CN1209739A - 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

Be used for enzyme is delivered to the medicament forms that forms on the spot of wound

The sensitive materials that are used for treatment of wounds for example clean a wound and promote the enzyme of wound healing, as collagenase, chymase or deoxyribonuclease.Thus, be applied in closely specific medicament forms usually that very irregular wound surface is necessary, this is normally by using solution, powder, and powder, spray, ointment, gel or emulsifiable paste are finished.

A major defect of said medicine form is a exact dose that can not determine active substance on whole medication surface usually.In addition, the solution importing is had the wound of a lot of ejections and active substance is remained in wound (this is essential for agglutination) for a long time is infeasible, can be flushed to the binder on every side by the ejection of discharging rapidly because contain the solution of active substance, thereby make active substance ineffective from wound.For powder, reach powder and spray and also can observe similar phenomena.

Although semi-solid dosage form (ointment, gel or emulsifiable paste) is obviously better for the treatment wound, but because its denseness, can just be administered on the very sensitive wound through contact (thereby painless), and must it is absorbed in wound by the mechanical friction wound surface usually.In addition, ointment, gel and emulsifiable paste can make its part lose original viscosity under skin temperature, and promptly viscosity reduces, and therefore, might be washed out by the wound ejection.Although pure hydrophobic preparations can provide some protections to avoid this situation, because its above-mentioned concrete property, therefore can not be with it without contact the pattern that be adapted to wound surface (thereby painless).Similar powder, and powder and the such administration system of spray be not suitable for the wound of no ejection is because above-mentioned active substance needs moisture when having an effect usually.For above-mentioned reasons, the solution of administration form can not keep on exsiccant wound, but is absorbed by binder, as the situation at the wound that ejection is arranged.

Another shortcoming of more tacky system such as ointment, emulsifiable paste and (water) gel is that the long-time stability of enzyme in water system that clean a wound are bad usually.Specifically, according to its lid Lun Shi pharmacy form, collagenase can few to several minutes to a few hours in aqueous dosage forms obvious inactivation.Therefore, from the angle of stability, need a kind of system, this system allows only to add before use the enzyme that cleans a wound, and this system can stablize a few hours at least with enzyme with cleaning a wound in the hydrated matrix.In any case, can be maintained fixed in the wound and can be easy to and painless using, that is, the best treatment of wounds that (water) gel of medication can be as a medical control part without applying mechanism provides optimal conditions.

Therefore, need a kind of medicament forms with all superperformances of hydrogel, thereby this medicament forms can be liquid form if desired when using can be adapted to the wound surface pattern best, but solidify along with the rising (application temperature → skin temperature) of temperature, and make its can face with before, on wound with the enzyme that cleans a wound with use substrate and mix, under the specific situation (as give the serious burn patient carry out emergency operation the time) this mixing must will finish in the several seconds.

Document discloses aqueogel, and said preparation is a liquid in room temperature, is gel (J.Biomed.Mater.Res.21,1987,1135, Pharm.Technol.Europe, (1994), 46, or United States Patent (USP) 5298260) in higher temperature.In the enzyme, the particularly trial that collagenase carried out that is used to clean a wound in the described preparation of dissolving, because the special characteristics of collagenase, this process will be spent a few hours, and therefore, this is difficult to accept.In addition, this system can make the collagenase inactivation.In addition, prove that in United States Patent (USP) 5298260 specifically described hydrogel is not suitable for holonomic system owing to its special buffer and pH.

Theme of the present invention is the system that is used for the external active substance, and described active substance is to water sensitive and be difficult to gel media (Geliermittel) and admit, and this system contains:

1. hold the chamber of active substance,

2. hold the solvent that is used for the lytic activity material the chamber and

3. hold the chamber of gellant, wherein, the design of described chamber is that its inclusions is mixed rapidly.

The purposes of liquid is to make it solve the problem that adds active substance in the short time on the one hand in mode preferably in the chamber 2, makes active substance stability number hour on the other hand.

In order to produce medicament forms of the present invention, with the bottle of active substance filling, with the glass ampule of liquid filling as chamber 2 as chamber 1 with the simplest technical scheme.Double-chamber syringe is suitable especially, and the chamber 1 of this syringe is filled by active substance, and chamber 2 is by liquid filling.Chamber 3 is independent bottle or another the closed container that has suitable application device.These two kinds of components are stored under active substance and the subambient storage temperature being suitable for, use up to being about to specific user.Before facing usefulness, the liquid in the chamber 2 is added in the active substance of chamber 1, under the situation of double-chamber syringe, described liquid is pressed onto in the chamber 1, so active substance dissolves immediately with pipe.Then the active substance of the solution form in the bottle 1 or in the double-chamber syringe is transferred in the chamber 3, produced the liquid water gel therein, by simple oscillation several seconds homodisperse.Will be with the substrate that contains active substance of this method preparation by the drug-supplying system on the chamber 3, need not contact and just can be applied on the wound, owing to its liquid consistency, preparation is adapted to the pattern of wound surface best.After several seconds, preparation solidifies, and has sealed wound simultaneously.Prevented that like this active substance from being washed out by the wound ejection of any existence.

Be particularly suitable for is that structural formula is HO (C as gellant ₂H ₄O) _a(C ₃H ₆O) b (C ₂H ₄O) _aThe polyoxyethylene of H-polyoxypropylene copolymer, a=2-130 wherein, b=15-67.

The material that hydrogel component can contain following type is as auxiliary substance :-antiseptic such as parachlorometacresol, phenethanol, phenoxyethanol, methaform, P-hydroxybenzoic acid

Esters (parabene), geramine (Benzalkoniumchlorid), quarternary ammonium salt compound,

Ethanol, propanol or propylene glycol;-antioxidant such as ascorbic acid, Ascorbate, vitamin E and derivant thereof, gallic acid

Propyl ester, BHA or BHT;-wetting agent such as Polyethylene Glycol, polypropylene glycol or sugar alcohol;-defoamer such as polysiloxanes, Saponin, alginate esters or amine oxide.

Liquid in the chamber 2 is easy to miscible and be easy to dissolve the enzyme that cleans a wound (in appropriate circumstances with above-mentioned aqueogel, the enzyme that cleans a wound also had Stabilization), dewater outside (water is unique solvent that is applicable to this purpose), the liquid in the chamber 2 also can contain following composition :-antiseptic such as parachlorometacresol, phenethanol, phenoxyethanol, methaform, P-hydroxybenzoic acid

Esters, geramine, quarternary ammonium salt compound, ethanol, propanol or propylene glycol;-antioxidant such as ascorbic acid, Ascorbate, vitamin E and derivant thereof, gallic acid

Propyl ester, BHA or BHT;-wetting agent such as Polyethylene Glycol, polypropylene glycol or sugar alcohol;-be used for the bioactive auxiliary substance of the stable enzyme that cleans a wound, as mannitol, Fructus Vitis viniferae

Sugar, fructose, sucrose, cyclodextrin, glucosan, polyvinyl alcohol, polyvinylpyrrolidone,

The acetate of other starch derivatives or slaine such as alkali metal or alkaline-earth metal or hydrochlorate;-emulsion stabilizer such as nonionic emulsifier, amphoteric emulsifier, cationic emulsifier and anion

Emulsifying agent.

What can be used as active substance is, the enzyme that for example cleans a wound, and as chymase or deoxyribonuclease, these active substances can be the forms of lyophilizing and/or micropill.Suitable especially is collagenase or collagenase extract as active substance.Except that active substance, lyophilizing auxiliary substance such as mannitol, glucose, aminoacid (sic), fructose, sucrose, cyclodextrin, glucosan, polyvinyl alcohol, polyvinylpyrrolidone, other starch derivatives or slaine also can be contained in chamber 1.

New drug-supplying system of the present invention active substance can be transformed into quite stable and can be simply, the form used rapidly, described active substance is because its unstability in aqueous solution is difficult to independent external.

Another advantage of medicament forms of the present invention is will clean a wound with enzyme slow release within the specific limits.Because this medicament forms contacts with the wound ejection, the side that gel binder (body temperature is solid down) contacts with wound will be diluted by the wound ejection, say to a certain extent, this diluting effect has been guaranteed the continuous increase of fluid matrix in the solid gel, thereby makes the enzyme that cleans a wound be easy to be diffused in the wound.Because this occurs over just the zone that contacts with wound, will be as the bank of enzyme away from the gel layer of wound surface.So just prevented from for example using solution or powder the situation that the enzyme that occurs when reaching the powder dose form is rinsed.

Embodiment 1

76g water is added in the rustless steel container.Stir to add the 3g propylene glycol down and this mixture is cooled to temperature and be lower than 15 ℃.Then, under agitation add 21g polyoxyethylene/polyoxypropylene copolymer (POLOXAMER407), continue to be stirred to dissolving fully under the decompression.Mixture by polytetrafluoroethylene filter paper filtering sterilization, is joined by the liquid dispersion system then in batches and has in the plastic containers that measure applicator.

98g water is added in second container, and with 2g2: 1 glucosan/calcium acetate mixture is dissolved in wherein.With the solution filtration sterilization and with in the 1 milliliter every part chamber 2 that is distributed to double-chamber syringe.

The collagenase of 20 unit solid forms is packed in each chamber 1.Embodiment 2

76g water is added in the rustless steel container.Stir to add the 3g propylene glycol down and this mixture is cooled to temperature and be lower than 15 ℃.Then, under agitation add 21g polyoxyethylene/polyoxypropylene copolymer (POLOXAMER407), continue to be stirred to dissolving fully under the decompression.Mixture by polytetrafluoroethylene filter paper filtering sterilization, is joined by the liquid dispersion system then in batches and has in the plastic containers that measure applicator.

99.1g water is added in second container, 0.9g sodium chloride is dissolved in wherein.With the solution filtration sterilization and with disperse system with in every part of 1.5 milliliters of glass ampules that are distributed to as chamber 2.

85 ml waters are added in the 3rd container.The collagenase and the 5g mannitol of 5000 units under agitation are dissolved in wherein, and adding water to final volume is 100 milliliters.Join in the lyophilizing bottle of getting ready (chamber 1) with the solution filtration sterilization and with 1 milliliter every part.Carry out lyophilizing by conventional program then.Embodiment 3

76g water is added in the rustless steel container.Stir to add the 3g propylene glycol down and this mixture is cooled to temperature and be lower than 15 ℃.Then, under agitation add 21g polyoxyethylene/polyoxypropylene copolymer (POLOXAMER407), continue to be stirred to dissolving fully under the decompression.Mixture by polytetrafluoroethylene filter paper filtering sterilization, is joined by the liquid dispersion system then in batches and has in the plastic containers that measure applicator.

99.1g water is added in second container, 0.9g sodium chloride is dissolved in wherein.With the solution filtration sterilization and with disperse system with in every part of 1.5 milliliters of glass ampules that are distributed to as chamber 2.

85 ml waters are added in the 3rd container.The collagenase of 5000 units under agitation is dissolved in wherein, and adding water to final volume is 100 milliliters.Join in the lyophilizing bottle of getting ready (chamber 1) with the solution filtration sterilization and with 1 milliliter every part.Carry out lyophilizing by conventional program then.

Claims (2)

1. the system that is used for the external active substance, described active substance is to water sensitive and be difficult to gel media (Geliermittel) and admit, and this system contains:

1. hold the chamber of active substance,

2. hold the solvent that is used for the lytic activity material the chamber and

3. hold the chamber of gellant, wherein, the design of described chamber is that its inclusions is mixed rapidly.

2. the described system of claim 1, active substance wherein is a collagenase.