Note: Descriptions are shown in the official language in which they were submitted.
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This invention relates to antibiotic compositions suitable .
for pharmac~utiral use. More particularly, it relates to .
tetracycline solutions containing 2-pyrrolidune.
. Previous~efforts~made~to:prepare hig~ concentration
t~tracycline~solueions~have been unsuccessful. This is of
! particular importance in the case of veterinary parenteral : ,
co~positions for administration to large animals. ¦
U.S. Patent No. 2,990,331 disceloses parenteral solu~ions
'I of tetracycline hydrochIoride, containing a~fout 50 mg.JmL
: ~ 1, hàving a~pH valuf_ between 5 and 7, containin:g ~agnesium ions,
~'~ an, lkali ~isulfite and a carboxylic acid amide~ such as ' .
- ll lactic acid-hydroxyethyl amide. ~ ¦
; Jfapanese Patent Publication No. fSho 47-303 disclosesj ;:
- /~ stable aqueous solutions of p-biphenylmethyl ~dl-tropyl~ ,
, f~-tropinium) bromide, 2.5''h:, in which 2-pyrrolidone is present ~ :
: i in a concentration of 20%~. ;The us~e~of polyvinylpyrrolidone at ; ~ .
'~ a concentration of 30~/0: is al~,o -disclosed. The pH of these
'i solution~ is less than 7, the ~referred range beiog 3
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¦~ Japanese Patent Publica~ion No. Sho 43-1758 discloses
l! insecticidal solutions containing hexachloreyclohexane in
alcohol and 2-pyrrolidone as solvents. The use of N-methyl
I pyrrolidone as a co-soIven~ is also disclosed.
1I British Patent Specification No. 802,111 discloses
I Ipesticidal compositions containing 2-pyrrolidone or N-methyl
,pyrrolidone as solvents for DDT, diPldrin, aldrin and similar
insecticides. The use of 67-82% of 2-pyrrolidone is exemplified.
¦ British Patent Speciica~ion No. 805,026 discloses ~he
- 10 ¦ use of N-methyl pyrrolidione in concentra~ions o~ 40% as a
solvent for various medicaments intended for parenteral
administration, such as chloramphenicol, ~,N'-dibenzyl
` ethylenediamine-dipenicillin G and procaine penici11in.
U.S. Patent No. ~,987,437 discloses nematocidal
' 15 composi~ions of 3,4-dichlorotetrahydrothiophene, l,l-dioxide
i in 2-pyrrolidone.
' l ~ German Patent No. 1,091,287 ~discloses stab~e aqueous
,i solutions of tyrothricin 0.25% or subtilin 0~2~/o for nasal or
,, otic use prepared with the aid or pyrrolidone and/or
polyvinylpyrrolidone as solubilizers. Pyrrolidone is used in
a concentration of 0.5% and polyvinylpyrrolidone can be used
up to 10%. `
U.S. Patent No. 3,062,717 discloses aqueous parenteral
solutions of~tetracycline calcium complexes containing
; 25 35-80% of an amide o~ acetic or lactic acid, such as N,N-
dimethylacetamide or N-(~-hydroxyethyl) lactamide, at a pH of
7 to 9.5. C centrations ot lO to lOO Lg/ml are disclosed.
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J. Pharm. Sci. 46, p.458 (1957) discloses that .
. oxytetracycline forms soluble complexes with N~methyl .
¦pyrrolidone in aqueous solution. The de~ree of interaction is
ilimited by pH and solubility considerations.
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It has now been found that stable high potency sQlutions
o~ tetracycline can be provided by means of a novel pharma-
ceutical composition compxising an aqueous ~olution of from
about 1 to 15~ by weight of an antibiotic compound selecte~ ~ .
from tetracycline and the pharmaceutically acceptable acid
lO addi~ion salts thereof, abou~ 0.8 to l.3:molar proportions -
based on said antibiotic of:a pharmaceutically acce~table :
magnesium compound soluble in said solution, and from about
lO to 70~ by weight of 2-pyrrolidone, said com~osition having
. . a pH value in the range of from about 7~5 to 9.5.
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. Tetracycline, the therapeutically-active co~ponent of
:~ . this inven~ion, is a widely used tetracycline-type antibiotlc.
It is particularly described in U.S. Patent No. 2,699,054. .
An effective concentration range for tetracycline in the .
soLutions of i~ inventi~A is sener~l1y fro~ abo~ i o ~
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by we~ght of the.~total in the form of the free base or a
¦¦ pharmaceutically acceptable acid addition salt. ! The preferred
~i form is the free base with the preferred concentration being
¦I from about 5 to 15% by weight, with the especially preferred .
5 ¦', concentration being ~rom about 5 to 10~ b~ weight. .
~! F.xamples of suitable tetracycline ~cid addition salts
¦¦ which can be used include such pharmaceutically~acceptable
acid addition salts as hydrochloride 9 hydrobromide and sulfate.
~owever, the preferred acid addition sa~ is tetracycline .
~0 hydrochloride. -
I Magnesium ions combine with tetracyc~ e in solution to
¦ form magnesium-tetracycline chelates. M~gnesium oxide is a .
¦ convenient and preferred source of magnesi~m ions, but other
¦ magnesium compounds useful for the purpose o~ this invention
: 15 I include magnesium chloride, magnesium acetate and magnesium
sulfate. The molar ratio of magnesium to te~racycline in
¦ these compositions is about from 0.8 to 1.3 mole. This ratio
- is advLsable to produce ~lear stable solutlons. . .
2-Pyrrolidone is present as a co-sol~ent in a concentration
of rom about 10 to 70%, and preferably from about 60 to
. 7070, based on the total weight of the com~osi~ion. ~ . .
. 2-Pyrrolidone is also known as 2-pyrrolidinone, 2-oxopyrrolidine J
- . . a-pyrrolidone and 2-ketopyrrolidine. It has an oral LD50 of
¦ 8 gm/kg in rats and 3.8 gmlkg by intraperitoneal injection in
: - 2~ 1 mice. Its use allows ~or minimum volume ~er dose and excellent!I satisfactory due to low viscosity of the ~esultant compasition.
As an optional ingredient polyvinylpyrrolidone
lll may also be present in a concentration o from about 1 to 7%
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by weight. The polyvinylpyrrolidone preferred ~or this
invention is one having an average ~olecular weight of between
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 solu~ions or therapeutic
administra~ion is still further enchanced by the use of
¦ ~ntioxidants such a sodium or magnesium formaldehyde sulfoxylate
: and monothioglycerol at levels of from about 0.01 ~o 1.0% . .
by weight. .
The pH value is adjusted if necessary to pH 7.5 to 9.5. The
preferred range is pH 8 ~o 9. The pH can be adjusted with an
organic base such as monoethanolamine, ~r with an acid that is
pharmaceutically acceptable, such as hydrochlorie acid.
The compositions of ~his invention are readily prepared by
. mixing the magnesium compound with the 2-pyrrolldone and water
: at about 50C and slowly adding the tetracycline antibiotic .
.~ . wi~h s~irring until dissolved. The pH is then adjusted to the
: desired range. If polyvinylpyrrolidone is to be included it isadded to the 2-pyrrolidone and water before the addition of the
magnesium compound as previously described. ~
: . These compositions are also easy to syringe o~er a wide
temperature range and are sa~isfactory rom a physical and
chemical stability standpoint. - . - .
: 25 The use of these high potency tetracycline compositions
enables a reduction of the number of injections that must be
- administered to large animals, such as steers, in order to
receive an effecti~e dose.
The primary application is as a parenteral composition .
3 1¦ but the new compositions can also be used for topical or oral
. ¦ application.
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. ExamPle 1 , . , , .
The following solution containing 100 mg/ml of
tetracycline hydrochloride activity was prepared.
J100 ml
Tetracycline (based on a :
te~racycline hydrochluride potency of
~955 ~/mg plus a 5% overage) 10.995
Magnesium oxide 0.958
2-Pyrrolidone : 70.00
~: 10 Sodium formaldehyde sulfoxylate 1.00
Poly~Tinylpyrrolidone K-17 . 5. 00 1
Monoethanolamine, to adjust pH to 8.5 ~
. WatPr q.s. to , 100 ml `
The 2-pyrrolidona~was mixed with water. Polyvinyl- :
. 15 pyrrolidone was~then added and stirred until dissolved. The
solution was heated to about 50C and thP sodium formaldehyde :
~ sulfoxylate was:added and dissolved with stirring. . The ~ .
I magnesium oxide was then slurried with the solution; The .
tetracycline was slowly added with stirring until a clear ~ -
I solution resulted.~ Thè soiution was ~allowed to cool to room:
;~ temperature and thé pH adjusted to 8.5 with monoethanolam~ne. ;
The solution was then brought up to volume with water.
A comparable solution was made by using 60.00 ~m/100 ml
- of 2-pyrrolidone instead of 70.00 gm/100 ml. ;
- 25 ~ Example 2
The following solution containing 50 mg/ml of tetracycline .
. hydrochloride~ activity was prepared using the procedure described
in Example 1. -
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~/100 ml .
Tetracycline (based on a
. tetracycline hydrochloride potency of
955 ~/mg plus a 5% overage) 5.496
Magnesium oxide - 0.479
2-Pyrrolidone 70.00
Sodium::formaldehyde sul~oxylate ~.00
Polyvinylpyrrolidone K-17 5.00
Monoe~hanolamine, to adjust p~ to 8.5
Water q.s. to -100 ml
~:- A solution comparable to the above was also made by
us~ng 50.00 ~/100 ml of 2-pyrrolidone instead of 70.00 g/100 ml.
. Exampie 3 - - .
. . The following solution con~aining ~n mg/ml tetracycline
hydrochloride activity was prepared using the procedure described
. in Example 1.
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Tetracycline (based on a
. tetracycline hydrochloride potency of
- 20 9~5 ~Img plus a 5% overage) 5.496 .
. Magnesium oxide ` 0~479 - .
2-Pyrrolidone 60.00
: I Magnesium formaldehyde sulfoxylate 0.44 .
. ¦ Polyvinylpyrrolidone K-17 5.00
. 25 ¦ Monoethanolamine, to adjust pH to 8.5 .
¦ Water q-s- to ~ 100 ml
. ¦ Example 4 . . .
¦ The following solution containing 100 mg/ml of tetracycline
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I ~. , . j hydrochloride activity was prepared using the procedure described I
~ in ~xarple 1, excepC the polyvinylpyrrolidone is not presen~. !
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. . /100 ml
Tetracycline (based on a .
tetracycline hydrochloride potency of
955 ~/mg plus a 5% overage) 10.995
Magnesium oxide 0.958 .
2-Pyrrolidone 60.00 . .
Magnesium fonmaldehyde sulfoxylate . O.44
~Ionoethanolamine, to adjust pH to 8.9 ~.
Water q.s. to . 100 ml
. - 10 A comparable solution containing 70.00 glml of
2-pyrrolidone~with the RH adjusted to 8.8 was also prepared. .
Example 5 : . :
The following solution con~aining 50 mg/ml of tetracyclin~
- ~ hydrochloride a tivity was prepared using the procedur~ described
in Example 4. ~
; . . gmllOO ml
Tetracycline (based on a -
:tetracycline hydrochloride potency of
955 ~/mg plus a 5% overage) 5.496 .
. 20 M~gnesium oxide - . 0.479
. 2-Pyrrolidone ~ ~ 60.00
i . Magnesiu~ formaldehyde sulfoxylate . 0.44
. Monoethanolamine, to adjust pH to 8.8 .
Water q.s. to .100 ml .
A ~omparable solution containing 70.00 glml o~
. ' 2-prseolid~n with the ~H ad~usted to ~.7 wa3 ~l~o prep~re .
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~¦ Example 6
The following solution containing 100 mg/ml of tetracycline
hydrochloride activity was prepared using the procedure
l~described in Example 4.
1l ~/100 ml
IITetracycline ~ydrochlorid~ (based
i!on a ~etracycline hydrochloride
i¦potency of 980~ /mg~plus a 5% overage) 10.714
! Ma~nesium oxide ; O.g39
l~ , 2-Pyrrolidone 60.00
: ¦Sodium formaldehyde sulfoxylate l.00
¦ Monoethanolamine, to adjus~ pH to 8.5
! Water q.s. to . . . 100 ml
Example 7
, The following solution containing 10 mg/ml o tetracycline
~lhydrochloride activity was prepared following the procedure
I ¦¦ described in Example 4, except that the pH is adjusted with
concentrated hydrochloric acid.
~ m/lOO ml
20 11 Tetracycline (based on a .
!¦ tetracycline ~ydrochloride potency
of 955 ~/mg plus a 5% overage) -
l.Og9
. j Magnesium oxide 0.096 .
I 1 2-Pyrrolidone
30 00
- ~5 i! Sodi~m formaldehyde sulfoxylate
1.00 .
Concentrated hydrochloric acid, to
adjust pH to 7.5 .
ater q.s. to 100 ml
. Solutions comparable to the above were also made by
~: 30 ~ adjusting the pH to 6.5 and 5.2 respectively.
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