Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
  • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame

Definitions

• the present invention relates to stabilized liquid compositions of steroidal compounds, particularly adrenocorticosteroids. More particularly, the present invention relates to stabilized aqueous steroidal compositions.
• the autoxidation is strongly catalyzed by trace metal ions especially copper and the incorporation of a sequestering agent eliminates the metal catalysis.
• the oxidative degradation products have been characterized for hydrocortisone and flurandrenolide in cream base.
• the steroidal glyoxals 21- dehydro steroid derivatives
• Triamcinolone acetonide is a known pharmaceutically active ingredient used for the treatment of a variety of topical, nasal, bronchial and other inflammation conditions as described in US Patent Nos. 3,897,779 and 4,767,612, the disclosures of which are incorporated herein by reference.
• the present invention relates to a pharmaceutical composition
• a pharmaceutical composition comprising a therapeutically effective amount of triamcinolone acetonide in admixture with an aqueous pharmaceutical acceptable carrier providing said composition with properties resistant to triamcinolone acetonide degradation in the presence of contaminants.
• a special embodiment of the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of triamcinolone acetonide in admixture with an aqueous pharmaceutically acceptable carrier providing said composition with properties resistant to triamcinolone acetonide degradation in the presence of contaminants, wherein the pH of the composition is between about 4.9 and 5.1 , comprises an effective degradation inhibiting amount of EDTA.
• Figure 1 shows HPLC chromatograms of degraded triamcinolone acetonide in aqueous solutions at 70°C for 22 hours, (a) pH 4.0, (b) pH 6.1 , (c) pH 7.4, (d) pH 8.6
• Figure 2 shows time-courses for triamcinolone acetonide, I (o), the glyoxal hydrate, IV (o), the glycolic acid, V ( ⁇ ) and the etianic acid, VI ( ⁇ ) during
• Figure 3 shows the effect of borate buffer concentration on the rate of degradation of I in the presence (o) and absence (o) of EDTA at 70°C. pH, 9.2.
• Figure 4 shows the effect of EDTA concentration on the rate of degradation of I in carbonate buffer of pH 9.4 at 70°C.
• Figure 5 shows the effect of CuSO 4 concentration on the rate of degradation of I in borate buffer of pH 8.9 at 70°C.
• Figure 6 shows the log k-pH profiles for the degradation of I in aqueous
• Figure 7 shows a scheme of degradation products of triamcinolone acetonide (I).
• Triamcinolone acetonide was obtained from Upjohn (Kalamazoo, Ml). The purity of the drug substance was greater than 99 % as determined by HPLC analysis. Cupric acetate (Fisher, Pittsburgh, PA), periodic acid (Fisher), EDTA disodium salt (Fisher) and all other chemicals were of ACS reagent grade and used as received. Acetonitrile was HPLC grade.
• HPLC Analysis The chromatography system consisted of a pump (Perkin Elmer 410), an automatic injector (Perkin Elmer ISS 100), a photo diode array detector (Perkin Elmer 480), and a networking computer data acquisition system (Waters 860).
• the HPLC method employed a 250 mmx 4.6 mm i.d., 5 urn particle size, octyl- bonded silica stationary phase column which is sterically protected (Zorbax Rx- C8) and a mobile phase consisting of acetonitrile:water:trifluoroacetic acid (320:680:0.68, v/v/v).
• the flow rate was 1.5 mlJminute and the detector wavelength for UV absorbance detection was 238 nm.
• a low buffer concentration (0.02 M) was used to minimize possible catalysis by buffer species.
• an appropriate amount of CuS0 4 (5 x 10 *4 M) or Na 2 EDTA (1.1 x 10 "2 M) stock solution was added to the flask. No attempts were made to control the oxygen concentration in the system.
• the El mass spectrum of the isolated product (II in Fig. 7) showed a molecular ion at m/z 394 (C 21 H 27 FO6) and a peak at m/z 374(M + -HF).
• the carbon NMR spectrum showed the absence of peaks at 25,26 and 110 ppm which correspond to the carbons of the cyclic ketal group of triamcinolone acetonide.
• the proton NMR spectrum showed the absence of peaks at 1.0 and 1.3 ppm corresponding to the methyl protons of the ketal group.
• the mass and NMR spectra were identical to those of an authentic sample of triamcinolone (II).
• Example 2 The steroidal glvoxal hydrate (IV in Fi ⁇ . 7 ⁇ To a solution of 1 g of triamcinolone 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. HPLC analysis of the solution showed that the reaction was complete with only 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 ml of ethyl acetate. The ethyl acetate layer was washed with water and evaporated to dryness under vacuum. The residue was dissolved in a minimum amount of acetone.
• Example 3 The steroidal glycolic acid (V in Fig. 7)
• the glyoxal hydrate (IV) prepared from 1 g of triamcinolone acetonide was suspended in 250 mL of 0.1 N NaOH. The suspension was stirred at room temperature for two hours. HPLC analysis showed that the glyoxal hydrate was completely converted to the glycolic acid (V).
• the solution was filtered and the filtrate was acidified by adding 1 N HCl dropwise until the pH of the solution was approximately 3.
• the product was extracted with 250 mL of ethyl acetate and the ethyl acetate layer was washed with water. The ethyl acetate was removed under vacuum using a rotary evaporator.
• Example 4 The etianic acid derivative (VI) To a solution of 2 g of triamcinolone acetonide in 300 mL of methanol was added a solution of 4 g of periodic acid in 400 mL of water. The aqueous methanolic 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 1 N NaOH dropwise until the pH of the solution was 8-9. The solution was filtered and the filtrate was shaken with ethyl acetate (2x30 mL). The ethyl acetate layer was discarded.
• VI The etianic acid derivative
• the aqueous layer was acidified by dropwise addition of 1 N HCl until the pH of the solution was 2-3.
• the product was extracted with ethyl acetate (3x100 mL).
• the ethyl acetate layer was dried over 200 mg of anhydrous Na 2 SO 4 and removed under vacuum using a rotary evaporator. The residue was recrystallized from methanol. The white solid was dried under vacuum at 60°C for two hours.
• the El mass spectrum of the compound showed a molecular ion atm/z 420 and peaks at 405 (M-CH3) + and 400 (M-HF) + .
• the carbon NMR spectrum showed a resonance of C-20 at 174 ppm in place of 210 ppmin I and loss of C- 21 at 66 ppm in I.
• the proton NMR spectrum showed an acid proton at 12.8 ppm and loss of C-21 protons in I.
• the mass and NMR spectra agreed with the structure VI.
• the stability-specific HPLC method was used to follow the extent of the degradation of triamcinolone acetonide in aqueous solutions (Fig. 1).
• the approach taken in elucidating the degradation profile of the steroid had two stages.
• the first stage involved the partial identification of the degradates in the degraded sample solutions by molecular weight determination using an LC-MS technique.
• the second stage required the synthesis and characterization of potential degradation products followed by identification of such compounds in the degraded solutions by comparing their molecular weights and HPLC retention times.
• the glyoxal synthesized from I was characterized as a hydrate(IV) by elemental analysis, NMR and FAB mass spectra.
• the El mass spectrum of the compound yielded the highest m/z peak corresponding to the non-hydrated aldehyde, due to the loss of water during ionization of the sample.
• the co-injection of a degraded sample of I and the synthetic compound displayed one peak at 8.3 minutes.
• the ion-spray mass spectra of the synthetic and degraded samples produced identical peaks at m/z 451 (M+H) + and 492 (MH + +CH 3 CN) in the mobile phase.
• the degradate was identified as the steroidal glyoxal.
• the primary degradation pathway is autoxidation of the primary alcoholic group at C-21 as in other corticosteroids.
• the major degradation product is the steroid glyoxal hydrate (IV) as shown before (Fig. 2).
• the product further degrades to V in alkaline solutions. As the pH of the solution decreases below 4, this oxidative degradation pathway is absent (Fig. 1a). Instead, the cyclic ketal of triamcinolone acetonide is cleaved yielding triamcinolone (II).
• Cupric ion has been known to catalyze the oxidative degradation of 21- hydroxy corticosteroids.
• the addition of cupric salt to a borate buffer increased the degradation rate (Fig. 5), with the maximum rate at the concentration of 5x10 "6 M CuS0 4 .
• Ferric and nickel ions exhibited negligible catalytic effects.
• the degradation of triamcinolone acetonide was studied in aqueous solutions over the pH range of 1-10 at 70°C and ionic strength of 0.1. At constant pH and temperature, the degradation followed an apparent first-order process under all experimental conditions. The results are seen as the plot of logarithm of the rate constant versus pH (Fig. 6).
• the log k-pH profile shows a straight line with a slope of approximately -1 indicating that the degradation appears to be a specific-acid-catalyzed process.
• the same straight line was observed when the degradation proceeded in the presence of cupric ion or EDTA.
• the cleavage of the cyclic ketal is the dominant reaction yielding triamcinolone(ll).
• the non-oxidative cleavage reaction is not dependent on metal catalysis. Therefore, it is expected that incorporation of cupric ion or EDTA into the solutions would have no effect on the degradation rate as shown in Fig. 6.
• the predominant degradation product was the oxidation product (IV).
• Fig. 3 shows that the rate constant (1.2x10 '5 sec '1 ) extrapolated to zero buffer concentration coincide with that obtained in the presence of EDTA.
• the log k-pH profile in the present study shows no plateau when CuSO 4 or EDTA is incorporated into the solutions and the log k increases with increasing pH with a slope of +1. Cupric ion enhances the rate, whereas EDTA retards the rate. This observation strongly indicates that the plateau is not due to the ionization of steroid molecules but to a different degree of catalysis by trace-metal-ion contaminants present in the buffer components.
• k H , k 0H and k 0 were estimated from Fig. 6 to be 3.0x10 '4 sec “1 M '1 , 15.9 sec “1 M '1 and 4.6x10 “8 sec “1 , respectively, for the copper- catalyzed degradation reaction, and 3.0x10 "4 sec “1 M '1 , 0.11 sec “1 M “1 and 2.6x10 “8 sec “1 , respectively, for the metal-sequestered reaction. It is noteworthy that the cupric-ion-catalyzed degradation is 150 times as fast as that of the metal-sequestered degradation in neutral and alkaline pH regions.
• the steroidal glyoxal (III) undergoes further degradation to the corresponding glycolic acid (V) in alkaline solutions. It is seen that the formation of V goes through an induction period (Fig. 2).A small amount of the corresponding etianic acid (VI) was observed in the degradation of I in alkaline solutions (Fig. 2). This result indicates that a small amount of the steroid undergoes cleavage between C-20 and C-21 during the oxidation. It is likely that VI could have been formed by oxidative cleavage of the glyoxal (III).
• the experimental data described above and shown in the figures demonstrate the stability and degradation-resistant properties of embodiments and preferred embodiments according to the present invention under accelerated laboratory conditions.
• aqueous triamcinolone acetonide compositions of the present invention under normal use, at ambient temperature for storage times awaiting use by the distributor, pharmacist and patients. It is expected that the shelf life, required for the commercial acceptability of the present compositions, will be at least 6 months to one or more years, at room temperature, that is about 25 degrees C.
• compositions of this invention are useful in the treatment of patients suffering from certain medical disorders.
• compounds within the present invention are useful as bronchodilators and asthma-prophylactic agents, e.g. for the treatment of inflammatory airways disease, especially reversible airway obstruction or asthma, and for the treatment of other diseases and conditions characterized by, or having an etiology involving, morbid eosinophil accumulation.
• conditions which can be ameliorated may be mentioned inflammatory diseases, allergic rhinitis, adult respiratory distress syndrome.
• a special embodiment of the therapeutic methods of the present invention is the treating of asthma.
• compositions of the present invention may generally be administered by inhalation and may be presented in forms permitting administration suitable for use in human or veterinary medicine. These compositions may be prepared according to the customary methods, using one or more pharmaceutically acceptable adjuvants or excipients.
• the adjuvants comprise, inter alia, diluents, sterile aqueous media and the various non-toxic organic solvents.
• the compositions may be presented in the form of aqueous solutions or suspensions, and can contain one or more agents chosen from the group comprising surfactants, flavorings, colorings, or preservatives in order to obtain pharmaceutically acceptable preparations.
• Suitable compositions containing the compounds of the invention may be prepared by conventional means.
• compositions of the invention may be dissolved or suspended in a suitable carrier for use in a nebulizer or a suspension or solution aerosol.
• the percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained.
• several unit dosage forms may be administered at about the same time.
• the dose employed will be determined by the physician, and depends upon the desired therapeutic effect, the route of administration and the duration of the treatment, and the condition of the patient. In the adult, the doses are generally from about 0.001 to about 50, preferably about 0.001 to about 5, mg/kg body weight per day by inhalation. In each particular case, the doses will be determined in accordance with the factors distinctive to the subject to be treated, such as age, weight, general state of health and other characteristics which can influence the efficacy of the medicinal product.
• the products according to the invention may be administered as frequently as necessary in order to obtain the desired therapeutic effect. Some patients may respond rapidly to a higher or lower dose and may find much weaker maintenance doses adequate. For other patients, it may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological requirements of each particular patient. Generally, the active product may be administered orally 1 to 4 times per day. It goes without saying that, for other patients, it will be necessary to prescribe not more than one or two doses per day.

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• 1996
  • 1996-06-05 CA CA002223385A patent/CA2223385A1/en not_active Abandoned
  • 1996-06-05 WO PCT/US1996/009651 patent/WO1996040042A2/en not_active Ceased
  • 1996-06-05 AU AU61641/96A patent/AU6164196A/en not_active Abandoned
  • 1996-06-05 BR BR9608721-8A patent/BR9608721A/pt not_active Application Discontinuation
  • 1996-06-05 EP EP96919250A patent/EP0843548A4/de not_active Withdrawn
  • 1996-06-05 JP JP9501925A patent/JPH11507359A/ja active Pending

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