Fast-dissolving dosage forms for dopamine agonists

Details Fast-dissolving dosage forms for dopamine agonists Fast-dissolving dosage forms for dopamine agonists

2000-09-21

2001-11-13

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Tablets, lozenges, or pills

C424S484000, C424S485000, C424S486000, C424S488000, C514S289000

Reexamination Certificate

active

06316027

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to pharmaceutical compositions, a process for preparing such compositions, the use of such compositions for the treatment and/or evaluation of Parkinson's disease and products and kits for the administration of a dopamine agonist and the co-administration of a dopamine agonist and an anti-emetic and/or opioid antagonist.
BACKGROUND OF THE INVENTION
Parkinson's disease is a progressive neurodegenerative disorder caused by a loss of the cell bodies of dopaminergic neurons from the substantia nigra and degeneration of nerve terminals in the striatum resulting in low levels of dopamine in the substantia nigra and corpus striatum. Parkinson's disease is characterized by chronic, progressive motor dysfunction and its main symptoms are tremor at rest, muscle rigidity and a decrease in the frequency of voluntary movements (hypokinesia) with difficulty in stopping, starting and turning when walking. A persistent tremor is superimposed on hypertonicity of opposing muscle groups and initiation of movements becomes increasingly difficult and slow. In advanced stages, patients' movements become virtually “frozen” and patients are unable to care for themselves. Studies have shown that the symptoms of Parkinson's disease appear when the striatal dopamine content is reduced to 20-40% of normal. As Parkinson's disease is associated with a loss of dopamine from the striatum, it is commonly treated with drugs which replace dopamine, the most commonly used of these being levodopa. Levodopa is converted by dopa decarboxylase into dopamine in the brain and it is this dopamine which exerts a therapeutic effect. However, although levodopa is well absorbed from the small intestine, much of it is inactivated by monoamine oxidase in the wall of the intestine. Also, the plasma half-life of levodopa is short and about 95% of the drug is converted to dopamine in peripheral tissues, where dopa decarboxylase is widespread, with the result that less than 1% enters the brain. Consequently levodopa has to be administered in large and frequent doses. In addition, the production of dopamine in peripheral tissues gives rise to unwanted side effects. Accordingly, levodopa is normally given in combination with other drugs to enhance the effects of levodopa in the brain and minimize its peripheral effects. In particular, levodopa is usually given in combination with a peripheral dopa decarboxylase inhibitor which cannot cross the blood-brain barrier, such as carbidopa, which inhibits the breakdown of levodopa to dopamine outside the brain, thereby reducing peripheral unwanted effects. The inhibitor also ensures that a relatively large amount of an oral dose of levodopa reaches the brain and thus enables the dose of levodopa to be reduced which also reduces peripheral side effects. In addition, a peripheral dopamine antagonist which does not penetrate the blood-brain barrier, such as domperidone, may also be administered to reduce the nausea and vomiting side effects of levodopa.
In addition to the side effects mentioned above, further undesirable effects are associated with the prolonged use of levodopa. In particular, many patients develop involuntary choreiform movements, which are the result of excessive activation of dopamine receptors. These movements usually affect the face and limbs and can become very severe. Such movements disappear if the dose of levodopa is reduced but this causes rigidity to return. Moreover, the margin between the beneficial and the unwanted effect appears to become progressively narrower as the period of levodopa treatment increases. The traditional method of combating this effect is to increase the frequency of administration of levodopa while keeping the overall dose steady. This approach reduces end-of-dose deterioration and diminishes the likelihood of the patient developing the dyskinesias that occurs with high peak doses.
A further complication of long-term levodopa treatment is the development of rapid fluctuations between mobility and immobility for periods ranging from a few minutes to a few hours. This phenomenon is known as the “on-off effect”. The “on” state being the preferred state during which nearly normal motor functioning can be attained and the “off” state being characterized by dystonic postures during periods of decreased mobility. Indeed, this effect can produce such an abrupt loss of mobility that the patient may suddenly stop while walking or be unable to rise from a chair in which he had sat down normally a few moments earlier. This effect is commonly unaffected by manipulation of the dose of levodopa and may require treatment with alternative drugs.
In addition to the above long-term side effects of levodopa treatment, it has been found that the effectiveness of levodopa gradually declines with time until it is no longer effective. Also, an increased incidence of malignant melanoma has been observed in patients undergoing treatment with levodopa. Accordingly, the use of levodopa in the treatment of Parkinson's disease is far from ideal.
An alternative approach to the treatment of Parkinson's disease is the use of drugs that mimic the action of dopamine. Such drugs are collectively known as dopamine agonists because they directly stimulate dopamine receptors within the dopamine-deficient nigrostriatal pathway. Unlike levodopa, dopamine agonists do not need to be converted in the brain to active compounds. Also, dopamine agonists are effective in patients in the advanced stages of Parkinson's disease when levodopa is no longer effective because they act directly on the dopamine receptors and are therefore unaffected by the lack of dopamine-producing nerve cells in such patients. However, the action of such dopamine agonists on the dopamine receptors also causes unwanted dopaminergic effects, such as nausea, vomiting and extrapyramidal effects, which can be debilitating and some dopamine agonists, such as apomorphine, are associated with further undesirable side effects, especially when high doses are used, such as sedation, respiratory depression, hypotension, bradycardia, sweating and yawning.
The severity and nature of such side effects can be affected by the mode of administration of the drug. For instance, studies involving apomorphine have investigated a variety of routes for administration of this drug. However, oral administration of apomorphine tablets has required high doses to achieve the necessary therapeutic effect because apomorphine administered by this route undergoes extensive presystemic metabolism in the small intestine and/or liver (the first pass effect). Also, long-term studies involving such oral forms were stopped after 7-10 days due to unexplained rises in blood urea nitrogen. Sub-lingual administration of apomorphine tablets caused severe stomatitis on prolonged use with buccal mucosal ulceration in half the patients treated. Intranasal administration produced transient nasal blockage, burning sensation and swollen nose and lips and, in some of the patients tested, had to be withdrawn because of what was considered to be chemical inflammation of the nasal mucosa. Accordingly, the only satisfactory way of administering apomorphine which avoids high first pass metabolism has been found to be subcutaneous administration and, thus, the only commercially available formulation of apomorphine is a liquid for subcutaneous injection or subcutaneous infusion. Even so, subcutaneous administration does not avoid the normal dopamine agonist side effects, such as nausea and vomiting, and subcutaneous administration, whether by injection or infusion, is not easy to accomplish, particularly by patients whose motor functions are already impaired, and therefore requires training of patients and caregivers. Also, the injection site must be changed every 12 hours to minimize risks of skin discoloration and nodules forming. In view of these problems, it is not surprising that the use of dopamine agonists, such as apomorphine, in the treatment of Parkinson's diseas

Affiliated with

Also associated with

Rating

Fast-dissolving dosage forms for dopamine agonists does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Fast-dissolving dosage forms for dopamine agonists, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Fast-dissolving dosage forms for dopamine agonists will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2593743