FIELD OF INVENTION

The present invention relates to a macroporous polymer matrix for controlled release of active ingredient and a process of preparation thereof.

BACKGROUND OF THE INVENTION Skin is the most susceptible organ to pathogenic microorganisms present around. Any challenge to the integrity of the skin compromises this natural defense.This makes it necessary to protect and control wounds and injuries from microbial infection and induce faster wound healing. Thus use of topical bactericidal agent has become a regular practice in aseptic wound care. Many topical microbicidal agents have been used to this effect.

Iodine is one of the oldest and effective antiseptic agents. It is a powerful microbicidal with a broad antimicrobial spectrum including fungi and medium viruses. A number of antiseptic preparations for wound care are commercially available which utilizes iodine as antimicrobial agent. The antimicrobial activity of iodine partly depends upon its ability to penetrate the cell walls of microorganisms rapidly, and block certain essential hydrogen-bonding in amino acids. Also, it has a powerful, oxidizing effect on S-H, -S- S- groups, which are essential factors in protein production. It is effective against a wide range of microorganisms, including bacteria, tubercle bacilli (Mycobacteria), fungi, protozoa, lipid and medium , viruses, as well as non-lipid and small viruses. Iodine is designated as an intermediate germicide only because spores are not readily killed with weak concentrations. However, iodine has the greatest de-germing efficiency compared to the other halogens, chlorine and bromine, since it is deactivated by proteins at least three times slower than chlorine and four times slower than bromine. Therefore, under normal conditions of use where there is the presence of large amounts of dissolved proteins in blood, serum, or sputum, iodine would not be rendered ineffective. Iodine has the additional advantage that its disinfecting properties are independent of the pH value of its environment. Therefore, unlike chlorine, for example, iodine would not be rendered ineffective in an acid pH. It would likewise not be deactivated quickly in an alkaline pH.

Some of the limitation for the germicidal use of iodine is its high aqueous insolubility (0.034% at 25° C.) and high vapor pressure. While the aqueous solubility of iodine may be increased through the use of alcohol (as for example, tincture of iodine) or through the use of inorganic metallic salts as solubilizing agents (as for example, sodium iodide and/or potassium iodide in the preparation of Lugols' Solution), such iodine solutions also possess the same toxic tissue manifestations which generally limit the use of iodine germicidal solutions. Generally a simple iodine solution in form a tincture-iodine is highly cytotoxic if applied directly on wounds.

There have been several attempts to control the release of iodine and use its antimicrobial property. As described in Pat. No. US 1 ,867,222 effectively employs a two part dressing, using an iodide salt in one component and an oxidizer in the other which release iodine when in contact with moisture. To this effect efforts have been made to control the release of iodine by complexation of iodine with several complex forming polymers (iodophors). Iodophors are loose complexes of elemental iodine or triiodide, solubilizers, and a polymeric carrier that serves, not only to increase the solubility of the iodine but also to control the release of iodine in a sustained manner.

The general class of organic iodophor compounds comprises two distinct polymer groups; the first group consisting of only one member, polyvinylpyrrolidone, which is a non-detergent, non-ionic and non-surface active polymer, the second group comprises the broad variety of detergent-surface active polymers including non-ionic, anionic and cationic surface active polymers. Both polymer groups are complexed with elemental iodine to form the iodophor. The general method for the preparation of an iodophor complex is to bring into intimate contact, elemental diatomic iodine with the selected polymer either in the dry or powder form or in the presence of a suitable solvent. Heat may be used to accelerate complex formation. Upon completion of the reaction, the iodophor complex of the respective polymeric carrier with iodine is obtained in a certain reproducible proportions of one to the other. The carriers, heretofore, have been neutral, water soluble polymers, with mainly polyvinylpyrrolidones as principal commercialized polymer. Polyether glycols, polyacrylic acids, polyamides, polyoxyalkylenes, starches and polyvinylalcohol (PVA) also form iodophors. The most commonly used iodophor is polyvinylpyrrolidone also known as povidone-iodine. Patent No. US 4, 128,633 utilize polyvinylpyrrolidone (PVP) and Iodine (I ₂ ) for controlling rate of release of iodine. Patent No. US 5,242,585 describes about an iodophor of PVP/I ₂ in form of a free flowing aqueous soluble lightly crosslinked powder, for controlling the release of iodine from PVP based iodophor preparations. These iodophor complexes form micellar aggregates, which are dispersed upon dilution with body fluids or water and the iodine linkage to the polymer is progressively weakened until the iodine can be regarded as free to generate antimicrobial concentrations. A commercially available preparation of povidone-iodine is Betadine available as solution or cream. These iodine preparations have advantage over free iodine in that they greatly reduce the irritation to the tissue, unpleasant odour, staining of the tissue and corrosion of metal surfaces. The sustained release properties of PVP/I ₂ iodophors have encouraged their usage in preoperative skin preparations surgical scrubs, washes douches, lotions and ointments.

Although quite effective as antimicrobial agent these aqueous based iodophors have limitations in terms of limited iodine reserves and dilution factors leading to a disinfecting effect for relatively short period of time. Most water miscible broad spectrum antimicrobials exhibit this deficiency. Since the iodophors are water soluble they tend to dissipate their antimicrobial action quickly. The concentrations of iodine in water based systems can be much higher than what is required for its antimicrobial intent and iodine is dissipated by side reactions resulting in depletion of iodine reservoir leading to recolonization of microbes at wound site. In such cases continuous or repeated application of the antimicrobial agent is required to inhibit the increase in microbial population. For example, sustained release can be provided, with prolonged antibacterial activity under a plastic, self adhering surgical drape film. Pat. No. US 4,323,557, describes a process for incorporating N-vinylpyrrolidone (NVP) in the polymeric backbone of a pressure-sensitive adhesive of which the pyrrolidone component serves to complex and slowly release the iodine. The iodophor-based adhesive film provides a sterile operative surface, and acts as a barrier to isolate the incision from contaminating skin flora. This product is for use as an incisible self- adhering drape and is not intended for wound healing dressings or wound packings.

Iodophor preparations are described in terms of available or titratable iodine which is considered to be the iodine released from the complex to exert its germicidal action. However, such available iodine determinations do not either reflect the total iodine content of the iodophor or its germicidal potency. Iodophor solutions are also categorized on the basis of the amount of iodine extracted into an immiscible organic solvent which is expressed as the distribution coefficient for the preparation. Such extracted iodine is defined as uncomplexed or free iodine and is interpreted to reflect iodophor integrity. The uncomplexed iodine is postulated to be the cause of toxic responses, unstable and malodorous preparations and the distribution coefficient became the general measure to predict stability of the preparation on storage as well as the occurrence of toxic tissue responses.

It is important to establish the preferred range of concentration for equilibrium iodine to obtain optimal germicidal activity. Although in theory as long as equilibrium iodine is present, microbes will be destroyed. However, in the dynamics of the biologic system, the rate of microbial destruction must be greater than its regeneration. The microbicidal action of any substance depends upon multiple factors including inherent resistance of the organism to microbicides, number of organisms present, specific microbicidal potency of the germicide and regenerative power of the organism.

Patent No. US 4,946,673 describes about methods to determine the equilibrium iodine content responsible for microbicidal activity in aqueous iodophor preparations and methods to control the same. It is described that controlling the equilibrium iodine content in aqueous solutions preferably between 2-15 ppm provides predetermined germicidal activity.

It is known that iodine interacts with certain physiologic organic compounds, proteins, carbohydrates and reducing substances such as sulfhydryl groups present in blood, pus and other biologic fluids. These substances present in living cellular materials consume iodine to deplete both the equilibrium iodine and the reservoir iodine of the iodophor solution as it is used in degerming practice. The principle iodine resource for the regeneration of equilibrium iodine however, is the predominant iodine species I ₃ ^" , which exists both in the free state as well as being bound to the polar hydrophilic centers of the povidone polymer. It has been shown that the polymer povidone will combine with about one mol of iodine for each mol of monomer and such combination involves an ionic bond. Although certain iodine anion, as for example I5 ^" and I ₇ ^" form by the selective complexing between elemental iodine and the appropriate precursor derivative iodine anion, the recovery of iodine from I ₃ ^~ anion is the major iodine resource species to be considered for equilibrium iodine regeneration.

Low concentrations of iodine react relatively slowly as compared with proteins in general arid therefore it remains available to react with bacteria to which it generally has greater affinity. It is in this way that iodine can exhibit its unique advantageous selectivity towards microorganisms while maintaining a very low cytotoxicity to the host cells. However, because of iodine's physical and inherent chemical properties, its use as an antiseptic an antiseptic, broad spectrum antimicrobial has been limited because state of the art of delivery methods allows for the liberation of too much free iodine which can be toxic to living cells.Considering that as little as 0.2 ppm of iodine is sufficient to kill enteric bacteria (10 minutes at 25° C), and under the same conditions, 3.5 ppm and 14.6 ppm of iodine, respectively, are sufficient to kill amoebic cysts and enteric viruses, PVP/I2 complex solutions can instantaneously introduce thousands of excess parts of available iodine in one bolus (i.e., an uncontrolled burst of solution), dependent upon the site.

Patent No. US 5,071,648, describes polymerizing soluble PVA to form insoluble acetals in the form of foams, sheets or gels, and subsequently forms less soluble iodine complexes with these acetals with solutions of iodine, iodides, borates or their combinations. Such complexes of polyvinyl alcohol and iodine have a low solubility such that it releases iodine in a sustained and a controlled manner in an amount which will kill germ cells but not damage living tissue. An antimicrobial borate material may also be complexed with the polyvinyl alcohol. The complex may be with PVA or PVA acetal film, sponge, foam or gel and used as a wound dressing. The iodine is preferably complexed with hydroxylated polyvinyl acetal sponge and topically used. Additionally, the complex may be combined with a matrix, such as cloth or non-woven material.

Patent No. US 5,073,614, describes preparation of strongly swellable, moderately or lightly crosslinked PVP having a predetermined aqueous swelling parameter and a defined viscosity which had effective thickener and gelling properties. The reaction product of water soluble or water-insoluble PVP with elemental iodine, is marketed as a brown powder which contains about 1 1% of available iodine, i.e. active iodine, which can be titrated with sodium thiosulfate, and, in addition, contains about 5.5% of iodine in the form of iodide. At an iodine:iodide ratio of 2: 1 , the iodine bonding in the PVP- iodine complex is so strong that an iodine odor is no longer perceptible and a moist potassium iodide/starch paper introduced into the gas space above the PVP-iodine no longer acquires a color. In practice, the measure employed to assess whether the iodine is sufficiently firmly bonded is the partition coefficient of the iodine between an aqueous PVP-iodine solution and heptane, and this coefficient, as described, for example, in Patent No. US 3,028,300 should be about 200. Further it is necessary that in its formulations, in particular, in aqueous solution, the PVP-iodine complex should lose very little available iodine on storage, i.e. it should be very stable.

SUMMARY OF THE INVENTION One aspect of the present invention provides a controlled release macroporous polymeric matrix for administrating one or more active ingredient to a subject in need thereof, said matrix comprises 2% to 15% w/v polyvinylpyrrolidone or a combination of N-vinyl pyrrolidone and polyvinyl alcohol and 2% to 8% polyethyleneglycol diacrylate. Another aspect of the present invention provides a process for preparation of a controlled release macroporous polymeric matrix for administrating one or more active ingredient to a subject in need thereof, said process comprising polymerizing 2% to 15% w/v N-vinyl pyrrolidone alone or in combination with polyvinyl alcohol at a temperature in the range of about -10°C to -20°C for a period of about 10 to 20 hours in presence of 2% to 8% polyethyleneglycol diacrylate to obtain said polymer matrix.

BRIEF DESCRIPTION OF THE FIGURES

The above and other features, aspects, and advantages of the subject matter will become better understood with regard to the following description, appended claims, and accompanying drawings where: Figure 1 shows a macroporous polymer matrix of polyvinylpyrrolidone-iodine a) The pictures from left are polymer matrix; PVP/I ₂ polymer matrix; and a PVP/I ₂ in different formats; b) PVP/I ₂ -gelatin bilayer.

Figure 2 shows a scanning electron microscopic image of polyvinyl pyrrolidone polymer matrix Figure 3 shows a Polyvinyl pyrrolidone-Iodine layer germicidal activity against A) E. coli; B) Staphylococcus aureus. The arrows indicate the zone of inhibition which in both the cases lies between 1.8 to 2 cm. (The diameter of the macroporous PVP/I ₂ polymer matrix is 0.9cm)

Figure 4 shows cytotoxicity test results of PVP/I ₂ polymer matrix assay using MTT. Figure 5 shows rate of Iodine release from PVP-PEG Da-PVA-I ₂ and PVP-PEG Da-I ₂ DETAILED DESCRIPTION OF THE INVENTION

The terms "polymer matrix", "hydrogel", "hydrogel sheet" and "hydrogel film" are used interchangeably herein.

In accordance with the present invention in one embodiment of the present invention there is provide a controlled release macroporous polymeric matrix for administrating one or more active ingredient to a subject in need thereof, said matrix comprises 2% to 15% w/v N-vinyl pyrrolidone or a combination of N-vinyl pyrrolidone and polyvinyl alcohol and 2% to 8% polyethyleneglycol diacrylate.

In another embodiment of the present invention there is provided the macroporous polymeric matrix for administrating one or more active ingredient to a subject in need thereof, said matrix comprises 2% to 15% w/v N-vinyl pyrrolidone or a combination of N-vinyl pyrrolidone and polyvinyl alcohol and 2% to 8% polyethyleneglycol diacrylate, wherein thickness of the polymer matrix is in the range of about 0.5 mm to 20 mm.

In another embodiment of the present invention there is provided the macroporous polymeric matrix for administrating one or more active ingredient to a subject in need thereof, said matrix comprises 2% to 15% w/v N-vinyl pyrrolidone or a combination of N-vinyl pyrrolidone and polyvinyl alcohol and 2% to 8% polyethyleneglycol diacrylate, wherein pore size of the polymer matrix is in the range of about Ι μπι to 250μπι. In another embodiment of the present invention there is provided the macroporous polymeric matrix for administrating one or more active ingredient to a subject in need thereof, said matrix comprises 2% to 15% w/v N-vinyl pyrrolidone or a combination of N-vinyl pyrrolidone and polyvinyl alcohol and 2% to 8% polyethyleneglycol diacrylate, wherein the polyethyleneglycol diacrylate is in the range of about 2% to 4% w/v preferably 2%. In another embodiment of the present invention there is provided the macroporous polymeric matrix for administrating one or more active ingredient to a subject in need thereof, said matrix comprises 2% to 15% w/v N-vinyl pyrrolidone or a combination of N-vinyl pyrrolidone and polyvinyl alcohol and 2% to 8% polyethyleneglycol diacrylate, wherein the polyvinylpyrrolidone is in the range of about 5% to 6% w/v preferably 5%.

In another embodiment of the present invention there is provided the macroporous polymeric matrix for administrating one or more active ingredient to a subject in need thereof, said matrix comprises 2% to 15% w/v N-vinyl pyrrolidone or a combination of N-vinyl pyrrolidone and polyvinyl alcohol and 2% to 8% polyethyleneglycol diacrylate, wherein the polymeric matrix further comprises at least one active ingredient selected from a group consisting of antiseptic agents, antibacterial agents, antiviral agents, antipathogen agents, proteins, hormones, growth factors, immune modulators, enzymes and amino acids.

In another embodiment of the present invention there is provided the macroporous polymeric matrix for administrating one or more active ingredient to a subject in need thereof, said matrix comprises 2% to 15% w/v N-vinyl pyrrolidone or a combination of N-vinyl pyrrolidone and polyvinyl alcohol and 2% to 8% polyethyleneglycol diacrylate, wherein the polymer matrix comprises a combination of polyvinyl pyrrolidone and polyvinyl alcohol and polyethyleneglycol diacrylate. In another embodiment of the present invention there is provided the macroporous polymeric matrix for administrating one or more active ingredient to a subject in need thereof, said matrix comprises 2% to 15% w/v N-vinyl pyrrolidone or a combination of N-vinyl pyrrolidone and polyvinyl alcohol and 2% to 8% polyethyleneglycol diacrylate, wherein ratio of the polyvinylpyrrolidone to said polyvinyl alcohol is in the range of 1 : 1 to 5: 1 preferably 1.25: 1. In another embodiment of the present invention there is provided the macroporous polymeric matrix for administrating one or more active ingredient to a subject in need thereof, said matrix comprises 2% to 15% w/v N-vinyl pyrrolidone or a combination of N-vinyl pyrrolidone and polyvinyl alcohol and 2% to 8% polyethyleneglycol diacrylate, wherein the polymeric matrix further comprises iodine. In another embodiment of the present invention there is provided the macroporous polymeric matrix for administrating one or more active ingredient to a subject in need thereof, said matrix comprises 2% to 15% w/v N-vinyl pyrrolidone or a combination of N-vinyl pyrrolidone and polyvinyl alcohol and 2% to 8% polyethyleneglycol diacrylate, wherein the polymeric matrix further comprises iodine, wherein ratio of the polymer matrix to iodine is in the range of 2: 1 to 40: lw/w preferably 5: 1 w/w.

In another embodiment of the present invention there is provided the macroporous polymeric matrix for administrating one or more active ingredient to a subject in need thereof, said matrix comprises 2% to 15% w/v N-vinyl pyrrolidone or a combination of N-vinyl pyrrolidone and polyvinyl alcohol and 2% to 8% polyethyleneglycol diacrylate, wherein the polymeric matrix further comprises iodine, wherein the polymer matrix is capable of releasing iodine in a sustained manner for a period of 48 hours.

One embodiment of the present invention provides the polymer matrix of the present invention, wherein the polymer matrix is attached with gelatin.

In another embodiment of the present invention there is provided a process for preparation of a controlled release macroporous polymeric matrix for administrating one or more active ingredient to a subject in need thereof, the process comprising polymerizing 2% to 15% w/v N-vinyl pyrrolidone alone or in combination with polyvinyl alcohol at a temperature in the range of about -10°C to -20°C preferably at - 12°C for a period of about 10 to 20 hours preferably for 16 hours in presence of 2% to 8% polyethyleneglycol diacrylate to obtain the polymer matrix. In another embodiment of the present invention there is provided the process for preparation of a controlled release macroporous polymeric matrix for administrating one or more active ingredient to a subject in need thereof, the process comprising polymerizing 2% to 15% w/v N-vinyl pyrrolidone at a temperature in the range of about -10°C to -20°C preferably at -12°C for a period of about 10 to 20 hours preferably for 16 hours in presence of 2% to 8% polyethyleneglycol diacrylate to obtain the polymer matrix.

In another embodiment of the present invention there is provided the process for preparation of a controlled release macroporous polymeric matrix for administrating one or more active ingredient to a subject in need thereof, the process comprising polymerizing 2% to 15% w/v N-vinyl pyrrolidone at a temperature in the range of about -10°C to -20°C preferably at -12°C for a period of about 10 to 20 hours preferably for 16 hours in presence of 2% to 8% polyethyleneglycol diacrylate to obtain the polymer matrix and incubating said polyvinylpyrrolidone matrix with one or more active ingredient at a temperature in the range of about 70°C to 85°C preferably at about 75°C for a period of about 3 to 7 hours preferably for about 5 hours.

In another embodiment of the present invention there is provided a process for preparation of a controlled release macroporous polymeric matrix for administrating one or more active ingredient to a subject in need thereof, the process comprising polymerizing 2% to 15% w/v N-vinyl pyrrolidone in combination with polyvinyl alcohol at a temperature in the range of about -10°C to -20°C preferably at -12°C for a period of about 10 to 20 hours preferably for 16 hours in presence of 2% to 8% polyethyleneglycol diacrylate to obtain the polymer matrix.

In another embodiment of the present invention there is provided a process for preparation of a controlled release macroporous polymeric matrix for administrating one or more active ingredient to a subject in need thereof, the process comprising polymerizing 2% to 15% w/v N-vinyl pyrrolidone in combination with polyvinyl alcohol at a temperature in the range of about -10°C to -20°C preferably at -12°C for a period of about 10 to 20 hours preferably for 16 hours in presence of 2% to 8% polyethyleneglycol diacrylate to obtain the polymer matrix and subjecting said polyvinylpyrrolidone-polyvinyl alcohol matrix to 2 to 10 freeze thaw cycles at a temperature in the range of about -10°C to -30°C preferably at about f -20°C or a period of 5 to 20 hours. In another embodiment of the present invention there is provided a process for preparation of a controlled release macroporous polymeric matrix for administrating one or more active ingredient to a subject in need thereof, the process comprising polymerizing 2% to 15% w/v N-vinyl pyrrolidone in combination with polyvinyl alcohol at a temperature in the range of about -10°C to -20°C preferably at -12°C for a period of about 10 to 20 hours preferably for 16 hours in presence of 2% to 8% polyethyleneglycol diacrylate to obtain the polymer matrix; subjecting the polyvinylpyrrolidone-polyvinyl alcohol matrix to 2 to 10 freeze thaw cycles at a temperature in the range of about -10°C to -30°C preferably at about f -20°C or a period of 5 to 20 hours and further comprises incubating said polyvinylpyrrolidone- , polyvinyl alcohol matrix with one or more active ingredient at a temperature in the range of about 20°C to 40°C preferably at 25°C.for a period of about 30 minutes to 5 hours preferably for about 1 hour.

In another embodiment of the present invention there is provided a process for preparation of a controlled release macroporous polymeric matrix for administrating one or more active ingredient to a subject in need thereof, the process comprising polymerizing 2% to 15% w/v N-vinyl pyrrolidone in combination with polyvinyl alcohol at a temperature in the range of about -10°C to -20°C preferably at -12°C for a period of about 10 to 20 hours preferably for 16 hours in presence of 2% to 8% polyethyleneglycol diacrylate to obtain the polymer matrix; subjecting the polyvinylpyrrolidone-polyvinyl alcohol matrix to 2 to 10 freeze thaw cycles at a temperature in the range of about -10°C to -30°C preferably at about f -20°C or a period of 5 to 20 hours and further comprises incubating said polyvinylpyrrolidone- polyvinyl alcohol matrix with one or more active ingredient at a temperature in the range of about 20°C to 40°C preferably at 25°C.for a period of about 30 minutes to 5 hours preferably for about 1 hour, wherein the active ingredient is iodine.

Current drug delivery system options are most of the times ineffective due to the inefficient delivery of an active agent to a targeted site. For example with water soluble polymers, it has been shown that the use of such polymers in drug delivery applications can cause inflammatory complications in certain treatment.

The macroporous polymer matrix of the present invention provides a solution to the problems associated with current drug delivery options. For instance, the inventors have invented unique macroporous polymer matrices that allow convenient administration for the long-term sustained release of an active ingredient to a targeted site. This can allow the frequency of administrations to be reduced. The slow degradation of polymer network will result in slow release of the drug. Furthermore, since the degraded polymer produces acidic by-products, slow degradation will minimize any inflammation that results from acidic by-products (lower localized concentration of acids), which is common with bioerodable polymeric material.

The macroporous polymer matrix of the present invention can be used a transdermal drug delivery system to administer one or more active ingredient to a subject in need thereof.

The present invention further provides a macroporous polymer matrix coupled with iodine for controlled release of iodine. The present invention also provides a process of preparation of the macroporous polymer matrix. The polymer matrix disclosed in the present invention comprises a polymer cross-linked by polyethylene glycol diacrylate. The polymer used in the matrix is polyvinyl pyrrolidone or a combination of polyvinyl pyrrol idone and polyvinyl alcohol. The polymer matrix disclosed in the present invention is capable of releasing iodine in a sustained manner. The polymer matrix disclosed in the present invention can be used as an antiseptic wound dressing patch in the form of a bandage or thin sheet patch. The polymer matrix is synthesized at sub zero temperatures in thin sheet format by free radical polymerization and cross-linking using polyethylene diacrylate.

The present invention provides a PVP-Iodine antiseptic epidermal patch which can be used like an adhesive bandage for superficial wounds and burns. The antimicrobial hydrogel sheet will serve as a reservoir of iodine releasing iodine in a controlled manner. The macroporous hydrogel sheets are advantageous in a manner that they have superior physical properties such as biocompatibility, softness, high absorption of body fluids; by itself they do not support growth of microorganism. The iodine will not be washed out of complexes and remain active during the period of application thus repeated application is not required. Also these hydrophilic matrices will serve as reservoir of iodine which can release iodine in a sustained manner as well as protect the wound.

The present invention describes a polymeric macroporous hydrogel wound dressing composed of PVP/I ₂ in form of a hydrogel film or sheet. A macroporous hydrogel film/patch composed of PVP/I ₂ is intended to serve as moist wound dressing. Additionally, the complex may be combined with a matrix, such as cloth or non-woven material. One further modification of the invention is the use of an interpenetrating network of PVP- PVA in form of macroporous hydrogel thin sheet as iodophors. These PVP-PVA interpenetrating hydrogel iodophor sheets provide a more sustained and controlled release of iodine than the PVP/1 ₂ macroporous hydrogel sheet alone. An interpenetrating network (IPN) is a combination of two polymers, in network form, of which at least one is synthesized and/or cross-linked in the immediate presence of the other without any covalent bonds between them. These polymers are closely related to other multicomponent materials, containing completely entangled chains, such as polymer blends, grafts and blocks. But, the IPN can swell in solvents without dissolving and can suppress creep and flow. Most IPNs are heterogeneous systems comprised of one rubbery phase and one glassy phase which produce a synergistic effect yielding either high impact strength or reinforcement, both of which are dependent on phase continuity.

The use of hydrogels in the treatment and management of burns and wounds is well known in the art. Hydrogel dressings are desirable, in part, because they provide protection against infectious agents. Hydrogel dressings are further desirable because wound exudates do not generally dry and consolidate with hydrogels or hydrogel laminates as with the case with traditional gauze dressings. Consequently, removal of a hydrogel dressing is usually neither painful nor detrimental to the healing process. It has been suggested that hydrogel dressings may be particularly desirable for treatment of burns because they may accelerate healing. Although the mechanism by which hydrogels stimulate healing is not fully elucidated, it is documented that the high water content of hydrogels enables them to effect an immediate cooling of the wound surface and to sustain the reduced temperature for up to six hours. Maintaining a moist wound environment facilitates the wound-healing process. The beneficial effects of a moist versus a dry wound environment include: prevention of tissue dehydration and cell death, accelerated angiogenesis, increased breakdown of dead tissue and fibrin, i.e., pericapillary fibrin cuffs, and potentiating the interaction of growth factors with their target cells. In addition, pain is significantly reduced when wounds are covered with an occlusive dressing. However, there is always a concern that moisture in wounds would increase the risk of clinical infection. Use of a moist wound dressing in form of a hydrogel containing an antiseptic agent like iodine will help to reduce the risk, of this contamination and promote wound healing. A combination of hydrogel wound dressings with a bactericidal agent will have dual functionality of protecting the wound against infection and also faster wound healing. One embodiment of the present invention provides a thin hydrogel sheet containing iodine complexed with composed of PVP-PEG and polyvinyl alcohol (PVA) in form of interpenetrating network of PVA and /or PVP. One embodiment of the present invention provides a polymer matrix which overcomes the limitations of different topical water soluble formulations of iodine by complexing iodine to cross-linked macroporous hydrogel sheet and controlling iodine release for topical applications.

An important embodiment of the present invention is to provide an iodophor preparation in form of macroporous hydrogel sheets which can be used topically as wound dressing with or without the use of an adhesive secondary dressing. The antiseptic iodophor macroporous hydrogel sheet disclosed in the present invention protect the wound against infection and also provide a soft elastic hydrogel protective covering which can absorb various body fluids and dose not leave back any residues of fibers in the wound. One other advantage of this antiseptic macroporous wound dressing is that it dose not stick to the wound and can be removed easily without pain. Thin sheets of macroporous polymeric hydrogel complexed to iodine also present the advantage that, they do not contaminate the wound site by leaving behind healing inhibiting foreign materials, such as lint particles from gauze, or petroleum ointment jelly vehicles, to contain topical antibiotics.

As iodine is released, it is taken up by microbes forming an irreversible chemical reaction, killing the microbes. As released iodine is taken up, only then is more released, until equilibrium is maintained. A great reservoir of iodine is complexed in the PVP/I ₂ system and because of its limited solubility is not readily released to side reactions causing rapid iodine depletion and resulting loss of effectiveness common to other iodophors. PVP/1 ₂ has been reported to have a reservoir of available iodine of about 10,000 PPM, of which only up to 35 PPM is available immediately. Since only as little as 0.2 PPM may be required for bactericidal effectiveness, while still preserving the health of host cells over a prolonged period, increasing the stability of the iodine complex is desirable. Microorganisms are more sensitive to iodine than healthy cells; therefore keeping the free iodine concentration low enough, creates selectivity towards the killing of microorganisms. A combination of PVP and PVA reduces some of the disadvantages associated with PVP-I ₂ complex alone and provides a better sustained release of iodine than the PVP/I ₂ system. PVA alone forms a very strong complex with Iodine thus at any given time the free iodine or equilibrium iodine content required for antimicrobial activity is lesser than the PVP/I ₂ complexes. Thus a blend of PVP- PVA creates an appropriate balance of the reservoir iodine and free iodine resulting sustained release of iodine from the hydrogel sheets. Such controlled release helps to reduce the toxic side effects of free iodine. Also PVA/I ₂ based, less soluble complexes have a unique intrinsic colorimetric indicator which reveals when iodine content is depleted. As iodine depletion occurs, the polymer begins to turn from blue/black, which is the color of the complex, to lighter shades of blue or purple and eventually completely white, indicating that the iodine is depleted and the dressing should be changed.

An embodiment of the present invention provides the use of antiseptic macroporous hydrogel sheets as wound dressing and its topical application to small acute wounds, burns, exudative wounds like dermabrasion, chemical peels, superficial burns, laser wounds, friction blisters including epidermolysis bullosa and ulcers. The hydrogel wound dressing can be applied directly to the wounds with or without a supportive dressing.

Another embodiment of the present invention provides the use PVP-PEG/I ₂ or PVP- PEG-PVA/ I ₂ macroporous hydrogel sheet in a bilayer format along with gelatin as the primary layer for skin tissue engineering. This bilayer will help in skin regeneration.

An embodiment of the present invention provides the preparation of polymeric matrix by free radical polymerization of N-vinyl pyrrolidone (NVP) at subzero temperatures in presence of a crosslinker. Aqueous solution of the monomer NVP is made by dissolving NVP in water and stirring for some time. The preferred concentration of the monomer is from 2% to 15%. The crosslinker is then added to the aqueous solution and dissolved to get a homogenous solution of the NVP monomer and crosslinker. One of the preferred embodiments of the present invention provides use of polyethyleneglycol diacrylate as crosslinker in the concentration range of 0.5% to 6%. Other cross linkers which may be used divinylpyrrolidone, methylene bis acrylamide. The homogenous aqueous solution was then cooled at 4°C for 30 to 60 min. The monomeric solution was then mixed with free radical activators and initiators. Ammonium persulphate was added as aqueous solution to the above mixture kept under cold conditions. The preferred concentration varies from 0.1 to 0.5 % w/w. N, N', N, N' tetramethylethylene diamine was added. The preferred concentration varies from 0.1% to 0.5% v/v. The NVP monomeric aqueous solutions along with other components were then immediately poured into precooled moulds of desired shape and dimensions and placed at sub zero temperatures in a cryostat. The preferred range of temperature varies from -25°C to -30°C. A preferred mold is a dish of diameter varying from 2mm to 90mm. The mold can be made of any inert non-interactive material, dimensionally stable materials such as stainless steel, polypropylene, higher polyolefins, polyacrylates, polycarbonates, polysulfones, polystyrene and the like which may have coverings of polymer films. The monomeric solution was allowed to polymerize under frozen conditions. As soon as the monomeric solution is frozen at sub zero temperatures most of the liquid phase gets frozen and forms ice crystals. However a small volume of the liquid phase remains unfrozen and contains a highly concentrated solution of all the components added initially. This unfrozen liquid phase is known as non- frozen liquid phase (NFLP) and this where the free radical polymerization of the monomeric solution proceeds. The polymerization was found to reach to 90 to 100% completion in 5 to 20 hours depending upon the concentration of the monomer. Usually we found that a stable macroporous hydrogel sheet was formed between 12 to 16 hrs of incubation under frozen condition. The monomers are converted into polymeric chain via free radical polymerization and the polymeric chains were simultaneously crosslinked via the crosslinker leading to the formation of the polymeric hydrogel network along the sides of the ice crystals formed by the liquid phase. After completion of the polymerization the polymerized frozen hydrogels were taken out at room temperature. Thereupon thawing the ice crystals melts and macroporous hydrogel sheet is obtained. In a preferred embodiment of the invention the thickness of the macroporous hydrogel sheet varied from 0.5mm to 5mm. The resultant PVP-PEG Da hydrogel sheets were elastic, spongy, porous, and had a high swelling ratio and can hold up water upto 80 to 95%. The a _eq swelling equilibrium for the polymeric hydrogel varies from 400 to 3000 depending upon the monomer and crosslinker concentrations. The Oeq indicates the capacity of the maximum amount of water that can be retained when dried sheet of the macroporous hydrogel sheet is placed inside an aqueous environment. The equilibrium degree of swelling is expressed as: aeq = ((Weq - Wd)/Wd) ^χ 100, (1) where Weq is the weight of the swollen gel at equilibrium and Wd is the dried weight of the gel.

A yet another embodiment of the present invention provides addition of polyvinylalcohol (PVA) to the polymeric hydrogel sheet of PVP-PEG Da. The PVA may be added at the start of the polymerization to the monomeric solution of N- vinylpyrrolidone. Alternatively the PVA may be added to the formed macroporous hydrogel sheet of PVP-PEG Da. The polymeric matrix for this macroporous hydrogel sheet has been synthesized by free radical polymerization of N-vinyl pyrrolidone (NVP) at -12 °C in presence of a crosslinker. Aqueous solution of the monomer NVP is made by dissolving NVP in water and stirring for some time. The preferred concentration of the monomer is from 2% to 15%. The crosslinker is then added to the aqueous solution and dissolved to get a homogenous solution of the NVP monomer and crosslinker. A preferred embodiment used polyethyleneglycol as crosslinker in the concentration range of 0.5% to 8%. Other cross linkers which may be used are divinylpyrrolidone, methylene bis acrylamide. The homogenous aqueous solution was ■ then cooled at 4 °C for 30 to 60 min. simultaneously an aqueous solution of PVA was also prepared. The proper polymeric matrix for this PVA macroporous hydrogel sheet invention is selected from commercially available PVA's having molecular weights >50,000. PVA aqueous solution is made by heating a mixture of desired concentration of PVA and water preferably at 80° C. (preferably 60° C. to 100° C.) until a homogeneous solution is formed (usually 1 to 2 hours). The concentration of PVA in water can be as low as 1 % or as high as 20%. The preferred range of PVA concentrations is about 2% to 10%. The PVA aqueous solution and the NVP monomeric solution in water was mixed in equal volumes. The final concentration of the NVP monomer may vary from 1% to 12% and that of PVA from 1% to 20%. The crosslinker concentration and the monomeric solution was then mixed with free radical activators and initiators. Ammonium persulphate was added as aqueous solution to the above mixture kept under cold conditions. The preferred concentration varies from 0.1 to 0.5 % w/w. N, N', N, N' tetramethylethylene diamine was added. The preferred concentration varies from 0.1% to 0.5% v/v. The NVP monomeric aqueous solutions along with PVA solution mixed were then immediately poured into precooled moulds of desired shape and dimensions and placed at sub zero temperatures in a cryostat. The preferred range of temperature varies from 25 to - 30 °C. A preferred embodiment of the mold is a dish of diameter varying from 2mm to 90mm. The mold can be made of any inert non- interactive material, dimensionally stable materials such as stainless steel, polypropylene, higher polyolefins, polyacrylates, polycarbonates, polysulfones, polystyrene and the like which may have coverings of polymer films. The monomeric solution was allowed to polymerize under frozen conditions. As soon as the monomeric solution is frozen at sub zero temperatures most of the liquid phase gets frozen and forms ice crystals. However a small volume of the liquid phase remains unfrozen and contains a highly concentrated solution of all the components added initially. This unfrozen liquid phase is known as non- frozen liquid phase (NFLP) and this where the free radical polymerization of the monomeric solution proceeds. The polymerization was found to reach to 90 to 100% completion in 5 to 20 hours depending upon the concentration of the monomer. Usually we found that a stable macroporous hydrogel sheet was formed between 12 to 16 hrs of incubation under frozen condition. The monomers are converted into polymeric chain via free radical polymerization and the polymeric chains were simultaneously crosslinked via the crosslinker leading to the formation of the polymeric hydrogel network along the sides of the ice crystals formed by the liquid phase. After completion of the polymerization the polymerized frozen hydrogels were taken out at room temperature. Thereupon thawing the ice crystals melts and macroporous hydrogel sheet is obtained. In a preferred embodiment of the invention the thickness of the macroporous hydrogel sheet varied from 0.5mm to 5mm.

To synthesize the desired PVA cryogel compositions the mold and its contents were then subjected to cycles of freezing (0° to -80° C, usually -10° to -25° C.) and thawing (+1 ° to +30° C, usually +20° to +25° C). The number of freeze/thaw cycles can be as low as two or as high as time will allow. The strength of the PVA cryogel elastomer increased with each successive freeze/thaw cycle. Usually we found three to five freeze/thaw cycles were sufficient. The smaller increments of strength gained above five cycles are usually not significant. The durations of each freeze and thaw period can be as little as 2 minutes to as long as 16 hours. We observe that 20 to 30 minutes is all that is normally required. The resultant PVA cryogel shapes are tough, slippery, translucent, elastomeric shapes having 85 to 95% water content.

In one of the embodiment of the present invention, there is provided a macroporous polymeric matrix coupled with iodine, the polymer matrix comprises a polymer cross- linked by polyethyleneglycol diacrylate, wherein the polymer is polyvinyl pyrrolidone or a combination of polyvinylpyrrolidone and polyvinyl alcohol.

In another embodiment of the present invention there is provided a macroporous polymeric matrix coupled with iodine, the polymer matrix comprises a polymer cross- linked by polyethyleneglycol diacrylate, wherein the polymer is polyvinyl pyrrolidone or a combination of polyvinylpyrrolidone and polyvinyl alcohol, wherein thickness of the polymer matrix is in the range of about 0.5 mm to 20 mm. In another embodiment of the present invention there is provided a macroporous polymeric matrix coupled with iodine, the polymer matrix comprises a polymer cross- linked by polyethyleneglycol diacrylate, wherein pore size of the polymer matrix is in the range of about 1 μηι to 250μπι.

In another embodiment of the present invention there is provided a macroporous polymeric matrix coupled with iodine, the polymer matrix comprises a polymer cross- linked by polyethyleneglycol diacrylate, wherein ratio of the polymer matrix to the iodine is in the range of 2: 1 to 40: lw/w.

In another embodiment of the present invention there is provided a macroporous polymeric matrix coupled with iodine, the polymer matrix comprises a polymer cross- linked by polyethyleneglycol diacrylate, wherein ratio of the polymer matrix to the iodine is 5: 1 w/w.

In another embodiment of the present invention there is provided a macroporous polymeric matrix coupled with iodine, the polymer matrix comprises a polymer cross- linked by polyethyleneglycol diacrylate, wherein the polyethylene glycol diacrylate is in the range of about 2% to 8% w/v, preferably in the range of 2% to 4% w/v.

In yet another embodiment of the present invention there is provided a macroporous polymeric matrix coupled with iodine, the polymer matrix comprises a polymer cross- linked by polyethyleneglycol diacrylate, wherein the polyethylene glycol diacrylate is 2%. In yet another embodiment of the present invention there is provided a macroporous polymeric matrix coupled with iodine, the polymer matrix comprises a polymer cross- linked by polyethyleneglycol diacrylate, wherein the polyvinylpyrrolidone is in the range of about 2% to 15% w/v, preferably in the range of 5% to 6% w/v.

In yet another embodiment of the present invention there is provided a macroporous polymeric matrix coupled with iodine, the polymer matrix comprises a polymer cross- linked by polyethyleneglycol diacrylate, wherein the polyvinylpyrrolidone is 5% w/v. In yet another embodiment of the present invention there is provided a macroporous polymeric matrix coupled with iodine, the polymer matrix comprises a polymer cross- linked by polyethyleneglycol diacrylate, wherein the polymer matrix comprises polyvinylpyrrolidone and polyvinyl alcohol and polyethyleneglycol diacrylate.

In yet another embodiment of the present invention there is provided a macroporous polymeric matrix coupled with iodine, the polymer matrix comprises a polymer cross- linked by polyethyleneglycol diacrylate, wherein the polymer matrix comprises polyvinylpyrrolidone, polyvinyl alcohol and polyethyleneglycol diacrylate, wherein ratio of the polyvinylpyrrolidone to the polyvinyl alcohol is in the range of 1 : 1 to 5: 1 preferably 1.25: 1. In yet another embodiment of the present invention there is provided a macroporous polymeric matrix coupled with iodine, the polymer matrix comprises a polymer cross- linked by polyethyleneglycol diacrylate, wherein the polymer matrix is capable of releasing iodine in a sustained manner for a period of 48 hours.

In yet another embodiment of the present invention there is provided a macroporous polymeric matrix coupled with iodine, the polymer matrix comprises a polymer cross- linked by polyethyleneglycol diacrylate, wherein the polymer matrix is attached with gelatin.

In another embodiment of the present invention there is provided a process for preparation of a macroporous polymeric matrix coupled with iodine, the process comprising polymerizing N-vinyl pyrrolidone at a temperature in the range of about - 10°C to -20°C for a period of about 10 to 20 hours in the presence of polyethylene glycol diacrylate to obtain a polyvinyl pyrrolidone polymer matrix, and incubating the polyvinyl pyrrolidone polymer matrix with iodine at a temperature in the range of about 70°C to 85°C for a period of about 3 to 7 hours to obtain polymer matrix coupled with iodine In another embodiment of the present invention there is provided a process for preparation of a macroporous polymeric matrix coupled with iodine, the process comprising polymerizing N-vinyl pyrrolidone at a temperature of about -12°C for a period of about 10 to 20 hours in the presence of polyethylene glycol diacrylate to obtajn a polyvinyl pyrrolidone polymer matrix, and incubating the polyvinyl pyrrolidone polymer matrix with iodine at a temperature in the range of about 70°C to 85°C for a period of about 3 to 7 hours to obtain polymer matrix coupled with iodine.

In another embodiment of the present invention there is provided a process for preparation of a macroporous polymeric matrix coupled with iodine, the process comprising polymerizing N-vinyl pyrrolidone at a temperature in the range of about - 10°C to -20°C for 16 hours in the presence of polyethylene glycol diacrylate to obtain a polyvinyl pyrrolidone polymer matrix, and incubating the polyvinyl pyrrolidone polymer matrix with iodine at a temperature in the range of about 70°C to 85°C for a period of about 3 to 7 hours to obtain polymer matrix coupled with iodine.

In another embodiment of the present invention there is provided a process for preparation of a macroporous polymeric matrix coupled with iodine, the process comprising polymerizing N-vinyl pyrrolidone at a temperature in the range of about - 10°C to -20°C for a period of about 10 to 20 hours in the presence of polyethylene glycol diacrylate to obtain a polyvinyl pyrrolidone polymer matrix, and incubating the polyvinyl pyrrolidone polymer matrix with iodine at a temperature of about 75°C for a period of about 3 to 7 hours to obtain polymer matrix coupled with iodine.

In another embodiment of the present invention there is provided a process for preparation of a macroporous polymeric matrix coupled with iodine, the process comprising polymerizing N-vinyl pyrrolidone at a temperature in the range of about - 10°C to -20°C for a period of about 10 to 20 hours in the presence of polyethylene glycol diacrylate to obtain a polyvinyl pyrrolidone polymer matrix, and incubating the polyvinyl pyrrolidone polymer matrix with iodine at a temperature in the range of about 70°C to 85°C for about 5 hours to obtain polymer matrix coupled with iodine. In yet another embodiment of the present invention there is provided a process for preparation of a macroporous polymeric matrix coupled with iodine, the process comprising polymerizing N- vinylpyrrolidone and polyvinyl alcohol at a temperature in the range of -10°C to -20 °C for a period of about 10 to 20 hours in the presence of polyethyleneglycol diacrylate to obtain a polyvinylpyrrolidone-polyvinyl alcohol polymer matrix, subjecting the polyvinyl pyrrolidone-polyvinyl alcohol polymer matrix at a.temperature in the range of -10°C to -30°C for 5 to 20 hours followed by thawing, and incubating the polyvinylpyrrolidone-polyvinyl alcohol polymer matrix with aqueous iodine at a temperature in the range of about 20°C to 40°C for a period of about 30 minutes to 5 hours to obtain iodine coupled polymer matrix. A process for preparation of a macroporous polymeric matrix coupled with iodine disclosed in the present invention further comprises washing the iodine coupled polymer matrix with hexane.

In yet another embodiment of the present invention there is provided a process for preparation of a macroporous polymeric matrix coupled with iodine, the process comprising polymerizing N- vinylpyrrolidone and polyvinyl alcohol at a temperature of about -12°C for a period of about 10 to 20 hours in the presence of polyethyleneglycol diacrylate to obtain a polyvinylpyrrolidone-polyvinyl alcohol polymer matrix, subjecting the polyvinyl pyrrolidone-polyvinyl alcohol polymer matrix at a temperature in the range of -10°C to -30°C for 5 to 20 hours followed by thawing, and incubating the polyvinylpyrrolidone-polyvinyl alcohol polymer matrix with iodine at a temperature in the range of about 20°C to 40°C for a period of about 30 minutes to 5 hours to obtain iodine coupled polymer matrix.

In yet another embodiment of the present invention there is provided a process for preparation of a macroporous polymeric matrix coupled with iodine, the process comprising polymerizing N- vinylpyrrolidone and polyvinyl alcohol at a temperature in the range of -10°C to -20 °C for about 16 hours in the presence of polyethyleneglycol diacrylate to obtain a polyvinylpyrrolidone-polyvinyl alcohol polymer matrix, subjecting the polyvinyl pyrrolidone-polyvinyl alcohol polymer matrix at a temperature in the range of -10°C to -30°C for 5 to 20 hours followed by thawing and incubating the polyvinylpyrrolidone-polyvinyl alcohol polymer matrix with iodine at a temperature in the range of about 20°C to 40°C for a period of about 30 minutes to 5 hours to obtain iodine coupled polymer matrix. In yet another embodiment of the present invention there is provided a process for preparation of a macroporous polymeric matrix coupled with iodine, the process comprising polymerizing N- vinylpyrrolidone and polyvinyl alcohol at a temperature in the range of -10°C to -20 °C for a period of about 10 to 20 hours in the presence of polyethyleneglycol diacrylate to obtain a polyvinylpyrrolidone-polyvinyl alcohol polymer matrix, performing 3-5 cycles preferably 4 cycles of subjecting the polyvinyl pyrrolidone-polyvinyl alcohol polymer matrix to a temperature in the range of -10°C to -30°C for 5 to 20 hours followed by thawing, and incubating the polyvinylpyrrolidone- polyvinyl alcohol polymer matrix with iodine at a temperature in the range of about 20°C to 40°C for a period of about 30 minutes to 5 hours to obtain iodine coupled polymer matrix.

In yet another embodiment of the present invention there is provided a process for preparation of a macroporous polymeric matrix coupled with iodine, the process comprising polymerizing N- vinylpyrrolidone and polyvinyl alcohol at a temperature in the range of -10°C to -20 °C for a period of about 10 to 20 hours in the presence of polyethyleneglycol diacrylate to obtain a polyvinylpyrrolidone-polyvinyl alcohol polymer matrix, subjecting the polyvinyl pyrrolidone-polyvinyl alcohol polymer matrix at a temperature of about -20° for 5 to 20 hours followed by thawing, and incubating the polyvinylpyrrolidone-polyvinyl alcohol polymer matrix with iodine at a temperature in the range of about 20°C to 40°C for a period of about 30 minutes to 5 hours to obtain iodine coupled polymer matrix..

The invention will now be described in more details by reference to the following examples. The following examples illustrate embodiments of the subject invention wherein both essential and optional ingredients are combined. These are just illustrative purpose and dose not limit the scope of the invention any manner.

Advantages of the present invention include:

• prevention of tissue hydration and cell death.

• Accelerated angiogenesis. · controlled release of the active ingredient.

• The polymer matrix of the present invention comprising active ingredient can be applied directly to the wound with or without a supportive dressing.

EXAMPLES

The disclosure will now be illustrated with working examples, which is intended to illustrate the working of disclosure and not intended to take restrictively to imply any limitations on the scope of the present disclosure.

Example 1: Preparation of Macroporous PVP -PEG Da Hydrogel Sheet

An aqueous solution of the monomer NVP was made by dissolving 5ml of NVP in water in a suitable container and stirring for some time. Then 2ml of polyethylene glycol diacrylate was added to this mixture and stirred to get a homogenous solution. The final volume of the solution was made upto 100ml. The solution was then frozen at -20 C for 30 min and then thawed 30 min. This process was repeated for 3 times. The homogenous aqueous solution was then cooled at 4 °C for 30 to 60 min. The monomeric solution was then mixed with free radical activators and initiators. 200mg of ammonium persulphate was dissolved in 2 ml of water and added as aqueous solution to the above mixture kept under cold conditions. 250μ1 N, Ν', Ν,Ν' tetramethylethylene diamine was added. The NVP monomeric aqueous solutions along with other components were then immediately poured into precooled polystyrene petridishes (molds). Two sizes of petridishes were taken, one with a diameter of 35mm and the other with 60mm. The petridishes were the placed immediately in a methanol filled cryostat at -12°C. A stable macroporous hydrogel sheet was formed after 16 hrs of incubation at -12 °C. The formed macroporous sheet was then thawed at room temperature 25 °C and washed with water to remove unpolymerized monomers. In a preferred embodiment of the invention the thickness of the macroporous hydrogel sheet varied from 0.5mm to 5mm. The resultant PVP-PEG Da hydrogel sheets were elastic, spongy, porous (figure 2).

Example 2: Preparation of PVP-PEG Da - 1 ₂

Dried sheets of PVP-PEG Da were taken and weighed. The sheets were then placed in a glass container and some amount of water is added so that sheets absorb the water fully and swell. To the same glass container a known quantity of iodine was added which was l/5 ^th of the total dried weight of PVP-PEG Da sheets. The container was now closed with a lid and place in a dry air oven at 75 °C for 5 hours. The Iodine vapors formed in the process got complexed with the PVP-PEG Da sheets. The Iodine complexed PVP-PEG Da sheets were then removed and washed with hexane till all the free and uncomplexed iodine was removed. The sheets were than air dried. The product was a thin brownish yellow colored sheet with a thickness of l-2mm. Analysis: available iodine: 10.5%, Free Iodine :0.9%

Example 3: Preparation of PVP -PVA -PEG Da macroporous hydrogel sheets

An aqueous solution of the monomer NVP was made by dissolving 5ml of NVP in water in a suitable container and stirring for some time. Then 2ml of polyethylene glycol diacrylate was added to this mixture and stirred to get a homogenous solution.

The final volume of the solution was made upto 50ml. The solution was then frozen at -

20 °C for 30 min and then thawed for 30 min. This process was repeated for 3 times.

The homogenous aqueous solution was then cooled at 4°C for 30 to 60 min. simultaneously an aqueous solution of PVA was also prepared by dissolving 8 g of PVA in 50 ml water. The PVA was dissolved by heating the solution at 90°C for 30 min. The solution was the cooled to room temperature and kept at 4°C for 30 min. The monomeric solution of NVP was mixed with the PVA aqueous solution and then kept on shaker to allow mixing for 15 min. After this solution were incubated at 4 °C for 30 min. The final solution was then mixed with free radical activators and initiators. 200mg of ammonium persulphate was dissolved in 2 ml of water and added as aqueous solution to the above mixture kept under cold conditions. 250μ1 N, Ν', Ν,Ν' tetramethylethylene diamine was added. The aqueous solutions along with other components were then immediately poured into precooled polystyrene petridishes (molds). Two sizes of petridishes were taken, one with a diameter of 35mm and the other with 60mm. The petridishes were the placed immediately in a methanol filled cryostat at -12°C. A stable macroporous hydrogel sheet was formed after 16 hrs of incubation at -12 °C. The formed macroporous sheet was then thawed at room temperature 25 °C and washed with water to remove unpolymerized monomers. Further the sheets were subjected to cycles of freeze thaw. The sheets were kept at -20 °C for 12h and then thawed for an hour. This cycle was repeated for 4 to 5 times. The resultant PVP-PEG Da -PVA hydrogel sheets were elastic and spongy. Example 4: Preparation of PVP-PEG Da -PVA - 1 ₂

Dried sheets of PVP-PEG Da -PVA were taken and weighed. The sheets were then placed in a glass container and to it 5ml of 0.05M iodine aqueous solution (containing KI) was added. The container was now closed with a lid and placed at room temperature for 60 min. The Iodine complexed PVP-PEG Da -PVA sheets were then removed and washed with hexane till all the free and uncomplexed iodine was removed. The sheets were than air dried. The product was a thin brownish-black colored sheet with a thickness of 1 -2mm. Analysis: available iodine: 10.5%, Free Iodine: 0.9%

Example 5: Characterization of Polymer matrix Rate of Release of Iodine from PVP-PEG Da -PVA - h and PVP-PEG Da -h The rate of release of iodine from PVP-PEG Da -PVA - I ₂ and PVP-PEG Da -I ₂ was determined in aqueous system using water. Pre-dried and pre- weighed discs of PVP- PEG Da -PVA - I ₂ and PVP-PEG Da -I ₂ were placed in 10ml of water in separate compartments. 1ml of water was removed every hour and the released amount of iodine was estimated. Every time same amount of water (that was removed at regular intervals for iodine estimation) was added back to the system. After 4 hours samples were collected at an interval of 24 hours. Both PVP-PEG Da -PVA - 1 ₂ and PVP-PEG Da -I ₂ showed a controlled and sustained release and constant amount of iodine release over a period of 72 hours. However PVP-PEG Da -PVA - I ₂ showed a more controlled release of iodine and released lower amount of iodine in comparison to PVP-PEG Da - (Figure 3) _.

Germicidal activity

The antimicrobial activity of this layer has been tested both on pathogenic and non pathogenic strains, using E.coli and Staphylococus aureus. PVP-PEG Da -PVA - I ₂ and PVP-PEG Da -I ₂ thin sheets of diameter 0.9 cm were placed in LB-agar containing petriplates. Previously petriplates were inoculated with a lawn of respective bacteria namely E.coli and S.aureus (in different petriplates). The plates were then incubated at 37°C for 24 hours. The iodine from the PVP-PEG Da -PVA - I ₂ and PVP-PEG Da -I ₂ sheets diffused into the surrounding inhibiting the growth of microorganism in that area. The diameter of this zone of inhibition was measured.The macroporous polymeric PVP-PEG Da -PVA - I ₂ and PVP-PEG Da -I ₂ demostrated good inhibitory activity against both of the strains. The zone of inhibition for PVP-Iodine and PVP-PEG Da -I ₂ is 1.7 to 1.9 cm (Figure 4)

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