Oral transmucosal drug dosage using solid solution

• US 6,264,981 B1
• Filed: 10/27/1999
• Issued: 07/24/2001
• Est. Priority Date: 10/27/1999
• Status: Expired due to Term

• Current Assignee: Cephalon Incorporated (Teva Pharmaceutical Industries Limited)
• Original Assignee: Anesta Corporation (Teva Pharmaceutical Industries Limited)
• Inventors: Croft, Jed, Zhang, Hao
• Primary Examiner(s): AZPURU, CARLOS A
• Application Number:
  US09/428,071
• Time in Patent Office: 636 Days
• Field of Search: 424/451, 424/464
• US Class Current: 424/451
• CPC Class Codes: A61K 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats

Abstract

The present invention is directed toward formulation and method for oral transmucosal delivery of a pharmaceutical. The invention provides a drug formulation comprising a solid pharmaceutical agent in solid solution with a dissolution agent. The formulation is administered into a patient'"'"'s oral cavity, delivering the pharmaceutical agent by absorption through a patient'"'"'s oral mucosal tissue. The formulation and method provide for improved oral mucosal delivery of the pharmaceutical agent.

Claims

1. An improved oral transmucosal solid dosage form drug delivery formulation comprising:

a pharmaceutical agent capable of being absorbed into oral mucosal tissue having a dissolution rate in the solvents found in the oral cavity,

a dissolution agent having a dissolution rate in the solvents found in the oral cavity, said dissolution rate of said dissolution agent being greater than said dissolution rate of said pharmaceutical agent, and said pharmaceutical agent being in solid solution with said dissolution agent.

2. The formulation of claim 1 further comprising a buffer system.

3. The formulation of claim 2 wherein said buffer system is capable of maintaining a significant portion of said pharmaceutical agent in unionized form following dissolution of said pharmaceutical agent.

4. The formulation system of claim 2, wherein a for said system is chosen from the group consisting of:

phosphate, carbonate, tris, tartrate, borate, acetate, or maleate buffer.

5. The delivery system of claim 1, wherein said dissolution agent provides a physical barrier between pharmaceutical agent and said buffer while in storage.

6. The formulation of claim 4, wherein said pharmaceutical agent is unionizable.

7. The formulation of claim 6, wherein said pharmaceutical agent is an organic acid.

8. The formulation of claim 6, wherein said pharmaceutical agent is an organic base.

9. The formulation of claim 1, wherein said pharmaceutical agent is selected from the group consisting of:

androgen, estrogen, non-steroidal anti-inflammatory agents, anti-hypertensive agents, analgesic agents, antidepressants, antibiotics, anti-cancer agents, local anesthetics, antiemetics, antiinfectives, contraceptives, antidiabetic agents, steroids, antiallergy agents, antimigraine agents, agents for smoking cessation, and antiobesity agents.

10. The formulation of claim 1, wherein said pharmaceutical agent has an ionized form that is more stable in storage and more soluble in a solvent than the agent'"'"'s unionized form.

11. The formulation of claim 1, wherein said pharmaceutical agent has an unionized form that is more permeable than the agent'"'"'s ionized form.

12. The formulation of claim 1, wherein said pharmaceutical agent is brought into solution with said dissolution agent through the process of co-melting to form a solid solution.

13. The formulation of claim 1, wherein said pharmaceutical agent is brought into solution with said dissolution agent through the process of dissolving and freeze-drying to form a solid solution.

14. The formulation of claim 1, wherein said pharmaceutical agent is brought into solution with said dissolution agent through the process of wet granulation to form a solid solution.

15. The formulation of claim 1, wherein said pharmaceutical agent is brought into solution with said dissolution agent through the process of partial wet granulation to form a solid solution.

16. The formulation of claim 1, wherein said pharmaceutical agent is brought into solution with said dissolution agent through the process of dissolving and spray drying to form a solid solution.

17. The formulation of claim 1, wherein said pharmaceutical agent in solution with said dissolution agent provides a faster dissolution rate for said pharmaceutical agent.

18. The formulation of claim 1, wherein said pharmaceutical agent in solution with said dissolution agent provides more free drug for absorption.

19. The formulation of claim 1, wherein said pharmaceutical agent combined in solution with said dissolution agent provides an increased solubility for said pharmaceutical agent.

20. The formulation of claim 1, wherein said dissolution agent is selected from the group consisting of:

acacia, alginic acid, carbomer, carboxymethylcellulose, calcium, carboxymethylcellulose sodium, microcrystalline cellulose, cellulose, dextrates, dextrin, dextrose, ethylcellulose, fructose, gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactitol, lactose, lecithin, maltodextrin, mannitol, methylcellulose, poloxamer, polyethylene glycol, polymethacrylates, polyoxyethylene alkyl ethers, polyvinyl alcohol, propylene glycol alginate, sodium alginate, sodium ascorbate, sodium starch glycolate, sorbitol, starch, starch (pregelatinized), sucrose, tragacanth, trimethylglycine, xanthan gum, xylitol, or zein.

21. The delivery system of claim 1, wherein said dissolution agent controls the rate of dissolution of said pharmaceutical agent.

22. The formulation of claim 1, wherein said formulation is disposed within a oral transmucosal patch.

23. The formulation of claim 1, wherein said formulation is in a lozenge/troche dosage form.

24. The formulation of claim 1, wherein said formulation is in a lollipop dosage form.

25. The formulation of claim 1, wherein said formulation is in a chewing gum dosage form.

26. The delivery system of claim 1, further comprising at least one pharmaceutical ingredient selected from the group consisting of:

absorbents, buffering agents, colorants, flavorants, solvents and co-solvents, coating agents, direct compression excipients, disintegrants, glidants, lubricants, opaquants, polishing agents, suspending agents, sweetening agents, anti-adherents, binders, and capsule diluents, anti-fungal preservatives, antimicrobial preservatives, clarifying agents, emulsifying agents, antioxidants, levigating agents, plasticizers, surfactants, tonicity agents, and viscosity increasing agents.

27. The formulation of claim 1, wherein said pharmaceutical agent is selected from the group of:

piroxicam, droperidol, etomidate, nicotine, testosterone, estradiol, nitroglycerin, clonidine, dexamethasone, wintergreen oil, tetracaine, lidocaine, fentanyl, sufentanil, progestrone, insulin, Vitamin A, Vitamin C, Vitamin E, prilocaine, bupivacaine, sumatriptan, dihydroergotamine, COX₂ inhibitors, and peptides.

28. The formulation of claim 1, wherein said pharmaceutical agent is chosen from the group consisting of:

methohexital, pentobarbital, thiamylal, thiopental, fentanyl, alfentanil, sufentanil, lofentanil, carfentanil, naloxone, epam, lorazepam, midazolam, oxazepam, triazolam, droperidol, propanidid, etomidate, propofol, ketamine, diprivan, bretylium, captopril, clonidine, dopamine, enalapril, esmolol, furosemide, isosorbide, labetalol, lidocaine, metolazone, metoprolol, nadolol, nifedipine, nitroglycerin, nitroprusside, propranolol, benzquinamide, meclizine, metoclopramide, prochlorperazine, trimethobenzamide, clotrimazole, nystatin, carbidopa, levodopa, sucralfate, albuterol, amninophylline, beclomethasone, dyphylline, epinephrine, flunisolide, isoetharine, isoproterenol HCl, metaproterenol, oxtriphylline, terbutaline, theophylline, ergotamine, methysergide, propranolol, suloctidil, ergonovine, oxytocin, desmopressin, acetate, lypressin, vasopressin, insulin, beta-endorphin, enkephalins, bradykinin, aniotensin I, gonadotropic hormones, adrenocorticotropic hormone (ACTH), calcitonin, parathyroid hormone, growth hormone, polysaccharides (such as heparin), antigens, antibodies, and enzymes.

29. The formulation of claim 1, wherein said pharmaceutical agent belongs to a drug class chosen from the group consisting of:

barbiturate, opioid agonist, benzodiazepine, buterophenone, eugenol, GABA stimulator, substituted phenol, phencyclidine, antiarrhythmic, ACE inhibitor, antihypertensive, renal vascular, antihypertensive/angina, diuretic, angina, hypotensive, antiemetic, antifungal, antiparkinson with levodopa, antiparkinson, antisecretory, bronchodilator, antimigraine, oxytocic, antidiuretic, and antihyperglycemic.

43. The method of claim 27, wherein said pharmaceutical agent and said dissolution agent are combined in solution through a process of dissolving and spray drying.

30. A method for oral transmucosal delivery of a pharmaceutical agent comprising the steps of:

providing a drug formulation comprising a solid pharmaceutical agent in solid solution with a dissolution agent,

administering said drug formulation into a patient'"'"'s oral cavity, and

delivering said pharmaceutical agent by absorption through a patient'"'"'s oral mucosal tissue.

31. The method of claim 30, wherein the step of providing a drug formulation further comprises a buffer system.

32. The method of claim 30, wherein said buffer maintains a pH level such that ionization of said pharmaceutical is controlled by said buffer system.

33. The method of claim 30, wherein said drug formulation further comprises at least one excipient.

34. The method of claim 30, wherein said pharmaceutical agent is an unionizable compound.

35. The method of claim 34, wherein said pharmaceutical agent is an organic base.

36. The method of claim 34, wherein said pharmaceutical agent is an organic acid.

37. The method of claim 33, wherein said pharmaceutical agent is selected from the group of:

androgen, estrogen, non-steroidal anti-inflammatory agents, anti-hypertensive agents, analgesic agents, anti-depressants, antibiotics, anti-cancer agents, local anesthetics, antiemetics, anti-infectants, contraceptives, anti-diabetic agents, steroids, anti-allergy agents, anti-migraine agents, agents for smoking cessation, and anti-obesity agents. Specific drugs can include without limitation piroxicam, droperidol, etomidate, nicotine, testosterone, estradoil, nitroglycerin, clonidine, dexamethasone, wintergreen oil, tetracaine, lidocaine, fentanyl, sufentanil, progestrone, insulin, Vitamin A, Vitamin C, Vitamin E, prilocaine, .

38. The method of claim 30, wherein said dissolution agent is selected from the group of acacia, alginic acid, carbomer, carboxymethylcellulose, calcium, carboxymethylcellulose sodium, microcrystalline cellulose, cellulose, dextrates, dextrin, dextrose, ethylcellulose, fructose, gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, latitol, lactose, lecithin, maltodextrin, mannitol, methylcellulose, poloxamer, polyethylene glycol, polymethacrylates, polyoxyethylene alkyl, ethers, polyvinyl alcohol, povidone, propylene glycol alginate, sodium alginate, sodium ascorbate, sodium starch glycolate, sorbitol, starch, starch (pregelatinized), sucrose, tragacanth, trimethylglycine, xanthan gum, xylitol, or zein.

39. The method of claim 30, wherein said pharmaceutical agent and said dissolution agent are combined in solution through a process of co-melting.

40. The method of claim 30, wherein said pharmaceutical agent and said dissolution agent are combined in solution through a process of dissolving and freeze-drying.

41. The method of claim 30, wherein said pharmaceutical agent and said dissolution agent are combined in solution through a process of wet granulation.

42. The method of claim 30, wherein said pharmaceutical agent and said dissolution agent are combined in solution through a process of partial wet granulation.

44. The method of claim 30, wherein said step of administering said drug formulation into a patient'"'"'s oral cavity comprises disposing said drug formulation within the oral cavity, said drug formulation having a lozenge trache dosage form.

45. The method of claim 30, wherein the step of administering said drug formulation comprises disposing said drug formulation within the oral cavity of the patient, said drug formulation having a lollipop dosage form.

46. The method of claim 30, wherein the step of delivering said pharmaceutical agent comprises maintaining said drug formulation in the patient'"'"'s oral cavity for a period of time sufficient to dissolve said drug formulation.

47. The method of claim 30, wherein said oral mucosal tissue is located in a patient'"'"'s pharynx.

48. The method of claim 30, wherein said oral mucosal tissue is in a patient'"'"'s esophagus.

49. The method of claim 30, wherein said pharmaceutical agent is chosen from the group consisting of:

methohexital, pentobarbital, thiamylal, thiopental, fentanyl, alfentanil, sufentanil, lofentanil, carfentanil, naloxone, epam, lorazepam, midazolam, oxazepam, triazolam, droperidol, propanidid, etomidate, propofol, ketamine, diprivan, bretylium, captopril, clonidine, dopamine, enalapril, esmolol, furosemide, isosorbide, labetalol, lidocaine, metolazone, metoprolol, nadolol, nifedipine, nitroglycerin, nitroprusside, propranolol, benzquinamide, meclizine, metoclopramide, prochlorperazine, trimethobenzamide, clotrimazole, nystatin, carbidopa, levodopa, sucralfate, albuterol, aminophylline, beclomethasone, dyphylline, epinephrine, flunisolide, isoetharine, isoproterenol Hcl, metaproterenol, oxtriphylline, terbutaline, theophylline, ergotamine, methysergide, propranolol, suloctidil, ergonovine, oxytocin, desmopressin, acetate, lypressin, vasopressin, insulin, beta-endorphin, enkephalins, bradykinin, aniotensin I, gonadotropic hormones, adrenocorticotropic hormone (ACTH), calcitonin, parathyroid hormone, and growth hormone), polysaccharides (such as heparin), antigens, antibodies, or enzymes.

50. The method of claim 30, wherein said pharmaceutical agent belongs to a class of drugs chosen from the group consisting of:

barbiturate, opioid agonist, opioid antagonist, benzodiazepine, buterophenone, eugenol, GABA stimulator, substituted phenol, phencyclidine, or substituted phenol.

51. An oral mucosal drug formulation comprising:

a solid solution micro-environment within the drug formulation,

a drug and a dissolution agent disposed within the solid solution micro-environment, and

a pharmaceutical ingredient segregated from the micro-environment.

52. The formulation of claim 51, wherein said micro-environment facilitates rapid dissolution of the drug in solvents of in the oral mucosal cavity.

53. The formulation of claim 51, wherein said micro-environment acts as a physical barrier between said drug and said pharmaceutical ingredient.

54. The formulation of claim 51, wherein said pharmaceutical ingredient improves absorption of the drug.

55. The formulation of claim 51, wherein said micro-environment permits dissolution of the drug in a free state.