JPS61100256A - Preparation for gradually releasing iodine - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to pharmaceutical compositions for topical application that release iodine in a gradual and constant manner over an extended period of time.

The new composition provides disinfection of wounds and skin lesions and facilitates wound healing.

[Conventional technology]

Iodine has been used as a disinfectant for many years.

It has a long tradition and is known to be very effective as a topical antiseptic when applied to the skin. Traditional liquid preparations containing iodine have been associated with skin damage and toxic effects (1,
2) gives birth. To overcome these drawbacks of iodine, iodophor, a combination of iodine with detergents, solubilizers, complexing agents or polymers, was created, Wein-Williams Br, f.

! 2”°”°°”′°ゝ180.5g146N (1
9651□).

The physical state of iodophor is semi-solid (soft cream, cream) and liquid. These are spread over the bandage. Generally, the iodine in iodophor is retained in a loose chemical combination in which only a portion of the iodine is utilized and its bactericidal activity is retained. Most of them have about 1% available iodine and Martinzol's I: ctrapharm, 27th edition 1978
823-828), it is released gradually but not in a predetermined manner as a result of the many variables involved in the method of release.

US Pat. No. 3,978,855 relates to polyurethane foam surgical bandages. This foam has a microporous open structure. GB 1450201 relates to absorbable polyurethane foam surgical bandages. French patent application No. 2
No. 156068 relates to surgical bandages or tampons. It states that various fungicides can be incorporated into the foam. No. 2,557,607 relates to water-insoluble adducts (iodophors) formed from polymers containing repeating polyvinylpyrrolidone units and iodine. These can be painlessly applied to and removed from wounds.

U.S. Pat. No. 4,094,967 relates to an iodine-borivinylpyrrolidone solid product that can be applied to polyester bandages.

The D'Avreux R.G.A. Company, Chemical Division, produces a product named Hypol(R). It is a foamable hydrophilic prepolymer that produces a strong white transparent polyolethane foam that can hold up to 20 times its weight in water. They can be used in particular to bandage wounds and can also be used in the production of drug-releasing products.

Although common iodophors are less irritating to the skin than iodine solutions, they leave varying amounts of detergent or pond carrier residue on the skin. A major drawback of current iodofalls is the discomfort f! use/iM and in the lack of gas and vapor exchange through the occluded skin. The novel composition for topical iodine application aims to overcome the above-mentioned disadvantages and has advantageous properties.

[Disclosure of the invention]

Pharmaceutical compositions for topical application to the skin or ulcers include:
It contains iodine as the active ingredient in essentially dry form, in combination with a polyurethane polymer or synthetic skin as a carrier.

The combination of the special physical properties of the carrier and the bactericidal properties of iodine result in infection prevention/control, exudate absorption, scab removal, and rapid healing of ulcers through sustained release of iodine from the novel topical composition.

The preparation according to the invention has been tested for the treatment of skin infections of the skin and proved to be highly effective. The dry composition of the present invention was applied to skin burns and prevented infection while healing was faster. A skin ulcer in an elderly patient was treated by applying a composition according to the invention, resulting in rapid healing of the ulcer and prevention of further infection.

Compositions according to the invention are advantageous over antibiotic compositions in that they are not subject to potential resistance, they are non-irritating, they can be easily applied dry, they allow the skin to breathe, and they do not cause exudation. It has an advantage over ordinary iodophor by absorbing things into the buttocks. They release iodine at a controlled rate and they provide rapid healing of infected wounds.

Among the suitable carriers, most preferred are certain hydrophilic polymers such as polyurethane derivatives. Evans
Nieby's Polyurethane Foam in the Treatment of Burns; see Wallace Nieby, Willinn Adam's Research Impanes.

In addition to the active ingredient and carrier, additional components such as excipients, surfactants, modifiers, and the like may be used to facilitate the manufacture of unit dosage forms.

Synthetic polymers and polyurethanes are also known as carriers for various materials. These are generally used in wet form and do not release the active ingredient in a constant and controlled manner. The present invention is used in essentially dry form and produces a constant sustained release of iodine over a long period of time in essentially steady state, i.e. released at the same rate per unit time (t1/2) over the entire release period. The invention relates to the particular use of hydrophilic polyurethane in the form of synthetic skins in the form of ponds as carriers of iodine.

When applied to the skin, iodine is gradually released. In vitro release rates are discussed below. Up to 100% of the initially bound iodine can be released.

The new preparation preferably contains 0.5 to 90 1% by weight of bound iodine. A variety of carrier sizes can be used, with typical values ranging from about 0.1 mm to about 100 mm thick. From about 6 to about 500 capes of iodine are bound for such a device 1ai.

Such polyurethane devices, characterized by their permeability to gases, do not adhere to wounds, are non-allergenic, pharmacologically inert, scorchable, and can be cut into cedar to any size. Among the additives used are surfactants (
5pan85, polaxomara), K engineering, Na
engineering, ethyl alcohol, Lugol's solution and Mail)
We can list 1'.

Manufacturing method 1 A prepolymer of the Hypol® type is mixed with an aqueous mixture of iodine and a surfactant, and the mixture is then spread between the faces in sheets of various predetermined thicknesses or in molds of various shapes. Inject inside.

The ratios between prepolymer, water, iodine wax, surfactant, and additives or solvents, along with the temperature of each component before mixing, reaction temperature, and platform temperature, are variables that govern the hydrophilicity and effectiveness of the final product. It is a parameter.

Iodine is optionally introduced into the mixture in the form of step 8 or using the individual components together with auxiliaries or organic solvents such as alcohols. The product is stable and can be stored for long periods of time.

i method 2 Polyurethane synthetic skin (Synthaderm: i
f, IIA Trademark) was cut into uniformly sized batches, weighed and NMed in an iodine-containing solvent at 22°±2°C for a period of time. The wet patch containing iodine bound by a carrier was dried in an evaporator under controlled conditions for 24 hours.

The amount of iodine bound by a given area and weight of synthetic skin depends on the soaking time, type, composition and volume of the soaking medium,
Controlled by parameters such as temperature during the bonding step, time and temperature during the drying step (Fig. 1, Fig. 2, Fig. 3).
figure).

Immersion medium aqueous iodine solution, Lugol's solution, iodine in ethyl alcohol, iodine in isopropyl alcohol, hydroalcoholic mixtures of iodine.

The iodine wax bound to the synthetic skin varied from 110% by weight to 5% by weight, calculated based on the overlay of the synthetic skin.

The invention is illustrated by the following examples, which are illustrative and not limiting.

Example 1 Hypol of type yHp 2002 is mixed with Span 85® and Lugol's solution in the following amounts.

High Pole tHp 2002 9.2P Span 85 0.7p Lugol
7.71 The mixture is injected into flexible polyurethane sheets of various thickness 21 mm, which contain a certain amount of iodine.

Example 2 A 1 d pre-weighed round sample of synthetic skin Synthaderm® was injected with 5% w/v iodine and 10% w/v.
The specimens were immersed in an aqueous solution of 100% containing varnish for 24 hours. The sample was heated at 220°C in an evaporator with a constant air blowing force.
It was dried for 24 hours.

The degree of iodination calculated by formula 1 was 100%±5%.

s where Hx is the degree of iodination (support), W3 is the initial weight of the dry sample, and Ws is the weight after iodination.

Example 3 Iodine sustained release profile.

The iodine-containing composition prepared in method 2 was applied to an area of 2.14
cmj circles, weighed and glued in a glass cylinder holder with inert glands. The holder was placed in the center of the release medium (IN saline) at 37° C. and rotated with a constant speed stirrer.

Experimental conditions were carefully modified to provide the correct fluid in the system.
n, J, Ph&rm, Vol. 49, No. 97-106, 198
The decision was made in accordance with the terms published by E. Tritow and M. Dombrow in 2010. Constant rotational speed was measured by a tachometer. The release medium was replaced with fresh saline at 1 hour intervals, and each experiment lasted at least 9 hours. The samples were analyzed by the titration method described in USP 1980, 20th edition.

The experiment was performed twice and was found to be reproducible within 3%.

The cumulative % and amount of iodine released from formulations containing 30 cape iodine/cd are shown in Table 1, and the release profile is shown in Table 1.
f, shown in Figures 4 and 5. ! A cumulative plot of drug released versus the square root of time (1) (Figure 5) shows that the drug release profile follows the Higuchi qt relationship as described above. The method of iodine release from topical preparations studied under thread conditions was controlled by a matrix diffusion mechanism.

1 3.7 3.52
7, 4 7.03 11
．． 4 10.94 14.9
14.35 18.0
17.36 20.7 19.8
7 23.2 22.28
25.2 24.19 2
7.2 26.1 氐★Q=20Dt---(Equation 2) The bactericidal properties of the bacteria were determined as γu by measuring the radius at which bacterial growth stops using the diffusion method according to European Pharmacoboeia, 11th edition (8).

The medium containing 2% agar and 0.8% nutrient broth (N, B,) was liquefied, then sterilized and poured into the dish to create the required depth. 1% agar and 0.8% N,B,
The second layer of is treated as described above, cooled at 45°C,
Bacterial suspension was added before injection into IJ dishes.

Bacterial suspensions were made with Staphylococcus aureus (Oxford) in N, BJ solution for 8-10 hours to ensure a population of 10 or more. This suspension was poured into the second layer medium at a ratio of 1:10 at 45°C. The temperature is optional in order to prevent the sterilization effect at high temperatures, and the solidification of the pre-pouring medium at low temperatures is also optional.

The patch was applied onto the agar inoculated with the sample and the top area was measured and tested.

A sample of the measured size of the new composition made in method 2 was
This was applied to the surfaces of four different types and analyzed. One sample was placed in the center of 6 dishes.

A commercially available patch of Betadine Swaab (The Purdue Frederick Co., Norwalk, Conn., USA) was used as a reference.

The radius of inhibition was measured with a microcaliber. Table 2 shows the results.
Shown below.

Betadine Swaab 65±0.5 5.25±1
．． 17 Iodine (new) 6.5±0.5 20.00±2.
6 10th Order <High Hole IPD2002 Color 0
．． A transparent film with a thickness of 7 to 0.8 mm was made.

& a “Ybor FHP2002
9.25L span 85 Q,
5pb, Hipol 1'HP2002
9.25F span 85
Q, 0.55c iodine. IN solution
6.020+” Ybor IFHP2002
9.254 span 85
0.5? water
6.0? The engineering spectra of the transparent film were obtained through the film.These show that iodine does not easily penetrate between polymer molecules, and that hydrogen bonds or complexes exist between the functional groups of the polymer and iodine. This indicates that the skeleton of the fusion was not affected.

The compositions of the invention are advantageously used in para-V forms of predetermined size and shape. These are used in essentially dry form and they consist of polyurethane-based polymers that carry the necessary iodine that is continuously released into the skin over a long period of time. Advantageously, the polymeric sheet is of open pore type, the surface of which is permeated from the skin having an open structure which is smaller than the pores of the surface facing the skin. The compositions of the present invention are self-supporting and do not require additional supports or carriers. They are flexible and can be applied directly to the skin or other tissue. The compositions can also be used for various purposes such as the prevention of pressure sores, and can also be in the form of wound dressings, in the form of pillows that slowly release iodine. Typical compositions of the invention are of thickness from about 0.1 in. to about 100+o+ for special purposes.

D'Avreux, Lexington, Massachusetts, U.S.A.
Formation of compositions from prepolymers such as Hypol foamable americophilic prepolymers such as Hypol FI (P, Hypol 2002, Hypol 50oO, etc.) made by R. Brace Ant 0 Company or the compositions of the present invention. This can be done by incorporating iodine in the form of a solution before forming the polymer sheet, or alternatively by making such a sheet and impregnating it with an iodine solution and drying.

The amount of iodine per unit area of the composition depends on the thickness of the sheet and the protective purpose. Sustained release of iodine occurs over long periods of time and these depend on the nature of the carrier (e.g. pore size).
The time period can be adjusted from a few hours to about 24 hours.

[Brief explanation of the drawing]

First? l is a graph showing the relationship between u time of immersion in rutile and degree of iodization, Figure 2 is a graph showing the relationship between immersion d@ffl and degree of iodination, and Figure 3 is a graph showing the relationship between immersion u time in rutile and degree of iodination.
Figure 4 shows the cumulative sustained release profile of iodine from topical devices, and Figure 5 shows the relationship between iodine absorption and its double and triple concentrations. Φ Mr. Jerusalem C I) 1 HL and 1-2L2- Cummulative 5u
stained release profile
of Iodine from then
w topical device. time, hours ■Lshi Q-t relatxon for Iodi
ne release from the 5ynth
etic 5kin. , 1/2. 1/2 [
tjm (t, rnJn Procedural amendment (1) August 27, 1985 Patent Office dispatcher Manabu Shiga gu1, case display @ & olAg 18/2t) 3rd/No. 3, person making amendment case Relationship with the person A Kugi Nami φ 懺 in and out” 1 fortune = Omi 4, agent

Claims (1)

Claims: 1. Pharmaceutical compositions for topical application in human and veterinary medicine, generally for sustained release of iodine, containing a hydrophilic polyurethane as a carrier for iodine. 2. Carrier is Hypol (registered trademark)
The composition according to claim 1, which is of the Synthaderm (registered trademark) type. 3. The composition is in the form of a dry, flexible, self-supporting, open-pored polymer sheet adapted to be applied directly to the skin or other human tissue.
Compositions as described in Section. 4. Any one of claims 1 to 3, wherein iodine is in the I^0 form or I^-_3 form, and the weight ratio of carrier to iodine is 100:1 to 1:1. The composition described in. 5. The composition according to any one of claims 1 to 4, which also contains additives selected from excipients, modifiers and surfactants. 6. The composition according to any one of claims 1 to 5, in the form of a unit dosage of sheets of defined shape and size, or in the form of a wound dressing or a soft supportive pillow. thing. 7. A composition according to claim 6 in the form of a patch of a certain shape and size of active material surrounded by a rim provided with a layer of adhesive for application to the skin. 8. A method for producing a pharmaceutical composition according to claim 1, characterized in that the polyurethane prepolymer is mixed with an iodine solution and a surfactant to form a sheet of desired thickness and size. 9. Pharmaceutical composition according to claim 1, characterized in that a solution of iodine is applied to a polyurethane artificial skin and dried to obtain an essentially dry sheet suitable for direct topical application. manufacturing method.