U.S. patent application number 12/424765 was filed with the patent office on 2009-08-13 for novel pharmaceutical composition and its use in a method for treatment of patients with upper respiratory mucosal congestion.
This patent application is currently assigned to AFT PHARMACEUTICALS LIMITED. Invention is credited to Hartley Campbell Atkinson.
Application Number | 20090203727 12/424765 |
Document ID | / |
Family ID | 37532532 |
Filed Date | 2009-08-13 |
United States Patent
Application |
20090203727 |
Kind Code |
A1 |
Atkinson; Hartley Campbell |
August 13, 2009 |
NOVEL PHARMACEUTICAL COMPOSITION AND ITS USE IN A METHOD FOR
TREATMENT OF PATIENTS WITH UPPER RESPIRATORY MUCOSAL CONGESTION
Abstract
The present invention relates to a pharmaceutical composition
including loratadine or a pharmaceutically acceptable form thereof,
and phenylephrine or a pharmaceutically acceptable form thereof,
for treating upper respiratory/mucosal congestion, optionally by
administering to a patient four times a day.
Inventors: |
Atkinson; Hartley Campbell;
(Auckland, NZ) |
Correspondence
Address: |
Hallihan IP Partners, LLC
117 N. Jefferson Street, Suite 200
Chicago
IL
60661
US
|
Assignee: |
AFT PHARMACEUTICALS LIMITED
Auckland
NZ
|
Family ID: |
37532532 |
Appl. No.: |
12/424765 |
Filed: |
April 16, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11922271 |
Feb 17, 2009 |
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PCT/NZ2005/000132 |
Jun 17, 2005 |
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12424765 |
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Current U.S.
Class: |
514/290 |
Current CPC
Class: |
A61K 31/137 20130101;
A61K 31/4545 20130101; A61P 11/02 20180101; A61K 31/137 20130101;
A61K 2300/00 20130101; A61K 31/4545 20130101; A61K 2300/00
20130101 |
Class at
Publication: |
514/290 |
International
Class: |
A61K 31/4545 20060101
A61K031/4545 |
Claims
1. A pharmaceutical composition including loratadine or a
pharmaceutically acceptable form thereof, and phenylephrine or a
pharmaceutically acceptable form thereof, for treating upper
respiratory/mucosal congestion.
2. A pharmaceutical composition according to claim 1, wherein the
composition is for administering to a patient four times a day.
3. A composition according to claim 1, wherein the pharmaceutically
acceptable form of loratadine is a salt form of such substance.
4. A composition according to claim 1, wherein the pharmaceutically
acceptable form of phenylephrine is a salt form of such
substance.
5. A composition according to claim 1, which is for administration
on a qid basis.
6. A composition according to claim 1, wherein the phenylephrine is
present as a hydrochloride salt.
7. A composition according to claim 1, which is in a solid dosage
form.
8. A pharmaceutical composition according to claim 1, which is in
the form of a pill, capsule or tablet.
9. A pharmaceutical composition according to claim 1, comprising
lactose, maize starch, pregelatinised starch, quinoline yellow,
sodium metabisulphite, disodium EDTA, talc and magnesium
stearate.
10. A pharmaceutical composition according to claim 1, having
synergistic therapeutic activity.
11. A pack including a pharmaceutical composition according to
claim 1, wherein the pack includes instructions to administer the
composition to a maximum of 4 times a day.
12. The use of loratadine or a pharmaceutically acceptable form
thereof, and phenylephrine or a pharmaceutically acceptable form
thereof, in the manufacture of a pharmaceutical composition for
treating upper respiratory/mucosal congestion.
13. A use according to claim 12, wherein the composition is for
administering to a patient four times a day.
14. A use according to claim 12, wherein the pharmaceutically
acceptable form of loratadine is a salt form of such substance.
15. A use according to claim 12, wherein the pharmaceutically
acceptable form of phenylephrine is a salt form of such
substance.
16. A use according to claim 12, wherein the pharmaceutical
composition is for administration on a qid basis.
17. A use according to claim 12, wherein the phenylephrine is
present in the composition as a hydrochloride salt.
18. A use according to claim 12, wherein the composition is a solid
dosage form.
19. A use according to claim 12, wherein the composition is in the
form of a pill, capsule or tablet.
20. A use according to claim 12, wherein lactose, maize starch,
pregelatinised starch, sodium metabisulphite, disodium EDTA, talc,
and magnesium stearate are also used in the manufacture of the
pharmaceutical composition.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. Ser. No. 11/922,271
filed on 20 Dec. 2007 which is a national phase application from
PCT/NZ2005/000132, with an international filing date and earliest
priority date of 17 Jun. 2005.
INTRODUCTION
[0002] The present invention relates to a pharmaceutical
composition including loratadine, its use in the treatment of upper
respiratory mucosal congestion and a method of administration of
the composition. Particularly, though not exclusively, the
invention relates to a pharmaceutical composition including
loratadine in an amount suitable for administration a maximum of 4
times a day, and a second active that is phenylephrine, or a salt
thereof.
BACKGROUND
[0003] Upper respiratory mucosal congestion caused by infections
such as the common cold and influenza, or allergic rhinitis, can
lead to a number of nasal and ocular symptoms. These include
rhinitis and sinusitis, nasal and sinus congestion or excessive
secretions, headaches, sneezing and itching and excessive
lacrimation. Infections such as the common cold can be very common
over the winter months, while the symptoms of rhinitis are also
common in some parts of the world.
[0004] Such symptoms can be treated with antihistamine containing
products and with decongestant containing products. The products
are generally sold as part of non-prescribed medicines which are
available to patients through outlets such as pharmacies.
[0005] There are a number of antihistamine actives available
including non-sedating antihistamines such as loratadine,
cetirizine or fexofenadine. These products provide less sedation in
comparison to normal antihistamines, and therefore more readily
allow a user to perform tasks such as driving or operating
machinery.
[0006] Fexofenadine is an active carboxylic acid metabolite of
terfenadine. The latter has been withdrawn due to serious
cardiotoxic reactions and drug interactions. In depth information
regarding the risk of these reactions is not available for
fexofenadine. But according to the AHFS Drug Information 2004 as a
result of comparative studies between fexofenadine and terfenadine,
it is thought that the clinical efficacy of terfenadine is
attributable to fexofenadine. The risk of similar reactions to
terfenadine being created by the use of fexofenadine has not been
ruled out.
[0007] Cetirizine is another non-sedating antihistamine. However,
in comparison to loratadine, cetirizine has been reported to have a
higher incidence of adverse drug reactions (ADRs), especially
central nervous system ADRs<1>. Some studies have also
indicated that cetirizine has a higher incidence of somnolence than
loratadine.
[0008] Loratadine is disclosed in U.S. Pat. No. 4,282,233 as a
non-sedating antihistamine useful as an anti-allergy agent in, for
example, the treatment of seasonal allergic rhinitis symptoms such
as sneezing and itching. Loratadine has a maximum over the counter
(OTC) dose of 10 mg per day. It is generally administered once a
day at the maximum dose for a number of reasons including perceived
efficacy and patient compliance. However, there are adverse effects
that can occur at peak concentration and also with end-of-dose
diminution of effect.
[0009] There are also a number of decongestant agents available.
Phenylephrine has in the past been used as a decongestant agent.
However, its use has now been surpassed by the next generation of
decongestant products including pseudoephedrine. Pseudoephedrine
tends to act with a higher efficacy and has a longer half-life than
previous generation products such as phenylephrine, providing an
increase in the efficiency for relieving symptoms.
[0010] Combination antihistamine and decongestant products are
available as a result of a demand for combination products that
meet the problems associated with multiple product ingestion.
Combinations of loratadine and new generation decongestants such as
pseudoephedrine have been disclosed with a view to administering
the combination once or twice a day. Disclosure of such
combinations has been made in WO 98/18470 to Schering Corporation
for example.
[0011] Combinations of the older style decongestant drugs, such as
phenylephrine, and sedating antihistamines are available in liquid
preparations. The use of such products has however been superseded
by use of combinations using the newer style decongestant drugs,
such as pseudoephedrine, for the reasons mentioned above.
[0012] There are several solid dose products currently available
which combine the newer style drugs, such as pseudoephedrine,
together with non-sedating antihistamine. Examples of those
available in Australasia are given in Table 1 below.
TABLE-US-00001 TABLE 1 Current Combination Non-Sedating
Antihistamine and Nasal Decongestant Solid Dose Form Products
Available in Australasia Non-sedating Product Decongestant
Antihistamine Daily Dose Clarinase 12 Hour Pseudoephedrine
Loratadine 1 tablet twice 240 mg 5 mg daily Clarinase 24 Hour
Pseudoephedrine Loratadine 1 tablet daily Relief 240 mg 10 mg
Demazin Pseudoephedrine Loratadine 1 tablet twice Non-Drowsy 240 mg
5 mg daily Telfast Pseudoephedrine Fexofenadine 1 tablet twice
Decongestant 240 mg 60 mg daily Zyrtec Pseudoephedrine Cetirizine 1
tablet twice Decongestant 240 mg 5 mg daily
[0013] However, products containing pseudoephedrine are now subject
to abuse problems associated with illicit drug use in the
community. The pseudoephedrine component of these medications can
be converted to potent stimulants such as methamphetamine and
methcathinone both of which are CNS stimulants with great potential
for habituation and physical and/or psychic dependence. This has
resulted in pharmacy hold-ups, stolen stock from warehouses and
significant related crime. The resulting crime, and its effects on
the outlets which supply these medications to the market, means
that some outlets are choosing not to stock these products, or at
least restrict their availability. This makes them less accessible
to those with a genuine need for the medications. In the United
States, for example, legislation restricts the threshold content of
pseudoephedrine OTC ("over the counter") products, for example, can
contain no more than 3 g of pseudoephedrine (in terms of the base)
packaged in packs of 1 or 2 dosage units per pack or as package
size liquid preparations.
[0014] It would be beneficial to have an alternative medication
capable of being available without a prescription which is
effective in treating the symptoms of upper respiratory mucosal
congestion and which mitigates at least some of the problems
identified above.
[0015] An object of the invention is to at least provide the public
with a useful choice.
SUMMARY OF THE INVENTION
[0016] According to one aspect of the invention there is provided a
pharmaceutical composition including loratadine or a
pharmaceutically acceptable form thereof, and phenylephrine or a
pharmaceutically acceptable form thereof, optionally for treating
upper respiratory/mucosal congestion.
[0017] Optionally the pharmaceutical composition is for
administering to a patient four times a day.
[0018] Optionally the pharmaceutically acceptable form of
loratadine is a salt form of such substance.
[0019] Optionally the pharmaceutically acceptable form of
phenylephrine is a salt form of such substance.
[0020] Optionally the composition is for administration on a qid
basis.
[0021] Optionally the phenylephrine is present as a hydrochloride
salt.
[0022] Optionally the composition is in a solid dosage form.
[0023] Optionally the composition is in the form of a pill, capsule
or tablet.
[0024] Optionally the composition comprises lactose, maize starch,
pregelatinised starch, quinoline yellow, sodium metabisulphite,
disodium EDTA, talc and magnesium stearate.
[0025] Optionally the composition is provided in a pack, wherein
the pack includes instructions to administer the composition to a
maximum of 4 times a day.
[0026] According to a further aspect of the invention there is
provided the use of loratadine or a pharmaceutically acceptable
form thereof, and phenylephrine or a pharmaceutically acceptable
form thereof, in the manufacture of a pharmaceutical composition,
optionally for treating upper respiratory/mucosal congestion.
[0027] Optionally the pharmaceutical composition is for
administering to a patient four times a day.
[0028] Optionally the pharmaceutically acceptable form of
loratadine is a salt form of such substance.
[0029] Optionally the pharmaceutically acceptable form of
phenylephrine is a salt form of such substance.
[0030] Optionally the composition is for administration on a qid
basis.
[0031] Optionally the phenylephrine is present in the composition
as a hydrochloride salt.
[0032] Optionally the composition is a solid dosage form.
[0033] Optionally the composition is in the form of a pill, capsule
or tablet.
[0034] Optionally lactose, maize starch, pregelatinised starch,
sodium metabisulphite, disodium EDTA, talc, and magnesium stearate
are also used in the manufacture of the pharmaceutical
composition.
DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT
[0035] In a preferred embodiment the invention provides a method of
treating upper respiratory mucosal congestion using a
pharmaceutical composition which includes loratadine, preferably in
amounts suitable for administration 4 times a day, plus
phenylephrine as a decongestant.
[0036] Furthermore the inventor has recognised that the selection
of a decongestant that is a hydroxyl-[alpha]-[(methylamino)
methyl]-benzenemethanol, or salt thereof, does not result in the
disadvantages that accrue from the selection of a decongestant that
is a [alpha]-[1-(methylamino) ethyl]-benzenemethanol.
[0037] The lower efficacy and shorter half life of the selected
decongestant can be offset, at least to a limited extent, by its
use in combination with loratadine. The advantages of this
particular combination have not before been recognised for the
compositions disclosed in the specifications accompanying
international application no. PCT/IB03/01197 (Publication no. WO
03/089007) or international application no. PCT/US2003/029095
(Publication no. WO 2004/023984).
[0038] The preferred composition contains loratadine (a
non-sedating antihistamine) and phenylephrine (a decongestant). The
preferred composition is safe to be supplied on a non-prescription
basis and can therefore be purchased over the counter ("OTC").
TABLE-US-00002 TABLE 2 Dose Rates of Phenylephrine and
Pseudoephedrine Agent Dose Reference Phenylephrine 10 mg 3-4 times
a day Martindale 28.sup.th edition 10 mg q 4 hours Drug Tx,
4.sup.th edition Pseudoephedrine 60 mg 3-4 times a day Martindale
28.sup.th edition 60 mg qid or 120 mg bd Drug Tx, 4.sup.th
edition
[0039] As stated in the Martindale reference a number of suitable
phenylephrine salts can be used.
[0040] The phenylephrine component can be delivered as any suitable
salt form (e.g. HCl, tartrate). The base form could also be used.
Suitable salts will be well known to the skilled person. Reference
herein to the use of phenylephrine is intended to include reference
to delivery as a suitable salt.
[0041] Loratadine has a maximum OTC daily administration of 10 mg
per day. As for phenylephrine, suitable salts could also be used to
deliver the loratadine as would be known to the skilled person.
Reference herein to loratadine is intended to include
administration as a suitable salt.
[0042] By way of example, it has been found that the use of about
2.5 mg loratadine administered 4 times daily (e.g. qid) has
therapeutic advantages over the usual 10 mg administered once a
day. It is thought that this may be due to the ideal
concentration-time profile for continuous effect being a constant
concentration over time (as would occur with a continuous
infusion). As the 2.5 mg loratadine use flattens out the
differences between peak and trough concentrations in the plasma,
this administration regime most closely resembles the effect of a
continuous infusion. The flatter concentration-time profile
provides advantages of fewer peak concentration adverse effects,
and less end-of-dose diminution of effect. Administration of the
composition, in terms of loratadine effect, provides distinct
advantages to the user.
[0043] While the use of a combination of a non-sedating
antihistamine and a decongestant is known for the treatment of
upper mucosal respiratory congestion, this previously involved the
latest generation of decongestant medications and ordinarily
involves the use of maximum OTC doses of the actives in a single
administration. Phenylephrine, an earlier generation medication,
has a different potency to pseudoephedrine on a milligram by
milligram basis. The development of decongestants such as
pseudoephedrine, which provide more efficient means of
decongestion, means that the older generation of decongestants,
like phenylephrine are not actives that would ordinarily be
included in combination medications. The development of a
loratadine plus phenylephrine product which allows the therapeutic
and use advantages of the present invention is therefore unexpected
and is a significant advance.
[0044] The inventor has recognised that the use of an older
generation drug (phenylephrine) while less efficient would, in
combination with an effective non-sedating antihistamine, still
provide a helpful medication to alleviate the symptoms of upper
mucosal respiratory congestion.
[0045] Administration of the combination including phenylephrine
(preferably in a suitable salt form e.g. hydrochloride, tartrate) 4
times a day (e.g. qid preferably) provides therapeutic and use
advantages that mitigate the therapeutic effect of using the older
style drug while offering additional advantages. This enables an
alternative medication to be accessible to symptom sufferers,
without restraints being placed on the availability of this
medication due to social issues resulting from the use of the newer
style drugs. In using such an older generation medicament in
combination with a non-sedating antihistamine the inventor has also
recognised the importance of minimising the potential for adverse
drug reactions.
[0046] The administration of phenylephrine 4 times a day allows
peak effects of this drug to be delivered quarterly over the day
thus mitigating the fast half-life effect of phenylephrine on
decongestant efficacy. It is the combination of the preferably
quarterly administration of the loratadine and the phenylephrine
and the interaction of effect between them, that allows the
preferred pharmaceutical composition to provide the user with such
a useful alternative to combinations that use new style
decongestant drugs. Optionally, the phenylephrine could be included
such that it is released slowly from the composition but it is not
considered that this is necessary. It may be that the combined
effect of the two drugs when administered 4 times per day could be
termed synergistic from this perspective. In the preferred
embodiment it is the combination of the beneficial effects stemming
from the preferably quarterly administration of both drugs that
allows the user to receive benefits over and above those provided
by simply administering the drugs individually or in combination to
meet the maximum daily dose once or twice per day. Administration
for treatment of severe symptoms is 4 times daily and as close to
qid as possible. This is to maximise the advantages gained from the
flat peak/trough concentrations of the loratadine in the plasma.
This allows the composition to provide a useful alternative to
existing compositions that use new generation decongestants from an
efficacy perspective, and provides a composition that does not
suffer from the social problems that hinder use of the new
generation decongestants (e.g. pseudoephedrine). This combination
effect (loratadine and phenylephrine) forms the basis of another,
or additional, aspect of the invention.
[0047] The 2.5 mg or 2.5 mg/10 mg qid regimen does have
disadvantages over the other regimens in terms of drug compliance.
Once daily and twice daily regimens are superior to qid regimens in
terms of compliance. However compliance is also related to the
severity of symptoms, and patients are ordinarily reminded to be
compliant if their symptoms persist. In this case, non compliance
when symptoms have diminished is not likely to be a disadvantage.
While once or twice daily administration may have compliance
advantages, the beneficial effect of the 2.5 mg loratadine 4 times
a day (e.g. qid) to treat severe upper respiratory mucosal
congestion symptoms individually or together with phenylephrine is
still significant.
[0048] The pharmaceutical combination according to the preferred
form of the invention allows for the delivery of a total of around
10 mg loratadine and 40 mg phenylephrine per day, administered in 4
doses. The pharmaceutical composition may include loratadine in an
amount of about 2.5 mg and phenylephrine (preferably as the
hydrochloride salt) in an amount of about 10 mg. The amount of
actives used in the composition will of course be within the
margins of error allowed for pharmaceutical use.
[0049] The preferred compositions also include non-active
components such as binders and other excipients as would be known
by a person skilled in the art. The ingredients can be formulated
into a tablet, pill or capsule using known pharmaceutical carriers
and excipients (such as diluents, binders, colourants,
antioxidants, chelating agents, glidants and/or lubricants). The
composition is formulated into a tablet of a size capable of
containing the amounts of ingredient preferred. Preferably the
composition is manufactured using pharmaceutically acceptable
ingredients as would be known to the skilled person, such as maize
or pre-gelatinised starch, lactose (e.g. monohydrate)
microcrystalline cellulose, magnesium stearate, quinoline yellow,
sodium metabisulphite, EDTA, talc.
[0050] Purified water will preferably be used. As will be
appreciated by persons skilled in the art, purified water may be
used during the formulation process, which includes a drying
process. The drying process evaporates the water from the
composition, meaning that the water does not contribute to the
final weight of the composition.
[0051] The tablets/pills will preferably be presented to the
consumer as part of a pharmaceutical pack, such as a blister pack,
as will be well known. The pack should have an even number of pills
contained within it and have instructions about the maximum number
of pills/tablets to be taken at any one time and within a set
timeframe. In the present case, one tablet/pill/capsule should be
taken 4 times per day (preferably qid). It is of course possible
that the pills/tablets/capsules could be sold contained in a
bottle, the pills held loosely within that bottle. Again,
instructions on administration 4 times daily (preferably qid) would
be included.
[0052] In a further alternate embodiment the pharmaceutical
composition can be a syrup for administration to children, and
patients with difficulty swallowing pills. Standard methods for the
production of such syrups are well known in the art. The syrup may
be contained in a bottle, vial or like container and prepared in a
manner capable of delivering about 2.5 mg loratadine, and
preferably about 10 mg phenylephrine per dose, 4 times daily. This
would be achievable by producing a syrup having a specified
concentration of the actives, in conjunction with instructions
about how much of the syrup should be taken per quarterly dose.
With regard to doses for younger children it will be recognised
that lower doses of such a syrup are appropriate. In respect of
loratadine the dose for children under 12 years should be less than
5 mg/day.
[0053] In some embodiments the invention can therefore be seen to
be a method of treating upper respiratory mucosal congestion in a
patient in need thereof using a pharmaceutical composition
including about 2.5 mg loratadine and preferably about 10 mg
phenylephrine, that is administered to a patient 4 times a day.
[0054] A preferred composition is shown in Table 3 below.
Example
[0055] The components shown in Table 3 are combined into a single
tablet and taken by either adults or children aged 12 years or
older. The tablet may be taken up to 4 times a day giving a maximum
dose of 10 mg of loratadine and 40 mg of phenylephrine per day.
TABLE-US-00003 TABLE 3 Combination Composition Formulation Qty. per
Reference to Name of Ingredient tablet Function specifications
Active ingredient: Phenylephrine 10.00 mg Active ingredient Ph.
Eur. Hydrochloride Loratadine 2.50 mg Active ingredient IHS Other
Ingredients: Lactose 180.40 mg Diluent Ph. Eur. Maize starch 140.00
mg Diluent, binder Ph. Eur. Pregelatinised starch 10.365 mg Binder
Ph. Eur. Lake of quinoline 0.20 mg Colourant IHS yellow Sodium
metabisulphite 0.40 mg Antioxidant Ph. Eur. Disodium EDTA 0.14 mg
Chelating agent Ph. Eur. Talc 3.00 mg Glidant Ph. Eur. Magnesium
stearate 3.00 mg Lubricant Ph. Eur.
[0056] The formulation administered 4 times daily provides
effective 24 hour treatment of the symptoms of upper respiratory
mucosal congestion with reduced adverse effects and without using
pseudoephedrine as the decongestant.
[0057] Where in the foregoing description there has been made
reference to specific components or integers of the invention
having known equivalents then such equivalents are herein
incorporated as is individually set forth.
[0058] Although this invention has been described by way of example
only and with reference to possible embodiments thereof it is to be
understood that modifications or improvements may be made without
departing from the scope or spirit of the invention as defined in
the accompanying claims.
REFERENCES
[0059] (1) The American Society of Health System Pharmacists Drug
Information 2004. G. K. McEvoy (Editor), Bethesda, USA
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