WO1992011236A1 - Aerosol formulations - Google Patents
Aerosol formulations Download PDFInfo
- Publication number
- WO1992011236A1 WO1992011236A1 PCT/US1991/002177 US9102177W WO9211236A1 WO 1992011236 A1 WO1992011236 A1 WO 1992011236A1 US 9102177 W US9102177 W US 9102177W WO 9211236 A1 WO9211236 A1 WO 9211236A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- aerosol
- salt
- monohydrate
- ethanediamine
- thio
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/56—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
Definitions
- This invention relates to an aerosol formulation comprising a triester of sorbitan and a salt of an LTD4 antagonist analog of the peptido-leukotriene series, a substituted phenylcarboxy- alkylthioalkanoic acid. More particularly, this invention relates to an aerosol formulation made up of a long chain aliphatic triester of sorbitan and the 1 ,2-ethanediamine salt of [R-(R*,S*)]- ⁇ -[(2- carboxyethyl)thio]- ⁇ -hydroxy-2-(8-phenyloctyl)benzenepropanoic acid.
- this invention relates to the monohydrate form of the 1,2-ethanedi amine salt (1:1) of [R-(R*,S*)]- ⁇ -[(2- carboxyethyl)thio]- ⁇ -hydroxy-2-(8-phenyloctyl)benzenepropanoic acid, a stable polymorph thereof and methods for making both.
- Aerosol technology provides a convenient means for remotely dispensing and applying a host of different materials. These formulations are now a commonly used means for dispersing onto a surface any numbers of solid materials in a powder or liquid form. Aerosols are routinely used in the cosmetic industry, for painting, for dispensing insecticides and herbicides, for foaming materials, for applying cleaning and preservative agents and for administering drugs, to name a few of the various numerous applications of the aerosol technology. Aerosols are quickly applied. Small amounts or a thin layer material can be rapidly applied over a large area in a repetitive fashion. Aerosol container are sealed. There is no back-aspiration during application so content contamination is greatly reduced in comparison with sprays or other forms of airborne application.
- aerosol is classically defined as a collodial suspension of finely divided liquids or solid particles dispersed in and surrounded by a gas.
- An ae-osol spray is obtained by forcing a mixture of gas and a liquid, semi-solid or solid material through a specially designed valve system resulting in a finely divided liquid or solid particles being dispersed in the gas stream.
- Aerosol formulations have found use as a means for drug delivery and drug application. Pharmaceutical-based aerosol formulations are most frequently used orally or topically. Diseases in the throat and lungs are frequently treated via aerosol formulations. Topical diseases such as acne or where there is need for first aid have utilized aerosol preparations. Anesthetics, antiseptics, germicides, body rubs, dermatological products and foot preparations are often applied via aerosols.
- This invention is primarily concerned with the oral delivery of an anti-allergy agent. It is a particularly useful means for administering these drugs to prevent or treat asthma and other allergy-related or induced diseases of the mouth, throat or lungs.
- Applicants have discovered that there are two unique phenomena associated with preparing an aerosol dispersion formulation of a certain asthma drug. First, a monohydrate of a polymorph is considerably more stable in the aerosol formulation.
- this invention covers a pharmaceutically acceptable aerosol formulation
- a pharmaceutically acceptable aerosol formulation comprising a sorbitan triester of Cj Q to C20 aliphatic acids, at least one propellant and the 1,2- ethanediamine salt of [R-(R*,S*)]- ⁇ -[(2-carboxyethyl)thio]- ⁇ - hydroxy-2-(8-phenyloctyl)benzenepropanoic acid monohydrate in an amount sufficient to deliver a therapeutically effective dose when inhaled.
- this invention covers a method for preparing a stable aerosol of the 1,2-ethanediamine salt of [R-(R*,S*)]- ⁇ -[(2- carboxyethyl)thio]- ⁇ -hydroxy-2-(8-phenyloctyl)benzenepropanoic acid monohydrate which comprises mixing the monohydrate with about a 10-fold excess of a sorbitan triester of CJQ to C20 aliphatic acids and a propellant.
- this invention relates to a monohydrate form of the 1,2-ethanediamine salt (1:1) of [R-(R*,S*)]- ⁇ -[(2- carboxyethyl)-thio]- ⁇ -hydroxy-2-(8-phenyIoctyl)benzenepropanoic acid, a stable polymorph thereof and methods for making both.
- the acid salt of this invention is represented by the following formula.
- This compound is believed to be useful in treating asthma, especially when administered directly to the lung, a topical application for all intents and purposes. This indicated an aerosol formulation would be a useful means of administering this drug for treating asthma, as well as for other allergy-related diseases of the respiratory tract.
- the anhydrous 1,2-ethanediamine salt material was used. It was not stable. It took up water, which in certain instances changed the characteristics of the formulations in which it was confected (for example, the aerosol formulation described herein). Research showed the 1,2-ethanediamine salt would form a monohydrate which then remained stable in various formulations, that is it did not take up more water or lose water as it was being formulated or during storage.
- Isopropanol/water and tetrahydrofuran/water mixtures may produce an unstable polymorph form of the monohydrate which must then be acted on further to convert it to the stable polymorph.
- Solvents and solvent mixtures which produce satisfactory product, the stable polymorph of the monohydrate are methanol, methanol containing up to 50% ethyl acetate, methanol/acetonitrile, and methanol/tetrahydrofuran, all containing about 1% water.
- the preferred solvent system is methanol or methanol/ethyl acetate/water, particularly this solvent in a 75:25:1 ratio. These figures are expressed in terms of volume/volume ratios.
- Reagents and substrates may be mixed together in any order at ambient temperature, and then heated to about 60°C.
- the substrate may be heated to 60°C in the chosen solvent system followed by the addition of reagents.
- the stable polymorph can also be prepared by heating the unstable form to about 60°C, preferably in a solvent.
- the stable polymorph of this invention is characterized by the differential scanning calorimetry (DSC) readout shown in Figure 1 and a crystal habit of thin blades or needles up to 100 microns long and 35 microns wide.
- DSC differential scanning calorimetry
- the unstable polymorph shows a crystal habit of rectangular plates approximately 350 microns by 250 microns. It is possible to distinguish between the two polymorphs based on powder X-ray diffraction; however, the differences are much more subtle than those exhibited by DSC.
- the thermal behavior of the desired polymorph can be described and compared with the undesirable form thusly:
- the stable (desired) form exhibits a broad endotherm (onset about 100°C ) followed by a large sharp endotherm (onset about 148°C) followed by a small sharp endotherm (onset about 165°C).
- This form corresponds to the blade/needle form.
- the other polymorph (undesired form) is characterized by a large sharp skewed endotherm (onset about 130°C) followed by a moderate sharp endotherm (onset about 145°C ) followed by a small sharp endotherm (onset about 165°C).
- Aerosol Formulations corresponds to the plate form.
- a number of suspending agents were tested, oleyl alcohol, sorbitan monooleate, and oleic acid.
- the monohydride 1,2-ethanediamine salt was soluble in each of these to a degree which caused concern for product stability. It was projected that over time the fraction of solubilized monohydrate salt would recrystallize on existing monohydrate salt particles, thereby increasing the size of the monohydrate salt particles. This would not only affect the deposition pattern in the lung but could also impair the mechanical function of the valve. Then sorbitan trioleate was evaluated. It was found that the salt was very insoluble in this triester, especially as compared to the other suspending agents which had been tested.
- Sorbitan refers to the 1 ,4-sorbitan. It is made by dehydrating sorbitol. That process leaves three reactive hydroxyl groups one or more of which can be esterifed. In this case the triesters are formed by esterifying all three hydroxyl groups with a CI Q-C-20 acid. Standard esterification processes are used to form these esters. Acids used to form these compounds may be fully saturated or have one or more double bonds. Preferably they will be mono- unsaturated or saturated. It is further preferred that each ester be formed using an acid of the same structure. However, it is expected that mixtures of acids and mixtures of esterified sorbitans could be used.
- the amount of drug used in the aerosol formulation will be based on the amount of material delivered each time the device is used. In this particular instance, it is most preferred to deliver between 100 ⁇ g of anhydrous free acid during each valve actuation. That means about 117 ⁇ g of the monohydrate 1,2-ethanediamine salt must be delivered each time. This represents what is believed to be an effective dose for treating asthma. But the therapeutically effective amount required to treat any given disease could vary between about 50 and 500 ⁇ g per dose depending on the disease, its response to this drug, how the aerosol container is used, and other factors affecting the effectiveness of the drug and the efficiency of delivery.
- the drug will be present in an amount between about 0.05 mg and 10.0 mg per gram of formula, most preferably about 2 mg per gram.
- the components from which aerosols are formed require a source of gas to act as the propellant and a solid, semi-solid or a liquid which becomes dispersed in the gas as it is being dispensed through a valve system.
- Aerosols can be classified as liquid-gas systems, compressed gas systems, and a third catch-all category which usually involves some type of piston or flexible bag device which assist in expelling the gas/solid dispersion through the valve system.
- a general discussion of the several aerosol systems routinely employed with pharmaceutical formulations can be found in Remington's Pharmaceutical Sciences, 17th edition, Mac Publishing Company, Easton, Pennsylvania, USA (1985).
- a liquified gas as the propellant source for forming the aerosol.
- This method introduces a liquified gas into a container. There an equilibrium is set up between a gaseous and liquid phase. The gaseous phase or vapor phase exerts a pressure on the system which is sufficient to dispel any portion of the liquified gas, it also contains the active ingredient, through a specially designed nozzle which forms the aerosol spray.
- Liquified gas systems usually are two phase systems. A solution or suspension of an active ingredient is combined with a liquified gas and introduced into a sealed container with the appropriate aerosol valve system. As the name implies, a two-phase system once formulated in a can contains only a gas and a liquid propellant. The active ingredient can either be miscible, in solution, or immiscible, " solid particles.
- Compressed gas aerosol systems utilize an inert gas such as nitrogen, carbon dioxide or nitrous oxide, for example.
- Compressed gas is placed in a container and expands through the valve when the valve is opened providing the means for dispensing or expelling the container contents.
- Valve structures and container forms and structures are known in * e art.
- Remington's Pharmaceutical Sciences 17th Ed. illustrates a number of oral devices.
- Specialized aerosol applicators have been developed for oral administration of medicaments. These devices take into consideration the anatomical and physiological parameters and structure of the respiratory pathway. Most devices deliver an accurately metered dose of material in order to control the amount of medicament which is administered per use.
- the propellants used in this invention may be liquified gases or compressed gases. Liquified gases are preferred. This class is made up of the halocarbons and hydrocarbons. Halocarbons have found greater use as they are inflammable as contrasted with hydrocarbons. Halocarbons are normally chloro or fluoro-substituted alkanes, most often of one or two carbons.
- Fluorochlorocarbons are identified by two or three digit numbers which represent the number of fluoro, chloro, and hydrogen atoms in a particular propellant.
- Pi 2 is dichlorodifluoromethane.
- Mixtures of these simple fluorochlorocarbons, that is the methane forms, are useful in the practice of this invention. But other combinations of these methane- based gases as well as other fluorochlorocarbons can be used.
- Hydrocarbon gases are now also successfully used in pharmaceutical aerosols. Propanes, butanes and pentanes are frequently used in pharmaceutical aerosols. Dimethyl ether is also useful as a propellant in certain formulations, particularly because of its high water solubility as compared with the alkane-based propellants.
- Compressed gases have at times been used in pharmaceutical formulations.
- the dispensed product may be a mist, foam or semisolid. Only the mist form will be of real utility in this invention.
- Liquified gas formulations are of most interest in this invention.
- Bulk concentrates are prepared by dispersing a known quantity of the 1,2-ethanediamine salt in a known quantity of a sorbitan triester/trichlorofluoromethane mixture by homogenization. This process should be carried out below room temperature (5-8°C). Preferably, it will be carried out under sterile conditions. Thereafter this dispersion is filled i ⁇ itr an appropriate container for administering an aerosol orally.
- the system is pressurized with a propellant in a such a manner as to provide the desired amount for metering at a particular dose size per use.
- the solution was seeded with 0.30 g of authentic monohydrate of the 1,2-ethanediamine salt (1 :1) of [R-(R*,S*)]- ⁇ -[(2-carboxyethyl)thio]- ⁇ - hydroxy-2-(8-phenyloctyl)benzenepropanoic acid and then slowly cooled to ambient temperature over a period of 3 hours. After stirring at ambient temperature for approximately 16 hours, the mixture was filtered and washed two times with 1.5L of cold methanol containing 1% of deionized water. The product was air dried on the filter for 1 hour, then dried in vacuo (high vacuum) at ambient temperature until a constant weight was obtained (36 hours). The title product was obtained as a "/hite powder.
- the solution was seeded with 0.30 g of authentic title compound and then slowly cooled to ambient temperature over a period of 3 hours. After stirring at ambient temperature for approximately 16 hours, the product was isolated by filtration and washed two times with 1.5 L of methanol containing 1% of deionized water. The product was air dried in the filter for 1 hour, then dried in vacuo (hi-vacuum) at ambient temperature for 36 hours to a constant weight.
- the monohydrate form of the 1,2-ethanediamine salt when formulated with sorbitan trioleate, did not demonstrated crystal growth after six months storage at 30°C and three months storage at 50°C and 40°C at 75% relative humidity.
- trioleate As crystal growth is a function of solubility the trioleate was deemed to be a superior suspending agent for use in making an aerosol formulation of this salt.
- An aerosol formulation was prepared by mixing the following ingredients and amounts.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Pulmonology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Otolaryngology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP3516136A JPH06503066A (en) | 1990-12-19 | 1991-03-28 | aerosol formulation |
KR1019930701923A KR930703251A (en) | 1990-12-19 | 1991-03-28 | Aerosol formulations |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US63011490A | 1990-12-19 | 1990-12-19 | |
US630,114 | 1990-12-19 | ||
US64585091A | 1991-01-25 | 1991-01-25 | |
US645,850 | 1991-01-25 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1992011236A1 true WO1992011236A1 (en) | 1992-07-09 |
Family
ID=27091083
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1991/002177 WO1992011236A1 (en) | 1990-12-19 | 1991-03-28 | Aerosol formulations |
Country Status (8)
Country | Link |
---|---|
EP (1) | EP0563048A1 (en) |
JP (1) | JPH06503066A (en) |
KR (1) | KR930703251A (en) |
AU (1) | AU8642391A (en) |
CA (1) | CA2098298A1 (en) |
IE (1) | IE913482A1 (en) |
PT (1) | PT99869A (en) |
WO (1) | WO1992011236A1 (en) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000030608A1 (en) * | 1998-11-25 | 2000-06-02 | Chiesi Farmaceutici S.P.A. | Pressurised metered dose inhalers (mdi) |
US6964759B2 (en) | 2000-02-22 | 2005-11-15 | Chiesi Farmaceutici S.P.A. | Formulations containing an anticholinergic drug for the treatment of chronic obstructive pulmonary disease |
US6967017B1 (en) | 1999-07-23 | 2005-11-22 | Chiesi Farmaceutici S.P.A. | Formulations of steroid solutions for inhalatory administration |
US7018618B2 (en) | 2000-05-22 | 2006-03-28 | Chiesi Farmaceutici S.P.A. | Stable pharmaceutical solution formulations for pressurized metered dose inhalers |
US7381402B2 (en) | 2004-02-27 | 2008-06-03 | Chiesi Farmaceutici S.P.A. | Stable pharmaceutical solution formulations for pressurized metered dose inhalers |
US7601336B2 (en) | 1997-06-13 | 2009-10-13 | Chiesi Farmaceutici S.P.A. | Pharmaceutical aerosol composition |
US7696178B2 (en) | 2001-07-02 | 2010-04-13 | Chiesi Farmaceutici S.P.A. | Optimised formulation of tobramycin for aerosolization |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4820719A (en) * | 1985-04-19 | 1989-04-11 | Smithkline Beckman Corporation | Leukotriene antagonists |
-
1991
- 1991-03-28 KR KR1019930701923A patent/KR930703251A/en not_active Application Discontinuation
- 1991-03-28 CA CA002098298A patent/CA2098298A1/en not_active Abandoned
- 1991-03-28 WO PCT/US1991/002177 patent/WO1992011236A1/en not_active Application Discontinuation
- 1991-03-28 AU AU86423/91A patent/AU8642391A/en not_active Abandoned
- 1991-03-28 EP EP91917474A patent/EP0563048A1/en not_active Withdrawn
- 1991-03-28 JP JP3516136A patent/JPH06503066A/en active Pending
- 1991-10-03 IE IE348291A patent/IE913482A1/en not_active Application Discontinuation
- 1991-12-19 PT PT99869A patent/PT99869A/en not_active Application Discontinuation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4820719A (en) * | 1985-04-19 | 1989-04-11 | Smithkline Beckman Corporation | Leukotriene antagonists |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8420058B2 (en) | 1997-06-13 | 2013-04-16 | Chiesi Farmaceutici S.P.A. | Pharmaceutical aerosol composition |
US7601336B2 (en) | 1997-06-13 | 2009-10-13 | Chiesi Farmaceutici S.P.A. | Pharmaceutical aerosol composition |
WO2000030608A1 (en) * | 1998-11-25 | 2000-06-02 | Chiesi Farmaceutici S.P.A. | Pressurised metered dose inhalers (mdi) |
US7223381B2 (en) | 1998-11-25 | 2007-05-29 | Chiesi Farmaceutici S.P.A. | Pressurised metered dose inhalers (MDI) |
US7347199B1 (en) | 1998-11-25 | 2008-03-25 | Chiesi Farmaceutici S.P.A. | Pressurised metered dose inhalers (MDI) |
US8142763B2 (en) | 1998-11-25 | 2012-03-27 | Chiesi Farmaceutici S.P.A. | Pressurized metered dose inhalers (MDI) containing a solution comprising ipratropium bromide, HFA propellant, and co-solvent and comprising a container with a specific internal surface composition and/or lining |
US6967017B1 (en) | 1999-07-23 | 2005-11-22 | Chiesi Farmaceutici S.P.A. | Formulations of steroid solutions for inhalatory administration |
US6964759B2 (en) | 2000-02-22 | 2005-11-15 | Chiesi Farmaceutici S.P.A. | Formulations containing an anticholinergic drug for the treatment of chronic obstructive pulmonary disease |
US7018618B2 (en) | 2000-05-22 | 2006-03-28 | Chiesi Farmaceutici S.P.A. | Stable pharmaceutical solution formulations for pressurized metered dose inhalers |
US7939502B2 (en) | 2001-07-02 | 2011-05-10 | Chiesi Farmaceutici S.P.A. | Optimised formulation of tobramycin for aerosolization |
US7696178B2 (en) | 2001-07-02 | 2010-04-13 | Chiesi Farmaceutici S.P.A. | Optimised formulation of tobramycin for aerosolization |
US8168598B2 (en) | 2001-07-02 | 2012-05-01 | Chiesi Farmaceutici S.P.A. | Optimised formulation of tobramycin for aerosolization |
US7381402B2 (en) | 2004-02-27 | 2008-06-03 | Chiesi Farmaceutici S.P.A. | Stable pharmaceutical solution formulations for pressurized metered dose inhalers |
Also Published As
Publication number | Publication date |
---|---|
AU8642391A (en) | 1992-07-22 |
KR930703251A (en) | 1993-11-29 |
EP0563048A1 (en) | 1993-10-06 |
JPH06503066A (en) | 1994-04-07 |
PT99869A (en) | 1992-11-30 |
IE913482A1 (en) | 1992-07-01 |
CA2098298A1 (en) | 1992-06-20 |
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