KR19990081901A - Medicinal form configured at that location to release the enzyme into the wound - Google Patents

Abstract

The system of the present invention is for externally applicable active substances which are sensitive to water and are not well absorbed by the gelling agent. The system is characterized by (1) a chamber for the active substance, (2) a chamber for the solvent to dissolve the active substance and (3) a chamber for the gelling agent. The chambers are shaped to ensure that their respective contents are quickly mixed with each other.

Description

Medicinal form configured at that location to release the enzyme into the wound

Wound treatment particularly employs enzymes that disinfect and facilitate wound healing of sensitive substances such as collagenase, chymotrypsin or deoxyribonuclease. In this respect it is indispensable to be in the form of special drugs which are usually applied without gaps on very uneven wound surfaces, which are usually caused by the use of solutions, dispersants, sprays, ointments, gels or creams.

One of the major drawbacks of such drug forms is that generally the precise dosage of the active substance over the entire area of application cannot be guaranteed. In addition, with the prolonged retention of the active substance in wounds essential for the treatment process, the introduction of the solution into a wound with high secretions causes the solution containing the active substance to be immediately ejected by the wound secretion of the wound into the surrounding dressing and no longer useful. It is not allowed because it cannot. Similar phenomena are observed with dispersants and sprays.

Although semi-solid dosage forms (ointments, gels or creams) are obviously better at wound healing, their roughness cannot be applied without contact, i.e. painlessly, to very sensitive wounds, and generally mechanically rubbing the wound surface It must be absorbed into the wound. Ointments, gels and creams also lose some of their original viscosity at skin temperatures. It becomes less viscous and can be washed away by the wound discharge. Pure hydrophobic formulations can prevent this to some extent, but due to their properties as above, they cannot adapt to the surface topography of the wound without contact, ie without pain. Application systems such as dispersants and sprays are generally unsuitable for nonsecretory wounds because the active materials require moisture to function. The solution in the form of application does not remain in the dry wound for this reason, but is absorbed by the dressing as in the case of a wound giving off secretions.

In addition, another disadvantage of more viscous systems of ointments, creams and (hydro) gels is the fact that the long term stability of wound disinfecting enzymes in aqueous systems is often insufficient. Collagenase, in particular, can undergo significant inactivation in minutes to hours in aqueous dosage forms, depending on the pharmaceutical form. Therefore, from the standpoint of stability, it is preferable to include the wound disinfecting enzyme immediately before use, and to stabilize the wound disinfecting enzyme for several hours or more in an aqueous substrate. However, (hydro) gels that remain fixed to the wound and that can be applied easily and painlessly, ie without mechanical influences, will provide the best conditions for optimal wound treatment as a medical care part.

Thus, it has all the beneficial properties of hydrogels and is an applicable liquid form so that it can be optimally adapted to the surface topography of the upper body, solidifies as the temperature rises (coating temperature → skin temperature), and immediately wounds only before use on the wound. There is a need for useful drug forms that can be mixed with disinfecting enzymes with the application substrate, but such mixing is possible within seconds in certain situations (eg, emergency surgery in severe burn patients).

J. Biomed. Mater, Res. 21, 1987, 1135, Pharm. Technol. Europe, (1994), 46 or US Pat. No. 5,298,260 describe hydrogel formulations in liquid form at room temperature and in gel form at higher temperatures. The dissolution of wound disinfecting enzymes, especially collagenase, in the formulations described herein is unacceptable because this process takes several hours due to the nature of the collagenase. Moreover, the system results in inactivation of collagenase. The hydrogels, especially described in US Pat. No. 5,298,260, have proven unsuitable for complete systems due to their specific buffering and pH.

The present invention

1. Chamber for active substance,

2. chamber for a solvent to dissolve the active substance, and

3. consisting of chambers for gel formers, which are designed to allow their contents to be quickly mixed together, which may be applied to an active material that can be applied externally, sensitive to water and difficult to be absorbed by the gelling agent. A system for

The use of the liquid present in chamber 2 makes it possible to solve the short term incorporation of the active substance on the one hand and the stability for several hours on the other hand in an excellent way.

In the simplest technical embodiment to prepare the drug form according to the invention, the vial is filled with the active material as chamber 1 and the glass ampoule as liquid as the chamber 2. Particularly suitable are double chamber syringes in which chamber 1 is filled with the active substance and chamber 2 is filled with liquid. Chamber 3 is a hermetically sealed container equipped with a separate vial or a suitable application device. These two components are stored at a storage temperature that is suitable for the active substance and below room temperature until just before use by a particular user. Immediately before use, the liquid present in chamber 2 is added to the active material of chamber 1 via a cannula, or in the case of a double chamber syringe it is forced into chamber 1 when the active material dissolves immediately. The active substance present in solution in a vial 1 or double chamber syringe is transferred to chamber 3 in which the liquid hydrogel formulation is present and uniformly dispersed therein by simply shaking for a few seconds. The substrate comprising the active material produced in this way is dispensed without contact through the application system of Chamber 3, and the formulation is optimally adapted to the topography of the wound surface because of its liquid roughness. After a few seconds, the preparation solidifies and at the same time the wound is closed. This prevents the active material from being washed away by all wound secretions present.

Particularly suitable as gel formers are the formulas HO (C ₂ H ₄ O) _a (C ₃ H ₆ O) _b (C ₂ H ₄ O) _a H (where a is from 2 to 130 and b is from 15 to 67). ) Polyoxyethylene / polyoxypropylene copolymer.

The hydrogel component may include the following kinds of materials as additional auxiliary materials.

preservatives such as p-Cl-m-cresol, phenylethyl alcohol, phenoxyethanol, chlorobutanol, parabens, benzalkonium chloride, quaternary ammonium compounds, ethanol, propanol or propylene glycol;

Antioxidants such as ascorbic acid, ascorbate, tocopherol and derivatives thereof, propyl gallate, BHA or BHT;

Wetting agents, such as polyethylene glycol, polypropylene glycol or sugar alcohols;

Antifoaming agents such as silicones, saponins, alginic acid esters or amine oxides.

Liquids (chamber 2) which mix very easily with the hydrogel formulations and which dissolve the wound disinfecting enzyme very easily (and, if appropriate, can give a stable effect to the final disinfecting enzyme) have been found to be suitable for this purpose. In addition to water, which is the only solvent, it may also contain the following auxiliary substances:

preservatives such as p-Cl-m-cresol, phenylethyl alcohol, phenoxyethanol, chlorobutanol, parabens, benzalkonium chloride, quaternary ammonium compounds, ethanol, propanol or propylene glycol;

Antioxidants such as ascorbic acid, ascorbate, tocopherol and derivatives thereof, propyl gallate, BHA or BHT;

Wetting agents, such as polyethylene glycol, polypropylene glycol or sugar alcohols;

Biological treatment of wound disinfecting enzymes such as mannitol, glucose, fructose, sucrose, cyclodextrin, dextran, polyvinyl alcohol, polyvinylpyrrolidone, other starch derivatives, or metal salts such as alkali metal or alkaline earth metal acetates or chlorides Auxiliary substances for stabilizing activity;

-Emulsion stabilizers such as nonionic emulsifiers, amphoteric emulsifiers, cationic emulsifiers and anionic emulsifiers.

As the active substance, wound disinfecting enzymes such as chymotrypsin or deoxyribonuclease, which may be in lyophilized and / or pelletized form, may be used. Collagenase or collagenase extracts are particularly suitable as active substances. In addition to the active substance, Chamber 1 also contains auxiliary substances for freeze drying such as mannitol, glucose, amino acids, fructose, sucrose, cyclodextrin, dextran, polyvinyl alcohol, polyvinylpyrrolidone, other starch derivatives or metal salts. do.

Due to the instability in aqueous solutions, the novel application system allows the conversion of externally applicable active materials with difficulties, into a form that is fairly stable, simple and quick to apply.

Another advantage of the drug form according to the invention is that the release of wound disinfecting enzyme therefrom can be controlled within certain limits. Since the drug form is in contact with the wound secretion, the side contacting the wound surface of the gel dressing, which coagulates at human temperature, will be diluted by the wound secretion, at which point the liquid substrate gradually derives from the solid gel from which It ensures that the wound disinfecting enzyme can easily diffuse into the wound. Because this occurs only at the site of contact with the wound, the gel layer further away from the wound surface acts as a reservoir for the enzyme. This prevents, for example, washing off with the solution or dispersant dosage form when it occurs.

<Example 1>

76 g of water were placed in a stainless steel container. 3 g of polyethylene glycol were added with stirring and the mixture was cooled to T <15 ° C. Then 21 g of polyoxyethylene / polyoxypropylene copolymer (POLOXAMER 407) was incorporated with stirring, and stirring was continued under reduced pressure until dissolution was completed. The mixture was sterilized by filtration with a Teflon filter and partitioned into a plastic container equipped with a metering applicator by a liquid dispensing system.

98 g of water was placed in a second vessel and 2 g of a 2: 1 dextran / calcium acetate mixture was dissolved in it. The solution was sterilized by filtration and 1 ml each was dispensed into chamber 2 of a double chamber syringe with a dispensing system.

Twenty units of collagenase in solid form were packed in each of the remaining chambers 1.

<Example 2>

76 g of water were placed in a stainless steel container. 3 g of polyethylene glycol were added with stirring and the mixture was cooled to T <15 ° C. Next, 21 g of the polyoxyethylene / polyoxypropylene copolymer (poloxamer 407) was mixed while stirring, and stirring was continued under reduced pressure until dissolution was completed. The mixture was sterilized by filtration with a Teflon filter and dispensed into portions in a plastic container with a metering applicator by a liquid dispensing system.

99.1 g of water was placed in a second vessel and 0.9 g of sodium chloride was dissolved in it. The solution was sterilized by filtration and 1.5 ml aliquots were dispensed into glass ampoules as chamber 2 with a dispensing system.

85 ml of water was placed in a third vessel. 5000 units of collagenase were dissolved in it with stirring with 5 g of mannitol and water was added to a final volume of 100 ml. The solution was filtered and sterilized and 1 ml each of the prepared lyophilized vials (chamber 1). Lyophilization was then performed with a standard program.

<Example 3>

76 g of water were placed in a stainless steel container. 3 g of polyethylene glycol were added with stirring and the mixture was cooled to T <15 ° C. Next, 21 g of the polyoxyethylene / polyoxypropylene copolymer (poloxamer 407) was mixed while stirring, and stirring was continued under reduced pressure until dissolution was completed. The mixture was sterilized by filtration with a Teflon filter and dispensed into portions in a plastic container with a metering applicator by a liquid dispensing system.

99.1 g of water was placed in a second vessel and 0.9 g of sodium chloride was dissolved in it. The solution was sterilized by filtration and 1.5 ml aliquots were dispensed into glass ampoules as chamber 2 with a dispensing system.

85 ml of water was placed in a third vessel. With stirring, 5000 units of collagenase were dissolved in it and water was added to a final volume of 100 ml. The solution was filtered and sterilized and 1 ml each of the prepared lyophilized vials (chamber 1). Lyophilization was then performed with a standard program.

Claims (2)

1. Chamber for active substance, 2. chamber for a solvent to dissolve the active substance, and 3. consisting of chambers for gel formers, which are designed to allow their contents to be quickly mixed together, which may be applied to an active material that can be applied externally, sensitive to water and difficult to be absorbed by the gelling agent. System. The system of claim 1, wherein the active substance is collagenase.