WO2009157884A2

WO2009157884A2 - Local drug application device (ldad)

Info

Publication number: WO2009157884A2
Application number: PCT/TR2009/000079
Authority: WO
Inventors: Erturk Genc
Original assignee: Erturk Genc
Priority date: 2008-06-27
Filing date: 2009-06-29
Publication date: 2009-12-30
Also published as: TR200804721A2; WO2009157884A3

Abstract

LDAD basically captures the drug administered in the area between two balloons by inflating two balloons around the LDAD's tube within the canals, bladders and cavities. The drug takes its all effect intensively and for the desired time only between two balloons. The drug that is unable to go beyond two balloons has not any adverse or unnecessary effect for the other tissues. It is also selective in the drug application area (2) by means of the filler balloon (17). The device may be used for the cancer treatment and infection treatment. In the case of infection treatment, as well as antimicrobial drug is administered to the area, the PH and oxygenization of area is also modified and it is possible to attack microorganisms in three ways. In order to benefit from the synergistic effect of oxygen on the certain antibiotics, both can be administered in the same time. Any hollow device also acts as a stent.

Description

LOCAL DRUG APPLICATION DEVICE (LDAD)

Related Field of Incentive

This incentive is used for treatment of cancer etc. superficial pathological tissues and infections in the canals such as oesophagus, trachea, larynx, pharynx, nasal cavity, outer ear path, Eustachian canal, large intestines, rectum, urethra, penis, and vagina and cysts such as urinary bladder, lung, uterus, and stomach, and cavities such as maxillary sinus. It is applied intraoperatively to the canals and cysts inside that body that are inaccessible from outside through a clearance as in the formations that we have listed hereinabove. It can also be used to regress stenos in the cancers of the organs of the non-operable patients listed above, to extend their lifetime and to provide a more comfortable life.

Local chemotherapeuticals, radiosynthesizers, photosynthesizers, cryogenic agents, chemosurgery agents used for treatment of cancer, agents such as ionized argon gas used in the organ plasma technique, liquids used for thermodynamic treatment, liquid local haemostatics, antimicrobial drugs, antimycotic drugs used for treatment of resistant infections (candida oesophagitis, Barret oesophagus, chronic sinusitis etc.) and some drugs and stains used for endoscopic treatment and the drugs used to facilitate tissue healing can be applied on the application tract in this way. Drugs can be applied in aerosol form for sinuses. Present Known Condition of Local Drug Application Technique

Today, drugs such as photosynthesizers, radiosynthesizers including the chemotherapeutical drugs used for cancer treatment are rather administered systemically. Locally, they are administered intraperitoneal, intraarterial, intrapleural, intratecal and intravesical.

However, it is possible for a cytotoxic drug to penetrate into urethra and then to the kidney in intravesical applications, for instance, when applied with single balloon devices. As the tissue surface that the drug is contact increases, the quantity that proceeds to the systemic circulation will increase. Proportionally, the quantity of drug needed will increase (increasing cost). Chemotherapeuticals that proceed to the systemic circulation have significant reversible and irreversible effects.

Local drug production towards treatment of cancer and resistant - chronic infections has not so developed. The reason underlying it is the lack of devices that will apply the drugs by limiting them locally, but not lavage-like application on the organs. As the drugs that can be applied locally have not developed satisfactorily, there is a tendency to use systemic drugs for treatment of cancer and infection. For example, the first treatment that is in mind for chronic sinusitis is the systemic antibiotherapy. We can talk about lavages that do not have much efficiency as local application.

As local drug application devices are insufficient, the local drug development efforts have become insufficient and the success of local treatments has been overridden by the treatments of systemic drugs. It has reached to such extent that the articles regarding cancer treatments contain expressions such as "chemotherapy is not used, local chemotherapy is not much efficient, and the actual treatment is surgery".

There are not local applications except for intratumoral injection and broncholveolar lavage in oesophagus, larynx, pharynx, trachea and lung cancers. Even though the lesion is superficial or even if a superficial effect is assumed in non-operable cases, there are not local drug application devices that limit the administered drug, but systemic chemotherapy applications are made. Photosynthesizers used for treatment of cancer are administered as LV. and it takes 1-5 days for them to become efficient in the body (delay in treatment) and the adverse effects in the form of susceptibility of patient to light take weeks. Serious problems arise in the patients that are exposed to light.

Thermotherapy and thermochemotherapy agents cannot be applied on the aforesaid canals, cysts and cavities due to heat and as the dispersion of liquid is not restricted in a tract. Superiorities of LDAD to Single Balloon or Systemic Drug Application

Another important problem with systemic chemotherapy and antibiotherapy applications is failure to reach the desired satisfactory intensity in the relevant organ tract. This problem is tried to be solved with high dosage and frequent drug applications. And this increases the cost and the adverse effects related to the systemic chemotherapy and antibiotherapy causes superinfections, and disintegration and release of drugs in the organs cause increasing destructions in proportion with the quantity of drug that is used.

Whereas, LDAD, by capturing the drug between proximal (4) and distal (5) balloons;

1. ensures drug application only on the desired tract: It prevents adverse effect of the drugs on the healthy tissues. 2. ensures reaching the desired drug intensity in the specific tract. It is impossible to reach this intensity in systemic chemotherapy and antibiotherapy applications.

• Increasing success of treatment, Shortening the treatment duration

3. It keeps the drug intensity on the specific tract as long as it is desired. 4. It allows very little quantity of drug to enter into the systemic circulation.

And this allows:

• Less systemic adverse effect (this is very important in chemotherapeuticals)

• Avoidance of superinfection in antibiotherapy • As the quantity of drug that is to enter into the systemic circulation is quite little, the drug can be used safely in the cases such as treatment of cancer even though the drug is very toxic.

• Less restraint and destruction on liver and kidneys. 5. By local application of the photosynthesizer drugs used for treatment of 85 cancer:

• While the effect of drug starts late in systemic application, this duration is shortened much by application of the drug directly on the mass.

• Photosynthesization that is observed in systemic application and that takes weeks is not observed in local applications.

90 6. Radiosynthesizers are applied locally and become more efficient in shorter time.

7. It is impossible to administer the cryogenic and thermodynamic treatment drugs locally in the fields of use of LDAD by restricting it noticeably with the present known methods. It may easily penetrate beyond the target tissues.

95 Therefore, such type of agents cannot be used easily for cancer treatment of many canals, cysts and cavities. Thanks to LDAD, this can be achieved easily by capturing these drugs between the proximal and distal balloons.

8. The administered drug can stay in the tract as long as it is wished. This means continuation of the efficiency of drug as long as it is wished. This can

100 be made with a single application or if it is considered that the drug will be inefficient after a while, the drug that becomes inefficient can be absorbed from the tract and new drug can be administered before removing the device out. For example, some microorganisms have to be under the influence of antimicrobial drugs for a certain time to vanish. This is achieved by

105 administering drugs frequently and intensively for a long time in the systemic applications. In the local application, there is a single application, ie. if the microorganism vanishes as a result of interaction with drug Y at intensity X, as intensity X can be achieved easily with local application and it will be easy to keep the drug there for Y minutes, certain results will be

110 obtained at the end of Y minutes. For instance, it will be advantageous to use local drug in the cases such as Barret oesophagitis, stomach ulcer and chronic sinusitis. 9. As long as the device is not removed out of the tract, same or different drugs can be administered easily one after another on the tract. For example, in the

115 event of bleeding after application of a drug related to the methods used for treatment of cancer, a local haemostatic drug, and if infection has occurred, an antimicrobial drug can be administered successively.

10. In the endoluminal and mixed tumours of trachea that cause stenos, LDAD that is designed empty as the endotracheal canal (ref. Figure 8/9) serves as a

120 stent besides its main function. This is achieved by placing the proximal (4) and distal (5) balloons near to each other or by placing a support balloon (12) between them if necessary. When trachea is held open due to thickness of tube and the supplemental stress caused by the balloons, this device allows continuing with the treatment of cancer while ensuring administration

125 of drugs for treatment of cancer between the distal and proximal balloons.

The presently known stents only function as stent, but cannot provide the function of local drug application, which is provided by LDAD.

11. There is no local application method or device that will keep the tract in interaction with oxygen for a long time to destroy the microorganisms for

130 destruction of the anaerobic microbes. Anaerobic microbes are destroyed with conventional methods, e.g. by means of systemic antibiotherapy. However, anaerobes within canals, cysts and cavities can also be made with oxygen or liquid or antibiotics in aerosol form that are captured exactly in the relevant tract. pH of the tract can be changed to help this process. In the

135 event of availability of devices that will restrict the drugs in gas form to the desired tract in the organs, the drug manufacturers will seek ways to manufacture these drugs.

12.pH of the tract can be changed to help to the process. Basic agents may be administered to the drug application tract (2) for the microorganisms living

140 in acid pH, and acid agents may be administered for the microorganisms living in basic pH 13. There is no efficient local drug application for treatment of canal, cyst and cavity cancers where LDAD is applied. There are applications such as intravaginal and intravesical applications that are restricted and that cannot

145 fully achieve the desired objective. With the presently known single balloon systems, the drug can only be applied on the organs such as bladder and uterus, the front of which is closed, in which case the urethra, kidneys, tubas and ovaries following these cysts are subject to adverse effects of the administered drugs. As the surface that the drug reaches increases, the

150 quantity of drug that enters into the systemic circulation and the quantity of drug needed for application increase as well.

14.Many irreversible and reversible adverse effects of systemic chemotherapy are known. Some adverse effects restrain the patient biologically and spiritually for a long time even though they are reversible.

155 15. As the Double Balloon Interescopy system that includes a tube that contains scopy and a larger second tube that moves on in and one balloon at each end of both tubes does not ensure sealing between these two tube systems, it cannot restrict the drug locally and it is already a device that has been developed to make endoscopic inspection on the small intestines. The

160 only similarity with LDAD is that both of them contain double balloons.

Their functions are completely different. lό.Medical therapeutic apparatus (Patent no Us 7,399,290, B2)

While administering the drug on one hand, the device will have to continually discharge the air on the other hand as there is no supplemental

165 air discharge canal to discharge the air in the area where the drug is applied between two balloons. The device is more of a lavage machine nature.

• If it is considered that especially the chemotherapeutical drugs and antibiotics are extremely expensive drugs and also that they are 170 applied several times during the treatment process, it is understood that the drug cost will highly increase. For economic reasons, only the low-priced lavage liquids can be used with this device. In LDAD, however, the drug application area is completely filled with the drug (2) since the drug is administered directly to the device through an 175 injector and the air in the drug application area is discharged through the air discharge canal (36). In this way, drug saving is ensured to a great extent.

• As the device transmit the liquids it takes from the tanks through the common drug administration - discharge canals (the area T between

180 54 A, B and C), there is the sterilization problem with the device. The entire device is not for single use. In LDAD, however, the device is for single use.

• While applying with the device in long canals, the canals may adhere the device and the drug may not be applied effectively to all surfaces

185 of the canal since the support balloons (12) included in our application are not available.

• As the device has no system to obstruct the ostium on the nasal wall of maxillary sinus by compressing like a sandwich, it will be insufficient in drug application to maxillary sinus and even in

190 irrigation.

• As the end of the tube continues after the distal balloon, the drug application to the tissues behind the balloon will not be possible in the cavities such as maxillary sinus, uterus and bladder. The device seems to be able to be used only in the canals by this nature of it.

195 • As the device has no canal to ensure ventilation at the center, it cannot be used in trachea. However, our device shown in the Figure 11 can be easily used in trachea applications as there is a large canal at the center of our device, through which it will be possible to ensure ventilation. In this type of cases, the device will be able to apply drug

200 to the lesion area between the balloons while serving as a stent. • Also, the device cannot be used in trachea, larynx applications made through general anesthesia since it has no canal to send the anesthetic gases to the lung. However, LDAD has an appropriate canal (19) for these applications.

205 • As the end of the tube continues after the distal balloon, there is the possibility to damage the ear membrane in external auditory canal applications. In LDAD shown in the Figure 5, however, this problem is not in question as the end of the tube (1 1) is in alignment with the distal edge of the distal balloon (10).

210 • The absence of the filler balloon (17) is a disadvantage of the medical therapeutic apparatus for such aspects of it as more drug consumption and not being selective.

• Critical problems will occur in the event of a complication such as inability to deflate the balloons due to the absence of backup inflating

215 - deflating canals of the balloons. In our device, this risk has been resolved by adding a reserve inflating - deflating canal for each balloon.

• The device has no large canal such as the ventilation, anesthetic gas, nutrition and urine drainage canal (19) in our device to discharge the

220 urine during long-term applications in the urinary canals and to ensure nutrition during oesophagus applications.

• It is difficult for the jagged structure ensuring the extension of the medical therapeutic apparatus and shown in the designations of 45, 46 to be formed in the devices to be used in thin canals such as ureter for

225 the physical properties of the material.

• The application of cryogenic gases is difficult with this device.

Shape Structure of System, Functions of Parts in the System 1. Criteria to be taken into consideration in fabricated preparation of tubes and balloons

230 Tube is fabricated rigid or flexible as full inside or in the form of canal according to the intended purpose and organ that it will be applied.

Balloons and tube are prepared at different diameters, thicknesses, sizes and forms according to age, gender and personal differences.

Distances of distal (5) and proximal (4) balloons to each other (2) and outside 235 the body are prepared at different lengths as fabrication based on the statistical data.

In selecting the optimum design for the patient, BT, MRI images, endoscopic examinations, 3D images and models obtained through volumetric tomography are used. 240 Balloons and tube will have the flexibility that will not irritate the tissue and that will adapt to the surrounding anatomic structure easily.

2. Shape of tube

Tube is design in different ways according to the anatomy of the canal that it will be applied to (gradient, diameter and length of canal etc.) and its intended 245 function.

There are letters that are useful for distinguish front (32), back (33) and left (34), right (35) at the proximal end of the tube. Thus, the filler balloon (17) will be positioned correctly.

3. Distal End of Tube (11):

250 Distal end (1 1) is terminated in the form of U to facilitate proceeding and it is made longer than the distal edge (10) of the distal balloon Thus, any irritation does not occur on the tissues while proceeding. Edges at the end of the tube are rounded to prevent irritation. All surfaces are smooth and glazed.

• Mouth of air pressure neutralizing canal (45) : This is the starting 255 mouth of the air pressure neutralizing canal at the distal end of the tube

(Figure 5).

4. Proximal End of Tube (1): This is located outside the body. Content: a. Balloons inflating- deflating (main) holes: There is one hole at the beginning of the inflating - deflating canals of all balloons used in the

260 system. While inflating, deflating balloon, the air is charged and discharged through this hole.

• Proximal balloon inflating - deflating canal hole (22)

• Distal balloon inflating - deflating canal hole (25)

• Support balloon inflating - deflating canal hole (53)

265 • Proximal safety balloon inflating-deflating canal hole (59)

• Filler balloon inflating - deflating canal hole (64)

• Distal safety balloon inflating-deflating canal hole (69) b. Balloons inflating - deflating (reserve) holes: Reserve inflating- deflating canals of all balloons used in the system starts with a hole. In

270 the event of a problem in the principal inflating- deflating systems of balloons, reserve holes are opened and balloon is deflated. They are in the form of a plug.

• Reserve inflating- deflating canal hole of distal balloon (31)

275 • Reserve inflating- deflating canal hole of proximal balloon

(43) : This is not available in the application devices where the proximal balloon (4) is close to outside the body.

• Reserve inflating- deflating canal hole of support balloon (56)

280 • Reserve inflating- deflating canal hole of proximal safety balloon (61)

• Reserve inflating- deflating canal hole of filler balloon (66)

• Reserve inflating- deflating canal hole of distal safety balloon (21)

285 c. Small balloons of the balloons : These are the small balloons that are located behind each principal hole and useful for feeling the air pressure within the balloon. • Small balloon of the proximal balloon (23)

• Small balloon of the distal balloon (26) 290 • Small balloon of the support balloon (54)

• Small balloon of the proximal safety balloon (58)

• Small balloon of the filler balloon (63)

• Small balloon of the distal safety balloon (70)

d. Inlet (valve) of drug administration-discharge canal (40) : The

295 drug is administered through an injector by means of the hole herein.

This is in the form of a plug. The valve is brought to the OFF position when the drug administration process is ended. After the application, the valve is turned on again and the drug is discharged by retracting the injector piston through this inlet. This hole may serve as the mouth

300 (valve) of the air discharge canal according to the position of the drug depending on the gravity. e. Inlet end of fiberoptic system (72) : This is the beginning of the fiberoptic system to monitor the drug application area (2) at the proximal end (1) of the tube.

305 f. Direction letters at the proximal end of the tube (1) :

• Front (F) (32), Back (B) (33), Left (L) (34), Right (R) (35) g. Mouth of air discharge canal (37) : This is the valve at the mouth of the air discharge canal (36) that ensures the discharge of the air in the area where the drug is applied while administering the drug. This is in 310 the form of a plug. The valve is turned off as the drug starts to get out.

It remains in OFF position during the application period. It is used as a reserve drug discharge canal as well when necessary. It will be possible to connect the end of this valve to an aspirator. h. Mouth (valve) of supplemental air discharge canal of the systems 315 containing support balloons (51): This is the mouth of the supplemental air discharge canal of the systems containing support balloons. This is in the form of a plug. 5. Content of tube body : a. Main inflating-deflating canals : There is available a separate 320 inflating- deflating canal for each balloon in the system.

• Proximal balloon inflating deflating canal (24)

• Distal balloon inflating deflating canal (27)

• Support balloon inflating deflating canal (52)

• Proximal safety balloon inflating deflating canal (57) 325 • Filler balloon inflating deflating canal (62)

• Distal safety balloon inflating deflating canal (7) b. Reserve inflating-deflating canals : There is available a separate reserve inflating- deflating canal for each balloon in the system. Reserve inflating- deflating canal may not be available for the proximal balloon (4)

330 in the applications such as urethra, nasal cavity, external auditory canal, rectum and column which are easily reached from the outside.

• Reserve inflating deflating canal of proximal balloon (42)

• Reserve inflating deflating canal of distal balloon (30)

• Reserve inflating deflating canal of support balloon (55)

335 • Reserve inflating deflating canal of proximal safety balloon (60)

• Reserve inflating deflating canal of filler balloon (65)

• Reserve inflating deflating canal of distal safety balloon (20)

C. Drug administration - discharge canal (39) : The drug reaches to the drug application area (2) through this canal. When the process is ended, the drug 340 is discharged through this canal. This canal is wider in the devices considered to carry out lavage function. This may be used as the air discharge canal, d. Outlet of drug administration - discharge canal (41): The drug (39) coming through the drug administration- discharge canal is discharged to the

345 drug application area (2) through this hole. This is over the tube part in front of the distal edge (8) of the proximal balloon. However, in some applications, this hole is the at the edge of the distal end of the tube (3) (Figures 8, 9). Hole of the drug administration and discharge canal on the body are designed as fabrication by determining the position of patient during

350 application and by calculating the area that the liquid will accumulated in accordance with the rule of gravity and it is applied by making front (32) - back (33), left (34) - right (35) distinctions of the tube during application. From time to time, it may serve as the inlet hole of the air discharge canal based on the position of the patient during the application and the

355 relationship of the drug with the gravity accordingly.

6. Supplemental drug administration - discharge canal (46)

This is the drug charge-discharge canal of the supplemental division formed by support balloon (12).

f. Outlet hole of supplemental drug charge - discharge canal (47): This is 360 the hole which the canal in the area over the proximal edge (13) of the support balloon belonging to the supplemental drug charge-discharge canal (46) begins from.

g.Mouth (hole) of supplemental drug administration - discharge canal

(48) : This is the valve of the supplemental drug charge-discharge canal in 365 the form of a plug. h. Air discharge canal (36) : The air in the area where the drug is applied (2) is discharged through this canal. Thus, the liquid drug covers entirely the drug application area (2). It may be used as reserve drug administration- discharge canal when necessary. This canal is wide in the

370 devices considered to carry out lavage function as well. i. Mouth (hole) of air discharge canal (37) : This is the valve that is located at the beginning of the air discharge canal (36). j. Inlet of air discharge canal (38) : This is the hole through which the air in the drug application area (2) enters into the air discharge canal (36). This 375 hole is located at the edge (3) of the distal end of the tube in the devices in which compression like a sandwich technique is used as shown in the figures 8 and 9. k. Supplemental air discharge canal of the systems containing support balloons (49) : This is the canal that discharges the air in the 380 second division formed by the support balloon (12). ^"

1. Inlet hole of the supplemental air discharge canal of the systems containing support balloon (50) : This is the hole through which the air in the drug application area (2) enters into the supplemental air discharge canal (49). This is located under the distal edge (14) of the support balloon

385 on the tube. m. Thin linear structure to give radioopaque appearance (67): This is seen all along the tube. It is used in interferential radiography. It may not be used in the devices of some applications such as external auditory canal application.

390 n. Ventilation, anesthetic gas, nutrition and urine discharge canal (19)

(Figure 11) : This canal serves as ventilation canal in the applications of the device in the respiratory system in which it is wished for it to serve as stent as well as drug application, as anesthetic gas canal in the cases the application is made through general anesthesia, as nutrition canal in farynx, 395 oesophagus applications and as urine discharge canal in the applications made in urinary canals. o. Air pressure neutralizing canal (44) : This is the canal that discharges the pressure air occurring while inflating the distal balloon (5) to outside the body in external auditory canal applications (Figure 5). 00 6. Types and number of balloons

Shape of outer edges of the balloons (6) is formed according to the anatomy of the area. The devices of which the drug application area (2) is at different length are selected according to the length of the lesion. Proximal balloon (4) : This is the balloon that is closest to outside the body. It

405 prevents the administered agent from flowing outside the body, thus prevents the drug from causing a systemic effect and abortive use of the drug. Distal balloon (5) : This is the balloon that is distal to the canal mouth. Its function is to prevent the drug to go deeper, and hence enter into the systemic circulation. Furthermore, it prevents abortive use of the drug. Its function is

410 identical to the proximal balloon with these characteristics The drug is captured in the drug application area (2) by means of distal (5) and proximal (4) balloons. This is the essence of LDAD. Proximal safety balloon (15) and distal safety balloon (16) : In the event of a rupture or leakage on the distal (5) and proximal (4) balloons in very toxic drugs

415 particularly, it prevents the agent from extending to the undesired tracts and entering into the systemic circulation. Distal safety balloon (16) is located immediately behind the distal balloon (5) and the proximal safety balloon (15) is located immediately in front of the proximal balloon (4). In applications such as vagina, penis, urethra, external auditory canal, nasal cavity etc., the proximal safety

420 balloon (15) is unnecessary as the drug will leave the body rapidly and easily even in the event of rupture of the proximal balloon (4).

Support balloon (12) : In cases where the area to be applied is long or the tonus of tissues that constitute the canal is too much, support balloon (12) is placed at the intermediate section so that the adhesion of canal is prevented. In this case, there

425 will be supplemental drug administration- discharge canal outlet hole (47) and supplemental air discharge canal outlet hole (50) that will administer the drug and discharge the air in the area between the compartments in the tube body. Filler balloon (17) : They are placed at different heights and sides in the area where the drug is applied for positioning on the side of healthy tissue in order not

430 to affect the sound tissues if it is wished to affect only one part on the structures such as stomach, oesophagus, bladder, uterus and maxillary sinus. In this way, it is ensured that less drug enters into the systemic circulation, that the healthy tissues are less affected from the adverse effects of drug, if any, and that the valuable drugs are less used. The outer edge (18) of the filler balloon may be in alignment 435 with the tissue contact edge (6) of the proximal balloon or may be more inside.

Filler balloon may surround the tube as in the figures 7 and 8.

In case of antimicrobial drug use, as entire canal is infected in the respective area, the devices that do not contain filler balloons are used.

Filler balloons are designed to be shaped according to the organ that they will be 440 used. For example, in the case of stomach cancer, it is designed to obstruct upper

2/3 of the stomach if the cancer is in the lower 1/3, and upper 1/3 if the caner is in the medium 1/3, and lower and medium 2/3 totally if the cancer is in the upper 1/3.

Outer edge of filler balloon (18) : This is the filler balloon's edge that is closest to or in contact with tissue. 445 7. Monitoring and Imaging:

• Fiberoptic system (28) : This system is used in order to observe the formations and developments in the drug application area (2).

• Imaging system (29) : This is the endoscopic system from the proximal end (1) of the tube to the distal end (11) in order to understand from where the

450 tube progressing within the canal, to where it arrives, whether it passes by the distal edge of the lesion or infection or not and its approaching stage to the ear membrane.

• Inlet end of imaging system ( 71 ) : This is the inlet at the proximal end (1) of the imaging system.

455 TUBE APPLICATION

1. Selection of application device

The data that are obtained by using the methods such as endoscope, BT, MRI etc. before the application, the 3D images and the models that are obtained through volumetric tomography are studied and the tube length, balloon quantity, type and 460 shape and the length of the drug application area (2) are determined. The devices complying with this data are selected. Matching 3D image of the application area and 3D fabrication images of LDAD on computer will also be helpful for making the selection. 2. Determination of volume of drug to be administered

465 As the canal length, and the distance between distal and proximal balloons are known, the approximate diameter of canal that will be reached through inflation is pre-defined and the amount of liquid to be administered can be pre-defined through the method of determining the cylinder volume except for the cases where filler balloons will be used. When the filler balloon is

470 inflated at a specific tonus, as its volume is known as fabrication, this value is subtracted from the general volume and the volume of liquid drug to be administered in the applications with filler balloon can be estimated.

3. Tube application

• The procedure is started by adjusting the right (35), the left (34), the front 475 (32) and the back (33) of the tube.

• The tube is made slippery with a drug that will not irritate the tissue, that will not have adverse reaction with the drugs to be administered and that will not cause infection or any undesired change on the lesion in order to facilitate its penetration.

480 • The tube is advanced with proper manoeuvres within the canal through the endoscopic system (29). The process is stopped when the proximal edge (9) of the distal balloon passes by the distal edge of the lesion or infection area. It is now the turn of inflating the distal balloon (5).

4. Inflating the balloons and sequence of inflation

485 Firstly, the distal balloon (5) is started to be inflated. Tonus of the distal balloon is felt from the small balloon of the proximal end by the time and the inflation process continues. When sufficient tonus is obtained, the inflation process is ended. The same method is used for inflating all other balloons.

5. Distal safety balloon (16), if any, is inflated in the same manner.

490 6. Support balloon (12), if any, is inflated. During this period, the mouth (valve) of the drug discharge canal (37) and the mouth (valve) of the supplemental discharge canal (51) of the systems including support balloon are kept open and the occurrence of air pressure in the area is prevented. 7. Filler balloon (17), if any, is inflated. During this period, the mouth of the air 495 discharge canal (37) is kept open and the occurrence of air pressure in the area is prevented.

8. Proximal balloon (4) is inflated.

10. Proximal safety balloon (15), if any, is inflated.

11. Drug administration

500 • Before drug administration, the patient is positioned in the manner so that the drug accesses to the target tissue in the easiest manner by the gravity. It is positioned to avoid leakage in any case during the application process. For example, the patient lies on his/her sinus side where application is made during the application process in the event of sinus applications made

505 through nasal cavity. If an aerosol application is made to the sinus, the patient lies on the side where application is not made during the application process.

• Drug is administered through an injector through the mouth of drug administration- discharge canal (40).

510 • Volume of the administered drug is noted. This will serve to understand whether there remains liquid in the canal or not after discharging the canal when the process will be terminated. Particularly, this fact will be important in cases where it is not desired to have toxic substances in the canal. Equality between the input and output liquid shows that there is no drug

515 remaining in the canal. This will be an assurance of the fact that the drug has not entered into the systemic circulation.

• During drug administration, the mouth of the air discharge canal (37) is open. As the drug is administered, the air inside the canal is discharged through this mouth. Thus, while administering the drug, any resistance is not

520 encountered and as the entire canal is filled with drug, it is made sure that there is no air small balloon inside it. The drug starting to come from the mouth of air discharge canal shows that the canal is full of drug. The drug administration process is stopped. Mouth of air discharge canal (37) is closed. 525 12. Discharging the drug

• Mouth of drug administration- discharge canal (40) is opened. It is ensured that the liquid is drained. The liquid is collected in a vessel with a degree.

• If the output liquid is different from the content of the original liquid and 530 contains particles, they will be filtered and the volume is tried to be estimated by considering that the remaining amount is the pure drug that has been administered approximately.

• If the output liquid is less than the input liquid and if the amount that remains in the application area is important in terms of systemic effects,

535 the drug is tried to be aspired by installing an aspirator to the mouth of drug administration - discharge canal (40).

• If there is blood in the output liquids, the local haemostatic agents in the form of liquid or pomade are administered to the area by means of the same method before deflating the balloons after discharging the drug.

540 (Such kind of liquid local haemostatics may develop over time upon the operation of LDAD.)

13. Discharging the drug

The steps given under "drug administration" are repeated if necessary.

14. Terminating the application

545 • The steps given under "discharging the drug" are carried out.

• Proximal safety balloon (15), if any, is deflated completely.

• Proximal balloon (14) is deflated completely.

• Support balloon (12), if any, is deflated completely.

• Filler balloon (17), if any, is deflated completely. 550 • Distal balloon (5) is deflated completely.

• Distal safety balloon (16), if any, is deflated completely.

• The tube is taken out. SPECIFIC APPLICATIONS

Basic rule in the application is that the lesion or infection area is left in the drug

555 administration area (2). GIS applications Pharynx application

LDAD in the Figure 1 1 is used. The distal balloon (5) is inflated in the lower bound of pharynx, immediately behind the ending area of lesion; the proximal

560 balloon (4) is inflated just in front of the upper bound of lesion, within the pharynx. If necessary, a filler balloon (17) may be inserted into the drug administration area (2). Ventilation, anesthetic gas, nutrition and urine drainage canal (19) in the middle of tube acts as a nutrition canal here. The device administers drug in the applications of pharynx, nasopharynx, trachea and oesophagus on the one

565 hand, and continues its stent function on the other hand.

Oesophagus applications

The device in the figure 1 is used in the short-term applications, and the device in the figure 11 is used in the long-term applications. The ventilation, anesthetic gas, nutrition and urine drainage canal (19) of the device shown in the figure 11 acts as

570 a nutrition canal in the oesophagus applications. The lesion is taken to the drug administration area (2), and the application is carried out. Stomach application

The distal balloon (5) is inflated in the pylorus area at the level of duodenum, and the proximal balloon (4) is inflated in the joint area of stomach- oesophagus at the

575 level of ostium cardiacum.

If the mass is in the lower section, filler balloons (17) with a volume and shape that can cover the middle and upper section of stomach may be used; if the mass is in the upper section, filler balloons (17) that will occupy the lower and middle sections of the stomach may be used; and if the mass is in the middle section,

580 filling balloons (17) with a sufficient number and shape that can cover the upper and lower sections of the stomach may be used.

Duodenum application LDAD in the Figure 1 is used. The distal balloon (5) is inflated in the pars horizontalis, and the proximal balloon (4) is inflated in the pylorus.

585 Rectum and colon applications

LDAD in the Figure 1 is used. If necessary, such devices with distal supplemental safety balloon (16), filler balloon (17) or support balloon (12) may also be used. In the case of irrigation using the device, the devices with wide administration- discharge canal (39) and air discharge canal (36) are preferred.

590 Maxillary sinus application

In all maxillary sinus applications, the function of proximal (4) and proximal safety (15) balloons is to occlude the ositum by compressing the nasal wall of the sinus taken to the compression area (68) like a sandwich if the procedure is carried out from the nasal cavity, or to prevent the drug from leaking back from the

595 surgical procedure area by taking the bone around the surgical procedure hole to the compression area (68) and compressing it like a sandwich, if the procedure is carried out from the fossa canina.

If there is still some leakage despite this structure, the patient is tipped toward the side of application, and drug administration is stopped at the moment leakage starts.

600 In the maxillary sinus applications from the nasal cavity, if it is not especially intended that the distal balloon (5) acts as a filler balloon (figures 6, 7), the devices in the figures 8 and 9 are used. These devices contain only proximal (4) and proximal safety (15) balloons. Filler balloon (17) includes part or all of the tube circumference. In the case of

605 infection, the filler balloon enclosing the tube is inflated in some degree so as not to contact with the walls of sinus in order to use fewer drugs. If the procedure is carried out surgically from the fossa canina, the devices in the figures 6 and 7 are used. The distal balloon (5) is inflated inside of the nasal wall of sinus, and the proximal balloon (4) is inflated inside of the side wall of sinus,

610 and the proximal safety balloon (15) is inflated on the exterior surface of maxilla. Here, while the distal balloon (5) occludes the ostiums and prevents the drug from passing to the nasal cavity, and the proximal balloon (4) and proximal safety balloon (15) compress the bone like a sandwich in the surgical procedure area and prevent the drug from leaking to the fossa canina area. If necessary, filler balloons

615 (17) with various shapes may be used between the distal (5) and proximal (4) balloons (Figure 7).

In the maxillary sinus applications carried out from the fossa canina (Figures 6,7), the distal end of tube (11) is in alignment with the distal edge of distal balloon (10). Respiratory System Applications

620 In all respiratory system canals (nasal cavity, larynx, trachea), the devices with ventilation, anesthetic gas, nutrition and urine drainage canal (19) in the figure 11 are used. Therefore, the ventilation is not precluded, and drugs are administered to the drug administration area (2). If the application will be carried out with general anesthesia, anesthetic gases are given from this canal. If no general anesthesia will

625 be used, it is used as a ventilation canal.

The device also acts as a stent in the respiratory system applications.

Nasal Cavity application

Distal balloon ( 5 ) is inflated in the choana dextra, and the proximal balloon (4) is inflated in the vestibulum nasi. 630 Nasopharynx Application

The proximal balloon (4) is inflated in the choana dextra, and the distal balloon (5) is inflated in the nasopharyngeal isthmus.

Trachea application

The lesion is taken to between distal (4) and proximal (5) balloons. The ventilation 635 or anesthetic gas delivery is carried out from the ventilation, anesthetic gas, nutrition and urine drainage canal (19). The device also acts as a stent during the application.

Urinary canal applications

While the device in figure 1 is used in the short-term applications in the urinary

640 canals, the device in figure 11 is used in the long-term application in order not to preclude the urine drainage. Here, the ventilation, anesthetic gas, nutrition and urine drainage canal (19) acts as a urine drainage canal. The device also acts as a stent here.

Urethral application in men

645 The distal balloon (5) is inflated in the front line of prostate, and thus the prostate is prevented from being affected by the drug. This distal bound may further be brought forward according to the layout of lesion. The proximal balloon (4) will be inflated in front of the front bound of the lesion. Where it is desired that the prostate is also affected, the distal balloon (5) is inflated in the bladder bottom.

650 Urethral application in women

The proximal balloon (4) is inflated at the beginning of urethra, and the distal balloon (5) is inflated in front of the bladder.

Bladder application

LDAD in the Figure 10 is used. The distal balloon (5) is inflated on the top of

655 bladder, and the proximal balloon (4) is inflated in the ostium urethra internum. Ureter application

While the device in the figure 1 is used in the short-term applications, the device in the figure 11 is used in the long-term applications. The distal balloon (5) is inflated in the section of ureter close to the kidney, and the proximal balloon (4) is inflated

660 in the section of ureter close to the bladder. Prostate application

The proximal balloon (4) is inflated just in front of the prostate, and the distal balloon (5) is inflated in the ostium uretra internum. Uterus and cervix application

665 If the lesion is at the bottom of uterus or in the cervix, the proximal balloon (4) of device in the figure 1 is inflated in front of the cervix, and its distal balloon (5) is inflated so as to be in the uterus. If the lesions are in the upper section of uterus, the LDAD in the figure 9 is used. The drug is prevented from returning by inflating the proximal balloon in the cervix area, and inflating the proximal safety balloon at

670 the bottom of uterus, and compressing the bottom of uterus like a sandwich. Where it is desired that the cervix is also affected, both balloons (4, 15) are also inflated in front of the cervix and a full sealing toward the front is provided. External auditory canal application

The device in the figure 5 is used in order that the distal end of tube (11) will not 675 damage the tympanic membrane. The air pressure that occurs during the inflating of distal balloon is neutralized by means of the air pressure neutralizing canal (44). The mouth of this canal, namely the air pressure neutralizing canal (45) in the proximal (1) and distal (11) ends of the tube is open.

Legends of Figures

680 Figure 1 - Main device including the proximal (4) and distal (5) balloons.

Figure 2 - Device including the support balloon (12).

Figure 3 - Device including the proximal safety (15) and distal safety balloons (16).

Figure 4 - Device including the support balloon (17).

685 Figure 5 - Device of which inside is in the form of a canal and of which the distal edge of distal balloon (10) and the distal end of tube (11) are in alignment.

Figure 6 - Device without a filler balloon (17) and with a distal balloon (5) and with a feature of compressing like a sandwich.

Figure 7 - Device with a filler balloon (17) and a distal balloon (5) and a feature of 690 compressing like a sandwich.

Figure 8 - Device with a filler balloon (17) and without a distal balloon (5) and with a feature of compressing like a sandwich.

Figure 9 - Device without a filler balloon (17) and without a distal balloon (5) and with a feature of compressing like a sandwich.

695 Figure 10 - Device of which inside is full and of which the distal edge of distal balloon (10) and the distal end of tube (11) are in alignment.

Figure 11 - Device of which middle section is in the form of a canal and including proximal (4) and distal (5) balloons. 700 Description of parts numbered in the figures

1. Proximal end of tube

2.Drug application area

3.Edge of distal end of tube

4.Proximal balloon 705 5. Distal balloon ό.Tissue contact edge of proximal balloon

7. Distal safety balloon inflating- deflating canal δ.Distal edge of proximal balloon

9. Proximal edge of distal balloon 710 lO.Distal edge of distal balloon

1 1.Distal end of tube

12.Support balloon

13.Proximal edge of support balloon

H.Distal edge of support balloon 715 15.Proximal safety balloon lό.Distal safety balloon

17. Filler balloon

18. Edge of filler balloon

19.Ventilαtion, anesthetic gas, nutrition and urine discharge canal 720 2O.Reserve inflating- deflating canal of distal safety balloon

21. Valve of reserve inflating- deflating canal of distal safety balloon

22. Valve of proximal balloon inflating- deflating canal

23. Small balloon of proximal balloon

24. Proximal balloon inflating- deflating canal 725 25. Valve of distal balloon inflating- deflating canal

26.Small balloon of distal balloon

27.Distal balloon inflating- deflating canal

28. Fiberoptic system

29.1maging system 730 3O.Reserve inflating- deflating canal of distal balloon

31. Valve of reserve inflating- deflating canal of distal balloon

32. Mark showing front of tube 33. Mark showing back of tube 34.Mark showing left of tube

735 35.Mark showing right of tube

36. Air discharge canal

37.Mouth (valve) of air discharge canal

38.1nlet hole of air discharge canal

39.Drug administration- discharge canal 740 40.Mouth (valve) of drug administration- discharge canal

41. Outer hole of drug administration-discharge canal

42.Reserve inflating- deflating canal of proximal balloon

43.Valve of reserve inflating- deflating canal of proximal balloon

44.Air pressure neutralizing canal 745 45. Mouth of air pressure neutralizing canal

46. Supplemental drug charge-discharge canal of systems containing support balloon

47. Outlet hole of supplemental drug administration- discharge canal of systems containing support balloon

750 48.Mouth (valve) of supplemental drug administration- discharge canal of systems containing support balloon 49.Supplemental air discharge canal of systems containing support balloon

5O.Inlet hole of supplemental air discharge canal of systems containing support balloon

755 51.Mouth (valve) of supplemental air discharge canal of systems containing support balloon

52. Support balloon inflating- deflating canal

53. Valve of support balloon inflating- deflating canal

54.Small balloon of support balloon 760 55. Reserve inflating- deflating canal of support balloon

56.Valve of reserve inflating- deflating canal of support balloon

57.Proximal safety balloon inflating- deflating canal

58. Small balloon of proximal safety balloon

59. Valve of proximal safety balloon inflating- deflating canal 765 όO.Reserve inflating- deflating canal of proximal safety balloon

61. Valve of reserve inflating- deflating canal of proximal safety balloon

62. Filler balloon inflating- deflating canal

63. Small balloon of filler balloon

64. Valve of filler balloon inflating- deflating canal 770 65. Reserve inflating- deflating canal of filler balloon

66. Valve of reserve inflating- deflating canal of filler balloon

67. Line to give radioopaque appearance

68. Compression zone

68.Valve of distal safety inflating- deflating canal 775 70. Small balloon of distal safety balloon

71. Inlet end of imaging system

Claims

LOCAL DRUG APPLICATION DEVICE (LDAD)780CLAIMS

1. It is a Local Drug Application Device (LDAD) for the drugs in the form of liquid, gas, pomade and powder; in which it is characterized that it consists

785 of a tube and proximal balloon (4), distal balloon (12), support balloon (12), proximal safety balloon (15), distal safety balloon (16), and filler balloon (17) on the tube, and inflating - deflating canal holes belonging to these balloons (as listed above) (22, 25, 53, 59, 69, 64), reserve inflating - deflating holes belonging to these balloons (43, 31, 56, 61, 21, 66), main

790 inflating - deflating canals belonging to these balloons (24, 27, 52, 57, 7, 62), reserve inflating - deflating canals belonging to these balloons (42, 30, 55, 60, 20, 65), small balloons belonging to these balloons (23, 26, 54, 58, 70, 63), drug administration - discharge hole (40), air discharge hole (37), supplemental air discharge hole (51), supplemental drug administration -

795 discharge hole (48), supplemental air discharge hole (49), supplemental drug charge - discharge hole (46), air pressure neutralizing canal (44), mouth of air pressure neutralizing canal (45), endoscopic system (29), fiberoptic system (28), thin linear structure to give radioopaque appearance (67), ventilation, anesthetic gas, nutrition and urine discharge canal (19), and

800 compression area (68).

2. It is the local drug application device in the Claim 1 ; in which it is characterized that it captures the drugs administered to the drug application area (2) and have proximal (4) and distal (5) balloons.

3. It is the local drug application device in the Claim 1; in which it is 805 characterized that the proximal safety balloon (15) that will provide an additional sealing is in the front of proximal balloon (4) and the distal safety balloon (16) is behind the distal balloon (5).

4. It is the local drug application device in the Claim 1 ; in which it is characterized that there is a filler balloon (17) surrounding part or whole of

810 the tube circumference between the proximal (4) and distal (5) balloons.

5. It is the local drug application device in the Claim 1 ; in which it is characterized that there is a support balloon (12) between the proximal (4) and distal (5) balloons in order that the tissues in the area of long drug application area (2) will not adhere to the tube.

815 6. It is a version of the local drug application device in the Claim 1 which has been developed for the bladders and cavities (Figures 6, 7, and 8); in which it is characterized that the width of compression area (68) is equal to the wall thickness of tissue to be compressed.

7. It is the local drug application device in the Claim 1 ; in which it is 820 characterized that the distal end of tube (1 1) is beyond the distal edge of last balloon in some versions (figures 1, 2, 3, 4, 8, 9, and 11), and the distal end of tube (11) is in alignment with the distal edge of last balloon in some other versions.

8. It is the local drug application device in the Claim 1 ; in which it is 825 characterized that its tube is full (figure 1) or empty in the canal form (figure

5, 11).

830

835