PHARMACEUTICAL COMPOSITION FOR TOPICAL APPLICATION

Abstract

A pharmaceutical composition comprises a solution having a pH of from 5 to 7.5, including loratadine and/or desloratadine. The composition is suitable for treatment of e.g. allergic rhinitis and allergic conjunctivitis.

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention concerns a pharmaceutical composition for topical application. In particular, the present invention concerns a pharmaceutical composition which is suitable for nasal mucosa administration.

Aqueous pharmaceutical compositions for nasal administration comprising solutions of loratadine are disclosed in WO-A-04082589 and solutions of loratadine and desloratadineare disclosed in WO-A-03101434. The nasal pharmaceutical compositions disclosed in these prior art references comprise relatively low levels of antihistamine in solution.

It is an object of the present invention to provide nasal pharmaceutical compositions which may comprise relatively higher amounts of antihistamine in solution than the prior art solutions but which do not demonstrate increased mucosa irritation.

In accordance with the present invention, there is provided a pharmaceutical composition comprising an aqueous solution having a pH of from 5 to 7.5, preferably from 5 to 7, comprising:

	Amount
Component	(wt %)	Example
a) At least one	0.02-0.1
antihistamine
selected from
Loratadine and
Desloratadine
and their
pharmaceutically
acceptable salts
b) At least one	5.0-15.0	PEG 200, PEG 300,
polyethylene glycol		PEG 400, PEG 600:
with a molecular		PEG 400 is preferred
weight of from
100 to 600 g/mole
(co-solvent)
c) Propylene glycol	5.0-15.0
(co-solvent)
d) At least one non-ionic	1.0-10.0	Lutrol F127-(non-
ethylene oxide/		ionic EO/PO block
propylene oxide		copolymer with
(EO/PO) block		Mw of about
copolymer with weight		12,500)
average molecular
weight (Mw)
from 10,000 to
15,000 (solubilizer)
e) polyoxyethylene	0.5-5.0	Tween 20, Tween 80:
(20) sorbitan		Tween 80
monolaurate and/or		(polyoxyethylene
polyoxyethylene		(20) sorbitan
(20) sorbitan		monooleate)
monooleate (solubilizer)		is preferred
f) Stabilizer for	0.05-0.5	Salts of EDTA,
antihistamine,		salts and esters of
preferably a		gallic acid,
chelator stabilizer		salts and esters of
		ascorbic acid, salts
		of metabisulfite,
		cysteine and
		derivatives thereof:
		Stabilizers
		which are chelators
		for the antihistamine
		are preferred. Alkali
		salts are preferred
		e.g. Na2 EDTA
Other optional additives	<20	Sorbitol, glycerine
Water	balance to
	100.0%
Lutrol is a trademark of BASF SE.
Tween is a trademark of Uniquema Americas LLC.

In one embodiment of the present invention, the pharmaceutical composition comprises an aqueous solution having a pH from 5 to 7.5 comprising:

Component	Amount (wt %)	Example
Loratadine or a	0.02-0.1
pharmaceutically
acceptable salt thereof
At least one polyethylene	5.0-15.0	PEG 200, PEG 300,
glycol with a molecular		PEG 400, PEG 600
weight of from 100 to
600 g/mole (co-solvent)
Propylene glycol (co-	5.0-15.0
solvent)
At least one non-ionic	1.0-10.0	Lutrol F127-Mw 12,500
EO/PO block copolymer
with weight average
molecular weight (Mw)
from 10,000 to 15,000
(solubilizer)
polyoxyethylene (20)	0.5-5.0	Tween 20, Tween 80,
sorbitan monolaurate
and/or polyoxyethylene
(20) sorbitan monooleate
(solubilizer)
Stabilizer	0.05-0.5	Salts of EDTA, salts and
		esters of gallic acid, salts
		and esters of ascorbic acid,
		salts of metabisulfite,
		cysteine and derivatives
		thereof
Other optional additives	<20	Sorbitol, glycerine
Water	balance to
	100.0%

A particularly preferred pharmaceutical composition of this embodiment comprises an aqueous solution having a pH from 5 to 7 comprising:

Component                    Amount (wt %)
Loratadine or salt thereof   0.06
PEG 400                      10.0
Propylene glycol             10.0
At least one non-ionic EO/PO 5.0
block copolymer with weight
average molecular weight (Mw)
of about 12,500
Polysorbate 80               1.8
Na2EDTA                      0.1
Water                        balance to 100.0%

In another embodiment of the present invention, the pharmaceutical composition comprises an aqueous solution having a pH from 5 to 7.5 comprising:

Component	Amount (wt %)	Example
Desloratadine or a	0.02-0.1
pharmaceutically
acceptable salt thereof
At least one polyethylene	5.0-15.0	PEG 200, PEG 300,
glycol with a molecular		PEG 400, PEG 600
weight of from 100 to
600 g/mole (co-solvent)
Propylene glycol	5.0-15.0
(co-solvent)
At least one non-ionic	1.0-10.0	Lutrol F127-Mw 12,500
EO/PO block copolymer
with weight average
molecular weight (Mw)
from 10,000 to 15,000
(solubilizer)
polyoxyethylene (20)	0.5-5.0	Tween 20, Tween 80,
sorbitan monolaurate
and/or polyoxyethylene
(20) sorbitan monooleate
(solubilizer)
Stabilizer	0.05-0.5	Salts of EDTA, salts and
		esters of gallic acid, salts
		and esters of ascorbic
		acid, salts of
		metabisulfite,
		cysteine and derivatives
		thereof
Other optional additives	<20	Sorbitol, glycerine
Water	balance to 100.0%

A particularly preferred pharmaceutical composition of this embodiment comprises an aqueous solution having a pH from 5 to 7 comprising:

Component                     Amount (wt %)
Desloratadine or salt thereof 0.06
PEG 400                       10.0
Propylene glycol              10.0
At least one non-ionic EO/PO  5.0
block copolymer with weight
average molecular weight (Mw)
12,500
Polysorbate 80                1.8
Na2EDTA                       0.1
Water                         balance to 100.0%

In comparison to the prior art formulations, by using a combination of the four components b), c), d) and e), pharmaceutical compositions of the present invention contain higher dosage levels of antihistamine in solution but overall lower dosages of potential irritants. For example, if component b) was eliminated, higher levels of component c) would be required to solubilise the antihistamine, and visa-versa: higher levels of b) or c) on their own in the composition causes irritation on the nasal mucosa, which in turn leads to a reduction the time the composition may be effective. Similarly, if component d) was eliminated, higher levels of component e) would be required to solubilise the antihistamine, and visa-versa: higher levels of d) or e) on their own in the composition causes irritation on the nasal mucosa, which in turn leads to a reduction the time the composition may be effective.

The pharmaceutical composition of the present invention may contain, in addition to co-solvents b) and c), one or more other co-solvents, such as sorbitol and glycerine, but such co-solvents should be used at non-irritating levels.

The pharmaceutical composition of the present invention may contain, in addition to co-solubilizers b) and c), one or more other co-solubilizers, but such co-solubilizers should be used at non-irritating levels.

The stabilizer is preferably a chelator for the antihistamine.

The aqueous solution may require pH adjustment to the range 5 to 7.5, preferably 5 to 7. This can be achieved readily by a person skilled in the art. For example, if the pH of the solution is lower than 5, then the pH may be raised by the incorporation of an appropriate amount of alkali, such as NaOH solution.

The pharmaceutical composition is especially suitable for nasal administration, for example for the treatment of allergic rhinitis, though it may also be suitable for ocular administration, for example for the relief of allergic conjunctivitis.

The invention in its various embodiments shall now be further described by way of exemplification only:

A pharmaceutical composition according to the present invention was prepared as follows:

10.0 parts by wt PG (Propylene Glycol) and 10.0 parts by wt PEG₄₀₀ (Macrogol 400) are mixed. The amount of 0.06 parts by wt Loratadine is dissolved in the obtained mixture to obtain Solution A.

Separately, 5.0 parts by wt Lutrol F127 (Poloxamer 407), 1.8 parts by wt Tween 80 (Polysorbate 80) and 0.1 parts by wt Na.sub.2EDTA are dissolved in 70 parts by wt purified water, preheated to 60° C., to obtain Solution B.

Solution A is added to Solution B at constant stirring to obtain Solution C.

Solution C is adjusted as necessary to pH 5.5 with 1M solution of Sodium Hydroxide and is complemented to a total of 100 parts w/w with purified water to obtain the final composition.

The composition is as shown in Table 1.

TABLE 1
	Component	Amount (wt %)
	Loratadine	0.06	active drug
	PEG400	10.0	co-solvent
	PG	10.0	co-solvent
	Lutrol F127	5.0	solubilizer
	Tween 80	1.8	solubilizer
	EDTA	0.1	stabilizer (chelator)
	Water	balance to 100.0%	—

The pharmaceutical composition has the characteristics shown in Table 2:

TABLE 2
Appearance	clear, colorless
pH	5.5
Density	at 20° C.	ps = 1.0273
	at 25° C.	ps = 1.0251
Dynamic viscosity 11,	at 20° C.	η = 54.57 · ( 2.4100 − 1.0273 ) ·
mPa · s		0.07752 = 5.84
	at 25° C.	η = 45.93 · ( 2.4100 − 1.0251 ) ·
		0.07752 = 4.93
Loratadine content	0.06
Na2EDTA content	0.1

Claims

1. A pharmaceutical composition comprising an aqueous solution having a pH of from 5 to 7.5 comprising:

2. The pharmaceutical composition as claimed in claim 1, which comprises an aqueous solution having a pH from 5 to 7.5 comprising:

3. The pharmaceutical composition as claimed in claim 2, which comprises an aqueous solution having a pH from 5 to 7 consisting of:

4. The pharmaceutical composition as claimed in claim 1, which comprises an aqueous solution having a pH from 5 to 7.5 comprising:

5. The pharmaceutical composition as claimed in claim 4, which comprises an aqueous solution having a pH from 5 to 7 consisting of:

6. A method for reducing histamine production wherein said method comprises nasally administering, to a subject in need of reduced histamine production, a pharmaceutical composition of claim 1.

7. The method, according to claim 6, wherein said composition is an aqueous solution that consists of: a) an antihistamine in an amount between 0.02% and 0.1% of the total weight of the composition (wt %), the antihistamine being selected from the group consisting of loratadine, desloratadine, and pharmaceutically acceptable salts thereof;b) polyethylene glycol with a molecular weight between 100 to 600 g/mole in an amount from 5.0 to 15.0 wt %;c) a propylene glycol, in an amount from 5.0 to 15.0 wt % ;d) a non-ionic block copolymer, wherein the block copolymer is an ethylene oxide and propylene oxide block copolymer, and wherein the block copolymer is present in an amount from 1.0 to 10.0 wt %; ande) a polyoxyethylene sorbitan monolaurate and/or monooleate, wherein the polyoxyethylene sorbitan monolaurate and/or monooleate is present in an amount from 0.5 to

5. 0 wt % and wherein the composition is in an aqueous solution having a pH of from 5 to 7.5.

8. A method for relieving allergy symptoms wherein said method comprises nasally administering, to a subject in need of such relief, a pharmaceutical composition of claim 1.

9. The method, according to claim 8, wherein said composition is an aqueous solution that consists of: a) an antihistamine in an amount between 0.02% and 0.1% of the total weight of the composition (wt %), the antihistamine being selected from the group consisting of loratadine, desloratadine, and pharmaceutically acceptable salts thereof;b) polyethylene glycol with a molecular weight between 100 to 600 g/mole in an amount from 5.0 to 15.0 wt %;c) a propylene glycol, in an amount from 5.0 to 15.0 wt % ;d) a non-ionic block copolymer, wherein the block copolymer is an ethylene oxide and propylene oxide block copolymer, and wherein the block copolymer is present in an amount from 1.0 to 10.0 wt %; ande) a polyoxyethylene sorbitan monolaurate and/or monooleate, wherein the polyoxyethylene sorbitan monolaurate and/or monooleate is present in an amount from 0.5 to 5.0 wt % andwherein the composition is in an aqueous solution having a pH of from 5 to 7.5.