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| United States Patent |
4,393,236
|
|
Klosa
|
July 12, 1983
|
Production of nonhygroscopic salts of 4-hydroxybutyric acid
Abstract
A method for the production of nonhygroscopic magnesium and/or calcium
salts of 4-hydroxybutyric acid. A member of the group consisting of
magnesium hydroxide, magnesium oxide, magnesium carbonate, calcium
hydroxide, calcium oxide and calcium carbonate is reacted with
4-hydroxybutyric acid and/or 4-butyrolactone in an aqueous solution. The
solution is crystallized at a sufficiently low temperature for producing a
solid nonhygroscopic salt. Waterfree calcium-4-hydroxybutyrate and
waterfree as well as hydrated magnesium-4-hydroxybutyrate are added to
pharmaceutically acceptable carrier or filler material for production of
tranquilizing and/or sleeping drugs.
| Inventors:
|
Klosa; Joseph (Janickestrasse 13, D-1000 Berlin 37, DE)
|
| Appl. No.:
|
282419 |
| Filed:
|
July 13, 1981 |
| U.S. Class: |
562/579; 424/317 |
| Intern'l Class: |
C07C 059/00 |
| Field of Search: |
562/579
424/317
|
References Cited [Referenced By]
U.S. Patent Documents
| Foreign Patent Documents |
| 465270 | May., 1950 | CA | 562/579.
|
| 39-6962 | Nov., 1964 | JP | 562/579.
|
| 922029 | Mar., 1963 | GB | 562/579.
|
Primary Examiner: Killos; Paul J.
Attorney, Agent or Firm: Kasper; Horst M.
Claims
1. Waterfree calcium-4-hydroxybutyrate of the formula Ca(COOCH.sub.2
CH.sub.2 CH.sub.2 OH).sub.2.
2. Magnesium-4-hydroxybutyrate of the formula Mg(COOCH.sub.2 CH.sub.2
CH.sub.2 OH).sub.2.
3. Magnesium-4-hydroxybutyrate according to claim 2 furthermore free from
water of hydration.
4. Magnesium-4-hydroxybutyrate according to claim 2 further comprising 4
molecules of water of hydration for each molecule of Mg(COOCH.sub.2
CH.sub.2 CH.sub.2 OH).sub.2 resulting in a composition of the formula
Mg(COOCH.sub.2 CH.sub.2 CH.sub.2 OH).sub.2.4H.sub.2 O.
5. Magnesium-4-hydroxybutyrate according to claim 2 further comprising 5
molecules of water of hydration for each molecule of Mg(COOCH.sub.2
CH.sub.2 CH.sub.2 OH).sub.2 resulting in a composition of the formula
Mg(COOCH.sub.2 CH.sub.2 CH.sub.2 OH).sub.2.5H.sub.2 O.
6. A method for the production of magnesium and/or calcium salts of
4-hydroxybutyric acid comprising
reacting a member of the group consisting of 4-hydroxybutyric acid,
4-butyrolactone and mixtures thereof with a member of the group consisting
of magnesium hydroxide, magnesium oxide, magnesium carbonate, calcium
hydroxide, calcium oxide, calcium carbonate and mixtures thereof in an
aqueous solution; and
crystallizing the resulting solution at initial temperatures of from about
40.degree. to 80.degree. C. sufficiently low to produce a solid
nonhygroscopic salt.
7. The method according to claim 6 further comprising adding to the aqueous
solution a nonsolvent for the respective 4-hydroxybutyrate before and/or
during the crystallizing step.
8. The method according to claim 7 wherein the nonsolvent is acetone.
9. The method according to claim 6 further comprising recrystallizing
calcium 4-hydroxybutyrate from an organic solution to provide
nonhygroscopic, nonhydrated calcium 4-hydroxybutyrate.
10. The method according to claim 6 wherein the crystallizing of the
magnesium 4-hydroxybutyrate is performed at a temperature below about
40.degree. C. to obtain a non-hygroscopic salt containing about 5 moles of
water for each mole of magnesium 4-hydroxybutyrate Mg(COOCH.sub.2 CH.sub.2
CH.sub.2 OH).sub.2.
11. The method according to claim 10 further comprising drying the
magnesium 4-hydroxybutyrate hydrated with about 5 molecules of water for
removal of about 1 molecule of water to provide Mg(COOCH.sub.2 CH.sub.2
CH.sub.2 OH).4H.sub.2 O containing about 4 molecules of water of hydration
for each molecule of magnesium 4-hydroxybutyrate.
12. The method of claim 6 further comprising drying the product according
to claim 6 to remove all water of hydration for obtaining a nonhygroscopic
salt.
13. A pharmaceutical composition providing narcotic effects comprising
a nonhygroscopic salt of 4-hydroxybutyric acid; and
a pharmaceutically acceptable carrier and/or filler material.
14. A method for the production of magnesium and/or calcium salts of
4-hydroxybutyric acid comprising reacting a member of the group consisting
of 4-hydroxybutyric acid, 4 butyrolactone and mixtures thereof with a
member of the group consisting of magnesium hydroxide, magnesium oxide,
magnesium carbonate, calcium hydroxide, calcium oxide, calcium carbonate
and mixtures thereof in an aqueous solution; and crystallizing the
resulting material in the presence of a non-solvent at a temperature
sufficiently low to produce a solid nonhygroscopic salt.
15. The method according to claim 14 wherein the nonsolvent is acetone.
16. The method according to claim 14 wherein the calcium 4-hydroxy butyrate
is crystallized at a temperature of less than about 80.degree. C.
17. The method according to claim 14 further comprising recrystallizing
calcium 4-hydroxybutyrate from an organic solution to provide
nonhygroscopic, nonhydrated calcium 4-hydroxybutyrate.
18. The method according to claim 14 wherein the crystallizing of the
magnesium 4-hydroxybutyrate is performed at a temperature below about
40.degree. C. to obtain a non-hygroscopic salt containing about 5 moles of
water for each mole of magnesium 4-hydroxybutyrate Mg(COOCH.sub.2 CH.sub.2
CH.sub.2 OH).sub.2.
19. The method according to claim 18 further comprising drying the
magnesium 4-hydroxybutyrate hydrated with about 5 molecules of water for
removal of about 1 molecule of water to provide Mg(COOCH.sub.2 CH.sub.2
CH.sub.2 OH).4H.sub.2 O containing about 4 molecules of water of hydration
for each molecule of magnesium 4-hydroxybutyrate.
20. The method according to claim 14 further comprising drying the product
according to claim 16 to remove all water of hydration for obtaining a
nonhygroscopic salt.
21. The method according to claim 14 further comprising crystallizing the
magnesium 4 hydroxybutyrate from an aqueous solution at a temperature up
to about the boiling point of water.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the production of nonhygroscopic alkaline
earth salts of 4-hydroxybutyric acid suitable in the production of
pharmaceutical preparations.
2. Brief Description of the Background of the Invention Including Prior Art
It is known that 4-hydroxy-butyric acid is liquid and a crystalline form
can ony be obtained with difficulty. Also 4-hydroxybutyric acid is not
available commercially in a pure composition. The sodium salts of the
4-hydroxybutyric acid are hygroscopic. The calcium salts known from
British Pat. No. 922,029 of the 4-hydroxybutyric acid have been disclosed
as being suitable for application only in liquid form in solution. A
melting point for the calcium salt was not provided, presumably because it
could not be determined based on the strong hygroscopicity. According to
British Pat. No. 922,029 the hygroscopic calcium salt is obtained by
reacting 4-butyrolactone with a solution of calciumhydroxide. This is a
general method of operation, however the reaction is very violent and
strongly exothermic, such that side reactions can occur resulting in final
products which are difficult or not all suitable for crystallization.
Presently completely unknown are magnesium salts of .gamma.-hydroxybutyric
acid.
Therefor, up to now a general and wider therapeutic application was
excluded for the 4-hydroxybutyric acid and its salts be it in the form of
tablets, dragees and/or capsules. Based on the difficulties of production
and handling of the 4-hydroxy-butyric acid and its salts, these are also
very expensive.
It is further known that 4-hydroxybutyric acid has narcotic effects. It is
successfully applied in medicine as an intravenously injectable anesthetic
in the form of the sodium salt. The sodium salt, depending on the dose,
generates a sleeping state from which the patient can be waked up.
However the free 4-hydroxybutyric acid as well as its sodium salt and the
calcium salt taught in British Pat. No. 922,029 have not been applicable
on a broad scale in pharmacy because of their strong hygroscopic action.
However, there is a large desire for these materials especially as sleeping
agent and as a tranquilizer, since virtually all the known sleeping agents
and tranquilizers such as barbiturates, amides, but also diazepams are
associated with large side effects upon continuous application, but also
directly associated with undesired aftereffects. In particular all present
sleeping agents and tranquilizers interfere in an undesirable way with the
metabolism of the nerves and this is also true for the plant derived
agents such as those of valerian. Especially they are transformed into
uncontrollable metabolites with obscure action and they frequently damage
the liver irreversibly.
It is in fact known from the non-poisonous 4-hydroxybutyric acid that it
acts as a sleeping drug (compare G. Kuschinsky, Taschenbuch der modernen
Arzneibehandlung, 8th edition, 1980, page 328), however a handy oral
application in the form of tablets, dragees or capsules of the compounds
known in this respect has been impossible up to now because of the strong
hygroscopicity of the known compounds. Even as solutions the known
compounds were not exactly measurable as a dose, since hygroscopic
materials always rapidly attract water, even upon weighing, such that in
large scale production of pharmaceutical agents constant doses cannot be
maintained.
SUMMARY OF THE INVENTION
1. Purposes of the Invention
It is an object of the present invention to provide non-hygroscopic salts
of 4-hydroxy-butyric acid.
It is another object of the present invention to provide a salt of
4-hydroxybutyric acid suitable for producing solid and/or liquid
pharmaceutical compositions.
It is another object of the present invention to provide salts of
4-hydroxybutyric acid, which do not act burning and etching to the mucous
membrane of the mouth.
These and other objects and advantages of the present invention will become
evident from the description which follows.
2. Brief Description of the Invention
The present invention provides a waterfree calcium-4-hydroxybutyrate
Ca(COOCH.sub.2 CH.sub.2 CH.sub.2 OH).sub.2. The present invention further
provides magnesium-4-hydroxybutyrate Mg(COOCH.sub.2 CH.sub.2 CH.sub.2
OH).sub.2, which can be free of water of hydration, which can comprise 4
molecules of water of hydration for each molecule of Mg(COOCH.sub.2
CH.sub.2 CH.sub.2 OH).sub.2 and/or which can comprise about 5 molecules of
water of hydration for each molecule of Mg(COOCH.sub.2 CH.sub.2 CH.sub.2
OH).sub.2.
There is also provided a method for the production of magnesium and/or
calcium salts of 4-hydroxybutyric acid which comprises reacting a member
of the group consisting of 4-hydroxybutyric acid, 4-butyrolactone and
mixtures thereof with a member of the group consisting of magnesium
hydroxide, magnesium oxide, magnesium carbonate, calcium hydroxide,
calcium oxide, calcium carbonate and mixtures thereof in an aqueous
solution, and crystallizing the resulting solution at a temperature
sufficiently low to produce a solid nonhygroscopic salt. Before and/or
during the crystallizing step a nonsolvent for the respective calcium or
magnesium 4-hydroxybutyrate can be added to the aqueous solution and a
preferred nonsolvent is acetone. Preferably waterfree calcium-4-hydroxy
butyrate is crystallized at a temperature of less than about 80.degree. C.
Calcium-4-hydroxybutyrate can be recrystallized from an organic solution
to provide nonhygroscopic, nonhydrated calcium-4-hydroxybutyrate.
Magnesium-4-hydroxybutyrate can be crystallized at a temperature below
about 40.degree. C. to obtain a nonhygroscopic salt containing about 5
moles of water for each molecule of magnesium-4-hydroxybutyrate. The
magnesium-4-hydroxybutyrate hydrated with about 5 molecules of water for
each molecule Mg(COOCH.sub.2 CH.sub.2 CH.sub.2 OH).sub.2 can be dried to
provide Mg(COOCH.sub.2 CH.sub.2 CH.sub.2 OH).sub.2.4H.sub.2 O containing
about 4 molecules of water of hydration for each molecule of
magnesium-4-hydroxybutyrate.
The hydrated calcium and/or magnesium salts of 4-hydroxybutyric acid can be
dried to a nonhygroscopic product of (Ca,Mg)(COOCH.sub.2 CH.sub.2 CH.sub.2
OH).sub.2 free of water of hydration. The magnesium butyrate can be
crystallized from an aqueous solution at a temperature up to about the
boiling point of water.
There is also provided a pharmaceutical composition which comprises a
nonhygroscopic salt of 4-hydroxybutyric acid and a pharmaceutically
acceptable carrier and/or filler material.
The invention accordingly consists in the compositions, methods of
preparation and applications which will be exemplified in the method and
compositions of matter hereinafter described and of which the scope of
application will be indicated in the appended claims.
DESCRIPTION OF INVENTION AND PREFERRED EMBODIMENTS
In accordance with the present invention it was surprisingly found that
both the water-free calcium salts of the 4-hydroxybutyric acid as well as
the magnesium salts of this acid are not hygroscopic and are suitable for
unlimited storage. The present invention provides in one aspect a method
for the production of non-hygroscopic salts of the 4-hydroxybutyric acid
characterized in that either (a) 4-hydroxybutyric acid is neutralized with
hydroxides, oxides or carbonates of magnesium or calcium in an aqueous
solution or (b) 4-butyrolactone is hydrolytically split with an hydroxide,
oxide or carbonate of calcium or magnesium according to the reaction
formula
##STR1##
where .nu.=0, 4, 5 or 6, whereupon the use of calcium hydroxide, calcium
oxide or calcium carbonate temperatures below 80.degree. C. and preferably
temperatures from about 40.degree. C. to 60.degree. C. are employed, and
whereupon the use of magnesiumhydroxide, magnesium oxide or magnesium
carbonate temperatures around the boiling point of water are employed.
The waterfree calcium salt of the 4-hyxdroxybutyric acid in accordance with
the present invention has a constant melting point of from about
166.degree. to 168.degree. C. and even after hours of storage at air no
water is attracted, that is the salt remains completely dry. It was found
in accordance with the present invention that it can be obtained in
crystalline form already then when .gamma.-butyrolactone is reacted with
calcium hydroxide, calcium oxide or calcium carbonate such that the
temperature remains below 80.degree. C., and is preferably between
40.degree. and 60.degree. C. The water-free calcium 4-hydroxybutyrate and
the waterfree magnesium 4-hydroxybutyrate can be produced by removal of
water by drying hydrated calcium 4-hydroxybutyrate and/or magnesium
4-hydroxybutyrate.
As it had been known that water containing calcium salts of the
4-hydroxybutyric acid are hygroscopic, it was the more surprising to find
in accordance with the present invention that the magnesium salts of this
acid, which were hitherto unknown, are neither in the water-free nor in
the hydrated state hygroscopic. The magnesium salts of 4-hydroxybutyric
acid according to the present invention can bind up to at most 6 moles of
water of crystallization. After short drying in air the water contents is
reduced to from about 4 to 5 moles. All these magnesium salts are not
hygroscopic, are well suited for being stored and are as well as the above
mentioned water-free calcium salt suitable for the preparation of various
pharmaceutical preparations.
In particular 4-hydroxybutyric acid derivatives do not show poisonous
effects or side effects such as those associated with the known narcotical
or tranquilizing compositions. 4-hydroxybutyric acid is completely
degraded in the human body and is closely related to the natural
metabolites of the body such as lactic acid. In particular,
4-hydroxybutyric acid does not affect the liver as is observed with
tranquilizing and hypnotic preparations.
The difficulties encountered with the hygroscopic compunds are eliminated
with the non-hygroscopic salts of the 4-hydroxybutyric acid. The materials
according to the invention allow without effort to produce solid or liquid
forms to be administered and also the disadvantages of the preparations of
solutions of free acid and sodium salt are avoided, which act burning and
etching on the mucous membrane of the mouth.
It has been found that the nonhygroscopic calcium and magnesium salts of
the 4-hydroxybutyric acid are administered in a dose from about 100 to
2000 mg and preferably from about 300 to 500 mg orally as tablets, dragees
or capsules and they develop an excellent effect of generating sleep or of
tranquilizing. Pharmacological investigations have shown however an
excellent analgetic effect of the compounds of the present invention. In
combination with pain-relieving agents such as salicylic amide,
acetylsalicylic acid or p-acetylaminophenol the analgetic effect is
increased. The compounds of the present invention open up new
possibilities of pain-relief, such as a possible pain-relieving
alternative with the analgesic asthma syndrome. Painful stress as occurs
with chronic pains is decreased and eliminated. Therefor, the combination
of the invention salts with analgesic and antirheumatically active
pharmaceutical preparations is advantageous. Such a combination can be
provided without problem with the salts of the present invention in
contrast to the known hygroscopic materials, which interact chemically
with the combination partners.
The calcium and magnesium salts of the present invention derived from
4-hydroxybutyric acid are solid, nonhygroscopic and storable and they can
be recrystallized. They can be pressed to tablets in combination with
tablet additives, they can be coated or as a powder they can be filled
into capsules. They dissolve in water to a clear solution and they can be
dispensed as injection solutions, but also as drops, or in drinks or as
suppositories while maintaining a stable situation.
The invention is further illustrated by way of the following examples which
are to be considered as examplary and not in a limiting sense.
EXAMPLE 1
A suspension of 37 g calcium hydroxide in 80 ml water is added in portions
and under stirring to 86 g 4-butyrolactone. The mixture warms up. The
addition of the aqueous calcium hydroxide suspension is controlled such
that no boiling occurs. After terminating the addition the colorless
reaction product is allowed to stand for several hours. Usually a
colorless solution is obtained, otherwise any precipitate is decanted and
the colorless, somewhat sirupy solution is freed from water on a water
bath, possibly under reduced pressure. The residue crystallizes to a mass
of colorless crystals, which is after dried at temperatures from about
60.degree. to 80.degree. C. Yield: about 105 g. Melting point
164.degree.-166.degree. C. The chemical analysis finds 16.21 weight
percent calcium (calculated 16.26 weight percent calcium). The product is
Di-(4-hydroxybutyric) calcium. It is recrystallized by dissolving in
little methanol followed by adding of acetone to cloudiness.
EXAMPLE 2
74 g analytically pure calcium hydroxide are suspended in 200 ml of tap
water. 160 ml 4-butyrolactone are added in portions (each portion about 5
to 10 ml) and under stirring to this suspension at room temperature. After
addition of 20 ml the reaction mixture warms to about 50.degree. to
60.degree. C. The addition of 4-butyrolactone is controlled such that the
temperature remains between about 50.degree. and 60.degree. C., which
takes about 1 hour. During this time the calcium hydroxide has dissolved
practically completely. The reaction material is contaminated with a
slight rust-yellow precipitate. It is thinned down with 300 ml methanol,
is left for four hours to itself and is then filtered through a folded
filter. The clear filtrate is cautiously treated with 200 ml acetone in
the way that after each portion of acetone causing a precipitate time is
allowed for the precipitate to redissolve. A water-clear solution is
obtained which is placed for crystallization. After two hours of standing
colorless crystals start to deposit. In this state the crystallization is
accelerated by continuous addition of acetone (in total 100 ml). The
crystallization time is 24 hours. The crystals are sucked off and are
washed initially with 50 ml methanol and then additionally with 60 ml
acetone. The crystals are dried at temperatures from about 60.degree. to
80.degree. C. in a drying cabinet. Yield: 230 g. Melting point
166.degree.-168.degree. C. (immediately). The product is the waterfree
nonhygroscopic calcium salt of the 4-hydroxybutyric acid. It is
dissolvable as desired in water, the aqueous solution has a pH-value of 7
to 7.5. The salt can be stored as long as desired and does not change in
air. Even upon storage no water is attracted from the air.
EXAMPLE 3
As described in Example 2, 74 g calcium hydroxide are reacted with 160 ml
4-butyrolactone in 200 ml water. The sirupy reaction material is thickened
by evaporation on a water bath and is allowed to stand for several days
such that it crystallizes to a hygroscopic mass of crystals. They are
comminuted and are warmed together with 300 ml methanol under stirring on
a water bath. The raw calcium salt of the 4-hydroxybutyric acid is not
hygroscopic and melts weakly at 164.degree.-166.degree. C. Yield: 204 g.
The salt dissolves readily in water, however cloudy contaminants remain.
For purification the raw product is dissolved in 500 ml methanol and 80 ml
water and then filtered. The water-clear filtrate is compounded with 100
ml methanol and is then under stirring mixed with 400 ml acetone in
portions. No precipitate is allowed to occur. After several hours
crystallization starts and continues for 24 to 48 hours. The crystals are
sucked off and washed initially with 60 ml methanol and then with 100 ml
acetone and are dried at 60.degree. to 80.degree. C. Yield: 220 g in
analytical quality. Melting point 166.degree.-168.degree. C. Instead of
methanol also ethanol and isopropanol can be employed for
recrystallization with the same success. Without employing water
containing alcohols as recrystallization medium or as additive of the
recrystallization and purification no stable and in particular no
nonhygroscopic calcium salts are obtained. The percentage of water in the
alcohols should be from about 3 to 10 percent by volume.
The such obtained final product does easily dissolve in water, is not
hygroscopic and has a pleasant aromatic odor.
EXAMPLE 4
42 g magnesium carbonate in 100 ml water are added to 86 g 4-butyrolactone
under stirring and warming on a water bath to about 50.degree. to
62.degree. C. Carbon dioxide developes. After termination of the addition
the solution is heated on the water bath an additional 3 to 5 minutes
until complete dissolution. Then the water-clear solution is thickened by
evaporation in a dish on a water bath. A colorless sirup is obtained,
which solidifies if allowed to stand for 14 days. The mass of crystals in
a yield of 120 g still contains water of crystallization (melting point
105.degree.-107.degree. C. under effervescence) and the water can be
removed by drying at about 60.degree. to 80.degree. C. Melting point
172.degree.-174.degree. C. The analysis showed 10.47 weight percent
magnesium (calculated 10.55 weight percent magnesium). The product is the
magnesium salt of the 4-hydroxybutyric acid. Sum formula: C.sub.8 H.sub.14
O.sub.6 Mg (Molecular weight 230.39). It dissolves easily in water,
methanol and ethanol, it does not dissolve in ether and hydrocarbons, it
is not hygroscopic, is storable and has a pleasant aromatic odor.
EXAMPLE 5
60 g magnesium hydroxide (pro analysis) are suspended in 200 ml tap water
under stirring. In a stream and under stirring 160 ml 4-butyrolactone are
mixed into this suspension. Then the mixture is heated on a water bath for
6 hours under stirring in a 2-liter-flask. The magnesium hydroxide
dissolves practically completely. The flask is allowed to stand over
night, while contaminants deposit and the solution is decanted without
effort from the contaminant deposit. The water clear decantate is
initially stirred with 100 ml acetone for 10 minutes. The colorless sirupy
liquid, which now turned more viscous, is mixed again with 100 ml acetone
as described above, the acetone is again removed by decanting and the
fairly viscous, colorless sirup is left to itself at room temperature for
about 2 to 4 hours. It solidifies to a colorless crystal mass, which is
comminuted in a mortar and dried for several hours in air. Melting point
76.degree. to 78.degree. C.
Yield: 314 g in analytically pure from.
Sum formula: C.sub.8 H.sub.14 O.sub.6 Mg.5H.sub.2 O. This magnesium salt
contains about 5 mole of water of hydration. It is not hygroscopic, is
stable and can be stored for arbitrary long times. By drying over several
hours at 40.degree. to 50.degree. C. it loses part of its water (1 mole)
of crystallization and then melts at 118.degree. to 120.degree. C.
Waterfree magnesium 4-hydroxybutyrate can be produced by removal of water
by sublimation and/or evaporation of water under decreased partial
pressure of water and at elevated temperature or by crystallization from a
solution containing an organic solvent.
The waterfree salt melts at 172.degree.-174.degree. C. The chemical
analysis shows 10.50 weight percent magnesium (calculated 10.55 weight
percent magnesium).
All modifications are nonhygroscopic and stable during storage. 1 g of the
magnesium salt dissolves in 2 ml water at room temperature, the pH of the
aqueous solution is 7.
EXAMPLE 6
Production of tablets:
______________________________________
Di(4-hydroxybutyric) calcium
500 mg
Tablet additive (in conventional manner)
ad 1000 mg
______________________________________
EXAMPLE 7
Production of capsules:
______________________________________
D(4-hydroxybutyric) magnesium
300 mg
Lactose 120 mg
Microcrystalline cellulose sold under trademark
Avicel by FMC Corp. 30 mg
Highly dispers, pyrogeneous silica containing
more than 99.8 percent SiO.sub.2 sold under trademark
Aerosil 200 by Degussa Corp, Teterboro, N.J.
2 mg
Magnesium stearate 3 mg
Weight of the capsule 455 mg
______________________________________
EXAMPLE 8
Production of suppositories:
______________________________________
Di(4-hydroxybutyric)-calcium
500 mg
Suppository mass, a clear oily hydrocarbon
(monolene) 1500 mg
Weight of the suppository
2000 mg
______________________________________
EXAMPLE 9
Production of honey liquid: 10 g magnesium salt according to example 4 are
mixed into 80 g bee honey. A yellow honey sirup was obtained having a well
tasting consistency.
EXAMPLE 10
Tablets against pain:
______________________________________
Di(4-hydroxybutyric)calcium
100 mg
Salicylic amide 300 mg
Tablet additives ad 1000 mg
______________________________________
EXAMPLE 11
Production of dragees:
______________________________________
Di(4-hydroxybutyric)calcium
200 mg
Phenylbutazone 100 mg
Dragee additive ad 600 mg
______________________________________
EXAMPLE 12
Production of capsules
______________________________________
Di(4-hydroxybutyric)calcium
200 mg
Acetylsalicylic acid
250 mg
Sorbitol 50 mg
Total: 500 mg
______________________________________
* * * * *
