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.

Description

CROSS REFERENCE TO RELATED APPLICATIONS

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

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

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.

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.

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.

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 The latter has been withdrawn due to serious cardiotoxic reactions and drug interactions.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.

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.

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.

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.

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.

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.

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 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

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.

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.

An object of the invention is to at least provide the public with a useful choice.

SUMMARY OF THE INVENTION

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.

Optionally the pharmaceutical composition is for administering to a patient four times a day.

Optionally the pharmaceutically acceptable form of loratadine is a salt form of such substance.

Optionally the pharmaceutically acceptable form of phenylephrine is a salt form of such substance.

Optionally the composition is for administration on a qid basis.

Optionally the phenylephrine is present as a hydrochloride salt.

Optionally the composition is in a solid dosage form.

Optionally the composition is in the form of a pill, capsule or tablet.

Optionally the composition comprises lactose, maize starch, pregelatinised starch, quinoline yellow, sodium metabisulphite, disodium EDTA, talc and magnesium stearate.

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.

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.

Optionally the pharmaceutical composition is for administering to a patient four times a day.

Optionally the pharmaceutically acceptable form of loratadine is a salt form of such substance.

Optionally the pharmaceutically acceptable form of phenylephrine is a salt form of such substance.

Optionally the composition is for administration on a qid basis.

Optionally the phenylephrine is present in the composition as a hydrochloride salt.

Optionally the composition is a solid dosage form.

Optionally the composition is in the form of a pill, capsule or tablet.

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

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.

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.

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).

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 2
Dose Rates of Phenylephrine and Pseudoephedrine
Agent	Dose	Reference
Phenylephrine	10 mg 3-4 times a day	Martindale 28th edition
	10 mg q 4 hours	Drug Tx, 4th edition
Pseudoephedrine	60 mg 3-4 times a day	Martindale 28th edition
	60 mg qid or 120 mg bd	Drug Tx, 4th edition

As stated in the Martindale reference a number of suitable phenylephrine salts can be used.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

A preferred composition is shown in Table 3 below.

Example

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 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.

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.

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.

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

• (1) The American Society of Health System Pharmacists Drug Information 2004. G. K. McEvoy (Editor), Bethesda, USA

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.