Nausea is an unpleasant feeling in the stomach that may or may not be followed by vomiting. Vomiting is the sudden, forceful expulsion of the stomach contents which may or may not be preceded by nausea. They very often occur together but can also occur independently of each other. It is most common in patients with cancer undergoing chemotherapy. Postoperative nausea and vomiting (PONV) and postdischarge nausea and vomiting (PDNV) are common post-surgical complications. PONV typically refers to nausea and vomiting which occurs after surgery, such as immediately after surgery. PDNV refers to post-surgical nausea and vomiting, but specifically refers to the nausea and vomiting occurring after the patient has been discharged, after the immediate effects of anesthesia have worn off and the patient is relatively ambulatory.
The chemical triggering zone (CTZ) for nausea and vomiting is located at the area postrema on the floor of the 4th ventricle of the brain, and raised intracerebral pressure is thought to cause vomiting via increased pressure at the ventricle. The CTZ is extremely sensitive to emetic stimuli. Various neurotransmitter types and receptors have been implicated in nausea and vomiting, including serotonin, acetylcholine, dopamine, muscarine, neurokinin-1, histamine, opioid, and 5-HT3. Stimulation of the vestibular-cochlear, glossopharyngeal, or vagus nerves may also be involved. Accordingly, the risk factors for nausea and vomiting are complex, and known antiemetic agents vary widely in their effectiveness.
Antiemetics are typically administered via an oral route prior to the start of moderately emetogenic chemotherapy or radiotherapy, or inpatient or outpatient ambulatory surgery, or intravenously during surgery (e.g., in the final stages of surgery) in order to have an immediate prophylactic effect, and are often not administered subsequently unless or until the patient experiences nausea and/or vomiting. In some cases, oral, immediate release antiemetics are administered. 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, A L. Drugs; 59(2): 213-243).
5-HT3 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. The recommended IV dose of ondansetron is 4 to 8 mg IV in adults, and 50 to 100 μg/kg in children. As a practical matter, it is difficult or inconvenient to administer IV antiemetics post-discharge. Oral administration is more convenient, less costly, and safer.
Ondansetron is currently available only as an immediate release tablet (e.g., conventional tablets, ZOFRAN Tablets, 4 and 8 mg (containing ondansetron HCl dihydrate equivalent to 4 and 8 mg of ondansetron, respectively), orally disintegrating tablets, ZOFRAN ODTs, 4 and 8 mg (containing ondansetron base), or an oral suspension, ZOFRAN Oral Solution (each 5 mL containing 5 mg of ondansetron HCl dihydrate equivalent to 4 mg of ondansetron). For immediate release dosage forms, the relatively short in-vivo half-life of ondansetron results in an 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.
For example, for prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy, the recommended oral dosage of ZOFRAN in pediatric patients at least 12 years of age and adults is one 8-mg ZOFRAN Tablet or one 8-mg ZOFRAN ODT Tablet or 10 mL (2 teaspoonfuls equivalent to 8 mg of ondansetron) of ZOFRAN Oral Solution given twice a day. The first dose should be administered 30 minutes before the start of emetogenic chemotherapy, with a subsequent dose 8 hours after the first dose. Oral administration twice a day (every 12 hours) should be continued for 1 to 2 days after completion of chemotherapy. For pediatric patients 4 through 11 years of age, the recommended dose is 4 mg of ondansetron given 3 times a day.
For prevention of nausea and/or vomiting associated with radiotherapy in patients receiving either total body irradiation, single high-dose fraction to the abdomen, or daily fractions to the abdomen, the recommended dose is 8-mg ondansetron administered 1 to 2 hours before radiotherapy and continued for 1 to 2 days after completion of radiotherapy.
For prevention of postoperative nausea and/or vomiting, the recommended dose is 16 mg of ondansetron administered 1 hour before induction of anesthesia. As with other antiemetics, routine prophylaxis is not recommended for patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively. In patients where nausea and/or vomiting must be avoided postoperatively, ZOFRAN tablet, ODT or Oral Solution is recommended even where the incidence of postoperative nausea and/or vomiting is low.
However, the type of pharmacokinetic profile achieved in the dosing regimens recommended above 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 symptoms, i.e. nausea and vomiting. This makes the therapeutic effect unpredictable both between patients and upon repeated dosing. Repeat dosing schedules also pose other problems for patients who are distressed, experiencing nausea and vomiting, and may have difficulty swallowing. To these factors are added the noncompliance with administration schedules associated with repeat dosage schedules. All of these factors reduce the effectiveness of prophylactic oral doses of antiemetics. Accordingly, it would be advantageous to provide orally administrable once-daily dosage forms containing 5-HT3 receptor antagonists such as ondansetron effective to prevent nausea and/or vomiting in cancer patients undergoing chemo- or radiotherapy or in subjects at moderate to high risk to PONV or PDNV in at least the first 24 hr period following surgery.
Difficulty in swallowing conventional tablets and capsules due to fear of choking, dysphagia, or actual pain, especially in cancer patients, is common among all age groups. For example, it is observed in about 35% of the general population, as well as an additional 30-40% of elderly institutionalized patients and 18-22% of all persons in long-term care facilities, many of whom are required to consume medications on a regular basis to maintain their quality of life. There are potential advantages of avoiding taking the medication with water by patients undergoing surgery (Gan, T J. et al. Anesth. Analg. 2002; 94: 1199-1200). Zofran ODT, a freeze-dried oral formulation based on the Zydis® technology, has shown superiority in terms of reduced incidence of nausea over placebo in patients after ambulatory surgery, outpatient gynecological laperoscopy (Table 1). All patients received a prophylactic dose of ondansetron 4 mg IV at induction. Prior to discharge, patients were randomly allocated to receive ondansetron ODT 8 mg or placebo tablet and a second dose 12 hrs after. Table 1 compares incidence of nausea, emesis, patient satisfaction, and acceptability of study drug. Patients rated the taste of the ondansetron ODT less favorably than the placebo ODT due to the bitter aftertaste of the drug.
The compositions of the present invention fill a currently unmet need for a once-daily, user-friendly antiemetic dosage form (e.g., an orally disintegrating tablet) that can be conveniently orally administered without grittiness and aftertaste issues, which will provide an immediate prophylactic effect as well as a continuing beneficial effect up to 24 hrs post-dosing.
The present invention is directed to an orally disintegrating tablet (ODT) comprising a multiparticulate, selective serotonin 5-HT3 blocking agent-containing pharmaceutical composition and rapidly dispersing microgranules. The rapidly dispersing microgranules comprise at least one super disintegrant and at least one sugar alcohol or a saccharide with a mean primary particle size of not more than 30 μm, and the multiparticulate, selective serotonin 5-HT3 blocking agent-containing pharmaceutical composition comprises immediate-release beads with rapid release characteristics similar to that of the reference product, combined with one or more timed pulsatile-release (TPR) bead populations. The TPR beads comprise a TPR (lag-time) coating, a weakly basic selective serotonin 5-HT3 blocking agent, an organic acid, and a sustained release membrane. Upon oral administration without water, the ODT of the present invention rapidly disintegrates in the oral cavity into a smooth (non-gritty), easy-to-swallow suspension, that can be easily swallowed by patients, e.g., patients at moderate to high risk of PONV/PDNV prior to undergoing inpatient or outpatient ambulatory surgery or by cancer patients prior to undergoing moderately emetogenic cancer chemotherapy, radiotherapy receiving total body irradiation, single high-dose fraction to the abdomen, or daily fractions to the abdomen for the prevention of nausea and/or vomiting for up to 24 hours post-dosing.
The method of making a once-daily dosage form as an orally disintegrating tablet of a selective serotonin 5-HT3 blocking agent such as ondansetron HCl dehydrate is disclosed in one or more of the embodiments of the present invention, wherein Ondansetron ODT CR in accordance with the disclosures in U.S. 2007/0196491 and U.S. 2009/0232885, comprises rapid-release (RR)/immediate-release (IR) beads with rapid release characteristics similar to that of the reference product, Zofran® and one or more timed pulsatile-release (TPR) bead populations, wherein the TPR beads comprise a TPR (lag-time) coating, an organic acid layer with a sustained release membrane that not only prevents mixing between the organic acid in the inner layer and the drug in the outer layer, but also controls the rate of acid diffusion into the drug layer to synchronize the drug release with that of the acid. The rapid release drug particles and immediate release (IR) beads to be developed into TPR beads in accordance with the above invention comprising a selective serotonin 5-HT3 blocking agent are designed in the form of beads comprising the drug (e.g., ondansetron HCl) layered on small particle size inert cores (e.g., smaller than 425 μm or more preferably less than 250 μm), or pellets comprising at least one pharmaceutically acceptable excipient and optionally an organic acid, granulated/extruded/spheronized or formed by controlled spheronization or powder layering using Granurex from Vector/Freund Corporation or the like, exhibiting rapid release similar to that of the reference product under discriminating dissolution conditions, i.e., USP Apparatus 2 in 500 mL buffer at pH 6.8.
In certain other embodiments of the present invention, the extended release ODT dosage form of the present invention comprises at least one TPR bead population with each bead comprising a sustained-release (SR) or a TPR coating disposed over an organic acid crystal, a polymeric binder layer comprising the selective serotonin 5-HT3 antagonist, an optional sustained-release (SR) coating layer disposed over the drug layer, and/or an external TPR coating layer, in order to insure solubilization of the selective serotonin 5-HT3 antagonist inside the coated bead prior to its release into the alkaline pH environment of the intestinal tract where the drug is practically insoluble, thereby providing a method of treating or preventing nausea and vomiting comprising orally administering to patients in need thereof a once-daily ODT dosage form prior to or following postoperative surgery, chemotherapy, or radiation therapy.
In one embodiment, the extended release dosage form of the present invention comprises timed, sustained-release (TSR) beads and IR beads; wherein each TSR bead comprises a core coated first with an SR layer and second with a TPR layer; the core comprises a selective serotonin 5-HT3 antagonist and a pharmaceutically acceptable organic acid, wherein the selective serotonin 5-HT3 antagonist and the pharmaceutically acceptable organic acid are separated from each other by an SR or TPR layer; the TPR layer comprises a water insoluble polymer and an enteric polymer; the SR layer comprises a water insoluble polymer; and the IR beads, each bead comprising the selective serotonin 5-HT3 antagonist, releases at least about 80 wt. % of the selective serotonin 5-HT3 antagonist in about 15 minutes when dissolution tested using United States Pharmacopoeia dissolution methodology (Apparatus 2—paddles@ 50 RPM, 0.1N HCl at 37° C.).
In a particular embodiment, the extended release dosage form of the present invention comprises TPR beads and IR beads; wherein the TPR beads each comprise: an inert bead; an acid layer disposed over the inert bead, comprising the pharmaceutically acceptable organic acid such as fumaric acid; the SR or TPR layer disposed over the acid layer; a drug layer disposed over the SR layer (e.g., comprising ethyl cellulose, optionally plasticized), wherein the drug layer comprises a selective serotonin 5-HT3 antagonist such as ondansetron (or a salt and/or solvate thereof); and the TPR layer (e.g., comprising ethyl cellulose and hydroxypropyl methylcellulose phthalate, optionally plasticized) is disposed over the drug layer and optionally on the organic acid layer. The IR particles may optionally comprise a granulate of the pharmaceutically acceptable organic acid (e.g. fumaric acid), the selective serotonin 5-HT3 antagonist (e.g. ondansetron or a salt and/or solvate thereof), and an optional binder (e.g. hydroxypropyl cellulose), as well as one or more additional excipients (e.g. a fillers such as lactose and/or microcrystalline cellulose, a disintegrant such as crospovidone, etc.).
In certain embodiments of the present invention, the extended release dosage form developed in the form of a patient-friendly orally disintegrating tablet is intended for oral administration, once-daily, in patients at moderate to high risk of postoperative nausea and vomiting (PONV) or post discharge nausea and vomiting (PDNV) prior to and/or following inpatient or outpatient ambulatory surgery, and optionally, once-daily up to additional 4 days following the first dose.
In certain other embodiments of the present invention, the extended release dosage form developed in the form of a patient-friendly orally disintegrating tablet is intended for oral administration, once-daily, in cancer patients for the prevention of nausea and vomiting prior to undergoing emetogenic cancer chemotherapy, and optionally, once-daily up to additional 2 days following the first dose.
In yet certain other embodiments of the present invention, the extended release dosage form developed in the form of a patient-friendly orally disintegrating tablet is intended for oral administration, once-daily, in cancer patients for the prevention of nausea and vomiting prior to receiving total body irradiation, single high-dose fraction to the abdomen, or daily fractions to the abdomen, and optionally, once-daily up to additional 2 days following the first dose.
All documents cited herein are incorporated by reference in their entirety for all purposes; the citation of any document is not to be construed as an admission that it is prior art with respect to the present invention.
As used herein, various terms are defined as described in “How to study postoperative nausea and vomiting”, Acta Anaesthesiol. Scand. 2002:46:921-928:
Co-pending U.S. patent application Ser. No. 11/668,167 filed Jan. 29, 2007 (Publication No. U.S. 2007/0196491) and U.S. patent application Ser. No. 12/209,285 filed on Mar. 12, 2008 (Publication No. U.S. 2009/0232885), disclose once-daily ondansetron HCl ER Capsules comprising immediate release (IR) beads or rapid-release (RR) granules and timed pulsatile-release (TPR) beads, which provide target plasma profiles suitable for a once-daily regimen as evident in the pilot pharmacokinetic study in healthy volunteers that compared plasma concentration-time profiles of once-daily test formulations with that of Zofran IR tablets orally dosed bid 8 hrs apart. These capsules are designed to be swallowed whole, and thus may be difficult to administer to certain patients having difficulty swallowing.
In a co-pending Provisional patent application Ser. No. 12/688,493, filed on Jan. 14, 2010, entitled “Methods of Treating PDNV and PONV with Extended Release Ondansetron Compositions” a PK/PD model based on ondansetron exposure, AUC0-2 hr (area under plasma concentration curve during the first 2 hours of post-dose) and the corresponding onset and duration of antiemetic responses for Zofran®, an IR ondansetron formulation, with nausea, vomiting, and rescue medication as incidence endpoints was used to compare ondansetron bioavailability for three modified-release formulations of ondansetron and Zofran® (bid). The model shows that oral administration of once-daily MR ondansetron capsules is as effective, if not superior to Zofran® administered bid in preventing nausea and/or vomiting in subjects at moderate to high risk of PONV or PDNV following inpatient or outpatient ambulatory surgery.
As used herein, as well as in specific examples thereof, reference to a drug or drug class (e.g., selective serotonin 5-HT3 antagonist, ondansetron, etc.) includes the drug itself, as well as pharmaceutically acceptable salts, polymorphs, stereoisomers and mixtures thereof.
As used herein, the term “immediate release” (IR) 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 0.1N HCl, or within about one hour following administration of the dosage form. Immediate release particles (IR particles) are drug-containing particles which provide immediate release of the drug.
As used herein, the term “immediate-release (IR)” refers to drug-containing particles which release greater than about 50% of the drug within about 30 minutes of dosing. “Rapid release” (RR) refers to drug-containing particles in which at least about 80% of the drug contained in particle is released in about 30 minutes or less for example when dissolution tested using United States Pharmacopoeia (USP) dissolution methodology (Apparatus 2—paddles@ 50 RPM, 0.1N HCl at 37° C., more preferably) and provides a drug release profile similar to that of RLD (reference-listed drug; e.g., the test drug release profile having a similarity factor (f2) of greater than 50, preferably greater than 75, more preferably greater than 85% when compared to the drug release profile for the corresponding RLD such as Zofran®). For example, RR particles can include, but are not limited to particles in which the drug is layered on 45-60 mesh, or 60-80 mesh sugar spheres, as well as water-soluble microgranules comprising the drug and a filler, (e.g., lactose) and an organic acid (e.g., fumaric acid). Rapid release particles are a particular type of IR particles with relatively high rates of drug release.
The term, “TPR (timed, pulsatile release) bead” or “TPR dosage form”, as defined here, is characterized by an immediate release pulse or a sustained release profile after a pre-determined lag time. The term “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 hours up to 10 hours when dissolution is tested by United States Pharmacopoeia (USP) dissolution methodology (Apparatus 2—paddles@ 50 RPM and a two-stage dissolution medium at 37° C. (first 2 hours in 0.1N HCl followed by testing in a buffer at pH 6.8) is achieved by coating typically with a combination of water-insoluble and enteric polymers (e.g., ethylcellulose and hypromellose phthalate). Similarly, a TPR coating or TPR layer refers to a layer, membrane, or coating which provides such properties. As described herein, 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. If the drug particles are provided with a barrier coating prior to applying a lag time coating, such beads are more appropriately referred to as timed, sustained release (TSR) beads, as these beads are likely to provide a sustained-release profile following a preset lag time.
The term “SR layer”, “SR coating”, etc. refers to a layer or coating comprising a pharmaceutically acceptable water insoluble polymer, optionally plasticized with one or more pharmaceutically acceptable plasticizers.
The clinical terms “plasma concentration—time profile”, “Cmax”, “AUC”, “Tmax”, and “elimination half life” have their generally accepted meanings, and hence, are not redefined. Unless indicated otherwise, all percentages and ratios are calculated by weight based on the total composition.
The term “coating weight” refers to the dry weight of a coating as a percentage of the weight of the substrate prior to coating. For example, a 10 mg particle coated with 1 mg coating (dry weight) has a coating weight of 10%.
The terms “similarity factor” and “f2” refer to a simple measure for the comparison of the drug release profiles of test and reference listed drugs. It is a function of the mean differences in dissolutions and it takes values in the range of from 0 and 100. A convenient critical value of 50 for similarity of dissolution profiles based on mean difference of 10% at all sampling time points (V. P. Shah, Y. Tsang, P. Sathe, J.-P. Liu, In vitro dissolution profile comparison—statistics and analysis of the similarity factor, f2. Pharmaceutical Research 15, 889-896 (1998).
The present invention is a method of preparing once-daily orally disintegrating tablet formulations comprising a selective serotonin 5-HT3 antagonist for orally administering prior to the start of moderately emetogenic chemotherapy or radiotherapy, or inpatient or outpatient ambulatory surgery, for the treatment or prevention of nausea and/or vomiting and optionally every 24 hours for an additional 2 to 4 days thereafter. The dosage form comprises TPR particles and IR beads (particularly those with rapid release (RR) characteristics similar to that of a reference listed drug (RLD), an IR product (e.g. Zofran®)), each comprising a selective serotonin 5-HT3 antagonist (e.g. ondansetron). The TPR particles comprise a core comprising the selective serotonin 5-HT3 antagonist and a pharmaceutically acceptable organic acid (e.g. fumaric acid) separated from each other by an SR layer comprising a water insoluble polymer (such as ethyl cellulose). The IR particles comprise the selective serotonin 5-HT3 antagonist, and release at least 80 wt. % of the selective serotonin 5-HT3 antagonist in about 30 minutes (using USP dissolution methodology (Apparatus 2—paddles @50 RPM in 0.1 N HCl at 37° C.)).
In one embodiment, the oral dosage form for use in the method of the present invention can be prepared as described in copending U.S. patent application Ser. No. 12/209,285, filed Sep. 12, 2008 (Publication No. U.S. 2009/0232885), which is herein incorporated by reference in its entirety for all purposes.
Specific embodiments of the present invention will be described in further detail with reference to the accompanying
In one embodiment, the pharmaceutical compositions suitable for use in the method of the present invention comprise a plurality of TPR and IR particles, wherein the TPR particles each comprise a core coated with a TPR layer; the core comprises a selective serotonin 5-HT3 antagonist (e.g. ondansetron) and a pharmaceutically acceptable organic acid separated from each other by an SR layer; and the IR particles each comprise the selective serotonin 5-HT3 antagonist (e.g. ondansetron) in combination with suitable excipients.
In certain other embodiment, the pharmaceutical compositions suitable for use in the method of the present invention comprise IR particles and one or more TPR bead populations differing in lag time.
In a particular embodiment, the TPR particles comprise an inert core (e.g., a sugar bead etc.) sequentially coated with a pharmaceutically acceptable organic acid (e.g., fumaric acid) and a pharmaceutically acceptable binder (e.g., hydroxypropyl cellulose); a sustained release (SR) layer (e.g., comprising a pharmaceutically acceptable water insoluble polymer such as ethyl cellulose, optionally plasticized with a pharmaceutically acceptable plasticizer such as triethyl citrate or polyethylene glycol); a drug layer comprising the selective serotonin 5-HT3 antagonist (e.g., ondansetron or a pharmaceutically acceptable salt and/or solvate thereof) and a pharmaceutically acceptable binder (e.g., povidone); an optional sealing layer (e.g. comprising a water soluble polymer such as hydroxypropyl methylcellulose); and a TPR layer (e.g., comprising a water insoluble polymer such as ethyl cellulose, an enteric polymer such as hydroxypropylmethylcellulose phthalate, and an optional pharmaceutically acceptable plasticizer such as triethyl citrate).
In certain embodiments of the present invention, the IR beads/particles release at least about 50% of the selective serotonin 5-HT3 antagonist within about 30 minutes when dissolution tested in 0.1N HCl, or achieve Cmax within about one hour or similar to that of the RLD following administration of the dosage form. In particular embodiments, the IR particles are RR particles, and release at least about 80 wt. % of the selective serotonin 5-HT3 antagonist in about 30 minutes when dissolution tested using United States Pharmacopoeia (USP) dissolution methodology (Apparatus 2—paddles@ 50 RPM, 0.1N HCl at 37° C.
In a particular embodiment of the present invention, the IR or RR particles can have any suitable structure which provides the required rapid release properties. For example, the IR/RR particles can comprise the selective serotonin 5-HT3 antagonist deposited directly on an inert core (e.g., 60-80 mesh sugar sphere, cellulose sphere (e.g., Celphere 102 from Asahi Kesahi or Cellets 100 or Cellets 200 from Glatt), cellulose-lactose sphere with a smaller average diameter) and optionally, with a pharmaceutically acceptable hinder. In certain other embodiments to achieve faster release similar to that of Zofran, the RR (IR) particles comprise the selective serotonin 5-HT3 antagonist disposed over seal coated organic crystals or organic acid-containing cores which are prepared by depositing an organic acid-polymeric binder layer onto inert cores. In contrast IR particles comprising the selective serotonin 5-HT3 antagonist to be further processed into TPR beads comprise the selective serotonin 5-HT3 antagonist disposed over an SR or TPR coated organic acid crystals or SR coated organic acid-containing cores which are prepared by depositing an organic acid-polymeric binder layer onto inert cores.
In a particular embodiment, the preferred extended release oral dosage form useful for the prevention of nausea and vomiting is an orally disintegrating tablet (ODT) compressed with required amounts of TPR beads and IR or RR particles, wherein the TPR particles comprise inert cores sequentially coated with an organic acid and a binder (e.g., hydroxypropyl cellulose); a sustained release (SR) layer comprising a water-insoluble polymer (e.g., ethyl cellulose) or a timed, pulsatile release layer comprising a water-insoluble polymer in combination with an enteric polymer (e.g., hypromellose phthalate, HP-55) and an optional plasticizer (e.g., optionally triethyl citrate); a drug layer comprising a elective serotonin 5-HT3 antagonist and a binder (e.g., povidone); an optional sealing layer (e.g. hydroxypropyl methylcellulose); and a TPR layer comprising ethyl cellulose, hydroxypropylmethylcellulose phthalate, and an optional plasticizer (e.g., optionally triethyl citrate); and the IR/RR particles comprise a serotonin 5-HT3 antagonist and a binder disposed over an SR-coated or a seal-coated coated organic acid such as fumaric acid, crospovidone, microcrystalline cellulose, and hydroxypropyl cellulose.
A non-limiting list of selective serotonin 5-HT3 antagonists suitable for use in the extended release compositions include ondansetron, tropisetron, granisetron, dolasetron, palonosetron, ramosetron, and salts and/or solvates thereof. In a particular embodiment, the selective serotonin 5-HT3 antagonist is ondansetron, or salts and/or solvates thereof.
A non-limiting list of water-insoluble polymers, suitable for use in the TPR and SR layers includes ethylcellulose, cellulose acetate, cellulose acetate butyrate, polyvinyl acetate, neutral copolymers of ethyl acrylate and methylmethacrylate, copolymers of acrylic and methacrylic esters containing quaternary ammonium groups, and waxes. The water-insoluble polymer used in the TPR layer can be the same as or different from the water-insoluble polymer used in the SR layer. In a particular embodiment, the water-insoluble polymer for both the TPR and SR layers is ethylcellulose.
A non-limiting list of enteric polymers suitable for use in the TPR layer includes cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, pH-sensitive copolymers of methacrylic acid and methylmethacrylate, and shellac. In a particular embodiment, the enteric polymer of the TPR layer is hydroxypropyl methylcellulose phthalate.
A non-limiting list of pharmaceutically acceptable organic acids includes citric acid, lactic acid, fumaric acid, malic acid, maleic acid, tartaric acid, succinic acid, oxalic acid, aspartic acid, and glutamic acid. In a particular embodiment, the pharmaceutically acceptable organic acid is fumaric acid.
As discussed and exemplified herein, the IR microparticles can be optionally taste-masked with a taste-masking membrane. The taste-masking membrane can comprise a water-insoluble polymer, which may be unplasticized or plasticized. A non-limiting list of suitable water-insoluble polymers include ethylcellulose, polyvinyl acetate (for example, Kollicoat SR#30D from BASF), cellulose acetate, cellulose acetate butyrate, neutral copolymers based on ethyl acrylate and methylmethacrylate, copolymers of acrylic and methacrylic acid esters with quaternary ammonium groups such as Eudragit NE, RS and RS30D, RL or RL30D and the like.
The taste-masking membrane can further include a gastrosoluble pore former. Representative examples of gastrosoluble organic or inorganic pore-forming agents include, but are not limited to, calcium carbonate, calcium phosphate, calcium saccharide, calcium succinate, calcium tartrate, ferric acetate, ferric hydroxide, ferric phosphate, magnesium carbonate, magnesium citrate, magnesium hydroxide, magnesium phosphate, and the like and the mixtures thereof. The ratio of water-insoluble polymer to gastrosoluble organic or inorganic pore-former for producing taste-masked particles may typically vary from about 95/5 to about 1/1, or in some embodiments from about 9/1 to 1/1.
In another embodiment, the gastrosoluble pore-former is a polymeric material, for example a terpolymer based on aminoalkyl acrylate or methacrylate, butyl acrylate or methacrylate, and a methacrylate. In another embodiment, the pore-forming polymeric material may be a terpolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate; and in yet another embodiment, the terpolymer has an average molecular weight of 150,000 and the ratio of the monomers is 1:2:1 of methyl methacrylate, N,N-.dimethylaminoethyl methacrylate, and butyl methacrylate. An example of a polymeric gastrosoluble pore-forming material is a polymer of the EUDRAGIT® E series (e.g., EUDRAGIT® E100 or EUDRAGIT® EPO). A polymer of this series has a pKa of 6.3, is soluble in gastric fluid below pH 5 while it swells and/or is permeable in water and buffer solutions above pH 5.0. The saliva is typically in the pH range of about 6.7 to 7.4. Another example of gastrosoluble pore-forming polymer is poly(vinylacetal diethylaminoacetate) e.g., AEA® available from Sankyo Company Limited, Tokyo (Japan). In one embodiment, the gastrosoluble pore-forming polymer is a terpolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate. In another embodiment, the terpolymer has an average molecular weight of 150,000 and the ratio of the monomers is 1:2:1 of methyl methacrylate, N,N-dimethylaminoethyl methacrylate, and butyl methacrylate. The ratio of water-insoluble polymer to pore-forming polymeric material may typically vary from about 95/5 to about 1/1, or about 9/1 to about 1/1.
As discussed herein, the TPR and SR layers can each optionally include a plasticizer. In some cases, it may be desirable to omit a plasticizer (e.g. in order to reduce cost, reduce exposure of patients to plasticizers, etc.). One of skill in the pharmaceutical arts can select suitable grades of water-insoluble polymers and/or enteric polymers amenable to forming a coating without plasticizer. Alternatively, it may be desirable to incorporate a plasticizer into one or both of the TPR and SR layers (e.g. in order to adjust the physical properties of the respective layers, or adjust the release rate of the drug and/or organic acid). When a plasticizer is used, a non-limiting list of suitable plasticizers includes triacetin, tributyl citrate, triethyl citrate, acetyl tri-n-butyl citrate, diethyl phthalate, dibutyl sebacate, polyethylene glycol, polypropylene glycol, castor oil, acetylated mono- and di-glycerides and mixtures thereof. When a plasticizer is used in both the TPR and SR layers, the plasticizer can be the same or different. In one embodiment, the plasticizer of the SR layer is triethyl citrate. In another embodiment, the plasticizer of the TPR layer is triethyl citrate. In yet another embodiment of plasticizer of both the TPR and SR layers is triethyl citrate.
As described herein, the method of making an orally disintegrating tablet of the present invention further comprises the process of making rapidly dispersing microgranules comprising at least one super disintegrant and at least one sugar alcohol or one sugar saccharide at a ratio of 10:90 to 1:99 using purified water by high shear granulation followed by fluid-bed drying or dry in a tray drying oven.
In one embodiment, the TPR particles comprise “layered beads” in which the organic acid and drug are layered onto an inert core. The inert core can be any pharmaceutically acceptable inert core; in particular those with an average particle size of 50-400 μm. A non-limiting list of suitable inert cores includes sugar spheres, cellulose spheres, lactose spheres, lactose-MCC spheres, mannitol-MCC spheres, and silicon dioxide spheres.
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 (PONV) or postdischarge nausea and vomiting (PDNV), or to prevent nausea and vomiting undergoing moderately emetogenic cancer chemotherapy or radiotherapy.
The ODTs of the present invention may be administered to a patient in need thereof, or may be administered in combination with an oral dosage form comprising another type of antiemetic drug. For example, the method of combination treatment comprising treating or preventing PONV and/or PDNV by administering at least one extended release ODT dosage form comprising a selective serotonin 5-HT3 antagonist to a surgical patient in need thereof, in most embodiments prior to, in some after surgery, or at discharge, and further administering at least one additional oral antiemetic comprising one or more NK-1 antagonist, dopamine antagonist, H1 histamine receptor antagonist, cannabinoid, benzodiazepine, anticholinergic, steroid, etc, preferably in a patient-friendly orally disintegrating tablet form. The coadministration of the extended release dosage form comprising a selective serotonin 5-HT3 antagonist in the additional oral antiemetic dosage form can include administration of the two dosage forms more or less simultaneously; or at different times, such that clinically significant plasma levels of the selective serotonin 5-HT3 antagonist and the additional oral antiemetic are present in the patient at more or less the same or different time periods.
In methods of combination treatment as described above, in which an extended release dosage form comprising a selective serotonin 5-HT3 antagonist is coadministered with an additional oral antiemetic, the NK-1 antagonist can include aprepitant or casopitant; the dopamine antagonist can include domperidone, droperidol, haloperidol, chlorpromazine, or prochlorperazine; the H1 histamine receptor antagonist can include cyclizine, diphenhydramine, dimenhydrinate, meclizine, promethazine, or hydroxyzine; the cannabinoid can include cannabis, dronabinol, or nabilone; the bezodiazepine can include midazolam or lorazepam; the anticholinergic can be scopalamine; and the steroid can be dexamethasone.
In methods of combination treatment, the extended release ODT 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. For example, 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-HT3 antagonist which provides protection against PONV/PDNV immediately after surgery, at discharge, as well as for an extended postoperative period, thereby providing enhanced patient compliance and quality of life, and also reduce medical costs.
In one embodiment, the method of the present invention, as described herein, can be used to treat patients at moderate to high risk to PONV or PDNV undergoing inpatient or outpatient surgical procedures. For example, although intravenous administration is more readily available for inpatient procedures, the present method of administering an extended release dosage form comprising a selective serotonin 5-HT3 antagonist avoids the risks and expense associated with intravenous administration. For outpatient surgical procedures, it is generally difficult to administer antiemetics intravenously after discharge, and accordingly administration of an oral dosage form is substantially more convenient and less costly. In addition, the present method of administering an extended release ODT dosage form comprising a selective serotonin 5-HT3 antagonist is a substantial improvement over the currently available immediate release dosage forms, because immediate release dosage forms require multiple daily administrations in order to provide continuous treatment or prophylaxis of PDNV, whereas the present method provides for once-daily administration, resulting in improved compliance and reduced incidence of PDNV. Thus, for example, the extended release dosage form comprising a selective serotonin 5-HT3 antagonist described herein can be administered immediately prior to discharge and/or once-daily subsequent to discharge (e.g., beginning about 24 hours after discharge, for example in the morning following discharge) for up to one week (for example up to 5 days after discharge) to treat or ameliorate PONY and/or PDNV.
In some embodiments, the extended release ODT dosage form comprising a selective serotonin 5-HT3 antagonist is effective for prophylaxis or treatment of PONV/PDNV for surgical patients administered postoperative opioids for analgesia. Such opioids can include, for example, codeine, morphine, thebaine, oripavine, diacetyl morphine, dihydrocodeine, hydrocodone, hydromorphone, nicomorphine, oxycodone, oxymorphone, fentanyl, α-methyl fentanyl, alfentanil, sufentanil, remifentanil, meperidine, buprenorphine, etorphine, methadone, and tramadol.
The method of the present invention can be used generally for both cancer patients undergoing moderately emetogenic cancer chemotherapy or total body radiotherapy.
Fumaric acid crystals were also coated as described above using different ratios of ethylcellulose and PEG. More specifically, fumaric acid crystals were coated with a solution of EC-10/PEG 400 at a ratio of either 75/25 or 67.5/32.5, providing a coating weight of up to 10% by weight for each ratio.
Although 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.
The present application claims priority to U.S. Provisional Application No. 61/265,233, filed Nov. 30, 2009, the disclosure of which is herein incorporated by reference in its entirety for all purposes.
Number | Date | Country | |
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61265233 | Nov 2009 | US |