CZ2001365A3 - Pharmaceutical preparation for injections based on paracetamol - Google Patents

Abstract

A pharmaceutical composition characterized in that a) contains i) paracetamol, ii) 1 to 4 parts by volume low molecular weight alcohol per part and (iii) from 1 to 5 parts by volume polyethylene glycol for each part of paracetamol; is substantially anhydrous, and c) forms a clear solution for injection with 4 up to 10 parts by volume of water per part by weight paracetamol.

Description

Technical field

The present invention relates to a pharmaceutical composition for injection based on paracetamol.

In particular, in the first aspect, the present invention relates to a pharmaceutical composition for injection comprising paracetamol, a low molecular weight alcohol and polyethylene glycol.

BACKGROUND OF THE INVENTION

It has been known for a long time to use paracetamol as an analgesic and an antipyretic.

Due to its very satisfactory tolerability, paracetamol, in some cases, is even preferred over non-steroidal anti-inflammatory drugs (NSAIDs) and especially over aspirin.

Indeed, paracetamol, such as aspirin, exerts its activity by inhibiting the synthesis of prostaglandins produced by cyclooxygenase. However, unlike most non-steroidal anti-inflammatory drugs, its inhibition occurs almost exclusively in the brain and, to a much lesser extent, in peripheral tissues (stomach, kidney and platelets). For these reasons, its use does not produce side effects typical of non-steroidal anti-inflammatory drugs such as heartburn and gastric damage with possible blood loss.

The only possible complication associated with its use is hepatic cytolysis, although this only occurs when: · φ · · · · «φφφ

φ φ * »overdose (Flower RJ, Vane JR, Nature 240, 410-41)

(1972); Lanz R., Poster P., J. Pharmacol 130, 105 až 109 (1986); Black M., Annual Reviewes of Medicine 35 , 577 to 593 (1984)). Yippee also known that paracetamol is very little soluble ve

Water (The Merck Index, 12th Edition, No. 45, p. 9, 1996).

This is a major obstacle to its injection. In addition, in the presence of water, paracetamol undergoes degradation, which also produces pink to brown colored derivatives. The most common type of degradation is hydrolysis to paminophenol and / or oxidation, for example by oxygen dissolved in water. This second reaction appears to be responsible for the formation of said derivatives.

WO 98/05314 attempts to overcome the above drawbacks with a composition comprising a solution of paracetamol in an aqueous solvent in combination with a buffer having a pH of 4 to 8 and a free radical scavenger. In addition, the above document recommends the removal of any trace of oxygen that may be present in said solvent by purging with a water-insoluble inert gas.

Pharmaceutical compositions exemplified herein include those capable of dissolving most of paracetamol except water, PEG-400, and propylene glycol.

In particular, according to the above document, a solution consisting of 30% propylene glycol, 40% PEG-400 and 30% water is capable of dissolving up to about 200 mg / ml paracetamol at 20 ° C (WO 98/05314, page 9, lines 7 through 12).

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I

However, this solvent mixture is very viscous (see Comparative Example 1) and is therefore unsuitable for administration by injection.

Thus, there is still a great need for paracetamol-based pharmaceutical compositions which, in addition to containing therapeutic levels of paracetamol, can be easily injected without bruising.

SUMMARY OF THE INVENTION

It has now surprisingly been found that low molecular weight alcohols promote the dissolution of paracetamol in polyethylene glycol.

As can be seen in the examples, the amount of paracetamol dissolved by the mixture of low molecular weight alcohol and polyethylene glycol (Example 1) is greater than the amount dissolved by the equivalent volume of low molecular weight alcohol alone and polyethylene glycol alone (Comparative Examples 2 and 3).

All this is all the more surprising considering that, according to the above-mentioned WO 98/05314, the addition of ethanol does not increase the solubility of paracetamol in polyethylene glycol (p. 11, last line).

In a first aspect, the present invention provides a pharmaceutical composition characterized in that:

(a) contains:

and) paracetamol, (ii) from 1 to 4 parts by volume of alcohol with low molecular weight per part weight paracetamol, and

φ 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 od od 9 9 iii iii iii iii od iii od od od od iii od iii for each part by weight of paracetamol,

(b) it is essentially anhydrous; and

(c) form a clear solution for injection with 4 to 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 comprising a clear solution for injection, characterized in that it comprises paracetamol, and for each part by weight paracetamol,

i) from 1 to 4 parts by volume of low molecular weight alcohol; ii) from 1 to 5 parts by volume of polyethylene glycol; and iii) from 4 to 10 parts by volume of water.

In the description and in the claims that follow, it is understood that the term substantially anhydrous means a composition containing less than 0.1% by weight of water.

Preferably, for each part by weight of paracetamol, the parts by volume of the low molecular weight alcohol are between 1.5 and 3, and even more preferably between 2 and 2.5.

Consequently, 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.

Finally, for each part by weight of paracetamol, the parts by volume of water are preferably between 5 and 8.

Preferably, the low molecular weight alcohol contains from 1 to 4 carbon atoms. A typical example of a preferred low molecular weight alcohol is absolute ethanol.

9 9

9 9 «9 9999«

Preferably, the polyethylene glycol is selected from the group consisting of PEG-200, PEG-300, PEG-400, PEG-1000, PEG-1540, PEG4000, and PEG-8000.

Typically, the polyethylene glycol is PEG-400.

The paracetamol organic solution of the first aspect of the present invention is very stable as paracetamol does not precipitate or undergo degradation, even after sterilization at 121 ° C for 30 minutes followed by storage at 30 ° C under constant illumination of 11,000 lux, for at least one months. This stability is found even in the absence of preservatives, stabilizers, surfactants, buffers, free radical scavengers and / or antioxidants.

By adding water and by simple hand whipping, a clear aqueous solution is then easily formed, in accordance with the second aspect of the present invention.

Typically, the clear aqueous injectable solution thus obtained has a viscosity of between 2 and 10 cP. Preferably, the amount of low molecular weight alcohol, polyethylene glycol and water is adjusted such that said viscosity is between 4 and 7 cP.

Thus, in another aspect, the present invention relates to a clear pharmaceutical solution for injection, characterized in that it contains ethanol, PEG-400, water and from 10 to 25% (w / v) paracetamol and that there are amounts of ethanol, PEG-400 and water adjusted such that the viscosity of said solution is between 4 and 7 cP.

This solution also has the additional advantage that it contains no preservatives, stabilizers, surfactants,

·· ♦ *

9 buffers, free radical scavengers and / or antioxidants.

The pharmaceutical composition of the present invention can be prepared according to techniques well known in pharmaceutical chemistry including mixing, dissolving, sterilizing and the like.

The present invention will be further described by the following examples, which are given for illustrative purposes only and should not be construed as limiting the invention.

Examples of the invention

Example 1

Organic solutions of paracetamol

Solution A

Component paracetamol absolute ethanol PEG-400

Quantity 50 g 100 ml 100 ml

Absolute ethanol and PEG-400 are added to paracetamol at room temperature. This mixture was then stirred until paracetamol was completely dissolved (about 30 minutes).

A portion of the solution thus obtained is dispensed into 60 5-ml vials at a dose of 3 ml per vial.

For some freshly prepared samples (time 0), the following checks are performed:

paracetamol titer: HPLC (mg / ml) • 4 p-aminophenol titer: HPLC (mg / ml) and control for any colored degradation products: spectrophotometry at 475 nm and the following results are obtained:

average paracetamol titer: 214.1 p-aminophenol: absent average absorption: 0.0075

The above samples are then stored for one month under the following conditions:

at 4 ° C (samples A), at room temperature (samples B) at 30 ° C in the room and under illumination of 11,000 lux (samples C).

The results obtained are shown in Table 1 below.

Table 1

Sample Titr paracetamol (mg / ml) Titr p-aminophenol (mg / ml) Abrospce 475 nm AND 213.0 absent 0.0083 (B) 218.0 absent 0.0082 C 217.0 absent 0,0250

Other freshly prepared specimens (Sample D) exhibit the following characteristics:

paracetamol titer: 204.0 (time 0) • 0 • 0 • ···· 0 0 p-aminophenol: absent absorption: 0.0062

The samples are stored for one month at 30 ° C in a room under 11,000 lux illumination and exhibit the following characteristics:

paracetamol titer: 203.0 p-aminophenol: no absorption: 0.0162

Finally, another set of samples (Ε samples), freshly prepared (time 0) and after sterilization (121 ° C for 30 minutes), exhibits the following characteristics:

paracetamol titer: 202.8 p-aminophenol: no absorption: 0.0100

The samples are stored for one month at 30 ° C in a room under 11,000 lux illumination and exhibit the following characteristics:

paracetamol titer: 202.0 p-aminophenol: no absorption: 0.0104

Solutions B and C

Similar results are obtained with samples having the following composition:

Solution B

Component

Amount of paracetamol absolute ethanol

PEG-400 g 100 ml

150 ml

9

9 9 · 9 9

998 9 9

9

Solution C

Component

Amount of paracetamol absolute ethanol

PEG-400 g 200 ml

200 ml

Example 2

Aqueous solution for injection

Solution A (8 mL), prepared as described in Example 1 above, was added to a bottle (20 mL). Add distilled water for injection (12 mL). The bottle is then shaken manually until a clear solution is obtained (about 10 to 40 seconds).

The solution thus obtained exhibits the following physicochemical characteristics:

Appearance: Clear, colorless

Viscosity * 5,068 cP

Osmolarity calculated: 529.2 Osmol / L

Specific Gravity **: 1.02600 g / cm ³ * measured with a Carri-Med CSL 50 Rheometer;

** measured with Mettler Toledo DA-310 M densitometer

Comparative Example 1

Aqueous injection solution according to WO 98/05314

Component Quantity paracetamol 1,600 mg propylene glycol 2.7 ml

PEG-400 3.6 ml sodium acetate 20 mg

44

4 4 4 ·

4 4 4 4 · 443 4 4

4 · · · ·

44 4 reduced glutathione 20 mg hydrochloric acid as needed to pH 6

The above formulation, prepared as described in WO 98/05314, is transferred to a 15-ml bottle. Distilled water for injection (3.7 ml) was added and the mixture was allowed to stir until a clear solution was obtained (30 minutes).

Chemical solution obtained in this way: Appearance:

Viscosity*:

Osmolarity calculated:

Density**:

By a similar treatment, a second formulation of paracetamol was prepared

Chemical solution obtained in this way: Appearance:

Viscosity*:

Osmolarity calculated:

Density**:

showed the following physically clear, high 37.40 cP

088.8 mOsmol / 1 1.09685 g / cm ³ as above, containing instead of 1600 mg, 800 mg the following physically clear, colorless 26.34 cP 560 mOsmol / 1 1.09433 g / cm ³

Comparative Example 2

Non-alcoholic organic solution of paracetamol

Ingredient paracetamol

PEG-400

Quantity g

ml

0 00

0 0 0

0 0 0

0,000 ·

0 ·

0 00

0 0

0 0 0 ·

0 *

PEG-400 is added to paracetamol at room temperature. The mixture was allowed to stir for 2 hours at room temperature.

ml of the above suspension is centrifuged in an Eppendorf tube at 7,000 rpm for 30 minutes at 25 ° C.

Analysis by high performance liquid chromatography of the supernatant thus obtained shows that the solubility of paracetamol is 18-19%.

Comparative example

Organic solution of paracetamol without PEG

Component Quantity paracetamol 5 g absolute ethanol 10 ml

Absolute ethanol is added to paracetamol at room temperature. The mixture was then allowed to stir for 2 hours at room temperature.

ml of the above suspension is centrifuged in an Eppendorf tube at 7,000 rpm for 40 minutes at 4 ° C.

Analysis of the supernatant by high performance liquid chromatography shows that the solubility of paracetamol is 9 to 10

Claims (12)

PATENT CLAIMS What is claimed is: 1. A pharmaceutical composition comprising: (b) (c) contains: i) paracetamol, ii) from 1 to 4 parts by volume of molecular weight for each part of paracetamol, and iii) from 1 to 5 parts by volume of polyethylene glycol for each part by weight of paracetamol, is substantially anhydrous, forming a clear solution for injection by volume of water for each part of paracetamol. with low weight 4 to 10 parts by weight 2. A pharmaceutical composition comprising a clear solution for injection, comprising paracetamol and paracetamol by weight, i) from 1 to 4 parts by volume of low molecular weight alcohol; ii) from 1 to 5 parts by volume of polyethylene glycol; and iii) from 4 to 10 parts by volume of water. Pharmaceutical composition according to claim 1 or 2, characterized in that for each part by weight of paracetamol, the parts by volume of the low molecular weight alcohol are between 1.5 and 3. Pharmaceutical composition according to claim 3, characterized in that for each part by weight of paracetamol there are parts by volume of a low molecular weight alcohol between 2 and 2.5. • • • Pharmaceutical composition according to claim 1 or 2, characterized in that: characterized in that for each part by weight of paracetamol, the parts by volume of polyethylene glycol are between 1.5 and 4. 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. Pharmaceutical composition according to claim 1 or 2, characterized in that parts by volume of water, for each part by weight of paracetamol, are between 5 and 8. Pharmaceutical composition according to claim 1 or 2, characterized in that the low molecular weight alcohol contains from 1 to 4 carbon atoms. The pharmaceutical composition of claim 8, wherein the low molecular weight alcohol is absolute ethanol. Pharmaceutical composition according to claim 1 or 2, characterized in that the polyethylene glycol is selected from the group consisting of PEG-200, PEG-300, PEG-400, PEG-1000, PEG-1540, PEG-4000, and PEG-8000. The pharmaceutical composition of claim 10, wherein the polyethylene glycol is PEG-400. 12. A clear pharmaceutical solution for injection comprising ethanol, PEG-400, water and from 10 to 25% (w / v) paracetamol, and wherein the amount of ethanol,