Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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This invention relates to antibiotie compositions suitable ¦
for pharmaceutical use. More particularl~ it relates to
chlortetracycline solutions containing 2-pyrrolidone. ~ ¦
Previous efforts made to prepare high concentration chlor- '
5 i tetracycline solutions have been unsuccessful. This is of ¦
I particular importance in the case of veter;nary parenteral
; compositions for administration to large animals.
Japanese Patent Publication No. Sho 47-303 discloses
stable aqueous solutions of p-biphenylmethyl ~dl-tropyl-
a-tropinium) bromide, 2.5%l in which 2 pyrrolidone is present
in a concentration o 20%. The use of polyvinylpyrrolidone at
a concentration of 30~/O is also disclosed. The pH o~ these ¦
solutions is less than 7, the preferred range being 3~4.
' Japanese Patent Publication No. Sho 43-1758 discloses
insecticidal solutions containing hexachlorcyclohexane in
alcohol and 2-pyrrolidone as solvents. T~le use o N-methyl
pyrrolidone as a co-solvent is also disclosed.
British Patent Specification No. 802,111 discloses
pesticidal compositions containing 2-pyrrolidone or N~methyl ,
pyrrolidone as solvents ~or DDT, dieldrin9 aldrin and similar ' I
-~ insecticides. The use of 67-82% of 2-pyrrolidone is exemplified,l
.
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British Patent Specification No. 805~026 discloses the
!use of N-methyl pyrrolidone in concentrations of ~0% as a
¦solvent for various medicaments intended for parenteral
¦! administration, such as chloramphenicol, ~3~ dibenzyl
l~ ethylenediamine-dipenicillin G and procaine penicillin.
U.S. Patent No. 2,987,437 discloses nematocidal
compositions of 3,4-dichlorotetrahydrothia~hene, l,l-dioxide
in 2-pyrrolidone.
German Patent No. 1,091,287 discloses stable aqueous
solutions of tyro~hricin 0.25~L or subtili~ 0.2% for nasal or
otic use prepared with the aid of pyrrolidione and/or ,
polyvinylpyrrolidone as solubilizers. Pyrrolidone is used in
a concentration of 0.5% and polyvLnylpyrro~idone can be used
up to 10%.
I U.S. Patent No. 3,062,717 discloses a~ueous parenteral
¦ solutions of tetracycline calcium complexes containing 35-80%
o an amide o~ acetic or lactic acid, such as N,M-dimethyl-
acetamide or N-(~-hydroxyethyl) lactàmide, at a pH of 7 to 9.5.
Concentrations o~ 10 to 100 mg/ml are disclosed.
J. Pharm. Sci. 46, p. 458 (1957) discloses that
oxytetracycline forms soluble complexes with N-methyl
¦ pyrrolidone in aqueous solution. The degree o~ interaction is
limited by pH and solubility considerations.
U.S. Patent Application Serial No. 64~,295
discloses oxytetracycline solutions conta;ning from about 1
to 40 percent oxytetracycline in an aqueous vehicle containing
from about 10 to 50 percent by weight of 2-pyrrolidone, about
i 0.8 to 1.3 molar proportions of a pharmaceutically acceptable
¦ magnesium compound soluble in the said solution, said solution
3o having a pH value in the range of from ab~ut 7.5 to 9.5.
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It h~s now been found that stable high potency solutions
of chlortetracycline can be provided by means of a novel pharma-
ceutical composition comprising an aqueous solution of fromI 1
about 5 to 20% by weight of an antibiotic compound selected
S ¦from chlortetracycline and the pharmaceuticaily acceptable acid
1 addition salts thereof, about 2 to 4 molar proportions
¦based on said antibiotic of a pharmaceutically acceptablecalcium compound soluble in said solution, and from about 50
to 70% by weight of 2-pyrrolidone, said composition having .
a pH value in the range of from about 8 to 10
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Chlortetracycline, the therapeutically-active componen~ of
this invention, is a widely used tetracycline-type antibiotic.
It is particularly described in U.S. Patent No. 2,482,055.
An effective concentration range for chlortetr~cycline in the
solutions of ~his invention is generally from about 5 to 20%
by weight of the total in the form of the free base or a
pharmaceutically acceptable acid addition salt. The preferred
form is the acid addition salt with the pre~erred concentra~ion
bein~ from about 10 to 20% by weight, with the especially
preferred concentration being from about 10 to 15% by weigh~.
Examp~es of suitable chlortetracycline acid addition salts
1l~hich can be used include such pharmaceutically acceptable
I; acid addition salts as hydrochloride, hydrobromide and sulf2te.
IHowever, the preferred acid addition sale ~s chlortetracycline
25 I hydrochloride.
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Calcium ions combine with chlortetracycline in solution to
form calcium-tetracycline chela~es. Calcium chloride is a
convenient and preferred source of calcium ions, but other
compounds useful for the purpose of this invention
, include calcium oxide, calcium acetate and calcium sulfate.
The molar ratio of calcium to chlortetracycline in
these compositions is about from 2 to 4. This ratio is
advisable to produce clear stable solut}ons.
'll 2-Pyrrolidone is present as a co-solvent in a concentration I
of from about 50 to 70%, and preferably from abou~ ~0 to 70%
based on the total weight of the composition. 2-Pyrrolidone t
is also known as 2-pyrrolidinone, 2-oxopyrxolidine,
, a-pyrrolidone and 2-ketopyrrolidine. It has an oral LD50 of
, 8 gm/kg in rats and 3.8 gm/kg by intrape~itoneal injection in
15 ~; mice. Its use allows for minimum volume per dose and excellent
', satisfactory due to low viscosity of t'ne resultant composition.
, As an optional ingredient polyvinylpyrrolidone
! may also be present in a concentration of from about 1 to 7%
,, by weight. The polyvinylpyrrolidone preferred for this
20 'I inyention is one having an average molecular weight o bet~een
about 5,000 and 100,000 (K-12 to 30) and especially between
, about 10,000 and 17,000 ~K - 17). It is present in
` part as a cosolubilizer and may improve tissue toleration.
,~ The stability of these solutions for therapeutic
25 , administration is still further enchanced by the use of
antioxidants such as sodium or magnesium formaldehyde sulfoxylate
and monothioglycerol at levels of from about 0.01 to 100%
by weight. -
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¦I The pH value is adjusted if necessary to pH 8 to 10. The
¦ preferred range is pH 8.5 to 9. 5. The pH can be adjusted with an
! organic base such as monoethanolamine or with a pharmaceutically
¦l acceptable acicl, such as hydrochloric acid.
5 ¦~ The compositions of this invention are readily prepared by
mixing the calcium compound with the 2-pyrrolidone and water
at about 50C and slowly adding the chlortetracycline antibiotic !
with stirring and adjusting the pH to the
desired range. If polyvinylpyrrolidone is to be included it is
added to the 2-pyrrolidone and wa~er before the addition of the
¦ calcium compound as previously described.
These compositions are also easy to syringe over a wide
temperature range and are satisfactory from a physical and
¦ chemical stability standpoint.
¦ The use of these high potoncy chlortetracycline compositions
¦¦ enables a reduction of the numb~or of injections that must be
administered to large animals, such.as steers, in order to
receive an effective dose.
The primary application is as a parenteral composition
¦, but the new compositions can also be used for topical or oral
~ ap~lication.
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EX~PLE 1
¦il The following solution con~aining 100 mg/ml of chlortetra-
¦, cycline hydrochloride activity was prepared.
Il gm~100 ml
5 i¦ Chlortetracycline hydrochloride (based on
a chlortetracycline hydrochloride potency
llf 950~/mg plus a 5~ overage) 11.053
¦I Calcium chloride ~.96
ji 2-Pyrrolidone 60.00
10 ,I Monothioglycerol 1.00
Il Monoethanolamine, to adjust pH to 8.8
¦IWater q.s. to 100 ml
I¦ The 2-pyrrolidone was mixed with water. The solution was
¦!heated to about 50C. and the monothioglycerol was added and
i dissolved with stirring. The calcium chloride was then slurried
¦~with the solution. The chlortetracycline hydrochloride was
!islowly added with stirring and the pH raised with monoethanol-
¦¦ amine until solution resulted. The solution was allowed to cool
lito room temperature and the pH adjusted to 8.8 with monoethanol- i
20 1¦ amine. The solution was then brought up to volume with water.
Solutions comparable to the above were also made by adjustin~
the pH to 8.0 and 9.5 respec~ively.
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EXA~iPLE 2
The following solution containing 100 mg/ml of chlortekra~
¦ cycline hydrochloride activity was prepared using the procedure
, described in Example 1.
5 I gm/100 ml
Chlortetracycline hydrochloride (based on
a chlortetracycline hydrochloride potency
of 950~/mg plus a 5~ overage) 11.053
Calcium chloride 9.92
1 2-Pyrrolidone 60.00
Monothioglycerol 1.00
Monoethanolamine, to adjust pH to 8.8
I Water q.s. to 100 ml
¦i Solutions comparable to the above were also made by adjusting
the pH to 8.0 and 9.5 respectivelyf
_XAMPLE 3
The following solution containing 50 mg~ml of chlortetra-
l cycline hydrochloride activity was prepared.
¦ gm/100 ml
1 Chlortetracycline h~drochloride (based on
a chlortetracycline h~drochloride potency
¦ of 950 ~/mg plus a 5~ overage) 5.527
Calcium chloride 2.48
1 2-Pyrrolidone 50.00
25 i Polyvinylpyrrolidone 5.00
I~ Monothioglycerol 1.00
! Monoethanolamine, to adjust pH to 8.8
¦I Water q.s. to 100 ml
l~ The 2=pyrrolidone was mixed with water~ Polyvinylpyrrolidone
I" was then added with stirring until dissolved. The procedure
described in Example 1 was then followed.
Solutions comparable to the above were also made by adjusting
the pH to 8.0 and 9.5 respectively.
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EXAMPLE 4
The follow.ing solution containing 200 mg/ml of chlortetra-
I cycline hydrochloride activity was prepared using the procedure
¦described in Example 1.
m/100 ml
~ Chlo~tetracycline hydrochloride (based on
¦ a chlortetracycline hydrochloride potency
f 950 ~/mg plus a 5% overage~ ~2,1Q6
¦ Calcium chloride 9.92
!2-Pyrrolidone 60.00
¦ Monothioglycerol . ~.00
iMonoethanolamine, to adjust pH to 8.8
~jWater q.s. to 100 ml
I Solutions comparable to the above were also made by adjusting
1l the pH to 8.0 and 9.5 respectively.
i EX~lPLE 5
The following solution containing 100 mg/ml of chlortetra-
cycline hydrochloride activity was prepared using the procedure
Ijdescribed in Example 1.
2~ m/100 ml
¦,Chlortetracycline hydrochloride (based on
a chlortetracycline hydrochloride potency
11f 950 ~/mg plus a 5% overage) 11.053
IiCalcium chloride 4.9~
2~ ~12-Pyrrolidone 70,00
.IMonothioglycerol 1~00
Monoethanolamine, to adjust pH to 8.8
Water q.s. to 100 ml
I, Solutions comparable to the above were also made by adjusting
3 I the pH to 8.0 and 9.5 respectively.
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l EXAMPLE 6 l
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The following solu~ion containing lOO m~/ml of chlortetra-
cycline hydrochloride activity was prepare~ using the procedure
Idescribed in Example 3. ` .
5 ! gm/lOO ml
Chlortetracycline hydrochloride (based on . .
a chlortetracycline hydrochloride potency
of 950 ~/mg plus a ~% overage) 11.053
!Calcium chloride 4.96
2-Pyrrolidone . 60.00
¦Polyvinylpyrrolidone 5.00
¦Monothioglycerol 1,00
¦ ~onoethanolamine, to adjust pH to 8.8
~jWater q.s. to lOO ml
~I Solutions comparable to the above were also made by adjusting
~ llthe pE to 8 0 and 9.5 respectively.
_g_ ~
