Development Pharmaceutics of Doxepin Hydrochloride Orally Disintegrating Tablets for Dosing Flexibility to Physicians and Patient Compliance
Abstract
An attempt was made to formulate, evaluate and commercialize Doxepin Hydrochloride orally disintegrating tablets 3 mg, 6 mg, 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg. A direct blending and compression process by scale-up and scale-down approach / dose-proportional approach was followed to make the product. The excipients include 55% of Pearlitol Flash (Co-processed excipient of 80% D-Mannitol & 20% Maize Starch), 18% of Ludipress (Co-processed excipient of 93% Lactose Monohydrate, 3.5% Povidone K30 & 3.5% Polyplasdone XL), 0.2% of Peppermint Flavor 501500 TP0504, 0.4% of Sucralose and 1.4% of Magnesium Stearate. The composition and process was optimized as per IIG1 and SUPAC IR guidance document2. The final product exhibited rapid disintegration time complying with CDER’s guidance on orally disintegrating tablets3. The organoleptics of the final product was found acceptably flavored, exhibited smooth mouth feel and tasted pleasantly. Doxepin Hydrochloride is a BCS Class I drug (High Soluble and High Permeable) and accordingly the formulated ODT exhibited rapid disintegration and dissolution profile and hence qualifies for Bio-waiver4,5 The manufactured product was packed in both multi-dose bottle pack and special child lock enabled push-through provisioned unit dose amber colored PVC – ACLAR blister pack. The packed product was found to be stable for 6 months in ICH recommended accelerated stability storage condition at 40°C / 75%RH, hence qualifies for 2 years shelf life period at room temperature condition. The designed product was successfully commercialized under brand name InnAR-PZTM and found to be a cost-effective and differentiated alternative to tablet, capsule & oral liquid concentrate available in the market.
Keywords: Doxepin, co-processed excipients, direct blending, compression, orally disintegrating tablet
Keywords:
Doxepin, co-processed excipients, direct blending, compression, orally disintegrating tabletDOI
https://doi.org/10.22270/jddt.v14i12.6909References
1. https://www.accessdata.fda.gov/scripts/cder/iig/index.cfm .
2. https://www.fda.gov/media/70949/download .
3. https://www.fda.gov/media/70877/download .
4. https://www.accessdata.fda.gov/drugsatfda_docs/psg/PSG_016798.pdf
5. https://www.accessdata.fda.gov/drugsatfda_docs/psg/PSG_022036.pdf
6. Singh H, Becker PM. "Novel therapeutic usage of low-dose doxepin hydrochloride". Expert Opinion on Investigational Drugs. 2007;16(8):1295-305. https://doi.org/10.1517/13543784.16.8.1295 PMid:17685877
7. Shaha DP. Insomnia Management: A Review and Update. J Fam Pract. 2023 Jul;72(6 Suppl):S31-S36. https://doi.org/10.12788/jfp.0620 PMid:37549414
8. Yang Y, Liu G, Jia J, Zhong J, Yan R, Lin X, Zheng K, Zhu Q. In-vitro antiviral activity of doxepin hydrochloride against group B coxsackievirus. Virus Res. 2022 Aug;317:198816. https://doi.org/10.1016/j.virusres.2022.198816 PMid:35598772
9. Sio TT, Le-Rademacher JG, Leenstra JL, Loprinzi CL, Rine G, Curtis A, Singh AK, Martenson JA Jr, Novotny PJ, Tan AD, Qin R, Ko SJ, Reiter PL, Miller RC. Effect of Doxepin Mouthwash or Diphenhydramine-Lidocaine-Antacid Mouthwash vs Placebo on Radiotherapy-Related Oral Mucositis Pain: The Alliance A221304 Randomized Clinical Trial. JAMA. 2019 Apr 16;321(15):1481-1490. https://doi.org/10.1001/jama.2019.3504 PMid:30990550 PMCid:PMC6484809
10. Tao F, Zhu J, Duan L, Wu J, Zhang J, Yao K, Bo J, Zu H. Anti-inflammatory effects of doxepin hydrochloride against LPS-induced C6-glioma cell inflammatory reaction by PI3K-mediated Akt signaling. J Biochem Mol Toxicol. 2020 Feb;34(2):e22424. https://doi.org/10.1002/jbt.22424 PMid:31743544
11. Myers B, Reddy V, Chan S, Thibodeaux Q, Brownstone N, Koo J. Optimizing doxepin therapy in dermatology: introducing blood level monitoring and genotype testing. J Dermatolog Treat. 2022 Feb;33(1):87-93. https://doi.org/10.1080/09546634.2020.1762841 PMid:32347140
12. Golden RN, Evans DL, Nau CH Jr. Doxepin and tinnitus. South Med J. 1983 Sep;76(9):1204-5. https://doi.org/10.1097/00007611-198309000-00046 PMid:6612411
13. McCleane G. Topical application of doxepin hydrochloride, capsaicin and a combination of both produces analgesia in chronic human neuropathic pain: a randomized, double-blind, placebo-controlled study. Br J Clin Pharmacol. 2000 Jun;49(6):574-9. https://doi.org/10.1046/j.1365-2125.2000.00200.x PMid:10848721 PMCid:PMC2015036
14. Asl AD, Bohlooli S, Dadkhah M, Shirmard LR. Topical delivery of doxepin using liposome containing cream: An emerging approach in enhancing skin retention. Pak J Pharm Sci. 2023 Sep;36(5):1497-1506.
15. Norman TR, Burrows GD, Bianchi GN, Maguire KP, Wurm JM. Doxepin plasma levels and anxiolytic response. Int Pharmacopsychiatry. 1980;15(4):247-52. https://doi.org/10.1159/000468444 PMid:7021450
16. Norman TR, Judd F, Holwill BJ, Burrows GD. Doxepin and visual hallucinations. Aust N Z J Psychiatry. 1982 Dec;16(4):295-6. https://doi.org/10.3109/00048678209161271 PMid:6963177
17. Hoyos CL, Peñuelas Leal R, Echevarría AG, Esquembre AC, Spröhnle JL, Magdaleno Tapial J, Zaragoza Ninet V. Systemic allergic dermatitis from doxepin: A case report. Contact Dermatitis. 2023 Aug;89(2):137-139. https://doi.org/10.1111/cod.14354 PMid:37237446
18. Lu T, Chou CT, Liang WZ, Yu CC, Chang HT, Kuo CC, Chen WC, Kuo DH, Ho CM, Shieh P, Jan CR. Effect of Antidepressant Doxepin on Ca²⁺ Homeostasis and Viability in PC3 Human Prostate Cancer Cells. Chin J Physiol. 2015 Jun 30;58(3):178-87. doi: 10.4077/CJP.2015.
19. Linnoila M, Seppala T, Mattila MJ, Vihko R, Pakarinen A, Skinner T 3rd. Clomipramine and doxepin in depressive neurosis. Plasma levels and therapeutic response. Arch Gen Psychiatry. 1980 Nov;37(11):1295-9. https://doi.org/10.1001/archpsyc.1980.01780240093011 PMid:7436691
20. Zhang M, Huang F, Jiang F, Mai M, Guo X, Zhang Y, Xu Y, Zu H. Clinical efficacy and safety of low-dose doxepin in Chinese patients with generalized anxiety disorder: A before-after study. Medicine (Baltimore). 2022 Oct 21;101(42):e31201. https://doi.org/10.1097/MD.0000000000031201 PMid:36281170 PMCid:PMC9592331
21. Sudoh Y, Cahoon EE, De Girolami U, Wang GK. Local anesthetic properties of a novel derivative, N-methyl doxepin, versus doxepin and bupivacaine. Anesth Analg. 2004 Mar;98(3):672-6, table of contents. https://doi.org/10.1213/01.ANE.0000100742.87447.C1 PMid:14980917
22. Lose G, Jørgensen L, Thunedborg P. Doxepin in the treatment of female detrusor overactivity: a randomized double-blind crossover study. J Urol. 1989 Oct;142(4):1024-6. https://doi.org/10.1016/S0022-5347(17)38976-0 PMid:2795725
23. Groene D, Martus P, Heyer G. Doxepin affects acetylcholine induced cutaneous reactions in atopic eczema. Exp Dermatol. 2001 Apr;10(2):110-7. https://doi.org/10.1034/j.1600-0625.2001.010002110.x PMid:11260249
24. Ojemann LM, Friel PN, Trejo WJ, Dudley DL. Effect of doxepin on seizure frequency in depressed epileptic patients. Neurology. 1983 May;33(5):646-8. https://doi.org/10.1212/WNL.33.5.646 PMid:6682502
25. Kaye NS. Doxepin for treatment of mania. Am J Psychiatry. 1989 Jun;146(6):802-3. https://doi.org/10.1176/ajp.146.6.802b
26. Cohn ML, Machado AF, Bier R, Cohn M. Piroxicam and doxepin--an alternative to narcotic analgesics in managing advanced cancer pain. West J Med. 1988 Mar;148(3):303-6.
27. Godfrey RG. A guide to the understanding and use of tricyclic antidepressants in the overall management of fibromyalgia and other chronic pain syndromes. Arch Intern Med. 1996 May 27;156(10):1047-52. https://doi.org/10.1001/archinte.156.10.1047 PMid:8638990
28. Täschner KL. A controlled comparison of clonidine and doxepin in the treatment of the opiate withdrawal syndrome. Pharmacopsychiatry. 1986 May;19(3):91-5. https://doi.org/10.1055/s-2007-1017162 PMid:3523550
29. Whelan AM, Davis SK. Doxepin in smoking cessation. DICP. 1990 Jun;24(6):598-9.
30. Seymour Diamond, George Urban, chapter 44 - Cluster Headache, Editor(s): Steven D. Waldman, Joseph I. Bloch, Pain Management, W.B. Saunders, 2007, Pages 474-491, ISBN 9780721603346, https://doi.org/10.1016/B978-0-7216-0334-6.50048-0
32. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5b4dba99-6b66-4091-94f1-bf5f021c688a
33. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1533343b-f1ed-4c3a-bb36-23a748452b05
34. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=71cff7cd-0410-4194-9cdd-af404a869edd
35. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f350afed-120b-422d-9e6e-3aaa0f72a5fb
37. https://www.apollopharmacy.in/medicine/dox-10mg-tab-10-s
38. https://www.fda.gov/media/92988/download
39. https://www.researchgate.net/figure/Sample-Locations-in-Double-Cone-Blender_fig1_341452657
40. https://www.fda.gov/media/70936/download
41. https://database.ich.org/sites/default/files/Q1A%28R2%29%20Guideline.pdf
42. Witold Brniak, Renata Jachowicz, Przemyslaw Pelka. The practical approach to the evaluation of methods used to determine the disintegration time of orally disintegrating tablets (ODTs). Saudi Pharmaceutical Journal (2015) 23, 437-443. https://doi.org/10.1016/j.jsps.2015.01.015 PMid:27134547 PMCid:PMC4834683
43. Allen LV Jr. Quality Control: Water Activity Considerations for Beyond-use Dates. Int J Pharm Compd. 2018 Jul-Aug;22(4):288-293. PMID: 30021184.
44. https://pqri.org/wp-content/uploads/2015/08/pdf/PQRIBlisterWVTRReportFinal05_11_10.pdf
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Copyright (c) 2024 Packiaraj Jeyachandran Manohari, Aswin Iyappan Seethalakshmi, Samuel George, Janakiraman Kunchithapatham, Samuel Ezhumalai, Asaithambi Ramesh, Srihariteja Seelamantula, Guhan Himadeep Chowdary Eswara Rao, Induprasad Munirathnam, Narendra Reddy Parvatha Janarthana Reddy, Jegatheesh Uthayasuriyan, Kamalakkannan Venkatachalam, Madhavan Kumar, Venkateswaran Chidambaram Seshadri, Rohith Sekar
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