Europäisches Patentamt

(19) European Patent Office *EP001094802B1*

Office européen des brevets (11) EP 1 094 802 B1
(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.7: A61K 31/165, A61K 9/08,
of the grant of the patent: A61K 47/10, A61P 29/00
23.01.2002 Bulletin 2002/04
(86) International application number:
(21) Application number: 99944308.8 PCT/EP99/05486

(22) Date of filing: 27.07.1999 (87) International publication number:

WO 00/07588 (17.02.2000 Gazette 2000/07)

(54) PHARMACEUTICAL COMPOSITION FOR INJECTION BASED ON PARACETAMOL

INJIZIERBARE ARZNEIZUBEREITUNG BESTEHEND AUS PARACETAMOL
COMPOSITION PHARMACEUTIQUE POUR INJECTIONS A BASE DE PARACETAMOL

(84) Designated Contracting States: (56) References cited:

AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU WO-A-98/05314 US-A- 4 307 073
MC NL PT SE
Designated Extension States: • CHEMICAL ABSTRACTS, vol. 109, no. 14, 3
AL LT LV MK RO SI October 1988 (1988-10-03) Columbus, Ohio, US;
abstract no. 115998, XP002125072 & I.R.PENIN
(30) Priority: 31.07.1998 IT MI981795 ET AL.: "DEVELOPMENT OF INJECTABLE
PARACETAMOL" REV. ASOC. ESP. FARM.
(43) Date of publication of application: HOSP., vol. 11, no. 4, 1987, pages 249-254,
02.05.2001 Bulletin 2001/18 • DATABASE WPI Week 9444 Derwent
Publications Ltd., London, GB; AN 94-355463
(73) Proprietor: AZIENDE CHIMICHE RIUNITE [44] XP002097935 & KR 9 311 994 B (DAEKWANG
ANGELINI FRANCESCO A.C.R.A.F. S.p.A. PHARM. CO.) 23 December 1993 (1993-12-23)
00181 Roma (IT) • DATABASE WPI Week 9045 Derwent
Publications Ltd., London, GB; AN 90-335491
(72) Inventors: [45] XP002097936 & DD 279 405 A (VEB BERLIN
• CAVALLO, Giovanni CHEMIE) 6 June 1990 (1990-06-06)
I-00122 Ostia (IT) • CHEMICAL ABSTRACTS, vol. 105, no. 26, 29
• PINZA, Mario December 1986 (1986-12-29) Columbus, Ohio,
I-20094 Corsico (IT) US; abstract no. 232386, XP002125073 & Z. YAN
ET AL.: "PREPARATION OF PARACETAMOL
(74) Representative: Marchi, Massimo et al INJECTIONS" YAOXUE TONGBAO, vol. 21, no.
c/o Marchi & Partners s.r.l., Via Pirelli, 19 7, 1986, pages 387-389,
20124 Milano (IT)
EP 1 094 802 B1

Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give
notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in
a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art.
99(1) European Patent Convention).

Printed by Jouve, 75001 PARIS (FR)

 EP 1 094 802 B1

Description

[0001] The present invention relates to a pharmaceutical composition for injection based on paracetamol.
[0002] In particular, in a first aspect, the present invention relates to a pharmaceutical composition for injection com-
5 prising paracetamol, a low molecular weight alcohol and a polyethylene glycol.
[0003] It has been known practice for a long time to use paracetamol as an analgesic and an antipyretic.
[0004] By virtue of its very satisfactory tolerability, paracetamol is, in some cases, preferred to other NSAIDs (non-
steroidal anti-inflammatory drugs) and, in particular, to aspirin.
Indeed paracetamol, like aspirin, exhibits its activity by inhibiting the synthesis of the prostaglandins produced by
10 cyclooxygenase. However, unlike most NSAIDs, its inhibition is exerted almost exclusively on the brain and, to a much
smaller level, on the peripheral tissues (stomach, kidneys and blood platelets). For this reason its use does not produce
the side effects typical of NSAIDs such as, for example, heartburn and gastric lesions with possible loss of blood.
[0005] The only possible complication associated with its use is liver cytolysis, although this occurs only in the case
of an overdose (Flower R.J., Vane J.R., "Nature", 240, 410-411, 1972; Lanz R., Poster P., "J. Pharmacol", 130, 105-109,
15 1986,; Black M., "Annual Reviews of Medicine", 35, 577-593, 1984).
[0006] It is also known that paracetamol is very slightly soluble in water ("The Merck Index", 12th edition, page 9,
No. 45, 1996).
[0007] This characteristic represents a major obstacle to its administration by injection. Moreover, in the presence
of water, paracetamol undergoes degradations which also give rise to pink- to brown-coloured derivatives. The most
20 common types of degradation are hydrolysis to p-aminophenol and/or oxidation by, for example, oxygen dissolved in
water. This second reaction appears to be responsible for the formation of the said derivatives.
[0008] Patent application WO 98/05314 attempts to overcome the above-mentioned drawbacks by means of a com-
position containing a solution of paracetamol in an aqueous solvent in combination with a buffer having a pH of from
4 to 8 and an agent capable of capturing free radicals. In addition, the above-mentioned document recommends re-
25 moving any oxygen which may be present in the said solvent by means of flushing with a water-insoluble inert gas.
[0009] Among the pharmaceutical compositions given as examples in the above-mentioned patent application, those
capable of dissolving the majority of paracetamol contain, besides water, PEG-400 and propylene glycol.
[0010] In particular, according to the above-mentioned document, a solution consisting of 30% propylene glycol,
40% PEG-400 and 30% water is able to dissolve up to about 200 mg/ml of paracetamol at 20°C (WO 98/05314, page
30 9, lines 7-12).
[0011] However, this solvent mixture is very viscous (see Comparative Example 1) and is thus unsuitable for admin-
istration by injection.
[0012] There is thus still a great need for a paracetamol-based pharmaceutical composition which, besides containing
therapeutic levels of paracetamol, can be injected easily and does not give rise to weals.
35 [0013] It has now been found, surprisingly, that low molecular weight alcohols promote the dissolution of paracetamol
in a polyethylene glycol.
[0014] As can be seen in the examples, the amount of paracetamol dissolved by a mixture of a low molecular weight
alcohol and of a polyethylene glycol (Example 1) is greater than that dissolved, for an equal volume, by the low molecular
weight alcohol and polyethylene gtycol alone (Comparative Examples 2 and 3).
40 [0015] This is all the more surprising if one considers that, according to the above-mentioned patent application WO
98/05314. the addition of ethanol does not increase the solubility of paracetamol in a polyethylene glycol (page 11, last
line).
[0016] In a first aspect, the present invention provides a pharmaceutical composition, characterized in that

45 a) it comprises

i) paracetamol,
ii) from 1 to 4 parts by volume of ethanol for each part by weight of paracetamol, and
iii) from 1 to 5 parts by volume of a polyethylene glycol for each part by weight of paracetamol,
50
b) it is substantially anhydrous, and
c) it forms a clear solution for injection with 4-10 parts by volume of water for each part by weight of paracetamol,

[0017] In a second aspect, the present Invention relates to a pharmaceutical composition consisting of a clear solution
55 for injection, characterized in that it comprises paracetamol and, for each part by weight of paracetamol,

i) from 1 to 4 parts by volume of ethanol,

ii) from 1 to 5 parts by volume of a polyethylene glycol, and

2
 EP 1 094 802 B1

iii) from 4 to 10 parts by volume of water, and it does not contain any preserving agents, stabilizers, surfactants,
buffers, agents for capturing free radicals, antioxidants.

[0018] In the description and in the claims which follow, the term "substantially anhydrous" Is understood to mean a
5 composition containing less than 0,1% by weight of water.
[0019] Preferably, for each part by weight of paracetamol, the parts by volume of ethanol are between 1.5 and 3,
and even more preferably between 2 and 2.5.
[0020] In turn, for each part by weight of paracetamol, the parts by volume of polyethylene glycol are preferably
between 1.5 and 4, and even more preferably between 2 and 3.
10 [0021] Lastly, the parts by volume of water for each part by weight of paracetamol are preferably between 5 and 8.
[0022] Preferably, the polyethylene glycol is chosen from the group comprising PEG-200. PEG-300, PEG-400, PEG-
1,000, PEG-1,540, PEG-4,000 and PEG-8,000.
[0023] Typically, the polyethylene glycol is PEG-400.
[0024] The organic paracetamol solution according to the first aspect of the present invention is very stable, since
15 the paracetamol does not precipitate out or undergo degradations, even after sterilization at 121°C for 30 minutes
followed by storage at 30°C under constant illumination at 11,000 lux for at least one month. This stability is found
even in the absence of preserving agents, stabilizers, surfactants, buffers, agents for capturing free radicals and/or
antioxidants.
[0025] By addition of water and simple beating by hand, It then readily forms a clear aqueous solution, in accordance
20 with the second aspect of the present invention.
[0026] Typically, the dear aqueous solution for injection thus obtained has a viscosity of between 2 and 10 mPa·s
Preferably, the amount of low molecular weight alcohol, polyethylene glycol and water is adjusted such that the said
viscosity is between 4 and 7 mPa·s.
[0027] According to another aspect, the present invention thus relates to a clear pharmaceutical solution for Injection,
25 characterized in that It comprises ethanol, PEG-400, water and from 10 to 25% (w/v) of paracetamol and in that the
amounts of ethanol, of PEG-400 and of water are adjusted such that the viscosity of the said solution is between 4
and 7 mPa·s
[0028] This solution also has the further advantage of not containing any preserving agents, stabilizers, surfactants,
buffers, agents for capturing free radicals and/or antioxidants.
30 [0029] The pharmaceutical composition of the present invention can be prepared according to techniques that are
well known in pharmaceutical chemistry, comprising mixing, dissolution, sterilization and the like.
[0030] The present invention will be further described by the following examples, which are given for purely illustrative
purposes and should. not be interpreted in a limiting sense.

35 EXAMPLE 1

Organic paracetamol solutions

[0031]
40

Solution A
Component Amount
Paracetamol 50 g
45 Absolute ethanol 100 ml
PEG-400 100 ml

[0032] The absolute ethanol and the PEG-400 were added to the paracetamol at room temperature. This mixture
was then stirred until the paracetamol had completely dissolved (about 30 minutes).
50 [0033] Some of the solution thus obtained was divided between 60 5-ml bottles In a proportion of 3 ml per bottle.
[0034] On some samples, freshly prepared (time 0), the following controls were carried out:

- paracetamol titre: HPLC (mg/ml)

- p-aminophenol titre: HPLC (mg/ml) and
55 - check for any coloured degradation products: spectrophotometry at 475 nm

and the following results were obtained:

3
 EP 1 094 802 B1

- average paracetamol titre: 214.1

- p-aminophenol: absent
- average absorption:0.0075

5 [0035] The above-mentioned samples were then stored for one month under the following conditions:

- at 4°C (Samples A),

- at room temperature (Samples B)
- at 30°C in a room under an illumination of 11,000 lux (Samples C).
10
[0036] The results obtained are given in Table 1 below.

Table 1
Sample Paracetamol titre (mg/ml) p-aminophenol titre (mg/ml) Absorption 475 nm
15
A 213.0 absent 0.0083
B 218.0 absent 0.0082
C 217.0 absent 0.0250
20
[0037] Other samples (Samples D), freshly prepared (time 0), showed the following characteristics:

- paracetamol titre: 204.0

- p-aminophenol: absent
25 - absorption: 0.0062

[0038] They were stored for one month at 30°C in a room under an illumination of 11,000 lux and showed the following
characteristics:

30 - paracetamol titre: 203.0

- p-aminophenol: absent
- absorption: 0.0162

[0039] Lastly, another group of samples (Samples E), freshly prepared (time 0) and after sterilization (121°C for 30
35 minutes), showed the following characteristics:

- paracetamol titre: 202.8

- p-aminophenol: absent
- absorption: 0.0100
40
[0040] They were stored for one month at 30°C in a room under an illumination of 11,000 lux and showed the following
characteristics:

- paracetamol titre: 202.0

45 - p-aminophenol: absent
- absorption: 0.0104

Solutions B and C

50 [0041] Similar results were obtained with samples having the following compositions:

Solution B
Component Amount
Paracetamol 50 g
55
Absolute ethanol 100 ml
PEG-400 150 ml

4
 EP 1 094 802 B1

Solution C
Component Amount
5 Paracetamol 80 g
Absolute ethanol 200 ml
PEA-400 200 ml

EXAMPLE 2
10
Aqueous solution for injection

[0042] Solution A (8 ml), prepared as described in Example 1 above, was introduced into a bottle (20 ml). Distilled
water for injection (12 ml) was added. The bottle was then shaken manually until a clear solution was obtained (about
15 10-40 seconds).
[0043] The solution thus obtained showed the following physicochemical characteristics:

Appearance clear, colourless

Viscosity* 5.068 mPa.s
20
Osmolarity calculated 529.2 mOsmol/litre
Density** 1.02600 g/cm3
*measured with a Carri-Med CSL 50 Rheometer viscoslmeter;
** measured with a Mettler Toledo DA-310 M densitometer.
25
COMPARATIVE EXAMPLE 1

Aqueous solution for injection according to patent application WO 98/05314

30 [0044]

Component Amount
Paracetamol 1,600 mg
Propylene glycol 2.7 ml
35
PEG-400 3.6 ml
Sodium acetate 20 mg
Reduced glutathione 20 mg
Hydrochloric acid qs pH 6
40
[0045] The above-mentioned composition, prepared as described in patent application WO 98/05314, was introduced
into a 15-ml bottle. Distilled water for injections (3.7 ml) was added thereto and the mixture was left stirring until a dear
solution was obtained (30 minutes).
[0046] The solution thus obtained showed the following physicochemical characteristics:
45

Appearance clear, colourless

Viscosity* 37,40 mPa.s
Osmolarity calculated 1,088.8 mOsmol/litre
Density** 1.09685 g/cm3
50

[0047] By working in a similar manner to that described above, a second composition was prepared containing 800
mg of paracetarnol instead of 1,600 mg.
[0048] This solution showed the following physicochemical characteristics:
55
Appearance clear, colourless
Viscosity* 26.34 mPa.s

5
 EP 1 094 802 B1

(continued)
Osmolarity calculated 560 mOsmol/litre
Density** 1.09433 g/cm3
5

COMPARATIVE EXAMPLE 2

Alcohol-free organic paracetamol solution

10 [0049]

Component Amount
Paracetamol 5g
15 PEG-400 10 ml

[0050] The PEG-400 was added to the paracetamol at room temperature. This mixture was then kept stirring at room
temperature for 2 hours.
[0051] 4 ml of the above-mentioned suspension were centrifuged in an Eppendorf tube at 25°C for 30 minutes at a
20 speed of 7,000 rpm.
[0052] HPLC analysis of the supernatant thus obtained showed that the solubility of the paracetamol was 18-19%.

COMPARATIVE EXAMPLE 3

25 PEG-free organic paracetamol solution

[0053]

Component Amount
30
Paracetamol 5g
Absolute ethanol 10 ml

[0054] The absolute ethanol was added to the paracetamol at room temperature. This mixture was then kept stirring
35 at room temperature for 2 hours.
[0055] 4 ml of the above-mentioned suspension were centrifuged in an Eppendorf tube at 4°C for 40 minutes at a
speed of 7,000 rpm.
[0056] HPLC analysis of the supernatant thus obtained showed that the solubility of the paracetamol was 9-10%.

40
Claims

1. Pharmaceutical composition, charactertzed in that

45 a) it comprises

i) paracetamol,
ii) from 1 to 4 parts by volume of ethanol for each part by weight of paracetamol, and
iii) from 1 to 5 parts by volume of a polyethylene glycot for each part by weight of paracetamol,
50
b) it is substantially anhydrous, and
c) It forms a clear solution for Injection with 4-10 parts by volume of water for each part by weight of paracetamol.

2. Pharmaceutical composition consisting of a clear solution for injection, characterized in that it comprises para-
55 cetamol and, for each part by weight of paracetamol,

i) from 1 to 4 parts by volume of ethanol

ii) from 1 to 5 parts by volume of a polyethylene glycol, and

6
 EP 1 094 802 B1

iil) from 4 to 10 parts by volume of water, and it does not contain any preserving agents, stabilizers, surfactants,
buffers, agent for capturing free radicals, antioxidants.

3. Pharmaceutical composition according to claim 1 or 2, characterized in that for each part by weight of paraceta-
5 mol, the parts by volume of ethanol are between 1.5 and 3.

4. Pharmaceutical composition according to claim 3, characterized in that for each part by weight of pamcetamol,
the parts by volume of ethanol are between 2 arid 2.5.

10 5. Pharmaceutical composition according to claim 1 or 2, characterized in that for each part by weight of paraceta-
mol, the parts by volume of polyethylene glycol are between 1.5 and 4.

6. Pharmaceutical composition according to claim 5, characterized in that for each part by weight of paracetamol,
the parts by volume of polyethylene glycol are between 2 and 3.
15
7. Pharmaceutical composition according to claim 1 or 2, characterized In that the parts by volume of water for each
part by weight of paracetarnol are between 5 and 8.

8. Pharmaceutical composition according to claim 1 or 2, characterized In that the polyethylene glycol Is chosen
20 from the group comprising PEG-200, PEG-300, PEG-400, PEG-1,000, PEG-1,540, PEG-4,000 and PEG-8,000.

9. Pharmaceutical composition according to claim 8, characterized in that the polyethylene glycol is PEG-400.

10. Clear pharmaceutical solution for injection, characterized in that it comprises ethanol, PEG-400, water and from
25 10 to 25% (w/v) of paracetamol and In that the amounts of ethanol, of PEG-400 and of water are adjusted such
that the viscosity of the said solution is between 4 and 7 mPa·s.

Patentansprüche
30
1. Pharmazeutische Zusammensetzung, dadurch gekennzeichnet, dass sie

(a) umfasst:

35 (i) Paracetamol,
(ii) von 1 bis 4 Volumenteilen Ethanol für jedes Gewichtsteil Paracetamol und
(iii) von 1 bis 5 Volumenteilen eines Polyethylenglykols für jedes Gewichtsteil Paracetamol,

(b) im wesentlichen wasserfrei ist und

40
(c) eine klare Lösung zur Injektion mit 4 bis 10 Volumenteilen Wasser für jedes Gewichtsteil Paracetamol bildet.

2. Pharmazeutische Zusammensetzung, bestehend aus einer klaren Lösung für die Injektion, dadurch gekenn-
zeichnet, dass sie Paracetamol und für jedes Gewichtsteil Paracetamol (i) von 1 bis 4 Volumenteilen Ethanol, (ii)
45 von 1 bis 5 Volumenteilen eines Polyethylenglycols und (iii) von 4 bis 10 Volumenteilen Wasser umfasst und keine
Konservierungsmittel, Stabilisatoren, oberflächenaktive Mittel, Puffer, Mittel zum Einfangen freier Radikale, Anti-
oxidanzien umfasst.

3. Pharmazeutische Zusammensetzung nach Anspruch 1 oder 2, dadurch gekennzeichnet, dass für jedes Ge-
50 wichtsteil Paracetamol die Volumenteile an Ethanol zwischen 1,5 und 3 sind.

4. Pharmazeutische Zusammensetzung nach Anspruch 3, dadurch gekennzeichnet, dass für jedes Gewichtsteil
Paracetamol die Volumenteile an Ethanol zwischen 2 und 2,5 sind.

55 5. Pharmazeutische Zusammensetzung nach Anspruch 1 oder 2, dadurch gekennzeichnet, dass für jedes Ge-
wichtsteil Paracetamol die Volumenteile an Polyethylenglykol zwischen 1,5 und 4 sind.

6. Pharmazeutische Zusammensetzung nach Anspruch 5, dadurch gekennzeichnet, dass für jedes Gewichtsteil

7
 EP 1 094 802 B1

Paracetamol die Volumenteile an Polyethylenglykol zwischen 2 und 3 sind.

7. Pharmazeutische Zusammensetzung nach Anspruch 1 oder 2, dadurch gekennzeichnet, dass die Volumenteile
an Wasser für jedes Gewichtsteil Paracetamol zwischen 5 und 8 sind.
5
8. Pharmazeutische Zusammensetzung nach Anspruch 1 oder 2, dadurch gekennzeichnet, dass das Polyethylen-
glykol ausgewählt ist aus der Gruppe, umfassend PEG-200, PEG-300, PEG-400, PEG-1.000, PEG 1.540, PEG
4.000 und PEG 8.000.

10 9. Pharmazeutische Zusammensetzung nach Anspruch 8, dadurch gekennzeichnet, dass das Polyethylen PEG-
400 ist.

10. Klare pharmazeutische Lösung zur Injektion, dadurch gekennzeichnet, dass sie Ethanol, PEG-400, Wasser und
von 10 bis 25% (G/V) Paracetamol umfasst und dass die Mengen an Ethanol, PEG-400 und Wasser so eingestellt
15 sind, dass die Viskosität der Lösung zwischen 4 und 7 mPas ist.

Revendications

20 1. Composition pharmaceutique, caractérisée en ce que :

a) elle comprend

i) du paracétamol,
25 ii) 1 à 4 parties en volume d'éthanol pour chaque partie en masse de paracétamol et
iii) 1 à 5 parties en volume de polyélylèneglycol pour chaque partie en masse de paracétamol,

b) elle est substantiellement anhydre et

c) elle forme, avec 4 à 10 parties en volume d'eau pour chaque partie en masse de paracétamol, une solution
30 injectable limpide.

2. Composition pharmaceutique constituée par une solution injectable limpide, caractérisée en ce qu'elle comprend
du paracétamol et, pour chaque partie en masse de paracérmol,

35 i) 1 à 4 parties en volume d'éthanol,

ii) 1 à 5 parties en volume de polyéthylèneglycol et
iii) 4 à 10 parties en volume d'eau

et en ce qu'elle ne contient aucun agent conservateur, stabilisant, tensioactif. tampon, agent pour piéger les ra-
40 dicaux libres, antioxydant.

3. Composition pharmaceutique selon la revendication 1 ou 2, caractérisée en ce que, pour chaque partie en masse
de paracétamol, les parties en volume d'éthanol sont entre 1,5 et 3.

45 4. Composition pharmaceutique selon la revendication 3, caractérisée en ce que, pour chaque partie en masse de
paracétamol, les parties en volume d'éthanol sont entre 2 et 2,5.

5. Composition pharmaceutique selon la revendication 1 ou 2, caractérisée en ce que, pour chaque partie en masse
de paracétamol, les parties en volume de polyéthylèneglycol sont entre 1,5 et 4.
50
6. Composition pharmaceutique selon la revendication 5, caractérisée en ce que, pour chaque partie en masse de
paracétamol, les parties en volume de polyéthylèneglycol sont entre 2 et 3.

7. Composition pharmaceutique selon la revendication 1 ou 2, caractérisée en ce que, pour chaque partie en masse
55 de paracétamol, les parties en volume d'eau sont entre 5 et 8.

8. Composition pharmaceutique selon la revendication 1 ou 2, caractérisée en ce que le polyéthylèneglycol est

choisi dans le groupe constitué par le PEG-200, le PEG-300, le PEG-400, le PEG-1 000, le PEG-1 540, le PEG-

8
 EP 1 094 802 B1

4 000 et le PEG-8 000.

9. Composition pharmaceutique selon la revendication 8, caractérisée en ce que le polyéthylèneglycol est le PEG-

400.
5
10. Solution pharmaceutique injectable limpide, caractérisée en ce qu'elle comprend de l'éthanol, du PEG-400, de
l'eau et de 10 à 25 % (masse/volume) de paracétamol et en ce que les quantités d'éthanol, de PEG-400 et d'eau
sont ajustées de telle façon que la viscosité de ladite solution soit entre 4 et 7 mPa.s.

10

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