AU2016218950C1 - Analgesic formulation - Google Patents

Analgesic formulation Download PDF

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AU2016218950C1
AU2016218950C1 AU2016218950A AU2016218950A AU2016218950C1 AU 2016218950 C1 AU2016218950 C1 AU 2016218950C1 AU 2016218950 A AU2016218950 A AU 2016218950A AU 2016218950 A AU2016218950 A AU 2016218950A AU 2016218950 C1 AU2016218950 C1 AU 2016218950C1
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pain
unit dose
paracetamol
per unit
ibuprofen
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AU2016218950A
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AU2016218950A1 (en
AU2016218950B2 (en
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Angelo PRICOLO
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Anlar Pty Ltd
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Anlar Pty Ltd
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Priority claimed from AU2015900470A external-priority patent/AU2015900470A0/en
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    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • 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
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • 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
    • 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

Abstract

The present invention relates to compositions, methods and kits for the treatment of pain. In particular, the compositions, methods and kits are for the treatment of pain associated with headache or migraine or period pain. In particular, the invention includes a pharmaceutical combination for treating pain comprising a first pharmaceutical composition comprising paracetamol and / or a NSAID and a pharmaceutically acceptable diluent, excipient or carrier; and a second pharmaceutical composition comprising paracetamol and/or a NSAID, a sedating antihistamine and a pharmaceutically acceptable diluent, excipient or carrier. Preferably, the NSAID is ibuprofen.

Description

Analgesic formulation
Field of the invention
The present invention relates to compositions, methods and kits for the treatment of pain. In particular, the compositions, methods and kits are particularly useful, but not limited to, the treatment of pain associated with headache, migraine or period pain.
Background of the invention
Pain management remains a ubiquitous clinical problem. In addition to injury, nearly every disease or pathological condition from arthritis to cancer to HIV infection and diabetes has a major pain component. Pain causes a great deal of suffering and is a sensory experience distinct from sensations of touch, pressure, heat and cold. It is often described by sufferers by such terms as bright, dull, aching, pricking, cutting or burning and is generally considered to include both the original sensation and the reaction to that sensation. This range of sensations, as well as the variation in perception of pain by different individuals, renders a precise definition of pain difficult. Where pain is "caused" by the stimulation of nociceptive receptors and transmitted over intact neural pathways, this is termed nociceptive pain. Pain may also be caused by damage to neural structures, and pain is often manifested as neural supersensitivity; this type of pain is referred to as neuropathic pain. A sufferer can experience pain over a relatively long period of time, for example over the course of several days, but may need, or be required, to function through daily activities. In particular, a sufferer of pain may need to continue to work or attend to the care of dependents.
While there are products available for the treatment of pain, these products do not provide a treatment regime that provides flexibility to a suffer of pain to manage their treatment at various times of the day or before, or during, particular events.
There is a need for improved compositions and methods for the treatment and management of pain in a subject that allows flexibility in treatment options. In particular, there is a need for compositions and methods for pain treatment that allows a sufferer to manage their treatment in accordance with their desired level of activity or alertness. More specifically, there is a need for a formulation that offers a patient the flexibility with one purchase to allow for variation in intensity of pain symptoms as well as the required level of attention or sedation needed. Reference to any prior art in the specification is not an acknowledgment or suggestion that this prior art forms part of the common general knowledge in any jurisdiction or that this prior art could reasonably be expected to be understood, regarded as relevant, and/or combined with other pieces of prior art by a skilled person in the art.
Summary of the invention The invention provides a pharmaceutical combination for treating pain comprising: a first pharmaceutical composition comprising paracetamol and / or a NSAID (non-steroidal anti-inflammatory drug); and a second pharmaceutical composition comprising (i) paracetamol and / or a NSAID, and (ii) a sedating antihistamine, and a pharmaceutically acceptable diluent, excipient or carrier. Preferably, the
NSAID is selected from the group consisting of ibuprofen, ketoprofen, diclofenac, aspirin, indomethacin, mefanamic acid and naproxen. More preferably, the NSAID is ibuprofen. The purpose of the invention is for the first pharmaceutical to be taken by a subject needing pain relief during the day and the second pharmaceutical composition to be taken by the same subject needing pain relief at night. The first pharmaceutical composition is designed to be taken at a time of the day when sedation or sleep is not desirable or contraindicated and the second pharmaceutical composition is designed to be taken at a time of the day when sedation or sleep is desirable or not contraindicated.
The day/night analgesic or painkiller of the invention can provide a patient the flexibility, with one purchase, to allow for variation in intensity of pain symptoms as well as the required level of attention or sedation needed.
Preferably, no other pharmaceutically active component is present other than paracetamol, a NSAID and a sedating antihistamine, ie, the combination is free of other pharmaceutically active components. The invention also provides a pharmaceutical combination for treating pain comprising: a first pharmaceutical composition comprising paracetamol, ibuprofen or both; and a second pharmaceutical composition comprising paracetamol, ibuprofen or both, and a sedating antihistamine, and a pharmaceutically acceptable diluent, excipient or carrier.
The invention also provides a pharmaceutical combination for treating pain comprising: a first pharmaceutical composition comprising paracetamol; and a second pharmaceutical composition comprising paracetamol and a sedating antihistamine, and a pharmaceutically acceptable diluent, excipient or carrier.
The invention also provides a pharmaceutical combination for treating pain comprising: a first pharmaceutical composition comprising paracetamol and ibuprofen; and a second pharmaceutical composition comprising paracetamol, ibuprofen and a sedating antihistamine, and a pharmaceutically acceptable diluent, excipient or carrier.
The invention also provides a pharmaceutical combination for treating pain comprising: a first pharmaceutical composition comprising paracetamol, naproxen or both; and a second pharmaceutical composition comprising paracetamol, naproxen or both, and a sedating antihistamine, and a pharmaceutically acceptable diluent, excipient or carrier.
The invention also provides a pharmaceutical combination for treating pain comprising: a first pharmaceutical composition comprising paracetamol and naproxen; and a second pharmaceutical composition comprising paracetamol, naproxen and a sedating antihistamine, and a pharmaceutically acceptable diluent, excipient or carrier.
In some embodiments, the first composition, which includes paracetamol, ibuprofen or both as described above, also includes caffeine.
The invention also provides a pharmaceutical combination for treating pain comprising: a first pharmaceutical composition comprising one or more analgesics; and a second pharmaceutical composition comprising one or more analgesics and a sedating antihistamine, and a pharmaceutically acceptable diluent, excipient or carrier.
Preferred analgesics include aceclofenac, acemetacin, aspirin, celecoxib, codeine, dexibuprofen, diclofenac, diflunisal, dihydrocodeine, dipyrone, etodolac, etoricoxib, fenbufen, fenoprofen, flurbiprofen, gabapentin, codeine, caffeine, oxycodone, indometacin, ibuprophen, ketoprofen, dexketoprofen, lornoxicam, lumiracoxib, mefenamic acid, meloxicam, nabumetone, naproxen, nefopam, dextropropoxyphene, paracetamol, piroxicam, rofecoxib, sulindac, tenoxicam or tiaprofenic acid. However, where there is more than one analgesic in a unit dose there should not be more than one NSAID.
The invention also provides a pharmaceutical composition for treating pain comprising one or more analgesics, a sedating antihistamine and a pharmaceutically acceptable diluent, excipient or carrier. Preferably the analgesic is paracetamol, ibuprofen or both. Preferably, the sedating antihistamine is promethazine. In one embodiment, the composition is a tablet and provided, for example, in a blister card. It is preferred that the composition or blister card of tablets is sold with instructions to take the composition when sedation or sleep is desirable or not contraindicated.
The invention provides a method of treating pain in a subject comprising: administering a first pharmaceutical composition comprising paracetamol and / or a NSAID at a time of the day when sedation or sleep is not desirable or contraindicated; and administering a second pharmaceutical composition comprising (i) comprising paracetamol and / or a NSAID, and (ii) a sedating antihistamine at a time of the day when sedation or sleep is desirable or not contraindicated, thereby treating pain in a subject. Preferably, the NSAID is selected from the group consisting of ibuprofen, ketoprofen, diclofenac, aspirin, indomethacin, mefanamic acid and naproxen. The invention provides a method of treating pain in a subject comprising: administering a first pharmaceutical composition comprising paracetamol, ibuprofen or both at a time of the day when sedation or sleep is not desirable or contraindicated; and administering a second pharmaceutical composition comprising paracetamol, ibuprofen or both and a sedating antihistamine at a time of the day when sedation or sleep is desirable or not contraindicated, thereby treating pain in a subject.
In some embodiments the first composition administered in the above methods also includes caffeine. The invention also provides the use of paracetamol and / or a NSAID in the preparation of a first composition and use of (i) paracetamol and / or a NSAID, and (ii) a sedating antihistamine in the preparation of a second composition, the first and second compositions being used for treating pain, wherein the second medicament is for administration when sedation or sleep is desirable or not contraindicated. Preferably, the NSAID is selected from the group consisting of ibuprofen, ketoprofen, diclofenac, aspirin, indomethacin, mefanamic acid and naproxen.
The invention also provides the use of paracetamol, ibuprofen or both in the preparation of a first composition and use of paracetamol, ibuprofen or both and a sedating antihistamine in the preparation of a second composition, the first and second compositions being used for treating pain, wherein the second medicament is for administration when sedation or sleep is desirable or not contraindicated.
In some embodiments caffeine is also used in the preparation of the first composition.
The invention also provides a kit for treating pain comprising at least two dosage units, wherein the kit is adapted to allow access to each dosage unit at different times, wherein a first dosage unit comprises at least one analgesic compound selected from paracetamol and / or a NSAID, and a pharmaceutically acceptable diluent, excipient or carrier; and wherein a second dosage unit comprises at least one analgesic compound selected from paracetamol and / or a NSAID, a sedating antihistamine and a pharmaceutically acceptable diluent, excipient or carrier. Preferably, the NSAID is selected from the group consisting of ibuprofen, ketoprofen, diclofenac, aspirin, indomethacin, mefanamic acid and naproxen. More preferably, the NSAID is selected from the group ibuprofen, diclofenac, aspirin and naproxen. The invention also provides a kit for treating pain comprising at least two dosage units, wherein the kit is adapted to allow access to each dosage unit at different times, wherein a first dosage unit comprises at least one analgesic compound selected from the group consisting of paracetamol, ibuprofen or both, and a pharmaceutically acceptable diluent, excipient or carrier; and wherein a second dosage unit comprises at least one analgesic compound selected from the group consisting of paracetamol, ibuprofen or both, a sedating antihistamine and a pharmaceutically acceptable diluent, excipient or carrier.
Optionally the kit also includes written instructions directing the user to administer a dosage unit at a particular time of the day or event. The instructions may also direct the user to administer multiple dosage units, for example 2 dosage units, at a particular time or event. Preferably, the written instructions direct the user to administer the dosage unit containing the sedating antihistamine when sedation or sleep is desirable or not contraindicated. Preferably the kit is adapted to allow identification of the first and second dosage units.
The invention also provides a kit for treating pain comprising:
A first dosage unit comprising at least one analgesic compound selected from the paracetamol and / or a NSAID, and a pharmaceutically acceptable diluent, excipient or carrier;
A second dosage unit comprising at least one analgesic compound selected from the paracetamol and / or a NSAID, a sedating antihistamine and a pharmaceutically acceptable diluent, excipient or carrier; indicia distinguishing the first and second dosage units from each other; instructions for coordinating the administration of each of the first and second dosage units as an analgesic treatment regimen whereby the second dosage unit is for administration during a particular time of day or event when sedation or sleep is desirable or not contraindicated; and a container which incorporates the indicia, the instructions and a plurality of first and second analgesic dosage units. Preferably, the NSAID is selected from the group consisting of ibuprofen, ketoprofen, diclofenac, aspirin, indomethacin, mefanamic acid and naproxen. Typically, the kit is in the form of a blister card. In some embodiments, two of the first dosage units are administered at the time for administration of the first dosage unit and two of the second dosage unit are administered at the particular time of day or event when the second dosage unit is instructed to be administered.
The invention also provides a kit for treating pain comprising:
A first dosage unit comprising at least one analgesic compound selected from the group consisting of paracetamol, ibuprofen or both, and a pharmaceutically acceptable diluent, excipient or carrier;
A second dosage unit comprising at least one analgesic compound selected from the group consisting of paracetamol, ibuprofen or both, a sedating antihistamine and a pharmaceutically acceptable diluent, excipient or carrier; indicia distinguishing the first and second dosage units from each other; instructions for coordinating the administration of each of the first and second dosage units as an analgesic treatment regimen whereby the second dosage unit is for administration during a particular time of day or event when sedation or sleep is desirable or not contraindicated; and a container which incorporates the indicia, the instructions and a plurality of first and second analgesic dosage units. Typically, the kit is in the form of a blister card.
In some embodiments, two of the first dosage units are administered at the time for administration of the first dosage unit and two of the second dosage unit are administered at the particular time of day or event when the second dosage unit is instructed to be administered.
In some embodiments, the first dosage unit of the kits described above also include caffeine. In these embodiments the instructions for coordinating the administration of each of at least one of the first and second dosage units as an analgesic treatment regimen whereby the first dosage unit is for administration during a particular time of day or event when sedation or sleep is not desirable or is contraindicated.
The invention also provides a kit for promoting the proper sequential oral administration (i.e. a first dosage unit for when sedation or sleep is not desirable or contraindicated and a second dosage unit for prior to sleep or when sedation or sleep is desirable or not contraindicated) of a pharmaceutically active ingredient, said kit comprising
(a) at least one first dosage unit comprising paracetamol and / or a NSAID;
(b) at least one second dosage unit comprising paracetamol and / or a NSAID, and a sedating antihistamine; and
(c) a blister card individually and releasably containing the unit doses; wherein said dosage units are arranged horizontally or vertically in order of their use across the blister card. Preferably, the NSAID is selected from the group consisting of ibuprofen, ketoprofen, diclofenac, aspirin, indomethacin, mefanamic acid and naproxen. Preferably, the invention provides a kit for promoting the proper sequential oral administration of a pharmaceutically active ingredient, said kit comprising (a) at least one first dosage unit comprising paracetamol, ibuprofen or both;
(b) at least one second dosage unit comprising paracetamol, ibuprofen or both, and a sedating antihistamine; and
(c) a blister card individually and releasably containing the unit doses; wherein said dosage units are arranged horizontally or vertically in order of their use across the blister card.
Preferably, the blister card is characterized by two or four horizontal rows of unit doses, wherein each horizontal row is characterized by one second dosage unit to every two first dosage units. Alternatively, the blister card is characterized by two or four vertical rows of unit doses, wherein each horizontal row is characterized by one second dosage unit to every two first dosage units. Preferably, the first and second dosage units have different appearance such that they are distinguishable by a subject, those differences may be in colour, shape or markings. Preferably the packaging of the first dosage unit is different from the packing of the second even when present on the same blister pack, for example, a different colour background is present on the face or back side of a blister pack. Typically, the first and second dosage units and their packaging are different.
The invention also provides a pharmaceutical presentation comprising: a first dosage unit and one or more second dosage units, the first dosage unit comprising paracetamol and / or a NSAID, preferably selected from ibuprofen, ketoprofen, diclofenac, aspirin, indomethacin, mefanamic acid and naproxen, the second dosage unit comprising paracetamol and / or a NSAID, preferably selected from ibuprofen, ketoprofen, diclofenac, aspirin, indomethacin, mefanamic acid and naproxen, and a sedating antihistamine, both dosage units further comprising a pharmaceutically acceptable diluent, excipient or carrier. Preferably the pharmaceutical presentation comprises: a first dosage unit and one or more second dosage units, the first dosage unit comprising paracetamol, ibuprofen or both, the second dosage unit comprising paracetamol, ibuprofen or both, and a sedating antihistamine, both dosage units further comprising a pharmaceutically acceptable diluent, excipient or carrier. Preferably, each dose is for administration every 6 to 8 hours. Preferably, there are more first dosage units than second dosage units, for example twice as many. Preferably, the dosage unity is a solid dosage unit such as a tablet or capsule, even more preferably the dosage unit is a tablet. Typically, the first and second dosage units have different appearance such that they are distinguishable by a subject, those differences may be in colour, shape or markings. Preferably the packaging of the first dosage unit is different from the packing of the second even when present on the same blister pack, for example, a different colour background is present on the face or back side of a blister pack. Typically, the first and second dosage units and their packaging are different.
In one preferred form, the pharmaceutical presentation above is a blister pack wherein the second dosage unit is darker in colour or housed in the packaging with a darker colour and there are at least twice as many first dosage units present to second dosage units.
The invention provides a pharmaceutical composition for treating pain comprising paracetamol and / or a NSAID, a sedating antihistamine and a pharmaceutically acceptable diluent, excipient or carrier. In one embodiment, the only active ingredients present in the composition are paracetamol, ibuprofen or both, and a sedating antihistamine. Preferably, the NSAID is selected from the group consisting of ibuprofen, ketoprofen, diclofenac, aspirin, indomethacin, mefanamic acid and naproxen.
The invention provides a pharmaceutical composition for treating pain comprising as active ingredients paracetamol and / or a NSAID, a sedating antihistamine and a pharmaceutically acceptable diluent, excipient or carrier. In one embodiment, the only active ingredients present in the composition are paracetamol, ibuprofen or both, and a sedating antihistamine. Preferably, the NSAID is selected from the group consisting of ibuprofen, ketoprofen, diclofenac, aspirin, indomethacin, mefanamic acid and naproxen.
The invention provides a pharmaceutical composition for treating pain comprising as main ingredients paracetamol and / or a NSAID, a sedating antihistamine and a pharmaceutically acceptable diluent, excipient or carrier. In one embodiment, the only active ingredients present in the composition are paracetamol, ibuprofen or both, and a sedating antihistamine. Preferably, the NSAID is selected from the group consisting of ibuprofen, ketoprofen, diclofenac, aspirin, indomethacin, mefanamic acid and naproxen. The invention also provides a pharmaceutical composition for use in treating pain comprising paracetamol and / or any one of ibuprofen, ketoprofen, diclofenac, aspirin, indomethacin, mefanamic acid and naproxen, a sedating antihistamine and a pharmaceutically acceptable diluent, excipient or carrier. Preferably, the NSAID is selected from the group consisting of ibuprofen, ketoprofen, diclofenac, aspirin, indomethacin, mefanamic acid and naproxen. The invention also provides a pharmaceutical composition for use in treating pain comprising paracetamol, ibuprofen or both, a sedating antihistamine and a pharmaceutically acceptable diluent, excipient or carrier.
In any aspect of the invention described herein, the at least one analgesic compound is selected from paracetamol, ibuprofen or both. In any aspect of the invention described herein, paracetamol or the NSAID is substituted by tramadol in the second pharmaceutical composition or second dosage unit, that is, in the composition or unit dose for administration when sleep is desirable or not contraindicated. Where the tramadol is included in the second pharmaceutical composition or the second dosage unit it may be included in addition to the sedating antihistamine or, because of its sedating effect, it may replace the sedating antihistamine. In any aspect of the invention described herein, paracetamol or the NSAID is, in another form of the invention, substituted by aceclofenac, acemetacin, aspirin, celecoxib, codeine, dexibuprofen, diclofenac, diflunisal, dihydrocodeine, dipyrone, etodolac, etoricoxib, fenbufen, fenoprofen, flurbiprofen, gabapentin, codeine, caffeine, oxycodone, indometacin, ketoprofen, dexketoprofen, lornoxicam, lumiracoxib, mefenamic acid, meloxicam, nabumetone, naproxen, nefopam, dextropropoxyphene, piroxicam, rofecoxib, sulindac, tenoxicam or tiaprofenic acid, with the proviso that an NSAID cannot be combined with a second NSAID.
Paracetamol may be present in any aspect of the invention described herein at an amount per unit dose of about 50mg to about 700mg, preferably 100mg to 670mg, preferably 100mg to about 665mg, preferably about 1 50mg to about 665mg, preferably about 330mg to about 500mg, preferably about 450mg to about 500mg, or about 300mg, about 400mg, about 500mg or about 665mg. Ibuprofen may be present in any aspect of the invention described herein at an amount per unit dose of about 10mg to about 150mg, preferably about 25mg to about 1 50mg, preferably about 50mg to about 100mg, preferably about 150mg. Alternatively, the ibuprophen may be present in any aspect of the invention described herein at an amount per unit dose of about 10mg to about 400mg, preferably about 150mg to about 200mg, most preferably 1 50mg or 200mg. Propacetamol may be present in the amounts above but may also be present up to an amount of about 2000mg.
Ketoprofen may be present in any aspect of the invention described herein at an amount per unit dose of about 100mg. Diclofenac may be present in any aspect of the invention described herein at an amount per unit dose of about 10mg to about 200mg, preferably about 25mg to about 1 50mg, preferably about 25mg to about 100mg, preferably 50mg to about 100mg, preferably at about 100mg. Aspirin may be present in any aspect of the invention described herein at an amount per unit dose of about 50mg to about 700mg, preferably about 100mg to about 650mg, preferably about 200mg to about 500mg, preferably about 200 mg to about 400mg. Indomethacin may be present in any aspect of the invention described herein at an amount per unit dose of about 25mg to about 1 00mg. Mefanamic acid may be present in any aspect of the invention described herein at an amount per unit dose of about 50 to about 400mg, preferably about 100mg to about 300mg, preferably about 1 00mg to about 250mg. Naproxen may be present in any aspect of the invention described herein at an amount per unit dose of about 100rmg to about 1500mg, preferably about 200mg to about 1 200mg, preferably about 250mg to about l OOOmg, preferably about 275mg to about l OOOmg, preferably about 500rmg to about l OOOmg. Most preferably about 250mg, about 275rmg or about 500mg. Tramadol may be present in the second pharmaceutical composition or second dosage unit of any aspect of the invention described herein at an amount per unit dose of about 1 0rmg to about 300mg, about 25mg to about 200mg, about 50mg to about 200mg, about 100mg to about 200mg.
In any aspect of the invention described herein, the sedating antihistamine may be selected from the group consisting of brompheniramine, chlorphenamine, dexchlorpheniramine, pheniramine, diphenhydramine, doxylamine (e.g. doxylamine succinate), promethazine (e.g. promethazine hydrochloride), trimeprazine, phenyltoloxamine, cyproheptadine, alimemazine, chlorphenamine, clemastine, cyproheptadine, hydroxyzine, ketotifen, mepyramine, antazoline, tripelennamine, carbinoxamine, orphenadrine, bromazine, dimenhydrinate, dexchlorpheniramine, chlorpheniramine, dexbrompheniramine, brompheniramine, tripolidine, cyclizine, chlorcyclizine, hydroxyzine, meclizine, and azatadine. Preferably, the sedating antihistamine may be selected from the group consisting of diphenhydramine, doxylamine, promethazine, trimeprazine and phenyltoloxamine. More preferably, the sedating antihistamine may be selected from the group consisting of diphenhydramine, doxylamine (e.g. doxylamine succinate) and promethazine (e.g. promethazine hydrochloride). Preferably, the sedating antihistamine is promethazine. Diphenhydramine may be present in any aspect of the invention described herein at an amount per unit dose of about 5mg to 100mg, 5mg to about 50mg or 12.5 to 100mg, preferably about 1 0mg to about 25mg, preferably about 25mg. Doxylamine succinate may be present in any aspect of the invention described herein at an amount per unit dose of about 0.1 mg to about 25mg, about 0.25mg to about 25mg or about 0.1 mg to about 10mg of the succinate salt or an equivalent amount of an alternate form, preferably about 1 to about 5mg, preferably about 5rmg. Promethazine may be present in any aspect of the invention described herein at an amount per unit dose of about 1 to about 50mg, preferably about 5 to about 40mg, preferably about 5 to about 30mg, preferably about 10mg to about 25mg, preferably about 1 0mg or about 25mg. Trimeprazine may be present in any aspect of the invention described herein at an amount per unit dose of about 2.5mg to about 25mg, preferably about 5 to about 20mg, preferably about 5mg or 10mg. Phenyltoloxamine may be present in any aspect of the invention described herein at an amount per unit dose of about 10mg to about 50mg. Mepyramine may be present in any aspect of the invention described herein at an amount per unit dose of about 1 2.5mg to about 100mg. Antazoline may be present in any aspect of the invention described herein at an amount per unit dose of about 50mg to about 1 00mg. Tripelennamine may be present in any aspect of the invention described herein at an amount per unit dose of about 12.5mg to about 100mg. Carbinoxamine may be present in any aspect of the invention described herein at an amount per unit dose of about 2mg to about 6rmg. Orphenadrine may be present in any aspect of the invention described herein at an amount per unit dose of about 30mg to about 1 00mg. Bromazine may be present in any aspect of the invention described herein at an amount per unit dose of about 5mg to about 20mg. Clemastine may be present in any aspect of the invention described herein at an amount per unit dose of about 0.5mg to about 2mg. Dimenhydrinate may be present in any aspect of the invention described herein at an amount per unit dose of about 12.5mg to about 100mg. Pheniramine may be present in any aspect of the invention described herein at an amount per unit dose of about 30mg to about 80mg. Dexchlorpheniramine may be present in any aspect of the invention described herein at an amount per unit dose of about 1 mg to about 4mg. Chlorpheniramine may be present in any aspect of the invention described herein at an amount per unit dose of about 1 rmg to about 1 0mg. Dexbrompheniramine may be present in any aspect of the invention described herein at an amount per unit dose of about 6mg to about 30mg. Brompheniramine may be present in any aspect of the invention described herein at an amount per unit dose of about 1 mg to about 1 2mg. Tripolidine may be present in any aspect of the invention described herein at an amount per unit dose of about 1 mg to about 5mg. Dimetindene may be present in any aspect of the invention described herein at an amount per unit dose of about 1 mg to about 4mg. Cyclizine may be present in any aspect of the invention described herein at an amount per unit dose of about 12.5mg to about 100mg. Chlorcyclizine may be present in any aspect of the invention described herein at an amount per unit dose of about 5mg to about 50mg. Hydroxyzine may be present in any aspect of the invention described herein at an amount per unit dose of about 25mg to about 100mg. Meclizine may be present in any aspect of the invention described herein at an amount per unit dose of about 12.5mg to about 100mg. Alimemazine may be present in any aspect of the invention described herein at an amount per unit dose of about 5mg to about 10mg. Cyproheptadine may be present in any aspect of the invention described herein at an amount per unit dose of about 1 mg to about 6mg. Azatadine may be present in any aspect of the invention described herein at an amount per unit dose of about 1 mg to about 6mg. Ketotifen may be present in any aspect of the invention described herein at an amount per unit dose of about 1 mg to about 6mg.
Caffeine may be present in any aspect of the invention described herein at an amount per unit dose of about 40 to about 200mg, preferably about 60 to about 1 00mg, more preferably at about 65mg.
The skilled person will understand that active ingredients may be free form, in various salt forms or in various hydration states etc. If, for example, a different salt form of an active ingredient is used in the invention, the skilled person will understand that the amount will need to be adjusted proportionally to the change in molecular weight. In one preferred form, either or both of the first and second pharmaceutical compositions or dosage units do not contain codeine. It is more preferred that all dosages of the pharmaceutical composition according to this invention are codeine free. In an alternate embodiment of the invention, one or more of the first unit dose and the second unit dose do contain codeine.
In any aspect of the invention, the pain treated is one described herein, for example, neuropathic pain, inflammatory pain, nociceptive pain, rheumatic pain, headache, lower back pain, pelvic pain, myofascial pain, vascular pain, migraine, wound associated pain, inflammatory pain, arthritic pain, diabetic pain, period pain, post-herpetic pain, pain from cancer, mixed neuropathic and nociceptive pain, mixed pain or somatic visceral pain, all in both acute and chronic forms. Preferably, the pain treated by the invention is migraine or headache. As used herein, except where the context requires otherwise, the term "comprise" and variations of the term, such as "comprising", "comprises" and "comprised", are not intended to exclude further additives, components, integers or steps.
Further aspects of the present invention and further embodiments of the aspects described in the preceding paragraphs will become apparent from the following description, given by way of example and with reference to the accompanying drawings.
Detailed description of the embodiments
It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention.
Further aspects of the present invention and further embodiments of the aspects described in the preceding paragraphs will become apparent from the following description, given by way of example.
Reference will now be made in detail to certain embodiments of the invention. While the invention will be described in conjunction with the embodiments, it will be understood that the intention is not to limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present invention as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described.
All of the patents and publications referred to herein are incorporated by reference in their entirety.
For purposes of interpreting this specification, terms used in the singular will also include the plural and vice versa.
The present invention provides for a pharmaceutical combination that includes a composition having certain analgesic compounds for administration when a subject is desirous of being active or alert and a further composition also including certain analgesic compounds but further including a sedating antihistamine for administration to the subject when sedation or sleep is desirable or not contraindicated. The present invention has the advantage of providing flexibility to a subject experiencing pain to have a composition that treats pain at a time when a sedative or calmative effect is not required or to be avoided, for example during work hours, when operating a machine or when attending to dependents, but also provides a composition that treats pain that further includes a sedative or calmative for assisting the subject to relax or fall asleep. While typically the composition having the sedative or calmative will be taken at night and the other composition having only one or more analgesics as active ingredients during the day, it is appreciated that certain vocations such as shift work, or during particular events, require a person to be active at night and to relax or sleep during the day.
The presence of a NSAID, particularly ibuprofen, has the advantage of also providing anti-inflammatory effects. The sedating antihistamines that have an antiemetic effect are particularly useful for treating headache and migraine, especially when these conditions are associated with nausea or vomiting. In this regard, promethazine is particularly useful given its pronounced antiemetic effect. This may also be useful when taken with other drugs that may cause nausea, like the opioid class of drugs or NSAIDs. The sedating antihistamines have a calmative and relaxant effect which can also provide some muscle relaxant effect. Further the presence of a sedating antihistamine also potentiates the analgesic. For example, promethazine, a phenothiazine derivative, is a long acting antihistamine with mild atropine-like anticholinergic effects, and because of its marked effect on the central nervous system (CNS), it acts as an antiemetic, tranquilliser and a potentiator of analgesics, making it a particularly preferred sedating antihistamine.
In certain forms of the invention the compositions or methods do not involve codeine. This is advantageous as codeine is constipating in certain individuals and has abuse potential. Further, codeine is sedating and therefore undesirable to be used in a treatment when sedation or sleep is not desirable or contraindicated. Further, there are also enzyme differences in individuals that can render it ineffective for some. Polymorphisms for CYP2D6 estimated to occur in 6% to 1 0% of non-Hispanic whites, 0% to 4.8% of Asians, 2.2% to 6.6% of Hispanics, and 1 .9% to 7.3% of African American populations.
Codeine is a popular analgesic, trusted by many patients and regarded by many has an analgesic for serious or long term pain, for example, it is on the WHO Model List of Essential Medicines, a list of the most important medication needed in a basic health system. However, codeine is a weak opioid analgesic. It has to be converted to morphine to elicit an effect, but there is significant inter-individual variation in its pharmacokinetics which results in variable effectiveness. Codeine's efficacy in clinical trials is generally modest and while its adverse events are usually mild, serious adverse events, including death, have occurred. Tolerance and drug dependence can occur. There is a risk of toxicity especially if combination products containing codeine and other drugs are misused. The relevance of slow metabolisers confirms the variable effects of codeine in the population so that up to 20% of Africans will find codeine markedly more potent and 30% much less potent. Drugs which inhibit CYP2D6, including many antidepressants such as paroxetine, sertraline and citalopram, may reduce the efficacy of codeine.
The term "NSAID" (nonsteroidal anti-inflammatory drug) typically indicates a chemical entity which acts as lipoxygenase, cyclooxygenase-1 or cyclooxygenase-2 antagonist. Non-limiting examples of NSAIDs include ibuprofen, ketoprofen, diclofenac, aspirin, indomethacin, mefanamic acid, naproxen, diflunisal, salsalate, dexibuprofen, fenoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, tolmetin, sulindac, etodolac, ketorolac, aceclofenac, nabumetone, piroxicam, meloxicam, tenoxicam, droxicam, lormoxicam, iosoxicam, phenylbutazone, meclofenamic acid, flufenamic acid, tolfenamic acid, celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, firocoxib, nimesulide, clonixin and licofelone. As used herein "ibuprofen" refers to any one or more of ibuprofen, an ibuprofen salt (e.g. Ibuprofen sodium salt or ibuprofen lysine salt), an ibuprofen ester, an ibuprofen derivative, polymorph, isomer, prodrug, solvate, hydrate, or derivative thereof. Ibuprofen has the lUPAC name (RS)-2-(4-(2-methylpropyl)phenyl)propanoic acid. Ibuprofen may be in a racemic form or in the (R)-ibuprofen or (S)-ibuprofen enantiomers. Preferably, the (S)-ibuprofen enantiomer is present in a greater proportion than the (R)-ibuprofen enantiomer.
As used herein "paracetamol" or "N-acetyl-p-aminophenol" refers to any one or more of paracetamol (also known as acetaminophen), a paracetamol salt, a paracetamol ester, a paracetamol derivative (e.g. Propacetamol and Phenidine), polymorph, isomer, prodrug, solvate, hydrate, or derivative thereof. Paracetamol has the lUPAC name N-(4- hydroxyphenyl)ethanamide or N-(4-hydroxyphenyl)acetamide. Paracetamol may be provided in either powder or crystalline form.
In any aspect of the invention described herein, paracetamol or the NSAID is substituted by tramadol in the second pharmaceutical composition or second dosage unit, that is, the composition or unit dose for administration when sleep is desirable or not contraindicated. Where tramadol is included in the second pharmaceutical composition or second dosage unit, it may, because of its sedating effect, replace the sedating antihistamine.
A subject in need of treatment is one experiencing one of more of the types, or symptoms of, pain described herein. The subject may be one that has been diagnosed by a medical professional, such as a pharmacist, as suffering from one or types, or symptoms of, pain described herein. However, the subject may also be self-diagnosed.
Pain classifications have been based on duration, etiology or pathophysiology, mechanism, intensity, and symptoms. The term "pain" as used herein may refer to any category of pain, including pain that is described in terms of stimulus or nerve response, e.g., somatic pain (normal nerve response to a noxious stimulus) and neuropathic pain (abnormal response of an injured or altered sensory pathway, often without clear noxious input); pain that is categorized temporally, e.g., chronic pain and acute pain; pain that is categorized in terms of its severity, e.g., mild, moderate, or severe; and pain that is a symptom or a result of a disease state or syndrome, e.g., inflammatory pain, cancer pain, AIDS pain, arthropathy, migraine, trigeminal neuralgia, cardiac ischaemia, and diabetic peripheral neuropathic pain (see, e.g., Harrison's Principles of Internal Medicine, pp. 93-98 (Wilson et al., eds., 12th ed. 1991 ); Williams et al., J. of Med. Chem. 42: 1481 -1485 (1 999), herein each incorporated by reference in their entirety). "Pain" is also meant to include mixed etiology pain, dual mechanism pain, allodynia, causalgia, central pain, hyperesthesia, hyperpathia, dysesthesia, and hyperalgesia.
Major categories of pain to be treated include post-operative and post trauma pain; non- malignant chronic pain disorders such as osteoarthritis and rheumatoid arthritis, fibromyalgia, multiple sclerosis, migraine and headache; period pain (dysmenorrhoea), neuropathic pain such as that associated with peripheral nerve damage, diabetes, and Human Immunodeficiency Virus (e.g., HIV-1 , AIDS) infection; back pain such as that associated with disc avulsion or nerve compression; and cancer pain, including pain secondary to chemotherapy. Neuropathic pain includes chronic pain resulting from injury to the nervous system, e.g., an injury to the central nervous system (brain and spinal cord) or the peripheral nervous system (nerves outside the brain and spinal cord). In some cases, neuropathic pain occurs after trauma and is associated with pathologic conditions such as multiple sclerosis and stroke. Neuropathic pain is also associated with shingles (post-herpetic neuralgia due to Varicella-zoster virus).
Further, pain and pain associated conditions and diseases to be treated according to the present invention can include acute pain, chronic pain, somatogenic pain, neuropathic pain, psychogenic pain, heat induced pain, physical pain and nociception in general, hyperalgesia, or any other forms of pain or pain associated conditions which may not be listed in the aforementioned groups. In particular embodiments the pain is selected from neuropathic pain, inflammatory pain, nociceptive pain, rheumatic pain, headache, lower back pain, pelvic pain, myofascial pain, vascular pain, migraine, wound associated pain, inflammatory pain, arthritic pain, diabetic pain, post-herpetic pain, pain from cancer, mixed neuropathic and nociceptive pain, mixed pain or somatic visceral pain, all in both acute and chronic forms. The pain can also be related to phantom pain, pain from a part of the body that has been lost or from which the brain no longer receives physical signals. Pain can also be related to untoward events or injury in the central nervous system e.g. post-stroke pain .
The treatment of any acute or chronic pain is subject matter of the present invention. Acute pain is usually associated with a specific cause such as a specific injury and is often sharp and severe. Acute pain begins suddenly and is not persistent. Chronic pain is long-term pain, with a typical duration of more than three months leading to significant psychological and emotional problems. Chronic pain is generally associated with clinical conditions characterised by chronic and/or degenerative lesions. Common examples of chronic pain are neuropathic pain (e.g. painful diabetic neuropathy, post-herpetic neuralgia), rheumatoid arthritis, osteoarthritis, fibromyalgia, back pain, lower back pain with or without radiculopathy, headache, carpal tunnel syndrome, cancer pain, and chronic postsurgical pain. Pain can also be divided into a number of different subtypes according to differing pathophysiology, including nociceptive, inflammatory and neuropathic pain. Also some types of pain can be classified in multiple categories, for example pain associated with cancer can have a nociceptive and neuropathic component. Nociceptive pain consists of somatic pain (musculo-skeletal pain) and visceral pain (pain associated with the viscera, which encompass the organs of the abdominal cavity). Common causes of somatic pain include cancer metastasis such as to the bone and postsurgical pain from a surgical incision in addition to musculo-skeletal disorders such as dystro-phinopathy, myalgia and polymyositis. Nociceptive pain also includes tissue injury-induced pain and inflammatory pain such as that associated with arthritis. Another type of inflammatory pain is visceral pain which includes pain associated with gastrointestinal disorders (Gl) such as functional bowel disorder (FBD) and inflammatory bowel disease (IBD). Further examples of visceral pain include the pain associated with dysmenorrhea, cystitis and pancreatis and pelvic pain. Additional pain types include dysfunctional pain such as fibromyalgia, Temporomandibular Joint Disorder (TMJ) , Irritable bowel syndrome (IBS) and musculo-skeletal pain. Neuropathic pain is caused by damage to the peripheral or central nervous system. Examples of central neuropathic pain include pain from spinal cord injury, multiple sclerosis, strokes and fibromyalgia. Diabetes and related metabolic disorders are a common cause of peripheral neuropathic pain (diabetic neuropathy) . Some of the human conditions and pathologies characterised by the presence of neuropathic pain include, but are not limited to, cancer (cancer neuropathy), HIV neuropathy, Parkinson's disease, epilepsy, immunodeficiency, post-herpetic syndromes, trauma, ischaemia, sciatica, multiple sclerosis, peripheral neuropathy, trigeminal neuralgia, back pain (preferably lower back pain), phantom limb pain, carpal tunnel syndrome, central post-stroke pain and pain associated with chronic alcoholism, hypothyroidism, uraemia, spinal cord injury, and vitamin deficiency. The pain may be neuropathic pain, such as trigeminal neuralgia, such as post-herpetic neuralgia, such as painful diabetic neuropathy, such as painful diabetic peripheral neuropathy, such as diabetic polyneuropathy, such as sciatic pain, such as radiculopathy, such as radicular pain or such as noninflammatory neuropathic pain. Pain may be selected from fibromyalgia, postoperative pain, trigeminal neuralgia, post-herpetic neuralgia, painful diabetic neuropathy, painful diabetic peripheral neuropathy, diabetic polyneuropathy, sciatic pain, radiculopathy, radicular pain, lumbar pain. The pain may be caused by the conditions as mentioned above related to the given pain type. In particular the pain type can be the only pain type in a subject. E.g. preferably a neuropathic pain is caused by affected nerves but not caused by inflammation, i.e. neuropathic pain is the only pain in the subject and is noninflammatory. The neuropathic pain may be associated with transitory or persistent inflammation, such as with transitory inflammation, such as with persistent inflammation. Chronic pain may in certain embodiments of the invention be nociceptive, such as inflammatory in nature. Furthermore, chronic pain may also be mixed nociceptive and neuropathic. Finally, chronic pain may also be of a central origin, deriving from processes/conditions in the central or peripheral nervous system, such as e.g. post stroke pain or post-amputation pain/phantom limb pain, which may, in certain circumstances, also be considered neuropathic in nature.
As used herein, "migraine" is a subset of headaches characterized by unusually severe, unilateral, throbbing head pain that often includes additional symptoms described herein. Migraine is meant to include, for example, migraine without aura (e.g., common migraine), migraine with aura (e.g., classical migraine), migraine with typical aura, migraine with prolonged aura, migraine without headache, hemiplegic migraine (e.g., familial hemiplegic migraine), basilar migraine (e.g., basilar artery migraine), carotidynia, abdominal migraine (e.g., periodic syndrome), hormonal migraine (e.g., pregnancy- induced migraine), exertion migraine, migraine with acute onset aura, ophthalmoplegic migraine, status migrainous, transformed migraine, retinal migraine, nocturnal migraine, childhood periodic syndromes that may be precursors to or associated with migraine, benign paroxysmal vertigo of childhood, alternating hemiplegia of childhood, and migrainous infarction.
As used herein, "treating" or "treatment" means reducing, ameliorating or providing relief from pain or at least one clinical or subclinical symptom of pain before or after its onset. It also includes ameliorating the severity, incidence, progression or duration of pain or a clinical or subclinical symptom of pain experienced by a subject. As compared with an equivalent untreated control, such amelioration or relief is at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 100%, as measured by any biochemical or clinical measurement that may be measured by using standard medical methods of evaluating and scoring pain, e.g., the McGill Pain Questionnaire. The benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician.
As used herein, the term "treatment" encompasses both disorder-modifying treatment and symptomatic treatment, either of which may be prophylactic, i.e. before the onset of symptoms, in order to prevent, delay or reduce the severity of symptoms, or therapeutic, i.e. after the onset of symptoms, in order to reduce the severity and/or duration of symptoms. Patients may include but are not limited to primates, especially humans, domesticated companion animals such as dogs, cats, horses, and livestock such as cattle, pigs, sheep, with dosages as described herein. A compound or active agent, such as paracetamol, ibuprofen or a sedating antihistamine as described herein is present in a composition or combination in an amount effective to provide the desired therapeutic or physiological effect or outcome. This effect may be the treatment, alleviation, diminishment or amelioration of pain or at least one of its various symptoms and manifestations. Undesirable effects, e.g. side effects, are sometimes manifested along with the desired therapeutic effect; hence, a practitioner balances the potential benefits against the potential risks in determining what is an appropriate "effective amount". The exact amount required will vary from subject to subject, depending on the species, age and general condition of the subject, mode of administration and the like. An appropriate "effective amount" in any individual case may be determined by one of ordinary skill in the art using only routine experimentation. "Blister cards" are for packaging unit doses. In general, blister cards typically include a front side, which is the side that includes one or more blisters and an opposite back side through which the unit dose is removed from the blister. Blister cards may come in any variety of shapes such as rectangular, rounded such as circular, etc. A "face" of the blister card refers to one or more visible surfaces on the front side of the blister card. The term "blister" refers to an enclosure formed by an outer covering that is raised at the face thereby forming a cavity for housing a unit dose.
The term "regulatory information" broadly refers to information that is required to be provided with a product by a governing body, such as the U.S. Food and Drug Administration (FDA). Regulatory information for unit doses may include ingredients; warnings, if any; dosing instructions; manufacturer's or distributor's name; lot number; expiration date; opening or access instructions (e.g., for child-resistant packaging); and a statement of any tamper evident feature.
The term "daily" in the context of a unit dose dispensing system described herein refers to administering multiple doses of the same or different ingredients within the same day or 24 hour period. For example, a single daily blister card may include multiple doses that are all to be taken in the same 24 hour interval, if required.
The term "unit dose" or "unit dosage" means a dosage form containing an amount of an active or nutrient suitable for administration in one single dose, according to sound medical practice.
Pharmaceutical compositions may be formulated for any appropriate route of administration including, for example, topical (for example, transdermal or ocular), oral, buccal, nasal, vaginal, rectal or parenteral administration. The term parenteral as used herein includes subcutaneous, intradermal, intravascular (for example, intravenous), intramuscular, spinal, intracranial, intrathecal, intraocular, periocular, intraorbital, intrasynovial and intraperitoneal injection, as well as any similar injection or infusion technique. In certain embodiments, compositions in a form suitable for oral use or parenteral use are preferred. Suitable oral forms include, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Within yet other embodiments, compositions provided herein may be formulated as a lyophilizate. The various dosage units are each preferably provided as a discrete dosage tablet, capsules, lozenge, dragee, gum, or other type of solid formulation. Capsules may encapsulate a powder, liquid, or gel. The solid formulation may be swallowed, or may be of a suckable or chewable type (either frangible or gum-like). The present invention contemplates dosage unit retaining devices other than blister packs; for example, packages such as bottles, tubes, canisters, packets. The dosage units may further include conventional excipients well-known in pharmaceutical formulation practice, such as binding agents, gellants, fillers, tableting lubricants, disintegrants, surfactants, and colorants; and for suckable or chewable formulations. Compositions intended for oral use may further comprise one or more components such as sweetening agents, flavouring agents, colouring agents and/or preserving agents in order to provide appealing and palatable preparations. Tablets contain the active ingredient in admixture with physiologically acceptable excipients that are suitable for the manufacture of tablets. Such excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents such as corn starch or alginic acid, binding agents such as starch, gelatine or acacia, and lubricating agents such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
Formulations for oral use may also be presented as hard gelatine capsules wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatine capsules wherein the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin or olive oil.
Formulations for oral use, in particular tablet formulations, may be prepared as rapid release formulations. One method of preparing a rapid release formulation is by the inclusion of a disintegrant in the formulation. Aqueous suspensions contain the active ingredient(s) in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as naturally-occurring phosphatides (for example, lecithin), condensation products of an alkylene oxide with fatty acids such as polyoxyethylene stearate, condensation products of ethylene oxide with long chain aliphatic alcohols such as heptadecaethyleneoxycetanol, condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol mono-oleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides such as polyethylene sorbitan monooleate. Aqueous suspensions may also comprise one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and/or flavouring agents may be added to provide palatable oral preparations. Such suspensions may be preserved by the addition of an antioxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, such as sweetening, flavouring and colouring agents, may also be present.
Pharmaceutical compositions may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as olive oil or arachis oil, a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifying agents include naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides such as sorbitan monoleate, and condensation products of partial esters derived from fatty acids and hexitol with ethylene oxide such as polyoxyethylene sorbitan monoleate. An emulsion may also comprise one or more sweetening and/or flavouring agents.
Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also comprise one or more demulcents, preservatives, flavouring agents and/or colouring agents.
Compounds may be formulated for local or topical administration, such as for topical application to the skin or mucous membranes, such as in the eye. Formulations for topical administration typically comprise a topical vehicle combined with active agent(s), with or without additional optional components. Suitable topical vehicles and additional components are well known in the art, and it will be apparent that the choice of a vehicle will depend on the particular physical form and mode of delivery. Topical vehicles include organic solvents such as alcohols (for example, ethanol, iso-propyl alcohol or glycerine), glycols such as butylene, isoprene or propylene glycol, aliphatic alcohols such as lanolin, mixtures of water and organic solvents and mixtures of organic solvents such as alcohol and glycerine, lipid-based materials such as fatty acids, acylglycerols including oils such as mineral oil, and fats of natural or synthetic origin, phosphoglycerides, sphingolipids and waxes, protein-based materials such as collagen and gelatine, silicone-based materials (both nonvolatile and volatile), and hydrocarbon- based materials such as microsponges and polymer matrices. A composition may further include one or more components adapted to improve the stability or effectiveness of the applied formulation, such as stabilizing agents, suspending agents, emulsifying agents, viscosity adjusters, gelling agents, preservatives, antioxidants, skin penetration enhancers, moisturizers and sustained release materials. Examples of such components are described in Martindale - The Extra Pharmacopoeia (Pharmaceutical Press, London 1 993) and Martin (ed.), Remington's Pharmaceutical Sciences. Formulations may comprise microcapsules, such as hydroxymethylcellulose or gelatine-microcapsules, liposomes, albumin microspheres, microemulsions, nanoparticles or nanocapsules.
A topical formulation may be prepared in a variety of physical forms including, for example, solids, pastes, creams, foams, lotions, gels, powders, aqueous liquids, emulsions, sprays and skin patches. The physical appearance and viscosity of such forms can be governed by the presence and amount of emulsifier(s) and viscosity adjuster(s) present in the formulation. Solids are generally firm and non-pourable and commonly are formulated as bars or sticks, or in particulate form. Solids can be opaque or transparent, and optionally can contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product. Creams and lotions are often similar to one another, differing mainly in their viscosity. Both lotions and creams may be opaque, translucent or clear and often contain emulsifiers, solvents, and viscosity adjusting agents, as well as moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product. Gels can be prepared with a range of viscosities, from thick or high viscosity to thin or low viscosity. These formulations, like those of lotions and creams, may also contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product. Liquids are thinner than creams, lotions, or gels, and often do not contain emulsifiers. Liquid topical products often contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.
Emulsifiers for use in topical formulations include, but are not limited to, ionic emulsifiers, cetearyl alcohol, non-ionic emulsifiers like polyoxyethylene oleyl ether, PEG-40 stearate, ceteareth-12, ceteareth-20, ceteareth-30, ceteareth alcohol, PEG-100 stearate and glyceryl stearate. Suitable viscosity adjusting agents include, but are not limited to, protective colloids or nonionic gums such as hydroxyethylcellulose, xanthan gum, magnesium aluminum silicate, silica, microcrystalline wax, beeswax, paraffin, and cetyl palmitate. A gel composition may be formed by the addition of a gelling agent such as chitosan, methyl cellulose, ethyl cellulose, polyvinyl alcohol, polyquaterniums, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carbomer or ammoniated glycyrrhizinate. Suitable surfactants include, but are not limited to, nonionic, amphoteric, ionic and anionic surfactants. For example, one or more of dimethicone copolyol, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, lauramide DEA, cocamide DEA, and cocamide MEA, oleyl betaine, cocamidopropyl phosphatidyl PG-dimonium chloride, and ammonium laureth sulfate may be used within topical formulations. Preservatives include, but are not limited to, antimicrobials such as methylparaben, propylparaben, sorbic acid, benzoic acid, and formaldehyde, as well as physical stabilizers and antioxidants such as vitamin E, sodium ascorbate/ascorbic acid and propyl gallate. Suitable moisturizers include, but are not limited to, lactic acid and other hydroxy acids and their salts, glycerine, propylene glycol, and butylene glycol. Suitable emollients include lanolin alcohol, lanolin, lanolin derivatives, cholesterol, petrolatum, isostearyl neopentanoate and mineral oils. Suitable fragrances and colours include, but are not limited to, FD&C Red No. 40 and FD&C Yellow No. 5. Other suitable additional ingredients that may be included in a topical formulation include, but are not limited to, abrasives, absorbents, anticaking agents, antifoaming agents, antistatic agents, astringents (such as witch hazel), alcohol and herbal extracts such as chamomile extract, binders/excipients, buffering agents, chelating agents, film forming agents, conditioning agents, propellants, opacifying agents, pH adjusters and protectants.
Typical modes of delivery for topical compositions include application using the fingers, application using a physical applicator such as a cloth, tissue, swab, stick or brush, spraying including mist, aerosol or foam spraying, dropper application, sprinkling, soaking, and rinsing. Controlled release vehicles can also be used, and compositions may be formulated for transdermal administration (for example, as a transdermal patch).
A pharmaceutical composition may be formulated as inhaled formulations, including sprays, mists, or aerosols. For inhalation formulations, the composition or combination provided herein may be delivered via any inhalation methods known to a person skilled in the art. Such inhalation methods and devices include, but are not limited to, metered dose inhalers with propellants such as CFC or HFA or propellants that are physiologically and environmentally acceptable. Other suitable devices are breath operated inhalers, multidose dry powder inhalers and aerosol nebulizers. Aerosol formulations for use in the subject method typically include propellants, surfactants and co-solvents and may be filled into conventional aerosol containers that are closed by a suitable metering valve.
Inhalant compositions may comprise liquid or powdered compositions containing the active ingredient that are suitable for nebulization and intrabronchial use, or aerosol compositions administered via an aerosol unit dispensing metered doses. Suitable liquid compositions comprise the active ingredient in an aqueous, pharmaceutically acceptable inhalant solvent such as isotonic saline or bacteriostatic water. The solutions are administered by means of a pump or squeeze-actuated nebulized spray dispenser, or by any other conventional means for causing or enabling the requisite dosage amount of the liquid composition to be inhaled into the patient's lungs. Suitable formulations, wherein the carrier is a liquid, for administration, as for example, a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.
Pharmaceutical compositions may also be prepared in the form of suppositories such as for rectal administration. Such compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols.
Pharmaceutical compositions may be formulated as sustained release formulations such as a capsule that creates a slow release of modulator following administration. Such formulations may generally be prepared using well-known technology and administered by, for example, oral, rectal or subcutaneous implantation, or by implantation at the desired target site. Carriers for use within such formulations are biocompatible, and may also be biodegradable. Preferably, the formulation provides a relatively constant level of modulator release. The amount of modulator contained within a sustained release formulation depends upon, for example, the site of implantation, the rate and expected duration of release and the nature of the condition to be treated or prevented.
It will be understood, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination (i.e. other drugs being used to treat the patient), and the severity of the particular disorder undergoing therapy. However, over the counter analgesics are typically provided to patients as fixed dose, for example, tablets. Patient dosage may be adjusted by adjusting the number of fixed dose, for example, tablets taken or by adjusting the timing for the next dose. It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention.
Example formulations
(1) Day / night formulation
Day time formulation - each unit dose, preferably tablet or capsule, contains:
Paracetamol 330mg to 665mg per unit dose, preferably 500rmg
Ibuprofen 1 0Omg to 200mg per unit dose, preferably 200mg
Night time formulation - each unit dose, preferably tablet or capsule, contains:
Paracetamol 330mg to 665mg per unit dose, preferably 500mg
Ibuprofen 1 0Omg to 200mg per unit dose, preferably 200mg
Promethazine 5mg to 25mg per unit dose, preferably 1 0mg or 25mg
(2) Night formulation only
Each unit dose, preferably tablet or capsule, contains
Paracetamol 330mg to 665mg per unit dose, preferably 500mg
Ibuprofen 1 0Omg to 200mg per unit dose, preferably 200mg
Promethazine 5mg to 25mg per unit dose, preferably 1 0mg or 25mg
Examples
Example 1 - paracetamol day/night formulation
Day time formulation - each unit dose, preferably tablet or capsule, contains:
Paracetamol 500mg per unit dose
Night time formulation - each unit dose, preferably tablet or capsule, contains:
Paracetamol 500mg per unit dose Promethazine 25mg per unit dose
Alternatively, the paracetamol may be from 330mg to 665mg per unit dose. The promethazine may be from 5mg to 25mg per unit dose. The promethazine may also be substituted by from 12.5rmg to 100mg diphenhydramine per unit dose, from 12.5mg to 100mg doxylamine succinate per unit dose, from 2.5mg to 25mg trimeprazine per unit dose or from 10mg to 50mg phenyltoloxamine per unit dose. For example:
Day time formulation - each unit dose, preferably tablet or capsule, contains:
Paracetamol 500mg per unit dose Night time formulation - each unit dose, preferably tablet or capsule, contains: Paracetamol 500mg per unit dose
Diphenhydramine 25mg per unit dose
OR
Day time formulation - each unit dose, preferably tablet or capsule, contains: Paracetamol 500mg per unit dose Night time formulation - each unit dose, preferably tablet or capsule, contains:
Paracetamol 500mg per unit dose
Doxylamine succinate 5mg per unit dose (or an equivalent amount of an alternate form of doxylamine)
Example 2 - ibuprofen day/night formulation Day time formulation - each unit dose, preferably tablet or capsule, contains:
Ibuprofen 200mg per unit dose Night time formulation - each unit dose, preferably tablet or capsule, contains: Ibuprofen 200mg per unit dose Promethazine 25mg per unit dose Alternatively, the ibuprofen may be from 100mg to 400mg per unit dose. The promethazine may be from 5mg to 25mg per unit dose. The promethazine may also be substituted by from 12.5rmg to 100mg diphenhydramine per unit dose, from 12.5mg to 100mg doxylamine per unit dose, from 2.5mg to 25mg trimeprazine per unit dose or from 1 0mg to 50mg phenyltoloxamine per unit dose.
Example 3 - naproxen day/night formulation
Day time formulation - each unit dose, preferably tablet or capsule, contains:
Naproxen 275mg per unit dose Night time formulation - each unit dose, preferably tablet or capsule, contains: Naproxen 275mg per unit dose
Promethazine 25mg per unit dose
Alternatively, the naproxen may be from 250mg to 550mg per unit dose. The promethazine may be from 5mg to 25mg per unit dose. The promethazine may also be substituted by from 12.5rmg to 100mg diphenhydramine per unit dose, from 12.5mg to 100mg doxylamine per unit dose, from 2.5mg to 25mg trimeprazine per unit dose or from 1 0rmg to 50mg phenyltoloxamine per unit dose.
Example 4 - tramadol day/night formulation
Day time formulation - each unit dose, preferably tablet or capsule, contains:
Paracetamol 500mg per unit dose Night time formulation - each unit dose, preferably tablet or capsule, contains:
Tramadol 50mg per unit dose optionally, promethazine 25rmg per unit dose optionally, paracetamol 500rmg per unit dose
Alternatively, the tramadol may be from 10mg to about 300mg per unit dose. The promethazine may be from 5mg to 25mg per unit dose. The paracetamol may be from 330mg to 665mg per unit dose. The promethazine may also be substituted by from 12.5mg to 1 00mg diphenhydramine per unit dose, from 12.5mg to 100mg doxylamine per unit dose, from 2.5mg to 25rmg trimeprazine per unit dose or from 10mg to 50mg phenyltoloxamine per unit dose. Day time formulation - each unit dose, preferably tablet or capsule, contains:
Ibuprofen 200mg per unit dose
Night time formulation - each unit dose, preferably tablet or capsule, contains:
Tramadol 50mg per unit dose optionally, Promethazine 25mg per unit dose optionally, ibuprofen 200mg per unit dose
Alternatively, the ibuprofen may be from 100mg to 400mg per unit dose. The promethazine may be from 5mg to 25mg per unit dose. The promethazine may also be substituted by from 12.5rmg to 100mg diphenhydramine per unit dose, from 12.5mg to 100mg doxylamine per unit dose, from 2.5mg to 25mg trimeprazine per unit dose or from 1 0mg to 50mg phenyltoloxamine per unit dose.
Example 5 - paracetamol and ibuprofen day/night formulation
Day time formulation - each unit dose, preferably tablet or capsule, contains: Paracetamol 500mg per unit dose Ibuprofen 200mg per unit dose Night time formulation - each unit dose, preferably tablet or capsule, contains:
Paracetamol 500mg per unit dose Ibuprofen 200mg per unit dose Promethazine 25mg per unit dose
Optionally, tramadol 50mg per unit dose (if tramadol is added to the formulation, it may be in addition to or it may replace the promethazine) Alternatively, the ibuprofen may be from 100mg to 400mg per unit dose. The paracetamol may be from 330rmg to 665mg per unit dose. The promethazine may be from 5rmg to 25mg per unit dose. The promethazine may also be substituted by from 12.5mg to 1 00mg diphenhydramine per unit dose, from 12.5mg to 100mg doxylamine per unit dose, from 2.5mg to 25rmg trimeprazine per unit dose or from 10mg to 50mg phenyltoloxamine per unit dose.
Example 6 - paracetamol and naproxen day/night formulation
Day time formulation - each unit dose, preferably tablet or capsule, contains:
Paracetamol 500mg per unit dose Naproxen 330mg per unit dose
Night time formulation - each unit dose, preferably tablet or capsule, contains:
Paracetamol 500mg per unit dose
Naproxen 330mg per unit dose
Promethazine 25mg per unit dose Alternatively, the naproxen may be from 330mg to 650mg per unit dose. The paracetamol may be from 330rmg to 665mg per unit dose. The promethazine may be from 5rmg to 25mg per unit dose. The promethazine may also be substituted by from 12.5mg to 1 00mg diphenhydramine per unit dose, from 12.5mg to 100mg doxylamine per unit dose, from 2.5mg to 25rmg trimeprazine per unit dose or from 10mg to 50mg phenyltoloxamine per unit dose.
Example 7 - tramadol and paracetamol day/night formulation
Day time formulation - each unit dose, preferably tablet or capsule, contains:
Paracetamol 500mg per unit dose Night time formulation - each unit dose, preferably tablet or capsule, contains:
Tramadol 50mg per unit dose Paracetamol 500mg per unit dose
Promethazine 25mg per unit dose
Alternatively, the tramadol may be from 10mg to about 300mg per unit dose. The paracetamol may be from 330mg to 665mg per unit dose. The promethazine may be from 5rmg to 25mg per unit dose. The promethazine may also be substituted by from 12.5mg to 1 00mg diphenhydramine per unit dose, from 12.5mg to 100mg doxylamine per unit dose, from 2.5mg to 25mg trimeprazine per unit dose or from 10mg to 50mg phenyltoloxamine per unit dose.
Example 8 - tramadol and ibuprofen day/night formulation Day time formulation - each unit dose, preferably tablet or capsule, contains:
Ibuprofen 200mg per unit dose Night time formulation - each unit dose, preferably tablet or capsule, contains:
Tramadol 50mg per unit dose
Ibuprofen 200mg per unit dose Promethazine 25mg per unit dose
Alternatively, the tramadol may be from 10mg to about 300mg per unit dose. The ibuprofen may be from 100mg to 400mg per unit dose. The promethazine may be from 5mg to 25mg per unit dose. The promethazine may also be substituted by from 12.5mg to 100mg diphenhydramine per unit dose, from 12.5mg to 1 00mg doxylamine per unit dose, from 2.5mg to 25mg trimeprazine per unit dose or from 10mg to 50mg phenyltoloxamine per unit dose.
Example 7 - caffeine containing day/night formulation
Day time formulation - each unit dose, preferably tablet or capsule, contains: Paracetamol 500mg per unit dose Caffeine 65mg per unit dose Night time formulation - each unit dose, preferably tablet or capsule, contains:
Paracetamol 500mg per unit dose
Promethazine 25mg per unit dose
Alternatively, the paracetamol may be from 330rmg to 665mg per unit dose. The caffeine may be from 40mg to 200rmg per unit dose. The promethazine may be from 5mg to 25mg per unit dose. The promethazine may also be substituted by from 12.5mg to 100mg diphenhydramine per unit dose, from 12.5mg to 100mg doxylamine per unit dose, from 2.5mg to 25mg trimeprazine per unit dose or from 10mg to 50mg phenyltoloxamine per unit dose. Day time formulation - each unit dose, preferably tablet or capsule, contains:
Ibuprofen 200mg per unit dose
Caffeine 65mg per unit dose Night time formulation - each unit dose, preferably tablet or capsule, contains:
Ibuprofen 200mg per unit dose Promethazine 25mg per unit dose
Alternatively, the ibuprofen may be from 1 00mg to 400mg per unit dose. The caffeine may be from 40mg to 200rmg per unit dose. The promethazine may be from 5mg to 25mg per unit dose. The promethazine may also be substituted by from 12.5mg to 100mg diphenhydramine per unit dose, from 12.5mg to 100mg doxylamine per unit dose, from 2.5mg to 25mg trimeprazine per unit dose or from 10mg to 50mg phenyltoloxamine per unit dose.
Day time formulation - each unit dose, preferably tablet or capsule, contains:
Paracetamol 500mg per unit dose
Ibuprofen 200mg per unit dose Caffeine 65mg per unit dose Night time formulation - each unit dose, preferably tablet or capsule, contains:
Paracetamol 500mg per unit dose
Ibuprofen 200mg per unit dose
Promethazine 25mg per unit dose Alternatively, the ibuprofen may be from 1 00mg to 400mg per unit dose. The caffeine may be from 40mg to 200mg per unit dose. The paracetamol may be from 330mg to 665mg per unit dose. The promethazine may be from 5mg to 25mg per unit dose. The promethazine may also be substituted by from 12.5mg to 100rmg diphenhydramine per unit dose, from 12.5mg to 100rmg doxylamine per unit dose, from 2.5mg to 25mg trimeprazine per unit dose or from 10mg to 50mg phenyltoloxamine per unit dose.
Day time formulation - each unit dose, preferably tablet or capsule, contains:
Paracetamol 500mg per unit dose
Caffeine 65mg per unit dose Night time formulation - each unit dose, preferably tablet or capsule, contains: Tramadol 50mg per unit dose optionally, promethazine 25mg per unit dose optionally, paracetamol 500mg per unit dose
Alternatively, the tramadol may be from 10mg to about 300mg per unit dose. The caffeine may be from 40mg to 200mg per unit dose. The paracetamol may be from 330mg to 665mg per unit dose. The promethazine may be from 5mg to 25mg per unit dose. The promethazine may also be substituted by from 1 2.5mg to 100mg diphenhydramine per unit dose, from 12.5mg to 100rmg doxylamine per unit dose, from 2.5rmg to 25rmg trimeprazine per unit dose or from 1 0mg to 50mg phenyltoloxamine per unit dose. Day time formulation - each unit dose, preferably tablet or capsule, contains:
Paracetamol 500mg per unit dose Ibuprofen 200mg per unit dose
Caffeine 65mg per unit dose
Night time formulation - each unit dose, preferably tablet or capsule, contains:
Tramadol 50mg per unit dose optionally, paracetamol 500rmg per unit dose optionally, ibuprofen 200mg per unit dose optionally, promethazine 25mg per unit dose
Alternatively, the tramadol may be from 10mg to about 300mg per unit dose. The caffeine may be from 40mg to 200mg per unit dose. The ibuprofen may be from 100mg to 400mg per unit dose. The paracetamol may be from 330mg to 665mg per unit dose. The promethazine may be from 5mg to 25mg per unit dose. The promethazine may also be substituted by from 12.5mg to 100mg diphenhydramine per unit dose, from 12.5mg to 100mg doxylamine per unit dose, from 2.5mg to 25mg trimeprazine per unit dose or from 1 0rmg to 50mg phenyltoloxamine per unit dose.

Claims (18)

1 . A pharmaceutical combination for treating pain comprising: a first pharmaceutical composition comprising paracetamol and / or a NSAID (non-steroidal anti-inflammatory drug); and a second pharmaceutical composition comprising (i) paracetamol and / or a
NSAID, and (ii) a sedating antihistamine, and a pharmaceutically acceptable diluent, excipient or carrier.
2. A pharmaceutical combination according to claim 1 , wherein the NSAID is selected from the group consisting of ibuprofen, ketoprofen, diclofenac, aspirin, indomethacin, mefanamic acid and naproxen.
3. A pharmaceutical combination for treating pain comprising: a first pharmaceutical composition comprising paracetamol, ibuprofen or both; and a second pharmaceutical composition comprising paracetamol, ibuprofen or both, a sedating antihistamine, and a pharmaceutically acceptable diluent, excipient or carrier.
4. A method of treating pain in a subject comprising: administering a first pharmaceutical composition comprising paracetamol and / or a NSAID at a time of the day when sedation or sleep is not desirable or contraindicated; and administering a second pharmaceutical composition comprising (i) comprising paracetamol and / or a NSAID, and (ii) a sedating antihistamine at a time of the day when sedation or sleep is desirable or not contraindicated, thereby treating pain in a subject.
5. A method according to claim 4, wherein the NSAID is selected from the group consisting of ibuprofen, ketoprofen, diclofenac, aspirin, indomethacin, mefanamic acid and naproxen.
6. A method of treating pain in a subject comprising: administering a first pharmaceutical composition comprising paracetamol, ibuprofen or both at a time of the day when sedation or sleep is not desirable or contraindicated; and administering a second pharmaceutical composition comprising paracetamol, ibuprofen or both and a sedating antihistamine at a time of the day when sedation or sleep is desirable or not contraindicated, thereby treating pain in a subject.
7. A kit for treating pain comprising at least two dosage units, wherein the kit is adapted to allow access to each dosage unit at different times, wherein at least one dosage unit comprises at least one analgesic compound selected from the group consisting of paracetamol, ibuprofen or both, and a pharmaceutically acceptable diluent, excipient or carrier; and wherein at least one dosage unit comprises at least one analgesic compound selected from the group consisting of paracetamol, ibuprofen or both, a sedating antihistamine and a pharmaceutically acceptable diluent, excipient or carrier.
8. A kit according to claim 7, further comprising written instructions directing the user to administer a dosage unit at a particular time of the day or event.
9. A kit according to claim 8, wherein the written instructions direct the user to administer the dosage unit containing the sedating antihistamine when sedation or sleep is desirable or not contraindicated.
10. A kit for treating pain comprising: a first dosage unit comprising at least one analgesic compound selected from the group consisting of paracetamol, ibuprofen or both, and a pharmaceutically acceptable diluent, excipient or carrier; a second dosage unit comprising at least one analgesic compound selected from the group consisting of paracetamol, ibuprofen or both, a sedating antihistamine and a pharmaceutically acceptable diluent, excipient or carrier; indicia distinguishing the first and second dosage units from each other; instructions for coordinating the administration of each of the first and second dosage units as an analgesic treatment regimen whereby the second dosage unit is for administration during a particular time of day or event when sedation or sleep is desirable or not contraindicated; and a container which incorporates the indicia, the instructions and a plurality of first and second analgesic dosage units.
1 1 . A kit according to any one of claims 7 to 10, wherein the kit is in the form of a blister card.
12. A pharmaceutical combination, method, kit or pharmaceutical composition according to any one of the preceding claims, wherein the sedating antihistamine is selected from the group consisting of brompheniramine, chlorphenirmine, dexchlorpheniramine, pheniramine, diphenhydramine, doxylamine (e.g. doxylamine succinate), promethazine (e.g. promethazine hydrochloride), trimeprazine and cyproheptadine.
13. A pharmaceutical combination, method, kit or pharmaceutical composition according to claim 12, wherein the sedating antihistamine is selected from the group consisting of diphenhydramine, doxylamine (e.g. doxylamine succinate) and promethazine (e.g. promethazine hydrochloride).
14. A pharmaceutical combination, method, kit or pharmaceutical composition according to claim 13, wherein the sedating antihistamine is promethazine.
15. A pharmaceutical combination, method, kit or pharmaceutical composition according to any one of the preceding claims, wherein the pain is selected from the group consisting of neuropathic pain, inflammatory pain, nociceptive pain, rheumatic pain, headache, low back pain, pelvic pain, period pain, myofascial pain, vascular pain, migraine, wound associated pain, inflammatory pain, arthritic pain, diabetic pain, postherpetic pain, pain from cancer, mixed neuropathic and nociceptive pain, mixed pain or somatic visceral pain, all in both acute and chronic forms.
16. A pharmaceutical combination, method, kit or pharmaceutical composition according to claim 15, wherein the pain is migraine or headache pain, or period pain.
17. A pharmaceutical combination, method, kit or pharmaceutical composition according to any one of the preceding claims, wherein either or both of the first and second pharmaceutical compositions do not contain codeine.
18. A pharmaceutical combination for treating pain comprising: a first pharmaceutical composition comprising at least one analgesic; and a second pharmaceutical composition comprising at least one analgesic, and (ii) a sedating antihistamine, and a pharmaceutically acceptable diluent, excipient or carrier.
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