AU715587B2 - A drug form which is formed in situ for delivering enzymes to wounds - Google Patents
A drug form which is formed in situ for delivering enzymes to wounds Download PDFInfo
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- AU715587B2 AU715587B2 AU15442/97A AU1544297A AU715587B2 AU 715587 B2 AU715587 B2 AU 715587B2 AU 15442/97 A AU15442/97 A AU 15442/97A AU 1544297 A AU1544297 A AU 1544297A AU 715587 B2 AU715587 B2 AU 715587B2
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- Prior art keywords
- wound
- active substance
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- chamber containing
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- 206010052428 Wound Diseases 0.000 title description 37
- 208000027418 Wounds and injury Diseases 0.000 title description 37
- 102000004190 Enzymes Human genes 0.000 title description 16
- 108090000790 Enzymes Proteins 0.000 title description 16
- 229940079593 drug Drugs 0.000 title description 8
- 239000003814 drug Substances 0.000 title description 8
- 238000011065 in-situ storage Methods 0.000 title description 2
- 239000013543 active substance Substances 0.000 claims description 27
- 239000000203 mixture Substances 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 102000029816 Collagenase Human genes 0.000 claims description 11
- 108060005980 Collagenase Proteins 0.000 claims description 11
- 229960002424 collagenase Drugs 0.000 claims description 11
- 238000012876 topography Methods 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 3
- 239000003349 gelling agent Substances 0.000 claims description 2
- 235000009917 Crataegus X brevipes Nutrition 0.000 claims 1
- 235000013204 Crataegus X haemacarpa Nutrition 0.000 claims 1
- 235000009685 Crataegus X maligna Nutrition 0.000 claims 1
- 235000009444 Crataegus X rubrocarnea Nutrition 0.000 claims 1
- 235000009486 Crataegus bullatus Nutrition 0.000 claims 1
- 235000017181 Crataegus chrysocarpa Nutrition 0.000 claims 1
- 235000009682 Crataegus limnophila Nutrition 0.000 claims 1
- 235000004423 Crataegus monogyna Nutrition 0.000 claims 1
- 240000000171 Crataegus monogyna Species 0.000 claims 1
- 235000002313 Crataegus paludosa Nutrition 0.000 claims 1
- 235000009840 Crataegus x incaedua Nutrition 0.000 claims 1
- 238000007789 sealing Methods 0.000 claims 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 15
- 229940088598 enzyme Drugs 0.000 description 15
- 238000003756 stirring Methods 0.000 description 14
- 239000007788 liquid Substances 0.000 description 13
- 238000004140 cleaning Methods 0.000 description 11
- 239000000499 gel Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 238000001914 filtration Methods 0.000 description 8
- -1 polyoxyethylene Polymers 0.000 description 7
- 239000000017 hydrogel Substances 0.000 description 6
- 229920001451 polypropylene glycol Polymers 0.000 description 6
- 238000004108 freeze drying Methods 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 208000012313 wound discharge Diseases 0.000 description 5
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 4
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 235000010323 ascorbic acid Nutrition 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 4
- 239000006071 cream Substances 0.000 description 4
- 238000010410 dusting Methods 0.000 description 4
- 239000003995 emulsifying agent Substances 0.000 description 4
- 239000002674 ointment Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- 229920002307 Dextran Polymers 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 3
- 239000004809 Teflon Substances 0.000 description 3
- 229920006362 Teflon® Polymers 0.000 description 3
- 239000003708 ampul Substances 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 239000004033 plastic Substances 0.000 description 3
- 229920003023 plastic Polymers 0.000 description 3
- 229920001992 poloxamer 407 Polymers 0.000 description 3
- 229940044476 poloxamer 407 Drugs 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 229910001220 stainless steel Inorganic materials 0.000 description 3
- 239000010935 stainless steel Substances 0.000 description 3
- QCDWFXQBSFUVSP-UHFFFAOYSA-N 2-phenoxyethanol Chemical compound OCCOC1=CC=CC=C1 QCDWFXQBSFUVSP-UHFFFAOYSA-N 0.000 description 2
- CFKMVGJGLGKFKI-UHFFFAOYSA-N 4-chloro-m-cresol Chemical compound CC1=CC(O)=CC=C1Cl CFKMVGJGLGKFKI-UHFFFAOYSA-N 0.000 description 2
- 108090000317 Chymotrypsin Proteins 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- 102000016911 Deoxyribonucleases Human genes 0.000 description 2
- 108010053770 Deoxyribonucleases Proteins 0.000 description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 2
- 229930091371 Fructose Natural products 0.000 description 2
- 239000005715 Fructose Substances 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 229940027983 antiseptic and disinfectant quaternary ammonium compound Drugs 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 125000003289 ascorbyl group Chemical class [H]O[C@@]([H])(C([H])([H])O*)[C@@]1([H])OC(=O)C(O*)=C1O* 0.000 description 2
- 229960000686 benzalkonium chloride Drugs 0.000 description 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 229960004926 chlorobutanol Drugs 0.000 description 2
- 229960002376 chymotrypsin Drugs 0.000 description 2
- 229940097362 cyclodextrins Drugs 0.000 description 2
- 238000007599 discharging Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229960004756 ethanol Drugs 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000003906 humectant Substances 0.000 description 2
- 230000002779 inactivation Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 235000019426 modified starch Nutrition 0.000 description 2
- 229960005323 phenoxyethanol Drugs 0.000 description 2
- 229940067107 phenylethyl alcohol Drugs 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 229960005335 propanol Drugs 0.000 description 2
- 235000010388 propyl gallate Nutrition 0.000 description 2
- 239000000473 propyl gallate Substances 0.000 description 2
- 229940075579 propyl gallate Drugs 0.000 description 2
- 229960004063 propylene glycol Drugs 0.000 description 2
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 150000005846 sugar alcohols Chemical class 0.000 description 2
- 229930003799 tocopherol Natural products 0.000 description 2
- 239000011732 tocopherol Substances 0.000 description 2
- 125000002640 tocopherol group Chemical class 0.000 description 2
- 235000019149 tocopherols Nutrition 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 1
- 229960005147 calcium acetate Drugs 0.000 description 1
- 235000011092 calcium acetate Nutrition 0.000 description 1
- 239000001639 calcium acetate Substances 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 208000028659 discharge Diseases 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229930182490 saponin Natural products 0.000 description 1
- 150000007949 saponins Chemical class 0.000 description 1
- 235000017709 saponins Nutrition 0.000 description 1
- 239000008299 semisolid dosage form Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/4886—Metalloendopeptidases (3.4.24), e.g. collagenase
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Materials For Medical Uses (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Description
0650/01022 A drug form which is formed in situ for delivering enzymes to wounds 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 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 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 approved because the solution containing active substance is 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 forms (ointments, gels or creams) are 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 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 topography of the wound without contact and thus painlessly.
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 wound, for the abovementioned reasons, but is 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 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 2 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 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 as the temperature increases (application temperature skin temperature) and makes it possible to mix the wound-cleaning enzyme with the application base only immediately before use on the wound, it being necessary for this mixing to be possible within seconds in certain circumstances (eg. in emergency 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 Biomed. Mater. Res. 21, 1987, 1135, Pharm.
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 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.
The invention relates to a system for active substances which can be applied externally, are sensitive to water and difficult to take up in gelling agents, which comprises i. 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, 0650/01022 3 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 possible to solve in an elegant manner on the one hand the problem of the short-period incorporation of the active substance, and on the other hand its stabilization for several hours.
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 glass ampule as chamber 2 is filled with liquid. A double-chamber syringe which is filled in chamber 1 with the active substance and in chamber 2 with the liquid is 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 temperature which is appropriate for the active substance and is below room temperature. Immediately 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 syringe, is forced into chamber i, whereupon the active substance immediately dissolves. The active substance which is now present as a solution in the vial 1 or the 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 containing active substance which has been prepared in this way is distributed on the wound without contact by means of an application system on chamber 3, and the preparation optimally adapts, because of its 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 present.
Specifically suitable as gel formers are polyoxyethylene/polyoxypropylene copolymers of the formula HO(C2H40)a(C 3
H
6 0)b(C 2
H
4 0)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 4 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; 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 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: S 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, ascorbates, tocopherols and derivatives thereof, propyl gallate, BHA or BHT; S 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; emulsion stabilizers such as nonionic emulsifiers, amphoteric emulsifiers, cationic emulsifiers and anionic emulsifiers.
It is possible to use as active substance, for example, wound-cleaning enzymes such as chymotrypsin or deoxyribonuclease, 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 [sic], 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 because of their instability in aqueous solution, into a form which is reasonably stable and can be applied simply and rapidly.
0650/01022 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 discharge, the side, which is in contact with 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 easily diffuse out of this into the 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 cooled to T 15 0 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 is sterilized by filtration through a Teflon filter and dispensed by a liquid dispensing system in portions into plastic containers 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 solution is sterilized by filtration and dispensed in 1 ml portions in a dispensing system into chamber 2 of double-chamber syringes.
units of collagenase in solid form are packed into each of the remaining chambers i.
Example 2 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 0 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 is sterilized by filtration through a Teflon filter and dispensed by a liquid dispensing system in portions into plastic containers with fitted metering applicator.
0650/01022 6 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.
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 introduced into prepared lyophilization vials (chamber 1).
Lyophilization is then carried out by a standard program.
Example 3 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 0 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 is sterilized by filtration through a Teflon filter and dispensed by a liquid dispensing system in portions into plastic containers with fitted metering applicator.
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 Lyophilization is then carried out by a standard program.
Claims (4)
1. A system of active substances which are applied externally, are sensitive to water and difficult to take up in gelling agents, which includes: a. a chamber containing the active substance including collagenase, b. a chamber containing a solvent in which the active substance dissolves, and c. a chamber containing a gel former, where the chambers are designed so that'their contents are mixed together rapidly to form a mixutre for immediate application without contact to the surface of an external wound, the mixture adapting to the surface topography of the wound. to:
2. A system of active substances according to claim 1 and as herein O "described with reference to the examples.
3. A method of applying an active substance to an external wound using the system of claim 1, including the steps of adding the active substance to the solvent in which the active substance dissolves to form a solution, t rapidly adding the solution to the gel former to form a mixture, immediately applying the mixture without contact to the surface of an external wound, the mixture adapting to the topography of the wound and subsequently solidifying and simultaneously sealing the external wound. 8
4. A method according to claim 3 and as herein described with reference to the examples. DATED this 21st day of September 1999 KNOLL AKTIENGESELLSCHAFT WATERMARK PATENT TRADEMARK ATTORNEYS 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA LCG:cLR:VRH DOC 28 AWl 544297.wPc
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19602208 | 1996-01-23 | ||
| DE19602208A DE19602208A1 (en) | 1996-01-23 | 1996-01-23 | Pharmaceutical form formed in situ for the delivery of enzymes to wounds |
| PCT/EP1997/000284 WO1997026861A1 (en) | 1996-01-23 | 1997-01-22 | Medicament forms constituted in situ for releasing enzymes into wounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU1544297A AU1544297A (en) | 1997-08-20 |
| AU715587B2 true AU715587B2 (en) | 2000-02-03 |
Family
ID=7783390
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU15442/97A Ceased AU715587B2 (en) | 1996-01-23 | 1997-01-22 | A drug form which is formed in situ for delivering enzymes to wounds |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP0876139A1 (en) |
| JP (1) | JP2001518063A (en) |
| KR (1) | KR19990081901A (en) |
| CN (1) | CN1209739A (en) |
| AU (1) | AU715587B2 (en) |
| BR (1) | BR9707058A (en) |
| CA (1) | CA2243528A1 (en) |
| CZ (1) | CZ230198A3 (en) |
| DE (1) | DE19602208A1 (en) |
| HU (1) | HUP9900942A3 (en) |
| IL (1) | IL125148A (en) |
| NO (1) | NO983373L (en) |
| WO (1) | WO1997026861A1 (en) |
| ZA (1) | ZA97514B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2194144A (en) * | 1986-08-22 | 1988-03-02 | American Cyanamid Co | Therapeutic gels |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5580856A (en) * | 1994-07-15 | 1996-12-03 | Prestrelski; Steven J. | Formulation of a reconstituted protein, and method and kit for the production thereof |
-
1996
- 1996-01-23 DE DE19602208A patent/DE19602208A1/en not_active Withdrawn
-
1997
- 1997-01-22 CN CN97191838A patent/CN1209739A/en active Pending
- 1997-01-22 HU HU9900942A patent/HUP9900942A3/en unknown
- 1997-01-22 JP JP52653297A patent/JP2001518063A/en active Pending
- 1997-01-22 CA CA002243528A patent/CA2243528A1/en not_active Abandoned
- 1997-01-22 EP EP97901581A patent/EP0876139A1/en not_active Withdrawn
- 1997-01-22 BR BR9707058A patent/BR9707058A/en unknown
- 1997-01-22 AU AU15442/97A patent/AU715587B2/en not_active Ceased
- 1997-01-22 ZA ZA97514A patent/ZA97514B/en unknown
- 1997-01-22 WO PCT/EP1997/000284 patent/WO1997026861A1/en not_active Application Discontinuation
- 1997-01-22 KR KR1019980705613A patent/KR19990081901A/en not_active Application Discontinuation
- 1997-01-22 CZ CZ982301A patent/CZ230198A3/en unknown
- 1997-01-22 IL IL12514897A patent/IL125148A/en not_active IP Right Cessation
-
1998
- 1998-07-22 NO NO983373A patent/NO983373L/en not_active Application Discontinuation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2194144A (en) * | 1986-08-22 | 1988-03-02 | American Cyanamid Co | Therapeutic gels |
Also Published As
| Publication number | Publication date |
|---|---|
| HUP9900942A3 (en) | 2000-06-28 |
| CA2243528A1 (en) | 1997-07-31 |
| BR9707058A (en) | 1999-07-20 |
| CN1209739A (en) | 1999-03-03 |
| DE19602208A1 (en) | 1997-07-24 |
| KR19990081901A (en) | 1999-11-15 |
| WO1997026861A1 (en) | 1997-07-31 |
| NO983373L (en) | 1998-09-21 |
| IL125148A (en) | 2001-03-19 |
| JP2001518063A (en) | 2001-10-09 |
| HUP9900942A2 (en) | 1999-08-30 |
| EP0876139A1 (en) | 1998-11-11 |
| ZA97514B (en) | 1998-07-22 |
| AU1544297A (en) | 1997-08-20 |
| IL125148A0 (en) | 1999-01-26 |
| NO983373D0 (en) | 1998-07-22 |
| CZ230198A3 (en) | 1999-02-17 |
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Legal Events
| Date | Code | Title | Description |
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| FGA | Letters patent sealed or granted (standard patent) | ||
| MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |