EP1164994A1 - Opioid agonist in a fast dispersing dosage form - Google Patents
Opioid agonist in a fast dispersing dosage formInfo
- Publication number
- EP1164994A1 EP1164994A1 EP00912152A EP00912152A EP1164994A1 EP 1164994 A1 EP1164994 A1 EP 1164994A1 EP 00912152 A EP00912152 A EP 00912152A EP 00912152 A EP00912152 A EP 00912152A EP 1164994 A1 EP1164994 A1 EP 1164994A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- composition
- active ingredient
- composition according
- fentanyl
- pain
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—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
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
Definitions
- This invention relates to a pharmaceutical composition in the form of a fast dispersing dosage form and to a process for preparing such a composition.
- the invention also relates to the use of such a composition as an analgesic for the treatment of chronic pain and/or breakthrough pain, as an anesthetic premedication for the induction of anesthesia as a sedative and as a treatment for anxiety.
- Fentanyl (N-phenyl-N-[l-(2-phenylethyl)-4-piperidinyl]propanamide) is a potent synthetic opioid ( ⁇ receptor) agonist, related to pethidine, which possesses a fast onset and a moderate duration of action.
- the agonists useful in the present invention are chemical substances capable of combining with a receptor on a cell and initiating a reaction or activity that is characteristics of opiate narcotics, but which is not derived from opium.
- Fentanyl like other opioid agonists, interacts predominantly with ⁇ binding sites in the brain, spinal cord and other tissues. Its principal pharmacological actions of therapeutic value are analgesia and sedation and, in this respect, fentanyl is approximately 100 times more potent than morphine and 7,500 times more potent than pethidine. It is therefore primarily used for its analgesic properties as a component of anesthesia and is normally administered by intravenous or intramuscular injection, although transdermal and transmucosal dosage forms have also been developed.
- Intravenous fentanyl When administered by the intravenous route, the onset of activity is almost immediate and the duration of analgesia is about 30 to 60 minutes after a single dose of up to 0J mg. Following intramuscular administration of fentanyl, the onset of activity is 7 to 8 minutes with a duration of activity of 1 to 2 hours. Intravenous fentanyl may therefore be utilized for analgesic action of short duration during the anesthetic periods of premedication, induction and maintenance and in the immediate postoperative period (recovery room) as the need arises.
- It may also be used as a narcotic analgesic supplement in general or regional anesthesia and, with a neuroleptic agent such as droperidol, as an anesthetic premedication for the induction of anesthesia and as an adjunct in the maintenance of general and regional anesthesia.
- a neuroleptic agent such as droperidol
- an anesthetic premedication for the induction of anesthesia and as an adjunct in the maintenance of general and regional anesthesia.
- selected high risk patients such as those undergoing open heart surgery or certain
- Typical dosages for use as a premedication or postoperatively are 50 to lOO ⁇ g/kg of body weight. When used as an adjunct to general anesthesia, doses may range from 2 ⁇ g/kg to 20-50 ⁇ g/kg depending upon the complexity and duration of the operation.
- Intravenously administered fentanyl tends to accumulate in skeletal muscle and fat from where it is slowly released into the blood. Repeated doses therefore lead to accumulation and prolonged activity.
- the plasma protein binding decreases with increasing ionization of the drug and alterations in pH may therefore affect the distribution of fentanyl between plasma and the central nervous system.
- Fentanyl is primarily transformed in the liver and a high first pass effect is therefore observed when the drug is administered by non-parenteral routes.
- about 75% of an intravenous dose of fentanyl is recovered in the urine with less than 10% as the unchanged drug, the main metabolites being norfentanyl and despropionylfentanyl which are both inactive.
- fentanyl may cause alterations in mood, euphoria, dysphoria and drowsiness. Moreover, therapeutic levels of fentanyl may cause nausea and vomiting directly by stimulation of the chemoreceptor trigger zone. However, nausea and vomiting are significantly more common in ambulatory than in recumbent patients.
- hypoventilation This is seen as a reduction in the respiratory rate (breaths per minute) and in the oxygen saturation level of the blood. Indeed, this hypoventilation may last longer than the analgesic effect. It is therefore necessary to ensure that an opioid antagonist, intubation equipment and oxygen are readily available when fentanyl is injected.
- Fentanyl may also cause muscle rigidity, particularly in the muscles of respiration. This may occur in the postoperative period and patients should therefore be carefully monitored, especially those receiving a high dose of fentanyl. Should this effect occur, it may be reversed by administration of naloxone or overcome by neuromuscular-blocking drugs. As with other opioid agonists, fentanyl increases the tone and decreases the propulsive contractions of the gastrointestinal tract leading to constipation. However, at therapeutic dosages, fentanyl exerts minimal effects on the cardiovascular system, although orthostatic hypotension and fainting may occur in some patients and vagally- mediated bradycardia has been reported.
- the transdermal dosage form is available as a range of patches offering a range of release rates from 25 to lOO ⁇ g of fentanyl per hour over 3 days.
- fentanyl is released as a free base.
- the actual amount released from the patch varies with time and also between patients.
- the skin absorbs fentanyl and a depot of fentanyl concentrates in the upper skin layers.
- the serum fentanyl concentrations gradually increase until levelling off with peak serum concentrations being attained between 24 and 72 hours. After several sequential 72- hour applications, patients reach and maintain a steady state serum concentration. After removal of the patch, the serum fentanyl concentrations gradually decline with levels falling by 50% in about 17 hours.
- the transdermal patch is indicated for the management of chronic pain in patients who require continuous opioid analgesia for pain that cannot be managed by paracetamol-opioid combinations, non-steroidal analgesics or PRN dosing with short acting opioids. It is not indicated for the management of acute or postoperative pain because of the risk of hypoventilation (4% incidence) and should not be administered to children under 12 unless used in an authorized research setting.
- the oral transmucosal system consists of a lozenge of fentanyl citrate attached to a handle.
- the lozenge is sucked until complete dissolution is achieved (normally within about 12 to 15 minutes).
- a bioavailability study of this device in comparison with intravenous and oral solution administration showed that the absolute bioavailability from the device was 51%, as compared to 32% from the oral solution, and that the t max was also faster from the device. It is estimated that about 75% of the total dose from the device is swallowed and a third of this amount reaches the systemic circulation in addition to the 25% of the dose which is absorbed sublingually.
- the oral transmucosal device has been approved for use for anesthetic premedication in children and adults and for use in anesthesia or monitored anesthesia
- the approved dose for this dosage form for premedication is between 5-15 ⁇ g/kg (400 ⁇ g) for adults.
- this product is only authorized for administration in hospital settings where there is immediate access to life support equipment, including oxygen, facilities for endotracheal intubation, intravenous fluids and opioid antagonists. Also, there is a restriction on personnel authorized to administer this product.
- compositions for oral administration comprising a carrier and, as active ingredient, an opioid ( ⁇ receptor) agonist, characterized in that the composition is in the form of a fast-dispersing dosage form designed to release the active ingredient rapidly in the oral cavity.
- pre-gastric absorption thus includes buccal, sublingual, oropharyngeal and oesophageal
- An opioid ( ⁇ receptor) agonist such as fentanyl
- An opioid ( ⁇ receptor) agonist such as fentanyl
- absorbed by such pre- gastric absorption passes straight into the systemic circulatory system thereby avoiding first pass metabolism in the liver. Accordingly, bioavailability of an opioid ( ⁇ receptor) agonist, such as fentanyl, absorbed in this way may also be increased. This means that the dose of fentanyl or other opioid ( ⁇ receptor) agonist may be reduced while still producing the desired beneficial effects and this decrease in dose will result in a corresponding reduction of unwanted side effects.
- U.S. Patent No. 5,120,549 discloses a fast-dispersing matrix system which is prepared by first solidifying a matrix-forming system dispersed in a first solvent and subsequently contacting the solidified matrix with a second solvent that is substantially miscible with the first solvent at a temperature lower than the solidification point of the first solvent, the matrix-forming elements and active ingredient being substantially insoluble in the second solvent, whereby the first solvent is substantially removed resulting in a fast-dispersing matrix.
- U.S. Patent No. 5,079,018 discloses a fast-dispersing dosage form which
- a porous skeletal structure of a water soluble, hydratable gel or foam forming material that has been hydrated with water, rigidified in the hydrated state with a rigidifying agent and dehydrated with a liquid organic solvent at a temperature of about 0°C or below to leave spaces in place of hydration liquid.
- U.S. Patent No. 5,298,261 discloses fast-dispersing dosage forms which comprise a partially collapsed matrix network that has been vacuum-dried above the collapse temperature of the matrix. However, the matrix is preferably at least partially dried below the equilibrium freezing point of the matrix.
- Published International Application No. WO 91/04757 discloses fast-dispersing dosage forms which contain an effervescent disintegration agent designed to effervesce on contact with saliva to provide rapid disintegration of the dosage form and dispersion of the active ingredient in the oral cavity.
- EP-A-0627218 discloses a fast-dispersing dosage form which comprises a tablet comprising a sugar alcohol or the like as principal ingredient which is prepared by the wet granulation method in which a kneaded mixture of the sugar alcohol or the like with a drug is compression molded before drying.
- fast-dispersing dosage form refers to compositions which disintegrate/disperse within 1 to 60 seconds, preferably 1 to 30 seconds, more preferably 1 to 10 seconds and particularly 2 to 8 seconds, of being placed in the oral cavity. It therefore encompasses all the types of dosage forms described in the preceding paragraphs as well as any other equivalent dosage form. However, it is particularly preferred that the fast-dispersing dosage form is of the type described in U.K. Patent No.
- a solid fast-dispersing dosage form comprising a network of the active ingredient and a water-soluble or water-dispersible carrier which is inert towards the active ingredient, the network having been obtained by subliming solvent from a composition in the solid state, that composition comprising the active ingredient and a solution of the carrier in a solvent.
- the composition will preferably contain, in addition to the active ingredient, matrix forming agents and secondary components.
- Matrix forming agents suitable for use in the present invention include materials derived from animal or vegetable proteins, such as the gelatins, dextrins and soy, wheat and psyllium seed proteins; gums such as acacia, guar, agar, and xanthan; polysaccharides; alginates; carboxymethylcelluloses; carrageenans; dextrans; pectins; synthetic polymers such as polyvinylpyrrohdone; and polypeptide/protein or polysaccharide complexes such as gelatin-acacia complexes.
- matrix forming agents suitable for use in the present invention include sugars such as mannitol, dextrose, lactose, galactose and trehalose; cyclic sugars such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminium silicates; and amino acids having from 2 to 12 carbon atoms such as a glycine, L-alanine, L-aspartic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine and L-phenylalanine.
- sugars such as mannitol, dextrose, lactose, galactose and trehalose
- cyclic sugars such as cyclodextrin
- inorganic salts such as sodium phosphate, sodium chloride and aluminium silicates
- amino acids having from 2 to 12 carbon atoms such as a glycine, L-alanine, L-aspartic
- One or more matrix forming agents may be incorporated into the solution or suspension prior to solidification.
- the matrix forming agent may be present in addition to a surfactant or to the exclusion of a surfactant.
- the matrix forming agent may aid in maintaining the dispersion of any active ingredient within the solution or suspension. This is especially helpful in the case of active agents that are not sufficiently soluble in water and must, therefore, be suspended rather than dissolved.
- Suitable coloring agents include red, black and yellow iron oxides and FD&C dyes such as
- Suitable flavoring agents include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grape flavors and combinations of these.
- Suitable pH modifiers include citric acid, tartaric acid, phosphoric acid, hydrochloric acid, maleic acid and sodium hydroxide.
- Suitable sweeteners include aspartame, acesulfame K and thaumatic.
- Suitable taste-masking agents include sodium bicarbonate, ion-exchange resins, cyclodextrin inclusion compounds, adsorbates or microencapsulated actives.
- the compositions of the invention comprise an opioid ( ⁇ receptor) agonist as an active ingredient.
- Representative drugs within this class include, but are not limited to, alfentanil, codeine, diamorphine, dihydrocodeine, fentanyl, hydromorphine, methadone, morphine, morphine-6-glucoronide, oxymorphine, pethidine, sufentanil and tramadol and salts of these compounds.
- Such drugs are commercially available and their routes of administration and dosage rates are reported in the literature.
- compositions for oral administration comprising a carrier and, as active ingredient, an opioid agonist characterized in that the composition is in the form of a fast dispersing dosage form designed to release the active ingredient rapidly in the oral cavity.
- a preferred active ingredient for use in the invention is fentanyl or a salt thereof. If a salt is used, it is preferred that the salt is an acid-addition salt of fentanyl, especially the citrate salt. However, since it is known that the un-ionized form of fentanyl penetrates mucosal membranes better than the ionized form, the composition
- a suitable pH range typically 7 to 7.5 by addition of an acid or alkaline substance.
- the active ingredient is generally present in the composition in an amount from 0.2 to 95%, normally 1 to 20%, by weight of the composition of dried dosage form. Generally the active ingredient is present in an amount from 0J to 200 mg, normally 0.2 to 20 mg per dose depending upon the particular drug.
- the active ingredient is fentanyl it is preferably incorporated in the composition in an amount of from 0.5 to 10% by weight of the dried dosage form.
- a process for preparing a pharmaceutical composition as previously defined which comprises bringing a carrier into association with the active ingredient.
- the invention provides the use of a fast-dispersing dosage form designed to release active ingredient rapidly in the oral cavity to deliver an opioid ( ⁇ receptor) agonist, such as fentanyl, or a salt thereof.
- a method of administering an opioid ( ⁇ receptor) agonist, such as fentanyl, or a salt thereof to a patient which comprises introducing into the oral cavity of the patient a composition
- the invention also provides, in another aspect, a composition as defined above for use as an analgesic.
- the composition is particularly useful for the treatment of chronic pain, especially in a patient already receiving opioid therapy.
- the composition of the invention could provide the possibility of more individual titration of dose when required when the pain is most severe, especially during the night.
- the composition of the invention provides a rapidly acting, potent analgesic which would reduce the pain for the required time and then wear off fairly quickly thereby minimizing the side-effects of the active ingredient. Accordingly, the invention also provides a composition for use in the treatment of breakthrough pain in a patient experiencing chronic pain.
- composition of the invention is easier and quicker to administer than any of
- the invention therefore also provides a composition for use as an anesthetic premedication, for the induction of anesthesia, for use as a sedative and/or for the treatment of anxiety.
- a method of treating pain, especially chronic pain or breakthrough pain, or anxiety comprises introducing into the oral cavity of a patient a therapeutically effective amount of a composition as previously defined.
- the invention also provides a method of inducing an anesthetic effect or a sedative effect in a patient which comprises introducing into the oral cavity of the patient a pre-determined amount of a composition as previously defined calculated to induce anesthesia or sedation respectively in the patient.
- Gelatin (765g) and mannitol (540g) were dispersed in a portion of purified water (16kg) by mixing thoroughly in the bowl of a vacuum mixer. The mix was then heated to 40°C ⁇ 2°C and homogenised for ten minutes to allow complete dissolution of the solids. The mix was cooled down to room temperature (20-24°C).
- the blister laminate comprised 200 ⁇ m PVC (polyvinyl chloride) coated with 40gsm PVdC (polyvinyl dichloride).
- the product was frozen immediately in a liquid nitrogen freeze tunnel.
- the frozen product was then stored below -20°C for a minimum of 12 hours prior to freeze-drying in a freeze drier using a drying temperature of +10°C and a chamber pressure of 0.5 mbar.
- the freeze dried units were then inspected for the presence of critical defects and the remainder of the batch sealed with lidding foil consisting of a paper/foil laminate (20 ⁇ m aluminium).
- Each blister was then coded with a batch number and overwrapped in a preformed sachet by placing the blister in the sachet and sealing the open end of the sachet completely.
- Each sachet was then labelled with the product name, batch number, date of manufacture and suppliers name.
- Examples 1 to 4 using fentanyl citrate correspond to 200, 400, 800 and lOOO ⁇ g of fentanyl base respectively.
- the present invention provides a dosage form that can be efficiently and economically used by patients for the management of their breakthrough pain. This is benefit tot he patients and to the caregivers.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Zoology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
Claims
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9904911.6A GB9904911D0 (en) | 1999-03-03 | 1999-03-03 | Pharmaceutical compositions |
GB9904911 | 1999-03-03 | ||
PCT/US2000/005531 WO2000051539A1 (en) | 1999-03-03 | 2000-03-02 | Opioid agonist in a fast dispersing dosage form |
Publications (2)
Publication Number | Publication Date |
---|---|
EP1164994A1 true EP1164994A1 (en) | 2002-01-02 |
EP1164994A4 EP1164994A4 (en) | 2004-05-26 |
Family
ID=10848897
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP00912152A Withdrawn EP1164994A4 (en) | 1999-03-03 | 2000-03-02 | Opioid agonist in a fast dispersing dosage form |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP1164994A4 (en) |
AU (1) | AU3393000A (en) |
GB (1) | GB9904911D0 (en) |
WO (1) | WO2000051539A1 (en) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU1623801A (en) | 1999-11-19 | 2001-05-30 | Palatin Technologies, Inc. | Opioid metallopeptide compositions and methods |
US20020106407A1 (en) * | 2000-12-11 | 2002-08-08 | Dennis Coleman | Method and apparatus for treating breakthrough pain |
US20020160043A1 (en) * | 2001-02-27 | 2002-10-31 | Dennis Coleman | Compositions and method of manufacture for oral dissolvable dosage forms |
EP1897543A1 (en) | 2006-08-30 | 2008-03-12 | Euro-Celtique S.A. | Buprenorphine- wafer for drug substitution therapy |
PL2493457T3 (en) | 2009-10-30 | 2018-01-31 | Ix Biopharma Ltd | Fast dissolving solid dosage form |
LT3150199T (en) | 2012-05-02 | 2018-11-12 | Orexo Ab | New alfentanil composition for the treatment of acute pain |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5576014A (en) * | 1994-01-31 | 1996-11-19 | Yamanouchi Pharmaceutical Co., Ltd | Intrabuccally dissolving compressed moldings and production process thereof |
WO1997006786A1 (en) * | 1995-08-18 | 1997-02-27 | R.P. Scherer Limited | Oral fast-dissolving compositions for dopamine agonists |
WO1997028788A1 (en) * | 1996-02-09 | 1997-08-14 | Quadrant Holdings Cambridge Ltd. | Solid formulations containing trehalose |
US5776492A (en) * | 1995-08-19 | 1998-07-07 | Gruenenthal Gmbh | Rapidly disintegrating medicinal form of tramadol or a tramadol salt |
WO1998042344A1 (en) * | 1997-03-24 | 1998-10-01 | R. P. Scherer Limited | Pharmaceutical composition |
WO2000051593A2 (en) * | 1999-03-02 | 2000-09-08 | West Pharmaceutical Services Drug Delivery & Clinical Research Centre Limited | Oral drug delivery system |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2919771B2 (en) * | 1995-04-17 | 1999-07-19 | 佐藤製薬株式会社 | Method for producing fast-dissolving tablet and fast-dissolving tablet produced by the method |
-
1999
- 1999-03-03 GB GBGB9904911.6A patent/GB9904911D0/en not_active Ceased
-
2000
- 2000-03-02 AU AU33930/00A patent/AU3393000A/en not_active Abandoned
- 2000-03-02 EP EP00912152A patent/EP1164994A4/en not_active Withdrawn
- 2000-03-02 WO PCT/US2000/005531 patent/WO2000051539A1/en not_active Application Discontinuation
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5576014A (en) * | 1994-01-31 | 1996-11-19 | Yamanouchi Pharmaceutical Co., Ltd | Intrabuccally dissolving compressed moldings and production process thereof |
WO1997006786A1 (en) * | 1995-08-18 | 1997-02-27 | R.P. Scherer Limited | Oral fast-dissolving compositions for dopamine agonists |
US5776492A (en) * | 1995-08-19 | 1998-07-07 | Gruenenthal Gmbh | Rapidly disintegrating medicinal form of tramadol or a tramadol salt |
WO1997028788A1 (en) * | 1996-02-09 | 1997-08-14 | Quadrant Holdings Cambridge Ltd. | Solid formulations containing trehalose |
WO1998042344A1 (en) * | 1997-03-24 | 1998-10-01 | R. P. Scherer Limited | Pharmaceutical composition |
WO2000051593A2 (en) * | 1999-03-02 | 2000-09-08 | West Pharmaceutical Services Drug Delivery & Clinical Research Centre Limited | Oral drug delivery system |
Non-Patent Citations (3)
Title |
---|
"Rapid-Dissolve Technology: An Interwiew With Loyd V. Allen, Jr. PhD, RPh" INTERNATIONAL JOURNAL OF PHARMACEUTICAL COMPOUNDS, [Online] vol. 7, no. 6, November 2003 (2003-11), pages 449-450, XP002275269 Retrieved from the Internet: URL:http://www.ijpc.com/_pdf/rapid.pdf> [retrieved on 2004-03-29] * |
DATABASE WPI Section Ch, Week 199718 Derwent Publications Ltd., London, GB; Class A96, AN 1997-196011 XP002275270 & JP 08 291051 A (SATO SEIYAKU KK) 5 November 1996 (1996-11-05) * |
See also references of WO0051539A1 * |
Also Published As
Publication number | Publication date |
---|---|
EP1164994A4 (en) | 2004-05-26 |
AU3393000A (en) | 2000-09-21 |
WO2000051539A1 (en) | 2000-09-08 |
GB9904911D0 (en) | 1999-04-28 |
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