MX2007005681A - Pharmaceutical manufacturing process for heat sterilized glucocorticoid suspensions - Google Patents

Abstract

The present invention provides a method for preparing a sterile suspension of a glucocorticosteroid. The glucocorticosteroids used in the invention are preferably anti­inflammatory glucocorticosteroids. By making the last stage of product preparation be the sterilization process, the potential for contamination during manufacture and heat degradation of products is greatly reduced.

Description

PHARMACEUTICAL AGENT MANUFACTURING PROCESS TECHNICAL FIELD OF THE INVENTION The present invention relates to a pharmaceutical agent manufacturing process and particularly to a process for sterilizing glucocorticosteroids. BACKGROUND OF THE INVENTION Sterile pharmaceutical products provide numbers of benefits, both from a medical perspective and from an economic perspective. Medical settings that require sterile drug preparations know that the use of non-sterile preparations can subject the patient to an unnecessary risk of secondary infection of the contaminating microbe, a microbe that is at least resistant to the drugs in the preparation. Furthermore, even if the contaminant is safe, growth may result in the loss of active pharmaceutical products per se with possible concomitant generation of toxic byproducts. Economically, contaminated pharmaceutical products have a shorter shelf life, which requires increased production costs to replace the product more frequently.

Methods are required for the preparation of sterile products for use by the patient. However, the problem associated with many sterilization procedures is that the process often results in unfavorable changes in the profile of the drug. These changes in the drug profile may range from loss of activity to increased creation of degradation products or a possible alteration of the chemical or physical characteristics of the sterilized compound. These problems are especially noticeable when glucocorticosteroids are sterilized. The sterilization of materials is based on the introduction of sufficient energy to be lethal for any potential microbial contamination. Numerous methods, including application of heat, radiation, and chemicals, have been proposed for the sterilization of glucocorticosteroids. However, to date, these methods frequently result in excessive production of degradation agents and a loss of activity for the glucocorticosteroids being sterilized. In addition, as in the case of glucocorticosteroid suspension formulations for dose inhalation, commonly used sterilization procedures frequently result in unacceptable changes in the size of drug particles. Chemical sterilization has essentially been based on exposure to toxic compounds such as, for example, ethylene oxide. However, when used to sterilize glucocorticosteroids, the ethylene oxide leaves residual amounts of ethylene oxide in the pharmaceutical preparation. Ethylene oxide is toxic and residual levels are often above the pharmaceutically acceptable limits established by most regulatory agencies. Radiation-based sterilization is known and has been recommended in the case of glucocorticosteroids (see Illum and Moeller in Arch. Pharm. Chemi, Sci., Ed. 2, 1974, pp. 167-174). However, significant degradation has been reported when radiation has been used to sterilize micronized glucocorticosteroids. WO 00/25746 (Chiesi) discloses a process for repairing a suspension of a glucocorticosteroid. In a first step, an aqueous vehicle is mixed in a turboemulsifier and sterilized by heat treatment or by filtration. In a second step, a micronized active ingredient (eg, a glucocorticosteroid) pre-sterilized with gamma irradiation is added to the aqueous vehicle. WO 03/086347 (Chiesi) describes some of the disadvantages of WO 00/25746 and discloses an improvement in the process through which the active ingredient is introduced into a turboemulsifier in the form of a powder by exploiting the vacuum in the turboemulsifier. Again, the active ingredient is sterilized before dispersing the aqueous vehicle.

None of these documents disclose sterilization by heating an aqueous suspension of a glucocorticosteroid and therefore the problem of particle size growth during heating and subsequent cooling step is not solved. US 3,962,430 (O'Neill) discloses a method for the production of sterile isotonic solutions of medicinal agents. The method comprises the addition of the medicinal agent to a saturated solution of sodium chloride in water at 100 ° C. The drug / saturated sodium chloride solution is then heated to 100-130 ° C. This method is allegedly based on the The theory that sodium chloride ions agglomerates free water thus avoiding a hydrolytic degradation, is not suitable for suspensions of fine particles of glucocorticosteroids contemplated for inhalation, since the procedure produces unfavorable changes to the size of the particles. In addition, the procedure can result in bridging between drug particles that produce large aggregates, which do not break when administered. To solve the problem of particle growth, US Pat. No. 6,392,036 (Karlsson) discloses a method for sterilization by heating in a dry state glucocorticosteroid powder which can be used for pharmaceutical formulations. However, this method results in unacceptable levels of thermal degradation products. WO 2004/078102 (Dompe) discloses a method for sterilizing an aqueous suspension of a glucocorticosteroid consisting of glucocorticosteroid and water only. Minimal details are provided in relation to the sterilization apparatus. SUMMARY OF THE INVENTION The present invention provides a method for preparing a sterile suspension of a glucocorticosteroid, comprising the following steps: (i) heating a glucocorticosteroid suspension comprising a glucocorticosteroid, water and a surfactant in a mixing vessel to sterilize the glucocorticosteroid suspension, (ii) recirculate the glucocorticosteroid suspension through a homogenizer before, during and / or after step (i) and subsequently, (iii) mix the glucocorticosteroid suspension with sterile water or a sterile excipient liquid comprising water and one or more pharmaceutically acceptable excipients. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 represents the apparatus used for the sterilization of a glucocorticosteroid suspension according to the present invention. Figure 2 is a flow diagram showing the methodology for sterilizing the glucocorticosteroid suspension using the apparatus shown in Figure 1. Figures 3-5 are representations of specific parts of the apparatus depicted in Figure 1. DETAILED DESCRIPTION OF THE INVENTION As used herein, the term "glucocorticosteroid" refers to any element of a group of spheroidal hormones (including derivatives, synthetic analogs, and prodrugs), such as, for example, cortisone, which are produced by the adrenal cortex. These compounds are involved in the metabolism of carbohydrates, protein and fats. In addition, glucocorticosteroids may have anti-inflammatory properties. Non-limiting examples of glucocorticosteroids that can be used in the present invention include beclomethasone, budesonide, ciclesonide, cortivazole, deflazacort, flumethasone, flunisolide, fluocinolone, fluticasone, mometasone, rofleponide, tipredane and triamcinolone. Preferably, budesonide, beclomethasone (for example, dipropionate), ciclesonide, fluticasone, mometasone and triamcinolone are used. With special preference, budesonide and beclomethasone (for example, dipropionate) are used. Technical and scientific terms used herein have the meanings commonly understood by a person skilled in the art to which the present invention pertains, unless otherwise stated. Reference is made here to several methodologies and materials known by a person with knowledge in the field. Standard reference works that establish the general principles of pharmacology include The Pharmacological Basis of Therapeutics, by Goodman and Gilman, tenth edition, McGraw Hill Companies Inc., New York (2001). Any suitable material and / or method known to those skilled in the art can be used to carry out the present invention. The patent literature and the scientific literature mentioned here establish the knowledge of people with experience in the subject and are incorporated by reference in their entirety in the same way as if each of them was specific and individually indicated as incorporated by reference. Any conflict between any reference mentioned here and the specific teachings of this specification will be resolved in favor of the latter. In the same way, any conflict between a definition comprised in the technique of a word or expression and a definition of the word or expression in accordance with what is specifically taught in this specification will be resolved in favor of the latter. In the specification and in the appended claims, singular forms, including the singular forms "a", "an", "the", and "the", also specifically encompass the plurals of the terms to which they refer unless the context clearly indicate otherwise. In addition, as used herein, unless specifically indicated otherwise, the word "or" is used in the sense "inclusive" and "and / or" and not in the "exclusive" sense of "or". As used in this specification, whether in a transition phrase or in the body of a claim, the terms "comprise (n)" and "comprising" should be construed as having an open meaning. That is, the terms must be interpreted synonymously with the expressions "having at least" or "including at least". When used in the context of a process, the term "comprises" means that the process includes at least the steps mentioned but may include additional steps. When used in the context of a compound or a composition, the term "comprises" means that the compound or composition includes at least the mentioned features or components, but may also include additional features or components. Reference is now made in detail to specific embodiments of the invention. While the invention will be described in combination with these specific embodiments, it will be understood that it is not intended to limit the invention to such specific embodiments. On the contrary, it is intended to cover alternatives with modifications and equivalents that may be included within the spirit and scope of the present invention in accordance with that defined by the appended claims. In the following description, numerous specific details are presented in order to provide a complete understanding of the present invention. The present invention can be practiced without some or all of these specific details. In other cases, well-known process operations have not been described in detail in order not to obscure the present invention unnecessarily. Figure 1 shows a schematic representation of the apparatus 1 used to manufacture and fill batches of a sterile glucocorticosteroid suspension. A carrier liquid, preferably an excipient solution, is prepared in a first container 2. Alternatively, the first container 2 is simply charged with water. The first container 2 is equipped with a mixer 3 and a recirculation line. The concentrated glucocorticosteroid suspension is then manufactured and sterilized before being diluted with sterile water or sterile excipient liquid. Therefore, the apparatus 1 is equipped with a second container 5 and a third container 6. The second container 5 and the third container 6 are connected to the first container 2 by the line 7 having a filter of sterilization degree 8. Before, during and After the sterilization of the concentrated glucocorticosteroid suspension, the suspension is recirculated through a recirculation line 9 and homogenizer 10. After sterilization, the sterilized concentrated glucocorticosteroid suspension is passed through a recirculation line 11 for dilution with the sterile water or liquid excipient in the second container 5. The suspension is then passed through line 12 for packaging in appropriate containers in a blow-fill-seal machine (BFS) 13. These process steps are summarized in Figure 2. Each step will now be described in more detail. The excipient liquid is prepared in a first container 2. Prior to mixing, the first container 2 is cleaned and sanitized or sterilized in place, for example, using hot water for injections (WFI) followed by steam sanitization using a stream at temperatures not lower than 100 ° C for not less than 15 minutes. After sanitization or sterilization, the water is introduced or the excipient liquid is prepared as required. The excipient liquid comprises water and a pharmaceutically acceptable excipient, such as a surfactant, and further preferably comprises other pharmaceutically acceptable excipients, diluents, etc., such as, for example, at least one buffer, at least one salt, and at least one wetting agent. of stabilization, and / or isotonic agent. Pharmaceutically acceptable surfactants are well known in the art and examples thereof are Polysorbates, for example Polysorbate 80. The components can be added in any order even though preferably the amount of water required, for example WFI, is charged into the mixing vessel followed by by the other components that are added to the circulating water through an addition hopper (not shown). Preferably, at least about 50%, more preferably about 70-90% of the total amount of the surfactant required in the sterile glucocorticosteroid suspension is added in this step. After this addition, the addition hopper is rinsed with the circulating solution and the solution is mixed, for example for 10 minutes, to ensure complete dissolution using a mixer 3 and recirculation line 4 to form the excipient liquid which is preferably a homogeneous excipient solution. A concentrated suspension of a glucocorticosteroid is prepared and sterilized in the third container 6 (also referred to as the "concentrate container"). The third container 6 has a recirculation line 9 incorporating a homogenizer 10. However, before sterilization of the glucocorticosteroid suspension, the remainder of the apparatus 1 including the second container 5, the third container 6 and the filtration line 7 , as well as any additional component, can be cleaned and sterilized in place, for example using water for hot injection followed by currents at temperatures of about 122 ° C to about 138 ° C for not less than 30 minutes. After sterilization, the second container 5 and any other cleaned and sterilized component of the apparatus 1 are continuously maintained under positive pressure in order to maintain the sterility of the system and the contents during the subsequent batch manufacture and filling. The positive pressure can be maintained using sterile compressed air. The water or excipient liquid is sterilized and the second container 5 and the third container 6 are charged with the water or excipient liquid. The sterilization of the water or excipient liquid is effected by filtering through a sterilization-grade filter 8 during the transfer of the water or excipient solution from the first container 2 to the second container 5 and to the third container 6. However, alternative methods of sterilization could be used as for example the thermal treatment of the excipient liquid. The third container 6 is isolated from the second container 5 and the third container 6 is open. In this step, surfactant is added to the water or additional surfactant can be added to the excipient liquid in the third vessel 6 in order to facilitate the formation of a stable suspension. Preferably, the concentration of the surfactant in the concentrated glucocorticosteroid suspension is from about 0.2 to about 300, more preferably from about 0.2 to about 60 mg / ml. The glucocorticosteroid is then added to the third container 6. The glucocorticosteroid does not need to have been sterilized at this stage. An excess of glucocorticosteroid can be added if there are losses in the glucocorticosteroid process during the manufacture of the suspension of bulk product and filling. The concentration of the glucocorticosteroid in this "concentrated" glucocorticosteroid suspension is preferably from about 15 to about 300, more preferably from about 15 to about 150 mg / ml. Furthermore, it is preferable that at least 50% of the glucocorticosteroid in the glucocorticosteroid suspension be in the form of a suspension during heating, the rest remaining in solution. More preferably, at least 60% is in the form of a suspension. The third container 6 is then sealed. The contents of the third container 6 are preferably recirculated, for example for at least about 1 minute, preferably for at least about 10 minutes, forming a homogeneous suspension of glucocorticosteroid. The third container 6 has at least two openings served by a recirculation line 9. The recirculation line 9 allows the contents of the third container 6 to be removed from the third container 6 in a first opening and recharged in the third container 6 in a second one. opening. It is preferable that the first opening is at the bottom of the third container 6 and that the second opening is at the top. The force required to recirculate the contents is provided through the homogenizer 10. The content of third container 6 also passes through the homogenizer 10 as it is recirculated. Since the homogenization of the content, ie the glucocorticosteroid suspension, occurs as it passes through the recirculation line 9, the third container 6 does not require any internal mechanism for stirring the contents. In fact, in a preferred embodiment, the third container 6 is free of agitation mechanism and more preferably the third mechanism 6 consists essentially of a metal box (for example, stainless steel9 having several openings for loading and evacuating the container. While the shape of the third container 6 is not critical, to avoid dead space where the contents can be trapped and can not be evacuated, the third container is preferably cylindrical and more preferably has a conical bottom to be used towards the first opening. The simplicity of the third container 6 is particularly advantageous since it reduces the number of working parts and the overall surface area in which the glucocorticosteroid suspension comes into contact, thereby reducing any drug loss by adhesion to the surfaces, reducing the possible cause of contamination and reducing the time required to clean the appliance The heat is applied to the third sealed container 6 using a heater 14, such as a steam jacket. The glucocorticosteroid suspension, third vessel 6, recirculation line 9 and homogenizer 10 are sterilized in situ through heat transfer from the heater. The heating is carried out at an effective sterilization temperature during an effective sterilization time, preferably a temperature of from about 101 to about 145 ° C, more preferably from about 122 ° C to about 138 ° C, from about 2 to about 180 minutes, more preferably over at least about 30 minutes. In this step, the glucocorticosteroid suspension is circulated around the third vessel 6, recirculation line 9 and homogenizer 10 to ensure effective sterilization of the glucocorticosteroid system and suspension. Figure 3 shows the recirculation of the glucocorticosteroid suspension during thermal sterilization detailing the recirculation line 9. Optionally, the concentrate can be pretreated in order to reduce the particle size distribution of the glucocorticosteroid to a pre-specified value, including by circulation through the homogenizer. The glucocorticosteroid suspension is preferably circulated during the heating step even though it can alternatively or additionally be subjected to circulation before or after the heating step. By recirculating the concentrated glucocorticosteroid suspension through a homogenizer 10, an undesired increase in particle size can be avoided. The homogenizer 10 is a device known in the art in which a suspension of a particulate material, here the glucocorticosteroid suspension, is subjected to an energy cut in accordance with the forced suspensions to pass through said device. The homogenizer provides a sufficiently high cutting force to cause the breakage of the aggregates of particles in the suspension and a reduction in the sizes of solid particles. A precise numerical range for the cut level is not appropriate since the cut level will depend on the viscosity of the suspension. The homogenizer 10 can be a high-inline homogenizer (for example, a Silverson 150L) or, for more efficient and better reduction of the particle sizes, a high-pressure homogenizer (for example, a Niro Panda). A high cut homogenizer typically has a mixing work head comprising rotating rotor blades and a stator pierced with the rotor blades located within the stator. A high pressure homogenizer typically comprises a pump that can deliver pressures of up to about 1500 bar, and one or more interaction chambers wherein the passage of fluid through minute flow passage under high pressure and controlled flow action subjects the fluid to high turbulence and cutting conditions. The sterilized glucocorticosteroid suspension is then mixed with the sterile water or sterile excipient solution maintained within the second container 5 through a recirculation line 11 to form a diluted sterilized glucocorticosteroid suspension, as shown in Figure 4. Typically, the glucocorticosteroid solution is diluted with the sterile water or with the sterile excipient liquid to a pharmaceutically suitable concentration. Preferably recirculation is carried out for about 45 minutes. The diluted glucocorticosteroid suspension is maintained within the second container 5 until required for filling. During maintenance of the suspension said suspension is continuously circulated through the recirculation line 12 between the second container 5 and the BFS 13 machine to keep the active material in suspension, as shown in Figure 5. BFS machines are well known in the technique and examples of these are the Rommelag Blow Fill Seal 3012, 305 and 4010 machines as well as the eiler Engineering ASEP-TECH Blow Fill Seal 624, 628 and 640. Before filling, the BFS 13 machine is sterilized, for example , by steam at temperatures of about 122 ° C to about 138 ° C for not less than 30 minutes. The BFS machine 13 can use any pharmaceutically acceptable primary container material. Low density polyethylene granulate is typically used to form the primary container / lid system in the BFS 13 machine even though high density polyethylene can also be used, polypropylene, polyvinyl chloride, or polyethylene terephthalate. Mixtures of these materials can also be used. The BFS machine 13 is configured to present units with open top to the filling head for each machine filling cycle. The sterile glucocorticosteroid suspension is filled into the units formed through a time / pressure / dosing unit that provides an accurate measurement of the suspension through filling needles. After filling, the filling needles are removed and the head section of the mold is closed to seal the units completely. The filled units are then removed from the BFS 13 machine. Being "sterile" means that a product or composition meets the sterility criteria in accordance with the North American Pharmacopoeia 27 / NF22, 2004, or its equivalent in other jurisdictions, and that it offers a therapeutically acceptable glucocorticosteroid and / or pharmaceutical formulation. The term "approximately" is used here to refer to approximately, in the region of, more or less, or around. When the term "approximately" is used in combination with a numerical range, it modifies this range by extending the limits above and below the established numerical values. In general, the term "approximately" is used here to modify a numerical value above and below the value established by a variation of 20%. As used herein, the fact of mentioning a numerical range for a variable is intended to indicate that the invention can be practiced within the variable equal to any of the values within this range. Therefore, for an inherently discrete variable, the variable can be equal to any integer value in the numerical range, including the end points of the range. Similarly, for a variable that is inherently continuous, the variable can be equal to any real value in the numerical range, including the end points of the range. By way of example, a variable described as having values between 0 and 2, can be 0, 1 or 2 for inherently discrete variables, and can be 0.0, 0.1, 0.01, 0.001, or any other real value in the case of variables inherently continuous The methods and compositions of the present invention are contemplated for use with any mammal that can derive a benefit from the methods of the present invention. Among these mammals, human beings are mentioned first, even though the invention is not intended to be limited to them and can also be used in the veterinary field. Accordingly, in accordance with the present invention, "mammalian" or "mammalian requiring" includes humans as well as non-human mammals, particularly domesticated animals, including, without limitation, cats, dogs, and horses.Another aspect of the present invention offers sterilized glucocorticosteroid suspension compositions prepared in accordance with the methods of the first aspect of the present invention. In certain embodiments, the composition is a pharmaceutical composition for treating or mitigating the symptoms of allergic and / or inflammatory conditions in a mammalian patient. In these embodiments, the compositions comprise a therapeutically effective amount of labile glucocorticosteroid (s) sterilized in a pharmaceutically acceptable carrier. The term "therapeutically effective amount" is used to refer to treatments in effective dosages to achieve the desired therapeutic result. In addition, a person skilled in the art will observe that the therapeutically effective amount of the compound of the present invention can be reduced or increased by tuning and / or by administration of more than one compound of the present invention, or by administration of a compound of the invention with another compound. The invention therefore offers a method for adapting the administration / treatment to the particular requirements specific to a given mammal. Other embodiments contemplate compositions that present the glucocorticosteroid in combination with a second active ingredient. In certain embodiments, the second active ingredient may be selected from albuterol, ipratropium bromide, cromolyn, formoterol, tiotropium, oxitropium and azelastine. In other embodiments of this aspect, the compositions of the present invention are formulated to be suitable for oral, inhalation, rectal, ophthalmic (including intravitreal or intracameral), nasal, topical (including buccal and sublingual), vaginal, or parenteral administration (including subcutaneous, intramuscular, intravenous, intradermal, and intratracheal). Preferably, the composition is formulated for inhalation in which case the size of the glucocorticosteroid particles is preferably such that DvlOO is less than 20 μP ?, Dv90 is less than 10 μm, and Dv50 is less than 5 μm, where Dvn represents the volumetric diameter in the n-ava percentile. The volumetric diameter is a term known in the art and indicates the diameter that a sphere would have when it has the volume of the particle. The particle sizes can be measured by standard techniques such as by laser diffraction as described in the examples below. Such particle sizes can be achieved using the thermal sterilization conditions described herein. The formulations of the compositions of the invention can conveniently be presented in unit dosage form and can be prepared by conventional pharmaceutical techniques. Such techniques include the step of associating the compounds of the invention and the pharmaceutically acceptable carrier (s), such as a diluent or an excipient. In general, the compositions are prepared by uniformly and intimately associating the active ingredient with liquid or finely divided solid carriers or both, and then, if necessary, shaping the product. Sterile glucocorticosteroids prepared in accordance with the present invention are optionally formulated in a pharmaceutically acceptable carrier with any of the well known pharmaceutically acceptable carriers, including diluents and excipients (see Remington's Pharmaceutical Sciences 18 Edition, Gennaro, Mack Publishing Co., Easton , PA 1990 and Remington: The Science and Practice of Pharmacy, Lippincott, Williams and Wilkins, 1995). The type of carrier / pharmaceutically acceptable carrier that is employed in the generation of the compositions of this aspect of the invention will vary according to the mode of administration of the composition to the mammal. In general, pharmaceutically acceptable carriers are physiologically inert and non-toxic. Formulations of compositions in accordance with the present invention may contain more than one type of pharmacologically active ingredient useful for the treatment of the symptom / condition being treated. In another aspect, the invention offers methods for using compositions of the invention for the treatment or for the mitigation of the symptoms of allergic and / or inflammatory conditions in a mammalian patient. Such methods comprise the administration of a therapeutically effective amount of the labile glucocorticosteroid in a pharmaceutically acceptable carrier. In various embodiments of this aspect, the administration of a therapeutically effective amount of the glucocorticosteroid, either alone or in combination with a second active agent, is effected by oral administration, by inhalation, by rectal, ophthalmic, vaginal or parenteral administration. In certain embodiments, the glucocorticosteroid is budesonide while in other embodiments the glucocorticosteroid is beclomethasone. The invention further provides a sterile glucocorticosteroid, preferably an anti-inflammatory glucocorticosteroid, for use in the treatment of allergic and / or inflammatory conditions. The allergic and / or inflammatory conditions to be treated need not be limited to an anatomical site, for example, the nose or the lungs, and the compositions of the invention are formulated for appropriate administration to the treatment site. Allergic and / or inflammatory conditions, include, without limitation, contact dermatitis, asthma, rhinitis, or chronic obstructive pulmonary disease. The invention also provides the use of sterile glucocorticosteroid compositions, in the manufacture of a drug (preferably a sterile drug) for use in the treatment of allergic and / or inflammatory conditions. The following examples are contemplated to illustrate certain additional embodiments of the invention and are not limiting. Those skilled in the art will recognize or be able to determine, using only routine experiments, numerous equivalents to the specific substances and procedures described herein. EXAMPLES Examples 1 to 3: Thermal Sterilization of Budesonide Three batches of a sterile suspension of budesonide were prepared. Example 1 (applicant's batch W15711) contained 0.125 mg / ml budesonide, Example 2 (applicant batch W15641) contained 0.25 mg / ml budesonide and Example 3 (applicant batch Z00581) contained 0.5 mg / ml budesonide . A 500 L stainless steel mixing vessel was cleaned using hot water for injections (WFI) and sanitized with steam. Water was added to the vessel for injections at 25 ° C. The vessel was then loaded with the following excipients in the following order: sodium chloride USP, citric acid monohydrate USP, trisodic citrate dihydrate USP, disodium edetate dihydrate USP and Polysorbate 80 USP from an addition hopper. In the case of Examples 1 and 3, 80 g of Polysorbate 80 was added in this step. In the case of Example 2, 30 g of Polysorbate 80 was added in this step. The amounts of each component are presented in Table 1. The solution was then recirculated through a mixer and a stainless steel line for 10 minutes in order to ensure complete dissolution. During circulation, the addition hopper was rinsed with the circulating solution. Table 1. Materials in the whole lot Example 1 Example 2 Ex empl Water for injection 500 Kg 250 500 Sodium chloride 4250 g 2125 4250 Acid monohydrate 155 g 77.5 155 citric Citrate dihydrate 250 g 125 trisodium edetate Dihydrate 50 g 25 g 50 g disodium Polysorbate 80 100 g 50 g 100 A stainless steel 500 L excipient container and a 4 L stainless steel concentrate container were cleaned and sterilized on site, using hot water for injections followed by steam. The excipient and concentrate containers were loaded with the excipient liquid that had been passed through a sterilization-grade filter (0.1 μp filter? Fluorodyne PVDF, PALL Europe Limited). The concentrate container was isolated and an additional 20 g of Polysorbate 80 was added. The composition of the concentrated suspension is set forth in Table 2. Table 2. Materials in drug concentrate (batch portion that was thermally sterilized) Example 1 Example 2 Example 3 Water for injection 4 Kg 4 kg 4 kg Budesonide 66.7 g 64.1 g 251.2 g Sodium chloride 34 g 34 g 34 g Acid monohydrate 1.24 g 1.24 g 1.24 g citric dihydrate 2 g 2 g trisodium edetate dihydrate 0.4 g 0.4 g 0.4 g Disodic Polysorbate 80 20.64 g 20.48 g 20.64 g The concentrated suspension was then sterilized under the conditions set forth in Table 3. Before, during and after sterilization, the concentrated solution was recirculated through a Silverson 150L homogenizer through a stainless steel recirculation line. Table 3. Sterilization conditions. Example 1 Example 2 Example 3 Temperature 126 - 129 ° C 124 - 129 ° C 124 - 132 ° C Time 32 minutes 32 minutes 32 minutes The suspension of sterilized glucocorticosteroid was then mixed with the sterile excipient solution maintained in the excipient container for form a suspension of dilute sterilized budesonide. The concentration of the final product was 0.125 mg / ml for the suspension of Example 1, 0.25 mg / ml in the case of the suspension of Example 2 and 0.5 mg / ml for the suspension of Example 3. A sample of the suspension was analyzed for related substances / impurities using HPLC and the results are presented in the Table. Analysis of the suspension showed a pharmaceutically acceptable level of impurities. Table 4. Related substances / impurities after sterilization (percentage by weight based on the amount of budesonide Example 1 Example 2 21-dehydro-budesonide 0.11 0.11 Desonido ND ND 16a-hidroxipredinisolona < 0.05 ND Budesonide 1,2 dihydro ND ND 22-methyl homolog ND ND D-homobudesonido ND ND 14, 15-dehydrobudesonide ND ND S-ll-keto budesonide < 0.05 < 0.05 R-ll-keto budesonide < 0.05 < 0.05 S-21-acetate budesonide ND ND R-21-acetate budesonide ND ND Individual maximum < 0.05 < 0.05 unknown Total impurities 0.11 0.11 (ND = Not Detected, <0.05 = Reporting Level) (Continuation of Table 3) Example 3 21-dehydro-budesonide 0.08 Desonido ND? ßa-hydroxypridinisolone ND Budesonido 1,2 dihydro ND 22-methyl homologue < 0.05 D-homobudesonide < 0.05 14, 15-dehydrobudesonide ND S-ll-keto budesonide < 0.05 R-ll-keto budesonide < 0.05 S-21-acetate budesonide ND R-21-acetate budesonide ND Individual maximum < 0.05 unknown Total impurities 0.08 (ND = Not Detected, <0.05 = Report Level) The diluted suspension was continuously circulated through a Rommelag 3012 BFS machine and packaged in containers using low density polyethylene. Samples of the suspension were analyzed to determine the particle size distribution by laser light diffraction using a Malvern Mastersizer S. The parameters considered are the volumetric diameters in μp? from percentiles 10, 50 and 90 of the particles, expressed as DvlO, Dv50 and Dv90, respectively, which are determined assuming that the particles have a geometric shape equivalent to a sphere. The results are presented in Table 5. Table 5. Distribution of particle sizes after sterilization. Example 1 Example 2 Example 3 DvlO 0.6 0.6 0.7 Dv50 2.3 2.5 2.7 Dv90 4.7 5.4 5.6 The particle size distributions obtained are within the recognized region required for effective administration in products for inhalation.

The lots were subjected to the sterility test and met the sterility requirements of the European Pharmacopoeia and USP. Examples 4 and 5: Thermal sterilization of BDP Two batches of a sterile suspension of BDP (Beclomethasone Dipropionate) were prepared. Example 4 (applicant batch W16531) and Example 5 (applicant batch W17211) both contained 0.4 mg / ml BDP. A 500 L stainless steel mixing vessel was cleaned using hot water for injections (WFI) and sanitized with steam. Hot water for injections was added to the vessel at a temperature of 25 ° C. The vessel was then loaded with the following excipients in the following order: sodium chloride EP, Polysorbate 20 EP and Span 20 EP from an addition hopper. In the case of Example 4, 400 g of Polysorbate 20 was added in this step. In the case of Example 5, 475 g of Polysorbate 20 and 65 g of Span 20 were added in this step. The amounts of each component are presented in Table 6. The solution was then recirculated through a mixer and a line of stainless steel for 10 minutes to ensure complete dissolution. During circulation, the addition hopper was rinsed with the circulating solution. Table 6. Whole batch materials Example 4 Example 5 Water for injection 500 Kg 500 Kg Sodium chloride 4500 g 4500 g Polysorbate 20 500 g 500 g Span 20 100 g 100 g A container for 500 l stainless steel excipient and a container for 4 L stainless steel concentrate were cleaned and sterilized in place, using water for hot injection followed by steam. The containers for excipient and for concentrate were loaded with the excipient liquid that had passed through a sterilization-grade filter (Example 4 - 0.1 μm filter Fluorodyne PVDF, PALL Europe Limited; Example 5-filter of 0. μ ?? Fluorodyne PVDF, PALL Europe Limited). The concentrate container was isolated and additional Polysorbate 20 was added (100 g in the case of Example 4, 25 g in the case of Example 5) and Span 20 (100 g in the case of Example 4, 5 g in the case of Example 5). The composition of the concentrated suspension is presented in Table 7. Table 7. Materials in drug concentrate (batch portion that was thermally sterilized). Example 4 Example 5 Water for injection 4 Kg 4 Kg BDP 206 g 210 g Sodium chloride 36 g 36 g Polysorbate 20 103.2 g 28.8 g Span 20 100 g 5.8 g The concentrated suspension was then sterilized under the conditions set forth in Table 8. Before, and during sterilization, the concentrated suspension was recirculated through a lobe pump through a stainless steel recirculation line. After sterilization, the concentrated suspension was recirculated through a homogenizer through the lobe pump and stainless steel recirculation line. Table 8. Sterilization conditions Example 4 Example 5 Temperature 124 - 132 ° C 124 - 132 ° C Time 32 minutes 32 minutes The sterilized glucocorticosteroid suspension was then mixed with the sterile excipient solution kept in the excipient container in order to form a diluted sterilized BDP suspension. The concentration of the final product was 0.4 mg / ml in the case of the suspension of Example 4 and Example 5. A sample of the suspension was analyzed for related substances / impurities using HPLC and the results are presented in Table 9. The suspension analysis showed pharmaceutically acceptable levels of impurities. Table 9. Related substances / impurities after sterilization (weight percentage based on the amount of BDP Example 4 Example 5 Beclomethasone ND ND Beclomethasone 17 Propionate 0.05 ND Beclomethasone 21 Propionate ND ND Beclomethasone 21 acetate 21 ND ND Propionate Beclomethasone Dipropionate 0.60 0.12 9β, 11 epoxanalogue ß Beclomethasone Dipropionate ND ND 9 Analog Bromide Beclomethasone Dipropionate ND ND? 9, 11 Analog Dipropionate Beclomethasone ND ND 21 Butyrate Dipropionate Beclomethasone ND ND 6OI Chloride Beclomethasone Dipropionate ND ND 6a Bromine Maximum Individual 0.12 0.08 Unknown Total impurities 0.89 0.20 (ND = Not Detected) The diluted suspension was continuously circulated through a BFS machine and packaged in containers using low density polyethylene. Samples of the suspension were analyzed to determine the particle size distribution by laser light diffraction using a Malvern Mastersizer S. The parameters considered are the volumetric diameters in ym of the percentiles 10, 50 and 90 of the particles, expressed as DvlO, Dv50 and Dv90, respectively, which are determined considering that the particles have a geometric shape equivalent to a sphere. The results are presented in Table 10. Table 10. Distribution of particle sizes after sterilization. Example 4 Example 5 DvlO 0.4 0.4 Dv50 1.4 1.5 Dv90 3.6 3.6 The particle size distributions obtained are within the recognized region required for effective product administration by inhalation. The lots were subjected to the sterility test and met the sterility requirements of the European Pharmacopoeia.

Claims (21)

1. CLAIMS 1. A method for preparing a sterile glucocorticosteroid solution, said method comprising the following steps: (i) heating a glucocorticosteroid suspension comprising a glucocorticosteroid, water, and a surfactant in a mixing vessel to sterilize the glucocorticosteroid suspension , (ii) recirculating the glucocorticosteroid suspension through a homogenizer before, during and / or after step (i), and subsequently (iii) mixing the glucocorticosteroid suspension with sterile water or an excipient liquid comprising water and one or various pharmaceutically acceptable excipients.
2. 2. A method according to claim 1, further comprising, before step (iii), the step of preparing the sterile water or sterile excipient liquid by passing the water or an excipient liquid through a grade filter. of sterilization.
3. 3. A method according to claim 1 or 2, wherein a sterile excipient liquid and the pharmaceutically acceptable excipient or the various pharmaceutically acceptable excipients comprise (n) a surfactant.
4. 4. A method according to any one of the preceding claims, wherein the pharmaceutically acceptable excipient or pharmaceutically acceptable excipients comprise (n) at least one buffer, a salt, a wetting agent, a stabilizing agent and an isotonic agent.
5. 5. A method according to any of the preceding claims, wherein recirculation in step (ii) occurs during heating in step (i).
6. 6. A method according to any of the preceding claims, wherein the glucocorticosteroid concentration in the glucocorticosteroid suspension is from about 15 to about 300 mg / ml.
7. 7. A method according to any one of the preceding claims, wherein at least 50% of the glucocorticosteroid in the glucocorticosteroid suspension has the form of a suspension during heating.
8. 8. A method according to claim 7, wherein at least 60% of the glucocorticosteroid in the glucocorticosteroid suspension has the form of a suspension during heating.
9. 9. A method according to any of the preceding claims, wherein the glucocorticosteroid is selected from at least one of the following: beclomethasone, budesonide, ciclesonide, cortivazole, deflazacort, flumethasone, flunisolide, fluocinolone, fluticasone, mometasone, rofleponide, tipredane and triamcinolone.
10. 10. A method according to claim 8, wherein the glucocorticosteroid is beclomethasone or budesonide.
11. 11. A method according to any one of the preceding claims, wherein the concentration of the surfactant in the glucocorticosteroid suspension is from about 0.2 to about 300 mg / ml.
12. 12. A method according to any of the preceding claims, wherein the heating is carried out at a temperature from about 101 ° C to about 145 ° C.
13. A method according to claim 12, wherein the heating is effected at a temperature of about 122 ° C to about 138 ° C.
14. A method according to any one of the preceding claims, wherein the heating is carried out for about 2 to about 180 minutes.
15. 15. A method according to claim 14, wherein the heating is carried out for at least about 30 minutes.
16. 16. A method according to any of the preceding claims, wherein the homogenizer is an inline homogenizer or a high pressure homogenizer.
17. 17. A method according to any one of the preceding claims, wherein in step (iii), the glucocorticosteroid suspension is diluted with the sterile excipient liquid in a pharmaceutically suitable concentration.
18. 18. A method according to any of the preceding claims, wherein, after step (iii), the sterile suspension of a glucocorticosteroid is packaged.
19. 19. A method according to claim 18, wherein the sterile suspension of a glucocorticosteroid is packaged by a blow-fill-seal machine (BFS).
20. 20. A composition obtainable by the method of any of the preceding claims.
21. 21. A sterile aqueous suspension comprising a glucocorticosteroid obtained by the method of any of claims 1 to 19, wherein the particle size of the glucocorticosteroid is such that the DvlOO is less than 20 μm, the Dv90 is less than 10 μp? and the Dv50 is less than 5 μp ?.