TRANSMUCOSAL DELIVERY OF PHARMACEUTICAL ACTIVE SUBSTANCES

• US 20070292387A1
• Filed: 08/29/2007
• Published: 12/20/2007
• Est. Priority Date: 01/23/2006
• Status: Abandoned Application

• Current Assignee: Anygen Co., Ltd.
• Original Assignee: Gwangju Institute of Science and Technology
• Inventors: LEE, Jin Ju, JON, Sangyong, LEE, In-Hyun, LEE, Eunhye
• Application Number:
  US11/847,237
• Publication Number:
  US 20070292387A1
• Time in Patent Office: Days
• US Class Current: 424/85.1
• CPC Class Codes: A61K 47/61 the organic macromolecular compound being a polysaccharide or a derivative thereof
• CPC Class Codes: A61K 9/0034 Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 14/62 Insulins

Abstract

Provided is a conjugate including a pharmacologically active substance covalently bound to chitosan or its derivative and a method for transmucosal delivery of a pharmacologically active substance using the same. Specifically, a conjugate includes a pharmacologically active substance covalently bound via a linker to chitosan; and a pharmaceutical composition for transmucosal administration of a drug includes the aforementioned conjugate and a pharmaceutically acceptable carrier. Further provided is a method for in vivo delivery of a pharmacologically active substance via a transmucosal route, by covalent binding of the active substance with chitosan or its derivative via a linker. The conjugate in accordance with the present invention exhibits excellent absorption rate and biocompatibility in biological mucous membranes, particularly mucous membranes of the alimentary canal (especially the gastrointestinal tract), in vivo degradability, and superior bioavailability even with oral administration, thus enabling treatment of diseases via oral administration of a drug.

Claims

1. A conjugate for transmucosal delivery comprising a pharmacologically active substance covalently bound via a linker to chitosan or its derivative.

2. The conjugate according to claim 1, wherein the pharmacologically active substance is selected from the group consisting of a protein, a peptide and a chemical drug.

3. The conjugate according to claim 2, wherein the pharmacologically active substance includes a protein or peptide selected from the group consisting of insulin, insulin-like growth factor 1 (IGF-1), growth hormones, interferons (IFNs), erythropoietin, granulocyte-colony stimulating factor (G-CSFs), granulocyte/macrophage-colony stimulating factor (GM-CSFs), interleukin-2 (IL-2), epidermal growth factor (EGF), calcitonin, adrenocorticotropic hormone (ACTH), atobisban, buserelin, cetrorelix, deslorelin, desmopressin, dynorphin A (1-13), elcatonin, eleidosin, eptifibatide, GHRH-II (growth hormone releasing hormone-II), gonadorelin, goserelin, histrelin, leuprorelin, lypressin, octreotide, oxytocin, pitressin, secretin, sincalide, terlipressin, thymopentin, thymosine α

1, triptorelin, bivalirudin, carbetocin, cyclosporin O, exedine, lanreotide, LHRH (luteinizing hormone-releasing hormone), nafarelin, parathyroid hormone, pramlintide, T-20 (enfuvirtide), thymalfasin and ziconotide.

4. The conjugate according to claim 3, wherein the protein is insulin or calcitonin.

5. The conjugate according to claim 3, wherein the pharmacologically active substance includes a chemical drug selected from the group consisting of cisplatin, carboplatin, procarbazine, mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, bisulfan, docetaxel, camptothecin, nitrosourea, dactinomycin (actinomycin-D), daunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, etoposide, tamoxifen, paclitaxel, transplatinum, 5-fluorouracil, adriamycin, vincristine, vinblastine and methotrexate.

6. The conjugate according to claim 5, wherein the chemical drug is paclitaxel, docetaxel, doxorubicin or camptothecin.

7. The conjugate according to claim 3, wherein the pharmacologically active substance is the chemical drug of which transmucosal absorption is inhibited by P-glycoprotein.

8. The conjugate according to claim 7, wherein the chemical drug is selected from the group consisting of cisplatin, methotrexate, paclitaxel, daunorubicin, doxorubicin, vincristine, vinblastine, carboplatin, procarbazine, mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, bisulfan, docetaxel, camptothecin, nitrosourea, dactinomycin (actinomycin-D), bleomycin, plicomycin, mitomycin, etoposide, tamoxifen, transplatinum, 5-fluorouracil, adriamycin, quinolone, ciprofloxacin, progesterone, teniposide, estradiol, epirubicin, taxanes, prostaglandins, amphotericin B, testosterone, beclomethasone, Vitamin E, cortisone, dexamethasone, triamicinolone, aldosterone, methylprednisolone, betamethasone valerete, nifedipine, griseofulvin, cyclosporin, digoxin, itraconozole, carbamazepine, piroxicam, fluconazole, indomethacin, ibuprofen, diazepam, finasteride, diflunisal, digoxin, diltiazem, verapamil and talinolol.

9. The conjugate according to claim 1, wherein the chitosan or its derivative has a molecular weight of 500 to 20000 Da.

10. The conjugate according to claim 1, wherein the pharmacologically active substance is a protein or peptide and each —

NH₂ group of chitosan and the protein or peptide is covalently bound via an amide bond to the linker represented by the following formula;

—

CO—

(CH₂)_n—

S—

S—

(CH₂)_n—

CO—

, and

wherein n is an integer having a value from 1 to 5.

11. The conjugate according to claim 1, wherein the pharmacologically active substance is a chemical drug,

wherein chitosan and the chemical drug are covalently bound via a succinyl group (—

CO—

CH₂—

CH₂—

CO—

) as the linker,

wherein chitosan is covalently bound to the succinyl group via an amide bond, and

wherein the chemical drug is bound to the succinyl group via an ester bond.

12. The conjugate according to claim 1, wherein the conjugate delivers the pharmacologically active substance via buccal, nasal, rectal, vaginal, urethral, throat, alimentary canal, peritoneal or ocular mucosae.

13. The conjugate according to claim 10, wherein the conjugate delivers the pharmacologically active substance via the alimentary canal mucosa.

14. A pharmaceutical composition for transmucosal administration of a drug, comprising:

the conjugate of claim 1;

and

a pharmaceutically acceptable carrier.

15. The pharmaceutical composition according to claim 14, wherein the pharmacologically active substance is selected from the group consisting of a protein, a peptide and a chemical drug.

16. The pharmaceutical composition according to claim 15, wherein the pharmacologically active substance is the protein selected from the group consisting of insulin, insulin-like growth factor 1 (IGF-1), growth hormones, interferons (IFNs), erythropoietin, granulocyte-colony stimulating factor (G-CSFs), granulocyte/macrophage-colony stimulating factor (GM-CSFs), interleukin-2 (IL-2), epidermal growth factor (EGF), calcitonin, adrenocorticotropic hormone (ACTH), atobisban, buserelin, cetrorelix, deslorelin, desmopressin, dynorphin A (1-13), elcatonin, eleidosin, eptifibatide, GHRH-II (growth hormone releasing hormone-II), gonadorelin, goserelin, histrelin, leuprorelin, lypressin, octreotide, oxytocin, pitressin, secretin, sincalide, terlipressin, thymopentin, thymosine α

1, triptorelin, bivalirudin, carbetocin, cyclosporin O, exedine, lanreotide, LHRH (luteinizing hormone-releasing hormone), nafarelin, parathyroid hormone, pramlintide, T-20 (enfuvirtide), thymalfasin and ziconotide.

17. The pharmaceutical composition according to claim 16, wherein the protein is insulin or calcitonin.

18. The pharmaceutical composition according to claim 15, wherein the pharmacologically active substance is the chemical drug selected from the group consisting of cisplatin, carboplatin, procarbazine, mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, bisulfan, docetaxel, camptothecin, nitrosourea, dactinomycin (actinomycin-D), daunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, etoposide, tamoxifen, paclitaxel, transplatinum, 5-fluorouracil, adriamycin, vincristine, vinblastine and methotrexate.

19. The pharmaceutical composition according to claim 18, wherein the chemical drug is paclitaxel, docetaxel, doxorubicin or camptothecin.

20. The pharmaceutical composition according to claim 15, wherein the pharmacologically active substance is the chemical drug of which transmucosal absorption is inhibited by P-glycoprotein.

21. The pharmaceutical composition according to claim 20, wherein the chemical drug is selected from the group consisting of cisplatin, methotrexate, paclitaxel, daunorubicin, doxorubicin, vincristine, vinblastine, carboplatin, procarbazine, mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, bisulfan, docetaxel, camptothecin, nitrosourea, dactinomycin (actinomycin-D), bleomycin, plicomycin, mitomycin, etoposide, tamoxifen, transplatinum, 5-fluorouracil, adriamycin, quinolone, ciprofloxacin, progesterone, teniposide, estradiol, epirubicin, taxanes, prostaglandins, amphotericin B, testosterone, beclomethasone, Vitamin E, cortisone, dexamethasone, triamicinolone, aldosterone, methylprednisolone, betamethasone valerete, nifedipine, griseofulvin, cyclosporin, digoxin, itraconozole, carbamazepine, piroxicam, fluconazole, indomethacin, ibuprofen, diazepam, finasteride, diflunisal, digoxin, diltiazem, verapamil and talinolol.

22. The pharmaceutical composition according to claim 14, wherein the chitosan or its derivative has a molecular weight of 500 to 20000 Da.

23. The pharmaceutical composition according to claim 14, wherein the pharmacologically active substance is a protein or peptide and each —

NH₂ group of chitosan and the protein or peptide is covalently bound via an amide bond to the linker represented by the formula;

—

CO—

(CH₂)_n—

S—

S—

(CH₂)_n—

CO—

, and

wherein n is an integer having a value from 1 to 5.

24. The pharmaceutical composition according to claim 14, wherein the pharmacologically active substance is a chemical drug,

wherein chitosan and the chemical drug are covalently bound via a succinyl group (—

CO—

CH₂—

CH₂—

CO—

) as the linker,

wherein chitosan is covalently bound to the succinyl group via an amide bond, and

wherein the chemical drug is bound to the succinyl group via an ester bond.

25. The pharmaceutical composition according to claim 14, wherein the conjugate delivers the pharmacologically active substance via buccal, nasal, rectal, vaginal, urethral, throat, alimentary canal, peritoneal or ocular mucosae.

26. The pharmaceutical composition according to claim 25, wherein the conjugate delivers the pharmacologically active substance via the alimentary canal mucosa.

27. A method for in vivo delivery of a pharmacologically active substance via a transmucosal route, comprising:

preparing a conjugate by binding covalently the pharmacologically active substance to chitosan or its derivative via a linker; and

administering the conjugate to a subject via the transmucosal route.

28. The method according to claim 27, wherein the pharmacologically active substance is selected from the group consisting of a protein, a peptide and a chemical drug.

29. The method according to claim 28, wherein the pharmacologically active substance is the protein selected from the group consisting of insulin, insulin-like growth factor 1 (IGF-1), growth hormones, interferons (IFNs), erythropoietin, granulocyte-colony stimulating factor (G-CSFs), granulocyte/macrophage-colony stimulating factor (GM-CSFs), interleukin-2 (IL-2), epidermal growth factor (EGF), calcitonin, adrenocorticotropic hormone (ACTH), atobisban, buserelin, cetrorelix, deslorelin, desmopressin, dynorphin A (1-13), elcatonin, eleidosin, eptifibatide, GHRH-II (growth hormone releasing hormone-II), gonadorelin, goserelin, histrelin, leuprorelin, lypressin, octreotide, oxytocin, pitressin, secretin, sincalide, terlipressin, thymopentin, thymosine α

1, triptorelin, bivalirudin, carbetocin, cyclosporin O, exedine, lanreotide, LHRH (luteinizing hormone-releasing hormone), nafarelin, parathyroid hormone, pramlintide, T-20 (enfuvirtide), thymalfasin and ziconotide.

30. The method composition according to claim 29, wherein the protein is insulin or calcitonin.

31. The method according to claim 27, wherein the pharmacologically active substance is the chemical drug selected from the group consisting of cisplatin, carboplatin, procarbazine, mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, bisulfan, docetaxel, camptothecin, nitrosourea, dactinomycin (actinomycin-D), daunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, etoposide, tamoxifen, paclitaxel, transplatinum, 5-fluorouracil, adriamycin, vincristine, vinblastine and methotrexate.

32. The method according to claim 31, wherein the chemical drug is paclitaxel, docetaxel, doxorubicin or camptothecin.

33. The method according to claim 27, wherein the pharmacologically active substance is the chemical drug of which transmucosal absorption is inhibited by P-glycoprotein.

34. The method according to claim 33, wherein the chemical drug is selected from the group consisting of cisplatin, methotrexate, paclitaxel, daunorubicin, doxorubicin, vincristine, vinblastine, carboplatin, procarbazine, mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, bisulfan, docetaxel, camptothecin, nitrosourea, dactinomycin (actinomycin-D), bleomycin, plicomycin, mitomycin, etoposide, tamoxifen, transplatinum, 5-fluorouracil, adriamycin, quinolone, ciprofloxacin, progesterone, teniposide, estradiol, epirubicin, taxanes, prostaglandins, amphotericin B, testosterone, beclomethasone, Vitamin E, cortisone, dexamethasone, triamicinolone, aldosterone, methylprednisolone, betamethasone valerete, nifedipine, griseofulvin, cyclosporin, digoxin, itraconozole, carbamazepine, piroxicam, fluconazole, indomethacin, ibuprofen, diazepam, finasteride, diflunisal, digoxin, diltiazem, verapamil and talinolol.

35. The method according to claim 27, wherein the chitosan or its derivative has a molecular weight of 500 to 20000 Da.

36. The method according to claim 27, wherein the pharmacologically active substance is a protein or peptide and each —

NH₂ group of chitosan and the protein or peptide is covalently bound via an amide bond to the linker represented by the formula;

—

CO—

(CH₂)_n—

S—

S—

(CH₂)_n—

CO—

, and

wherein n is an integer having a value from 1 to 5.

37. The method according to claim 27, wherein the pharmacologically active substance is a chemical drug,

wherein chitosan and the chemical drug are covalently bound via a succinyl group (—

CO—

CH₂—

CH₂—

CO—

) as the linker,

wherein chitosan is covalently bound to the succinyl group via an amide bond, and

wherein the chemical drug is bound to the succinyl group via an ester bond.

38. The method according to claim 27, wherein the conjugate delivers the pharmacologically active substance via buccal, nasal, rectal, vaginal, urethral, throat, alimentary canal, peritoneal or ocular mucosae.

39. The method according to claim 38, wherein the conjugate delivers the pharmacologically active substance via the alimentary canal mucosa.

40. A method for increasing the transmucosal absorption of a pharmacologically active substance of which transmucoal absorption is inhibited by P-glycoprotein, comprising:

preparing a conjugate by binding covalently the pharmacologically active substance to chitosan or its derivative via a linker; and

administering the conjugate to a subject via the transmucosal route.

41. The method according to claim 40, wherein the pharmacologically active substance is selected from the group consisting of a protein, a peptide and a chemical drug.

42. The method according to claim 41, wherein the pharmacologically active substance is the protein selected from the group consisting of insulin, insulin-like growth factor 1 (IGF-1), growth hormones, interferons (IFNs), erythropoietin, granulocyte-colony stimulating factor (G-CSFs), granulocyte/macrophage-colony stimulating factor (GM-CSFs), interleukin-2 (IL-2), epidermal growth factor (EGF) and calcitonin, adrenocorticotropic hormone (ACTH), atobisban, buserelin, cetrorelix, deslorelin, desmopressin, dynorphin A (1-13), elcatonin, eleidosin, eptifibatide, GHRH-II (growth hormone releasing hormone-II), gonadorelin, goserelin, histrelin, leuprorelin, lypressin, octreotide, oxytocin, pitressin, secretin, sincalide, terlipressin, thymopentin, thymosine α

1, triptorelin, bivalirudin, carbetocin, cyclosporin O, exedine, lanreotide, LHRH (luteinizing hormone-releasing hormone), nafarelin, parathyroid hormone, pramlintide, T-20 (enfuvirtide), thymalfasin and ziconotide.

43. The method according to claim 41, wherein the pharmacologically active substance is the chemical drug selected from the group consisting of cisplatin, carboplatin, procarbazine, mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, bisulfan, docetaxel, camptothecin, nitrosourea, dactinomycin (actinomycin-D), daunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, etoposide, tamoxifen, paclitaxel, transplatinum, 5-fluorouracil, adriamycin, vincristine, vinblastine, methotrexate, carboplatin, procarbazine, mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, bisulfan, docetaxel, camptothecin, nitrosourea, quinolone, ciprofloxacin, progesterone, teniposide, estradiol, epirubicin, taxanes, prostaglandins, amphotericin B, testosterone, beclomethasone, Vitamin E, cortisone, dexamethasone, triamicinolone, aldosterone, methylprednisolone, betamethasone valerete, nifedipine, griseofulvin, cyclosporin, digoxin, itraconozole, carbamazepine, piroxicam, fluconazole, indomethacin, ibuprofen, diazepam, finasteride, diflunisal, digoxin, diltiazem, verapamil and talinolol.

44. The method according to claim 40, wherein the chitosan or its derivative has a molecular weight of 500 to 20000 Da.

45. The method according to claim 40, wherein the pharmacologically active substance is a protein or peptide and each —

NH₂ group of chitosan and the protein or peptide is covalently bound via an amide bond to the linker represented by the following formula;

—

CO—

(CH₂)_n—

S—

S—

(CH₂)_n—

CO—

, and

wherein n is an integer having a value from 1 to 5.

46. The method according to claim 40, wherein the pharmacologically active substance is a chemical drug;

chitosan and the chemical drug are covalently bound via a succinyl group (—

CO—

CH₂—

CH₂—

CO—

) as the linker;

chitosan is covalently bound to the succinyl group via an amide bond; and

the chemical drug is bound to the succinyl group via an ester bond.

47. The method according to claim 40, wherein the conjugate delivers the pharmacologically active substance via buccal, nasal, rectal, vaginal, urethral, throat, alimentary canal, peritoneal or ocular mucosae.

48. The method according to claim 47, wherein the conjugate delivers the pharmacologically active substance via the alimentary canal mucosa.