Abstract:
The application refers to hypodermic needles ( 101 ) for the parenteral administration of liquids. The needles incorporate at their sharp-end an obstruction ( 102 ) of rapidly water-soluble material that dissolves within living tissues once the needle is injected. These needles ensure that the end user can only operate the syringe, or injection device, once the needle has been injected. The use of these hypodermic needles avoids the possibility of the user expelling any amount of liquid prior injection, ensuring the administration of the complete dose. These hypodermic needles are of special interest in preloaded injection devices and in the administration of small volumes of liquid were ejection of part of the dose by the user may result in the administration of only a fraction of the intended dose.

Description:
INVENTION FIELD 
       [0001]    The invention refers to hypodermic needles for the parenteral administration of liquids and medicines. The hypodermic needles incorporate a simple addition that ensures that the user cannot expel any amount of the liquid before injection of the needle into the receiving animal or human. 
       BACKGROUND 
       [0002]    Many drugs are administered parenterally by means of injection by trained medical personnel. The misconception that the air container in the needle can become a problem upon injection has lead to the widespread custom of eliminating the air from the needle by means of a gentle pressure over the syringe until a small amount of liquid is expelled through the sharp end of the needle. This does not generally represent a problem in the administration of large volumes where the potential loss represents a small fraction of the total volume of liquid to be injected. However, this practice can become a serious limitation in the injection of small volumes of liquids or in situations in which the first fractions of liquid to be injected contains a large fraction of the dose of the drug to be administered. 
         [0003]    Un example of preloaded devices that incorporate small volumes for the low cost administration of medicines is exemplified by Uniject™ Devices of this kind have also been proposed for the administration of formulations that do not require refrigeration. Examples of these formulations are described in patent application WO-98/41188 that incorporates solid suspensions in injectable oils, and also in patent application WO-02/032402 that incorporates fluorocarbons as a means to suspend solid soluble particles containing a drug or vaccine. However, in these preloaded devices incorporating small volumes, the common practice of expelling the air contained in the needle can result in the loss of a considerable fraction of the dose to be administered. 
         [0004]    Another method proposed in the administration of drugs and vaccines incorporates the stabilisation of drugs in a solid form in a cartridge located at the syringe end of the hypodermic needle. Devices of this kind are an object of an innovation program promoted by the World Health Organisation [Lloyd J. (2000)  Technologies for Vaccine Delivery in the  21 st Century . WHO/V&amp;B/00.35]. Examples of these devices are described in patent application US200310068354 that incorporates a membrane on which the DNA material which constitutes the vaccine is lyophilised, and in patent application WO2007/057717 which incorporates a cartridge holding a fibrillar support with a large surface area on which the drug or vaccine is stabilised within a fine film of dry amorphous glass. 
         [0005]    In both cases, the injection of an aqueous solution through the cartridge results in the rapid dissolution and carry over of the medicament, most of it in the first fraction of the liquid. Once more, the ejection of a small amount of liquid prior to injection can result in the administration of a suboptimal dose of the drug or vaccine. 
         [0006]    In general, the existing devices for the parenteral administration of liquids do not provide a method to avoid the user in expelling a small amount of liquid through the injection needle prior to the injection, and this can originate a considerable reduction of the dose to be administered. 
         [0007]    It would therefore be desirable to have simple means in the parenteral administration of liquids that prevents the end user from expelling a fraction of the medicament prior to injection. This would be of particular interest in the administration of non-aqueous suspensions of medicines, or in the administration of medicines which are stabilised within a cartridge at the syringe-end of the needle, were the initial disposal of a small volume may carry-over a considerable proportion of the total dose to be administered. 
       INVENTION SUMMARY 
       [0008]    The common custom of sanitary personnel to expel an amount of liquid before proceeding to the injection of a drug or medicament can result in the administration of a fraction of the recommended dose. This is particularly relevant in the parenteral administration of small volumes, in preloaded devices, or in devices that incorporate the drug or vaccine in a cartridge in-line within the syringe-end of the needle. The incorporation of a soluble obstruction within the sharp-end of the hypodermic needle provides needles that are only operational once they are injected and the soluble obstruction dissolves in the tissues of the injected human or animal subject. These needles avoid the possibility that the user can expel part of the dose prior to injection and facilitate the administration of the full dose of the drug or vaccine. 
     
    
     
       DESCRIPTION OF THE FIGURES 
         [0009]      FIGS. 1A-D . Represent the steps in the process of injection of a hypodermic needle which contains a soluble obstruction at its sharp-end.  FIGS. 1A-D  represent longitudinal sections of the different moments in the injection process of a hypodermic needle  101  that incorporates in its sharp-end an obstruction  102  with a soluble material.  FIG. 1A  represents a hypodermic needle prior being used.  FIG. 1B  represents a hypodermic needle at the moment of injection in the human or animal tissues  105 .  FIG. 1C  represents a hypodermic needle at the moment immediately alter injection once the obstruction  102  has dissolved trough contact with the surrounding tissues.  FIG. 1D  represents the hypodermic needle at the moment in which the drug or vaccine in liquid solution or suspension  104  is administered. 
           [0010]      FIGS. 2A-B . Represent a preloaded device loaded with a drug or vaccine in a liquid format and incorporating a soluble obstruction at the sharp-end of the hypodermic needle.  FIG. 2A  represents a longitudinal section of an injector device  203  for drugs and vaccines in a liquid solution or suspension  204  that incorporate a soluble obstruction  202  at the sharp-end of a hypodermic needle  201 .  FIG. 2B  represents an amplified view of the sharp-end of the hypodermic needle  201  and the soluble obstruction  202 . 
           [0011]      FIGS. 3A-B . Represent a device containing a drug or vaccine in a solid format within a cartridge of a hypodermic needle and containing a soluble obstruction at the sharp-end of the hypodermic needle. 
           [0012]      FIG. 3A  represents a longitudinal section of a device that at the sharp-end of a hypodermic needle  301  incorporates a soluble obstruction  302 . The drug  306  in a solid format is incorporated within a cartridge  305  located at the syringe end of the hypodermic needle  301 . The injection device  303  contains water for injection  304 .  FIG. 3B  represents an amplified view of the sharp-end of the hypodermic needle  301  and the soluble obstruction  302 . 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0013]    The present invention refers to hypodermic needles  101 ,  201  or  301  for the administration of solutions and suspensions of drugs, medicines and vaccines, that contain at their sharp-end a water-soluble obstruction  102 ,  202  or  302 , as is represented in  FIGS. 1A-D ,  2 A-B and  3 A-B. 
         [0014]    Penetration of the hypodermic needles  101 ,  201  or  301  in living tissue of a human or animal subject results in the almost instantaneous dissolution of the obstruction  102 ,  202  or  203 , and permits the injection of the liquid containing the drug or vaccine. The incorporation of the obstruction  102 ,  202  or  302  avoids the user from expelling part of the liquid contained within the injection device prior to the needle penetrating the tissues of the receiving animal or human subject. The hypodermic needles  101 ,  201  or  301  have preferred internal diameters ranking from 0.1 mm y 1 mm, and the capacity of administering drugs and vaccines by injection to depths up and over 5 cm. However it is acknowledged that larger internal diameter needles may be applicable in other fields of animal and plant health. The obstruction  102 ,  202  or  302  is preferably composed by materials which are rapidly soluble in aqueous media and that dissolve once the needle penetrates living tissues. Examples of these include, with out limitation, carbohydrates, sugar alcohols, amino acids, proteins, polymers, salts and/or mixtures thereof. Applicable carbohydrates and sugar alcohols include, with out limitation, maltodextrin, trehalose, raffinose, cellobiose, melezitose, glucose, fructose, maltulose, iso-maltulose, lactulose, maltose, gentobiose, lactose, galactose, isomaltose, manose, maltitol, lactitol, eritrol, palatinitol, inositol, xilitol, mannitol, sorbitol, dulcitol and/or ribitol and mixtures thereof. Preferably the carbohydrates are chosen from those that are acceptable for injection, with great solubility, and solid at a temperature of at least 45° C., like for example mannitol, trehalose, raffinose, sucrose and/or glucose. Preferably the amino acids are chosen among those that are acceptable for injection, highly soluble and solid at a temperature up to 45° C. like for example proline, cysteine, arginine, glutamine and/or glycine, and mixtures thereof. Applicable proteins include, with out limitation, collagen, hyaluronic acid, fibronectin, gelatine, and/or agaroses, and mixtures thereof. The applicable polymers, include with out limitation, polyvinyl alcohols, polyvinylpyrrolidone and/or polyethylene glycols, and mixtures thereof. Compatible solutes such as, with out limitation, glycine-betaine, ectoin, hydroxyectoin, can also be incorporated. Moreover, the obstruction  102 ,  202  or  302  can incorporate materials that result in an effervescent reaction when in contact with an aqueous media. Examples of this, with out limitation, include sodium carbonates. Other acceptable salts which are rapidly soluble and have the additional benefit of being efflorescent include, sodium sulphate, acetate trihydrate, tetraborate decahydrate (Borax), bromoiridite dodecahydrate, carbonate heptahydrate metaperiodate trihydrate, metaphosphate hexahydrate, hydrogen orthophosphate dodecahydrate, sulphite heptahydrate, thiosulphate pentahydrate, calcium lactate, magnesium salicylate tetrahydrate, magnesium sulphate heptahydrate, and ammonium sulphate. 
         [0015]    The incorporation of the obstruction  102 ,  202  or  302  in the hypodermic needle can be done by means of the incorporation of solutions of the soluble material and subsequent solidification by evaporation. The obstruction can also be incorporated by heating of the solid obstruction materials at temperatures in which they become malleable or liquid. The incorporation of a predetermined volume and subsequent cooling results in the fabrication of the desired soluble obstruction. Other methods that permit the incorporation of a soluble obstruction include the incorporation of soluble membranes or puncture with the needle of a solid matrix that becomes incorporated at the needle end. 
         [0016]    The present invention is applicable, among others, to preloaded devices such as those represented in  FIG. 2A-B . The incorporation of the obstruction  202  ensures that administration of the drug or vaccine  2004  contained in the reservoir  203  is only possible once the hypodermic needle has been injected and the obstruction  202  has dissolved in the receiving living tissues. One preferred realisation of the present invention incorporates devices preloaded with solutions or suspensions of the drug or vaccine in non aqueous liquids, such as, and with out limitation, oils or fluorocarbons. Preferably the material that composes the obstruction  202  is not soluble in these non-aqueous liquids and therefore does not dissolve until the needle has penetrated the receiving living tissue. 
         [0017]    In another realisation represented in  FIGS. 3A-B , the hypodermic needle  301  that incorporates at its sharp-end the obstruction  302 , also incorporates a cartridge  305  that contains the drug or vaccine  306  stabilised in a solid format. Administration of the drug or vaccine involves the assembly with an injector device  303  containing saline or water for injection  304 . Injection of the hypodermic needle into living tissues results in the dissolution of the obstruction  302  permitting the flow of the water for injection  304  through the cartridge, and carry over of the dissolved drug or vaccine  306 . 
         [0018]    The hypodermic needles describes in the present invention incorporate at their sharp-end a soluble obstruction  102 ,  202  or  302  which makes them functional only once they encounter an aqueous media such as a living tissue, as is illustrated, with out limitation, in the following three examples. 
       Example 1 
     Injection of Tetanus Vaccine Formulated as Suspension in Oil by Means of a Preloaded Device Incorporating a Hypodermic Needle with a Soluble Obstruction at its Sharp-End 
       [0019]    The device represented in  FIGS. 2A-B  was made to incorporate a soluble obstruction  202  of trehalose at the sharp-end of a 0.6 mm internal diameter stainless steel bevelled hypodermic needle  201 . For this, the sharp-end of the needle was dipped in a trehalose melt at about 100° C. Cooling of the tip resulted in the formation of an obstruction  202  of solid amorphous trehalose glass. The needle incorporating the obstruction was assembled to a flexible PVC ampoule as injector device  203 . As a model drug or vaccine  204 , the ampoule contained 1 ml of a suspension in sesame seed oil of 1-10 μm trehalose particles containing stabilised tetanus vaccine. Pressure of the final user on the pre-filled ampoule did not result in the ejection of any amount of the contained suspension. Intramuscular injection of the needle in a guinea pig resulted in the immediate dissolution of the obstruction  202  and permitted the administration of the complete dose of the vaccine suspension by gentle pressure by the user over the ampoule. 
       Example 2 
     Injection of a Hepatitis B Vaccine Stabilised in a Solid Format in a Cartridge Located at the Syringe End of a Hypodermic Needle Incorporating a Soluble Obstruction at its Sharp-End 
       [0020]    The device represented in  FIGS. 3A-B  was manufactured to incorporate a soluble obstruction  303  of mannitol at the sharp end of a 0.3 mm internal diameter stainless steel bevelled hypodermic needle  201 . For this the sharp-end tip of the hypodermic needle was introduced in a 60% mannitol solution in water at about 70° C. Removal of the needle and cooling of the tip resulted in the formation of a solid obstruction with a mannitol crystal at the sharp-end of the needle. The needle carried at the syringe end a cartridge  305  containing as a model drug or vaccine  306  a hepatitis B vaccine stabilised in an amorphous water-soluble trehalose glass. Prior to injection a conventional syringe  303  containing 1 ml of water for injection, was assembled to the hypodermic needle  301 . Once assembled, pressure over the syringe  303  did not result in the ejection of any amount of liquid trough the syringe. Subcutaneous injection of the needle into a guinea pig and gentle pressure over the syringe resulted in the immediate dissolution of the obstruction  302  permitting the flow of water for injection  304  through the cartridge  305  and administration of a full dose of the drug  306 . 
       Example 3 
     Evaluation of Suitability of Different Needle Obstruction Materials 
       [0021]    A hypodermic bevelled stainless steel needle, as for example in  101 , with an internal diameter of 0.8 mm was used to evaluate suitability of different materials to create the sharp-end obstruction  102 . The needles containing approximately 1-3 mm 3  volume of the different obstruction materials were assembled on to a syringe containing 1 ml sesame seed oil and injected into a set 3% gelatine block at 25° C. as a model of a living tissue  103 . Dissolution time was estimated from the time of injection. Rapidly dissolving materials generally categorised as suitable needle-end obstruction materials (++++) while slower dissolving materials generally resulted in delayed injection and were categorised as less suitable obstructing materials (+). 
         [0000]    
       
         
               
               
               
             
           
               
                   
                   
               
               
                   
                   
                 Suitability as 
               
               
                   
                   
                 needle 
               
               
                   
                   
                 obstructing 
               
               
                   
                 Obstruction Material 
                 material 
               
               
                   
                   
               
             
             
               
                   
                 Trehalose (from melt) 
                 +++ 
               
               
                   
                 Trehalose + 2% sodium bicarbonate (from melt) 
                 ++++ 
               
               
                   
                 Trehalose + 5% Calcium Lactate + 2% sodium 
                 ++++ 
               
               
                   
                 bicarbonate 
               
               
                   
                 Sucrose (from solution) 
                 +++ 
               
               
                   
                 Sucrose + 5% Sodium Sulphate (from solution) 
                 ++++ 
               
               
                   
                 Trehalose + 5% Calcium Lactate (from solution) 
                 +++ 
               
               
                   
                 20% Mannitol + 70% Trehalose (from melt) 
                 ++++ 
               
               
                   
                 Mannitol (from melt) 
                 ++++ 
               
               
                   
                 Hydroxyectoine (from solution) 
                 ++++ 
               
               
                   
                 Glycine Betaine (from solution) 
                 ++++ 
               
               
                   
                 Polyvinyl alcohol (from solution) 
                 + 
               
               
                   
                 Proline 
                 ++++ 
               
               
                   
                 Arginine•HCl 
                 ++++ 
               
               
                   
                 Cysteine 
                 + 
               
               
                   
                 Alanine 
                 ++++ 
               
               
                   
                 Tyrosine 
                 +