WO1998038983A2 - Swallow tablet comprising paracetamol - Google Patents

Swallow tablet comprising paracetamol Download PDF

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Publication number
WO1998038983A2
WO1998038983A2 PCT/EP1998/001284 EP9801284W WO9838983A2 WO 1998038983 A2 WO1998038983 A2 WO 1998038983A2 EP 9801284 W EP9801284 W EP 9801284W WO 9838983 A2 WO9838983 A2 WO 9838983A2
Authority
WO
WIPO (PCT)
Prior art keywords
paracetamol
sodium bicarbonate
tablet
tablets
starch
Prior art date
Application number
PCT/EP1998/001284
Other languages
French (fr)
Other versions
WO1998038983A3 (en
Inventor
Timothy James Grattan
Original Assignee
Smithkline Beecham Plc
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
Priority to IL13155298A priority Critical patent/IL131552A/en
Priority to APAP/P/1999/001638A priority patent/AP1084A/en
Priority to EP98913664A priority patent/EP0981334B1/en
Priority to HU0001501A priority patent/HU224983B1/en
Priority to DE69814850T priority patent/DE69814850T2/en
Priority to DK98913664T priority patent/DK0981334T3/en
Priority to PL335502A priority patent/PL190988B1/en
Priority to SK1197-99A priority patent/SK282277B6/en
Priority to JP53816998A priority patent/JP2001513801A/en
Priority to UA99094955A priority patent/UA59388C2/en
Priority to EA199900709A priority patent/EA001918B1/en
Priority to SI9830474T priority patent/SI0981334T1/en
Priority to CA002283408A priority patent/CA2283408C/en
Priority to KR10-1999-7007976A priority patent/KR100465895B1/en
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to AT98913664T priority patent/ATE240720T1/en
Priority to AU68282/98A priority patent/AU721851B2/en
Priority to NZ337418A priority patent/NZ337418A/en
Priority to US09/380,453 priority patent/US6316025B1/en
Priority to BR9807992-1A priority patent/BR9807992A/en
Publication of WO1998038983A2 publication Critical patent/WO1998038983A2/en
Publication of WO1998038983A3 publication Critical patent/WO1998038983A3/en
Priority to NO19994294A priority patent/NO327456B1/en
Priority to HK00105436A priority patent/HK1027026A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/485—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect

Definitions

  • the present invention relates to pharmaceutical compositions containing N- acetyl-p-aminophenol, known by the generic names paracetamol, acetaminophen and APAP (hereinafter referred to as paracetamol).
  • paracetamol N- acetyl-p-aminophenol
  • the invention relates to a fast acting paracetamol formulation in the form of a swallow tablet or capsule which has a greatly improved rate of absorption following ingestion by the patient.
  • Paracetamol is an analgesic and antipyretic agent which is widely used in prescription and non-prescription medicines, often in combination with other biologically active compounds.
  • a solid form such as a tablet or capsule
  • the rate of absorption and hence the onset of pharmacological activity has been found to vary from patient to patient and can sometimes be very slow.
  • Many attempts have been made to improve the rate of onset of activity, for example by speeding up the disintegration of tablets by making effervescent formulations.
  • United Kingdom patent publication GB 2 103 087 (Bristol-Myers) describes an analgesic composition containing paracetamol that has an increased rate of absorption.
  • GB 2 103 087 refers to a publication (J. Wojcicki et al, Zbl. Pharm. , 118, (1979), Vol 2-3) describing investigations into the pharmacokinetics of paracetamol in which a single oral dose of 1000 mg of paracetamol was administered with 4000 mg of antacid in the form of calcium carbonate. According to the reference in GB 2 103 087, the combination was found to decrease the rate of absorption of paracetamol, when compared with the rate of absorption from paracetamol (1000 mg ) alone.
  • an improved rate of absorption is achieved by co-administering a therapeutic dose comprising from about 150 mg to about 2000 mg of paracetamol with from about 60 mg to about 1200 mg of an antacid.
  • a therapeutic dose comprising from about 150 mg to about 2000 mg of paracetamol with from about 60 mg to about 1200 mg of an antacid.
  • the publication states that any antacid or combinations thereof commonly used to neutralise stomach acids may be used.
  • GB 2 103 087 identifies antacids of special interest to be calcium carbonate, magnesium carbonate, a combination of calcium carbonate and magnesium carbonate, sodium bicarbonate and magnesium hydroxide.
  • GB 2 103 087 exemplifies compositions comprising combinations of paracetamol with calcium carbonate, with a mixture of calcium carbonate and magnesium carbonate and with sodium bicarbonate.
  • the examples in GB 2 103 087 include two tablet formulations containing paracetamol and sodium bicarbonate; one such formulation comprises 325 mg of paracetamol and 225 mg of sodium bicarbonate wherein the weight ratio of sodium bicarbonate to paracetamol is 0.69 to 1, and the second formulation comprises 500 mg of paracetamol and 225 mg of sodium bicarbonate wherein the weight ratio of sodium bicarbonate to paracetamol is 0.4 to 1.
  • the various formulations exemplified in GB 2 103 087 were administered to healthy volunteers it was found that, for all the formulations tested, the actual increase in rate of absorption, was between 7 and 31 % compared to conventional paracetamol tablets.
  • the rate of absorption following oral admimstration of such a solid dosage form comprising paracetamol and sodium bicarbonate also shows an improvement over that obtained following oral admimstration of an aqueous solution of a commercially available soluble product containing paracetamol and sodium bicarbonate.
  • an increase in the rate of abso ⁇ tion may be demonstrated as an increased in C max , where C rozx is the maximum concentration of paracetamol in the serum, or by measuring the area under the concentration vs time curve in the first 20 minutes after dosing (AUC 0-2 o) when compared with other paracetamol compositions.
  • a swallow tablet or capsule formulation comprising from 300mg to 600mg of paracetamol and from 300mg to 1200mg of sodium bicarbonate wherein the weight ratio of sodium bicarbonate to paracetamol is at least 0.74 to 1.
  • a swallow tablet is a tablet which is intended to be swallowed whole and not one which is intended for dissolution or suspension in water prior to administration, for example a tablet containing a substantial amount of an effervescent couple.
  • the tablet or capsule formulation of the invention preferably contains either 325 mg or 500 mg of paracetamol.
  • the amount of sodium bicarbonate present in the formulation is favourably at least 370 mg, eg at least 400 mg or 500 mg and suitably is no greater than 1000 mg, preferably no greater than 800 mg and more preferably no greater than 700 mg.
  • the weight ratio of sodium bicarbonate to paracetamol is favourably at least 0.8 to 1, preferably at least 1 to 1, and more preferably at least 1.25 to 1.
  • Formulations of the invention will generally contain at least one pharmaceutically acceptable excipient conventionally used in the art of tablet and/or capsule formulation.
  • Suitable excipients which may be inco ⁇ orated include lubricants, for example magnesium stearate and stearic acid; disintegrants, for example cellulose derivatives; starches; binders, for example modified starches and cellulose derivatives; glidants, for example colloidol silicas; compression aids, for example cellulose derivatives; as well as preservatives, suspending agents, wetting agents, flavouring agents, bulking agents, adhesives, colouring agents, sweetening agents appropriate to their form.
  • formulations of the invention may also contain other pharmaceutically active agents, for example other analgesics, anti- inflammatory analgesic agents, decongestants, antihistamines, antitussive agents, etc..
  • Formulations may also contain a pharmaceutically acceptable analgesic adjuvant, for example caffeine.
  • the invention also provides a process for the preparation of the tablet or capsule formulation of the invention, which process comprises the admixture of paracetamol and sodium bicarbonate together with any pharmaceutically acceptable excipients, additional pharmaceutically acceptable active agents or adjuvants.
  • the paracetamol and sodium bicarbonate may be mixed together with one or more binders and granulated using water.
  • the resulting granule may then be dried, sieved and mixed with additional excipients such as a lubricant and disintegrant before being compressed into tablets.
  • additional excipients such as a lubricant and disintegrant
  • the sodium bicarbonate may be omitted from the granulation step and subsequently added with the other excipients.
  • tablets may be prepared using direct compression grades of paracetamol including commercially available forms which obviates the need for a granulation step. Tablets may also be prepared by other processes known in the art such as by shaping of an extruded mixture.
  • the paracetamol and sodium bicarbonate may be mixed and granulated as for tablet production and filled into suitably sized capsule shells to the desired fill weight.
  • the formulations according to the invention have an increased C ⁇ , where C max is the maximum concentration of paracetamol in the serum, when compared with other paracetamol compositions. Comparative experiments have demonstrated an increased C ⁇ with respect to that obtained not only from swallow tablets containing only paracetamol or paracetamol plus calcium carbonate but also from proprietary soluble paracetamol formulations. Furthermore the formulations according to the invention have an increased (AUC 0 . 20 ), indicating an increased rate of abso ⁇ tion of paracetamol, when compared to conventional paracetamol swallow tablets. .
  • the plasma profile for the paracetamol formulations in accordance with the present invention is comparable to that expected to be achieved with a dose of paracetamol administered intravenously.
  • Intravenous dosing of drugs is generally recommended in order to achieve a rapid maximum therapeutic effect which is not obtainable via oral dosing.
  • intravenous dosing can be both painful and inconvenient.
  • the present invention accordingly offers considerable practical benefit.
  • the addition of sodium bicarbonate in the weight ratio of the present invention has the potential added advantage that it may reduce the potential for patients to suffer toxic effects of paracetamol overdose, which can have fatal consequences or, at the very least, lead to irreversible liver damage.
  • An intake of about 40 paracetamol tablets containing 500mg paracetamol usually causes serious liver damage and sometimes proves fatal.
  • the emetic dose of sodium bicarbonate is such that for most patients it would be achieved after swallowing tablets of the present invention well before the intake of paracetamol reaches a level that would prove fatal.
  • formulations of the present invention are clearly of benefit.
  • a granule suitable for compression into tablets was prepared from the following ingredients
  • Tablets were prepared from the following ingredients:
  • Each tablet contained paracetamol 500mg and sodium bicarbonate 630mg, with a ratio of sodium bicarbonate: paracetamol of 1.26 : 1
  • Example 3
  • Tablets (target weight 1023.82mg) were prepared by a similar method to than described in examples 1 and 2, but using different levels of ingredients such that the final formula was as follows:
  • Each tablet contained paracetamol 500mg and sodium bicarbonate 400mg, with a ratio of sodium bicarbonate: paracetamol of 0.8 : 1
  • Tablets (target weight 993.82mg) are prepared by a similar method to that described in examples 1 and 2, but using different levels of ingredients such that the final formula is as follows:
  • Each tablet contains paracetamol 500mg and sodium bicarbonate 370mg, with a ratio of sodium bicarbonate: paracetamol of 0.74 : 1
  • Example 5
  • Tablets (target weight 1430.7mg) are prepared by a similar method to that described in examples 1 and 2, but using different levels of ingredients such that the final formula is as follows:
  • Each tablet contains paracetamol 500mg and sodium bicarbonate 800 mg, with a ratio of sodium bicarbonate: paracetamol of 1.6 : 1
  • Tablets (target weight 923.82mg) are prepared by a similar method to that described in examples 1 and 2, but using different levels of ingredients such that the final formula is as follows:
  • Each tablet contains paracetamol 400mg and sodium bicarbonate 400mg, with a ratio of sodium bicarbonate: paracetamol of 1 : 1
  • Example 7
  • Tablets (target weight 1223.82mg) are prepared by a similar method to that described in examples 1 and 2, but using different levels of ingredients such that the final formula is as follows:
  • Each tablet contains paracetamol 600mg and sodium bicarbonate 500mg, with a ratio of sodium bicarbonate: paracetamol of 0.83 : 1
  • Tablets (target weight 819.46mg) are prepared by a similar method to that described in examples 1 and 2, but using different levels of ingredients such that the final formula is as follows:
  • Each tablet contains paracetamol 325mg and sodium bicarbonate 409.5mg, with a ratio of sodium bicarbonate to paracetamol of 1.26 : 1
  • Example 9
  • Tablets (target weight 1291.56mg) are prepared by blending ingredients 1 to 7 together and compressing using a suitable tablet press:
  • Each tablet contains paracetamol 500mg and sodium bicarbonate 630mg, with a ratio of sodium bicarbonate to paracetamol of 1.26 : 1
  • Capsules are prepared as follows:
  • Each capsule contains paracetamol 325mg and sodium bicarbonate 409.5mg, with a ratio of sodium bicarbonate to paracetamol of 1.26 : 1 Comparative Example A
  • Tablets (target weight 988.23mg) were prepared by a similar method to that described in examples 1 and 2, but using different levels of ingredients and substituting calcium carbonate for sodium bicarbonate, such that the final formula was as follows:
  • Each tablet contained paracetamol 500mg and calcium carbonate 375 mg, with ratio of calcium carbonate to paracetamol of 0.75 : 1
  • test formula E the 2 tablets were dissolved in the lOOmls of water prior to swallowing.
  • Blood samples were taken at 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 75, 90, 120, 180, 240, 360, 480, and 720 minutes post dose.
  • Serum paracetamol levels were determined by HPLC and paracetamol serum levels vs time profiles were plotted for each volunteer. There were no significant differences in the area under the serum level vs time curve (AUC 0 ⁇ ,) for any of the formulae.
  • the Cmax for formula A was statistically significantly higher than that seen for formula C (p ⁇ 0 .0002), D (p ⁇ 0.002) and E (PO.02). There was no statistically significant difference between the Cmax for formula A and B.
  • the Cmax for formula B was significantly higher than that seen for formula C (p ⁇ 0.01) and formula D (p ⁇ 0.02)
  • test formula A 245 mg.min/L test formula B 177 mg.min/L test formula C 76.0 mg . min/L test formula D 69.7 mg.min/L test formula E 199 mg.min/L
  • the (AUC 0 . 20 ) for formulation A was 3.5 times greater than for formulation D and the (AUC 0 . 20 ) for formulation B was 2.5 times greater than for formulation D, both of these differences were statistically significant, indicating that the rate of paracetamol abso ⁇ tion from the invention was increased by a factor of up to 250% compared to conventional paracetamol swallow tablets.

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Abstract

A swallow tablet or capsule formulation is described comprising paracetamol, sodium bicarbonate and at least one pharmaceutically acceptable excipient.

Description

SWALLOW TABLET COMPRISING PARACETAMOL
The present invention relates to pharmaceutical compositions containing N- acetyl-p-aminophenol, known by the generic names paracetamol, acetaminophen and APAP (hereinafter referred to as paracetamol). In particular, the invention relates to a fast acting paracetamol formulation in the form of a swallow tablet or capsule which has a greatly improved rate of absorption following ingestion by the patient.
Paracetamol is an analgesic and antipyretic agent which is widely used in prescription and non-prescription medicines, often in combination with other biologically active compounds. Following ingestion of paracetamol in a solid form, such as a tablet or capsule, the rate of absorption and hence the onset of pharmacological activity has been found to vary from patient to patient and can sometimes be very slow. Many attempts have been made to improve the rate of onset of activity, for example by speeding up the disintegration of tablets by making effervescent formulations.
United Kingdom patent publication GB 2 103 087 (Bristol-Myers) describes an analgesic composition containing paracetamol that has an increased rate of absorption. GB 2 103 087 refers to a publication (J. Wojcicki et al, Zbl. Pharm. , 118, (1979), Vol 2-3) describing investigations into the pharmacokinetics of paracetamol in which a single oral dose of 1000 mg of paracetamol was administered with 4000 mg of antacid in the form of calcium carbonate. According to the reference in GB 2 103 087, the combination was found to decrease the rate of absorption of paracetamol, when compared with the rate of absorption from paracetamol (1000 mg ) alone.
According to GB 2 103 087, an improved rate of absorption is achieved by co-administering a therapeutic dose comprising from about 150 mg to about 2000 mg of paracetamol with from about 60 mg to about 1200 mg of an antacid. The publication states that any antacid or combinations thereof commonly used to neutralise stomach acids may be used. GB 2 103 087 identifies antacids of special interest to be calcium carbonate, magnesium carbonate, a combination of calcium carbonate and magnesium carbonate, sodium bicarbonate and magnesium hydroxide. GB 2 103 087 exemplifies compositions comprising combinations of paracetamol with calcium carbonate, with a mixture of calcium carbonate and magnesium carbonate and with sodium bicarbonate. The examples in GB 2 103 087 include two tablet formulations containing paracetamol and sodium bicarbonate; one such formulation comprises 325 mg of paracetamol and 225 mg of sodium bicarbonate wherein the weight ratio of sodium bicarbonate to paracetamol is 0.69 to 1, and the second formulation comprises 500 mg of paracetamol and 225 mg of sodium bicarbonate wherein the weight ratio of sodium bicarbonate to paracetamol is 0.4 to 1. When the various formulations exemplified in GB 2 103 087 were administered to healthy volunteers it was found that, for all the formulations tested, the actual increase in rate of absorption, was between 7 and 31 % compared to conventional paracetamol tablets.
It has now been found unexpectedly that by selecting sodium bicarbonate and combining it with paracetamol in a tablet or capsule formulation such that it is present in an amount of at least 300 mg per tablet and the weight ratio of bicarbonate to paracetamol is at least 0.74 to 1, a swallow tablet or capsule can be produced which gives a statistically significant improvement in the rate of absorption over that obtained from a commercially available paracetamol tablet containing no sodium bicarbonate. This improvement is not observed when other antacids, eg. calcium carbonate, are combined with paracetamol in a solid dosage form at equivalent levels. More surprisingly, the rate of absorption following oral admimstration of such a solid dosage form comprising paracetamol and sodium bicarbonate also shows an improvement over that obtained following oral admimstration of an aqueous solution of a commercially available soluble product containing paracetamol and sodium bicarbonate. In the context of the present invention, an increase in the rate of absoφtion may be demonstrated as an increased in Cmax, where Crozx is the maximum concentration of paracetamol in the serum, or by measuring the area under the concentration vs time curve in the first 20 minutes after dosing (AUC 0-2o) when compared with other paracetamol compositions. According to the present invention there is provided a swallow tablet or capsule formulation comprising from 300mg to 600mg of paracetamol and from 300mg to 1200mg of sodium bicarbonate wherein the weight ratio of sodium bicarbonate to paracetamol is at least 0.74 to 1.
For the avoidance of doubt, a swallow tablet is a tablet which is intended to be swallowed whole and not one which is intended for dissolution or suspension in water prior to administration, for example a tablet containing a substantial amount of an effervescent couple.
The tablet or capsule formulation of the invention preferably contains either 325 mg or 500 mg of paracetamol. The amount of sodium bicarbonate present in the formulation is favourably at least 370 mg, eg at least 400 mg or 500 mg and suitably is no greater than 1000 mg, preferably no greater than 800 mg and more preferably no greater than 700 mg. The weight ratio of sodium bicarbonate to paracetamol is favourably at least 0.8 to 1, preferably at least 1 to 1, and more preferably at least 1.25 to 1.
Formulations of the invention will generally contain at least one pharmaceutically acceptable excipient conventionally used in the art of tablet and/or capsule formulation. Suitable excipients which may be incoφorated include lubricants, for example magnesium stearate and stearic acid; disintegrants, for example cellulose derivatives; starches; binders, for example modified starches and cellulose derivatives; glidants, for example colloidol silicas; compression aids, for example cellulose derivatives; as well as preservatives, suspending agents, wetting agents, flavouring agents, bulking agents, adhesives, colouring agents, sweetening agents appropriate to their form.
In addition to paracetamol, sodium bicarbonate and a pharmaceutically acceptable excipient, formulations of the invention may also contain other pharmaceutically active agents, for example other analgesics, anti- inflammatory analgesic agents, decongestants, antihistamines, antitussive agents, etc.. Formulations may also contain a pharmaceutically acceptable analgesic adjuvant, for example caffeine.
The invention also provides a process for the preparation of the tablet or capsule formulation of the invention, which process comprises the admixture of paracetamol and sodium bicarbonate together with any pharmaceutically acceptable excipients, additional pharmaceutically acceptable active agents or adjuvants. Thus the paracetamol and sodium bicarbonate may be mixed together with one or more binders and granulated using water. The resulting granule may then be dried, sieved and mixed with additional excipients such as a lubricant and disintegrant before being compressed into tablets. Alternatively, the sodium bicarbonate may be omitted from the granulation step and subsequently added with the other excipients. In an alternative process, tablets may be prepared using direct compression grades of paracetamol including commercially available forms which obviates the need for a granulation step. Tablets may also be prepared by other processes known in the art such as by shaping of an extruded mixture. For capsule production, the paracetamol and sodium bicarbonate may be mixed and granulated as for tablet production and filled into suitably sized capsule shells to the desired fill weight.
As stated above, the formulations according to the invention have an increased C^, where Cmax is the maximum concentration of paracetamol in the serum, when compared with other paracetamol compositions. Comparative experiments have demonstrated an increased C^ with respect to that obtained not only from swallow tablets containing only paracetamol or paracetamol plus calcium carbonate but also from proprietary soluble paracetamol formulations. Furthermore the formulations according to the invention have an increased (AUC0.20), indicating an increased rate of absoφtion of paracetamol, when compared to conventional paracetamol swallow tablets. .
Indeed, the plasma profile for the paracetamol formulations in accordance with the present invention is comparable to that expected to be achieved with a dose of paracetamol administered intravenously. (Seymore R A, European J. Clin. Pharmacol., 2Ω, 215-218, (1981), quotes 23.7 mg/litre in blood plasma following a 1000 mg iv dose of paracetamol.) Intravenous dosing of drugs is generally recommended in order to achieve a rapid maximum therapeutic effect which is not obtainable via oral dosing. However, intravenous dosing can be both painful and inconvenient. Moreover, since for a drug such as paracetamol which has poor solubility, intravenous formulations are not generally available, the present invention accordingly offers considerable practical benefit.
Furthermore, the addition of sodium bicarbonate in the weight ratio of the present invention has the potential added advantage that it may reduce the potential for patients to suffer toxic effects of paracetamol overdose, which can have fatal consequences or, at the very least, lead to irreversible liver damage. An intake of about 40 paracetamol tablets containing 500mg paracetamol usually causes serious liver damage and sometimes proves fatal. The emetic dose of sodium bicarbonate is such that for most patients it would be achieved after swallowing tablets of the present invention well before the intake of paracetamol reaches a level that would prove fatal.
Another potential advantage of the formulations of the present invention is in the treatment of migraine. Proprietary products, for the alleviation of migraine headaches, which contain paracetamol also contain ingredients such as for example metaclopramide which is included to overcome the gastric stasis which accompanies migraine and promote gastric emptying in order to increase serum levels of paracetamol. Such ingredients can result in undesirable side effects. The formulations of the present invention which have an unexpectedly increased rate of absoφtion and thus obviate the need for additional ingredients carrying side effects, are clearly of benefit.
The following Examples (1 to 10) are illustrations of the invention. Comparative Example A is outside the scope of the invention but is included to further demonstrate the advantages o the invention.
Example 1
A granule suitable for compression into tablets was prepared from the following ingredients
ingredient mg/tablet batch size g^
1. paracetamol (fine) 500.00 9000.00
2. sodium bicarbonate (fine) 630.00 11340.00
3. starch (maize) 11.40 205.20
4. starch (pregelatinised) 50.00 900.00
5. Povidone K25 2.00 36.00
6. potassium sorbate 0.60 10.80
Ingredients 1 -6 were sieved through a 16 mesh sieve into a suitable mixer and granulated with a suitable quantity of deionised water to form a medium/heavy granule. The granule was dried in a suitable oven at 45°C, until the water content was <1%. The resulting dried granule was then passed through a 12 mesh seive to give a white granule (yield 20.250kg)
Example 2
Tablets were prepared from the following ingredients:
ingredient mg/tablet r >atch size (g)
1. granule from example 1 1194.00 19104.00
2. starch (maize) 10.00 160.00
3. talc 15.00 240.00
4. stearic acid 5.00 80.00
5. Acdisol 36.70 587.20
Total 1260.70 20171.20
Ingredients 1-5 were sieved through a 16 mesh sieve into a suitable blender and mixed. The resulting blend was then compressed into tablets using suitable capsule shaped tooling to give white capsule shaped tablets (target weight of 1260.7mg), The final composition of the tablets was as follows:
ingredient
1. paracetamol (fine) 500.00
2. sodium bicarbonate (fine) 630.00
3. starch (maize) 21.40
4. starch (pregelatinised) 50.00
5. Povidone K25 2.00
6. potassium sorbate 0.60
7. talc 15.00
8. stearic acid 5.00
9. Acdisol 36.70
Total 1260.70
Each tablet contained paracetamol 500mg and sodium bicarbonate 630mg, with a ratio of sodium bicarbonate: paracetamol of 1.26 : 1 Example 3
Tablets (target weight 1023.82mg) were prepared by a similar method to than described in examples 1 and 2, but using different levels of ingredients such that the final formula was as follows:
ingredient
1. paracetamol (fine) 500.00
2. sodium bicarbonate (fine) 400.00
3. starch (maize) 21.40
4. starch (pregelatinised) 50.00
5. Povidone K25 2.00
6. potassium sorbate 0.60
7. talc 15.00
8. stearic acid 5.00
9. Acdisol 29.82
Total 1023.82
Each tablet contained paracetamol 500mg and sodium bicarbonate 400mg, with a ratio of sodium bicarbonate: paracetamol of 0.8 : 1
Example 4
Tablets (target weight 993.82mg) are prepared by a similar method to that described in examples 1 and 2, but using different levels of ingredients such that the final formula is as follows:
ingredient
1. paracetamol (fine) 500.00
2. sodium bicarbonate (fine) 370.00
3. starch (maize) 21.40
4. starch (pregelatinised) 50.00
5. Povidone K25 2.00
6. potassium sorbate 0.60
7. talc 15.00
8. stearic acid 5.00
9. Acdisol 29.82
Total 993.82
Each tablet contains paracetamol 500mg and sodium bicarbonate 370mg, with a ratio of sodium bicarbonate: paracetamol of 0.74 : 1 Example 5
Tablets (target weight 1430.7mg) are prepared by a similar method to that described in examples 1 and 2, but using different levels of ingredients such that the final formula is as follows:
ingredient mg/tablet
1. paracetamol (fine) 500.00
2. sodium bicarbonate (fine) 800.00
3. starch (maize) 21.40
4. starch (pregelatinised) 50.00
5. Povidone K25 2.00
6. potassium sorbate 0.60
7. talc 15.00
8. stearic acid 5.00
9. Acdisol 36.70
Total 1430.70
Each tablet contains paracetamol 500mg and sodium bicarbonate 800 mg, with a ratio of sodium bicarbonate: paracetamol of 1.6 : 1
Example 6
Tablets (target weight 923.82mg) are prepared by a similar method to that described in examples 1 and 2, but using different levels of ingredients such that the final formula is as follows:
ingredient
1. paracetamol (fine) 400.00
2. sodium bicarbonate (fine) 400.00
3. starch (maize) 21.40
4. starch (pregelatinised) 50.00
5. Povidone K25 2.00
6. potassium sorbate 0.60
7. talc 15.00
8. stearic acid 5.00
9. Acdisol 29.82
Total 923.82
Each tablet contains paracetamol 400mg and sodium bicarbonate 400mg, with a ratio of sodium bicarbonate: paracetamol of 1 : 1 Example 7
Tablets (target weight 1223.82mg) are prepared by a similar method to that described in examples 1 and 2, but using different levels of ingredients such that the final formula is as follows:
ingredient mg/tablet
1. paracetamol (fine) 600.00
2. sodium bicarbonate (fine) 500.00
3. starch (maize) 21.40
4. starch (pregelatinised) 50.00
5. Povidone K25 2.00
6. potassium sorbate 0.60
7. talc 15.00
8. stearic acid 5.00
9. Acdisol 29.82
Total 1223.82
Each tablet contains paracetamol 600mg and sodium bicarbonate 500mg, with a ratio of sodium bicarbonate: paracetamol of 0.83 : 1
Example 8
Tablets (target weight 819.46mg) are prepared by a similar method to that described in examples 1 and 2, but using different levels of ingredients such that the final formula is as follows:
ingredient
1. paracetamol (fine) 325.00
2. sodium bicarbonate (fine) 409.50
3. starch (maize) 13.91
4. starch (pregelatinised) 32.50
5. Povidone K25 1.30
6. potassium sorbate 0.39
7. talc 9.75
8. stearic acid 3.25
9. Acdisol 23.86
Total 819.46
Each tablet contains paracetamol 325mg and sodium bicarbonate 409.5mg, with a ratio of sodium bicarbonate to paracetamol of 1.26 : 1 Example 9
Tablets (target weight 1291.56mg) are prepared by blending ingredients 1 to 7 together and compressing using a suitable tablet press:
Ingredient mg/tablet
1. paracetamol direct compression grade (90%) 555.56
2. sodium bicarbonate 630.00
3. microcrystalline cellulose 50.00
4. Explotab (Na Starch Glycolate) 25.00
5. Crosspovidone XL 10 25.00
6. sodium lauryl sulfate 3.00
7. magnesium, stearate 3.00
Total 1291.56
Each tablet contains paracetamol 500mg and sodium bicarbonate 630mg, with a ratio of sodium bicarbonate to paracetamol of 1.26 : 1
E ample 1Q
Capsules are prepared as follows:
The granulation, seiving and blending steps from examples 1 and 2 are repeated. The resulting powder is then filled into hard gelatin capsules with a target fill weight of 819.46mg, such that the final formula is as follows:
ingredient
1. paracetamol (fine) 325.00
2. sodium bicarbonate (fine) 409.50
3. starch (maize) 13.91
4. starch (pregelatinised) 32.50
5. Povidone K25 1.30
6. potassium sorbate 0.39
7. talc 9.75
8. stearic acid 3.25
9. Acdisol 23.86
Total 819.46
Each capsule contains paracetamol 325mg and sodium bicarbonate 409.5mg, with a ratio of sodium bicarbonate to paracetamol of 1.26 : 1 Comparative Example A
Tablets (target weight 988.23mg) were prepared by a similar method to that described in examples 1 and 2, but using different levels of ingredients and substituting calcium carbonate for sodium bicarbonate, such that the final formula was as follows:
mg/dose
1. paracetamol (fine) 500.00
2. calcium carbonate 375.00
3. starch (maize) 21.40
4. starch (pregelatinised) 50.00
5. Povidone K25 2.00
6. potassium sorbate 0.60
7. talc 15.00
8. stearic acid 5.00
9. Acdisol 19.23
Total 988.23
Each tablet contained paracetamol 500mg and calcium carbonate 375 mg, with ratio of calcium carbonate to paracetamol of 0.75 : 1
Biostudy
The following products were compared in a five way cross over pharmacokinetic study using 15 fasted healthy human volunteers:
test formula A Tablets from Example 2 test formula B Tablets from Example 3 test formula C Tablets from Comparative Example A test formula D Commercially available swallow tablets containing paracetamol (500mg) and no sodium bicarbonate test formula E Commercially available soluble tablets containing paracetamol (500mg) and sodium bicarbonate (1342mg)
Each volunteer swallowed 2 tablets of one of the formulations, followed by lOOmls of water on 5 separate occasions at least 48 hours apart. For test formula E, the 2 tablets were dissolved in the lOOmls of water prior to swallowing. Blood samples were taken at 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 75, 90, 120, 180, 240, 360, 480, and 720 minutes post dose. Serum paracetamol levels were determined by HPLC and paracetamol serum levels vs time profiles were plotted for each volunteer. There were no significant differences in the area under the serum level vs time curve (AUC0^,) for any of the formulae.
The maximum concentrations of paracetamol in serum (Cmax) following dosing were as follows:
test formula A 30mg/L test formula B 26mg/L test formula C 15mg/L test formula D 17mg/L test formula E 20mg/L
The Cmax for formula A was statistically significantly higher than that seen for formula C (p<0 .0002), D (p<0.002) and E (PO.02). There was no statistically significant difference between the Cmax for formula A and B. The Cmax for formula B was significantly higher than that seen for formula C (p<0.01) and formula D (p<0.02)
The mean area under the serum concentration vs time curve between 0 and 20 minutes (AUC 0.20) following dosing were derived, results were as follows:
test formula A 245 mg.min/L test formula B 177 mg.min/L test formula C 76.0 mg . min/L test formula D 69.7 mg.min/L test formula E 199 mg.min/L
The (AUC 0.20) for formulation A was 3.5 times greater than for formulation D and the (AUC 0.20) for formulation B was 2.5 times greater than for formulation D, both of these differences were statistically significant, indicating that the rate of paracetamol absoφtion from the invention was increased by a factor of up to 250% compared to conventional paracetamol swallow tablets.

Claims

Claims
1. A swallow tablet or capsule formulation comprising from 300mg to 600mg of paracetamol and from 300mg to 1200mg of sodium bicarbonate together with at least one pharmaceutically acceptable excipient, wherein the weight ratio of sodium bicarbonate to paracetamol is at least 0.74 to 1.
2. A formulation according to claim 1 comprising at least 370 mg of sodium bicarbonate.
3. A formulation according to claim 1 or 2 comprising no greater than 1000 mg of sodium bicarbonate.
4. A formulation according to any one of claims 1 to 3 containing 500 mg of paracetamol.
5. A formulation according to any one of claims 1 to 3 containing 325 mg of paracetamol.
6. A formulation according to any one of claims 1 to 5 wherein the weight ratio of sodium bicarbonate to paracetamol is at least 0.8 to 1.
7. A process for preparing a swallow tablet or capsule formulation as defined in any one of claims 1 to 6 which process comprises the admixture of paracetamol and sodium bicarbonate together with any pharmaceutically acceptable excipients, additional pharmaceutically acceptable active agents or adjuvants.
PCT/EP1998/001284 1997-03-05 1998-02-27 Swallow tablet comprising paracetamol WO1998038983A2 (en)

Priority Applications (21)

Application Number Priority Date Filing Date Title
AU68282/98A AU721851B2 (en) 1997-03-05 1998-02-27 Swallow tablet comprising paracetamol
EP98913664A EP0981334B1 (en) 1997-03-05 1998-02-27 Swallow tablet comprising paracetamol
HU0001501A HU224983B1 (en) 1997-03-05 1998-02-27 Swallow tablet comprising paracetamol
DE69814850T DE69814850T2 (en) 1997-03-05 1998-02-27 PARACETAMOL CONTAINING SLICKABLE TABLET
DK98913664T DK0981334T3 (en) 1997-03-05 1998-02-27 Swallowing tablets containing paracetamol
PL335502A PL190988B1 (en) 1997-03-05 1998-02-27 Paracetamol containing oral tablet
SK1197-99A SK282277B6 (en) 1997-03-05 1998-02-27 Swallow tablet or capsule formulation and process for production
JP53816998A JP2001513801A (en) 1997-03-05 1998-02-27 Swallow tablets containing paracetamol
UA99094955A UA59388C2 (en) 1997-03-05 1998-02-27 Swallow tablet comprising paracetamol
EA199900709A EA001918B1 (en) 1997-03-05 1998-02-27 Swallow tablets comprising paracetamol
SI9830474T SI0981334T1 (en) 1997-03-05 1998-02-27 Swallow tablet comprising paracetamol
IL13155298A IL131552A (en) 1997-03-05 1998-02-27 Swallow tablet comprising paracetamol
KR10-1999-7007976A KR100465895B1 (en) 1997-03-05 1998-02-27 Swallow tablet comprising paracetamol
CA002283408A CA2283408C (en) 1997-03-05 1998-02-27 Swallow tablet comprising paracetamol
AT98913664T ATE240720T1 (en) 1997-03-05 1998-02-27 ERRORABLE TABLET CONTAINING PARACETAMOL
APAP/P/1999/001638A AP1084A (en) 1997-03-05 1998-02-27 Swalow tablet comprising paracetamol.
NZ337418A NZ337418A (en) 1997-03-05 1998-02-27 Paracetamol composition with improved rate of absorption
US09/380,453 US6316025B1 (en) 1997-03-05 1998-02-27 Swallow tablet comprising paracetamol
BR9807992-1A BR9807992A (en) 1997-03-05 1998-02-27 Pills to swallow which comprise paracetamol
NO19994294A NO327456B1 (en) 1997-03-05 1999-09-03 Formulations containing paracetamol and sodium bicarbonate as well as processes for the preparation thereof
HK00105436A HK1027026A1 (en) 1997-03-05 2000-08-30 Swallow tablet comprising paracetamol

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9704524.9A GB9704524D0 (en) 1997-03-05 1997-03-05 Composition
GB9704524.9 1997-03-05

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WO1998038983A3 WO1998038983A3 (en) 1998-12-17

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EP1103257A2 (en) * 1999-11-24 2001-05-30 McNEIL-PPC, INC. Method for treating migraine symptoms using acetominophen
WO2005115344A1 (en) * 2004-05-28 2005-12-08 Imaginot Pty Ltd Oral delivery system
WO2006024638A2 (en) * 2004-08-31 2006-03-09 Aristocon Verwaltungs-Gmbh Peroral dosage forms to achieve a sustained-release effect after medicament dosage with a meal
EP1750677A1 (en) * 2004-05-28 2007-02-14 Imaginot Pty Ltd. Oral therapeutic compound delivery system
KR100702069B1 (en) * 2005-10-31 2007-03-30 (주)이엘티사이언스 The composition of paracetamol water soluble powder and a Method thereof
WO2007118063A1 (en) 2006-04-07 2007-10-18 Smithkline Beecham Corporation Fast release paracetamol tablets
EP1893183A1 (en) * 2005-06-13 2008-03-05 Paul Rosenberg Emetic embedded capsule
US7993673B2 (en) 2001-06-08 2011-08-09 Smithkline Beecham Limited Swallow tablet comprising paracetamol
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BRPI0520000A2 (en) * 2004-10-28 2009-04-07 Novartis Ag composition comprising acetaminophen, caffeine and optionally aspirin together with an alkaline agent for enhanced absorption
US9060950B2 (en) * 2005-06-13 2015-06-23 Paul H. Rosenberg, Proximate Concepts, LLC. Emetic embedded capsule
US20080014228A1 (en) * 2006-07-14 2008-01-17 Olivia Darmuzey Solid form
US20080311162A1 (en) * 2007-05-16 2008-12-18 Olivia Darmuzey Solid form
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US7060730B2 (en) 1999-06-10 2006-06-13 Cathy Klech Gelotte Rapidly absorbed liquid compositions
US6211246B1 (en) 1999-06-10 2001-04-03 Mcneil-Ppc, Inc. Rapidly absorbed liquid compositions
EP1103257A2 (en) * 1999-11-24 2001-05-30 McNEIL-PPC, INC. Method for treating migraine symptoms using acetominophen
EP1103257A3 (en) * 1999-11-24 2001-11-28 McNEIL-PPC, INC. Method for treating migraine symptoms using acetominophen
US7993673B2 (en) 2001-06-08 2011-08-09 Smithkline Beecham Limited Swallow tablet comprising paracetamol
EP1750677A4 (en) * 2004-05-28 2012-01-25 Imaginot Pty Ltd Oral therapeutic compound delivery system
AU2005247047C1 (en) * 2004-05-28 2010-03-11 Glaxo Group Limited Oral delivery system
EP1761250A1 (en) * 2004-05-28 2007-03-14 Imaginot Pty Ltd. Oral delivery system
US20130065885A1 (en) * 2004-05-28 2013-03-14 Imaginot Pty Ltd. Oral therapeutic compound delivery system
WO2005115344A1 (en) * 2004-05-28 2005-12-08 Imaginot Pty Ltd Oral delivery system
EP1761250A4 (en) * 2004-05-28 2007-05-09 Imaginot Pty Ltd Oral delivery system
EP1750677A1 (en) * 2004-05-28 2007-02-14 Imaginot Pty Ltd. Oral therapeutic compound delivery system
AU2005247047B2 (en) * 2004-05-28 2009-08-20 Glaxo Group Limited Oral delivery system
EA013429B1 (en) * 2004-08-31 2010-04-30 Аристокон Фервальтунгс - Гмбх Peroral dosage forms to achieve a sustained-release effect after taking active pharmaceutical ingredient (api) together with a meal
WO2006024638A2 (en) * 2004-08-31 2006-03-09 Aristocon Verwaltungs-Gmbh Peroral dosage forms to achieve a sustained-release effect after medicament dosage with a meal
WO2006024638A3 (en) * 2004-08-31 2007-04-05 Aristocon Verwaltungs Gmbh Peroral dosage forms to achieve a sustained-release effect after medicament dosage with a meal
EP1893183A1 (en) * 2005-06-13 2008-03-05 Paul Rosenberg Emetic embedded capsule
EP1893183A4 (en) * 2005-06-13 2010-08-18 Paul Rosenberg Emetic embedded capsule
KR100702069B1 (en) * 2005-10-31 2007-03-30 (주)이엘티사이언스 The composition of paracetamol water soluble powder and a Method thereof
US9757455B2 (en) 2005-11-28 2017-09-12 Johnson & Johnson Consumer Inc. Oral therapeutic compound delivery system
WO2007118063A1 (en) 2006-04-07 2007-10-18 Smithkline Beecham Corporation Fast release paracetamol tablets
EA017157B1 (en) * 2006-04-07 2012-10-30 Смитклайн Бичем Корпорейшн Fast release paracetamol tablets
AU2007234864B2 (en) * 2006-04-07 2012-11-22 Glaxosmithkline Consumer Healthcare (Uk) Ip Limited Fast release paracetamol tablets
US8461210B2 (en) * 2006-04-07 2013-06-11 GlaxoSmithKline, LLC Fast release paracetamol tablets
CN101466359B (en) * 2006-04-07 2013-09-25 史密丝克莱恩比彻姆公司 Fast release paracetamol tablets

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CO4940406A1 (en) 2000-07-24
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EA001918B1 (en) 2001-10-22
US6316025B1 (en) 2001-11-13
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PL335502A1 (en) 2000-04-25
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CY2367B1 (en) 2004-06-04
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HUP0001501A2 (en) 2000-09-28
DE69814850T2 (en) 2004-03-11
BG103714A (en) 2000-05-31
ID22233A (en) 1999-09-23
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NO994294D0 (en) 1999-09-03
PE68899A1 (en) 1999-09-26
KR100465895B1 (en) 2005-01-13
AR011919A1 (en) 2000-09-13
ATE240720T1 (en) 2003-06-15
CA2283408A1 (en) 1998-09-11
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SK282277B6 (en) 2002-01-07
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IL131552A0 (en) 2001-01-28
GB9704524D0 (en) 1997-04-23
NO327456B1 (en) 2009-07-06
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IL131552A (en) 2004-08-31
ZA981832B (en) 1998-12-11
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