CZ230198A3 - In situ formed medicamentous forms for releasing enzymes in a wound - 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

Dosage forms formed in situ for the release of enzymes in the wound

Technical field

The present invention relates to a dosage form formed in situ for the release of enzyme in the wound.

BACKGROUND OF THE INVENTION

In the treatment of wounds, inter alia, e.g. sensitive, for example wound cleansing or wound healing enzymes, such as collagenase, chymotrypsin or even desoxyribonuclease. In this case, uniform application of the medicament in question is inevitable, which is generally carried out using solutions, powder, powder, spray, ointment, jelly or cream.

One of the major drawbacks of the medicaments described above is that it is generally not possible to ensure accurate dosing of the active ingredients over the entire application area.

Remotely, application of the solution to heavily wet wounds is not permissible in conjunction with prolonged residence of the active ingredient in the wound required for the healing process since the active ingredient solution is immediately washed out of the wound fluid into the surrounding dressing and is no longer available. Similar phenomena have been observed with powder, powders and sprays.

Semi-solid administered forms (ointments, jellies or creams) are considerably better usable in wound care due to their consistency, but they are non-contacting and thus cannot be painlessly applied to very sensitive wounds and must usually adapt to the wound surface. In addition, ointments, jellies and creams partially lose their original viscosity at the skin temperature, i. that they thin out and can be washed out of the wound by the liquid. Purely hydrophobic preparations offer some protection against this, but due to their specific properties they are not tear-free as described above and thus cannot be painlessly adapted to the wound surface. Powder, powder and spray delivery systems are not less suitable for non-wound wounds since the active ingredients described above generally need moisture to be effective. The application form of the solution does not remain on the dry wound for the reasons described above but is sucked into the dressing as in the case of a wet wound.

Another drawback of the somewhat viscous system of ointment, cream and (hydro) jelly is often the lack of stability of wound cleansing enzymes in aqueous systems for a longer period of time. In particular, collagenase can experience marked deactivation in the water-containing formulations in a time-span of several minutes to several hours, depending on the galenic form. From the standpoint of stability, a system would be desirable to allow the addition of this cleaning enzyme for the morning just prior to use and to stabilize the enzyme in a water-containing substrate for at least several hours. Within the framework of medical provision should be offered (hydro) jelly, which remains in the wound in place and which can be done well and painlessly, ie, without mechanical influence, with the best prerequisites for optimal treatment of r an.

Therefore, there is a need to use a dosage form which exhibits all the positive properties of a parsley, which is available as a liquid when applied and is thereby optimally adapted to the wound surface, but at increasing temperature (from application temperature to skin temperature) it solidifies and allows the cleaning enzyme to be mixed first with the application base just prior to use on the wound, which mixing must be possible in a matter of seconds (eg emergency surgery of a patient with severe burns).

Hydrogen preparations are known from the literature which behave as liquid at room temperature and as jelly at higher temperature [J. Biomed, Mater. Res. 21, 1135 (1987),

Pharm. Technoi. Europe, 1994, page 46 et seq.] Or also) US Patent No. 5,293,260]. In attempts to dissolve wound cleansing enzymes, especially collagenase, in these preparations described above, this process takes several hours due to the specific properties of collagenase and is thus unacceptable. The system further leads to the inactivation of collagenase. Remarkably, especially in US Patent No. 5,298,260, the disclosed hydrogees have proved to be unsuitable for the overall system based on their specific buffer and pH value.

SUMMARY OF THE INVENTION

SUMMARY OF THE INVENTION The present invention provides a system for externally applicable water-sensitive active ingredients which are difficult to absorb gelling agents, characterized in that it comprises (1) one active substance chamber, (2) one solvent chamber in which and (3) one chamber for the gel-forming agent, the chambers being arranged in such a way that their contents can be mixed rapidly.

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By using the fluid present in the chamber 2, the problem of short-term incorporation of the active substance and of its stabilization for several hours is elegantly solved.

In its simplest technical embodiment, for the manufacture of the dosage form according to the invention, one vial as a chamber 1 is filled with a substance and a glass ampoule as a chamber 2 is filled with liquid. Particularly suitable is a two-chamber syringe in which the chamber 1 is filled with the active substance and the chamber 2 is filled with liquid. The chamber 3 is a separate vial or other container with a closure and associated delivery device. Both parts are stored until immediately prior to use by the respective user at a storage temperature below room temperature adapted to the active ingredient. Immediately prior to use, fluid from chamber 2 is added to the drug through chamber through the insertion tube to chamber 1 or, in the case of a two-chamber syringe, is dispensed into chamber 1 to dissolve the drug immediately. The active substance, which is now present in solution in the vial 1 or in the bicameral syringe, is added to the chamber 3 to the liquid hydrogel preparation and mixed homogeneously with a simple shaking in a few seconds. The active substance base thus produced is distributed in a contactless manner on the wound by means of the application system on the chamber 3, the preparation being optimally adapted to the wound surface due to its fluid consistency. After a few more seconds, the product solidifies and at the same time closes the wound. The leaching of the active substance by the possibly present liquid is thus prevented.

Polyoxyethylene-polyoxypropylene copolymers of the formula are particularly suitable as gel-forming agents. :::. '..i ·;

HO (C; H _; O) JCO (J) Q), H, wherein a has a value from 2 to 130 and b has a value from 15 to 67.

As additional excipients, the hydrogel components may have the following types of substances:

- Preservatives such as P-Cl-m-cresol., Phenylethyl alcohol, phenoxyethanol, chlorobutanol, paraben, benzalkonium chloride, quaternary ammonium compounds, ethanol, propanol or propylene glycol,

- Antioxidants such as ascorbic acid, ascorbates, tocopherols and their derivatives, propyl gallates, BHA or BHT,

- Humectants such as polyethylene glycols, polypropylene glycols or sugar alcohols,

- Antifoams, such as silicones, saponins, alginate esters or amine oxides.

This liquid readily miscible with the hydrogel formulations described above, in which the frame cleaning enzyme can dissolve very easily (or which, for example, may exhibit a stabilizing effect on the resulting cleaning enzyme, for wounds), in addition to the only water acceptable for this purpose, the following excipients:

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

- Antioxidants such as ascorbic acid, ascorbates, tocopherols and their derivatives, propyigalate, 3HA and BHT,

- Humectants, such as polyethylene glycols, polyproplylene glycols or sugar alcohols,

- Auxiliaries to stabilize the biological activity of frame cleansing 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 acetates or chlorides,

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

For example, wound cleansing enzymes such as chymotrypsin or desoxyribonuclease may be used as active ingredients, and these may be available in lyophilized and / or pelleted form. A particularly suitable active ingredient is collagenase or collagenase extracts. The active ingredient chamber 1 may also contain freeze-drying aids such as mannitol, glucose, amino acids, fructose, sucrose, cyclodextrins, dextran, polyvinyl alcohols, polyvinylpyrrolidones and other starch derivatives or metal salts.

This new delivery system makes it possible to bring the active substances which, due to their instability in the aqueous solution, are difficult to apply outside, to a truly stable form which can be easily and quickly applied.

Another advantage of the dosage form of the present invention is that the wound cleansing enzyme can be released to a certain level in a controlled manner. Because the dosage form is in contact with the body fluid excreted from the wound, it occurs on the side

contacting the wound surface of a solid body gel bandage to dilute which, to some degree, causes the solid gel to become an increasingly fluid base from which the wound cleansing enzyme can easily penetrate the wound. Since this occurs only on the wound contact area, the gel layers which are at a greater distance from the wound surface act as an enzyme reservoir. Leaching of the enzyme, as occurs, for example, in the form of solution, powder or powder administered, is thereby prevented.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

76 g of water are introduced into a stainless steel dissolution vessel. While stirring, 3 g of propylene glycol are added and the mixture is cooled to below 15 ° C. 21 g of a polyoxyethylene-polyoxypropylene copolymer (POLOXAMER 407) are then mixed with stirring and mixed under vacuum until complete dissolution. The batch is sterile filtered through a Teflon filter and is filled in batches into plastic containers with a dispensing applicator mounted on the liquid filling device.

A second dissolution vial was charged with 98 g of water, and then 2 g of a 2: 1 mixture of dextran and calcium acetate was dissolved therein. The solution is sterilized and filled in 1-ml aliquots into chamber 2 of the double spray chamber on a filling device.

20 units of collagenase in solid form are filled into each of the remaining chambers 1.

Example 2

76 g of water are introduced into a stainless steel dissolution vessel. While stirring, 3 g of propylene glycol are added and the mixture is cooled to below 15 ° C. 21 g of polyoxyethylene-polyoxypropylene copolymers (POLOXAMER 407) are then mixed with stirring and mixed under vacuum until complete dissolution. The batch is sterile filtered through a Teflon filter and is loaded in batches into plastic containers with a dispensing applicator mounted.

A second dissolution vessel was charged with 99.1 g of water and 0.9 g of sodium chloride was dissolved therein. The solution is sterile filtered and filled with 1.5 ml portions into glass ampoules as chamber 2.

In a third dissolution vessel, 85 ml of water is introduced, in which 5000 units of collagenase are dissolved while stirring with 5 g of mannitol and made up to 100 ml with water. The solution is sterile filtered and filled in portions of 1 ml into the prepared lyophilization vials. It is then lyophilized according to a standard program.

Example 3

76 g of water are introduced in a stainless steel dissolving vessel. 3 g of propylene glycol are added with stirring and the mixture is cooled to a temperature below 15 ° C. Thereafter, 21 g of polyoxyethylene-polyoxypropylene copolymers (POLOXAMER 407) are incorporated with stirring and mixed under vacuum until complete dissolution. The batch is sterile filtered through a Teflon filter and the liquid filling device is filled in batches into plastic containers with a dispensing applicator mounted.

A second dissolution vessel was charged with 99.1 g of water and 0.9 g of sodium chloride was dissolved therein. Sterile solution «·

1 ') is filtered and filled with 1.5 ml portions into glass ampoules such as chamber 2.

A third dissolution vessel was charged with 55 mL of water.

5000 units of collagenase are then dissolved with stirring and made up to 100 ml with water. The solution is sterile filtered and filled in 1 ml increments into the prepared 1 ml vials (chambers 1). It is then lyophilized according to a standard program.

Claims (3)

Patent claims 1. A system for water-sensitive active ingredients which can be applied externally and which are difficult to mix with gelatinising agents, comprising: 1. one active substance chamber, 2. one solvent chamber in which the active substance is soluble; and 3. one chamber for the gel-forming substance, the chambers being arranged in such a way that their contents can be mixed rapidly. The system according to claim 1, characterized in that it contains collagenase as the active substance. utv