Note: Descriptions are shown in the official language in which they were submitted.
~OS7196
PHARMA OE UTICAL COMPOSITIONS
-` ~ The present invention relates to a pharmaceutical
composition comprising aggregates of diameter of at most 20,000 A,
comprising:- component a) comprising at least one pharmaceutically
acceptable active agent, and
component b) comprising at least one pharmaceutically ac~eptable
emulsifier,
component b) having a mean HLs value of 10 to 30 and present in
an amount greater than 10 times by weight of component a).
More particularly, the present inventioniresides in a
pharmaceutical comprising aggregates of diameter of at most
20,000 A, comp~ising
component a) an ergot alkaloid, and
component b) a pharmaceutically acceptable ~thoxylated
cholesterin emulsifier having an HLB value of from 10 to 30
and present in an amount greater than 10 times by weight of the
ergot alkaloid.
Component a) is preferably an active agent which is
difficultly absorbable into the bloodstream on enteral, e.g.
oral, administration. Such difficultly absorbable active
agents are those which are absorbed by the body at a cumulative
percentage absorption up to 45% at most, e.g. in amounts below
35~i or even below 25% as indicated by standard tests. For
example, in one test material is administered p.o. in a ca. 0.008%
w/v aqueous solution to the bile fistula rat. The cumulative
percentage elimination of material in the bile and in the urine is
measured in conventional manner.
~057196
The dose of material admininistered is chosen such that the
cumul~tive percentage absorption substantially levels out after
48 hours. In the same test the initial rate of elimination of
-aterial in e.g. the bile is also determined in conventional
manner.
me present composition exhibits enhanced resorption
properties as indicated in standard tests, e.g. by a greater
cumulative percentage absorption and initial rate of absorption
in the above-indicated test than would be expected for such
1~ compositions.
m e present compositions are therefore indicated for
use with active agents for the treatment of migraine or
hypertension or possibly analgesic or antibiotics, when it is
desired to obtain high blood level values in the bloodstream as
rapidly as possible.
Examples of component a) include nitrogen-containing
compounds, i.e. high molecular, especially heterocyclic compounds,
e.g. lysergic acid derivatives, alkaloids such as ergot alkaloids
or synthetic or semisynthetic alkaloid derivatives, e.g. ergolene.
Preferred examples are e.g. ergotamine or synthetic of semi-
synthetic lysergic acid derivatives, e.g. hydrogenated derivatives
of ergot alkaloids, e.g.
~-2--
.~
~. :
1057196 100-4195
dihyd.roergotoxine, dihydroergocristine and the
13-bromoderiva~ive therPof, dihydroergonine, di-
hydroergocryptine, dihydroergotamine and the 13-bromo
derivative thereo., dihydroergocornine and dihydro-
ergovaline.
Other examples include low molecular weightcompounds such as dopamine derivatives such as dopamine
double molecule derivatives.
An example of a dopamine derivative is N,N'-
, 10 (2-methyl-4,5-dihydroxyphenethyl)hexan~Rthylenediamine,
or N,N'-Bi 5 [ 6-[(3,4-hydroxyphenyl~ethylamino]hexyl]
hexamethylene diamine.
The active agent content may naturally vary
considerably and may be adjusted to the desired close
depending on the type of active agents used and the
condition to be treated, the. amount to be admlnistered
per unit dose ~nd the type of composition.
However, in order to obta.in a specific thera-
peutic result, the amount of actlve agent aclminlstered
per dose in the compositlon of the invention may be
smaller than the amount of the same active agent in
one of the hitherto used formulations requlred for the
obtention of an equal result. In the case of 5ingle
dosage form, component a), may amoun~ up to 5% e.g.
up to 2.5% by weight in the case of solid preparalions
and in the case of li~uid preparations
- 4 - 100-4195
~057196
up to 1 ~ by weight of the composition. For example,
component a~ in drop solutions preferably amounts
to between 0.05 % and 0.6 % and in tablets and
capsules preferably between 0.2 ~ and 4.0 ~, especially
0.2 and 2.5 ~, e.g. from 0.4 to 2.5 ~.
H.L.B. value (hydrophilic/lipophilic balance)
of component b) is a measure for the relative portion
of hydrophilic groups in an emulsifier molecule
[see Pharm.~ct.Helv. 44, 9 (1969) and H.P. Fiedler,
Lexikon der Hilfsstoffe f~r Pharmazie, Kosmetik und
angrenzencle Gebiete, page 263, Edicio Cantor KG. 1971J.
It is preferred to use one or more physio-
logically tolerable emulsifiers having a rnean H.L.B.
value of 10 to 20, especially 12 to 16. For the
production of solid compositions it is preferred to use
emulsifiers or emulsifier mixtures which are solid at
room temperature. Examples of sui.table physioloc3ically
tolerable emulsifiers of the group of the non-ionoyenic
tensides are the tensides of the type of the polyol
fatty acid esters or the polyol ethers with higher
aliphatic or cyclic alcohols or polyalcohols having
emulsifyincJ properties such as polymerization products
from ethylene oxide and propylene oxide or propylene
~lycol. ~xamples of suitable polyol fatty acid esters
are irter _lla polyethyler.e glycol sorbitan fatty
- - 5 - iOO-4195
~057196
acid esters, e.g. polyoxyethylene-4--sorbitan mono-
stearate, such as Tween ~ 61 (Atlas Chemical
Industries), polyethylene glycol fatty acid esters,
e.g. polyoxyethylene-10-stearate such as Myr~ ~ 52
~Atlas Chemical Industries), polyethylene glycol-400-
stearate DAB7, polyoxyethylene glyco3 glycerin fatty
acid esters, e.g. polyoxyethylene castor oil, such
as Cremophor ~ EL (Bad. Anilin u. Sodafabrik). Examples
of suitable polyol ethers of higher alcohols are ~nter
alia polyol ethers of higher fatty alcohols, e.g.
polyoxyethylene-20-cetylic ether, such as Brij ~ 56
~Atlas Chemical Industries), ethoxylated wool fat
alcohols (e.g. with 16 mols of ethylene oxide, such as
Solulan ~ 16 (American Cholesterol Comp.) or polyo]s
etherified with cholesterin, e.g. cholesterin
ethoxylated with approximately 24 mols of ethylene
oxide, such as Solulan ~ C 29 ( American Cholesterol Comp~).
Suit~ble oxy-ethylenoxy-prc)pylene polvmerixation products
are, for example, polymerization products having a
mean molecular weight of approximately 1000 to 10000,
e.g. an oxy ethylenoxy-propylene polymer containing
40 ~ of polyoxyethylene and having a mean molecular
weight of approximately 2900, such as Pluronic ~ L 64
(Wyandotte Chemicals), an oxy-ethylenoxy-propylene
polymer having a m2an molecu]ar weigh-t of approximately
3500, such as ~ ronic ~ P 65 (Wyandotte Chemicals)
- 6 100-~195
1057196
or an oxy-ethylenoxy-propylene polymer containing
80 % of polyoxyethylene and having a mean molecular
weight of approximately 8700, such as Pluronic ~ F 68
(Wyandotte Chemicals). The alkyl groups in the dialkyl-
sulpho-succinates may contain from 4 to 10 carbon atoms.
A suitable salt isan alkali metal salt, e.g. sodium.
A preferred example of a dialkyl-sulphosuccinate is
sodium dioctyl sulphosuccinate, such as ~erosol ~ OT
(American Cyanamid Co.).
It may be convenient to use different types
o~ emulsifiers depending on the chemical and physical
properties, molecule size and form of the component a)
used and component c), mentioned hereafter.
When ergot alkaloids or synthetic or semi-
synthetic lysergic acid derivatives are used, then it is
particularly convenient to use polyoJs etheri~iccl with
cholesterin, e.g. chol~8terin ethoxyla~ed with about
24 mols o~ etllylelle oxide
It is also convenient to u~e oxy-ethyleno~:y-
propylene polymers, e.g. Pluronic ~ IJ 64 or
Pluronic ~ P 65 or emulsifier mixtures containing
oxy-ethylenoxy-propylene polymers.
Also sui~able are polyethylene glycol
fatty acid esters, e.g. polyG~:yethylene-40-steara'e
or polyethylene glycol-400-stearate DAB7.
- 7 - 100-4195
1057196
The amounts of emulsifier to be used may
vary depending on the emulsifier used, especially i~s
chemical and physical properties, the type and amount
of adjuvants used, the type of active agents used and the
desired extent of imprGvement in resorption. The upper
limit of the amount of emulsifier to be used will natu-
rally depend on the physiological tolerability of said
emulsifier, taking into consideration the planned dura-
tion of treatment and frequency of administration. The
-components in the composition are preferably present
in such amounts that the total amount of component b)
does not exceed 50 mg/unit dose. The ratio of total
amount of component b) to component a) may, for example,
be fxom 10:1 to 50:1, preferably 20:1 to 30:1. In
anhydrous administration forms, the total quantity of
emulsifier may amount to 60~, e.g. in unit-dose
preparations preferably between 20% and 50%. In water-
containing compositions, the concentration of component
b) conveniently is between the critical micelle
concentration (CMC) and maximal addition concentration
(MAC) of the emulsifiers used. The total amount of
component b) in water-containing administration forms
preferably is between 1~ and 5~.
The aygregates may convenientl~ contain as
25 component c) a furthex pharmaceutical carrier, prefera-
. ~0571~6 - 8 - 100-4195
bly a lipoid carrier. Component c) is preferably present
in an amount 25 times or especially up to 10 times the
amount of component a) present.
Lipoid carrier materials which may be used are,
for example, monovalent or polyvalent lower alcohols
partially or completely esterified with higher aliphatic
carboxylic acids, preferably alcohols of 2-3 carbon atoms,
especially glycerin or propylen~ glycol, or condensates
thereof, e.g. polyglycerins. For the production of solid
compositions it is convenient to use lipoid carrier
materials which are solid at room temperature, and for
the production of liquid medicinal preparations liquid
lipoid carrier materials or mixtures of solid and/or
liquid lipoid carrier materials which are liquid at
room temperature. Especially suitable solid lipoid carrier
materials are only partially esterified alcohols,
especially saturated monoglycerides and diglycerides.
The aliphatic carboxylic acids contained ln the solid
esters may preferably contain 12 to 20 carbon atoms and
may be straight chain or branched and/or hydroxylated.
Especially suite.d for the production of liquid medicinal
preparations are completely esterified alcohols, especial-
ly triglycerides, e.g. esters of unsaturated carboxylic
acids or saturated carboxylic acids, preferably contain-
ing 8 to about 12 carbon atoms. Examples of suitable
lOS7196 - 9 - 100-4195
esters are inte~ alia monoglycerides, diglycerides or
triglycerides of saturated orunsaturated fatty acids,
e.g. glycerin monolaurate, monomyristate, monooleate
or monoricinoleate, peanut oil, oily triglyceride
mixtures of saturated vegetable fatty acids containing
8 to 12 carbon atoms or propylene glycGl esters, e.g.
propylene glycol monostearate.
The non-aggregate portion of the composition
may contain further pharmaceutical carriers or diluents
[component d)] which do not hinder the formation of the
active agent- and emulsifier-containing aggregates or
impair the stability of the resulting aggregates.
For example, it is convenient to add water-
soluble solid or liquid physiologically tolerable mono-
valent or polyvalent alcohols. Examples of suitablealcohols are: ethanol, propylene glycol, ylycerin, su~ar
alcohols and polyethylene glycols having a mean molecular
weight of, for example, 300 to 10000. An addition of
polyalcohols, e.g. polyeth~lene glycol, which will pro-
mote the solubilization of the active agents which aredifficultly soluble in water, is particularly desirable
when the emulsifi.er mixture used contains no oxyethylen-
oxy-propylene polymers or only small amounts thereof.
For the product.ion of liquid administration forms it
is preferred to add liquid alcohols, e.g. lower mono-
- 10 100 4195
lQ57i96
valent or polyvalent alcohols and/or polyethylene glycols
with mean molecular weights ~elow 2000, preferably bet-
ween 300 and 1500. For solid medicinal preparations it
is convenient to use alcohols which are solid at room
temperature, e.g. sugar alcohol.s and/or polyethylene
glycols having mean molecular weights over 1800, preferabl~-
~etween 2000 and 10000, especially 5000-7000.
The porti.on of the composition comprising
polyalcohols and emulsi.fiers may be cornposed of one
~ or several non emulsifying polyalcohols, preferably
polyethylene ylycols, and one or several non-ionic
tensides of the polyol fatty acid ester type,
preferably polyoxyethylene-sorbitan fatty acid esters,
and/or of the ethoxylated higher alcohol type,
preferably ethoxyl.ated cholesterin, and/or d.ialkyl-
sulphosuccinates, or may consist of polyalcohols having
emulsifying properti.es, such as polyoxyethylene--
polyoxypropylene polymers, optional].y ln adm.txture
with one or several of thc-~ terlsides mentloned above
and/or non-emulsiyiny polyalcohols. Especially suitable
is a combination of ethoxylated cholesterin and poly~
ethylene ylycols and/or pol.yoxyetllylene-polyoxypropvlene
polymers.
- 11 - 100~41~5
10~7~96
Water-containing compositions of the
invention may contain between 20 % and ~5 e.g.up to 90 %,
preferably between 30 ~ and 70 %, e.g. ~etween 30 and
50 % by ~teight of water and optionally further ad-
juvants. The alcohol or polyol content of the aqueous
liquid may, for example, be between 0 % and 50 ~,
preferably between 20 ~ and 40 ~ by weight of the
formulation.
Anhydrous liquid preparations may con-..ain
the active agent-and emulsifier-containing aggregates
finely distributed in a water-soluble and/or water
dispersible liquid carrier material consisting of one
or several liquid carriers and optionally further
adjuvants. Suitable liquid car-cier materials are
especially physiologically tolerable lower monovalent
or polyvalent alcohols and/or liquid polye'chylene
glycols, e.g. polyethylene glycols having mean mol~cular
weights below 2000.
Liquid compositions may contain
~ as further components additional pharmaceutical
- 12 - 100-4195
1057196
adjuvants, e~g~ preserviny and flavouring agents and
bu~fer materials. The liquid preparations may contain
further physiologically tolerable water-soluble and/or
~ater-dispersible solid ma~erials, especially when they
are to be wor~ed up into solid dosaye forms.
The solid medicinal preparations of the in-
vention contain the active agent and emulsifier-containing
aggregates finely distributed in a carrier material which
is ormed from one or several water-soluble and/or water-
dispersible solid materials and optionally further pharma-
ceutical adjuvants.
5uitable physioloyically tolerable, water-
soluble solid materials are, for example, polyethylene
glycols which are solid at room temperature, preferably
polyethylene glyco]s having a mean molecular weight
between about 2000 and 10000, preferably between 6000 and
10000, polyvinyl pyrrolidones, excess solid oxy-
ethylenoxy-propylene polymers, sugar~,e.cJ~ lacl:ose,
sugar alcohols, e.g. ~annitol or sorbitol, and carboxy-
methyl cellulose.
The solid materials dispersible in waterare preferably used in the form of finely dispersed
powders which owing to their larye surface are capable
of absorbing the finely distributed active agent- and
emulsifier-containing aggregates~
- 13 - 100-4195
lOS7196
Suitable solid materials are, for example, pnysiologically
tolerable, in water dispersible, non-swelling inorganic
and/or organic carrier materials, insofar as they do
not irreversibly bind the active agents used. Suita~le
inorganic carrier materials are, for example, dicalcium
phosphates or highly dispersed silicic acids having
a tapped volume preferably between 250 and 1000 cc,~00 g,
especially wet precipitated silicic acid.
Depending on the desired formulation! the
solid medicinal preparations may contain as further
components additional physiologically tolerahle pharma-
ceutical adju~ants, e.g. preserving and flavouring agents
and any desired tabletting adjuvants generally used in
the producti.on of tablets o.r any desired suppository
r.lasses used in the production of supposi.tories.
The active agent-conLaining agyregates
present --~ may have a
diameter up to 20 000 A, preerably betw~ell 100 alld
10 000 ~, espec.icllly below 2000 A. or above 400 A~
In a~ueous medicinal preparations the
distribution of the emulsifier~ and active ayent-containirlg
aggregates in the aqueous liquid preferably is so fine
that transparent or slightly opalescent liquids are ob-
tained. The diameter of the active agent- and emulsi~
2~ fier~containing aggregates preferably is less than 2000,
- 14 - 100-41~5
1057196
especially less than 1000 A.
The anhydrous solid or liquid
compositions Of the invention are dried preparations or
liquid preparations which contain the active agent-
containing aggregates preferably so finely distributedthat when brought into an aqueous medium they rapidly
give a transparent or slightly opalescent liquid, wherein
the difficultly absorbable acti.ve agent or agents are
solubilized in the form of finely distributed active
agent- and emulsifier-containing aggregates.
The new compositions of the
invention may be liquid or solid and are preferably ad-
ministered orally. The liquid compositions of the inven-
tion may, for example, be a~ninistered as a drop soluticn
or s~rup. Anhydrous liquid compositions may also be
filled lnto soft gelatin capsules or the production of
unit-dose administrati.on forrns. T}le pre~erre~ water-
containing compositions are drop solutions. Suit~ble
solid administration forms are, for example, powders,
granulates, capsules, tablets or film tablets fc;r oral
adrnini~tration, or suppositories for rectal adrninistra-
tion.
15 100 41~i
1057196
A preferred form of the compositions of the
invention are liquid or preferably solid galenic pre
parations of ergot alkaloids or synthetic or semi-
synthetic lysergic acid derivatives, wherein the total
amount of polyalcohols and emulsifiers in the case of
water-containing preparations preferably is between
15 % and 80 e.g.up to 70~ of the total formulation
and in the case of anhydrous preparations between 40
and 99 ~ of the total formulation.
The compositions may be obtained by a
process including the step of formulating aggregates
havin~ at most a diameter of 20~000 A of components
a) and b) as defined above.
The production of the liquid compositions
may be effected in accordance with the invention by
dispersing components a) and b) if desired with the
addition of further pharmaceutlccll ad.jllvants, in the
liquid carrier m~terlal, e.~. in an anhyd~ous rnedium
or in water or in a water--containing medium, preferably
using u].trasonic waves and/or high speed stirrers.
- 16 - 100-4195
1057~96
In accordance with an embodiment of the
process the active agents may first be dissolved with
slight heating in the tensides, optionally with the
addition of lipoid carrier materials and homogenized
while treating with ultrasonic wave or high-speed stirrers.
The production of the solid compositions
may also be effected in accordance with the invention by
caxefully removing the liquid carrier materials, e.g.
water and/or lower alcohols, from primarily produced
lLquid preparations and converting the resulting powdery
or spongy porous dry preparation in known manner into the
desired administration form.
The careful drying of the liquid preparations
may be effected in known manner, e.g. by freeze-drying
or spray-drying. For example, the liquid preparations
may be frozen at temperatures between -80 and -50C and
then lyophilized in a high vacuum, or the liquid pre-
parations may be atomized in a drying chamber and
dried by a warm air stream, e.g. at temperatures from
120 to 180C.
~f desired, the resulting dry preparations
may subsequently be worked up in known manner, optionally
with the addition of further suitable pharmaceutical ad-
juvants such as tabletting adjuvants and suppository
mass, e.g. filled into capsules, granulated, tabletted
- 17 - 100-4195
~0S~'196
or moulded into suppositories.
In the following non-limitative Examples
all temperatures are indicated in degrees Centigrade.
"Polytron" is a trade mark.
1 O 57~ 9 6 ~ 18 - 100-4195
EXAMPLES l - 30 Water-containing dro~ solutions of
_______________ ____ _____________
difficultly absorbable active a~ents
The formulations of Examples 1 - 28 having
the composition indicated in the following Table 1, are
produced as ollows:
The difficultly absorbable active agents
are dissolved with slight heating (at temperatures bet-
ween 30 and 50) in the emulsifiers and any lipoid
carrier materials which may be present, optionally with
the addition of part of the polyalcohols.
The water or an aqueous solution of any
further adjuvants or a mixture of water and any poly-
alcohols used is added to the above solution while
stirring vigorously with a "Polytron" homogenizer, and
the resulting mixture is homogenized for 5 to 6 minutes
by treatment with ultrasonic wave and/or a "Polytron"
homogenizer
The resulting homogenous liquids are
filled into bottles fitted with droppers.
~057196 _ lg _ 100-4195
a) Solulan C 2 ~ of Ame~ican Cholesterol Comp.
b) Pluronic L 6 ~ " Wyandotte Chemicals
c) " P 65~ " " "
d) " F 6 ~ " " "
e) Tween 6 ~ " Atlas Chemical Industries
f) Myrj 52~ " " " "
g) Brij 56~ " " " "
h) Cremophor EL~ . " Badische Anilin- und Sodafabrik
i) Cremophor AP~ " " " . " . "
j) Miglyol 81 ~ " Henkel
k) Tegomuls 7 ~ " Goldschmidt AG
1) Tween 65~ " Atlas Chemical Indus~ries
m) Aerosol OT~ " American Cyanamid Co.
105~196 100-4195
Table 1
Water-containing drop eolutions
_, , . _ _ _
Example No. 1 2 3 4 5 6 7 8
. . ._ _ . _ _
mg of active agents:
Dihydroergocristine j 360 400 400 800 800 800 800
Dihydroergovaline 400
Dihydroergotoxine
Dihydroergocornine
Dihydroergocryptine
Ergotamine
13-bromo-dihydroergotamine
13-bromo-dihydroergocryptine
N,N-(2-methyl-4,5-dihydro-
xyphenethyl)-hexamethylenediamine
. . _. _ _ _
g of emulsifiers:
Cholesterin ethoxylated with ) 2.5 2.0 2.0 3.0
approx. 24 mols of ethylene oxide
Oxy-ethylenoxy propylene polymer, 6.0 .0 1.5 13 12
mean molecular weight 2900bJ
Oxy-ethylenoxy-propylene polymer,
mean molecular weight 3500C~
Oxy-ethylenoxy-propylene polymer~ 2.0 8
mean molecular weight 8700d)
Polyoxyethylene-4-sorbitan 2.5 5
monostearate e) f ~
Polyoxyethylene-40-stearate ) ) 2.5 5
Polyoxyethylene-10-cetylic h~her
Polyoxyethylene castor oil
Polyeit)hylene glycol-400-stearate
DAB7 1~
Polyethylelle-20-sorbitan triste~rate _
Sodium dioctyl sulphosuccinatem)
_ _ __ .
g of lipoid carrier ma~erials:
.
Liquid triglyceride o~ saturated 0.9 1.8 1.8 3.5 3.5
fatty acids of 8-12 carbon atomsJ)
Glycerin monolaurate k) 2.0
Glycerin monostearate palmitate 8
Glycerin monoricinoleate
Glycerin monooleate
Propylene glycol nonostearate
Glycerin monomyristate
Glycerin monoisostearate _
- 21 - 100-4195
1057~96
Table 1
Water-containing drop solutions
Example No. 1 2 3 4 5 6 7 8
g of polyalcohols: .
Polyethylene glycol 300 20 20 40 40
Polyethylene glycol 400 .
Polyethylene glycol 600 -16
Polyethylene glycol 1500 10 18 40
Polyethylene glycol 2000
Glycerin
_ l ___
g of further adjuvants:
Water 20 2015 27* 295 38.7 50.7 82.:
* Buffered to pH value 4.3 with a buffer mixture of sodium acetate/
acetic acid.
~057~96 - 22 - 100-4195
Table 1
_
Water-containing drop solutions
Example No. 9 1 10 11 12 13 14 15 16 ;
_ _ _
mg of active agents:
Dihydroergocristine 80
Dihydroergovaline 800 800 800
Dihydroergotoxine 400 400
Dihydroergocornine 800
Dihydroergocryptine 600
Ergotamine
13-bromo-dihydroergotamine
13-bromo-dihydroergocryptine
N.N-(2-methyl-4,5-dihydroxyphen-
- ethyl)-hexamethylenediamine
, ___ _
g of emulsifiers:
Cholesterin ethoxylated with 3 3
approx. 24 mols of ethylene
oxide~)
Oxy-ethylenoxy-propyiene 10 10 10 12 6 10
polymer, mean molecular
weight 2900b)
Oxy-ethylenoxy-propylene
polymer, mean molecular
weight 3500C)
Oxy-ethylenoxy-propylene po~ymer 5
mean molecular weight 8700 J
Polyoxyethylene-4-sorbitan
monostearate e)
Polyoxyethylene-40-stearate
Polyoxyethylene-10-cetylic
ether g)
Polyoxyethylene castor oilh) 10 5
Polyethylene gl~col-400-
8 tearate DAB7 5
8 teYaraYte ~ ) 10
Sodium dioctyl sulphosuccinatem) . . .
_ __ . _
g of lipoid carrier materials:
Liquid triglyceride of satura- 1.0 1.5
ted fatty acids of 8-12 carbon
atoms j)
Glycerin monolaurate 5
Glycerin monostearate
palmitatek)
_ _ _ __ __
- 23 - 100-4195
~057196
.
Table 1
.
Water~containing drop solutionæ
. ! -- -- I _ ~ ~ .
Example No. 9 10 11 12 13 14 15 16
_ - __ _. _ . . _ _ . _, _ _
Glycerin monoricinoleate
Glycerin monooleate
Propylene glycol monosteara~e
Glycerin monomyristate
Glycerin monoisostearate
_ _ __ ._ __ _ _ _ _.
g of polyalcohols:
Polyethylene glycol 300 40 40 45 40 40
Polyethylene glycol 400 40
Polyethylene glycol 600 5.5
Polyethylene glycol 1500 40
Polyethylene glycol 2000
Glycerin 28
_. . _
g of further adjuvants:
Water 34.2 39.2 39.2 44.2 71.6 I9.5 S4.2 42~9
*Buffered to pH value 4.3 with a buffer mixture of sodium acetate/
acetic acid.
1057~9~ - 24 - 100-4195
Table 1
Water-containing drop solutions
Example No. 17 13 19 20 ~ 23 24
mg of active agents: _ _ _ .
Dihydroergocristine 400 400 400 200 200 800 200
Dihydroergovaline
Dihydroergotoxine
Dihydroergocornine
Dihydroergocryp~ine
Ergotamine 800
13-bromo-dihydroergotamine
13-bromo-dihydroergocryptine
N,N-(2-methyl-4,5-dihydroxyphen-
ethyl)-hexamethylenediamine
g of emulsifiers:
Cholesterin ethoxylated with
-approx.)24 mols of ethylene
oxide a
Oxy-ethylenoxy-propylene
polymb~, mean molecular weight
2900
Oxy-ethylenoxy-propylene 8
po~ymer, mean molecular
weight 3500C)
Oxy-ethylenoxy-propylene
polymer, mean molecular
weight 8700d) .
Polyoxyethylene-4-sorbitan
monostearate e) ,!
Polyoxyethylene-40-stearatef)
Polyoxyethylene~10-cetylic
ether &)
Polyoxyethylene castor oilh)
Polyethylene glycol-400-
stearate DAB7 i)
Polyethylene-20-sorbitan
tristearate 1)
Sodium dioctyl sulpho-
succinate m)
g of liPoid carrier materials _
Liquid triglyceride of
saturated fatty acids of
8-12 carbon atoms j~ _ _ _
~ns7~6
- 25 - 100-4195
Table 1
~ater-containing drop solutions
__ , _ _
Example No. 7 l8 19 20 21 22 23 24
_
Glycerin monolaurate _ 2 _ -
Glycerin mo~Qstearate
palmitate J
Glycerin monoricinoleate 2
Glycerin monooleate ~ 1
Propylene glycol monostearate 1
Glycerin monomyristate 1
Glycerin monoisostearate 0.5
. . __ _ _
g of pc ~ alcohols
Polyethylene glycol 300
Polyethylene glycol 400
Polyethylene glycol 600 40
Polyethylene glycol 1500
Polyethylene glycol 2000
Glycerin 10 _ _
g of further adjuvants:
Water 81 2 89 6 91.6 91.6 95.~ 95.8 53.2 96.8
1057~6
- 26 - 100-4195
Table 1
Water-containing drop solutions
Exa=ple No. 25 26 27 2829 30 .
_ ~
mg of active agents:
Dihydroergocristine 800
Dihydroergo~ine 600
Dihydroergotamine 300
Dihydroergocornine
Dihydroergocryptine
Ergotamine
13-bromo-dihydroergotamine 120
13-bromo-dihydroergocryptine 50
N,N-(2-methyl-4,5-dihydroxyphen- 80
ethyl)-hexamethylenediamine _
g of emulsifiers-
Cholesterin ethoxylated with 3 5.8 5 6 3
approx )24 mols of ethylene
oxide
Oxy-ethylenoxy-propylene 2.25
polymb~, mean molecular weight
2900
Oxy-ethylenoxy-propylene
polymer, mean molecular
weight 3500C)
Oxy-ethylenoxy-propylene l
polyn~er~ ~an molecular .
weight 8700d)
Polyoxyethylene-4-sorbitan
monostearate e)
Polyoxyethylene-40-stearatef~
Polyoxyethylene-10-cctylic .
ether g)
Polyoxyethylene castor oilh)
Polyethylene glycol-400-
stearate DAB7 i)
Polyethylene-20-sorbitan
tristearate 1)
Sodium dioctyl sulpho-
succinate m) _ _
g of lipo d carrier materials
Liquid triglyceride of 3.5
saturated fatty acids of
8-12 carbon atoms j) _ _ _ _ _ _ _
__
10~7~96
- - 27 - 100-4195
Table 1
Water-containing drop solutions
Example No. 25 26 27 28 29 3G
Glycerin monolaurate
Glycerin mo~)ostearate
palmitate
Glycerin monoricinoleate
Glycerin monooleate
Propylene glycol monostearate
Glycerin nomyristate
Glycerin monoisostearate
.. _ _
g of_polyalcohols
Polyethylene glycol 300 45 47 25
Polyethylene glycol 400 3 30
Polyethylene glycol 600
Polyethylene glycol 1500
Polyethylene glycol 2000 . .
Glycerin _ _ _ ~
g of further adjuvants: 4647 3 40 50 4G ,
*Buffered to pH value 4.3 with a buffer mixture of sodium acetate~
scetic acid.
10~7196
- 28 - 100-4195
~XAMPLE 31: Dihydroer~otamlne-containin~ dro~ solution
- 60 mg of dihydroergotamine mesylate are added
together with 1.5 g of cholesterin ethoxylated with
approx. 24 mols of ethylene oxide a) to 60 cc of water
adjusted to pH 4.1 with a buffer mixture of sodium
acetate/acetic acid, and homogenized with a "Polytron"
homogenizer. The clear liquid is filled into bottles
fitted wi h droppers.
EXAMPLE 32: Dihydroer~otamine-containin~ anhydrous
dro~ Solutions
a) 2 g of dihydroergotamine are added together with 50 g
of cholesterin ethoxylated with approx. 24 mols of
ethylene oxide a) to 500 g of polyethylene glycol
400 while heating to 50 in a water bath, treatment
is effected with ultrasonic waves for 5 minutes,
and the resulting clear liquid is filled into
bottles fitted with droppers.
b) The process ls effected as described ln section a)
above, except that a mlxture of 250 g of polyethylene
glycol 400 and 250 g of glycerin is used in place of
50 g of polyethylene glycol 400.
EXAMPLE 33: Dihvdroer~onine-containlnq soft ~elatin
ca~sules
3 g of dihydroergonine are added together with
75 g of cholesterin ethoxylated with approx. 24 mols of
~OS7~9~
- ~9 - 100-4195
ethylene oxide a) to 150 cc of polyethylene glycol 300
while heating in a water bath of 50 and subjecting to
ultrasonic waves. The clear liquid is subsequently filled
into soft gelatin capsules in quantities of 100 mg/
capsule.
EXAMPLE 34: Dihydroer~ocristine-conta~ninq ca~sules
300 mg of dihydroergocristine are dissolved
together with 1.7 g of cholesterin ethoxylated with
approx. 24 mols of ethylene oxide aj and 1.2 g of glycerin
monolaurate while heating to 40, and homogenized with
the addition of 30 g of a 22% solution of oxy-ethylenoxy-
propylene polymers having a mean molecular weight of
8700d) in water. After diluting with 50 cc of water,
freezing is rapidly effected in a rotating flask at -80
and lyophilization is effected in a high vacuum. As
lyophilization progresses the dry material is gradually
heated to 25-30. The resulting dry preparation is
subse~uently filled into capsules in quantities of 50 mg/
capsule.
EXAMPLE 35: Dihy~roer~otamine-containir~~ caEsules
30 mg of dihydroergotamine are dissolved
together with 750 mg of cholesterin ethoxylated with
approx. 24 mols of ethylene oxide a) in 50 cc of absolute
ethanol, and the solution is evaporated to dryness in a
vacuum at 30. The residue is homogenized with a'poly-
.
105'7~
- 30 - 100-4195
tron~homcgenizer for about 5 minutes while gradually
adding 100 cc of distilled water. 225 mg of highly dis-
persed silicic acid ) are suspended in the resulting
clear liquid, and the suspension is homogenized by
treatment with ultrasonic waves at 30 for 3 minutes.
The suspension is frozen at -80 and subsequently
lyophilized. The lyophilized product is filled into
gelatin capsules in quantities of lO0 mg/capsule.
EX~MPLE 36: Dihxdro r~ovaline-containin~ lyophilized
E~roduct__n_freeze-dried tam~oules
400 mg of dihydroergovaline are dissolved
together with 10 g of cholesterin ethoxylated with
approx. 2~ mols of ethylene oxide a) and 40 g of
polyethylene glycol 2000 in 300 cc of absolute ethanol.
lS The solution is evaporated to dryness in a rotary
evaporator at 30. 200 cc o~ disti'led water are slcwly
added to the residue while homogenized continually with
the polytron homogenizer. The clear micellar solution
of the active agent is illed into ampoules (2mg of
dihydroergovaline per ampoule) and the ampoules are
rapidly frozen at -80, lyophilized and sealed in a
vacuum.
The dry preparations having the composition
indicated in Table 2 may also be produced in a manner
analogous to that described in Examples 34-36, and
1057196
- 31 - 100-4195
filled into capsules or dry ampoules or granulated and/
or tabletted with the addition of suitable galenic
adjuvants:
n) Silicic acid K320 (tapped volume about 500 cc/lOO~g)
of the firm Degussa
o) Solulan C16 of the firm American Cholesterol Comp.
p) PVP K30 of the firm Badische Anilin- und Sodafabrik
q) Primojel of the firm Scholten's Chemische Fabrieken
N~V.
10~
- 32 -100-4195
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- 33 - 100-4195
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