Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
  • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
  • B65D23/00—Details of bottles or jars not otherwise provided for
  • B65D23/08—Coverings or external coatings
  • B65D23/0807—Coatings
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
  • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
  • B65D23/00—Details of bottles or jars not otherwise provided for
  • B65D23/08—Coverings or external coatings
  • B65D23/0807—Coatings
  • B65D23/0814—Coatings characterised by the composition of the material
  • B65D23/0821—Coatings characterised by the composition of the material consisting mainly of polymeric materials

Definitions

• the invention relates to safety containers for biologically active substances, in particular cytotoxic substances, with increased or high resistance to breakage and splintering as well as a contamination-free outer surface, a method for the production thereof, and the use of a medium which contains at least one polymer for decontaminating the outer surface a container filled with a biologically active substance, sealed and possibly labeled.
• Bioly active substances are used every day in all areas of life.
• the use of pharmaceuticals in human and veterinary medicine or of crop protection agents such as herbicides, fungicides and insecticides in crop protection are particularly worth mentioning here.
• the fields of application of biologically active substances in human and veterinary medicine are, for example, the therapy of diseases, such as the chemotherapy of tumor diseases through the administration of cytostatics, the diagnosis of diseases and hereditary systems (for example as a substrate for enzyme reactions), analysis (for example as Reference substances) and genetic engineering (e.g. for the selection of cell lines).
• cytostatics must be administered to the patient by injection or infusion. Numerous people, such as pharmacists, doctors, nurses and nursing staff, are involved in the preparation and implementation of such administrations for inpatient treatment in hospitals or outpatient treatment in specialized medical practices.
• the pharmaceutical industry must ensure that no traces of the biologically active substance, for example the cytotoxic substance, adhere to the outer surface of the container after the packaging process or that they are only present in an inactive form that no longer pollutes the environment.
• the biologically active substance for example the cytotoxic substance
• the packaging unit for example the injection bottle (vial) containing the biologically active substance, such as a cytotoxic substance
• a washing medium preferably a washing solution.
• traces of the order of a few ng of the biologically active substance per vial can still be detected after the washing process.
• a common limit is, for example, ⁇ 1 ⁇ g per injection bottle.
• the packaging unit has been covered in the prior art with a "sleeve” or "clear cylindrical shrink-wrap film” made of plastic proposed.
• the disadvantage of this method is that the packaging unit or the container is covered by the "sleeve" only on the sides and not on the underside.
• Another disadvantage is that the production must be carried out at temperatures above room temperature. This can impair the purity, shelf life, effectiveness and the visual appearance of temperature-sensitive substances.
• Another disadvantage is that a separate "sleeve" must be adapted for different dimensions (height, width, depth) and shape of the packaging unit. This makes the production time and cost intensive.
• the Doxorubicine preparation from Faulding Asta Medica is a practical example of a sleeve insert.
• the second solution to the problem described in the prior art is to wrap the packaging unit with a second packaging, for example made of plastic.
• a suitable "overpack" must be made depending on the size of the packaging unit.
• the overall packaging becomes very voluminous and bulky.
• the handling is also complicated: The people handling the packaging unit (e.g. pharmacist, doctor, nursing staff) first have to open the outer packaging in order to be able to access the packaging unit in the first place. Furthermore, the opening process represents an additional source of danger for the protective equipment (e.g. tear-sensitive gloves) of the handling personnel.
• the protective equipment e.g. tear-sensitive gloves
• containers that are filled with a biologically active substance must have a high resistance to breakage and splintering.
• the breaking strength of the container containing the biologically active substance depends on the one hand on the material of the container.
• Containers made of plastic are usually more break-proof than containers made of glass. Compared to glass, however, plastic has the disadvantage that it ages more quickly (material fatigue), that it can react with the biologically active or other ingredients to chemical and / or physical reactions or contaminate them (e.g. due to the release of plasticizers from the plastic) and that In contrast to glass, it is difficult for certain plastics to be shaped into the desired shaped articles.
• the splinter resistance depends, for example, on the elasticity and the brittleness of the material of the molded body or container.
• Containers made of plastic usually have an increased resistance to splintering compared to containers made of glass. Due to the higher elasticity, plastic absorbs more impact or impact energy.
• the resistance to breakage and splintering must also be present during the transport of the containers, usually in a larger container.
• the safety container and packaging e.g. a cardboard box or plastic material, e.g. Styropor ®
• the safety container and packaging e.g. a cardboard box or plastic material, e.g. Styropor ®
• there should be increased resistance to breakage and splintering so that a suitable packaging can be adapted. Breakage and splinter resistance is particularly preferred in the event that the security containers come into contact with one another, since then a simpler and therefore less expensive and more space-saving packaging can be selected.
• safety containers for biologically active substances with increased or high resistance to breakage and splintering as well as contamination-free outer surface can be obtained by completely or partially coating the outer surface of the filled, closed and, if necessary, labeled container by the treatment has been applied with a medium which contains at least one polymer.
• the term “wholly or partially” is to be understood to mean that preferably all of the container areas relevant for stability or contamination are coated.
• the container eg glass vial
• the top neck area of the container could only be partially coated, with the top neck area of the The container remains uncoated, which is unproblematic if this part of the container never bursts and it does not belong to the handle area either, so that contamination of the container possibly remaining in this uncoated area has no consequences based on the present disclosure of the invention and the circumstances that may need to be added (for example the degree of toxicity of the substance to be filled) within the scope of his routine work.
• a filled, closed and possibly labeled safety container for biologically active substances with increased or high resistance to breakage and splintering and contamination-free outer surface the container being a hollow body with at least one opening, one closure per opening, if necessary comprises a label and at least one biologically active substance filled in the hollow body, characterized in that a coating has been applied in whole or in part to the filled, closed and possibly labeled container.
• a security container is provided which has been provided with a label before the coating is applied.
• a safety container which has been treated with a washing medium before the application of the coating to the filled, closed and possibly labeled container.
• a security container according to one of the above aspects and embodiments, characterized in that the coating takes place at room temperature, is provided.
• the safety container according to the invention is therefore particularly suitable as a packaging container for temperature-sensitive, biologically active substances.
• a security container according to one of the above aspects and embodiments, characterized in that the coating has been applied completely or almost completely to the container, is provided.
• a security container according to one of the above aspects and embodiments, characterized in that the container is made of glass, plastic or glass coated with plastic on the inside or outside, is provided.
• Suitable types of glass are, for example, glass types I - III. Glass type I can be used for liquid products and glass type III for solids, for example. The nature of the types of glass is described in USP and EP (USP 26 - 2003; Chapter 661 Containers; Pages 2142 - 2145 // EP 4th edition: Grundtechnik 2002; Chapter 3.2 Containers; Pages 331 - 335).
• Suitable plastics are, for example, polyethylene, polypropylene, polyvinyl chloride and Topas® (cycloolefin copolymer from Ticona).
• a security container according to one of the above aspects and embodiments is characterized in that it comprises at least one closure, e.g. consisting of a rubber stopper and a crimp cap or an alternative closure system.
• at least one closure e.g. consisting of a rubber stopper and a crimp cap or an alternative closure system.
• Rubber stopper and Bioset® Rubber washer and crimp cap; Closure systems from Becton & Dickinson, melting glass with or without predetermined breaking point.
• a security container according to one of the above aspects and embodiments is characterized in that the designation is a designating surface, preferably a labeled label (label) made of paper and / or plastic.
• a safety container according to one of the above aspects and embodiments, characterized in that the biologically active substance has a liquid, solid or amorphous state of aggregation at room temperature.
• Suitable biologically active substances or materials can be, for example, the substances mentioned below (in alphabetical order according to the Red List 2002):
• Bacampicillin Bacillus cereus, Bacillus firmus, Bacillus IP 5832, Bacillus subtilis, Bacitracin, Baclofen, bearberry, club moss, wild garlic, bacterial autolysate, valerian, valerian oil, balloon vine, balsamic cucumber, bambuterol, bamethane, bamipin, disc, barium carbonate, barium acetate , Barium sulfate, beard lichen, basil, basiliximab, tree lichen, tree sponge, becaplermin, beclometasone, comfrey, bemeticide, benazepril, bencyclan,
• Clostridium histolyticum collagenase Clotrimazol, Clozapin, Co-carboxylase, Cochenillelaus, Cocosbutter, Cocospropylendiaminguadinium, Cocospropylenediaminguaniacetat, Codeine, Codeincamphersulfonat, Codonopsis, Coenzyme A, Caffeine, Colchicololinolate, Col. Colchicolol, Col. Col.
• Fabian herb Fabian herb, famciclovir, famotidine, fango, faulbaum, febuprol, fig, felbamat, felbinac, felodipine, felypressin, fennel, fenchone, fendiline, fenetylline, fenipentol, fenofibrate, fenoterol, fentanyl, fenticonazole, fats, essexadilinole, ferumoxadilinole, ferucoxotilinole, ferucoxotilinole, ferucoxotinilene, ferucoxotiline, ferucoxotinilene, ferucoxotilinole, ferucoxotinilene, ferucoxotinilene, ferucoxotinilene, ferucoxot
• Hydroxyprogesterone caproat hydroxyzine, hyetellose, hymecromon, hyoscyamus, pituitary, hypromellose
• Ibandronic acid ibuprofen, icodextrin, idarubicin, idoxuridine, ifosfamide, ignatia, lloprost, imidapril, imiglucerase, imipenem, imipramine,
• Levetiracetam Levobunolol, Levocabastin, Levocarnitin, Levocetirizine, Levodopa, Levofloxacin, Levoglutamid, Levomenol, Levomenthol, Levomepromazin, Levomethadon, Levonorgestrel, Levothyroxine, Levothyroxin sodium, Lidocaine, Linodinole, Linodinole, Linodinole, Linodinol, Linodinol, Linodinol, Linodin, 12,12 ; -Liponic acid, ( ⁇ ) - & a!
• Piperonyl butoxide Pipoxolan, Piprinhydrinat, Piracetam, Pirenoxin, Pirenzepin, Piretanid, Piribedil, Piritramid, Piroxicam, Pizotifen, Placenta, Plasmafibronectin, Plasma proteins, human, Plasma protein, human with factor VIII inhibitor, bypass activity, with human factor VIII correcting factor VIII plasma protein Plasma protein, animal, platinum, platinum chloride,
• Rabeprazole [224Ra] radium chloride, tansy, raloxifene, ramipril, ranitidine, rasburicase, ratanhia, rhombus, rauwolfia, rauwolfia vomitoria, Rebendolde, partridge berry, reboxetine, remifentanil, repaglinide, reproterol, reserpine, resorcinol, retrinatrinase n , Rhubarb, rhododendron, ribavirin, riboflavin, riboflavin-5'-phosphate, ribonucleic acid, rifabutin, rifampicin, riluzole, rimexolone, marigold, risedronic acid, risperidone, ritonavir, rituximab, rizatrizolinidirin, rizatriptan
• Valaciclovir valine, valproic acid, valsartan, vanadium, vancomycin, varicella viruses, petroleum jelly, white, vecuronium bromide, venlafaxine, verapamil, verteporfin, vigabatrin, viloxazin, vinblastine, vincamine, vincristine, vindesin, vinorelbin, knot
• Suitable biologically active substances or materials are: Mafosfamid, BNP 7787, D-63153, D-24851, D-70166, D-64131, Cematodin LU 103793, LU 223651, A-299620, Onconas® Ranpinase, ZD-6126 (ANG-453), BMS-188797, BMS -275183, BMS-247550, Paclitaxel polyglutamate CT-2103 / Xyotax, E- 7070 ER-35744, ABT-751 / E-7010, Cryptophycin 52 LY-355703, LY-290293, Rhizoxin, Anhydrovinblastin, Cantuzumabmertansine HuC SB-408075, HuN901-DM1, MLN-591 DM1, N ° 6529, IDN-5109, Vincristin Inex, Vinca Alkoloids, Vincristine Alza, Dolastatin 10, Combrestatin A-4, Oxi-COM-102, ET
• a security container according to one of the above aspects and embodiments, characterized in that the biologically active substance is a cytotoxic substance, is provided.
• Cytotoxic or generally cytotoxic substances in the sense of the invention are in particular cytostatics (cytostatics; chemotherapeutics for the treatment of cancer), metastasis inhibitors and other antineoplastic agents.
• cytostatics cytostatics; chemotherapeutics for the treatment of cancer
• metastasis inhibitors and other antineoplastic agents.
• Suitable biologically active substances are also protective agents such as Mesna or BNP7787.
• Suitable cytotoxic substances or protective agents can also be the substances mentioned below:
• biologically active substances are: inorganic and organic active substances, inorganic or organic toxins, vaccines, viruses, bacteria, vectors
• Vaccines hepatitis, rubella, diphtheria, polio, smallpox, tetanus, cholera, measles,
• Cytostatics organic: cyclophosphamide, fluorouracil, cisplatin, ifosfamide,
• Trofosfamide carmustine, lomustine, vinblastine, vincristine, vindesine, vinorelbine, etoposide, teniposide, nimustine, mitoxantrone, methotrexate, oxaliplatin, taxol,
• Appendix A-IV Sublist D Streptomyces griseus Streptomyces cyaneus Streptomyces venezuelae
• Sublist E One way transfer of Streptococcus mutans or Streptococcus lactis DNA to Streptococcus sanguis
• This appendix contains such biological agents or agents that are known to be human and selected animal agents that pose a theoretical risk when inoculated with humans. Are attached Lists of representative genera and species known to be pathogenic.
• RG1 Risk Group 1
• RG2 Risk group 2 agents which are associated with human diseases, which are rarely serious and for which preventive or therapeutic interventions are often available.
• Risk group 3 agents which are associated with serious and fatal diseases for which preventive or therapeutic interventions may be available (high individual risk but low community risk).
• Risk group 4 agents that are likely to cause serious and fatal human diseases for which preventive or therapeutic interventions are usually not available (high individual risk and high community risk)
• RG1 agents are not associated with diseases in healthy adult humans.
• RG1 agents include: asporogenic Bacillus subtilis or Bacillus licheniformis (see Appendix C-IV-A, Bacillus subtilis or Bacillus licheniformis host-vector systems, exceptions); Adeno-associated virus (AAV) types 1 to 4; and
• AAV constructs in which the transgene does not code for either a potential tumorigenic gene product or a toxin molecule and which are produced in the absence of the helper virus.
• a strain of Escherichia coli see below.
• Appendix C-Il-A Escherichia co // K-12 Host Vector Systems, Exceptions
• an active virulence factor e.g., toxins
• RGs risk groups 2, 3 and 4
• RGs risk groups 2, 3 and 4
• a risk assessment must be made based on their known or potential properties and their relationships with the listed agents.
• RG2 Agents that are associated with human diseases that are rarely serious and for which preventive or therapeutic interventions are often available.
• M. avium complex except those listed in Appendix B-Ill-A (RG3)
• M. avium complex including M. asiaticum, M. bovis BCG vaccine strain, M. chelonei, M. fortuitum, M. kansasii, M. leprae, M. malmoense, M. marinum, M. paratuberculosis, M. scrofulaceum, M. simiae, M. szulgai, M. ulcerans, M. xenopi
• -Salmonella including S. arizonae, S. cholerasuis, S. enteritidis, S. gallinarum-pullorum, S. meleagridis, S. paratyphi, A, B, C, S. typhi, S. typhimu um
• Streptococcus including S. pneumoniae, S. pyogenes
• E. -Echinococcus including E. granulosis, E. multilocularis, E. vogeli
• Leishmania including L. braziliensis, L. donovani, L. ethiopia, L. major, L. mexicana, L. peruvania, L. tropica
• N. americanus -Onchocerca filaria worms including, O. volvulus
• T. brucei brucei T. brucei gambiense
• T. brucei rhodesiense T. cruzi -Wuchereria bancrofti filaria worms
• RG2 Viruses Adenoviruses, human - all types Alphaviruses (Togaviruses) - Group A Arboviruses -Eastern equine encephalomyelitis virus -Venezuelan equine encephalomyelitis vaccine strain TC-83 --Western equine encephalomyelitis virus Arenaviruses (lymphocytic virus) lymphocytic virus non-lymphocytic virus-lomenocytic virus-lomenocytic virus-lomenocytic virus-lomenocytic virus -lomino virus virus strains)
• Coronaviruses Flaviviruses (Togaviruses) - Group B Arboviruses
• Poxviruses - all types except Monkeypox virus see Appendix B-III-D,
• RG3 Risk group 3 (RG3) - viruses and prions) and restricted poxviruses including Alastrim, Smallpox, and Whitepox
• Reoviruses all types including coltivirus, human rotavirus, and orbivirus
• Togaviruses see Alphaviruses and Flaviviruses.
• RG3 agents associated with serious and fatal diseases for which preventive or therapeutic interventions may be available (high individual risk but low community risk).
• RG2 Risk group 2 - bacterial agents including Chlamydia), M. tuberculosis -Pasteurella multocida type B - "buffalo” and other virulent strains
• Alphaviruses (Togaviruses) - Group A Arboviruses - Semliki Forest virus
• LCM -Lymphocytic choriomeningitis virus
• Flaviviruses (Togaviruses) - Group B arboviruses
• TAE Transmissible spongioform encephalopathies
• Retro viral human immunodeficiency virus (HIV) types 1 and 2 are retro viral human immunodeficiency virus (HIV) types 1 and 2
• HTLV Human T cell lymphotropic virus
• Flaviruses (Togaviruses) - Group B arboviruses
• Herpes virus simiae Herpes B or Monkey B virus
• animal etioiogical agents is attached to the list of human etioiogical agents. None of the agents are associated with diseases of healthy adult people. They are usually used for laboratory experiments. Certain agents, e.g. amphotropic and xenotropic strains of murine leukemia virus, can infect human cells.
• Murine retroviral vectors are used for human transfer experiments
• a security container according to one of the above aspects and embodiments is characterized in that the cytotoxic substance from the group consisting of ifosfamide, cyclophosphamide, trofosfamide, mafosfamide, acridine derivatives is filed in accordance with international patent application No. PCT / US98 / 532 on January 6, 1998 (WO 98/30545), such as the compound S303 ( ⁇ -alanine-N-acridin-9-yl-2 [bis (2-chloroethyl) amino] ethyl ester) described there on pages 32-40, mitoxantrone, LHRH agonists, LH-RH antagonists such as e.g.
• PCT / EP97 / 04474 filed on August 16, 1997
• PCT / EP99 / 01918 filed on March 22, 1999
• PCT / EP00 / 09390 filed on September 26, 2000
• the tubulin inhibitor D-24851 N-pyridyl-4-yl) - [1- (4-chlorobenzyl) indol-3-yI] -glyoxylamide), glufosfamide, mesna (for example as a protective agent) and BNP7787 (Dimesna, 2,2'-dithio-bis-ethane sulfonates (for example as disodium salt) (for example as a protective agent) has been provided.
• a security container according to one of the above aspects and embodiments is characterized in that the coating is carried out by the steps i) treating the filled, closed and optionally marked container with a medium which contains at least one polymer, and ii) subsequently Drying of the container treated with the medium has been provided.
• a safety container according to one of the above aspects and embodiments, characterized in that the treatment has been carried out by spraying, is provided.
• a security container according to one of the above aspects and embodiments is characterized in that the spraying has been carried out by using shear forces (eg using a nozzle) and / or using centrifugal forces (eg using a turntable).
• a security container according to one of the above aspects and embodiments, characterized in that the treatment has been carried out by immersion, is provided. According to a further embodiment, a security container according to one of the above aspects and embodiments, characterized in that the treatment is carried out by Application of a powder (powder) has been provided.
• a security container according to one of the above aspects and embodiments is characterized in that the medium containing at least one polymer from the group consisting of powder powder), dispersion, emulsion, suspension, solution and multicomponent systems (for example two- or three-component systems ; the individual components are only brought together shortly before application).
• the medium containing at least one polymer from the group consisting of powder powder), dispersion, emulsion, suspension, solution and multicomponent systems (for example two- or three-component systems ; the individual components are only brought together shortly before application).
• a security container according to one of the above aspects and embodiments, characterized in that the polymer has been selected from the group consisting of polyurethane, polyester and polyester-polyurethane mixtures.
• a method for producing a filled, closed and, if appropriate, labeled security container for biologically active substances with increased or high resistance to breakage and splintering as well as contamination-free outer surface the container being a hollow body with at least one opening, one each Closure per opening, possibly a label, and at least one biologically active substance filled in the hollow body and wherein on the outside of the filled, closed and, if necessary, marked container, one or all of them Coating has been applied, characterized by the steps i) treating the filled, closed and optionally labeled container with a medium which contains at least one polymer, and ii) drying the container treated with the medium.
• the procedure is simple to carry out.
• a particular advantage is that the method according to the invention can be adapted to all common container shapes and sizes in a simple and quick manner. This results in no or only short set-up times, which is why shorter or no machine downtimes, no or lower storage costs for format parts and overall lower manufacturing costs per safety container.
• a method according to the above-mentioned aspect of the present invention is provided, characterized in that, prior to treatment, the filled, closed and optionally labeled container with a washing medium (for example, water for injection purposes (WFI) or, if WFI is not is required, water of a lower water quality can also be used) is provided.
• a washing medium for example, water for injection purposes (WFI) or, if WFI is not is required, water of a lower water quality can also be used
• a method according to one of the above-mentioned aspects and embodiments characterized in that the treatment takes place at about room temperature (for example 20 ° C.-25 ° C.).
• a method is provided according to one of the above-mentioned aspects and embodiments, characterized in that the drying takes place at about room temperature (for example 20 ° C.- 25 ° C.).
• a method according to one of the above-mentioned aspects and embodiments, characterized in that the coating is applied completely or almost completely to the container, is provided.
• a security container according to one of the above aspects and embodiments, characterized in that the container is made of glass, plastic or glass coated with plastic on the inside or outside, is provided.
• Suitable types of glass are e.g. glass types I - III.
• Glass type I can be used for liquid products and glass type III for solids, for example.
• the nature of the glass types is described in USP (USP 26 - 2003; Chapter 661 Containers; Pages 2142 - 2145) and EP (EP 4th edition: Grundtechnik 2002; Chapter 3.2 Containers; Pages 331 - 335).
• the size of the containers used can vary within a wide range from very small to very large containers.
• Suitable plastics are, for example, polyethylene, polypropylene, polyvinyl chloride and Topas® (cycloolefin copolymer from Ticona).
• the requirements for plastic containers are described in the USP and EP (USP 26 - 2003; Chapter 661 Containers; Pages 2142 - 2143; 2145 - 2148; EP 4th Edition; Grundtechnik 2002; Chapter 3.2 Containers; Pages 331; 335 - 343).
• the size of the containers used can vary within a wide range from very small to very large containers.
• a method is characterized according to one of the above-mentioned aspects and embodiments, that it comprises at least one closure, for example consisting of a rubber stopper and a crimp cap, or of an alternative closure system.
• Rubber stopper and Bioset® Rubber washer and crimp cap; Becton & Dickinson closure systems; Melting glass with or without a predetermined breaking point.
• a method is provided according to one of the above-mentioned aspects and embodiments, characterized in that the marking or designation is a marked or designating surface, preferably a labeled label (label) made of paper and / or plastic.
• a method is provided according to one of the above-mentioned aspects and embodiments, characterized in that the biologically active substance has a liquid, solid or amorphous state of aggregation at room temperature.
• a method according to one of the above-mentioned aspects and embodiments, characterized in that the biologically active substance is a cytotoxic substance, is provided.
• Suitable biologically active substances or materials cytotoxic substances are those as detailed above.
• a method according to one of the above-mentioned aspects and embodiments is characterized in that the cytotoxic substance from the group consisting of ifosfamide, cyclophosphamide, trofosfamide, mafosfamide, S303, mitoxantrone, an LHRH antagonist such as D-63153, Mesna (e.g. as a protective agent), BNP7787 (e.g. as a protective agent) and glufosfamide has been provided.
• Suitable cytotoxic substances are those as detailed above.
• a method according to one of the above-mentioned aspects and embodiments, characterized in that the treatment has been carried out by spraying, is provided.
• a method is characterized according to one of the above-mentioned aspects and embodiments, characterized in that the spraying has been carried out by using shear forces (for example using a nozzle) and / or using centrifugal forces (for example using a turntable) ,
• a method according to one of the above-mentioned aspects and embodiments, characterized in that the treatment has been carried out by immersion, is provided.
• a method is provided according to one of the above aspects and embodiments, characterized in that the treatment is carried out by applying a powder.
• a method according to one of the above-mentioned aspects and embodiments is characterized in that the medium containing at least one polymer from the group consisting of powder, dispersion, emulsion, suspension, solution and multicomponent systems (for example two- or three-component systems; the individual components are only brought together shortly before application).
• the medium containing at least one polymer from the group consisting of powder, dispersion, emulsion, suspension, solution and multicomponent systems (for example two- or three-component systems; the individual components are only brought together shortly before application).
• a method according to one of the above-mentioned aspects and embodiments, characterized in that the polymer has been selected from the group consisting of polyurethane, polyester and polyester-polyurethane mixtures, is provided.
• a safety container for biologically active substances with increased or high resistance to breakage and splintering and contamination-free outer surface which can be produced according to the method according to one of the above-mentioned aspects and embodiments, is provided.
• a medium which contains at least one polymer for the treatment of a filled, sealed and optionally labeled container for biologically active substances the container having a hollow body provided with at least one opening, one closure each Includes opening, a designation and at least one biologically active substance filled in the hollow body and wherein the treatment with the medium a coating is applied to the outside of the filled, closed and optionally labeled container provided.
• the coating can be carried out in a single or multiple work steps.
• the multiple coating can take place simultaneously with the first coating, after application and before the drying of the first layer or after the application and drying of the first layer. What has just been said applies accordingly to the application of a third or further layer.
• the properties of the layers can be different, for example the adhesiveness of the layer applied first to the container material can be particularly advantageous and the second layer can have a particularly advantageous abrasion resistance.
• the person skilled in the art will adjust the properties of the individual layers in such a way that the properties of the security container according to the invention are particularly advantageous.
• the use of a medium which contains at least one polymer is used for the decontamination of the Outer surface and / or increase in the breaking and splintering strength of a container filled with a biologically active substance, sealed and possibly labeled, for biologically active substances, the container having a hollow body provided with at least one opening, one closure per opening, one designation and at least one comprises a biologically active substance filled in the hollow body and the decontamination is carried out by applying a coating to the outside of the filled, closed and, if appropriate, labeled container.
• the use according to one of the above-mentioned aspects and embodiments characterized in that the filled, closed and optionally labeled container is treated with a washing medium (usually WFI water) before the treatment.
• a washing medium usually WFI water
• the washed containers are then preferably dried under air or nitrogen flows. A visual inspection for complete drying is usually carried out. Extensive drying is a prerequisite for subsequent labeling. If the coating is applied before the label is applied, small amounts of residual WFI water do not interfere with the use of water-soluble polymer coatings.
• the use is provided according to one of the above-mentioned aspects and embodiments, characterized in that the treatment takes place at about room temperature (for example 20 ° C.- 25 ° C.).
• the use is provided according to one of the above-mentioned aspects and embodiments, characterized in that the drying takes place at about room temperature (for example 20 ° C.- 25 ° C.).
• the use according to one of the above-mentioned aspects and embodiments is thereby characterized that the coating is applied completely or almost completely on the container.
• the use is provided according to one of the above-mentioned aspects and embodiments, characterized in that the container is made of glass, plastic or glass coated with plastic on the inside or outside.
• suitable materials are the following plastics: Topas®, which is the brand name for cycloolefin copolymers (amorphous thermoplastics) from Ticona, polypropylene, HD and LD polyethylene, polyvinyl chloride.
• container types and shapes are suitable, for example: injection bottle for single or multiple withdrawal, infusion bottle or bag, ampoule, cartridge or molded syringe body.
• the use according to one of the above-mentioned aspects and embodiments is characterized in that it comprises at least one closure, e.g. consisting of a rubber stopper and a crimp cap or an alternative closure system.
• at least one closure e.g. consisting of a rubber stopper and a crimp cap or an alternative closure system.
• adapter systems e.g. Bioset Luer, Bioset Infusion (Baxter).
• the use according to one of the above-mentioned aspects and embodiments is characterized in that the marking or designation is an indicative surface, preferably a labeled label (label) made of paper and / or plastic.
• a labeled label label
• Other suitable markings or designations are: Direct printing, for example in the screen printing process.
• the label can be printed both iri-line in the labeling machine (white line technology) and off-line at the label manufacturer.
• the use is provided according to one of the above-mentioned aspects and embodiments, characterized in that the biologically active substance has a liquid, solid or amorphous state of aggregation at room temperature.
• Suitable forms of the biologically active substance are, for example: lyophilisate with or without additives, crystals with or without additives, solution for injection, powder, shaped bodies (rods) for implantation (polylactic acid)
• the use according to one of the above-mentioned aspects and embodiments, characterized in that the biologically active substance is a cytotoxic substance, is provided.
• the use according to one of the above-mentioned aspects and embodiments is characterized in that the cytotoxic substance from the group consisting of ifosfamide, cyclophosphamide, trofosfamide, mafosfamide, S303, mitoxantrone, LHRH antagonists, mesna (eg as a protective agent) , BNP7787 (eg as a protective agent) and glufosfamide has been provided.
• the use according to one of the above-mentioned aspects, and embodiments is characterized in that the spraying by using shear forces (for example using a nozzle) and / or use of centrifugal forces (eg use of a turntable) has been provided.
• the use according to one of the above aspects and embodiments, characterized in that the treatment is carried out by applying a powder, is provided.
• the powder can be applied, for example, by electrostatic spraying.
• the use according to one of the above-mentioned aspects and embodiments is characterized in that the medium comprising at least one polymer from the group consisting of powder, dispersion, emulsion, suspension and, solution and multicomponent systems (for example two- or three-component systems; the individual components are only brought together shortly before application).
• the medium comprising at least one polymer from the group consisting of powder, dispersion, emulsion, suspension and, solution and multicomponent systems (for example two- or three-component systems; the individual components are only brought together shortly before application).
• the use according to one of the above-mentioned aspects and embodiments is characterized in that at least one polymer which is contained in the medium has been selected from the group consisting of polyurethane, polyester and polyester-polyurethane mixtures, provided.
• polystyrenes polyethylenes, polypropylenes, acrylic copolymers, polycarbonates, poly (methyl) methacrylates, epoxy resins, butadiene copolymers, polyolefins, acrylic resins, methacrylic resins, ethylene-vinyl acetate copolymers, vinyls, vinyl chlorides, polyvinylidene chlorides (polyvinylidenes) Chlorides), polyamides, ionomeric polyamides, acrylonitrile, acrylonitrile Butadiene-styrene resins, and mixtures thereof.
• the medium which contains at least one polymer, can contain additives such as, for example, inorganic (pigments) or organic dyes or light protection factors against visible and / or UV light (thereby additional light protection effect).
• additives such as, for example, inorganic (pigments) or organic dyes or light protection factors against visible and / or UV light (thereby additional light protection effect).
• Other additives alone or in combination with the aforementioned additives, in a suitable amount in each case, catalysts for the polymerization of components, anti-foaming agents (defoaming agents), flow and filling agents (flow and leveling agents), rheology modifiers (rheology modifiers), Be photostabilizers (photostabilizers) or combinations thereof.
• the coated containment should preferably meet one, some, or all of the following properties / criteria:
• the coating should also be checked for freedom from bubbles. Air bubbles in the coating reduce the protective function
• a haptic check can be used to check whether the bottle is not too rough and whether it sticks to the tester's hand or glove.
• the coating should be as smooth as the surface of the container and must not stick anywhere later during handling.
• Puncture resistance or splinter protection and breaking strength The impact resistance of the security container can be checked using a drop test in accordance with DIN 55441-2 (free fall). Breaking strength and splinter protection are particularly important criteria Lubricity (important for further processing)
• the friction behavior can be checked by determining the static and sliding friction values according to DIN 53375.
• the coating should, as far as possible, leave or improve the grip and feel when touching the container.
• attention can nevertheless be drawn to the safety properties of the container by attaching a corresponding reference to the name.
• the handling does not change with a coating.
• the thickness of the coating can vary depending on the shape and material of the container, the type and amount of components of the medium to be applied, the decontamination to be achieved and / or resistance to breakage and splintering.
• the thickness can be, for example, 50-150 ⁇ m.
• the wall thickness of the container can be reduced by the coating while maintaining the original breaking strength. As a result, the weight of the coated container can be reduced compared to the uncoated container. An increase in the breaking strength is preferably sought and achieved by maintaining the wall thickness.
• the medium to be applied should meet some or all of the following criteria: non-flammable or flame-retardant, odorless ("odorless”), do not cause skin reactions (“not irritate the skin”), free of organic solvents (“solvent-free”), not systemically toxic in contact with skin, resistant to aging.
• the outside of the coating should have no or almost no adhesive properties under the usual local temperature conditions worldwide (from tropical hot to Antarctic cold), since this could impair handling.
• This can be carried out by means of a drying step (ie supplying heat) or a separate curing process controlled by UV light, which takes place instead of or in addition to the drying step with dehumidified air.
• thermosetting properties are favorable for hardening by supplying heat.
• thermoplastic properties the addition of separate curing components or the application of a separate second coating with thermosetting properties is advantageous.
• Embodiment 1 is intended to explain the invention without restricting it thereto.
• the starting point for the painting are the isolated vials that come from the labeling.
• the size of the vials is either 20H, 30H, 50H, 75H and 100H (according to DIN 58366; each filled with 50mg (vial size 20H or 30H according to DIN 58366), 1g (vial size 50H or 75 H according to DIN 58366 ) and 2g (vial size 100H according to DIN 58366) sterile crystalline cyclophosphamide
• the glass type of the vials is either glass I or III.
• a chain conveyor picks up the vials on the bottle head (for example, a) pneumatically via sucker or gripper or b.) or mechanically controlled grippers) and conveys them into a spray booth, where they are painted in a so-called omega loop.
• the vials run through a labyrinth before and after the spray booth.
• the vials surround the painting unit almost completely.
• the distance covered corresponds to the shape of the Greek letter omegas ( ⁇ ). This is where the term Omega Loop comes from.
• the chain conveyor is e.g. be protected from the paint by masking.
• the paint is applied using a rotating disc, a so-called disc atomizer.
• the paint emerges from the bottom in the middle and migrates outwards due to the centrifugal forces.
• the paint is atomized at the edge of the pane and continues to fly horizontally.
• the viscosity of the varnish must be chosen so that the varnish does not dry in the pipes or on the pane.
• Another advantage of this method is the easy-to-control, slowly building up paint application (homogeneous, easily controllable paint layer).
• the paint film can be regulated both by the speed of rotation of the disc or by adjusting the amount of paint to be atomized per unit of time as well as by the throughput speed through the omega loop.
• Air sink rate min. 0.3 m / sec.
• Hydro-peeling varnish 3995.10 from Hemmelrath, Klingenberg, Germany The main component of the paint system is a water-dilutable, solvent-free polyurethane dispersion. Additional paint components are additives that serve defoaming, theological properties and adhesive strength. In the delivery form (undiluted) the solids content is 40%, which means that the remaining 60% is water. 1.5% oleic acid acroside is the only component that is listed as a dangerous ingredient in the safety data.
• the paint has the following properties: Flash point: 100 ° C
• Viscosity thixotropic flow behavior; approx. 8 d Pa * s after stirring
• the rotating vials are transferred to a dryer which is dehumidified up to max. 25 ° C works.
• the moisture content of the drying air is significantly reduced by freezing out water, so that the water absorption capacity is increased according to the Mollier diagram.
• the flow velocity in the dryer is selected in such a way that optimal drying is guaranteed within a minimum of time.
• a condensation of moisture in the dryer should be avoided by a suitable choice of the air humidity and the air flow rate. After drying, they are handed over to the cartoner (interface to conventional production).
• Embodiment 1a
• the size of the vials is optionally 20H, 30H, 50H, 75H and 100H according to DIN 58366; each filled with 50mg (vial size 20H or 30H according to DIN 58366), 1g (vial size 50H or 75H according to DIN 58366) and 2g (vial size 100H according to DIN 58366) sterile crystalline cyclophosphamide.
• the glass type of the vials is either glass type I or III.
• the paint according to embodiment 1 is used, and its viscosity can be adjusted to suit use in a spray gun, if necessary.
• This method also requires a spray booth in the vacuum (with Labyrinth).
• the vials are rotated during the painting process. Possible is a clocked 'painting process in which the vials stop in front of the spray gun and to be painted by a lifting movement of the gun from the bottom up to the flanged cap.
• the spray gun can perform a horizontal movement in addition to vertical movement and accompany the vials as they pass through the cabin (advantage: continuous production; disadvantage: larger cabin).
• the paint is atomized pneumatically.
• the pressure and the shape of the nozzle should be chosen so that the nozzle cannot become blocked, an even product transport is guaranteed and an even layer of paint is possible.
• the pressure should also meet the requirements of the spray pattern.
• the painting process can be optimized by applying high voltage to the paint and earth potential on the vial. This process creates more overspray.
• the edge delimitation of the order is less precise than that in exemplary embodiment 1.
• the spray gun offers more flexibility compared to the disk.
• the rotating vials are transferred to a dryer which is dehumidified up to max. 25 ° C works.
• the moisture content of the drying air is significantly reduced by freezing out water, so that the water absorption capacity is increased according to the Mollier diagram.
• the flow velocity in the dryer is selected in such a way that optimal drying is guaranteed within a minimum of time. A condensation of moisture in the dryer should be avoided by a suitable choice of the air humidity and the air flow rate.
• Working example 2a Like working example 2 with the difference that unlabelled vials are painted. The labeling is done after drying and before delivery to the cartoner.
• Embodiment 3
• the starting point for the painting are the isolated vials that come from the labeling, whereby the coating takes place in an immersion bath.
• the size of the vials is optionally 20H, 30H, 50H, 75H and 100H according to DIN 58366; each filled with 50mg (vial size 20H or 30H according to DIN 58366), 1g (vial size 50H or 75H according to DIN 58366) and 2g (vial size 100H according to DIN 58366) sterile crystalline cyclophosphamide.
• the glass type of the vials is either glass I or III.
• the varnish according to embodiment 1 is used, and its viscosity can optionally be adjusted to suit use in an immersion bath.
• the vials picked up on the head pass through an immersion bath which is matched to the vial size to be processed. Complete wetting is achieved by rotating around its own axis. After leaving the immersion bath, the vials continue to rotate to ensure that the excess amount of paint runs off evenly. Furthermore, the vials are slightly inclined during the draining time so that the excess lacquer can run off better over the resulting deepest point.
• the amount of paint applied is dosed by adjusting the viscosity.
• lowest point greatest layer thickness
• the rotating vials are transferred to a dryer which is dehumidified up to max. 25 ° C works.
• the moisture content of the drying air is significantly reduced by freezing out water, so that the water absorption capacity is increased according to the Mollier diagram.
• the flow velocity in the dryer is selected in such a way that optimal drying is guaranteed within a minimum of time. A condensation of moisture in the dryer should be avoided by a suitable choice of the air humidity and the air flow rate.
• Embodiment 3a After drying, they are handed over to the cartoner (interface to conventional production).
• lacquer in an analogous embodiment to the exemplary embodiments 1-3, 1 a, 2a, 3a, the following lacquer can also be used instead of the lacquer mentioned in exemplary embodiments 1-3 and 1a, 2a, 3a:
• the paint system consists of a water-thinnable polyester-polyurethane dispersion. Additional paint components are additives that serve defoaming, rheological properties and adhesive strength. The solids content is approx. 45%. The rest is water.
• tubular glass bottles according to DIN ISO 8362-1 can be used instead of the so-called cottage glass bottles according to DIN 58366 mentioned there.
• the vials of the sizes 20H, 30H, 50H, 75H and 100H Qeweils made of plastic are filled with an appropriate amount of sterile crystalline cyclophosphamide (50mg for vials 20H and 30H, 1g for vials 50H and 75H and 2g for vials 100H) and sealed with a stopper and crimp cap. Then washed with washing solution. Then coated according to the invention (according to working examples 1 and 4).
• Table 2 Comparative tests on the breaking strength of conventional containers (without coating) and the container according to the invention (with coating). Breaking strength: - Case study with 10 coated and uncoated vials of sizes 20H, 30H, 50H, 75H and 100H of glass types I and III (each with a stopper and flanged, but not filled for safety reasons) (free fall from approx.1.5 m Height on stone surface).
• the coating according to the invention was carried out in accordance with exemplary embodiments 1 and 4.
• Fracture defects means: broken vials, which could lead to an uncontrolled release of the vial contents into the environment
• Table 3 Comparative tests on the splinter resistance of conventional containers (without
• A uncoated
• B with the exception of the crimp cap (1) having a coating (4), the coating (4) gradually decreasing (C) in the area of the neck of the metallized glass surface in the vicinity of the crimp cap (1).
• Fig. 4 Schematic representation of a top view of the so-called omega loop (3) with an additional side view of the disc atomizer (spray disk) (2) and a container (1): the container (1), possibly each their own axis rotating either clockwise ( ⁇ ) or counterclockwise ( ⁇ -), run on a belt (5) around which the spray disk (2) rotates clockwise ( ⁇ ) or counterclockwise ( ⁇ -), the polymer-containing medium being fed centrally to the rotating disk (2a) and leaving the disk (2a) centrifugally, thereby creating a star-shaped spray area (4) largely lying in one plane.
• X the level of the spray area (4) can be changed depending on the size and height of the container (1).
• Fig. 5 A: Takeover of the container behind the labeling:
• a gripper which is constructed on the principle of a mechanical pencil, grabs the containers out of the star.
• the mechanics of the gripper should preferably be protected against overspray.

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• Engineering & Computer Science (AREA)
• Mechanical Engineering (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Medical Preparation Storing Or Oral Administration Devices (AREA)
• Details Of Rigid Or Semi-Rigid Containers (AREA)
• Wrappers (AREA)
• Laminated Bodies (AREA)

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• 2004
  • 2004-01-09 PL PL377761A patent/PL377761A1/pl unknown
  • 2004-01-09 BR BR0406668-5A patent/BRPI0406668A/pt not_active IP Right Cessation
  • 2004-01-09 WO PCT/EP2004/000098 patent/WO2004063036A1/de active Application Filing
  • 2004-01-09 CA CA002512788A patent/CA2512788A1/en not_active Abandoned
  • 2004-01-09 EP EP04700982A patent/EP1585679A1/de not_active Withdrawn
  • 2004-01-09 MX MXPA05007383A patent/MXPA05007383A/es unknown
  • 2004-01-09 AU AU2004203918A patent/AU2004203918A1/en not_active Abandoned
  • 2004-01-09 JP JP2006500539A patent/JP2006516235A/ja active Pending
• 2005
  • 2005-07-29 NO NO20053708A patent/NO20053708L/no not_active Application Discontinuation

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