Abstract:
For the prevention of contamination of a vial with traces of medicinal fluids, for example cytostatics and antibiotics, which may be spilt on the outside of the vial while filling, the vial is provided with a tight-fitting protective envelope, preferably made of a transparent synthetic material, as a last step in the production process. Because of this, a possible contamination which remains on the outside of the vial is encapsulated between the vial and the envelope. Hereby, a user is no longer exposed to toxic substances, because the user will not touch the vial itself, but will touch the envelope. An additional advantage of the provision of the envelope is that if breaking of the vial occurs, the envelope will keep the pieces of broken glass together and will possibly prevent the medicinal fluid from leaking away.

Description:
FIELD OF THE INVENTION  
       [0001]     The invention relates to a method for manufacturing a protected vial and to a protected vial which can be manufactured according to this method.  
       BACKGROUND OF THE INVENTION  
       [0002]     Vials are frequently used in medical practice. Usually, vials consist of a container filled with a medicinal fluid and sealed with a seal which can be pierced with a hypodermic needle. The vial is often also provided with a protective cap which needs to be removed before use. In the process of producing these vials, there is a considerable chance of medicinal fluid ending up on the outside of the vial. Therefore, after filling and sealing, the vials are rinsed in order to remove this fluid. However, it is known from practice that the outside of a vial is not always clean, i.e. free from contamination with an active substance. In that case, rinsing has not led to complete removal, and still traces of the active substance have remained.  
         [0003]     Often, the fact that traces of an active substance remain does not constitute a problem, but in certain cases, such as for example in the case of cytostatics and antibiotics, this is different. For instance, it is known that cytostatics can absorb on glass. This may then cause hospital and pharmacy employees, in dealing with such vials, to undesirably get in contact with these possibly highly toxic substances. In the case of antibiotics, contamination on the outside is undesirable, because this may lead to faster resistance of micro-organisms against the antibiotics concerned when these micro-organisms get in contact with the vial, or when the antibiotics concerned get in contact with micro-organisms carried by hospital and pharmacy employees.  
       SUMMARY OF THE INVENTION  
       [0004]     An important objective of the present invention is to cancel the above-mentioned disadvantages and thereby preventing its negative consequences. To that end, the present invention provides a method for manufacturing a protected vial, wherein a tight-fitting envelope is applied around a vial after its filling and sealing.  
         [0005]     Because of this, a possible contamination which remains on the outside of the vial after rinsing the vial is encapsulated between the vial and the tight-fitting envelope. Hereby, a user is no longer exposed to toxic substances, because the user will not touch the vial itself, but will touch the envelope. Because the envelope fits tightly around the vial, one keeps the normal physical “feeling” with the vial during use, so that its further processing remains the same. With regard to developing resistance, micro-organisms now do not get a chance to get in contact with traces of antibiotics on the outside of the vial. An additional advantage is that if a vial breaks, the envelope will still take care of holding the pieces of glass together, and possibly the fluid is prevented from leaking away.  
         [0006]     The application of a protective envelope takes place after successively filling and sealing the vial; however, it is also possible that the vial is first provided with a sealing member, then filled and subsequently provided with the protective envelope.  
         [0007]     In a preferred embodiment of the invention, a glass vial is provided with a tight-fitting synthetic envelope over its entire outside, with the exception of the protective cap. This envelope has been slid over the vial with little space and has shrunk under application of heat, and is thereby fitted tightly around the vial. The envelope may exist as one piece. However, it may also be composed of two parts, wherein the bottom of the vial is covered by a sticker and the side wall is covered by a sleeve, partly overlapping the sticker along a circumferential edge of the bottom. 
     
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0008]     These and other aspects, features and advantages of the present invention will be further explained by the following description with reference to the attached drawing, in which:  
         [0009]      FIG. 1  shows a cross section of a protected vial according to the invention,  
         [0010]      FIG. 1A  shows a cross section of a protected vial according to the invention with a bottom sticker, and  
         [0011]     FIGS.  2 A-E schematically illustrate the successive steps of manufacturing of the protected vial of  FIG. 1 . 
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0012]     In  FIG. 1 , a cross section is shown of a filled and sealed protected vial  1  according to the present invention. The protected vial  1  consists of a glass vial  2  known per se with a side wall  201 , a bottom  202  and an access opening  3 . In the vial  2 , a medicinal fluid  7  is present. The protected vial  1  is provided with a pierceable sealing member  4 , for example of rubber, and a protective cap  5 , for example of metal. On the outside of the vial  2 , an envelope  6  is fitted tightly over almost the entire vial  2 , leaving the protective cap  5  free. Preferably, the envelope  6  is made of a transparent synthetic material, for example a film of PE, PP, PVC or the like. A suitable value for the thickness of the envelope  6  is 0.05 mm; but the value for the thickness may also be higher or lower. For sake of clarity, in  FIG. 1 , some parts of the protected vial  1  are shown in an exaggeratedly thick fashion.  
         [0013]     In  FIG. 1A , a cross section is shown of a slightly different embodiment of the protected vial. In the following, this vial will be referred to as protected vial  100  with a bottom sticker. The above description of the protected vial  1  as shown in  FIG. 1  is also applicable to the protected vial  100  with a bottom sticker, with the difference that the envelope  6  comprises two parts, namely a sleeve  601  covering a the side wall  201  of the vial  2 , while leaving almost the entire bottom  202  of the vial  2  free, and a separate bottom sticker  602  covering the bottom  202  of the vial  2 . The sleeve  601  partly overlaps the bottom sticker  602  along a circumferential edge of the bottom  202 . Preferably, the bottom sticker  602  is also made of a transparent synthetic material and has a thickness in the order of approximately 0.15 mm. Furthermore, it is preferable that the bottom sticker  602  is self-adhesive, but this is not necessary within the scope of the invention.  
         [0014]     The protected vial  1  is manufactured in steps which are described in the following and which are illustrated in the FIGS.  2 A-E, in a simplified way. At first an empty vial  2 , known per se, is provided ( FIG. 2A ). Then, this vial  2  is filled with a medicinal fluid  7 , through the access opening  3  ( FIG. 2B ). Subsequently, a sealing member  4  is attached to the access opening  3  and a protective cap  5  is attached ( FIG. 2C ). Then, the whole is rinsed in order to remove the fluid which has possibly been spilt on the outside of the vial  2  during filling. Subsequently, a synthetic envelope  6  is slid over the vial  2  ( FIG. 2D ). As last step, the synthetic envelope  6  is subjected to a heat treatment, in such a way that it shrinks and thereby becomes fitted tightly around the vial  2  ( FIG. 2E ).  
         [0015]     Alternatively, filling the vial  2  may also take place after attaching the sealing member  4 .  
         [0016]     In a manufacturing process suitable for manufacturing a protected vial  100  with a bottom sticker, a bottom sticker  602  is attached to the bottom  202  of the vial  2  before the synthetic sleeve  601  is slid over the vial  2 .  
         [0017]     In order to investigate the effect of providing vials  2  with a sleeve  601  and a bottom sticker  602  on an outside contamination of the vials, tests have been performed (Report for Pharmachemie BV, Haarlem, The Netherlands, by Exposure Control BV, Wijchen, The Netherlands and University Medical Center Nijmegen, Nijmegen, The Netherlands), during which the outside contamination of protected vials  100  and unprotected vials  2  containing cisplatin was measured. Extracts from the outside of the vials were destructed into platinum and analyzed with stripping voltametry (Metrohm Application Bulletin No. 220/1. Determine of ultratrace levels of platinum by stripping voltametry). Details of the tests are presented in the following table.  
                                                     Batch   Vials without protection   Protected vials                                Number of vials   7566   4067       Cisplatin (mg)   25   50       Volume cisplatin (ml)   50   100       Cisplatin (mg/ml)   0.5   0.5       Surface area (cm 2 )   120   180       Extraction volume (ml HCl)   70   300                  
 
         [0018]     The tested vials were put in a single container. The containers were filled with 0.5 M HCl until the vials were completely immersed. The containers were closed, and after ultrasonification for 30 minutes, the vials were removed from the containers. During ultrasonification, cisplatin contamination on the outside of the vials was assumed to be dissolved in the HCl solvent.  
         [0019]     Sample pre-treatment and analysis with stripping voltametry was performed according to standard procedures. One ml of the cisplatin extract was destructed into a platinum-complex using hydrogen peroxide, formaldehyde and UV-light, resulting in the formation of platinum (Pt). It is a known fact that cisplatin contains about 65% platinum. Analysis of platinum was performed in triplicate with a relative standard deviation of 2-3%. The limit of detection was 10 ng/l of extract. Samples were diluted and reanalyzed in case high concentrations were encountered. Ten blank samples (empty vials) were extracted, analyzed and compared to the cisplatin vials to correct for background values of platinum (50 ng/l extract).  
         [0020]     Values of absolute amounts of contamination found on the vials (Pt-abs) were compared between the protected vials  100  and the unprotected vials  2  with a Wilcoxon test. This test was also applied on the values of contamination per area surface (Pt-area), the values of contamination related to the contents of the vial (Pt-ratio out/in) and to all values corrected for blanks. P-values of 0.05 or less were considered significant. Data were characterized by median, range and quartiles.  
         [0021]     Results of the tests are presented in the following table.  
                                                                                                               Unprotected vials   Protected vials                Pt-abs   PT-area   Pt-ratio out/in   Pt-abs   PT-area   Pt-ratio out/in       Batch   (ng)   (ng/cm 2 )   (×10 −6 )   (ng)   (ng/cm 2 )   (×10 −6 )                    Min   3   0.02   0.17   BV*   BV*   BV*       Max   79   0.66   4.85   146   0.81   4.49       Median   7   0.06   0.43   4   0.02   0.11                 *BV = Background Values             
 
         [0022]     It is clear from the above table, in particular from the median data, that all parameters are significantly lower for the protected vials  100  compared to the unprotected vials  2 . This proves that providing the vial  2  with an envelope  6  leads to a significant reduction of the outside contamination of the vial  2 .  
         [0023]     In order to investigate the effect of providing vials  2  with a sleeve  601  and a bottom sticker  602  on risks associated with accidental dropping of the thus obtained protected vials  100 , drop tests have been performed (Report for Pharmachemie BV, Haarlem, The Netherlands, by Topa Instituut, Voorhout, the Netherlands; report number T04-1068). The applied test procedure consists of the following parts:  
         [0000]     1) Drop Test from Drop Height of 120 cm  
         [0024]     This test has been performed to simulate the accidental dropping of protected vials  100  from a table on a hospital floor. The drop height is 120 cm on random positions of the vials  100  (top, bottom or side). The surface on which the drops have taken place is a “Linoleum” plate, which simulates a hospital floor. Five drops have been performed with three different types of vials, namely 10 ml vials, 50 ml vials and 100 ml vials.  
         [0000]     2) Drop Test from Drop Height of 185 cm  
         [0025]     This test has been performed to see what happens if the protected vial  100  falls from a shelf on a hospital floor. The drop height is 185 cm on random positions of the vials  100  (top, bottom or side). The surface on which the drops take place is the above-mentioned “Linoleum” plate.  
         [0026]     The results of the drop test from the drop height of 120 cm are presented in the following table. For sake of completeness, it is noted that, in the table, the protected vials  100  are indicated as vials with cover, whereas unprotected vials  2 , i.e. vials  2  without an envelope  6 , are indicated as vials without cover.  
                                                                                                               Drop height 120 cm                10 ml vials       50 ml vials       100 ml vials               With cover   Without cover   With cover   Without cover   With cover   Without cover           Results   Results   Results   Results   Results   Results                        Drop on bottom   1   ok   ok   ok   ok   ok   ok           2   ok   ok   ok   ok   ok   ok       Drop on top   1   ok   ok   ok   ok   ok   ok           2   ok   ok   ok   ok   ok   ok       Drop on side   1   ok   ok   ok   ok   ok   ok       Total % intact       100%   100%   100%   100%   100%   100%                  
 
         [0027]     The results of the drop test from the drop height of 185 cm are presented in the following table.  
                                                                                                               Drop height 185 cm                10 ml vials       50 ml vials       100 ml vials               With cover   Without cover   With cover   Without cover   With cover   Without cover           Results   Results   Results   Results   Results   Results                        Drop on bottom   1   ok   ok   ok   ok   ok   ok           2   ok   ok   ok   ok   ok   ok           3   broken   ok   ok   ok   ok   ok           4   ok   ok   ok   ok   broken   ok           5   ok   ok   ok   ok   ok   ok           6   ok   ok   ok   ok   —   —           7   ok   ok   ok   ok   —   —           8   ok   broken   ok   ok   —   —           9   ok   ok   ok   ok   —   —           10   ok   ok   ok   ok   —   —       Drop on top   1   ok   ok   ok   ok   ok   ok           2   ok   ok   ok   ok   ok   ok           3   ok   ok   ok   ok   ok   ok           4   ok   ok   ok   ok   ok   ok           5   ok   ok   ok   ok   ok   ok           6   ok   ok   ok   ok   —   —           7   ok   ok   ok   ok   —   —           8   ok   ok   ok   ok   —   —           9   ok   ok   ok   ok   —   —           10   ok   ok   ok   ok   —   —       Drop on side   1   ok   ok   broken   broken   broken   broken           2   ok   ok   cracked   ok   broken   broken           3   ok   ok   ok   broken   broken   broken           4   ok   ok   ok   ok   broken   broken           5   ok   ok   ok   ok   broken   broken           6   ok   ok   ok   broken   cracked   ok           7   ok   ok   cracked   ok   cracked   broken           8   ok   ok   cracked   ok   ok   broken           9   ok   ok   ok   ok   cracked   broken           10   ok   ok   ok   ok   broken   broken       Total % intact       96.7%   96.7%   86.7%   90.0%   50.0%   50.0%                  
 
         [0028]     From the results of the drop tests, it is concluded that providing a vial  2  with a sleeve  601  and a bottom sticker  602  does not lead to an improved protection of the vials  2  against breakage, However, it has appeared that if such a vial  2  sustains damage, the vial  2  often gets cracked rather than broken. Furthermore, it has appeared that if such a vial  2  breaks or cracks, in 50% of these cases, the vial  2  still contains its contents. In all cases of breakage of an unprotected vial  2 , the contents are spilled over the floor. Therefore, the conclusion is justified that the application of the sleeve  601  and the bottom sticker  602  leads to a safer handling of the vials.  
         [0029]     The above-described embodiments are merely illustrations of possibilities of the present invention. Several modifications and adjustments are possible within the scope of protection of the invention as defined by the attached claims.