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Patent application title:

PHARMACEUTICAL COMPOSITION FOR TOPICAL APPLICATION

Publication number:

US20180289688A1

Publication date:
Application number:

16/005,149

Filed date:

2018-06-11

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.

Inventors:

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Classification:

  1. Human necessities
  2. Medical or veterinary science; hygiene

A61K9/0043 »  CPC further

Medicinal preparations characterised by special physical form; Galenical forms characterised by the site of application Nose

A61K9/00 IPC

Medicinal preparations characterised by special physical form

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of co-pending application Ser. No. 13/578,425, filed Sep. 23, 2013; which is a National Stage Application of International Application Number PCT/IB2009/055140, filed Nov. 18, 2009; which claims priority to European Application No. 0821298.7, filed Nov. 21, 2008; all of which are incorporated herein by reference in their entirety.

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 60Β° 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% β€”

The pharmaceutical composition has the characteristics shown in Table 2:

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

Claims

We claim:

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

Component Amount (wt %)
a) At least one antihistamine selected 0.02-0.1 
from Loratadine and Desloratadine and
their pharmaceutically acceptable salts
b) At least one polyethylene glycol with  5.0-15.0
a molecular weight of from 100 to 600
g/mole
c) Propylene glycol  5.0-15.0
d) At least one non-ionic ethylene  1.0-10.0
oxide/propylene oxide (EO/PO) block
copolymer with weight average
molecular weight (Mw) from 10,000 to
15,000
e) polyoxyethylene (20) sorbitan 0.5-5.0
monolaurate and/or polyoxyethylene
(20) sorbitan monooleate
f) Stabilizer 0.05-0.5 
Other optional additives <20
Water Balance to 100.0%

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

Component Amount (wt %)
Loratadine or a pharmaceutically 0.02-0.1 
acceptable salt thereof
At least one polyethylene glycol with a  5.0-15.0
molecular weight of from 100 to 600
g/mole
Propylene glycol (co-solvent)  5.0-15.0
At least one non-ionic EO/PO block  1.0-10.0
copolymer with weight average
molecular weight (Mw) from 10,000 to
15,000
polyoxyethylene (20) sorbitan 0.5-5.0
monolaurate and/or polyoxyethylene
(20) sorbitan monooleate
Stabilizer 0.05-0.5 
Other optional additives <20
Water Balance to 100.0%

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

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

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

Component Amount (wt %)
Desloratadine or a pharmaceutically 0.02-0.1 
acceptable salt thereof
At least one polyethylene glycol with a  5.0-15.0
molecular weight of from 100 to 600
g/mole
Propylene glycol  5.0-15.0
At least one non-ionic EO/PO block  1.0-10.0
copolymer with weight average
molecular weight (Mw) from 10,000 to
15,000
polyoxyethylene (20) sorbitan 0.5-5.0
monolaurate and/or polyoxyethylene
(20) sorbitan monooleate
Stabilizer 0.05-0.5 
Other optional additives <20
Water Balance to 100.0%

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

Component Amount (wt %)
Desloratadine or a pharmaceutically 0.6
acceptable salt thereof
PEG 400 10.0
Propylene glycol 10.0
At least one non-ionic EO/PO block 5.0
copolymer with weight average
molecular weight (Mw) of about 12,500
Polysorbate 80 1.8
Na2EDTA 0.1
Water Balance to 100.0%

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 %; and

e) 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 %; and

e) 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.

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