Polymeric substrates containing povidone-iodine as a control release biologically active agent

A polymeric substrate such as rubber or latex incorporates povidone-iodine as a control release biologically active agent.

FIELD OF INVENTION 
This invention relates to polymeric healthcare articles, for example 
surgical and medical goods and equipment, which are useful in preventing 
the contamination, transmission and penetration of various diseases and/or 
infections to humans and animals and to the process of preparing same. 
More particularly, this invention relates to rubber articles, for example 
films, coatings, and like substrates, comprising a rubber polymer 
incorporating as a control release biologically active agent, the proven 
antimicrobial povidone-iodine, when the substrate is exposed to a polar 
liquid so as to prevent contamination by a viable pathogen, such as a 
virus, bacteria, or fungus. This invention can be used to prepare various 
healthcare articles such as medical gloves (examination and surgical), 
condoms, and durable and disposable medical equipment, such as catheters, 
to prevent contamination, transmission and penetration by various diseases 
and/or infections such as hepatitus, venereal diseases, AIDS, and the 
like. 
Viruses, in particular, have limited life outside the human body, but are 
quite virulent once inside the human body. Other viruses, such as AIDS, 
hepatitis and the herpes simplex virus, for example, are relatively easy 
to kill outside the body, but once inside become quite difficult to 
control and may be fatal. Thus control of these pathogens is an ongoing 
healthcare objective. In comparison to the general population, people 
involved in health care incur a higher probability of encountering 
diseases because they are in contact with the diseases on a daily basis 
while handling body fluids such as blood, urine, mucous secretions and the 
like. Each day, physicians, nurses, other medical personnel handle and are 
exposed to these body fluids, with the only protection being barrier 
prophylactic articles, such as gloves, gowns and masks. Some of these 
articles may be porous and therefore allow some pathogens to penetrate 
through to the skin and transmitted to the individual through abrasions, 
scratches and wounds. Other barrier articles such as condoms are suggested 
for use by the general public to prevent the transmission of venereal 
disease or infection by the pathogens. While these prophylactic articles 
are comparatively effective, they are not guaranteed to prevent the 
transmission of the above mentioned bacteria, viruses or funguses. 
In healthcare facilities, the transmission, penetration and contamination 
can occur in many ways. Gloves, for example, are used by various medical 
personnel. Surgeons wearing initially sterilized gloves, encounter patient 
fluids during surgery which may contain pathogens. Should defects exist or 
be developed in the glove, pathways therethrough can bring the pathogens 
into direct contact with the surgeon's hand and create the potential for 
infection at any open wound or abrasion. Similarly, if a glove and 
consequently the surgeon's hand are cut during treatment, pathogens may be 
drawn by the instrument into the cut thereby creating a potential 
infection site. All medical personnel involved in patient treatment are 
likewise exposed to pathogenic fluids. In addition to penetration problems 
of the type referenced above, there is also the clear possibility that the 
glove may directly contact infected fluids and accordingly may be a source 
of contamination for the wearer, other personnel or patients or 
surrounding equipment. Other durable and disposable healthcare goods, even 
if packaged sterile, may become contaminated during patient treatment 
thereby creating infection sites and transmission paths for further 
infection of the patient. Patients treated with interdwelling catheters, 
in particular urinary catheters, commonly develop infections which can 
spread to other tissue and organs. For general healthcare, latex condoms 
are regarded as the best barrier protection against sexually transmitted 
diseases. The thin wall sections of condoms are likewise prone to defects, 
ruptures or tears, all of which destroy the barrier protection thereby 
creating pathways for the transmission of infected body fluids. 
Polymeric materials are commonly used for the above and other healthcare 
goods. Latex is the material of choice for barrier articles in many 
medical and health applications, both durable and disposable. Natural 
latex, in particular, dominates other materials for gloves and condoms and 
is a significant manufacturing material for catheters. The unique 
combination of high tensile strength and elasticity, low modulus, and the 
ability to form coherent wet and dry conformal films makes natural latex 
ideally suited for the high speed manufacture of dip formed healthcare 
articles. Unlike other polymeric materials, conformal dip coating provides 
finished articles of desired shape, without seams, in accurately 
controllable thicknesses. Compared to alternative polymers, such as 
thermoplastics, latex films have significant structural and functional 
advantages. Additionally, the superior elongation permits manufacture of 
articles which can accommodate large size ranges of body parts while 
maintaining tight conformal contact. The ability to form extremely thin 
walls, provides superior tactility for the user. 
Notwithstanding the above structural and functional advantages, latex is a 
difficult material with which to manufacture articles. Natural latex is a 
complex colloidal system which contains high molecular weight 
cis-polyisopropene polymer, proteins, lipids, phosphlipids, sugars, 
inorganic salts, resins and other chemical compositions. The organic 
components of natural latex, derived from trees in tropical, humid 
climates, may have been exposed to various bacteria, enzymes, and oxygen. 
Accordingly, preservatives and controlled processing are required to 
inhibit adverse reactions. Certain components, such as salts, must be 
removed before manufacture. Further chemicals are added for mechanical 
stability, chemical stability, curing and vulcanization. Lastly, 
antioxidants, antiozanants, sequestrants, plasticizers, colorants and 
fillers are added to obtain desirable physical properties and extended 
properties for the finished articles. The resultant formulation is 
accordingly extremely complex and oftentimes contains 40 or more distinct 
chemicals. 
Polymeric materials, such as plastics and rubber, are used in the 
manufacture of medical equipment, and the desirability of self-sterilizing 
polymers therefor has become recognized. There have been attempts to 
combine such polymeric materials with antibacterial agents for the 
manufacture of various medical goods and equipment, such a gloves, condoms 
and the like. However, the aforementioned complexity of the latex 
formulation has limited their incorporation into dipped or coated latex 
health care goods. 
For example, Laurin et. al, U.S. Pat. No. 4,603,152 discloses a catheter 
incorporating compounds of physiological, antimicrobial metals in various 
polymers, including latex. Release of the metals requires interrelation of 
metal particle size and the dielectric constant of the resin. The 
composition also requires thorough mixing to obtain an even dispersion of 
the particles. LeVeen et al U.S. Pat. No. 4,381,380 discloses a post 
formation treatment with iodine solutions to incorporate a releasable 
antimicrobial into narrowly defined sparingly cross linked polyurethanes. 
Wepsic, U.S. Pat. No. 3,598,127, discloses a polysiloxane rubber 
incorporating an antibacterial which diffuses through the substrate and is 
incorporated through post formation absorption or physical entrapment in 
an adjacent component. James et. al., U.S. Pat. No. 4,499,154, discloses 
the post formation bonding to rubber articles of a lubricating hydrogel 
incorporating a bactericidal cationic surfactant. Vorhauer et. al., U.S. 
Pat. No. 4,393,871, discloses the incorporation of drugs into a 
polyurethane prepolymer which is which is foamed and utilized as a vaginal 
device. European Patent Application No. 88306760.5 published on Jan. 25, 
1989 discloses a medical glove which is post formation treated with an 
antimicrobial agent with an antimicrobial slurry polyurethane or 
polyethylene incorporating an antimicrobial. 
It is apparent that none of the foregoing approaches provides a dip formed 
latex substrate incorporating a releasable antimicrobial and applied in an 
operation compatible with existing manufacture. 
BRIEF SUMMARY OF THE INVENTION 
In accordance with this invention, the medical goods and equipment can be 
manufactured from a latex capable of control releasing a biologically 
active agent when in contact with a polar solution such as blood or mucous 
membrane tissue, body liquids and the like. These goods can be rendered 
self-sterilizing by coating a film of the latex on the goods or by 
manufacturing the goods from a latex material incorporating a releasable 
biologically active agent. 
More particularly, latex substrates incorporate povidone-iodine, both as a 
control releasable antimicrobial agent and also as a vulcanizing or cross 
linking agent. The film forming process for making such a latex substrate 
is compatible with existing manufacturing processes. This process can be 
utilized for making the entire article substrate or for making a substrate 
coating on the article. Moreover, the agent may be provided in discrete 
layers and, as such, provide select zones or layers of antimicrobial 
protection for such articles. Articles so formed are capable of 
control-releasing povidone-iodine when in contact with a polar liquid to 
prevent contamination, transmission or penetration by pathogens. Examples 
of such latex articles are gloves, condoms, catheters, tubings, and other 
elastomeric materials used for a variety of medical or health related 
applications. 
According to the present invention, latex substrates, in single or multiple 
layers, incorporate povidone-iodine, which is controlled in chemical 
bonding with the latex, so as to be releasable upon contact with polar 
liquids. Generally, the release of povidone-iodine is achieved by 
controlled processing of a mixture of povidone iodine and latex 
concentrate so as to retain the povidone-iodine in the substrate through 
secondary forces or van der Waals bonds, to the predetermined exclusion of 
chemical bonding with the latex. Such controlled processing provides 
controlled release of the agent, both as to concentration and duration, in 
accordance with the requirements of the environment to which the substrate 
is applied. The controlled processing, without limitation, includes 
controlled mixing and viscosity, emulsification, heating time temperature 
and rate. These process parameters can be controlled, individually or in 
combination, to achieve the desired predetermined exclusion of chemical 
bonding between the antimicrobial and the latex. 
More specifically, in the manufacture of surgical gloves, the latex 
substrate comprises at least one layer of the substrate which contains a 
sufficient amount of the biologically active agent to effectively kill a 
broad range of pathogens. A multilayer article may have different amounts 
of the agent in each layer, and accordingly different release rates for 
each layer. 
The latex substrates of the present invention can be used for making 
various specialty goods. For instance, gloves can be made with discrete 
control release layers having benefit in many healthcare applications. 
Medical personnel handling potentially infected body fluids over a 
prolonged period of time could be provided with a high dosage, fast 
release outer layer and a slow release low concentration inner layer. In 
the event of contact with such body fluids, the release at the outer layer 
would have a cidal effect and prevent touch contamination by such injected 
fluids. The inner layer would be released by wearer perspiration and 
provide protection against penetration of the fluids. A dentist's glove 
would benefit from a design with minimal release from the outer layer in 
contact with the patient while providing the aforementioned bathing layer 
at the inner layer/hand interface. In such instances, the outer layer may 
be formed by conventional formulations and techniques. Alternatively, the 
outer layer may be formed of the antimicrobial latex utilizing the above 
mentioned process controls. A layer with such characteristics can be 
effectively formed by slow, low temperature drying of the outer layer. 
Substrates formed in this manner show no ascertainable release of 
povidone-iodine when exposed polar solutions. Similar release rates can be 
obtained by using aged mixtures in which substantially all the 
povidone-iodine is chemically bound with the latex. Such a layer, while 
not releasing the povidone-iodine upon contact with polar solutions, will 
nonetheless prevent a nidus of infection from-developing in storage or in 
use. 
For the very small group of people having a mild allergic reaction to 
povidone iodine, the above glove construction could be reversed to place 
the no release substrate on the inner surface with the desired release 
rate on the outer surface in accordance with the necessary processing 
parameters.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
Referring to the drawings for the purpose of describing the preferred 
embodiments only, FIG. 3 shows a multilayered polymeric substrate 10 
comprising an outer layer 12, an inner layer 14, and a middle layer 16. 
The layers each comprise a polymeric film having dispersed therewithin an 
antimicrobial agent which is control releasable upon contact with a polar 
solution to thereby prevent the penetration of a pathogen through the 
film. As described in greater detail below, the agent is dispersed in the 
polymer layers under controlled processing conditions limiting the 
chemical bonding therebetween. The amount of biologically active agent 
dispersed in the polymeric film may range up to about 25% by weight of the 
film, and preferably in amounts ranging from about 0.01 to 10% by weight 
of the polymeric film. The agent is added to the polymer in the form of 
concentrated solution, typically water solutions containing up to 25% by 
weight of agent. 
Each layer may contain a different amount of the control release 
biologically active agent in comparison to the other layers. As described 
in greater detail below, each layer is formed through controlled 
processing including, without limitation, controlled mixing and holding, 
controlled viscosity, and controlled heating conditions including 
temperature, time and rate. 
The various articles that can be prepared from the polymeric substrates 
include surgical covers or gloves, tubes, sponges, pads, catheters, 
sutures, surgical tape, condoms and the like. 
Particularly effective for the foregoing is the incorporation of povidone 
iodine into natural latex as a preferred embodiment and the description 
will proceed with particular reference thereto. However, it will be 
apparent that other like polymers may be used with the povidone-iodine. 
For instance, film-forming polymeric barrier material containing a double 
bond in the polymer chain and capable of being vulcanized or cross linked 
such as natural or synthetic rubber, rubber latexes, silicone rubber, 
butyl rubbers, and more specifically, various synthetic rubbers such as 
the polyisoprenes, butadiene-styrene polymers, and neoprene rubbers. Other 
polymeric film-forming materials include polymers prepared by 
homopolymerization or copolymerization of monomers with the monomers 
having at least one double bond such as ethylene, propylene, butene, 
pentene, isobutylenes, cyclobutene, cyclohexane, and the like, and also 
with monomers having at least two double bonds such as the dienes, 
butadiene, neoprene, pentadiene, and the like capable of being vulcanized 
or cross linked. Other elastomeric film forming polymers include 
copolymers derived from vinyl acetate, vinyl ethers, styrene, vinyl 
chlorides, acrylic derivatives such as acrylic and methacrylic acid, e.g. 
methyl methacrylate, with monomers having at least two double bonds 
capable of being vulcanized or cross linked. 
More specifically, latex barrier articles such medical and surgical gloves 
are used by health care professional, in including doctors and nurses, to 
protect them against the transmission of a multitude of pathogens, for 
example viral, bacterial, and fungal pathogens which are encountered 
regularly while handling body fluids such as blood, urine, mucous 
secretions and the like. Thus, physicians, nurses, and various laboratory 
personnel who come into contact with these body fluids are in need of such 
article to provide protection against the transmission of these diseases. 
While the latex gloves presently used by health care professions are very 
helpful in preventing the transmission of disease, some are porous and 
allow the pathogens to penetrate through to the skin of the wearer, and if 
there happens to be an open wound, or if the individual touches the mouth, 
that particular disease may be transmitted. Thus, even though the articles 
presently available are comparatively effective, they are not absolutely 
foolproof in preventing the transmission of a number of infectious 
pathogens. 
The povidone-iodine is used in therapeutically effective amounts ranging up 
to about 25% by weight of the polymeric film, and preferably in amounts 
ranging from about 0.01 to 10% by weight of the polymeric film. 
Povidone-iodine is known to kill gram-positive and gram-negative bacteria, 
as wells as fungi, viruses, protozoa, and yeast. Povidone-iodine is 
approved by the FDA for skin, oral, and vaginal applications. Moreover, 
povidone-iodine may be utilized in latex substrate at relatively low 
concentrations without adversely affecting the physical properties of the 
substrate. Further, povidone-iodine has high efficacy in low 
concentrations and may be incorporated in relatively small amounts, 
ranging from about 0.01 to 5% by weight of substrate. 
Natural latex, in particular, is noted for a combination of properties not 
possessed by the other polymeric substrates used for medical and health 
related goods. Its high tensile strength, excellent elasticity, low 
modulus and ability to form coherent wet and dry films leads to 
applications such as medical gloves, balloons, and condoms. However, 
natural latex is a complex colloidal system containing high molecular 
weight cis polyisoprene polymer, proteins, lipids, phospholipids, sugars, 
inorganic salts, resins and other chemical structures not presently 
identified. Accordingly, it bears little similarity to other 
thermoplastics particularly with regard to the addition of additives. 
Therefore the aforementioned attempts to provide antimicrobial properties 
through additives in specific polymers are far more uncertain in the case 
of latex. 
It has been determined that the mere combination of latex and 
povidone-iodine will not produce releasable antimicrobial agents unless 
the processing occurs under controlled conditions. For instance, the 
resulting admixture must be carefully monitored with time. It has been 
found that the povidone-iodine will chemically bond with the latex over 
time such that the povidone-iodine is not releasable in the presence of 
polar solutions. Moreover, the bond is not convertible. Thus, if the 
mixture is used contemporaneously with mixing and processed under 
controlled heating conditions, the povidone-iodine is bound to the latex 
polymer with secondary or van der Waals bonds controlledly to the 
exclusion of the chemical or cross-link bonds such that the 
povidone-iodine is releasable from the substrate in the presence of a 
polar liquid. This is observable and controllable. After mixing the 
admixture has a distinctive brown color which gradually shifts to an ivory 
color over a 24 hour time period. The color shift also correlates to a 
change in viscosity. Further, the releasability can be controlled by 
control of the drying of the wet film. Air drying for instance provides a 
latex substrate with insignificant release of the povidone-iodine, 
indicated both by the color of the substrate, off white, and the lack of 
release in polar liquids. Moreover, the heating rate, heating time and 
temperature significantly affect the releasability of the povidone-iodine. 
In accordance with this invention, the concentration or the amount and 
speed of release of the agent from the latex films can be controlled by 
regulating the degree of temperatures and rate of heating or drying of the 
film. The rate of heating and the temperature at which the mixture is 
heated, together with the concentration of the agent, are means of 
controlling the time release of said biological agent from the films. 
EXAMPLE 1 
Two samples of a mixture of a low ammonia latex concentrate (Hartex 103 
manufactured by Firestone) and a 10% aqueous solution of povidone iodine 
were prepared in equal volumes by weight with the povidone-iodine 
uniformly dispersed therewithin. One sample was held for a period of 24 
hours and the change of color noted. Over this period the mixture changed 
from brownish color similar to the povidone-iodine solution to a whitish 
color similar to the latex concentrate. 
EXAMPLE 2 
Latex films were formed from each mixture sample prepared in accordance 
with Example 1. The films were dried at a temperature of 200.degree. F. 
for 20 minutes. A towel, moistened with ordinary tap water, was applied to 
the film prepared from a fresh mixture. A brown color blotch 
characteristic of povidone-iodine was noted on the towel indicative of 
antimicrobial release. A damp towel was applied to film prepared from the 
24 hour aged mixture. No color change was noted after removal. 
As mentioned above, viscosity is another aspect of controlled processing of 
the mixture which can be used in providing the desired release of the 
povidone-iodine. Viscosity can be used to determine the amount of chemical 
bonding between the povidone iodine and the latex. Thus the condition of 
the mixture can be compared against standards to effect steady state 
dipping conditions and along with heating conditions and concentration the 
releasability of the povidone-iodine. An example illustrating the effect 
of holding time on viscosity follows. 
EXAMPLE 3 
Two mixtures were prepared in accordance with Example 1 above. Both samples 
were tested for viscosity on a Carri-Med CSL Rheometer available from 
Mitech Corporation of Twinsburg, Ohio. The aged sample had a higher 
viscosities at increasing shear rates than the fresh mixed sample 
indicating that povidone-iodine is incorporated within the polymer. 
Thus, it is apparent that, in one aspect of controlled processing, the 
holding time as a function of color shift and/or viscosity can be used to 
control the release rate of the povidone-iodine. Moreover, these 
parameters also permit the makeup blending of fresh mixture into the 
dipping tanks to maintain predictable release control. 
In accordance with a further aspect of the process for controlled release 
of the present invention, the concentration or the amount and speed of 
release of the antimicrobial agent from the latex film substrate can be 
controlled by regulating the drying temperature and rate of heating or 
drying. The rate of heating and the temperature at which the film is 
heated, together with the concentration of the agent, are means of 
controlling the time release of the agent from the film substrate upon 
contact with polar solutions as illustrated in Examples 4 through 6. 
EXAMPLE 4 
A natural rubber latex (Hartex 103, from Firestone Corporation) was mixed 
with different amounts of a 10% aqueous povidone-iodine solution. The 
latex was mixed with the solution at temperatures ranging from about 
20.degree. to 35.degree. C. The povidone-iodine was added to the latex in 
amounts of 0.15:1, 0.1:1, and 0.05:1 by weight, and spread to films of 
about 20 mils. The films were subsequently heated for about 40 minutes at 
about 200.degree. F. Slices of 140 milligrams were severed from the dried 
films and placed in 2 cc of normal saline water for specified periods of 
time. The povidone-iodine was found to be released into the saline water 
and the absorption measured at 378 nanometers, using a Beckman 
spectrophotometer. A standard curve was generated to ascertain the amount 
of povidone-iodine at a given absorption. Referring to the drawings, FIG. 
1 shows the amount of povidone-iodine released from the latex films as a 
function of its concentration in the rubber latex. As the amounts 
increased from 0.05:1 to 0.1:1 and then to 0.15:1, the amount of the 
povidone-iodine released over a period of about 8 minutes into the water 
increased substantially from 0.6 (curve A) to about 2.0 (curve B), then to 
about 15.5 micrograms (curve C). 
EXAMPLE 5 
Polymeric films were prepared by the process set forth in Example 2. The 
mixture of 0.1:1 povidone iodine solution to rubber latex was heated for 
periods ranging from 20 minutes to 40 minutes and then to 90 minutes. As 
shown in FIG. 2, there is a significant decrease in the rate of release of 
the povidone-iodine as a function of heating, i.e., heating time, which 
can be regulated to control the amount of povidone-iodine to be released 
from the film. For example, the period of heating an agent and the latex 
mixture preferably is inversely proportional to the temperature. Thus, as 
the temperature increases, the amount of time needed to heat the latex 
mixture may decrease. As shown by FIG. 2, there is a significant decrease 
in the release of the povidone-iodine from the film as the heating time of 
the latex mixture is increased. Therefore, depending on the release rates 
needed for the particular article being manufactured, the temperature and 
the heating time can be appropriately controlled. 
EXAMPLE 6 
Three polymeric films were prepared from a mixture of the povidone-iodine 
and rubber latex in accordance with Example 2. The films were heated for 
20, 40, and 90 minutes, respectively. The films were cut into 140 
milligram samples. The samples were then placed in 2 ml of distilled water 
and the amount of povidone iodine released to the water from each sample 
was determined at time intervals by light absorption at 378 nanometers and 
compared to a standard povidone-iodine absorption curve at 378 nanometers. 
As illustrated in FIG. 2, the release of povidone-iodine from the film is 
an inverse function of the heating time for a given heating temperature. 
The sample (Curve D) heated for 20 minute released about 10 micrograms of 
the povidone-iodine from the rubber latex film after a period of about 8 
minutes whereas the sample (Curve E) heated for 40 minutes released 2.5 
micrograms and the sample heated for 90 minutes released 1.0 micrograms. 
From the foregoing examples, it is apparent that concentration of the 
antimicrobial agent and the heating time of the latex film will permit 
control, in whole or in part, of the release of the povidone-iodine. 
As mentioned above, the antimicrobial substrate may be incorporated into 
healthcare article in single or multiple layers, with each layer having a 
controllable release of the povidone-iodine. One embodiment is set forth 
in the following Example 7. 
EXAMPLE 7 
A mixture of 0.05:1 povidone-iodine (10% solution) to latex was cast and 
then heated for 90 minutes at temperatures not exceeding 200.degree. F. An 
0.15:1 mixture of the povidone-iodine 10% solution to latex was prepared 
and applied over a glove mold and heated for 40 minutes. Talc powder was 
applied to the exposed outer layer and the glove removed from the mold. 1 
cc of normal saline solution was applied to the 0.15:1 mixture and to the 
0.05:1 latex agent mixture on surfaces covering identical areas and 
allowed to sit for about 8 minutes. The higher concentration of 0.15:1 
latex agent mixture (outer side) of the supernatant liquid showed a 
release of about 23 micrograms of povidone-iodine, while the lower 
concentration of 0.05:1 latex-agent mixture (inner side) gave a release of 
about 2 micrograms of povidone-iodine. 
This multilayered glove with a slow release rate on the outer layer, a 
surgeon's glove, for example, has important biomedical implications in 
that the surgeon would benefit from the longer heat treatment for 90 
minutes of the 0.05:1 mixture of latex on the inner layer of the glove 
which provides a more stable, slower release rate on the outside of the 
surgical glove. Should an inadvertent puncture of the glove occur, the 
surgeon's hand would be bathed in the povidone-iodine which would be 
carried into the wound. Since only very small amounts of free iodine are 
necessary to kill bacteria and various viruses, including the AIDS virus, 
this method of preparing surgical gloves provides effective protection 
against the transmission of diseases. 
As shown in FIGS. 1 and 2, as the concentration of the povidone-iodine was 
increased from 0.05:1 to 0.1:1, the amount of the povidone iodine released 
from the latex film increased from about 0.6 micrograms as shown in Curve 
A to about 2.0 micrograms as shown in Curve B, and to about 15 micrograms 
as shown in Curve C as the amount of the povidone-iodine was increased 
from 0.05 to 0.1 and then to 0.15. 
It was found further that as the period of time for heating the polymeric 
film-forming material decreased, for example, from about 90 minutes at 
200.degree. F. to 40 minutes and then to 20 minutes, the amount of 
povidone-iodine released from the latex increased from about 1.0 
micrograms, as shown in Curve F to about 2.0 micrograms, as shown in Curve 
E, and ultimately to about 10.0 micrograms as shown in Curve D. Thus by 
varying the heating and/or curing time, e.g., from about 20 to 90 minutes 
at a constant heating temperature of about 200.degree. F., the amount of 
release of the biologically active agent, e.g. povidone-iodine, can be 
controlled depending on not only the concentration of the biologically 
active agent present in the polymeric film, but also by varying the 
heating temperature with respect to the period of heating. The amount of 
the biologically active agent released, in the presence of a polar liquid, 
can be controlled in one or more layers of the polymeric film by heating 
each film at a different temperature for a different period of time with 
different concentrations of the biologically active agent. Therefore, in 
preparing surgeon's latex glove, from a plurality of polymeric films in 
accordance with this invention, each film of the glove can have a 
different concentration of the agent and be heated at a different 
temperature for a different period of time to obtain a plurality of 
polymeric films wherein each film releases the biologically active agent 
at a different rate based on the amount, i.e.,concentration, of the 
biologically active agent, the temperature, and the period of heating each 
film. 
The following examples illustrate the process of preparing the latex films 
capable of time-releasing the active agent in accordance with these 
aspects of the present invention. 
Specifically, a surgeon's glove was prepared by dipping a hand form into a 
tank containing a freshly prepared mixture of one part by weight of a 10% 
povidone iodine solution and one part by weight of a synthetic latex. The 
form was removed from the tank and dried for about 40 minutes at 
200.degree. F. it was found that the amount of povidone-iodine released 
from the first layer of latex film into saline water, simulating moist 
skin, was about 3 micrograms/2 cc. Repeating the process, a second layer 
was applied and the form was dried for 20 minutes at 200.degree. F. The 
second layer was found to release the povidone-iodine at 10 micrograms/2 
cc. Thus, the first layer provides a more stable and longer term barrier 
film with respect to the penetration of bacteria or viruses. However, 
since the second outer layer of the glove will be exposed to a greater 
pathogenic environment, a greater amount of the viricidal agent will be 
released over a shorter period of time in comparison to the inside layer. 
Thus, by wearing a surgical glove impregnated with the biologically active 
agent taught by this invention, large quantities of the agent can be 
released rather quickly by having larger amount of the agent in the outer 
layers and by heating the latex for shorter periods of time or at a lower 
temperature. 
Where it is necessary to provide viricidal protection to surgeons or other 
health care personnel over a longer period, a more stable outer layer can 
be prepared which will release the povidone-iodine more slowly in the 
presence of a polar liquid. Thus, the inside layer of the glove may 
comprise a polymeric film having a higher concentration of the agent and 
subjected to a different heating temperature during the preparation of the 
film. The inside layer is in contact with the skin and, hence, hand 
perspiration causes the skin to be bathed in the povidone-iodine. 
Consequently, if the glove were to be punctured by a surgical blade or 
needle, the puncturing object would, by necessity, carry some of the 
povidone-iodine into the open wound, thus providing some protection 
against accidental inoculation. 
For example, surgical gloves comprising multilayers can be manufactured 
wherein each layer contains the same or a different amount of the povidone 
iodine. The rate of release can be controlled or timed by varying the 
heating or drying period and temperature following the dispersion of the 
agent in the latex. A laboratory technician working in a hazardous 
environment may accidentally cause penetration of both glove and skin and 
would benefit from a surgical latex glove comprising a triple layer, for 
example a slow release middle layer with two fast release outer and inner 
layer of latex. This type of glove would provide a more stable, 
slow-release middle layer with a faster release layer on both the exterior 
and interior of the glove. 
EXAMPLE 8 
As an illustration of stability of shelf life, a mixture of a 1:1 
povidone-iodine solution and latex was prepared and heated for about 40 
minutes and then formed into a film. These films were held for abut 18 
months and compared to similarly prepared latex films recently 
manufactured, and it was found that the release rates of the latex films 
held for 18 months in Saran wrap were substantially the same as the 
release rates for the samples of the recently prepared films, thus 
indicating a long shelf life. 
As indicated above, gloves made with natural latex rubber and 
povidone-iodine can also be dried at higher temperatures 
(200.degree.-400.degree.) for periods of around 20 to 25 minutes. Gloves 
made in this manner readily release povidone-iodine when in contact with a 
polar liquid. However, if longer periods of drying are used, for example 
greater than about 10 minutes, at the higher temperatures, little or no 
povidone-iodine exudes from the glove on contact with a polar liquid. 
With the former case above, it appear that the rubber micelles quickly 
coalesce and therefore the iodine has difficulty in penetrating the rubber 
polymer matrix to react with the unsaturated bonds. However, paths are 
available for the povidone-iodine to exude to the surface. In the latter 
case, the povidone-iodine is quickly trapped and the paths blocked, and 
some iodine may also react with the polymer. The amount of povidone-iodine 
released is inversely proportional to the drying time. This aspect of the 
present invention is illustrated by Example 9 below. 
EXAMPLE 9 
Two latex films were formed from the mixtures prepared in accordance with 
Example 1 above using a mixture holding time of about 1 hour. One film was 
dried at 400.degree. F. for 5 minutes and the other film was dried at the 
same temperature for 10 minutes. Both samples were wiped with moist 
towels. The first sample produced a brown color blotch characteristic of 
povidone-iodine while the second sample produced no color when wiped with 
a moist towel. 
EXAMPLE 10 
Films were formed from the mixture prepared in accordance with Example 1 
using a holding time for the mixture of 24 hours. The films were dried in 
the conventional manner with air drying for 20 minutes. Very little or no 
povidone-iodine was detected when the films were in contact with a polar 
liquid. The dried films above were heated at 400.degree. F. for 5 minutes, 
and the presence of free iodine was readily observed on the surface of the 
films when in contact with polar liquid. During the holding period of the 
above mixture, iodine added to the double bonds of the latex. This 
chemical reaction was then reversed by the post heat treatment of the 
iodopolymer. This would also be the case with any iodine substitution. 
The aforementioned controlled release of the povidone-iodine from the latex 
may also be beneficially incorporated into durable medical equipment such 
as catheters. Interdwelling urinary catheters, in particular are frequent 
and life-threatening sources of bacterial infection. The usual sequence of 
urinary infection in cathetered patients is an irritation of the urethral 
mucosa with a secondary bacterial infection which can spread to the 
bladder and ascend to the the kidney via the ureters. 
The present invention can be utilized to provide catheters that have 
controlled release antimicrobial agents. For instance, the entire catheter 
may be conventionally molded from latex incorporating the antimicrobial 
agent. Alternatively, the catheter may be made with conventional materials 
and thereafter selectively or entirely coated with the antimicrobial 
substrate. Referring to FIG. 4 this is shown an interdwelling catheter 20, 
of the Foley type, which comprises an elongated tubular structure having a 
central passage 22 therein. The catheter 20 has a posterior section 24 
located outside the patient. The section 24 includes a drainage section 26 
adapted to be connected to a conventional receptacle for the receipt of 
urine and an injection section 28 for the delivery through the catheter 
passage 22 of medical solutions exiting at the anterior end at an opening. 
The catheter has three generally defined sections, 30, 32, 34, which may 
be coated or not coated with the same or different antimicrobial coatings. 
For indentification, the various sections may be identified by bands 36. 
Section 30 is located outside the patient and may or may not have 
antimicrobial properties as desired. Section 32 has a length generally 
coextensive with the urethral mucosa. Nothwithstanding the low patient 
toxicity to povidone-iodine, Section 32 is coated with a slow release 
substrate and preferably a coating without appreciable release formed in 
accordance with the process described above. In either case, the 
antimicrobial substrate is effective to prevent a nidus of infection while 
minimizing possible mucosal irritation. The section 34 is adapted to 
reside within the bladder and has a coating providing a slow, relatively 
high concentration release of povidone-iodine. The high concentration, 
slow release properties of this section continually sterilizes the urine, 
thus preventing an ascending infection from the bladder, to the ureter, 
and ultimately to the kidney. Thus, the multiple zone catheter interrupts 
the usual sequence of interdwelling infections. 
In addition to the aforementioned controlled release of antimicrobial 
agent, it has been demonstrated that povidone-iodine is an effective 
curing agent for compounded or uncompounded latex at room temperature, and 
is further activated upon application of heat to the formed film. 
Unexpectedly, mixtures of natural latex rubber and povidone-iodine, 
without any vulcanizing agent, yield cast films which are vastly superior 
to cast films made from natural latex rubber without any vulcanizing agent 
or povidone iodine and comparable to films cast from mixtures of natural 
latex rubber and sulfur as the vulcanizing agent. 
The excellent physical properties of the natural rubber latex and the 
povidone-iodine is due to the iodine functioning as a curing agent, 
initiating the polymerization of the double bonds of the natural rubber 
polymer and thereby cross linking the system. Only a very small amount of 
iodine free radicals need to be formed to cross link the polymer. While 
not wishing to be bound by any particular theory, it appears that the 
povidone-iodine in solution has available free iodine. The iodine is in 
constant equilibrium as follows: 
EQU I.sub.2 =2I.degree. 
Thus the free radical I.degree. moiety can facilitate the cross linking of 
rubber polymers as described below: 
EQU I2.fwdarw.2I.degree. 
EQU I.degree.+C.dbd.C.fwdarw.IC-C.degree.+C.dbd.C.fwdarw.IC-C-C-C.degree. 
In addition to the above, the iodine adds to the unsaturated rubber to form 
the polyiodo derivative. However, this derivatization reaction is readily 
reversible and decomposes into iodine and the unsaturated moiety. Also, as 
the double bonds are cross linked they cease to be a scavenger of the 
povidone-iodine. These factors along with the stability of the povidone 
iodine complex account for the ability to control the release of povidone 
iodine to the surface of barrier articles by manipulating their 
manufacturing process variables. 
This curing ability is demonstrated by the following example. 
EXAMPLE 11 
A 10% solution of povidone-iodine was admixed with an equal volume by 
weight of a natural, low ammonia latex emulsion, Hartex 104 manufactured 
by Firestone. The admixture was gently mixed until a uniform dispersion 
was achieved. The admixture was spread on a forming plate to a thickness 
of 10 mils and dried at 40.degree. C. for a period of 20 minutes. The 
aforementioned latex emulsion is not compounded with any curing agents 
such as sulfur or other vulcanizing agents. The dried film latex substrate 
was stripped from the forming plate and cut into 2 inch by 2 inch samples. 
Second, a natural, low ammonia latex emulsion, Hartex 104 manufactured by 
Firestone, was spread on a forming plate to a thickness of 10 mils and 
dried at 40.degree. C. for a period of 20 minutes. The resulting dried 
film substrate was stripped from the forming plate and cut into 2 inch by 
2 inch samples. 
Third, a commercially available examination glove having a thickness of 10 
mils was cut into 2 inch by 2 inch samples. 
The three sets of samples were then subjected to elongation in both 
directions and to penetration by a sharp object. The povidone-iodine cured 
latex substrate and the examination glove were stretched to an elongation 
of 800%. Neither broke, ruptured or developed holes. The latex emulsion 
substrate without curing agent severed at about 200% elongation and 
intrasubstrate holes were noticed at an elongation of less than 50%. 
A sample of each substrate was mounted about the periphery. An object with 
a sharp point was located at the center of each sample and deflected. A 
point penetrated the latex emulsion substrate without curing agent at less 
that 1/2 inch deflection. The povidone-iodine cured latex was penetrated 
by the point at 2 inch deflection. The examination glove was penetrated by 
the point at a 1.8 inch deflection. 
The above clearly indicates that the povidone-iodine, in addition to the 
controlled release as an antimicrobial, can be used as a curing or 
vulcanizing agent for latex, in combination with or as replacement for 
current curing agents without a lessening of physical properties. 
Various other embodiments and modifications of the above described 
embodiment will be apparent to those skilled in the art. Accordingly the 
scope of the invention is defined only by the accompanying claims.