Tuesday, May 12, 2009

Sterilization process

[0001] The present invention relates to a process for the sterilization of steroids, particularly glucocorticosteroids and to the use of steroids so sterilized in sterile pharmaceutical formulations.

[0002] Sterilization is a process performed to ensure that there is complete freedom from microbial contamination. Sterilization is especially done for pharmaceutical formulations which are to be directly introduced into the body and its cavities. Such formulations explicitly include ophthalmic preparations, nasal preparations, ocular preparations, injectables, transdermal patches, depot preparations and the like. Such sterilized preparations involve two main methods of preparation. First route is that the active ingredient is sterilized and the formulation is prepared aseptically or the final is prepared, packed in the desired container and then sterilized. The second route is known as a terminal sterilization technique.

[0003] Certain formulations such as respules or aqueous nasal preparations, ophthalmic preparations and the like that involve steroids as the active ingredient are usually prepared by the first method described above. The most important reason being that these formulations are usually packed in containers made from LDPE which are not suitable for terminal sterilization.

[0004] Several patents disclose the methods of sterilization of active ingredients. PT-A-69652 discloses the cold sterilization of micronized glucocorticosteroids using mixtures of ethylene oxide and carbon dioxide, since according to PT-A-69652, steroids in powder form are not stable at temperatures above 60.degree. C. Specific examples of glucocorticosteroids are prednacindone, budesonide, dexamethasone and prednisolone, and salts, esters and fluro derivatives thereof, including dexamethasone acetate, dexamethasone phosphate, prednisolone pivalate and 9-alphafluoro prednisolone.

[0005] However, ethylene oxide is toxic and when it is used to sterilize glucocorticosteroids it has been found that the residual amounts of the ethylene oxide contravene pharmaceutical guidelines, which require very low levels of residual ethylene oxide. Accordingly this method has been found to be unsuitable for producing therapeutically acceptable glucocorticosteriods and formulations thereof.

[0006] U.S. Pat. No. 3,962,430 discloses a method for the production of sterile isotonic solutions of medicinal agents, which comprises adding the agent to a saturated solution of sodium chloride in water at 100.degree. C. and then heating the mixture at 100-130.degree. C. This method is not suitable for suspensions of fine particles of steroids, which are intended for inhalation because the water, and the heating and cooling involved, produce unfavourable changes in the size of particles. Indeed it can lead to the formation of bridges between the fine particles producing large, hard aggregates, which will not deaggregate into the desired fine particles upon administration.

[0007] A putative alternative is dry heat sterilization. According to the European Pharmacopoeia (1996, pp. 283-4) a normal heat sterilization process runs at 180.degree. C. for 30 min or at a minimum of 160.degree. C. for at least 2 hours. According to Pharmacopeia Nordica (1964, pp. 16) such sterilization can be carried out at 140.degree. C. for 3 hours. However at the temperatures of these processes glucocorticosteroids suffer significant degradation and are subject to changes in their surface structure.

[0008] Sterilization by .beta. or .gamma.-irradiation is also known. Indeed Illum and Moeller in Arch. Pharm. Chemi. Sci., Ed. 2, 1974, pp. 167-174 recommend the use of irradiation to sterilize glucocorticosteroids. However when such irradiation is used to sterilize certain finely divided, e.g., micronized steroids such as glucocorticosteroids, they are significantly degraded.

[0009] WO-A-96/09814 to Andaris Ltd. relates to spray-dried particles of a water-soluble material with a mass median particle size of 1 to 10 .mu.m. The aim of the invention is to produce forms and respirable particles for use in dry powder inhalers. The water-soluble material is preferably a human protein or a fragment thereof, in natural or recombinant form, e.g., human serum (HAS), alpha-1 antitrypsin or alcohol dehydrogenase. Also combinations of an active material with a carrier were produced e.g., budesonide and lactose. It is stated generally that the microparticles produced can be sterile without teaching how this could or would be neither achieved or showing any proof thereof.

[0010] WO-A-96/32095 to Astra AB relates to a process for the preparation of respirable particles by dissolving an inhalation compound in a solvent, introducing the resulting solution containing the inhalation compound in droplet form or as a jet stream into an anti-solvent which is miscible with the solvent and which is under agitation. Budesonide with a mass median diameter (MMD) of less than 10 .mu.m is produced with the process. There is no information n WO-A-96/32095 about sterilization or sterile particles.

[0011] A method for sterilizing biological materials by irradiation over a temperature gradient is discussed in U.S. patent application No. 20040033160 by MacPhee et al. U.S. patent application No. 20040022673 by Protic. deals with a sterilization process and apparatus therefore. U.S. patent application No. 20040001774 by Williams et al. (Johnson & Johnson) discloses sterilization with temperature-controlled diffusion path. A chemical vapour sterilization process and system with heat pump operated vaporizer/condenser is discussed is U.S. patent application No. 20040033161 by Kendall et al. (Johnson & Johnson). High pressure sterilizing of sensitive active principles, particularly peptides, oligonucleotides and proteins are disclosed in U.S. patent application No. 2003103863 by Grislain et al. Attempts at terminal sterilization of pharmaceutical formulations, especially suspensions, e.g., aqueous suspensions, of glucocorticosteroids have all proved unsatisfactory. Such suspensions can not normally be sterilized by sterile filtration as most of the particles of glucocorticosteroids will be retained on the filter. Moist heat sterilization, e.g., steam treatment of glass vials containing the product, leads to an unacceptable change in particle size.

[0012] Various aqueous suspensions of finely divided glucocorticosteroids are known e.g., the budesonide-containing product known as Pulmicort.RTM. nebulising suspension. (Pulmicort.RTM. is a trademark of Astra AB of Sweden). Similar formulations of fluticasone propionate are known from WO-A-95/31964.

[0013] WO 99/25359 discloses a process for the sterilization of a glucocorticosteroid which process comprises heat-treating the glucocorticosteroid in the form of a powder at a temperature of from 100 to 130.degree. C. However, we have found that by this method final formulations show a considerable rise in impurity levels.

[0014] We have now found that, surprisingly, steroids, particularly glucocorticosteroids such as budesonide, can in fact be satisfactorily sterilized without resorting to irradiation or dry sterilization techniques or to the use of saturated solutions of sodium chloride.

[0015] According to the present invention there is provided a process for the sterilization of a steroid which process comprises heat treating the steroid in the form of a wet mass comprising steroid, water and an excipient.

[0016] The present process produces a much lower level of total impurities, in particular degradation products of the steroid, than the prior art sterilizations.

[0017] The invention seeks to provide a sterilized wet mass which comprises active ingredient selected from steroids and such other drugs of this class without degradation of the active ingredient.

[0018] The present invention also aims at providing the use of this sterile wet mass, which can be used in preparations, or formulations, which are required to be sterile but cannot be terminally sterilized.

[0019] The present invention relates of a method of active pharmaceutical molecules, that are susceptible to high temperatures. The method involves forming a wet mass of the active ingredient preferably along with one or more pharmaceutically suitable excipients and one or more vehicles therefor. The sterilized mass containing the sterilized active ingredient thereof can be used in the preparation of formulations that are required to be sterile.

[0020] The steroids which may be used in the present invention include but are not limited to betamethasone, fluticasone (e.g., as propionate), budesonide, tipredane, dexamethasone, beclomethasone (e.g., as diproprionate), prednisolone, flucinolone, triamcinolone (e.g., as acetonide), mometasone (e.g., as furoate), rofleponide (e.g., as palmitate), flumethasone, flunisolide, ciclesonide, deflazacort, cortivazol, 16a,17a-butylidenedioxy-6a,9a-difluro-11 ss, 21-dihydroxy-pregna-1,4-diene3,20-dione; 6a,9a-difluro-11 ss-hydroxy-16a,17a-butylidenedioxy-17ss-methylthio-androsta-4-ene-3-one; 16a,17a-butylidenedioxy-6a,9a-difluoro-11 ss-dydroxy-3-oxo-androsta-1,4-d- iene-17p-carbothioic acide S-methyl ester; methyl19a-chloro-6a-fluoro-11 ss-hydroxy-16oc-methyl-3-oxo-17a-propionyloxy-androsta-1,4-diene-17a-carb- oxylate; 6a,9a-difluoro-11 ss-hydroxy-16a-methyl-3-oxo-17a-propionyloxy-an- drosta-1,4-diene-17p-carbothioic acid-(2-oxo-tetrahydrofuran-3-yl) ester; optionally in their pure isomeric forms (where such forms exist) and/or in the form of their esters, acetals or salts, where applicable. For use in preparations where the drug must reach the small cavities, such at the bronchi, the cornea and such other minute cavities, the active pharmaceutical ingredient is preferably in finely divided particulate form. For example, it may be micronised before sterilization. The mass median diameter (MMD) of the particles is preferably less than about 10 .mu.m.

[0021] The steroid is preferably in finely divided particulate form, with 90% of the particles preferably having a diameter of less than 10 .mu.m. More preferably, 90% of the particles have a diameter of less than 5 .mu.m. The present sterilization method does not significantly affect the particle size and this is an advantageous feature. Generally speaking, after sterilization according to the present invention, the particle size is substantially the same as it was before sterilization.

[0022] Particularly preferred steroids include budesonide, fluticasone (especially as the propionate), triaminolone (especially as the acetonide), prednisolone, and mometasone (especially as the furoate).

[0023] We have found water which is relatively free, preferably substantially free of ionic species to be particularly satisfactory. We prefer to use purified water, distilled water or water for injection (WFI). These terms are well understood in the art, and reference can be made to US Pharmacopoeia (USP) 23 Monograph for further definitions.

[0024] The invention is, in part, based upon using as little water as necessary in the wet mass. The exact quantity may vary and will depend upon the steroid used, but in principle the amount of water will be less than that required for the steroid to go into solution, or at least to dissolve and recrystallise in any significant amount. The wet mass, is, therefore, preferably a moist slurry. During sterilization preferably most of the water in the wet mass turns to steam, thus effectively "steam treating" the steroid so as to render it sterile. Suitably, therefore, the wet mass comprises a sufficient amount of water so as to give enough steam for sterilization of the steroid.

No comments: