GB2160420A - Preparation for controlled release of iodine - Google Patents

Abstract

A pharmaceutical composition for topical application, for the gradual predetermined release of iodine comprises a hydrophilic polyurethane sheet as carrier of iodine. The composition can be a polyurethane type artificial skin impregnated with an iodine solution and dried; or it can be prepared by forming a sheet from a polyurethane prepolymer, surfactant and iodine. Essentially dry flexible patches of such self-supporting iodine-carrying polyurethane sheets can be applied directly to wounds, sores and burns.

Description

SPECIFICATION Preparation for Controlled Release of iodine The invention relates to a pharmaceutical composition for topical application, which releases iodine in a gradual predetermined manner during a prolonged period of time. The novel composition results in the disinfection of wounds and skin damages, and facilitates wound healing.

Iodine has been used as an antiseptic for many years. It has a long tradition and is known to be very effective as a local antiseptic when applied to the skin. The traditional liquid preparations containing iodine result in skin damage and toxic effects (1, 2). In order to overcome these drawbacks of iodine, iodophores, i.e. combinations of iodine with detergents, solubilizers, complexing agents or polymers-have been prepared, Wynn-Williams Br. f. Plast. Surg. 18 146 (1965).

The physical state of iodophores is semi-solid (ointment, cream), liquid. These are spread on a dressing. Generally, in an iodophore the iodine is held on a loose chemical combination where part of the iodine is available and retains its bactericidal activity. Most of them have about 1% available iodine, Martindale, Extra Pharm. 27th Ed., 1978 p.823-8, which is slowly but not predictably released as a result of many variables involved in the release process.

U.S. Patent No. 3,978,855 relates to polyurethane foam surgical dressings. The foam has a microporous open structure. British patent No. 1,450,201 relates to absorbent polyurethane foams surgical dressings.

French Patent Application No. 2,156,068 relates to a surgical bandage or tampon. It is stated that various antibacterial agents can be incorporated in the foam. German DOS 2,557,607 relates to water-insoluble adducts (lodophores) formed from iodine and from polymers containing vinylpyrrolidone repeating units. These can be painlessly applied to wounds and removed from same. U.S. Patent No.

4,094,967 relates to a iodine-polyvinyl pyrrolidone solid product which can be applied to a polyester dressing.

W. R. Grace & Co., Chemical Division, produce a product designated as Hypol (T.M.), which is a foamable hydrophilic prepolymer which results strong white clean polyurethane foams which can hold up to 20 times their weight of water. They can be used, amongst others, for wound dressings and also for the production of drug release products. Though the common iodophores are less irritating to the skin than iodine solutions, they leave on the skin varying quantities of detergents or other carrier residues. Important disadvantages of the existing iodophores are unpleasant application and the lack of gas and vapour exchange by the occluded skin. The novel compositions for topical iodine application are designed to overcome the above described disadvantages and have advantageous properties.

In accordance with the present invention there is provided a pharmaceutical composition for topical application in human or veterinary medicine, for the general gradual release of iodine, comprising hydrophilic polyurethane as carrier of the iodine.

The topical application may be to the skin or on sores, pharmaceutical composition, for topical skin application thereby being applied as an active ingredient in combination with a polyurethane polymer or a synthetic skin as a carrier, in essentially dry form.

The combination of the specific physical properties of the carrier and the germicidal properties of iodine results in the prevention/control of infection, in exudate absorption, in crust removal, in rapid healing of sores, by sustained release of iodine from the novel topical compositions.

Preparations according to the present invention were tried out for the treatment of various skin infections and proved to be highly effective. Dry compositions of the invention were applied to skin burns and prevented infections, while healing was speeded up. Skin sores in elderly patients were treated by application of compositions according to the invention, and resulted in a rapid healing of the sores, preventing further infections.

The compositions according to the present invention, have the advantage over antibiotic compositions in that they are not subject to potential resistance, and over common iodophores in that they are non-irritant, they are dry, easily applied, permit skin respiration and exudate absorption. They release iodine according to controlled kinetics and they allow quick healing of infected wounds.

Amongst suitable carriers the most suitable ones are certain hydrophilic polymers such as polyurethane derivatives, Evans, A.: Polyurethane foam in the treatment of burns; Wallace A. B. Willinson A. WED: Research in Burns. In addition to the active ingredient and carrier, further constituents may be employed such as excipients, surface agents, modifying agents, etc., which faciliate the preparation of unit dosage forms.

Synthetic polymers, and also polyurethanes are known as carriers of various substances. These are generally used in a wet form, and do not release the active ingredient in a predetermined controlled manner. The present invention relates to a specific use of the hydrophilic polyurethane type in form of synthetic skin of other forms, as carriers of iodine, which is used in essentially dry form and which results in the gradual predetermined release of said iodine over a prolonged period of time in an essentially steady manner, i.e., there is released about the same quantity per unit time (t:) over the entire period of release.

When applied to the skin, the iodine is released in a gradual manner. The kinetics of release in vitro are illustrated hereinafter. There can be released up to about 10% of the initially bound iodine. The novel preparations advantageously contain from 0.5 weight-% and up to 90 weight-% of bound iodine. Carriers of various thicknesses may be used, representative values being from about 0.1 mm to about 100 mm thickness. Thus, per square cm of such a device there is bound from about 6 mg to about 500 mg of iodine.

Such polyurethane devices characterized by permeability to gases, do not adhere to wounds, are non-allergenic, pharmacologically inert, flexible and can be cut to any desired size and shape. Amongst additives which can be used there may be mentioned surfactants (Span 85, polaxomers), KI, Nal, ethyl alcohol, Lugol solutions and NaCI).

The following Methods of Preparation and Examples are given in order to illustrate the invention.

Reference is made therein to the accompanying drawings.

In the drawings: Figures 1 to 3 show how iodine intake by synthaderm from lugol solution is controlled by the parameters referred to in Method of Preparation-2,and Figures 4 & 5 show the release of the iodine as described in Example 3.

Method of Preparation-1: Prepolymer of HypolR type is mixed with an aqueous mixture of iodine and surfactant, after which the mixture is poured between surfaces into sheets of different predetermined desired thickness, or in moulds of various forms.

The ratio between prepolymer, water, amount of iodine, surfactants, and additives or solvents, along with temperature of each ingredient before mixing, reaction temperature and platform temperature, are all together changeable parameters governing hydrophilicity and porosity of end product.

Iodine is introduced into the mixture using various ingredients in the form of i2, 13 or with the aid or organic solvents, e.g., alcohol. The product is stable and can be stored over prolonged periods of time.

Method of Preparation-2: Polyurethane synthetic skin (Synthaderm(0)) was cut to patches of predetermined size, weighed and immersed in a solvent containing iodine for a determined period of time at 22"+2"C. The wet patches containing iodine, bound by the carrier, were dried in an evaporator under controlled conditions for 24 hours.

The quantity of iodine bound by a given area and weight of synthetic skin is controlled by parameters such as time of immersion, type, composition and volume of the immersion medium, temperature during the binding process, time and temperature of the drying process (Figures 1, 2, 3).

Immersion Media: Aqueous iodine solution, Lugol solution, iodine in ethyl alcohol, iodine in isopropyl alcohol, hydroalcoholic mixtures of iodine. The quantities of iodine bound to the synthetic skin varied from 110% by weight to 5% by weight calculated on the weight of the synthetic skin.

EXAMPLE 1: HypolR of type FHP 2002 is mixed with solutions of Span 85X) and Lugol in the following amounts: Hypol FHP 2002R 9.2 g Span 85 0.7 g Lugol 7.7 g The mixture is poured into 2 mm thick flexible polyurethane sheets of various porosity which contain a predetermined amount of iodine.

EXAMPLE 2: Preweighted round samples of 1 cm2 of synthetic skin, Synthaderm, were immersed for 24 hours in 100 cc aqueous solution containing 5% w/v iodine and 10% w/v KI. The samples were dried 24 hours at 22"C in an evaporator with a constant air blowing power.

The degree of iodination calculated by means of equation 1 was 100%+5%.

Wsl-W, H,= %100 (Eq. 1) Ws where H, is the degree of iodination (%) W5 is the initial weight of the dry sample, and Wsl is the weight after iodination.

EXAMPLE 3: iodine Sustained Release Profile Compositions containing iodine prepared by Method 2 were cut to circles, 2.14cm2 in area, weighed and adhered by means of an inert glue to a glass cylinder holder. The holder was centered in 500 ml of a release medium (normal saline) at 370C and rotated by means of a constant speed stirrer. To provide correct hydrodynamics within the system the experimental conditions were in accord with those published by E.

Touitou and M. Donbrow, Intern. J. Pharm. Vol. 9, pages 97 to 106, 1981. The constant speed of rotation was measured by means of a tachometer. The release medium was replaced by fresh saline solution at 1 hour intervals, each experiment being continued for at least 9 hours. The samples were analyzed by means of the titrimetric method described in USP XX.

The experiments were duplicated and were found to be reproducible to within 3%.

The cumulative percent and quantity of iodine released from a preparation containing 30 mg iodine/cm2 is given in Table 1 and the profiles of release in Figures 4,5. The linear plot of the cumulative amount of drug released (Q) against the square root of the time (t2) (Figure 5), shows that the drug release profile follows the Higuchi's Q-t1 relationship*. The process of iodine release from the topical preparations studied under the above described system conditions, was controlled by matrix diffusion mechanism.

TABLE 1 Release of iodine from lodinated Synthetic Skin Hours mg released % I released 1 3.7 3.5 2 7.4 7.0 3 11.4 10.9 4 14.9 14.3 5 18.0 17.3 6 20.7 19.8 7 23.2 22.2 8 25.2 24.1 9 27.2 26.1 EXAMPLE 4: Method of Microbiological Assay The antibacterial properties ofthe novel dosage form was determined by measuring the radius of inhibition of growth of bacteria using the diffusion method according to the European Pharmacopoeia (8).

A medium containing 2% Agar and 0.8% Nutrient Broth (N.B.) was liquified, then sterilized and poured into dishes to produce the required depth. A second layer of 1% Agar and 0.8% N.B. was treated as above, cooled at 45"C and before pouring into Petry dishes, the bacterial suspension was added.

The bacterial suspension was prepared by incubating viable Staphylococcus aureus (Oxford) in 10 ml N.B. solution for & 0 hours to ensure population above 108. This suspension was poured at ratio of 1:10 into the second layer medium at 450C. The temperature was optional to prevent a bactericidal effect, at a highertemperature, or solidifying of the medium before pouring art a lower temperature.

Samples were tested by application of patches on inoculated agar and measurement of the inhibition zone.

Samples of determined sizes of the novel composition prepared by Method 2 were assayed by applying them to the surface of the inoculated agar. One sample was centered on each dish. As reference commercial Betadine swab patches produced by The Purdue Fredrick Company, Norwalk, Conn., U.S.A.

were used. The radius of inhibition was measured by means of a microcaliber. The results are given in Table 2.

Q=2C Dt2...Eqn.2) Q-Amount of drug released per unit surface area of the devices.

d-diffusion coefficient of drug in the matric phase TABLE 2 Inhibition Values Obtained by Diffusion Method Sample Inhibition diameter radius Number Formulation mm+SD mm+SD of samples Betadine**swab 6.5+0.5 5.25+1.1 7 iodine (novel) 6.5+0.5 20.00+2.6 10 Transparent films of a thickness of 0.7 mm to 0.8 mm were prepared from Hypol FP 2002 as follows: a. Hypol FHP 2002 9.2 g Span 85 0.5 g iodine Solution (30 g KI, 15 g I, water up to 100 ml) 6.0 g b. Hypol FHP 2002 9.2 g Span 85 0.5 g 0.1 N solution of iodine 6.0 g c.Hypol FHP 2002 9.2 g Span 85 0.5 g Water 6.0 g IR spectra of the transparent films were obtained, through the films, and these indicate that iodine is not simply intercalated between the polymer molecules, but there exists either hydrogen bonding or complexation between functional groups of the polymer and iodine, while the skeleton of the polymer was not affected.

The compositions of the invention are advantageously used in the form of pads of predetermined size and shape. These are used in essentially dry form; they comprise a polyurethane type polymer carrying the required quantity of iodine, which is released in gradual manner over a prolonged period of time to the skin.

The polymer sheet is advantageously of the open pore type, the surface of it facing away from the skin may be of a less open structure than that facing the skin, as is known from artifical skin products. The compositions of the invention are self-supporting and require no additional support or carrier. They are flexible and can be applied directly to the skin or other tissues. The compositions can also be in the form of wound dressings, in the form of soft pillows which gradually release iodine and which can be used for various purposes, such as prevention of decubitus. Typical compositions of the invention are of an order of thickness of from about 0.1 mm and up to about 100 mm for special purposes.

The formation of compositions from prepolymers such as the HypolR foamable hydrophilic prepolymers, such as Hypol FHP, Hypol 2002, Hypol 5000 and the like, produced by W. R. Grace & Co., Lexington Mass, U.S.A. are suitable for preparing compositions of the invention which are prepared by incorporating the iodine in solution form before forming the polymer sheet, or which comprises preparing such sheets, impregnating same with an iodine solution and drying the composition.

The quantity of iodine per unit area of the composition will depend on the thickness of the sheet and on the intended use. Sustained release of the iodine takes place during prolonged periods of time, and these can be adjusted by the nature of the carrier (pore size etc.), and can be of the order of from a few hours and up to about 24 hours.

It will be understood that the foregoing Methods of Preparation and Examples are given for purposes of illustration only and that various departures may be made therefrom without departing from the scope of the invention claimed.

Claims (12)

1. A pharmaceutical compositionfortopical application in human or veterinary medicine,forthe general gradual release of iodine, comprising hydrophilic polyurethane as carrier of iodine.

2. A composition according to Claim 1 wherein the carrier is of the Hypole or SynthadermQ type.

3. A composition according to either of Claims 1 or 2 wherein the composition is in the form of a dry flexible self-supporting open-pore structure polymer sheet adapted to direct application to the skin or other human tissue.

4. A composition according to any of Claims 1 to 3, wherein the iodine is in the form of 10 or in the form of 1%, and wherein the weight ratio of carrier to iodine is from 100:1 to 1:1.

5. A composition according to any of Claims 1 to 4, containing also an additive selected from excipients, modifying agents and surfactants.

6. A composition according to any of Claims 1 to 5, in unit dosage form of a sheet of predetermined shape and size, or in the form of wound-dressing, or in the form of a soft, supporting pillow.

7. A composition according to Claim 6, in the form of a patch of predetermined shape and size of the active material surrounded with a margin provided with a layer of adhesive for attachment to the skin.

8. A pharmaceutical composition for topical application, for the gradual release of iodine to the skin, comprising a polyurethane sheet carrying iodine, substantially as hereinbefore described and illustrated by reference to the Examples.

9. A process for the production of a pharmaceutical composition as claimed in Claim 1, which comprises admixing a suitable polyurethane prepolymerwith a solution of iodine and with a surfactant and forming a sheet of desired thickness and size.

10. A process for the production of a pharmaceutical composition claimed in Claim 1, which comprises applying a solution of iodine to a polyurethane type artificial skin and drying same to obtain an essentially dry sheet suited for direct topical application.

11. A process for the production of a topical pharmaceutical composition as claimed in Claim 1, substantially as hereinbefore described and illustrated by reference to the Examples.

12. A method for the treatment of skin infections, of sores (decubitus etc.) and for the treatment of burns, which comprises applying to the afflicted area a composition as claimed in any of Claims 1 to 8.

Amendments to the claims have been filed, and have the following effect: Claim 12 above has been deleted.