WO2001008662A1 - Liquid pharmaceutical composition based on paracetamol - Google Patents

Liquid pharmaceutical composition based on paracetamol Download PDF

Info

Publication number
WO2001008662A1
WO2001008662A1 PCT/EP2000/006871 EP0006871W WO0108662A1 WO 2001008662 A1 WO2001008662 A1 WO 2001008662A1 EP 0006871 W EP0006871 W EP 0006871W WO 0108662 A1 WO0108662 A1 WO 0108662A1
Authority
WO
WIPO (PCT)
Prior art keywords
paracetamol
solution
present
peg
liquid pharmaceutical
Prior art date
Application number
PCT/EP2000/006871
Other languages
French (fr)
Inventor
Mario Pinza
Giovanni Cavallo
Vilma Rossi
Alberto Campana
Original Assignee
Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. filed Critical Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A.
Priority to AU65651/00A priority Critical patent/AU6565100A/en
Publication of WO2001008662A1 publication Critical patent/WO2001008662A1/en

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/16Amides, e.g. hydroxamic acids
    • A61K31/165Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to a liquid pharmaceutical composition based on paracetamol. More particularly, the invention relates to an anhydrous liquid pharmaceutical composition based on paracetamol.
  • paracetamol is used extensively as an analgesic and antipyretic agent by virtue of its good tolerability.
  • NSAID non-steroidal antiinflammatory drugs
  • acetylsalicylic acid since it does not produce the typical side effects of NSAIDs such as, for example, heartburn and gastric lesions.
  • the only possible complication associated with its use is hepatic cytolysis, which, however, occurs only in cases of overdosing.
  • paracetamol is generally administered in solid pharmaceutical dosage forms because its solubility in water is of about 1 % (w/v).
  • liquid dosage forms which are suitable, for example, for nasal, ocular, otological and parenteral administration.
  • liquid dosage forms are also very useful for oral administration both because they allow greater accuracy in dosing the drug as a function of the body weight, as well as of the type and seriousness of the pathology to be treated, but also because they are suitable in all cases in which the patient displays difficulty in swallowing, such as, for example, children and the elderly.
  • Effervescent tablets have been proposed to overcome this last drawback. However, they are relatively complex and expensive to produce and package since they require special machinery and suitable premises for processing powders with a controlled moisture content.
  • the type of packaging required consists of aluminium blister packs coupled with plastic films that are impermeable to air and moisture. Furthermore, this particular type of packaging contributes towards making these effervescent tablets even more expensive. It has now been found, surprisingly, that it is possible to obtain high concentrations of paracetamol in PEG-200, up to a maximum concentration of about 22% (w/v).
  • PEG-200 is a mixture of ethylene glycols with an average molecular weight of about 200, a density of about 1.1 -1.3 g/cm 3 and a viscosity of about 40-50 cp.
  • commercial PEG-200 has the following percentage composition: monoethylene glycol, 0.1 %; diethylene glycol, 3.4%; triethylene glycol, 21.2%; tetraethylene glycol, 31.2%; pentaethylene glycol, 24.4%; hexaethylene glycol, 14.0%; heptaethylene glycol, 5.4%; octaethylene glycol, 0.3%.
  • the present invention thus relates to a liquid pharmaceutical dosage form, characterized in that it consists of a solution comprising at least 10% (w/v) of paracetamol in anhydrous PEG-200.
  • the amount of paracetamol in the solution of the present invention ranges from 15 to 22% (w/v). Even more preferably, this amount ranges from 18 to 22% (w/v). The advantages of the present invention are particularly great when the amount of paracetamol is between 20 and 22% (w/v).
  • the solution of the present invention can readily be sterilized with steam.
  • the solution has good stability at room temperature.
  • the solution of the present invention may further contain other active principles and/or additives of conventional type, such as, for example, preserving agents, flavourings, colorants, sweeteners and the like.
  • the amount required is less than the norm.
  • the amount which may be present in the solution of the present invention will range from 0.001 to 0.005% (w/v), whereas it is usually between 0.005 and 0.01 % (w/v).
  • the amount which may be present in the solution of the present invention will range from 0.001 to 0.005% (w/v), whereas it is usually between 0.005 and 0.25% (w/v).
  • the amount which may be present in the solution of the present invention will range from 0.001 to 0.005% (w/v), whereas it is usually between 0.005 and
  • the amount which may be present in the solution of the present invention will range from 0.001 to 0.0025% (w/v), whereas it is usually 0.005% (w/v).
  • the amount which may be present in the solution of the present invention will range from 0.001 to 0.005% (w/v), whereas it is usually 0.01 % (w/v).
  • PEG is not hygroscopic, even in the presence of high humidity (B ⁇ hler V., Vademecum for Vitamin Formulations, Stuttgart 1988, pp. 57 and 87).
  • PEG-200 does not compromise the good gastric tolerability of paracetamol.
  • the LD 50 (mg/kg) of PEG-200 is
  • the solution of the present invention can be dispensed using suitable known devices which allow the administration of accurate doses, such as, for example, mechanical pumps, medical droppers, spray dispensers and the like.
  • the solution of the present invention can also be used for preparing syrups, at the time of use, by mixing it, before use, with suitable diluents such as, for example, aqueous or aqueous-alcoholic diluents, optionally comprising conventional additives such as, for example, preserving agents, flavourings, colorants, sweeteners and the like.
  • the dose will be, for example, 200 ⁇ l per nostril (1 spray) of a 20% (w/v) solution, equal to 80 mg of paracetamol. If necessary, the amount of paracetamol administered may be increased by increasing the number of sprays in each nostril, optionally sufficiently quickly one after the other, or by administering a more concentrated solution.
  • the solution of the present invention may be administered as it is or added before use with a suitable diluent capable of giving a final solution having preselected isotonicity and/or pH.
  • a suitable diluent capable of giving a final solution having preselected isotonicity and/or pH.
  • Batch A consisted of an anhydrous 20% (w/v) paracetamol solution prepared as described in Example 1 above.
  • Batch B consisted of a 20% (w/v) solution of paracetamol in a 99/1 (v/v) PEG 200/water mixture.
  • the possible degradation of the paracetamol was evaluated by subjecting the test samples to 4 cycles of sterilization at 121 °C for 25 minutes/cycle and determining the amount of p-aminophenol (PAP) formed due to degradation of the paracetamol.
  • PAP p-aminophenol
  • PAP0 indicates the amount of p-aminophenol found in fresh solutions prepared before sterilization
  • PAP1 indicates the amount of p-aminophenol found in the solutions after the first sterilization cycle
  • PAP2 indicates the amount of p-aminophenol found in the solutions after the second sterilization cycle
  • PAP4 indicates the amount of p-aminophenol found in the solutions after the fourth sterilization cycle.
  • the amount of p-aminophenol is expressed in ⁇ g/ml.
  • Solution A paracetamol (20% w/v) in PEG 200
  • Solution B PEG 200
  • Solution C paracetamol (20% w/v) in PEG 200 and phosphatidylcholine
  • test solution was administered to male New Zealand White rabbits by means of nasal instillation of a total volume of 0.8 ml divided into four doses (100 ⁇ l) per nostril, at intervals of 90 minutes in one day.
  • One group of animals received no treatment (negative control).
  • Each treatment group consisted of 3 animals. All the animals were weighed and examined to evaluate any side reactions to the treatment.
  • nasal cells were taken from all the animals by means of interdental toothbrushes soaked with Hank's solution supplemented with bovine serum albumin (0.1% w/v).
  • - solution 2 having the following composition: paracetamol (20.3 g), PEG 200 (qs 100 ml) and phosphatidylcholine (5 g); (titre: 19.7% w/v)); and - solution 3 having the following composition: paracetamol (20.8 g),
  • the study was carried out by administering 5 mg/kg of paracetamol to male New Zealand White rabbits by means of intranasal instillation of solutions 2 and 3.
  • the volumes administered corresponded to 25.4 ⁇ l/kg for solution 2 and 22.5 ⁇ l/kg for solution 3.
  • the bioavailability was calculated with reference to the intravenous administration of 120 ⁇ l/kg of solution 1 , equivalent to 5 mg/kg of paracetamol, to male New Zealand White rabbits.
  • the samples were centrifuged at 1600 g/min for 15 minutes at 0°C (Heraeus Sepatech centrifuge).
  • the plasma was transferred into polypropylene test tubes and stored at -20°C until the time of analysis.
  • the paracetamol concentrations in the plasma samples were determined using an HPLC/MS/MS method.
  • the pharmacokinetic parameters were calculated using the SipharTM programme release 4.0 (Simed).
  • Table 3 shows that both solutions 2 and 3 are rapidly absorbed in the nose and that the solution of paracetamol in PEG 200 (solution 3) also has better bioavailability than solution 2 containing phosphatidylcholine.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Engineering & Computer Science (AREA)
  • Pain & Pain Management (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Rheumatology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

A liquid pharmaceutical dosage form consisting of a solution comprising at least 10 % (w/v) of paracetamol in anhydrous PEG-200.

Description

"Liquid pharmaceutical composition based on paracetamol"
* * * * * * *
The present invention relates to a liquid pharmaceutical composition based on paracetamol. More particularly, the invention relates to an anhydrous liquid pharmaceutical composition based on paracetamol.
It is known that paracetamol is used extensively as an analgesic and antipyretic agent by virtue of its good tolerability. In a number of cases, it is also preferred to non-steroidal antiinflammatory drugs (NSAID) such as, for example, acetylsalicylic acid, since it does not produce the typical side effects of NSAIDs such as, for example, heartburn and gastric lesions. The only possible complication associated with its use is hepatic cytolysis, which, however, occurs only in cases of overdosing. It is also known that paracetamol is generally administered in solid pharmaceutical dosage forms because its solubility in water is of about 1 % (w/v). In addition, in aqueous medium, paracetamol is hydrolysed relatively rapidly, with formation of para-aminophenol and/or is oxidized by the action, for example, of the oxygen dissolved in the water. This second reaction appears to be responsible for the formation of pink- to brown-coloured derivatives. To overcome these drawbacks, attempts have been made to dissolve paracetamol in anhydrous pharmaceutically acceptable solvents and/or to potentiate its activity, particularly in the case of pharmaceutical forms for nasal administration, with many types of potential enhancers having been investigated, but, as far as the Applicant is aware, satisfactory practical results have not been obtained to date.
Thus, there is still a great need for anhydrous liquid pharmaceutical dosage forms which are suitable, for example, for nasal, ocular, otological and parenteral administration. Moreover, liquid dosage forms are also very useful for oral administration both because they allow greater accuracy in dosing the drug as a function of the body weight, as well as of the type and seriousness of the pathology to be treated, but also because they are suitable in all cases in which the patient displays difficulty in swallowing, such as, for example, children and the elderly.
Effervescent tablets have been proposed to overcome this last drawback. However, they are relatively complex and expensive to produce and package since they require special machinery and suitable premises for processing powders with a controlled moisture content. In addition, the type of packaging required consists of aluminium blister packs coupled with plastic films that are impermeable to air and moisture. Furthermore, this particular type of packaging contributes towards making these effervescent tablets even more expensive. It has now been found, surprisingly, that it is possible to obtain high concentrations of paracetamol in PEG-200, up to a maximum concentration of about 22% (w/v).
As is known, PEG-200 is a mixture of ethylene glycols with an average molecular weight of about 200, a density of about 1.1 -1.3 g/cm3 and a viscosity of about 40-50 cp. Typically, commercial PEG-200 has the following percentage composition: monoethylene glycol, 0.1 %; diethylene glycol, 3.4%; triethylene glycol, 21.2%; tetraethylene glycol, 31.2%; pentaethylene glycol, 24.4%; hexaethylene glycol, 14.0%; heptaethylene glycol, 5.4%; octaethylene glycol, 0.3%. The present invention thus relates to a liquid pharmaceutical dosage form, characterized in that it consists of a solution comprising at least 10% (w/v) of paracetamol in anhydrous PEG-200.
Preferably, the amount of paracetamol in the solution of the present invention ranges from 15 to 22% (w/v). Even more preferably, this amount ranges from 18 to 22% (w/v). The advantages of the present invention are particularly great when the amount of paracetamol is between 20 and 22% (w/v).
The solution of the present invention can readily be sterilized with steam. In addition, the solution has good stability at room temperature. Depending on the route of administration selected and the pathology which it is intended to treat, the solution of the present invention may further contain other active principles and/or additives of conventional type, such as, for example, preserving agents, flavourings, colorants, sweeteners and the like. According to another advantageous aspect of the present invention, in the case of preserving agents, the amount required is less than the norm. For example, in the case of benzalkonium chloride, the amount which may be present in the solution of the present invention will range from 0.001 to 0.005% (w/v), whereas it is usually between 0.005 and 0.01 % (w/v). In the case of methyl paraben, the amount which may be present in the solution of the present invention will range from 0.001 to 0.005% (w/v), whereas it is usually between 0.005 and 0.25% (w/v). In the case of a mixture of ethyl, propyl and butyl paraben, the amount which may be present in the solution of the present invention will range from 0.001 to 0.005% (w/v), whereas it is usually between 0.005 and
0.03% (w/v). In the case of sodium edetate (EDTA), the amount which may be present in the solution of the present invention will range from 0.001 to 0.0025% (w/v), whereas it is usually 0.005% (w/v). In the case of Thiomerosal, the amount which may be present in the solution of the present invention will range from 0.001 to 0.005% (w/v), whereas it is usually 0.01 % (w/v).
The absence or, at most, the presence of small amounts of preserving agents is particularly advantageous in the case of nasal and ocular administration. Another particularly advantageous aspect of the present invention is that PEG is not hygroscopic, even in the presence of high humidity (Bϋhler V., Vademecum for Vitamin Formulations, Stuttgart 1988, pp. 57 and 87). Yet another advantage of the present invention is that PEG-200 does not compromise the good gastric tolerability of paracetamol.
Moreover, the LD50 (mg/kg) of PEG-200 is
- orally: > 29,000 in rats and mice, and > 19,000 in rabbits;
- intraperitoneally: > 13,000 in rats and mice; - intravenously: > 7,000 in rats and mice.
Depending on the route of administration chosen, the solution of the present invention can be dispensed using suitable known devices which allow the administration of accurate doses, such as, for example, mechanical pumps, medical droppers, spray dispensers and the like. The solution of the present invention can also be used for preparing syrups, at the time of use, by mixing it, before use, with suitable diluents such as, for example, aqueous or aqueous-alcoholic diluents, optionally comprising conventional additives such as, for example, preserving agents, flavourings, colorants, sweeteners and the like. In the case of nasal administration with mechanical spray systems, the dose will be, for example, 200 μl per nostril (1 spray) of a 20% (w/v) solution, equal to 80 mg of paracetamol. If necessary, the amount of paracetamol administered may be increased by increasing the number of sprays in each nostril, optionally sufficiently quickly one after the other, or by administering a more concentrated solution.
In the case of otological and ocular administration, the solution of the present invention may be administered as it is or added before use with a suitable diluent capable of giving a final solution having preselected isotonicity and/or pH. The examples and tests below serve to illustrate the present invention without, however, limiting it.
EXAMPLE 1 Preparation of a 22% (w/v) solution Paracetamol (2.2 g) was added to PEG 200, making up to a volume of 10 ml with magnetic stirring at room temperature.
The characteristics of the final solution were: titre (w/v): 22% density* (g/cm3) 1.4606 viscosity** (cp) 168.4
* the density was measured using a Mettler Toledo DA310M machine; ** the viscosity was measured using a Cammed CSL50 rheometer.
EXAMPLE 2 Sterilization The degradative effect of water was also evaluated in the sterilization tests on a number of embodiments of the present invention.
Batch A consisted of an anhydrous 20% (w/v) paracetamol solution prepared as described in Example 1 above.
Batch B consisted of a 20% (w/v) solution of paracetamol in a 99/1 (v/v) PEG 200/water mixture.
The possible degradation of the paracetamol was evaluated by subjecting the test samples to 4 cycles of sterilization at 121 °C for 25 minutes/cycle and determining the amount of p-aminophenol (PAP) formed due to degradation of the paracetamol. This quantitative analysis of the p-aminophenol was carried out by the reverse-phase
HPLC method with UV detection.
The results are given in Table 1 below, in which PAP0 indicates the amount of p-aminophenol found in fresh solutions prepared before sterilization; PAP1 indicates the amount of p-aminophenol found in the solutions after the first sterilization cycle; PAP2 indicates the amount of p-aminophenol found in the solutions after the second sterilization cycle; PAP4 indicates the amount of p-aminophenol found in the solutions after the fourth sterilization cycle. The amount of p-aminophenol is expressed in μg/ml.
TABLE 1
Figure imgf000007_0001
These results show that the degradation of the paracetamol is also promoted by small amounts of water.
TEST 1 Tolerabilitv of paracetamol solutions in rabbits The intranasal tolerability of paracetamol in rabbits was evaluated using the method of Frattola et al. ("Arch. Toxicol.", Suppl. 14, 272-275, 1991 ).
The following solutions were used: Solution A: paracetamol (20% w/v) in PEG 200; Solution B: PEG 200;
Solution C: paracetamol (20% w/v) in PEG 200 and phosphatidylcholine
(5% w/v); Solution D: PEG 200 and phosphatidylcholine (5% w/v); Solution E: sodium taurocholate (5% w/v) (positive control). The test solution was administered to male New Zealand White rabbits by means of nasal instillation of a total volume of 0.8 ml divided into four doses (100 μl) per nostril, at intervals of 90 minutes in one day. One group of animals received no treatment (negative control). Each treatment group consisted of 3 animals. All the animals were weighed and examined to evaluate any side reactions to the treatment. Three days before the administration and 24 and 72 hours after the final dose (on days -3, 1 and 3, respectively, of the study) nasal cells were taken from all the animals by means of interdental toothbrushes soaked with Hank's solution supplemented with bovine serum albumin (0.1% w/v).
After taking the samples, the brushes were immersed in the abovementioned solution (1 ml) and agitated to separate the cells. The following parameters were evaluated: differential and total number of cells (epithelial cells and leukocytes). Table 2 shows that the intranasal instillation of solutions A and C did not induce any intolerance reactions, caused no increase of the nasal cells or, in particular, of the leukocytes which generally increase by the action of migration towards inflamed regions, as did occur, however, in the case of the animals treated with solution E containing sodium taurocholate, a known mucosal irritant.
TABLE 2
Figure imgf000009_0001
co
Figure imgf000009_0003
Figure imgf000009_0002
TEST 2 Bioavailabilitv of paracetamol solutions in rabbits The study was carried out using the following solutions:
- solution 1 having the following composition: paracetamol (4.16 g), Tween 20 (20 g), absolute ethanol (20 ml), water (qs 100 ml); (titre:
4.16% (w/v));
- solution 2 having the following composition: paracetamol (20.3 g), PEG 200 (qs 100 ml) and phosphatidylcholine (5 g); (titre: 19.7% w/v)); and - solution 3 having the following composition: paracetamol (20.8 g),
PEG 200 (qs 100 ml); (titre: 22% w/v)).
The study was carried out by administering 5 mg/kg of paracetamol to male New Zealand White rabbits by means of intranasal instillation of solutions 2 and 3. The volumes administered corresponded to 25.4 μl/kg for solution 2 and 22.5 μl/kg for solution 3.
The bioavailability was calculated with reference to the intravenous administration of 120 μl/kg of solution 1 , equivalent to 5 mg/kg of paracetamol, to male New Zealand White rabbits.
At 0, 5, 15 30, 45, 60, 90, 120, 150, 180, 210 and 240 minutes after the treatment, blood samples were taken using heparinized syringes.
The samples were centrifuged at 1600 g/min for 15 minutes at 0°C (Heraeus Sepatech centrifuge). The plasma was transferred into polypropylene test tubes and stored at -20°C until the time of analysis. The paracetamol concentrations in the plasma samples were determined using an HPLC/MS/MS method.
The pharmacokinetic parameters were calculated using the Siphar™ programme release 4.0 (Simed). The bioavailability (F%) was calculated according to the following equation: F = (average AUC(o-m)i-n./average AUC(o-tn)i.v.)x(i.v. dose/i.n. dose)x100 The results obtained are given in Table 3 and can be summarized as follows: a) solution 2 gave a maximum plasma concentration (Cmaχ) equal to 1.41 μg/ml in 16.25 minutes, an area under the curve (AUC(o-inf)) equal to 89 μg*min/ml, half-life time (t1/2) of 87 minutes and a bioavailability (F) of 21%; and b) solution 3 gave a maximum plasma concentration (Cmax) equal to
2 μg/ml in 16.25 minutes, an area under the curve (AUC(o-inf)) equal to 157.9 μg*min/ml, half-life time (t1/2) of 74.8 minutes and a bioavailability (F) of 37%.
Thus, Table 3 shows that both solutions 2 and 3 are rapidly absorbed in the nose and that the solution of paracetamol in PEG 200 (solution 3) also has better bioavailability than solution 2 containing phosphatidylcholine.
TABLE 3
Figure imgf000012_0001

Claims

CLAIMS 1. A liquid pharmaceutical dosage form, characterized in that it consists of a solution comprising at least 10% (w/v) of paracetamol in anhydrous PEG-200. 2. A pharmaceutical dosage form according to the preceding claim 1 , characterized in that it comprises from 15 to 22% (w/v) of paracetamol. 3. A pharmaceutical dosage form according to the preceding claim 1 or 2, characterized in that it comprises from 20 to 22% (w/v) of paracetamol.
PCT/EP2000/006871 1999-07-30 2000-07-18 Liquid pharmaceutical composition based on paracetamol WO2001008662A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU65651/00A AU6565100A (en) 1999-07-30 2000-07-18 Liquid pharmaceutical composition based on paracetamol

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI99A001697 1999-07-30
IT1999MI001697A IT1313579B1 (en) 1999-07-30 1999-07-30 PARACETAMOL-BASED LIQUID PHARMACEUTICAL COMPOSITION.

Publications (1)

Publication Number Publication Date
WO2001008662A1 true WO2001008662A1 (en) 2001-02-08

Family

ID=11383451

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2000/006871 WO2001008662A1 (en) 1999-07-30 2000-07-18 Liquid pharmaceutical composition based on paracetamol

Country Status (4)

Country Link
AR (1) AR024959A1 (en)
AU (1) AU6565100A (en)
IT (1) IT1313579B1 (en)
WO (1) WO2001008662A1 (en)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2862872A1 (en) * 2003-12-02 2005-06-03 Palbian Snc AQUEOUS COMPOSITION FOR THE PERFUSABLE APPLICATION OF AN ACTIVE, PARTICULARLY PHARMACOLOGICAL PRINCIPLE SUCH AS PARACETAMOL
WO2008135601A2 (en) * 2007-05-08 2008-11-13 Docpharma Nv/Sa Storage-stable formulation of oxidation-sensitive phenolic drug, especially paracetamol, comprises aqueous drug solution deoxygenated by a temperature-controlled manufacturing process of the formulation
WO2009019555A3 (en) * 2007-08-07 2009-04-30 Univ Stellenbosch Ophthalmic formulation containing paracetamol
EP2243477A1 (en) * 2009-04-22 2010-10-27 Fresenius Kabi Deutschland GmbH Paracetamol for parenteral application
WO2012001494A3 (en) * 2010-06-30 2012-05-18 Troikaa Pharmaceuticals Limited Pharmaceutical compositions comprising paracetamol and process for preparing the same
ITMI20110106A1 (en) * 2011-01-28 2012-07-29 Abiogen Pharma Spa PHARMACEUTICAL COMPOSITION LIQUID CONTAINING PARACETAMOL
US20150141518A1 (en) * 2013-11-21 2015-05-21 Emphascience, Inc. Water-miscible stable solution composition for pharmaceutically active ingredients that are poorly soluble in water and susceptible to chemical degradation
US20160144033A1 (en) * 2014-11-21 2016-05-26 Emphascience, Inc. Concentrated acetaminophen solution
WO2016097899A1 (en) 2014-12-20 2016-06-23 Troikaa Pharmaceuticals Limited Injectable formulations of paracetamol
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9585849B2 (en) 2006-04-17 2017-03-07 The Burlington Hc Research Group, Inc. Broad spectrum antiviral and methods of use
US9707184B2 (en) 2014-07-17 2017-07-18 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10195153B2 (en) 2013-08-12 2019-02-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US10959958B2 (en) 2014-10-20 2021-03-30 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988002625A1 (en) * 1986-10-17 1988-04-21 R.P. Scherer Corporation Solvent system for an ionizable pharmaceutical agent
WO1995004527A1 (en) * 1993-08-05 1995-02-16 R.P. Scherer Corporation Gelatin capsules containing a highly concentrated acetaminophen solution
WO1995023595A1 (en) * 1994-03-02 1995-09-08 The Procter & Gamble Company Concentrated acetaminophen solution compositions
WO1998005314A1 (en) * 1996-08-05 1998-02-12 Scr Pharmatop Novel stable liquid paracetamol compositions, and method for preparing same

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988002625A1 (en) * 1986-10-17 1988-04-21 R.P. Scherer Corporation Solvent system for an ionizable pharmaceutical agent
WO1995004527A1 (en) * 1993-08-05 1995-02-16 R.P. Scherer Corporation Gelatin capsules containing a highly concentrated acetaminophen solution
WO1995023595A1 (en) * 1994-03-02 1995-09-08 The Procter & Gamble Company Concentrated acetaminophen solution compositions
WO1998005314A1 (en) * 1996-08-05 1998-02-12 Scr Pharmatop Novel stable liquid paracetamol compositions, and method for preparing same

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005053747A1 (en) * 2003-12-02 2005-06-16 Zeeweld Bv Composition containing peg for perfusion of an active agent in particular paracetamol
FR2862872A1 (en) * 2003-12-02 2005-06-03 Palbian Snc AQUEOUS COMPOSITION FOR THE PERFUSABLE APPLICATION OF AN ACTIVE, PARTICULARLY PHARMACOLOGICAL PRINCIPLE SUCH AS PARACETAMOL
US9849143B2 (en) 2006-04-17 2017-12-26 The Burlington Hc Research Group, Inc. Broad spectrum antiviral and methods of use
US9585849B2 (en) 2006-04-17 2017-03-07 The Burlington Hc Research Group, Inc. Broad spectrum antiviral and methods of use
WO2008135601A2 (en) * 2007-05-08 2008-11-13 Docpharma Nv/Sa Storage-stable formulation of oxidation-sensitive phenolic drug, especially paracetamol, comprises aqueous drug solution deoxygenated by a temperature-controlled manufacturing process of the formulation
EP1992334A1 (en) * 2007-05-08 2008-11-19 Docpharma NV/SA Storage-stable formulation of oxidation-sensitive phenolic drug, especially paracetamol, comprises aqueous drug solution deoxygenated by a temperature-controlled manufacturing process of the formulation
WO2008135601A3 (en) * 2007-05-08 2009-06-18 Docpharma Nv Sa Storage-stable formulation of oxidation-sensitive phenolic drug, especially paracetamol, comprises aqueous drug solution deoxygenated by a temperature-controlled manufacturing process of the formulation
AU2008285244B2 (en) * 2007-08-07 2015-02-19 Stellenbosch University A medicament
WO2009019555A3 (en) * 2007-08-07 2009-04-30 Univ Stellenbosch Ophthalmic formulation containing paracetamol
US9072704B2 (en) 2007-08-07 2015-07-07 Stellenbosch University Compositions and methods for treatment of glaucoma
WO2010121762A1 (en) * 2009-04-22 2010-10-28 Fresenius Kabi Deutschland Gmbh Paracetamol for parenteral administration
EP2243477A1 (en) * 2009-04-22 2010-10-27 Fresenius Kabi Deutschland GmbH Paracetamol for parenteral application
EP2626068A1 (en) 2009-04-22 2013-08-14 Fresenius Kabi Deutschland GmbH Paracetamol for parenteral administration
US8741959B2 (en) 2009-04-22 2014-06-03 Fresenius Kabi Deutschland Gmbh Paracetamol for parenteral administration
CN102958519B (en) * 2010-06-30 2016-01-13 特罗伊卡药品有限公司 Pharmaceutical composition comprising acetaminophen and preparation method thereof
CN102958519A (en) * 2010-06-30 2013-03-06 特罗伊卡药品有限公司 Pharmaceutical compositions comprising paracetamol and process for preparing the same
EA023022B1 (en) * 2010-06-30 2016-04-29 Троикаа Фармасьютикалз Лимитед High concentration parenteral composition of paracetamol and process for preparing the same
JP2013529675A (en) * 2010-06-30 2013-07-22 トロイカ ファーマスーティカルズ リミテッド Pharmaceutical composition containing paracetamol and method for producing the same
WO2012001494A3 (en) * 2010-06-30 2012-05-18 Troikaa Pharmaceuticals Limited Pharmaceutical compositions comprising paracetamol and process for preparing the same
US9616128B2 (en) 2010-06-30 2017-04-11 Troikaa Pharmaceuticals Ltd Pharmaceutical compositions comprising paracetamol and process for preparing the same
ITMI20110106A1 (en) * 2011-01-28 2012-07-29 Abiogen Pharma Spa PHARMACEUTICAL COMPOSITION LIQUID CONTAINING PARACETAMOL
US10639281B2 (en) 2013-08-12 2020-05-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US10195153B2 (en) 2013-08-12 2019-02-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US20150141518A1 (en) * 2013-11-21 2015-05-21 Emphascience, Inc. Water-miscible stable solution composition for pharmaceutically active ingredients that are poorly soluble in water and susceptible to chemical degradation
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10792254B2 (en) 2013-12-17 2020-10-06 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9707184B2 (en) 2014-07-17 2017-07-18 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
US10959958B2 (en) 2014-10-20 2021-03-30 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form
US20160144033A1 (en) * 2014-11-21 2016-05-26 Emphascience, Inc. Concentrated acetaminophen solution
WO2016097899A1 (en) 2014-12-20 2016-06-23 Troikaa Pharmaceuticals Limited Injectable formulations of paracetamol

Also Published As

Publication number Publication date
AU6565100A (en) 2001-02-19
ITMI991697A0 (en) 1999-07-30
IT1313579B1 (en) 2002-09-09
AR024959A1 (en) 2002-10-30
ITMI991697A1 (en) 2001-01-30

Similar Documents

Publication Publication Date Title
EP0742714B1 (en) Liquid pharmaceutical compositions comprising thyroid hormones
WO2001008662A1 (en) Liquid pharmaceutical composition based on paracetamol
EP1439830B1 (en) Pharmaceutical composition of 2-(4-isobutylphenyl) propionic acid
JP2005505590A (en) Orally administered liquid composition comprising guaifenesin and a polyoxyalkylene block copolymer
US9532947B2 (en) Formulation for oral transmucosal administration of analgesic and/or antispasmodic molecules
US6727286B2 (en) Pharmaceutical composition of 2-(4-isobutylphenyl) propionic acid
AU2002224475A1 (en) Pharmaceutical composition of 2-(4-isobutylphenyl) propionic acid
US20220096489A1 (en) Oral liquid compositions including chlorpromazine
EP4017473A1 (en) Pharmaceutical eutectic salt formulation
JP2010513525A (en) Stable anti-emetic oral spray formulations and methods
US8178112B2 (en) Ketoprofen compositions and methods of making them
US20110257149A1 (en) Formulation for oral transmucosal administration of lipid-lowering drugs
PT2101730E (en) Galenic form for the transmucosal delivery of paracetamol
US20240024481A1 (en) Injectable ibuprofen formulation
US20040132823A1 (en) Pharmaceutical composition of 2-(4-isobutylphenyl) propionic acid
EP1646393B1 (en) A stable clozapine suspension formulation
CA2010085C (en) Pentamidine solutions
BR112020024399A2 (en) waterless liquid composition and system for oral transmucosal administration of an active ingredient through a liquid composition
CN118542852B (en) Sublingual film composition containing orally administered dexmedetomidine, and preparation method and application thereof
EP0323762B1 (en) Antitussive compositions and their preparation
WO2021105524A1 (en) Pharmaceutical composition of ibuprofen salt with lysine in the form of an oral solution
WO2024062443A1 (en) Pharmaceutical compositions
ES2775648A1 (en) Pharmaceutical composition in the form of an oral solution of ibuprofen salt with lysine (Machine-translation by Google Translate, not legally binding)
TR201510144A2 (en) NEW ORAL SOLUTION FORMULATION

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP