SA05260262B1 - Use of aqueos medicament preparations for the production of propellent gas free aerosols - Google Patents

Abstract

Abstract: This invention relates to pharmaceutical preparations in the form of aqueous solutions for the production of propellent-free gas-aerosols.

Description

¥ Use of Aqueous Medicament Preparations for the Production of Propellent Gas-Free Aerosols 3 Use of Aqueous Medicament Preparations for the Production of Propellent Gas-Free Aerosols Full Description Background of the Invention 2 This invention is a partial application of the original application filed with Patent Office at King Abdulaziz City for Science and Technology No. 99718609757 dated 41/414 1H. The present invention relates to the use of pharmaceutical preparations in the form of aqueous solutions to produce 0 propellent-free aerosols for inhalation in the last twenty years; The use of metering aerosols has been known as a fixed part for the treatment of obstructive lung diseases, especially asthma. Fluorochlorohydrocarbons are used as repellant gases +10 6 m20 m. Realizing that these propellant gases may harm the ozone layer; Several attempts have been made to develop alternative solutions. One of these alternative solutions is the development of nebulizers 68, which are used to spray aqueous solutions of pharmacologically active substances under pressure, which leads to the production of a mist of inhalable ALE particles. The advantage of these nebulizers is In that no propellant gases are needed at all. vo These vaporizers have been described; For example; In Gay's International Patent Application PCT No. AVVEETA cited in this release for reference. In the nebulizers described here, active ingredient solutions of certain volumes containing active substances are sprayed; through small jets at high pressure; to produce aerosols

: v The micrometer is 01 micrometers that can be inhaled, with an average particle size range of ? To the Treaty by Description Another developed embodiment of the atomizers previously mentioned in the European patent + bearing the atomizer described in Figure AT 4701 (Cooperation Patent No.

Registered trademark - Respimat®

° and usually; Pharmaceutical preparations used for inhalation are dissolved in an aqueous or ethanolic solution. It may also be appropriate to use mixtures of water and ethanol solvents (Tabac) ethanol on the properties of the active substances in the solution.

Other components of the solvent may be used; In addition to water and/or ethanol (cothanol) and optionally 5 yal cosolvents, the pharmaceutical preparation may also contain 0 flavoring agents 5 and other pharmacological additives. Abd cosolvents include those compounds containing hydroxyl groups or other polar groups; Jia alcohols alcohols, particularly isopropylalcohol, and glycols, especially propylene glycol 7©0p0071606m » Polyethylene Glycol cpolyethyleneglycol Polypropylene glycol ¢polypropyleneglycol | 0 cglycolether, glycerol, polyoxyethylene alcohols and esters. Fatty acids for polyoxyethylene (-polyxoyethylene fatty acid esters) and (Akal) the use of co-solvents because they increase the solubility of the adjuvant material and the active ingredients if necessary. And the ratio of the dissolved pharmaceutical compound in the vulnerary pharmaceutical preparation ranges from (0) from (nee) to 776, preferably from 0.08 to IF, especially from 1-.. to IY (weight/volume) and the maximum concentration of the compound depends Pharmaceutical compounds for the treatment of respiratory diseases All suitable substances for inhalation that are soluble in the specified solvent may be used as pharmaceutical compounds in new preparations © Pharmaceutical compounds used for the treatment of respiratory diseases Of particular interest.therefore.; 1.4

In particular, cbetamimetics, anticholinergics 085, “cantiallergics,” antihistamines, and 5M steroids are used in addition to the use of combinations of these active ingredients. And he found; when performing several checks; The atomizer described above exhibits some spraying anomalies when aqueous pharmaceutical solutions (usually double distilled or demineralised (ion exchanged) water are used as the solvent) and exhibits anomalies. This Toa is used in the aerosol application method, so in severe cases the accuracy of the dose given to the patient cannot be guaranteed because of the change in the mean droplet size distribution (variation with respect to the fraction of aerosol Ve that can reach the lung). This spraying is particularly so when the sprayer is used intermittently Hin for three days Lyi or more between each use This abnormal spraying which in severe cases may lead to disruption of the yall can be caused by the presence of microscopic deposits in the Nozzle opening General description of the invention It was discovered surprisingly; that this spray anomaly does not appear fa when the aqueous pharmaceutical preparations to be sprayed contain a specified effective amount of a complexing agent and in particular EDTA ( ethylenediaminetetraacetic acid or its salts. The aqueous pharmaceutical preparations used [Lay of the invention] contain water as a solvent; However ethanol YT may be added as necessary to increase the solubility to a value not exceeding 7700 (by volume); © to 0 (by size) is preferred. Other pharmacological adjuvants may be added; Such as preservatives, especially benzalkonium chloride. The preferred amount of the preservative, especially cbenzalkonium chloride, ranges from A to VY Yo mg/100 ml of solution. Y.14

° The compounding agents suitable for use are 3 ke from those that are approved by the medical authorities. EDTA is c¢nitrilotriacetic acid citric acid. Citric acid, ascorbic acid and their salts are particularly suitable. In particular, the disodium salt of ethylenediaminetetraacitic acid is preferred, and the amount of compound-forming agent is chosen so that an effective amount is added to avoid any additional splashing dad. The effective amount of complex forming agent 1188018 ranges from 01 to Vere 0 mg/100 mL of solution; Especially from 0 to Os Ja 001/mgm 001 solution. The preferred range is from the amount of complex forming agent of YO VO mg/100 mL of solution; Especially from YO to 500 mg/100 mL of solution. The following named compounds can theoretically be used as active ingredients; either alone or in combination; In the pharmaceutical preparation ad, of the invention. and in isolated cases; Higher Vo ethanol or a solubilizer may need to be added to improve solubility. ctiotropium bromide bromide '-[(hydroxy Y = Al thinyl acetyl) SUA A=] us Michelle-+/-azonia octisene(7)-1?; ARPA is bicyclic .3-[(hydroxydi-2-thienylacetyl)oxy]-8, 8-dimethyl-8-azoniabicyclo[3,2,1] oct-6-ene-bromide and includes betamimetics. For example, the following are not limited to: Bambuterol Bitolterol Carbuterol Formoterol Clenbuterol Fenoterol Hexoprenaline Procaterol Tbuterol 21001801 Salmeterol Tulobuterol Reproterol Salbutamol Sulfonterol Terbutaline 1.4

1-(1-fluoro-;-hydroxyphenyl)-?-1?-(1-benzimidazolyl)-"-methyl-7-butyl[isd|ethanol 1-(2-fluoro-4-) hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2- <butylamino]ethanol erythro -* '-hydroxy-8'-(1-hydroxy-7-isopropyl aminobutyl) -1-117;-©benzoxazine-7-(014)-en erythro-5'-hydroxy-8'-(1-hydroxy-2-isopropylaminobutyl)-2H-¢1,4-benzoxazin-3 -(4H)-one (D0 5 AST sisal) fluoromethylphenyl)-7-th-butyl-amino) eschaol-14 amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butyl- amino)ethanol 1-(4-ethoxycarbonylamino-7-cyano-5-fluorophenyl)-?-(th-biogylamino) Ve ethanol _(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl) )-2-(tert-butylamino)ethanol 1 Sa anticholinergics include: ipratropium bromide oxitropium bromide trospium chloride VO methobromide 7 “7-beta N-B-fluorethylene nortropine benzylate .methobromide 5 steroids include, for example, the following: budesonide beclomethasone (or VY 17-dipropionate (17,21-dipropionate) Ye dexamethasone-1 "-isonicotinate dexamethasone-2 1-isonicotinate Flunisolide Flunisolide Se antiallergics include: disodium cromoglycate nedocromil 8 | Epinastine .epinastine

Y

Examples of 5E steroids that may be used as active ingredients in the pharmaceutical formulation within the scope of the present invention include: Seratrodast, Mycophenolate mofetil, Praniukast, Zileutone.

Budesonide Budesonide Butixocort Butixocort

Deflazacort Deflazacort

Promedrol Fluticasone Fluticasone

Tipredane Mometasone furoate Mometasone furoate

Icomethasone enbutate Beclomethasone, Douglas Beclomethasone; Douglas

Cloprednol Cloprednol Ciclometasone Cyclometasone

Halometasone Fluocortin butyl Fluocortin butyl

Alclometasone Deflazacort Deflazacort

Alisactide Ciclometasone Cyclomethasone Prednicarbate Hydrocortisone Butyrate Propionate

Hydrocortisone-butyrate propionate

Alclometasone- Tixocortol-pivalate Tixocortol-pivalate dipropionate

Canesten-HC 116- Canesten Lotrisone Fluticasone-propionate Fluticasone propionate Deprodone Halopredone-acetate Haloperidone liad Methylprednisolone Clg

Methylprednisolone-aceponate

Mometasone-furoate Mometasone furoate Mometasone Mometasone Hydrocortisone mometasone saponate

Hydrocortisone-aceponate

Aminoglutethimide Ulobetasol propionate Aminoglutethimide

A

Hydrocortisone Triamcinolone Fluorometholone Meprednisone Betamethasone Dexamethasone Fluchlorolone acetonide Medrysone Paramethasone-acetate Paramethasone acetate Fluocinolone acetonide fluocinolone

Aristocort- Aristocort diacetate Deprodone Propionate diacetate

Mazipredone Fluocinonide Fluocinonide Betamethasone valerate Betamethasone valerate Difluprednate Difluprednate Clomefazone propionate SD Dexamethasone Dexamethasone isonicotinate

Beclomethasone-Dipropionate isonicotinate

Formocortal Fluocortolone capronate Fluocortolone capronate

Cloprednol

Triamcinolone-Hexacetonide

Clobetasone Clobetazone Formebolone Flunisolide Flutisulide Endrisone Endrizone Fluazacort Fluzacort Halcinonide Halcinonide 17-Nozetrocordia Pipebuterate Clobetasol Hydrocortisone-17-Butyrate Fluocortin Diflorasone Diflurazone

Betamethasone Amcinonide Dipropionate Betamethasone Cortivazol Cortivazol Adamantoate Trilostane Fluodexane Fluodexan q

Clobetasone Clobetazone Budesonide Trimacinolon Macinolone Bentonide (D0 Demetex) Demetex Benetonide Enanth-Afla-117-ATP-11 Methyl-4-alpha-chloro-6-alpha-fluoro-tannopurb 11-RTSA kelisoprec-atep-11-nya ;-androstad Vm nS Je lV = Sg a 9-o-chloro-6-a..-fluoro-11-B-17-0-dihydroxy-1-6 a..-methyl-3-oxo-1,4-androstadiene-17- B- .carboxylic acid-methylester-17-propionate It includes other active ingredients particularly suitable for use in the production of aqueous pharmaceutical preparations for use by inhalation: ¢ B-sympathomimetics Gy Parasympathomimetics Terbutaline formoterol Formoterol Salbutamol 00:01 salbutamol Ju intermediate; Ipatropium Jie steroids Steroids budesonide Budesonide beclomethasone dipropionate Coote ols such as dipropionate Flunisolide and flunisolide Peptides Vo insulinsulin Insulin Jia pain killers Pain relievers fentanyl Such as fentanyl, and it turns out that it is possible to use those drug-acceptable salts dissolved in the solvent according to the invention when needed. Ye

01

Lait) Description The advantages of the new use of the pharmaceutical preparation according to the invention will be clarified in the following, more fully by reference to the examples. solution) has a pH of 0 7 mg/© ml). And 0 mg / 0 (with a concentration of benzalkonium chloride preservative carla 1 mg; 100 at concentrations of EDTA contained some solutions that were subjected to testing, while disodium salt was not in ml Picture of disodium salt 0 l mg and both mg / others contain it.

Unused Respimat® (Registered Trademark) Ye Unused Respimat® evaporators used approximately 11 microliters for the test (Technical information: The volume of the pharmaceutical preparation used was two streams merged out of two orifices after which the pressure reached (lB) and the pressure reached 700 bar He specified the mode of operation in the test so that the units would be used five times. Each group of measurement systems Table VO shows the results for spray anomalies. 1 Ludgla Test period (day) Cn ap Test (mg/100ml) Spray anomaly eae x]

Le Le ee

Y.14

11 ae Te a. (Ipatropium bromide and Fenoterol) Example formulations (For Fenoterol ml) 0 Ingredients Composition (mg/

AYY.Y Fenoterol 0 Benzalkonium chloride Benzalkonium chloride A *EDTA Add sufficient amount to deliver 0 2.7 N (pH) to 1 (concentration 06 ml) 0 Ingredients Composition ( mg/ 1771. Ipatropium bromide 01 Benzalkonium chloride Benzalkonium chloride M8 * EDTA A sufficient amount is added to deliver 1 N 1 with a concentration of 01 3.4 pH to: Prepared solutions: The following (AGH on the examples Lud, Sams art aaa the active rectifier the solvent ml) | Berodual Water on Ye 17-61 (atrovent) 0.4

YY

Water 8 1 Lacquer 6 (Berotec) Combivent Water Ye 01 1. Hati |

Tiotropium Bromide HA SAH [aw | Como to Commas disodium salt sodium JU in the form of EDTA salt there is * “fenoterol hydrobromide to the active ingredient Berotec 0 ipatropium bromide to the active substance ipatropium bromide Atrovent Atrovent refers to 0” refers to the active ingredient of a combination of ipatropium bromide “Berodual” refers to “fenoterol hydrobromide and ipatropium bromide °®” refers to the active ingredient of a combination of Combivent M. “Combivent” refers to salbutamol and salbutamol ipatropium bromide sx9 SLY! sf Ym Sy pa AIT stands for bromide BEA 2108 Br “Dicyclic [10 7 oY] acetyl(oxy)-;-dimethyl-*/-azoniaoctane 3-[(hydroxydi-2-) thienylacetyl)oxy]-8, 8-dimethyl-8-azoniabicyclo(3,2,1 Joct-6-ene-bromide Ve (see page 4); and oxyvent 4 to the active ingredient oxytropium bromide © oxtiropium bromide from 001 ml/mg 100001 mg to 100 mg and it is safe to use a concentration ranging from the active ingredients, depending on the amount of dose in each application and its solubility.Doses are approximately Vo per 11 microliters which are Ladle determined based on single effective dose 1.4

VY

Use of 0 and the concentration of the active ingredient in pharmaceutical preparations may change when the single dose amount is changed. The concentration of the complexing agents (such as 074-disodium (DiNa-EDTA) varies between 01 and 1000 mg/100 mL last depending on the pH of the solution). The preferred 0 concentration is between 75 and 100 mg/100 mL. The concentration of benzalkonium chloride should range from 4 to VY mg/001 ml. The pH of the solutions is set between 7.? and 4.? By adding HCL with a concentration of 0.1 or 1 M. All concentrations have been calculated with respect to the volume of the final active ingredient solution, which is Ye equal to 100 ml. 1.4

Claims (1)

B "Protective Elements". 1-1 Using a pharmaceutical preparation, Sle, in the form of a solution, to produce aerosols free of Y Propellent-free aerosols containing a pharmacologically active substance 1 or a combination of active substances; The pharmaceutical preparation ¢ is distinguished in that it contains a compounding agent and optionally contains ethanol in an amount not exceeding 170 vol. 1?- Gay use of Claim 1; characterized by the use of the active substance or combination of Y of active substances by inhalation. La gad 5 cinhalation to treat v respiratory tract diseases.respiratory tract ‏ 1 *- Use Gg of claim 1 or ? ; It is characterized by the selection of the active ingredient from Y, the mimics of Vin, and it is a mediator of anticholinergics, antiallergics and/or antihistamines. 1 4- Gig's use of any of the protections 1 to ; It is distinguished in that the compounding agent Y chooses from cnitrilotriacetic acid v citric acid v ascorbic acid as its salts. 1 #- use Gy for any of claims 1 through 4; It is distinguished in that the Y-complexing agent is EDTA (ethylenediaminetetraacitic acid v) or a salt thereof. \o 1-1 use pursuant to any claim 1 to ©; It is distinguished in that the concentration of the compounding agent ranges from ©? to 100 mg/100 mL of solution. 1 7- Use according to any of the claims 1 to 6 is distinguished in that the pharmaceutical preparation Y contains ethanol in an amount not exceeding 7170 (vol / volume). =A Use Gy for any of the claims 1 through 7; It is characterized by the fact that the pharmaceutical preparation contains ethanol in an amount ranging from 0 to 710 (volume / volume). 1 9- The use of “(ad) for any of the protection elements (1) to (A);” is distinguished in that the pharmaceutical preparation (Y) contains an active substance with a concentration ranging from (Soe) y ¥ g/100 mL of solution. -01 1 use Gy for any claim 1 to 4; It is distinguished in that the pharmaceutical product does not contain ethanol p14