KR20120114829A - Tube-shaped devices with controlled geometry for programmed drug delivery - Google Patents

Abstract

PURPOSE: A geometrically controlled tube shaped device for programmable drug delivery is provided to facilitate drug delivery at low cost. CONSTITUTION: A geometrically controlled tube shaped device for programmable drug delivery comprises a drug tube in which drug powder is stored and drug delivery tubes which include diffusion disorder tubes in which the diffusion disorder materials are saved while being connected to the drug tube. The plurality of drug delivery tubes are connected in parallel or serially. The lower circumference surface of the drug tube and the upper circumference surface of the diffusion disorder tube are sealed by being welded with medical adhesive. The system additionally includes an outer tube for storage in which the drug tube and the diffusion disorder tube can be inserted and stored inside. Both ends of the outer tube for storage are sealed by the medical adhesive in order to prevent leakage of the minute drug powder. The diffusion disorder material is a biocompatible material.

Description

Tube-shaped devices with controlled geometry for programmed drug delivery

The present invention relates to a drug delivery system in the form of a tube and a method for manufacturing the same, comprising one or more drug delivery tubes by serially joining a drug tube and a diffusion barrier tube, which may have different lengths, and such one or more drug delivery tubes. By connecting in series or in parallel, the present invention relates to a drug delivery system in the form of a tube and a method for producing the same, which enables easier drug release.

Recently, in drug delivery systems, there is an increasing interest in improving the clinical efficacy by improving the bioavailability of drugs and reducing side effects.

To achieve this goal, various drug delivery systems are being developed, which focus on the ability of the drug to be released in sustained release while maintaining a constant drug concentration in the appropriate drug concentration range over a long period of time.

Although such sustained release performance is an advantageous function for drugs such as anti-inflammatory drugs, this therapy is not always applicable to all different types of drugs.

For example, pulsatile drug release may be particularly advantageous to meet the rhythm requirements of the biological cycle of the disease, and lag of drug release to treat diseases similar to asthma and angina pectoris. may be necessary. In particular, pulsatile drug release profiles can also be very useful for the delivery of certain biologics such as hormones or vaccines. In this sense, it can be seen that a programmed drug delivery shape (pulsatile and sustained drug delivery) is required to implement a suitable drug delivery profile for various types of drugs.

In addition, various types of drug delivery devices or devices have been proposed to achieve pulsatile or continuous drug release.

For example, polymeric microparticles have been extensively studied for drug delivery for a long time due to the simplicity of administration and ease of manufacture. However, microparticles have a problem that precise control of the drug release shape is not very easy because the drug release shape is determined by a wide size distribution or the decomposition rate of the drug loaded polymers. In addition, microparticles composed of many polymers tend to release large amounts of drug at the beginning of drug release, and thus there is also a problem that it may not be particularly suitable for drugs having a hydrophilic or small molecular weight.

In addition, one strategy for more active control of drug delivery is to use microfabricated devices. In particular, sophisticated structures can be implemented on a micro-scale, moreover, accurate drug quantities can be loaded and programmed drug release shapes can be implemented. As such, many devices have been finely fabricated to provide fluidic flow paths, porous membranes and needles embedded on microchips with micro-pumps or valves to actively control drug release. However, these devices usually require additional devices, such as bulky power supplies, that are generally bulkier than drug delivery systems, and as a result have the problem of being bulky for use. In addition, the microfabrication process is not simple because it requires a multi-step process requiring high technology.

Thus, to solve these problems, the present inventors have developed a simple combination of drug delivery tubes, ie pulsatile or continuous release, and tube-forms that can be applied to various types of drug administration. It has come to invent a tube-shaped drug delivery system and a method of making the same.

SUMMARY OF THE INVENTION The present invention has been made in view of the above-described problems, and an object of the present invention includes one or more drug delivery tubes consisting of a drug tube storing fine drug powder and a diffusion barrier tube containing a diffusion barrier material. To provide a drug delivery system in the form of a tube and a method of manufacturing the same that allow for programmed drug release by connecting one or more drug delivery tubes in series or in parallel and / or by adjusting the length of the diffusion barrier tube.

The drug delivery system according to the present invention is characterized in that the drug tube in which the fine drug powder is stored and the diffusion barrier tube in which the diffusion barrier material is stored are connected with the drug tube.

Preferably, the drug delivery tube is characterized in that the plurality is connected in series or in parallel.

Preferably, the length of each diffusion barrier tube of the drug delivery tube is the same or different from each other.

Preferably, the length of each drug tube of the drug delivery tube is the same or different from each other.

Preferably, the lower outer circumferential surface of the drug tube and the upper outer circumferential surface of the diffusion barrier tube are bonded and sealed with a medical adhesive.

Preferably, the drug delivery tube further comprises a storage outer tube in which the drug tube and the diffusion barrier tube can be inserted and received therein.

Preferably, the length of the storage outer tube is configured to be shorter than the entire length of the drug delivery tube, and the diffusion barrier tube is protruded below the storage outer tube.

Preferably, both ends of the storage outer tube is sealed with a medical adhesive to prevent leakage of the fine drug powder.

Preferably, the diffusion barrier material is characterized in that the material of any one or more of porous ceramics, polymers.

Preferably, the diffusion barrier material is polyethylene oxide (PEO), poly (lactic-co-glycolic acid) (poly (lactic-co-glycolic acid)), polylactic acid, polyglycolic acid (polyglycolic acid) and mixtures thereof. Note, on the other hand, that the diffusion barrier material is not limited to the polymers described above and may comprise essentially any biocompatible material.

Preferably, the drug delivery tube is characterized in that for controlling the delivery period and the release timing of the fine drug powder by adjusting the length of the diffusion barrier tube.

Preferably, the drug delivery system is characterized in that the drug powder is controlled to be released continuously or rhythmically by adjusting the number of drug delivery tubes.

Preferably, the material of the drug delivery tube is characterized in that the silicone or biodegradable material.

In addition, the method of manufacturing a drug delivery system according to the present invention comprises the steps of (a) filling a drug tube with fine drug powder or a mixture of drug and additive powder (b) filling a diffusion barrier material in a diffusion barrier tube and (c) A) bonding the drug tube and the diffusion barrier tube in series using a medical adhesive.

Preferably, the step of cutting the drug tube to a predetermined length between the step (a) and the step (b).

Preferably, the method comprises cutting the diffusion barrier tube to a predetermined length or a different length between the steps (a) and (b).

Preferably, the step (b) is characterized in that the diffusion barrier material dissolved at 50 ° C to 200 ° C is filled by negative pressure, and cured at room temperature for a predetermined time to solidify the filled diffusion barrier material. Here, the constant time is preferably about 1 hour to 5 hours.

Preferably, the diffusion barrier material is polyethylene oxide (PEO), poly (lactic-co-glycolic acid) (poly (lactic-co-glycolic acid)), polylactic acid, polyglycolic acid (polyglycolic acid) and mixtures thereof. Note, on the other hand, that the diffusion barrier material is not limited to the polymers described above and may comprise essentially any biocompatible material.

Preferably, (d) further comprising the step of inserting the drug tube and the diffusion barrier tube bonded to the portion of the diffusion barrier tube protruding out of the storage outer tube into the storage outer tube.

Preferably, (e) further comprising the step of sealing both ends of the storage outer tube with a medical adhesive to prevent the leakage of the fine drug powder.

Looking at such a drug delivery system and its preparation method according to the present invention in more detail.

First, a drug tube filled with a model drug (e.g. sodium fluorescein is used) as a fine drug powder was prepared, and a diffusion barrier material (e.g., polyethylene oxide, a biocompatible polymer) was prepared. (PEO)) filled diffusion barrier tubes.

Here, sodium fluorescein used as a model drug and polyethylene oxide used as a diffusion barrier material are merely exemplary, and the types of drugs that can be used as fine drug powders and biocompatible materials that can be used as diffusion barrier materials have special limitations. Note that none.

A single drug delivery tube is made by connecting these two separate tubes in series. The drug tube acts as a drug reservoir and the diffusion barrier tube acts as a diffusion barrier.

With drug delivery tubes made in this way, there is a constant delay time as water diffuses into the diffusion barrier tube. After diffusion, water reaches the drug tube and dissolves the fine drug powder to provide freely moveable drug molecules in solution. The drug molecule then diffuses out through the diffusion barrier tube and is released.

Therefore, in order to effectively control the rate of drug release from the drug delivery tube, it is possible to more easily control the rate of drug release by adjusting the length of the diffusion barrier tube. For example, the longer the diffusion barrier tube, the slower the release point of the drug and the longer the drug delivery period. In addition, the shorter the length of the diffusion barrier tube, the faster the release time of the drug and the shorter the drug delivery period.

Moreover, a variety of drug release profiles can be obtained by combining a plurality of drug delivery tubes, each provided with one or more different lengths of diffusion barrier tubes. For example, to achieve pulsatile drug release, drug delivery tubes with wide intervals between drug release times are combined. That is, a plurality of drug delivery tubes are combined that are configured to make a large difference in the length of the diffusion barrier tubes. Also drug delivery tubes with small intervals between the release times of the drug are combined, for example, to achieve continuous or sustained drug release for a long period of time. That is, a plurality of drug delivery tubes are combined that are configured to make a small difference in the length of the diffusion barrier tubes. Through this configuration, it is possible to obtain various drug release profiles.

On the other hand, the diameter of the drug tube and the diffusion barrier tube is preferably configured to be up to about 2mm. This is because not only can be readily used with minimal permeability but also can be used together with typical implantable electrodes or catheters for clinical use.

According to the invention, there is provided at least one drug delivery tube consisting of a drug tube for storing fine drug powders and a diffusion barrier tube comprising a diffusion barrier material, wherein the one or more drug delivery tubes are connected in series or in parallel; Alternatively, by adjusting the length of the diffusion barrier tube, it is possible to provide a drug delivery system and a method of manufacturing the same capable of programmed drug release.

Specifically, by combining one or more drug delivery tubes, specifically by properly combining diffusion barrier tubes with different lengths, pulsatile drug release or continuous drug release can be achieved more easily and at lower cost.

In addition, according to the present invention, it is possible to minimize the number of materials used to provide a drug delivery system more suitable for living bodies.

In addition, according to the present invention, the drug delivery tubes are designed to have a maximum diameter of about 2 mm and a length of 3.8 cm (ie, less than 30 μl volume) so that they can be easily used even in places that are difficult to access within the body. Since only the very small tip (approximately 1.5 mm in diameter) of this diffusion barrier tube is released, the effect is that highly targeted or local drug delivery is possible.

1 is a view schematically illustrating a method of manufacturing a drug delivery system according to an embodiment of the present invention.
Figure 2 is a photograph showing the cross section (a) and the cross section (b) of the hollow silicone tube of the diffusion barrier tube used in the drug delivery system according to the present invention.
3 shows an optical image of five drug delivery systems with diffusion barrier tubes having different lengths made in accordance with the present invention.
4 is a graph showing the penetration rate of water into the diffusion barrier tube.
FIG. 5 is a graph showing drug release profiles of five drug delivery tubes with diffusion barrier tubes having different lengths.
6 shows a drug release profile (a) and a drug delivery tube consisting of 1 mm diffuse barrier tube and 3 mm of a drug delivery tube consisting of a 0.5 mm diffuse barrier tube and a combined drug delivery tube consisting of a 1.5 mm diffuse barrier tube. It is a graph showing the drug release profile (b) of the combined drug delivery tube of the drug delivery tube consisting of diffusion barrier tubes.
FIG. 7 shows a drug release profile (a) of a drug delivery tube consisting of a 1 mm diffuse disorder tube and a drug delivery tube consisting of a 1.5 mm diffuse disorder tube and a drug delivery tube consisting of a 1 mm diffuse disorder tube, 1.5 mm It is a graph showing the drug release profile (b) of the combined drug delivery tube of the drug delivery tube consisting of the diffusion barrier tube and the drug delivery tube consisting of the 2 mm diffusion barrier tube.

Hereinafter, preferred embodiments of the present invention are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the contents of the present invention are not limited by the examples.

material

Polyethylene oxide (PEO; average MW: 600,000) as diffusion barrier material and sodium fluorescein as model drug were purchased from Sigma (MO, USA). Medical epoxy (EPO-TEK 301-2) was purchased from Epoxy Technology (Billerica, USA) as a medical adhesive. Two different size silicone tubes (drug tube and diffusion barrier tube: inner diameter 1 mm and outer diameter 1.5 mm, storage outer tube: inner diameter 1.5 mm and outer diameter 2 mm) were purchased from Hanmi (Korea). Phosphate buffered saline (PBS; pH 7.4) was purchased from the Clinical Research Center of Seoul National University Hospital.

Preparation Example-Preparation of Drug Delivery Tube

1 is a view schematically showing a method of manufacturing a drug delivery system according to an embodiment of the present invention. As shown in FIG. 1, drug delivery tubes were prepared by assembling drug tubes and diffusion barrier tubes in series. More specifically, it is as follows.

In order to prepare a drug tube, i.e., a tube serving as a drug reservoir, an approximately 7 cm empty silicone tube (inner diameter: 1 mm and outer diameter: 1.5 mm) was densely packed with fine drug powder of sodium fluorescein. The tubes were then cut to lengths of about 0.3 cm, 0.4 cm or 0.5 cm, with the result that drugs were loaded proportionally to each tube.

To prepare a diffusion barrier tube, that is, a tube serving as a diffusion barrier, a liquid PEO dissolved at about 90-100 ° C. in an empty silicon tube (inner diameter: 1 mm and outer diameter: 1.5 mm) of about 5 cm uses negative pressure. And then cured at room temperature for about 3 hours to solidify the PEO in the tube. The tubes were then cut to a length of about 0.5 cm, 1 cm, 1.5 cm, 2 cm or 3 cm to produce diffuse barrier tubes with five different lengths.

The drug tube and diffusion barrier tube were then joined in series using medical epoxy (EPO-TEK 301-2; Epoxy Technology; Billerica, Mass., USA). Then, the joined tubes were inserted into a larger silicone tube, that is, a storage outer tube (inner diameter: 1.5 mm and outer diameter: 2 mm) to prepare a drug delivery tube. The storage outer tube is characterized in that it is shorter than the total length of the bonded drug tube and the diffusion barrier tube, due to this configuration the tip of the diffusion barrier tube can be located outside the storage outer tube, so that water intrusion and drug conversion It only functions as an opening for the dragon. Also, to prevent leakage more effectively, both ends of the storage outer tube were sealed by medical epoxy. (This configuration allows water to diffuse into the drug delivery tube only through the diffusion barrier tube and to reach the drug tube to dissolve the drug powder, and the drug powder diffuses through the same diffusion barrier tube towards the release medium.)

Through this process, five different drug delivery tubes were prepared in which 0.5 cm, 1 cm, 1.5 cm, 2 cm and 3 cm diffusion barrier tubes and 0.5 cm drug tubes were joined. Hereinafter, these five drug delivery tubes will be referred to as 0.5DDT, 1DDT, 1.5DDT, 2DDT and 3DDT. These five drug delivery tubes are shown in FIG. 3.

Experimental Example-Observation by scanning electron microscopy (SEM)

To examine the cross-section of the diffusion barrier tube, the diffusion barrier tube and the hollow tube, each cut to a length of 5 mm, were placed on the SEM sample mount and sputter coated with platinum for about 10 minutes (208HR, Cressington Scientific, England). The two samples were taken with an electron scanning microscope (7401F, Jeol, Japan). This result is shown in FIG.

Experimental Example-Quantitative Analysis of Drug-Load

To analyze the amount of drug filled in the drug tube, drug tubes cut to 0.3 cm, 0.4 cm and 0.5 cm were soaked in 100 ml of phosphate buffered saline (PBS; pH 7.4) respectively to completely dissolve the drug, and UV The amount of drug was measured using a / VIS Spectrophotometer (UV-1800, SHIMADZU, USA). More than three samples were prepared and measured for each length of drug tube. These results are shown in Table 1.

Experimental Example-Measurement of Water Penetration Rate into Diffusion Barrier Tubes

To investigate the water penetration rate into the diffusion barrier tube, about 3.5 cm of diffusion barrier tube with one end sealed with medical epoxy was immersed in 5 ml PBS (pH = 7.4) at 37 ° C. At predetermined intervals, a boundary between water and solid PEO in the diffusion barrier tube was found and the distance between these boundaries and the opening of the diffusion barrier tube (ie, the end not sealed with epoxy) was measured. This experiment was performed three times. The results of this experiment are shown in FIG. 4.

Experimental Example-In Vitro Drug Release Study

To investigate the in vitro drug release profile, five drug delivery tubes (0.5DDT, 1DDT, 1.5DDT, 2DDT, and 3DDT) were continuously stirred at 125 rpm in a shaking incubator at 37 ° C. each with 40 ml PBS ( pH = 7.4). At scheduled intervals, aliquots (5 ml) of release medium were collected and equal amounts of fresh medium were added again to maintain saturation. Sampled subsamples were measured using a UV / VIS Spectrophotometer (UV-1800, Shimadzu, USA). This experiment was repeated three times for each type of drug delivery tubes. The results of this experiment are shown in FIG. 5.

Evaluation of Drug Delivery Tubes

Figure 2 is a photograph showing the cross section (a) and the cross section (b) of the hollow silicone tube of the diffusion barrier tube used in the drug delivery system according to the present invention.

Referring to FIG. 2, it can be seen that the PEO is densely packed inside the diffusion barrier tube when compared to the hollow silicon tube.

3 shows an optical image of five drug delivery systems with diffusion barrier tubes having different lengths made in accordance with the present invention.

Wherein the length of the drug delivery tube is 1.3 cm, 1.8 cm, 2.3 cm, 2.8 cm and 3.8 cm for 0.5DDT, 1DDT, 1.5DDT, 2DDT and 3DDT, respectively. In addition, the maximum diameter of the drug delivery tube is about 2 mm.

Table 1 shows the amount of drug filled in the drug tube along the length of 0.3 cm, 0.4 cm or 0.5 cm.

Drug tube length (cm) Amount of drug (mg) 0.3 1.856 mg ± 0.028 0.4 2.141 mg ± 0.050 0.5 2.620 mg ± 0.039

Referring to Table 1, it can be seen that the payload of the drug is changed in a reproducible manner according to the length of the drug tube. In particular, in the above preparation example, a 0.5 cm drug tube was used, and the drug loading amount was about 2.62 mg ± 0.04 mg.

Infiltration rate measurement result of water into diffusion barrier tube

Since the time for water to reach the drug tube is determined by the drug release profile of the drug delivery tube produced, the penetration rate of water into the diffusion barrier tube was investigated.

4 is a graph showing the penetration rate of water into the diffusion barrier tube.

Referring to Figure 4, when the diffusion barrier tube is immersed in PBS medium (pH = 7.4), water is immersed through the 3.5 cm long diffusion barrier tube in a diffusion manner. Therefore, according to these results, the time for water to reach the drug tube is 0.5, 1, 4, 6 and 1 for each 0.5 cm, 1 cm, 1.5 cm, 2 cm and 3 cm long diffusion barrier tube. Takes 15 days That is, the longer the diffusion barrier tube is, the slower the water reaches the drug tube. The drug release time, on the other hand, is expected to be later than the time for water to reach the drug tube, taking into account the additional delay caused by the dissolution of the drug powder followed by the diffusion of the drug via the diffusion barrier tube.

Drug Release Profile Results

In the drug delivery tube made in accordance with the present invention, the drug release profile of the drug delivery tube in PBS medium (pH 7.4) was investigated at 37 ° C. As mentioned above, to initiate drug release, water must diffuse into the diffusion barrier tube and reach the drug tube to dissolve the drug powder. Thereafter, the drug in the solution must diffuse out through the same diffusion barrier tube filled with a solution containing the water of PEO after water soaking.

FIG. 5 is a graph showing the in vitro drug release profile of five drug delivery tubes with diffusion barrier tubes having different lengths.

Referring to FIG. 5, the onset time of drug release is increased as the length of the diffusion barrier tube is increased. Specifically, drug release will be initiated at 0.5 days, 1 day, 5 days, 8 days and 17 days for each 0.5DDT, 1DDT, 1.5DDT, 2DDT and 3DDT. In other words, since diffusion barrier tubes of different lengths were used as diffusion obstacles, the difference in drug release time is evident for each type of drug delivery tube. On the other hand, as predicted in FIG. 4, the drug release time is later than the time for water to reach the drug tube. And the duration of sustained drug release also increases with the length of the diffusion barrier tube. Thus, after the day of drug release, at least 90% of the drug will be released for 2, 4, 5, 6 and 9 days for each 0.5DDT, 1DDT, 1.5DDT, 2DDT and 3DDT.

Beating drug release from a combination of drug delivery tubes

In order to achieve pulsatile drug release, a combination drug delivery tube was prepared by joining together the drug delivery tubes prepared in the above preparations in parallel with the medical epoxy, specifically 2 representing a distinct interval between drug release times. Drug delivery tubes were combined. In particular, a combination drug delivery tube of 0.5DDT and 1.5DDT and a combination drug delivery tube of 1DDT and 3DDT were prepared. In such combination drug delivery tubes, drug delivery tubes having short diffusion barrier tubes start and end drug release before the start time of drug release from the long diffusion barrier tube, thereby enabling pulsating drug release or periodic drug release.

FIG. 6 is a graph showing the drug release profile (a) of the combined drug delivery tubes of 0.5DDT and 1.5DDT and the drug release profile (b) of the combined drug delivery tubes of 1DDT and 3DDT.

Referring to FIG. 6, two distinct pulses of drug release were observed in both combinations of drug delivery tubes. It can be seen that the combination of 0.5DDT and 1.5DDT initiates drug release for the first time at 0.5 days and second drug release at 5 days. It can be seen that since the longer diffusion barrier tube was used for the combination of 1DDT and 3DDT, the time of the pulse is increased. That is, it can be seen that drug release begins on day 1 and shows stagnation for 5 to 12 days, followed by a second onset of drug release on day 17. It can be seen that these profiles are consistent with the data predicted from each drug release profile of the individual drug delivery tubes shown in FIG. 5.

Continuous drug release from the combination of drug delivery tubes

In order to achieve continuous drug release, a combination drug delivery tube was prepared by joining together the drug delivery tubes produced in the above preparations in parallel with a medical epoxy, specifically with a small gap between the initiation times of drug release. Two or more drug delivery tubes were combined. In particular, combination drug delivery tubes of 1DDT and 1.5DDT and combination drug delivery tubes of 1DDT, 1.5DDT and 2DDT were prepared. In such combination drug delivery tubes, the end time of drug release from the short tube (i.e., the time when drug release is complete) overlaps the start time of drug release from the long tube, thereby providing continuous drug release without stagnation. Will be.

FIG. 7 is a graph showing the drug release profile (a) of the combined drug delivery tube of 1DDT and 1.5DDT and the drug release profile (b) of the combined drug delivery tube of 1DDT, 1.5DDT and 2DDT.

5 and 7, the end time of drug release from 1DDT was 5 days, which corresponds to the start time of drug release from 1.5DDT. Thus, this combination will result in continuous drug release (nearly linear drug release from day 2 to day 9) for 9 days after drug release is initiated at day 1 (see FIG. 7 (a)). For longer drug release, this can be achieved by combining three different drug delivery tubes (1DDT, 1.5DDT and 2DDT). This combination allows for continuous drug release for 14 days after drug release is initiated at day 1 (see FIG. 7 (b)). The onset time of drug release from 2DDT was 7 days, which corresponds to the end time of drug release from 1.5DDT (see FIG. 5). In this combination, a nearly linear emission pattern is observed for longer periods from 2 to 14 days. It can be seen that the drug release profiles from these combined tubes correspond to the data predicted from the drug release profile of the individual drug delivery tubes shown in FIG. 5.

discussion

In order to provide an effective treatment regimen, different types of drugs need to have their optimal therapies. For drugs that benefit from sustained tissue exposure, sustained drug release may be appropriate for the delivery profile. On the other hand, drugs such as hormones or vaccines, the time schedule for administration is more important than the duration of their release. However, across the drug delivery platform, many systems provide sustained drug release and thus have limitations in the flexibility of the delivery scenario. Therefore, drug delivery systems that can be readily manufactured according to release profiles are essential for a wide range of applications in many different types of drug therapies.

We therefore propose to combine or combine the assembled drug delivery tubes to provide various drug delivery profiles. Individual drug delivery tubes can be readily prepared by serially joining a drug tube serving as a drug reservoir and a diffusion barrier tube serving as a diffusion obstruction. In this way, the drug dosage and drug release pattern can be precisely programmed by the geometric parameters (ie, length) of the diffusion barrier tube (see FIGS. 4 and 5) and the drug tube (see Table 1). In addition, this structural simplicity ensures ease of manufacturing process and thereby lowers manufacturing costs.

By diffusion barrier tube, the drug delivery tube exhibits a biphasic release pattern (no drug release with respect to delay time following sustained drug release). Importantly, the onset time and duration of drug release can be determined only by the length of the diffusion barrier tube. Therefore, pulsatile or continuous release profiles can be easily customized by a combination of appropriate drug delivery tubes, each having a different length of diffusion barrier tube.

As mentioned above, by combining 0.5DDT and 1.5DDT, two drug release pulses could be achieved at 0.5 d and 5 d (see FIG. 6 (a)), which pulse is longer than diffusion diffusion tubes, 1DDT and The combination of two drug delivery tubes with 3DDT can be changed to 1 d and 17 d (see FIG. 6 (b)). The duration of continuous drug release can also be set to nine days by combining 1DDT and 1.5DDT (see FIG. 7 (a)), in order to extend this period, by adding 2DDT (ie, 1DDT, 1.5DDT and 2DDT). It can be seen that the drug is released continuously for 14 days (see FIG. 7 (b)).

On the other hand, it is noted that PEO is used as a diffusion barrier material that dissolves rapidly as the water is immersed. If stronger diffusion barriers are used (eg poly (lactic-polymerized-glycolic acid), polylactic acid, polyglycolic acid, etc.), the duration of such drug release can be extended and the variability of drug release To contribute more.

For ease of implantation, the drug delivery tubes produced in this experiment are advantageously designed to have a diameter of up to about 2 mm and a length of 3.8 cm (up to 30 μl volume). This is because these sizes do not differ significantly from those of clinically used tubular medical devices. For this reason, drug delivery tubes can be used in places that are difficult to access, such as intraocular, intrabladder, intrathecal, intracranial or endotracheal tissue. In these cases, highly targeted or local drug delivery is possible because the drug is released only at the very small tip (about 1.5 mm in diameter) of the diffusion barrier tube.

In view of biocompatibility, this work minimized the number of materials used to prepare drug delivery tubes. Only silicon and PEO were selected and used as tube and diffusion-wall materials, respectively. All of these are known as biocompatible materials. Although the silicone tube has the disadvantage of not being degraded in the body, it is contemplated that in the device according to the invention the tube material can be replaced with any type of implantable and biocompatible material which has a biodegradation period which is longer than the period of complete drug release. Can be.

conclusion

Drug delivery systems that allow for programmed drug delivery are very advantageous because they can be widely applied to many types of drugs because the optimal dosing schedule or duration of tissue exposure will depend on the type of drug. The inventors therefore invented a drug delivery tube assembled by two separate tubes filled with a drug or a diffusion-blocking substance, PEO, respectively. Such drug delivery tubes can release the drug in a sustained manner after a delayed period, as well as varying the start time and duration of drug release depending on the length of the diffusion barrier tube.

To program the drug release profile, a simple combination of multiple drug delivery tubes is proposed. Combinations of drug delivery tubes with diffusion length tube lengths that differ in length can achieve pulsatile drug release because the time of the pulse can be determined by the length of the diffusion barrier tube. Continuous drug release can also be achieved by the overall combination of multiple drug delivery tubes with a small difference in diffusion barrier tube length. In this operation, a combination of three different drug delivery tubes, each with a 0.5 cm, 1 cm or 1.5 cm diffuse disorder tube, allows the drug to be released continuously for about 14 days without a stagnation of drug release.

The drug delivery tubes used in the present invention are small in size (up to 2 mm in diameter), which corresponds to the diameter of the device in the form of a clinically used tube, and the smallest number (silicon and PEO to provide for ease of implantation). ) Made of materials. Therefore, drug delivery tubes and combinations thereof can be implanted in areas that are not easily accessible in the body.

As mentioned above, although the present invention has been illustrated and described with reference to specific embodiments, the present invention is not limited thereto, and the scope of the following claims is not limited to the scope of the present invention. It can be easily understood by those skilled in the art that can be modified and modified.

Claims (20)

Drug tubes in which fine drug powders are stored and
And a drug delivery tube connected to the drug tube and having a diffusion barrier tube in which the diffusion barrier material is stored.
Drug delivery system.
The method of claim 1,
The drug delivery tube is characterized in that the plurality is connected in series or in parallel,
Drug delivery system.
The method of claim 2,
The length of each diffusion barrier tube of the drug delivery tube is the same or different from each other,
Drug delivery system.
The method of claim 3,
The length of each drug tube of the drug delivery tube is the same or different from each other,
Drug delivery system.
The method of claim 1,
The lower outer circumferential surface of the drug tube and the upper outer circumferential surface of the diffusion barrier tube are bonded and sealed with a medical adhesive,
Drug delivery system.
The method of claim 5,
The drug delivery tube,
The drug tube and the diffusion barrier tube further comprises a storage outer tube which can be inserted therein and accommodated,
Drug delivery system.
The method of claim 6,
The length of the storage outer tube is configured to be shorter than the full length of the drug delivery tube, and
The diffusion barrier tube is characterized in that it protrudes below the outer tube for storage,
Drug delivery system.
The method of claim 7, wherein
Both ends of the storage outer tube is sealed with a medical adhesive to prevent leakage of the fine drug powder,
Drug delivery system.
The method according to any one of claims 1 to 8,
The diffusion barrier material is characterized in that the biocompatible material,
Drug delivery system.
10. The method of claim 9,
The polymeric material in the diffusion barrier material is polyethylene oxide (PEO), poly (lactic-co-glycolic acid) (poly (lactic-co-glycolic acid)), polylactic acid (polylactic acid), polyglycolic acid ( characterized in that it is selected from the group consisting of biocompatible polymers such as polyglycolic acid) and mixtures thereof,
Drug delivery system.
The method according to any one of claims 1 to 8,
The drug delivery tube is characterized in that for controlling the release period and the start time of the fine drug powder by adjusting the length of the diffusion barrier tube,
Drug delivery system.
The method of claim 11,
Wherein the drug delivery system controls the drug powder to be released continuously or pulsating by adjusting the number of drug delivery tubes,
Drug delivery system.
The method according to any one of claims 1 to 8,
The material of the drug delivery tube is characterized in that the silicone or biodegradable material,
Drug delivery system.
In the manufacturing method of the drug delivery system,
(a) filling a micro drug powder into a drug tube
(b) the diffusion barrier material is filled into the diffusion barrier tube; and
(c) bonding the drug tube and the diffusion barrier tube in series with a medical adhesive;
Method of making a drug delivery system.
15. The method of claim 14,
And cutting the drug tube to a predetermined length between step (a) and step (b).
Method of making a drug delivery system.
16. The method of claim 15,
Cutting the diffusion barrier tube to a predetermined length or a different length between the steps (a) and (b),
Method of making a drug delivery system.
17. The method according to any one of claims 14 to 16,
The step (b)
Characterized in that the diffusion barrier material dissolved at 50 ° C. to 200 ° C. is filled by negative pressure, and cured at room temperature for a predetermined time to solidify the filled diffusion barrier material.
Method of making a drug delivery system.
18. The method of claim 17,
The diffusion barrier material is polyethylene oxide (PEO), poly (lactic-co-glycolic acid) (poly (lactic-co-glycolic acid)), polylactic acid (polylactic acid), polyglycolic acid (polyglycolic acid) Characterized in that it is selected from the group consisting of biocompatible polymers and mixtures thereof, such as
Method of making a drug delivery system.
17. The method according to any one of claims 14 to 16,
(d) inserting the drug tube and the diffusion barrier tube bonded to a portion of the diffusion barrier tube to protrude out of the storage outer tube into the storage outer tube,
Method of making a drug delivery system.
20. The method of claim 19,
(e) sealing both ends of the storage outer tube with a medical adhesive to prevent leakage of the fine drug powder, further comprising:
Method of making a drug delivery system.

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