SYNERGISTIC COMBINATION OF DECARBOXYLASE INHIBITORS AND L-DOPA PELLETS

COMBINAISON SYNERGETIQUE D'INHIBITEURS DE DECARBOXYLASE ET DE GRANULES L-DOPA

English Abstract

ABSTRACT OF THE DISCLOSURE
Synergistic combination of L-dopa pellets and
decarboxylase inhibitors as a medicament against Parkinson's
disease.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A product containing as active ingredient L-dopa in
the form of pellets and decarboxylase inhibitors or salts of
these compounds with physiologically acceptable acids or bases as
combination preparation for simultaneous or separate
administration.

2. A product according to claim 1, in which the
combination includes in each case 0.5 to 100 parts by weight of
L-dopa to one part by weight of decarboxylase inhibitor.

3. A product according to claim 1, in dosage unit form
containing 10 - 100 mg of decarboxylase inhibitor and 50 to 1,000
mg of L-dopa (in the form of pellets).

4. A product according to claim 3, in dosate unit form
containing 25 - 50 mg of decarboxylase inhibitor and 100 to 5,00
mg of L-dopa (in form of pellets).

5. A product according to claim 1, 2 or 3, in which
the decarboxylase inhibitor is benserazide or carbidopa.

6. A process for the preparation of a perorally
administrable product which comprises mixing or homogenizing 1
part by weight of decarboxylase inhibitor and 0.5 to 100 parts by
weight of L-dopa, which comprises may be in the form of salts
with physiologically acceptable acids or bases, together with
conventional carrier and/or dilution or auxiliary substances at
temperatures between 10 and 80°C, preparing from the mixture
obtained pellets and filling the pellets into capsules or bags so
that 10 - 100 mg of decarboxylase inhibitor and 50 to 1,000 mg of
L-dopa are contained in a dosage unit.

29

7. A process according to claim 6, in which the
pellets are coated.

8. A process as claimed in claim 6, in which 1 part by
weight of decarboxylase inhibitor and 0.5 to 100 parts by weight
of L-dopa, or salts thereof with physiologically acceptable acids
or bases, are processed as follows: a) the decarboxylase
inhibitor is processed with conventional auxiliary and carrier
substances to a solid formulation; and b) L-dopa is processed
with conventional auxiliary and carrier substances into pellets,
the formulations obtained by separately or together filled into
capsules or bags.

9. A process according to claim 8, in which the
pellets are provided with a lacquer film.

10. A process as claimed in claim 6, in which 1 parts
by weight of decarboxylase inhibitor and 0.5 to 100 parts by
weight of L-dopa or salts thereof with physiologically acceptable
acids or bases are processed by: a) mixing the decarboxylase
inhibitor with at least one of the auxiliary substances mannitol,
sorbitol, lactose, starch, and cellulose, mixing the mixture with
magnesium stearate and highly disperse silicon dioxide; b) mixing
L-dopa with at least one of the auxiliary substances cellulose,
cellulose derivatives, lactose, starch, mannitol, sorbitol,
polysorbate, saccharose, and glucose, forming the mixture into
pellets or applying L-dopa onto neutral pellets which are
subsequently provided with a lacquer film and subsequently
combining the formulations of steps a) and b), into a medicinal
packing so that the dosage unit contains 10 to 100 mg of
decarboxylase inhibitor and 50 to 1,000 mg of L-dopa.

11. A process according to claim 10, in which in step
(a) the mixture is granulated before mixing with magnesium
stearate and highly disperse dioxide.



12. A process according to claim 11, in which in step
(a) the mixture is also mixed with starch or cellulose or both.

13. A process according to claim 10, 11 or 12, in which
the mixture is tabletted.

14. A process according to claim 10, in which the L-
dopa in step (b) is also mixed with binding agents.

15. A process according to claim 14, in which the
binding agents are selected for polyvinylpyrrolidone,
vinylacetate-vinyl-pyrrolidone-copolymer, gelatine,and cellulose
derivatives in the form of solutions.

16. A process according to claim 14 or 15, in which the
pellets are provided with a lacquer film.

17. A process according to claim 10, in which the
formulations of steps (a) and (b) are firstly filled into
capsules or bags.

18. A process according to claim 10, 11 or 12, in which
the decarboxylase inhibitor is benserazide or carbidopa.

19. A process for preparation of L-dopa in the form of
pellets which contain 50 to 1,000 mg of L-dopa for combination
with simultaneous or separate administration of a decarboxylase
inhibitor for the treatment of Parkinson's disease, which
comprises a) mixing 50 to 1,000 mg of L-dopa at a temperature
between 10 and 80°C with conventional auxiliary and carrier
substances and pressing the mixture into pellets having a
diameter between 0.1 and 2 mm, or b) form of a mixture of 50 to
1,000 mg of L-dopa and conventional auxiliary and carrier
substances at a temperature between 10 and 60°C with a
conventional solvent into a paste and pressing the resultant
plastic mass through perforated discs, dividing, rounding off and



31

drying the resultant strands, or c) droping and causing to
solidify 50 to 1,000 mg of L-dopa and at a temperature between 10
and 80°C in a melt of fat-like substances or waxes, or d)
applying 50 to 1,000 mg L-dopa at a temperature between 10 and
60°C onto neutral pellets, or e) binding 50 to 1,000 mg L-dopa to
particles of an acid ion exchanger.

20. A process according to claim 19, in which in steps
(a) to (e) the L-dopa is in combination with 10 to 100 mg of
decarboxylase inhibitor.

21. A process according to claim 19 or 20, in which
the pellets obtained according to e) are coated with at least a
conventional coating substance.

22. A process according to claim 19, which comprises
mixing L-dopa with at least one of the auxiliary substances
cellulose, cellulose derivatives, lactose, starch, mannitol,
sorbitol, polysorbate, saccharose, glucose, sodium alginate,
sodium alginate/calcium salts and forming the mixture into
pellets, or applying L-dopa with at least one of the above named
auxiliary substances onto neutral pellets.

23. A process according to claim 22, in which the
pellets are coated with at least one conventional coating
substance.

24. A process according to claim 22, in which the L-
dopa is also mixed with a binding agent.

25. A process according to claim 24, in which the
binding agent is selected from polyvinylpyrrolidine,
inylacetate-vinylpyrrolidone copolymer, gelatine and cellulose
derivatives in the form of solutions.

26. A process according to claim 19, in which comprises

32

mixing 50 to 1000 mg of L-dopa and, with at least one hydrophilic
polymer or hydrocolloid molding the mixture into pellets or
applying mixture to the neutral pellets and providing the pellet
thus obtained with a coating that is resistant to gastric juices.

27. A process as claimed in claim 26, wherein at least
one of the following substances is used as hydrophilic polymers
or hydrocolloid: cellulose derivatives, acrylic acid
homopolymers, acrylic acid copolymers, pectins, hydrophilic gum
types or alginates, and their physiologically acceptable salts.

28. A process according to claim 26, in which the L-
dopa is in combination with 10 to 100 mg of decarboxylase
inhibitor.

29. A process according to claim 26, 27 or 28, in which
the L-dopa is also mixed with at least one of conventional
binders and/or solvents.

30. L-dopa pellets containing 50 to 1,000 mg of L-dopa
produced by the process of claim 10, 11 or 12.

31. L-dopa pellets containing 50 to 1000 mg of L-dopa
and 10 to 100 mg of decarboxylase inhibitor which produced the
process of claim 26 or 27.



33

Description

39L5~9~

The present invention is a Synergistic combination of
decarboxylase inhibitors and L-dopa pellets

Decarboxylase inhibitors are medically active
substances having the proper-ty to block peripheral decarboxylases
(that is decarboxylases present in the intes~ine and blood
circulation). Decarboxylase inhibitors which may be used are
benserazide [DL-serine-2-~2,3,4-trihydroxybenzyl)-hydrazide],
carbidopa ( (-)-L-dC-hydrazino-3,4-dihydroxy-d~-methyl-
hydrocinnamic acid), L-serine-2-(2,3,4-trihydroxybenzyl)-
hydrazide, glycine-2-(2,3,4-trihydroxybenzyl)-hydrazide, L-
tyrosine-2-(2,3,4-trihydroxybenzyl)hydrazide, in particular
benserazide.

L-dopa [ (S)-2-amino-3-(3,4-dihydroxyphenyl) propionic
acid] is a medically active substance with pronounced
antiparkinsonian activity.

The comblnation of the decarboxylase inhibitor
benserazide and L-dopa has been known since 1960. The L-dopa was
not present in pellet form in this case. This formulation has
the disadvantage that, when used in the treatment of Parkinson's
disease, this combination leads to severe fluctuations in plasma
level and thus to considerable response fluctuations, for example
to so-called on~off symptoms (particularly in later stages of the
illness), whereby the patient is suddenly overcome by immobility.

For a long time now there has therefore been a need for
an improved dosage form with prolonged action with which, for
example, the on-off symptoms are reduced lsee S.M. Stahl, New
Drug Delivery Systems - a new approach to Parkinson's disease,
Symposium HarlowJGB 8.7.1985).

The present invention provides an improved medicament
composed of decarboxylase inhibitors and L-dopa with prolonged
and improved effect or the treatment of Parkinson's disease.

~3~ 913

It has now surprisingly been found that with the use of
a combination of decarboxylase inhibitors and L-dopa pellets,
wherein the pellets can also demonstrate a delayed release (a so-
called retardation) of the active substance, a prolonged andimproved effect may be observed in the treatment of Parkinson's
disease, particularly in its advanced stages.

Thus, for example, the following improvement is
achieved as compared to the hitherto conventional treatment with
the combination of decarboxylase inhibitors and L-dopa:




. .

~3~
Patients need to take the sustained release combination less
frequently than the standard combinations for the same or
improved antiparkinsonian efficacy~ Thanks to the delayed
absorption, peak concentrations in the serum and the side
effects connected therewith (dyskinesias) ar~ avoided~ Using the
sustained release combination, effective L-dopa serum
concentrations are built up over a longer period of time than
with the stnndard combination. For this reason, and because of
the lo~er frequency of admini~tration of the sustained relea~e
combination, the therapeutic L-dopa dosage can be cumulatively
reduced. Since the L-dopa side effects syndrome depends on
cumulative dosage, the sustained release combination also makes
it possible to reduce this long-term side effect.



The improvement and prolongation of the effect of the
combination of the invention can be demonstrated as follows as
compared to the standard combination: following the
administration of the oombination to Parkinson patients in the
evening, patients' nocturnal movements are measured by
acaelerometry of the arms and legs. In the akinesia stage,
Parkinson patients commence their attempts at mo~ement with the
legs. A ahange over from movement of the leg~ to that of the
arms indicates an improvement in the clinical picture of the
patient.




- 3

~3~



Reduced morning akinesia after administration of the combinatlon
in the evening is a further parameter for the improved efficacy
of the combination of the invention as compared to the standard
combination.



US patent 3 557 292 also describes inter alia a combination of
L-dopa and benserazide in which, ho~ever, the L-dopa is also not
present in pellet form. The combination of the invention has the
following surprising advantages as compared to this known
combination: lower frequency of administration, reduction in the
rate of side effects, more even effect.



Furthermore, German published patent 3 232 873 discloses a
combination of L-dopa with the decarboxylase inhibitors
carbidopa and benserazide. Here, too, the L-dopa is not used in
pellet form. The disadvantage of this known combination as
compared to the combination of the invention is that the known
combination has only insufficient antiparkinsonian efficacy
whereby, in particular, the dyskinesias of the patients are
prolonged.



The invention relates to medicaments according to the patent
claims as well as to the use of decarboxylase inhibitors and

their salts with physiologically acceptable acids or bases
together with L-dopa p~llets, also in separate formulations in
each case.


~L3~56~

The amounts or parts by weight quoted herein relate in
each case to the pure active substances, that is, not to salts of
these active substances. Should salts be used, the amounts
change according to the altered gram-molecular weight of the
salts.

The benserazide is preferably used as a
pharmaceutically acceptable acid addition salt, salts with
halohydric acids (for example the hydrochloride, hydrobromlde) or
also with organic acids (for example embonic acid, maleic acid,
citric acid, tartaric acid) being particularly suitable.
Carbidopa and L-dopa are generally not used in the form of
pharmaceutically acceptable salt. Should L-dopa be used as a
pharmaceutically acceptable salt this is, for example, a salt
with physiologically acceptable alkali or alkaline earth metals.

The daily doses of the combination of the invention
consist, for example, of 10 to 800 mg, preferably 20 to 300 mg
and in particular 75 to 250 mg of decarboxylase inhibitor and 50
to 8,000 mg, preferably 100 to 3,000 mg, in particular 300 to
1,500 mg of L-dopa.

The daily doses may be given in the form of a single
administration of the total amount or in the form of 1 to 10, in
particular 2 to 8 partial doses per day. In general,
administration 3 to 6 times, in particular 4 to 5 times daily,

3~




-- 5 --




.

~3~



is preferred. The preferred dose of the combination of
decarboxyl`ase inhibitor and L-dopa is for example 25 to 50 mg of
decarboxylase inhibitor and about 100 to 500 mg of L-dopa 2 to 6
times daily. In particular this dose is about 25 mg of
decarboxylase inhibitor and about 100 mg of L-dopa 3 to 5 times
daily.



Decarboxylase inhibitors and L-dopa are, for example, used in
the following weight ratios in accordance ~ith the invention: 1
part by weight of decarboxylase inhibitor is for example used or
combined with 0.5 to 100 parts by weight of L-dopa, preferably 1
part by weight of dacarboxylase inhibitor with 1 to 50 parts by
weight of L-dopa, in particular 1 part by weight of
dacarboxylas~ inhibitor with 2 to 20 parts by weight of L-dopa.



For the combination, 50 to 1,000 mg of L-dopa and 10 to 100 mg
o decarboxylase inhibitor, preferably 100 to 500 mg of L-dopa
and 25 to 50 mg of decarboxylase inhibitor may, for example,
easily be formulated into the medication.



The dosage unit of the combination of the invention can for
~xample contain~




10 to 100 mg of deca~boxylase inhibitor, preferably 10 to 50 mg,
in particular 25 to 50 mg of decarboxyl~se inhibitor and 50 to
1,000 mg, preferably 50 to 500 mg, in particular 100 to 500 mg


~3~LS6~



of L-dopa. These doses can, for example, be administered 1 to 8,
preferably 2 to 6, in particular 3 to 5 times daily.



It is, of course, also possible to prepare pharmaceutical
formulations which contain the stated dosage units 2 to, for
example, 5 times.



The doses and parts by weight given in the preceding pages which
relate to application in humans are in each case related to the
free bases and fr~e acids respectively.



The term pellets should be understood to cover spherical or
cylindrical shapes having a diameter between 0.1 and 2 mm. Thay
are produced by pressing suitable powder mixtures with
tabletting presses, compactors or perforated rubber plates or by
pasting through addition of solutions or solvents, pressing the
resulting plastic mass through perforated discs, dividing,
rounding off and drying the resulting strands.



Another possible mnnner of preparation lies in the simultaneous
or successive application of the active substances with or

without binding agents onto neutral pellets having no active
substance (so-called nonpareils).




'

~3~s~a


A further possibility lies in binding the active substance
L-dopa to ion exchangers, for example through binding of L-dopa
to physiologically acceptable ion exchangers. The following may
for example be used as ion exchangers of this kind:
acrylic and methacrylic resins with exchangeable proton, i.e.
acid, in particular weakly acid, yroups such as COOe (for
example AmberliteR IRP-64);
polystyrene resins with exchangeable Na+, acid groups:
S03e (for example AmherliteR IRP-69).



The ion exchangers are acid ion axchangers. The maximum ratio of
L-dopa : ion exchanser is ca. 1:1, the minimum ratio about 1
part by weight of L-Dopa to ~00 parts of ion exchanger
resin. Preferably 1 to 400 parts by weight of ion exchanger,
quite particularly preferably 1 to 100 parts by weight of ion
exchanger are used per 1 part by weight of .L-Dopa.



The binding of the L-dopa is effacted by allowing an L-dopa
solution to flow through a bed of the ion exchanger in a column.
The charged ion exchanger is dried at temperatures up to about

~0 C. The chargsd ion exchanger particles are pr~ferably also
providQd with a coating such as described, for example, in
US-A-4,~21,776 An advantage of th~ additional coating is that
the releasQ rate of the~active sub~tance can be changed and
influenced by the choice of tha aoating material. Hot air at




-- 8 --

13~L5G9O



70 C to 90 C can be used to dry the charged ion exchanger
particles provided with the coating. The charged ion exchangers
can then be filled, for example, into hard gelatine capsules.



It is also possible to obtain pellets through the dropping of
melts of fatty substances, for example of cetylstearyl alcohol
or waxes. The spray hardening or vibration dropping methods used
herefor are known in the art.



The preparation of the pellets used according to the invention
is effected in the conventional manner.



Pellets with controlled release of the active substance are
preferably used, whereby khese may be pellets which either only
contain L-dopa or pellets which contain both L-dopa and
decarboxylase inhibitor. The pellets with controlled release are
preferably obtained by coating pellets prepared in the
conventional manner with the named active substances in known
manner with at least one coating substance. Coating substances
that can be used are: polymerisates as well as copolymerisates
of acrylic acid and/or methacrylic acid and/or their esters;
copolymerisates of acrylic and methacrylic acid esters with a


low content of ammonium groups te.g. EudragitR RS),
copolymerisates of acrylic and methacrylic acid esters and

trimethylammonium methacrylate le.g. EudragitR ~L);
polyvinylacetate; fats, oils, waxes, fatty alcohols;


_




-
"'' .

~3~5~


hydroxypropylmethylcellulose phthalate or -acetate succinate;
cellulose-, st~rch- and polyvinylacetate phthalata;
carboxymethyl cellulose; methyl cellulose-phthalate,-succinate,
-phthalate succinate as well as -phthalate acid semiester; zein;
ethyl cellulose and -succinate; shellac; gluten;
ethylcarboxyethyl cellulose; ethacrylate maleic acid anhydride
copolymer; maleic acid anhydride-vinylmethylether copolymer;
styrene-maleic acid copolymerisate; 2-ethylhexylacrylate maleic
a~id anhy~ride; crotonic acid-vinylacetate copolymer; glutamic
acid/glutaminic acid ester copolymer;
carboxymethylethylcellul~se ylycerine monooctanoate; cellulose
acetate succinate; polyarginine.



It is, for example, also favourable to use 2 separate coating
layers; one for the controlled release (such as the above named,
whereby these then contain no, or only few, free carboxy groups)
and one for the gastric juice resistance, that is a coating
layer which,prevents release in the stomach~ This is in
particular to be considered for the pure L-dopa pellets.
Saparate coating substances for gastric juice resistance are the
conventional ones, ~or example physiologically acceptable
polymers with free carboxy groups such as copolymerisates of
~crylic acid and/or methacrylic acid, hydroxypropyl methyl
cellulose phthalate, cellulose acetate phthalate, methyl
cellulose phthalate à~d other phthalates.




-- 10 ~




: . :,. ..

~3~5~


Plasticizing agents that can be used for these coating
substances are: citric and tartaric acid ester (acetyltriethyl-,
acetyltributyl-, tributyl-, triethylcitrate); glycerine and
glycerine esters (glycerine diacetate, -triacetate, acetylated
monoglycerides, castor oil); phthalic acid esters (dibutyl-,
diamyl-, diethyl-, dimethyl-, dipropyl-phthalate), D-(2-methoxy
or ethoxyethyl)-phthalate, ethylphthalyl, butylphthalylethyl-
and butylglycolate; alcohols (propylene glycol, polyethylene
glycol of various chain lengths), adipates (diethyladipate,
di(2.-methoxy- or ethoxyethyladipate)); benzophenonQ; diethyl-
and dibutylsebacate, -succinate, -tartrate; diethyleneglycol-
dipropionate; ethyleneglycol diacetate, -dibutyra~e,
-dipropionate tributylphospha'e, tributyrin; hydroxypropyl
cellulose, hydroxypropyl methyl cellulose, polyethyleneglycol-
sorbitane monooleate (polysorbates such as polysorbat 80);
sorbitane monooleate, polyvinylpyrrolidone



For the coating layer it is possible to use one or several of
the coating substances mentioned as well as one or several of
the plasticizing agQntS mentioned. The coating layer can contain
additional substances for controlling the release of the L-dopa.
Thesa are water-soluble substances such as polyethylene glycols,
polyvinylpyrrolidone, copolymerisates of polyvinylpyrrolidone
and polyvinylacetate,~olyvinylacetate and similar. For the same
purpose it is, however, also possible to use the already
mentioned plasticizing agents hydroxypropyl cellulose and/or




:

~ 5~9~ 1



hydroxypropyl methyl cellulose. In this case their amount is,
for example, 0.1 to 5 weight%, preferably 1 to 3 weight~ related
to the coating substance.




The application of the coating layer is effected through
spraying of solutions of the mentioned substances in organic
solvents or suspensions of the mentioned substances in organic
solvents or water, wheraby further auxiliary substances may be
added to optimize workability ~uch as, for example, surface
activa substances, solid substances such as talcum andJor
magnesium stearate and/or pigments.



The spraying is effected, for example, in a coating drum or in
perforated drums with controlled supply of the drying medium or
in an air suspension procedure: working generally being at
temperatures between 10 C and 80 C.




In the preparation of L-dopa pellets through dropping a mslt of
L-dopa into fat-like substances or waxes, the following
substances can, for example, be used: glycerides of saturated
fatty acids C8H162 to C1gH16O2~ hydrated peanut
oil, hydrated castor oil, hydrated cottonseed oil, stearic acid,
p&lmitic acid, esters of aliphatic saturated or unsaturated
fatty acids (2 to 22 carbon atoms, in particular 10 to 18 carbon
atoms~ with monovalent aliphatic alcohols (1 to 20 carbon
atoms), carnauba wax, beeswax, fatty alcohols (straight or




- . .:


. .

~3~5~


branched chains) of chain length CgH170H to C30H610H, in
particular c12H25oH to ~24H49H



In the case of preparation through application on neutral
pellets, binding agents that may, for example, be used are:
gelatine, gum arabic, starch paste, cellulose derivatives
(methyl cellulose, carboxymethyl cellulose, hydroxyethyl
cellulose, hydroxypropyl cellulose), sodium alginate, pectin,
tragacanth, polyvinylpyrrolidone, polyvinylacetate, polyvinyl
~lcohol, copolymerisate of vinylpyrrolidone and vinylacetate.



The pellets may~ however, also be prepared by embedding L-dopa
into the following substances or mixtures of the following
substances:



- digestible fats, for example
triglycerides of saturated fatty acids CgH1602 to
C1gH3602 and thair mixtures, peanut oil and hydrated

peanut oil, castor oil and hydrated castor oil, olive oil,
sesame oil, cottonseed oil and hydrated cottonseed oil, corn
oil, wheat germ oil, sunflower seed oil, cod liver oil,
mixtures of mono-, di-, triasters of palmitin and stearic
acid with glycerine, glycerine trioleate, diglycolstearate,

stearic acid.



- undigestible fats or fat-like substances, for example


- 13 -


:.
: . :

,~

6~ ~



esters of aliphatic saturated or unsaturated fatty acids (2
to 22 carbon atom~, in particular 10 to 18 carbon atoms)
with monovalent aliphatic alcohols (1 to 20 carbon atoms),
carnauba wax, beeswax, fatty alcohols (straight chain or
branched chain) of chain length C8H17OH to C30H61OH,
in particular C12H25OH to C24~49OH.
. .

- polymers such as
polyvinyl alcohol, poly~inyl chloride, polyacrylic acid;
anionic polymerisates of methacrylic acid and methacrylic

acid estQrs (EudragitR L, EudragitR S), acrylic and
methacrylic acid ester copolymerisates with trimethyl

ammonium methacrylate (EudragitR RL, EudragitR RS),
copolymerisate of acrylic acid ethyl- and methacrylic acid

methyl esters EudragitR NE 30 D), as well as from acrylic
acid, methacrylic acid as well as their estera (ratio of

free carboxy groups to the ester groups 1:1) (Eudragit~ L
30 DJ, polyethylene, polyglycol acid, polyhydroxybutyric
acid, polylactic acid, copolymers of lactic acid and
glycolic acid (manufacturer: Boehringer Ingelheim),
copolymers of lactic acid and ethylene oxide as well as
glycolic acid and ethylene oxide, hydroxypropylmethyl
cellulose-phthalate or -acetate succinate; cellulose acetate
phthalate, starch acetate phthalate, ns well as
polyvinylacetats phthalate; carboxymethyl cellulose;

methylcellulose-phthalate, -succinate, -phthalate succinate,


- 14 -

~s~

me-thylcellulose phthalic acid half ester; zein; ethyl cellulose;
shellac, gluten; ethylcarboxyethyl cellulose; ethacrylate-maleic
acid anhydrlde copolymer; maleic acid anhydride-vinylmethylether
copolymer; styrol-maleic acid-copolymerisate; 2-e-thylhexyl-
acrylate-maleic acid anhydride; crotonic acid-vinylacetate
copolymer; glutamic acid/glutaminic acid ester copolymer;
carboxymethylcellulose-glycerine monooctanoate; cellulose acetate
succinate; polyarginine.

Swelling agents such as methyl cellulose, hydroxypropyl
cellulose, hydroxypropyl methyl cellulose (Pharmacoat, Methocel E
= propyleneglycol ether of methyl cellulose), alginic acid and
its salts (Na-Ca-salt, also mixtures of alginic acid and calcium
salts, e.g. CaHPO4), starch, carboxymethyl starch, carboxymethyl
cellulose and their salts (e.g. Na-salt), galactomannan, gum
arabic, karaya gum, ghatti gum, agar agar, carrageen, xanthane
rubber, guar rubber and its derivatives, carob bean kernel flour,
propylene glycol alginate, pectin, tragacanth.

Particulary, for example, an embedment of L-dopa and,
when reqired, of the decarboxylase inhibitor in hydrophilic
polymers ~or hydrocolloids, when required, with further
processing aids, is also suitable.

These hydrophilic polymers or hydrocoloids are
substances that are soluble in water or swelling therein, such as
cellulose derivatives and varous types of gum. The hydrocolloid
preferably contains cellulose derivatives, namely cellulose alkyl
3~ hydroxylates, such as hydroxy-propyl methyl cellulose, hydroxy-
propyl cellulose, hydroxy-methyl cellulose or hydroxy-ethyl
cellulose; cellulose alkyl carboxylates such as carboxy-methyl
cellulose or carboxy-ethyl sellulose and alkali metal salts of
cellulose alkyl carboxylates, such as sodium-carboxy methyl and
sodium-carboxy ethyl cellulose or acrylic acid homopolymers or
copolymers or their alkali metal salts.

- 15 -

-` ~31S6~

The molecular weigh-t ancl the degree of other
substitution of the cellulose ether are not critical and any of
the commercial products can be used in the present invention.




The cellulose ther used usually has a viscosity of 3 to
100 OQ0, preferably 3 to 10 000 and particularly preferred 6 to 6
000 centipoises as determined in an aqueous 2 percent by weight
solution at 20C.

Furthermore, the cellulose ether used usually has a
degree of ether substitution of 0.1 to 6, preferably 0.4 to 4.6.

The acrylic acid copolymer can be a copolymer from
acrylic acid with allyl saccharose, methyl acrylate, methacrylic
acid, methyl methacrylate, hydroxy-ethyl methacrylate, styrene or
a monomer of vinyl ether, such as methyl-vinyl ether. The
proportion of comonomer can be varied within the range in which
the copolymer is soluble in water or capable of swelling therein.
The proportion usually is not higher than approximately 20 moles,
relative to the copolymer.

A commercial mixture of acrylic acid having homopolymer
or copolymer with a small amount (usually not more than 20 % by
weight) of anther water-soluble polymer ~for e~ample, a
methacrylic acid homo or heteropolymer or its salt or
polyethylene glycol) can also be used. Suitable
pharmacoligically acceptable salts of acrylic acid homopolymers
or copolymers are alkali metal salts, such as sodium or potassium
salts and ammonium salts. The degree of neutralization of the
salts is not limited.

The acrylic acid homopolymers or copolymers or their
pharmacologically acceptable salts can have any molecular weight.
They usually have a viscosity of 36O to 165 000, preferably 3600
to 165 000 centipoises. The viscosity is determined in a 2.2 %

- 15a -

- ~3~5~9~

by weight aqueous solution oE the sodium salt having a pH value
of 7 to 7.5 at 25C + 0.5C.

The acrylic acid homo or copolymers or their
pharmacologically acceptable salts can be used individually or as
mixture. In the preparations according to the present invention
other known hydrocolloids can also be used, as for example,
acacia gum, guar gum, gum tragacanth, gum xanthane, pectin,
ammonium or sodium alginate, mlxtures of sodium or ammonium
alginate wlth physiologically acceptable calcium salts (for
example, calcium gluconate, calcium hdyrogen phosphate, calcium
chloride) or their mixtures.

Preferred hydrocolloids are sodium carboxy-methyl
cellulose, hydroxy-propyl-methyl cellulose (such as Celacol HPM
or Methocel E or K), polyacrylic acid (such as Carbopol 934P) or
the above-mentioned alginates.

In particular ~t is, for example, also possible to
effect the embedding of L-dopa and optionally the decarboxylase
inhibitor in hydrophilic polymers and hydrocolloids respectively,
optionally together with other conventional auxiliary substances.




- 15b -
-




"

-~ ~3:~L5~



In the case of these sustained release components it is possible
for example to use 1 to 800 parts by ~eight of sustained release
components, preferably 1.5 to 600 parts by weight, quite
particularly preferred 2.0 to 400 parts by weight to 1 part by
weight of L-dopa. The preparation of these formulations is
effected at temperatures between 18 C and 80 C.



The preparation of this dosage form can be effected:
by dissolving or dispersing L-dopa or its salts in the mentioned
fats or fat-like substances or mixtures thereof, also by melting
the mentioned substances and subsequent recooling, breaking up
into small pieces, possibly adding other substances such as the
above mentioned water soluble substances or substances that
swell in water, and forming into pellets~ The cooling of the
melt and breaking up into small pieces can also be combined in
one step by disper~ing the melt in cold water or subjecting it
to a spray hardening or dropp;ng with v;bration.
~hrough mixing of L-dopa with the mentioned fats, polymers or
swelling agents or mixtures of these substances, also with the
use of heat, And forming of the mixtures, possibly after
addition of other auxiliary substancesj into pellets;
through mixing of L-dopa with solutions of the mentioned fats or
polymers in WAter or organic solvents suah as, for example,
ethanol, ethyl acetate, acetone or isopropanol, possibly mixing
with carrier materials such as celluloses, as well as su~sequent
evaporation of the solvents and mixing the embedded active



l lo -

., .

131569~



ingredient obtained with other auxiliary substances and working
into pellets;
by moistening a mixture of L-dopa and the mentioned swelling
agents with organic solvents such as ethanol, ethyl acetate,
acetone or isopropanol, possibly with addition of binding agents
such as polyvinylpyrrolidone or copolymers of
polyvinylpyrrolidone and polyvinylac0tate and subsequent
formation of pellets which ar~ subse~uently dried.


The pharmaceutical compositions or medications contain as active
substance the combination of the invention in a formulation. The
individual active sub~tances of the combination can, however,
also be present in each case in separate formulations, whereby
the already cited amounts of active substance are used in each
case for the corresponding dosage unit. The active substances or
the activa substance combination is optionally present in
mixture with other pharmacologically or pharmaceutically active
substances. The preparation of the medications is effected in
known manner, whereby the known and conventional pharmaceutical
auxiliary substances as well as other conventional carrier and
diluting agents can be used.

For example the pelle~ts can be worked into tablets which
disintegrate in the stomach or intestine and release the pellets
there.


- 17 -




. ~ .

~3~56~



Carriers and auxiliary substances which can be used for the
pharmaceutical formulations are, for example, those substances
which are recommended or quoted in the follo~ing literature
references as auxillary substances for pharmacy, cosmetics and
related fields: Ullmanns Encyklopaedie der technischen Chemie,
Volume 4 (1953), pages 1 to 33; Journal of Pharmaceutical
Sciences, Volume 52 (1963), pages 918 et seq.,
H.v.Czetsch-Lindenwald, Hilfsstoffe fuer Pharmazie und
angrenzende Gebiete, Pharm. Ind., Issue 2, 1961, pages 72 et
seq.; Dr. H.P. Fiedler, Lexikon der Hilfsstoffe fuer Pharmazie,
Kosmetik und angrenzende Gebiete Cantor KG. Aulendorf in
Wuerttemberg 1981~



Examples hereof are gelatine, natural sugars such as cane sugar
or milk sugar, lecithin, pectin, starch (for example corn
starch), cyclodextrine and cyclodextrine derivatives,
polyvinylpyrrolidone, polyvinylacetate, gelatine, gum arabic,
alginic acid, tylose, talcum, lycopodium, silicic acid (for
example colloidal), cellulose, cellulose derivatives (for
example cellulose ether in which the cellulose hydroxy groups
are partially etherified with lower saturated aliphatic alcohols
and/or lower saturated aliphatic oxyalcohols, for example
methyloxypropyl cellulose, methyl cellulose, hydroxypropyl
methyl cellulose hydroxypropylmethyl cellulose phthalate); fatty
acids as well as magnesium-, calcium- or aluminium ~nlts of
fatty acids with 12 to 22 carbon atoms, in particular the


_ 18 ~

.... - -

-` ~a3~L~6~ 1



saturated (for example stearates), emulsifiers, oils and fats,
in particular vegetable (for example peanut oil, castor oil,
olive oil, sesame oil, cottonseed oil, corn oil, wheat germ oil,
sunflower seed oil, cod liver oil, in each case also hydrated;
mono-, dl- and triglycerides of saturated fatty acids
C12H242 to C18H362 and their mixtures), pharma-
ceutically tolerated mono or multivalent alcohols and
polyglycols such as polyethylene glycols as well as derivatives
hereof, esters of aliphatic saturated or unsaturated fatty acids
(2 to 22 carhon atoms, in particular 10 to 18 carbon atoms) with
monovalent aliphatic alcohols (1 to ~0 carbon atoms) or
multivalent alcohols such as glycols, glycerine, diethylene
glycol, pentaerythritol, sorbitol, mannitol and so on, which may
optionally also be etherified, esters of citric acid with
primary alcohols and acetic acid, benzylbenzoate, dioxolanes,
glycerine formals, tetrahydrofurfuryl alcohol, polyglycol ether
with C1-C12 alcohols, dimethylacetamide, lactamide, lactate,
ethyl carbonate, silicons (in particular medium viscous
polydimethyl siloxanes), calcium carbonate, sodium carbonate,
calcium phosphate, sodium phosphate, magnesium carbonate and
similar.


.
Other auxiliary substances which can be considered are
substances which bring about disintegration tso called
disintegrants), such as: cross-linked polyvinylpyrrolidone,
sodium carboxymethyl starch, sodium carboxymethyl cellulose as


well as cross-linked or mlcrocrystalline cellulose.
- 14-


: .
, :

:

5Çi~




For the preparation of solutions or suspensions it is, for
example, possible to use water or organic solvents, for example
methanol, ethanol, propanol, isopropanol, dichloromethane,
trichloroethane, acetone~ 1,2-propylene glycol, polyglycols and
their derivatives, dimethylsulphoxide, fatty alcohols, .
triglyceride~, partial esters of glycerine, paraffins and
similar. I



In the preparation of the formulations it is possible to use
known and conventional solubilizars or emulsifiers. Solubilizers
and emulsifiers which may, for example, be used are:
polyvinylpyrrolidone, sorbitane fatty acid esters such as
sorbitane trioleate, phosphatides such as lecithin, acacia,
tragacanth, polyoxyethylated sorbitane monooleate and other
ethoxylated fatty acid esters of sorbitane, polyoxyethylated
fats, polyoxyethylated oleotriglycerides, linolisated
oleotriglycerides, polyethylene oxide condensatian products of
fatty alcohols, alkylphenols or fatty acids or also
1-methyl-3-(2-hydroxyethyl)-imidazolidone-(2). Polyoxyethylated
means here that the substances in question contain
polyoxyethylene chains, the degree of polymerization of which
genarally lies between~2 and 40 and in particular between 10 and
20.




- 20 -

`' ' ~ . '
.


'

31S~9~



Polyoxyethylated substances of this type may, for example, be
obtainad through reaction of hydroxyl group containing compounds
(for example mono- or diglycerides or unsaturated compounds such
as those containing oleic acid radicals) with ethylene oxide
(for example 40 Mol of ethylene oxidQ per Mol of glyceride).



Examples of oleotriglycerides are olive oil, peanut oil, castor
oil, sesame oil, cottonseed oil, corn oil.
See also Dr. H.P. Fiedler "Lexikon der Hilfsstoffe fuer
Pharmazie, Kosmetik und angrenzende Gebiete" 1971, pages 191 to
195.



Antioxidants that may, for example, be used are sodium
metabisulphite, ascorbic acid, gallic acid, gallic acid alkyl
ester, butylhydroxyanisol, nordihydroguaiacic acid, tocopherols
as well as tocopherols + synergists (substances which form heavy
metals through formation of complexes, for examplQ lecithin,
ascorbic acid, phosphoric acid). The use of synergists
considerably boosts the antioxygenic action of the tocopherols.



Tha pharmaceutical and galenic treatment of the active
substancas is effQcted using the conventional standard methods.
For~example active substance(s) are thoroughly mixed with.

auxiliary or carrier a~ubstances through stirring or homogenizing
(for example using conventional mixing apparatus), working
generally bQing at temperatures between 20 and 80 C,




' , '
: - '

5~




preferably 20 to 50 C, in particular at room temperature.
Reference is made here to the following standard work: Sucker,
Fuchs, Speiser, Pharmazeutische Technologie, Thieme-Verlag
Stuttgart, 1978.



Application may be in the interior of the body, for example oral
or enteral.



The ccmbination of the invention may also be present as a
product in which the two individual active substances are in
each case present in separate formulations so that
administration may be separate or at differently graded times.



Should such separate formulations be present, these are to be
adapted to each other and contain in each case the active
substances in the dosage unit in the amounts and corresponding
weight ratios in which they may be present in the combined
mixture.



In the case of separate administration, it is also possible for

the two combination partners not to be given at the same time.
In`such cases L-dopa may be given 5 to 300 minutes after
administration of the`~ecarboxylase inhibitor.




.

~3~ V



The acute toxicity of the combination of the invention,
expressed in the LD 50, is for example above 1,700 mg/kg i~ the
case of oral application (applies for various animals such as,
for example, mouse, rat).



Example 1: Capsules containing 100 mg of L-dopa in pellet form
and 28.5 mg of benserazide hydrochloride



2,000 g of L-dopa are mixed with 220 g of microcrystallina
cellulose and the mixture thoroughly moistened with a solution
of 60 g of Polysorbate 80 in 820 g of purified water. The moist
mass is fed through an extruder (perforation size 0.8 mm) and
the strands obtained divided and rounded off using a
spheronizer. The moist pellets obtained are dried in a fluidized
air bed dryer to a relative humidity (equilibrium humidity) of
25-35 ~. The dried pellets are sieved. Only the sieve fraction
of 0.5 to 1.25 mm is further processed~



1,600 g of the pellets are sprayed with a film suspension which
is prepared as follows:
28 g of tri~thylcitrate are emulsified with 0.3 g of Polysorbate
80 ln 110 g of purified water and the emulsion mixed with 460 g
o~ a 30 % suspension o~copolymerisates of acrylic and

methacrylic acld esters with a purified content of ammonium
groups (for example EudragitR RS 30 D). 68 g of talcum are
suspended in 515 g of purified water with the aid of a

- 23

: , . . .
- - . ' ~

,~ : ,
:.

,

1~1569U


conventional homogenizing apparatus and the suspension i5
stirred into the above obtained dispersion after addition of a
few drops of silicon antifoaming oil. The application of the
suspension thereby obtained (coating for the sustained release)
onto the pellets is effected in conventional manner, for example
using a fluidized air bed granulator at an air inlet temperature
of 40 - 50 C and a maximum outlet air temperature of 40 C.
The drying of the pellets is effected under the same conditions.
The above described suspension is sprayed on until the total
weight oE the dried pellets is 1,628 g.



1,500 g of pellets of the sieve fraction below 1.25 mm are then j~
sprayed with the following lacquer suspension (coating ~or
gastric juice resistance):



32 g of triethyl citrate are emulsified with 0.3 g of
polysorbate 80 in 130 g of purified water and the emulsion mixed
with 1,068 g of a suspension of a copolymerisate with anionic
character on the basis of poly(meth)acrylic acid and
poly(meth)acrylic acid esters (for example EudragitR L 30 D).
160 g of talcum are suspended in 620 g of purified water using a
conventional homogenizing apparatus and the suspension ~tirred
into the above obtained dispersion after addition of a few drops
of ~ilicon antifoaming ~il. Coating of the suspension thus
obtained onto the pellets is effected as described above.
Suspension is sprayed on until the total weight of the dried


pellets is 1,978 g.
- 24 -

`` ~3~5~




570 g of benserazide hydrochloride are mixed wikh 420 g of
lactosa and granulated with a solution of 20 g of gelatine in
180 g of purified water in the conventional manner. Eollowing
drying and sieving of the granulate through a sieve of mesh size
0.8 mm, 6 g of magnesium stearate and 4 g of highly disperse
silicon dioxide are added with mixing.



51 mg of the mixture together with in each case 153 mg of the
~bove described lacquered pellets are filled into size 2 hard
gelatinQ capsules. I
i'
One hard gelatine capsu~le contains 100 mg of L-dopa in the form
of pellets and 28.5 mg of benserazide hydrochloride.



The release of L-dopa from this dosage form is tested according
to the process set out in US Pharmacopoeia, 21st Edition (USP
XXI) using the dissolution test appliance, apparatus 2. The
releass of the L-dopa in 900 ml of buffer solution is determined

at 37C at a paddle revolution speed of 120 rpm. For the first
2 hours the test solution consists of 0.06 molar salt solution, I
after which the pellets are transferred to a phosphate buffer
solution pH 6 . 8 of the European Pharmacopoeia~ The release of
the L-dopa from the bùf~er solutions is measured in each case.




The release of the L-dopa is

- 25

. .

~' ' , ~`

-~ ~3~
.. '



after 1 hour 0.1 - 0.2 % in 0.06 m HCl
2 hours 0.3 - 0.9 %
3 hours 32 - 37 ~
4 hours 55 - 60 ~ in phosphate huffer
5 hours 72 - 75 % pH 6.8
6 hours 81 - 84 %
In a similar manner it is possible to prepare capsules which,
apart from the benserazide hydrochloride granulate mixture



a) contain unlacquered L-dopa pellets



b) contain L-dopa pellets which were only lacquered with
one of the suspensions mentioned
.

` c) contain mixtures of unlacquered and lacquered pellets.



To obtain these pellets the lacquering process should be changed
accordingly. I


', ' : I .


,: I
- 26 -
.

,..,...,


.

~3:~L5~

Example 2

Capsules containing 100 mg of L-dopa in the form of
microtablets and 28.5 mg of benserazide hydrochloride.

In a mixer 9 kg of L-dopa are homogeneously mixed with
2.7 kg of methyl-hdyroxy-propyl cellulose (viscosity of 2%
solution: 15 OOOcP), 9 kg of sodium alginate, 9 ky of calcium
hydrogen phosphate and 0.06 kg of magnesium stearate. The
mixture is compressed so as to form biconvex -tablets having a
diameter of 2 mm and a thickness of 2 mm. The tablets are coated
in the usual manner with a film that is resistant to gastric
juices. For example, the following procedure can be used: - 24 g
of titanium dioxide and 240 g of talc are homogeneously suspended
in a solution 45 g of sodium carboxy-methyl cellulose in 1000 g
of purified water.

Subsequently 54 g of 1,2-propylene glycol and 597 g of
water are added. This suspension is added to 1500 g of an
aqueous dispersion of an anionic copolymer (50:50) based on
methacrylic acid and acrylic methyl ester (EudragitR L 30 D)
while stirring.

Approximately 500 g of the varnish suspension thus
produced are required for 1 kg of tabletsO The coating process
is carried out, for example, by using a fluidized bed apparatus
at an air inlet temperature of 40 to 50C and an air outlet
temperature of maximally 40C.

570 g of benserazide hydrochloride are mixed with 420 g
of lactose, 6 g of magnesium stearate and 4 g of highly dispersed
silicon dioxide.

This mixture ~s drawn off in batches of 50 mg together
with 369 mg of the previously obtained varnished tablets into

- 27 -




'


.
;, '

31 ;3~5~
hard gelatin capsules having the size 0.

A hard gelatin capsule contains 100 mg of L-dopa in the
form of pellet-like micro-tablets and 2~.5 mg of benserazide
hydrochloride~ The liberation of L-dopa is tested as in Example
1 by means of the process of USP XXI, but at a speed of rotation
of the paddle of 50 r.p.m.

The liberation of L-dopa is
after 1 hour 0.5 - 1.5 % ~ in 0.06 m HCI
2 hours 2 - 4 %
3 hours 23 - 27 %
4 hours 50 - 55 %
5 hours 71 - 76 % ~ in phosphate buffer
6 hours 82 - 88 % ~ pH 6.8
7 hours more than 90 %J




- 28 -