Levodopa formulations

Levodopa is a chemical formulation found in plants and animals that is converted into dopamine by nerve cells in the brain. Levodopa does cross die blood-brain barrier, and a small amount is dien converted to dopamine. This allows the drug to have a pharmacologic effect in patients witii Parkinson s disease (Pig. 29-1). Combining levodopa witii another drug (carbidopa) causes more levodopa to reach die brain. When more levodopa is available, the dosage of levodopa may be reduced. Carbidopa has no effect when given alone. Sinemet is a combination of carbidopa and levodopa and is available in several combinations (eg, Sinemet 10/100 has 10 mg of carbidopa and 100 mg of levodopa Sinemet CR is a time-released version of die combined drugs). 

A number of azetidine-based compounds have been disclosed in patent applications from Aventis Pharma for CBi-modulated treatment of diseases such as obesity, Parkinson s disease, schizophrenia, respiratory and neurological diseases [330-334]. Compound (556) was specifically claimed for use in two formulation patent applications [330, 331] for a stable semi-solid composition and oral emulsion composition, respectively. The optional coadministration of an agent that activates norepinephrinergic and se-rotoninergic neurotransmission (for example, sibutramine) or dopaminergic neurotransmission was also claimed for the treatment of obesity. The optional use of a dopamine agonist (for example, levodopa) was claimed... 

The controlled-release (CR) formulation is more slowly absorbed and longer acting than immediate-release tablets. Patients need to increase the total daily dose by 30%, as it is not as bioavailable as the immediate-release levodopa/carbidopa. The CR formulation has a delayed onset (45 to 60 minutes) compared to the standard formulation (15 to 30 minutes). Thus, patients may also need to take immediate-release tablets or even a liquid formulation when they want a quicker onset of effect, such as with the first morning dose.1,8,25... 

Patients with severe dyskinesias and off periods may achieve more constant blood concentrations (lower peak and higher trough concentrations) by taking a liquid formulation of levodopa with carbidopa. Each day patients make a 1 mg/mL levodopa... 

Pharmacology These agents are used in combination because carbidopa inhibits decarboxylation of levodopa and makes more levodopa available for transport to the brain. There is less variation in plasma levodopa levels than with the conventional formulation. However, the extended-release form is less systemically bioavailable (70% to 75%) and may require increased daily doses to achieve the same level of symptomatic relief. 

Entacapone can be combined with the immediate- and sustained-release formulations of levodopa/carbidopa. 

Carbidopa/levodopa - There is no experience in transferring patients currently treated with formulation of carbidopa/levodopa other than immediate release carbidopa/levodopa with a 1 4 ratio (controlled release formulations, or standard release presentations with a 1 10 ratio of carbidopa/levodopa) and entacapone to carbidopa, levodopa, and entacapone combination. 

With long term levodopa therapy the risk for the occurrence of on-off effects, periodically and paroxysmally occurring periods of the therapy becoming ineffective, increases. Decreasing the peak-trough fluctuations with slow-release levodopa/ carbidopa formulations could possibly diminish these on-off effects. 

I Contraindications Nonselective MAOl therapy, hypersensitivity to levodopa or any component of its formulation. 

Fig. 3 Relationship between the dissolution parameter tgo-io of effervescent enteric tablets of levodopa and the amount of sodium bicarbonate formulated in the tablet. The number of strokes was fixed at 5/min and the pH was 7.5. Key ( ) = uncoated tablet (O) = enteric tablet. (From Ref. "l)...

Nishimura, K. Sasahara, K. Araj, M. Nitanai, T. Ikegami, Y. Morioka, T. Nakajima, E. Dosage form design for improvement of bioavailability of levodopa VI formulation of effervescent enteric-coated tablets. J. Pharm. Sci. 1984, 73, 942-946. 

Levodopa, benserazide Pharmaceutical formulations UV-Vis 4.1-20.3 x 10 1 mol L-1 0.85-4.25 x 1CT4 mol L 1 168 Multidimensional partial least-square regression/zone stopping [67]... 

Ting, S. Liquid chromatographic determination of levodopa, levodopa-carbidopa, and related impurities in solid dosage forms. J.Assoc.Off.Anal.Chem., 1986, 69, 169-173 [simultaneous carbidopa, levodopa acetaminophen is IS formulations]... 

Due to the on/off phenomena and concerns about the exact role of dopamine s contribution to free radical generation and tissue damage, most practitioners use levodopa only when the symptoms of PD cause functional impairment. When levodopa levels are maintained constant by intravenous infusion, dyskinesias and fluctuations are greatly reduced, and the clinical improvement is maintained for up to several days after returning to oral levodopa dosing. A sustained-release formulation and division of the total daily dose into more frequently administered portions have been used to overcome the on/off phenomenon. 

CNS Scopolamine is standard therapy for motion sickness this drug is one of the most effective agents available for this condition. A transdermal patch formulation is available. Benztropine, biperiden. and trihexyphenidyl are representative of several antimuscarinic agents used in parkinsonism. Although not as effective as levodopa (see Chapter 28), these agents may be useful as adjuncts or when patients become unresponsive to levodopa. Benztropine is sometimes used parenterally to treat acute dystonias caused by antipsychotic medications. 

Warn patients of this additive effect. Consider increasing the dose of levodopa. Consider changing the formulation to a sublingual nitrate spray... 

The addition of a chiral crown ether [(+)-(18-crown-6)-2,3,ll,12-tetracarboxylic acid] to the background electrolyte allowed Blanco and Valverde [147] to separate the enantiomers of benser-azide and determine the enantiomeric purity of Dopa (3,4-dihydroxyphenyl-alanine). Levodopa is the main active ingredient in the pharmaceutical formulation Madopar , which is used to treat Parkinson s disease, while dextradopa causes unwanted side effects. The dextradopa impurity was clearly resolved from the main peak and determined to be 0.5%. 

The estimation of catechol and its derivatives such as dopamine hydrochloride, levodopa, methyldopa, and adrenaline hydrochloride in both pure form and in pharmaceutical formulation is based on the interaction of diazotized sulfanilamide with catechol derivatives in the presence of molybdate ions in acidic medium. Absorbance of the resulting red-colored product is measured at 490 nm for pyrocatechol and at 500 nm for other catechol derivatives. The color reaction is stable for 24-30 h. 

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