MXPA00003329A - Methods of treating capsules and dry, powdered pharmaceutical formulations - Google Patents

Abstract

Undesirable materials present in gelatin, cellulose or plastic capsules used for storing a dry, powdered pharmaceutical formulation are extracted by supercritical fluids. The method is also used for removing undesirable material from drug powder. The amount of powder retained in the capsules following inhalation is minimized.

Description

METHODS OF TREATMENT OF CAPSULES AND DRY AND PULVERIZED PHARMACEUTICAL FORMULATIONS Field of the Invention This invention is directed to methods for extracting undesirable materials present in capsules, capsules which are used to store and maintain powdered pharmaceutical formations. In particular, the present invention relates to a method of treating capsules used to contain said powder formulations in order to reduce the amount of undesirable materials such as molding lubricants or impurities that may be present in said capsules. The molding lubricant can cause retention of the powder formulation, and result in inconsistent dosing of active drug. This invention also relates to a method for separating undesirable material from the powder of a drug or the material forming the capsule. The undesirable material in the capsules may be moisture or impurities which, over a period of time, may come into contact with the contents of the capsule. Finally, the invention also relates to capsules treated according to the method REF .: 32952 previous BACKGROUND OF THE INVENTION Capsules are frequently used as a storage medium for finely divided pharmaceutical powders comprising active drug to be delivered to a patient by inhalation. For example, in order to avoid the use of propellant gases, some of which (chlorofluorocarbons or CFCs) have been involved with environmental deterioration (depletion of the ozone layer in the atmosphere), the dry dust that comprises the drug is introduced into a capsule to be used with a dry powder inhaler (DPI). Generally, such devices cut or perforate the capsules comprising the dry powder before administration, and thereafter the powder is inhaled by the patient. The capsules are usually constituted by (2) halves which are generally supplied by the capsule manufacturer in an assembled (closed) but not locked condition. During the filling of the capsule the two halves are separated, filled with the pharmaceutical powder formation comprising the active drug and then closed and locked. The locked capsules are then inserted into the DPI. Often, the capsule is a hard gelatin capsule. Hard cellulose and hard plastics suitable for storage of pharmaceutical powders are also used. These capsules are available from Capsugel (Belgium), Su-Heung (South Korea) and Elanco (USA), among other manufacturers. In cases where the active drug in the powdered pharmaceutical formulation is to be delivered to the upper respiratory tract (ie, intranasally), the active drug particles should have a size of about 20 to about 100 μm. In cases where administration of the active drug is to be done to the lower respiratory tract (i.e., intrapulmonary route), the active drug particles are preferably less than about 5 μm in size. Such sizes present handling problems (ie, filling of the capsules during manufacture), such that the active drug is usually mixed with a coarse-grained carrier. The vehicle is typically glucose, lactose or mannitol. Additionally, many drugs used in inhalation therapy are administered in small doses, ie, less than about 250 micrograms, whereby the vehicle can also serve as a bulking agent for such drugs. See, for example, U.S. Pat. 5,254,335. In addition, the vehicle can also be used to increase the aerodynamic flow of the formulation, and possibly to allow the dispersion of the particles during inhalation. Ipratropium bromide (I.B.) is an active drug that is typically administered by inhalation and is marketed by Boehringer Inqelheim Pharmaceuticals, Inc. under the trade name ATROVENT®. It presents problems for use in devices of type DPIs, since the amount of I.B. to administer is very low (<50 micrograms). Accordingly, I.B. it has to be mixed with a bulking agent such as lactose or glucose for administration via DPIs. During the manufacture of gelatin capsules, the internal surfaces of said capsules become coated with mold release lubricants. This is due to the fact that the manufacturing process of said capsules involves immersing the screws of the mold in the molded capsule forming material, removing the spindles from the bath of material forming the capsules, and then letting the material forming the capsules harden on the spindles. The hard capsules are then separated from the spindles. In order to separate the casings from the capsules without deterioration, it is necessary to lubricate the molding spindles. It is this lubricant which can coat the inner surface of the capsule Y is this lubricant which can cause the retention of the active drug in the capsule by "sticking" the pharmaceutical formulation to the walls of the capsule instead of being inhaled. The problem of drug retention in the capsules is complicated by the fact that the amount of lubricant in the capsules varies not only from one batch to another, but also within each batch from one capsule to another. The lack of reproducibility in the fraction of drug reaching the lungs, ie the inhalable fraction, can therefore be due not only to the "presence of lubricant but also to the relatively large variance in the amount of lubricant contained in the Capsules None of these factors have been shown to be easy to control during the manufacture of the capsules. On the other hand, as can be perfectly imagined, the level of ambient humidity in addition to the moisture levels of the powdered pharmaceutical formulation, or of the capsules, can also affect the consistency in the dosage of active drug. Said factor can lead to retention of the powder formulation in the walls and surfaces of the capsules. It has been shown that lubricants are responsible for most of the dust retention in hard gelatin capsules. Brown, S.

(Boehringer Ingelheim Pharmaceuticals, Inc., Results not published, 1994) and later Clark, A.R. and Gonda I., (US Patent 5,641,510) have addressed this problem by extracting the lubricant material from the capsules by the use of organic liquid solvents. Brown clearly demonstrated that removal of the lubricant from the capsules by washing with an organic solvent leads to a marked reduction in retention. However, the use of said solvents can introduce new impurities and contamination with solvent, and does not allow the elaboration of the capsules in their closed state. Another possible solution is to limit the amount of oil used by the manufacturer of the capsules, in order to minimize the adhesion of the powder to the internal surface of the capsule. It has been shown that this is not feasible in practice. Accordingly, it is an object of the present invention to develop a method for reducing the retention of a dry and powdered pharmaceutical formulation in the capsules. Another object of the present invention is to reduce the variation in the amount of active drug delivered in a dose from a DPI. Another object of the invention is to remove moisture or impurities from the capsules and also from active powder drug formulations. Other objects and advantages of the present invention will be apparent to those of ordinary skill in the art.

Brief Description of the Invention The present invention addresses the problems of retaining the powder formulation in the capsules in a simple and non-intrusive manner. The invention provides a new and original means to minimize the amount of powder retained in the capsules after inhalation, thereby increasing the amount of active drug reaching the lungs of the patient, while improving their reproducibility. This invention also provides a means for controlling the moisture level of the capsules. The use of supercritical fluids (SCFs) to extract lubricant material from the capsules provides great flexibility in processing. The amount and nature of the fraction not extracted from the lubricant material remaining in the capsules may be affected by any change in extraction time, pressure, temperature, and / or flow rate of the pure SCF, or by the addition of small amounts of an organic solvent to the pure SCF in order to increase or decrease the solvent power of the SCF mixture.

- Contrary to the extraction with liquid solvents, the present method also allows the extraction of the capsules in their open, closed, or locked state, without any apparent physical change. The ability to extract the closed capsules is important, since the capsules are provided by the capsule manufacturer in their closed state, and are fed to the capsule filling machine in the closed state, so it would be preferable to extract them in this state without forcing the opening of them. It has been unexpectedly discovered that SCFs can be used in place of organic solvents, aqueous solvents or solid substances to treat the capsules in order to achieve less retention of drug and vehicle in the capsule after inhalation, and at the same time achieve a supply greater and more consistent drug use of DPIs. It has been found that SCFs selectively remove the fraction of the lubricant material that is responsible for most of the drug retention of open, closed or locked capsules. Additionally, it has been discovered that the SCFs can also be used to remove traces of impurities and moisture from the capsules, and from the drug and carrier particles in order to achieve more consistent surface prties, without any observed deterioration of the capsule or formulation. It has been found that the selective extraction of the lubricant material has a surprising positive effect on the retention of drug in the capsule and the mass of fine particles (particles less than 5%)., 8 μm) in a cascade impactor used to determine the aerodynamic distribution of particle sizes of the powder and thereby determine approximately the amount of drug that will reach the patient's lungs. It has been found that extraction with SCFs provides a means to remove most of the adhesive fraction from the lubricant material, leaving an almost solid to completely solid residue on the inner surface of the capsules. This new method therefore provides a means for removing the components of the lubricant material that are largely responsible for the drug retention in the capsule, and for making the surface the capsules more uniform and more consistent by leaving a residue essentially solid on the inner surface of the capsules. It has been found that the same technique provides a means to reduce the moisture content of the capsules to a level which is similar to the desired level immediately before the IPD packaging.

BRIEF DESCRIPTION OF THE FIGURES Fig. 1 is a schematic diagram of a unit that can be used to carry out the method of the present invention. Fig. 2 is a graph showing the temporal change of pressure during a typical dynamic extraction experiment with supercritical fluids (SFE). Fig. 3 is a graph showing the temporal change of pressure in a typical SFE experiment of capsules with pressure oscillation. Fig. 4 is a schematic diagram of the sample taker with Andersen Mark II size particle sorting with pre-separator and an inhaler. Fig. 5 is a schematic diagram of the stage mapping of the Andersen sample taker with the human respiratory system.

Fig. 6 is a graph of the amount of lubricant extracted by SFE as a function of time. Fig. 7 is a graph of the amount of lubricant extracted in two hours of dynamic SFE as a function of pressure. Fig. 8 is the HPLC chromatogram of the elution solvent system of the mixture. Fig. 9 is an HPLC chromatogram of lubricant in capsules. Fig. 10 is an HPLC chromatogram of lubricant residue in capsules after capsule SFE according to this invention. Fig. 11 is a micrograph taken with the scanning electron microscope (SEM) of an internal surface of a "control capsule." Figure 12 is a SEM micrograph of an internal surface of a capsule treated by SFE according to the present invention. Fig. 13 is a graph showing the difference between drug retention in control capsules and drug retention in capsules treated by SFE according to the present invention.

Figure 14 is a graph showing the difference between the fine particle mass (FPM) of drug produced by control capsules and the drug FPM produced by capsules treated by SFE according to the present invention. Figure 15 is a graph showing the difference between vehicle retention in control capsules and vehicle retention in capsules treated by SFE according to the present invention. Figure 16 is a graph showing the difference between the vehicle FPM produced by control capsules and the vehicle FPM produced by capsules treated by SFE according to the present invention. Figure 17 is a graph illustrating the reproducibility of drug retention in control capsules. Figure 18 is a graph illustrating the reproducibility of drug retention in capsules treated by SFE according to the present invention. Figure 19 is a graph illustrating the reproducibility of the FPM of drug produced by control capsules.

Figure 20 is a graph illustrating the reproducibility of drug FPM produced by capsules treated by SFE according to the present invention. Figure 21 is a graph showing the difference in drug retention in control capsules and drug retention in capsules drawn on a large scale according to the present invention. Figure 22 is a graph showing the difference in drug FPM produced by control capsules and FPM produced by capsules extracted on a large scale according to the present invention. Figure 23 is a graph illustrating the reproducibility of drug retention in control capsules. Figure 24 illustrates the reproducibility of drug retention in capsules treated by SFE on a large scale according to this invention.

DETAILED DESCRIPTION OF THE INVENTION The word "capsule", when used in this specification, refers to a telescopic capsule -constituted by two parts: a body and a lid of slightly larger diameter that fits without slack at its open end. The pharmaceutical powder formulation with active drug is introduced into the space defined by the inner walls of the body and the lid. The capsule is generally suitable for storing a pharmaceutical compound that must be administered to the patient in the form of an aerosol. The capsule is "hard", which means that it is sufficiently rigid to allow the pharmaceutical powder to be stored inside it, and yet it is capable of being cut or perforated before its use, to allow the administration of the pharmaceutical powder to the patient. Examples of suitable capsules include hard gelatin, cellulose and plastic capsules, which are made primarily from mixtures of gelatin, cellulose and plastic materials, respectively, but may contain colorants, opacifying agents, plasticizers and preservatives, for example. In the manufacture of said capsules, mold release lubricants are used to facilitate the separation of the mold screws from the capsule forming core, and therefore lubricant remains on the inner surface. The "lubricant" means a material capable of reducing friction between the molding spindles and the inner surface of the capsule formed.The lubricant is compatible with the capsule (that is, it must not degrade the capsule). ), facilitates the separation of the capsule from the mold screws and is pharmaceutically e acceptable (that is, non-toxic). While the lubricant may be a single lubricant compound, it may also be a "lubricant composition" having one or more lubricating compounds and, optionally, other additives or diluents present therein. Many suitable lubricants are available and used in the manufacture of capsules. Examples of possible lubricants include: silicone oil; sodium or magnesium lauryl sulfate; fatty acids (e.g., stearic acid and lauric acid); stearates (e.g. magnesium, aluminum or calcium stearate); boric acid; vegetable oils; mineral oils (e.g. paraffin); phospholipids (e.g., lecithin); polyethylene glycols; sodium benzoate; and mixtures of the above. In many cases, other components are present in the lubricant. For example, calcium soap may be dispersed in the lubricating oil. Sometimes the lubricant is dissolved in petroleum ether, for example. Such lubricating compositions are well known in the art and are intended to be encompassed by the term "lubricant". The term "pharmaceutical powder", when used throughout this application, refers to a powder comprising at least one active drug and, optionally, a pharmaceutically acceptable carrier or excipient. The pharmaceutical powder is generally administered to the respiratory tract of the patient by inhalation. The invention is especially useful for low dosage drugs. The average particle size of the pharmaceutical powder containing the therapeutic agent is preferably in the range of 0.1 to 20 microns, more preferably 1 to 6 microns. Typically, at least 50% of the particles will be of a size that falls within these ranges. Examples of active drugs that can be administered to the respiratory tract of a patient include agents with anti-histaminic and anti-allergic action such as sodium cromoglycate, β-agonists, anticholinergics such as ipratropium bromide, tiotropium bromide, oxitropium bromide and chloride of thiazinamide, sympathomimetic amines such as terbutaline, albuterol, clenbuterol, pirbuterol, reproterol, procaterol and fenoterol, steroids, especially corticosteroids such as beclomethasone dipropionate, and mucolytics such as ambroxol. The active drug can also be constituted by polypeptides, such as growth hormones, parathyroid hormone, thyroid stimulating hormone, anticoagulation factors and pulmonary surfactants, among others. Generally, the polypeptide is a peptide or a protein having more than about 10 amino acids. Examples of other active drugs that could be usefully incorporated into the hard gelatin capsule include hypnotics, sedatives, tranquilizers, anti-inflammatory agents, anti-histamines, anti-tussives, anti-convulsants, muscle relaxants, anti-spasmodics, cardiovascular agents, antibacterials such as pentamidine, antibiotics and hypoglycemic agents. Generally, due to the handling and doses involved, as discussed above, the pharmaceutical powder includes a pharmaceutically acceptable carrier or excipient. For example, a physical mixture of the active drug and the vehicle can be manufactured, in which the fine particles of the active drug adhere to the relatively larger particle of the vehicle. Alternatively, a uniform mixture of the active drug particles and the excipient can form the pharmaceutical powder. Examples of pharmaceutically acceptable carriers or excipients include, but are not limited to, salt compounds (e.g., sodium chloride) or compounds of the sugar class (e.g., glucose, fructose, lactose, mannitol, trehalose, and sucrose). Compounds of the sugar class may be crystalline, amorphous or mixtures thereof. Other compounds may be present in the pharmaceutical powder if required or desired.

For example, a bronchodilator (eg, isoprenaline, rimiterol, ephedrine, ibuterol, isoetharine, fenoterol, carbuterol, clenbuterol or pharmaceutically acceptable salts thereof) or a coloring or flavoring agent, or preservatives, such as those conventionally incorporated into compositions Inhalation of dry powders may be present in the pharmaceutical powder A "supercritical fluid" (SCF) is a substance or a mixture of substances that are above their critical temperature and their critical pressure. The term "supercritical fluid" is also used to refer to a fluid that is gaseous under atmospheric conditions and that has a moderate critical temperature (i.e., less than 200 ° C). An SCF such as carbon dioxide above its critical temperature and pressure (31 ° C, 75.2 kg / cm2 gauge) behaves like a compressed gas. The density, and in general, the solvent power of a SCF increases with the increase in pressure to a point where it approaches that of many organic solvents. However, due to its gaseous nature, a SCF is characterized by a higher diffusivity than liquids, and therefore has the ability to more rapidly transport the material extracted from a matrix such as capsules to the bulk phase of C02. Contrary to extraction with liquids, a SCF is also easily expelled from an extractor by ventilation, leaving no residue in the extracted matrix (ie, the capsules) and without any need for further drying. A wealth of information concerning the properties of SCFs, including the solubility of lipid material similar to the lubricants used in the manufacture of capsules in SCFs is available in the technical literature (McHugh, M. and Krukonis, V. "Supercrit ical Fluid Extraction, Principies and Practice ", 2nd edition, Butterworths, 1993). An SCF such as C02 has a special affinity for lipid materials such as the lubricants used for the release of the capsule mold, and is therefore particularly suitable for such an application. However, SCFs such as C02 are more selective in what they extract than most organic solvents. Therefore, the insoluble lubricating components in C02 that are generally solid and dry are not extracted, and remain on the inner surface of the capsules. This is compared with the method of extracting lubricating material with organic solvents, which tend to extract practically all of the lubricant and leave residual solvent contamination in the capsule. The present invention can also be used to extract lubricants that are totally soluble in the SCF of choice or under operating conditions of temperature, pressure, flow rate, extraction time and SCF modifier such that the lubricant is completely extracted, without leaving any residue. It should be noted that, in accordance with this invention, it is also possible to devise a lubricating material composition such that, after the capsules are subjected to the SFE, any residue would have the optimum composition and texture to produce the minimum desired retention in the capsules. The residue can also act as a barrier against the diffusion of moisture in the contents of the capsules, (ie, the active drug and the excipient or vehicle material). This invention can also be used to extract solvent or other soluble material used in the formulation of a drug, to leave a dry product in the capsule. Another distinctive feature of this invention is that, unlike liquid solvents, SCFs can be used to extract empty open capsule lubricants, empty closed capsules or sealed full capsules without leaving any solvent contamination. An SCF such as C02 does not alter the color, appearance or physical properties of the capsules either. In particular, under certain conditions, C02 does not extract any substantial amount of the active drug, or bulking agents, such as lactose, in such a way that impurities at the trace level can be extracted from the surface of the particles without alter the formulation. In addition, it has been found that C02 provides a means to dry the capsules to a level that is just sufficient to minimize the effects of moisture on drug retention. This invention has further determined that the selective extraction of some lubricating compounds provides a simpler, more efficient, less intrusive and more feasible method to minimize the effect of the lubricant material than any other known method. It has been found that extraction with SCF (SFE) produces capsules that exhibit a lower force of interaction with the drug and vehicle particles than the non-extracted capsules. Additionally, this method allows drying the capsules and the drug and vehicle particles to a desired level, and eliminating traces of contamination of the surfaces of the drug and vehicle particles. The present invention provides great flexibility in processing. The amount and nature of the fraction not extracted from the lubricant material remaining in the capsules may be affected by changes in extraction time, pressure, temperature, or flow rate of the SCF, or by the addition of small amounts of an organic solvent to the SCF in order to increase or decrease the solvent power of the SCF mixture. Alternatively, C02 can also be used in its subcritical form (gaseous or liquid), to extract the lubricating material. The present invention is therefore an original method for: 1. extraction of lubricant material from the capsules; 2. extraction of undesirable material from the capsules and their contents; 3. drying the capsules to a desired humidity and level of fragility; and 4. removal of impurities or undesirable material from the drug and vehicle particles.

This technique, contrary to the techniques mentioned above, is not intrusive (does not introduce any solid substance, liquid substance or new impurity), does not leave any appreciable amount of residue, and does not require further drying. The procedure is simple to design and scale up, and can be completed in a few hours. It leaves the capsules essentially without any deterioration or change in their appearance or color. The present invention makes use of non-intrusive SCFs to treat the surfaces of the capsules in such a way that dramatically reduces the amount of drug or vehicle retained in the capsules after inhalation and concomitantly increases the amount of drug delivered and the reproducibility of the dosages from an DPI. The present invention is simpler to implement than prior techniques such as extraction with organic solvents, and can be used to treat: (1) open capsules for the purpose of extracting the lubricant fraction which is partly responsible for the high retention of drug in the capsule after the drug is inhaled by the patient, (2) empty capsules closed for the purpose of removing the lubricating oil without opening the capsules, (3) full capsules for the purpose of extracting the lubricating oil (if the capsules they had not previously been extracted with a SCF before filling with the powder mixture), the solvent used in the drug formulation, or trace level impurities from the vehicle or drug particles, (4) impurities from the particles of drug or vehicle not yet introduced into the capsules, (5) capsules, vehicle or drug particles to reach a level of moisture content immediately prior to product packaging, or (6) any combination of such actions. In all applications of this invention, C02 or any appropriate SCF is brought into contact with the material to be treated to effect the removal of lubricant, moisture or impurities from the capsules, vehicle particles or drug particles. This invention may find use in all those areas in which capsules are used for medicinal purposes, including DPI and capsules administered orally, regardless of the type of drug involved. Studies have been carried out on the extraction susceptibility of crude lubricant materials as well as lubricants from hard gelatine capsules. Results of the extraction of crude lubricant material were used to determine the conditions in which the lubricant will be extracted quantitatively from the open capsules. The capsules were extracted on an experimental scale in their open, closed or locked state. Capsules in their closed state are also extracted on a large scale to investigate the escalation susceptibility of the process to larger amounts of capsules. The results of the large-scale extraction are presented in a separate section. The effects of the drug and the vehicle on retention and FPM are also presented in a separate section. The lubricant extract and the residue were analyzed by HPLC. The fragility of the capsules was determined before and after the extraction and Lzó SEM was used to analyze the changes in the surface of the capsules produced by the SFE procedure. Drug retention and FPM produced by both capsules treated by SFE and non-extracted capsules (i.e., control capsules such as are supplied by the manufacturer) were evaluated using a cascade impactor (C.I.) Andersen.

EQUIPMENT AND PROCEDURES Extraction experiments were carried out experimental using an SFE unit constructed in the laboratory of the inventors. The extraction procedures and the analytical methods were all developed also in the laboratory of the inventors. Large-scale demonstrative demonstrations of the feasibility of scale-up of the procedure were performed by a specialized SFE corporation. The following section describes the experimental SFE unit. The SFE unit on a larger scale operates according to similar principles.

SFE EXPERIMENTAL EQUIPMENT As indicated above, the present invention involves the use of SCFs. Figure 1 shows a flow diagram of an experimental unit, which can be used to perform the SFE of capsules or drug formulations, which constitute the subject of the present invention The SFE unit, together with a system of control and observation of the procedure, they were designed and assembled from components and equipment from various suppliers. However, an SFE unit from ISCO Inc. (Lincoln, NE) and Applied Separations (Allentown, PA) can also be purchased. The unit consists of three sections: the feeding section (1-15), the extraction section that also covers the observation and control of the procedure parameters (16-22), and the section measuring flow and recovery of the extract (23-25). A computer (26) equipped with a data acquisition and control system, together with a micro-control system for valve control, is used to observe and control the pressure in the extraction vessel (19), and to observe the temperature in the vessel. extraction vessel and the flow through the mass flow meter (25). A separate unit, associated with the water bath (20), is used to observe and control its temperature. The SFE unit can be used, for example, to extract a drug and / or vehicle, crude lubricant, lubricant from open capsules, closed empty capsules or full capsules locked. The fundamental procedures are similar for such uses.

EXPERIMENTAL SFE OF DRUG POWDER, GROSS LUBRICANT OR OPEN CAPSULES The extraction procedure for drug powder, crude lubricant or open capsules is in general terms as follows. Referring to Figure 1, a known quantity of the material to be extracted is loaded into a 350 ml high pressure vessel (19) (High Pressure Equipment (HPE), Erie, PA, model # GC-9). The container (19) is then sealed and introduced into an isothermal water bath (20) (Polyscience, Niles, IL)). The container (19) is then allowed to reach thermal equilibrium with the water bath (20) for a few minutes. It can be used for carbon dioxide extraction with variable purity levels, including food grade C02 (minimum purity 99.2%), SCF quality C02 for chromatography used in this laboratory study (minimum purity of 99.9999% ), or C02 of SFE quality that may contain impurities at a level as low as 100 parts per trillion. C02 in a bottle (1) equipped with an eductor or syphonic tube (2) and a pressure gauge (3), is left in the container until the pressure reaches approximately 63.3 kg / cm2 gauge. C02 is then pumped at a constant rate using a high pressure piston pump (4) (Thermo Separation Products, Riviera Beach, FL, model # 396-89), until the pressure in the extraction vessel reaches the desired level. The pump head (4) is cooled, for example, with a solution of ethylene glycol at -10 ° C pumped with a circulating water bath. Alternatively, CO2 gaseous can be pumped through the unit using a compressor.

In this way C02 is pumped from the bottle (1) through a check valve (5) (Norwalk Valve &Fitting (NV &F), Shelton, C) to prevent the backflow of C0 to the pump (4), a safety disc (16) (HPE) for safe evacuation of the contents of the unit to the hood of smoke in the event that overpressure develops in the unit, one or more safety valves (7) (NV &F) to control the rate at which C02 is first introduced into the container (19), a shut-off valve (8) (NV &F), and a 3.18 mm outer diameter heat exchange stainless steel pipe (15) before entry into the high pressure vessel (19). The effluent shut-off valve (21) is kept initially closed until the pressure in the container (19) reaches the desired extraction pressure. Once the desired pressure has been reached, the effluent shut-off valve (21) is opened and the flow is established through the micro-dosing valve (22), (Autoclave Engineers (AE) model 30VRMM). The control of the pressure is carried out using a digital control system, a pressure transducer (17) (Omega, Stamford, CT, model PX605) and a graduated speed motor (model # M061-LE08) coupled with a booster Torque with gear ratio 50/1 (both from Minarik Co., Bristol, CT). The pressure is normally controlled up to + 1.4 kg / cm2 gauge using a proportional-integral-derivative control scheme. A manometer of 351.5 kg / cm2 gauge (16) (AE), and a thermocouple of 1.59 mm (18) (Omega) inserted in a thermometric box through the lid of the high pressure vessel (19) they use to observe the temperature and pressure in the container (19), respectively. The C02 loaded with extract, is expanded through the microdosing valve (22) in a cold finger trap (24) for the extract, and the virtually pure C02 then flows through an electronic mass flow meter (25) (Omega, model FMA 1700) to the atmosphere. Figure 2 represents a typical temporal change in pressure in an SFE experiment. A dynamic extraction period refers to the period in which the pressure is controlled at 176 kg / cm2 gauge while maintaining the continuous flow of C02 through the microdosing valve.

A pressure expansion valve of 0.7 kg / cm2 gauge (23) is used to discharge the effluent C02 into the atmosphere and thereby protect the mass flow meter (25) in the event that excess pressure develops in the pipeline of effluent. At the end of the dynamic extraction period, the pressure is slowly reduced to the atmospheric level, and the residual material not extracted is removed from the container, weighed and prepared for analysis. The extract trapped in the effluent piping is flushed with a solution of 60% ethanol / 40% THF, combined with the extract recovered in the cold finger trap (24) and then stored in amber bottles in a refrigerator which is ready for HPLC analysis. The extracted capsules are stored in small aluminum bags and sealed until they are ready for analysis in terms of brittleness, dust retention and fine particle mass. Weight loss is determined immediately after discharge from the container.

SFE CAPSULES CLOSED The object of the extraction is to efficiently remove the lubricant material dissolved in the C02 present in the capsules. Due to the resistance to the mass transfer between the inside of a closed capsule and the mass phase of C02, the extraction of the capsules closed by conventional SFE, that is to say, at constant pressure as in the case of the open capsules, does not results in a complete removal of the removable lubricant from the capsules within a reasonably short extraction period. The calculations made by the inventors indicate that approximately 20% of the lubricant in the content of the C02 phase of the capsules is • transferred to the bulk phase within a period of 2 hours. Approximately 55% of the lubricant content of an encapsulated CO 2 phase could be removed by purging the capsule in 5 hours of dynamic extraction. While several techniques can be used to increase the extraction of the lubricant from the closed capsules, including an increase in extraction time, pressure, temperature or flow rate of C02 and fluidization of the capsule bed with C02, a process of pressure oscillation by which the content of the capsules is partially evacuated each time the pressure is reduced seems to be efficient in resolving the mass transfer barrier. For this reason, a pressure oscillation procedure was developed by which the contents of the capsules are partially evacuated each time the pressure is reduced, in order to improve the extraction efficiency. The extraction process for closed capsules thus consists in allowing relatively large pressure oscillations to take place during the extraction period. This extraction with pressure oscillation is carried out by placing the container at a high level (for example 176 kg / cm gauge), allowing the extraction by loads inside the capsules during 5 minutes, and then allowing the pressure to be slowly reduced to a level lower (105 kg / cm2 gauge). This last level of pressure imparts a density of C02 that is approximately 10% less than at 176 kg / cm2 gauge, but is still high enough that the extracted material remains dissolved in the C02 phase of the capsule. A density reduction of 10% means that 10% of the lubricant in the C02 phase of the capsule is removed by purge within each cycle of oscillation of the pressure. The pressure is then increased to 176 kg / cm2 gauge and the operation is repeated approximately 20 times. At the end of the 20 cycles of pressure oscillation the concentration of lubricant material in the C02 phase of the capsule is low (<7% of the initial concentration) and a final reduction of the pressure to the atmospheric level ensures that all the removable lubricant is removed from the capsules without substantially reprecipitating any amount of lubricant material inside the capsules. This procedure improves the mixing in the C02 phase of the capsule during the pressure increaseAnd increases therefore schemes mass transfer of lubricant from the capsule surface to the C02 phase of the capsule, while forcing extracted material out of the capsule in phase C02 mass. Under these conditions, the calculations made by the inventors indicate that almost 100% of all extractable material will be removed from the capsules by purging. Figure 3 represents the change in pressure that occurs during a typical SFE experiment with pressure oscillation. It should be noted that the upper pressure level may be as high as desired, but preferably less than 703 kg / cm gauge, and the lower level may be as low as desired. Depending on the concentration of lubricant in the capsules and the conditions and extraction procedure, the number of pressure oscillations necessary to extract an appreciable fraction of the lubricant may also vary.

FRAGILITY OF THE CAPSULES The fragility of the capsules before and after the extraction was determined using an instrument designed to determine the impact energy needed to drill a capsule. The instrument consists essentially of a prong attached to the bottom of a lever that oscillates from increasing heights and that hits the capsule. The minimum height at which the capsule is pierced by the incident barb determines the energy needed to pierce the capsule. The greater the energy (mJ) necessary to perforate the capsule, the smaller the fragility of the capsule.

FILLED WITH POWDER OF THE CAPSULES A mixture of lactose powder and ipratropium bromide (I.B.) was prepared. The uniformity of the powder mixture was then determined by HPLC analysis for drug and vehicle. 5.5 mg of the powder mixture I.B. They consisted of 5,454 mg of lactose and 5,046 mg of I.B. The powder mixture was loaded into capsules treated by SFE and control capsules. In order to be sure that most of the lactose will not be aspirated into the lungs, the particle size distribution of the powder should be such that most of the lactose mass is made up of particles larger than 5 in size. , 8 μm. On the contrary, in order to ensure that a large fraction of the drug can potentially reach the patient's lungs, the particle size distribution of I.B. it is such that the majority of its mass is constituted by particles smaller than 5.8 μm. The capsules extracted on an experimental scale were filled manually with the same powder charge and compared with control capsules filled manually with the same powder. The capsules extracted on a large scale were filled with a capsule filling machine on an industrial scale, with different charges of the same powder mixture, and compared with control capsules that had been filled with the same machine.

ASSEMBLY OF THE CASCADE IMPACTOR A waterfall impactor (C.I.) is a standard instrument that simulates the human respiratory system. It is used to estimate an aerodynamic fraction of fine particles of drug that could be expected to reach the lower respiratory tract (lungs) of a patient after inhalation of the drug. Figures 4 and 5 are schematic representations of C.I. Andersen, and an illustration of the particle size distribution in C.I., and its correspondence with the various segments of the human respiratory system, respectively. The CI. used in this study (Andersen 8 Stage 1, ACFM non-viable particle size sample taker Mark II, Andersen Sampler, Inc., Atlanta, Georgia, USA) is equipped with a pre-separator and an inhaler comprising the buccal piece and the filled capsule, and has been calibrated in such a way that the size ranges for each stage are as shown in Figure 5. It is constituted by a series of pre-separation stage and eight metallic stages with orifices of decreasing size from the upper end to the bottom of the pile, separated by metal collection plates. For the operation, the capsule is pierced first with two prongs and the inhaler is closed. The perforation button is then released, and a vacuum pump is used to aspirate the sample into the capsule through the stack of stages. The smaller the particle, the longer it stays in the air stream and the smaller the stage it can reach. In order to prevent particles from bouncing off the stage plates and being entrained in the air stream, the collection plates and pre-separator were coated with an adhesive material (Brij 35 in glycerol) (Broadheat, J., Edmond Rouan, SK, Rhodes, CD, "Dry Powder Inhalers; Evaluation of Testing Methodology and Effect of Inhaler Design", Pharmaceutica Acta Helvetiae, 70, 1995, PP .. 125-131). The plates were cleaned and re-coated after each operation. The pre-separator was coated once every six operations. The CI. It is equipped with a control system that allows air to be aspirated through the inhaler for a defined period of time. The air flow rate and sampling time were adjusted to 28, 3L / min, and 15 seconds respectively. Under these conditions, the pressure loss due to the flow resistance was 31 cm of water at a flow rate of 2.35 m3 / h and at an air pressure of 1000 hPa. A bypass tube is used to verify that the pressure losses are within defined tolerances before conducting the test with the capsule punched in the nozzle. The retention of the powder mixture I.B. lactose-drug (previously described) in the capsules and the mass of fine particles (FPM, that is, the mass of particles with size <5.8 μm) in stages 2-7 of C.I., which approximates the amount of drug delivered to the lungs of a patient. The particles collected in steps 0-1 are greater than 5.8 μm, and do not reach the bronchiolar or alveolar regions of the lungs. The particles collected from plates 2-7, which represent the respirable fraction (size less than 5.8 μm), were extracted together with 20 ml of 0.01 N HCl. The solution was then filtered through a Gelman filter. PTFE, 0.45 μm. The HPLC analysis was then used to determine the amount of material in plates 2-7, ie the FPM. Retention of powder in the capsules was determined by first opening the capsule, transferring the body and cap together with the residual powder to a 20 ml scintillation vial with a screw cap, adding 10 ml of 0.01 N HCl, treating by ultrasound in an ice bath for 1 minute, filtering the solution through a 0.45 μm Gelman PTFE filter, and subsequently analyzing by HPLC for IB and lactose. For each batch of capsules, the determination of the "retention" and the FPM in batches of extracted or control capsules was repeated at least 6 times. The retention and FPM for the capsules extracted on an experimental scale were carried out for individual capsules. For large-scale capsules, drug and vehicle reception was determined for individual capsules, and FPM was determined for each stage of the impactor using the combined 10-capsule reservoirs on the impactor plates. This was done to counteract the limitations in sensitivity 'detection of the HPLC methodology.

HPLC ANALYSIS OF LUBRICATING OIL The free linoleic acid component of lecithin has been found to be predominant in the HPLC chromatogram of the type of lubricant used to make the capsules used in this study. For this reason, linoleic acid was used as a reference component to evaluate the amount of lubricant in the inhalation capsules. To determine the amount of linoleic acid in the crude lubricant, pure linoleic acid was injected at five different levels (4-12 μg) into the system, HPLC, and a calibration curve was obtained for the peak area as a function of the amount of injected linoleic acid. The analysis was conducted using a column of 4.6x250 mm, 5 μm Zorbax SB-Phenyl and a mobile phase 70/30 (volume / volume) of acetonitrile / 0.1% phosphoric acid at 1.0 ml / min. The temperature of the column was adjusted to 35 ° C, the injection volume was 25 μl, the wavelength of the UV detector was 210 nm, and the operating time was 45 min.

The amount of lubricant in the capsules was determined as follows: first, 100 gelatin capsules were opened and mixed with approximately 80 ml of ethanol / tetrahydrofuran (60/40, volume / volume), after which they were treated by ultrasound in a water bath for about 5 minutes. The extract solution was then carefully transferred to a 250 ml Pyrex bottle. The pods were extracted twice with approximately 40 ml of mixed solvent, and the extract solutions were then introduced into the Pyrex bottle. The extract was then evaporated to dryness in N2 stream. The residue was then dissolved in 5 ml of mixed solvent solution. The solution was filtered through an Acrodisc CR PTFE filter, and the filtrate was analyzed by HPLC. The amount of lubricant in the inner wall of the capsules was evaluated on the basis of the amount of linoleic acid obtained from the extraction of the capsules. The quantity of linoleic acid is converted into the amount of lubricant based on the determined percentage of linoleic acid in the specific lubricant object of the study.

HPLC ANALYSIS OF F RMACO AND VEHICLE The analysis of I.B. using a 4.6x150 mm column Zorbax SB-C18 in reverse phase and a mobile phase of sodium salt of 0.008 M 1-pentanesulfonic acid / acetonitrile 82:18 (volume / volume) at a flow rate of 1.5 ml / min. The "column temperature was 35 ° C, the injection volume was 100 ml, the wavelength of 100 UV was 210 mm, and the operating time was at least 10 minutes. The lactose analysis was performed "using an ion exclusion column 7.8x300 mm Bio-Rad A without HPX-87H and a mobile phase of sulfuric acid 0.012 N at 1.0 ml / min. The temperature of the column was 40 ° C, the injection volume was 100 μl, the detection was performed by refractive index, and the operating time was at least 15 minutes.

MICROGRAPHIES OF THE CAPSULES TO THE ELECTRONIC SCAN MICROSCOPE (SEM). A scanning electron microscope (SEM, Hitachi S-4000) was used to examine changes in the inner surface of the capsules produced by the SFE procedure. The capsules were cut using a heated wire and then adhered to an aluminum spike using a double silver adhesive tape. The inner surface was then coated by sputtering with a thin layer of platinum.

SFE OF GROSS LUBRICANT MATERIAL Laboratory studies were conducted involving the extraction of crude lubricant material used by manufacturer A in the manufacture of capsules. These studies were used to determine the conditions under which efficient extraction of the lubricant material from the capsules can be achieved. In this study, a known quantity of lubricating oil is poured first into a small glass of previously weighed glass. The beaker and oil are then weighed together and placed in the extraction vessel. In all the experiments, the temperature of the water bath was maintained at 35 ° C, and the flow rate of the C02 pump was approximately 1.6 SLM. At this flow rate, the pressure reaches 176 kg / cm 2 gauge after 47 ± 2 minutes, and a subsequent dynamic extraction for 2 hours at 176 kg / cm 2 gauge would allow the exchange of approximately 1 volume of the 350 ml container. The temperature of 35 ° C was selected for all operations since it is slightly higher than the critical temperature of C02, however, it is low enough so that the density of C02 is relatively high at reasonable pressures and no thermal degradation occurs. of the lubricant or the gelatin material. The amount of lubricant used in all operations was 0.37 ^ 0.01 g, except in the operation at 176 kg / cm2 gauge with 2 hours of dynamic extraction, in which 0.33 g of lubricating oil was used. After extraction, the yield is calculated from the relative difference between the oil level prior to extraction and the mass of residual oil remaining in the glass vessel. Figures 6 and 7 illustrate the results of the extraction of the lubricant with C02 under different conditions of pressure and dynamic extraction time. Figures 6 and 7 indicate that both time and pressure affect the extraction performance. Figure 6 shows that the extraction performance increases with the dynamic extraction time; however, no appreciable increase in extraction yield is achieved beyond two hours of dynamic extraction at 176 kg / cm2 gauge. Thus, a maximum of 73.7% of the lubricant is extractable with C02 at 176 kg / cm2 gauge and 35 ° C. Figure 7 shows that an increase in pressure from 176 kg / cm2 gauge to 281 kg / cm2 gauge does not produce a significant increase in performance. An appreciable precipitation of lubricant was observed during the reduction of the pressure only in the case of the extraction in which no period of dynamic extraction was allowed, that is, for the operation in which the C02 phase of the vessel was slowly purged as soon as the pressure reached 176 kg / cm2 gauge. Figure 6 indicates that 25.6% of the lubricant material, ie 94 mg of lubricant material constituted mainly by the lightest fraction of the lubricant, dissolved in the CO 2 phase when the pressure reached for the first time 176 kg / cm2 gauge . In this way a maximum lubricant concentration of 0.26 mg / ml was reached, a value that is greater than the maximum possible concentration of lubricant in an encapsulated phase of CO2 (0.13 mg / ml based on a capsule content of 40 μg and a capsule volume of 0.3 ml). This means that, during the extraction of the capsules, in the absence of particular mass transfer limitations for the capsules, most of the most soluble fraction of the lubricant will be in the C02 phase of the capsules as soon as the pressure reaches 176 kg / cm2 gauge. Oil residues from the experiments at 176 kg / cm2 gauge and dynamic extraction time greater than or equal to two hours, appeared as quasi-solid vitreous material, while residues from other experiments appeared as liquid-like, although more viscous than pure lubricating oil. Therefore, two hours of dynamic extraction at 176 kg / cm2 gauge should lead to an essentially optimal recovery of the extractable lubricant from the capsules and to the extraction of virtually all of the liquid fraction of the lubricant that is presumed to be responsible for most of the drug retention in the capsules. The effect of the addition of an organic solvent to C02 on its ability to extract more lubricant was also investigated. In this study, 30.8 i of ethanol was first poured into the vessel, followed by loading 0.38 g of lubricating oil into a glass vessel. This method of adding a modifier, as opposed to pumping the modifier separately and mixing it with C02 before entering the extraction vessel, is simpler and can be used to ensure that the C02 / ethanol phase that is in contact with the lubricant is unsaturated or quasi-saturated and is in supercritical conditions. The extraction was conducted at 176 kg / cm2 gauge for 8 hours to verify that all of the ethanol has been completely purged from the container at the end of the dynamic extraction period. HPLC analysis of the extract recovered in the cold trap indicates that the presence of ethanol increases the recovery of the lubricating oil compounds such as linoleic acid, but the overall recovery was still similar to that obtained with pure CO2 at 176 kg / cm2 gauge and 4 hours of extraction time (73.7%). This study indicates, therefore, that the operation at 176 kg / cm2 gauge during 2 hours should lead to a practically maximum recovery of extractable oil from the capsules and to the extraction of practically the entire liquid fraction of the lubricating oil. The extraction of the capsules was conducted both on a laboratory scale (experimental scale, 112 capsules), a pilot scale (9,000 capsules), and on a large scale (250,000 capsules). The following section presents the results of capsule extraction on an enlarged scale up to 9,000 capsules.

EXTRACTION IN LABORATORY OF THE LUBRICATING MATERIAL OF THE CAPSULES: EFFECT ON THE LOSS OF WEIGHT OF THE CAPSULES, THE FRAGILITY, THE INTERIOR SURFACE AND THE RETENTION AND FPM OF THE DRUG AND VEHICLE After the extraction, the weight loss of the capsules was determined. fragility and retention of drug and vehicle, as well as FPM. The results were then compared with the respective properties of control capsules.

DEVELOPMENT CONSIDERATIONS Previous studies of the lubricant material extraction and analyzes indicate that, preferably, when using this specific lubricant and the extraction temperature and the previous C02 flow rate, in order to achieve a quasi-complete elimination of the fraction soluble of the lubricant, the open capsules should be removed at a pressure _ > 176 kg / cm2 gauge and a dynamic extraction time of 2 hours, and the closed capsules must be extracted using the pressure oscillation method. In fact, the studies carried out by the authors of the present invention indicate that the extraction of the open capsules at 176 kg / cm 2 gauge and with a time of 1 hour dynamic extraction produces capsules with overall loss of weight of the capsules similar ( that is, loss of moisture + lubricant + other possible impurities), and less retention than the control capsules (ie, not extracted), but greater retention than the capsules extracted during 2 hours at the same pressure. This indicates that 1 hour of dynamic extraction time is insufficient to effect a complete elimination of the extractable lubricant, and that 2 hours of extraction are sufficient to achieve the optimum improvement in the efficiency of the capsules. Similarly, the extraction of closed capsules at a constant pressure of 176 kg / cm2 gauge and a dynamic extraction time of 2 hours also produced capsules with a similar overall weight loss and lower retention than the control capsules, but a much higher retention of drug and vehicle that the capsules extracted by the method of oscillation of the pressure. It is thus concluded that the removal of moisture and possibly some small amounts of other extractable material other than lubricant does not appreciably contribute to a reduction in drug and vehicle retention, and that the transfer of the content of the C02 encapsulated phase, ie C02 + lubricant, to the phase of C02 by mass (practically pure C02) is necessary to effect a large reduction of drug retention. The results of the studies of the effect of the extraction of the capsules under quasi-optimal conditions, that is to say at a pressure of 176 kg / cm2 gauge and a dynamic extraction time of 2 hours for open capsules and use of the method of oscillation of the pressure for closed capsules, on the retention of drug and vehicle and the FPM. Table 1 represents the capsule extraction conditions from two different manufacturers. The batch numbers of single-digit capsules (1-4) refer to the control lots. Four batches of pigmented hard gelatin capsules from different manufacturers and having different dust retention characteristics were used in this study. The batch numbers of the capsules followed by E indicate capsules removed under the conditions specified in Table 1. The lots of capsules 1-3 are regular, ie, commercially available gelatin capsules from manufacturer A. The batch of capsules 4 is constituted by regular gelatin capsules from manufacturer B. Except for the batch of capsules 1 which was extracted on a pilot scale (~ 9,000 capsules), all the other batches were extracted on a laboratory scale. All the capsules used in this study C.I. they were filled manually with the same batch of I. B. / lactose powder mixture (previously described).

Table 1. Reference conditions for the extraction of open capsules (176 kg / cm2 gauge, 35 ° C, 2 hours of dynamic SFE) and closed capsules under conditions of pressure oscillation (1786-105 kg / cm2 manometric, 35 ° C ) - value not determined Most of the capsules have small grooves and differentiated protuberances, designed to avoid the accumulation of air pressure and the possible deterioration of the capsules when locking them. It is believed that these slits facilitate the transfer of supercritical C02 towards the inside and outside of the capsules without any physical deterioration; however, closed capsules better support the SFE procedure when the pressure buildup is carried out at a relatively slow rate. All the capsules can be extracted in their closed state without any deterioration if the initial increase in pressure is relatively slow. For this study, the color and overall appearance of the capsules treated by SFE were similar to those of the control capsules. The capsules of batch 4 are minimally affected by the SFE procedure, whatever the operating conditions and whether they are extracted in their open state or in the closed or even locked state. Open capsules are not affected by the SFE procedure.

Capsule Weight Loss Due to SFE As shown in Table 1, a weight reduction of the capsules was observed after each extraction. A wide range of weight loss is observed (0.2-2.4%). East. Weight change, however, is only approximate given that the capsules tend to recover some of their weight loss after exposure to the atmosphere subsequent to the discharge of the container. The relative humidity (RH) prevailing in the atmosphere before extraction also affects the moisture content of the capsules and consequently their relative weight loss due to the SFE treatment.

The weight loss of the capsules manufacturer A varied within a relatively narrow range (1.5-2.4%) even though the experiments were carried out over a period of five months in which they potentially occurred large changes in atmospheric relative humidity (RH). Weight loss is minimal for lot 4 The validity of the latter result was found in a SFE treatment on a larger scale of lot 4 (30,000 capsules) in which the weight loss amounted to 0.3%. Therefore, lot 4 seems to contain the minimum amount of extractable material (moisture + lubricant + possibly other extractable material). Due to the small total amount of lubricant in the capsules (< 4.5 g), it is evident that this weight loss (80-130 mg) can not be explained solely by the removal of the lubricant. The inventors have determined that the adsorption isotherms of moisture desorption of all the capsules are practically identical, ie, equal to that of the gelatin material; therefore, most of the observed differences in weight loss should be explained by -differences in relative humidity prevailing before extraction and differences in the loss of extractable material other than moisture. In order to eliminate the effect of prevailing atmospheric RH and determine the fraction of extractable material attributable to material other than lubricant and moisture, the capsules of control batches 2 and 4 were conditioned in an environment with 53.3% RH on a saturated solution of Mg (N03) 2 for 48 hours before its extraction. The capsules were then weighed and extracted in their open state for 2 hours at 176 kg / cm 2 gauge. The extracted capsules were then conditioned for 48 hours in the same solution, and then weighed again to determine the fractional weight loss that is not due to moisture loss. Under these conditions, the weight loss for lots 2 and 4 was 0, 52% and 0.45% respectively, ie 239 μg and 217 μg respectively, for a capsule weight of 46 mg. Accordingly, analogously to the previous results obtained by the authors of the present invention on the basis of non-conditioned capsules, the batch of capsules 4 exhibits smaller amounts of extractable material other than moisture and lubricant respectively. With the exclusion of the loss of lubricant that is present at a level of 40 μg / capsule or less, these losses would amount to approximately 170-200 μg / capsule. These losses, while statistically significant, are very small, and can be attributed to the extraction of material such as organic impurities or low molecular weight gelatin material. The present invention can therefore be used as a method of extracting impurities, soluble material or mobile material such as moisture, within the matrix of the capsules which may otherwise come into contact with or react with the powder mixture. The diffusion of low molecular weight compounds through the gelatin material is a mechanism by which undesirable material may come into contact with the powder mixture. The same method can be applied for the extraction of impurities from capsules made of a material other than gelatin, such as plastic and cellulose. HPLC OF THE EXTRACT AND THE RESIDUE OF THE CAPSULES Figures 8 and 9. are cro atograms of the elution system with solvent (ethanol: THF) and of a capsule extract using this solvent system. The lubricant includes a wide variety of compounds including saturated fatty acids, unsaturated fatty acids, including linoleic acid, and lecithin complex materials. Figure 10 is an example of a chromatogram of lubricant residue in capsules after their extraction by SFE. Lubricating compounds eluting near the solvent peaks are found in high concentration in the untreated capsules, but are not detected in the residue. Several other compounds in the untreated capsules eluted in the window of retention times of 4. -14 minutes, either they are in very low concentrations, or they are not observed at all in the capsules treated by SFE. Therefore, these compounds were extracted. It is evident that the size and presence of these peaks in the waste can be significantly affected by the conditions of the SFE process. Even under the relatively moderate conditions of SFR used for these SFE extractions, it is found that up to 90% of the linoleic acid component in the capsules is extracted.

FRAGILITY OF CAPSULES AFTER SFE Table 2 shows that capsules subjected to SFE are more fragile than untreated capsules. This level of brittleness is similar to that reached by kinetic drying at 21 ° C and 22% RH with the aim of reducing the moisture content of the capsules to a level below 12.4% and thereby minimizing contact between moisture and moisture. the drug powder. Excessive humidity can, for some products, lead to agglomeration of the particles and possible hydrolysis of the drug molecules. The SFE technique can therefore be used alternatively to achieve this same level of dryness of the capsules. Table 2. Strength (mJ) required to drill the control capsules (untreated) and open and closed capsules treated by SFE at 176 kg / cm2 manomotric and 35 ° C Table 2 shows that the capsules treated by SFE conditioned in an environment with 53.3% of RH exhibit a brittleness that is slightly lower than that of the conditioned control capsules, but much less than that of the non-conditioned capsules, treated by SFE. This indicates that the change in the fragility of the capsules after the SFE is reversible and is caused mainly by the elimination of moisture by the C02. In fact, the straining, the mechanical properties and the chemical properties of the extracted and conditioned capsules are identical to those of the control capsules. The slightly lower fragility of the capsules conditioned and treated by SFE, coupled with the small weight loss in the capsules (200 μg / capsule) observed for the extracted capsules, points to the possibility that the extracted material was replaced by moisture upon reaching the balance of the capsules treated by SFE.

SEM OF THE CAPSULES The SEM micrographs of the internal surfaces of the control capsules show that the lubricant material is distributed throughout the capsule in the form of droplets of different contact angles with the surface of the gelatin. The lubricant droplets also appear to be of different sizes. In contrast, the capsules treated by SFE do not show any amount of the fluid lubricant material. The surface appears to be dry, and the peaks and valleys on the gelatin surface are visualized better than in the control capsules due to the removal of the lubricant. Figures 11 and 12 illustrate this discovery.

DRUG AND VEHICLE RETENTION. AND PARTICULA5 FINE MASS (FPM) Tables 3-6 show the results of determinations C.I. Andersen drug and vehicle retention and FPM. Figures 13-16 are graphic illustrations of these results. Tables 3 and 5 and Figures 13 and 15 show that the capsules treated by SFE retain less drug and vehicle than the control capsules regardless of the manufacturer and that the capsules are removed in the open or closed state.

Table 3. Drug retention (μg / capsule) in control capsules and capsules treated by SFE Table 4. Mass of fine particles (μg / capsule) of drug produced by the control capsules and capsules treated by SFE Table 5. Vehicle retention (μg / capsule) in control capsules and capsules treated by SFE Table 6. Mass of fine particles (μg / capsule) of vehicle produced by control capsules and capsules treated by SFE Among the control capsules, capsules from manufacturer B (lot 4) exhibited maximum FPM and minimal retention. The FPM of the control capsules of lot 2 is close to that of lot 4, but its retention is substantially higher. Retention in capsules treated by SFE from manufacturer A is 2-4 times less than retention in their corresponding control capsules. Minimum levels of drug and lactose retention were achieved with the capsules of lot 2. Lot 2 treated by SFE also reproducibly produces drug FPM of the order of 18.5 μg (40% of the total dose). The reduction in drug retention in the capsules of lot 4 by SFE is lower than that corresponding to other capsules, due to the fact that the control capsules of lot 4 already contain relatively small amounts of drug.; however, unlike the control capsules of batch 4, which exhibited a retention comprised in the range of 2.2-7.8 μg, the retention of the capsules in the capsules extracted from the same batch is within 3, 8-5.1 μg. Therefore, the capsules treated by SFE have more uniform retention properties than the untreated capsules, regardless of their retention properties, and therefore the SFE can be used to check the quality of the capsules regardless of their origin. Tables 3 and 4 show that all capsules can be treated by SFE to produce average drug retentions in the range of 2.0-5.0 μg (4.11%) and FPM in the range of 16.5-19 , 0 μg (36-41%), regardless of the batch of capsules and the manufacturer of the capsules. This compares with an average drug retention in the range of 4.5-10.5 μg (10-23%) and average FPM in the range of 12.0-15.0 μg (26-33%) in the corresponding control capsules. The greater retention of drug in the control capsules than in the extracted capsules demonstrates that the SFE procedure significantly attenuates the drug retention capacity of the capsules. As expected, the lower drug retention in the SFE capsules is accompanied by a commensurable increase in FPM. The overall retention and FPM for the combined batches 1-4 amount to 3.5 + 0.9 μg and 17.7 + _0.9 μg respectively. Therefore, the standard deviations in both the retention and the FPM for the combined batches are small. Tables 5 and 6 and Figures 15 and 16 show that the vehicle retention in the extracted capsules is much lower in the capsules treated by SFE than in the control capsules, and that the FPM of the vehicle produced by the extracted capsules is generally greater than that produced by the capsules - control. Within a batch of capsules, the reproducibility of capsule to capsule in vehicle retention is generally higher for the extracted capsules. The FPM of the vehicle is greater for the extracted capsules, except in the case of lot 4, in which the FPM of the vehicle was not essentially affected. Therefore, both vehicle retention and vehicle FPM are positively affected by the SFE treatment. The improvement in reproducibility from capsule to capsule in drug retention and FPM by the SFE of the capsules is illustrated more conclusively - in Figures 17-20 which combine all data for lots 1-4. Figures 17 and 18 illustrate the dramatic reduction in drug retention and the large increase in reproducibility of drug retention when the capsules are treated by SFE. The retention of drug in the extracted capsules varies within the range of 1-6 μg, while the retention in the control capsules varies in the range of 2-15 μg. Figures 19 and 20 illustrate the improvement in drug FPM and its reproducibility achieved by the extraction of the capsules with supercritical C02. The RPM of the drug produced by the extracted capsules is, in general, within +2 μg with indifference of the batch of capsules. Much greater variations are observed for the control capsules. Similar reproducibility improvements are observed for the vehicle. The above results, including the hardness measurements, chromatographic analysis of extract and residue, SEM of the capsules and retention and FPM of drug and powder, all combine to demonstrate that the SFE procedure allows the extraction of the fraction of the material lubricant responsible for high drug retention and erratic dosing without any deterioration of the capsules.

SFE IN GREAT SCALE OF CLOSED CAPSULES This study is designed to demonstrate that the present invention can be used to treat large-scale batches. Capsules of different batches were loaded accordingly, in their closed state into bags in their closed state in separate cotton bags and tied separately with plastic tapes. The cotton bags were then loaded successively into an 80 L cylindrical vessel and extracted by the pressure swing method (176-105 kg / cm2 gauge, 35 ° C) using supercritical C02. Each cotton bag contained approximately 15,000 capsules. Approximately 315,000 capsules were extracted in three operations of approximately 105,000 capsules each. A batch of industrial scale can amount to several million capsules. Various batches of capsules removed together with their corresponding control batches were then filled in an industrial filling machine with different batches of the I.B./Lactose powder mixture described previously. A total of 10 batches of I.B. / lactose capsules were produced from 3 batches of regular capsules from manufacturer A (1, 3 and 5) and one batch of regular capsules from manufacturer B (batch 4). The capsules were then conditioned in an environment with 53.3% RH and then analyzed for drug retention and FPM using the C.I. Andersen The evaluation of drug and vehicle retention per capsule was repeated 10 times for each batch. Each individual stage of C.I. it was analyzed in terms of drug and powder grouped from 10 successive operations of C.I. The content of 10 capsules distributes a sufficient amount of powder to the pre-separator and the 8 stage plates to make possible the exact determination of the dust collection in each stage. This study demonstrated that the procedure of extracting the capsules by SFE with the purpose of reducing the retention of dust and increasing the FPM is susceptible to escalation to large quantities of capsules. All the extracted capsules retained less dust and produced a higher FPM of drug and vehicle than their corresponding control capsules, regardless of the lactose batch and the I.B. Figures 21 to 24 illustrate this discovery for I.B. Similar results were obtained for the lactose. Figure 21 indicates that the capsules treated by SFE retain less drug than their corresponding control capsules regardless of the capsule lot, the drug lot or the vehicle lot. For combined batches, the drug retention in the capsules treated by SFE is distributed within a narrower range than the retention in the control capsules (1, 5-3.5μg versus 2.5-5.5μg). The average retention in the capsules treated by SFE and the control capsules amounted to 2.6 + _0.6μg and 4.5 + _l, 0μg respectively. As in the laboratory-scale study, it is again in this case that the drug retention in the control capsules and the capsules treated by SFE from manufacturer B retain the minimum amount of drug. Figure 22 shows that the capsules treated by SFE produce a higher drug FPM than the control capsules regardless of the capsule batch, the drug batch or the vehicle batch. The FPM produced by the capsules of manufacturer B and their corresponding capsules treated by SFE are, in general, slightly larger than the FPM produced by the capsules of manufacturer A. The FPM produced by the capsules extracted from manufacturer A is practically constant (16, 7-19, 2μg), regardless of the batch of capsules, drug lot or vehicle lot. In contrast, the FPM in the control capsules varies between 13.0 and 17.5μg. Overall, combining all the capsules, the average FPM produced by the capsules treated by SFE and the control capsules amount to 18.5 + _ 1.7 μg and 14.8 + _ 1.5 μg, respectively.

Figures 23 and 24 illustrate the difference in the reproducibility of capsule to drug retention capsule in the control capsules and capsules treated by SRS. The drug retention in the control capsules varies between 1, 0 and 10.5 μg. In contrast, the drug retention in the capsules treated by SFE varies in a much narrower range (1.0-5.6). The capsules treated by SFE, behave, therefore, analogously with regard to drug retention, regardless of the batch of capsules. Therefore, as shown in the laboratory-scale studies, greater reproducibility in drug retention, and therefore in drug dosing, can be achieved with the capsules treated by SFE than with the control capsules.

EFFECT OF THE EXTRACTION OF DRUG, VEHICLE AND DRUG POWDER WITH SUPERCRITICAL C02: RESULTS AND ANALYSIS Studies of extraction of the constituents of the drug powder were carried out to determine if the adhesion properties of the vehicle can be affected by the extraction of the impurities of the surface of the particles using supercritical C02. This technique can potentially provide the ability to render the surfaces of the vehicle particles and drug uniform and reproducible, and thereby improve the reproducibility and mass yield of fine particles. Full and closed capsules were also extracted with supercritical C02. This allows the alternative possibility of treating the capsules by SFF after they have been filled with drug powder.

SACT OF LACTOSE, DRUG AND MIXTURE OF DUSTS Lactose and I.B. at 176 kg / cm2 at 35 ° C for 2 hours of dynamic extraction with C02. It was observed that there was no detectable loss of mass from any of the extractions and no change in the overall size and appearance was detected in the SEM micrographs of lactose, indicating that both lactose and I.B. They are good candidates for treatment by SFE. Thus, SFE can extract impurities from both substances without substantially affecting the Formulation. The impurities are generally in trace amounts, and therefore can generally be dissolved in a SCF such as C02. For the protein-like impurities found generally in lactose, a pressure increase at levels closer to 703 kg / cm2 may be necessary in order to effect their extraction. Tables 7 and 8 illustrate the discoveries of the inventors. It is found that drug powders formed from extracted lactose, as opposed to control lactose provided by the manufacturer, exhibit a higher FPM. No appreciable change occurs in the retention of dust by the extraction of lactose. Thus, retention depends solely on the properties of the capsules and the surface properties of the lactose are important in determining the strength of adhesion of a drug to the vehicle. Thus, lactose extraction can provide a means to control FPM, conditioning of the capsules in an environment with 53.3% R.H. it seems to increase FPM slightly and reduce retention.

Table 7. Effect of lactose extraction on drug and vehicle retention and FEM. The lactose batch 1 and the drug batch 2 were mixed to form the drug powder. The drug powder was introduced into the batch of capsules 5. u: untreated; e: extracted; c: capsules conditioned to 53.3% of RH; C: capsules; L: lactose Table 8. Effects of the extraction of the azcla powder on the retention of drug and vehicle and? VM. Lactose batch 1 or 2 and drug batch 1 were mixed to form the drug powder. The powder was introduced into the batch of capsules 5. uB: untreated mixture; eB: extracted mixture It is observed that the extraction of the drug powder, ie the drug and the vehicle mixed, has no effect on the FPM of the drug or on retention. The lack of effect on FPM indicates that the adhesion properties of the drug and the vehicle were not altered by the extraction process. Taking into account the discoveries of the inventors in the sense that the surface of the lactose is affected by the SFE process, and that the mixtures of powder with lactose extracted have a different FPM than the mixtures of powder with lactose of control, the authors of the invention have come to the conclusion that the extraction of the mixture does not affect the adhesion surface between the drug and the vehicle. For this reason, the adhesion area between the drug and between the drug or vehicle is not affected by the Extraction procedure. In turn, this implies that the adhesion area is not accessible to C02 or that the interactive forces of adhesion between the drug and the drug or vehicle are stronger than the solubilizing power of C02 for the surface components of the vehicle.

SFE OF FULL AND TREATED CAPSULES Four batches of untreated capsules from manufacturer A (lots 1, 5 and 6) and B (lot 7) were filled with the previously described IB / lactose powder mixture, closed and locked, and then extracted at 35 ° C. the extraction method with pressure oscillation. Drug and vehicle FPM and retention were then determined both in the extracted capsules and in their corresponding full control capsules. Since the lubricant is • extracted in the presence of the drug powder, some of the lubricant removed can be distributed between the powder phase and the supercritical phase inside the capsule. The adsorption of the lubricant in the powder is expected to induce particle agglomeration and therefore reduce the FPM if it is not completely removed during the extraction process. Therefore, it may be necessary that the extraction be carried out for a longer period of time in order to ensure the complete removal of the lubricant from the capsule and the powder.

Table 9 represents the retention and FPM of the powder in these capsules. In general, dust retention, especially vehicle retention, is lower in the extracted capsules than in the control capsules. Except for the batch of capsules 1 in which the FPM was slightly reduced by the extraction procedure, the FPM is not modified or improved by the extraction, which shows that the lubricant was extracted from the capsules locked. For the combined batches, the FPM of the drug in the untreated capsules amounted to 16.0 μg, while in the extracted capsules it amounted to 17.1 μg. The retention of the drug in the untreated or extracted capsules is low, and essentially the same (4.3 and 4.4 μg, respectively). This study shows, therefore, that the lubricant in the locked and filled capsules can be extracted by SFE to produce formulations with generally higher RPM and low dust retention.

Table 9. SFE of the filled capsules: effect on the retention of drug and vehicle and FPM. Lactone batch 2 and drug batch 1 were mixed to form the drug powder. u untreated; e: extracted Note that the retention of the vehicle from the untreated capsules is much greater than the retention of the vehicle in the '' extracted capsules. (132.1 μg versus 93.6 μg). This suggests that the extracted lubricant is preferentially fixed to the drug particles which would then have a greater tendency to stick to the capsule walls during inhalation. In fact I.B. It is a basic substance and is expected to interact more strongly with stearic acid and the extracted fatty acids present in the lubricant. This observation also explains why the drug retention in the extracted capsules is not substantially less than in the untreated capsules, despite the removal of the lubricant from the capsules. Lactose is an acidic substance and therefore it is not expected to interact as strongly as I.B. with the lubricant material extracted. The extraction of the lubricant from the capsules was demonstrated by SFE methods. The methods can be used to extract lubricant material from open capsules, closed capsules, capsules locked, or capsules locked and filled without any apparent physical or chemical deterioration of the capsules. It has been shown that lubricant extraction reduces drug and vehicle retention, increases drug FPM, and improves reproducibility in both retention and FPM. It has also been shown that the methods are useful in extracting moisture or other impurities from capsules, drug or vehicle. The SFE extraction of closed capsules, open capsules, bound capsules, vehicle or drug can be conducted under conditions in which the temperature is in the range of 0.6-1.4 Tc, where Te is the critical temperature in K, and the pressure is in the range of 0.5-100 Pc. Therefore, the SCF can be used both in its subcritical form and in its supercritical form. The extraction can also be conducted directly; by mixing the contents of the container while the material to be extracted is in contact with the SCF; by fluidization of the material to be extracted with the SCF; or by SFE with pressure oscillation. Preferably, the extraction is conducted within a temperature range of 1.0-1.1 Tc, and a pressure comprised in the range of 1-10 Pc. In the case of extraction with C02, conditions of 31-90 ° C and 75.2-703 kg / cm2 gauge are preferred. Likewise, C02 or any other suitable SCF, including sulfur hexafluoride, nitrous oxide, trifluoromethane, ethane, ethylene, propane, butane, isobutane and mixtures thereof, may also be used Modifying organic solvents may also be added to any of the SCFs to modify its solvent properties, including ethanol, methanol, acetone, propanol, isopropanol, dichloromethane, ethyl acetate, dimethyl sulfoxide, and mixtures thereof Organic modifiers are preferably used at relatively low concentrations (0-20% -). , light gases such as N2, 02, He, air, H20, CH4 and their mixtures in various proportions can also be added to the SCF to alter their extraction and transport properties.It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the contents of the following are claimed as property:

Claims (17)

1. - A method of treatment of gelatin, cellulose or plastic capsules used to store a dry powdered pharmaceutical formulation, wherein the capsule has SCF extractable material on its surfaces, characterized in that it comprises exposing the capsule to a SCF to remove the extractable material by SCF.

2. - The method indicated in claim 1, characterized in that the extractable material is molding lubricant used in the manufacture of the capsules.

3. - The method indicated in claim 1, characterized in that the capsules are open.

4. - The method indicated in claim 1, characterized in that the capsules are closed.

5. - The method indicated in claim 1, characterized in that the capsules are locked.

6. - The method indicated in claim 5, characterized in that the locked capsules are filled with a pharmaceutical formulation.

1 . - The method indicated in claim 1, characterized in that the capsules contain a pharmaceutical formulation.

8. - The method indicated in the claim 1, characterized in that the SCF is carbon dioxide.

9. - The method indicated in claim 1, characterized in that the pharmaceutical formulation comprises lactose.

10. - The method indicated in claim 1, characterized in that the pharmaceutical formulation comprises ipratropium bromide

11. - A gelatin, cellulose or plastic capsule used to store a dry and powdered pharmaceutical formulation, characterized in that the capsule has been exposed to a SCF to remove the extractable material by SCF from the surfaces of the capsule.

12. - A method for drying gelatin capsules or cellulose, characterized in that it comprises exposing the capsule to a SCF to remove moisture from it.

13. - A method for drying gelatin, cellulose or plastic capsules which have stored therein a powdered pharmaceutical formulation, characterized in that it comprises exposing the capsule to a SCF in order to remove moisture from it.

14. - A method for 'removing surface impurities of one or more substances used in a pharmaceutical formulation, characterized in that it comprises exposing the substance to a SCF to remove the extractable material by the SCF.

15. A non-invasive method for extracting extractable material by SCF from porous containers or matrices, characterized in that it comprises contacting the containers or the porous matrices with a high-pressure SCF, and then reducing the pressure.

16. - The method indicated in the claim 15, characterized in that it comprises the further step of increasing the pressure after reducing the pressure.

17. - The method indicated in the claim 16, characterized in that the pressure is reduced and increased several times. METHODS OF TREATMENT OF CAPSULES AND DRY AND PULVERIZED PHARMACEUTICAL FORMULATIONS SUMMARY OF THE INVENTION This invention is directed to methods for extracting undesirable materials present in gelatin, cellulose or plastic capsules which are used to store and maintain powdered pharmaceutical formulations that are extracted from a supercritical fluid. The method is also used to separate undesirable material from the powder of a drug. The invention provides a means for minimizing the amount of powder retained in the capsules after inhalation.