sign in sign up
<<
Home , Fenoxazoline, Metizoline

US 20070 104791A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0104791 A1 Popov et al. (43) Pub. Date: May 10, 2007

(54) METHOD OF PREPARING A Publication Classification PHARMACEUTICAL COMPOSITION AND PHARMACEUTICAL COMPOSITIONS (51) Int. Cl. OBTANABLE THEREBY A6IR 9/14 (2006.01) (75) Inventors: Todor Alexandrov Popov, Sofia (BG); (52) U.S. Cl...... 424/488 Christo Tzachev Tzachev, Sofia (BG) Correspondence Address: (57) ABSTRACT GOMEZ INTERNATIONAL PATENT OFFICE, LLC An aqueous pharmaceutical composition comprising: a) 15O1 N. RODNEY STREET 0.005 to 10% by wt of one or more water-soluble pharma SUTE 101 ceutically active ingredients or pharmaceutically acceptable WILMINGTON, DE 19806 (US) salts thereof; b) from 0.01 to 10% by wt hydroxypropyl methyl cellulose having a viscosity of from 2500 to 5500 cps (73) Assignee: Fortune Apex Development Limited, (mPas); and c) a buffer for maintaining the pH of the Tortola (VG) aqueous pharmaceutical composition from 5 to 7; can be prepared by a method which comprises: i) dissolving the (21) Appl. No.: 11/312,887 above components in water to form an aqueous solution, and (22) Filed: Dec. 20, 2005 ii) filtering the aqueous solution formed in i) through a sieve having a mesh size from 21 micron but is 10 microns. The (30) Foreign Application Priority Data compositions obtainable by this method are capable of demonstrating improved mucoadhesive consistency and sta Oct. 24, 2005 (GB) ...... 0521708.8 bility. US 2007/01 04791 A1 May 10, 2007

METHOD OF PREPARING A PHARMACEUTICAL active Substance e.g. hydrochloride in an COMPOSITION AND PHARMACEUTICAL amount of from 0.01 up to 10.00 wt %, mucoadhesive COMPOSITIONS OBTANABLE THEREBY substance e.g. HPMC in an amount of from 0.1 up to 10 wt 0001. This invention is concerned with a method of %, preservative e.g. disodium EDTA in an amount of from preparing a pharmaceutical composition and pharmaceutical 0.01 up to 5.00 wt %, and a phosphate buffer system, and compositions obtainable thereby. More particularly, this wherein the composition has a pH of from 5 to 7. In this invention is concerned with a method of preparing an document, a mucoadhesive solution is prepared by mixing aqueous pharmaceutical composition which comprises one HPMC and EDTA in small proportions to a warm phosphate or more water soluble pharmaceutically active ingredients buffer solution and allowing the solution to cool to 20° C. and hydroxypropyl methyl cellulose and to aqueous phar After the solution is allowed to stand for 24 hours and bubbles removed under reduced pressure, the active ingre maceutical compositions obtainable thereby. dient is added and stirred for 2 hours at 20° C. There is no 0002 Pharmaceutical compositions have been used for disclosure in this document of the pharmaceutical compo the treatment of , sinusitis, hay fever and other sition being Subjected to any filtering steps at any stage inflammatory conditions of the nasal cavities for many during its preparation. years. Often, the pharmaceutical compositions are adminis tered nasally in the form of drops or sprays. The Success of 0008 WO-A-99038492 discloses an aqueous nasal phar treatment of a particular condition may not only depend maceutical composition which comprises: upon the nature of the pharmaceutically active ingredient in 0009 (a) one or more active substances suitable for pharmaceutical composition but can also depend upon the nasal administration, such as vasoconstrictors, anti ability of the other ingredients in the composition to dis allergic agents and ; and tribute and retain the active ingredient over the mucosal membranes within the nasal cavity and, if appropriate, the 0010) (b) a water-soluble C-C alkyl-cellulose deriva nasolacrimal canal. The distribution and retention properties tive, such as HPMC. of a pharmaceutical composition over a mucosal membrane are hereafter generally referred to as the mucoadhesive 0011. In the preparation of the pharmaceutical composi properties of the composition. tion, once all the ingredients have been mixed and dissolved, the final solution is disclosed to be filtered through a mesh 0003. The mucoadhesive properties of a pharmaceutical screen of approximately 50 um. composition are of great interest to pharmaceutical formu lators and drug delivery Scientists, as they can contribute to 0012. The HPMC-based pharmaceutical compositions the controlled release of the active ingredient on the mucosal prepared in accordance with the preparation processes dis membranes. closed in the above documents are difficult to formulate to a consistent level of mucoadhesion, particularly as the 0004) The term “adhesion” refers to the intermolecular mucoadhesive properties of a specific composition can vary forces which hold matter together, particularly contiguous quite considerably from one temperature to another. More Surfaces of neighbouring media. An “adhesive' is a Sub over, the known HPMC-based pharmaceutical compositions stance capable of joining two materials by adhesion. "Bio adhesion' implies that at least one of the two materials is of tend to demonstrate instability of mucoadhesion over an biological origin. When one surface is the adherent mucus extended period of time. layer covering the mucosal epithelia, the term “mucoadhe 0013. It is known that bacteria, which generally have a sion' is used. Mucoadhesion is specific type of bioadhesion, size in the range of from 0.2 to 600 um, can be removed from not a synonym thereof. Mucoadhesive materials may be pharmaceutical preparations, or components thereof, to ren useful to provide prolonged adhesion, and so improved der them sterile by passing them through a Sub-micron filter, efficacy, of pharmaceutically active ingredients on mucosal for example as disclosed in US-A-2005058699. tissue. 0014. It is an object of the present invention to produce 0005) Hydroxypropyl methyl cellulose (HPMC) is used aqueous pharmaceutical compositions to a consistent level in aqueous pharmaceutical compositions for the nasal of mucoadhesion. administration of various pharmaceutically active ingredi ents. In these applications, the HPMC is being used to 0015. It is a further object of the present invention to prolong the adhesion of the active ingredient on the mucosal provide aqueous pharmaceutical compositions with membranes. Examples of prior art publications include U.S. improved mucoadhesive stability. Pat. No. 4,603,131, WO-A-03070213 and WO-A- 0016. In accordance with a first aspect of the present 99.038492. invention there is provided a method for the preparation of 0006 U.S. Pat. No. 4,603,131 discloses a composition an aqueous pharmaceutical composition comprising: for preventing and treating irritation of the mucous mem 0017 a) 0.005 to 10% by wit, preferably 0.01 to 5% by wit, branes of the nose, the composition comprising a tricyclic more preferably 0.25 to 2.5 wt %, most preferably 0.25 to anti-depressant in combination with a vasoconstrictor. 1.5% by wt of one or more water-soluble pharmaceuti HPMC is disclosed as a possible viscosity agent. Other than cally active ingredients or pharmaceutically acceptable describing the compositions of the worked examples as salts thereof. Such as a water-soluble pharmaceutically having been prepared at room temperature by conventional active ingredient or salt thereof selected from vasocon mixing techniques, this document provides no details of the strictors, antiallergic agents, antiemetics, bronchodilators, preparation techniques employed. antiseptics, local anesthetics, cytostatics, analgesics (nar 0007 WO-A-03-70213 discloses a liquid mucoadhesive cotic and non-narcotic), Steroidal and non-steroidal anti pharmaceutical composition containing a pharmaceutically inflammatories, topical antibiotics, antiparasitics, antibac US 2007/01 04791 A1 May 10, 2007

terials, anticonvulsants, antispasmodics and administration. The compositions should be presented in a anticholinergics, antifungals, antivirals, antidiabetics, format Suitable for appropriate administration, as would be antimigraines, hormones, sedatives, antianaphylactics, understood by a person skilled in the art. For example, the beta-adrenoceptor agonists, diagnostic drugs, and vac composition may be administered as one or more drops (e.g. cines; for nasal, ocular or oral administration), as a spray (e.g. for b) from 0.01 to 10% by wit, preferably from 0.05 to 5% by nasal or oral inhalatory administration), as an injectable wit, more preferably 0.1 to 5% by wit, most preferably 0.1 liquid (e.g. for oral, rectal or vaginal administration), or as to 2% by wit, hydroxypropyl methyl cellulose, having a a mouthwash or thin syrup (for oral administration). viscosity of from 2500 to 5500 cps (mPas), preferably 0025. Whilst a person skilled in the art would expect more than 3000 to less than 5000 cps (mPas), more aqueous pharmaceutical compositions made with HPMC to preferably from 3200 to 4800 cps (mPa's), (Ubbelohde, 2 demonstrate excellent mucoadhesive properties, it has been wt % solution in water, 20°C., in accordance with United found that the compositions made by the process of the first States Pharmacopoeia, hereafter "USP), and c) a buffer aspect of the present invention demonstrate Surprisingly for maintaining the pH of the aqueous pharmaceutical consistent mucoadhesive properties in comparison to simi composition from 5 to 7, wherein the method comprises: larly formulated compositions which are either not filtered or are filtered through a sieve having a mesh size signifi 0018 i) dissolving the above components in water to cantly greater than 10 microns. Further, the compositions of form an aqueous Solution, and the present invention retain their mucoadhesive properties 0.019 ii) filtering the aqueous solution formed in i) for Surprisingly longer than similarly formulated composi through a sieve to form an aqueous pharmaceutical com tions which have not been filtered or which have been position; filtered with larger mesh sizes. 0026. It is believed that the above benefits of the present characterised in that the sieve through which the aqueous invention will, to a greater or lesser extent, be demonstrated solution is filtered has a mesh size from 21 micron but for all water Soluble pharmaceutically active ingredients. s 10 microns, preferably from 1.5 to 5 microns, most However, it is preferred that the pharmaceutically active preferably 2 to 4 microns, e.g. 3 microns. ingredients employed in the present invention are water 0020. In accordance with another aspect of the present soluble vasoconstrictors, antiallergic agents, antiemetics, invention there is provided an aqueous pharmaceutical com bronchodilators, antiseptics, local anesthetics, cytostatics, position comprising: analgesics (narcotic and non-narcotic), steroidal and non steroidal anti-inflammatories, topical antibiotics, antipara 0021) a) 0.005 to 10% by wit, preferably 0.01 to 5% by wit, sitics, antibacterials, anticonvulsants, antispasmodics and more preferably 0.25 to 2.5 wt %, most preferably 0.25 to anticholinergics, antifungals, antivirals, antidiabetics, anti 1.5% by wt of one or more water-soluble pharmaceuti migraines, hormones, sedatives, antianaphylactics, beta cally active ingredient or pharmaceutically acceptable salt adrenoceptor agonists, diagnostic drugs, and vaccines. thereof Suitable for nasal administration, such as one or more water soluble pharmaceutically active ingredients 0027. In the present invention, suitable water-soluble Selected from vasoconstrictors, antiallergic agents, anti vasoconstrictors may be selected from Xylometazoline e.g. emetics, bronchodilators, antiseptics, local anesthetics, Xylometazoline hydrochloride, Xylometazoline, indanaZo cytostatics, analgesics (narcotic and non-narcotic), Steroi line, , e.g. naphazoline hydrochlo dal and non-steroidal anti-inflammatories, topical antibi ride, e.g. fenoxazoline hydrochloride, otics, antiparasitics, antibacterials, anticonvulsants, anti e.g. oxymetazoline hydrochloride, tetrahy spasmodics and anticholinergics, antifungals, antivirals, drozoline, , , e.g. phe antidiabetics, antimigraines, hormones, sedatives, anti nylephrine hydrochloride, e.g. d- anaphylactics, beta-adrenoceptor agonists, diagnostic hydrochloride, or epinephrine. Preferably, the water-soluble active ingredient is selected from Xylometazoline, e.g. drugs, and Vaccines: Xylometazoline hydrochloride, and oxymetazoline, e.g. 0022 b) from 0.01 to 10% by wit, preferably from 0.05 to oxymetazoline hydrochloride. In one embodiment of this 5% by wit, more preferably 0.1 to 5% by wit, most invention, the water-soluble active ingredient is Xylometa preferably 0.1 to 2% by wit, hydroxypropyl methyl cel Zoline, e.g. Xylometazoline hydrochloride. lulose, having a viscosity of from 2500 to 5500 cps 0028. In the present invention, suitable water soluble (mPas), preferably more than 3000 to less than 5000 cps antiallergic agents may be selected from (1) cromoglycic (mPas), more preferably from 3200 to 4800 cps (mPas), acid or a pharmaceutically acceptable salt thereof, e.g. (Ubbelohde, 2 wt % solution in water, 20° C., in accor disodium cromoglycate), or (2) H1 receptor antagonists, dance with USP), and Such as dimethindene or a pharmaceutically acceptable salt 0023 c) a buffer for maintaining the pH of the aqueous thereof, e.g. dimethindene maleate, acrivastine, , pharmaceutical composition from 5 to 7. brompheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, bromodiphenhydramine, clemastine, phenyl wherein the composition is obtainable or obtained by the toloxamine, piprinhydrinate, pyrilamine, tripelennamine, method of the first aspect of the invention. cetirizine, levocetirizine, hydroxy Zine, methdilazine, 0024. The pharmaceutical compositions made by the promethazine, trimeprazine, azatadine, cyproheptadine, process of the present invention are solutions, thereby ren loratadine, desloratadine, astemizole, diphenhydramine, or dering them Suitable for administration to mucosal epithelia. orterfenadine. Typically, the compositions are for oral e.g. inhalatory, 0029. In the present invention, suitable water soluble Sublingual or peridontal, ocular, nasal, rectal, or vaginal anti-inflammatories include the steroidal anti-inflammato US 2007/01 04791 A1 May 10, 2007

ries e.g. corticosteroids, Such as those corticosteroids 0047. In the present invention, suitable water-soluble selected from beclomethasone e.g. beclomethasone dipropi vaccines include for immunotherapy and oral onate, and e.g. , and non bacterial vaccines used as immunomodulators. steroidal anti-inflammatories e.g. diclofenac and celecoxib. 0048. In the present invention, all the water soluble active 0030. In the present invention, suitable water soluble ingredients which are capable of Salt formation may be antiemetics may be selected from metoclopramide Such as present in the pharmaceutical composition either in free metoclopramide hydrochloride, ondansetron, granisetron, form or in the form of a pharmaceutically acceptable salt. dronabinol, prochloperazine and chlorpromazine. In one 0049. In the present invention, mixtures of more than one embodiment of this invention, the water-soluble active water soluble active ingredient may be employed in the ingredient is metoclopramide Such as metoclopramide pharmaceutical composition, e.g. a combination of a vaso hydrochloride. constrictor and an antiallergic agent, Such as Xylometazoline 0031. In the present invention, suitable water-soluble plus cromoglycic acid or phenylephrine plus dimethindene, narcotic and non-narcotic analgesics include e.g. morphine, or a combination of a vasoconstrictor and a , hydromorphine, pentazocine, and acetaminophen. Such as Xylometazoline plus beclomethasone. 0050. In the present invention, the water-soluble pharma 0032. In the present invention, suitable water-soluble ceutically active ingredient is preferably selected from one anesthetics include local anesthetics such as lidocaine, or more of Xylometazoline, indanazoline, metizoline, nap pramoxine, and benzocaine. haZoline, fenoxazoline, oxymetazoline, tetrahydrozoline, 0033. In the present invention, suitable water-soluble tramaZoline, tymazoline, phenylephrine, ephedrine, epi topical antibiotics include and bacitracin. nephrine, cromoglycic acid, dimethindene, acrivastine, aZelastine, brompheniramine, chlorpheniramine, dexchlor 0034. In the present invention, suitable water-soluble pheniramine, triprolidine, bromodiphenhydramine, clemas antiparasitics include metronidazole and quinolines. tine, phenyltoloxamine, piprinhydrinate, pyrilamine, tripe 0035) In the present invention, suitable water-soluble lennamine, cetirizine, levocetirizine, hydroxy Zine, antibacterials include tetracycline, erythromycin, quinolone methdilazine, promethazine, trimeprazine, azatadine, cypro antibacterials, and azithromycin. heptadine, loratadine, desloratadine, astemizole, diphenhy dramine, levocabastine, terfenadine, beclomethasone, fluti 0036). In the present invention, suitable water-soluble CaSOne, diclofenac, celecoxib, metoclopramide, anticonvulsants include phenyloin, gabapentin, phenobar ondansetron, granisetron, dronabinol, prochloperazine, bital and carbamazepine. chlorpromazine, morphine, hydromorphine, pentazocine, acetaminophen, lidocaine, pramoxine, benzocaine, neomy 0037. In the present invention, suitable water-soluble cin, bacitracin, metronidazole, tetracycline, erythromycin, antispasmodics and anticholinergics include atropine and quinolone antibacterials, azithromycin, phenyloin, gabapen Scopolamine. tin, phenobarbital, carbamazepine, atropine, Scopolamine, miconazole, econazole, terconazole, acyclovir, behenyl 0038. In the present invention, suitable water-soluble alcohol, glipizide, glyburide, Sumatriptan, ergotamine, insu antifungals include miconazole, econazole and terconazole. lin, Steroidal hormones, calcitonin, melatonin, tissue growth 0039. In the present invention, suitable water-soluble factors, barbiturates, benzodiazepines, , epineph antivirals include acyclovir and behenyl alcohol. rine, salbutamol/albuterol, fenoterol, clenbuterol, salme terol, formoterol, phenolsulfonphthalein, Dye T-1824, vital 0040. In the present invention, suitable water-soluble dyes, potassium ferrocyanide, Secretin, pentagastrin, cer antidiabetics include glipizide and glyburide. ulean, allergens for immunotherapy and oral bacterial vac 0041. In the present invention, suitable water-soluble cines used as immunomodulators, or a pharmaceutically antimigraines include Sumatriptan and ergotamine. acceptable salt thereof. 0051) The hydroxypropyl methyl cellulose (HPMC) 0042. In the present invention, suitable water-soluble employed in the present invention must be of a grade which hormones include insulin, Steroidal hormones, calcitonin, itself has a viscosity of from 2500 to 5500 cps (mPas). melatonin and tissue growth factors. Preferably, the HPMC has a viscosity of more than 3000 to less than 5000 cps (mPas), more preferably from 3200 to 0043. In the present invention, suitable water-soluble 4800 cps (mPas), e.g. 4000 cps (mPas). Viscosity of the sedatives include barbiturates and benzodiazepines. HMPC is measured using an Ubbelohde viscometer on a 2 0044) In the present invention, suitable water-soluble wt % solution in water at 20° C., in accordance with USP. antianaphylactics include adrenaline and epinephrine. Suitable grades of HPMC materials which achieve the specified viscosities are well know to those skilled in art and 0045. In the present invention, suitable water-soluble are commercially available from various sources such Dow, beta-adrenoceptor agonists include ephedrine Hydrochlo Hercules, JRS and Ronas Chemicals. ride, salbutamol/albuterol, fenoterol, clenbuterol, salmeterol and formoterol. 0052 A buffer is employed in the present invention to maintain the pH of the pharmaceutical composition in the 0046. In the present invention, suitable water-soluble range of from 5 to 7, preferably from 6 to 7, e.g. pH 6.6. diagnostic drugs include phenolsulfonphthalein, Dye Typical buffers which may be employed in the composition T-1824, Vital dyes, potassium ferrocyanide, Secretin, penta include disodium phosphate dodecahydrate and Sodium gastrin and cerulean. dihydrogen phosphate dihydrate. The amount of buffer US 2007/01 04791 A1 May 10, 2007

employed should be sufficient to retain the pH of the fenoxazoline hydrochloride, oxymetazoline e.g. oxymetazo composition within the specified range. For example, the line hydrochloride, tetrahydrozoline, tramaZoline, tymazo amount of buffer may be from 0.1 to 1% by wt. Preferably, line, phenylephrine e.g. phenylephrine hydrochloride, ephe a phosphate buffer pH 6.6 (USP23) is employed. drine e.g. d-pseudoephedrine hydrochloride, or epinephrine. The water soluble vasoconstrictor is most preferably Xylom 0053. In the present invention, the pharmaceutical com etazoline e.g. Xylometazoline hydrochloride. The water position may include a chelating agent, such as the disodium soluble antiallergic agent is preferably selected from (1) salt of ethylene diamine tetraacetic acid (hereafter EDTA). cromoglycic acid or a nasally acceptable salt thereof, e.g. The amount of chelating agent may be from 0.01 to 10% by disodium cromoglycate), or (2) H1 receptor antagonists, wit, preferably 0.1 to 5% by wit, more preferably 0.1 to 1% Such as dimethindene or a nasally acceptable salt thereof, by wt. The EDTA can also act as a preservative in the e.g. dimethindene maleate, acrivastine, brompheniramine, pharmaceutical composition. chlorpheniramine, dexchlorpheniramine, triprolidine, bro 0054. In the present invention, the pharmaceutical com modiphenhydramine, clemastine, phenyltoloxamine, piprin position may include an isotonicity regulator. Such as hydrinate, pyrilamine, tripelennamine, azelastine, cetirizine, Sodium chloride. The isotonicity regulator may be present in levocetirizine, hydroxy Zine, methdilazine, promethazine, the composition in an amount of from 0.01 to 5% by wit, trimeprazine, azatadine, cyproheptadine, loratadine, deslo preferably from 0.1 to 1% by wt. ratadine, astemizole, diphenhydramine, levocabastine orter 0055. In the present invention, the pharmaceutical com fenadine. The water soluble corticosteroid is preferably position may comprise one or more other components, e.g. selected from beclomethasone e.g. beclomethasone dipropi preservatives, such as benzalkonium chloride, and crystal onate, and fluticaSone e.g. fluticasone propionate. The water lisation inhibitors, such as sorbitol. However, it is preferred soluble antiemetic is preferably metoclopramide e.g. meto that the composition is free of benzalkonium chloride. It is clopramide hydrochloride. The active ingredient may also preferred that the composition is free of sorbitol. It is comprise a mixture of more than one water soluble active even more preferred that the composition is free of both ingredient. benzalkonium chloride and sorbitol. 0063. The aqueous nasal pharmaceutical composition 0056. According to one particular embodiment, the may include disodium phosphate dodecahydrate and/or present invention provides a method for the preparation of Sodium dihydrogen phosphate dihydrate as a buffering an aqueous nasal pharmaceutical composition comprising: agent. 0057) a) 0.005 to 10% by wit, preferably 0.01 to 5% by wit, 0064. The aqueous nasal pharmaceutical composition more preferably 0.25 to 2.5 wt %, most preferably 0.25 to may include a chelating agent, such as the disodium salt of 1.5% by wt of one or more water-soluble pharmaceuti ethylene diamine tetraacetic acid. cally active ingredients suitable for nasal administration; 0065. The aqueous nasal pharmaceutical composition may include an isotonicity regulator, Such as Sodium chlo 0.058 b) from 0.01 to 10% by wit, preferably from 0.05 to ride. 5% by wit, more preferably 0.1 to 5% by wit, most preferably 0.1 to 2% by wit, hydroxypropyl methyl cel 0066. The aqueous nasal pharmaceutical composition is lulose having a viscosity of from 2500 to 5500 cps preferably free of a preservative which is not also a chelating (mPas), preferably more than 3000 to less than 5000 cps agent. (mPas), more preferably from 3200 to 4800 cps (mPas), 0067. The composition may also contain other ingredi and ents commonly found in nasal pharmaceutical compositions. 0059 c) a buffer for maintaining the pH of the aqueous 0068. In the present invention, the aqueous nasal phar pharmaceutical composition at from 5 to 7, maceutical composition is preferably provided in a form wherein the method comprises: Such that it can be administered as one or more drops or as a Spray. 0060 i) dissolving the above components in water to form an aqueous Solution, and 0069. In the present invention, the composition to be filtered can be prepared as a solution using conventional 0061 ii) filtering the aqueous solution formed in i) mixing and dissolution techniques. The solution is then through a sieve to form an aqueous nasal pharmaceutical filtered through a sieve with a mesh of the above specified composition; size using conventional filtering techniques. characterised in the that the sieve through which the aqueous 0070 The invention shall now be illustrated by way of solution is filtered has a mesh size from 21 micron but the following worked examples and with reference to the s 10 microns, preferably from 1.5 to 5 microns, most drawing, which examples are not intended to be limiting preferably 2 to 4 microns, e.g. 3 microns. upon the scope of the invention. 0062. In this particular embodiment, the water soluble 0071 FIG. 1 is a view of apparatus used in Example 8. pharmaceutically active ingredient is preferably selected EXAMPLE 1. from vasoconstrictors, antiallergic agents, antiemetics, bron chodilators, antiseptics, anesthetics, cytostatics and corticos Method for Preparation of Pharmaceutical teroids. The water-soluble vasoconstrictor is preferably Composition Comprising 10 mg/g Xylometazoline selected from Xylometazoline e.g. Xylometazoline hydro Hydrochloride chloride, Xylometazoline, indanazoline, metizoline, nap 0072 A pharmaceutical composition having the formu haZoline e.g. naphazoline hydrochloride, fenoxazoline e.g. lation set out in Table 1 below was prepared substantially in US 2007/01 04791 A1 May 10, 2007

accordance with the disclosure of Example 2 of WO-A- in Examples 2-7 Solution C was filtered through a 3 micron O3O70213. sieve, whereas in Examples 2"-7" Solution C was not filtered.

EXAMPLE 8

Components % by wt Method for Examination of the Relative Adhesive HPMC (Grade 4000 cps (mPa s)) 0.75 Capacity of Pharmaceutical Compositions 2-7 and Nal EDTA O.S 2-7 Xylometazoline hydrochloride O.1 NaCl O.38 0078. The relative adhesive capacity of the pharmaceu Phosphate Buffer pH 6.6 (US Pharmacopoeia 23) Balance to 100 tical compositions prepared in each of Example 2-7 and 2-7 was determined by the testing procedure for Solutions set out 0073. Accordingly, to 98.27 parts by wt. of an aqueous in Example 8 of WO-A-03070213. Using the apparatus phosphate buffer solution with a pH 6.6 at 20° C., is added described in Example 8 and illustrated in FIG. 1, the testing 0.38 parts by wt NaCl, continuously mixing with a magnetic procedure was repeated except that the polymer Solutions mixer (1000 rp.m.) for 10 min. After that the solution is evaluated in WO-A-03070213 were replaced by the filtered heated to 50° C. Then 0.75 parts by witHPMC (grade 4000 or unfiltered pharmaceutical solutions of Examples 2-7 and cps) is mixed with 0.50 parts by wt EDTA-disodium salt. 2.7'. The mixture is added in small quantities to the 15 parts of the 0079 The apparatus used in the evaluation comprises a buffer solution, continuously mixing at 1000 rp.m. The microbalance 1 including raising/lowering screw 2, calibra mixing is continued for 10 min. at 50° C., and then gradually tion screw 3, and a microforce balance 4. cooled to 20° C. over the next 3 hours. The obtained gel is 0080. In summary, and with reference to FIG. 1 hereof, left for 24 hours at 18-20°C. The gel is diluted by addition the pharmaceutical solution which is going to be tested is of 68.65 parts by wt. buffer at 20° C. under continuous placed into a 15 ml glass vial 6, maintained at a constant stirring at 1000 rp.m. and then continuously stirred for a temperature by water bath 7. A glass plate 5 is covered with further 30 min. to provide Solution A. a gelatin film, which acts as a reference polymer imitating 0074 Xylometazoline hydrochloride (0.1 parts by wt) is the mucus in the nasal cavity. The pharmaceutical Solutions dissolved in 15 parts by wt of the phosphate buffer at 20°C. are tested for adhesion. The plate (18x18 mm) 5 is sus by continuous stirring at 1000 rp.m. and then continuously pended from a microforce balance 4 (WAGATORSJJNA stirred for a further 10 min. to provide Solution B. WT. Techniport, Poland). Using screw 2, the plate 5 is 0075 Solution B is added to Solution A at 20° C. while immersed in the 15 ml glass vial 6 filled with the test continuously stirring at 1000 rp.m. and then continuously solution. After a defined time for contact (5 min), the plate stirred for a further 10 min. The resultant solution from the is raised gradually, using screw 2. The force required for mixing of Solution A and Solution B is complemented to 100 detachment of the plate from the Solution is measured using parts by weight of distilled water, if necessary, and the device 4 and shown on Scale 8. The maximum force required bubbles removed with stirring (500 rp.m.) under lowered to draw the plate out of the solution is considered to relate pressure to provide Solution C. to the adhesive force between the pharmaceutical solution and the mucus. As a standard, the clean plate is tested before 0.076 Solution C is then filtered through a 3 um sieve to and after coating with the polymer. The force for detachment provide a pharmaceutical composition of the present inven of the coated plate is expressed as a percentage of the clean tion. plate detachment force, i.e. the results have relative values. EXAMPLES 2-7 AND 2-7 0081. The polymer film was prepared by dropping 0.5 ml of a 1% solution of gelatin and spreading it over the whole Method for Preparation of Pharmaceutical plate surface. After a 24h period (at 20-22 C), necessary for Composition Comprising 2, 3, 6, 8, 10 and 15 forming a smooth film on a leveled Surface, the film was oven-dried at 40°C. to a constant weight. The films obtained mg/g HPMC were uniform and exhibited a good reproducibility of their 0.077 Examples 2-7 and 2-7 were prepared according to weight (sdz5%). the method set out above for Example 1, except that the amount of HPMC was varied to provide pharmaceutical 0082) The tests were carried out at 20, 25, 30 and 37° C. compositions having the specified level of HPMC. Further, 0083) The results of the tests are shown in Table 2.

Relative adhesive capacity (%) of HPMC 4000 solutions (mean isd Example No. Concentration (mg/g) 20° C. 25o C. 30° C. 37o C. HPMC 4000 through 3 m filter

2.2 104.1 3.03 118.9 6.23 93.5 - 1.4 87.8 1.93 3.3 111.9 4.61 122.7 4.24 105.7 2.6 101.1 2.83 US 2007/01 04791 A1 May 10, 2007

-continued

Relative adhesive capacity (%) of HPMC 4000 solutions (mean isd Example Nof Concentration (mg/g) 20° C. 25o C. 30° C. 37 o C.

46 114.3 3.53 125.0 - 7.07 108.2 4.24 101.2 - 2.73 5.8 113.6 3.21 123.24.69 107.0 2.83 100.7 - 141 6.10 111.4 2.93 120.4 4.16 102.0 - 3.21 93.2 228 7/15 1394 4.95 128.2 4.24 97.3 - 1.67 822 - 1.68 HPMC 4000 without filtering

2'2 98.2 404 113.5 - 8.69 88.3 - 3.14 87.5 - 3.78 3'3 100.7 6.95 109.2 6.12 95.1 4.97 98.1 - 4:19 46 107.5 - 5.9 117.0 8.5S 93.7 S.12 98.4 4.619 5'8 106.5 - 6.13 116.0 - 6.18 98.1 6.46 94.7 - 4.31 6'10 107.25.81 115.0 - 7.32 99.0 - 544 84.O 5.2 7'? 15 111.1 - 7.47 108.4 8.93 95.2 5.96 70.2 S.83

0084. The results of Table 2 illustrate that filtering the graines, hormones, sedatives, antianaphylactics, beta Solution in accordance with the present invention (Examples adrenoceptor agonists, diagnostic drugs, and vaccines. 2-7) provides pharmaceutical Solutions having consistent 3. A method as claimed in claim 1, wherein the pharma relative adhesive capacities. These improved results will be ceutically active ingredient is a water-soluble vasoconstric found by filtering solutions through sieves up to 10 micron. tor selected from Xylometazoline, indanazoline, metizoline, Filtering the solutions through sieves above 10 um does not naphazoline, fenoxazoline, oxymetazoline, tetrahydrozo cause any improvement in consistency in the reproducibility line, tramazoline, tymazoline, phenylephrine, ephedrine and of relative adhesive capacities. epinephrine. 0085. Further, it will be noted that the compositions of 4. A method as claimed in claim 1, wherein the pharma Examples 2-7 will retain their relative adhesive capacities ceutically active ingredient is a water-soluble antiallergic for longer than the unfiltered compositions 2'-7", when left to agent selected from (1) cromoglycic acid, or (2) H1 receptor stand without stirring at 20° C. for up to 18 months. antagonists. 5. A method as claimed in claim 1, wherein the pharma ceutically active ingredient is a water-soluble steroidal or 1. A method for the preparation of an aqueous pharma non-steroidal anti-inflammatory selected from corticoster ceutical composition comprising: oids, diclofenac and celecoxib. a) 0.005 to 10% by wt of one or more water-soluble 6. A method as claimed in claim 1, wherein the pharma pharmaceutically active ingredients or pharmaceuti ceutically active ingredient is a water-soluble antiemetic cally acceptable salts thereof; selected from metoclopramide, ondansetron, granisetron, dronabinol, prochloperazine and chlorpromazine. b) from 0.01 to 10% by wt hydroxypropyl methyl cellu 7. A method as claimed in claim 1, wherein the pharma lose, having a viscosity of from 2500 to 5500 cps ceutically active ingredient is a water-soluble narcotic and (mPas); and non-narcotic analgesic selected from morphine, hydromor c) a buffer for maintaining the pH of the aqueous phar phine, pentazocine, and acetaminophen. 8. A method as claimed in claim 1, wherein the pharma maceutical composition from 5 to 7: ceutically active ingredient is a water-soluble anesthetic wherein the method comprises: selected from lidocaine, pramoxine and benzocaine. 9. A method as claimed in claim 1, wherein the pharma i) dissolving the above components in water to form an ceutically active ingredient is a water-soluble topical anti aqueous solution; and biotic selected from neomycin and bacitracin. ii) filtering the aqueous solution formed in i) through a 10. A method as claimed in claim 1, wherein the phar sieve to form an aqueous pharmaceutical composition; maceutically active ingredient is a water-soluble antipara sitic selected from metronidazole and quinolines. characterised in that: 11. A method as claimed in claim 1, wherein the phar the sieve through which the aqueous solution is filtered maceutically active ingredient is a water-soluble antibacte has a mesh size from e1 micron but is 10 microns. rial selected from tetracycline, erythromycin, quinolone 2. A method as claimed in claim 1, wherein the one or antibacterials, and azithromycin. more water-soluble pharmaceutically active ingredients or 12. A method as claimed in claim 1, wherein the phar pharmaceutically acceptable salts thereof is selected from maceutically active ingredient is a water-soluble anticonvul Vascoconstrictors, antiallergic agents, antiemetics, bron sant selected from phenyloin, gabapentin, phenobarbital and chodilators, antiseptics, local anesthetics, cytostatics, anal carbamazepine. gesics (narcotic and non-narcotic), Steroidal and non-steroi 13. A method as claimed in claim 1, wherein the phar dal anti-inflammatories, topical antibiotics, antiparasitics, maceutically active ingredient is a water-soluble antispas antibacterials, anticonvulsants, antispasmodics and anticho modic or anticholinergic selected from atropine and Scopo linergics, antifungals, antivirals, antidiabetics, antimi lamine. US 2007/01 04791 A1 May 10, 2007

14. A method as claimed in claim 1, wherein the phar 25. A method for the preparation of an aqueous nasal maceutically active ingredient is a water-soluble antifungal pharmaceutical composition comprising: selected from miconazole, econazole and terconazole. 15. A method as claimed in claim 1, wherein the phar a) 0.005 to 10% by wit, preferably 0.01 to 5% by wit, more maceutically active ingredient is a water-soluble antiviral preferably 0.25 to 2.5 wt %, most preferably 0.25 to include acyclovir and behenyl alcohol. 1.5% by wt of one or more water-soluble pharmaceu 16. A method as claimed in claim 1, wherein the phar tically active ingredients suitable for nasal administra maceutically active ingredient is a water-soluble antidiabetic tion; selected from glipizide and glyburide. b) from 0.01 to 10% by wit, preferably from 0.05 to 5% by 17. A method as claimed in claim 1, wherein the phar wit, more preferably 0.1 to 5% by wit, most preferably maceutically active ingredient is a water-soluble antimi 0.1 to 2% by wit, hydroxypropyl methyl cellulose graine selected from Sumatriptan and ergotamine. having a viscosity of from 2500 to 5500 cps (mPas), 18. A method as claimed in claim 1, wherein the phar preferably more than 3000 to less than 5000 cps maceutically active ingredient is a water-soluble hormones (mPa's), more preferably from 3200 to 4800 cps selected from insulin, steroidal hormones, calcitonin, mela (mPas), and tonin and tissue growth factors. c) a buffer for maintaining the pH of the aqueous phar 19. A method as claimed in claim 1, wherein the phar maceutically active ingredient is a water-soluble sedatives maceutical composition at from 5 to 7. selected from barbiturates and benzodiazepines. wherein the method comprises: 20. A method as claimed in claim 1, wherein the phar maceutically active ingredient is a water-soluble antiana i) dissolving the above components in water to form an phylactic selected from adrenaline and epinephrine. aqueous solution, and 21. A method as claimed in claim 1, wherein the phar ii) filtering the aqueous Solution formed in i) through a maceutically active ingredient is a water-soluble beta sieve to form an aqueous nasal pharmaceutical com adrenoceptor agonists selected from ephedrine hydrochlo position; ride, salbutamol/albuterol, fenoterol, clenbuterol, salmeterol and formoterol. characterised in the that the sieve through which the 22. A method as claimed in claim 1, wherein the phar aqueous solution is filtered has a mesh size from 21 maceutically active ingredient is a water-soluble diagnostic micron but s 10 microns, preferably from 1.5 to 5 drug selected from phenolsulfonphthalein, Dye T-1824, vital microns, most preferably 2 to 4 microns, e.g. 3 microns. dyes, potassium ferrocyanide, Secretin, pentagastrin and 26. A method as claimed in claim 25, wherein the water cerulean. soluble pharmaceutically active ingredient is selected from 23. A method as claimed in claim 1, wherein the phar Vascoconstrictors, antiallergic agents, antiemetics, bron maceutically active ingredient is a water-soluble vaccine. chodilators, antiseptics, anesthetics, cytostatics and corticos 24. A method as claimed in claim 1, wherein the water teroids. soluble pharmaceutically active ingredient is selected from 27. A method as claimed in claim 26, wherein the water one or more of Xylometazoline, indanazoline, metizoline, soluble vasoconstrictor is selected from Xylometazoline e.g. naphazoline, fenoxazoline, oxymetazoline, tetrahydroZo Xylometazoline hydrochloride, indanazoline, metizoline, line, tramaZoline, tymazoline, phenylephrine, ephedrine, naphazoline e.g. naphazoline hydrochloride, fenoxazoline epinephrine, cromoglycic acid, dimethindene, acrivastine, e.g. fenoxazoline hydrochloride, oxymetazoline e.g. aZelastine, brompheniramine, chlorpheniramine, dexchlor oxymetazoline hydrochloride, tetrahydrozoline, tramaZo pheniramine, triprolidine, bromodiphenhydramine, clemas line, tymazoline, phenylephrine e.g. phenylephrine hydro tine, phenyltoloxamine, piprinhydrinate, pyrilamine, tripe chloride, ephedrine e.g. d-pseudoephedrine hydrochloride, lennamine, cetirizine, levocetirizine, hydroxy Zine, or epinephrine. methdilazine, promethazine, trimeprazine, azatadine, cypro 28. A method as claimed in claim 25, wherein the water heptadine, loratadine, desloratadine, astemizole, diphenhy soluble active ingredient is selected from Xylometazoline, dramine, levocabastine orterfenadine, beclomethasone, flu e.g. Xylometazoline hydrochloride, oxymetazoline, e.g. ticasone, diclofenac, celecoxib, metoclopramide, oxymetazoline hydrochloride, and metoclopramide, e.g. ondansetron, granisetron, dronabinol, prochloperazine, metoclopramide hydrochloride. chlorpromazine, morphine, hydromorphine, pentazocine, 29. A method as claimed in claim 28, wherein the water acetaminophen, lidocaine, pramoxine, benzocaine, neomy soluble active ingredient is Xylometazoline e.g. Xylometa cin, bacitracin, metronidazole, quinolines, tetracycline, Zoline hydrochloride. erythromycin, quinolone antibacterials, azithromycin, phe 30. A method as claimed in claim 26, wherein the water nyloin, gabapentin, phenobarbital, carbamazepine, atropine, soluble antiallergic agent is selected from (1) cromoglycic Scopolamine, miconazole, econazole, terconazole, acyclovir, acid or a nasally acceptable salt thereof, e.g. disodium behenyl alcohol, glipizide, glyburide, Sumatriptan, ergota cromoglycate), or (2) H1 receptor antagonists, such as mine, insulin, Steroidal harmones, calcitonin, melatonin, dimethindene or a nasally acceptable Salt thereof, e.g. dime tissue growth factors, barbiturates, benzodiazepines, adrena thindene maleate, acrivastine, brompheniramine, chlorphe line, epinephrine, salbutamol/albuterol, fenoterol, clen niramine, dexchlorpheniramine, triprolidine, bromodiphen buterol, salmeterol, formoterol, phenolsulfonphthalein, Dye hydramine, clemastine, phenyltoloxamine, piprinhydrinate, T-1824, Vital dyes, potassium ferrocyanide, Secretin, penta pyrilamine, tripelennamine, azelastine, cetirizine, levoceti gastrin, cerulean, allergens for immunotherapy and oral rizine, hydroxy Zine, methdilazine, promethazine, trimepra bacterial vaccines used as immunomodulators, or a pharma Zine, azatadine, cyproheptadine, loratadine, desloratadine, ceutically acceptable salt thereof. astemizole, diphenhydramine, levocabastine orterfenadine. US 2007/01 04791 A1 May 10, 2007

31. A method as claimed in claim 26, wherein the water b) from 0.01 to 10% by wit, preferably from 0.05 to 5% by soluble corticosteroid is selected from beclomethasone e.g. wit, more preferably 0.1 to 5% by wit, most preferably beclomethasone dipropionate, and fluticasone e.g. flutica 0.1 to 2% by wit, hydroxypropyl cellulose having a Sone propionate. viscosity of from 2500 to 5500 cps (mPa's), preferably 32. A method as claimed in claim 26, wherein the water more than 3000 to less than 5000 cps (mPas), more soluble antiemetic is metoclopramide e.g. metoclopramide preferably from 3200 to 4800 cps (mPa's), and hydrochloride 33. A method as claimed in claim 1, wherein the active c) a buffer for maintaining the pH of the aqueous phar ingredient comprises a mixture of more than one water maceutical composition at from 5 to 7. soluble active ingredient. wherein the composition is obtainable or obtained by the 34. A method as claimed in claim 1, wherein the phar method claimed in any one of the preceding claims. maceutical composition includes disodium phosphate 40. A method as claimed in claim 25, wherein the active dodecahydrate and/or sodium dihydrogen phosphate dihy ingredient comprises a mixture of more than one water drate. soluble active ingredient. 35. A method as claimed in claim 1, wherein the phar 41. A method as claimed in claim 25, wherein the phar maceutical composition includes a chelating agent, Such as maceutical composition includes disodium phosphate the disodium salt of ethylene diamine tetraacetic acid. dodecahydrate and/or sodium dihydrogen phosphate dihy 36. A method as claimed in claim 1, wherein the phar drate. maceutical composition includes an isotonicity regulator, 42. A method as claimed in claim 25, wherein the phar Such as Sodium chloride. maceutical composition includes a chelating agent, Such as 37. A method as claimed in claim 1, wherein the phar the disodium salt of ethylene diamine tetraacetic acid. maceutical composition is free of a preservative which is not 43. A method as claimed in claim 25, wherein the phar also a chelating agent. maceutical composition includes an isotonicity regulator, 38. A method as claimed in claim 1, wherein the hydrox Such as Sodium chloride. ypropyl methyl cellulose has a viscosity of from 2500 to 44. A method as claimed in claim 25, wherein the phar 5500 cps (mPas), preferably more than 3000 to less than maceutical composition is free of a preservative which is not 5000 cps (mPa's), more preferably from 3200 to 4800 cps also a chelating agent. (mPas). 45. A method as claimed in claim 25, wherein the hydrox 39. An aqueous pharmaceutical composition comprising: ypropyl methyl cellulose has a viscosity of from 2500 to a) 0.005 to 10% by wit, preferably 0.01 to 5% by wit, more 5500 cps (mPas), preferably more than 3000 to less than preferably 0.25 to 2.5 wt %, most preferably 0.25 to 5000 cps (mPa's), more preferably from 3200 to 4800 cps 1.5% by wt of one or more water-soluble pharmaceu (mPas). tically active ingredients or pharmaceutically accept able salt thereof;