10
OFIGINAL CONTRIBUTION
Mapopar DIsPERSIBLE: A Fast RELEASE
FORMULATION OF LEVODOPA IN THE
TREATMENT OF PARKINSON’S DISEASE
F. Fomadi,
F.Milani,and M. Werner
Parkinson Klinit, Bad
‘Nauheim, Germany
Suamary
Parcinsonian patients with difficulties in swallowing or phenomena like
proonged early morning akinesia, delayed on., and wearirg-off-periods, in
gereral require new ways of treatment, So we have treated total of 195
patents during 1992-1993 with the dispersible formulationof levodopa plus
berserazide 4:1 (Madopar Dispersibley. During medticattonwith Madopar
Disoersible we found that patients with the Parkinson's disease (PD)
synpioms mentioned above, significantly improved on the same dosage as
tha of Madopar standard. In addition to this improvement 4% of patients,
as vell as the nursing staff, described a greater ease of administration of the
dispersible form. We have also administered Madopar Dispersible to
patents being fed via nasogastric (NG) tube or gastrostomy. In some of
these cases improvement of akinesia allowed the removal cf the tube and
we-ontinued Maciopar Dispersible per os, in 19 patients we statistically
evauated the improvement of the neurological status.
Pullished data and our own experiences have indicated a sgnificantly
shatter response time (latency to “on”) of Madopar Dispersible than that of
Matopar standard. We found that patients suffering from early-moming
akinesia and delayed “on”-periods benefited considerably irom the
accilerated response. In addition, we compared the efficacy of 4 different
formulations of Madopar (capsule, tablet, HBS, and Madofar Dispersible)
in agroup of 20 patients suffering from early morning akinssia, We found
tha Madopar Dispersible had the shortest response time, which can be
explained by the lack of disintegration step in the gastric fluid and by the
accilerated resorption.
IN"RODUCTION
‘The variety of ways of treating advanced PD have been widened by the
development of Madopar Dispersible:a fast release formuhtion of
levaclopa. Elderly patients especially, with difficulties in swallowing, can
nov be supported by the use of this medication in liquid ferm.
Furthermore, by using stable and well-balanced dispersien, a more
acctrate dosage will be gained. Several studies examining Maclopar
Dispersible“* have revealed identical efficacy, dosage equivalence, good
acciptability, and no differences in side effects from Madopar standard
(tatle 1),
Patents with various difficulties in swallowing benefit fron the
adninistration of the dispersible formulation. Tablets or capsules cause
these patients considerable problems: nurses often find residues of tablets in
patents’ mouths, because some elderly and especially mertally afflicted
patients du nut owallow the tablets, but keep Ghent in their mouths or spit
them out later. Thus, in many cases the dispersible form isa relief for both
Focus on Parkinson's Disoace, April 1006ORIGINAL
CONTRIBUTION
“Taute 1 «Indications (or treatment with Madopar Dépersible
Difficulty in swallowing pills or capsules: dysphagia
Fooding via nasagastic tube, gastrostomy
Early-moring akinesia
Delayed on-periods
‘Wearing of-periods
End-of dose ¢ystonia
Disturbances of levodopa resorption
(delayed gastic emplying, protein akinesia)
Fine adjustment of lavodopa dosage
Levodopa-test
patients and nursing staff, Staff of long-tem
care units or intensive-care units will
appreciate the possibility of feeding levodopa
through the nasogastric tube in a dispersitie
form, because there is no need for pulveriing
tablets with the tisk of a loss of dose and,
therefore, often a loss of efficacy. The
dispersion itself can be rapidly prepared and
thus helps save time. In many cases patients
can be treated with the dispersion perorally,
after akinesia has improved.
‘The shorter response time also recommends
Madopar Dispersible for special uses in th>
treatment of PD. Delayed “on’-petiods® in the early morning and prolnged
“olf"-periods ding the day, may be shortened by the use of liquid
Madopar, becarse of the accelerated resorption of the dispersible tablet
which can be e:plained by the lack of disintegration by gastric fluid,
The accelerate passage through the stomach may also be of advantage for
patients with potein akinesia.
When performng the levadopa-test with 200 mg for untreated patients we
prefer Madopar Dispersible because of the shorter latency to “or
These tests shold help to decide whether or not there is a levodopa
responsivenessto symptoms which are suspected as belonging to the TD.
Patients sufferiyg from severe peak-dose hyperkinesia and dystonia can
also benefit fron the use of Madopar Dispersible. In these cases Madogar
dispersion pernits even more of an accurate dose adjustment of levodepa.!*
Unfortunately, Madopar Dispersible is only of occasional benefit in
“random on-of” fluctuations which are not dependent on medication in
general.
METHODS AND RESULTS
In 1992 and 19S 195 patients suffering from advanced PD were treatec
with Madopar dispersible in our Parkinson-hospital. We have compiled the
indications anc the efficacy in a retrospective analysis (table 2).
Table 2 shows swallowing disruptions are the main reason for the
introduction of Madopar Dispersible. According to statements given by the
patients and tle views of physicians and nurses, 84% of the 195 patients
undergoing this treatment benefited from the change from the standard to
the dispersibleformulation. Administration of medication in a dispersible
form was more reliable for patients with swallowing disruptions and many
of them improved without an increase in dosage or any further changes in
medication. The ease of dispersion administration was generally appreved
for all patients,except for 3 who had more difficulties with this methoc.
Adverse event: experienced by some patients receiving standard Madopar
remained afterswitching to Madopar Dispersible. A bitter teste wes ncted
by5 patients, another patient was reported to have vegetative sensations,
dizziness, and veat sensations. In spite of these side effects the majority of
patients treatec with Madopar Dispersible still preferred this liquid form of
fevodopa. in £6% of the patients we did not observeany improvement and
the Madopar Dispersible medication was terminated.
Focus on Parkinson‘s Disease, April 1998 u12
ORIGINAL CONTRIBUTION
“TAILE2 - Patlens treated with Madopar Dispersible in our Parkinson Centr (1992-99),
Indeations Patients ‘Benefit *
‘Swallowing disruptions 63 53 84
Navogastic tube, gastrostomy 9 5 56
Eary-meming akinosia 45 37 2
Wearing (in ot phase) 48 29 a
Detyed on Ey 14 o
Radom “on-off 14 2 4
Tobl 195
Nineeen patients with dysphagia were collected for more dehiled
evaliations conceming the efficacy of Madopar Dispersible incomparison to
the stnclard formulation. These patients did not undergo any changes in
medication except for a switching from standard Madopar to Madopar
Dispusible. Before treatment with Madopar Dispersible and zt least 1 week
after witching, the UPDRS motor subscore of these patients vere registered.
In actlition to the medication patients received physiotherapy, ergotherapy,
and speech therapy. The data of the patients are shown in table 3.
Of these 19 patients, 70.4% showed an improvement of the UPDRS motor
score Akinesia and rigor were reduced. In 4 pationts we did rot observe
any improvement according to the UPDRS motor subscore and 1 patient
deterorated by 1 point. The improvement in the UPDRS motor subscore
‘was considered to be significant by statistical evaluation (tabk 4).
Anoher important inclication for the use of Madopar Dispersible is early
‘motring akinesia. Due to the very short latency to“on” we expected
improved results of the levodopa dispersion in this specific stuation. We,
thercore, treated 54 patients suffering from early-morning akinesia, by
changing the first levodopa dosage to the dispersible formuletion, Eighty-
two percent of these patients reported a marked benefit witha very short
respanse time in the moming. In this group, in many cases the latency to
“on""period was <25 minutes.
Longduration of delayed “on’-periods’ could be successfully influenced as
‘well. Two-thirds of these patients responded to an additional
administration of Madopar Dispersible by interrupting this period within a
shorttime (table 2).
A markedly short latency to “on” was observed in many of the patients
treated with Madopar Dispersible. Therefore, we intended te supplement
Taste 3- Madopar Dspersible in swallowing disruptions.
Paient data ‘Mean 8D Maxinurr Minimum
Age (years) 6605 3.32 "0 54
Duation of PO (years) 953 353 7 4
Lerodopa duration (years) 805 334 “4 1
Heaha-Yahr 389 os? 5 é
Se (malefemale) 90
‘Number ot patients w
Focus on Parkinson's Disease, April 1996ORIGINAL CONTRIBUTION
‘TasLe 4. UPDRS molor aubscore aftor changing from Madopar standard to Madopat
Dispersibie in svaliowing disruptions.
Madopar standard Madopar Dispersibie
Mean ara 38.89
sD 683 745
Minimum 23 a
Maximum 7 49
these observations by performing an open, single-dose, intraindividual
comparative stuty to reexamine these results. Twenty patients suffering
from early-moning akinesia on 4 subsequent days received 100 mg,
levodopa on anempty stomach, each day in a different fort: Madopar
125 mg tablet, Nadopar 125 mg capsule, Maclopar HBS capsule, and
Madopar Dispessible tablet. These patients were not treated with any
levodopa sustained release preparations or agonists with a long half-life,
‘The dose prior b this examination was given the evening before at
After the intakeof the test medication the patients were observed for 3
hours and the lctency to “on,” duration of effect, improvement in the
UPDRS motor sibscore and hyperkinesia were recorded (table5).
‘The recorded dita of the observations are shown in expanded form in
table 6. The statstical evaluation of the registered data was carried out with
SPSS-PC + Vers 5.0. The Mann-Whitney U test and the I-way variance
analysis were wed. First of all, the significant differences between Madopar
Dispersible andall other formulations concerning the latency to “on’
should be emplasized. Madopar Dispersible’s latency to “on” was, at a
mean of 24.88 ninutes, significantly shorter than that of the tablet and
capsule (both approximately 39 minutes). The latency to “on” with HBS
was approximaely 75 minutes and considerably longer than with the cther
formulations.
A surprising observation was found conceming the effect of a single-dese
duration of the tifferent formulations which did not vary significantly irom
approximately "9-87 minutes. Even the long acting controlled release
formulation HES was subsequent to Madopar Dispersible for the duraton
of effect. The UPDRS motor subscore revealed only 1 significant differerce
concerning the notor benefit: the improvement in the Madopar HBS gioup
amounted to a bwer level than those of the Madoper Dispersible group,
‘TasteS - Data fom single-dose open study with diferent formulations of Madopar.
Patent data ‘Mean so ‘Maximum rime
‘Age (years) 65.00 89 0 50
Duration of PD years) 9.94 458 2 4
Levodopa duraton (yeas) 8.38 440 8 1
Hoohn-Yahr 344 063 5 3
Sex (maleftemae) ne
Number of patios 20
Focus on Parkingon’s Disease, April 1996 134
ORIGINAL CONTRIBUTION
ARLE 6 - Detsiledsinglo-doco opon study with diferont formulations of Madopar.
Madopar = Mean sD Minimum — Maximum
Latoncy toon" (ma) Capsule 9956 18.26 30 73
Tablet 131388 20 7
Hes. 7577 3033 30 120
Disporsiblot 24.28 8.08 2 38
Duratonotetiet —_Capaule 7975 2751 30 125
(min) Tablet e219 21.13 50 120
Hes 438 (2957 60 165
Disporsblo §7.62 «30.86 45 130
Motor benefit Capsule 1381 489 6 2
(Gif. in UPDRS) Tablet 14.62 528 6 25
monnrcthevwra) HAG tus. 670 4 21
Dispersible 16.52 549 T 8
Hyperkinesia (0-4) Capsule ous
Tablet os
HBS: 023
Dispersble 0.66
“p0.01; “p<0.05; Mann-Whitney U test.
The side effects observed did not vary remarkably except for the HBS group
whichshowed a lower tendency to dyskinesia. This finding isin agreement
with the slower resorption and the lower levodopa peaks of the sustained-
release formulations (table 6).
Discussion
The development of levodopa therapy led to different formulations which
corresponded to the needs of different patients suffering fromadvanced
PD. The modern treatment, therefore, consists of a combination of
antipackinsonian drugs in order to minimize complications during long-
term heatment. The progression of PD is characterized by nansowing of the
so-called “therapeutic window” with appearance of motor fluctuations,
dyskiresia, and a loss of efficacy? Therefore, it is necessary to