United States Patent [19J
`Hettche
`
`[54] AZELASTINE CONTAIMNG
`MEDICAMENTS
`
`[75]
`
`Inventor: Helmut Hettche, Dietzenbach, Fed.
`Rep. of Germany
`[73] Assignee: Asta Pharma AG, Fed. Rep. of
`Germany
`[21] Appl. No.: 551,644
`[22] Filed:
`
`Jul. 12, 1990
`
`Related U.S. Application Data
`
`[63]
`
`[30]
`
`Continuation of Ser. No. 268,772, Nov. 9, 1988, aban(cid:173)
`doned.
`
`Foreign Application Priority Data
`
`Nov. 13, 1987 [DE] Fed. Rep. of Germany ....... 3738681
`Int. CJ.5 ........................ A61K 9/14; A61K 31/55
`[51]
`[52] U.S. Cl. ...................................... 424/489; 424/43;
`424/45; 424/464; 424/422; 514/212
`[58] Field of Search ................... 424/43, 464, 422, 45,
`424/489; 514/212; 222/394; 141/24; 239/302;
`248/108
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`158.564 1/1875 Barnes- ................................... 141/24
`2,119,643 6/1938 Mend! ................................. 222/394
`2,136.940 11/1938 Ehbrecht ............................. 222/394
`
`I 111111111111111111111 IIIII IIIII IIIII IIIII IIIII IIIII IIIII IIIIII Ill lllll llll
`US005164194A
`5,164,194
`[11] Patent Number:
`[45] Date of Patent: Nov. 17, 1992
`
`2,457,024 12/1948 Arp ..................................... 248/108
`2,995,308 8/1961 Ashkencz ............................ 239/302
`3,813.384 5/1974 Vogelsang .......................... 546/133
`4,704,387 11/1987 Engel et al. ......................... 514/212
`4,769,369 9/1988 Thomas et al. .................. 514/234.5
`
`FOREIGN PATENT DOCUMENTS
`2164058 7/1972 Fed. Rep. of Germany ...... 546/133
`3530793 3/1986 Fed. Rep. of Germany ...... 514/212
`1377231 1/1972 United Kingdom .
`
`OTHER PUBLICATIONS
`Negwer,. Organic-Chemicals, Drugs and Their Syn(cid:173)
`onyms, vol. II, (1987) p. 1145.
`European Search Report.
`Org.-Chem. drugs and their synonyms, vol. Ill, No.
`6496 (1987).
`Arzneimitte1, Fortschritte 1972-1985, pp. 936 and 939
`(1977).
`
`Primary Examiner-Thurman K. Page
`Assistant Examiner-Neil S. Levy
`Attorney, Agent, or Firm-Cushman, Darby & Cushman
`
`[57]
`ABSTRACT
`A medicament for nasal use or for use in the eye which
`contains as active ingredient azelastine or a physiologi(cid:173)
`cally acceptable salt.
`
`12 Claims, No Drawings
`
`

`

`1
`
`5,164,194
`
`AZELASTINE CONTAINING MEDICAMENTS
`
`is a continuation of application Ser. No.
`This
`07/268,72, filed Nov. 9, 1988, now abandoned.
`The present invention relates to the treatment of nasal
`and eye tissues with azelastine.
`BACKGROUND OF THE INVENTION
`Azelastine is a phthalazinone derivative having the 10
`following structural formula:
`
`25
`
`2
`taste is barely perceptible when the sprayed azelastine
`solution or suspension runs down into the pharynx.
`Therefore, the object of the present invention is to
`provide a well tolerated and improved remedy based on
`5 azelastine or its salts for the treatment both of the aller(cid:173)
`gy-related and vasomotor-related conditions as well as
`rhino virus-related cold and its accompanying symp(cid:173)
`toms.
`A further object of the present invention is to provide
`medical formulations which are adapted to direct appli(cid:173)
`cation to nasal and eye tissues.
`The preferred embodiment of the invention is a sterile
`and stable aqueous solution of azelastine or one or more
`of its salts which can be used in the form of drops,
`15 ointments, creams, gels, insuffiatable powders or, in a
`particularly preferred embodiment, in the form of a
`spray (preferably a nasal spray). The spray can be
`formed by the use of a conventional spray-squeeze bot(cid:173)
`tle or a pump vaporizer. In addition, it is also possible to
`20 use compressed gas aerosols. For example 0.03 to 3 mg
`of azelastine base should be released per individual
`actuation.
`Through the use of nasal drops or a nasal spray, the
`dosage of azelastine required for the treatment of the
`cold is lowered approximately tenfold and hence the
`incidence of the appearance of side effects is considera(cid:173)
`bly lower than in the case of the application of azelas(cid:173)
`tine in orally taken dosage forms such as tablets or syr-
`30 ups which distribute the active substance throughout
`the entire body. In the treatment of a banal illness such
`as a cold, a low incidence of side effects is particularly
`important and thus represents a considerable medical
`advance.
`Solvents which may preferably be used for the for-
`mulations of the invention are: water, saturated ali(cid:173)
`phatic mono and polyvalent alcohols which contain 2-3
`carbon atoms (for example ethanol, isopropanol, 1,2-
`propylene glycol, glycerine), liquid polyglycols (molec-
`ular weight 200 to 600).
`The solvent used is preferably water or mixtures of
`water with other physiologically acceptable solvents
`(for example those mentioned above). Preferably, the
`amount of the latter solvent in the aqueous mixture
`should not exceed 15% by weight.
`The solutions or formulations preferably contain pre(cid:173)
`servatives and stabilizers. These include, for example:
`ethylene diamine tetra-acetic acid (edetic acid) and their
`alkali salts (for example dialkali salts such as disodium
`salt, calcium salt, calcium-sodium salt), lower alkyl
`p-hydroxybenzoates, chlorohexidine (for example in the
`form of the acetate or gluconate), phenyl mercury bo(cid:173)
`rate. Furthermore, it is possible, for example, to use
`generally
`ethylmercurithio)-benzoate
`sodium-(2-
`55 known as "thimerosal" which may be present in an
`amount of 0.001 to 0.05, preferably from 0.005 to 0.02,
`for example 0.01 % (weight/volume in liquid formula(cid:173)
`tions, otherwise weight/weight). Other suitable preser-
`vatives are: pharmaceutically useful quaternary ammo(cid:173)
`nium compounds, for example cetylpyridinium chlo(cid:173)
`ride, tetradecyltrimethyl ammonium bromide, generally
`known as "cetrimide", benzyldimethyl-[2-[2-[p-(l, 1,3,3-
`tetramethyl- butyl)]phenoxy]ethoxy]-ammonium chlo(cid:173)
`ride, generally known as "benzethonium chloride" and
`myristyl-:-picolinium chloride. Each of these com(cid:173)
`pounds may be used in a concentration of 0.002 to 0.05,
`for example 0.02% (weight/volume in liquid formula(cid:173)
`tions, otherwise weight/weight). Preferred preserva-
`
`Cl
`
`0
`cc ~-cN-CH,
`
`II
`0
`
`The chemical designation is: 4-(4-chlorobenzyl)-2-
`(perhydro-l-methyl-azepine-4-yl)-l-(2H)phthalazinone.
`Azelastine is used in particular for prophylactic treat(cid:173)
`ment of asthma. Azelastine also has anti-allergic and
`antihistamine properties, see German Patent No. 21 64
`058.
`
`SUMMARY OF THE INVENTION
`It has now been found that azelastine and its physio(cid:173)
`logically acceptable salts display particularly advanta- 35
`geous and surprising effects when the corresponding
`formulations are applied directly in the nose and/ or to
`the conjunctiva] sac of the eye.
`Elimination or marked relief has thus been achieved
`not only in allergy-related rhinitis, but also in the nor- 40
`ma! common cold (caused, for example, by rhino vi(cid:173)
`ruses) as well as in the vasomotor cold and the symp(cid:173)
`toms of illness triggered thereby.
`It is surprising in this context that local nasal applica(cid:173)
`tion also has a favorable effect on the mucous mem- 45
`brane of the eye (elimination or relief of reddening of
`the eye and of eye irritation) so that the additional use of
`eye drops is frequently superfluous.
`Other indications for the application/use of the in(cid:173)
`vention are, for example: non-specific conjunctivitis, 50
`allergy-related conjunctivitis, allergic blepharoedema,
`catarrhal conditions in the eye or nose, coryza.
`Surprisingly, in addition, none of the tiredness that
`arises with other applications was observed with use
`according to the invention.
`Furthermore the invention provides a way to over(cid:173)
`come problems which arise because of azelastine's ex(cid:173)
`ceptionally penetrating, bitter taste. The degree of the
`bitter taste is so intense that it is even found to be un(cid:173)
`pleasant in a dilution of I : 706. This problem has hith- 60
`erto prevented oral application of azelastine solutions,
`since patients refuse to take such azelastine solutions or
`suspensions. It wa surprisingly found in trial subjects
`that this bitter taste was no longer in evidence when the
`azelastine formulations of the invention were sprayed 65
`into the nose. As a result, it is possible in this manner to
`apply solutions or suspensions of azelastine and its salts
`nasally without taste impairment. Moreover the bitter
`
`

`

`5,164,194
`
`3
`tives among the quaternary ammonium compounds are,
`however, alkylbenzyl dimethyl ammonium chloride
`and mixtures thereof, for example the compounds gen(cid:173)
`erally known as "benzalkonium chloride". These latter
`consist of a mixture of the compounds of formula,
`
`10
`
`55
`
`4
`p-hydroxybenzoic acid ester (for example a mixture of
`the methyl ester and propyl ester 7 : 3): 0.05-0.15,
`preferably 0.1%.
`The preservative used is preferably a combination of
`5 edetic acid (for example as the disodium salt) and benz(cid:173)
`alkonium chloride. In this combination, the edetic acid
`is used in a concentration of 0.05 to 0.1 %, benzalkonium
`chloride being used in a concentration of 0.005 to
`0.05%, preferably 0.01%.
`In the case of solutions/suspensions reference is al(cid:173)
`ways made to percent by weight/volume, in the case of
`solid or semi-solid formulations to percent by weight/(cid:173)
`weight of the formulation.
`Further auxiliary substances which may, for example,
`be used for the formulations of the invention are: poly(cid:173)
`vinyl pyrrolidone, sorbitan fatty acid esters such as
`sorbitan trioleate, polyethoxylated sorbitan fatty acid
`esters (for example polyethoxylated sorbitan trioleate),
`sorbimacrogol oleate, synthetic amphotensides (tri(cid:173)
`tons), ethylene oxide ethers of octylphenolformalde(cid:173)
`hyde condensation products, phosphatides such as leci-
`thin, polyethoxylated fats, polyethoxylated oleotri(cid:173)
`glycerides, polyethoxylated fatty alcohols. In this con(cid:173)
`text, polyethoxylated means that the relevant sub(cid:173)
`stances contain polyoxyethylene chains, the degree of
`polymerization of which is generally between 2 to 40, in
`particular between 10 to 20. These substances are pref(cid:173)
`erably used to improve the solubility of the azelastine
`components.
`In the case of dosage forms containing water, it is
`optionally possible to use additional
`isotonization
`agents. Isotonization agents which may, for example, be
`used are: saccharose, glucose, glycerine, sorbitol, 1,2-
`propylene glycol, NaCl.
`The isotonization agents adjust the osmotic pressure
`of the formulations to the same osmotic pressure as
`nasal secretion. For this purpose these substances are in
`each case to be used in such amount that, for example,
`in the case of a solution, a reduction in the freezing
`point of 0.50° to 0.56° C. is attained in comparison to
`pure water. In Example 1, for instance, such substances
`would be used in such an amount which is iso-osmotic
`with 68 g of sodium chloride (0.68%).
`In Example 1, it is possible to use instead of NaCl per
`100 ml of solution, for example:
`Glucose lH2O 3.81 g; saccharose 6.35 g; glycerine
`2.2 g; 1,2-propylene glycol 1.617 g; sorbitol 3.84 g (in
`the case of mixtures of these substances correspond(cid:173)
`ingly less may optionally be used).
`Moreover, it is possible to add thickening agents to
`the solutions to prevent the solution from flowing out of
`the nose too quickly and to give the solution a viscosity
`of about 1.5 to 3, preferably 2 mPa.s. Such thickening
`agents may, for example, be: cellulose derivatives (for
`example cellulose ether) in which the cellulose-hydroxy
`groups are partially etherified with lower unsaturated
`aliphatic alcohols and/or lower unsaturated aliphatic
`oxyalcohols (for example methyl cellulose, carboxy(cid:173)
`methyl cellulose, hydroxypropylmethylcellulose), gela(cid:173)
`tin, polyvinylpyrrolidone, tragacanth, ethoxose (water
`soluble binding and thickening agents on the basis of
`ethyl cellulose), alginic acid, polyvinyl alcohol, poly(cid:173)
`acrylic acid, pectin and equivalent agents. Should these
`substances contain acid groups, the corresponding
`physiologically acceptable salts may also be used.
`In the event of the use of hydroxypropyl cellulose,
`0.1 % by weight are, for example, used for this purpose.
`
`25
`
`30
`
`in which R represents an alkyl group having the for(cid:173)
`mula CnH2n+ I, wherein n represents a whole number 15
`from 8 to 18. The use of a mixture of compounds in
`which n represents 10 to 14 is particularly preferred and
`in particular
`the
`special compound
`in which
`R=C12H25 "Benzalkonium chloride" and the com(cid:173)
`pounds of the above formula can be used in concentra- 20
`tions of 0.005 to 0.10, preferably of 0.005 to 0.05, for
`example of 0.01 % (weight/volume for liquid formula(cid:173)
`tions, otherwise weight/weight) and they may option(cid:173)
`ally be used in combination with 0.2 to 2.0, for example
`0.4% (weight/ volume) of 2-phenylethanol.
`The formulations of the invention (solutions, suspen(cid:173)
`sions as well as oily solutions or suspensions, ointments,
`emulsions, creams, gels, dosage aerosols) contain 0.0005
`to 2, preferably 0.001 to 1, in particular 0.003 to 0.5%
`(weight/weight) of azelastine (related to the free azelas(cid:173)
`tine base). Should the azelastine be present-as a salt, the
`amounts should be recalculated as necessary to give the
`amounts of azelastine itself mentioned above. In the
`case of the eye drops, the same azelastine concentra- 35
`tions apply as in the case of the nasal forms.
`In the case of powders, the concentration of azelas(cid:173)
`tine base is 0.0005 to 2 percent by weight related to the
`solid carrier substances.
`In the case of solutions, the dosage per nostril is, for 40
`example, 0.01 to 0.2 ml, in particular 0.05 to 0.15 ml.
`Such a dosage should be applied once to several times,
`preferably 1 to 5 times daily (optionally also hourly).
`In the case of use at the eye (eye drops) the dosage is
`for example 1 drop (about 0.05 ml) of the solution or 45
`corresponding amounts of the semi-solid formulation
`forms.
`Possible acid components for azelastine salts are, for
`example: hydrohalic acids (HCI, HBr), sulphuric acid,
`phosphoric acids (H3PO4, metaphosphoric acid, poly- 50
`phosphoric acids), nitric acid, organic mono-, di- or
`tricarboxylic acids of aliphatic, alicyclic, aromatic or
`heterocyclic organic acids (embonic acid, citric acid,
`tartaric acid), aliphatic and aromatic sulfonic acids (for
`example camphorsulfonic acid).
`The total amounts of preservatives in the formula(cid:173)
`tions (solutions, ointments, etc.) is between 0.001 to
`0.10, preferably 0.01 g per 100 ml of solution/suspen-
`sion or 100 g of formulation.
`In the case of preservatives, the following amounts of
`individual substances can, for example, be used:
`thimero sal 0.002-0.02%;
`benzalkonium chlorie 0.002 to 0.02% (in combination
`with thimero sal the amount of thimero sal is, for 65
`example =0.002 to 0.005%;);
`chlorhexidine acetate or gluconate 0.01 to 0.02%;
`phenyl mercuric/nitrate, borate, acetate 0.002-0.004%;
`
`60
`
`

`

`5,164,194
`
`6
`DETAILED DESCRIPTION OF PREFERRED
`EMBODIMENTS
`The invention is illustrated by the following exam(cid:173)
`s ples.
`
`5
`It is also possible to add to the formulations buffer
`substances such as citric acid / sodium hydrogensul(cid:173)
`phate borate buffer, phosphates (sodium hydroge(cid:173)
`hydrogenphosphate),
`disodium
`northophosphate,
`tromethamol or equivalent conventional buffers in or(cid:173)
`der, for example, to adjust the formulation to a pH value
`of 6 to 7.5, preferably 6.5 to 7.1.
`The amount of citric acid is, for example, 0.01 to 0.14,
`preferably 0.04 to 0.05 g, the amount of disodiurn hy- 10
`drogenphosphate 0.1 to 0.5, preferably 0.2 to 0.3 g per
`100 ml of solution. The weights given relate in each case
`to the anhydrous substances.
`In the case of solutions and suspensions, the maximum
`total concentration of active agent and buffer should be 15
`less than 5%, in particular less than 2% (weight(cid:173)
`/volume).
`For the nasal application a solution or suspension is
`preferably used which is applied as an aerosol, i.e. in the
`form of a fine dispersion in air or in another conven- 20
`tional carrier gas, for example by means of a conven(cid:173)
`tional pump vaporizer.
`Application as a dosage aerosol is, however, also
`possible. Dosage aerosols are defined as being pressure 25
`packings which contain the azelastine or its salts in the
`form of a solution or suspension in a so-called propel(cid:173)
`lant. Propellants are pressurized liquid chlorinated,
`fluorinated hydrocarbons or mixtures of various chlori(cid:173)
`nated, fluorinated hydrocarbons as well as propane, 30
`butane, isobutane or mixtures of these among them(cid:173)
`selves or with chlorinated, fluorinated hydrocarbons
`which are gaseous at atmospheric pressure and room
`temperature. The pressure packing has a dosage valve
`which, on actuation, releases a defined amount of the
`solution or suspension of the medicament. The subse(cid:173)
`quent very sudden vaporization of the propellant tears
`the solution or suspension of azelastine into the finest
`droplets or minute particles which can be sprayed into
`the nose or which are available for inspiration into the 40
`nose. Certain plastic applicators are used to actuate the
`valve and to convey the sprayed suspension into the
`nose. Propellants that may, however, also be used are:
`CO2, nitrous oxide and compressed air.
`In the case of application as an aerosol, it is also possi(cid:173)
`ble to use a conventional adapter.
`When suspensions are used, the maximum particle
`size of the solid substances (azelastine +auxiliary sub(cid:173)
`stances) should not exceed 30 µ,m.
`In the- case of use in the form of an insufflatable pow(cid:173)
`der, the maximum particle size of the substances should
`not be greater than 20 µ,m .
`What occurs is, for example, a vaporizing of solid
`azelastine or its salts. In this case the azelastine or its salt 55
`is, for example, mixed with inert carrier substances or
`drawn up onto inert carrier substances. Carrier sub(cid:173)
`stances which may, for example, be used are: sugars
`such as glucose, saccharose, lactose and fructose. Also
`starches or starch derivatives, oligosaccharides such as
`dextrins, cyclodextrins and their derivatives, polyvinyl(cid:173)
`pyrrolidone, alginic acid, tylose, silicic acid, cellulose,
`cellulose derivatives (for example cellulose ether), sugar
`alcohols such as mannitol or sorbitol, calcium carbon- 65
`ate, calcium phosphate. The concentration of azelastine
`is 1 part by weight of azelastine to 50 to 200,000 parts by
`weight of carrier substance (0.0005 to 2% of azelastine).
`
`60
`
`EXAMPLE 1
`Nasal spray or nasal drops or eye drops with O.l %
`azelastine hydrochloride as active ingredient
`The following are dissolved, in the following order,
`into 9.00 kg of water: 10 g of azelastine hydrochloride,
`5 g of edetic acid disodium salt. 2 H2O, 68 g of sodium
`chloride, 1.25 g of alkyl-benzyldimethylammonium
`chloride (benzalkonium chloride), 4.38 g of citric acid,
`64.8 g of sodium monohydrogen-phosphate. 12 H2O as
`well as 10 g of hydroxypropylmethyl cellulose.)1
`1 Commercially available product. for example methocel E4M pre(cid:173)
`mmm.
`The solution obtained is diluted to 10.05 kg = 10 liters
`with water. The solution is filtered through a membrane
`filter of pore size 0.2 µ,m after careful mixing, the first
`500 ml of filtrate being discarded. The filtrate has a pH
`value of 6.8 ±0.3. This is filled into plastic bottles
`which are closed with a conventional spray insert or
`into plastic or glass bottles which are closed with a
`conventional pump sprayer. In the latter case, pumps
`with nasal spray inserts are, for example used, which
`spray about 0.14 ml of solution per actuation. In this
`manner, 0.14 mg of azelastine hydrochloride are
`sprayed into the nose per actuation in the form of the
`solution.
`If the above obtained filtrate is filled into the bottles
`with dropper pipettes conventionally used for nasal
`drops or eye drops, the solution can be dripped into the
`35 nose or eye using a dropper pipette.
`EXAMPLE 2
`Nasal ointment with 0.1 % of azelastine hydrochloride
`5 kg of polyoxyethylene stearate2, 8 kg of cetylstearyl
`alcohol (Lanette 0), 20 kg of white Vaseline, 15 kg of
`liquid paraffin and 0.5 kg of silicon oil are melted to(cid:173)
`gether in a heatable vessel. 126 g of p-hydroxybenzoic
`acid methyl ester and 53 g of p-hydroxybenzoic acid
`propyl ester are dissolved in the melt (temperature of
`45 the melt 80' C.). Subsequently, a solution heated to 70'
`C. of 0.1 kg of azelastine hydrochloride, 140 g of p(cid:173)
`hydroxybenzoic acid methyl ester and 60 g ofp-hydrox(cid:173)
`ybenzoic acid propyl ester in 51.021 kg of purified
`water are emulsified with the aid of a high speed stirrer
`50 and the emulsion obtained is stirred until cold and re-
`peatedly homogenized at regular time intervals.
`Polyoxyethylene-40-stearate, solid, wh11e to cream-colored mass, D.25
`ca. I.I , F. 40° -44' C. Solidification point ca. 41 • C.
`The ointment is filled into tubes which have a tubular
`extension beyond the thread and are thus particularly
`suitable for applying the ointment into the nose.
`EXAMPLE 3
`Dosage aerosol giving off 0.5 mg of azelastine
`hydrochloride per stroke
`About 8.0 kg of a mixture of 70 parts by weight of
`difluorodichloromethane and 30 parts by weight of
`1,2dichlorotetrafluoroethane are cooled to about -55°
`C. in an appropriate cooling vessel. A mixture of 0.086
`kg of precooled sorbitantrioleate and 0.8600 kg of pre(cid:173)
`cooled trichlorofluoromethane are dissolved with stir(cid:173)
`ring into this mixture at - 55' C. 0.0688 kg of micron(cid:173)
`ized azelastine hydrochloride and 0.0688 kg of micron-
`
`

`

`5,164,194
`
`7
`ized lactose are then incorporated in portions into the
`solution thereby obtained with intensive stirring. The
`total weight of the suspension thereby obtained is made
`up to 9.547 kg through addition of more of the mixture
`of 70 parts by weight of difluorodichloromethane and
`30 parts by weight of 1,2-dichlorotetrafluoroethane
`cooled to about -55° C.
`Following closure of the cooling vessel the suspen(cid:173)
`sion is again cooled to about - 55° C. under intensive
`stirring. It is then ready to be filled.
`With continued stirring the suspension is filled into
`the conventional suitable aluminum monobloc tins. The
`monobloc tins are closed immediately after the suspen(cid:173)
`sion has been filled using conventional dosage valves
`which release 0.05 ml of suspension per valve actuation.
`Actuation of the valve thus releases 0.5 mg of azelastine
`hydrochloride. Presentation is effected in conjunction
`with a conventional applicator which permits introduc(cid:173)
`tion of the active substance into the nose of the patient.
`
`8
`1. A method for the treatment of irritation or disor(cid:173)
`ders of the nose and eye which comprises applying
`directly to nasal tissues or to the conjunctiva] sac of the
`eyes a medicament which contains a member selected
`5 from the group consisting of azelastine and its physio(cid:173)
`logically acceptable salts.
`2. A method as set forth in claim 1 in which the medi(cid:173)
`cament contains 0.0005 to 2% (weight/weight) of
`azelastine or an amount of a physiologically acceptable
`10 salt of azelastine which contains 0.0005 to 2% (weight/(cid:173)
`weight) azelastine.
`3. A method as set forth in claim 2 in which the medi(cid:173)
`cament contains 0.001 to I% (weight/weight) of azelas(cid:173)
`tine or an amount of a physiologically acceptable salt of
`15 azelastine which contains 0.001 to I% (weight/weight)
`azelastine.
`4. A method as set forth in claim 1 in which the medi(cid:173)
`cament contains 0.003 to 0.5% (weight/weight) of
`azelastine or an amount of a physiologically acceptable
`20 salt of azelastine which contains 0.003
`to 0.5%
`(weight/weight) azelastine.
`5. A method as set forth in claim 1 in which the medi(cid:173)
`cament contains a pharmaceutically usable preservative
`in an amount of0.001 to 0.1%.
`6. A method as set forth in claim 1 in which the medi(cid:173)
`cament is a solution.
`7. A method as set forth in claim 1 in which the medi(cid:173)
`cament is an aqueous solution.
`8. A method as set forth in claim 1 in which the medi(cid:173)
`cament is a solution which contains 0.001 to 0.05%
`(weight/volume of solution) of sodium-2-(ethylmer(cid:173)
`curithio)-benzoate or 0.001 to 0.1% (weight/volume of
`solution) of alkylbenzyldimethyl ammonium chloride.
`9. A method as set forth in claim 1 in which the medi-
`cament is applied by spraying.
`10. A method as set forth in claim 1 in which the
`medicament is applied as drops.
`11. A method as set forth in claim 1 in which the
`medicament is a powder.
`12. A method for the treatment of a patient suffering
`from allergy-related, or vasomotor or rhino-related
`colds or symptoms which comprises applying directly
`to the patient's nasal tissues or to the conjunctiva! sac of
`the patient's eye a medicament which contains a mem(cid:173)
`ber selected from the group consisting of azelastine and
`its physiologically acceptable salts.
`* * * * *
`
`30
`
`EXAMPLE 4
`Eye drops with 0.05% of azelastine hydrochloride
`140 g of polyvinylalcohol (trade name for example:
`Mowiol 26-88 / Hoechst AG, Frankfurt 80) are stirred 25
`into 4 liters of cold water for injection purposes, the
`suspension is heated to 90° C. and left at this tempera(cid:173)
`ture for 45 minutes. After cooling, the solution obtained
`is mixed with the following solutions:
`5 g of azelastine hydrochloride in 1 liter of water for
`injection purposes, 0.2 g of phenyl mercuric nitrate in 2
`liters of water for injection purposes, 70 g of sodium
`chloride in I liter of water for injection purposes.
`The mixture is adjusted to a pH value of 6.8 through 35
`addition of 0.1 N sodium hydroxide solution, mixed
`with a solution of 15 g of sodium dihydrogen phos(cid:173)
`phate.2 H2O and 21 g of disodium hydrogen phos(cid:173)
`phate.2 H2O in 1 liter of water for injection purposes
`and filled up to 10 liters with water for injection pur- 40
`poses.
`Following careful mixing the solution is filtered
`through a membrane filter of pore size 0.2 µm with glass
`fiber pre-filter and filled into sterile eye drop bottles
`under aseptic conditions after discarding a first 500 ml 45
`of filtrate.
`What is claimed is:
`
`50
`
`55
`
`60
`
`65
`
`

`

`UNITED STATES PATENT AND TRADEMARK OFFICE
`CERTIFICATE EXTENDING PATENT TERM
`UNDER 35 U.S.C. § 156
`
`PATENT NO.
`
`5,164,194
`
`ISSUED
`
`November 17, 1992
`
`INVENTOR(S)
`
`Helmut Hettche
`
`PATENT OWNER
`
`Asta Medica, AG
`
`This is to certify that there has been presented to the
`
`COMMISSIONER OF PATENTS AND TRADEMARKS
`
`an application under 35 U.S.C. § 156 for an extension of the patent term. Since it
`appears that the requirements of the law have been met, this certificate extends the term of
`the patent for the period of
`
`349 days
`
`from November 17, 2009, the original expiration date of the patent, subject to the payment
`of maintenance fees as provided by law, with all rights pertaining thereto as provided by
`35 u.s.c. § 156(b).
`
`I have caused the seal of the Patent and Trademark
`Office to be affixed this 27th day of Februazy 1998.
`
`fka.~
`
`Bruce A. Lehman
`Assistant Secretary of Commerce and
`Commissioner of Patents and
`
`