RADIATION STERILIZABLE ANTIMICROBIAL OINTMENT AND PROCESS TO MANUFACTURE

Abstract: Sterilized povidone-iodine (polyvinylpyrrolidone-­ iodine) in an ointment form is obtained by preparation of a mixture of purified water, povidone-iodine, a non-ionic gelling agent, and a non-ionic low suds surfactant. The ointment is a liquid in the temperature range of about 2° C to 9° C because of the influence of the non-ionic gelling agent. At room temperature, the mixture forms a free standing ointment which can be sterilized by gamma radiation without degradation of its antimicrobial efficacy, viscosity or shelf life. The ointment is easily prepared by using chilled purified water which maintains the mixture as a liquid while all of the ingredients are mixed together. At room temperature the mixture becomes a free standing ointment.

Description: This invention relates to the preparation and sterilization of povidone-iodine ointment used for topical disinfection. Ointments are recognized as salves or unguents for application to the skin as a semi-solid medicinal preparation. The idea of an ointment is to have a soft unctuous preparation which at room temperature exists as primarily a separate soft free standing solid that does not flow. The ointment should have a wet or moist looking surface appearance with no visible separation of the solid and wet portions. Povidone-iodine ointments used in the topical antimicrobial treatment of human and animal skin are formulated with povidone-iodine (a complex of povidone and iodine) and contain sufficient iodine in active form to kill microbes. Consequently, povidone-iodine treats wounds and skin abrasions. Topical disinfection solutions containing povidone-iodine are used as cleansing and patient pre-operative preparing agents and are well recognized as a germicidal agent which is safe, non-irritating to the skin and shelf stable for a commercially acceptable period of time. Povidone-iodine powder has been used in making iodophor ointments for topical disinfection. Polyvinylpyrrolidone is a homo-polymer of 1-ethenyl-2-pyrrolidinone also known as 1 vinyl-2-pyrrolidinone polymer. A common name for this chemical substance is povidone and the compound is sometimes designated as PVP. Povidone is a synthetic polymer having linear 1-vinyl-2-pyrrolidinone groups polymerized into polymer chains of various molecular weights, generally having mean molecular weights ranging from about 10,000 to 700,000. Polymers of both lesser and higher molecular weights are known. Povidone is available as, either as a dry powder or in aqueous solution for use in a wide variety of chemical, pharmaceutical and food manufacturing processes as well as special industrial compositions such as inks, paints and emulsions, cosmetics and germicidal products. Povidone, in manufacture and formulation of different compositions, contributes to the viscosity of the fluid medium being used. The viscosity contribution of povidone ranges from higher to low viscosity as a function of the average molecular weight of the polymer. Povidone is classified by K-values which are assigned to the various povidone polymers, the smaller the K-value, the lower the intrinsic viscosity of the polymer solution. The more common commercially available povidone polymers have K-values of K-17, K-30, K-60 and K-90. In aqueous solutions, povidone K-17 and povidone K-30 have little effect on viscosity in concentrations below 10%, whereas povidone K-60 and povidone K-90 have considerable influence on the flow properties of a solution at such concentrations. Moreover, certain organic solvents have a particular effect on the viscosity contribution of povidone, the intensity of which is related to the polarity of the particular organic solvent. Cross-linkage of the povidone polymer is influenced by diverse factors as for example, actinic light, diazo compounds, oxidizing agents and heat. Cross-linking of the povidone polymer is a serious limitation to its use since the povidone polymer is altered into an aqueous insoluble form. The presence of certain substances in the povidone solution will accelerate cross-linking at even lower temperatures. When a povidone solution is heated to 100°C., in the alkaline pH range, the polymer becomes permanently altered to be irreversibly insoluble. Similar cross-linked changes occur when alkaline sodium phosphate buffers are used and when an oxidizing agent such as ammonium persulfate is added to a povidone solution, cross-linking gel formation occurs in about 30 minutes when the combination is heated at moderate temperatures of about 90° C. Therefore, aqueous solutions of povidone subjected to autoclaving to sterilize povidone preparations, may cause degradation of the polymer. Thus for example, povidone which is stable to moderate heat will darken in color and decrease in water solubility when heated to about 150 °C. The cross-linking of the polymer caused by heat, oxidizing agents, salts and other substances presents special problems in the manufacture and processing of certain compositions containing povidone, when these povidone solutions are intended for parenteral use, since the formed insoluble cross-linked povidone may initiate thrombotic episodes and other noxious events When povidone is used in the manufacture of those preparations requiring sterilization but containing oxidizing agents or other oxygen sources, then similar incompatibility occurs to limit the use of povidone in the preparations. For medical products gamma radiation, an effective sterilizing process, is notoriously unsuited for use with povidone polymers. The particular degradative effects followed by cross-linkage and gelation occurring when povidone is exposed to even minimal gamma radiation dosage is well known. The formation of a stable ointment to be subject to gamma radiation is of concern. The actions of radiation on povidone, together with radiolysis products formed in the composition, results in macroradical polymer chain formation and these macroradicals further inter-react so that the ultimate effect of radiation is either cross-linkage gelation or chain scission. When povidone solutions are irradiated with gamma radiation, gelation occurs when the concentration of povidone in solution is above the critical limit of from 0.3% to 1% by weight of povidone, dependent upon the molecular weight. For the lower molecular weight of K-30 and below the critical concentration factor is between 0.5% and 1% by weight while for values above K-30 this critical concentration is between 0.3% and 0.5%. Below this critical concentration limit, macrogelation to form a wall to wall gel, is not readily observed. The sensitivity of povidone to low dosages of gamma radiation is so pronounced that adverse gelation crosslinkage effects are observed after irradiation with doses as low as 0.1 kilorad, when the particular critical concentration of povidone in solution is exceeded The use of povidone in most industrial, agricultural and pharmaceutical manufacturing procedures exceeds the critical concentration limits established for the gamma radiation of povidone. The critical concentration level for povidone is further adversely modified by ionizing solutions, oxidizing agents and pH. This destructive, degradative response of povidone to gamma radiation which destroys its desirable properties in the formulation precludes the use of gamma radiation as a means to render povidone and povidone-containing compositions free of microbial contamination. Thus, attempts to produce sterilized povidone-iodine by irradiation of the povidone prior to formulation of the povidone-iodine are complicated by the described problems of gamma radiation of the povidone. The sterilization of povidone-iodine after formation is found to be unsatisfactory because the irradiation has the effect of decreasing the amount of available iodine with consequent reduction in antibacterial activity. Most commercially available povidone-iodine ointments are prepared by using cellulosic thickeners which upon irradiation undergo severe degradation turning into liquids with a water like consistency. A povidone-iodine ointment which is easy to mix and sterilize without loss of viscosity or antimicrobial activity has not been available. The ability to gamma radiate to sterilize the mixture without viscosity changes to the free standing ointment without significant loss to available iodine or reduction in antibacterial activity over a reasonable shelf life time period is unknown. French patent specification 2,267,112 describes the use of aqueous detergent solutions of block copolymers of ethylene oxide and propylene oxide for the cleansing of contaminated wounds. The cleansing solutions may be formulated as surgical scrub solutions and may contain iodophors such as polyvinylpyrrolidoneiodine. The present invention comprises the formation of an ointment including povidone-iodine which can be gamma irradiated without significant loss of the antimicrobial efficacy, without loss of viscosity or thickness and without a decrease in shelf life. The present invention provides a radiation sterilized ointment of stable ointment viscosity having effective iodine concentration for disinfection of skin, comprising a mixture of purified water, povidone-iodine, a non-ionic gelling agent which is a polyol being a poly-(oxypropylene) poly-(oxyethylene) included in the range of twenty to thirty percent by weight of the mixture, and a non-ionic low suds surfactant. In accordance with the present invention, there is also provided the use of a mixture for the preparation of a radiation sterilized ointment for disinfection of skin, the mixture comprising purified water, povidone-iodine, a non-ionic gelling agent which is a polyol being a poly-(oxypropylene) poly-(oxyethylene) included in the range of twenty to thirty percent by weight of the mixture, and a non-ionic low suds surfactant, the mixture having effective iodine concentration after radiation sterilization and stable ointment viscosity after radiation sterilization. The present invention further provides a method for making an antimicrobial ointment mixture including the following steps: chilling purified water to a temperature range of 2°C to 9°C; mixing into the chilled purified water an antimicrobial agent to form a homogenous solution; adding a non-ionic gelling agent being a polyoxyethylene and polyoxypropylene block copolymer surfactant included in the range of twenty to thirty percent by weight of the mixture to the solution at a temperature of 2°C to 9°C; increasing the temperature of the mixture to form a free standing iodophor ointment from the mixture when the temperature of the homogenous solution increases to above about 9°C; and irradiating the free standing ointment mixture to sterilize without significant degradation of its iodine antimicrobial efficacy, viscosity or stability. A preferred embodiment of the present invention includes primarily water as the main constituent being about two thirds of the mixture by weight. Purified water as used in the mixture is deionized or distilled water. A non-ionic gelling agent is by weight almost one-quarter of the mixture. About ten percent of the weight of the mixture is povidone-iodine in powder form, and the smallest portion of the mixture is a non-ionic low sudsing surfactant which is added at about one-fifth of a percent by weight. These ingredients are mixed in the purified water chilled to the range of about 2° C to 9° C. At that temperature the ingredients are in the form of an easily mixed liquid. The mixture is a liquid of viscosity about 1000CPS when cooled to approximately 3° C. thus greatly facilitating manufacturing and packaging. While the mixture may be mixed at a higher or lower temperature, the ease of mixing the liquid is preferred. When the temperature of the liquid mixture is raised to room temperature, in particular above 9° C and preferably around 20° C to 25° C, a very high viscosity semi-solid mass referred to herein as a free standing ointment occurs. It is the elevation of the temperature which increases the viscosity of the mixture from that of a liquid to that of a semi-solid mass or free standing ointment. The ointment can be sterilized by gamma radiation in the range of 1.8 to 3.0 Mrad which causes an acceptable drop from 0.98% to 0.72% in available iodine concentration. The irradiated mixture has a long shelf life and is found to have extremely stable iodine concentration and physical properties when measured after storage at 60 °C, 52° C, 42° C, 37° C, and room temperature for intervals of up to two years. In the preferred method of forming the ointment the non-ionic low sudsing surfactant is added to and mixed with the purified water, chilled to between 2 °C and 9° C. Next, the povidone-iodine in powder form is added into the solution in a manner to prevent lumps from forming such that a solution can be made. The non-ionic gelling agent is added to that chilled solution to form a chilled liquid mixture. Upon warming the chilled liquid solution to room temperature, a free standing ointment in the form of a homogenous solution results. The ointment has iodine but can be sterilized by gamma radiation without significant degradation of the antimicrobial efficacy of available iodine, without changing the semi-solid viscosity of a free standing ointment or without incurring instability during long term shelf life testing. While this invention is satisfied by embodiments in many different forms, there is described in detail a preferred embodiment of the invention, with the understanding that the present disclosure is to be considered as exemplary of the principles of the invention. The iodophor ointment includes an antimicrobial povidone-iodine complex. In the preferred embodiment povidone-iodine powder in accordance with the standards of The United States Pharmacopeia The National Fomulary, referred to herein as USP, published by United States Pharmacopeial Convention, Inc., Rockville, Maryland is used. As defined in the USP, the powder contains between 9% and 12% available iodine if calculated on its dried basis. The K-value of the povidone used in the povidone-iodine is typically K-30. The percent weight of the povidone-iodine powder is formulated to give the ointment an available iodine in the aqueous solution of about 0.85% to 1.2%. The antimicrobial properties of the ointment are provided entirely by the ability of the iodine portion of the povidone-iodine to kill microbes. In order to make the ointment, chilled purified water in the range of 2° C to 9° C is used. The greatest portion of the mixture is chilled purified water which represents about two-thirds of the mixture by weight percentage. To obtain the right consistency of the ointment, a non-ionic gelling agent having the unique property of increased solubility with decrease in temperature of the water used provides the base of the free standing ointment. In the preferred embodiment, Pluronic F-127 is used as the non-ionic gelling agent and it is available from BASF Wyandotte Corporation, Parsippany, New Jersey. This material is in a powder form and is supplied as a gelling agent soluble in either hot or cold water. Pluronic F-127 is a polyol being a poly-(oxypropylene) poly-(oxyethylene) condensate and is known to form a gel in water at concentrations of about 20%. With this specific nonionic gelling agent the result is expected to be a wall-to-wall gelatinous material which will sustain a vibration when in the form of a gel. The free standing ointment of the present invention retains the moist or wet appearance of a liquid on its surface but will not flow. The ointment formed is not gelatinous (in the sense that gels vibrate when suitably stressed). The preferred viscosity of the ointment was established by tests run with different concentrations of a non-ionic gelling agent added to the chilled purified water. Evaluations conducted on various samples having different concentrations of Pluronic F-127 in the purified water included solutions with concentrations of non-ionic gelling agent varying from 21% to 30%, by weight. All were prepared by mixing/dissolving the components at 3°C with varying the amounts of pluronic F-127 and purified water in each mixture to make the different concentrations of non-ionic gelling agent. A test solution was prepared for use in formulating a series of samples each having a different viscosity. In the test solution the povidone-iodine powder is prepared from povidone K-30 powder and iodine powder mixed together. The non-ionic low sudsing surfactant was not added since it is in the mixture at less than a half of a percent by weight. These ingredients, in the basic solution are kept at their preferred weight percentages, so only the amount of the gelling agent was varied. Each mixture was then held at 3° C until suspended air escaped and then each was mixed again to insure homogeneity. The Pluronic F-127 non-ionic gelling agent, used at various concentrations by weight concentration, is evaluated for the consistency at room temperature. Observations were made about the physical characteristics of each of the various Pluronic F-127 concentrations. Sample 1 with a 30% weight concentration of nonionic gelling agent in chilled (3° C) purified water had solid, undissolved Pluronic F-127. This concentration is excessive. Sample 2 with a 27.5% weight concentration of non-ionic gelling agent in chilled (3° C) purified water made a very thick nearly solid solution wherein still some Pluronic F-127 remained undissolved. Sample 3 with a 25% weight concentration of the Pluronic F-127 non ionic gelling agent in chilled (3° C) purified water produced a solution which was complete but solidified at room temperature and showed a firm, dry character with no tendency to flow or separate. Sample 4 with a 23.5% weight concentration of the Pluronic F-127 non-ionic gelling agent in chilled (3° C) purified water resulted in the preferred embodiment as an ointment was prepared which appeared moist at room temperature. Although it is a solid and it does not flow at room temperature, the free standing gel has a wet looking surface appearance with no visible separation of the solid and liquid portions. Sample 5 with a 22.8% weight concentration of the Pluronic F-127 non ionic gelling agent in chilled (3° C) purified water solution was not stable and separated after several weeks at room temperature. Sample 6 with 22.5% weight concentration of the Pluronic F-127 non-ionic gelling agent in chilled purified water is very soft at room temperature. It tends to flow and it slightly separates after about 4 hours at room temperature. Sample 7 with a 22% weight concentration of the non-ionic gelling agent in chilled purified water is very weak as it slowly flows. After a few minutes at room temperature separation becomes evident. The practical range of concentration of Pluronic F-127 in water to make a free standing gel could range from 20% to 30% by weight depending on the temperature at which the mixture is to be stored and used, the exact consistency and shelf life required. Near 20% no semi-solid forms, the mixture exists as separate solid and liquid phases and at 30% no solution forms because there is insufficient water to dissolve the Pluronic F-127 non-ionic gelling agent. The specific percentage by weight of non-ionic gelling agent will vary to some degree depending on the particular non-ionic gelling agent or polyol used as a surfactant and the other ingredients specified for the mixture. For example, if the povidone K-value is higher than its typical K-30, the amount of non-ionic gelling agent necessary for an ointment could change. In the preferred embodiment the povidone-iodine powder is prepared from povidone K-30 powder and iodine powder mixed together. The Pluronic F-127 non ionic gelling agent is used at a 23.5% by weight concentration. The preferred mixture of Pluronic F-127 non-ionic gelling agent and purified water represents 90% of the total mixture by weight. The antimicrobial povidone iodine powder USP (as specified in The United States Pharmacopoeia) is nearly the remaining 10%. The surfactant is less than one half of a percent. The preferred range for the purified water is between 62% and 69% percent by weight in the mixture. The preferred range for the non-ionic gelling agent, Pluronic F-127, is between 20% and 30% by weight in the mixture. The preferred range for the povidone-iodine in the mixture is in the range of 10.4% to 11.5% by weight in the mixture. A non-ionic low sudsing surfactant is added to aid in the use of the free standing antimicrobial ointment in connection with skin oils. Oily skin on the patient to which this material is applied is effectively treated due to the addition of a slight amount of non-ionic low sudsing surfactant. Only a slight amount of such a material is generally required, in particular, less than a half of one percent by weight. The specifically preferred material is a polyol, Pluronic L-62LF, also from BASF Wyandotte Corporation. While ranges have been given for the ingredients used in forming a free standing antimicrobial iodophor ointment, the preferred embodiment includes 65.4% chilled purified water, 23.5% Pluronic F-127, 10.9% povidone-iodine powder USP, and 0.2% Pluronic L-62LF. All of these percentages are by weight of the total mixture. The viscosity of the free standing ointment is temperature dependent wherein viscosity increases with increasing temperature but does not present a problem to the manufacture of the finished product. The preferred mixture when manufactured at 3° C and allowed to warm from 3° C demonstrates increasing viscosity. At 3° C the viscosity is 1000 CPS, at 4° C 1125 CPS, at 5° C 1425 CPS, at 6° C 1688 CPS, at 7° C 2150 CPS, at 8.5° C 2650 CPS, and at 9° C and above a free standing ointment occurs. The mixture can be maintained at low temperature as a liquid without adverse effects. The liquid form of the chilled mixture is ideal for easy filling during packaging. Accurate fill volumes and weights are obtained with the chilled liquid. The ingredients of the preferred mixture are mixed at a temperature of 2° C to 4° C. The main component, purified water, is held at 2° C to 4° C during the mixing operation. The addition of the ingredients is done in such a way that the temperature of the mixture throughout its manufacture is maintained in the 2°C to 4° C range. The free standing ointment does not occur until the temperature is raised to above 9 ° C. The preferred free standing ointment consistency (a solid with a moist liquid surface appearance) is stable at room temperature (20° C.). The specific method used to form the free standing ointment of the preferred embodiment includes providing the chilled water in the 2° C to 4° C range, preferably 3 °C, adding the non-ionic surfactant Pluronic L-62LF and mixing, then adding the povidone-iodine powder USP in a manner adequate to avoid clumping so as to obtain a homogeneous solution without lumps. Finally, the Pluronic F-127, the non-ionic gelling agent is added. The entire mixture is maintained in the 2° C to 4° C range and is stirred for one hour in order to produce a homogeneous liquid solution. The solution is allowed to warm up to above 9° C and the liquid turns into a free standing ointment. The appearance of the free standing ointment at room temperature is a solid with a moist or liquid surface. Because of the iodine, the iodophor ointment has a reddish brown color. It is an opaque substance with a mild, not sharp, iodine odor. The pH is in the range of 1.8 to 2.5 and the available iodine is between .90 % and 1.2%. This is before the substance is gamma radiated for sterilization. After gamma radiation, the available iodine drops about .25% when the radiation level is 2.5 Mrad. The available iodine in the free standing ointment after radiation is relatively stable when tested by means of accelerated shelf life tests at elevated temperatures of 60 °C, 52 ° C, 42° C, 37° C, and 25° C. Therefore, it is expected to have a commercial shelf life of greater than 10 years. In order to prove that the product of the preferred mixture is useful, bactericidal efficacy testing was performed using the non-irradiated and irradiated product treated with 2.5 Mrads of gamma radiation. The test procedure used required nutrient agar in 100 x 15 mm petri dishes and pinicylinders with a cup size of approximately 8 x 8 mm. Microbial culture challengers were prepared in tryptic soybroth The agar plates were inoculated by swabbing each plate with a selected test organism using sterile cotton swabs saturated with the culture resulting in confluent growth. Each cup was then filled with test agar. All agar plates were incubated for a minimum of 48 hours at 30° C to 35° C. The recorded zone of inhibition is taken from measurements of the distance from the edge of the cup to the point where the microbial growth is inhibited. The greater the area of the inhibition zone the more effective the iodophor ointment will be in terms of killing microbes after the ointment is applied to the patients skin. From the above results, it can be appreciated that the preferred mixture is effective over a measurable area as an antimicrobial for a range of organisms, even though it has been irradiated. As mentioned the gamma radiation does effect the iodine slightly but not such that the active iodine is destroyed To test the iodophor ointment for irritation with the maximum iodine content, non-irradiated iodophor ointment of the formulation of the preferred embodiment was tested in four ways for safety and toxicity. The tests were primary skin irritation, dermal sensitization, primary eye irritation, and vaginal mucosal irritation. The primary skin irritation test proved negative, the dermal sensitization test proved negative, the primary eye irritation test proved positive, and the vaginal mucosal irritation test proved positive. The primary skin irritation test was in accordance with the procedure in CFR Title 16, chapter II, part 1500.41. The testing done on the skin of rabbits includes applying the preferred iodophor ointment to gauze that is attached to shaved skin on the back of a rabbit. Two sites are selected, one slightly abraded and the other not. After 24 hours and 72 hours the two sites were examined. The dermal sensitization test is according to Buehler patch test procedure found in Archives of Dermatology, 91, 171-175. In another test guinea pigs are treated three times a week, Monday, Wednesday and Friday. The treatment consists of shaving the mid back area and applying ointment covered with tape (to prevent evaporation) for a period of six hours for each treatment. After the treatment the site is cleaned and examined for erythema or edema. At least 24 hours lapse between treatments. After 14 days, new animals plus the tested animals are again treated with the patch test to determine whether any of the tested animals have developed a sensitivity. The primary eye irritation test was conducted with three rabbits wherein the ointment was put in the rabbits lower conjunctival sac. The eyes were examined at 24, 48 and 72 hours after the ointment was placed. The scoring of the reaction is in accordance with Illustrated Guide For Grading Eye Irritation By Hazardous Substances from the U.S. Department of Health, Education and Welfare, Food and Drug Administration, Washington, D.C. The test procedure is in CFR 15, part 1500 of the Federal Hazardous Substances Act. The last test was vaginal mucosal irritation. This test was run in accordance with CFR 21, part 58 according to Good Laboratory Practice Regulations. The procedure requires testing of three female rabbits on five consecutive days wherein two milliliters of the ointment were delivered to the vaginal vault by means of a catheter. Twenty-four hours after the last dose the rabbits were sacrificed and examined. Tissues were prepared for histological microscopic examination.

Claims: Use of a mixture for the preparation of a radiation sterilized ointment for disinfection of skin, the mixture comprising purified water, povidone-iodine, a non-ionic gelling agent which is a polyol being a poly-(oxypropylene) poly-(oxyethylene) included in the range of twenty to thirty percent by weight of the mixture, and a non-ionic low suds surfactant, the mixture having effective iodine concentration after radiation sterilization and stable ointment viscosity after radiation sterilization. Use according to Claim 1 wherein the weight of the purified water is in the range of 62% to 69% by weight in the mixture. Use according to Claim 1 or 2, wherein the weight of the povidone-iodine is in the range of 9.0% to 12.0% by weight in the mixture. Use according to Claim 3 wherein said povidone-iodine is 10.9 by weight percentage of the mixture. Use according to any preceding Claim wherein the mixture has a relatively liquid viscosity at temperatures below about 9°C and with an ointment consistency at temperatures above about 9°C. Use according to any preceding Claim wherein the weight of the non-ionic low suds surfactant is in the range of less than 0.5% by weight in the mixture. A radiation sterilized ointment of stable ointment viscosity having effective iodine concentration for disinfection of skin, comprising a mixture of purified water, povidone-iodine, a non-ionic gelling agent which is a polyol being a poly-(oxypropylene) poly-(oxyethylene) included in the range of twenty to thirty percent by weight of the mixture, and a non-ionic low suds surfactant. A method for making an antimicrobial ointment mixture including the following steps: chilling purified water to a temperature range of 2°C to 9°C; mixing into the chilled purified water an antimicrobial agent to form a homogenous solution; adding a non-ionic gelling agent being a polyoxyethylene and polyoxypropylene block copolymer surfactant included in the range of twenty to thirty percent by weight of the mixture to the solution at a temperature of 2°C to 9°C; increasing the temperature of the mixture to form a free standing iodophor ointment from the mixture when the temperature of the homogenous solution increases to above about 9°C; and irradiating the free standing ointment mixture to sterilize without significant degradation of its iodine antimicrobial efficacy, viscosity or stability. A method according to Claim 8 with the additional step of adding a non-ionic low suds surfactant after chilling the purified water. A method according to Claim 8 or 9 wherein the antimicrobial ointment is irradiated in the range of 1 to 3 Mrads.

Inventors: KHAN, MOHAMMED A., MOELLMER, JOHN F.
Applicants: BECTON DICKINSON AND COMPANY
Application year: 1990
Main classification: A61K33
IPC codes: A61K9, A61K33, A61K47, A61K31