Patent Document

FIELD OF THE INVENTION 
       [0001]    The present invention relates to intradermal, subcutaneous or intramuscular drug delivery. More particularly, the present invention relates to rapidly implanting an active pharmaceutical ingredient into the body painlessly. 
       BACKGROUND OF THE INVENTION 
       [0002]    Administration of drug into human bodies is one of the most important interventions in medical treatment and disease prevention. There are two general drug administration routes that are commonly practiced, namely enteral and parenteral drug administration. The enteral administration route involves the esophagus, stomach, and intestines and parenteral administration route involves injection and infusion by needles. The most common enteral administration is oral administration (i.e. eating or drinking the drug). The advantage of this route is that it is easy to do, but the disadvantage is that the drug may be disintegrated or degraded by the gastro-intestinal tract and therefore much higher dose is needed, which may be toxic to the body. For this reason, all biologics are not suitable to be administered orally because the gastro-intestinal tract will digest or degrade them. 
         [0003]    On the other hand, parenteral administration generally involves injection or infusion via cannulas, which includes subcutaneous, intradermal, intramuscular and intravenous injections using stainless steel needles. Parenteral injections avoid the gastro-intestinal tract so is ideal for biological drugs such as peptides, hormones, vaccines and antibodies. Its other advantages are fixed and accurate doses and short administration times, normally within 3-5 seconds for injections (except for infusion). Its main disadvantage is the pain incurred during the short period of time. The pain associated with parenteral injections is caused by two separate actions, namely the insertion of needle and the injection of liquid into the body. There is a long-felt need to eliminate the pain caused by parenteral injections. 
         [0004]    Microneedles were invented to provide a solution to eliminate the pain due to parenteral injections. There are two kinds of microneedles: the first kind is solid microneedles in which drug is loaded on the microneedles and is delivered to the body when the microneedles penetrate into the skin; another kind is hollow microneedles in which drugs are injected into the skin through the hollow microneedles. The insertion of solid and hollow microneedles is quite painless due to the micron-size of the microneedles. But due to the size of the solid microneedles, the amount of the drug which can be loaded on the microneedles is very limited. 
         [0005]    As a matter of fact, there are many problems associated with delivering drug using solid microneedles. For example, there are commonly two ways to load the drugs on the solid microneedles: (a) the drugs may be coated on the surface of non-dissolving microneedles or (b) the drugs may be mixed with dissolving materials such as hyaluronic acid and moulded into dissolvable microneedles. The solid microneedles by the first method, apart from having limited drug loading capacity, is not able to deliver complete dose because the coated drug will come off the needles&#39; surface and stay outside the skin. The U.S. Pat. No. 8,361,022 B2 awarded to Alza Corp. and U.S. Pat. No. 7,846,488 B2 awarded to 3M Innovative Properties Company reported the inventions involving the coating of drugs on solid microneedles. 
         [0006]    The second method to load drugs on the solid microneedles is to mix the drug with the dissolving material and mould the mixture into dissolvable microneedles. The dissolving materials may be hyaluronic acid, chitosans, hydrogels and other polymers that dissolve upon making contact with the skin. Among other problems, the paramount issue is that the drug mixture becomes a new form of drug and therefore requires separate clinical approval if the drugs involved are controlled by the regulatory bodies. This imposes great impedance for the technology to reach the market because the clinical trials involved are lengthy and expensive, and each drug has to undergo a new drug approval process. U.S. Pat. No. 8,167,852 B2 awarded to Cosmed Pharmaceutical Co. Ltd and U.S. Pat. No. 8,506,980 B2 awarded to Bioserentach Co. Ltd reported inventions related to this type of microneedles. 
         [0007]    We mentioned earlier that drugs can also be injected via hollow microneedles. In this case, the insertion of hollow microneedles into the skin is quite painless and they can continuously inject liquid drugs into the skin, which in this case increase tremendously the deliverable amount of the drug. But the injection of liquid via hollow microneedles into the skin causes pain, and since the hollow microneedles&#39; injection rate is much lower than that of the conventional cannulas, the pain is felt much longer (the delivery time for 0.5 ml is 5-30 minutes for hollow microneedles compared to 3-5 seconds for cannulas). Therefore, microneedles do not totally solve the pain associated with parenteral injections. PCT application WO 2011/014514A1, which was filed by 3M Innovative Properties Company reported such a technology. 
         [0008]    There is yet another new technology developed by Glide Pharma involves inserting a drug load at a few metre per second with the help of a pioneer projectile, which is made of a biodegradable material. Typical drug may not have the required hardness for penetrating the skin, so a biodegradable pioneer projectile, which has sufficient hardness to penetrate the skin, is used as an ‘introducer’ for allowing the drug load to enter the skin. The introduction of a foreign material into the skin for the purpose of drug delivery may not be desirable. The foreign material, although biodegradable, may be considered as a new excipient and makes the drug a new drug, which is then subjected to new drug registration process. 
         [0009]    It can be seen that the current drug administration techniques including enteral, parenteral and microneedle administrations fail to provide a painless and high-dose drug administration platform. To achieve these three requirements, a device has to be designed to address these three issues, which are inter-dependent. 
         [0010]    To start with, a substantial drug loading capacity has to be viable to fulfil most dosage (a few micro grams to a few milligrams), which should be achieved without introducing any new excipients because any new mixture will be treated as a new drug. A typical drug load of these dosages normally amounts to a few nanolitres to a few microliters of volume, which must be transported into the body painlessly. Injecting drug loads at this size into the body will certainly cause pain because the body will need to make space for the drug load which is foreign to the body. 
         [0011]    Secondly, the delivery of the drug load should be done as quickly as possible. Currently the parenteral injections are done within 3-5 seconds and the new delivery system should not take more than that because the psychological stress under which a patient is subjected may be too huge and one second more may be unacceptable to the patient. Lastly and most importantly, the rapid delivery of substantial drug load has to be carried out painlessly, otherwise such a device is no better than current needles and syringes. 
         [0012]    There is a long-felt need in administering drug to a body painlessly, rapidly, and completely. The present invention seeks to provide a solution for drug administration to the body which is painless, rapid and high dosing. 
       SUMMARY OF THE INVENTION 
       [0013]    The present invention provides a solution for addressing the design requirements for delivering drug rapidly and painlessly with high and complete dose, which cannot be achieved by microneedles or conventional needles. The present invention relates to a drug implant device which delivers a drug load to a body painlessly. The present invention achieves the drug implantation by adopting two principles: (1) rapid perpendicular insertion of fine cannula is painless and that (2) pain is incurred only when the occupied volume caused by the implant process is increased. Therefore, instead of inserting a cannula and injecting a volume of drug, which increases the additional volume for accommodating the additional volume of the drug during the injection process (i.e. the occupied volume), the present invention retracts the cannula in order to dispose expose the drug into the body. The retraction of cannula does not increase the occupied volume therefore incurs no pain. (In fact, it reduces the occupied volume of the implant process.) 
         [0014]    The present invention involves essentially rapid perpendicular insertion of a small amount of drug into the body intradermally, subcutaneously or intramuscularly in a painless manner. In the first preferred embodiment  100 , the present invention comprises a fine cannula  300 , which has a beveled tip for rapidly penetrating the body, a drug load  320  and an inner rod  340 , wherein the drug load  320  and the inner rod  340  are slidably disposed within the cannula  300  and that the drug load  320  is disposed at the beveled end of the cannula  300  (i.e. the forward position) while the inner rod  340  is disposed adjacent to the drug load  320  (i.e. the rearward position). When the first preferred embodiment  100  is in use, the cannula  300 , the drug load  320  and the inner rod  340  are rapidly inserted together into the body (in a substantially perpendicular manner in order to eliminate pain) so that the drug load  320  is transported to the desired depth, after which the cannula  300  is retracted while the inner rod  340  and the drug load  320  remain stationary relative to the cannula  300 , thereby disposing the drug load  320  at the desired depth of the body, and after which the cannula  300  and the inner rod  340  are fully removed from the body. 
         [0015]    The first preferred embodiment  100  may be used with a spring applicator  500  for achieving the desired insertion speed. The spring applicator  500  comprises a slidable casing  520 , a transparent cap  540 , a returning spring  560 , an actuation spring  580 , a button  600 , and a vault  620 . When in operation, device  100  is inserted into spring applicator  500  and is attached to the vault  620 . Next, the slidable casing  520  is pulled backward to compress the actuation spring  580 , the returning spring  560  will return the slidable casing  520  back to its original position. Lastly, button  600  is depressed to release the vault  620  and the actuation spring  580  will propel the device  100  with the desired speed for rapid insertion. 
         [0016]    In the second embodiment, the drug implanting device  1000 , a simplified version of the first preferred embodiment is provided. The drug implanting device  1000  comprises a top casing  1100   a , a bottom casing  1100   b , a lever button  1200  disposed on the top casing  1100   a , a compression spring  1300 , a cannula  1400 , a cannula holder  1500  on which the cannula  1400  is fastened, an inner rod  1600  slidably disposed within the cannula  1600 , a rod stopper  1700  on which the inner rod  1600  is fastened, and a drug load  1800  disposed within the tip of the cannula  1400 . 
     
    
     
       BRIEF DESCRIPTIONS OF THE DRAWINGS 
         [0017]      FIG. 1  shows the three-dimensional view of the preferred embodiment of the present invention 
           [0018]      FIG. 2  shows the front view of the preferred embodiment of the present invention with the cap removed. 
           [0019]      FIG. 3  shows the steps of implanting a drug into a body by the first preferred embodiment of the present invention. 
           [0020]      FIG. 4  shows the close-up section view of the first preferred embodiment of the present invention after the cannula penetrates into the body. 
           [0021]      FIG. 5  shows the close-up section view of the first preferred embodiment of the present invention after the cannula retracts from the body, exposing the drug in the body. 
           [0022]      FIG. 6  shows the close-up section view of the first preferred embodiment of the present invention after the cannula and the inner rod retracts from the body, implanting the drug in the body. 
           [0023]      FIG. 7  shows a perspective view of the first preferred embodiment when used with a spring-loaded applicator. 
           [0024]      FIG. 8  shows a section view of the first preferred embodiment of the present invention when used with a spring-loaded applicator. 
           [0025]      FIG. 9  shows a perspective view of the second preferred embodiment of the present invention. 
           [0026]      FIG. 10  shows an exploded view of the second preferred embodiment of the present invention. 
           [0027]      FIG. 11  shows a section view of the second preferred embodiment of the present invention. 
           [0028]      FIG. 12 ( a ) to ( d )  shows the operation of the second preferred embodiment of the present invention. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0029]    The present invention aims to provide a painless means to deliver a sizeable drug load into the body. As discussed previously, the injection method is painful, partially due to the insertion of the needle into a body, but more significantly due to injecting a finite volume of drug into the body, which has to make space for that finite volume. The present invention achieves its objectives by two principles. The first principle is that when a cannula is rapidly inserted into the body in a substantially perpendicular manner, provided that the size is small enough, i.e. gauge size of 27 G to 34 G, i.e. with outer diameter between 0.4 mm-0.18 mm and that the insertion speed exceeds 1 m/s, the insertion of the cannula into the body is quite painless. Therefore, the present invention incorporates a rapid perpendicular insertion of cannula to eliminate pain due to needle insertion. 
         [0030]    The second principle is that pain is incurred only when the occupied volume caused by the implantation is increased; for example, injecting liquid drug into the body increases the occupied volume as the body needs to make space for the liquid, which causes pain. Instead of injecting any drug, which causes the body to make up the occupied volume for the drug (which is very painful), the present invention pre-loads a drug load  320  in the cannula  300  and rapidly inserts the drug-loaded cannula  300  into a body, after which the cannula  300  is retracted while keeping the drug load  320  in the body. This is achieved by having an inner rod  340  which is disposed in the cannula  300  to hold the drug load  320  in place during the retraction of the cannula  300 . In this way, the occupied volume caused by the insertion of the cannula  300  does not increase, but it actually decreases after the cannula  300  is retracted, causing no pain. Once the drug load  300  is disposed in the body, it is wetted by the interstitial fluid in the tissue and is fused to the tissue in the body and will not leave the body easily. Finally, the cannula  300  and the inner rod  340  are removed from the body completely. 
         [0031]    It is worth noting that while the insertion of the cannula  300  requires high speed, such as 1 m/s or more, the retraction of cannula  300  requires much lesser speed to prevent the drug load  320  from ‘splashing’ when the cannula  300  retracts. The reason is that the drug load  320  is always in physical contact with the inner surface of the cannula  300 , if the cannula  300  retracts in high speed, the surface friction will pull the drug load  320  together, the consequences are a portion of drug may stay in the cannula, and that the drug load  320  may be dispersed to other undesirable depths, causing the drug delivery un-controllable. The retraction speed can be achieved by reducing the actuation speed provided by a compression spring  280 . The speed reduction method may be employing a sliding piston that remains in good contact with the stationary surface during sliding, dampening the initial actuation force of the compression spring  280 . The sliding pistons are made of silicone rubber, or any material that is able to provide firm contacts between sliding surfaces. The retraction speed for the cannula should be less than 20 mm/s to ensure good implant quality. 
         [0032]    The present invention incorporating these two principles can be represented by two preferred embodiments, which are discussed in the following paragraphs.  FIGS. 1-6  describe the first preferred embodiment and  FIGS. 7 and 8  describe the second preferred embodiment. 
         [0033]    Now, we will describe the first preferred embodiment of the present invention. In  FIG. 1 , a perspective view of the device (first preferred embodiment)  100  is presented. The first preferred embodiment  100  comprises a housing  120  and a protective cap  140 , which is removed when the device is in use.  FIG. 2  shows a front view of the device  100  without the protective cap  140 . In this figure, the device  100  further comprises a trigger  200 , a slider  220 , a first piston  240 , a second piston  260 , a compression spring  280 , a cannula  300 , which has a beveled tip pointing forward, i.e. pointing away from the housing  120 , and a sliding slot  160  disposed on the housing  120 . Although not shown in the figure, it is important to know that there is an inner rod  340  and a drug load  320  disposed within the cannula  300 . The first piston  240  is fastened to the inner rod  340  and the first piston  240  will resist any unwanted movement due to its firm contact with the housing  120 . Similarly, the second piston  260  is fastened to the cannula and the second piston  260  will resist any unwanted movement due to its firm contact with the housing  120 . The material for making the pistons is silicone rubber, or any material that remains in good contact between sliding surfaces. 
         [0034]    The device  100  relies on manual insertion.  FIG. 3  shows how the device  100  operates for implanting a drug load into the body painlessly. First, the protective cap  140  (not shown) is removed to expose the trigger  200 , and the device  100  is brought near to a skin site with the trigger  200  pointing at the skin site. Next, the device  100  is compressed against the skin; this action pushes the trigger  200  rearward and at the same time rapidly inserts the cannula  300  in to the body. This rapid insertion by manual compression can be achieved by providing a thrust to the skin site while holding the device  100 . The slider  220 , to which the cannula  300  is fastened, which is latched originally, resists the penetration force exerted on the cannula  300 . At the same time, the first piston  240 , which is fastened to the inner rod  320  (not shown) and the second piston  260 , which is fastened to the cannula  300 , are held firmly in their respective position by surface friction. The pistons are made of silicone rubber or any other material which provides excellent compressibility and surface friction as seen in typical syringe plunger. 
         [0035]    The trigger  200  serves to conceal the cannula  300  when not in use. As the trigger  200  continues to be pushed rearward, it engages and unlatches the slider  220 ; as a result, the compressed compression spring  280  releases its potential energy and pushes rearward the slider  220 , which is fastened to the second piston  260  and the cannula  300 , sliding on the sliding slot  160 . This action retracts the cannula  300  while it is still in the body, disposing the drug load  320  to the body. The compression spring  280  continues to push the slider  220  and the second piston  260  rearward until the second piston  260  hits the first piston  240 , after which both pistons  240 ,  260  move rearward together. As the two pistons  240 ,  260  move rearward together, the cannula  300  and the inner rod  340  retract from the body together completely. This completes the drug implant process. The implanted drug load is properly disposed in the desired depth, normally within penetration depth of 1 mm-25 mm under the skin. 
         [0036]    It is vital to understand the exact mechanism of how the implant of drug load into a body can be achieved.  FIGS. 4 to 6  show the close-up schematic diagrams for implanting a drug load into a body using the device  100 .  FIG. 4  shows the device after the cannula is inserted into the body. As shown in  FIG. 4 , the cannula  300  is inserted in the body with depth of 1 mm-25 mm (intradermal to intramuscular range), the drug load  320  is disposed within the cannula  300  near the tip (i.e. the forward position) and the inner rod  340  is disposed within the cannula  300  and right behind the drug load  320  (i.e. the rearward position). The cannula  300  can be made of typical hypodermic needle with a beveled tip and the needle size (gauge size) ranges from 27 G-34 G, i.e. with outer diameter between 0.4 mm-0.18 mm and inner diameter between 0.2 mm-0.1 mm. The cannula  300  is fastened to the second piston  260  and the slider  220 . Two main functions of the cannula  300  are to penetrate the body and to carry the drug load  320  to the desired depth. 
         [0037]      FIG. 5  shows the state after the cannula  300  is retracted from the body, disposing the drug load  320 . It can be seen that the inner rod  340  which remains stationary prevents the drug load  320  from sticking to the cannula  300 . The inner rod  340  is a metal wire or plastic rod with a diameter the same as the inner diameter of the cannula  300 , which is fastened to the first piston  240 .  FIG. 6  shows the state after both the cannula  300  and the inner rod  340  are retracted from the body, leaving the drug load  320  in the body. The drug load  320  is made of solid drug with total volume of 0.16 uL-0.63 uL, or 0.16 mg-0.63 mg of active pharmaceutical ingredient (this is a very rough conservative estimate). 
         [0038]    The first preferred embodiment of the present invention can be used with a spring loaded applicator, which is shown in  FIGS. 7 and 8 . In this configuration, the first preferred embodiment uses a spring applicator  500  to propel the device  100  toward the body for consistent and repeatable insertion speed. The spring applicator  500  comprises a slidable casing  520 , a transparent cap  540 , a returning spring  560 , an actuation spring  580 , a button  600 , and a vault  620 . When in operation, device  100  is loaded into spring applicator  500  and is attached to the vault  620 . Next, the slidable casing  520  is pulled backward to compress the actuation spring  580 , and subsequently the returning spring  560  will return the slidable casing  520  back to its original position. Then, the spring applicator  500  is pointed to a body site with the transparent cap  540  resting on the skin site such that the spring applicator  500  is largely perpendicular to the body site. Lastly, the button  600  is depressed to release the vault  620  and the actuation spring  580  propels the device  100  towards the body with the desired speed (i.e. at least 1 m/s) for achieving consistent and repeatable rapid insertion. Once the device  100  is propelled to hit the body and the cannula is inserted into the body, the retraction of the cannula  300  and the inner rod  340  will automatically be carried out as shown in  FIG. 3  and  FIGS. 4-6 . 
         [0039]    There is a need to provide a simpler device to carry out the drug implant function in the present invention.  FIG. 9  shows the perspective view of the second preferred embodiment of the present invention, the drug implanting device  1000 , which is a simplified version of the first preferred embodiment.  FIG. 10  shows the exploded view of the drug implanting device  1000 . The drug implanting device  1000  comprises a top casing  1100   a  and a bottom casing  1100   b , a lever button  1200  disposed on the top casing  1100   a , a compression spring  1300 , a cannula with a beveled tip  1400 , a cannula holder  1500  on which the cannula with a beveled tip  1400  is fastened, an inner rod  1600  slidably disposed within the cannula with a beveled tip  1600 , a rod stopper  1700  on which the inner rod  1600  is fastened, and a drug load  1800  disposed within the tip of the cannula with a beveled tip  1400 . The drug load  1800  is disposed at the tip of the cannula  1400  and the inner rod  1600  is disposed adjacent to the drug load  1800  within the cannula  1400  such that drug load  1800  is held stationary by the inner rod  1600  when the cannula with a beveled tip  1400  is retracted, thereby disposing the drug load  1800  in the skin  2000 . 
         [0040]      FIG. 12 ( a ) to ( d )  shows the operation of the drug implanting device  1000 . In the initial stage, the cannula  1600  is exposed outside the drug implanting device  1000 . As shown in  FIG. 12( a ) , the cannula  1600  is rapidly inserted into the skin  2000  by hand so that the drug load  1800  is buried in the skin  2000 . Next, as shown in  FIG. 12( b ) , the lever button  1200  is depressed, causing a turning moment  3000 , thereby unlatching the lever latch  1200   a  from the cannula holder  1500 , which in turn releases the compressed spring  1300 . The compressed spring  1300  pushes the cannula  1400  and the cannula holder  1500  backward so as to expose the drug load  1800  in the skin  2000 . During this retraction of cannula  1400 , the inner rod  1600  is held stationary by the rod stopper  1700 . Finally, the inner rod  1600  and the cannula  1400  are removed from the skin site, leaving behind the drug load  1800  in the skin.

Technology Category: 1