Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
  • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the chemical triggering zone (CTZ) for nausea and vomiting is located at the area postrema on the floor of the 4 th ventricle of the brain, and raised intracerebral pressure is thought to cause vomiting via increased pressure at the ventricle.
• CTZ chemical triggering zone
• PONV and PDNV can result in patient discomfort (mild to severe), but can also have significant clinical consequences such as resulting in damage to delicate surgical sites, prolonging the time patients stay in post anesthesia care units, interrupting or delaying the administration of oral medications or fluid/food intake, and ultimately cause unplanned readmission or hospitalization following ambulatory surgery, thereby increasing medical costs (Kovac, AL. Drugs; 59(2): 213-243).
• PDNV events have not been scrutinized to the same extent as PONV, some patients will experience PDNV for up to 5 days (Caroll NV, et al. Ansesth. Analg. 1995; 80(5):903-909; Pfisterer M, et al. Ambul Surg. 2001; 9(1): 13- 18; Odom-Forren J and Moser DK. J. Ambul. Surg. 2005;12: 99-105).
• 5-HT 3 receptor antagonists such as ondansetron are highly specific and selective for nausea and vomiting, and are known to be most effective when given orally prior to surgery, intravenously (IV) at the end of surgery, or IV after surgery in the early part (i.e., 0-2 hr period) of PONV.
• IV intravenously
• the recommended IV dose of ondansetron is 4 to 8 mg IV in adults, and 50 to 100 ⁇ g/kg in children.
• Ondansetron is currently available only as an immediate release tablet (conventional tablet or orally disintegrating tablet (ODT)).
• ODT conventional tablet or orally disintegrating tablet
• Ondansetron plasma concentration characterized by sharp peaks and troughs, thereby requiring that the dosage form be administered periodically in order to be effective over a 24-hour period.
• this type of pharmacokinetic profile is often associated with alternating periods of increased side effects and inefficacy as the plasma concentrations of drug cycle outside of the ideal therapeutic range. This cycling of drug plasma levels can result in the break through of symptoms, i.e. nausea and vomiting. This makes the therapeutic effect unpredictable both between patients and upon repeated dosing.
• the present invention is directed to a method of treating or preventing PONV or PDNV comprising orally administering to a surgical patient in need thereof, at least one extended release dosage form comprising a selective serotonin 5-HT 3 antagonist, prior to and/or after surgery.
• FIG. 1.B illustrates a cross-section of a TPR bead comprising an SR coated, fumaric acid-containing core.
• FIG. 4 illustrates the ondansetron plasma concentration - time profiles of MR capsule formulations (PF391EA0001, PF392EA0001, and PF379EA0001) comprising RR Granules (rapid release granules) and TPR beads of Example 3.
• FlG. 11B demonstrates the corresponding incidence exposure vs. (0-1 hr) exposure response.
• immediate release refers to the release of greater than or equal to about 50%, in some embodiments greater than about 75%, or more than about 90%, and in certain embodiments greater than about 95% of the drug within about 30 minutes when dissolution tested in 0.1 N HCl, or within about one hour following administration of the dosage form.
• Immediate release particles are drug-containing particles which provide immediate release of the drug.
• TPR timed, pulsatile release bead
• TPR dosage form is characterized by an immediate release pulse or a sustained release profile after a pre-determined lag time.
• lag-time refers to a time period wherein less than about 10%, more particularly substantially none, of the dose (drug) is released, and a lag-time of from at least about 2 to 10 hours is achieved by coating typically with a combination of water-insoluble and enteric polymers (e.g., ethylcellulose and hypromellose phthalate).
• a TPR coating or TPR layer refers to a layer, membrane, or coating which provides such properties.
• TPR coatings or layers comprise a pharmaceutically acceptable water insoluble polymer combined with an enteric polymer, optionally plasticized with one or more pharmaceutically acceptable plasticizers.
• the present invention is a method of treating or preventing PONV and/or
• the IR particles comprise the selective serotonin 5-HT 3 antagonist, and release at least 80 wt.% of the selective serotonin 5-HT 3 antagonist in about 5 minutes (using USP dissolution methodology (Apparatus 2 - paddles @50 RPM in 0.1 N HCl at 37 0 C)).
• the TPR particles comprise an inert core (e.g., a sugar bead etc.) sequentially coated with a pharmaceutically acceptable organic acid
• the extended release oral dosage form for use in the methods of the present invention comprises a capsule filled with a combination of TPR particles and RR particles, wherein the TPR particles comprise sugar beads sequentially coated with fumaric acid and a binder (e.g., hydroxypropyl cellulose); a sustained release (SR) layer comprising ethyl cellulose and an optional plasticizer (e.g., optionally triethyl citrate); a drug layer comprising ondansetron and a binder (e.g., povidone); an optional sealing layer (e.g.
• a binder e.g., hydroxypropyl cellulose
• SR sustained release
• a plasticizer e.g., optionally triethyl citrate
• a drug layer comprising ondansetron and a binder (e.g., povidone)
• an optional sealing layer e.g.
• Antiemetic drugs such as domperidone, granisetron, cyclizine, droperidol, dexamethasone, and ondansetron, as well as combinations of these drugs have been used to treat postoperative nausea and vomiting. Most commonly, antiemetic drugs are administered prophylactically by IV either prior to surgery, or immediately after surgery, and any breakthrough nausea and vomiting experienced postoperatively are treated with "rescue" doses of IV or immediate release oral antiemetics. Oral antiemetics are generally considered less effective than IV antiemetics because the "first pass" metabolism of oral antiemetics results in lower bioavailability. In addition, it may be difficult or impossible to administer an oral dosage form to patients suffering from postoperative nausea and vomiting.
• the method of the present invention also includes administration of an oral extended release dosage form comprising a selective serotonin 5-HT 3 antagonist in combination with oral dosage forms comprising other types of antiemetic drugs.
• the method of the present invention comprising treating or preventing PONV and/or PDNV by administering at least one extended release dosage form comprising a selective serotonin 5-HT 3 antagonist to a surgical patient in need thereof, in most embodiments after surgery or at discharge, and further administering at least one additional oral antiemetic comprising one or more NK-I antagonist, dopamine antagonist, Hl histamine receptor antagonist, cannabinoid, benzodiazepine, anticholinergic, steroid, etc.
• the extended release oral dosage form can be administered prior to surgery, immediately after surgery, or at discharge, or can be used in combination with prophylactic administration of an IV antiemetic administered before, during, immediately after surgery, or at discharge.
• the extended release dosage form can be administered prior to surgery instead of the prophylactic IV antiemetic, thereby providing an effective prophylactic dose of selective serotonin 5-HT 3 antagonist which provides protection against PONV/PDNV immediately after surgery, at discharge, as well as for an extended postoperative period.
• the IV antiemetic can be administered immediately before or following surgery, and the extended release dosage form comprising a selective serotonin 5-HT 3 antagonist can be administered prior to or at discharge, thereby providing effective protection against PONV and/or PDNV for an extended period of time, e.g. until the day following surgery.
• the extended release dosage form comprising a selective serotonin 5-HT 3 antagonist can be further administered once-daily for one or more days following surgery in order to provide extended protection against PDNV.
• the extended release dosage form comprising a selective serotonin 5-HT 3 antagonist can be administered at discharge, and/or the day following discharge (e.g. in the morning following discharge), and optionally up to five days following discharge (e.g. once-a- day administration each morning following discharge).
• the method of the present invention e.g. as described in the examples, provides clinically significant prophylaxis, treatment, or amelioration of PONV and/or PDNV, which is equivalent or superior to the prophylaxis, treatment, or amelioration of PONV and/or PDNV provided by conventional therapies.
• employing a once-per-day extended oral release dosage form is more convenient and more effective compared to conventional immediate release oral dosage forms, and safer than IV administration.
• the method of the present invention can be used for both inpatient and outpatient surgical procedures.
• intravenous administration is more readily available for inpatient procedures
• opioids can include, for example, codeine, morphine, thebaine, oripavine, diacetyl morphine, dihydrocodeine, hydrocodone, hydromorphone, nicomorphine, oxycodone, oxymorphone, fentanyl, ⁇ -methyl fentanyl, alfentanil, sufentanil, remifentanil, meperidine, buprenorphine, etorphine, methadone, and tramadol.
• LA SR-Coated Fumaric Acid Crystals 40-80 mesh fumaric acid crystals (3750 g) were charged into a Glatt GPCG 5 fluid-bed coater equipped with a 9" bottom spray Wurster insert, 10" column length and 16 mm tubing.
• the fumaric acid crystals were coated with a solution (6% solids) of 250 g of ethylcellulose (EC-10: Ethocel Premium 10 cps) and 166.7 g of polyethylene glycol (PEG 400) at an EC- 10/PEG 400 ratio of 60/40, dissolved in 98/2 acetone/water (6528.3 g), for a coating weight of up to 10% by weight.
• EC-10 Ethocel Premium 10 cps
• PEG 400 polyethylene glycol
• SR-coated fumaric acid crystals (3000 g) obtained from Example LA, above, were coated in the Glatt GPCG 5 with the ondansetron solution (5% solids) while maintaining the product temperature at 40 ⁇ 1°C; inlet air volume at 180-195 cfrn and with a spray rate increasing from about 8 to 15 g/min.
• the resulting drug- layered beads were provided with a protective seal-coat of Opadry Clear (hypromellose 2910; 3 cps) (2% coating weight) to form IR beads.
• Fig. 2 shows the release profiles of both fumaric acid and ondansetron from TPR beads comprising SR-coated acid crystals. More specifically, the TPR Beads evaluated in Fig. 2 have the following composition:
• the ondansetron release is significantly faster than the fumaric acid release, it will be apparent to a person skilled in the art that by decreasing the thickness of the barrier-coat (SR layer) on the fumaric acid crystals and/or additionally applying a SR layer under the TPR layer to sustain the drug release, the release profiles for both ondansetron and fumaric acid can be synchronized.
• SR layer barrier-coat
• Example LA fumaric acid cores (3750 g) from Example 2.A were coated with a solution of EC-10 mixed with either PEG 400 (B.I) at a ratio of 60/40 or TEC (B.2) at a ratio of 90/10 as the plasticizer, dissolved in 98/2 acetone/water (6% solids), providing a coating weight of 10%.
• 3.D SR-coated Fumaric Acid Cores The fumaric acid-containing cores (3750 g) from Example 3.C were coated with a solution of 177.6 g of ethylcellulose (EC-10) and 19.7 g of tri ethyl citrate (TEC) at a ratio of 90/10, dissolved in 95/5 acetone/water (7.5% solids), providing a coating weight of 5%.
• EC-10 ethylcellulose
• TEC tri ethyl citrate
• Ondansetron hydrochloride IR beads (3500 g) from Example 3.E, above, were coated with a TPR coating of ethylcellulose (389.1 g), HP-55 (135.9 g) and TEC (92.6 g) (ratio:
• the granulation was dried at a process air temperature of 77 0 C and an air volume of 800 cfm, until a loss on drying value of ⁇ 2% was obtained.
• the granules were then sieved through a 30 mesh screen (oversized material was discarded) and blended with magnesium stearate (0.17 kg per 77.8 kg of beads) in a 10 cu.ft. V blender rotating at 17.5 rpm for 6 minutes, then discharged into 41 gallon drums double-lined with polyethylene bags.
• Treatment 4 the following doses of ondansetron were administered in the morning: Day 1 : a single dose of Zofran ® , Day 2: one placebo capsule; Day 3: a single 16 mg dose of ondansetron (2x 8 mg Zofran ® ); Day 4 and 5: two placebo capsules on each day; and Day 6: a single 24 mg dose of ondansetron (3 x 8 mg Zofran ® tablet).
• Blood samples (2 x 6 mL) were collected by venipuncture in pre-cooled Vacutainer tubes containing K2 EDTA at appropriate pre- and post-dose timings (preselected for each treatment) and analyzed using a validated HPLC/MS assay with an analytical range of approximately 0.5 to 300 ⁇ g/mL.
• the patients receive one MR ondansetron capsule (24 mg capsule comprising RR and TPR particles as described herein) or placebo capsule prior to surgery and every 24 hr thereafter (or if discharged, patients are given a supply of MR ondansetron capsules/placebo capsules for self-administration on the appropriate schedule). Patients are asked to rate their symptoms of nausea, as well as any events of nausea or retching over a postoperative period of 48-72 hrs. In addition, the frequency of hospitalization will be recorded. Vomiting is evaluated as a binary event (yes or no), and nausea is quantified on a numeric 11 point scale (0 to 10).
• the target treatment efficacy is a 50% reduction, i.e., a decrease in incidence from 40% to 20% events. To achieve a 50% reduction, 90 and 120 evaluateable patients are required for 80% and 90% CI (confidence intervals), respectively.

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• 2010
  • 2010-01-15 US US12/688,493 patent/US20110003005A1/en not_active Abandoned
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