JPS6247880B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a unique crystalline form of flunisolide, a process for the preparation of this new crystalline form, the treatment of respiratory diseases using this form, and therapeutically useful formulations containing this unique form of flunisolide. Flunisolide is a known compound, 6
α-Fleol-11β, 21-dihydroxy-16α,
17α-isopropylidene dioxypregnane-1,
It is a common name for 4-diene-3,20-dione. This compound and its method of preparation are described in US Pat. No. 3,126,375 to Ringold et al. This compound has anti-inflammatory, glucogen synthesis, thoracic, anti-estrogenic, anti-androgenic and anti-pruritic activities and is primarily used in the treatment of local inflammatory conditions. This compound was not previously known to be polymorphic, but according to the present invention there are several polymorphic forms, one of which is particularly stable in the presence of an aerosol propellant and easily It has been found that it can be formulated to form an aerosol that is particularly useful in the treatment of respiratory diseases such as bronchial asthma, allergic rhinitis and other diseases that respond to treatment with appropriate steroids. It is generally known that certain steroids can be used in the treatment of asthma, for example hydrocortisone and prednisolone have been used as aerosol suspensions. [For example, J. J. Allergy, 29 (3), 214-221, 1958]. Other steroids used in various formulations include dexamethasone phosphate (US Pat. No. 3,282,791 to Macek);
No.: J. Allergy (J.Allergy), 34 (2),
119-126, March-April, 1963], Betamethasone 17-Warerate [ JAMA , 231(4), 406-
407, 1975, January 27] and triamcinolone acetanide [G.I. Allergies (J.
Allergy, 33 (1), January-May, January-February, 1962 and American Review of Respiratory Sciences.
Disese), 109 , 538-543, 1974]. Beclomethasone dipropionate (9α
-Chlor-16β-methyl-prednisolone-17
α,21-dipropionate) fluocinolone
Acetonide (6α,9α-diphreol-11β,21
-dihydroxy-16α,17α-isopropylidenedioxy-pregut-1,4-diene-3,20-
It is also known that it can be used in aerosol formulations as taught in DE 23 20 111 together with certain other steroids such as diones. However, this patent shows that when these steroids are placed in an aerosol formulation without prior treatment, the particles tend to increase in size;
It is taught that there is a tendency for deposits to build up on the walls of the can or around the mouth of the discharge tube, ultimately clogging the tube or causing changes in the concentration of the aerosol discharged. That is, this patent states that by the method described therein, when the steroid is first dissolved in a solvent, the solvated steroid does not tend to increase its particle size;
It also teaches that it is not lost from the dispersion during aerosol formulation. According to the present invention, it has been found that flunisolide is useful in the treatment of respiratory diseases such as bronchial asthma, allergic rhinitis, nasal fungus, and the like. The present invention also allows for the production of a unique crystalline form of flunisolide, which has been found to be stable in aerosol formulations using suitable fluorinated and carbonized hydrocarbon propellants. This previously unknown crystalline form forms easily dispersible crystals for use in the treatment of bronchial asthma, allergic rhinitis, or other chronic respiratory diseases when combined with another polymorphic form of flunisolide in a suitable solvent. It can be produced by contacting for a sufficient period of time to form a shape. Compounds useful for treating human respiratory complaints in the methods of the invention have the following formula: 6α-Fleol-11β,21-dihydroxy-16α,17α,2′-propylidenedioxy-
It is pregna-1,4-diene-3,20-dione (hereinafter referred to as flunisolide). This compound can be made as described in US Pat. No. 3,126,375, which is incorporated herein by reference as much pertinent description as possible. Novel crystal structure of flunisolide (Form A) The unique crystalline form according to the present invention is crystalline flunisolide, 6α-fleol-11β,21-dihydroxy-16α,17α-isopropylidenedioxypregna-1,4-diene-3, 20-dione, hereinafter referred to as type A. It was not previously known that flunisolide was a polymorph. The Form A crystal structure is a polymorphic structure, and it has been found that this form is particularly suitable for aerosol formulations due to its stability. The particle size of this unique crystalline form is suitably less than 100 microns (98% or more of the particles are smaller than 100 microns), preferably less than 25 microns. Particle sizes on the order of up to 10 microns are best to achieve uniform dispersion of Form A in a suitable fluorinated chlorinated hydrocarbon. This crystal structure has an X-ray diffraction pattern as shown in Table A below.

【table】

[Table] The theory and definition, as well as a general explanation of the general method of X-ray diffraction, can be found in the National Formulary, 902~
It is described in a 904-page paper. The X-ray diffraction pattern was obtained using a thief art having a copper anode tube with a Nickel filter and a 35mm Nonius camera with a diameter of 114.6mm.
Siefert Debeyflex Universal X-ray Generator Catalog No. 2200 (Siefert Debeyflex Universal
Created using X-ray generator Catalog No. 2200). Readings were taken using ground flunisolide powder placed in a suitable capillary tube with an internal diameter of approximately 0.5 mm placed in the X-ray beam. The crystal structure of this ground flunisolide exhibits a regular ternary pattern in which its atoms and molecules are packed together. In the above diffraction pattern, the symbol "d" is interplaner spacing,
In other words, it is the distance between the parallel planes on which the atoms of the crystal are placed. The spacing between each plane in the ternary lattice is measured from X-ray diffraction. The size of this space is expressed in terms of angstroms (Å). ``θ'' is half the angle between the main beam projection and the diffracted beam, while the ratio ``I/I ₁ '' is the relative intensity of the X-ray limit and ``I'' is the indicated ``d'' value. , and “I ₁ ” is the strongest extreme intensity of the pattern. Compare the strength when using film on a graduated scale. As indicated in the National Formulary article mentioned above, the intensity data in powder diffraction operations are only meant as a guide to the strong and weak X-ray limits. These can vary by at most about 25% between each experiment. Furthermore, the error in the data in the internal planar space (the "d" value) varies depending on the size of that space. The error in "d" is inversely proportional to "θ". Variations in the observed "d" values from the values given in Table A are acceptable up to a magnitude corresponding to ±0.3° θ (for copper target X-ray tubes). This is used to determine the A type. Production of Form A As previously mentioned, it was not known until now that flunisolide existed in polymorphic forms, and the existence of each of the forms defined below was newly recognized. . Form A of flunisolide can be prepared by recrystallizing the compound from a suitable neutral, non-polar hydrocarbon solvent or by recrystallizing the compound from a suitable neutral, non-polar hydrocarbon solvent.
or any suitable neutrality in which flunisolide does not dissolve fine particles in the form of another polymorph to a substantial extent;
It can be obtained by either contacting other polymorphic forms of non-polar compounds for a sufficient time to convert them to Form A. Suitably the particle size is less than 100 microns, preferably less than 25 microns. That a compound loses its crystalline state as it goes into solution will be confirmed by bringing the compound into aqueous solution. Form A has been found to be the form that flunisolide assumes whenever it is recrystallized from solution in a suitable solvent. Of course, flunisolide must be substantially soluble in the solvent in which Form A is precipitated. Particularly useful solvents for recrystallizing Form A include halogenated hydrocarbon solvents that are liquid at room temperature, especially chlorinated lower aliphatic hydrocarbons, such as methylene chloride. The method simply consists of dissolving any polymorph of flunisolide in a suitable solvent and allowing crystallization of flunisolide to develop Form A. This crystallization can be carried out by forcing flunisolide to crystallize out of solution, for example by adding another solvent in which flunisolide is only slightly soluble, for example a suitable aliphatic or aromatic liquid hydrocarbon. . Suitable aromatic hydrocarbons include benzene, toluene, etc., while suitable aliphatic hydrocarbons include carbon chains of medium length, such as those of 6 to 12 carbons, which may be branched or Or it can be linear.
Examples include iso-octane, hexane, heptane, nonane, decane or octane. Iso-octane, ie 2,2,4-trimethylpentane, is particularly effective. The fact that flunisolide in any other polymorph is converted to form A of flunisolide by contacting with a suitable non-solvent liquid means that in this way the crystal structure of the other polymorph is not obliterated by the solution. This is quite surprising since Form A appears to be produced by internal dislocations of the crystal without intermediate decomposition of the original crystal structure and without further grain growth. Compounds that have been found to be particularly useful in carrying out this transformation are halogenated lower aliphatic hydrocarbons, especially those containing one or more fluorine atoms, which are widely used as non-toxic propellants. These are known as freons, which is the trade name for a class of halogenated hydrocarbons (usually based on methane or ethane). Freon 12 (dichlorodifluoromethane), Freon 114 (dichlorotetrafluoroethane) and mixtures of these two and other Freons such as Freon 11 (trichlormonofluoromethane), Freon 22 (monochlor Freon 113 (trichlorotrifluoroethane),
Freon 21 (dichloromonofluoromethane),
Particularly useful are mixtures with Freon 13 (monochlorotrifluoromethane), Freon C318 (octafluorocyclobutane), Freon 115 (monochloropentafluoroethane), and the like. Other compounds that may be included include non-toxic lower alkanes containing up to 5 carbons such as butane or pentane. Form A can be prepared before forming the aerosol formulation, or it can be prepared by contacting the propellant in finely divided form with appropriately sized particles under suitable conditions to maintain the propellant as a liquid. can. Flunisolide's unique Form A is compatible with certain liquid propellants (e.g. Freon) that are ultimately used in the formulation.
12 and Freon 114), there is no need to first prepare Form A prior to formulation. The overall requirement is that the flunisolide be micronized to the desired particle size, ie, less than about 100 microns, suitably less than about 25 microns, and preferably less than about 5 microns. Conversion of the other polymorphic form of flunisolide to form A begins immediately upon contact with a suitable liquid compound. Substantially complete conversion is achieved in Freon at about 50 psig at room temperature in two weeks. Since Freon is generally gaseous at room temperature, care must be taken to use conditions that maintain the Freon in a liquid state. Therefore, a temperature below its boiling point must be used or the compound must be maintained under sufficient pressure to maintain it as a liquid. This is generally accomplished simply by using methods known in the art for the production of aerosols. The flunisolide is micronized to the desired particle size and then an aerosol "spray" or application product is prepared by known methods such as those described below. That is, if flunisolide is not first converted to Form A, the conversion occurs after the aerosol application has been prepared. As previously mentioned, it has been found that Form A is formed by contacting another polymorphic form of flunisolide with a suitable solvent such as those listed above. It is surprising to find that by heating form A to about 200° and then allowing the flunisolide to cool to room temperature, form A transforms into form B. Form B appears to be the most stable form as a free-flowing solid under atmospheric conditions. Form B has an X-ray diffraction pattern as shown in Table B below.

Table: Another polymorphism, referred to herein as Form C, also exists. This may be substantially pure flunisolide, or it may be in a form in which some amount of methanol is included in the holes of this particular crystal lattice, ie, forming a methanol clathrate. The X-ray diffraction pattern of Form C is shown in Table C. Form C can also be converted to stable Form B by heating to 200°C and then cooling to room temperature.

【table】

Treatment of Respiratory Diseases The method of the invention comprises administering by inhalation a therapeutically effective amount of flunisolide to a patient with a respiratory disease that responds to such treatment. This inhalation is performed through the center of the pharynx into the bronchi or into the nose,
A sufficient amount of the compound contacts the area of the disorder and causes its symptoms to improve. The affected portion of the respiratory system can be the nasal cavity, trachea, bronchi, lower airways or bronchioles. Flunisolide appears to be effective in bronchial asthma, bronchitis, pneumonia, occupational lung disease, allergic rhinitis, nasal fungus, and seasonal hay fever. In the treatment of respiratory tract allergies that typically reside primarily in the nasal region, such as allergic rhinitis, nasal mucus, or seasonal hay fever, a therapeutically effective amount of flunisolide may be administered ad libitum while the patient is inhaling through the nose. spray into the nasal cavity, but this inhalation is not necessary in each case. In the case of diseases of the trachea, bronchi or bronchioles, a calculated amount of aerosol (i.e. a gaseous suspension of solid particles) is ejected into the patient's mouth and the patient's mouth is misted; The active ingredient is most effectively applied by having the patient inhale at substantially the same time as the active ingredient is administered into the respiratory tract. Generally, the therapeutically effective amount for nasal disorders is about 0.01 milligrams (mg) per patient per day to about
5.0 mg, preferably 0.05 to 0.25 mg, while for other respiratory diseases, about 0.5 mg to about 5 mg, preferably 1 mg per day per patient.
A dose of 2 to 2 mg is effective. This amount may be administered in its entirety at once, or may be administered in small doses over several times at specified times during the day. This small amount can be anywhere from 0.01 to 1.0 mg per dose. The exact dosage will vary depending on, for example, the severity of the condition, the particular regimen used, other drugs used and individual differences involved. Flunisolide can be formulated using any method commonly known in the art, such as an aerosol or a sprayable liquid, such as a gaseous propellant for delivery as a gaseous suspension of solid particles (aerosol). solution, dispersion, in a suitable liquid carrier, which is filled under superatmospheric pressure or as a spray rigid bottle or compressed bottle with a pressure valve for dispersion of the droplets; It can be a solid or a suspension. Accordingly, one embodiment of the invention is contained in an aerosol composition in an amount of 0.001 to 20% by weight (calculated on the total composition) such that the composition is suitable for administration by inhalation. smaller than 100 microns, preferably 25 in a suitable container
6α-fluoro-11β,21 with particle size smaller than microns, particularly preferably smaller than 10 microns
-dihydroxy-16α,17α-isopropylidene dioxypregna-1,4-diene-3,20-dione. In this respect, a particle size smaller than 100 microns (or smaller than 25 microns, or also smaller than 10 microns) is defined as a particle size in which at least 98% of the particles considered are in the range between the size of a single molecule and the size of an aggregate of molecules. 100 microns (alternatively less than 25 microns, alternatively less than 10 microns). In the case of an aerosol, there is no need to solvate flunisolide prior to formulation, contrary to the teachings of the aforementioned German patents which require solvation treatment of beclamethasone dipropionate or fluocinolone acetonide prior to formulation. This is because the aerosol formulation surprisingly does not suffer from the problem of crystal growth. Generally, when using an aerosol, flunisolide is a finely divided solid material suspended with a non-ionic surfactant that is liquid at ambient temperature in a suitable liquefied propellant that also serves as a suspending medium. will be in powder form. Representative examples of self-propelling powder pharmaceutical compositions known in the art include those described in Patent No. 3,014,844 to Thiel et al. or Patent No. 3,322,625 to Shimmin; The relevant majority of the patent is incorporated herein by reference. More particularly, in the aerosol compositions useful in the methods of the invention, the active ingredient is generally a finely divided powder and can represent from about 0.01 to about 20% by weight of the total composition. A particularly suitable range is from about 0.05 to about 10%, and a preferred range is from about 0.1 to about 3% by weight of the total composition. Generally, the particle size of the finely divided solid powder should be less than 100 microns in diameter, more suitably less than 25 microns, and preferably less than 5 microns in diameter. The particles should be of sufficient size that they are deposited in the respiratory tract and are not expelled by the patient after inhalation. Also, the particle size of the powder should be substantially uniform for best results. Additionally, the surfactant present is approximately 0.1 of the total composition.
It may represent from about 20% by weight, preferably from 0.25 to 5%, preferably from about 0.25 to 1% for the purpose of treating respiratory diseases. The remainder of the composition is liquefied propellant. The surfactant used is preferably a liquid non-ionic surfactant, with a hydrophilicity of less than 10 -
Should have a lipophilic balance (HLB) ratio.
This HLB ratio is an experimental value that serves as a guideline for the surface activity of a surfactant. The lower the HLB ratio, the more lipophilic the drug, whereas the higher the HLB ratio, the more hydrophilic the drug. The HLB ratio is well known and has been published by colloid chemists. The measurement method is
Written by WCGriffin in the Journal of the Society of Cosmetic Chemistry
Cosmetic Chemists), Vol. 1, No. 5, pp. 311-326 (1949). Preferably the surfactant used should have an HLB ratio of about 1 to 5. HLB within these ranges by itself
Surfactants having no ratio can also be used, as long as they are used in combination with another surfactant having an HLB ratio that provides a mixture with an HLB ratio within said range. Surfactants that are soluble or dispersible in the propellant are useful. Additionally, propellants - soluble surfactants are the most effective. It is also important that the surfactant is non-irritating and also non-toxic. Among the liquid nonionic surfactants that can be used in the compositions according to the invention are caproic acid, octonic acid, lauric acid, palmitic acid, stearic acid,
Aliphatic polyhydric alcohols of fatty acids having 6 to 22 carbon atoms such as linoleic acid, linolenic acid, eleostearic acid and oleic acid or their cyclic anhydrides (e.g. ethylene glycol, glycerol, erythritol, arabitol, mannitol) , sorbitol, hexitol anhydride derived from sorbitol (sorbitan ester commercially available under the trade name ``Spanz''), and polyoxyethylene and polyoxypropylene derivatives of these esters. Mixed esters such as mixed or natural glycerides can also be used. Preferred surfactants are oleate esters of sorbitan,
For example, "Arlacel C" (sorbitan sesquioleate), "Span 80" (Span
80) (Sorbitan Monooleate) and “Span 85” (Sorbitan Trioleate)
It is commercially available under the trade name. Specific examples of other surfactants that can be used include sorbitan monolaurate polyoxyethylene sorbitol tetraoleate polyoxyethylene sorbitol pentaoleate. The liquefied propellant used is one that is gaseous at room temperature (65〓) and atmospheric pressure (760 mm mercury), ie has a boiling point below 65〓 at atmospheric pressure, and is also non-toxic. Among the suitable liquefied propellants that can be used are lower alkanes having 5 carbon atoms such as butane and pentane. The most suitable liquefied propellant is "Freon"
Fluorinated and fluorinated lower alkanes such as those sold under the trade name (Freon). Mixtures of the aforementioned propellants may also be suitably used. As the fluorinated or fluorine-chlorinated lower alkanes, those containing no more than four carbon atoms and at least one fluorine atom are intended. Suitable halogenated lower alkane compounds have the formula C <sub>n</sub> H <sub>o</sub>
Cl <sub>y</sub> F <sub>z</sub> (where m is a positive number smaller than 5, n is a positive number or 0, y is a positive number or 0, and z is a positive number, n+y+z=2m+2 It can be generally shown that Examples of such propellants include dichlorodifluoromethane (“Freon 12”), dichlortetrafluoroethane (“Freon 114”), monochloropentafluoroethane (“Freon 115”), trichlormonofluoroethane (“Freon 115”), Methane (“Freon 11”), dichloromonofluoromethane (“Freon 21”), monochlorodifluoromethane (“Freon 22”), trichlorotrifluoroethane (“Freon 113”), octafluorocyclobutane (“Freon C318”) ”), and monochlorotrifluoromethane (“Freon 13”). Certain mixtures of these compounds, such as "Freon" and "Freon 12" or "Freon 12" and "Freon
By using ``114'', a propellant with improved vapor pressure properties can be obtained. For example, dichlorodifluoromethane, which has a vapor pressure of about 70 psig, and 1, which has a vapor pressure of about 13 psig,
2-dichloro-1,1,2,2-tetrafluoroethane (“Freon 114”) in various proportions to achieve a medium vapor pressure well suited for use in relatively low pressure vessels. It is possible to form a propellant with The vapor pressure of the propellant used is itself about 25 to 65 psig at 70〓, preferably about 30 to 65 psig at 70〓.
Most preferably 40 psig. The one-component propellant specified for use in the compositions of the present invention can provide compositions with gauge pressures in the range of 55 to 65 psig at 70°C, and such compositions can be safely used with metal containers. can. Two-component propellants, such as an equal weight mixture of Freon 12 and Freon 11, are 20 to 40 psig at 70°.
gage pressures in the range of 100 to 100 ml, and such compositions can be safely used with specially reinforced glass containers. Generally, it can be used safely in a simple container and within the limits given by the desired specific gravity of the propellant, to prevent the pressure from becoming too high that the dispersion of the powder aerosol becomes too wide. It is desirable to keep the gas pressure as low as possible. If a strong container, such as a stainless steel container, can be used, and the active solid drug is to be inhaled into the lungs, it is advantageous to use a propellant with a gauge pressure of 40 to 50 psig; this is because the aerosol stream Allows complete aerosolization before reaching the back of the pharynx. Since the drug powder is already present in the composition, dispersed with the desired particle size, there is no need for further dispersing action in the valve or applicator, and a valve of simple construction can be used. It also requires special nozzles or expansion spaces, such as are normally required when the material to be dispersed is dissolved in the propellant or in a liquid that is emulsified by the propellant. Nor. In preparing the aerosols useful in the method of the present invention, a propellant containing finely ground powder in suspension is first charged into a container equipped with a suitable valve. The vessel can first be charged with a substantial amount of dry powder ground to a predetermined particle size, or alternatively, it can be charged with a slurry of material in a cooled liquid propellant. Another preferred method is to
The powder in the surfactant can first be ground or homogenized to a uniform paste, for example with a pestle and mortar. This paste is then dispersed into the cooled liquefied propellant. This method promotes uniform wetting of the powder particles. Furthermore, the container may be filled by introducing the powder and propellant by normal filling methods, or alternatively by filling the container with a slurry of powder in a propellant component boiling above room temperature. Good too. The appropriate amount of propellant can then be introduced by closing the valve and pressurizing it through the valve nozzle. Operation of the valve vaporizes the powder and disperses it into a propellant stream that provides an aerosol dry powder. The amount provided by each valve operation may be measured by any method known in the art. Through the manufacture of this formulation,
If the powder is adversely affected by water, it is desirable to take care to minimize water absorption. This can be easily accomplished by carrying out the process in a dehumidified atmosphere using only dry materials and drying equipment. Suitably, nasal diseases such as allergic rhinitis, rhinitis or seasonal hay fever may be treated by an aerosol formulation as described above or by a nebulizable liquid solution of flunisolide. If an aerosol is used for this purpose, the outlet is shaped to be suitable for delivery into the nasal passageway instead of into the mouth. Such applications are well known in the art. On the other hand, liquid solutions of flunisolide are easily dispensed from flexible spray bottles or other sprayable devices. The composition of this nasal spray solution is approximately flunisolide.
0.001 to 0.1% by weight, 0 to 0.1% by weight of a suitable organic solvent
50% by weight, 0 to 5% by weight of a suitable pharmaceutical carrier and the balance water. This solution is preferably isotonic and about
It has a PH of 4.0-8.0, especially about 5.0-7.0. Suitable organic solvents include glycols, alcohols or compatible mixtures thereof. Satisfactory glycol solvents include propylene glycol; polyethylene glycol with a molecular weight (MW) of 200 to 20,000; glycerol, butylene glycol and hexalene glycol. Among these, propylene glycol, polyethylene glycol and mixtures thereof having a molecular weight of 3,000 to 10,000 are preferred. Suitable alcoholic solvents include isopropyl alcohol, ethanol, and the like. Suitable formulation excipients include those that inhibit microbial growth (preservatives), maintain a suitable pH (buffers), prevent oxidation (antioxidants), or increase or maintain the effectiveness of the solution. Non-toxic substances known to be effective are included. Suitable preservatives include benzalkonium chloride, chloroethanol, methylparaben, propylparaben and any known in the art. Suitable buffers include inorganic or organic acid-base pairs such as citrate, phosphate, tartrate, and the like. A preferred buffer is citrate buffer. Suitable antioxidants include citric acid, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),
Includes propyl gallate and the like. A particularly useful formulation for nasal spray is Flunisolide 0.001
or 0.01% by weight, 0 polyethylene glycol
20% to 20% by weight, propylene glycol 15 to 20% by weight, suitable excipients 0.01 to 1.0% by weight.
and the remainder water, with the pH adjusted to 6.0±1.0. The method for preparing the solution for nasal application consists of first dissolving flunisolide in a solvent, then dissolving the excipients in water and finally mixing the two solutions. Examples of formulations useful in the method of the invention are shown below. These examples are merely illustrative and do not describe the scope of the invention or otherwise limit its apparent scope. For aerosols, these formulations exemplify flunisolide in combination with effective amounts of propellants (carriers) and surfactants, while for nasal sprays, flunisolide is combined with suitable solvents and excipients. Figure 2 represents a representative aqueous formulation combined with a pharmaceutically effective amount. Example 1 Aerosol flunisolide (1 to 5 micron particle size range) 3.0% Span 85 (sorbitan trioleate)
1.0 Freon 11 (Trichlormonofluoromethane) 30.0 Freon 114 (Dichlorotetrafluoroethane) 41.0 Freon 12 (Dichlorofluoromethane) 25.0 Example 2 Aerosol Flunisolide (1 to 5 micron particle size range) 0.5% Span 85 0.5% Propellant B 99.0% Propellant B is Freon 11 10%, Freon 114
50.4%, Freon 12 31.6% and Butane 8.0
It consists of %. Example 3 Aerosol flunisolide 1.00% Span 85 0.25% Freon 11 5.0% Freon W 93.75% Freon W consists of 61.5% Freon 114 and 38.5% Freon 12. Example 4 Aerosol flunisolide 0.50% Span 80 0.50% Propellant C 99.0% Propellant C consists of 30.0% Freon 11 and 70% Freon W. Example 5 Aerosol Flunisolide 0.88% Span 85 1.00 Propellant consisting of 50% Freon 12, 25% Freon 11 and 25% Freon 114 98.12 Example 6 Nasal spray solution Flunisolide 0.025% Polyethylene Glycol 6000 15.0% Propylene Glycol 20.0% Benzalkonium Chloride 0.01% Citric acid (anhydrous) 0.05% Water Adjust the PH to 100% Example 7 Flunisolide nasal spray solution 0.01% Sodium chloride 0.7% Propylene glycol 20.0% Benzalkonium chloride 0.01% Water Adjust to 100% Dosage Example 8 Nasal Spray Solution Flunisolide 0.01% 95% Ethanol USP 7.00% Sodium Chloride 0.8% Benzalkonium Chloride 0.01% Water Dosage Example 9 to 100% Preparation of Form A Flunisolide 122 g, containing some Form A material and mainly B A mixture consisting of methylene chloride
Dissolve in 800 ml and then filter to remove solid material. Iso-octane (2,2,4
- Add 1200 ml of trimethyl pentane) and leave at room temperature for 2 hours. The resulting solution is evaporated to 1000 ml and then left overnight at room temperature. The precipitate that forms is collected, dried and then analyzed by X-ray diffraction as described above. This precipitate was found to have substantially the same X-ray diffraction pattern as shown in Table A above, even after micronization. Example 10 Preparation of Form A The same procedure as described in Example 7 is carried out, except that the solution of flunisolide in methylene chloride is poured into isooctane. By X-ray diffraction, the resulting precipitate was found to have substantially the same X-ray diffraction pattern as shown in Table A.

Claims (1)

[Claims] 1. A crystalline compound, 6α-fluoro-11β,21-dihydroxy-16α,17α-isopropylene, having a particle size smaller than 100 microns and an X-ray diffraction pattern shown in Table A below. Dendioxypregna-1,4-diene-3,20-dione. [Table] [Table] [Table] 2. Compound 6α-fluoro-11β,21-dihydroxy-16α, in crystalline form with particle size smaller than 100 microns and having the x-ray diffraction pattern shown in Table A below. In the process for producing 17α-isopropylidenedioxypregnane-1,4-diene-3,20-dione, a period of time effective to convert substantially all of the other polymorphic forms to the above crystalline form. A method characterized in that said compound in the form of a liquid is brought into contact with a liquid halogenated lower alkane. [Table] [Table] 3. The process according to claim 2, wherein the alkane is Freon 12, Freon 114 or a mixture thereof. 4. The method of claim 2, wherein the compound of claim 2 in any polymorphic form is dissolved in a halogenated, lower hydrocarbon liquid solvent and crystallized from said solvent. 5. The method according to claim 4, wherein the solvent is methylene chloride. 6 (a) A crystalline compound, 6α-fluoro-11β,21-dihydroxy-16α,17α-, having a particle size smaller than 100 microns as an active ingredient and having an x-ray diffraction pattern as shown in Table A below.
Isopropylidene dioxypregna-1,4-
An inhalable composition for the treatment of respiratory diseases in humans, characterized in that it contains a diene-3,20-dione and (b) a pharmaceutically acceptable liquid aerosol propellant. 7. Claim 6, wherein the aerosol propellant is one type of Freon or a mixture of several types of Freon.
The composition described in Section. 8 Propellant is 50% Freon 12, 25% Freon
11. The composition of claim 6 comprising 25% Freon 114. 9. The composition of claim 6, comprising 0.001 to 0.1% by weight active ingredient, 0 to about 50% by weight solvent, 0 to about 5% pharmaceutically acceptable excipient, and the balance water. . 10. The steroid of claim 6 of the active ingredient has a particle size of less than 100 microns, preferably less than 25 microns, particularly preferably less than 10 microns (calculated on the total composition) from 0.001 to A composition according to claim 6, containing in an amount of 20% by weight.