GB2469849A - Unit dose sachets comprising Ibuprofen - Google Patents

Unit dose sachets comprising Ibuprofen Download PDF

Info

Publication number
GB2469849A
GB2469849A GB0907410A GB0907410A GB2469849A GB 2469849 A GB2469849 A GB 2469849A GB 0907410 A GB0907410 A GB 0907410A GB 0907410 A GB0907410 A GB 0907410A GB 2469849 A GB2469849 A GB 2469849A
Authority
GB
United Kingdom
Prior art keywords
pharmaceutical formulation
unit dose
sachet
ibuprofen
dose sachet
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
GB0907410A
Other versions
GB0907410D0 (en
Inventor
Martin Crawford
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Perrigo
Original Assignee
Perrigo
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 Perrigo filed Critical Perrigo
Priority to GB0907410A priority Critical patent/GB2469849A/en
Publication of GB0907410D0 publication Critical patent/GB0907410D0/en
Publication of GB2469849A publication Critical patent/GB2469849A/en
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/009—Sachets, pouches characterised by the material or function of the envelope
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds

Abstract

A unit dose sachet containing a pharmaceutical formulation of Ibuprofen (400mg) or a pharmaceutically acceptable salt thereof. Preferred salts of Ibuprofen include the Lysine and sodium salts. An additional active ingredient selected from paracetamol, guaifenesin, cetyl pyridinium chloride and phenylephrine HCl may be present. The pharmaceutical formulation may be in the form of a liquid, a powder, granules or pellets. In another aspect, a process for the preparation of the unit dose sachet comprising the steps of a) preparing the pharmaceutical formulation, b) introducing the pharmaceutical formulation into a sachet and c) sealing the sachet. In yet another aspect, the use of said unit dose sachet as a General Sales List medicament. The unit dose sachet may be useful in the treatment of fever, colds, influenza, arthritis, primary dysmenorrhoea, pain including rheumatic and muscular pain, sprains, strains, backache, neuralgia, migraine, headache, toothache, menstrual pain, Alzheimer's disease and Parkinson's disease.

Description

Formulation The present invention relates to a novel unit dose form of Ibuprofen.
Ibuprofen (2-[4-(2-methylprophy)phenyl]propanoic acid) is a non-steroidal anti-inflammatory drug which is widely used as an analgesic, anti-inflammatory and antipyretic. It is commonly used to relieve the symptoms of fever, colds and influenza, arthritis and primary dysmenorrhoea, and in the treatment of acne and orthostatic hypotension. It is also used for the treatment of pain including rheumatic and muscular pain, sprains and strains, backache, neuralgia, migraine, headache, toothache and menstrual pain. Long term use has been shown to have a prophylactic effect on Alzheimer's and Parkinson's disease, and it has a mild anti-platelet effect.
Ibuprofen is widely administered in solid form and as an aqueous solution, in particular as tablets, sugar coated tablets, gel capsules and suppositories.
Ibuprofen has been available under prescription in the UK since 1969, and has subsequently been one of the most widely prescribed non-steroidal anti-inflammatory drugs. It was launched as an over-the-counter medicine in 1983 and received General Sales List (GSL) status in 1996. As a result of its GSL status, Ibuprofen is available not only from pharmacies but also non-pharmacy outlets such as supermarkets, newsagents and general retailers, without prescription.
The recommended dose of Ibuprofen varies with body mass and indication, but is generally considered to be 200-400 mg every 4 -6 hours for adults, or 5 -10 mg/kg every 4 -6 hours for children. The maximum daily dose for over-the-counter use is usually considered to be 800 -1200 mg.
Ibuprofen is generally provided in the form of 200mg or 400mg tablets. For most widely available analgesics and anti-inflammatories, the adult dose necessitates the consumption of two tablets. However, as the adult dose of Ibuprofen is 400mg, only a single 400mg Ibuprofen tablet should be taken at any one time. In the United Kingdom, both 200mg and 400mg tablets are available on prescription or over-the-counter at pharmacies. This is on the grounds that a medical practitioner, be they a doctor, nurse or pharmacist, will be on hand to provide advice to the patient regarding the dosage at the point of purchase or prescription. Thus, the medical practitioner will advise that the tablets being prescribed or purchased are 400mg tablets, and thus the adult dose is in fact only a single tablet. However, 400mg tablets do not have GSL status, and are therefore not licensed for sale at non-pharmacy outlets. Medical practitioners will not be present at such non-pharmacy outlets to advise the patient regarding the correct dosage. As such, there is a greater risk that the patient will assume that the adult dosage requires the consumption of two tablets. If the tablets in fact comprise 400mg of Ibuprofen, a potentially damaging overdose may result.
In order to reduce the chance of such accidental overdoses, and comply with the regulatory guidelines and rules necessary for GSL status, the first aspect of the present invention provides a unit dose sachet containing a pharmaceutical formulation comprising 400m1 Ibuprofen or an equivalent amount of a pharmaceutically acceptable salt thereof.
For most existing pharmaceutical formulations sold in sachets, the adult dose necessitates the consumption of a single sachet. As such, the patient is more likely to assume, correctly, that the adult dose requires the consumption of a single sachet. Thus, the provision of the adult dose of 400mg of Ibuprofen in a unit dose sachet, rather than a tablet, will reduce the risk of an accidental overdose when the pharmaceutical is sold at non-pharmacy outlets, without the advice of a medical practitioner.
The pharmaceutical formulation may comprise any pharmaceutically acceptable salt of Ibuprofen. Pharmaceutically acceptable salts include the sodium, potassium, ammonium or lysine salt. Preferably, the pharmaceutical formulation comprises Ibuprofen Lysine or Ibuprofen Sodium.
The pharmaceutical formulation may comprise the R(-)-or S(+)-enantiomer of Ibuprofen, or the racemic mixture thereof.
Optionally, other active ingredients may be incorporated into the pharmaceutical formulation. Such active ingredients include other analgesics and anti-inflammatories, decongestants, bactericides and fungicides and cough medicaments such as expectorants.
Suitable analgesics include paracetamol and suitable decongestants include phenylephrine HC1. Suitable bactericides and fungicides include Cetyl pyridinium chloride, and suitable expectorants include Guaifenesin.
A particularly preferred pharmaceutical formulation comprises 400mg of Ibuprofen or an equivalent amount of a pharmaceutically acceptable salt thereof optionally in combination with Phenylephrine HC1.
The pharmaceutical formulation may comprise other ingredients, including pharmaceutically acceptable suspending agents, preservatives, sweeteners, artificial sweeteners, flavourings and colouring agents.
Optionally, the pharmaceutical formulation may comprise a pharmaceutically acceptable carrier, diluent or excipient.
Suitable carriers and/or diluents are well known in the art and include pharmaceutical grade starch, mannitol, lactose, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose (or other sugar), magnesium carbonate, gelatin, oil, alcohol, detergents, emulsifiers or water (preferably a European Pharmacopoeia! grade).
The pharmaceutical formulation can be formulated as a liquid, for example a solution, syrup, suspension or emulsion.
A liquid formulation will generally consist of a suspension or solution of the active ingredients or a physiologically acceptable salt thereof in a suitable aqueous or non-aqueous liquid carrier(s) for example water, ethanol, glycerine, polyethylene glycol or oil.
The liquid formulation may be a ready-to-use' liquid formulation, which can be consumed directly from the sachet. Alternatively, the liquid formation may be a concentrated liquid formulation, which can be diluted in water or another suitable liquid prior to consumption.
The pharmaceutical formulation can be formulated as a solid, for example a powder, granules or pellets.
The powder, granules or pellets may be ready-to-use' formulations, which can be consumed directly from the packet. Alternatively, the powders, granules or pellets may be formulated for reconstitution in water or another suitable liquid.
Such powders, granules or pellets may be effervescent, when combined with water or another suitable liquid.
As used herein, a unit dose sachet is a sachet containing a single adult dose of a pharmaceutical formulation.
The term sachet is used herein to describe any suitable container, package or bag to contain the pharmaceutical formulation. Preferably the sachet is sealed, using any appropriate method. Preferably, the sachet is disposable. The sachet may be formed of any suitable material, including plastic, metal foil, paper or a combination thereof. The sachet may be provided with any suitable means for opening thereof, including a perforated region or a nick in the edge of the sachet for ease of tearing. The sachet may be of any suitable size. Preferably, the sachet is of a size to conveniently fit in a pocket, wallet or handbag.
The unit dose sachet may be sold individually or as a collection of two or more sachets.
The sachet may be sold as part of a kit, including printed instructions setting forth the safe and effective use of the contents of the kit. The kit may include details of the General List Status of the medicament. The kit may contain only a single unit dose sachet, or may contain two or more unit dose sachets.
A further embodiment of the first aspect provides the unit dose sachet of the present invention for use as a General Sales List medicament. As such, the unit dose sachet of the present invention will be licensed for sale without prescription and may be sold at non-pharmacy outlets.
The second aspect of the present invention provides a process for the preparation of the unit dose sachet of the first aspect of the present invention comprising the steps of: a) preparing the pharmaceutical formulation as described in the first aspect of the present invention; b) introducing the pharmaceutical formulation into a sachet; and c) sealing the sachet.
The third aspect of the present invention provides a pharmaceutical formulation comprising 400mg Ibuprofen or an equivalent amount of a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease or condition in a patient in need thereof, wherein the pharmaceutical formulation is provided in a unit dose sachet.
Included within this aspect is the use of Ibuprofen or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of a disease or condition in a patient in need thereof, wherein the Ibuprofen or pharmaceutically acceptable salt thereof is provided as a 400mg dose in a unit dose sachet.
The third aspect also provides the unit dose sachet of the first aspect of the present invention for use in the treatment or prevention of a disease or condition in a patient in need thereof.
In one embodiment, the third aspect of the present invention comprises the steps of: a) opening the unit dose sachet; and b) consuming the pharmaceutical formulation.
In one embodiment, the pharmaceutical formulation is a ready-to-use' formulation which is consumed directly from the sachet. In an alternative embodiment, the pharmaceutical formulation is added to water or another suitable liquid prior to consumption. If the pharmaceutical formulation is a liquid, the formulation may be added to water or another suitable liquid for dilution. If the pharmaceutical formulation is a solid in the form of powder, granules or pellets, the formulation may be added to water or another suitable liquid for reconstitution or effervescence to create a solution, liquid dispersion or suspension.
In the third aspect of the present invention, the patient in need thereof may be suffering from any disease or condition which may be treated by Ibuprofen, or for which Ibuprofen may be used to control or alleviate the symptoms. Such diseases or conditions include but are not limited to fever, colds, influenza, arthritis, primary dysmenorrhoea, pain including rheumatic and muscular pain, sprains and strains, backache, neuralgia, migraine, headache, toothache and menstrual pain, Alzheimer's disease and Parkinson's disease, wherein the pharmaceutical formulation is provided in a unit dose sachet.
The fourth aspect of the present invention provides the use of a pharmaceutical formulation comprising 400mg Ibuprofen or an equivalent amount of a pharmaceutically acceptable salt thereof in the preparation of a General Sales List medicament, wherein the pharmaceutical formulation is provided in a unit dose sachet.
The unit dose sachet, the packaging thereof or the kit in which the unit dose sachet is sold may of course contain information regarding the General Sales List status of this medicament.
All of the embodiments of, and details regarding, the pharmaceutical formulation and sachet described herein apply mutatis mutandis to all aspects of the present invention.

Claims (11)

  1. Claims 1. A unit dose sachet containing a pharmaceutical formulation comprising 400mg Ibuprofen or an equivalent amount of a pharmaceutically acceptable salt thereof.
  2. 2. The unit dose sachet of claim 1 wherein the pharmaceutically acceptable salt of Ibuprofen is selected from the group consisting of Ibuprofen Lysine and Ibuprofen Sodium.
  3. 3. The unit dose sachet of claim 1 or 2 wherein the pharmaceutical formulation further comprises a second active ingredient selected from the group consisting of paracetamol, phenylephrine HC1, guaifenesin and cetyl pyridinium chloride.
  4. 4. The unit dose sachet of any preceding claim containing a pharmaceutical formulation comprising Ibuprofen or a pharmaceutically acceptable salt thereof and phenylephrine HC1.
  5. 5. The unit dose sachet of any preceding claim wherein the pharmaceutical formulation is in the form of a liquid.
  6. 6. The unit dose sachet of any of claims 1 -4 wherein the pharmaceutical formulation is in the form of a powder, granules or pellets.
  7. 7. The unit dose sachet of any preceding claim for use as a General Sales List medicament.
  8. 8. A process for the preparation of the unit dose sachet of any of preceding claim comprising the steps of: a) preparing the pharmaceutical formulation; b) introducing the pharmaceutical formulation into a sachet; and c) sealing the sachet.
  9. 9. A pharmaceutical formulation comprising 400mg Ibuprofen or an equivalent amount of a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease or condition in a patient in need thereof, wherein the pharmaceutical formulation is provided in a unit dose sachet.
  10. 10. The pharmaceutical formulation of claim 9 wherein the disease or condition is selected from the group consisting of fever, colds, influenza, arthritis, primary dysmenorrhoea, pain including rheumatic and muscular pain, sprains and strains, backache, neuralgia, migraine, headache, toothache and menstrual pain, Alzheimer's disease and Parkinson's disease.
  11. 11. The use of a pharmaceutical formulation comprising 400mg Ibuprofen or an equivalent amount of a pharmaceutically acceptable salt thereof in the preparation of a General Sales List medicament, wherein the pharmaceutical formulation is provided in a unit dose sachet.
GB0907410A 2009-04-29 2009-04-29 Unit dose sachets comprising Ibuprofen Withdrawn GB2469849A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
GB0907410A GB2469849A (en) 2009-04-29 2009-04-29 Unit dose sachets comprising Ibuprofen

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB0907410A GB2469849A (en) 2009-04-29 2009-04-29 Unit dose sachets comprising Ibuprofen

Publications (2)

Publication Number Publication Date
GB0907410D0 GB0907410D0 (en) 2009-06-10
GB2469849A true GB2469849A (en) 2010-11-03

Family

ID=40792025

Family Applications (1)

Application Number Title Priority Date Filing Date
GB0907410A Withdrawn GB2469849A (en) 2009-04-29 2009-04-29 Unit dose sachets comprising Ibuprofen

Country Status (1)

Country Link
GB (1) GB2469849A (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0418043A1 (en) * 1989-09-13 1991-03-20 Roche Consumer Health (Worldwide) Ltd Non-effervescent ibuprofen compositions
EP0769294A1 (en) * 1995-10-17 1997-04-23 RECKITT & COLMAN PRODUCTS LIMITED Taste-masked aqueous solutions comprising methol
WO1998025595A2 (en) * 1996-12-10 1998-06-18 The Boots Company Plc Aqueous drink composition comprising ibuprofen

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0418043A1 (en) * 1989-09-13 1991-03-20 Roche Consumer Health (Worldwide) Ltd Non-effervescent ibuprofen compositions
EP0769294A1 (en) * 1995-10-17 1997-04-23 RECKITT & COLMAN PRODUCTS LIMITED Taste-masked aqueous solutions comprising methol
WO1998025595A2 (en) * 1996-12-10 1998-06-18 The Boots Company Plc Aqueous drink composition comprising ibuprofen

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Arzneimittel-Forschung, Vol. 42, No. 4, 1992, (Ceppi Monti, N.; Gazzaniga, A.; Gianesello, V.; Stroppolo, F.; Lodola, E.), pages 556-9, ISSN: 0004-4172 *
Chirality, Vol. 9, No. 3, 1997, (Fornasini, Gianfranco et al), pages 297-302, ISSN: 0899-0042 *
Journal of Chromatography A, Vol. 1119, No. 1-2, 2006, ( Huidobro, A. L.; Ruperez, F. J.; Barbas, C.), pages 238-245, ISSN: 0021-9673 *
Monthly Index of Medical Specialities, April 2002, (Colin Duncan) *

Also Published As

Publication number Publication date
GB0907410D0 (en) 2009-06-10

Similar Documents

Publication Publication Date Title
US20110275718A1 (en) Pharmaceutical composition of ibuprofen and paracetamol and methods of using the same
JP6511492B2 (en) Treatment of symptoms related to female gastroparesis
RU2140782C1 (en) Improved pharmaceutical preparations containing ibuprofen and codeine
JP2010215611A (en) Medicinal preparation containing loxoprofen
WO2006093784A2 (en) Dosage forms of antibiotics and combinations of antibiotics ans symptomatic relief agents
US20220151960A1 (en) Treatment of symptoms associated with female gastroparesis
ES2671926T3 (en) Dry coated tablet containing tegafur, gimeracil and potassium oteracil
WO2005063219A2 (en) Ibuprofen-containing soft gelatin capsules
Hamilton et al. Tarascon pharmacopoeia
CA2846299A1 (en) Oral suspension
TW202038954A (en) Montelukast for the treatment of erosive hand osteoarthritis
JP5525324B2 (en) Loxoprofen-containing pharmaceutical preparation
GB2469849A (en) Unit dose sachets comprising Ibuprofen
JP5624367B2 (en) Loxoprofen-containing pharmaceutical preparation
WO1992004022A1 (en) Use of compositions containing 2-(6'-substituted-2'-naphthyl)-acetic acid derivatives for the treatment of respiratory disorders
JP2023529001A (en) Oral Formulations Containing Rabeximod in Crystalline Form
AU2013211546B1 (en) A Medicament
US20230310276A1 (en) Methods of preparing modified dosage forms and related components
JP5798735B2 (en) Loxoprofen-containing pharmaceutical composition
JP2011116733A (en) Loxoprofen-containing pharmaceutical preparation
UA146734U (en) READY-MADE MEDICINE FOR SYMPTOMATIC TREATMENT OF PAIN
UA145352U (en) READY-MADE MEDICINAL PRODUCT FOR SYMPTOMATIC TREATMENT OR PREVENTION OF COLD OR FLU
t EYE t EXTRAPYRAMIDAL SIDE EFFECTS (EPS)
RU2008100280A (en) A NEW PHARMACEUTICAL COMPOSITION AND ITS APPLICATION IN A METHOD FOR TREATING PATIENTS WITH HYPEREMIA AND MUMATED ELEMENT OF THE UPPER RESPIRATORY WAY
Gatoulis Voelker M, Schachtel BP, Cooper SA &

Legal Events

Date Code Title Description
WAP Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1)