MXPA97009431A - Steroid compositions stabilized and use of mis - Google Patents

Abstract

The degradation of triamcinolone acetonide in aqueous solutions is studied under accelerated storage conditions of 70 degrees Celsius on the pH scale of 1-10, the trace metal ions can notably accelerate the oxidative degradation in neutral and basic solutions, but the pH conditions and / or the inclusion of metal sequestering agents such as ethylenediamine tetraacetate (EDTA) in a preparation, decreases metal catalysis.

Description

STABILIZED ESTERQIDES COMPOSITIONS AND USE OF THEMSELVES FIELD OF THE INVENTION The present invention relates to stable liquid compositions of ester compounds, particularly adro-silicosteroids. have departed cu rily, the present invention relates to compositions es + ero? daLes cuos s e t b i 11 -? a «the - BACKGROUND OF THE INVENTION Many < The adrenocorties are shared by a cornun structural feature, namely the dihydroxy acelate side chain at C-17. A number of studies have shown that the dihydrox acetone side chain is prone to oxidative and hi-roly degradation in aqueous solutions. Kinetic studies related to this description include degradation in aqueous solutions of predmsolone, described by Tu + trnan, D.E. and Meister, PD, "The inetics of the basecatalyzed degradation of" predmsolone, "3. flrn. Pharm. ñssoc. 47 (1958) 773-778 and Oesterlmg, TO and Guttrnan, DE," Factors influenc ng stability of prednisolone m aqueous solution, "3. Pharm. 5c. 53 (1964) 1189-1192, of hrocortisone, described by Bundgard, H. and Hansen, 3.," tudies on the stability of corticosteroids. IV. Forma + ion and degí adatLon I- metics oí l dehi drocort cos * ero ds, key it rmedíate ', ín ihe oxidai ivo dücomposi i Lon o f- 21-dorudrocorticost eroids, lyi ntermed The and LGI the oxidative decornposi ion ot? lh drox? cort i cost eroids, "rch Pharm. Chern., cd. Fdn. ti (1980) 187-20 (5, Hansen, 3. and Bundgard, H", "tudies on the stability of cortí costeroíds T .. Kinetics of degradation of hydrocort i soné in aqueous solution," ñr 'h. Ph nn Chem., SCL. Edn "7 (L979) 135-146, Hansen, 3. and Dundgard, H.," tudies on the stability oí cor ti eos te oí s .. II Kmeties and ineeharusrn oí the ac -catalized clegradation of corticosteroid, "Hrch. Pharm. Chern., 5c i. Edn. 8 -5- 14 (1980), Hansen, 3. and Bundgard, H., "StudLes on the Stability of Coastal Costs. V. The degradation pattern of hydrocortisone Ln aqueous solution," Tnt. 3. Pharm. 6 (1980) 307-319 and Pit an, I.H., Higuchi, T., Alton, M. and Ui ey, R., "Deutepuin Lsotope effeets on degradation of hydr ocort i soné Ln aqueous solution," 3. Phann. Sc. 61 (1972) 918-920, of cloprednol, described by Johnson, D.M., "Degradation of clophednol in aqueous solution." The enolization step, "3. Qrg. Chein. 47 (1982) 198-201, and the tiariarcinolone acetomide, described by Gupta, V.D.

"Stability of tonnage acetonide solutions as determined by high-performance liquid chroinatography," 3. Phar'in. Sci. 72 (1983) 1453-1456 and Tirn ins, P. and Gray, E.A., "The degradation of triaincinolone acetonide in aqueous solution: mfluence of the eyclic ketal function," 3. Phann. Phrnacol. 35 (1982) 175- 177. Autooxidation has been reported as the main path of degradation under aerobic conditions in neutral and alkaline aqueous solutions. The autooxidation is uerternent or catalyzed by trace metal ions, especially copper, and the corporation of a sequestrant agent in the unica The catalysis of rne aL. The products of oxidative degradation have been characterized by hydroperoxide and flurandrenol do on cream basis. It was discovered that ester oxid glycosides (derivatives 21-dehydro steroids) were the key mediators in the oxidative decomposition of steroids. is. The acetonate of triarncmolone is a known active f-arnaceuticant ingredient used for the treatment of a variety of typical conditions, nasal, bronchial and other conditions of inflammation such as those described in U.S. Patents. Nos. 3,897,779 and 4,767,612, the disclosures of which are incorporated herein by reference.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of acetonide of t-parncinolone mixed with a pharmaceutically acceptable aqueous vehicle which provides said composition with properties resistant to the degradation by acetonide of riarncmolone in the presence of contaminants. is. A special embodiment of the invention relates to a pharmaceutical composition comprising a pharmaceutically effective amount of acetonate of triamotecannon mixed with a pharmaceutically acceptable aqueous carrier which provides said composition with properties resistant to degradation by acetonide of t cinol ona in the presence of contaminants, wherein the pH of the composition is between about "?" 9 and 5.1, and comprises a degradation inhibiting and effective amount of EDT.

BRIEF DESCRIPTION OF THE DRAWINGS Figure L shows HPLC crosslinked acetone granules degraded in aqueous solutions at 7 ° C for 22 hours, (a) pH 4.0, (b) pH 6.1, (c) pH 7.4, (d) pH 8.6 Figure 2 shows courses in time for acetonate of riarncmolone, I (o), glyoxaL hydrate, IV (o), glycolic acid, V () and ethyanic acid, VI () during oxidative degradation of T regulator of borate pH 8.9 at 70 ° C. The concentration of the pH regulator is 0.032 i "1. Figure 3 shows the effect of borate pH regulator concentration on the rate of degradation of 1 in the presence (o) and absence (o) of EDTA at 70 ° C. pH, 9.2 Ionic resistance, 0.1 Concentration of EDTA, 5X10-4 H. Figure 4 shows the effect of the concentration of EDTA in the rate of degradation of T in? Carbonate pH regulator from pH 9.4 to rO ° C, Figure b shows the effect of the concentration of CUSO * on the speed of (Jegradation of I in regulator do? l-1 (Jo borate (Jo pH 8.9 a / 0 ° C.) The figure shows the profiles (K-? H indication for the degradation of I in aqueous L? cions at 70 ° C in the absence (or ) and in the presence of 1x10-5 p | of Cuc »0« () or 5xL0 ~ 4 M of LDTA (o). The figure shows a scheme of degradation products of t-narneinolone acetonide (T).

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES 5e refers to the following non-limiting examples. These examples use the following materials, equipment, and analytical procedures.

Materials Acetonite of tory cmolone from Upjohn (Kalarnazoo, MI) was obtained. The purity of the medicinal substance was more than 99%, determined by means of CLAR analysis. Cupric acetate (Fisher, Pittsburgh, PA), periodic acid (Fisher), disodium salt of EDTA (Fisher) and all chemical derivatives were of reactive grade AC5 and were used as received. Fl acetonitrile was CLAR grade.

CLAR Analysis The chromatography system consisted of a pump (Per n Elmer 'ilO), an automatic injector (Perkin Eline L 5 100), a photo diode disposition detector (Perkin Elner 480), and a Network computer data acquisition (Wat rs 860). The CLAR emp Loo method has a stationary phase column of silica bonded with octyl of 250 mm x 4.6 mm, particle size of 5 μm, which is protected and protected (Zorbax Rx-08) and a mobile phase consisting of acetonitp Lo.agua.aci (Jo tp fl uoroacet co (320: 680: 0.68, v / v / v) .The flow velocity was 1.5 l / mm? to and the wavelength of the detector for the detection of absorbency of UV was (Je 238 nin.

Kinetic Method Solutions were prepared for the supply of tri-memolone acetonide (4 rnG / rnL) in methanol and pH regulators (0.2) in deionized water. An aliquot (0.5 ml) of the supply solution of acetonide of riarncinolone, an adequate quantity of pH regulator supply solution of hydrochloric acid (pH 1.1-2.0), chloroacetate (pH 3.0), acetate (pH 4.0-5.2) ), phosphate (pH 6.1-7.4), borate (pH 8.6-8.9) or carbonate (pH 9.0-10.0) and an adequate amount of 1 M NaCl to maintain an ionic strength of 0.1, were transferred to a volumetric flask of 100 rnL and filled with water. A low pH regulatory concentration (0.02 M) was used to minimize possible catalysis by means of pH regulating species. To study * the influence of the cupric ion or the GDG on the rate of oxidative degradation, an adequate amount of supply solution of CUSO-A 5x10-M) or N 2 EDTA (1.1x10) was added to the flask. -2 ri). No attempts were made to control the concentration of oxygen in the system.

Spectroscopy the NMR spectra of iH and 13C were regrouped in a Vanan VXRS 200 NMR spectrometer using CDCI3 or DMSO- (Je co or solvent.) The impact mass spectra (Je electrons (ET) obtained using a Finn gan 4500 mRNA spectrometer by direct input The energy of the electrons was 70 eV The mass spectra of FAB were obtained using a VG 70 5E mRNA spectrometer and nitrobenzyl alcohol as a matrix.

EXAMPLE 1 Acid solution degradation product Triamcinolone acetonide (200 mg) was suspended in 200 rnL of 0.1 N HCl and the suspension was brought to reflux for 24 hours. At the end of this period, the solution became clear. After cooling the solution a white solid material was precipitated from the solution. The solid was filtered and the product recrystallized from methanol < ? l 20% in water., The crystalline material was vacuum dried at 60 ° C for two hours. The mass spectrum of ET of the isolated product (TI in Fig. 7) showed a molecular ion in rn / z 394 (C 1 H27FÜ6) and a peak in m / z 74 (11+ -HF). The carbon NMR spectrum showed the absence of peaks at 25, 26 and 110 pprn which correspond to the carbons of the cyclic ketal group of acetoni or of the partial ring. Likewise, the proton NMR spec- trum showed the absence of rushes at 1.0 and 1.3 pprn corresponding to the methyl protons of the cetaL group. The spectra of mass and (Je NMR were identical to those of an authentic sample of tparncmolone (11).

EXAMPLE 2 Steroidal glyoxal hydrate (IV in Fig. 7) To a solution of 1 g of tnamcinolone acetonide in 125 ml of methanol was added a solution of 250 mg of cupric acetate in an equal volume of methanol. The solution was stirred at room temperature for one hour. The CLAR analysis of the solution showed that the reaction was complete only with one product. The methanol was removed under vacuum using a rotary evaporator. The residue was suspended in 500 ml of water and the product was extracted with 200 rnl of ethyl acetate. The ethyl acetate layer was washed with water and evaporated to dryness in vacuo. The residue was dissolved in a maximum amount of acetone. At the acetone solution, water was carefully added until the solution became slightly cloudy. The solution was kept in a refrigerator (overnight), and the starting material was filtered and dried at 60 ° C under vacuum for 2 hours. fast atoms (FAB) of the compound showed a protonated molecular ion (M + I-D + in m / z 451 and a p co in 43L (M + H-HF) +. but contained peaks in 432 (M-H2?) + and 412 (432-HF) +. The carbon-NMR spectrum showed a C-21 resonance at 85 pprn (doublets) instead of 66 pprn (tnplete) in 1. The theoretical theoretical analysis and the calculated values for C24H31FO7 are C 63.98, H.94, was found, C 62.70, H 7.06. The spectral information was in accordance with structure IV of figure 7.

EXAMPLE 3 The steroidal glycolic acid (V in Fig. 7) The glyoxal hydrate (IV) prepared from 1 g of triarncinolone acetonide was suspended in 250 rnl of 0.1 N NaOH. The suspension was stirred at room temperature for two hours. hours. The analysis of CLAR showed that the glyoxal hydrate was completely converted to glycolic acid (V). The solution was filtered and the filtrate was acidified by adding LN HCl by dripping until the pH of the solution was approximately 3. 11 product was extracted with 250 μL of otyl acetate and the ethyl acetate layer was washed with water. Water. The ethyl acetate was removed in vacuo using a rotary evaporator, the residue was dissolved in a minimum amount of methanol, and the solution was added slowly until no further precipitation occurred. It was dried under vacuum at 60 ° C (for two hours.) The mass spectrum of FAB showed a protonated molecular ion (M + H) + at m / z 451. Fl spectral mass (Je El also showed (MH -D + in 154 and peaks in 435 (M-CH3) + and 430 (M-HF. +.) The carbon NMR spectrum of the compound showed C-20 and C-21 in 71 (doublet) and 173 ppin (singlet) The proton NMR spectrum showed an acid proton at 125 pprn and a proton of C-20 not interchangeable at 4.3 pprn.The mass and NMR spectra were in accordance with Structure V.

EXAMPLE 4 The ethanic acid derivative (VI) To a solution of 2 g of tnarncmolone acetonide in 300 rnL of methanol, a solution of 4 g of periodic acid in 400 inL of water was added. The aqueous methanol solution was left at room temperature for two days in the dark. The methanol was removed under vacuum using a rotary evaporator and the residue was suspended in 200 mL of water. To the aqueous solution was added NaOH of LN by trickling until the pH of the solution was 8 9. The solon was filtered and the filter was stirred with ethyl acetate (2x30 inL). The ethyl acetate layer was discarded. The aqueous layer was acidified by the dropwise addition of 1 N HCl until the pH of the solution was 2-3. The product was extracted with ethyl acetate (3 × 100 μL). The ethyl acetate layer was dried over 200 mg of anhydrous Na 2 SO 4 and was removed in vacuo using a rotary evaporator. The white solid was dried under vacuum at 60 ° C (for 2 hours) The mass speci? cation of the compound showed a molecular ion at rn / z 420 and peaks at 405 (M-CH3) + and 400 fM-HF) + The carbon NMR spectrum showed a resonance of C 20 at 174 ppm instead of 210 pprn in 1 and loss of C-21 at 66 pprn in 1. The proton NMR spectrum showed a proton acid to 12.8 pprn and proton loss of C-21 in 1. The mRNA and NMR spectra were in agreement with the VT structure, the stability-specific HPLC method was used to follow the degree of acetom degradation or of riarncmolone in aqueous solutions (Figure 1) Due to the low solity of the drug in aqueous solutions, the concentrations of the degradation products they were not enough to isolate and identify most of the gradients. Therefore, the approach taken to elucidate the degradation profile of steroi.de had two stages. The first stage included the partial identification of the degreed in 1? sample solutions degraded by determining the molecular weight using an I.C-MS technique. The second stage required the synthesis and characterization of potential degradation products, followed by the identification of these compounds in degraded solutions by comparing their molecular weights and HPLC retention times. The glyoxaL synthesized from 1 was characterized as a hydrate (LV) by elemental analysis, PMN and FAI mass spectra). However, the mass spec- LC) compound produced the highest in / z peak that corresponded to non-iodinated aldehyde, due to the loss of water during the ionization of the sample. The co-injection of a degraded sample (Je 1 and the synthetic compound showed a peak at 8.3 minutes.) The spectrum of ion spray mist of the L5 synthetic and degraded samples produced identical peaks at rn / z 451 (M + H) + and 492 (MH ++ CH3CN) in the mobile phase. In this way, the gradient was identified as the steroidal glyoxal. It comes in hydrated form (IV) in the aqueous solutions, as well as in the solid state. The glyoxal hydrate peak appears first in the drug degradation solutions in neutral and alkaline l-1 regions (Fig. 1 b, c, d). In neutral and basic solutions, the path of primary degradation is the autooxidation of the primary alcohol group in C-21 as in other coastal areas. The main degradation product is the steroid glyoxal hydrate (IV) as shown previously (Figure 2). The 1 The pr oducts are additional to V in alkaline solutions, and as the pH of the solution decreases below 4, this path of oxidative degradation is absent (Figure 1). The acetyl of triacylnolone is reduced to produce a non-linear (TL). The speed (disappearance) of the riaincinolone acetonide exhibited a dependence on the concentration of pH regulator at a constant pH and resistance. Ionic (fLg.1) In the absence of EDFA, a graph of the velocity constant versus the concentration of the pH regulator is curved, and the velocity constant is unbalanced at high concentrations of the pH regulator. In the presence of EDTA, the rate constant is independent of the pH regulator concentration. The results strongly indicate that the pH regulating components have no catalytic influence, but that the increase in velocity is due to the catalytic effect of the trace metal contaminants present in the components of the pH regulator, similar observations were made in the degradation. of prednisolone (Oesterl g and Guttrnan, 1964) and hydrocortisone (Hansen and Bundgard, 1979) The effect of EDTA concentration on the rate of degradation constant is shown in Figure 4. The results show that EDTA , even at a very low concentration, it has a profound inhibitory effect, reaching the maximum inhibition level at the approximate concentration of LxLO-5 M. It is known that the cupric ion catalyzes the oxidative degradation of 2L-h? drox? cor The addition of cupric salt to a boron pH regulator increased the rate of degradation (Fig. '".), with the maximum velocity at the concentration of 1? xLü-6 1 1 of CUSOA - Ferric and nickel ions exhibited negligible catalytic effects. The degradation of the acetonide of tiarnion was studied in aqueous solutions on the scale of pH of L-10, at 70 ° C and a resistance lomea of 0.1,. At a constant pH and temperature, the degradation followed by an apparent first order procedure under all experimental conditions. The results are observed as the graph (logarithm of the velocity constant versus pH (Fig. 6).) In the pH region below 3, the k-pH indication profile shows a straight line with an inclination of approximately - 1 declaring that the degradation appears to be a specific acid-catalyzed process.The straight line is observed when the degradation took place in the presence of cupric ion or EDTA.In this region of pH, the cut of the cyclic setal is the dominant reaction that produces triarncinolone (II) The non-oxidizing cutting reaction does not depend on metal catalysis, therefore, it is expected that the incorporation of cupric ion or EDTA in the solutions will have no effect on the rate of degradation as shown in figure 6 Ib At a pH of more than 4, the predominant degradation product was the oxidation product (IV). Between a pH of 4 and 7, the profile shows a straight line with an inclination of approximately • * 1 indicating catalLsi of specific base. In this pH regulation, the incorporation of 1x10-5 M < ie CuSO * in the solutions had no effect on the rate of degradation, while 5x10_4 M of FDTA decreased the rate of degradation by two orders of magnitude. This observation indicates that the metal ions present in the pH regulating components catalyze the degradation to the maximum and, therefore, the additional cupric ion does not have an additional catalytic effect. In the pH region above 7, an independent plateau of pH is reached, followed by - a portion of Straight Line with an inclination of about +1 between pH B and 10. Between pH 7 and 1 0, the experimental points are scatters. Figure 3 shows that the velocity constant (1.2xlü_5 sec-i) extr-apolated at zero concentration of pH regulator, coincides with that obtained in the presence of EDTA. In this way, by eliminating the catalysis of the pH regulator (trace metal catalysis in pH-regulating components), the indication profile -pH would be superimposed on the one determined in the presence (He EDTA.The indication profile k-? H in the present study does not show plateaus when Cuso * or EDTA is incorporated in the solutions, and the indication k increases when increasing the pH with Lh a mcLinAtion of * 1. Cupric ion improves speed, while EDTA slows down velocity. This observation strongly indicates that the plateau is not bound to the ionization of steroid molecules, but rather to a different degree of catalysis by contaminants of trace metal ion present in the pH-regulating components. The expression of velocity for the reactions catalyzed by copper and sequestered by metal is given by? < - I H r? -? + 1 *? 0 * - I < O H i o? -n where K is the observed rate constant, KH and KOH are the respective second order constants and K0 is the spontaneous or water catalyzed reaction rate constant. The KH, KOH and Ko values were calculated from Figure 6 as 3.0xl0-4 seg-i M1, 15.9 seg-i M_1 and 4.6x10"8 sec-1, respectively, for the degradation reaction catalyzed by - copper, and 3.0x10-4 seg-1 M_1, 0.11 seg- i M_1 and 2.6xL0-8 seg-1, respectively, for the metal-sequestered reaction It should be mentioned that the degradation catalyzed by cupric ion is 150 times as The glyoxal is + eroidal (I TI) undergoes an additional degradation to the corresponding glycolic acid (V) in alkaline solutions. A small amount of the corresponding ethyanic acid (VI) was observed in the degradation of 1 in alkaline solutions (Figure 2) This result indicates that a small amount of the steroid suffers from the cut. between C-20 and C-21 during oxidation, it is possible that VI could have been fo It is reinforced by the oxidative cleavage of glyoxaL (III). The experimental data described above and shown in the figures demonstrate the properties of stability and resistance to the degradation of the preferred modalities and modalities according to the present invention under accelerated laboratory conditions.These properties provide long-term stability. The aqueous acetonide compositions of the present invention under normal use, at room temperature during storage times awaiting use by the distributor, pharmacist and patients. Commercial acceptability of the present compositions will be from at least 5 months to one or more years, at room temperature, which is about 25 ° C. The compositions of this invention are useful in the treatment of patients suffering from certain medical disorders . For example, the compounds within the present invention are useful as bronchodilators and prophylactic asthma agents, e.g., for the treatment of inflammatory airway disease, especially reversible airway obstruction or asthma, and for the treatment of other diseases or conditions characterized by, or having an etiology that includes the accumulation of morphine eosophilic eos. With additional examples of conditions that may be diminished, inflammatory diseases, allergic rhinitis and adult respiratory distress syndrome may be mentioned. A special odaLity of the therapeutic methods of the present invention is the treatment of asina. In practice, the compositions of the present invention may generally be administered by inhalation, and may be presented in forms that allow admixture suitable for use in human or veterinary medicine. These compositions can be prepared according to the common methods, using one or more pharmaceutically acceptable auxiliaries or excipients. The auxiliaries include, among others, diluents, sterile aqueous media and different non-toxic organic solvents. The compositions may be presented in the form of aqueous solutions or suspensions, and may contain one or more agents chosen from the group comprising surfactants, flavorants, dyes or preservatives to obtain pharmaceutically acceptable preparations. Suitable compositions containing the compounds of the invention can be prepared by conventional means. For example, the compounds of the invention can be dissolved or suspended in a suitable vehicle for use in a nebulizer or aerosol suspension or solution.The percentage of active ingredient in the compositions of the invention can be varied, being necessary that should be a proportion t L that a suitable dosage can be obtained Obviously, several dosage unit forms can be administered at approximately the same time The dose used will be determined by the doctor, and depends on the desired therapeutic effect, the route of administration and the duration of the treatment, as well as the condition of the patient.In the adult, the doses are generally from about 0.001 to about 50, preferably approximately 0.0001 to about 5, mg / kg of body weight. per day by inhalation In each particular case, the doses will be determined according to the distinguishing factors for the subject to be treated Such as age, weight, general health status and other characteristics that may influence the efficacy of the medicinal product. The products according to the invention can be administered as often as necessary to obtain the desired therapeutic effector. Some patients may respond quickly to a high or low dose, and may find many maintenance doses to be weaker. For other patients, it may be necessary to have long-term treatments in the regimen of 1 to 4 doses per day, according to the physiological requirements of each patient in particular. Generally, the active product can be administered orally 4 times a day. It is not necessary to say that, for other patients, it will be necessary to prescribe no more than one or two doses per day. The present invention can be incorporated into other specific forms without departing from the spirit or essential attributes of the same and, consequently, it is necessary to make the following addenda, from 1 to pcion doscp, regarding the reach of the mvendon.

Claims (6)

NOVELTY OF THE INVENTION CLAIMS

1. A pharmaceutical composition comprising a pharmaceutically acceptable aqueous vehicle that can be applied to a pharmaceutically acceptable aqueous vehicle that provides said composition with properties that are related to the degradation of the hydrogen peroxide. olona in the presence of conta inant s.

2. The composition according to claim 1, wherein said contaminants comprise a metal < race.

3. The composition according to claim 2, wherein said trace metal comprises copper ion.

4. The composition according to claim 1, comprising decorating a metal sequestering agent.

5. The composition according to claim 4, wherein the metal sequestering agent comprises EDTA.

6. The composition according to the r-ei vindication 1, which has a pH of about 3.5 to about 4.5. 7.- The composition in accordance with the m claim 6, which has a pH of approximately 4. The composition according to claim 4, which has a pH of about 3.5 to about i6"5 .. 9.- The composition (Conformity with claim 8, which has a pH of about 5. 10. The use of an effective amount (ie, the composition according to claim 1, in the preparation of a medicament for treating inflammation in a patient. suffering from inflammation 11. The use of an effective amount of the composition (in accordance with claim 4, in the preparation of a medicament for treating inflammation in a patient suffering from inflammation. An effective amount of the co-position according to claim 8, in the preparation of a medicament for treating inflammation in a patient suffering from inflammation 13. A composition according to claim 1, wherein the resistance i nica is approximately 0.1. 14. A pharmaceutical composition comprising a therapeutically effective amount of acetonide of t-parncinolone mixed with a pharmaceutically acceptable aqueous vehicle that provides said composition with properties resistant to the degradation of the acetonide of t-parncmolone in the presence of minan, where pH of the composition is between about 4.9 and 0.1, comprising an effective and inhibiting amount of degradation (EDTA, L5.- A pharmaceutical composition according to claim 14, wherein the amount of degradation inhibitor. (Je EDTA is at least approximately LxLO-5 M.