MXPA99008581A - Preparation of powder agglomerates - Google Patents

Abstract

The invention relates to a method of producing an agglomerate of drug and solid binder. The process involves producing individual agglomerate particles and then converting the convertible amorphous content of same, following agglomeration, by the application of, for example, moisture. Agglomerates capable of conversion as well as the finished agglomerates and oral and nasal dosing systems including same are also contemplated. The process produces agglomerates which are rugged but which will produce an acceptable fine particle fraction during dosing.

Description

PREPARATION OF POWDER AGGLOMERATES FIELD OF THE INVENTION The present invention relates in general to the formation of agglomerates. More specifically, the present invention relates to the field of designing pharmaceutical dosage forms, and in particular, the production of unique agglomerated dosage forms for administration of pharmacologically active agents to patients. The formulations according to this invention are particularly well suited for oral and / or nasal inhalation.

INTRODUCTION TO THE INVENTION There are several known methods for the treatment of diseases and conditions of the upper and lower respiratory passages, and of the lungs. These conditions include, for example, asthma and rhinitis. One such technique involves administering certain pharmacologically active agents or drugs, such as, for example, mometasone furoate, topically to the respiratory passages or lungs, in an immediately usable form. Mometasone furoate is a topically effective steroidal anti-inflammatory.

Oral inhalation therapy is a method of delivering such topically active drugs. This form of drug supply involves the oral administration of a dry powder drug directly to the affected area, in such a way that it is readily available for immediate benefit. However, inhalation therapy is a particularly demanding dosing system, and involves its own unique design game and performance issues. Among those problems is a concern about the accuracy and repeatability of the dosage. Try to ensure that the same amount of drug is administered each time. Furthermore, unlike pills, capsules, and creams, oral inhalation therapy must be concerned not only with the dosage form itself, but also with a drug delivery device and the interaction between them. To understand this problem we should only consider nasal sprays that are sold without a prescription. When a conventional pressure bottle is pressed, it is difficult to apply the same amount of force each time. With even a slight difference in strength, differences in the amount of drug administered may result. Even with more consistent pump style spray applicators, variations in dosages occur. While such variation is usually not a problem when administering OTC nasal sprays, the variation should be minimized when possible when administering prescription medications for severe conditions such as asthma. The dangers of over-medication or under-medication, and the consequences of such unwanted deviation can be profound. The problem becomes even more complex when the dose sizes are as small as they often are in oral inhalation therapy. To help mitigate these problems, companies such as Schering Corporation has developed complex and highly accurate inhaler systems for the administration of powdered medicaments, such as those described in PCT International Publication No. WO 94/14492 corresponding to Argentine Patent Application 326,932, which was published on 7 July 1994, the text of which is incorporated herein by reference. Such inhaler systems were designed to measure the extraction of an exact dose of a powder medication, using a dosing hole are then supplied to the patient through a mouthpiece. The dosing hole is then filled again for the next dose. These devices have been specifically designed to eliminate, as much as possible, the human error and the mechanically induced variability in the dosage. While such devices represent a significant advance in oral inhalation therapy, there are still some circumstances in which problems may remain. These problems often focus on the properties of the pharmacologically active agent, and its interaction with the inhaler. For example, certain drugs are not "free flowing," and that can hinder the movement of the drug from the storage of a reservoir, to the measurement in a dosing hole, to the supply from the inhaler. Other drugs may suffer from electrostatic charge problems, or they may exhibit an unacceptable degree of cohesive force. These drugs can be "sticky", even when they are in the form of dust. These drugs can lock the inhaler / applicator, affecting your ability to properly measure the proposed amount of medication. These powders can also adhere to the nozzle of the applicator, thereby reducing the amount of medication actually delivered. This is often referred to as "hanging". The drugs can also be "spongy", which makes handling and loading enough drug into the dosing hole a real challenge. To make matters worse, these and other physical properties of various pharmacologically active agents can vary within a single batch of material. This can beat attempts to compensate for them. In addition, related problems may arise, which are based on the small size of the particles that are generally used in inhalation therapy. Inhalation therapy commonly involves drug particles that are of the 10 μm or lower type. This ensures adequate penetration of the medication into the patient's lungs, as well as good topical coverage. To provide an adequate supply of such drugs, close control must be maintained over the size of the drug particles. However, powders of that size can be extremely difficult to work with, particularly when small dosages are required. Such powders are typically not free flowing, and are usually of a light, dusty, or spongy character, creating problems during handling, processing, and storage. In addition, it may be difficult to repeatedly and accurately load said materials into the metering hole of an inhaler. Consequently, not only the properties of the drug, but also the required size of the therapeutic particulate, can be combined to cause considerable problems in terms of handling and dosing. One method to improve the ability to administer fine powdered medicaments is by the inclusion of dry excipients, such as, for example, dry lactose. However, it has been determined that when particularly small doses of measurement are required, such as below approximately 100 - 200 μg of drug, the inclusion of conventional excipients may not adequately compensate for the problems associated with the use of fine drug particles. In addition, dry excipients, as commonly used, generally have taps of particles that are significantly larger than the particle size of the drug. Unfortunately, the use of such particles can have a significant impact on the amount of drug delivered from dose to dose. Furthermore, the proposed benefits of the use of such excipients begins to decrease as the size of the dose decreases. Therefore, the hanging of the drug, or retention within the dosing device or the inhalation nozzle, and other handling issues can become an increasing problem. Alternatively, the drug products can be processed to form agglomerates or pellets which are generally more free flowing and more mass. A method for agglomerating drugs is described in PCT International Publication No. WO 95/09616, published April 13, 1995. As described therein, agglomerates of finely divided powdered medicaments, such as micronized powders having a particle size smaller than 10 μm, which does not require binders. However, they can be formed with excipients. These agglomerates can then be administered through an inhaler for powdered medicaments. The ability to create particles without a binder is significant for inhalation therapy, and can represent a great advantage over other techniques that use water or other traditional binders in the formation of agglomerates. Pure drug agglomerates can provide great advantages when formulating and handling powders. However, it has been found that at doses of approximately 100-200 μg of a drug such as mometasone furoate, and lower, the drug agglomerates may suffer from hanging, and the variability of the dosages may be a real concern. Even in dosage systems designed to provide relatively larger doses of pharmacologically active agents, such as about 400 μg or more, the resulting agglomerates of pure drug may still suffer from integrity problems. These agglomerates are still relatively soft, and can break during dosing, thereby providing variability in the dosage. The material can also break down quite quickly, for example, dropping an inhaler from a height of approximately four feet. This would result prematurely in the formation of smaller particles that are more difficult to manipulate. In fact, it is the handling difficulties of fine drug particles that needed agglomeration in the first place. If the agglomerates containing binders are used, such agglomerates can be made by the methods described in, for example, U.S. Patent No. 4,161,516 and GB Patent 1,520,247, which disclose the use of certain binding materials, including water, for the production of agglomerates for oral inhalation. According to the processes described therein, before the agglomeration, the moisture content of certain "self-agglomerating" or hygroscopic micronized drugs rises. After the micronized powder has been raised to the desired level of water content, it agglomerates. The non-hygroscopic materials must be bonded with more traditional binders, as described therein. Likewise, WO 95/05805 discloses a process for the formation of agglomerates where a mixture of homogeneous micronized materials is treated with steam to eliminate any convertible amorphous content that may be destabilized at a later point. After the steam treatment, the now crystalline material is agglomerated. However, this application warns that if the vapor exposure is conducted after agglomeration, the product is "useless" in an inhalation device. "The effect of the moisture on the tabletting characteristics of anhydrous lactose is discussed in Sebhatu, Elamin and Ahlneck, "Effect of Humidity Sorption on the Characteristics of Tabletting and Lactose Dried (15% Amorphous) Spray ", Pharmaceutical Research, Vol. 11 No. 9, pages 1233-1238 (1994) .However, the article does not discuss the formation of agglomerates, or the production of agglomerates that can produce a" fine particle fraction "acceptable, also known as a" respirable fraction "when administered as part of oral inhalation therapy Sebhatu et al. article uses a method to determine amorphous content, which is described more fully by T. Sebhatu, M.

Angberg, and C. Ahlneck, "Evaluation of the Degree of Disorder in Cristalline Solids by Isothermal Microcalorimetry", International Journal of Pharmaceutics, Vol. 104, pages 135-144 (1994). An isothermal microcalorimeter is used to determine the specific heat of crystallization for totally amorphous lactose, and then the "percentage of disorder" (denoted herein, for purposes of the present invention, "percentage of convertible amorphous content") is determined by dividing the Specific heat of crystallization for a partially amorphous sample, by the value previously obtained for the totally amorphous material, then multiplying by 100. The equipment described for making these measurements is satisfactory for use in the present invention.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides an improved agglomerate and a process for doing the same; by design, the present invention takes advantage of the use of a solid binder in combination with fine drug particles, and of the amorphous characteristics that can be imparted to the solid binder and / or the drug; this occurs just when others seek to eliminate these characteristics; the present invention further results in unique crystalline agglomerates of a first material and a solid binder that are free flowing, of sufficient mass, and stable enough to be handled, dosed, and delivered, even in extremely small doses; at the same time, the interparticle binding intensity of the agglomerates is sufficiently brittle to allow the agglomerates to break during administration through an inhaler, so as to provide an acceptable fine particle fraction. All this is effected substantially without the use of an additional, more conventional antiglutanizer. In particular, the present invention provides a process for the production of agglomerates. The process includes providing particles of at least one first material, generally a pharmacologically active agent, and providing particles of at least one solid binder. At least one of these two particles, the drug or the solid binder, includes as part of it, a preselected amount of a convertible amorphous content that is sufficient for, with the crystallization thereof, to allow the formation of generally crystalline agglomerates. . The predetermined amorphous convertible content of the binder and / or the drug is capable of being converted to a crystalline form upon exposure to a preselected stimulus which includes, among other things, moisture. The particles are then agglomerated while maintaining the preselected or predetermined amount of convertible amorphous content. After the agglomeration is complete, the amorphous convertible content within the agglomerates is exposed to the preselected stimulus and converted to a crystalline form. By "crystalline", it is meant that the agglomerates of the present invention may still contain some amorphous content, predominantly non-convertible amorphous phase with some unconverted convertible amorphous content. The latter must be minimized. Without wishing to be bound by any particular scientific theory, it is believed that the conversion of the convertible amorphous content creates crystalline bonds between the particles. These bonds are strong enough to preserve the integrity of the agglomerates during handling, and dosage. However, they are soft enough to be held by commercially available inhalers, so as to provide a fine particle fraction acceptable with the dosage.

It is an important aspect of the present invention that the agglomerates contain a certain content of convertible amorphous content during formation. "Convertible" means that the amorphous content, when exposed to certain predetermined or preselected stimuli, will be converted from amorphous to a crystalline form. This amorphous convertible content may be present as the drug part, part of the solid binder, or both. The distribution of the amorphous content in the particles in general is not important, provided that sufficient convertible amorphous content is present, preferably substantially homogeneously, throughout the system. The fact that the solid binder may or may not contain any convertible amorphous content is not important in itself. In such cases, the solid binder still imparts certain advantageous properties to the resulting agglomerates, in terms of their ability to flow freely, their overall density, their intensity and the ability to retard hanging. In a more preferred embodiment, the present invention provides a method for the production of agglomerates of a pharmacologically active agent, which includes the steps of providing at least one pharmacologically active agent having an average particle size below about 10 μm and at least one solid binder. Preferably, the majority of the solid binder also exists as particles of less than about 10 μm. In general, the binder has a preselected amount of convertible amorphous content, which is sufficient to ensure the formation of agglomerates with the pharmacologically active agent, with crystallization by exposure to a preselected stimulus, such as atmospheric moisture. The next step involves the formation of a substantially homogeneous mixture of the particles, while maintaining the preselected amount of convertible amorphous content. The mixture is then agglomerated while still preserving the amorphous content. Finally, the convertible amorphous content of the solid binder and / or drug within the agglomerates is converted to a crystalline form by exposure to the preselected stimulus. The resulting agglomerates are free-flowing, and are characterized by bridges or bonds between particles, such as, for example, between the pharmacologically active agent and the solid binder, (or even between the same particles of the solid binder), which are sufficiently strong as to withstand handling, but weak enough to ensure delivery of an acceptable fine particle fraction of free particles of the pharmacologically active agent. The result of this preferred aspect of the present invention is the creation of a dosage form of a pharmacologically active agent, useful as part of oral and / or nasal inhalation therapy. The dosage form includes agglomerates of pharmacologically active agent particles, and crystalline solid binder particles. The particles preferably have an average particle size of 10 μm, or less.

The ratio of drug to binder in the agglomerate can vary widely according to the amount of drug to be administered, the desired fine particle fraction, and the amount and relative distribution of convertible amorphous content present as part of the drug and / or binder. . In fact, the ratio of drug to binder can vary from about 1000: 1 to 1: 1000 (drug: agglutinant). However, preferably, the drug and the binder are present in a ratio of between 100: 1 to 1: 500, and even more preferably, between 100: 1 to 1: 300. The agglomerates in general vary in sizes, from about 100 to about 1500 μm; and an average size between 300 and 1000 μm. The overall density of the resulting agglomerates is between about 0.2 and about 0.4 g / cm 3. Preferably, the ratio of drug to solid binder ranges from about 20: 1 to about 1: 20, and more preferably, 1: 3 to 1: 10. The agglomerates also preferably have an average size of between about 300 and about 800 μm, and more preferably, between about 400 and about 700 μm. In another aspect of the present invention, an intermediate agglomerate useful for the production of a free-flowing crystalline agglomerate dosage form of a pharmacologically active agent is provided. The intermediate agglomerate includes particles of a pharmacologically active agent, and solid binder particles, preferably anhydrous lactose. The particles of the binder and / or drug include a preselected amount of convertible amorphous content, which is sufficient to ensure the formation of crystalline agglomerates upon exposure to a preselected stimulus. The particles of the pharmacologically active agent and the binder particles have an average particle size of about 10 μm or less, and each is provided in a ratio of between about 100: 1 and about 1: 500, and even more preferably between approximately 100: 1 and approximately 1: 300.

The resulting agglomerates vary in size, from about 100 μm, to about 1500 μm, and have an average size of between 300 and 1000 μm. Their overall density generally ranges from about 0.2 to about 0.4 g / cm3. These intermediate agglomerates are too weak to withstand normal handling, and consequently are not suitable for a dosage form. They also have a relatively high index of hanging in the mouthpiece of an inhaler. Said agglomerates are also not stable. Over time, they will become an uncontrolled form, a crystalline form. This produces a higher level of variability in terms of link strength and dosing uniformity. However, these amorphous agglomerates are very useful in the formation of crystalline dosage forms in which, at least substantially all of the convertible amorphous content is converted to a crystalline form by exposure to a preselected stimulus.

A particularly preferred aspect of the present invention is the provision of a method to ensure a higher level of dosage uniformity for very small doses of pharmacologically active agents or drugs inhaled in oral form (approximately 400 μg of drug or less). The method includes dosing a dose of agglomerated pharmacologically active agent as previously described, and administering that dose of agglomerated pharmacologically active agent, to a patient in need thereof. The present invention further provides a metered dose of a pharmacologically active agent useful for administration by oral inhalation therapy. The measured dose can vary widely in size; including up to about 50,000 μg of the pharmacologically active agent by inhalation. The ability to accommodate such a wide range of dosage levels is a direct result of the advantages arising from the use of the present invention to manufacture agglomerates. However, the present invention is more useful in the context of very small doses including up to about 400 μg of particulate pharmacologically active agent, the balance being a lactose binder. More particularly, the dose contains approximately 100 μg of pharmacologically active agent, or less. It is these smaller dosage levels which are the most demanding about dosage forms. Oral inhalation of a pharmacologically active agent, as noted above, can be demanding, not only in terms of dosing equipment, but also in terms of formulations. The dosage form seems to need to simultaneously meet the number of criteria, many of which were thought to be mutually exclusive. For example, it is very important that the agglomerates are formed in a consistent, highly repeatable manner, with very little variation in terms of size, drug content, and binding intensity.

Nterparticle The agglomerates must also be solid enough to allow them to be worked, sieved, spheronized, and otherwise manipulated without breaking. At the same time, the agglomerates must be weak enough to allow them to break during inhalation, and produce, as far as possible, free and small particles of drugs in a form that is therapeutically effective. For another example, the agglomerates must be free enough fluid to allow them to be charged in an inhaler, and dosed through the inhaler, and dosed through the inhaler and supplied, with as little residue retained as possible. However, the formation of agglomerates of inherent free-flowing materials can be difficult. One of the most interesting aspects of the present invention is the discovery that, trying to balance these performance criteria often competitors, it is neither possible nor necessary. Instead, the invention uses certain properties when those properties are advantageous. Then, just when those same attributes would become disadvantages, the agglomerate is fundamentally changed to eliminate those properties completely. Instead, a new crystalline agglomerate is discovered. This new agglomerate does not retain any of those properties of the previous agglomerates that were useful for agglomerate formation, but harmful for handling, dosing, and administration. Instead, the new agglomerates, after conversion of the convertible amorphous content of the solid binder and / or the drug, are free flowing and very consistent in terms of agglomerate size and size distribution. In addition, the agglomerates are sufficiently harsh to allow them to be handled, dosed and even dropped while in the inhaler, without the adverse consequences found in the prior art. At the same time, when used in combination with an inhaler that can generate sufficient strength, the structural integrity of these rough agglomerates can be interrupted sufficiently to provide an acceptable fine particle fraction. Therefore, according to another aspect of the present invention, there is provided a crystalline agglomerate of a drug with an average particle size of 10 μm or less, and solid binder particles. These particles are joined as a result of conversion into a portion of a convertible amorphous region of either the drug, the binder, or both. No additional binder is required. These agglomerates are provided in combination with a nasal or oral inhaler, which is configured so as to provide a fine particle fraction of drug particles of at least 10%. In general, the resultant agglomerates have a breaking strength of between about 50 mg and about 5,000 mg. More preferably, the crystalline agglomerates according to the present invention have a breaking strength of between about 200 mg and about 1500 mg. Accordingly, the inhaler used to dose these agglomerates will have to provide, at a minimum, a force sufficient to break down the strength of the agglomerate, so as to result in a fine particle fraction of at least about 10% or more. This means that at least 10% of the drug will be reduced to a fine particle fraction, of particles having a size of 6.8 μm or less. It should not be surprising that if an inhaler is configured to provide a fine particle fraction of at least 10%, of the drug, when the strength of the agglomerate is 5,000 mg, the same inhaler will provide a fine particle fraction much larger if used in combination with agglomerates according to the present invention, having a strength of for example 500 mg. It has further been discovered that by providing a solid binder having a similar range of particle sizes when compared to the particle size of the drug particles, it is possible to obtain a substantially homogeneous distribution of drug in each measured dose, even when the doses measured of drugs are as small as approximately 400 μg or less.

In summary, it has been found that converting the amorphous content of the binder or the drug to a crystalline form within the preformed agglomerate, once the agglomeration is complete, desirable properties can be imparted. When the amorphous content of the agglomerates is converted to the crystalline form, the agglomerates become stable. In fact, they are less sensitive to factors such as humidity and temperature. The crystalline material is also free flowing, and exhibits reduced hanging in relation to the same agglomerates before conversion. It is easier to load and empty a dosing hole, and therefore, ensures a consistent metering. This together with a high stability and homogeneity, makes possible the consistent dosing of very small doses. It has therefore been discovered that, through the present invention, it is possible to provide materials that are ideally suited for agglomeration just when it is necessary to agglomerate said materials, and further it is possible to produce agglomerates that are ideally suited for administration of pharmacologically active substances to through an oral inhalation system. Another important aspect of the present invention is a change in the conventional perception of the amorphous content of the particles. The industry has long known the amorphous character imparted to certain materials by processes such as micronization, spray drying, freeze drying, and ball milling. A certain degree of amorphous character is inevitably imparted to materials when the particle size is reduced using such techniques. However, due to the variability that can result from such amorphous materials, the industry has long sought a way to minimize or eliminate the creation of amorphous content during the formation of microparticles. In fact, that is the very point of WO 05/05805. This PCT application seeks to form, as much as possible, a homogeneous mixture of particles, with characteristics as uniform as possible, in order to ensure the production of agglomerates that have a more closely controlled size. The theory seems to be that, if homogeneity can be assured in terms of particle size, particle mixture and crystallinity, it is easier to control the resulting size and composition of the particles. Therefore, moisture is added to the particles, before agglomeration, to ensure that their total amorphous convertible content is converted to crystalline form. However, according to the present invention, it has been discovered that the amorphous character of the drug and / or binder can be exploited to the advantage of the formulator. By using the amorphous content of the mixture as the binder, the need for additional binders can be eliminated. This can only be achieved, however, when algomeration occurs before exposure of significant amounts of atmospheric moisture. Once the particulate has been exposed to moisture, the conversion of the convertible amorphous content will prevent a solid state agglomeration, and a formation of direct intercrystalline bonds. Even more, it has been discovered that only imparting said amorphous content to the particles is not sufficient. Certainly, it has been known for a long time about micronized drugs. However, due to the natural stability of many drugs, they can not be easily transformed into crystalline agglomerates, as discussed herein. Rather, it has been found that by imparting a certain amount of amorphous character to a solid binder, a binder that is capable of being easily converted to a crystalline form, the advantages of the present invention can be observed. It has been discovered that the use of a solid metastable material as a binder provides advantages, both when the binder is in its amorphous form, and again when it is in its crystalline form, provided that the various forms are used intentionally at the correct time .

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph illustrating water absorption of the agglomerates of the present invention when exposed to moisture before and after being subjected to conversion.

Figure 2 is a block diagram illustrating a manufacturing scheme for agglomerates of either lactose alone, or mometasone furoate and lactose. Figure 3 is a graph illustrating the results of a drop evaluation at 122 cm (48 inches), where: ° is inhaler 1, • is inhaler 2, V is inhaler 3, ^ is inhaler 4, D is inhaler 5, B is inhaler 6,? it is inhaler 7, ^ is inhaler 8, 0 is inhaler 9, and ^ is inhaler 10. Figure 4 is a graph illustrating the results of a control for a drop evaluation of 122 cm (48 inches), where. ° is inhaler 1, • is inhaler 2, V is inhaler 3, ^ is inhaler 4, D is inhaler 5, • is inhaler 6,? is inhaler 7, - * • is inhaler 8, 0 is inhaler 9, and is inhaler 10.

DETAILED DESCRIPTION OF THE INVENTION An agglomerate according to the present invention is a bonded mass of small particles. The agglomerators include at least one first material and at least one solid binder. The first material, according to the present invention, can be any, since, in fact, the present invention can be broadly made to make free-flowing agglomerates for any application, including medicaments, cosmetics, foods, and flavorings, and the like. . However, preferably, the first material is a pharmacologically active agent or drug, which must be administered to a patient in need of some course of treatment. The pharmacologically active agent can be administered prophylactically as a preventative, or during the course of a medical condition, as a treatment or cure. More preferably, according to the present invention, the pharmacologically active agent or drug is a material capable of being administered in the form of a dry powder to the respiratory system, including the lungs. For example, a drug according to the present invention could be administered so that it is absorbed into the bloodstream through the lungs. More preferably, however, the pharmacologically active agent is a powder drug that is effective to treat some condition of the lungs or respiratory system, directly and / or topically. Particularly preferred pharmacologically active agents according to the present invention include, without limitation, corticosteroids such as: mometasone fuoroate; beclomethasone dipropionate; budenoside; fluticasone; dexamethasone; flunisolide; triamcinolone; (22R) -6,9a-difluoro-11β, 21-dihydroxy-16a-, 17a-propylmethylenedioxy-4-pregnen-3,20-dione; tipredano, and similar. ß-agonists (including ß1 and ß2 agonists), including without limitation, salbutamol (albuterol), terbutaline, salmeterol, and bitolterol, may also be administered. Formoterol (also known as eformoterol) for example, such as fumarate or tartrate, a highly selective long-acting β2-adrenergic agonist that has a bronchospasmolytic effect, is effective in the treatment of reversible obstructive pulmonary diseases of various genesis, particularly asthmatic conditions. Another long-acting β-agonist which can be administered according to the present invention is known as TA-2005, chemically identified as (21 H) -Quinolinone, 8-hydroxy-5- [1-hydroxy-2 - [[ 2- (4- (methoxyphenyl) -1-methyl-ethyl] amino] ethyl] -monoclorhydrate, [R- (R *, R *)] -, also identified by the Registo number of the Chemical Abstract Service 137888-1 1-0, and discovered in U.S. Pat. No. 4,579,854, the text of which is incorporated herein by reference. Anticholinergics such as ipratropium bromide and oxitropium bromide can be used. They can also do cromoglicato sodium, nedocromil sodium, and leukotriene antagonists, like zafirlukast and pranlukast. Bambuterol (for example as hydrochloride), fenoterol (for example hydrobromide), clenbuterol (for example as hydrochloride), procaterol (for example as hydrochloride), and broxaterol are highly selective β2-adrenergic agonists which can be administered. Several of these compounds could be administered in the form of esters, solvate salts, such as hydrates, or solvates of said esters or salts, if any, pharmaceutically acceptable. The term is also intended to cover both racemic mixtures, as well as one or more optical isomers. The drug according to the present invention may also be an inhalable protein or a peptide such as insulin, interferons, calcitonins, parathyroid hormones, granulocyte colony stimulating factor, and the like. "Drug" as used herein, may refer to a single pharmacologically active entity, or combinations of any two or more, being an example of a useful combination, a dosage form that includes both a corticosteroid and a β-agonist .

A preferred pharmacologically active agent for use in accordance with the present invention is mometasone furoate. To be topically effective in the lungs, or upper and / or lower respiratory passages, it is important that the pharmacologically active agent be delivered as particles of approximately 10 μm or less. See Working Group on Pulmonary Dynamics, Deposition and Retention Models for Internal Dosimetry of the Human Respiratory Tract, Health Pys, 12, 173, 1966. The ability of a dosage form to actually administer free particles, of these effectively and therapeutically configured particles , is the fine particle fraction. The fine particle fraction, therefore, is a measure of the percentage of bound drug particles released as drug-free particles, which have a particle size below some threshold during administration. The fine particle fraction can be measured using a multi-stage liquid interferer, manufactured by Copley Instruments (Nottingham) LTD, using the manufacturer's protocols. According to the present invention, an acceptable fine particle fraction is at least 10% by weight of the drug, which is made available as free particles having an aerodynamic particle size of 6.8 μm, or less, measured at an index of flow of 60 liters per minute.

The amount of drug administered will vary with a number of factors, including, without limitation, the age, sex, weight, condition of the patient, the drug, the course of treatment, the number of doses per day, and the like: For mometasone furoate, the amount of drug delivered per dose, ie, by inhalation, will generally vary from approximately . 0 μg to about 10,000 μg. Doses of 25 μg, 50 μg, 75 μg, 100 μg, 125 μg, 150 μg, 175 μg, 200 μg, 250 μg, 300 μg, 400 μg, and / or 500 μg are preferred. The drug may include some or all of the convertible amorphous content of the agglomerates, as discussed herein. The solid binder according to the present invention can be any substance that can be provided, or reduced, to a particle size that is approximately the size of the particles of the pharmacologically active agent, as previously described. For example, agglomerates of anhydrous mometasone furoate USP will preferably be provided having particles of at least 80% < 5 μm, and at least 95% = 10 μm (medium per volume distribution). The solid binder, such as anhydrous lactose, NF will be provided having particles of at least 60% < 5 μm, at least 90% below 10 μm, and at least 95% < 20 μm. The average particle size is approximately the same for both, and is less than 10 μm. When it is in a crystalline form, that is, when all, or almost all, of the convertible amorphous content of the solid binder is converted to a crystalline form, the binder must be stable, capable of supporting and maintaining an agglomerate and binding agent particles therapeutically active so that they can be released as a fine particle fraction of particles. The binder must further impart to the crystalline agglomerate a desired range of properties, including overall density, intensity, a free-flowing character, and storage stability. Preferably, the convertible amorphous content of the solid binder, if in fact, contains some or all of the convertible amorphous content of the agglomerate, will be converted from its amorphous form to its crystalline form upon exposure to a pre-selected or predetermined stimulus, such as atmospheric moisture. in the form of moisture. However, materials that meet all of the foregoing criteria and will become responsive to other preselected stimuli such as, for example, temperature, radiation, solvent vapor, and the like, may also be used. Preferred solid binders include polyhydroxy aldehydes, polyhydroxy ketones, and amino acids. Preferred polyhydroxy aldehydes and polyhydroxy ketones are hydrated and anhydrous saccharides, including, without limitation, lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose, mannitol, melezitose, starch, xylitol, mannitol, myoinositol, their derivatives, and Similar. Particularly preferred amino acids include glycine, alanine, betaine, and lysine.

When the drug is completely crystalline, or when it contains only non-convertible amorphous content, the solid binder must provide all the amorphous content of the agglomerated system, and vice versa. Neither the solid binder material nor the drug naturally need to have said amorphous content, provided that said amorphous content can be reversibly imparted thereto. It is possible that the drug, the binder, or both, contain a certain percentage of amorphous content, which is non-convertible or stable under the conditions of use and storage, as well as when the preselected stimuli are applied. This stable amorphous content is not part of the amorphous convertible content previously discussed. As is generally the case, this stable amorphous content plays some role in the interparticulate bond. However, it will not contribute to the interparticulate bond resulting from the conversion between amorphous and crystalline materials according to the present invention. Therefore, in certain formulations such as those using, for example, mometasone furoate, all the convertible amorphous content is contributed by the solid binder. As such, sufficient solid binder must be provided to impart sufficient convertible amorphous content to the agglomerated system. However, with another drug such as albuterol sulfate, which in itself may contain convertible amorphous content, it may be possible to use a binder without amorphous content, or use a mixture of a solid binder containing a certain lower percentage of amorphous content, together with albuterol. Too much convertible amorphous content can result in agglomerates that are tightly bonded together to produce the convenient fine particle fraction.

Generally, the amount of amorphous content in the system should vary from about 1 to about 50% by weight, and more preferably, from about 3 to 30% by weight. With further reference, the amount of amorphous content convertible in the system will vary from about 5 to about 25% by weight.

Of course, it is equally acceptable to characterize the amorphous content of either the binder or the drug, individually, in terms of the percentage of amorphous content in the system. Accordingly, when the binder contains the total convertible amorphous content, and when the binder contains an amorphous content of 20%, and is provided in a 1: 1 ratio by weight with the drug, the total convertible amorphous content in the system will be 10. % by weight. Some amorphous character can be imparted convertible to certain material, during the course of the particle size reduction thereof. Therefore, for example, if anhydrous lactose is micronized in a micronizer such as MICRON-MASTER® Jet Sprayer, which can be obtained from Jet Pulverizer Co., Palmyra, New Jersey, it is possible to obtain not only particles of the desired size, but also impart a certain amount of amorphous content. This can also be achieved using traditional microparticle generating devices, such as trituration, spray drying, or ball milling. See Briggner, Buckton, Bystrom, and Darcy, "The Use of Isothermal Microcalorimetry in the Study of Changes in Crystallinity Induced During Powder Processing", International Journal of Pharmaceutics, 105 (1994), pages 125-135. However, when others have tried to minimize the degree of amorphous content generated, and have considered this amorphous content as an unfortunate, but generally inevitable, side effect of reducing the particle size, the present invention seeks to encourage a certain amount of amorphous content. The present invention also seeks to control and maintain that amorphous character of the solid binder and / or the drug, up to a specific time in the agglomeration process. For this end, certain steps are carried out to impart a pre-selected amount of amorphous character, and to maintain the amorphous character of the solid binder and / or the drug. For example, when anhydrous lactose is sprayed using a Jet Sprayer as discussed above, spraying is carried out under considerable pressure, such as, for example, between about 50 and about 120 pisg (3.45 to 8.27 x 105 newton / m2). Approximately 80-100 psig (5.51 to 6.89 x 105 newton / m2) is preferred. The use of such high pressures results in particularly violent particle formation, and generally increases the amount of amorphous content. Moreover, applicants preferably use dry gas compressed nitrogen to pulverize the solid binder, as applicants have discovered that exposing amorphous content to humidity during particle formation can act to reconvert the amorphous content back to a crystalline form prematurely . Of course, it is also possible to impart an amorphous surface to particles of a solid binder and / or drug that is already of a correct particle size, or to use particulate which is inherently amorphous in character, and can be converted to a crystalline form. Once sufficient convertible amorphous content is present, that amorphous character must be maintained until such time as it is convenient to convert the particles to a completely crystalline form. For solid binders or drugs, such as lactose, which are sensitive to moisture, this can be done by processing and storage under low humidity conditions. Preferably, the micronized materials are subsequently stored and / or processed under conditions of less than about 30% relative humidity ("RH"), and more preferably, less than 20% RH at 21 ° C. By this it is meant that the micronized materials are processes and stored at atmospheric moisture content which is equivalent to that of an atmosphere of 30% RH at 21 ° C, or less. The exact amounts of moisture present in the atmosphere at various temperatures can be derived from Table 5.27, "Steam Mass Water in Saturated Air", on page 5.150 of John A. Dean, Lange's Handbook of Chemistry, edition 14, McGraw-Hill , Inc. New York (1992). It is particularly preferred to store any material that contains convertible amorphous content under humidity conditions of less than 10% RH at 21 ° C, and more preferably, as close as zero relative humidity as practicable. All processing can be carried out at any temperature. However, the processing is usually carried out more conveniently at 0 ° C to 38 ° C. Generally, any method of agglomerating the solid binder and the pharmacologically active agent, which may be effected without converting the amorphous content of the solid binder to a crystalline form, prematurely, and which does not require the use of additional binder, can be practiced according to the present invention. For this reason, the agglomeration process discovered in the aforementioned U.S. Patent No. 4,161,516 can not generally be practiced, since water and / or moisture are added as a binder before agglomeration. This would cause the premature conversion of some or all of the amorphous content to a crystalline form, which would actually retard the formation of the agglomerate and lead to variability. This variability could also cause the formation of agglomerates that are too hard and strong. Even when such agglomerates are administered using an inhaler that provides a particularly violent dispersing action, these agglomerates can not produce an acceptable fine particle fraction. It is important that the process produces agglomerates that vary in size from about 100 to about 1500 μm.

The agglomerates in general have an average size of between about 300 and about 1,000 μm. More preferably, the agglomerates have an average size of between about 400 and about 700 μm. More preferably, the agglomerates have an average size of between about 500 and 600 μm. The resulting agglomerates will also have a global density ranging from about 0.2 to about 0.4 g / cm3, and more preferably, from about 0.29 to about 0.38 g / cm3. More preferably, the agglomerates will have a global density ranging from about 0.31 to about 0.36 g / cm 3. It is also important for the dosage of the pharmacologically active agent that the agglomeration process produce a relatively narrow particle size distribution. In this context, particle size refers to the size of the agglomerates. Preferably, no more than about 10% of the agglomerates are 50% smaller or 50% larger than the size of the object or medium agglomerate. Therefore, for a desired agglomerate of 300 μm, no more than about 10% of the agglomerates will be smaller than about 150 μm, or larger than about 450 μm. A preferred method for preparing the agglomerates according to the invention, which meets all the foregoing criteria, involves mixing preselected amounts of one or more pharmacologically active agent (s) and the micronized amorphous content containing dry solid binder, in a ratio of between about 100: 1 and about 1: 500, and even more preferably between about 100: 1 and approximately 1300 (drug: binder), and preferably a ratio of between 20: 1 to about 1: 20. More preferably, the drug would be provided in an amount of 1: 3 to about 1: 10 relative to the amount of the solid binder. These particles are then preferably mixed in some form of mechanical mixing device. Preferably, the mixture will result in substantial homogeneity. Naturally, it may not be possible to obtain absolute homogeneity. However, a tolerance of ± 10% is acceptable during the combination, and ± 5% is acceptable during agglomeration. The combination of such ingredients in the form of a fine particle can be a challenge in itself. The combination can be effected, for example purposes only, using a V-shaped Patterson-Kelly mixer, which has a pin intensifier bar. Preferably, the combination process is carried out in the clean room, and, as previously noted, the humidity and temperature of the room should be controlled. At 21 ° C and 20% RH, for example, the conversion of the amorphous content is sufficiently low to allow the combination. Depending on the size of the lot, the combination can be made within approximately 3 to 15 minutes in total. If the mixture of micronized drug and solid binder will no longer be processed immediately, it should be stored again under conditions of low humidity and low temperature. For a particularly small amount of drug relative to the solid binder, the conventional combination technique may not result in an acceptably homogeneous mixture. In this case, the following approaches can be used: (1) combination of the drug or drugs and the solid binder before micronization; (2) when a mixture of pharmacologically active agents is used, and particularly when one is present in significantly greater amounts than the other, the combination of the two agents together, micronizing the combination and then, the combination with micronized solid binder having a convertible amorphous content; and / or (3) formation of microspheres by spray drying, such as: (a) dissolving or suspending the drug in an aqueous solution of a diluent or carrier, such as lactose, drying by spraying and then mixing the resulting microspheres with micronized solid binder. which has an amorphous convertible content; or (b) spray drying a non-aqueous solution or suspension of the drug, containing suspended micronized diluent or carrier particles, such as lactose, then mixing with solid binder particles having a convertible amorphous content. In fact, even with larger amounts of drugs, it may be convenient to use the first approach.

From the mixer, the mixed particles are dumped in a conventional screen / dish combination for the formation of the agglomerate.

The particles can now be considered as an agglomeration, because they no longer retain so much of their individual identity. They are not "agglomerated" as described herein, since they are not collections of smaller individualized particles of generally spherical shape and / or greater density. The screen and cymbal are then rotated in an eccentric circular motion in a plane parallel to the ground. This can be done manually, or using a screen shaker device. Intermittent strokes are applied perpendicular to the top of the pan, which forces or doses materials through the screen into the pan, below which the eccentric movement of the pan encourages agglomeration formation, as defined above. The agglomerates are also spheronized simultaneously. Naturally, this agglomeration process, as with any agglomeration process according to the present invention, must be carried out under low humidity conditions to avoid unwanted premature conversion of the amorphous content of the solid binder to crystalline form. After the agglomerates are formed and appropriately shaped, for example, by dumping through another screen, they can be exposed to preselected stimuli, such as higher humidity, to cause the substantially complete conversion of the convertible amorphous content contained within the agglomerates. , to a crystalline form. Naturally, the higher the humidity, the less time will be necessary for the exposure. However, a somewhat gradual and controlled conversion is preferred, since the strength of the agglomerates must be tightly controlled. The agglomerates containing amorphous convertible content can be exposed to relative humidity of between about 30% and about 80% (at 25 ° C) for a period of time which is sufficient to convert the total amorphous content. More preferably, the convertible amorphous content is converted by exposure to an atmosphere having a water content equivalent to a relative humidity of between about 40% and about 60% (measuring relative humidity at about 25 ° C). This is particularly useful when the solid binder is anhydrous, such as anhydrous lactose. The amount of time can vary dramatically with the size and density of the agglomerates and the surface area of exposure. For example, placing a thin layer of agglomerates on a flat open tray will produce a much faster conversion in general than placing the same amount of agglomerate in a narrow container. In certain cases, the amount of exposure will have to be of the tens of minutes type. In other cases, one or two days may be required. Because, preferably, the exposure is controlled at relative humidity of 65% or lower (at 25 ° C), there is relatively little concern as to overexposure. As long as sufficient time is allowed to allow all of the convertible amorphous content of the agglomerates to convert to crystalline form, the fact that additional exposure may take place generally has no consequence. If moisture levels above about 65% are used, however, then water vapor can actually act as a binder. While the use of water as a binder is well known, it is detrimental to the ability to generate a fine particle fraction, particularly when used in combination with the main mode of attachment described herein; to say, crystalline union. Therefore, it is still desirable to limit the exposure of the agglomerates to high humidity levels beyond the point necessary for complete conversion. After the conversion, the agglomerates have an interparticulate bond strength that is larger in terms of measurement, than the interparticulate bond strength before conversion. The resulting agglomerates are as described above, generally crystalline in nature, free flowing, rough and resistant to hanging. These agglomerates can be stored, handled, dosed, and dispensed, while maintaining their structural integrity. The agglomerates also have a size and size distribution very convenient and consistent. Perhaps more importantly, the crystalline agglomerates of the present invention have sufficient strength to allow them to be manipulated and abused. At the same time, the agglomerates remain soft enough to be broken sufficiently during dosing, so as to provide an acceptable fine particle fraction. In general, agglomerates have an intensity ranging from about 50 mg to about 5,000 mg, and more preferably, from about 200 mg to about 1,500 mg. The bankruptcy force was evaluated in a Thermomechanical Analyzer Seiko TMA / SS 120 C, which can be obtained from Seilko Instruments, Inc.

Tokyo, Japan, using procedures that can be obtained from the manufacturer.

It should be noted that the intensity measured in this way is influenced by the quality and range of the interparticle crystal bond described herein. However, the size of the agglomerates also plays a role in the intensity of bankruptcy measured. Generally, larger agglomerates require more force to break than smaller particles require. When the agglomerates produced according to the protocol reported in Example 1 were dosed at 100 μg per inhalation, using a powder inhaler as described in WO 94/14492, assigned to Schering Corporation, sufficient force was generated as to break down the agglomerates sufficiently to produce the desired level of free drug particles having a size of about 6.8 μm or less. Naturally, the degree of force that must be generated while the agglomerates are dispensed depends on the internal bond strength of the agglomerates. The greater the bond intensity, the greater the amount of force that will be required to produce an acceptable fine particle fraction. The agglomerates of the present invention, while being too strong and stable for certain inhalers, are nevertheless useful in other commercially available inhalers, and when dispensed therefrom, an acceptable fine particle fraction results. Such inhalers include, without limitation, the inhaler Schering as defined earlier, Diskhaler (Alien &Hanburys), Accuhaler (Alien &Hanburys), Diskus (Glaxo), Spiros (Hard), Easyhaler (Orion), Cyclohaler (Pharmachemie), Cyclovent (Pharmachemie), Rotahaler (Glaxo), Spinhaier (Fisons), FlowCaps (Hovione), Turbospin (PH &T), Turbohaler (Astra), EZ Breath (Norton Healthcare / IVAX), MIAT-HALER (Miat), Pulvinal (Chiesi), Ultrahaler (Fisons / Rhone Poulenc Rorer), MAG-Haler (GGU), Prohaler (Valois), Taifun (Leiras), JAGO DPI (JAGO), ML Laboratories' DPI (ML Laboratories). The inhaler must be able to produce enough force to break any agglomerate that is used, in order to produce an acceptable fine particle fraction. Therefore, an agglomerate having a bankruptcy strength of 1,000 mg as measured in the manner described herein, should be used in combination with an inhaler that can apply sufficient force to ensure that it results at least a fine particle fraction of 10%, of each dose thereof. As shown in Figure 1, agglomerates of mometasone: anhydrous lactose, at a ratio of 1: 5.8 (by weight) were exposed to 50% relative humidity at 25 ° C, both before and after the conversion. The graph using the unbroken line (I) demonstrates the moisture absorption of the agglomerates when they are exposed to moisture before the agglomerates are converted to crystalline form. Moisture is absorbed very quickly reaching a maximum point. At that point the conversion to the crystalline form takes place. As a result of that conversion, the water is actually expelled and the total moisture content falls. For the same reason, once the agglomerates that have been converted are exposed to moisture, they can absorb a small amount of moisture, but then, moisture absorption is fixed. See broken line (II). Among other things, Figure 1 demonstrates the resulting stability of the agglomerates that are formed in accordance with the present invention. The discovery and use of the increasing binding intensity of crystalline agglomerates is significant due to a number of reasons. First, the resulting agglomerates are free flowing, stable, and capable of being properly handled and packed. Second, the agglomerates provide the homogeneity and overall density needed to allow them to be consistently loaded into the metering hole of an inhaler, even in particularly small doses. Consequently, the crystalline agglomerates can be dosed, measured and supplied in an exact manner. This is properly demonstrated in Figure 2. When the process of the present invention was carried out in lactose alone, and when moisture was added to the lactose prior to agglomeration, the resulting lactose agglomerate proved to be too soft to handle. Therefore, significant problems would be noticed in the repeatable dosage. These same results were observed when mixtures of drug and lactose were exposed to moisture before agglomeration. In fact, in the formulation of a batch according to the present invention as described in Example 1, anhydrous lactose which had already been converted was used. The fact was not known at that time. When the resulting agglomeration protocol did not produce the desired results, the cause was investigated. Subsequently, the previous conversion of lactose was discovered. Therefore, it is important to maintain the amorphous convertible content of the drug and / or the binder in that state until after the formation of the agglomerates as described herein. In another experiment also illustrated in Figure 2, agglomerates containing mometasone were loaded in an inhaler prior to moisture stabilization. The final product was not stable, and provided a poor dose supply due to a high hanging in the mouthpiece of the inhaler and elsewhere. When the agglomerates containing the same drug were stabilized by exposure to moisture as discussed herein, the resulting agglomerates were hard, free flowing, and easily handled. The internal link strength was increased, allowing for appropriate handling characteristics. However, the agglomerates remained soft enough to produce an acceptable fine particle fraction. The present invention results in a higher degree of dosage uniformity. As shown in Table 1, the agglomerates produced according to the present invention were loaded into 10 inhalers as described in previously mentioned WO 94/11492. Inhalers were established to deliver 100 μg of mometasone furoate by inhalation. Mometasone furoate was provided in a ratio of 1: 5.8 to anhydrous lactose (680 μg total agglomerate), and was produced as described in Example 1.

TABLE 1 Uniformity of Dosage on the Number Labeling of Inhalations (Dose Issued) * The deal dose is 100 μg ** Percentage of Coefficient of Variation The dose emitted was determined using a dry powder inhaler dosing unit, similar to that described in Pharmaceutical Forum, Vol. 20, No 3, (1994), pages 7494. The emitted dose was collected using a separatory funnel attached at one end to a sintered glass filter, at an air flow rate of 60 L / minute, for a total of 4 seconds. The drug was then dissolved in a solvent and analyzed using HPLC, as is known in the art. It is clearly evident from a review of Table 1, that from a first dose of inhalation, to the number 120, there is great consistency. In addition, the consistency of inhaler to inhaler is significantly higher than what would normally be expected. Perhaps what is more important, is that the average over 120 doses for 10 inhalers shows great consistency. These numbers also indicate that very little material is lost during dosing. Consequently, the problems of hanging and dosing resulting from the loading of the dosing hole are minimized. The fine particle fraction (as a percentage of the total dose) resulting from these emitted doses was also evaluated (Table 2). The fine particle fraction (< 6.8 μm) was determined at a flow rate of 60 L / minute, using a multi-stage liquid interferer (5 stages) manufactured by Copley Industries (Nottingham) LTD.

TABLE 2 The fraction of measured fine particle of each inhaler was greater than 10%, and in addition, it was enormously uniform from the first dose to the dose 120.

A multistage interferer allows measuring the fraction of certain particles measured in each of its various stages. As illustrated in Table 3, there is great uniformity between dose 1 and dose 120 in terms of the cumulative fine particle fraction that is less than 13 μm, less than 6.8 μm, less than 3.1 μm, and less than 1.7 μm .

TABLE 3 * Average of three determinations Finally, as shown in Figures 3 and 4, the agglomerates of the present invention are very durable. Figure 4 illustrates the control. In this case, illustrate, graphically, the percentage of weight supplied to the dose emitted, in percentage by weight, of 10 inhalers over 120 doses each. The inhalers used were the previously identified Schering powder inhaler, and the doses were 100 μg of mometasone furoate with an anhydrous lactose binder produced as described in example 1. Figure 3 represents the same information for inhalers configured identically , after they had been dropped on a hard surface from a height of approximately 122 cm (48 inches). A comparison of the results memorialized in Figures 3 and 4 shows that very little change is exhibited in total. The present invention helps to ensure an unprecedented degree of agglomerate uniformity, which significantly reduced the variability of the dosage, as demonstrated above. For example, if moisture is added before or during agglomeration, a certain percentage of the solid binder will begin to convert to a crystalline form. The degree of crystal formation can vary greatly from particle to particle. As a result, the size of agglomerate and the physical intensity of the particulate bond can vary greatly. In addition, the binder can actually begin to dissolve, and this would create links that are too strong. This results immediately in a dose variability during inhalation, and a variability in terms of the fine particle fraction of drug delivered. The present invention overcomes this problem, and efficiently provides uniform agglomerates that are easy to produce, store, manipulate, and administer.

EXAMPLES EXAMPLE 1 To ensure the quality and uniformity of the product, the environmental conditions for the handling and manufacture of the agglomerates according to the present invention were the following: Micronization of mometasone and lactose: 21 ° C ± 2 °, and 20% RH ± 5% - Storage of micronized lactose: 21 ° C ± 2 °, and less than 15% RH - Combination of agglomeration powders: 21 ° C ± 2o, and 20% RH ± 5% - Conversion of powder agglomerates: 25 ° C ± 2o , and 50% RH ± 5% A V-shaped mixer from Patterson-Kelley installed with an intensifier bar was established in a clean room with controlled temperature and humidity at 21 ° C and 20% RH, respectively. Half of the micronized anhydrous lactose was loaded in the V mixer. Then the micronized anhydrous mometasone furoate was added. Then, the balance of micronized anhydrous lactose was added. The mixer V was turned on for 5 minutes, at a rotation speed of approximately 24 RPM. Then, the mixer V was rotated for 3 minutes with the clamp-on intensifier bar turned on during the first minute, at a clamp toe speed of approximately 9 meter / second. Then the combination protocol was repeated. Samples were taken from the right, left, and bottom of mixer V, to evaluate the uniformity of the combination using a unit dose sampling screen. To agglomerate this mixture, a screen shaker was established in a clean room with controlled temperature and humidity at 21 ° C and 20% RH, respectively. Thirty (30) mesh screens, saucers and stainless steel containers were washed with 70% alcohol, and dried. The screen / saucer combinations were assembled and placed in the shaker. In each set of 30 mesh screen and cymbal and 12 inches, 200 g of the combination of mometasone: lactose anhydrous in a ratio of 1: 5.8 (drug: binder) was added. The powder combination was spread on the screen, so that the level of the powder combination was less than the edge of the screen frame. The screen / pan was placed on the support plate of the shaker screen. A stainless steel screen cover was placed on the upper screen. The timer was then turned on for 10 minutes, and the device was turned on so as to produce an eccentric circular shake with an eccentric one-inch orbit at a speed of approximately 280 rpm. The screen / saucer was also hit at an index of 150 strokes / minute, to measure material across the screen. The process was stopped and multiple dishes were consolidated. The formed agglomerates were overturned on a 20 mesh screen, and the screen was slightly hit. The material retained on the 20 mesh screen was discarded. The agglomerates that passed through the 20 mesh screen were stored in the appropriate containers. When they were ready to convert the material, the agglomerates were scattered on a stainless steel tray and were exposed in a clean room that had a controlled temperature and humidity at 25 ° C and 50% RH, for 24 hours. The agglomerates were then combined and placed in a suitable container. The overall density was determined using a Vanderkamp hit density evaluator, set for a stroke. The particle size distribution of the agglomerates was determined using a Malvern 2650L particle size analyzer.

EXAMPLE 2 Three additional batches were produced according to the process generally described in Example 1. The batch size and the drug to binder ratios are illustrated below in Table 4: TABLE 4 REPRODUCTIBILIPAD OF AGGLOMERATES OF MOMETASONE: LACTOSE As will be appreciated without difficulty, despite the varied binder and drug ratios, as well as varied batch sizes, a high degree of repeatability was observed in terms of overall density and particle size distribution. The particle size in this context refers to the size of the agglomerate more than to that of the particulate binder and / or drug.

Claims (1)

NOVELTY OF THE INVENTION CLAIMS

1- A process for the production of agglomerates comprising the steps of: (a) providing particles of at least one first material and particles of at least one solid binder, at least one of said first material and said solid binder, having a preselected amount of convertible amorphous content that is capable of being converted to crystalline form upon exposure to a preselected stimulus, said convertible amorphous content being provided in an amount that is sufficient to ensure the formation of agglomerates; (b) agglomerating said particles of said first material and said solid binder, while maintaining said pre-selected amount of convertible amorphous content; and then (c) exposing said convertible amorphous content within said agglomerates, to said preselected stimulus, so as to convert said convertible amorphous content to a crystalline form. 2. The process of claim 1, wherein said first material comprises a pharmacologically active agent. 3. The process of claim 2, wherein said pharmacologically active agent comprises at least one member selected from the group consisting of corticosteroids, β-agonists, anticholinergics, leukotriene antagonists, and inhalable proteins or peptides. 4. The process of claim 2, wherein said pharmacologically active agent comprises at least one member selected from the group consisting of mometasone furoate; beclomethasone dipropionate; budenoside; fluticasone; dexamethasone; flunisolide; triamcinolone; salbutamol; Albuterol; terbutaline; salmeterol; bitolterol; ipratropium bromide; oxitropium bromide; sodium cromoglycate; nedocromil sodium; zafirlukast; pranlukast; formoterol eformoterol; bambuterol; fenoterol; clenbuterol; procaterol; broxaterol; (22R) -6a, 9a-difluoro-1β, 21-dihydroxy-16a, 17a-propylmethylenedioxy-4-pregnen-3,20dione;: TA-2005; tipredano; insulin; interferons; calcitonins; parathyroid hormones; and granulocyte colony stimulating factor. 5. The process of claim 2, wherein said pharmacologically active agent comprises mometasone furoate. 6. - The process of claim 2, wherein said particles of said pharmacologically active agent have an average particle size of 10 μm or less. 7. - The process of claim 1, wherein said solid binder comprises at least one member selected from the group consisting of polyhydroxy aldehydes, polyhydroxy ketones, and amino acids. 8. - The process of claim 1, wherein said solid binder comprises a hydrated or anhydrous saccharide. 9. - The process of claim 1, wherein said solid binder comprises anhydrous lactose or a hydrated lactose. 10. - The process of claim 1, wherein said solid binder comprises anhydrous lactose. 1. The process of claim 2, wherein said particles of said solid binder have a particle size of 10 μm or less. 12. - The process of claim 2, wherein said agglomerate contains between about 1% and about 50% convertible amorphous content. 13. - The process of claim 2, wherein said agglomerate contains about 3% and about 30% convertible amorphous content. 14. - The process of claim 2, wherein said agglomerate contains between about 5% and about 25% convertible amorphous content. 15. - The process of claim 2, further comprising the step of mixing said particles of pharmacologically active agent, and said solid binder before said agglomeration step. 16. The process of claim 14, wherein said particles of pharmacologically active agent and said solid binder are mixed to substantial homogeneity. 17. - The process of claim 2, wherein said particles of pharmacologically active agent and said solid binder are agglomerated in a dish rotated with an eccentric movement. 18. The process of claim 2, wherein said agglomerates have an average size of between about 300 and about 0.1 μm. 19. The process of claim 2, wherein said agglomerates have a size range between about 100 and about 500μm. 20. The process of claim 1, wherein said pre-selected stimulus is atmospheric moisture. 21. The process of claim 1, wherein said solid binder is maintained at a moisture content of less than or equal to that of a relative humidity of 25% when measured at 21 ° C, prior to crystallization. 22. The process of claim 1, wherein said solid binder is maintained at a moisture content of less than or equal to that of a relative humidity of 20% when measured at 21 ° C, prior to crystallization. 23. The process of claim 2, further comprising converting said convertible amorphous from said agglomerate to a crystalline form by exposing said agglomerates to an atmosphere having a moisture content equal to that of a relative humidity of between about 30% and approximately 80% when measured at 25 ° C. 24. The process of claim 23, wherein said convertible amorphous content is converted to a crystalline form by exposing said agglomerates to an atmosphere having a moisture content equal to that of a relative humidity of between about 40% and about 60% when measured at 25 ° C. 25. The process of claim 2, wherein said particles of said agglomerate are more strongly bonded to one another after the conversion of said amorphous content to a crystalline form, than before the conversion. 26. The process of claim 2, wherein said agglomerates have a breaking strength of between about 50 mg and about 5,000 mg after conversion of said convertible amorphous content. 27. The process of claim 2, wherein said agglomerates have a breaking force of between about 200 mg and about 1.500 mg after conversion of said convertible amorphous content. 28. The process of claim 1, further comprising the step of micronizing said solid binder and / or said first material, to impart thereto a preselected amount of amorphous content to the resulting particles before the step of providing said particles. 29. - The process of claim 28, wherein said solid binder is micronized using jet grinding with a substantially anhydrous gas. The process of claim 2, wherein said pharmacologically active agent and said solid binder are blended at a ratio of weight of between about 1000: 1 to 1: 1000. 31. The process of claim 2, wherein said pharmacologically active agent and said solid binder are blended at a weight ratio of between about 100: 1 to 1: 500. 32. The process of claim 2, wherein said pharmacologically active agent and said solid binder are blended at a weight ratio of between about 100: 1 to 1: 300. 33. The process of claim 2, wherein said pharmacologically active agent and said solid binder are agglomerated at a weight ratio of between about 20: 1 to 1: 20. 34. The process of claim 2, wherein said pharmacologically active agent and said solid binder are agglomerated at a weight ratio of between about 1: 3 to 1: 10. 35.- The product of the process of claim 1. 36.- The product of the process of claim 2. 37.- The product of the process of claim 3. 38.- A process for the production of agglomerates that contain an agent pharmacologically active, comprising the steps of: (a) providing at least one pharmacologically active agent having an average particle size of less than about 10 μm; (b) providing at least one solid binder having an average particle size of about 10μm, or less; at least one of said pharmacologically active agent, and said solid binder, having a preselected amount of convertible amorphous content, which is sufficient to ensure the formation of agglomerates upon conversion; (c) forming a homogeneous mixture of said particles of said pharmacologically active agent and said solid binder, while maintaining said pre-selected amount of convertible amorphous content; (d) agglomerating said mixture of said particles of said pharmacologically active agent and said solid binder, while maintaining said pre-selected amount of convertible amorphous content of said solid binder; and (e) then allowing said convertible amorphous content of said agglomerates to be converted to a crystalline form; to form (f) agglomerates that are free flowing, have bridges and are characterized by having a strength of between 50mg and 5000mg. 39.- The process of claim 38, wherein said pharmacologically active agent comprises at least one member selected from the group consisting of corticosteroids, β-agonists, anticholinergics, leukotriene antagonists, and inhalable proteins or peptides. 40.- The process of claim 38, wherein said pharmacologically active agent comprises mometasone furoate. 41. - The process of claim 38, wherein said solid binder comprises anhydrous lactose or a hydrated lactose. 42.- The process of claim 38, wherein said agglomerate contains between about 1% and about 50% convertible amorphous content before conversion. 43.- The process of claim 38, wherein said agglomerate contains between about 3% and about 30% convertible amorphous content before conversion. 44. The process of claim 38, wherein said agglomerate contains between about 5% and about 25% convertible amorphous content before conversion. 45.- The process of claim 38, wherein said agglomerates have a force of between 200 mg and approximately 1500 mg. 46.- A dosage form of an active agent useful for administration by oral inhalation therapy, consisting essentially of: agglomerates of particles of a pharmacologically active agent and particles of crystalline solid binder, said particles having an average particle size of 10μm or less, and being proportioned in a weight ratio of between 100: 1 to 1: 500, said agglomerates having an average size of between 400 and 700μm, a global density of between about 0.2 and about 0.4g / cm3, and an intensity of break between 200mg and approximately 1500mg. 47. - The dosage form of claim 46, wherein said crystalline solid binder comprises lactose. 48. The dosage form of claim 47, wherein said crystalline lactose comprises anhydrous lactose. 49.- The dosage form of claim 46, wherein said agglomerates have an overall density of between about 0.29 and about 0.38g / cm3. 50.- The dosage form of claim 46, wherein said pharmacologically active agent comprises at least one member selected from the group consisting of: corticosteroids, β-agonists, anticholinergics, leukotriene antagonists, and inhalable proteins or peptides. 51.- The dosage form of claim 46, wherein said pharmacologically agent comprises at least one member selected from the group consisting of: mometasone furoate; beclomethasone dipropionate; budenoside; fluticasone; dexamethasone; flunisolide; triamcinolone; salbutamol; Albuterol; terbutaline; salmeterol; bitolterol; Pratropium bromide; oxitropium bromide; sodium cromoglycate; nedocromil sodium; zafirlukast; pranlukast; formoterol eformoterol; bambuterol; fenoterol; clenbuterol; procaterol; broxaterol; (22R) -6a, 9a-difluoro-11β, 21-dihydroxy-16a, 17-propylmethylenedioxy-4-pregnen-3,20-dione;: TA2005; tipredano; insulin; interferons; calcitonins; parathyroid hormones; and granulocyte colony stimulating factor. 52. The dosage form of claim 46, wherein said agglomerate does not include binder other than said solid binder. 53. An intermediate agglomerate useful for the production of a dosage form of crystalline free-flowing agglomerate, of a pharmacologically active agent. , useful for administration by oral or nasal inhalation therapy, said intermediate agglomerates comprising: particles of said pharmacologically active agent and particles of solid binder, said pharmacologically active agent or said solid binder having a preselected amount of convertible amorphous content which is sufficient as to ensure the formation of crystalline agglomerates upon exposure to moisture, said particles of said pharmacologically active agent and said particles of said solid binder having an average particle size of 10 μm or less, and said particles being provided in a ratio of ion of weight between 1000: 1 to 1: 1000. 54.- The intermediate agglomerate of claim 53, having an average size of between 300 and 1000μm, and an overall density of between about 0.2 and about 0.4g / cm3. 55. The intermediate agglomerate of claim 53, wherein said lactose comprises anhydrous lactose. 56.- The dosage of claim 53, having a global density of between about 0.29, and about 0.38g / cm3. 57. - The intermediate agglomerate of claim 53, having an average size between 400 and about 700μm. 58. The intermediate agglomerate of claim 53, wherein said pharmacologically active agent comprises at least one member selected from the group consisting of corticosteroids, β-antagonists, anticholinergics, leukotriene antagonist, and inhalable proteins or peptides. 59. The intermediate agglomerate of claim 53, wherein said pharmacologically active agent comprises at least one member selected from the group consisting of: mometasone furoate; beclomethasone dipropionate; budenoside; fluticasone; dexamethasone; flunisolide; triamcinolone; salbutamol; Albuterol; terbutaline; salmeterol; bitolterol; ipratropium bromide; oxitropium bromide; sodium cromoglycate; nedocromil sodium; zafirlukast; pranlukast; formoterol eformoterol; bambuterol; fenoterol; clenbuterol; procaterol; broxaterol; (22R) -6a, 9a-difluoro-11β, 21-dihydroxy-16a, 17a-propylmethylenedioxy-4-pregnen-3,20-dione; TA-2005; tipredano; insulin; interferons; calcitonins; parathyroid hormones; and granulocyte colony stimulating factor. 60.- The intermediate agglomerate of claim 53, having a convertible amorphous content of between about 1 and about 50% by weight. 61.- A dosing system comprising: (a) an inhaler, said inhaler including a storage reservoir for storing an amount of a pharmacologically active agent in the form of a crystalline agglomerate, sufficient to provide a plurality of individual doses therein, a dosing device for measuring and dosing a pre-selected amount of said pharmacologically active agent from said storage reservoir, and a nozzle for providing said pharmacologically active agent from said «Dosing device to the mouth or nose of a patient; and (b) an amount of a pharmacologically active agent sufficient to provide a plurality of individual doses thereof, said pharmacologically active agent being stored within said storage reservoir, 10 being provided as an agglomerate of particles of said pharmacologically active agent and particles of a crystalline binder, wherein said particles have an average particle size of 10μm or less, i. the components thereof are provided in a weight ratio of between 1000: 1 to 1: 1000, said agglomerates having an average size of 15 between 300 and 1000μm, and a global density of between about 0.2 and about 0.4g / cm3, and said agglomerate and said inhaler, when used in combination, being able to produce a fine particle fraction of at least 10%, at an inhaled air rate of approximately 60L / min. 20 -62.- The dosage system of claim 61, wherein said crystalline agglomerates have an intensity of between about 200 mg and about 1,500 mg, and wherein said inhaler is designed in such a way that it will impart said pharmacologically active agent. agglomerate, an amount of force that is enough to produce a fine particle fraction of at least 10%, at an inhaled air flow rate of about 60 Urnin 63.- The dosage system of claim 61, wherein said crystalline agglomerates have an intensity of between about 200 mg and about 1,500 mg, and wherein said inhaler is designed in such a way that it will impart said agglomerated pharmacologically active agent, an amount of force that is enough to produce a fine particle fraction of at least 10%, at an inhaled air flow rate of approximately 60 Umin.