CA2076558A1

CA2076558A1 - Pharmaceutical compositions containing bradykinin antagonists for local use on the nose and eyes

Info

Publication number: CA2076558A1
Application number: CA002076558A
Authority: CA
Inventors: Heinz-Rudiger Seidel; Klaus Wirth; Norbert Giessler
Original assignee: Individual
Current assignee: Hoechst AG
Priority date: 1991-08-22
Filing date: 1992-08-21
Publication date: 1993-02-23
Also published as: HUT63060A; ZA926313B; AU2124592A; EP0529499A1; CZ256592A3; KR930003925A; IL102885A0; JPH05221873A; NO923293D0; NO923293L

Abstract

Abstract Pharmaceutical compositions containing bradykinin antagonists for local use on the nose and eyes Pharmaceutical compositions for local use on the nose or eyes are described, said compositions containing a bradykinin antagonist dissolved in a physiologically acceptable solvent.

Description

207~
HOECHST AKTIENOE SELLSCHAFT ~OE 91/F 264 Dr.D/YP

Description Phaxmaceutisal compositions containing bradykinin antagonist~ for local use on the nose and eyes 5 The invention relates to pharmaceutical compo~ikions containing bradykinin antagonists for local use on the nose and eyes, and to processe~ for the prepa~ation of ~uch compositions.

Bradykinin (~k) and bradykinin-related peptides are involved in diver~e pathological conditions of the organism~ For example, they cauee a decrea~e in blood pre6sure, bronchoconstriction and inflammatory reaction~
and trigger pain.

Bradykinin antagonistæ inhibit the~e effect6 even in low do~eR, with a period o~ action lasting for 6everal hour~
Thus, they prevent a Bk-i~duc~d decrease in blood pr*s-sure, relieve a bxonchoconstriction and reduce inflammations.

Bradykinin antagoni~t~ are descrîbed, for example, in EP-A-0 370 453 (corresponding to US Patent Applications N~s. 374 162 and 746 149~. Pharmaceutical preparations, int~r alia for ~asal use9 are described in general form.

It ha~ now ~een ~ound, surprisingly, that bradykinin antagonistg ~Bk~) have inflammation inhibiting, mucous membrane detume~cent and antiallergic ef~cts if, in the form of solution~, they are applied locally to the no~e or in~tilled into the conjunctival sac of the eye. This observation relates in particular to the antayoni~t ~ (D~-Arg-Arg-Pro-Hyp-Gly-~hi-Ser~(D)-Tic-O.ic-Arg-OH
3D (described in EP A-0 370 453), which is also designated HOE 140. Both allergic rhiniti~ and a viral rhinitis 2~7~8 .. ~
(normal, common cold) can be advantageou ly txeated in this way. Inflammation, ~ecretion and swelling of ~he nasal mucous membrane are reduced. Non~pecific con-junctivitis and allergic conjunctivitis can be treated in the same way.

~he object was, now, to provide BkA-containing formula-tions for these indications, for local application to the nose and eye~. Th~ object wa~ al~o to develop stable a~d physiologically acceptabl~ formulations.

The object i8 achie~ed by the provision of BkA solutio~s as core of the formulation~ according to the invention, which solution~ are used either in the foxm of drops or as a metered ~pray, or in the form of gels and ointments.

The invention there~ore xelates to a pharmaceutical composition for local u~e on the no e or eyes, which contain~
a) a bradykinin antagonist as active compound, b) a physiologically acceptable Isolvent for the active compound, c) optionally, a physiologically acceptable buffer, d) optionally, an isotonicity additive, e) optionally, a pre~ervative, f) optionally, a thickenex, and g) optionally, an ointment base~

Bradykinin antagoni~t6 are under~tood to be both the free compounds an~ the physiologically acc~ptable salts~

Bradykinin antagonists which can be u~ed are, in particular, the following:
1. H-D-Arg-Arg-~yp-Pro-Gly-~hi-Ser-D~Tic-Aoc-Arg-O~
2. H-D-~rg-Arg Pro-~yp-Gly-Thi-Sex-D-Tic-Aoc-Arg-OH

3. ~-D-Arg-ALg-Pxo-Hyp Gly-Thi-Ser-D-Tic-Tic-Arg-OH

4. ~-D-Arg~Arg-Pro-~yp-Gly-Thi-Ser-D-Tic-Oic-Arg-O~

5. H D-Arg-Arg-Pro-Pro-Gly-Thi-Ser-D-Tic-Oic~Arg-OH

2~7~

6. H-D-Arg-Arg-Pro-EIyp-Gly-Phe-S~r-D-~ic-Oic-Arg-OH

7. H-D-Arg-Arg-(N02 )-Pro-~yp-Gly-Phe-Ser-D-Tic-Aoc-Arg-OE~

8. H-Arg(To~)-Pro-Hyp~Gly-Thl-Ser-D-Tic-Oic-Arg-OH

9. ~-D-Arg-Arg-ProHyp~Gly-Leu Ser~D-Tic~Oic Arg-O~

10~ H-D-Arg-~rg-Pro-~yp-Gly Thi-Ser-D-Phe-Oic-Arg-OH

They are either described in EP-A-0 370 ~53 or are prepared in a manner analogous to that indicated in ~aid publication in Example 1.

Compounds ~, 4 and 8 are pxeferred and compound 4 (HQE 14Q) is particularly preferred, It is obvious tha$ the solvent~ and the additives indi cated under c) to g) mu~t be physiologically ac~eptable~

The preferred solvent for the formulations according to the invention is water. In addition~ aliphatic aompounds containing alcohol group~, such as ethanol, glycerol or 1,2-propylene glycol, can be usedt in particular also in mixtuxes with water.

In addition to the medicament, the f~olutions according to the invention appropriately cont~in pre6ervatives, auxiliaries to provide i50tonicity and/or buffer ~ub~tancesO ~hey can al o contain thickeners.

Suit~ble preservative~ are, for example, quaternary ammonium compound~, such a~ cetylpyridinium chloride or henzalkonium chloride, mercury compound~, ~uch a phenyl-mercury borate, acetate or nitrate, or thiomersal sodium.
They are preferably used in con~entrations of 0.002 -0.05~ Further preservative~ are chlorobutanol or phenyl-ethyl al~ohol, which appropriately are used in a con-centration of about 0.5% on their own or can be combinedwith the abovementioned preservatives.

4 2~7~8 A preferred preservative i8 benzalkonium chloride. It is an alkyl~benzyl~dimethylammo~ium chloride which is a mixture of compounds having alkyl chain lengths of C8-C18. As a supplement to the pre~ervatives, ~tabi-lizers, such a~ ethylenediaminetetraacetic acid and itssalts (di~odium salt, calcium salt), which intensify the germicidal effect, can also be added to the æolutions.

In order to improve the tolerability of the solutions according to the inven~ion~ agents which render the solutions iAo~onic are appropriately added, in order to adjust the osmotic pressure ~o that of the phy~iological environment. Suitable substances are, for example~ in addition to sodium chloride, polyhydric alcohols such as sorbitol or mannitol. Thu , aqueous eolutions of 0~9%
sodium chloride, 5.48% sorbitol and 5.07% mannitol are isoo~motic and ~how a freezing point depression of 0.57C. Con~equently, ~he ~aid sub~tance~ must be added in amounts such that the medicament olution~ achieve this valu~ for freezing point depression~

Furthermore, the ~ormulations accoxding to the invention can contain buffer ubstances, with which the pH value iB
ad~u~ted to a xange of 5 ko 6. It has been found that the buffer æy~tems acetic acid/~odium acetate and primary/secondary phosphate are particularly æuitable for the production of stable ~olutions. The said bu~fers are used in 0.005 - 0.~5 molar concentration, but preferably in an ~pproximately 0.02 molar amount.

It was al~o ~urprising that solution~ containing acetate buffer, like those containing the other buffer~, are suitable for nasal application, without irritating the nasal mucou~ membrane. This was not obviously to be expected, as, in contrast to phosphate buffer, acetate buffer i8 not expre~sly recommended for nasal formula-tions (see ~. Sucker, P. Fuchs and P. Speiser Pharma-zeutische Technologie (Pharmaceutical Technology), Georg Thieme Verlag Stuttgart 1978/ p. 292).

Finally, the solutions can contain thickeners in order toprevent relatively rapid run~off and thus to prolong the contact time. Such an effect i~ produced, for example, by gelatin or ~odium alginate. However, preferred thickeners are cellulose ether~, polyacrylic acid, polyvinyl alcohols and polyvinylpyrrolidone~0 Cellulose ethers which may be mentioned are methylcellulose, hydroxy-propylcellulose, hydroxypropylmethylcellulose, hydroxy-ethylce~lulose and carbox~methylcellulo~e. Methylcel-luloses are, for example, known under the trade name Methocel~ belonging to DOW. ~he thickener~ are added in a concentration such that the ~olutions prepared there-from have a 61ightly increa~ed vi~co~ity. ~or ex~mple, about 0~25% of ~ethocel E 4 M premium and about 1~ of Methocel E 15 premium i8 needed (percent by weight based on the total weight of the BkA 601ution ) .

Nasal application of the solutio~s i8 effected by drop~
from a pipette or by spraying from a plastic queeze bottle. Use in the form of an aeroæol by atomizing with the aid of a metering atomizer pump ig preferred.

The liquid formulation i~ suitable in the ~ame way for intraocular instillation.

In order to further prolong the dwell time in the eye or in the nose~ and thus the period of actionl it is necessary to u~e even more Vi8CVU3 ~ormulations, ~uch as ~el~ and ointments. Thus, viscosity~increasing substance~
(thickener ) ca~ be incorporated in the solution~ already described above in concentration~ such that gel-like, spreadable formulations are fonmed. For example, the already mentioned cellulose ether~ and al~o polyacrylic acid ( f or example known under the trade name Car~opol) are suitable for this purpose. In the case of the cellulo~e ethers, more highly viscous type~ are s - ~ ~ 7 ~
appropriately smployed~ Thu~, the proportion of Methocel K 100 M can be 1% and that of Methocel E 4 M
premium 2% (percent by weight ba~ed on the ~olution~.
When polyacrylic acid î~ used, gel fonmation takes place by adding alkali, in particular æodium hydroxide ~olution, until a pH o~ 5-6 is obtained; they are used in a concentration of about 0.25% (Carbopol 940) and G.5%
(Carbopol 923) (% by weight based orl the olution).

~ or application to the eyes, ointment3 are al~o suitable, the BkA solution being incorporated in the ointment base.
Suitable ba~es are hydrocarbons, to which water-in-oil emulsifiers are added~ Mixture of liquid paraf~in and yellow or white petroleum jelly with wool wax alcohol~
may be mentioned here. The latter impart to the ointment the ability to absorb water and to form water-in-oil emulsions. The wool wax alcohols can also be replaced by a mixture of wool fat and cetyl alcohol. The emulsifier-containing ointments enable the active compound to be incorporatPd in ~olution, lt being possible for said ointments also to contain preservatives, to be rendered isotonic and to be buffered.

The foxmulations (~olution~, gels~ ointment~) according to the invention contain 0.0005 to 1~ and pre~erably 0.001 to 0.5% (in each ca~e % by weight3 of ~OE 140, based on the free base, or another B~ in the æaid concentration~, ~he proce~s for the preparatisn of the compositions according to the invention comprise6 di ~olving a bradykinin antagonist in a physiologically acceptable ~olvent and optionally combining the solution with the auxiliaries and excipients indicated under c) to g).

In the ca e of 801ution8, the do~age per nostril i8 0-05 to 0.2 ml and preferably 091 ml, application being pos~ible several times per day, for example 1 to 5 times 7 2~7~

per day. The ~emi~solid ~ormulations are applied in a corre~ponding amount.

Usually 1 drop of ~olution corre~ponding to a volume of O.05 ml, or the corresponding amount of gel or ointment, i introduced into the eye.

In humans, cold ~mptoms can be triggered by nasal u~e of bradykinin. The effect of bradykinin on nasal discharge is particularly pronounced. It was possible to inhibit a bxadykinin-induced na~al discharge for several hours by means of a formulation according to the invention con-taining HOE 140. Therefore, both alleryic rhiniti~ and also viral xhinitis, which are mediated by endogeneously formed kinins, can be traated advantageously using HOE 140. Inflamma~ion, secretion and æwelling of the nasal mucous membrane are reduced. The compo~ition~
according to the inv~ntion are ther~fore suitable for the treatment of the said di~eases.

The following examples are intended to illustrate the subject of the invention in more det:ail without, however restricting it.

Example 1 No~e drop~ or nasal spray or eye dxop~
a) HO~ 140 50.0 mg Acetic acid 6.2 mg Sodium acetate x 3 H2O 165.5 mg ~enzalkonium chloride 10~0 mg Sodium chloride 835.0 mg Double distilled wat~r to make up to 100.00 g 8- 21~7~8 b) HOE 140 50.0 mg NaH2P04 X ~2~ 86.4 mg Na2~PO,, x 2 ~2 Benzalconium chloride 10.0 mg Sodium chloixde 880.0 mg Double dis~illed water to make up to 100.00 ~

c) HOE 140 50.0 mg Citric acid x ~zO 60.0 mg Trisodi~m citrate x ~2 428.0 mg Benzalkonlum chloride 10.0 mg Sodium chloride 850.0 mg Double di~tilled water to make up to 100.00 g The buffer 3ubstances, benzalkonium chloride and ~odi~m chloride are dissolved in one poxtion of wat~r. The medicament ia di6solved in a further portîon o water.
The two solution~ are combined and made up to the desired volume. After mixing the finished solution, a pH of 5.5 ~ O.3 re~ultæ. After filtering through a membrane filtar having ~ pore width of 0.2:2 ~m, the ~olution is filled into glas~ container~, which are sealed with a metering atomizer pump. On actuation of the pump, 100 ~l of spray~ corresponding to 50 ~g of ~OE 140, are relea~ed into the noae.

If the filled gla~s containers are pxovided with a pipette~ the ~olution can be introduced as drops into the nose or the eye.

The saLd solution~ were subjected to a stability test. At a storage temperature of 40C, the following value~ for the HOE 140 content were found after 3 (and 6) months: a) 99.5% (95.7%); b) 9~.7% (92.~%); c) 9604% (89.~%)~ The valuea ahow the particulax ~uit2bility of the ~olutions containing acetate buf:Eer or pho~phate buffer.

- 9 - 2~7~8 Example 2 Gel for use on the nose or eye a) HOE 140 50~00 mg Acetic acid 6.24 mg Sodium acetate x 3 H20 165.50 mg Benzalkonium chloride 10.00 mg Sodium chloride 835.00 mg Methocel E 4 M 1500.00 mg Double distilled water to make up to 100.00 g Methocel E 4 M is disper~ed in about 60 g of water and placed in an autoclave. A gel forms, to which an aqueous solution of the buffer substance~, benzalkonium chloride, 60dium chloride and ~OE 140, which ~olution ha~ been filtered through a membrane filter having a pore width of 0.2 ~m, is added. After adding the remaining water, the mixture i6 ~tirred until it i8 homogeneou~. The tran~
parent gel is filled into tubes with an extende~ appli-cation tip, b) HOE 140 50.00 mg Benzalkonium chloride 10,00 mg Sorbitol 5500.00 mg Carbopol 940 250.~0 mg Sodium hydroxide q.s.
Double distilled water to make up to 100.00 g Carbopol 940 i~ di~per~ed in a solution of thP
benzalkonium chloride and ~orbitol in about 50 g of water and the disper~ion is placed in an autoclave. After cooling the diapersion, a ~olution of HOE 140 in about 40 g of waterf which solution has been filtered through a membrane filter having a pore width of 0,22 ~m, is added.

-lo- 2076~8 2.5 N sodium hydroxide solution is added, with stirring, until a pH of 5.5 i~ obtained, gel ormation taking place. The ~el i6 made up to the end weight with waterS
The gel is stirred until i~ is homogeneous and .i8 filled into small tube~ with a drawn out application tip.

Example 3 Ointment for use on the eyes or no~e HO~ 140 50.00 mg Benzalkonium chloride 10.00 mg Twice distLlled wa~er 10.00 g Paraffin, high viæcosity 27.0 g Petroleum jelly, white 54.2 g Wool fat 6.3 g Cetyl alcohol 2.5 g After heat sterilization, the four constituents of the ointment base are meltsd on a waterbath and stirred until cold. A solution of HOE 140 and benzalkonium chloride in water, which solution has been filtered through a membr~ne filter having a pore width o~ 0.22 ~m, i~
introduced in portion~ into the ointment base, and emulsified, The soft ointment i~ filled into sma~l tubes, which can have an extended application tip for use in the nose.

Claims

1. A pharmaceutical composition for local use on the nose or eyes, which contains a) a bradykinin antagonist as active compound, b) a physiologically acceptable solvent for the active compound, c) optionally, a physiologically acceptable buffer, d) optionally, an isotonicity additive, e) optionally, a preservative, f) optionally, a thickener, and g) optionally, an ointment base.

2. The composition as claimed in claim 1, which con-tains, as bradykinin antagonist, .

3. The composition as claimed in claim 1, which con-tains (HOE 140) as bradykinin antagonist.

4. The composition as claimed in claim 1, wherein the bradykinin antagonist is HOE 140, the solvent is water and the physiologically acceptable buffer is sodium acetate.

5. A process for the preparation of a composition as claimed in claim 1, which comprises dissolving bradykinin antagonist in a physiologically acceptable solvent and optionally combining the solution with a physiologically acceptable buffer, an isotonicity additive, a preservative, a thickener and/or an ointment base.