Opioid agonist in a fast dispersing dosage form

Details Opioid agonist in a fast dispersing dosage form Opioid agonist in a fast dispersing dosage form

2002-01-14

2004-01-20

Krass, Frederick (Department: 1614)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Matrices

C424S485000, C424S486000, C424S487000, C424S488000, C424S439000, C424S441000, C424S465000, C424S466000, C514S329000, C514S816000, C514S817000, C514S818000

Reexamination Certificate

active

06680071

ABSTRACT:

TECHNICAL FIELD
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.
BACKGROUND OF THE INVENTION
Fentanyl (N-phenyl-N-[1-(2-phenylethyl)-4-piperidinyl]propanamide) is a potent synthetic opioid (&mgr; 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 &mgr; 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.
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 0.1 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. In selected high risk patients, such as those undergoing open heart surgery or certain complicated neurological or orthopaedic procedures, it may also be used as an anesthetic agent with oxygen.
Typical dosages for use as a premedication or postoperatively are 50 to 100 &mgr;g/kg of body weight. When used as an adjunct to general anesthesia, doses may range from 2 &mgr;g/kg to 20-50 &mgr;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. However, 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.
In addition to analgesia, 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.
One of the most serious adverse effects associated with use of intravenous fentanyl is 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 100 &mgr;g of fentanyl per hour over 3 days. In this dosage form, fentanyl is released as a free base. The actual amount released from the patch varies with time and also between patients. Essentially, 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. This slower elimination, as compared to that after intravenous administration, is due to continued absorption of drug from the depot in the skin after removal of the patch.
In view of the above, 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 care. The approved dose for this dosage form for premedication is between 5-15 &mgr;g/kg (400 &mgr;g) for adults. However, 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.
This device is clearly unsuitable for use during and after operations and can therefore only be used for some of the indications for which the intravenous injection form can be used. Also, although several clinical trials have shown that the oral transmucosal device is generally useful as a premedicant in children prior to surgery, there is a high incidence of adverse effects, some o

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