CA1072011A - Stable solutions of tetracycline in aqueous 2-pyrrolidone - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Tetracycline aqueous solutions containing 2-pyrrolidone as a co-solvent suitable for pharmaceutical use and especially useful for either oral, topical or parenteral administration are disclosed.

Description

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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 `` ` `iO~201 ¦~ 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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I . , . ` . -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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107Zoll 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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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 i . .
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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07Z~lt ~¦ 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 - ~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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Claims (3)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A stable tetracycline antibiotic liquid composition which comprises a solution of from about 1 to 15% by weight of tetracycline or a pharmaceutically-acceptable acid addition salt thereof and from about 0.8 to 1.3 molar proportions based on said tetracycline of a pharmaceutically-acceptable magnesium compound dissolved in aqueous 2-pyrrolidone, and the pH of the solution being from about 7.5 to 9.5, and the 2-pyrrolidone being present at a concentration of about 10 to 70% by weight of the said composition.

2. A composition according to claim 1, wherein the said magnesium compound is magnesium oxide.

3. A composition according to claim 1, wherein polyvinylpyrrolidone having an average molecular weight of from 5,000 to 100,000 is also present in a concentration of from about 1 to 7% by weight of the total composition.