MXPA00003476A - Mometasone furoate suspensions for nebulization - Google Patents

Abstract

An aqueous nebulizer suspension contains water, mometasone furoate monohydrate, a nonionic surfactant, a soluble salt and optionally a pH buffer. The suspension may be prepared by ultrasonication or jet milling techniques.

Description

SUSPENSIONS OF MOMETHASONE FUROATE FOR NEBULIZATION BACKGROUND OF THE INVENTION The present invention relates to aqueous suspensions of insoluble pharmaceutical substances in water, and more particularly to suspensions of substances intended for inhalation therapy. The use of inhaled therapeutic substances has become common for the treatment of respiratory tract disorders, said disorders include, without limitation thereof, asthma, infections, emphysema and various inflammatory conditions. Substances commonly supplied to the surfaces of the lower respiratory tract, that is, the trachea, bronchial tree and lungs, by oral or nasal inhalation include bronchodilators, corticosteroids, anti-infective and anti-inflammatory drugs. Various methods have been used for this supply, including pressurized metered dose inhalers, dry powder inhalers and nebulizers. Nebulizers are considered instruments that generate very fine particles of a liquid in a gas. As is well known, the particles intended for treatment of the lower respiratory tract, that is, the bronchial tree or the lungs, will generally be less than 10 microns in the largest dimension, in order to avoid unwanted deposition on surfaces of the respiratory tract. mouth and pharynx, and preferably will be less than 5 μ. In addition, particles much smaller than about 0.5 μ in the larger dimension often do not readily deposit at the desired site, and a large fraction of these will simply be exhaled by the patient. For these reasons, it is generally desired to produce particles of 1-7 μ on average in their largest dimension, while, preferably, the production of particles having sizes either less than about 0.5 or greater than about 10μ is reduced to a minimum. Preferred average particle sizes are on the 0.5-5μ scale. Nebulization, although used less frequently than other drug delivery techniques, has certain advantages for special patient groups, such as young children and very sick people. Although a somewhat uncomfortable equipment is needed and there may be stricter cleaning requirements than exist for some of the most common delivery techniques, no skill or coordination of the patient is required: the patient simply needs to breathe normally to introduce the medication into the airway. Therefore, the treatment can be given even to an unconscious patient or to an infant. Likewise, it is considered an advantage of the nebulizers that moisture quantities can be supplied to the respiratory tract; This can help to fluidize secretions and tends to increase patient comfort.

The typical nebulized drug is a water soluble substance that can form relatively dilute aqueous solutions. This is desired, due to the relatively large volumes of solution that will be entrained in an inhaled air stream, and to the very small amounts of medicament which will typically be delivered in a single treatment. The handling of a drug solution is not complicated: a desired volume of a solution (usually aqueous) is nebulized directly or measured in a larger volume of sterile water for nebulization. However, some very useful inhalation medications have little solubility in water, or essentially do not. Examples of such drugs are corticosteroids, typically administered in the treatment of asthma by inhalation of pressurized metered dose inhalers, either in an alcohol solution or as suspended micronized particles, or from dry powder inhalers of various types. The formation of an aqueous suspension of medicament particles for nebulization is also known. Commercial products, which are not available in all countries, currently include beclomethasone dipropionate (sold by Glaxo under the trade name BECOTIDE) and budesonide (formulated with a pH regulator of citrate-citric acid and surfactant of Polysorbate 80, and sold by Astra under the trade name PULMICORT). Corticosteroids have also been formulated in suspensions of liposomes in aqueous media, for delivery by nebulization, as in the patent of E.U.A. 5,192,528. The therapeutic benefits of mometasone furoate corticosteroid to treat lower respiratory tract disorders make this medication an advisable candidate for nebulization delivery. Because this drug is not soluble in aqueous media, it has become necessary to develop aqueous suspensions for nebulization.

BRIEF DESCRIPTION OF THE INVENTION The invention comprises an aqueous suspension of micronized mometasone furoate monohydrate, which also contains a nonionic surfactant, a water soluble salt and, optionally, a pH regulator. Preferred surfactants are those known as polysorbates. The soluble salt may be sodium chloride, in amounts necessary to make the isotonic solution phase. When the pH regulator is present, it will preferably be chosen to maintain a pH of the solution between about 3 and about 7.

BRIEF DESCRIPTION OF THE DRAWING Figure 1 is a graphical representation of the results of the experiment of Example 3.

DETAILED DESCRIPTION OF THE INVENTION The percentages expressed here are to indicate the percentage by weight, unless the context clearly specifies otherwise. The suspension formulations of the invention can be delivered to a patient using any of the usual nebulizer devices. Typical commercial nebulizer devices produce droplet dispersions in gas streams by one or two methods. Jet nebulizers use a supply of compressed air to raise a fluid by the action of a venturi tube and introduce it into a fluid gas stream, after which the fluid is caused to collide with one or more stationary deflectors to remove the fluid. excessively large drops. Ultrasonic nebulizers use an electrically driven transducer to subject a fluid to high frequency oscillations, producing a cloud of droplets that can be entrained in a moving gas stream; these devices are less preferred to provide suspensions. There are handheld nebulizers that atomize the fluid with an oppressive knob air supply, but the most widely used equipment includes a compressor that runs on electricity or is connected to a cylinder of compressed gas. Although the various devices that are commercially available vary considerably in their efficiency to deliver a given medicament, all are useful for the treatment of the present invention; it is necessary that the prescribing physician specify an exact amount of drug formulation that must be charged to each particular device, since the respective outlets of respirable drops are far from identical. Suitable suspension formulations for nebulization should, of course, contain solid particles of a breathable size (eg, preferably less than about 5 μ on average in the largest dimension and preferably less than 2 μ on average) and should maintain their particle size distribution suspended during storage. In addition, droplets containing particles formed during nebulization of the formulations should have adequate sizes for deposit in the desired area of the respiratory system. Because the formulations of the invention must be inhaled, it is necessary that they be free of pathogenic organisms. Therefore, they can be prepared and handled under sterile conditions, or they can be sterilized before or after being packed. In addition, instead of sterilization, a preservative can be included to minimize the possibility of microbial contamination. Also, all components of the formulations must be chosen to be safe to inhale, since the treated tissues are quite sensitive to irritants; It is commonly known that many of the common preservatives have considerable potential to cause irritation. The formulations of the invention comprise water, mometasone furoate monohydrate, a nonionic surfactant, a soluble salt and, optionally, a pH regulator. The water that is to be used in the formulations must meet or exceed the applicable regulatory requirements for use in inhaled medications. The specifications set forth by the United States Pharmacopeia in relation to "Sterile water for injection" or "Sterile water for inhalation" are examples of water suitable for use in the preparation of formulations of the invention. Mometasone furoate is a corticosteroid that has the chemical name 17- (2-furoate) of 9oc, 21-Dichloro-11β, 17-dihydroxy-16a-methylpregna-1,4-diene-3,20-dione, and is currently marketed by Schering Corporation in cream and lotion formulations for the treatment of dermatological conditions. The patent of E.U.A. 4,472,393 provides information concerning the preparation and properties of mometasone furoate. This compound can be used to prepare mometasone furoate monohydrate for use in the present invention. PCT International Application WO 92/04365 provides information concerning the preparation and properties of mometasone furoate monohydrate.

In general, the concentration of mometasone furoate included in the suspension formulation will depend on the dose to be delivered to the patient, ease of handling and the characteristics of the nebulizer equipment, since the devices vary considerably in their suspension capacities and nebulization efficiencies. Typical suspensions may contain about 5 mg / mL of mometasone furoate, although lower concentrations, such as 50 μg / mL to 1 mg / mL are more usual for most equipment. Surfactants are often categorized by their chemical nature, that is, as cationic, anionic or non-ionic. Cationic surfactants, such as cetylpyridinium chloride, and anionic surfactants, such as sodium docusate, do not appear to provide appropriate dispersions of particles in the formulations. Many nonionic surfactants are suitable for maintaining the suspensions formed of particles of the invention. These include surfactants identified as "polysorbates" in CTFA's International Dictionary of Cosmetic Ingredients; such surfactants are mixtures of fatty acid esters (predominantly monoesters) of sorbitol and sorbitol anhydrides, condensed with ethylene oxide. Although these surfactants vary widely in their hydrophilic-lipophilic balance numbers ("HLB"), they all seem to work with the invention.

Commercially available polysorbates that are useful in the invention include those listed in the following table, which shows the designation of CTFA (polysorbate number), identity of the fatty acid used to produce the material, and the number of moles of oxide of ethylene which was reacted with each mole of ester. The compositions identified with an asterisk are predominantly triesters.

Polysorbate Acid Moles EtO 20 Uric 20 21 Lauric 4 40 Palmitic 20 60 Stearic 20 61 Stearic 4 65 * Stearic 20 80 Oleic 20 81 Oleic 5 85 * Oleic 20 In general, the polysorbate surfactants will be present in a formulation at about 50 to 500 μg / mL. When the concentration of surfactant is below 20 μg / mL, the particles tend to form cakes, which are not easily redispersed.

Useful surfactants also include "Poloxamers", which are polyoxyethylene and polyoxypropylene block polymers, which generally correspond to the formula: HO (CH2CH2O) x [CH (CH3) CH2O] and (CH2CH2O) zH Representative commercially available poloxamer surfactants, wherein the designation CTFA (poloxamer number) and the average values of x, y, and z are provided.

NI J CD LO S- 0000 O M m iuO n n- »CO CD CO - T- O O O O O IO lO? O O O O O N N Y S T 'U' I N Y N N CN CN C C C C O O C CO O C O O O O O O O O N O N O N O N N Y IO lO CO CD CO CO XI CN CD w 0000 O CO C!) M m 'Í CM - 8 C lO 0) E ^ * - **) C0 C c? * ^ * ^ ^ ^ ~ "* ^ 8 ^ ^ ^" ^ ** "* ^ l *" ^ 8 < > J "* tf > co X - T- v- T- ^ - - T- r- T- r- ^ C CN C CM C C CN CN C CN C CO O O CO C ^ ^ '^ -' t o Q.

WHAT Poloxamer surfactants are used at concentrations similar to those for Polysorbates, although certain numbers are useful at concentrations up to 1 mg / mL. In general, the chosen surfactant should not increase the viscosity of the suspension formulation considerably, since the efficiency of the nebulization process is particularly sensitive to viscosity. Many nonionic surfactants are useful for preparing formulations of inhalation and / or injectable medicaments, and any of these should be suitable for use in the present invention. The formulations also include a soluble salt. This salt performs at least two functions: it minimizes the effects of the inhaled formulation on the normal cellular fluid balance of the airway cells and also stabilizes the suspension of the drug. For the first function, it is preferred to use sufficient salt concentrations to make the isotonic formulation; For this purpose, sodium chloride and potassium chloride are preferred. It has been found that adequate suspension stability is produced by isotonic concentrations (i.e., about 0.9 weight percent) of sodium chloride, although concentrations of from about 0.2 to about 2 weight percent are useful. Any soluble alkali metal salt or physiologically compatible alkaline earth metal soluble salt can be used in the present invention.

Optionally, the formulations will contain a pH regulator, in order to maintain the pH of the formulation between about 3 and about 7. It has been found that the stability of the drug (as measured by the absence of degradation reaction products) in suspension is improved by maintaining pH conditions below about 6. Due to reasons of tissue compatibility, excessively acidic products are not desired, so the pH should not be made to fall below about 3. Some experimentation may to be necessary to qualify specific pH regulators for use in the invention: phosphate pH regulators in concentrations of 1 to 50 millimolar do not appear to adequately prevent cake formation of the particles in the suspension when there is no soluble added salt . A citrate-citric acid pH regulator, which maintains a pH between about 4 and about 5, has been used with particularly good effect both to maintain the pH during storage, and to avoid any cake formation of particles in the absence of salts soluble. The citrate-citric acid pH regulator may be present in suspension formulations at concentrations of at least about 2 and up to about 50 millimolar. Although within the literature there are cough reports induced by such pH regulator systems, this seems to occur mainly at the level of 150-200 millimolar, although one report attributed only a concentration of 35 millimolar. Proper antimicrobial sterility or preservation of the final packaged formulation is necessary for patient protection. The use of antimicrobial preservatives is less advisable, since some of these have been related to unfavorable clinical effects, such as bronchospasm. Alternative methods that can be considered to achieve sterility will generally not include sterilization steps for the substance or formulation of micronized medicament, since it has been found that the medicament undergoes degradation under the influence of gamma-ray irradiation and heat conditions of sterilization. Generally sterilization by filtration will not be viable, due to the nature of suspension of the formulation. Therefore, it is preferred to produce mometasone furoate monohydrate under sterile conditions, to carry out the micronization of the medicament in a sterile environment, and to perform a sterile packing operation. Methods for reducing particle sizes in the ladder scale are known, including mechanical grinding, ultrasonic energy application and other techniques. Mechanical grinding often generates high surface temperatures in the particles, and this is not advisable for mometasone furoate monohydrate which tends to lose some of its hydration under the influence of high temperatures. Ultrasonic techniques are quite slow in their action, usually requiring very long procedure times, but are capable of producing acceptable suspensions. Suspensions of drug particles can rapidly undergo particle size reduction when subjected to "grinding to choro" techniques (particle grinding in high pressure liquid). A currently preferred jet milling process for producing the formulations of the invention involves the use of the "Microfluidizer" system sold by Microfluidics International Corporation of Newton, Massachusetts, E.U.A. This device divides a fluid stream, which flows under high pressures (up to approximately 2.76 x 108 newton / meter2, between two separate microchannel paths and then recombines them, usually from perpendicular directions to create forces of shear stress, impact and very high cavitation, continuously recirculating suspensions through the system for a predetermined time, it is possible to reproducibly create particle size distributions in desired microns and submicrons. Because the particles are always completely surrounded by liquid, their surfaces will not develop high temperatures under the influence of the size reduction forces, and the water of hydration in the crystals of the drug will remain intact. Other useful equipment that uses related technology can be obtained from Avestin Inc., Ottawa, Ontario, Canada.

The following examples are provided to better illustrate and explain certain aspects of the invention, and in no way attempt to limit the scope of the invention, as defined by the appended claims.

EXAMPLE 1 The sterile mometasone monohydrate furoate is prepared by a process that includes the following steps: (1) loading 250 grams of mometasone furoate to a solution vessel containing 4250 mL of acetone, and mixing to form a clear solution; (2) pour the solution through a sterilization filter, such as a filtration medium with pores not exceeding 0.2 μ in diameter, in a sterile precipitation vessel provided with stirring means and means for heating the contents (note that sterile equipment and a sterile environment should be used during all subsequent steps); (3) heat the sterile solution to approximately 45-50 ° C and add slowly, for approximately 15 minutes, 1000 mL of sterile purified water while maintaining the temperature; (4) while maintaining the elevated temperature, add 750 mL of additional water slowly, with agitation for approximately 30 minutes; (5) continue stirring and maintain the temperature for an additional 30 minutes, during which time a precipitate will start to form; (6) slowly add 5250 mL of additional water for approximately 60 minutes, while maintaining rapid agitation and elevated temperature; (7) continue stirring at the elevated temperature for approximately 60 minutes; (8) cooling the mixture to room temperature, with continuous stirring; (9) filter the precipitate (mometasone furoate monohydrate) and wash it with two 500 mL portions of the sterile purified water; and (10) drying in a vacuum oven at 30-35 ° C for 12-24 hours.

The dry sterile mometasone monohydrate furoate product should have a water content, as measured by a standard Karl Fischer titration, of 3.3 weight percent and contains 96.7 weight percent of mometasone furoate.

EXAMPLE 2 A batch of 40 liters of a sterile aqueous suspension of mometasone furoate monohydrate is prepared using the following procedure: (1) consecutively loading 2.0 grams of Polysorbate 80, 7.24 grams of citric acid monohydrate and 13.4 grams of sodium citrate dihydrate to about 1000 grams of purified water in a vessel equipped for agitation, shake to form a solution having a pH of 4.5 ± 0.5, add additional purified water to make 1315 grams of solution and filter the solution under pressure through a sterilization filter 0.2 μ in a sterile recirculation vessel, equipped for agitation; (2) add 360 grams of sodium chloride to approximately 1800 grams of purified water, stir to dissolve, add additional purified water to make 2000 grams of solution and filter under pressure through a 0.2 μ sterilization filter in a sterile container; (3) Add 21.73 grams of mometasone furoate monohydrate, prepared as in Example 1, to the sterile solution of step (1) and begin to stir the contents of the container to form a suspension; (4) Pass the mixture from the previous step through a Model 210B-EH Pilot Scale Microfluidizer that operates at a gauge pressure of 1.21 x 108 newton / meter2 ± 3.45 x 106 newton / meter2 for 40 ± 5 minutes while the discharge of the Microfluidizer in the stirred recirculation vessel; (5) transferring the suspension of micronized mometasone furoate from the recirculation vessel to the container of step (2); (6) Rinse the Microfluidizer with sterile purified water and add the rinse water to the suspension formed in the previous step, then add a sufficient additional amount of the water to form a suspension weighing 40100 grams; and (7) filling individual sterile containers with a desired amount of suspension (containing 0.5 mg of mometasone furoate per milliliter and having a specific gravity of 1,003 g / cm3) for use in a nebulizer. The weight for mometasone furoate monohydrate includes a 5 percent overload to compensate for manufacturing losses.

EXAMPLE 3 Using the procedure of the previous example, a suspension having the following composition and a pH of about 4.5 is prepared: Mometasone furoate 500 μg Polysorbate 80 50 μg Citric acid monohydrate 181 μg Sodium citrate dihydrate 335 μg Sodium chloride 9 μg Water for injection, USP to make 1 ml * Mometasone furoate monohydrate A particle size distribution is determined for suspension by a laser light scattering technique. A Malvern 2600 instrument, manufactured by Malvern Instruments, Malvern, Worcestershire, UK, is mounted with a liquid flow cell and a 63 mm lens, and operated in its "liquid particle" mode with water (containing a small amount of Polysorbate 80 as a wetting agent) as the carrier. The drug suspension is added until optimal light darkening is achieved, then the measurements are obtained. The data are calculated and expressed on a volume distribution basis, and are plotted as shown in figure 1. This suspension has a median particle size of 1.24 μ and a mean particle size of 1.34 μ.

EXAMPLE 4 Commercially available nebulizers are used to determine the delivery characteristics of the drug for the suspension of the previous example and two commercial suspension products: beclomethasone dipropionate suspension BECOTIDE (Glaxo) and suspension of PULMICORT budesonide (Astra). The nebulizers are WHISPER JET (Marquest Medical Products, Englewood, Colorado, E.U.A.) and PARÍ JET (PARI Respiratory Equipment, Inc., Richmond, Virginia, E.U.A.). The suspensions are placed in the nebulizers in quantities of 3 mL, and the equipment is connected to a compressor and operated according to the manufacturer's instructions. The nebulized medication is directed to the top of a 500 mL separatory funnel containing a 1 gram cotton plug, and the bottom outlet of the funnel is connected to a vacuum line. After the nebulizer dries, the vacuum line is disconnected and the funnel (with the cap) is washed with 25 mL of a solvent for the drug (eg, methanol), which is then collected and analyzed for the drug by High performance liquid chromatography to determine the percentage of originally loaded drug that was delivered to the funnel. The results are obtained as shown below, where the values are averages of four determinations: Percentage Supplied Product Pari Jet Whisper Jet Example 3 32.9 23.6 Becotide 23.5 13.4 Pulmicort 31.9 18.1 EXAMPLE 5 As in Example 3 above, the following suspension formulations are prepared containing enough each sterile water to make a final volume of 1 mL: Formula 5A 5B 5C Mometasone furoate, μg 250 500 500 Polysorbate 80, μg 50 500 50 Citric acid monohydrate, μg 181 181 80 Sodium citrate dihydrate, μg 335 335 470 Sodium chloride, mg 9 9 9 The content of mometasone furoate is provided by the mometasone furoate monohydrate.

EXAMPLE 6 As in Example 3 above, the following suspension formulations are prepared, each enough containing sterile water to make a final volume of 1 mL: Formula 6A 6B 6C Mometasone furoate, μg 500 500 750 Polysorbate 80, μg 50 50 50 Citric acid monohydrate, μg 294 181 181 Sodium citrate dihydrate, μg 174 335 335 Sodium chloride, mg 9 4.5 18 The content of mometasone furoate is provided by the mometasone furoate monohydrate.

Claims (22)

NOVELTY OF THE INVENTION CLAIMS

1. - A nebulizer suspension comprising water, mometasone furoate monohydrate, a nonionic surfactant and a soluble salt.

2. The suspension according to claim 1, further characterized in that the mometasone furoate monohydrate comprises from about 50 micrograms to about 5 milligrams, per milliliter.

3. The suspension according to claim 1, further characterized in that the surfactant comprises a polysorbate surfactant.

4. The suspension according to claim 1, further characterized in that the surfactant comprises Polysorbate 80.

5. The suspension according to claim 1, further characterized in that the surfactant comprises a Poloxamer surfactant.

6. The suspension according to claim 1, further characterized in that the surfactant comprises about 50 micrograms to about 1 milligram, per milliliter.

7. The suspension according to claim 1, further characterized in that the salt comprises sodium chloride.

8. The suspension according to claim 1, further characterized in that the salt comprises about 0.2 to about 2 weight percent.

9. The suspension according to claim 1, which further includes a pH regulator.

10. The suspension according to claim 9, further characterized in that the pH regulator comprises a pH regulator of citric acid-citrate. 1.

The suspension according to claim 9, further characterized in that the pH regulator maintains aqueous phase pH values of from about 3 to about 7.

12. The suspension according to claim 9, further characterized in that the pH regulator maintains aqueous phase pH values from about 3 to about 6.

13. The suspension according to claim 9, further characterized in that the pH regulator maintains aqueous phase pH values from about 4 to about 5.

14. - The suspension according to claim 1, further characterized in that the solid particles have average sizes less than about 5 μm.

15. The suspension according to claim 1, further characterized in that the solid particles have average sizes less than about 2 μm.

16. A process for producing a nebulizer suspension, comprising combining ingredients including water, mometasone furoate monohydrate, a nonionic surfactant and a soluble salt and subjecting the combination to particle size reduction by ultrasound or jet milling.

17. The method according to claim 16, further characterized in that the combination also includes a pH regulator.

18. The process according to claim 16, further characterized in that the reduction in particle size continues until solid particles having sizes less than about 10 μm are produced.

19. The method according to claim 16, further characterized in that the reduction in particle size continues until solid particles having average sizes of less than about 5 μm are produced.

20. - The method according to claim 16, further characterized in that the reduction in particle size continues to produce solid particles having average sizes less than about 2 μm.

21. The use, in combination of water, of mometasone furoate monohydrate, a nonionic surfactant and a soluble salt for preparing a nebulizer suspension as claimed in claim 1, for treating disorders of the respiratory tract.

22. The use, in combination of water, of mometasone furoate monohydrate, a nonionic surfactant and a soluble salt for preparing a nebulizer suspension as claimed in claim 16, for the manufacture of a medicament for treating disorders of the respiratory tract.