COMPOSITIONS A BASE D'OXYTRETRACYCLINE A ACTION PROLONGEE

LONG-ACTING OXYTETRACYCLINE COMPOSITION

Abrégé français

Une composition injectable présentant un effet résiduel supérieur avec des effets préjudiciables réduits tels que la douleur sur le site d'injection, le gonflement, l'irritation des tissus ou la nécrose, et contenant comme principe actif un composé de tétracycline, soit comme base libre soit comme sel de celle-ci avec un acide physiologiquement acceptable, transformé en complexe avec une dose sensiblement équimolaire d'un composé de magnésium et solubilisé dans un système de solvants miscibles à l'eau comprenant soit (i) a) du glycérol formal en une quantité comprise entre environ 10 et environ 50 % v/v; avec b) du polyethylène-glycol en une quantité comprise entre environ 1 et 15 % v/v; ou (ii) environ 25 à environ 75 % v/v de N-méthylpyrrolidone, ladite composition contenant facultativement un agent modificateur de pH en une dose suffisante pour maintenir un pH physiochimiquement acceptable, le solde étant constitué d'eau q.s.

Abrégé anglais

An injectable composition of higher residual effect with reduced detrimental
effects such as pain at injection site, swelling, tissue
irritancy or necrosis and containing as active principle a tetracycline
compound, either as the free base or a salt thereof with a physiologically
acceptable acid, complexed with a substantially equimolar amount of a
magnesium compound, is solubilised in a water miscible solvent
system comprising, either (i) a) glycerol formal in an amount of from about 10
to about 50 % v/v; with b) polyethylene glycol in an amount
of from about 1 to 15 % v/v; or (ii) from about 25 to about 75 % v/v of N-
methylpyrrolidone, said composition optionally containing a pH
modifier in an amount sufficient to maintain a physiochemically acceptable pH,
the balance being made up with water q.s.

Revendications

WHAT IS CLAIMED IS:
1. A composition containing as active principle an amount of a tetracycline
compound effective for antibiotic activity, either as the free base or a salt
thereof with a
physiologically acceptable acid, complexed with a substantially equimolar
amount of a
magnesium compound, solubilized in a water miscible solvent system comprising,

a) glycerol formal in an amount of from about 10 to about 50% (v/v); with
b) polyethylene glycol wherein,
(i) when the polyethylene glycol has a molecular weight of not more than
about 200, the polyethylene glycol is present in an amount of from about
1% to about 20%, (v/v);
(ii) when the polyethylene glycol has a molecular weight of not more than
about 400, the polyethylene glycol is present in an amount of from about
1% to about 15% (v/v);
(iii) when the polyethylene glycol has about molecular weight of not more than
about 6000, the polyethylene glycol is present in an amount of from about
1% to about 10% (v/v); and
(iv) when the polyethylene glycol has a molecular weight of greater than about
6000, the polyethylene glycol is present in an amount of from about 1% to
about 5% (v/v),
said composition optionally containing a ply modifier in an amount sufficient
to maintain
a physiologically acceptable pH, the balance being made up with water q.s.
2. The composition of claim 1, wherein the tetracycline compound is present in
an
amount of from about 15% to about 35% w/v.

3S. The composition of claim 1, wherein the tetracycline compound is present
in an
amount of about 30%.
4. The composition of claim 1, wherein the tetracycline compound is
oxytetracycline
base or its hydrochloride.
5. The composition according to claim 1, further comprising, as a thickener,
polyvinyl pyrrolidone in an amount of up to about 10% (w/v).
6. The composition according to claim 1, wherein the magnesium compound is
selected from the group consisting of magnesium oxide, magnesium salts and
magnesium
chloride.
7. The composition according to claim 1, wherein magnesium oxide is present in
an
amount of about 2.7% (w/v) and further comprising, as antioxidant, sodium
formaldehyde
sulphoxylate in an amount of about 0.4% (w/v).
8. The composition according to claim 1, wherein the composition contains
about
30% (w/v) oxytetracycline, about 40% glycerol formal, between about 1 % and
about 20% (v/v)
polyethylene glycol 200 with a magnesium containing complexing agent or
stabilizer,
antioxidant and water making up the balance.
9. The composition according lo claim 8, the magnesium-containing complexing
agent is magnesium oxide present in an amount of about 2.7% (w/v) and sodium
formaldehyde
sulphoxylate as an antioxidant in an amount of about 0.4% (w/v).

10. The composition according to claim 1, wherein the composition contains
about
30% (w/v) oxytetracycline, about 40% glycerol formal, between about 1% and
about 15% (v/v)
polyethylene glycol 400 with a magnesium-containing complexing agent or
stabilizer,
antioxidant and water making up the balance.
11. The composition according to claim 10, wherein the magnesium-containing
complexing agent is magnesium oxide present in an amount of about 2.7% (w/v)
and sodium
formaldehyde sulphoxylate as an antioxidant in an amount of about 0.4% (w/v).
12. The composition according to claim l, wherein the composition contains
about
30% (w/v) oxytetracycline, about 40% glycerol formal, between about 1% and
about 10% {v/v)
polyethylene glycol 800 with a magnesium-containing complexing agent or
stabilizer,
antioxidant and water making up the balance.
13. The composition according to claim 12, wherein the magnesium-containing
complexing agent is magnesium oxide present in an amount of about 2.7% (w/v)
and sodium
formaldehyde sulphoxylate as an antioxidant in an amount of about 0.4% (w/v).
14. The composition according to claim 1, wherein the composition contains
about
30% (w/w) oxytetracycline, about 40% glycerol formal, between about 1% and
about 10% (v/v)
polyethylene glycol 1500 with a magnesium-containing complexing agent or
stabilizer,
antioxidant and water making up the balance.
15. The composition according to claim 14, wherein the magnesium-containing
complexing agent is magnesium oxide present in an amount of about 2.7% (w/v)
and sodium
formaldehyde sulphoxylate as an antioxidant in an amount of about 0.4% (w/v).


16. The composition according to claim 1, wherein the composition contains
about
30% (w/v) oxytetracycline, about 40% glycerol formal, between about 1% and
about 10% (v/v)
polyethylene glycol 6000 with a magnesium-containing complexing agent or
stabilizer,
antioxidant and water making up the balance.
17. The composition according to claim 16, wherein the magnesium-containing
complexing agent is magnesium oxide present in an amount of about 2.7% (w/v)
and sodium
formaldehyde sulphoxylate as an antioxidant in an amount of about 0.4% (w/v).
18. The composition according to claim 1, wherein the composition contains
about
30% (w/v) oxytetracycline, about 40% glycerol formal, between about 1% and
about 5% (v/v)
polyethylene glycol 8000 with a magnesium-containing complexing agent or
stabilizer,
antioxidant and water making up the balance.
19. The composition according to claim 18, wherein the magnesium-containing
complexing agent is magnesium oxide present in an amount of about 2.7% (w/v)
and sodium
formaldehyde sulphoxylate as an antioxidant in an amount of about 0.4% (w/v).
20 A composition containing contains about 30% (w/v) oxytetracycline as active
principle, complexed with a substantially equimolar amount of a magnesium
compound,
solubilized in a water miscible solvent system comprising glycerol formal in
an amount of about
40 (v/v) with from about 1% to about 15% (v/v) polyethylene glycol 1500, said
composition
optionally containing a pH modifier in an amount sufficient to maintain a
physiologically
acceptable pH, the balance being made up with water q.s.

21 The composition according to claim 20, wherein the magnesium-containing
complexing agent is magnesium oxide present in an amount of about 2.7% (w/v)
and sodium
formaldehyde sulphoxylate as an antioxidant in an amount of about 0.4% (w/v).

Description

W096l01634 ~ l 9 4 57 ~ PCTlGB95I01583
1
Long-ACtiag Oxytetracycline Composition
This invention relates to injectable formulations
containing tetracyclines, particularly oxytetracycline,
which exhibit higher residual effect with less of the known
detrimental effects such as pain at injection site,
swelling, tissue irritancy or necrosis.
Preparation of pharmaceutical compositions containing
r
tetracyclines and oxytetracycline in-particular has always
presented a challenge due to aqueous solubility constraints
which firstly have impact upon composition stability, and
secondly upon parenteral administration.
Prior art oxytetracycline compositions have exhibited
relatively high viscosity at low temperatures which makes
injection difficult, have shown poor stability and suffered
limitations on strength of active principle. Thus
considerable research has gone into determining suitable
complexing agents and more favourable co-solvents to address
these shortcomings. A review of the art suggests that
presence of calcium, and especially magnesium in the
formulation now appears mandatory as-a complexing agent and
whereas some improvements have been made in stability and
delivery by adopting various co-solvent systems, higher
concentration loadings and residual effect remain areas in
which improvements are needed. This is especially of
interest for veterinary purposes where the need is to
deliver high effective doses with minimum effort in animal
handling and detrimental effect on the animal requiring
treatment.
At the current time prior art so-called-"long-acting"
oxytetracycline formulations typically contain 200 mg/ml
oxytetracycline and are administered at 20 mg/kg body
weight, having activity as determined by residual blood
levels of oxytetracycline detectable for up to about four
o days or so.
An object of this invention is to provide a composition
r. of substantially greater long acting effect whilst
minimising to the greatest extent possible the defects
observed in previously proposed formulations. In particular
the invention to be particularly described hereinbelow
SUBSTITUTE SHEET (RULE 26)

WO 96101634 PCTIGB95101583
2194576 2
provides for administratipn of an oxtetracycline formulation -
at dose rates of from l0 to 4D mg%kilogram bodyweight,
giving at 30 mg/kg in animals_an extendgd_duration_._of
effective plasma levels against susceptible organisms in
excess of 9 days which is a surprising achievement in the
light of the known prior art.
Solubility of oxytetracycline in non-aqueous solvents ;
was considered by Eugene Gans and Takeru Higuchi, Journal of -
the American Pharmaceutical Association, 1957, Vol XLVI, pp '
587-591. . __. _.. _. _. . _ . -- _. -_ ._ _. . _ _
The patent literature in this area is extensive and-one
could refer to the following patents which are illustrative
of the decades of research carried out-on formulation nf_
tetracycline compositions:
GB-A-894 619, GB-A-1'-131 007, GB-A-1 250 304,
GB-A-1 286 351, GB-A-1 427 882, GB-A-1 494 558,
GB-A-1 50-8 601, GB-A-1 514 838, GB-A-1 520 197,
GB-A-1 538 903 GB-A-1 563 478, GB-A-1--592 053,
GB-B-2 047 D97; EP-B-38 1D3, EP-B-96 942; US-A-2 516 080,
US-A-2 980 584, US-A-2 990 331,-US-A-3 062 717,
US-A-3 219 529, US-A-3 557 280, US-A-3 712 949,
US-A-3 957 972, US-A-4 011 313, US-A-4 018 889,
US-A-4 020 162, US-A-4 126 680, US-A-4 386 083,
US-A-4 399 127, US-A-4 772 460, US-A-4 957 972, and
US-A-5 075 295. _
From these documents it is apparent that a variety of
water-dispersible complex-stabilisers or-water-miscible co-
solvents have been proposed including2-pyrrolidone,
polyvinyl pyrrolidone, polyethylene glycols,-caprolactam~ 2-
piperidone, and glycerol formal (a reaction product of
glycerol-and ~ormaldehyde) in specific formulations-.-
However it is by no means clear that the said co-solvents
are equally interchangeable non can the effect of_,such a_
change be entirely predictable for a given formulation. ,
US-A-4 386 083 proposes useof glycerol formal in
conjunction with magnesium acetate and magnesium chloride,
whilst US-A-4 772 460 proposes use of N-methylpyrrolidone
(1-methyl-2-pyrrolidone) and a soluble magnesium compound.
SU B STTTTJT'E SH EET (RlD LE 26)

W O 96101634 219 4 5 7 6 PCTlGB95/01583
3
US-A-5-075 295-is particularly directed to a composition
aiming to achieve up to 30% oxytetracycline, which contains
polyethylene-glycol 400 and magnesium oxide, but examples
given only appear to show a capability of achieving up to
25% oxytetracycline and there is-to-applicant's knowledge no
current commercially available product capable of achieving
greater than 20%.
Accordingly this invention provides a composition
containing as active principle a tetracycline compound,
either as the free base or a salt thereof with a
physiologically-acceptable acid, complexed with a
substantially equimolaramount of a magnesium compound,
solubilised in a water miscible solvent system comprising, -
either
(i) a) glycerol formal in an-amount of from about 10 to
about 50% v/v; with
b) polyethylene glycol in an amount of from about 1 to
15% v/v; or
(ii) from about 25 to about 75% v/v of N-methylpyrrolidone,
said composition optionally containing a pH modifier in an
amount sufficient to maintain a physiochemically acceptable
pH, the balance being made up with water q.s.
The composition optionally contains a thickener such as
polyvinyl pyrrolidone in an amount of up to 10% w/v, and may
contain usual formulation aids or auxiliaries typically used
for such formulations. Thus the composition may contain
antioxidants, e.g. sodium formaldehyde sulphoxylate and pH
adjusting agents e.g. monoethanolamine, to provide a
preferred pH range of from about 7.5 to about 9.5, more
preferably from about 8.5 to about 9Ø
Preferably the composition contains a magnesium
compound such as magnesium oxide or a salt e.g magnesium
chloride.
The preferred compositions contain oxytetracycline ae
the base or its hydrochloride in an amount of from about 15
to about 35% w/v, complexed with an equimolar ratio of a
magnesium compound, preferably a salt, solubilised in a
solvent system comprising polyethylene glycol in an amount
SUBSTITUTE SHEET (RULE 26)

WO 96101634 ~ ~ g ~ ? 7 ~]- PCTIGB95101583
4
of from about 1 to about 154 v/v-and glycerol formal in-an
amount of from about 10 to about 50% v/v. In particularthe
most preferred composition contains about 30% w/v oxytet_ra-
cycline, about 40% glycerol formal, about i0% v/v poly-
ethylene glycol with a magnesium_containing complexing agent
or-stabiliser, antioxidant and-water making up the balance.
In that composition magnesium oxide is suitably present in ;
an amount of about 2.7% w/v and, as antioxidant, sodium
formaldehyde sulphoxylate in an amount of about 0-.4% w/v may
be used. Thus according to the present invention-there is
provided a formulation capable of providing from about 10 to
about 40 mg/kg bodyweight consisting of.: _.
Oxytetracycline 300 mg
Magnesium oxide - 27 mg
Sodium formaldehyde aulphoxylate _- 4-mg
Glycerol formal 0.4 ml
Polyethylene glycol ,-0.1 ml
Monoethanolamine q.s. pH 8.6 to 8-.8
Water for injections ~g 1 ml -
Theinvention will now be further deacribsd.by way of
example for the purposes of practical illustration only.
An oxytetracycline formulation was prepared according
to theprocedure indicated below using the following
components:
Active Ingredient -
Oxytetracycline 3D% w/v
Excipients -
Magnesium oxide 2.7% w/v
Sodium formaldehyde sulphoxylate q.4~ w/v
3D Glycerol formal 40% w/v
Polyethylene glycol 1D% w/v
Monoethanolamine q.s. pH 8.6 to 8-.8
Water for injections ~g !0D% w/v
A controlled environment having an inert atmosphere was
provided within which suitable mixing and temperature
controllable heating apparatus was assembled. A nitrogen
blanket is considered suitable for this purpose. The above
SUBSTITUTE SHE~T(RULE 26)

W O 96101634 2 I 9 4 ~ ~ ~ P~IGB95101583
components of the proposed composition were mixed by
initially mixing a proportion of the total water with the
selected solvents. The sodium formaldehyde sulphoxylate,
magnesium oxide-and oxytetra-cycline were added sequentially
5 whilst mixing continuously and maintaining a temperature of
approximately 65°C until all the-constituents have
dissolved. Thereafter, the composition is cooled to below
30°C and the pH is adjusted to lie within the range of 8.0
to 9.0, in this case by adding a sufficient amount of mono-
ethanolamine. Finally the volume is made up with water, the
pH checked and-adjusted if necessary, and the composition is
filtered through a 0.2 ~Cm filter and filled into appropriate
containers.
In alternative embodiments, where use of a thickener
such as polyvinyl pyrrolidone is called for then it should
preferably be added after the sodium formaldehyde
sulphoxylate.
The following Tables provide details of Examples 1 to
14-each of which provided compositions showing excellent
stability and which achieved the desired dosage levels and
long acting effect.
J
SUBSTITUTE SHEET (RULE 26)

WO 96/01634 ~ ~ g 4 5 7 b PCT/GB95/01583
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