating that comprises the step of forming a suspension that with ¹

29/30 comprises a polymeric film forming material, and a microbicidal agent comprising a material selected from the group of Houttuynia cordata, sodium houttuyfonate, new sodium houttuyfonate and mixtures thereof. In one form, the microbicidal agent comprises new sodium houttuyfonate. In another form, the microbicidal agent comprises sodium houttuyfonate. In another form, the microbicidal agent has an average particle size of less than about 100 pm. In another form, the microbicidal agent has an average particle size of less than about 50 pm. In another form, the microbicidal agent has an average particle size of less than about 40 pm. In another form, the microbicidal agent has an average particle size of less than about 40 pm and a standard deviation of particle size of less than about 30 pm. In another form, the polymeric film-forming material comprises a biodegradable and biocompatible polymer, copolymer, or mixtures thereof.

In a further aspect, a method for making a microbicidal medical device is provided, the method comprising the step of applying a microbicidal coating to the medical device, the microbicidal coating including a polymeric film-forming material, and a microbicidal agent, with the microbicidal agent including a material selected from the group consisting of Houttuynia cordata extract, sodium houttuyfonate and new sodium houttuyfonate, and mixtures thereof. In one form, the microbicidal agent comprises new sodium houttuyfonate. In another form, the microbicidal agent comprises sodium houttuyfonate. In another form, the microbicidal agent has an average particle size of less than about 100 pm. In another form, the microbicidal agent has an average particle size of less than about 50 pm. In another form, the microbicidal agent has an average particle size of less than about 40 pm. In another form, the microbicidal agent is present at a concentration of about 1 to about 15% by weight. In another form, the microbicidal agent is present at a concentration of about 1.5 to about 7.5%, by weight. In another form 30/30 ma, the method additionally comprises the stage of sterilization of the microbicidal medical device.

Although the present invention has been illustrated and described in detail in the drawings and in the aforementioned description, the forms presented are illustrative and not restrictive. It is intended to protect all changes and modifications that are within the scope of the invention.

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Claims (6)

1. Microbicidal composition for coating a medical device, characterized by the fact that it comprises: (a) a polymeric film-forming material comprising a biodegradable and biocompatible polymer, copolymer or mixture thereof, and (b) a microbicidal agent comprising a sodium houttuyfonate extract material, at a concentration of 1 to 15% w / p, wherein the particle size of the microbicidal agent is 30-100 pm, and the composition further comprises calcium stearate. 2. Microbicidal composition according to claim 1, characterized by the fact that the polymeric film-forming material is selected from aliphatic polyesters, poly (amino acids), copoly (ethers), polyalkylene oxalates, polyamides, poly (ethylene glycol) , poly (iminocarbonates), polyorthoesters, polyoxaesters, polyamidoesters, polyoxaesters containing amine groups, poly (anhydrides), polyphosphazene, polysaccharide gels and copolymers and mixtures thereof. 3. Microbicidal composition according to claim 2, characterized by the fact that the polymeric film-forming material is selected from homopolymers and copolymers of lactide, glycolide, epsilon-caprolactone, para-dioxanone, trimethylene carbonate, alkyl derivatives trimethylene carbonate, polyester monoglycerides, methyl cellulose carboxy hydrogels and mixtures thereof. 4. Medical device, characterized by the fact that it has a microbicidal composition as defined in any one of claims 1 to 3, wherein the medical device is in the form of a fiber, mesh, powder, microspheres, flakes, sponge, foam, tissue, nonwoven, tissue mat, a film, suture anchor device, suture, catheter, clamp, stent, surgical adhesive, clips, plate and thread, medication delivery device, barrier for adhesion prevention, and tissue adhesive. 5. Medical device, according to claim 4, characterized by the fact that the microbicidal composition is applied as of 05/25/2018, p. 9/14 2/2 coating on a surface of the medical device. 6. Method for manufacturing a microbicidal medical device, characterized by the fact that it comprises the step of applying a microbicidal coating to the medical device, the microbicidal coating 5 including a polymeric film-forming material, and a microbicidal agent, the microbicidal agent includes a sodium houttuyphonate extract material. Petition 870180044413, of 05/25/2018, p. 10/14 1/2 υ ο Ο • Λ (Λ C3 α s 4ί! Ζ2 + - * & Λ Τ3 Λ 4 = C (uidd) κιη) η§ nu a ^ BuojÃnjjnoij οιρο§ ap Λθ ^ Ι 2/2