Note: Descriptions are shown in the official language in which they were submitted.
1~9t796
The present invention relates to a pharmaceutical
preparation for enteral administration which contains as active
ingredient 0,05 to 40% of one or more analgesic peptides of
the endorphine type, in combination or admixture with at least
one inert physiologically tolerable carrier and/or adjunct.
This preparation can be used for medically treating diarrheal
conditions in mammals and especially in man by enteral adminl-
stration of a pharmacolo~ically e~fective ~ose thereof.
It is generally known that analgesics of the nar-
cotic type, such as opiates, diphenoxylate and loperamide, exert
a strong inhibiting effect on the peristalsis and can therefore
be used as effective antidiarrheal agents. In all probability,
the inhibiting effect on the peristalsis is causally connected
with the analgesic action. Peptides of the endorphine type are
known to belong to the most potent analgesics of the narcotic
type, but only on condition that they are administered by the
intraventricular route. When administered intraperitoneally,
on the other hand, the analgesic action is greatly reduced,
and no activity has been observed on enteral, for example oral,
administration. From this observation the conclusion was drawn
that, on enteral administration, the endorphine peptides are
also unable to exert any antidiarrheal effect and consequently
are ruled out for practical use in therapy on account of the
-- 2 --
'
11~9796
complicated and risky mode of administration.
However, the surprising discovery has now been made
that the endorphine peptides are able to inhibit the peristalsis
when administered enterally and have complete antidiarrheal
properties, viz. under conditions in which their analgesic
action is ineffective. The antidiarrheal agents on which this
unexpected observation is based have the intrinsic advantage,
compared with the other known analgesics of the narcotic type
which exert an antidiarrheal effect, such as those mentioned
above, that their active ingredients, i.e. the peptides of the
endorphine type, are fragments of endogenic hormones or closely
related analogues of such fragments. As such, they are to be
regarded as physiological with respect to the metabolism and
can be easily and completely decomposed by the metabolism in
the body, in every likelihood already in the lumen of the
bowels. Consequently they are able to exert their normalising
action on the peristalsis without giving rise to the customary
unpleasant symptoms of overdosage - for example an often
prolonged constipation or even the danger of habituation and
increasing the dose - which are well known to occur, especially
with opiates. In contrast to the endorphine peptides, all
other known antidiarrheal agents of the type discussed here
have the draw~ack that they cannot be rapidly and completely
decomposed by metabolic processes, but have to be much more
slowly and partially modified before they attain a form in
which they can be excreted from the organism.
_ 3 -
37~36
Accordingly, the invention provides pharmaceutical
preparations for enteral administration which exert an anti-
diarrheal effect and ~hich contain, as active ingredients,
one or more analgesic peptides of the endorphine type.
Enteral administration is to be understood as meaning
in particular oral, and also rectal, administration.
By peptides of the endorphine type are meant ~-
lipotropine fragments which are characterised by the amino
acid partial sequence from the 61st amino acid up to and in-
cluding at least the 65th and not more than the 91st amino
acid, as well as derivatives and analogues thereof. Particularly
advantageous compounds of this kind are the ~-lipo~ropine
fragments 61-67 and 61-66. Compounds to be singled out for
special mention however are the encephalines characterised by
(i.e. the leucine-encephaline
the pentapeptide fragment 61-65~of the formula H-Tyr-Gly-Gly-
Phe-Leu-~H and, in particular, the methionine-encephaline of
the formula H-Tyr-Gly-Gly-Phe-Met-OH. By analogues are meant
compounds which are modified by the exchange of an amino acid
of the original sequence for another amino acid, for example
D-Ala2-Met5-encephaline and encephalines in which the leucine-
radical is rep]aced by the L-valine, L-norvaline, L-iso-
leucine, L-norleucine or L-~-aminobutyric acid radical. All
these peptides can be in the free form or in the form of cor-
responding derivatives, for example salts, in particular acid
addition salts, or C-terminal amides Suitable acid components
of the acid addition salts are pharmaceutically acceptable in-
-- 4 --
1~9796
organic and or~anic acids, for example hydrohalic acids, suchas hydrobromic acid and especially hydrochloric acid, sul-
phuric acid, and phosphoric acids, as well as organic carboxy-
lic or sulphonic acids, such as aliphatic, alicyclic, aromatic
or heterocyclic carbo~ylic or sulphonic acids, for example
formic, acetic, propionic, palmitic, stearic, succinic, glyco-
lic, lactic, malic, tartaric, citric, ascorbic, pyruvic,
phenylacetic, benzoic, p-hydroxybenzoic, salicylic, p-amino-
salicylic, methanesulphonic, ethanesulphonic, hydroxyethane-
sulphonic, ethylene-1,2-disulphonic, benzenesulphonic, toluene-
- sulphonic or sulphanilic acid
- ~he peptidic active ingredients are known or they can
be prepared by conventional methods of peptide synthesis.
The preparations of the present invention contain the
above active ingredients preferably in combination or admix-
ture with the usual organic and/or inorganic solid or liquid
carriers and adjuncts which are physiologically tolerable,
inert to the active ingredient, and otherwise also suitable
for each individual desired enteral form of administration.
Preparations in solid form are preferred. The preparations
can contain in addition other therapeutically active substances
of the same or different kind.
The preparations of the present in~ention are prefer-
ably in dosage unit form. For administration to an adult, the
preparation will contain from about 0.5 to about 100 mg of
active ingredient or ingredients per dosage unit. The specific
individual dose depends primarily on the pharmacological
potency of each individual active ingredient and is, for ex-
ample for leucine-encephaline, in the range from about 5 to
about 100 mg, preferably from about 20 to 50 mg, and for
methionine-encephaline, in the range from about 0.5 to about
10 mg 3 preferably from about 2 to ~ mg. For other suitable
analogous peptides, the relative optimum individual dose can
be determined by routine pharmacological tests. It will be
readily understood that, in preparations for special use, for
example for children or mammals, the individual dose must be
adapted in accordance with the body weight of the specific re-
cipient. For this purpose it is also possible to use tablcts
with breaking notch.
The pharmaceutical preparations of the present inven-
tion are obtained in a manner known per se, for example by
~onventional mixing, granulating, coating and/or solution
methods. Accordingly, they can be obtained for example by com-
bining the active ingredients with solid carriers, optionally
granulating the resulting mixture and processing the mixture
or granules, if desired or necessary after the addition of
suitable adjuncts J to the desired form of administration.
Suitable preparations for rectal administration are for
example solutions for enema infusion and, in particular, sup-
positories and gelatin rectal capsules.
The solutions for enema application are preferably
aqueous solutions which are prepared immediately before ad-
1109796
ministration by dissolving a solid dosage unit form, preferablya tablet, in water of body temperature. Advantageously, such
solid preparations contain all essential constituents in a water-
soluble form, for example the active ingredient of the inven-
tion as an acid addition salt, such as the hydrochloride. Other
suitable constituents are especially the conventional hydro-
tropic agents, disintegrators, buffers and compounds for alter-
ing the osmotic pressure. Suitable methods of production are
the conventional tabletting methods.
Particularly preferred dosage forms for rectal adminis-
tration are suppositories, which consist in principle of a
combination of the active ingredients with a suppository base.
Examples of suitable suppositor~ bases are natural or synthetic
triglycerides, paraffin hydrocarbons, polyethylene glycols or
higher alkanols. It is furthermore also possible to use gelatin
rectal capsules which consist of a combination of the active
ingredients with a base material. Examples of suitable base
materials are liquid triglycerides and polyethylene glycols.
Particularly preferred dosage unit forms are solid pre-
parations for oral administration, such as table~s, sugar-
coated tablets and capsules. Particularly advantageous prepara-
tions of this kind are in turn those dosage forms which resist
solution in gastric fluid and are able to transport the active
ingredient or ingredients through the alimentary tract into the
small intestine intact, and, among such preparations, especially
those in which a portion of the active ingrediPnt is released
-- 7 --
9796
slowly and continuously over a prolonged period of time, for
example from 2 to 8 and preferably 4 to 6 hours. Such parti-
cularly preferred pharmaceutical forms of administration are
for example tablets or sugar-coated tablets which contain an
inner core consisting of a mixture for slow continuous release
of the active ingredient (slow or delayed-release composition).
Surrounding this core is an enteric coating consisting of a
mixture which releases the active ingredient instantly and
which is provided in turn with an external coating which resists
solution in gastric fluid but dissolves in the intestine.
Suitable carriers for solid preparations for oral ad-
ministration are in particular fillers, such as sugar, for ex-
ample, lactose, saccharose~ mannitol or sorbitol, cellulose
preparations and/or calcium phosphates, e.g. tricalcium phos-
phate or calcium hydrogen phosphate, also binders such as
starch pastes, for example maize, corn, rice or potato starch
paste, gelatin, tragacanth, methyl cellulose, hydroxypropyl-
methylcellulose, sodium carboxymethylcellulose and/or poly-
vinylpyrrolidone, and/or, if desired, disintegrators, such as
the above starches, also carboxymethyl starch, crosslinked
polyvinylpyrrolidone, agar, alginic acid or a salt thereof,
such as sodium alginate. Adjuncts are chiefly glidants and
lubricants, for example, silicic acid, talc, stearic acid or
salts thereof, such as magnesium stearate or calcium stearate,
and/or polyethylene glycol. Sugar-coated tablets cores are
provided with suitable coatings that can be resistant to
-- 8 --
1~9796
gastric juices, using, inter alia, concentrated sugar solu-
tions which may contain gum arabic, talc, polyvinylpyrrolidone,
polyethylene glycol and/or titanium dioxide, shellac solutions
in suitable organic solvents or solvent mixtures or, for the
preparation of coatings resistant to gastric juices, solutions
of suitable cellulose preparations, such as acetylcellulose
phthalate or hydroxypropylmethylcellulose phthalate. The
duration of effect of an intrinsically short-acting active in-
gredient can be prolonged for example by incorporating it in a
suitable carrier which effects its slow release, as described in
detail hereinafter. Dyes or pigments can be added to the
tablets or sugar-coated tablet cores, for example to identify
or indicate different doses of active ingredient.
Further pharmaceutical preparations for oral administra-
tion are dry-filled capsules, and also soft sealed capsules
made from gelatin and a plasticiser, such as glycerin or
sorbitol. The dry-filled capsules can contain the active in-
gredient in the form of granules, for example of those des-
cribed in more detail hereinafter. In soft capsules, the active
ingredient is preferably dissolved or suspended in suitable
liquids, for example in fatty oils, paraffin oil or liquid
polyethylene glycols, to which stabilisers can also be added.
A particularly advantageous form of the active in-
gredient/carrier mixture are granulates which are suit-
able for processing to tablets, sugar-coated tablets or cap-
sules. In addition to the active ingredient, such granulates
_ g _
11~9796
contain, inter alia, diluents or fillers, such as sugar, for
example lactose or saccharose, or sugar alcohols, for example
mannitol or sorbitol, cellulose preparations and/or calcium
phosphates, for example tricalcium phosphate or calcium hydro-
gen phosphate, as well as glidants, such as talc or colloidal
silicic acid, lubricants, such as stearic acid or salts ~here-
of, for example magnesium or calcium stearate, and/or poly-
ethylene glycol, and also glycerides, such as hydrogenated cot-
ton seed or castor oil.
Granulates of this kind can be prepared in a manner which
is known per se, with or without the use of moistening agents,
such as water or organic solvents, for example ethanol, or
mixtures thereof.
So that the release of the active ingredient is retarded
and yet remains constant, it must be reduced by addition of
and/or treatment with suitable adjuncts, excipients and/or
coating substances. Such substances are in particular film
formers for coatings, swelling substances with gel-forming
properties for retarding the diffusion, builders for embed-
dings, in particular lipids, and plastics with thermoplastic
properties.
To achieve the delayed and continuous release of the
active ingredient, only one adjunct of the above kind is nor-
mally used.
Usually water-insoluble adjuncts are used in particular
as film formers, for example water-insoluble cellulose ethers
- 10 -
9~796
or esters, such as corresponding cellulose lower alkyl ethers,
for example water-insoluble ethyl cellulose, or water-insoluble
cellulose esters containing hydroxyl groups which are esteri-
fied by lower alkanecarboxylic acids or dicarboxylic acids, for
example water-insoluble cellulose acetate or cellulose acetate
phthalate, polymers or copolymers of unsaturated aliphatic
esters of carboxylic acids with alcohols, such as polymers or
copolymers of esters of lower alkene-carboxylic acids with lower
alkanols, for example copolymers of ethyl acrylate and methyl
methacrylate (e.g. in the ratio of about 70 parts of ethyl
acrylate to about 30 parts of methyl methacrylate), and shellac.
The film formers, which comprise between about 1% and
10%, preferably between about 2% and 6%, of the total weight of
the preparation formulation, are used chiefly for coating active
ingredient particles or preferably of granulates, or also as
additive to granulates, which can be compressed to tablets. -
They can be applied or admixed in dissolved form using organic
solvents, for example alcohols, such as ethanol, or optionally
chlorinated aliphatic hydrocarbons, such as methylene chloride,
or ketones, for example acetone, or mixtures thereof, or in the
form of dispersions, such as coagulatable a~ueous dispersions.
Suitable swelling substances are in particular ethers
of cellulose which have a high degree of viscosity, such as
corresponding lower alkyl celluloses and in particular methyl
cellulose with an average degree of substitution of about 1.8,
and which are added preferably in powder form to the active
1~9~96
ingredient or especially to granulates thereof. The resultant
mixtures are then processed for example to tablets. By this
means there are obtained pharmaceutical preparations which, on
contact with water, swell with gel formation, resulting in the
formation of a diffusion barrier which is independent of the pH.
Lipids which are suitable water-insoluble builders are,
inter alia, fatty alcohols, in particular higher alkanols of
more than 13, in particular of 16 to 20, carbon atoms, for ex-
ample cetyl alcohol or stearyl alcohol, and mixtures thereof.
These lipids can be used for the release of the active ingre-
dient which is independent of the pH. Further suitable lipids
are fatty acids which effect a release of the active ingredient
that is dependent of the pH, in particular higher alkane-
carboxylic acids of more than 13, in particular of 16 to 20,
carbon atoms, for example stearic acid. Such lipids can be used
in powder or in fused form. Suitable lipids are also glycerides,
in particular hydrogenated vegetable oils, such as hydrogenated
vegetable oils, such as hydrogenated cotton seed oil or hydro-
genated castor oil, as well as mono-, di- or triesters of gly-
cerol with palmitic acid or stearic acid or preferably mix-
tures thereof. These lipids are normally used in powder form
and can be employed simultaneously, as mentioned above, as
glidants.
Plastics with thermoplastic properties which can be
used as water-insoluble builders are in particular polymers or
copolymers of the polyvinyl chloride or polyvinyl acetate type.
- 12 -
,
:
3796
The swelling substances and builders which are used in
amounts of about 5% to about 70%, preferably of about 10% to
about 40%, of the total weight of the preparation, are usually
mixed with the active ingredient or preferably with an active
ingredient/adjunct mixture, such as a granulated mixture, and,
if appropriate after the addition of further adjuncts, such
as glidants and lubricants, compressed to tablets or capsules.
It is a further object of the present invention to
provide a method of treating mammals, and especially man, to
alleviate and overcome diarrheal conditions by the enteral ad-
ministration of therapeutically effective doses of the anal-
gesic peptides of the endorphine type, espe~ially of those
specifically referred to herein, which comprises administering
the active ingredients, advantageously in the form of the
above described pharmaceutical preparations, in the indicated
general or specific individual doses and in the manner as des-
cribed above. Depending on the nature of the symptoms and
the form of administration, as well as according to individual
re~uirements, the individual doses can be taken once or repeat-
edly. As a rule, the total dosage shall not exceed 10 indi-
vidual doses in the course of 24 hours.
The following Examples illustrate the invention but
do not in any way restrict the scope thereof.
- 13 -
.
96
Example 1
Film-coated tablets which resist solution in gastric fluid
but disintegrate in the intestine, for combined rapid and slow
release of the active ingredient.
Using conventional mixing methods, homogeneous mixtures of
the following composition are prepared:
Mixture A
leucine-encephaline 100 g
lactose, anhydrous, for direct 950 g
tabletting
cellulose, microcrystalline 650 g
magnesium stearate 10 g
Mixture B
leucine-encephaline 150 g
lactose, microcrystalline, for direct 400 g
tabletting
hydrogenated castor oil, fine-grained 50 g
Mixtures A and B are compressed to enteric-coated tablets.
Mixture B is first compressed to the core with prolonged action
which weighs 60 mg and has a diameter of 6 mm. The enteric-
coating with rapid release of~the active ingredient is pre-
pared from mixture A in an amount of 171 mg. Slightly domed
punches having a diameter of 8 mm are used, so that enteric-
coated tablets having a total weight of 231 mg and containing
10 mg of the active ingredient in rapid-acting form and 15 mg
in the slow-release form are obtained.
- 14
)9~96
The enteric-coated tablets in batches of 100,000 are coated
in a coating drum o~ 65 cm diameter by means of automatic spray
equipment with a shellac solution of the following composition:
methylene chloride 18.2 kg
methanol 1.42 kg
cellulose acetate phthalate0.662 kg
diethyl phthalate 0.207 kg
shellac 0.211 kg
The temperature of the supply air is 60C and the temperature
of the cores is kept at about 25C. The finished film-coated
tablets are subsequently dried for 12 hours at 30C.
~ xample 2
Film-coated tablets which resist solution in gastric fluid and
disintegrate in the intestine for combined rapid and slow
release of the active ingredient are prepared in a manner
analogous to that described in Example 1. The tablets have a
total content of 10 mg of methionine-encephaline, viz. 4 mg
in the rapid-acting form and 6 mg in the slow-release form.
The mixtures required for preparing the tablets have the fol-
lowing composition:
Mixture A
methionine-encephaline 40 g
lactose, anhydrous, for direct1000 g
tabletting
~ 7 ~ 6
cellulose, microcrystalline 660 g
magnesium stearate 10 g
Mixture B
methionine-encephaline 60 g
lactose, anhydrous, for direct 490 g
tabletting
hydrogenated castor oil, fine-grained 50 g
Processing is carried out under the conditions indicated in
Example l.
Example 3
Dry-filled capsules which resist solution in gastric fluid
and disintegrate in the intestine.
A mixture of the following composition is prepared:
leucine-encephaline 500 g
maize starch 300 g
lactose, crystalline with an average 400 g
particle size of about 125 ,u
lactose, finely ground 200 g
calcium stearate 50 g
Size 2 hard gelatin capsules, which during the capsule manu-
facturing process have been made resistant to solution in
gastric fluid by being dipped in an organic solution of hydroxy-
propylmethylcellulose (type ~P 55), are each filled with 145 mg
of this mixture. The finished capsules contain 50 mg of active
ingredient.
- 16 -
`\
796
Example 4
Dry-filled capsules containing a total amount of 5 mg of
methionine-encephaline and which are resistant to solution in
gastric fluid and disintegrate in the intestine are prepared
in a manner analogous to that of Example 3. The mixture re-
quired for these capsules has the following composition:
methionine-encephaline 50 g
maize starch 750 g
lactose, crystalline (cf. Example 3) 400 g
lactose, finely ground 200 g
calcium stearate 50 g
The processing is carried out under the conditions indicated
i.n Example 3.
- 17 -
