WO1997026861A1 - Medicament forms constituted in situ for releasing enzymes into wounds - Google Patents

Abstract

A system is disclosed for externally applicable active substances which are water-sensitive and poorly absorbed by gelling agents. The system is characterised in that it comprises (1) a chamber for the active substance, (2) a chamber for a solvent in which the active substance is soluble, and (3) a chamber for a gelatinizing agent. The chambers are so shaped as to ensure that their respective contents mix rapidly with one another.

Description

Pharmaceutical form formed in situ for the delivery of enzymes to wounds

description

In wound treatment, i.a. sensitive substances e.g. B. wound cleansing or wound healing enzymes such as collagenase, chymotrypsin or deoxyribonuclease are used. A complete application of the respective pharmaceutical form on the mostly very uneven surfaces of wounds is essential, which is usually accomplished by using solutions, powders, powders, sprays, ointments, gels or creams.

One of the main disadvantages of the above-mentioned pharmaceutical forms is that an exact dosage of the active ingredients over the entire application area cannot generally be guaranteed. Furthermore, the introduction of solutions into heavily oozing wounds in connection with the longer dwell time of the active ingredient in the wounds, which is necessary for the healing process, is not permitted, since the solution containing the active ingredient is immediately flushed out of the wound with the wound fluid into the surrounding dressing and therefore no longer Available. Similar phenomena are observed with powders, powders and sprays.

Due to their consistency, the semi-solid dosage forms (ointments, gels or creams) are much better suited for wound treatment; but they are not contactless and therefore not painless to apply to the very sensitive wounds and usually have to be adjusted in the wound by mechanical rubbing of the wound surface. In addition, ointments, gels and creams sometimes lose their original viscosity at skin temperature, i. H. they become thinner and can thus be rinsed out with the wound fluid. Purely hydrophobic preparations offer some protection from this, but because of their specific properties, as described above, they are not contactless and therefore painless to adapt to the surface topography of the wound. The application systems powder, powder and spray are not very suitable for non-wetting wounds, since the above-mentioned active substances generally require moisture for their action. The application form solution does not remain on the dry wound for the reasons mentioned above, but is, as in the case of the wetting wound, absorbed by the dressing.

Another disadvantage of the somewhat more viscous ointment, cream and (hydro) gel systems is the often inadequate long-term stability of wound cleaning enzymes in water-containing systems. Ins Special collagenase can experience a clear deactivation in water-containing dosage forms within a period of several minutes to a few hours, ηe according to galenic form. From the point of view of stability, it would therefore be desirable to have a system which only allows the wound cleaning enzyme to be added immediately before use and which stabilizes the wound cleaning enzyme in a water-based basis at least over a period of a few hours. As part of medical care, however, a (hydro) gel, which remains stationary in the wound and can be applied well and painlessly, ie without mechanical influence, was able to offer the best conditions for optimal wound treatment.

There is therefore a need to have a pharmaceutical form which has all the positive properties of a hydrogel, is in the form of a liquid when applied, and can therefore adapt optimally to the surface topography of the wound, but does so with increasing temperature (application temperature → Skin temperature) and enables the wound cleaning enzyme to be applied to the wound only immediately before application to the wound

Mix application base, whereby this mixing may have to be possible within seconds (eg in emergency operations of severely burned patients).

Hydrogel preparations are known from the literature which are used in

Room temperature as a liquid and at a higher temperature as a gel (J. Biomed. Mater. Res. 21, 1987, 1135, Pharm. Technol. Europe, 1994, page 46 ff or also US Pat. No. 5,298,260). If one tries to dissolve wound cleaning enzymes, especially collagenase, in the preparations described there, this process takes several hours due to the specific properties of collagenase and is therefore not acceptable. The system continues to deactivate collagenase. Furthermore, the hydrogel described in US Pat. No. 5,298,260, in particular, proved to be unsuitable for the overall system owing to its specific buffering and the pH.

The invention relates to the system for externally applicable active substances which are sensitive to water and are difficult to absorb in gelling agents, characterized in that

1. a chamber for the active ingredient,

2. a chamber for a solvent in which the active substance is borrowed, and 3. a chamber for a gel former

contains, the chambers are designed so that their contents can be quickly mixed together.

By using the liquid in chamber 2, on the one hand, the problem of short-term incorporation of the active ingredient and, on the other hand, its stabilization can be elegantly solved over several hours.

To produce the pharmaceutical form according to the invention, in its simplest technical embodiment, a vial as the chamber 1 is filled with the active substance and a glass ampoule as the chamber 2 with liquid. A double-chamber syringe in the chamber 1 with the active substance and in the chamber 2 with the liquid is particularly suitable ¬ is filled. Chamber 3 is a separate vial or another closable vessel with a corresponding application device. Until immediately before use, these two components are stored at the respective user at a storage temperature below the room temperature, which is adapted to the active ingredient. Immediately before use, the liquid in chamber 2 is added to the active substance in chamber 1 by means of a cannula, or in the case of the double-chamber syringe, in chamber 1, the active substance immediately dissolving. The active ingredient now in solution in vial 1 or the double-chamber syringe is brought into chamber 3, in which the liquid hydrogel preparation is located, and homogeneously distributed within a few seconds by simple rubbing. The active substance-containing base thus produced is distributed onto the wound without contact with the aid of an application system in chamber 3, the preparation adapting itself optimally to the wound surface due to its liquid consistency. After a few more seconds, the preparation solidifies and closes the wound at the same time. This prevents the active ingredient from being washed out by any wound fluid that is present.

Particularly suitable gel formers are polyoxyethylene-polyoxypropylene copolymers of the formula HO (C ₂ H ₄ 0) _a (C ₃ H ₆ 0) b (C ₂ H ₄ 0) _a H with a = 2 to 130 and b = 15 to 67.

The hydrogel component can have the following types of substances as further auxiliaries:

Preservatives, such as p-Cl-m-cresol, phenylethyl ^"alcohol, phenoxyethanol, chlorobutanol, parabens, Benz alkoniumchlorid, quaternary ammonium compounds, ethanol, propanol or propylene glycol; Antioxidants, such as ascorbic acid, ascorbates, tocopherols and derivatives, propyl gallate, BHA or BHT; Humectants, such as polyethylene glycols, polypropylene glycols or sugar alcohols; - defoaming agents, such as silicones, saponins, alginic acid esters or amine oxides.

The liquid (chamber 2) which is very easily miscible with the above-mentioned hydrogel preparation, in which the wound cleaning enzyme dissolves very easily (and which may also have a stabilizing effect on the final cleaning enzyme), in addition to the one which is permitted only for this purpose Solvent water, also contain the following auxiliaries:

- preservatives, e.g. p-Cl-m-cresol, phenylethyl alcohol, phenoxyethanol, chlorobutanol, parabens, benzalkonium chloride, quaternary ammonium compounds, ethanol, propanol or propylene glycol; Antioxidants such as Ascorbic acid, ascorbates, tocopherols and derivatives, propyl gallate, BHA and BHT;

Humectants, such as B. polyethylene glycols, poly propylene glycols or sugar alcohols;

Auxiliaries for stabilizing the biological activity of the wound cleaning enzymes, such as B. mannitol, glucose, fructose, sucrose, cyclodextrins, dextrans, polyvinyl alcohols, polyvinylpyrrolidones, other starch derivatives or metal salts, such as alkali or alkaline earth metal acetates or chlorides; Emulsion stabilizers such. B. nonionic emulsifiers, amphoteric emulsifiers, cationic emulsifiers and anionic emulsifiers.

For example, wound-cleaning enzymes, such as chymotrypsin or deoxyribonuclease, can be used as the active ingredient, and these may be in lyophilized and / or pelleted form. Collagenase or collagenase extracts are particularly suitable as active ingredients. In addition to the active ingredient, chamber 1 can also contain auxiliaries for lyophilization, such as mannitol, glucose, amino acid, fructose, sucrose, cyclodextrins, dextrans, polyvinyl alcohols, polyvinylpyrrolidones, other starch derivatives or metal salts.

The new application system enables active ingredients that are difficult to apply externally due to their inconsistency in aqueous solution to be brought into a very stable form that can be applied quickly and easily. Another advantage of the pharmaceutical form according to the invention is that the wound cleaning enzyme can be released from it in a controlled manner within certain limits. Since the dosage form is in contact with wound fluid, thinning of the wound fluid will occur on the side of the gel dressing that is solid at body temperature, which, from a certain degree of dilution, ensures that the solid gel becomes an increasingly fluid basis results from which the wound cleaning enzyme can easily diffuse into the wound. Since this happens only on the contact surface to the wound, the gel layers located at a greater distance from the wound surface act as a reservoir for the enzyme. This prevents the enzyme from being washed away, as occurs, for example, with the dosage form solution, powder or powder.

example 1

76 g of water are placed in a stainless steel batch vessel. 3 g of propylene glycol are added with stirring and the mixture is cooled to T <15 ° C. Thereafter, 21 g of a polyoxyethylene-polyoxypropylene copolymer (POLOXAMER 407) are incorporated with stirring while stirring and stirred until completely dissolved under vacuum. The batch is sterile filtered through a Teflon filter and filled in portions on a liquid filling system into plastic containers with a dosing applicator attached.

98 g of water are placed in a second batch vessel and 2 g of a 2: 1 mixture of dextran / calcium acetate are dissolved therein. The solution is sterilized and filled in a 1 ml portion in chamber 2 of double-chamber syringes on a filling machine.

In the remaining chambers 1, 20 units of solid collagenase are filled.

Example 2

76 g of water are placed in a stainless steel batch vessel. 3 g of propylene glycol are added with stirring and the mixture is cooled to T <15 ° C. Thereafter, with stirring, 21 g of a polyoxyethylene-polyoxypropylene copolymer (POLOXAMER 407) are incorporated with stirring and stirred under vacuum until completely dissolved. The batch is sterile filtered through a Teflon filter and filled in portions on a liquid filling machine into a plastic container with a dosing applicator attached. 99.1 g of water are placed in a second batch vessel and 0.9 g of sodium chloride are dissolved therein. The solution is sterile filtered and filled into 1.5 ml portions in glass ampoules as chamber 2 on a filling system.

In a third batch, 85 ml of water are placed. 5000 units of collagenase are dissolved therein together with 5 g of mannitol, and the mixture is made up to a final volume of 100 ml with water. The solution is sterile filtered and filled with 1 ml each in prepared lyophilization vials (chamber 1). Thereafter, lyophilization is carried out according to a standard program.

Example 3

76 g of water are placed in a stainless steel batch vessel. 3 g of propylene glycol are added with stirring and the mixture is cooled to T <15 ° C. Thereafter, 21 g of a polyoxyethylene-polyoxypropylene copolymer (POLOXAMER 407) are incorporated with stirring while stirring and stirred until completely dissolved under vacuum. The batch is sterile filtered through a Teflon filter and filled in portions on a liquid filling machine into a plastic container with a dosing applicator attached.

99.1 g of water are placed in a second batch vessel and 0.9 g of sodium chloride are dissolved therein. The solution is sterile filtered and filled into 1.5 ml portions in glass ampoules as chamber 2 on a filling machine.

85 ml of water are placed in a third batch vessel. One dissolves 5000 units of collagenase with stirring and fills up

Water to a final volume of 100 ml. The solution is sterile filtered and filled in 1 ml each in prepared lyophilization vials (chamber 1). Then lyophilization is carried out according to a standard program.

Claims

claims

1. System for externally applicable active ingredients which are sensitive to water and are difficult to absorb in gelling agents, characterized in that it

1. a chamber for the active ingredient,

2. a chamber for a solvent in which the active ingredient is soluble, and

3. a chamber for a gel former

contains, the chambers are designed so that their contents can be quickly mixed together.

2. System according to claim 1, characterized in that it contains collagenase as the active ingredient.