Background Art Conventionally, a Ringer bottle containing a pharmaceutical composition is placed at a position higher than an injection position by using a separate stationary means, and the pharmaceutical composition is injected to a patient using gravity. A disposable pharmaceutical composition injection device, on the other hand, is operated in a manner such that the composition contained therein is injected via a silicon tube to a patient using the restoring force of the silicon tube, not gravity. Such a device may be used in delivering, in small doses, a pharmaceutical composition requiring an exact dosage, such as for epidural anesthesia during surgery, for pain alleviation after surgery, for acute and chronic pain relief of a cancer patient in a terminal stage, for injection of a local anesthetic to a pregnant patient who wishes to experience a painless delivery, and for injection of a narcotic or non-narcotic drug.

Such a disposable pharmaceutical composition injection device acts to deliver a pharmaceutical composition spinally or intravenously in a continuous manner and to always maintain a constant effective blood concentration. Therefore, pain can be continuously relieved and side effects

can be minimized.

Before the development of such a disposable pharmaceutical composition injection device, mechanical infusion pumps, syringe pumps and the like were used. However, they were too big and too heavy to carry, as well as being expensive. Therefore, their use was limited.

Meanwhile, in order to address these problems, U. S. Patent No. <BR> <BR> <P>5,120, 315 assigned to Baxter International Inc. , discloses a disposable infusion pump for administering a pharmaceutical composition. The infusion pump is a device used to deliver a compositon containing a medication, which is filled into a silicone tube, a kind of balloon, one end of which is provided with a glass rod having micro pores, to a patient, in small doses.

However, because the device is not provided with a separate filtering means, there is a likelihood that micro-bubbles in the composition may enter the body. Furthermore, the inner diameter of the glass rod must vary, depending on a desirable flow rate. Still further, because the tube is inflated in a lengthwise direction, rather than in a widthwise direction, the total length of the device is increased. Therefore, in order to support the tube inflated in a lengthwise direction, a long transparent cylindrical member is used. In addition, the device cannot use a general syringe when injecting of a pharmaceutical composition and thus requires a alternate means.

The Sidekick (trade name), commercially available from I-Flow corporation (America) manipulates a flow rate by varying a PVC tubing length ranging from a disposable infusion pump to a syringe. However, because the PVC tubing is sensitive to temperature, flow rate varies depending on the temperature. In particular, excess compositions may be injected to a patient under a high temperature environment.

Another injection device, commercially available from DIB corporation (Japan) is provided with a ceramic rod having micro pores as a flow regulator. Although the flow rate can be easily regulated, it is difficult

to manufacture the ceramic rod, and thus it is expensive.

The device disclosed in Korean Patent Application Laid-Open Publication No. 97-73614 regulates the flow rate using a glass rod, similar to the above U. S. Patent No. 5,120, 315. The device is provided with a filter in the form of a flat film in order to remove bubbles and insoluble materials in the composition. The tube thereof is designed to expand in a lengthwise direction. In this regard, this device is not so advanced, compared with the United States Patent as mentioned above. In particular, if the end of the glass rod used in regulating a flow rate is not finished well, there is likelihood that glass powder will enter the body.

The above conventional devices do not have a function for removing pyrogens generated after sterilization of a pharmaceutical composition and therefore contain a risk factor upon actual use. In addition to this problem, in order to provide variable doses of a composition, multiple flow controlling parts with different diameters must be manufactured separately. Multiple tubes with different elasticity must also be manufactured. Therefore, the flow rate is kept constant in one device. In this regard, the physician can select one of the multiple devices that are different in a flow rate, depending on the patient's condition. However, when the physician feels a need to change the flow rate during use, the device must be inconveniently changed to another device providing a desirable flow rate.

Therefore, there is a need for the development of such a device that is safe in use, is made of inexpensive materials, and can administer pharmaceutical composition at a constant flow rate without worry of excess injection, and which can effectively remove any materials dangerous to the body and be produced efficiently.

In this regard, the present inventor filed an application, which has now qualified as Korean Patent No. 301694. This patent relates to a pharmaceutical composition injection device, in which the flow rate can be regulated using a hollow fiber membrane that is contained in a central rod.

The present application has been invented to complement and improve the content of the patent. Because the hollow fiber membrane of the device disclosed in Korean Patent No. 301694 is contained in its central rod, it takes 30 minutes to 1 hour to allow the composition in the hollow fiber membrane to reach the syringe-connecting part via a PVC tubing. In addition, other units cannot be attached to the device. On the other hand, the hollow fiber membrane of the present invention is provided at the outside of a central rod, in particular, a syringe-connecting part. Therefore, the time required for a composition to reach a patient is shortened to about 2 minutes.

Furthermore, after the device is filled with pharmaceutical composition, the device may further comprise separate units that enable the control of a flow rate to a desirable level, or when a patient feels much pain, can help relieve the pain temporarily.

Disclosure of the Invention Therefore, the present invention has been made in view of the above problems, and it is an obj ect of the present invention to provide a disposable pharmaceutical composition injection device with a simple structure for administering the pharmaceutical composition at a constant flow rate.

It is another object of the present invention to provide a disposable pharmaceutical composition injection device for preventing impurities such as micro bubbles and pyrogens from entering the body, achieved by removing the impurities by improving the filter function.

It is a further obj ect of the present invention to provide a disposable pharmaceutical composition injection device, which can be used on a patient within a short period after filling of the pharmaceutical composition, and can be provided with separate units.

It is another object of the present invention to provide a disposable pharmaceutical composition injection device, further comprising a separate

unit for changing a flow rate, if needed, during use of the device.

It is yet another object of the present invention to provide a disposable pharmaceutical composition injection device, further comprising a separate unit which, during use of the device, provides a temporary pain relief when a patient feels much pain temporarily.

Brief Description of the Drawings The above and other objects, features and other advantages of the present invention will be more clearly understood from the following detailed description taken in conjunction with the accompanying drawings, in which : Fig. 1 is a schematic view showing the disposable pharmaceutical composition injection device according to the present invention; Figs. 2 and 3 are cross sectional views showing a central rod and a flow controlling part, respectively, in the device according to the present invention; Fig. 4 is an assembled cross sectional view showing a flow regulating unit in the device according to the present invention; Fig. 5 is an assembled cross sectional view showing a temporary pain relief unit in the device according to the present invention; Fig. 6 is a graph showing the variation in flow rate with time in respective devices according to the present invention and Baxter International Inc. (America); and Fig. 7 is a graph showing the variation in the total flux with time in respective devices according to the present invention and Baxter International Inc. (America).

Best Mode for Carrying Out the Invention

The above and other objects can be accomplished by the provision of a disposable pharmaceutical composition injection device using a hollow fiber membrane, which acts as a flow regulator and a filter at the same time.

In particular, the device can effectively remove pyrogens generated when sterilized. In addition, the surface area of the hollow fiber membrane can be regulated according to the desired flow rate. Because the hollow fiber membrane is provided at the outside of the central rod, the time required for a composition to reach a patient can be drastically shortened. Still more, the device may further comprise various units. Therefore, the unit production cost is lowered, thereby increasing productivity. In particular, in order to change a flow rate, there is no need to use new silicone rubber balloons with different elasticity. Therefore, a flow regulating unit or a temporary pain relief unit can be coupled with the silicone rubber balloon.

The present device may further comprise a flow regulating unit provided with pluralities of flow controlling parts 70 with different flow rates, the lower ends of which are coupled with valves 97, and operated in a manner such that the valves are closed or opened for effectively changing the flow rate while administering a pharmaceutical composition to a patient. In addition, the device may further comprise a temporary pain relief unit provided with two flow controlling parts 70 with different flow rates, in which a first part is directly connected to a patient and a second part is connected to a storage bag with a button, and operated in a manner such that when a patient feels much pain, the composition contained in the storage bag is altogether injected into the patient via the second part, by pushing the button for relieving the pain temporarily.

[Example 1] Fig. 1 is a schematic view showing the disposable pharmaceutical composition injection device according to the present invention. Referring to Fig. 1, the device comprises a central rod 10 made of polysulfone, a PVC

tubing 60 that is connected with the lower central end of the central rod, and a silicone tube 30 outside of the central rod. The PVC tubing is connected to a flow controlling part 70, a flow regulating unit 90, or a temporary pain relief unit 120. The device further comprises a composition inlet port 50 at the upper end of the central rod 10 for injecting the composition and a backflow prevention valve 14 in the inside of the central rod for preventing the injected composition from flowing backward. The composition inlet port 50 is sealed with a cap 20 for preventing any foreign substances from being introduced.

When the silicone tube 30 is filled with the pharmaceutical composition, it is inflated like a balloon and exerts an appropriate force on the pharmaceutical composition using its elasticity so as to expel the pharmaceutical composition toward the hollow fiber membrane. In this regard, the tube must have an effective elongation ratio and elasticity. The elongation ratio and elasticity depends on the use of the device. Generally, when the interior of the tube is filled with a desirable amount of the pharmaceutical composition, the elongation ratio and elasticity are selected such that the internal pressure is 1 to 100 psi, preferably 2 to 40 psi. The tube material is selected from the elastic rubber group consisting of natural rubber, synthetic rubber, silicone rubber, polyurethane, and copolymer thereof, depending on use. Considering that the tube must be applied to the human body and at the same time exert a small force on the pharmaceutical composition, the silicone tube is most preferable. The central rod 10 is covered with the silicone tube 30, which is sealed with a rubber ring. The silicone rubber balloon tube is disposed within an outer casing 40 for preventing the balloon from rupturing due to an environmental impact while being filled with the pharmaceutical composition.

In Fig. 1, reference numbers 80 and 100 indicate syringe needle coupling screws and reference number 110 indicates a cap for the syringe needle coupling screw. A button for a temporary pain relief unit is designated as 130 and a flow controlling part is designated as 70.

Fig. 2 is a cross sectional view showing the central rod of Fig. 1, and

Fig. 3 is a cross sectional view showing the flow controlling part of Fig. 1. In the Figures, the central rod 10 comprises an upper part 11, a central part 12, and a lower part 13. The length of the central rod can be regulated depending on the volume of the pharmaceutical composition. That is, if the volume of the pharmaceutical composition is 100 ml, the central rod is used in a state wherein all the parts are connected with each other; while, if the volume is 50 ml, the central rod is used in a state wherein the upper part and the lower part are directly connected with each other. The inner side of the upper part 11 is provided with a backflow prevention valve 14 made of silicone rubber.

Therefore, when the pharmaceutical composition is injected into the silicone tube from the inlet port, the pharmaceutical composition is prevented from backflowing toward the port. Referring to Fig. 3, reference number 71 indicates a cap for a flow controlling part, reference number 72 indicates a hollow fiber membrane fixing element, reference number 73 indicates a hollow fiber membrane, reference number 74 indicates an adhesive, and reference number 75 indicates an outer casing for the flow controlling part.

First, the hollow fiber membrane 73, one end of which is closed, is inserted into the hollow fiber membrane fixing element 72. Then, the lower part of the membrane is filled with the adhesive 74. After the adhesive is hardened, the end of the membrane is cut off. The adhesive 74, as used herein, comprises a silicone adhesive, a urethane adhesive, a hot melt adhesive and the like. A cold setting silicone adhesive with little effect on the human body is preferred.

The hollow fiber membrane 73 is a porous membrane through which a pharmaceutical composition permeates. The material, porosity, and pore size of the membrane are determined according to the use of the membrane.

The hollow fiber membrane 73 may be prepared using polysulfone, polyacrylonitrile, polyamide, polycarbonate, polypropylene, chlorinated PVC and the like. Polysulfone, polyamide and chlorinated PVC are most preferable.

Generally, it is known that bubbles can be removed using a filter having a pore size of 1. 2 or less, and pyrogens generated after sterilizing general bacteria of 1 to lOO, tan in size can be mostly removed using an ultrafiltration membrane with a molecular weight cut-off of 10,000. In order to completely remove pyrogens with a molecular weight of several thousands, it is preferable to use a membrane with a pore size of 0. 0005go. A pore size smaller than 0. 0005jan does not allow passage of a pharmaceutical composition. If a pharmaceutical composition is too large to permeate the membrane, the effect of the medication may be reduced. Therefore, the pore size of the hollow fiber membrane varies depending on the pharmaceutical composition. Meanwhile, in the case of using medications with high viscosity and high molecular weight such as polymeric medications and anticancer agents, pyrogens cannot be removed and only general bacteria can be removed. For this, the membrane must have a pore size of about I gm or less. Therefore, the hollow fiber membrane of the present invention was designed to have a pore size of 0.0005 to l, am.

The hollow fiber membrane has uniform porosity and pore size distribution per unit area. Because the flow rate of a pharmaceutical composition is linearly proportional to the surface area of the membrane, the degree of opening of the surface can be regulated by applying the adhesive 74 to the surface. As a result, it is possible to regulate the total flux and flow rate of the pharmaceutical composition.

In more detail, one end of the hollow fiber membrane is sealed with an adhesive, thereby preventing the pharmaceutical composition from being directly injected to the inside of the hollow fiber membrane. Alternatively, as shown in Fig. 3, both ends of the hollow fiber membrane are bent down.

Then, the adhesive 74 is introduced from the bottom to a space defined between the outside of the hollow fiber membrane and the inside of a central rod, so as to seal the space. Therefore, the pharmaceutical composition

enters inward through the surface of the hollow fiber membrane and then flows downward. As described above, the flow rate and flux of the pharmaceutical composition can be regulated by regulating the surface area of the hollow fiber membrane using variable amounts of the adhesive. More specifically, the amount of adhesive to be introduced can be regulated based on the fact that the flow rate of the pharmaceutical composition is linearly proportional to the surface area of the hollow fiber membrane. In this regard, when the adhesive is introduced from the bottom, the height of the adhesive 74 is regulated, thereby providing a different flux and flow rate by means of the blocking of the surface of the membrane. Where a preliminary test determines that the flow rate is too high, adhesive is further applied on the pre- filled adhesive through a tube having a diameter of 1 mm or less, in order to additionally block the surface of the membrane. The tube is inserted into the hollow fiber membrane fixing element via the upper end thereof. As a result, the flux and flow rate can be regulated in a desirable level.

Reference is now made to Fig. 4, which provides an assembled cross sectional view of a flow regulating unit. Multiple hollow fiber membrane fixing elements 72 with different flow rates are disposed within the outer casing 93 for a multi-stage flow controlling part. Circular silicone 0-rings 97 are slipped around the upper ends of the fixing elements. The outer casing is then covered with a cap 92 for the multi-stage flow controlling part. Then, the cap-covered outer casing is inserted within the outer casing for the flow regulating unit. Oval silicone 0-rings 97 are slipped around the top of lower ends of the fixing elements. Then, the outer casing of the flow regulating unit is covered with its cap. Respective flow regulating valves 96 are clamped into the corresponding holes of the lower side of the outer casing 93 of the flow controlling part. When needed, the flow regulating valve 96 regulates a flow rate in a manner such that it is opened or closed using a switch 95 for the flow regulating valve.

Reference is now made to Fig. 5, which shows an assembled cross

sectional view of a temporary pain relief unit. Reference number 122 indicates the lower layer of the temporary pain relief unit; reference number 123 indicates a pharmaceutical composition storage bag stationary board; reference number 124 indicates the upper side of the cap of the outer casing for a hollow fiber membrane fixing element; reference number 125 indicates the lower side of the cap of the outer casing for the hollow fiber membrane fixing element; reference number 126 indicates the body of the outer casing for the hollow fiber membrane fixing element; reference number 131 indicates a cut-off for the composition storage bag; and reference number 132 indicates a press operating button. Dual hollow fiber membrane fixing elements 72 are disposed within the body 126 of the outer casing for the hollow fiber membrane fixing element. A pharmaceutical composition is directed to a patient who needs a continuous administration of the pharmaceutical composition via a first fixing element. On the other hand, a second fixing element is connected to the storage bag, to which the button 130 is attached.

When a patient feels much pain, the second fixing element is used in a manner such that the pharmaceutical composition contained in the storage bag is additionally injected via the second fixing element to a patient by pushing the button 130. Usually, the movement of the pharmaceutical composition contained in the storage bag is prevented by the cut-off 131 for the composition storage bag.

The disposable pharmaceutical composition injection device of the present invention and the fusion pump of Baxter International Inc. (America), having the greatest market share, were evaluated under the conditions of a duration of 2 days and an initial flow rate of 2 cc/hr.

Both devices were filled with 98 cc of physiological saline as a pharmaceutical composition and were measured for the flux per time to obtain a flow rate. The results are presented in Figs. 6 and 7.

Referring to Fig. 6, there is provided the variation in flow rate with time (cc/hr). Both devices were set to discharge 98 cc of a pharmaceutical

composition at an average flow rate of 2 cc/hr for 48 hours. The conventional device exhibited a flow rate of about 1.3 cc/hr at the middle period of the discharge, which corresponds to about 60 to 70% of the set flow rate. On the other hand, the present device maintained a flow rate of 1.7 cc/hr or more until the termination of the discharge. This value corresponds to 80% or more of the set flow rate. Therefore, the present device guarantees a higher degree of accuracy in terms of a flow rate.

Referring to Fig. 7, there is provided a graph showing the total flux with time. A gradient in the graph was calculated using a linear regression analysis method and then the coefficient of concordance between the set average flow rate and the gradient of the linear line was determined.

In Figs. 6 and 7, the total flux and flow rate according to the present invention were expressed by""to easily see the results. The conventional device was expressed by The regression analysis result for a flow rate is presented in Table 2.

Table 2 Section Coefficient of concordance Gradient (cc/hr) (%) Inventive device 99. 99 1. 80 Conventional device 99. 90 1.34 It can be seen from Fig. 7 that as a total flux with time is closer to the linear line, the reliability of a flow rate increases. As shown in Table 2, according to the linear regression analysis result, the present device exhibited a higher coefficient of concordance of 99.99%, compared with a coefficient of concordance of the conventional device of 99.90%.

The gradient in the linear regression analysis result exhibits an average flow rate. The conventional device having a gradient of 1.34 cc/hr exhibited a considerable difference with the set flow rate of 2 cc/hr. On the other hand, the present device had a gradient of 1.8 cc/hr, which was

approximately equal to the set flow rate of 2 cc/hr.

As apparent from the above description, the pharmaceutical composition injection device according to the present invention can remove both bubbles and pyrogens using a hollow fiber membrane, thereby making it possible to use the device on a patient with greater safety. Furthermore, the prime cost of the present device is lower relative to other devices and can also be drastically decreased further, because it is not necessary to prepare respective devices with different flow rates. Still furthermore, because the accuracy of the flow rate is increased, a patient can use the device with safety and convenience. Meanwhile, the previous device, in which a hollow fiber membrane is contained in a central rod, has disadvantages in that it takes 30 minutes to 1 hour to allow a pharmaceutical composition to reach a syringe- connecting part from the hollow fiber membrane via a PVC tubing, and in that the device cannot be provided with other units. On the other hand, because the hollow fiber membrane of the present device is provided at the outside of a central rod, in particular, a syringe-connecting part, the time required for the pharmaceutical composition to reach a patient is shortened to about 2 minutes. Additionally, the device can be provided with a unit temporarily providing additional composition according to a patient's need, as well as a flow regulating unit according to a physician's judgment.

Industrial Applicability The disposable pharmaceutical composition injection device according to the present invention uses a hollow fiber membrane, which acts as a flow regulator and a filter, at the same time. In particular, the device can effectively remove pyrogens generated when sterilized. In addition, the surface area of the hollow fiber membrane can be regulated according to a desirable flow rate. Because the hollow fiber membrane is provided at the outside of the central rod, the time required for the pharmaceutical composition to reach a patient can be drastically shortened. Still

furthermore, the device can be further provided with various units.

Therefore, the unit production cost is lowered, thereby increasing productivity. In particular, in order to change the flow rate, there is no need to use new silicone rubber balloons with different elasticity. Therefore, a flow regulating unit or a temporary pain relief unit can be coupled with the silicone rubber balloon.

Although the preferred embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope and spirit of the invention as disclosed in the accompanying clairns.