WO1997045066A1

WO1997045066A1 - Urinary medical devices

Info

Publication number: WO1997045066A1
Application number: PCT/US1997/006137
Authority: WO
Inventors: Jeffrey C. Cerier; J. William Costerton; Carl J. Wisnosky
Original assignee: Uromed Corporation; Research And Development Institute, Inc.
Priority date: 1996-05-31
Filing date: 1997-04-14
Publication date: 1997-12-04
Also published as: AU2459497A

Abstract

The invention features a urinary medical device associated with an infection resistant agent (30) selected from lactic acid, lactic acid esters, poly-lactic acids, poly-lactic acid esters, poly-lactic acid copolymers, and a combination thereof. Another aspect of the invention features an incontinence device including a polymeric material (25), a portion of which contains an infection resistant agent (30).

Description

URINARY MEDICAL DEVICES

Background of the Invention The invention relates to urinary medical devices. Urinary medical devices include urinary incontinence devices and urinary catheters. While catheters generally do not occlude the urethra, incontinence devices control the flow of urine by occluding the urethra. Some urethral-occluding incontinence devices are inserted into the urethra. These insertion devices include a urethral plug, which may or may not have an expandable portion. An expandable portion may be fluidly expandable such as a balloon, or resiliently expandable wherein the device can assume a non-occluding shape during insertion, and a urethral-occluding shape after insertion into the urethra. Other urethral-occluding devices include an external barrier around the meatus, such as a urethral patch, plug, or cap. Some medical devices are provided with antibiotics or other therapeutic agents to treat existing infections in the urinary tract.

Summary of the Invention One aspect of the invention features a urinary medical device associated with an infection resistant agent selected from lactic acid, lactic acid esters, polylactic acids, polylactic acid esters, polylactic acid copolymers, and a combination thereof.

Preferred embodiments may include one or more of the following features. The lactic acid derivatives can be in D-, L- or DL-forms, and are preferably L-form lactic acid derivatives. In some embodiments, a portion of the device includes a polymeric material, and the infection resistant agent is disposed within the polymeric material. In other embodiments, the device bears a coating, pellet, gel, cream, or sheath that contains the infection resistant agent. Alternatively, the device is used with a wipe, wash, spray, or cream which includes the infection resistant agent for application to the meatus before application of the device.

The presentation (e.g., release or exposure) of the infection resistant agent is controlled in a time- dependent manner, to provide a selected amount of agent in a selected time interval. This effective amount of the agent is presented to the body in one or more dosages. The selected time interval can be less than 6 hours, less than 1 hour, or less than 1/2 hour. Where the agent is released, the plot of the amount of agent released over time can follow various curves, such as a single release of an effective amount, a substantially continuous release, or intermittent periods of release. Intermittent periods are particularly appropriate for longer-term devices, such as catheters, wherein multiple selected amounts of infection resistant agent are presented to the body in multiple time intervals. One urinary medical device is a urinary incontinence device. An incontinence device can be configured to block urine flow until the device is removed (e.g., remove-to-void devices), or to provide for selective urine flow (e.g., void-thru devices) . Urine flow can be blocked or controlled by a device configured for insertion into the urethra to occlude the urethra. A portion of a urethral insertion device can be fluidly expandable; be elastic and configured to assume a first non-occluding shape during insertion into the urethra, and a second urethral-occluding shape after insertion; or be a urethrally-injectable or -insertable gel. In addition to insertion devices, incontinence devices include a device configured for attachment to the tissue surrounding the meatus to provide an external barrier to the urethra, such as a plug, patch, or cap. In some embodiments, a barrier device includes an adhesive on a surface of the device that engages the meatus or the tissue surround the meatus. The adhesive can contain an infection resistant agent. Other urinary medical devices include catheters and shunts.

Lactic acid and its derivatives can be associated with a device in several ways, including forming biodegradable structural polymers or coatings; impregnating structural materials; and formulating gels or creams to be applied to a device. These and other methods described herein present lactic acid or its derivatives to the body by providing gradual or rapid release into the surrounding urine, or by presenting an infection resistant agent bonded at or near an exposed surface of a device. When chemically bonded to the bulk or surface material of a device, lactic acid and its derivatives present free acid moieties on the material surface, rather than being released. Whether solvated or chemically bonded, lactic acid, like other carboxylic acids, will lower the ambient pH, thereby inhibiting the growth of undesirable microbes such as E . coli . In addition, lactic acid promotes the growth of Lactobacillus casei by providing a favorable environment. This bacterium is not only known to be non-pathogenic to humans, but also interferes with the growth of undesirable microbes. Use of devices disclosed herein reduces the risk of device-related urinary tract infection. Another aspect of the invention features an incontinence device including a polymeric material, a portion of which contains an infection resistant agent. Preferred embodiments may include one or more of the following features. The incontinence device can be selected from the devices discussed above, or other similar devices. The infection resistant agent can be

(A) a carboxylic acid, a carboxylic acid ester, a polycarboxylic acid, or a polycarboxylic acid ester, a polycarboxylie acid copolymer, polyacids, or a combination thereof (e.g., lactic acid, a lactic acid ester, polylactic acid, a polylactic acid ester, a polylactic acid copolymer, or a combination thereof; or

(B) a biguanide or a triguanide, wherein the N- substituents are independently selected from H, CJ^_Q alkyl, C₂_₁₀ alkenyl, C₂_₆ heterocycle, and C₂_₆ heteroaryl (e.g., chlorhexidine, or a salt or ester thereof) . Incorporating an infection resistant agent into the bulk polymer before molding, such as mixing with a copolymer before blending or mixing with copolymers during blending, simplifies manufacture.

A third aspect of the invention features a method of using a urinary medical device, comprising (a) providing a urinary medical device associated with an infection resistant agent selected from lactic acid, lactic acid esters, polylactic acids, polylactic acid esters, polylactic acid copolymers, and a combination thereof (or an incontinence device including a polymeric material, a portion of which contains an infection resistant agent) ; and (b) applying the device to the urinary tract.

A fourth aspect features a method of inhibiting bacterial colonization on a urinary medical device, comprising (a) providing a urinary medical device associated with an infection resistant agent selected from lactic acid, lactic acid esters, polylactic acids, polylactic acid esters, polylactic acid copolymers, and a combination thereof (or an incontinence device including a polymeric material, a portion of which contains an infection resistant agent) ; and (b) applying the device to the urinary tract. The invention also features methods of manufacturing a urinary medical device, comprising (a) providing a urinary medical device; and (b) associating an infection resistant agent selected from lactic acid, lactic acid esters, polylactic acid, polylactic acid esters, polylactic acid copolymers, polyacids, and a combination thereof, with the urinary medical device. The providing and associating steps may be performed sequentially or simultaneously. Another method of manufacturing is a method of manufacturing an incontinence device, comprising (a) forming an incontinence device from a polymeric material; and (b) including an infection resistant agent in a portion of the polymeric material. Other aspects and advantages of the invention are disclosed in the following drawings, description, appended claims.

Brief Description of the Drawings Figs. 1 and 2 are cross-sectional views of a urinary incontinence device having an expandable balloon shown in a deflated (Fig. 1) and inflated state (Fig. 2) , wherein at least a portion of the device is made of a bulk polymer containing an infection resistant agent. Figs. 3 and 4 are cross-sectional views of a urinary incontinence device having an expandable balloon shown in a deflated (Fig. 3) and inflated state (Fig. 4) , wherein the shaft, balloon, and meatal plates have a coating containing an infection resistant agent.

Fig. 5 is a cross-sectional view of a urinary incontinence device having a pellet containing an infection resistant agent mounted on the distal end.

Fig. 6 is a cross-sectional view of a urinary incontinence balloon device having a gel containing an infection resistant agent on the shaft, balloon, and meatal plate. Figs. 7 and 8 are cross-sectional views of a urinary incontinence balloon device covered by a sleeve containing an infection resistant agent on the inner and outer surfaces of the sleeve, in deflated and inflated states, respectively.

Figs. 9 and 10 are a cross-sectional view and side view of an expandable urinary incontinence device, in inflated and deflated states, respectively.

Fig. 11 is a cross-sectional view of a urethral plug having an adhesive containing an infection resistant agent.

Fig. 12 is a cross-sectional view of a urethral plug having an applied pattern of alternating adhesive material and infection resistant material. Description of Preferred Embodiments

A. Introduction

The invention features a urinary medical device, such as an incontinence device, that is associated with an infection resistant agent. The device may contact the body for a short or long period of time. A short-term contact medical device contacts the body for a time period less than 24 hours, and preferably, less than 12 hours (e.g., less than 6 hours) . Incontinence devices include remove-to-void and void-thru male and female incontinence devices which block or otherwise occlude the urethra. Such devices include a fluidly expandable balloon, an expandable tip, and an external barrier. External barriers include an insertable urethral plug, patch, or cap covering the external opening of the urethra (see e.g., USSN , filed on December 14,

1995 John G. Simon et al., "Urinary incontinence device for men and method of controlling urinary incontinence by using same, Attorney docket number URO-151) , or a gel or paste that can be injected into the urethra, wherein the gel or paste forms a barrier to urine flow (USSN 08/541,647) .

A balloon device includes a shaft 20 which connects a fluidly expandable balloon 40 with a meatal plate 10, the latter lying outside the body adjacent to the meatus (Fig. 1) . See also, US 5090424 and US 5479945.

The invention provides several methods of associating an infection resistant agent with a material or surface, such as an incontinence device. First, infection resistant agent 30 is incorporated in a bulk material, such as a bulk polymer or plastic 25 that forms the walls of the device (Figs. 1 and 2) . Incorporation includes both a substantially homogeneous distribution of infection resistant agent 30, and a distribution gradient thereof. Fig. 1 shows a balloon incontinence device with infection resistant agent 30 present in discrete portions of the bulk polymer material 25 from which plate 10, shaft 20, and balloon 40 are made. However, in other embodiments, infection resistant agent 30 is present throughout the device (plate 10, shaft 20, and balloon 40) ; present on just balloon 40; present on just shaft 20 and plate 10 or just shaft 20 and balloon 40; or on other combinations. In a second method of associating infection resistant agent 30 with a balloon device, a coating substance 50 contains infection resistant agent 30 (Figs. 3 and 4) . In Fig. 3, coating 50 is shown covering almost the entire exterior surface of the balloon device, including plate 10, shaft 20, and balloon 40. In other embodiments, coating 50 covers different portions of the device. Coating 50 may be a continuous layer, or a non- continuous distribution across the surface of the device. Part or all of the coating may be soluble or insoluble in the urethral and bladder environment. A third method provides a pellet 60 containing infection resistant agent 30 (Fig. 5) . Although pellet 60 is shown mounted at the distal end of the device in Fig. 5, with minimal modification of the device, pellet 60 can be placed or mounted anywhere along balloon 40, shaft 20, or plate 10.

A fourth method associates gel 70 containing infection resistant agent 30 with the device (Fig. 6) . Although gel 70 is shown covering substantially all of the device exterior, gel 70 can be applied to all or part of the device, such as just the balloon 40, balloon 40 and upper shaft, and so on. Gel 70 is applied evenly, or in patterns, such as rings or parallel lines, before packaging or by the user. In addition, infection resistant agent 30 can be provided analogously as a spray, a liquid wash or rinse, a powder, a cream, or a wipe saturated with a substance containing infection resistant agent 30 (not shown) .

A fifth method associates sheath 80 containing infection resistant agent 30 with the device (Figs. 7 and 8) . Sheath 80 can be preassembled onto the device or, alternatively, applied by the user. All or part of sheath 80 can include infection resistant agent 30. For example, both the interior and exterior surfaces of sheath 80 are shown containing infection resistant agent 30 in Fig. 7. Although all of balloon 40 and most of shaft 20 are shown covered by sheath 80, in other embodiments the surface of the device can be wholly or partially covered by sheath 80. Although sheath 80 is shown with a closed tip, in other embodiments, sheath 80 may be open at the end, like a sleeve or tube.

Other embodiments include combinations of the above methods, such as use of coating 50 and gel 70, or use of a bulk polymer 25 containing infection resistant agent 30 and sheath 80. By analogy to the above description, infection resistant agent 30 can also be associated with different incontinence devices, such as a variable-shaped device having a tip that is configured to have a first shape before insertion and a second shape after insertion (Figs. 9 and 10) (see USSN 08/062,592; and USSN 08/124,264; and USSN 08/274,995). Each of the balloon devices (fluidly expandable device and variable- shape device) requires that the balloon portion be sufficiently elastic to inflate and deflate (see Table I below) .

TABLE I Suggested Material Properties for Elastic Insertion Devices

Still other incontinence devices with which infection resistant agent 30 can be associated include urethral plug 90 with tab 100 which is held in place with adhesive 110 and is associated with infection resistant agent 30 (Figs. 11 and 12) (see also USSN 08/478,327 and USSN 08/124,264). These types of devices are injection molded, elastomeric, and are preferably held place with adhesive 110. Adhesive 110 preferably anchors the device for between 2 and 6 hours; removal of plug 90 from the body is preferably comfortable, and adhesive 110 preferably leaves no residue. Infection resistant agent 30 is mixed or overlaps with adhesive 110 (Fig. 11) ; or infection resistant agent 30 and adhesive 110 are applied alternately in various patterns, such as the pattern shown in Fig. 12. Although adhesive 110 and infection resistant agent 30 are shown only on meatal plate 10, the infection resistant agent can be applied to all or any part of the plug, including the shaft and tip of the plug. Another incontinence device is configured to assume a first non-occluding shape 81 during insertion, preferably with the aid of an applicator 85 (Fig. 9) , and a second urethral-occluding shape 87 after insertion (Fig. 10) . In addition to incontinence devices, other short- term contact devices with which the infection resistant agent can be associated include needles, cannulae, dental instruments or tools (e.g., toothbrush) , disposable liners (bags or sheets) for public toilets, diaper bins, medical waste containers, instrument trays, containers for disposal of feminine hygiene products, feminine hygiene products, medical examination table paper, hospital gowns and slippers, surgical gloves, and surgical drapes. B. Infection resistant Agents

Infection resistant agent 30 inhibits the growth of one or more pathogens such as bacteria, fungi, and yeast. Infection resistant agent 30 may be bacteriostatic or bacteriocidal. An infection resistant agent may inhibit the establishment of pathogenic colonies on a surface of, e.g., meatal plate 10 or balloon 40 (i.e., infection resistant agent 30 is colonization-resistant) . Alternatively, agent 30 may cause cell lysis, prevent division, or interrupt RNA, DNA, or protein synthesis. Preferably, infection resistant agent 30 does not give rise to resistant strains. Infection resistant agent 30 inhibits the growth of at least one species of pathogenic or undesirable microbe, whether bacteria, fungi, or yeast. Regarding incontinence devices, undesirable microbes include Escherichia coli , Enterococcus faecaliε, Staphylococcus epidermidis , streptococcus, Klebsiella, Diptheroids , Proteus mirabilis, Enterobacter aerogenes, Citrobacter, D±plococcus, and Pseudomonas aeruginosa . Individual embodiments can employ a combination of infection resistant agents; or a combination of an infection resistant agent with another bioactive agent such as a topical analgesic (e.g. , aspirin) or anti- inflammatory agent (e.g., benadryl or hydrocortisone creams) , or adhesive 110 as shown in Figs. 11 and 12) . As mentioned previously, embodiments can employ a combination of methods for associating an infection resistant agent with a single material or article. Adjusting the combinations of agents and methods for associating those agents modulates the nature of infection-resistance (e.g., degree, duration, targeted pathogens, sensitivity to temperature, pH, solubility, and flow) .

A preferred infection resistant agent and the method of associating the agent with the material depends on the environmental conditions characteristic of ultimate use of the material or article. Environmental conditions include temperature, pH, salinity, humidity, and the presence of other substances such as plasma, leukocytes, proteins, sugars, quantity and character of flora, and high or low-flow conditions.

For example, urinary incontinence devices are exposed to temperatures of about 37°C, pH between 4.5 and and 8.0. Urine can contain salts and small molecules such as urea, uric acid, potassium, sodium, calcium, chloride, phosphate, and occasionally proteins, sugars, or blood. Incontinence devices typically contact the body for a period of time between 2 and 6 hours.

In view of the above, a suitable infection resistant agent should inhibit the growth or colonization of, for example, E . coli at human body temperatures. For example, the mechanism of action may be one or more of the following: (i) lower pH to a range between 2.2 and 5.0 and preferably between 2.8 and 4.0 or lower which is hostile toward E. coli ; (ii) promote growth of indigenous or introduced lactobacillus strains (e.g., L . casei or L . acidophiluε ) which naturally compete with the undesirable flora; or (iii) prevent surface colonization by causing cell lysis, inhibition of cell wall synthesis, protein synthesis, or metabolism upon contact.

Infection resistant agent 30 as shown in the Figures can be one or more of the substances in the following four classes: 1) metals, metal salts, and other elements; 2) inorganic and organic acids and acid anhydrides;

3) organic molecules; and 4) indigenous protective flora. These are described in detail below.

1. Metals. Salts, and Elements

Infection resistant agent 30 includes inorganic elements, salts, or oxygen-containing materials such as iodine (JP 56008057), metallic silver (US 5320908), silver halides or other salts (JP 6287504; JP 6080526, JP 6080507; JP 6227924; US 4906466, EP 251783) , silver and proteins or latex (JP 1136662; JP1136663) silver nitrate, lead, bismuth, cadmium, chromium, yttrium and barium silver powder (JP 2172467) , silicon dioxide and silicates (US 5256390; JP 6125970; US 4929431; US 5003638) . In addition, mono- or dialkyl tin (DE 3014291) , titanium oxide or other metal oxides (JP 6183728; JP 5140331; JP 7051125) , porous compositions of titanium or titania (JP 4231062,

JP 4126152) , copper, and silver; tetraethoxysilane; combinations of silver, copper, and zinc (US 5213801; JP 7233017) ; and copper and zinc salts (WO 9510940) can be used. Platinum, iridium, and gold can also be used (US 5474797) . Combinations of metal particles dispersed in a matrix are described in JP6293611. Infection resistant agents also include acrylonitriles (DE 3214610); CNC1, allyl isothiocyanates (JP 6199614) ; hydrogels formed from polymers, alkali metals, and cationic antimicrobial agents (WO 9206694) . Metals can be arranged in patterns or combinations to form galvanic couples (WO 9411058, US 5322520; WO 9211043) . Plasma after-glow polymerization can graft organometallic compounds to fibers, sheets, or moldings (DE 3522817) . Other examples include EP 636375, WO 9009736, and JP 7173452.

2. Inorganic and carboxylic acids, and anhydrides Some infection resistant agents are carboxylic acids. These agents may have linear, branched, substituted (e.g., halo, hydroxy, or alkoxy) , cyclic, aromatic, or heterocyclic moieties (e.g. , oxo-pyrido- benzoxadiazine carboxylic acid, DE 4329600, EP 203488) . Examples include linear or branched alkanoic acids (e.g., ^cι-ιo carboxylic acids include methanoic, ethanoic or acetic, propanoic, butanoic or butyric, and hexanoic acids) and unsaturated (alkenoic) carboxylic acids and their anhydrides (US 5137957) . Hydroxy-carboxylic acids and alkoxy- carboxylic acids include lactic (WO 9204413, US 5180765; DE 19506395), glycolic (JP 7223908, in conjunction with lactic acid, cinnamaldehyde, thymol, and mannitol; JP 5097619) , glyceric, tartronic, malic, tartaric, tropic, benzilic, salicylic, anisic, vanillic, veratric, piperonylic, gallic, formylsuccinic, naphthoic and substituted naphthoic, benzoic, and p-benzoylbenzoic acids. In addition, zosteric and phenolic acid esters are useful (US 5384176, WO 9413462), as are substituted phenols such as 5-chloro-2,4-dichloro phenoxy phenol (US 5238749) , and succinates and quinolinolate polymers (US 5066328) . Carboxylic acids can be used in conjunction with a metal salt of sulfonyl urea (US 4933178) . Esters such as methoxycarbonylaminobenzimidazole mixed in aqueous anionic resins such as polyurethane (JP 63301251) and dimeric cyclic esters (US5236560) ; fatty acid esters and isothiazolone compounds (EP 488606) ; polyamides (WO 9106593, US 5428078; US 4950256) or poly(amino acid ester) phosphazene matrices (US 4975280) ; and polycations (EP 596454) or quaternary ammonium compounds (US 5069899; US 5084096; JP 60080458) are also effective. Unless otherwise indicated, chemical compounds include (R) and (S) stereoisomers; or D-, L-, and racemic or meso DL forms, where such possiblities exist. In some embodiments, the L-forms, such as L-lactic acid and L- lactides, are preferred. Lactic acid derivatives include lactic acid, lactic acid esters, polylactic acids, polylactic acid esters, polylactic acid copolymers, polylactides, and combinations thereof. Several polylactides and polylactide-glycolide polymers are commercially available.

Infection resistant agents also include dicarboxylic or tricarboxylic acids such as malic acid, aspartic acid, glutamic acid, 2, 3,5-hexanetricarboxylic acid, and 1, 1, 5,6-heptanetricarboxylic acid.

Polycarboxylic acids can be reacted to form antimicrobial polyurethanes (US 5328954) . Polyamino acids (D and L forms) are also contemplated. Polyfunctional acids may be particularly suitable for some bulk polymer embodiments because some of the functional groups can form chemical bonds with copolymers while other functional groups remain free. Acids include diacids, triacids, and other polyacids. Esters and acid anhydrides of the above carboxylic acids are also useful.

Where an acidic pH (e.g., between 2.0 and 4.0, and preferably between 2.5 and 3.8) is itself infection resistant to the targeted microbe (e.g., E. coli) , one or more inorganic acids may also be used. Inorganic acids include hydrogen chloride; and sulfuric acid, phosphoric acid, carbonic acid, nitric acid, nitrous acid, and alkali metal or alkaline earth salts thereof. 3. Organic Infection resistant Agents Infection resistant agents include antibacterial, antifungal, and other antimicrobial materials such as chlorhexidine gluconate, hydroxypropyl cellulose, polyhexamethylene biguanide salts, cycloheximide, polymycin B (with collagen, JP 56161046) , triclosan (2,4,4'-trichloro-2'-hydroxydiphenyl ether) , isothiazalone, nitrofuran, allylisothiocyanate, gentamycin, sodium pyrithione, N- fluorodichloromethylthiophthalimide (EP 229862), EDTA and minocycline, rifampin, novobiocin (US 5217493, in a polymer matrix) , and a mixture of methoxyethyl aerylate and N-vinylpyrrolidone. Additional agents are described in US 5322520, US 5453275, WO 8904330, and EP 158374.

Biguanides and triguanides may be substituted at the available N positions (positions 1-5 for biguanides, and positions 1-7 for triguanides) . At each of these positions, an H of the parent guanide may be substituted with C_λ__1Q alkyl, C-^_Q alkoxy, C_λ_₁₀ alkenyl, C₆_₁₅ aryl (including alkylaryl and arylalkyl, e.g., C₆_₁₀ aryl), or ^c ₂-ιo heterocyclic (including heteroaryl) (e.g., C₃_₆ heterocyclic) (see, e.g., US 5142010, and US 4643180). These substituent s can be linear, branched, or cyclic; and unsubstituted or substituted with halo, hydroxy, amino, nitro, or thiol. Guanides can be poly- (polyalkylene) guanides, or monomeric guanides in salt and ester forms, such as chlorhexidine acetate, chlorhexidine gluconate, chlorhexidine hydrochloride, and chlorhexidine sulfate.

4. Indigenous protective flora

Infection resistant agents include bacteria and other flora which naturally compete with undesirable microbes. Preferably, the protective flora are naturally found in the area of the body in contact with the device. These protective flora include L . casei and other Lactobacillus spp . In addition, enzymes such as lactoperoxidase (EP 397227, US 5206156) are used as antimicrobials.

C. Associating Infection resistant Agent with a Device Other aspects of the invention provide infection resistant materials and surfaces, and methods of making them. Long-term contact devices such as Foley catheters may develop infectious biofilms.

Infection resistant short-term contact devices do not require the extended or periodic release of an infection resistant agent which is generally desirable for long-term contact devices. In addition, certain infection resistant agents which are inappropriate for long-term contact devices can be used for short-term contact devices. An agent may be inappropriate for long- term contact devices because it gives rise to agent- resistant strains; it is difficult to formulate for extended release because its activity rapidly decreases (e.g., activity lasts for less than 20 minutes) ; the agent diffuses too quickly; or the agent is too soluble or not soluble enough in aqueous solutions at body temperatures. In some cases, residual agent, immobilized pathogens, or dead cells are flushed away where the flow of a fluid (e.g., blood, tears, saliva, or urine) follows the removal of the short-term contact device. This washing action may ameliorate the induction of agent resistant strains, as well as promote general tissue health.

1. Infection resistant bulk polymer (Figs. 1. 2. 9. and 10)

Infection resistant bulk polymers contain one or more infection resistant agents 30 throughout the polymer material 25 (US 5408022; US 4789692; US 4933011; US

5319000; WO 9219289; US 5478563; US 5261896; JP 62062803; JP 59228856; US 4539234; EP 516184; US 5019096; US 7184545; and see coatings below which can be bulk polymers) . Infection resistant agent 30 can be added to a copolymer before polymerization, to a copolymer before blending, or to a blend of copolymers during or after blending. Agent 30 can be mixed with a polymer, for example, by occupying pores or interstitial spaces in the polymer matrix; such mixed or dispersed agents are generally of smaller molecular weight (e.g. , less than 500 daltons, and preferably less than 250 daltons) . In some embodiments, agent 30 is a small organic molecules having fewer than 30 carbon atoms, and at least one carboxylic acid moiety (salt or acid form) , or acid anhydride moiety. In some embodiments, agent 30 is formulated as a micronized powder, small particles, or as aggregates with a carrier, which is soluble or insoluble. The carrier may have polar moieties, nonpolar moieties, or both (e.g., a detergent) whereby the moieties assist in the dispersion of agent 30 in the polymer and solubility of agent 30 in the polymer; or the carrier may assist in diffusion of agent 30 out of the polymer, especially if the carrier is includes polar moieties.

The distribution of infection resistant agent 30 throughout bulk polymer 25 can be substantially homogeneous, or can be described by a gradient achieved by impregnating the polymer with a semi-permeating or permeating solution of infection resistant agent 30. In some embodiments, the distribution of agent 30 is substantially even throughout the device; or the distribution of agent 30 decreases along the length of the device; or the distribution decreases or increases across the cross-section of the device (radially) . Varying the solvent and the concentration of infection resistant agent 30 can produce the desired impregnation gradient, and therefore control the diffusion or delivery (presentation) of agent 30 as a function of time, temperature, and other conditions (e.g. , presence of water) . Exposing only a portion of the device will provide a gradient to that portion alone. Solvent effects may cause selective migration of agent 30 to the surface or to the center of the molded device.

Alternatively, agent 30 can be ionically-, covalently- , or hydrogen-bonded to one or more copolymers.

The chemical bond can be formed before the copolymer is blended or polymerized; or the chemical bond between agent 30 and the copolymer may be formed during the polymerization process with other linking agents or copolymers. Charge-bearing agents, especially metal- containing agents, may be coordinated to the polymer. Covalently-bonded agents generally have a plurality of nucleophilic functional groups such as hydroxyl and amino; electrophilic functional groups or leaving groups such as halides, carboxyl, keto groups, or dienes, or activated aryl groups with suitable electron-withdrawing groups such as nitro; or a combination thereof. The agent can have a dual function. For example, infection resistant agent 30 can also be an end-capping agent, a cross-linking agent, or a bifunctional polymeric segment or block. Macroscopically, organization and orientation of a polymer can be controlled by solvent effects, temperature, and careful consideration of the constituent copolymers or block copolymers. Therefore, infection resistant block copolymers can be encouraged to have loops or loose strands along the surface of the polymer, wherein the loops or loose ends contain an infection resistant agent.

Infection resistant bulk polymer 25 generally contains 0.01% - 30% by weight, and preferably 0.1% - 10% by weight of infection resistant agent(s) 30. The amount of agent 30 should be sufficient to impart the desired infection resistance without interfering with the processability and performance of the finished article or device. These characteristics include elongation at break, tensile modulus at 100%, tensile modulus at 300%, ultimate tensile strength, Shore hardness, glass transition temperature, melt flow index, melt temperature (e.g., rigidity, elasticity, and thermoplasticity (see Table A below) . For example, agent 30 must maintain its activity after exposure to the selected molding conditions (e.g., injection molding includes temperatures between 350-400°F) .

During contact with the body, infection resistant agent 30 can exert its activity primarily on the exposed surfaces of the device. Agent 30 may be dispersed throughout the polymer but may be too large or too soluble in the polymer to be released into the immediate vicinity (e.g., the urethra). Where agent 30 is bonded to the polymer matrix, the distribution and potency of the agent on the polymer surface is sufficient to resist microbial colonization. Agent 30 may serve to disable (e.g., lyse) , physically immobilize, or kill a microbe upon contact. In some embodiments, agent 30 can be released into the immediate vicinity. Agent 30 dispersed throughout the polymer matrix can diffuse towards the external surface(s) of the article. Bonds between agents and the polymer matrix which are susceptible to degradation can release agent 30. Degradation includes enzymatic or catalytic (acid or base) hydrolytic cleavage of esters or amides. Examples of such degradative release include polylactate polymers (lactic acid polymers) . 2. Coating (Figs. 3. 4. 11. and 12)

Infection resistant coating 50 is a substantially uniform layer, whether or not porous, which covers at least a portion of a device. In principle, no infection resistant agent 30 is present in the bulk of a merely coated material. Coating 50 can be applied to the underlying polymer material after the polymer material is formed. Coating 50 can be applied in molten form, as an emulsion, or as a solution (e.g. , sprayed, dipcoated, or painted) . Coating application can occur before, during, or after shaping of the polymer material into the device (US 4846844, EP 306212; US 5338565; JP 4364102; US 4749585) . Coating 50 may be solvent-based or polymer- based (e.g., WO 8602006, US 4603152; WO 8401721; JP 63139556; JP 58169511; JP 7080978; US 5344455; WO 9200747; US 5362754; WO 9413748) . As a result of the coating process and temperature or solvent system used, infection resistant agent 30 may or may not penetrate the polymer surface. There may or may not be bond formation between the infection resistant coating 50 and the polymer surface. The formulations may include a lubricant, an adhesive (WO 9302717) , or an analgesic. For example, a plug or patch anchored with an adhesive may have an infection resistant agent 30 combined with an adhesive 110 (Fig. 11) . Agent 30 and adhesive 110 may be physically mixed together or applied to the same area; or they may be applied in patterns on the device (e.g. , concentric rings or other patterns of alternating adhesive 110 and infection resistant agent 30) (Fig. 12) . Upon contact with an aqueous environment such as that found in the urethra or around the meatus, infection resistant coating 50 may be alternatively designed to slowly dissolve, to rapidly dissolve, to form a gel 70, or to remain insoluble when exposed to the aqueous environment in the body. Presentation of agent 30 includes release of agent 30 into the surrounding environment, migration or diffusion of agent 30 to the surface of the device, or simply exposure of agent 30 on the surface of the device. Insoluble coatings are effective to prevent biofilm formation or microbial colonization on the coated surface. Such as coating is a contact biocide or contact colonization resistant agent. Coating 50 may attract and neutralize pathogens, or it may resist colonization. A combination coating may include a microbial attractant and an antimicrobial. In some embodiments, the coating includes Lactobacilluε casei or other indigenous flora such as bacteria which naturally compete with undesirable microbes. The protective bacteria may be formulated in live form or dried form, and may be partially covered or encapsulated by materials which are rapidly solubilized in the body (e.g. urethra) , thereby exposing or releasing the protective bacteria. The device may be adapted to have depressions or other modifications for introducing the protective bacteria into the body. The amount, concentration, and distribution of infection resistant coating 50 must be sufficient to provide infection resistance without interfering with the introduction, operation, and removal of the device. The coating may be substantially dry, or it may have a viscous or wet character preserved by appropriate packaging. In other words, the user or a caregiver may remove packaging to expose a pre-applied gel, pellet, or sheath, as described below.

3. Pellet, gel, or sheath (Figs. 5-8) The user or a caregiver may apply infection resistant agent 30 to the device shortly before contacting the device with the user's body (e.g., insertion) . For example, a user may apply to the device gel 70, pellet 60, powder (e.g., US 5031245) , or sheath 80 containing infection resistant agent 30. Gel 70, pellet 60, powder, or sheath is provided separately or together with the device. Alternatively, the user may expose the contact area of the device to a wash, spray, or wipe/pad saturated with a formulation containing infection resistant agent 30.

Infection resistant agent 30 can be formulated with pharmaceutically-acceptable vehicles in the form of hydrogels, solutions (aqueous or dilute alcohol solutions) , creams, powders, aerosols, or sprays. Formulations may also include an adhesive, a lubricant, an analgesic, or combinations thereof. Pellet 60 can be formulated with pharmaceutically-acceptable coatings and carriers. The contents and size of each dosage and formulation (e.g, gel 70 or pellet 60) may vary depending on the age, condition, and health of the user.

The device can have a recess or other adaptation to hold pellet 60 at the distal end of the device during insertion. Upon insertion, pellet 60 may be mechanically released, or left in place to slowly dissolve. Sheath 80 may be made of an infection resistant material, or provided with infection resistant coating 50 on part or all of each inner and outer surface (DE 3916648, US 5049140) . Alternatively, the user or a caregiver may apply to a portion of sheath 80 an infection resistant formulation as described above.

4. External body wipe, wash, or spray In some embodiments, an infection resistant formulation is applied to the area of the body around the point(s) of contact between the device and the body immediately before use (e.g., insertion or application) of the device. Such application removes, disables, or immobilizes external contaminants on or near the area of contact. Such contaminants may include pathogens such as bacteria or yeast, as well as other matter. Infection resistant agents can be formulated with pharmaceutically- acceptable vehicles in the form of hydrogels, solutions (aqueous or dilute alcohol solutions) , creams, powders, and aerosols. The vehicle may also serve as a lubricant or adhesive. Porous or fibrous articles can be saturated with infection resistant formulations to provide wipes, pads, towelettes, sponges, puffs, and other single-use disposable articles. These formulations or articles may be packaged in single-use or multiple use units, and provided separately or with the device. D. Use

In view of the above, the disclosed methods of associating infection resistant agent 30 with a short- term contact medical device such as an incontinence device are adaptable to various conditions. For example, where the infection resistant agent is incorporated in the bulk polymer or provided in a coating on the device during manufacture, the user (or caregiver) need only remove the packaging and insert the device. Where the packaged device is not already associated with an infection resistant agent, the user removes the packaging, and applies the gel, cream, pellet, spray, sheath, and so on to the device before insertion. An infection resistant agent formulated as a body wash or body wipe is applied to the body area surrounding the insertion point before insertion. A wipe or wash may be used alone, or in combination with a device that is itself associated with an infection resistant agent. Where the short-term contact device is an incontinence device that is not a void-thru device, when urination is desired, the device is removed.

Without further elaboration, it is believed that the present invention can be utilized to its fullest extent. The following examples, therefore, are to be construed as illustrative, and not limitative, of the remainder of the disclosure. All publications and references cited herein are hereby incorporated by reference.

EXAMPLES

Example 1 Dry 0.20 pounds of Purasorb PL poly(L-lactide) polymer (Purac America, Lincolnshire, IL) in a vacuum oven at 230°F for 4 hours. Combine dried PLA with two pounds of C-Flex R70-001 SEBS thermoplastic elastomer (Consolidated Polymer Technologies, Inc., Largo, FL) . Mix in a Banbury mixer (Farrel Corp., Ansonia, CT) until a uniform polymer blend is obtained. Mold or cast polymer blend into standardized shapes for testing.

Example 2 Determine the durometer hardness (Shore A) of the polymer of Example 1 by using ASTM test method D2240. Determine the tensile modulus, ultimate tensile strength, and elongation at break by using ASTM test method D412. Example 3 After determination of the material properties of the bulk polymer of Example 1, the material properties are modified to suit specific needs. Blends with different grades of polylactide polymer are prepared. Polylactides are commercially available in molecular weights between 75 kD and 700 kD, such as 95 kD-120 kD and 85 kD-160 kD (Sigma Chemical, St. Louis, MO) , 144 kD and 256 kD (Aldrich, Milwaukee, WI) . In addition, the ratio of polylactide to C-Flex is varied to control the material properties of the resultant blend. A polymer with a lower durometer can be made by preparing a blend material with C-Flex R70-005 (Shore A 30) or another lower durometer grade of C-Flex. Similarly, a higher durometer material is prepared by increasing the proportion of a higher durometer C-Flex. In some embodiments, increased molecular weight will increase tensile modulus.

Example 4 Prepare a solvent system including tetrahydrofuran (THF) and an infection resistant agent such as 5% chlorhexidine acetate. Immerse a molded polymer article into the solvent system at room temperature for a period of time sufficient for the polymer to swell, and the infection resistant agent to permeate or penetrate the bulk polymer to the depth or concentration desired (e.g., 10 seconds) . Remove the device and air dry.

Example 5 Infection resistant properties are determined by methods known to those in the art, including those described in Costerton J.W. et al. , J . Bacteriology, 176(8), 2137-42 (1994); and McLean R.J.C. et al., In: Immobilized Biosystems: Theory and Practical Applications, I.A. Veliky and RJC. McLean, eds., Chapman & Hall, London, UK, Ch. 5, pp. 289-335 (1994) . Two methods are provided for illustration. In addition, bacterial adherence and agent release into an ambient fluid can be measured.

1. Direct contact method

A sample of material is placed in a sterile petri dish. Bacterial challenge organisms are pipetted onto the sample, directly contact with the material. The number of surviving organims are determined by the pore plate technique at 30 minute intervals for 7 days. A negative control is used.

2. Zone of inhibition

Controls and modified materials are tested to determine the degree to which anti-microbial compounds leach from the materials and prevent bacterial growth. 10⁶ cfu/ral of bacterial strain are applied to agar surfaces. Test samples are placed on the prepared agar, and the samples are incubated for a specified time period at 37°C. A bacterial growth inhibiting zone surrounding the sample indicates leaching of the anti-microbial compound. If the compound does not leach, no inhibiting zone is observed, and bacterial inhibition is observed in the area beneath the sample only where the agar contacted the sample.

3. Bound antimicrobial surface activity Concentrated bacterial suspensions are applied directly to the surface of the modified material. Test samples are incubated, and then sampling is performed by applying the innoculated surface to an Agar plate.

Sections of the test sample are evaluated for the number of viable organisms present at various sampling intervals. Example 6 A gel is formulated by mixing 1% by weight of chlorhexidine acetate with polyethylene glycol 300, and packaging the mixtures in a standard dispenser squeeze- tube. A pellet is formed by injection molding a bulk polymer mixed with polylactate. A pellet may be press- fit, or glued into place with cyanoacrylate.

Example 8 Combine 0.2 pounds of a chlorhexidine ester or salt (Bird Archer, Inc. , Canada) with two pounds of C- Flex R70-001 SEBS thermoplastic elastomer (Consolidated Polymer Technologies, Inc., Largo, FL) . Mix in a Banbury mixer until a uniform polymer blend is obtained. Mold or cast polymer blend into standardized shapes for testing. A polymer blend can be molded by any method known to those in the art, such as reaction-injection molding or injection molding.

Other Embodiments From the above description the essential characteristics of the invention can be ascertained. Without departing from the spirit and scope of thereof, various changes and modifications can be made to adapt to various usages and conditions. Thus, other embodiments are within the claims. For example, incontinence devices such as those described in U.S. Pat. Nos. 5,074,855 and 5,336,208, and in U.S. Serial Number 08/286,934, which has been allowed.

Claims

What is claimed is:

1. A urinary medical device associated with an infection resistant agent selected from lactic acid, lactic acid esters, polylactic acids, polylactic acid esters, polylactic acid copolymers, and a combination thereof.

2. The device of claim 1 wherein said lactic acid derivatives are D-, L-, or DL-forms.

3. The device of claim 1 wherein said infection resistant agent includes an L-form lactic acid derivative.

4. The device of claim 1 wherein a portion of the device includes a polymeric material, and said infection resistant agent is disposed within said polymeric material.

5. The device of claim 1, further comprising on the device a coating that contains said infection resistant agent.

6. The device of claim 1, further comprising on the device a pellet that contains said infection resistant agent.

7. The device of claim 1, further comprising a gel or cream that contains said infection resistant agent for application to said device.

8. The device of claim 1, further comprising a sheath for application to a portion of said device, said sheath including said infection resistant agent.

9. The device of claim 1, further comprising a wipe, wash, spray, or cream for application to the tissue surrounding the meatus before application of the device and which includes said infection resistant agent.

10. The device of claim 1 wherein said infection resistant agent is associated with said device to cause a selected amount of said infection resistant agent to be presented to the body in a selected time interval.

11. The device of claim 10 wherein the selected time interval is less than six hours.

12. The device of claim 10 wherein the selected time interval is less than 1 hour.

13. The device of claim 10 wherein multiple selected amounts of said infection resistant agents are presented to the body in multiple time intervals.

14. The device of claim 1 wherein said device is a urinary incontinence device.

15. The device of claim 14 wherein said device is configured to block urine flow until the device is removed.

16. The device of claim 15 wherein said device is configured for insertion into the urethra to occlude the urethra.

17. The device of claim 16 wherein a portion of said device is fluidly expandable.

18. The device of claim 16 wherein a portion of said device is elastic and configured to assume a first non-occluding shape during insertion into the urethra, and a second urethral-occluding shape after insertion.

19. The device of claim 16, wherein said device is a urethrally-injectable gel.

20. The device of claim 15 wherein said device is configured for attachment to the tissue surrounding the meatus to provide an external barrier to the urethra.

21. The device of claim 20 further comprising an adhesive on a surface of said device that engages the tissue surrounding the meatus.

22. The device of claim 21, wherein said adhesive contains said infection resistant agent.

23. The device of claim 14, wherein said device is configured to provide selective urine flow.

24. The device of claim 1, wherein the device is a catheter.

25. An incontinence device comprising a polymeric material, a portion of which contains an infection resistant agent.

26. The device of claim 25, wherein the infection resistant agent is selected from carboxylic acids, carboxylic acid esters, polycarboxylic acids, polycarboxylic acid esters, a polycarboxylic acid copolymers, and combinations thereof.

27. The device of claim 26, wherein the infection resistant agent is selected from lactic acid, lactic acid esters, polylactic acids, polylactic acid esters, polylactic acid copolymers, and combinations thereof.

28. The device of claim 25, wherein the infection resistant agent is a biguanide or a triguanide, wherein the N-substituents are independently selected from H, C_λ_ ₁₀ alkyl, C₂_₁₀ alkenyl, C₂_₆ heterocycle, and C₂_₆ heteroaryl.

29. The device of claim 25, wherein the infection resistant agent is chlorhexidine, or a salt or ester thereof.

30. The device of claim 25 wherein said device is configured to block urine flow until the device is removed.

31. The device of claim 30 wherein said device is configured for insertion into the urethra to occlude the urethra.

32. The device of claim 31 wherein a portion of said device is fluidly expandable.

33. The device of claim 31 wherein a portion of said device is elastic and configured to assume a first non-occluding shape during insertion into the urethra, and a second urethral-occluding shape after insertion.

34. The device of claim 31 wherein said device is a urethrally-injectable gel.

35. The device of claim 31 wherein said device is configured for attachment to the tissue surrounding the meatus to provide an external barrier to the urethra.

36. The device of claim 35 further comprising an adhesive on a surface of said device that engages the tissue surrounding the meatus.

37. The device of claim 25, wherein said device is configured to provide selective urine flow.

38. A method of treating the urinary tract with a urinary medical device, comprising

(a) providing a urinary medical device associated with an infection resistant agent selected from lactic acid, lactic acid esters, polylactic acids, polylactic acid esters, polylactic acid copolymers, and a combination thereof, said lactic acid derivatives being D-, L-, or DL-forms; and

(b) applying said device to the urinary tract.

39. A method of treating the urinary tract with a urinary medical device, comprising

(a) providing an incontinence device comprising a polymeric material, a portion of which contains an infection resistant agent; and

(b) applying said device to the urinary tract.

40. A method of inhibiting bacterial colonization on a urinary medical device, comprising

(b) applying said device to the urinary tract.

41. A method of manufacturing a urinary medical device, comprising

(a) providing a urinary medical device; and

(b) associating an infection resistant agent selected from lactic acid, lactic acid esters, polylactic acid, polylactic acid esters, polylactic acid copolymers, or a combination thereof, with said urinary medical device.

42. The method of claim 41 wherein steps (a) and (b) are performed sequentially.

43. The method of claim 42 wherein step (b) is performed during step (a) .

44. A method of manufacturing an incontinence device, comprising (a) forming an incontinence device from a polymeric material; and

(b) including an infection resistant agent in a portion of said polymeric material.