CA2243528A1 - 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

0650/01022 CA 02243~28 1998-07-20 A drug form which is formed in situ for delivering enzymes to wounds 5 Wound treatment makes use of, inter alia, sensitive substances, eg. enzymes which clean wounds and promote wound healing, such as collagenase, chymotrypsin or else deoxyribonuclease. In this connection it is indispensable that the particular drug form be applied without gaps to the wound surfaces, which are usually 10 very uneven, and this is, as a rule, brought about by using solutions, dusting powders, sprays, ointments, gels or creams.

One of the main disadvantages of the abovementioned drug forms is that, as a rule, accurate dosage of the active substances over 15 the entire area of application cannot be ensured. In addition, the introduction of solutions into wounds with heavy discharge, in conjunction with the lengthy residence of the active substance in the wounds which is necessary for the healing process is not ay~lo~ed because the solution cont~; n i ~g active substance is 20 immediately flushed by the wound discharge out of the wound into the surrounding dressing and thus is no longer available. Similar phenomena are observed with dusting powders and sprays.

Although semisolid dosage form$ (ointments, gels or creams) are 25 distinctly better for wound treatment, because of their consistency, they cannot be applied without contact, and thus painlessly, to the very sensitive wounds and must, as a rule, be assimilated in the wound by mechanically rubbing the wound surface. In addition, ointments, gels and creams lose part of 30 their original viscosity at the temperature of skin, ie. they become less viscous and may thus be rinsed out with the wound discharge. Although purely hydrophobic preparations provide a certain protection against this, they cannot, because of their specific properties as described above, be adapted to the surface 35 topography of the wound without contact and thus p~inlessly.
Application systems like dusting powders and sprays are unsuitable for non-discharging wounds because the abovementioned active substances require moisture for their action as a rule.
The solution as application form does not remain on the dry 40 wound, for the abovementioned reasons, but i5 absorbed by the dressing, as in the case of the discharging wound.

Another disadvantage of the somewhat more viscous systems of ointment, cream and (hydro)gel is moreover the fact that the 45 long-term stability of wound-cleaning enzymes in aqueous systems is often deficient. Collagenase in particular may experience a marked inactivation in aqueous dosage forms within as little as a 0650/01022 CA 02243~28 1998-07-20 few minutes to a few hours, depending on the pharmaceutical form.
Hence, from the stability viewpoint, it would be desirable to have a system which permits the wound-cleaning enzyme to be added only immediately before use, and which stabilizes the 5 wound-cleaning enzyme in the aqueous base at least for a few hours. However, a (hydro)gel which remains fixed in the wound and can be applied easily and painlessly, ie. without mechanical influences, would provide the best conditions for optimal wound treatment as part of medical management.
Hence there is a need to have available a drug form which has all the beneficial properties of a hydrogel, is in the form of a liquid where possible on application, and thus can be adapted optimally to the surface topography of the wound, but solidifies 15 as the temperature increases (application temperature - skin temperature) and makes it possible to mix the wound-cleaning enzyme with the application ba~e only immediately before use on the wound, it being necessary for this mixing to be possible within seconds in certain circumstances (eg. in emergency 20 operations on patients with serious burns).

The literature discloses hydrogel formulations which are in the form of a liquid at room temperature and of a gel at higher temperature (J. Biomed. Mater. Res. 21, 1987, 1135, Pharm.
25 Technol. Europe, (1994), 46 or US Patent No. 5,298,260). On attempting to dissolve wound-cleaning enzymes, specifically collagenase, in the formulations described therein, this process takes several hours, because of the specific properties of collagenase, and is thus unacceptable. Furthermore, the system 30 leads to inactivation of collagenase. In addition, the hydrogel described in particular in US Patent No. 5,298,260 proved to be unsuitable for the complete system because of its specific buffering and the pH.

35 The invention relates to a system for active substances which can be applied externally, are sen~itive to water and difficult to take up in gelling agents, which comprises 1. a chA~er for the active substance, 2. a chamber for a solvent in which the active substance dissolves, and 3. a chamber for a gel former, 0650/01022 CA 02243~28 l998-07-20 where the chambers are designed so that their contents can be mixed together rapidly.

The use of the liquid which is present in chamber 2 makes it 5 possible to solve in an elegant manner on the one hand the problem of the short-period incorporation of the active sub~tance, and on the other hand its stabilization for several hours.

10 To produce the drug form according to the invention in its simplest technical embodiment, a vial as chamber 1 is filled with the active substance and a glas~ ampule as chamber 2 is filled with liquid. A double-chA~er syringe which is filled in chamber 1 with the active substance and in chamber 2 with the liquid is 15 particularly suitable. Chamber 3 is a separate vial or another closable vessel with appropriate application device. These two components are stored until immediately before use by the particular user at a storage te~perature which is appropriate for the active substance and is below room temperature. Immediately 20 before use, the liquid which is present 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 ~yringe, is forced into chamber 1, whereupon the active substance immediately dissolves. The active sub-tance which is now present as a solution in the vial 1 or the 25 double-chamber syringe is transferred into chamber 3, in which the liquid hydrogel preparation is present, and homogeneously dispersed therein by simply shaking for a few seconds. The base cont~ining active sub~tance which has been prepared in this way is distributed on the wound without contact by means of an 30 application system on chamber 3, and the preparation optimally adapts, because of it$ liquid consistency, to the topography of the wound surface. A few seconds later, the preparation solidifies and simultaneously seals the wound. This prevents the active substance being washed out by any wound discharge which is 35 present.

Specifically suitable as gel formers are polyoxyethylene/polyoxypropylene copolymers of the formula H0(C2H40)a(C3H60)b(C2H40)aH with a = 2 to 130 and b = 15 to 67.
The hydrogel component may have the following types of substances as further ancillary substances:

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

0650/01022 CA 02243~28 l998-07-20 - antioxidants such as ascorbic acid, ascorbates, tocopherols and derivatives thereof, propyl gallate, BHA or BHT;
- humectants such as polyethylene glycols, polypropylene glycols or sugar alcohols;
5 - antifoams such as silicones, saponins, alginic esters or amine oxides.

The liquid ~chamber 2) which is very readily miscible with the abovementioned hydrogel preparation and in which the 10 wound-cleaning enzyme dissolves very easily (and which may also have, where appropriate, a stabilizing effect on the end-cleaning [sic] enzyme) may, besides the water which is the only solvent approved for this purpose, also contain the following ancillary substances:
- preservatives such as p-Cl-m-cresol, phenylethyl alcohol, phenoxyethanol, chlorobutanol, parabens, benzalkonium chloride, quaternary ammonium compounds, ethanol, propanol or propylene glycol;
20 - antioxidants such as ascorbic acid, ascorbates, tocopherols and derivatives thereof, propyl gallate, BHA or BHT;
- humectants such as polyethylene glycols, polypropylene glycols or sugar alcohols;
- ancillary substances for stabilizing the biological activity of the wound-cleaning enzymes, such as mannitol, glucose, fructose, sucrose, cyclodextrins, dextrans, polyvinyl alcohols, polyvinylpyrrolidones, other starch derivatives or metal salts, such as alkali metal or alkaline earth metal acetates or chlorides;
30 - emulsion stabilizers such as nonionic emulsifiers, amphoteric emulsifiers, cationic emul~ifiers and anionic emulsifiers.

It is possible to use as active substance, for example, wound-cleaning enzymes such as chymotrypsin or deoxyribonuclease, 35 it being possible for these to be in lyophilized and/or pelleted form. Collagenase or collagenase extracts are particularly suitable as active substance. Chamber 1 may, in addition to the active substance, also contain ancillary substances for lyophilization, such as mannitol, glucose, amino acid [sicl, 40 fructose, sucrose, cyclodextrins, dextrans, polyvinyl alcohols, polyvinylpyrrolidones, other starch derivatives or metal salts.

The novel application system makes it possible to convert active substances, which can be applied externally only with difficulty 45 because of their instability in aqueous solution, into a form which is reasonably stable and can be applied simply and rapidly.

0650/01022 CA 02243~28 1998-07-20 Another advantage of the drug form according to the invention is that the release of the wound-cleaning enzyme from it can be controlled within certain limits. Since the drug form is in contact with wound diw harge, the side, which is in contact with 5 the wound surface, of the gel dressing, which is solid at body temperature, will be diluted by the wound discharge, and the dilution ensures, from a certain degree onwards, that an increasingly liquid base results from the solid gel, and the wound-cleaning enzyme can easi}y diffuse out of this into the 10 wound. Since this takes place only on the area of contact with the wound, the gel layers which are further away from the wound surface act as reservoir for the enzyme. This prevents the enzyme being washed away as occurs, for example, with solution or dusting powder dosage forms.
Example 1:

76 g of water are introduced into a stainless steel vessel. While stirring, 3 g of propylene glycol are added, and the mixture is 20 cooled to T < 15~C. Then, while stirring, 21 g of a polyoxyethylene/polyoxypropylene copolymer (POLOXAMER 407) are incorporated while stirring [siC], and stirring is continued under reducod pressure until dissolution is complete. The mixture is sterilized by filtration through a Teflon filter and dispensed 25 by a liquid dispensing system in portions into plastic contAi~ers with fitted metering applicator.

98 g of water are introduced into a second vessel and 2 g of a 2:1 dextran/calcium acetate mixture are dissolved therein. The 30 solution is sterilized by filtration and dispensed in 1 ml portions in a dispensing syste~ into chA~her 2 of double-chamber syrlnges .
20 units of collagenase in solid form are packed into each of the 35 remaining c~ rs 1.

Example 2 76 g of water are introduced into a stainless steel vessel. While 40 stirring, 3 g of propylene glycol are added, and the mixture is cooled to T < 15~C. Then, while stirring, 21 g of a polyoxyethylene/polyoxypropylene copolymer ~POLOXAMER 407) are incorporated while stirring [sic], and stirring is continued under reduced pressure until dissolution is complete. The mixture 45 is sterilized by filtration through a Teflon filter and dispensed by a liquid dispensing system in portions into plastic cont~iners with fitted metering applicator.

0650/01022 CA 02243~28 l998-07-20 99.1 g of water are introduced into a second vessel, and 0.9 g of sodium chloride is dissolved th~rein. The solution is sterilized by filtration and dispersed in 1.5 ml portions in a dispensing system into glass ampules as chamber 2.

85 ml of water are introduced into a third vessel. 5000 units of collagenase are dissolved therein with stirring together with 5 g of mannitol, and water is added to a final volume of 100 ml. The solution is sterilized by filtration and 1 ml portions are 10 introduced into prepared lyophilization vials (chamber 1).
Lyophilization is then carried out by a standard program.

Example 3 15 76 g of water are introduced into a stainless steel vessel. While stirring, 3 g of propylene glycol are added, and the mixture is cooled to T ~ 15~C. Then, while stirring, 21 g of a polyoxyethylene/polyoxypropylene copolymer (POLOXAMER 407) are incorporated while stirring [sic], and stirring is continued 20 under reduced pressure until dissolution is complete. The mixture is sterilized by filtration through a Teflon filter and dispensed by a liquid dispensing system in portions into plastic containers with fitted metering applicator.
25 99.1 g of water are introduced into a second vessel, and 0.9 g of sodium chloride is dissolved therein. The solution is sterilized by filtration and dispersed in 1.5 ml portions in a dispensing system into glass ampules as chamber 2.

30 85 ml of water are introduced into a third vessel. 5000 units of collagenase are dissolved therein with stirring, and water is added to a final volume of 100 ml. The solution is sterilized by filtration and 1 ml portions are introduced into prepared lyophilization vials (chamber 1). Lyophilization is then carried 35 out by a st~n~rd program.

Claims (2)

We claim:

1. A system for active substances which can be applied externally, are sensitive to water and difficult to take up in gelling agents, which comprises

1. a chamber for the active substance, 2. a chamber for a solvent in which the active substance dissolves, and 3. a chamber for a gel former, where the chambers are designed so that their contents can be mixed together rapidly.

2. A system as claimed in claim 1, wherein the active substance is collagenase.