Drug-Coated Balloon Controllable In Drug Metabolism And Preparation Method Therefor

Abstract

The present invention provides a preparation method for a drug-coated balloon controllable in drug metabolism. A drug receptor protein inhibitor is mixed with drugs, water and ethanol to obtain a medicinal liquid, the medicinal liquid is sprayed onto the surface of a balloon back and forth by means of an ultrasonic spraying device, and drying is performed so as to prepare the drug-coated balloon. The drug receptor protein inhibitor can also be replaced with other agents such as a drug metabolism isoenzyme inhibitor, a drug metabolism isoenzyme inducer, or a mixture of the drug receptor protein inhibitor and the drug metabolism isoenzyme inhibitor for preparing the medicinal liquid, and a drug metabolic cycle of the drug-coated balloon can be further adjusted and controlled by adjusting the ratio of the addition quantity of the drug receptor protein inhibitor or the other agents to the drugs. The drug-coated balloon prepared by the method has the functions that effective controllable drug metabolism can be implemented without destroying the structure of an intima, the drug metabolism can be implemented to achieve the effect of drug treatment at an early stage of using the drug-coated balloon, and the effect period of the drugs can be prolonged by adjusting the ratio.

Claims

1. A method for preparing a drug-coated balloon controllable in drug metabolism, wherein the method comprises the following steps: step 1: mixing a drug receptor protein inhibitor, a drug, water, and ethanol to prepare a medicinal liquid; step 2: loading the medicinal liquid prepared in the step 1 into an ultrasonic spraying equipment, and setting flow parameters and a rotating speed of a balloon; step 3: adjusting a distance between an ultrasonic nozzle of the ultrasonic spraying equipment and the balloon, controlling an ambient temperature at 18-28° C., and wetting a surface of the balloon with ethanol before spraying; step 4: turning on the ultrasonic spraying equipment and spraying back and forth along an axial direction of the balloon; and step 5: drying the sprayed balloon to obtain the drug-coated balloon.

2. The method for preparing a drug-coated balloon controllable in drug metabolism according to claim 1, wherein the drug receptor protein inhibitor in the step 1 is replaced by a drug metabolism isoenzyme inhibitor or a drug metabolism isoenzyme inducer.

3. The method for preparing a drug-coated balloon controllable in drug metabolism according to claim 2, wherein the drug receptor protein inhibitor in the step 1 is mixed for use with the drug metabolism isoenzyme inhibitor.

4. The method for preparing a drug-coated balloon controllable in drug metabolism according to claim 1, wherein the drug is rapamycin, the drug receptor protein inhibitor is selected from an inhibitor of immunoaffinity protein FKBP12 protein: one or more of 3-pyridin-3-ylpropyl-(2S)-1-(3,3-dimethyl-2-oxo-pentanoyl)-pyrrolidine-2-carboxylate, (3R)-4-(p-Toluenesulfonyl)-1,4-thiazane-3-carboxylicacid-L-leucine ethyl ester, and (3R)-4-(p-Toluenesulfonyl)-1,4-thiazane-3-carboxylic acid-L-phenylalanine benzyl ester.

5. The method for preparing a drug-coated balloon controllable in drug metabolism according to claim 2, wherein the drug is rapamycin, and the drug metabolism isoenzyme inhibitor is selected from an inhibitor of CYP3A4 isoenzyme: one or more of posaconazole, erythromycin, telithromycin, HIV protease inhibitor, popravir, telaprevir, amiodarone, amprenavir, aprepitant, atonavir, cimetidine, ciprofloxacin, clarithromycin, diltiazem, doxycycline, enoxacin, fluconazole, fluvoxamine, imatinib, indinavir, itraconazole, ketoconazole, miconazole, nefazodone, ritonavir, saquinavir, telithromycin, verapamil, and voriconazole.

6. The method for preparing a drug-coated balloon controllable in drug metabolism according to claim 2, wherein the drug is rapamycin, and the drug metabolism isoenzyme inducer is selected from an inducer of CYP3A4 isoenzyme: one or more of aprepitant, barbiturates, bosentan, carbamazepine, efavirenz, felbamate, glucocorticoids, modafinil, nevirapine, oxcarbazepine, phenytoin, phenobarbital, primidone, etravirine, rifampicin, St. John's wort, pioglitazone and topiramate.

7. The method for preparing a drug-coated balloon controllable in drug metabolism according to claim 1, wherein a ratio of the drug receptor protein inhibitor to the drug is 0.25-4:1, and a drug metabolism slows down as a function of an increase of an addition amount of the drug receptor protein inhibitor.

8. The method for preparing a drug-coated balloon controllable in drug metabolism according to claim 2, wherein a ratio of the drug metabolism isoenzyme inhibitor to the drug is 0.25-4:1, and a drug metabolism slows down as a function of an increase of an addition amount of the drug metabolism isoenzyme inhibitor.

9. The method for preparing a drug-coated balloon controllable in drug metabolism according to claim 2, wherein a ratio of the drug metabolism isoenzyme inducer to the drug is 0.25-4:1, and a metabolic rate of the drug increases as a function of an increase of an addition amount of the drug metabolism isoenzyme inducer.

10. A drug-coated balloon controllable in drug metabolism prepared according to the method for preparing a drug-coated balloon controllable in drug metabolism according to claim 1, wherein the drug-coated balloon regulates a drug metabolic rate under a condition that a total drug load remains unchanged.

11. A drug-coated balloon controllable in drug metabolism prepared according to the method for preparing a drug-coated balloon controllable in drug metabolism according to claim 2, wherein the drug-coated balloon regulates a drug metabolic rate under a condition that a total drug load remains unchanged.

12. A drug-coated balloon controllable in drug metabolism prepared according to the method for preparing a drug-coated balloon controllable in drug metabolism according to claim 3, wherein the drug-coated balloon regulates a drug metabolic rate under a condition that a total drug load remains unchanged.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0029] FIG. 1 is a schematic diagram of spraying according to a preferred embodiment of the present invention;

[0030] FIG. 2 is a flow chart of preparing a drug-coated balloon according to a preferred embodiment of the present invention;

[0031] FIG. 3 is a schematic diagram of the active site of the drug receptor protein FBKP12 used in a preferred embodiment of the present invention;

[0032] FIG. 4 is an inhibitor 3-pyridin-3-ylpropyl-(2S)-1-(3,3-dimethyl-2-oxo-pentanoyl)-pyrrolidine-2-carboxylate of the drug receptor protein FBKP12 used in a preferred embodiment of the present invention;

[0033] FIG. 5 is an inhibitor (3R)-4-(p-Toluenesulfonyl)-1,4-thiazane-3-carboxylicacid-L-leucine ethyl ester of the drug receptor protein FBKP12 used in a preferred embodiment of the present;

[0034] FIG. 6 is an inhibitor (3R)-4-(p-Toluenesulfonyl)-1,4-thiazane-3-carboxylic acid-L-phenylalanine benzyl ester of the drug receptor protein FBKP12 used in a preferred embodiment of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] Hereinafter, a number of preferred examples of the present invention will be introduced with reference to the drawings in the specification to make the technical content clearer and easier to understand. The present invention can be embodied by many different forms of examples, and the protection scope of the present invention is not limited to the examples mentioned in the text.

[0036] In the following examples, rapamycin is selected as the drug, and a schematic diagram of spraying the drug-coated balloon is shown in FIG. 1. In FIG. 1, the ultrasonic spraying equipment includes a nozzle rail 1 and an ultrasonic nozzle 2 arranged on the nozzle rail 1 and moving along the nozzle rail 1. The distance between the ultrasonic nozzle 2 and the balloon 3 is L, and the ultrasonic nozzle 2 moves back and forth along the direction of the axis 4 of the balloon 3 for spraying.

[0037] As shown in FIG. 2, the method for preparing a drug-coated balloon is shown and includes:

[0038] step 1 101: formulating the medicinal liquid that needs to be sprayed on the balloon, which will be described in detail in the following content;

[0039] step 2 102: loading the medicinal liquid prepared in the step 1 into an ultrasonic spraying equipment, and setting flow parameters and a rotating speed of a balloon;

[0040] step 3 103: adjusting a distance L between the ultrasonic nozzle 2 of the ultrasonic spraying equipment and the balloon 3, controlling an ambient temperature at 18-28° C., and wetting a surface of the balloon 3 with ethanol before spraying;

[0041] step 4 104: turning on the ultrasonic spraying equipment and spraying back and forth along the direction of the axis 4 of the balloon 3; and

[0042] step 5 105: drying the sprayed balloon 3 to obtain the drug-coated balloon.

[0043] I. A Drug Receptor Protein Inhibitor was Used to Prepare the Drug-Coated Balloon Controllable in Drug Metabolism

[0044] Rapamycin blocks signal transduction and blocks the progression of T lymphocytes and other cells from G1 to S phase through different cytokine receptors. Rapamycin can block the calcium-dependent and calcium-independent signal transduction pathways of T lymphocytes and B lymphocytes. Rapamycin can bind to the immunophilin FKBP12 to form a RAPA-FKBP12 complex, which cannot bind to calmodulin, and rapamycin does not inhibit the early activation of T cells or directly reduce the synthesis of cytokines. The FKBP12 protein mainly forms hydrogen bonds with the inhibitor through Ile56 and form a hydrophobic interaction zone through Tyr82, and Tyr26, Phe46, Va155, Tyr59, His87 and Ile90 (the active sites of the FKBP12 protein are shown in FIG. 3). The binding of the inhibitor to FKBP12 can effectively slow down the binding rate of rapamycin to FKBP12 to extend the drug metabolism of the drug-coated balloon. Therefore, in the present invention, the purpose of extending the drug metabolism of the drug balloon is achieved by adding a inhibitor of rapamycin's receptor protein FKBP12, which binds to the FKBP12 in advance.

[0045] The main inhibitors of FKBP12 protein are 3-pyridin-3-ylpropyl-(2 S)-1-(3,3-dimethyl-2-oxo-pentanoyl)-pyrrolidine-2-carboxylate (abbreviated as drug a), (3R)-4-(p-Toluenesulfonyl)-1,4-thiazane-3-carboxylicacid-L-leucine ethyl ester (abbreviated as drug b), and (3R)-4-(p-Toluenesulfonyl)-1,4-thiazane-3-carboxylic acid-L-phenylalanine benzyl ester (abbreviated as drug c) (molecular structure diagrams are shown in FIGS. 4, 5, and 6 respectively). The ability to bind FKBP12 protein from strong to weak is drug c, drug b, and drug a. Therefore, in the following examples, the type and content of FKBP12 protein inhibitors added can be adjusted to regulate rapamycin metabolism.

Example 1

[0046] The drug-coated balloon was prepared according to the following ratio and method:

[0047] 1. FKBP12 inhibitor drug a (3%), rapamycin (1%), water (5-10%) and ethanol (82-93%) were mixed by weight ratio to obtain a medicinal liquid with rapamycin concentration at 52 mg/ml;

[0048] 2. The medicinal liquid was loaded into an ultrasonic spraying equipment, and the flow rate was set to 0.01-0.1 ml/min;

[0049] 3. The rotating speed of the balloon was set to 3 to 5.0 rev/s, and the surface of the balloon 3 was wet with ethanol before spraying;

[0050] 4. The distance L between the ultrasonic nozzle 2 of the ultrasonic spraying equipment and the balloon 3 was adjusted to 10-30 mm, and the ambient temperature was controlled at 18-28° C.;

[0051] 5. The ultrasonic spraying equipment was turned on, spraying was performed back and forth 10 times along the axial direction of the balloon 3, and the final drug content on the balloon 3 was controlled to 4.0 ug/mm.sup.2;

[0052] 6. The sprayed balloon 3 was placed in an environment of 18-28° C. and dried for 120 minutes.

Example 2

[0053] The drug-coated balloon was prepared according to the following ratio and method:

[0054] 1. FKBP12 inhibitor drug c (4%), rapamycin (4%), water (5-10%) and ethanol (82-93%) were mixed by weight ratio to obtain a medicinal liquid with rapamycin concentration at 52 mg/ml;

[0055] 2. The medicinal liquid was loaded into an ultrasonic spraying equipment, and the flow rate was set to 0.01-0.1 ml/min;

[0056] 3. The rotating speed of the balloon was set to 3 to 5.0 rev/s, and the surface of the balloon 3 was wet with ethanol before spraying;

[0057] 4. The distance L between the ultrasonic nozzle 2 of the ultrasonic spraying equipment and the balloon 3 was adjusted to 10-30 mm, and the ambient temperature was controlled at 18-28° C.;

[0058] 5. The ultrasonic spraying equipment was turned on, spraying was performed back and forth 10 times along the axial direction of the balloon 3, and the final drug content on the balloon 3 was controlled to 4.0 ug/mm.sup.2;

[0059] 6. The sprayed balloon 3 was placed in an environment of 18-28° C. and dried for 120 minutes.

Example 3

[0060] The drug-coated balloon was prepared according to the following ratio and method:

[0061] 1. FKBP12 inhibitor drug c (5%), rapamycin (1.25%), water (5-10%) and ethanol (82-93%) were mixed by weight ratio to obtain a medicinal liquid with rapamycin concentration at 52 mg/ml;

[0062] 2. The medicinal liquid was loaded into an ultrasonic spraying equipment, and the flow rate was set to 0.01-0.1 ml/min;

[0063] 3. The rotating speed of the balloon was set to 3 to 5.0 rev/s, and the surface of the balloon 3 was wet with ethanol before spraying;

[0064] 4. The distance L between the ultrasonic nozzle 2 of the ultrasonic spraying equipment and the balloon 3 was adjusted to 10-30 mm, and the ambient temperature was controlled at 18-28° C.;

[0065] 5. The ultrasonic spraying equipment was turned on, spraying was performed back and forth 10 times along the axial direction of the balloon 3, and the final drug content on the balloon 3 was controlled to 4.0 ug/mm.sup.2;

[0066] 6. The sprayed balloon 3 was placed in an environment of 18-28° C. and dried for 120 minutes.

[0067] II. A Drug Metabolism Isoenzyme Inhibitor or a Drug Metabolism Isoenzyme Inducer was Used to Prepare the Drug-Coated Balloon Controllable in Drug Metabolism

[0068] Rapamycin can be extensively metabolized by a CYP3A4 isoenzyme, so the absorption and the elimination of rapamycin after systemic absorption can be affected by a drug acting on this isoenzyme. An inhibitor of CYP3A4 can slow down the metabolism of rapamycin and increase the blood level of rapamycin; and an inducer of CYP3A4 can accelerate the metabolism of rapamycin and decrease the blood level.

[0069] Therefore, the present invention controls the metabolic rate of rapamycin by adding an inhibitor or an inducer of CYP3A4 isoenzyme, so as to achieve the purpose of controlling the drug metabolism of the drug-coated balloon.

[0070] Among them, the inhibitor of CYP3A4 can be selected from: one or more of posaconazole, erythromycin, telithromycin, HIV protease inhibitor, popravir, telaprevir, amiodarone, amprenavir, aprepitant, atonavir, cimetidine, ciprofloxacin, clarithromycin, diltiazem, doxycycline, enoxacin, erythrocin, fluconazole, fluvoxamine, imatinib, indinavir, itraconazole, ketoconazole, miconazole, nefazodone, ritonavir, saquinavir, telithromycin, verapamil, and voriconazole; the inducer of CYP3A4 can be selected from: one or more of aprepitant, barbiturates, bosentan, carbamazepine, efavirenz, felbamate, glucocorticoids, modafinil, nevirapine, oxcarbazepine, phenytoin, phenobarbital, primidone, etravirine, rifampicin, St. John's wort, pioglitazone and topiramate.

Example 4

[0071] The drug-coated balloon was prepared according to the following ratio and method:

[0072] 1. An CYP3A4 inhibitor (2%), rapamycin (2%), water (5-10%) and ethanol (80-92%) were mixed by weight ratio to obtain a medicinal liquid with rapamycin concentration at 52 mg/ml;

[0073] 2. The medicinal liquid was loaded into an ultrasonic spraying equipment, and the flow rate was set to 0.01-0.1 ml/min;

[0074] 3. The rotating speed of the balloon was set to 3 to 5.0 rev/s, and the surface of the balloon 3 was wet with ethanol before spraying;

[0075] 4. The distance L between the ultrasonic nozzle 2 of the ultrasonic spraying equipment and the balloon 3 was adjusted to 10-30 mm, and the ambient temperature was controlled at 18-28° C.;

[0076] 5. The ultrasonic spraying equipment was turned on, spraying was performed back and forth 10 times along the axial direction of the balloon 3, and the final drug content on the balloon 3 was controlled to 4.0 ug/mm.sup.2;

[0077] 6. The sprayed balloon 3 was placed in an infrared dryer to dry for 5 minutes.

Example 5

[0078] The drug-coated balloon was prepared according to the following ratio and method:

[0079] 1. An CYP3A4 inhibitor (4%), rapamycin (1%), water (5-10%) and ethanol (80-92%) were mixed by weight ratio to obtain a medicinal liquid with rapamycin concentration at 52 mg/ml;

[0080] 2. The medicinal liquid was loaded into an ultrasonic spraying equipment, and the flow rate was set to 0.01-0.1 ml/min;

[0081] 3. The rotating speed of the balloon was set to 3 to 5.0 rev/s, and the surface of the balloon 3 was wet with ethanol before spraying;

[0082] 4. The distance L between the ultrasonic nozzle 2 of the ultrasonic spraying equipment and the balloon 3 was adjusted to 10-30 mm, and the ambient temperature was controlled at 18-28° C.;

[0083] 5. The ultrasonic spraying equipment was turned on, spraying was performed back and forth 10 times along the axial direction of the balloon 3, and the final drug content on the balloon 3 was controlled to 4.0 ug/mm.sup.2;

[0084] 6. The sprayed balloon 3 was placed in an infrared dryer to dry for 5 minutes.

Example 6

[0085] The drug-coated balloon was prepared according to the following ratio and method:

[0086] 1. An CYP3A4 inducer (3%), rapamycin (3%), water (5-10%) and ethanol (80-92%) were mixed by weight ratio to obtain a medicinal liquid with rapamycin concentration at 52 mg/ml;

[0087] 2. The medicinal liquid was loaded into an ultrasonic spraying equipment, and the flow rate was set to 0.01-0.1 ml/min;

[0088] 3. The rotating speed of the balloon was set to 3 to 5.0 rev/s, and the surface of the balloon 3 was wet with ethanol before spraying;

[0089] 4. The distance L between the ultrasonic nozzle 2 of the ultrasonic spraying equipment and the balloon 3 was adjusted to 10-30 mm, and the ambient temperature was controlled at 18-28° C.;

[0090] 5. The ultrasonic spraying equipment was turned on, spraying was performed back and forth 10 times along the axial direction of the balloon 3, and the final drug content on the balloon 3 was controlled to 4.0 ug/mm.sup.2;

[0091] 6. The sprayed balloon 3 was placed in an infrared dryer to dry for 5 minutes.

Example 7

[0092] The drug-coated balloon was prepared according to the following ratio and method:

[0093] 1. An CYP3A4 inducer (4%), rapamycin (1%), water (5-10%) and ethanol (80-92%) were mixed by weight ratio to obtain a medicinal liquid with rapamycin concentration at 52 mg/ml;

[0094] 2. The medicinal liquid was loaded into an ultrasonic spraying equipment, and the flow rate was set to 0.01-0.1 ml/min;

[0095] 3. The rotating speed of the balloon was set to 3 to 5.0 rev/s, and the surface of the balloon 3 was wet with ethanol before spraying;

[0096] 4. The distance L between the ultrasonic nozzle 2 of the ultrasonic spraying equipment and the balloon 3 was adjusted to 10-30 mm, and the ambient temperature was controlled at 18-28° C.;

[0097] 5. The ultrasonic spraying equipment was turned on, spraying was performed back and forth 10 times along the axial direction of the balloon 3, and the final drug content on the balloon 3 was controlled to 4.0 ug/mm.sup.2;

[0098] 6. The sprayed balloon 3 was placed in an infrared dryer to dry for 5 minutes.

[0099] III. A Drug Receptor Protein Inhibitor and a Drug Metabolism Isoenzyme Inhibitor were Used to Prepare the Drug-Coated Balloon Controllable in Drug Metabolism

Example 8

[0100] The drug-coated balloon was prepared according to the following ratio and method:

[0101] 1. A mixture of a CYP3A4 inhibitor and a FKBP12 inhibitor (2.5%), rapamycin (2.5%), water (5-10%) and ethanol (80-92%) were mixed by weight ratio to obtain a medicinal liquid with rapamycin concentration at 52 mg/ml;

[0102] 2. The medicinal liquid was loaded into an ultrasonic spraying equipment, and the flow rate was set to 0.01-0.1 ml/min;

[0103] 3. The rotating speed of the balloon was set to 3 to 5.0 rev/s, and the surface of the balloon 3 was wet with ethanol before spraying;

[0104] 4. The distance L between the ultrasonic nozzle 2 of the ultrasonic spraying equipment and the balloon 3 was adjusted to 10-30 mm, and the ambient temperature was controlled at 18-28° C.;

[0105] 5. The ultrasonic spraying equipment was turned on, spraying was performed back and forth 10 times along the axial direction of the balloon 3, and the final drug content on the balloon 3 was controlled to 4.0 ug/mm.sup.2;

[0106] 6. The sprayed balloon 3 was placed in an environment of 18-28° C. and dried for 120 minutes.

[0107] In the above examples, a series of drug-coated balloons were prepared by adjusting the types and ratios of the reagents added to the medicinal liquid with rapamycin, and the instant, controllable and slow drug metabolism can be achieved by verification.

[0108] Among them, the FKBP12 inhibitor was added in Examples 1, 2, and 3. Since the binding capacity of drug c to FKBP12 protein was stronger than that of drug a, the drug-coated balloons prepared in Examples 2 and 3 had slower drug metabolism than in Example 1. In addition, the ratio of the inhibitor to the drug in Examples 2 and 3 was 50%:50% and 80%:20%, respectively. The content of the inhibitor in Example 3 was relatively high, and an extremely slow drug metabolism can be obtained.

[0109] The CYP3A4 inhibitor was added in Examples 4 and 5, and the ratio of the CYP3A4 inhibitor to the drug was 50%:50% and 80%:20%, respectively. The content of the inhibitor in Example 5 was relatively high, and an extremely slow drug metabolism can be obtained; The CYP3A4 inducer was added in Examples 6 and 7, and the ratio of the CYP3A4 inducer to the drug was 50%:50% and 80%:20%, respectively. The content of the inducer in Example 7 was relatively high, which can greatly accelerate the absorption of the drug, and can obtain an extremely fast drug metabolism.

[0110] In Example 8, the CYP3A4 inhibitor and the FKBP12 inhibitor were added, and the FKBP12 inhibitor was bound to the rapamycin's receptor protein FKBP12 to inhibit the FKBP12, and at the same time, the CYP3A4 inhibitor inhibited the metabolism of rapamycin by CYP3A4 isoenzyme. The effects of these two aspects work together to further slow down rapamycin metabolism.

[0111] Moreover, the drug-coated balloon controllable in drug metabolism prepared in the examples of the present invention can realize immediate drug release after being placed at the site of action, and there is no sustained-release waiting period, and in the process of action, due to the interaction between an inhibitor or an inducer and a protein, there will be no side effects of tearing of the intima caused by balloon inflation. Therefore, the drug-coated balloon of the present invention can achieve a better therapeutic effect and has a significant progress compared with the prior art disclosed in the field.

[0112] The preferred embodiments of the present invention have been described in detail above. It should be understood that those of ordinary skill in the art can make many modifications and changes according to the concept of the present invention without creative work. Therefore, any technical solution that can be obtained by logical analysis, reasoning or limited experiments based on the concept of the present invented by a person skilled in the art should be within the scope of protection claimed by the claims.