United States Patent
`
`1191
`
`[11] Patent Number:
`
`4,866,051
`
`Sep. 12, 1989
`Hunt et al.
`[45] Date of Patent:
`
`[54] MICRONISED BECLOMETI-IASONE
`DIPROPIONATE MONOHYDRATE
`COMPOSITIONS AND METHODS OF USE
`
`[75]
`
`Inventors:
`
`John H. Hunt, Hertford; John M.
`Padfield, Meldreth, both of England
`
`[73] Assignee: Glaxo Group Limited, London,
`England
`
`[21] App1.No.: 696,427
`
`[22] Filed:
`
`Jan. 30, 1985
`
`Related U.S. Application Data
`
`[63]
`
`Continuation of Ser. No. 532,003, Sep. 14, 1983, aban-
`doned, which is a continuation of Ser. No. 433,704,
`Oct. 12, 1982, abandoned.
`
`Foreign Application Priority Data
`[30]
`Oct. 19, 1931 [GB] United Kingdom ................... 131425
`
`Int. Cl.‘ ............................................ .. A61K 31/56
`[51]
`
`[52] U.S. Cl. .. . .. . . .. ..
`. . . . .. .. 514/180; 514/826
`[58] Field of Search ................. .. 260/397.45; 424/243;
`514/180
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`4,370,322
`4,391,755
`
`1/1983 Busse et al.
`7/1983 Wang et al.
`
`........ 424/243
`. .. ..
`
`.................... 260/397.45
`
`FOREIGN PATENT DOCUMENTS
`
`3/1974 Portugal ......................... 260/397.45
`61637
`71309 5/ 1980 Portugal ................ ..
`260/397.45
`
`1047519 11/1966 United Kingdom
`260/397.45
`1511820
`5/1978 United Kingdom ........... 260/397.45
`OTHER PUBLICATIONS
`
`Acta Crystallographica (1981), B.37, 383-387, W. L.
`Duax et al.
`The Theory and Practice of Industrial Pharmacy, Leon
`Lachman, Herbet A. Liebermann and J. L. Karug,
`(1976), p. 279.
`
`Primary Examiner—Douglas W. Robinson
`Assistant Examiner-—Joseph A. Lipovsky
`Attorney, Agent, or Firm-——Bacon & Thomas
`
`[57]
`
`ABSTRACT
`
`Beclomethasone dipropionate in the form of its micro-
`nised monohydrate substantially free from water other
`than water of crystallisation. Pharmaceutical composi-
`tions containing the compound are also described. The
`compositions may be in the form of powder inhalation
`cartridges especially suitable for the treatment and/or
`prophylaxis of asthma.
`
`8/1982 Tanskanen .......................... 424/243
`4,347,236
`4,364,923 12/1982 Cook et al. .......................... 424/243
`
`9 Claims, 1 Drawing Sheet
`
`MYLAN EX 1009, Page 1
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`MYLAN EX 1009, Page 1
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`U.S. Patent
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`Sep.12,1989
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`4,866,051
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`MYLAN EX 1009, Page 2
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`MYLAN EX 1009, Page 2
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`

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`1
`
`MICRONISED BECLOMETHASONE
`DIPROPIONATE MONOHYDRATE
`COMPOSITIONS AND METHODS OF USE
`
`4,866,051
`
`This application is a continuation of application Ser.
`No. 532,003,
`filed Sept. 14, 1983, now abandoned;
`which is a continuation of Ser. No. 433,704, filed Oct.
`12, 1982, also abandoned.
`This invention relates to improvements in or relating
`to pharmaceutical compositions comprising 9a.-chloro-
`1 1B-hydroxy-16B-methyl-17a,21-dipropionyloxypreg-
`na-1,4-diene-3,20-dione, which is known as beclometha-
`sone dipropionate.
`Beclomethasone dipropionate is a corticosteroid
`which exhibits a high topical antiinflammatory activity,
`and is described and claimed in U.K. patent specifica-
`tion No. 1,047,519. The compound may be formulated
`into preparations suitable for topical administration as,
`for example, lotions, creams, oitments and the like. In
`the management of asthma it has been found effective to
`spray the corticosteroid into the bronchial system pro-
`phylactically. Formulations containing beclomethasone
`dipropionate for the treatment of asthma include aero-
`sol formulations consisting of a suspension of the micro-
`nised corticosteroid in a chlorofluorohydrocarbon pro-
`pellant. Such formulations are dispensed using conven-
`tional pressurised aerosols or inhalers.
`It has been found, however, that when micronised
`beclomethasone dipropionate is formulated with aero-
`sol propellants, the active compound exhibits crystal
`growth which results in the formation of particles hav-
`ing a size above 20 um. Medicaments for administration
`by inhalation desirably have a controlled particle size.
`The optimum particle size for inhalation into the bron-
`chial system is usually 1-10 pm preferably 2-5 pm.
`Particles having a size above 20 pm are generally too
`large when inhaled to reach the small airways. U.K.
`patent specification No. 1429184 describes a method of
`converting an anti-inflammatory steroid, such as be-
`clomethasone dipropionate, exhibiting crystal growth
`in aerosol propellants, into a form which does not ex-
`hibit such growth, whereby the steroid is contacted
`with ahalogenated hydrocarbon to form a crystalline
`solvate therewith, the crystalline material so formed
`being reduced to a particle size permitting inhalation
`into the human bronchial system when dispersed as an
`aerosol.
`
`Similarly, German Offenlegungsschrift 3018550 de-
`scribes ethyl acetate solvates of antiinflammatory ste-
`roids (particularly beclomethasone dipropionate) and
`South African Patent Specification No. 80/2601 de-
`scribes solvates of beclomethasone dipropionate with
`alkanes having from 5 to 8 carbon atoms, both for use in
`aerosol formulations. All these solvates appear to have
`essentially the same type of crystal structure.
`An alternative inhalation form of beclomethasone
`dipropionate is a form suitable for powder inhalation
`especially valuable for treating patients who are unable
`to use the pressurised inhalers effectively or who might
`use them incorrectly. In this form the contents of a
`cartridge are inhaled using an inhalation device which
`releases the drug from the cartridge when the patient
`inhales. Such drug delivery systems are more reliable
`for many patients.
`We have found that when pharmaceutical powder
`compositions which contain beclomethasone dipropio-
`nate contained in conventional gelatin inhalation car-
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`tridges are stored in adverse conditions the particle size
`distribution of the powder changes. Thus the fraction of
`fine particles having the desired 1-10 pm size may de-
`crease to such an extent that an unsatisfactory product
`may result.
`We have now found that in pharmaceutical dry pow-
`der compositions for use in powder inhalation car-
`tridges, the above problem can be overcome by using
`beclomethasone dipropionate in the form of its mono-
`hydrate. We have found that the particle size of the
`micronised monohydrate in such powder compositions
`remains substantially constant even after storage for
`extended periods. Beclomethasone dipropionate mono-
`hydrate, which differs in its crystal structure from the
`previously described solvates referred to above, has
`never been proposed for use in powder formulations for
`bronchial inhalation.
`
`According to one aspect of the invention we provide
`beclomethasone dipropionate monohydrate substan-
`tially free from water other than water of crystallisa-
`tion, at least 90% by weight of the particles thereof
`having an effective particle size below 10 pm, prefera-
`bly between 2-5 pm.
`The new monohydrate of the invention has also been
`characterised by its infrared spectrum. The infrared
`spectrum of a sample of the monohydrate as a mull in
`mineral oil is shown in the FIGURE of the accompany-
`ing drawing.
`The principal absorption bands are at 3560, 3510,
`3300, 1730, 1710, 1663, 1630, 1285, 1190, 1120, 1090,
`1053, 973, 940, 890, 810, 785, and 700 cm—1.
`The invention further provides a pharmaceutical dry
`powder composition comprising micronised beclome-
`thasone dipropionate monohydrate in association with
`at least one pharmaceutically acceptable powder carrier
`or excipient.
`The monohydrate may be conventionally prepared
`by crystallisation from a mixed solvent system consist-
`ing of water and a water-miscible organic solvent. For
`example, the monohydrate may be prepared by slowly
`adding a solution of beclomethasone dipropionate in a
`water-miscible organic solvent to water, whereafter the
`monohydrate is crystallised. The beclomethasone di-
`propionate is conveniently first dissolved in the organic
`solvent at an elevated temperature e.g. at a temperature
`of mm 40° to 80° C., for example, at about 60° C. The
`organic solvent solution is then added slowly to water,
`preferably with stirring, while maintaining the solution
`at a temperature of e.g. 40° to 80° C., preferably about
`60° C. Upon cooling, of the resulting suspension, the
`crystalline monohydrate is formed.
`Water-miscible organic solvents which may be used
`in such a process include, for example, methanol, etha-
`nol, acetone and dioxan.
`After crystallisation, the monohydrate may be iso-
`lated by, for example, filtration and washed and dried in
`conventional manner. For example, the monohydrate
`may be dried by air drying, drying under reduced pres-
`sure, or drying in the presence of a sterile inert gas.
`The beclomethasone dipropionate monohydrate may
`be micronised to the desired particle size range by con-
`ventional techniques, for example using a ball mill or
`fluid energy mill or by ultrasonic means. The desired
`fraction may be separated out by air classification or
`sieving. The compositions may be prepared by inti-
`mately mixing the ingredients together, for example, in
`a high shear fluidising mixer. The compositions accord-
`ing to the invention may conveniently be filled into
`
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`MYLAN EX 1009, Page 3
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`

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`3
`gelatin, plastics or other capsules. Such capsules may be
`conventional two-part capsules or may be sealed. In
`general, No. 3 size hard gelatin two-part capsules are
`preferred.
`The monohydrate may also be prepared by commi-
`nuting beclomethasone dipropionate in the presence of
`water, for example, in a ball mill or by ultrasonic means.
`The compositions according to the invention exhibit
`the high topical antiinflammatory activity of beclome-
`thasone dipropionate. As indicated above, we have
`found that the particle size of the crystalline monohy-
`drate remains substantially constant even after storage
`for extended periods.
`These properties render the monohydrate of value in
`the preparation of the pharmaceutical powder composi-
`tions and their packaging in containers or packs.
`The compositions according to the invention are
`conveniently in the form of inhalation cartridges which
`may be used with an inhalation device, for example that
`described in U.K. Pat. No. 1561835 or British patent
`application No. 80 39174 (Publication No. 2064336).
`For use in the pharmaceutical powder compositions
`such as inhalation cartridges, the monohydrate is micro-
`nised, preferably such that at least 90% by weight of the
`particles have an effective particle size below 10 pm
`and preferably between 2 to 5 pm. Thus in a preferred
`embodiment we provide pharmaceutical powder com-
`positions such as inhalation cartridges, which comprise
`micronised beclomethasone dipropionate monohydrate,
`in which at least 90% by weight of the particles have an
`effective particle size below 10 pm, preferably between
`2-5 pm, and at least one pharmaceutically acceptable
`dry powder carrier or excipient. The carrier may be
`selected from diluents such as, for example,
`lactose,
`mannitol, arabinose or dextrose, but is preferably lac-
`tose. The carrier or excipient may be commercially
`available in the desired particle size range or may also
`be separated by air classification or sieving. The compo-
`sitions may also additionally contain a bronchodilator
`such as isoprenaline or salbutamol or an anticholinergic
`such as atropine or a drug used in the prophylaxis of
`allergic conditions such as sodium cromoglycate.
`The amount of the composition contained in the cap- 45
`sule will to some extent depend on the desired dosage.
`The compositions are conventiently in the form of
`dosage units (e.g. inhalation cartridges) containing be-
`clomethasone dipropionate monohydrate equivalent to
`from 10-1000 pg and preferably from 50-500 pg (e.g.
`20-250 pg) of beclomethasone dipropionate and from
`10-100 mg by weight and more especially from 25-50
`mg by weight of the carrier. Most preferably unit dos-
`ages of the compositions are such as to provide 100 to
`300 pg usually 200 pg of beclomethasone dipropionate.
`The average daily dosage of beclomethasone dipropi-
`onate monohydrate will depend on the age, weight and
`condition of the patient to be treated. In general, aver-
`age daily dosages lie in the range of 200 to 2000 pg,
`preferably 400 to 800 pg, of beclomethasone dipropio-
`nate. In the case of high dosage compositions, the daily
`dosage can be approximately about 4 mg of beclometha-
`sone dipropionate.
`The invention will now be illustrated with reference
`to the following non-limiting Examples. All tempera-
`tures are in “C. “Hplc” is high-pressure liquid chroma-
`tography, and “gc” is gas chromatography.
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`4,866,051
`
`4
`
`EXAMPLE 1
`
`Beclomethasone dipropionate (0.5 g), which had been
`previously dried to constant weight at 100°, was dis-
`solved in 15 ml ethanol. Water (100 ml) was added, with
`stirring, causing clouding followed by crystallisation.
`The crystalline hydrate in the form of long thin laths
`was removed by filtration and air-dried. Yield 0.5 g.
`The sample had the IR spectrum indicated in the
`FIGURE of the accompanying drawing.
`The crystals were subsequently micronised in a fluid
`energy mill to the particle size 2-5 pm.
`EXAMPLE 2
`
`Beclomethasone dipropionate (550 g) was dissolved
`in 3.2 liters of hot methanol and filtered. The filtrate
`held at a temperature of about 60° was added with stir-
`ring to 33 liters of deionised water, also at 60°. The
`mixture was cooled to 20° and the resulting crystalline
`monohydrate was removed by filtration, washed with
`water (1.0 liter) and air-dried. Yield 506 g.
`
`Analytical data
`Beclomethasone dipropionate
`w/w
`96.4%
`(hplc)
`w/w
`3.8%
`_
`Water (gc)
`
`Loss on drying (105°) w/w 3.5%
`
`
`The sample had the I.R. spectrum shown in the FIG-
`URE of the accompanying drawing.
`The crystals were subsequently micronised in a fluid
`energy mill to the particle size 2-5 pm.
`EXAMPLE 3
`
`Beclomethasone dipropionate (0.5 g) and water (25
`ml) were ball milled for 36 hours in a glass bottle with
`steatite balls. The solid in the form of fine particles of
`2-5 pm size was removed by filtration and air dried to
`give the monohydrate with the I.R. spectrum shown in
`the FIGURE of the accompanying drawing.
`EXAMPLE 4
`
`Deionised water (16.5 1) was heated to 60° and be-
`clomethasone dipropionate (250 g) dissolved in hot
`methanol (1.6 l) was added slowly at about 60° over a
`period of 2.5 minutes with stirring. The mixture was
`cooled to room temperature to give the precipitated
`hydrate which was collected by filtration, washed with
`water and dried in vacuo (ca 150 mmHg/40°). The
`product (253 g) had the I.R. spectrum indicated in the
`FIGURE. Loss on drying (105°) 3.19% w/w.
`The crystals were subsequently micronised in a fluid
`energy mill to the particle size 2-5 pm.
`EXAMPLE 5
`
`Beclomethasone dipropionate monohydrate: inhalation
`cartridges for use in a powder inhalation device
`
`Per cartridge
`
`Beclomethasone dipropionate
`monohydrate, micronised
`Lactose
`
`114 or 228 pg
`to 25 mg.
`
`The active ingredient and lactose are intimately
`mixed in a high shear lluidising mixer. The blend is
`encapsulated in No. 3 size hard gelatin capsules using an
`automatic machine. Each cartridge contains the equiva-
`
`MYLAN EX 1009, Page 4
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`MYLAN EX 1009, Page 4
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`5
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`4,866,051
`
`lent of 110 pg or 220 pg of beclomethasone dipropio-
`nate.
`
`EXAMPLE 6
`
`Beclomethasone dipropionate monohydrate and
`salbutamol: inhalation cartridges for use in a powder
`inhalation device
`
`
`
`Beclomethasone dipropionate
`monohydrate, micronised
`528 pg
`Salbutamol sulphate, micronised
`
`Lactose to 25 mg
`
`Per cartridge
`228 pg
`
`The active ingredients and lactose are intimately
`mixed as before and the blend is encapsulated in No. 3
`size hard gelatin capsules using an automatic machine.
`Each cartridge contains the equivalent of 220 pg of
`beclomethasone dipropionate and 440 pg of salbutamol.
`We claim:
`
`1. A pharmaceutical dry powder composition com-
`prising micronised beclomethasone dipropionate mono-
`hydrate in association with at least one pharmaceuti-
`cally acceptable dry powder carrier or excipient.
`2. A composition according to claim 1 wherein at
`least 90% by weight of the micronised beclomethasone
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`dipropionate monohydrate has an effective particle size
`below 10 pm.
`3. A composition according to claim 2 wherein at
`least 90% by weight of the micronised beclomethasone
`dipropionate monohydrate has an effective particle size
`between 2 to 5 pm.
`4. A composition according to claim 1 in the form of
`a dosage unit comprising a powder inhalation cartridge
`containing beclomethasone diproprionate monohydrate
`equivalent to from 10 to 1000 pg of beclomethasone
`dipropionate.
`5. A composition according to claim 4 wherein the
`dosage unit contains beclomethasone dipropionate
`monohydrate equivalent to from 50 to 500 pg of be-
`clomethasone dipropionate.
`6. A composition according to claim 1 additionally
`containing at least one compound selected from the
`group consisting of salbutamol and sodium cromogly-
`cate.
`
`7. A pharamaceutical composition as claimed in claim
`1 in association with a powder inhalation device."
`8. A powder inhalation device containing a pharma-
`ceutical composition as defined in claim 1.
`9. A method of treating bronchial conditions in a
`subject which comprises administering to said subject
`by inhalation techniques an effective amount of micro-
`nised beclomethasone dipropionate monohydrate in a
`pharmaceutical dry powder composition.
`IR
`*
`*
`*
`*
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