Abstract:
In a bypass type prefilled syringe having a tubular body formed with a bypass for establishing communication between front and rear compartments for preliminarily storing medicament and pharmaceutical liquid, respectively, a gasket for dividing interior space of the tubular body into the front and rear compartments includes a plurality of circumferential ribs, a plurality of annular recesses each formed between neighboring ones of the circumferential ribs and first and second axial slots formed on the circumferential ribs so as to define a bent outflow path for the pharmaceutical liquid at the time of communication between the front and rear compartments via the bypass.

Description:
BACKGROUND OF THE INVENTION  
         [0001]    1. Field of the Invention  
           [0002]    The present invention generally relates to a bypass type prefilled syringe in which a bypass for establishing communication between front and rear compartments for preliminarily storing two components, for example, powdery medicament and pharmaceutical liquid, respectively is formed on a tubular body and more particularly, to a gasket for dividing interior space of the tubular body of the bypass type prefilled syringe into the front and rear compartments.  
           [0003]    2. Description of the Prior Art  
           [0004]    [0004]FIGS. 6 and 7 show a sealing state and a communication state between a front compartment  6  and a rear compartment  7  of an elongated hollow tubular body  1  of a conventional bypass type prefilled syringe, respectively. A front assembly  15  includes an injection needle  10  and a cap  11  for covering the injection needle  10  so as to protect the injection needle  10  and is mounted on an outer periphery of a front end portion of the tubular body  1 . In FIG. 6, the conventional bypass type prefilled syringe includes a first sealing member  3  which is mounted in the front end portion of the tubular body  1 , a second sealing member  4  which is attached to a front end of a plunger rod  2  and is disposed at a rear end portion of the tubular body  1  and a gasket  5  which is slidably inserted between the first and second sealing members  3  and  4  in the tubular body  1  and divides interior space of the tubular body  1  into the front and rear compartments  6  and  7 . Powdery medicament P and pharmaceutical liquid L are preliminarily, respectively, stored in the front and rear compartments  6  and  7  so as to interpose the gasket  5  therebetween.  
           [0005]    A bypass  1   a  is formed by bulging a peripheral wall of the front compartment  6  of the tubular body  1  radially outwardly. On the other hand, a finger grip  12  is mounted on an outer periphery of the rear end portion of the tubular body  1 . By forwardly depressing the plunger rod  2  in the direction of the arrow a in FIG. 7 from the state of FIG. 6 to the state of FIG. 7, the gasket  5  is advanced by the second sealing member  4  by way of the pharmaceutical liquid L so as to be disposed between a front end portion and a rear end portion of the bypass  1   a . At this time, a gap for directly linking the front and rear compartments  6  and  7  is defined between the gasket  5  and the bypass  1   a , so that the front and rear compartments  6  and  7  are communicated with each other by the bypass  1   a  and thus, the pharmaceutical liquid L is introduced from the rear compartment  7  into the powdery medicament P in the front compartment  6  along a flow path indicated by the arrow b in FIG. 7. Then, when the powdery medicament P is sufficiently dissolved or dispersed in the pharmaceutical liquid L by shaking the tubular body  1 , injection liquid is formed.  
           [0006]    At the time of communication between the front and rear compartments  6  and  7  through the bypass  1   a  in this conventional bypass type prefilled syringe, the pharmaceutical liquid L is fed under pressure into the front compartment  6  in a state where the injection needle  10  is mounted on the tubular body  1 . At this time, the gasket  5  is disposed between the front end portion and the rear end portion of the bypass  1   a  and the gap for directly linking the front and rear compartments  6  and  7  is defined between the gasket  5  and the bypass  1   a  as described above. Thus, in case a user forcibly depresses the plunger rod  2  from the state of FIG. 6 to the state of FIG. 7, a so-called squirt phenomenon in which the pharmaceutical liquid L spouts from the bypass  1   a  vigorously may happen, thereby resulting in such an inconvenience that the pharmaceutical liquid L impinges on the first sealing member  3  and then, leaks out of the injection needle  10 .  
           [0007]    Meanwhile, FIG. 8 shows a sealing state between the front and rear compartments  6  and  7  of the tubular body  1  of a known bypass type prefilled syringe disclosed in U.S. Pat. No. 4,599,082. In this known bypass type prefilled syringe, a gasket  20  is employed. As shown in FIG. 9, the gasket  20  has a front end face  20   a  and a rear end face  20   b  and includes ribs  24 ,  26  and  27 . Meanwhile, an annular recess  25  is provided between the ribs  24  and  26  and a plurality of grooves  28  extending obliquely relative to an axis of the gasket  20  are formed on the rib  24  so as to open to the front end face  20   a . In order to improve agitation and mixing of the pharmaceutical liquid L and the powdery medicament P at the time of communication between the front and rear compartments  6  and  7  via the bypass  1   a , the pharmaceutical liquid L is introduced from the grooves  28  into the powdery medicament P obliquely relative to the axis of the gasket  20 .  
           [0008]    However, in contrast with the conventional construction shown in FIGS. 6 and 7 in which the injection needle  10  is mounted on the front end portion of the tubular body  1 , this known bypass type prefilled syringe has a construction in which a distal end cap  35  is mounted on a distal end  34  of the tubular body  1 . Thus, as described at column 8, lines 3 to 9 of the above mentioned U.S. patent, mixing operation of the pharmaceutical liquid L and the powdery medicament P is performed by depressing a plunger rod in a state where the distal end  34  of the tubular body  1  is directed upwardly after the distal end cap  35  has been removed from the distal end  34  of the tubular body  1 . Therefore, the gasket  20  merely serves to improve agitation and mixing of the pharmaceutical liquid L and the powdery medicament P and thus, does not serve to prevent leakage of the pharmaceutical liquid L from an injection needle due to the squirt phenomenon.  
         SUMMARY OF THE INVENTION  
         [0009]    Accordingly, an essential object of the present invention is to provide, with a view to eliminating the above mentioned drawbacks of prior art, a gasket for a bypass type prefilled syringe, which prevents a squirt phenomenon of pharmaceutical liquid at the time of communication between front and rear compartments of a tubular body by way of a bypass such that powdery medicament can be sufficiently dissolved or dispersed in the pharmaceutical liquid.  
           [0010]    In order to accomplish this object of the present invention, a gasket for a bypass type prefilled syringe having a tubular body formed with a bypass for establishing communication between front and rear compartments for preliminarily storing medicament and pharmaceutical liquid, respectively, according to the present invention divides interior space of the tubular body into the front and rear compartments and includes a plurality of circumferential ribs which include at least first, second and third circumferential ribs disposed sequentially further away from the front compartment. A plurality of annular recesses are each formed between neighboring ones of the circumferential ribs and include at least a first annular recess formed between the first and second circumferential ribs and a second annular recess formed between the second and third circumferential ribs. A first axial slot extends through the first circumferential rib and the first annular recess, while a second axial slot is formed at a circumferential position of the second circumferential rib deviating from the first axial slot so as to bring the first and second annular recesses into communication with each other. At the time of communication between the front and rear compartments via the bypass, a bent outflow path for delivering the pharmaceutical liquid into the front compartment in a state where the tubular body at a front end side of the bypass is closed by a front end portion of the gasket is sequentially formed by the second annular recess, the second axial slot, the first annular recess and the first axial slot. 
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0011]    This object and features of the present invention will become apparent from the following description taken in conjunction with the preferred embodiment thereof with reference to the accompanying drawings in which:  
         [0012]    [0012]FIG. 1 is an enlarged schematic fragmentary sectional view showing a sealing state between front and rear compartments of a bypass type prefilled syringe including a gasket according to one embodiment of the present invention;  
         [0013]    [0013]FIG. 2 is an enlarged schematic fragmentary sectional view showing a communication state between the front and rear compartments of the bypass type prefilled syringe of FIG. 1;  
         [0014]    [0014]FIGS. 3A, 3B and  3 C are, respectively, a left side elevational view, a front elevational view and a right side elevational view of a front gasket segment employed in the gasket of FIG. 1;  
         [0015]    [0015]FIGS. 4A, 4B and  4 C are sectional views taken along the lines IVA-IVA, IVB-IVB and IVC-IVC in FIG. 3B, respectively;  
         [0016]    [0016]FIG. 5 is a front elevational view of a rear gasket segment employed in the gasket of FIG. 1;  
         [0017]    [0017]FIG. 6 is a schematic sectional view showing a sealing state between front and rear compartments of a prior art bypass type prefilled syringe;  
         [0018]    [0018]FIG. 7 is a schematic sectional view showing a communication state between the front and rear compartments of the prior art bypass type prefilled syringe of FIG. 6;  
         [0019]    [0019]FIG. 8 is a schematic fragmentary sectional view showing a sealing state between front and rear compartments of a further prior art bypass type prefilled syringe; and  
         [0020]    [0020]FIG. 9 is a front elevational view of a gasket employed in the further prior art bypass type prefilled syringe of FIG. 8. 
     
    
       [0021]    Before the description of the present invention proceeds, it is to be noted that like parts are designated by like reference numerals throughout several views of the accompanying drawings.  
       DETAILED DESCRIPTION OF THE INVENTION  
       [0022]    Hereinafter, one embodiment of the present invention is described with reference to the drawings. FIGS.  1  to  5  show a gasket  50  for a bypass type prefilled syringe, according to the one embodiment of the present invention. In this bypass type prefilled syringe, powdery medicament P and pharmaceutical liquid L are, respectively, stored in a front compartment  6  and a rear compartment  7  of a tubular body  1  beforehand so as to interpose the gasket  50  therebetween, while a marked line  1   b  indicative of a position for temporarily stopping a front end of the gasket  50  at the time of communication between the front and rear compartments  6  and  7  via a bypass  1   a  is drawn forwardly of the bypass  1   a  as shown in FIG. 1. Since other constructions of the bypass type prefilled syringe are similar to those of a prior art bypass type prefilled syringe shown in FIGS. 6 and 7 in which a first sealing member  3  and a second sealing member  4  are provided and an injection needle  10  is mounted on a front end portion of the tubular body  1 , the description is abbreviated for the sake of brevity. FIGS. 1 and 2 show a sealing state and a communication state between the front and rear compartments  6  and  7  of the tubular body  1 , respectively.  
         [0023]    As shown in FIGS. 1 and 2, the gasket  50  is constituted by a front gasket segment  51  and a rear gasket segment  52  which are disposed so as to abut on each other. However, the gasket  50  is not required to be constituted by the two components but may also be formed by the single front gasket segment  51  only. In this case, the bypass  1   a  should be set at a small dimension in conformity with the front gasket segment  51 . The gasket  50  is made of elastomer such as synthetic rubber.  
         [0024]    [0024]FIGS. 3A, 3B and  3 C are a left side elevational view, a front elevational view and a right side elevational view of the front gasket segment  51 , respectively, while FIGS. 4A, 4B and  4 C are sectional views taken along the lines IVA-IVA, IVB-IVB and IVC-IVC in FIG. 3B, respectively. The front gasket segment  51  has a front end face  51   a  and a rear end face  51   b  each having four projections  72  and includes circumferential ribs  54 ,  55 ,  56 ,  57  and  58  arranged sequentially from the front end face  51   a  towards the rear end face  51   b . The front gasket segment  51  further has an annular recess  59  formed between the circumferential ribs  54  and  55 , an annular recess  60  formed between the circumferential ribs  55  and  56 , an annular recess  61  formed between the circumferential ribs  56  and  57  and an annular recess  62  formed between the circumferential ribs  57  and  58 .  
         [0025]    Meanwhile, an axial rib  63  is provided at each of four circumferential positions of the annular recess  60 . Likewise, an axial rib  64  is provided at each of four circumferential positions of the annular recess  61  and an axial rib  65  is provided at each of four circumferential positions of the annular recess  62 . At the time of communication between the front and rear compartments  6  and  7 , the axial ribs  63 ,  64  and  65  intercept the pharmaceutical liquid L flowing in the annular recesses  60 ,  61  and  62  so as to prevent the pharmaceutical liquid L from flowing through the annular recesses  60 ,  61  and  62 , respectively such that the pharmaceutical liquid L in the annular recesses  60 ,  61  and  62  is carried forwardly.  
         [0026]    Furthermore, two semicircular axial slots  70  are, respectively, formed at diametrically opposite ends of the circumferential rib  54  and extend through the circumferential rib  54  and the annular recess  59  so as to open to the front end face  51   a . On the other hand, four axial slots  71  are, respectively, formed at circumferential positions of the circumferential rib  55  deviating from the axial slots  70  so as to bring the annular recesses  59  and  60  into communication with each other. As will been seen from FIGS. 3A and 4A, a cross-sectional area of a flow path of the axial slot  70  is set to be larger than that of the axial slot  71 .  
         [0027]    By setting an outside diameter D 1  of the circumferential ribs  54  and  55  adjacent to the front end face  51   a  to be equal to or larger than an inside diameter of the tubular body  1  but smaller than an outside diameter D 2  of the circumferential ribs  56 ,  57  and  58 , the gasket  50  can be advanced smoothly while a sealing state between the tubular body  1  and the gasket  50  is being secured. Meanwhile, an outside diameter of the annular recesses  59  and  60  is also set to be smaller than that of the annular recesses  61  and  62 .  
         [0028]    [0028]FIG. 5 shows the rear gasket segment  52 . The rear gasket segment  52  has a front end face  52   a  and a rear end face  52   b  each having four projections  88  in the same manner as the front gasket segment  51  and includes circumferential ribs  81 ,  82  and  83  which are arranged sequentially from the front end face  52   a  towards the rear end face  52   b . The rear gasket segment  52  further has an annular recess  84  formed between the circumferential ribs  81  and  82  and an annular recess  85  formed between the circumferential ribs  82  and  83 . Meanwhile, in the same manner as the front gasket segment  51 , an axial rib  86  is provided at each of four circumferential positions of the annular recess  84  and an axial rib  87  is provided at each of four circumferential positions of the annular recess  85 . At the time of communication between the front and rear compartments  6  and  7 , the axial ribs  86  and  87  intercept the pharmaceutical liquid L flowing in the annular recesses  84  and  85  so as to prevent the pharmaceutical liquid L from flowing through the annular recesses  84  and  85 .  
         [0029]    At the time of communication between the front and rear compartments  6  and  7  by way of the bypass  1   a , the gasket  50  is advanced by a plunger rod (not shown) until the front end face  51   a  of the front gasket segment  51  reaches the marked line  1   b  of FIG. 1. At this time, as shown in FIG. 2, a gap is defined between a rear end portion of the rear gasket segment  52  and a rear end portion of the bypass  1   a , while a front end portion of the front gasket segment  51  is disposed forwardly of a front end portion of the bypass  1   a  such that the tubular body  1  at a front end side of the bypass  1   a  is closed by the front end portion of the front gasket segment  51 .  
         [0030]    Thus, the pharmaceutical liquid L fed under pressure into the gap between the bypass  1   a  and the gasket  50  as shown by the arrow b in FIG. 2 is initially introduced into the annular recesses  84  and  85  of the rear gasket segment  52  and the annular recesses  60  to  62  of the front gasket segment  51  but is intercepted by the axial ribs  86  and  87  of the rear gasket segment  52  and the axial ribs  63  to  65  of the front gasket segment  51  so as to be delivered forwardly. Then, as shown by the arrow c, the pharmaceutical liquid L is carried into the powdery medicament P along a U-shaped outflow path proceeding from the annular recess  60  to the axial slots  70  through the axial slots  71  and the annular recess  59 . This outflow path of the pharmaceutical liquid L is not restricted to the U-shaped configuration but may have an arbitrary bent shape, for example, a V-shaped configuration or an S-shaped configuration.  
         [0031]    Meanwhile, in the above described embodiment, the gasket  50  is applied to the bypass type prefilled syringe of a construction having an injection needle mounted on the front end portion of the tubular body  1  but is not restricted to the bypass type prefilled syringe of this construction. The gasket  50  may also be applied to a bypass type prefilled syringe of other constructions, e.g., a construction in which a distal end cap is mounted on a distal end of the tubular body  1  as shown in FIG. 8.  
         [0032]    Furthermore, in the above described embodiment, the powdery medicament P and the pharmaceutical liquid L are, respectively, preliminarily stored in the front and rear compartments  6  and  7 . However, in the two components stored in the front and rear compartments  6  and  7 , respectively, at least the component stored in the rear compartment  7  should be liquid and thus, the two components may be liquid. Meanwhile, in case only one of the two components is liquid, it is desirable that the other component is of simply dissoluble or dispersible dosage forms such as powder and solid medicine obtained by freeze-drying. The dosage forms include sustained release drug.  
         [0033]    For example, microsphere or the like may be recited as the sustained release drug. The microsphere includes microcapsule, microparticle, etc. More specifically, the microspheres or the microcapsules described in Japanese Patent Laid-Open Publication Nos. 60-100516 (1985), 62-201816 (1987), 02-124814 (1990), 04-321622 (1992), 05-112468 (1993), 05-194200 (1993), 06-293636 (1994), 06-145046 (1994), 06-192068 (1994), 08-169818 (1996), 09-132524 (1997), 09-221417 (1997) and 09-221418 (1997) are employed.  
         [0034]    As injections composed of the above two components, which can be administered by the two-compartment type prefilled syringe, i.e., biologically active substances, it is possible to specify, for example, biologically active peptide, antineoplastic agent, antibiotic, antipyretic, analgesic, antiphologistic, antitussive expectorant, sedative, muscle relaxant, antiepileptic, antiulcer agent, antidepressant, antiallergic agent, cardiotonic, antiarrhythmic drug, vasodilator, hypotensive diuretic, diabetic drug, antilipemic agent, anticoagulant, hemostatic, antituberculosis drug, hormone drug, narcotic antagonist, bone resorption inhibitor, osteoplasty accelerator, angiogenesis inhibitor, etc. However, it is needless to say that the injections are not restricted to these substances.  
         [0035]    Biologically active peptides are desirable as the biologically active substances. For example, biologically active peptide having a molecular weight of about 300 to 40,000, desirably about 400 to 30,000 and more desirably about 500 to 20,000 may be employed. Such biologically active peptide desirably has a basic group capable of forming a salt with, for example, weak acid having a pKa of not less than 4.0 including carbonic acid, acidic bicarbonate, boric acid and lower alkane monocarboxylic acid having 1 to 3 carbon atoms. Meanwhile, in place of the basic group, the biologically active peptide may also have a free acidic group or an acidic group forming a salt.  
         [0036]    Hormonal action can be recited as a typical activity of the biologically active peptides. Meanwhile, the biologically active peptides may be any one of a natural product, a synthetic, a semisynthetic product and a product of genetic engineering, or an analogue and/or a derivative thereof. Action of these biologically active peptides may be either agonistic or antagonistic.  
         [0037]    The biologically active peptides may include luteinizing hormone releasing agent (LH-RH) referred also to as “gonadotropin releasing agent (Gn-RH)”, insulin, somatostatin, somatostatin derivative such as Sandostatin in U.S. Pat. Nos. 4,087,390, 4,093,574, 4,100,117 and 4,253,998, growth hormone (GH) in Japanese Patent Laid-Open Publication Nos. 7-1018778 (1995) and 10-265404 (1998), growth hormone releasing hormone (GH-RH), prolactin, erythropoietin (EPO), adrenocorticotropic hormone (ACTH), ACTH derivative such as ebiratide, melanocyte-stimulating hormone (MSH), thyrotropin releasing hormone ((pyr)Glu-His-ProNh2; TRH), a salt and a derivative thereof in Japanese Patent Laid-Open Publication Nos. 50-121273 (1975) and 52-116465 (1977), thyroid stimulating hormone (TSH), luteinizing hormone (LH), follicle stimulating hormone (FSH), vasopressin, vasopressin derivative such as desmopressin, oxytocin, calcitonin, glucagon, gastrin, secretin, pancreozymin, cholecystokinin, angiotensin, human placental lactogen, human chorionic gonadotropin (HCG), enkephalin, enkephalin derivative in U.S. Pat. No. 4,277,394 and EP-31567-A, endorphin, kyotorphin, interferons such as interferon-α, interferon-β and interferon-γ, interleukins such as interleukins 1 to 12, taftsin, thymopoietin, thymosin, thymostimulin, thymic humoral factor (THF), scrum thymic factor (FTS) and its derivative in U.S. Pat. No. 4,229,438, tumor necrosis factor (TNF), colony stimulating factor (CSF, GCSF, GMCSF and MCSF), motilin, dinorphin, bombesin, neurotensin, cerulein, bradykinin, atrial natriuretic factor, nerve growth factor (NGF), cell growth factors such as EGF, TGF-β, PDGF, acidic FGF and basic FGF, neurotrophic factors such as NT-3, NT4, CNTF, GDNF and BDNF, peptide having endothelin antagonism and its analogue (derivative) in EP-436189-A, EP-457195-A, EP-496452-A and Japanese Patent Laid-Open Publication Nos. 3-94692 (1991) and 3-130299 (1991), insulin receptor, insulin-like growth factor (IGF)-1 receptor, IGF-2 receptor, transferrin receptor, epidermal growth factor, low density lipoprotein (LDL) receptor, macrophage scavenger receptor, GLUT-4 transporter, growth hormone receptor, peptide derived from α1 domain of major histocompatibility class I antigen complex (MHC-I) having activity for hampering endogeny of leptin receptor (“Proceedings of the National Academy of Sciences of the United States of America”, Vol. 91, p.p. 9086-9090 (1994) and Vol. 94, p.p. 11692-11697 (1997)) and its analogue (derivative), and a fragment or a fragment derivative thereof.  
         [0038]    In case the biologically active peptide is a salt, a pharmacologically acceptable salt or the like may be used. For example, in case the biologically active peptide has a basic group such as an amino group in its molecule, salts formed by the basic group and inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and boric acid or organic acids such as carbonic acid, acidic bicarbonate, succinic acid, acetic acid, propionic acid and trifluoroacetic acid may be used. Meanwhile, in case the biologically active peptide has an acidic group such as a carboxyl group in its molecule, salts formed by the acidic group and inorganic bases including alkaline metals such as sodium and potassium and alkaline earth metals such as calcium and magnesium or organic bases including organic amines such as triethylamine and basic amino acids such as arginine may be used. Furthermore, the biologically active peptide may form metal complex compounds such as a copper complex and a zinc complex.  
         [0039]    As concrete examples of the biologically active peptides desirable for use, it is possible to recite an LH-RH analogue and its salt effective for contraception and diseases dependent on either LH-RH of prostatic cancer, prostatic hypertrophy, endometriosis, myoma of the uterus, fibroma of the uterus, precocious puberty and breast cancer or a hormone derived from the LH-RH as well as a somatostatin derivative and its salt effective for diseases dependent on growth hormone and a hormone derived from the growth hormone and diseases of the digestive system such as peptic ulcer.  
         [0040]    Concrete examples of the LH-RH analogue and its salt may include peptides described in “Treatment with GnRH analogs: Controversies and perspectives” published in 1966 by The Parthenon Publishing Group Ltd., Japanese Patent National Publication No. 3-503165 (1991) and Japanese Patent Laid-Open Publication Nos. 3-101695 (1991), 7-97334 (1995) and 8-259460 (1996).  
         [0041]    As a concrete example of a biologically active peptide having LH-RH antagonism, i.e., an LH-RH antagonist, a biologically active peptide expressed by the following general formula [Ia] or its salt may be recited. 
         X-D2Na1-D4C1Phe-D3Pa1-Ser-A-B-Leu-C-Pro-DA1aNH 2   [Ia] 
         [0042]    In the formula, “X” denotes N(4H 2 -furoy1)G1y or NAc, “A” denotes a residual group selected from NMeTyr, Tyr, Aph(Atz) and NMeAph(Atz), “B” denotes a residual group selected from DLys(Nic), DCit, DLys(AzaglyNic), DLys(AzaglyFur), DhArg(Et 2 ), DAph(Atz) and DhCi and “C” denotes Lys(Nisp), Arg or hArg(Et 2 ).  
         [0043]    More specifically, the biologically active peptide having LH-RH antagonism, i.e., LH-RH antagonist may be NAcD2Na1-D4C1Phe-D3Pa1-Ser-NMeTyr-DLys(Nic)-Leu-Lys(Nisp)-Pro-DA1aNH 2 , N(4H 2 -furoy1)G1y-D2Na1-D4C1Phe-D3Pa1-Ser-NMeTyr-DLys(Nic)-Leu-Lys(Nisp)-Pro-DA1aNH 2 , cetrorelix, ganirelix, antarelix, detirelix, azaline, antide, ramorelix and abarelix. These peptides can be produced by the methods described in the above prior art documents or similar methods.  
         [0044]    As a concrete example of a biologically active peptide having LH-RH agonistic action, i.e., an LH-RH agonist, a biologically active peptide expressed by the following general formula [Ib] or its salt may be recited. 
         5-oxo-Pro-His-Trp-Ser-Tyr-Y-Leu-Arg-Pro-Z  [Ib] 
         [0045]    In the formula, “Y” denotes a residual group selected from DLeu, DA1a, DTrp, DSer(tBu), D2Na1 and DHis(ImBz1) and “Z” denotes NH—C 2 H 5  or G1y-NH 2 . Especially, a peptide in which “Y” is Dleu and “Z” is NH—C 2 H 5  or its salt is suitable. These peptides can be produced by the methods described in the above prior art documents or similar methods.  
         [0046]    A concrete example of the somatostatin derivative or its salt is described in, for example, “Proceedings of the National Academy of Sciences of the United States of America”, Vol. 93, p.p. 12513-12518 (1996) or the documents cited therein.  
         [0047]    Furthermore, as a concrete example of a somatostatin derivative selectively effective for tumor in somatostatin analogues, a biologically active peptide described in U.S. Pat. No. 5,480,870 or EP-505680-A and having the following formula may be recited.  
                         
 
         [0048]    Meanwhile, Sandostatin in U.S. Pat. Nos. 4,087,390, 4,093,574, 4,100,117 and 4,253,998 may be suitable.  
         [0049]    In the above described biologically active peptides, 5-oxo-Pro-His-Trp-Ser-Tyr-DLeu-Leu-Arg-Pro-NH—C 2 H 5  (leuprorelin) or its salt, especially, acetate is preferable.  
         [0050]    As the above biologically active substances, non-peptide drugs, etc. may be used. More specifically, compounds described in, for example, Japanese Patent No. 2946298 and Japanese Patent Laid-Open Publication Nos. 3-232880 (1991) and 4-364179 (1992) may be recited as the drugs.  
         [0051]    As is clear from the foregoing description of the gasket  50  for the bypass type prefilled syringe, according to the present invention, at the time of communication between the front and rear compartments  6  and  7  via the bypass  1   a , since the tubular body  1  at the front end side of the bypass  1   a  is closed by the front end portion of the front gasket segment  51  and the pharmaceutical liquid L is introduced into the powdery medicament P along the U-shaped outflow path proceeding from the annular recess  60  to the axial slots  70  by way of the axial slots  71  and the annular recess  59 , a squirt phenomenon of the pharmaceutical liquid L is prevented positively. As a result, since the powdery medicament P is sufficiently dissolved or dispersed in the pharmaceutical liquid L, satisfactory injection liquid can be prepared at all times.  
         [0052]    Meanwhile, in the gasket  50  for the bypass type prefilled syringe, according to the present invention, at the time of communication between the front and rear compartments  6  and  7  via the bypass  1   a , since the pharmaceutical liquid L carried into the annular recesses  84  and  85  of the rear gasket segment  52  and the annular recesses  60  to  62  of the front gasket segment  51  is intercepted by the axial ribs  86  and  87  and the axial ribs  63  to  65 , respectively so as to be delivered forwardly, the pharmaceutical liquid L is efficiently introduced into the powdery medicament P without incurring such a loss that the pharmaceutical liquid L remains in the annular recesses  84  and  85  of the rear gasket segment  52  and the annular recesses  60  to  62  of the front gasket segment  51  for a long time.  
         [0053]    Furthermore, in the gasket  50  for the bypass type prefilled syringe, according to the present invention, since the cross-sectional area of the flow path of the axial slot  70  opening to the front end face  51   a  of the front gasket segment  51  is set to be larger than that of the axial slot  71  formed on the circumferential rib  55 , delivery speed of the pharmaceutical liquid L in the axial slots  70  drops below that of the pharmaceutical liquid L in the axial slots  71  in the U-shaped outflow path at the time of communication between the front and rear compartments  6  and  7  via the bypass  1   a , so that the squirt phenomenon of the pharmaceutical liquid is prevented more positively.  
         [0054]    In addition, in the gasket for the bypass type prefilled syringe, according to the present invention, since the outside diameter D 1  of the circumferential ribs  54  and  55  is set to be equal to or larger than the inside diameter of the tubular body  1  but smaller than the outside diameter D 2  of the circumferential ribs  56  to  58 , the small-diameter circumferential ribs  54  and  55  are lightly fitted into the tubular body  1  forwardly of the bypass  1   a  at the time of communication between the front and rear compartments  6  and  7  via the bypass  1   a , so that an operation of advancing the front end of the gasket  50  to the marked line  1   b  can be performed smoothly.