Title: Mometasone furoate suspensions for nebulization
United States Patent: 6,187,765
Inventors: Harris; David (New Providence, NJ); Sequeira; Joel A. (Edison, NJ); Chaudry; Imtiaz A. (North Caldwell, NJ)Assignee: Schering Corporation (Kenilworth, NJ)
Appl. No.: 167512Filed: October 6, 1998
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.
DETAILED DESCRIPTION OF THE INVENTION
Percentages expressed herein are meant to indicate percent
by weight, unless the context clearly dictates otherwise.
The suspension formulations of the invention may be delivered to a patient
using any of the usual nebulizer devices. Typical commercial nebulizer
devices produce dispersions of droplets in gas streams by one of two
methods. Jet nebulizers use a compressed air supply to draw up a fluid by
venturi action and introduce it into a flowing gas stream, after which the
fluid is caused to impact one or more stationary baffles to remove
excessively large droplets. Ultrasonic nebulizers use an electrically
driven transducer to subject a fluid to high-frequency oscillations,
producing a cloud of droplets which can be entrained in a moving gas
stream; these devices are less preferred for delivering suspensions. There
are hand-held nebulizers which atomize the fluid with a squeeze bulb air
supply, but the more widely used equipment incorporates an electrically
powered compressor or connects to a cylinder of compressed gas. Although
the various devices which are commercially available vary considerably in
their delivery efficiency for a given medicament, they all are useful for
the treatment of the present invention; it is necessary for the prescriber
to specify an exact amount of medicament formulation which is to be
charged to each particular device, since their respective outputs of
respirable droplets are far from identical.
Suspension formulations suitable for nebulization must, of course, contain
solid particles of a respirable size (e.g., preferably averaging less than
about 5 .mu.m in the largest dimension and more preferably averaging less
than about 2 .mu.m) and must maintain their suspended particle size
distribution during storage. In addition, the particle-containing droplets
formed during nebulization of the formulations must have appropriate sizes
for deposition in the desired area of the respiratory system.
Since the formulations of the invention are to be inhaled, it is necessary
that they be free of pathogenic organisms. Thus, they may be prepared and
handled under sterile conditions, or may be sterilized before or after
packaging. In addition, or in lieu of sterilization, a preservative may be
incorporated to minimize the possibility of microbial contamination. In
addition, all components of the formulations must be chosen for inhalation
safety, as the treated tissues are quite sensitive to irritants; it is
commonly known that many of the common preservatives have a considerable
potential for causing irritation.
The inventive formulations comprise water, mometasone furoate monohydrate,
a nonionic surfactant, a soluble salt and optionally a pH buffer.
Water for use in the formulations should meet or exceed the applicable
regulatory requirements for use in inhaled drugs. Specifications
established by the United States Pharmacopoeia for "Sterile Water for
Injection" or "Sterile Water for Inhalation" are examples
of water suitable for use to prepare formulations of the invention.
Mometasone furoate is a corticosteroid having the chemical name
9.alpha.,21-Dichloro-11.beta.,17-dihydroxy-16.alpha.-methylpregna-1,4-dien
e-3,20-dione 17-(2-furoate), and is currently marketed by Schering
Corporation in cream and lotion formulations for the treatment of
dermatologic conditions. Information concerning the preparation and
properties of mometasone furoate is given in U.S. Pat. 4,472,393. This
compound may be used to prepare mometasone furoate monohydrate for use in
the present invention. Information concerning the preparation and
properties of mometasone furoate monohydrate is given in PCT International
Application WO 92/04365.
In general, the concentration of mometasone furoate included in the
suspension formulation will depend upon the dose to be delivered to the
patient, ease of handling and the characteristics of the nebulizer
equipment, as the devices vary considerably in their suspension capacities
and nebulization efficiencies. Typical suspensions may contain as much as
about 5 mg/mL of mometasone furoate, although lower concentrations, such
as 50 .mu.g/mL to 1 mg/mL are more customary for most equipment.
Surfactants are frequently categorized by their chemical nature, i.e., as
cationic, anionic or nonionic. Cationic surfactants, such as cetyl
pyridinium chloride, and anionic surfactants, such as docusate sodium, do
not appear to provide proper dispersions of particles in the formulations.
Many nonionic surfactants are suitable for maintaining the particulate
suspensions of the invention. These include surfactants identified as
"polysorbates" in the CTFA International Cosmetic Ingredient
Dictionary; such surfactants are mixtures of fatty acid esters
(predominately monoesters) of sorbitol and sorbitol anhydrides, condensed
with ethylene oxide. Although these surfactants vary widely in their
hydrophilic-lipophilic balance ("HLB") numbers, they all appear
to function well in the invention.
Commercially available polysorbates which are useful in the invention
include those listed in the following table, which shows the CTFA
designation (Polysorbate number), identity of the fatty acid used to
produce the material and the number of moles of ethylene oxide reacted
with each mole of ester. Compositions identified with an asterisk are
predominately triesters.
Polysorbate Acid Moles EtO
20 Lauric 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, Polysorbate surfactants will be present in a formulation at about 50 to 500 .mu.g/mL. When the surfactant concentration is below about 20 .mu.g/mL, the particles tend to form cakes which are not easily redispersed.
Useful surfactants also include the "Poloxamers," which are block polymers of polyoxyethylene and polyoxypropylene, generally corresponding to the following formula:
HO(CH2 CH2 O)x [CH(CH3)CH2 O]y (CH2 CH2 O)z H
Representative commercially available poloxamer surfactants are listed in the following table, wherein the CTFA designation (Poloxamer number) and average values of x, y and z are given.
Poloxamer x y z
101 2 16 2
105 11 16 11
108 46 16 46
122 5 21 5
123 7 21 7
124 11 21 11
181 3 30 3
182 8 30 8
183 10 30 10
184 13 30 13
185 19 30 19
188 75 30 75
212 8 35 8
215 24 35 24
217 52 35 52
231 6 39 6
234 22 39 22
235 27 39 27
237 62 39 62
238 97 39 97
282 10 47 10
284 21 47 21
288 122 47 122
331 7 54 7
333 20 54 20
334 31 54 31
335 38 54 38
338 128 54 128
401 6 67 6
402 13 67 13
403 21 67 21
407 98 67 98
Poloxamer surfactants are used at concentrations similar to those for the Polysorbates, although certain members are useful at concentrations up to about 1 mg/mL.
In general, the chosen surfactant should not materially increase the viscosity of the suspension formulation, since the efficiency of the nebulization process is particularly sensitive to viscosity. Many nonionic surfactants are useful for preparing inhalation and/or injectable drug formulations, and any of these should be suitable for use in the present invention.
The formulations further include a soluble salt. This salt performs at least two functions: it minimizes the effects of the inhaled formulation on the normal cell fluid balance of airway cells and also stabilizes the suspension of medicament. For the first function, it is preferred to use sufficient salt concentrations to render the formulation isotonic; sodium chloride and potassium chloride are preferred for this purpose. 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 about 0.2 to about 2 weight percent are useful. Any physiologically compatible alkali metal or alkaline earth metal soluble salt can be used in the present invention.
Optionally, the formulations will contain a pH buffer, to maintain the formulation pH between about 3 and about 7. It has been found that stability of the drug (as measured by the absence of degradation reaction products) in suspension is improved by maintaining pH conditions below about 6. For reasons of tissue compatibility, excessively acidic products are not desired, so the pH should not be made to be below about 3. Some experimentation may be needed to qualify specific buffers for use in the invention: phosphate buffers in concentrations of 1 to 50 millimolar do not appear to adequately prevent caking of the particulates in the suspension when there is no added soluble salt. A citrate-citric acid buffer, maintaining pH between about 4 and about 5, has been used with particularly good effect for both maintaining pH during storage and preventing any particulate caking in the absence of soluble salts.
The citrate-citric acid buffer may be present in suspension formulations at concentrations at least about 2 and up to about 50 millimolar. While the literature has some reports of cough being induced by such buffer systems, this seems to occur primarily at the 150-200 millimolar level, although one report attributed cough to only a 35 millimolar concentration.
Sterility or adequate antimicrobial preservation of the final packaged formulation is needed for patient protection. The use of antimicrobial preservatives is less desirable, since certain of these have been associated with adverse clinical effects, such as bronchospasm. Alternative processes which may be considered for achieving sterility usually will not include sterilization steps for the micronized drug substance or formulation, since it has been found that the drug undergoes degradation under the influence of gamma-ray irradiation and sterilizing heat conditions. Sterilization by filtration ordinarily will not be feasible, due to the suspension nature of the formulation. Thus, it is preferred to produce the mometasone furoate monohydrate under sterile conditions, conduct the drug micronization in a sterile environment, and perform a sterile packaging operation.
Methods are known for reducing particle sizes into the micrometer range, including mechanical milling, application of ultrasonic energy and other techniques. Mechanical milling frequently generates high surface temperatures on the particles, and this is undesirable for mometasone furoate monohydrate which tends to lose some part of its hydration under the influence of high temperatures. Ultrasonic techniques are quite slow in their action, generally requiring very long processing times, but are capable of producing acceptable suspensions.
Suspensions of drug particles can rapidly undergo particulate size reduction when subjected to "jet milling" (high pressure particle in liquid milling) techniques. A presently preferred jet milling procedure for producing the formulations of the invention involves the use of the "Microfluidizer" system sold by Microfluidics International Corporation of Newton, Mass., U.S.A. This device divides a fluid stream, flowing under high pressures (up to about 40,000 pounds per square inch, or 2.76 x 108 newton/meter2), between two separate microchannel paths and then recombines them from generally perpendicular directions to create very high shear, impact and cavitation forces. By continuously recirculating suspensions through the system for a predetermined time period, it is possible to reproducibly create desired distributions of micron- and submicron-sized particles. Since 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 hydration water in the drug crystals will remain intact. Other useful equipment which utilizes related technology is available from Avestin Inc., Ottawa, Ontario, Canada.
Claim 1 of 21 Claims
What is claimed is:
1. A nebulizer suspension consisting essentially of water, mometasone
furoate monohydrate, a nonionic surfactant, about 0.2 to about 2 weight
percent of sodium chloride or potassium chloride and, optionally, a pH
buffer.
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