Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2001-01-31
2002-07-23
Cook, Rebecca (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
active
06423749
ABSTRACT:
This is a 371 of PCT/EP99/05486 filed Jul. 27, 1999.
The present invention relates to a pharmaceutical composition for injection based on paracetamol.
In particular, in a first aspect, the present invention relates to a pharmaceutical composition for injection comprising paracetamol, a low molecular weight alcohol and a polyethylene glycol.
It has been known practice for a long time to use paracetamol as an analgesic and an antipyretic.
By virtue of its very satisfactory tolerability, paracetamol is, in some cases, even preferred to 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 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.
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, 1986,; Black M., “Annual Reviews of Medicine”, 35, 577-593, 1984).
It is also known that paracetamol is very slightly soluble in water (“The Merck Index”, 12th edition, page 9, No. 45, 1996).
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 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.
Patent application WO 98/05314 attempts to overcome the above-mentioned drawbacks by means of a composition 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 removing any oxygen which may be present in the said solvent by means of flushing with a water-insoluble inert gas.
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.
In particular, according to the above-mentioned document, a solution consisting of 30% propylene glycol, 40% PEG400 and 30% water is able to dissolve up to about 200 mg/ml of paracetamol at 20° C. (WO 98/05314, page 9, lines 7-12).
However, this solvent mixture is very viscous (see Comparative Example 1) and is thus unsuitable for administration by injection.
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.
It has now been found, surprisingly, that low molecular weight alcohols promote the dissolution of paracetamol in a polyethylene glycol.
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 glycol alone (Comparative Examples 2 and 3).
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).
In a first aspect, the present invention provides a pharmaceutical composition,
a) that comprises
i) paracetamol,
ii) 1 to 4 parts by volume of ethanol for each part by weight of paracetamol, and
iii) 1 to 5 parts by volume of a polyethylene glycol for each part by weight of paracetamol,
b) is substantially anhydrous, and
c) forms a clear solution for injection with 4-10 parts by volume of water for each part by weight of paracetamol.
In a second aspect, the present invention relates to a pharmaceutical composition consisting of a clear solution for injection, comprising paracetamol and, for each part by weight of paracetamol,
i) 1 to 4 parts by volume of ethanol,
ii) 1 to 5 parts by volume of a polyethylene glycol, and
iii) 4 to 10 parts by volume of water, and it does not contain any preserving agents, stabilizers, surfactants, buffers, agents for capturing free radicals, or antioxidants.
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.
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.
Lastly, the parts by volume of water for each part by weight of paracetamol are preferably between 5 and 8.
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.
Typically, the polyethylene glycol is PEG-400.
The organic paracetamol solution according to the first aspect of the present invention is very stable, since 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.
By addition of water and simple beating by hand, it then readily forms a clear aqueous solution, in accordance with the second aspect of the present invention.
Typically, the clear 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.
According to another aspect, the present invention thus relates to a clear pharmaceutical solution for injection, 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.
This solution also has the further advantage of not containing any preserving agents, stabilizers, surfactants, buffers, agents for capturing free radicals and/or antioxidants.
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.
REFERENCES:
patent: 4307073 (1981-12-01), Nelson
patent: WO 9805314 (1998-02-01), None
patent: WO 98 05314 (1998-02-01), None
patent: WO 9805314 (1998-03-01), None
Prakongpan et al, Chem. Pharm. ull., 32(1), 340-343, 1984.*
Penin et al;, Rev. Asoc. Esp. Farm. Hosp., 11(4), 249-54, 1987.*
Chemical Abstracts, vol. 109, No. 14, Oct. 3, 1998, Columbus, Ohio, US; abstract No. 115998, XP002125072 abstract & I.R. Penin et al., “Development of Injectable Paracetamol” Rev. Asoc. Esp. Farm. Hosp., vol. 11, No. 4, 1987, pp. 249-254.
Database WPI Week 9444, Derwent Publications Ltd., London, GB; AN 94-355463 '44! XP002097935 abstract & KR 9 311 994 B (Daekwang Pharm. Co.) Dec. 23, 1993.
Database WPI Week 9045, Derwent Publications Ltd. London, GB; AN 90-335491 '45! XP002097936 abstract & DD 279 405 A (Veb Berlin Chemie) Jun. 6, 1990.
Chemical Abstracts, vol. 105, No. 26, Dec. 29, 1986 Columbus, Ohio, US; abstract No. 232386, XP002125073 abstract & Z. Yan et al.: “Preparation of Paracetomal Injections” Yaoxue Tongbao, vol. 21, No. 7, 1986, pp. 387-389.
Cavallo Giovanni
Pinza Mario
Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.p.A.
Cook Rebecca
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