RO121407B1 - System for solid phase administration with controlled release of incorporated molecules and process of preparation - Google Patents

Abstract

The invention relates to systems for administering the therapeutical agents which are in the form of solid compositions for administration by inhalation, to a device for the release of the therapeutic agents and process for preparing the composition.

Description

The invention relates to a particulate composition for inhalation administration and to a process for obtaining such compositions.

Solid phase administration systems are used in a wide range of applications, such as the controlled release of labile molecules, especially bioactive materials, such as pharmaceuticals, enzymes, vaccines and biological control agents, such as fertilizers, pesticides and pheromones. .

Administration of solid doses of bioactive compounds to biological tissues, such as mucosal, dermal, ocular, subcutaneous, intradermal and pulmonary, offers various advantages over known methods, such as topical applications of liquids, transdermal administration through the so-called patch and hypodermic injections. Solid dose administration can be achieved by direct transdermal administration of the solid dose, which reduces the risk of infections by eliminating the use of conventional needles and syringes, presents a more accurate dosage than multidose vials, and reduces or eliminates the discomfort that often occurs with hypodermic injections. Various solid dose delivery systems are known, including transdermal and ballistic delivery devices.

Topical administration is used for many bioactive compounds, such as antibiotics for wound healing. These ointments, gels, creams etc. Topics must be applied repeatedly to be effective. This operation is difficult, especially in the case of wounds due to burns and ulcers.

Devices used for transdermal drug administration typically comprise laminated composites on which a backing layer containing the drug is applied and, together with the composite, is applied to the skin, for example, transdermal patch, as described in US Pat. 4906463. However, many drugs are not suitable for transdermal administration, nor are controlled release rates of transdermal drugs improved.

Subdermal implant therapeutic systems have also been formulated for the slow release of certain pharmaceutical agents, over extended periods of time, such as months or years. A well-known example is Norplant® for steroid hormone administration.

In controlled drug-permeable membrane type administration, it is encapsulated in a compartment that is inserted into a polymeric membrane, which allows the release of drugs at a limited rate. The drug reservoir may contain either drug particles or a solid drug dispersion (or solution) in a liquid or matrix-type dispersion medium. The polymeric membrane may be made of a polymeric, non-porous, homogeneous or heterogeneous material or a semipermeable membrane. encapsulation of the reservoir with the drug within the polymer membrane which can be accomplished by pouring, encapsulation, microencapsulation or other methods. Implants release drugs by dissolving the drug in the inner core and slowly diffusing to the outer matrix. The drug delivery from such a type of implantable therapeutic system should be relatively constant and is largely dependent on the rate of dissolution of the drug into the polymeric membrane or the rate of diffusion within the microporous or semipermeable membrane. The inner core may dissolve substantially over time; however, in the current means used, the outer matrix does not dissolve.

Implants are placed subcutaneously by making a skin incision and forced implantation between the skin and muscles. At the end of their use, if they have not dissolved, these implants are surgically removed. US 4244949 discloses an implant having an outer matrix of an inert plastic material, such as polytetrafluoroethylene resin. Examples of this type of implantable therapeutic system are Progestasert IUD and the Ocusert system.

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Other implantable therapeutic systems include controlled drug administration, of matrix diffusion type. The drug supply is formed by the homogeneous dispersion of the drug particles through a lipophilic or hydrophilic polymer matrix. Dispersing 3 drug particles into the polymer matrix may be accompanied by mixing the drug with a viscous liquid polymer or a semi-solid polymer, at room temperature, 5 followed by cross-linking the polymer or by mixing the polymer particles with a molten polymer, at a temperature. high. It can also be accomplished by dissolving the drug and / or polymer particles in an organic solvent, followed by mixing and evaporating the solvent in a mold, at high temperature or under vacuum. The rate of 9 drug delivery to this type of administration medium is not constant. Examples of this type of implantable therapeutic system are contraceptive vaginal rings and the Compudose 11 implant. In PCT / GB 90/00497, slow release systems for implantable means are described. The implants described are bioabsorbable and do not require 13 surgical removal. However, insertion is done by surgical means. Moreover, these means are strictly limited to the type of bioactive compound that can be incorporated which must be heat stable and / or solvents to enable incorporation into the release device. In controlled drug delivery by dissolution in a micro-reservoir, the drug dose, which is a suspension of drug particles in an aqueous solution of a water miscible polymer, forms a homogeneous dispersion of a plurality of particles. of microscopic, unfiltered, discrete drug in a polymer matrix. Micro-21 dispersion can be achieved using a high energy dispersion technique. Release of the drug from this type of drug delivery means follows either an interfacial division 23 or a controlled diffusion process in the matrix. An example of this type of drug delivery device is Syncro-Mate-C Implant. 25 In the case of implants with polymeric mold, bioactive compounds that are not resistant to organic solvents are not suitable for use. In the case of extruded polymeric systems, there are not 27 suitable for use bioactive compounds that cannot withstand the high temperatures required for implant formation. In all cases, they are unsuitable for use 29 bioactive compounds that are unstable at body temperature, especially for long periods of time. 31

A large number of formulations for aerosol administration on mucosal surfaces, in particular by inhalation (naso-pharyngeal or pulmonary), has been provided. Compositions for pharmaceutical administration by inhalation generally comprise a liquid formulation of the pharmaceutical agent and a means for dispensing the liquid as aerosols. Suitable compositions containing a pharmaceutically active substance, a biocompatible amphiphilic steroid and an organic bio-compatible propellant 37 (hydro / fluoro) are described in US Pat. Suitable compositions containing liposomes, pharmaceutically active substances and a quantity of alveolar, protein-based surfactant 39 capable of facilitating liposome transport to the pulmonary surface are described in U.S. Patent 500,6343.

A disadvantage of using aerosol compositions is that maintaining pharmaceutical agents in aqueous suspensions or solutions leads to agglomeration and loss of activity and bioavailability. Loss of activity can be partially prevented by 43 refrigeration; however, this limits the use of these compositions. This is especially the case for peptides and hormones. For example, synthetic gonadotropin-releasing hormone analogues, such as the naphthelin agonist or the ganirelex antagonist, are known for increased reactivity, increased hydrophobicity, and membrane binding. 47

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The compounds have a pronounced hydrophobic character, so that an agglomeration in aqueous solution takes place and an ordered structure is formed, which leads to increased viscosity over time. Thus, bioavailability in nasal or pulmonary compositions may be markedly decreased. The use of powdered compositions can overcome many of these shortcomings. The required particle size for such powders is 0.5-5 μ for deep alveolar storage in pulmonary administration. Unfortunately, the powders with particle size in the above field tend to absorb water and become congested, thus decreasing the deposition of the powder in depth in the alveolar spaces. Although powders with a larger particle size are suitable for administration in the nasal pharyngeal region, the tendency of powders to agglomerate decreases the surface of the particle upon contact with, and absorption through, these membranes. Means are used to disperse formed agglomerations through electrostatic interactions (eg Turbohaler ™); however, the agglomerations due to moisture are not removed in this way. It would be more advantageous to obtain powders that do not absorb moisture and do not agglomerate and thus increase the effective lung concentration.

Pharmaceutical carriers are known to deliver solid doses for transdermal, ballistic administration. For example, a ballistic animal implant comprising an outer polymeric film including a bioactive material for veterinary use is described in US Pat. Similarly, in US patent 4326524, a ballistic projectile is presented which contains the solid dose comprising the bioactive material and an inert binder, without an outer shell. Administration is by compressed gas or by explosion. US Patent 979993 also discloses ballistic projectiles for implant, of tranquilizing substances coated with gelatin. These ballistic means, however, are applicable only to veterinary uses in large animals, due to a relatively large amount of dose released, in the usual order of millimeters.

Ballistic administration at the cellular level has also been successfully tested. The general principle of ballistic management is the use of a supersonic wavefront, created by releasing compressed gas to propel the particles contained in an adjacent enclosure. For example, nucleic acids absorbed on tungsten microprojectile particles have been successfully administered to living plant epidermal cells, Klein (1987) shows in Nature 327: 7073. A better controlled means is particle inflow (PIG), according to Vain et al. (1993) in Plant Cell. Tissue and Organ Culture 33: 237-246.

US 4790824 and PCT / GB 94/00753 have been described in means in which flame-closed vials contained drugs using gas pressure. Various means of injecting fluids are also described in US Patent Nos. 5312335 and 4680027. There are different compositions suitable for ballistic administration. The powder formulations of pharmaceuticals are unsuitable for ballistic administration. The particles in the powders are generally irregular, varying in size, shape and density. This lack of uniformity results in the formation of powder deposits and loss of skin surface during administration and also creates problems in the control and depth of administration in subcutaneous and intradermal tissues.

Thus, for ballistic administration, it is advantageous to use solid drug delivery systems of defined size, shape and density, and dissolution rate, to ensure a more even distribution. Further advantages could result if the shape of the pharmaceutical carrier could be controlled to facilitate controlled penetration into the epidermis and into the strong layers of the skin. Small size administration systems, preferably coupled with administration at a given time, will also increase the convenience of administration,

RO 121407 Β1 with minimal tissue repercussions. Obtaining such solid-dose administration systems should be such that neither the vehicle agent nor the active substance to be released is impaired and their efficacy does not decrease. In addition, the active substance 3 must remain stable during conditioning, together with the carrier, so that efficient administration is achieved and storage of the administration system is thus facilitated. The production of the carrier for solid dose administration and its conditioning with active material to obtain a solid dose administration system 7 and the administration of the system should be relatively simple and economical.

The technical problem solved by the invention is to provide an improved solid phase administration system for inhalation administration of a therapeutic agent. 11

The disadvantages of known administration systems are eliminated by using the composition according to the invention, in the form of particles consisting of a solid solution, which comprises a therapeutic agent and a carbohydrate which forms a vitreous state, superior to a monosaccharide, and which is capable of stabilizing the agent. During spray drying and storage, provided that when the therapeutic agent is insulin, the solution does not contain citrate. 17

The composition for therapeutic use, suitable for inhalation administration, is in the form of particles consisting of a solid solution, comprising a tera-potassium agent and a carbohydrate that forms a vitreous state, superior to a monosaccharide, which is amorphous at elevated temperatures. . 21

The device for pulmonary release of a therapeutic agent according to the invention includes particles defined above.23

The process for obtaining the particles according to the invention comprises the steps of melting the carbohydrate which forms a vitreous state, the incorporation of the therapeutic agent therein, wherein the melting temperature is sufficient to fluidize the carbohydrate, but insufficient to substantially inactivate the therapeutic agent, cooling the melt and grinding. of the cooled product. 27

By applying the invention, compositions in the form of particles suitable for inhalation administration with good stability of the therapeutic agent are obtained during drying and spraying.

Fig. 1 is a graph representing the typical size distribution of trehalose glass powder particles 31, suitable for inhalation administration. Fig. 1 is described in example 2.33

Fig. 2A is a graph representing the particle size distribution limited to trehalose / glass powder with salt-buffered molecular water (MWPB). Fig. 2B 35 is a graph showing the absorption of water by different trehalose / MWPB glass powders and trehalose / chloride powders, after storage at ambient temperature and relative humidity. 37 Fig. 2B represents 51% relative humidity and MWPB (·), 80% relative humidity and MWPB (|), 51% relative humidity and chloride (□) and 80% relative humidity and chloride (X). Fig. 2 is 39 described in Example 2.

Fig. 3 is a graph showing the limited particle size distribution for trehalose glass powder, obtained by spray drying in a Lab-plant spray dryer. Fig. 3 is described in example 2. 43

Fig. 4 is a graph showing a comparison of the exact particle size distribution for trehalose glass powders (0.5M trehalose / 0.5M calcium lactate) prepared with 2 45 different spray dryers (Lab-Plant) (□) and Buchi ( A), as indicated. Fig. 4 is described in example 2. 47

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Fig. 5A is a graph representing the resistance of horseradish peroxidase to acetone by drying the enzyme with trehalose. The average values are shown for: no solvent plus trehalose (o), no solvent minus trehalose (*), acetone plus trehalose (open square at the bottom) and acetone minus trehalose (open square at the top). Fig. 5B is a graph representing the resistance of alkaline phosphatase to acetone, carried out by drying the enzyme with trehalose. in FIG. 5B open circles represent solvent-free exposure plus trehalose, closed circles represent solvent-free exposure minus trehalose, open squares at the bottom represent acetone plus trehalose and open squares at the top represent acetone minus trehalose. Fig. 5 is described in Example 3.

Fig. 6 is a graph representing MB9 release from selected metalcarboxylate glass films. The squares represent aluminum hexanoate film (100-200 μ), when release precedes the dissolution of the film. The circles represent calcium neodecanoate film (12 mm) when release follows after the film is dissolved. Fig. 6 is described in Example 7.

Fig. 7 is a graph representing the amount of blue acid dye 129 encapsulated from glass disk based on α-D-glucose pentaacetate (α-GPAC). Fig. 7 is discussed in Example 8.

Fig. 8 is a graph representing the release of MB9 from octaacetate trehalose glass disks (TOAC) (6 mm x 2.5 mm) in PBS solution. Fig. 8 is discussed in Example 9.

Fig. 9 is a graph representing the release of MB9 from TOAC / RUDA (octaacetate / raffinose undecacetate) matrix in deionized water. The different concentrations represented are: 95% TOAC, 0.61%, by dye weight (□); 75% TOAC, 1.17%, by weight, dye (o); 50% TOAC, 2.09%, by weight, dye (A) TOAC alone, 1.39%, by weight dye (o) and Ruda alone, 4%, by weight, dye (▼). Fig. 9 is described in Example 9.

Fig. 10 is a graph representing the variation in Tg dependent on mol% TOAC of the two HDC co-formulations. The squares represent glass based on trehalose octaacetate / sorbitol hexaacetate (TOAC / SHAC). The circles represent TOAC / RUDA based glass. The triangles represent glass based on trehalose octaacetate / α-glucose pantaacetate (TOAC / α-GPAC). Fig. 10 is described in Example 9.

Fig. 11 is a graph representing the mean% release of MB9 in PBS from selected TOAC / RUDA glass spheres (n = 4). Squares represent 10% RUDA. Circles represent 50% RUDA. The triangles represent only the RUDA. Fig. 11 is described in Example 9.

Fig. 12 is a graph representing the release of MP9 (1% by weight) from co-formulations of TOAC + 25% SOAC (*) and 25% COAC (*) (n = 5). Fig. 12 is described in Example 9.

Fig. 13 is a graph representing the release of MP9 (1% by weight) from TOAC / aGPAC in the following reports 90:10 (*). 75:25 (·), 50:50 (*) and 25:75 (») (n = 4). Fig. 13 is described in Example 9.

Fig. 14 is a graph representing the release of MP9 from TOAC (·) and TOAC / TOPR (25% by weight) (·) (n = 5). Fig. 14 is described in Example 9.

Fig. 15 is a graph representing the release of MP9 (1% by weight) from TOAC alone (·) and TOAC plus XPDO (5%) (*) (n = 5). Fig. 15 is described in Example 9.

Fig. 16 is a photomicrograph of a thin film from a glass co-formulation comprising 10% trehalose in TOAC dried from dimethylformamide (DMF). Fig. 16 is described in Example 10.

Fig. 17 is an enlarged photomicrograph of the co-formulation of FIG. 16. FIG. 17 is described in Example 10.

Fig. 18 is a photomicrograph of a glass co-formulation comprising 10% trehalose in TOAC with methyl green and red Oi dried in DMF. Fig. 18 is described in Example 10.

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The invention comprises solid, vitreous and carrier administration agents suitable for formulation with a wide variety of substances in order to obtain administration systems. The choice of the carrier agents, in vitro and in vitro, is influenced by the nature of the active substances and the desired rate of release of the active substance. The invention provides a wide variety of speeds and types of administration. Preferred active substances, 5 buffers, adjuvants and additional stabilizers are also provided. Management systems can be of different sizes and shapes for a variety of administration modes. 7

The invention comprises systems for rapid administration of soluble solid doses containing a stabilizing polyol (SP) and an active substance. These delivery systems can be shaped as powders with a homogeneous particle size and in larger, implantable forms. 11

The invention also contains carrier agents, vitreous, hydrophobic derivatized carbohydrates (HDCs). These HDCs are non-toxic and the release of the active substances from these 13 systems is controlled, in a superior way, so that the release of the active substances can be achieved over extended periods of time. Release from the HDC administration systems can be effected by devitrification, dissolution and / or hydrolysis. HDC administration systems are indicated for releasing active substances such as pesticides, pheromones, hormones 17 steroids, peptides, depeptide substitutes, antibiotics and other organic pharmaceuticals, such as synthetic corticosteroids, bronchodilators and immunomodulators and immunosuppressive (19 CSA) sun .

The invention also comprises co-formulations of different vitreous carrier agents, in order to obtain new combinations of administration systems. The combined administration systems comprise HDC together with SP and / or other in vitro water-soluble, slow-soluble materials, such as 23 in vitro carboxylate, nitrate or phosphate compositions, with solid dose delivery systems having new and varied properties. 25

The invention consists of multi-phase solid dose delivery systems comprising an outer shell of HDC, soluble slowly in an aqueous solution, and inside is a cavity with an inner portion comprising at least one SP and an effective amount. from the therapeutic point of view of at least one active substance. 29

The invention also consists of methods for releasing bioactive materials through the solid dose delivery systems described above and administering the system to a biological tissue. The administration can be performed at the level of the mucosa, orally, topically, subcutaneously, intradermally, intramuscularly, intravenously and by inhalation. 33

The invention also consists of methods for obtaining solid phase administration systems. SP and / or HDC, the active substances and the other components are mixed and processed by a wide variety of methods, including melt dissolution, followed by sudden cooling, spray drying, freeze drying, air drying, drying in 37 vacuum , fluidized bed drying, co-precipitation and evaporation of super-critical fluids. The resulting glass material can be heated to softening and then subjected to extrusion, pulled or spun into 39 solid fibers or the tube has. The dried components may also be mixed in aqueous or organic solutions and dried, for example, by spray drying, freeze drying, air drying, vacuum drying, fluidized bed drying, coprecipitation and super-fluid evaporation. critical. 43

The invention also provides methods of obtaining the appropriate administration systems for slow or pulsatile release of the active substances. The methods include 45 combining active substances in solid stabilizing solutions of polyols with glass and / or HDC formation and / or bottles with lower dissolution or degradation rates than SP and 47

EN 121407 Β1 processing of the components as described above. The proportions of the materials can be controlled so as to result in a wide range of precisely defined release rates. The co-formulations of SP and / or HDC and other water-soluble and / or biodegradable glass materials, plastics and glass modifiers, obtained, are part of the present invention.

The solid dosage management systems and methods of the invention according to the invention consist of solid dosage forms comprising fibers, spheres, tablets, disks, particles and needles, with a relatively homogeneous size distribution. The carrier agents can be microscopic or macroscopic.

A wide variety of active substances is recommended for use in the present invention, including, but not limited to, diagnostic, therapeutic, prophylactic, and other active agents. The administration systems and methods of their use refer to a variety of dosage schemes for the release of active substances and are suitable for a wide range of uses, including applications in agriculture, veterinary and human medicine.

The invention comprises solid phase delivery systems containing solid dose delivery agents and active substances. The administration systems are formulated in such a way as to allow the release of the active substances incorporated at precise speeds. Administration systems are especially indicated for the release of bioactive molecules in animals, including humans.

Also, in another embodiment of the invention are methods of delivering therapeutic agents including, but not limited to, administration at the mucosal, oral, topical, subcutaneous and intradermal, intramuscular, intravenous and inhalation levels.

The invention also relates to methods for obtaining administration systems.

By the term solid dose used herein, it is understood that an active substance incorporated in the carrier is rather in solid form than liquid and the solid form is the form used for release. The active substances are those molecules, macromolecules or macromolecular, synthetic and natural assemblies and cell fractions, living or dead cells, bacteria and viruses and other active substances incorporated in the carrier; a wide variety of active substances is indicated for this use and is described below. By effective amount of active substance, is meant a quantity for achieving the desired effect. For example, with a bioactive material, an effective amount is the one that performs the desired physiological reaction. The carrier is in solid form and is amorphous or vitreous in nature. Other additives, buffers, dyes, etc. can be incorporated into the administration systems. As used herein, the term carrier agent includes all glass-forming substances used in the present invention. The term administration system (s) includes solid dosage forms comprising carrier agents and active substances. Management systems made up of specific carrier agents have distinct data names as indicated; if not indicated, the term administration system includes each of them.

In one embodiment, the invention relates to solid dose systems with fast release rates of active substances. In this embodiment, the carrier is an SP. It has also been found that SP substances can be processed to obtain powders with a homogeneous distribution of particle sizes, in the form of microspheres or needles. SP substances can also be processed to obtain macroscopic release forms, suitable for the formulation of implantable means. The invention discloses a wide variety of dosage forms and methods for obtaining dosage forms. It has been found that these SP substances are especially usable when other denaturing conditions would make it impossible to formulate solid dosage forms of bioactive materials. In particular, such conditions include high temperatures (those above which the bioactive material is otherwise denatured) and the presence of organic solvents.

In another embodiment, the invention relates to solid dosing systems, with speeds 1 for the release of new, defined and controllable active substances. In this embodiment, the carrier is an organic carboxylate-based glass. It has been found that the organic carboxylates 3 form carrier agents, amorphous, stable by solvent evaporation. These organic bottles release the incorporated active substances, at precisely defined speeds, depending on the 5 carboxylate anion composite and the metal cation used. Like the carrier agents comprising SP, these bottles can be processed, either alone or in mixtures with other organic carboxylates 7 and / or SP and / or HDC, to obtain powders with a homogeneous particle size distribution. of microspheres, needles and / or implantable means, to obtain a wide variety of 9 macroscopic release forms.

In another embodiment, the invention relates to new, defined and controllable solid dosage systems with delivery rates 11 of the active substances. In this embodiment, the carrier is a hydrophobic carbohydrate (HDC) derivative. HDC 13 has been found to form stable, in vitro, carrier agents, which release active substances under aqueous conditions at precisely defined rates, depending on the carbohydrate, the hydrophobic radical (s) used to derivatize the carbohydrate and the degree of derivatization. Like carrier agents comprising SP, those comprising HDC can be processed to obtain powders with a homogeneous distribution of particle size, either in the form of microspheres or needles. HDC substances can also be processed to form a wide variety of macro-19 scopic release forms.

The invention describes dosage forms and methods for obtaining dosage forms 21 are described herein. These delivery systems are specifically intended for situations where the nature of the active substance would make it impossible to formulate solid dosage forms, 23 so that administration systems for hydrophobic active substances are indicated, which otherwise are difficult to formulate in dosage forms or for to obtain 25 effective physiological concentrations, due to the insolubility in aqueous solvents.

The administration systems exist as solid solutions, emulsions, suspensions or co-preservatives 27 of the active substance in the solid carrier. The active substance is resistant to higher temperatures in the carrier than alone. The exact temperature resistance depends on the carrier agent used. Thus, the components of the administration systems can be maintained as melts for short periods of time, without altering the active substances during the pre-work. In the same sense, the administration systems can be further processed and are resistant to working conditions during sintering with nitrate and / or carboxylate and / or HDC and / or 33 other glass-forming substances.

The invention also relates to the co-formulations of different carrier agents and delivery systems, 35 in order to obtain a wide variety of combinations of carrier agents.

The invention comprises compositions and methods for obtaining compositions. Although single forms may be used, more than one carrier may be present, more than one active substance and more than one additive. Determining the effective amounts of these 39 compounds is within the reach of the specialist.

The invention comprises solid dose delivery systems wherein the releasing carrier contains a stabilized polyol. These are called SP management systems.

It has been found that SP delivery systems can be processed in a wide variety of solid dosage forms 43, in particular, high for therapeutic administration of active substances.

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SP substances include, but are not limited to, carbohydrates. As used herein, the term carbohydrates includes, but is not limited to, monosaccharides, disaccharides, trisaccharides, oligosaccharides and their corresponding alcohols, polysaccharides and chemically modified carbohydrates such as hydroxyethylamidone and sugary copolymers (Ficoll). Both natural and synthetic carbohydrates are presented in the invention. Synthetic carbohydrates include, but are not limited to, those with a glycosidic bond replaced by a thiol or carbon bond. Both D and L forms of carbohydrates can be used. Carbohydrates can be non-reducing or reducing. Suitable carrier agents are those in which an active substance can be dried and stored without significant loss in subsequent actions, denaturation, aggregation or other mechanisms. The prevention of activity losses can be enhanced by adding different additives, such as the Maillard reaction inhibitors, described below. The addition of such inhibitors is particularly preferred together with reducing carbohydrates.

The reducing carbohydrates indicated for use in the present invention are known to those skilled in the art and include, but are not limited to, glucose, maltose, lactose, fructose, galactose, mannose, maltulose, isomaltulose and lactulose.

Non-reducing carbohydrates include, but are not limited to trehalose, raffinose, stasis, sucrose and dextran. Other usable carbohydrates include non-reducing glycosides of polyhydroxycompounds chosen from sugar alcohols and other branched chain polyalcohols. Among the glycosides of sugar alcohols, monoglycosides, in particular, compounds obtained by reducing disaccharides such as lactose, maltose, lactulose and maltulose, are preferred. The glycosidic group is preferably a glucoside or a galactoside and the sugar alcohol is preferably sorbitol (glucitol). In particular, preferred carbohydrates are maltitol (4-OPD-glucopyranosyl-D-glucitol), lactitol (4-OPD-galactopyranosyl-D-glucitol), palatinite (a mixture of GPS, α-glucopyranosyl-1-6-sorbitol and GPM). , aD-glucopyranosyl-1-6-mannitol and their individual alcohols, GPS and GPM components.

Preferably, SP is a carbohydrate that exists as a hydrate, including trehalose, lactitol and palatinite. More preferably, SP is trehalose. Surprisingly, it has been found that solid dose delivery systems containing certain sugars, such as trehalose, are devoid of the viscosity or adhesiveness of solid dosage forms containing other carbohydrates. Thus, for the production, packaging and administration, trehalose is the preferred SP substance.

Trehalose, (α-D-glucopyranosyl-α-D-glucopyranoside) is a naturally occurring, non-reducing disaccharide, which was initially shown to be associated with the prevention of dehydration-related diseases in certain plants and animals that can be dehydrated without being dehydrated. deterioration and which can be subsequently rehydrated. Trehalose has been shown to prevent protein, viruses and food products from being dehydrated during dehydration, as shown in US Pat. No. 4891319; 5149653; 5026566; Blakeley et al. (1990) Lancet 336: 854-855; Roser (July 1991) Trends in Food Sci. and Tech. 166-169; Colaco et al. (1992) Biotechnol. Internat., 345-350; Roser (1991) BioPharm. 4: 47-53; Colaco et al. (1992) Bio / Tech. 10: 1007-1011; and Roser et al. (May 1993) New Scientist, pp. 25-28.

Other SP substances indicated for use in the invention are described, for example, in WO 91/18091, WO 87/00196, US 4891319 and 5098893, which show the use of polyols for bottles to stabilize molecules during drying and storage, for reconstitution before use. The solid dosage forms included in the invention are indicated for direct use, as administration systems for the controlled release of the incorporated active substances. In addition, these polyols can be used in combination with other amorphous matrices to obtain delivery systems, which have been shown to have a wide range of release rates and features that are easily and precisely controllable to produce unique solid dosing systems. .

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It has also been found that the preferentially soluble active substances in organic solvents 1 can be dried in trehalose from a mixture of organic / aqueous solvent to obtain a co-formulation which is easily reconstituted in aqueous solvents. The invention comprises 3 solid dosage systems obtained in this way. Methods for producing dry material and compositions thus obtained are presented in the invention. The active substance is dissolved in an organic / aqueous solvent in combination with an effective amount of trehalose and then dried. A solid solution, emulsion, suspension or co-preservative of the active substance is obtained in a trehalose bottle which is then dissolved readily in an aqueous solution to obtain a finely dispersed suspension of the insoluble active substance. It was observed that the immunosuppressant 9 CSA (which is poorly soluble in water and normally administered as an oily solution) in a trehalose solution in an ethanol mixture: 1: 1 water, can be dried to obtain a clear glass 11 trehalose with CSA content.

This glass can be laminated to obtain a free, fluid powder, which can also be tableted, which when added water dissolves instantly, obtaining a fine, dispersed suspension of CSA in water. 15

The invention also provides solid dose delivery systems wherein the carrier contains at least one HDC. These are called 17 HDC management systems. HDC substances form a separate group of non-toxic carbohydrate derivatives, indicated for use in obtaining a solid dose carrier. Although 19 many HDC systems have been synthesized, the benefits of obtaining such glass have not been presented so far. The invention consists in obtaining HDC glass systems, which allow the formation of 21 matrices with an amorphous composition. HDC administration systems are, in particular, indicated for use in the controlled, rhythmic or delayed release of active substances. Any 23 of the active substances described herein may be incorporated into the HDC administration systems.

As shown here, HDC substances form bottles either from a melt by sudden cooling or by evaporation of the organic solvent. HDC substances can also be processed by the methods described for SP. 27

As used herein, HDC refers to a wide variety of hydrophobic carbohydrate derivatives, wherein at least one hydroxyl group is substituted with a hydrophobic radical, 29 including, but not limited to, esters and ethers. Numerous examples of recommended HDC substances and their synthesis are described in Developments in Food Carbohydrate, 31st ed. 2, C.K.Lee, Applied Science Publishers, London, (1980). Other syntheses are described, for example, in Akoh et al., (1987) J.Food Sci. 52: 1570; Khan et al., (1983) Tetra.Letts 34: 7767; 33

Khan (1984) Pure & AppI.Chem. 56: 833-844; and Khan et al. (1990) Carb.Res. 198: 275-283. Specific examples of HDC include, but are not limited to, sorbitol hexaacetate (SHAC), α-glucose pentaacetate (α-GPAC), β-glucose pentaacetate (β-GPAC), 1-O-octyl ^ -D-glucose tetraacetate (OGTA), octaacetate trehalose (TOAC), octapropanoate trehalose (TOPR), 37 octoacetate sucrose (SOAC), octoacetate cellobiosis (COAC), undacacetate raffinose (RUDA), octapropanoate sucrose, octapropanoate cellobiosis, octapropanate cellobiosis, 39 trehalose and d / -O-methyl-hexa-O-acetyl sucrose. An example of a suitable HDC, in which the carbohydrate is trehalose, is: 41

CH _Z R CH _Z R

In formula 1, R represents a hydroxyl group or its smallest hydrophilic derivative, such as an ester or an ether or any functional modification thereof, when at least one R is not a hydroxyl but a hydrophobic derivative. Suitable functional changes include, but are not limited to, those in which the oxygen atom is replaced by a heteroatom, such as N or S. The degree of substitution may also vary and may be a mixture of distinct derivatives. The total substitution of hydroxyl groups is not indicated, as it may alter the physical properties (such as solubility) of the carrier. R can be any chain length from C ₂ upwards and can be linear, branched, cyclic or modified. While formula 1 shows disaccharide-trehalose, any of the carbohydrates presented here may be the main carbohydrate and the position of the glycosidic bond and the length of the saccharide chain may vary. Typically, for reasons of cost and efficiency of the synthesis, it is practically a pentazaccharide, however, the invention is not limited to saccharides of a particular type, glycosidic bond or chain length. The invention also presents other aspects of HDC systems, which are not limited. For example, the saccharide components of each HDC system may also be varied, the position and nature of the glycosidic link between the saccharides may be altered, and the type of substitution may vary within an HDC. A representative example of HDC with mixed substitution with esters and ethers is 2,3,4,5 tetraacetate of 1-O-Octil-pD-glucopyranoside:

R wherein R is O ₂ CCH ₃ .

The ability to modify the properties of HDC substances by light transformations in composition makes them uniquely suitable for use as solid dose carriers, in particular, compared to polymeric systems, which often depend on crystallinity regions, in varying their properties, in particular bioerosion. HDC administration systems can be obtained in such a way that they have certain properties such as the release rates of the active substances. Such an arrangement can be made by varying the modifications of a certain carbohydrate or by combining a variety of different HDC substances.

It has been observed that pure bottles with a single HDC substance are stable at even higher ambient temperature, at least 60% humidity. Mixtures of HDC bottles incorporating certain active substances are, however, surprisingly stable at ambient and higher temperatures, at least 95% humidity. Remarkably, the incorporation of even 10% (w / v) of extremely hygroscopic active substances, such as corticosteroid 6a, 9a-difluoro-11β, 21-dihydro-16a, 17a-propylmethylenedioxy-4-pregnen-3 , 20-dione (XPDO) results in HDC bottles that are stable when exposed to 95% relative humidity, at room temperature, for more than one month, with immediate release of active substances, within 5-10 min. , after adding water. An identical effect of HDC glass stability was found on TOAC bottles, containing 10% (w / v) CSA incorporated as the active substance.

The authors found that by adding other HDC substances in the same proportions, mixed HDC systems were obtained, which had the same behavior when devitrifying, at a relative humidity of 95%. Thus, TOAC bottles containing 10% (weight / volume) of either GPAC or TOPR had a complete resistance to devitrification at a relative humidity of 95%. Interestingly, these composite HDC bottles behaved differently in water; The GPAC / TOAC glass deviated from the surface much faster than the TOPR / TOAC glass, according to fig. 13.14. This faster dissolution capacity of HDC composite bottles is recommended as controlled release agents.

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HDC bottles can be formed either by evaporation of the solvent or by sudden cooling of 1 HDC melt. Due to the low softening points of certain HDC bottles, the active substances, thermally labile, such as drugs and biological molecules, can be incorporated into 3 HDC melts during the processing of the administration system, without decomposition. Surprisingly, these active substances have demonstrated zero-order kinetic release rates, 5 when the compositions for amorphous matrix formation are eroded into aqueous solution. The release follows the surface devitrification process. HDC management systems can be easily modeled in 7 shapes, as described here. Such modeling can be done by extrusion, casting, etc. and any method known in the art. Carriers of 9 HDC administration are non-toxic and inert to any dissolved substances, which can be incorporated into them. 11

These HDC administration systems, when formulated as matrix and / or protective coatings, suffer from heterogeneous, surface erosion when placed in an aqueous environment. Not being confirmed by any theory, a possible mechanism for their degradation begins with an initial surface devitrification as a supersaturation that occurs at the interface, 15 followed by further erosion and / or dissolution of the surface layers, at a lower speed. The matrices can be modified by a careful selection of the components, to obtain the desired devitrification rates and hence the required release rates of the active substance, so that the devitrified matrix does not represent a barrier to the release of the active substance 19.

HDC melts are excellent solvents for many organic molecules. This fact is especially recommended for use in the release of bioactive materials, otherwise difficult to formulate. More than 20% by weight of organic molecules can be incorporated into 23 HDC administration systems. Notably, HDC substances are inert and do not exhibit reactivity to dissolved substances or active substances incorporated therein. As described in more detail below, HDC substances are suitable to form a dispersion of a fine suspension of SP administration system, thus obtaining 27 complex, composite administration systems. HDC components are synthesized at high purity, using stable synthetic, chemical or enzymatic principles. HDC and 29 active substances can be intimately mixed, in appropriate molar ratios and melted to transparency. Suitable melting conditions include, but are not limited to, melting in 31 glass containers open at 100 and 150 ° C for 1-2 minutes. This results in a fluid melt which can be allowed to cool slowly before dissolving the active substance in the melt, abruptly cooling the glass by pouring it over a brass plate or into a metal mold for shaping the carrier agents. Regardless of the way, the melt temperature can be carefully controlled and the active substances can be incorporated either in the pre-melted HDC formulation or mixed in the cooled HDC melt before abrupt cooling. 37

HDC melts are thermally stable and allow the incorporation of organic molecules without distortion or the suspension of internal particles without altering their physical nature. The 39 glass melts can also be used for particle size coating of microns, this is particularly important in the formulation of non-hygroscopic powders containing 41 active hygroscopic agents for inhalation administration of therapeutic agents.

Alternatively, in vitro and HDC carriers for administration may be formed by evaporation of HDC, and the active substance is incorporated into the solution in a solvent or solvent mixture. HDC component substances are easily dissolved in many organic solvents. Suitable solvents include, but are not limited to, dichloromethane, chloroform, dimethylsulfoxide

RO 121407 Β1 (DMSO), dimethylformamide (DMF) and higher alcohols. The type of solvent is non-essential and if it is completely eliminated when the administration system is formed. Preferably, the HDC component and the active substance are solvent soluble. However, the solvent can dissolve HDC and form a suspension with the active substance. By concentrating the solvent, crystallization does not occur with several usable HDC substances. instead, an amorphous solid is obtained, which has similar properties to the suddenly cooled glass. Again, the active substances can be easily incorporated either in solution or in the form of particulate suspension.

The transition temperatures of the HDC glass (Tg) are low, typically lower than 70 ° C and, surprisingly, are not predictable from the melting temperatures. In general, the tendency to crystallize, from a melting in cooling or with reducing solvent, is low. Both devitrification and fluidity of the melt at temperatures close to Tg, can be controlled with modifiers such as other sugary derivatives and certain organic active compounds. The following two tables present Tg and melting temperatures for a number of HDC compounds presented in the examples, recommended for use, either alone or in a composite glass.

Table 1

Material / glass Melting point / ° C Tg / ° C Molecular mass SHAC 100-104 -6 434.4 to GPAC 109-111 14 390.3 β-GPAC 130,131 17 390.3 OGTA 50-52 -10 460.5 Chops 101-103 50 678.6 TOPR 47-48 3 790.6 SOAC 87-89 25 678.6 bake 224-226 65 678.6 RELATIVE 87-88 55 966.9

Table 2

Glass system HDC molar reports in glass Tg / DEG C. Chops 100 50 RELATIVE 100 55 Q-GPAC: chop 10:90 47 25:75 44 50:50 32 75:25 22 SOAC: chop 25:75 41 Baking chop 25:75 55

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Table 2 (continued)

Glass system HDC molar reports in glass Tg / ° C TOPR: chop 22:78 37 RUDA: chop 10:90 52 25:75 53 50:50 52 75:25 54

The invention further provides carrier agents containing 9 combinations of different HDC substances which have been shown to be novel carrier agents with highly controllable Tg and other physicochemical properties such as viscosity and resistance to environmental degradation 11. aqueous.

The invention also relates to solid dose management systems comprising 13 HDC and SP substances and / or other glass-forming substances, in co-formulations and other combinations. These are called combinations of management systems. 15

At least two combination administration systems are produced by co-formulation of HDC and SP carrier agents to obtain administration systems. In one example, 17 SP administration microspheres are suspended in an HDC administration system. In the second example, HDC administration system microspheres are suspended in the SP administration system. These combinations of delivery systems allow the release of at least two different active substances, one hydrophobic and one hydrophilic, at at least two 21 different release rates.

Other combinations of management systems are formed by covering one administration system 23 with another. For example, an SP administration system, in implantable form, may be coated with a layer of HDC or HDC administration system, in order to obtain delayed release of the active substance in the SP administration system or a subsequent release of the various substances. active. A variety of such forms can be realized. The number 27 coverage is theoretically unlimited and is within the reach of the specialist.

Combinations of administration systems may also be formed by extrusion 29 of a strong cylindrical carrier containing a lumen, from a carrier or administration system (SP, HDC or a combination) and filling the lumen with another delivery system - 31 shots. These compositions are, in particular, suitable for the formation of injectable or implantable means. 33

As discussed below, the administration systems may also contain at least one physiologically acceptable bottle. Suitable bottles include, but are not limited to, carboxylate, phosphate, 35 nitrate, sulfate, bisulfate, HDC substances and combinations thereof. Carboxylates have also been used when water-soluble hard bottles have been requested and many of them are only 37 water-soluble. Such suitable bottles include, but are not limited to, those described in PCT / GB 90/00497. However, the formation of these carboxylate bottles has been done so far only 39 by sudden cooling of the melt.

The high temperature required to melt carboxylates severely limits carboxylation 41 which can be used to form in vitro and carrier agents, especially in the case of bioactive materials that tend to be labile in heat. The authors found, surprisingly, that 43 carboxylate-based bottles can be easily formed by evaporation of a solvent containing a

EN 121407 Β1 metal carboxylate with glass formation and the active substance to be incorporated. The invention also comprises methods for obtaining solid dose carriers and systems comprising dissolving a carboxylate component in a suitable solvent and then evaporating the solvent to obtain a glassy material. Carboxylate mixtures can be used, as mixtures of other components that can form bottles for new administration systems, which fall within the scope of the present invention.

The administration systems may also be coated with one or more layers of a physiologically acceptable glass, having a predetermined dissolution rate. They are especially effective for pulsatile release of active substances. The composition may also contain other water-soluble and biodegradable bottles. Suitable glass-forming substances include, but are not limited to, lactide and lactide / glycolide copolymers, glucuronide polymers and other polyesters, polyorthoesters and polyhydroxides.

Examples of types of active substances that may be used in carrier agents and methods of the invention include industrial chemicals such as colorants and perfumes and agricultural bioactive drugs or materials, suitable for in vivo and in vitro use. Suitable bioactive materials include, but are not limited to, pharmaceutical, therapeutic and prophylactic agents and agrochemicals such as pesticides and pheromones.

Suitable pharmaceutical agents include, but are not limited to, anti-inflammatory, analgesic, antiarrhythmic, antispasmodic, antidepressant, antipsychotic, tranquilizer, antioxylitic, narcotic antagonists, antiparkinsic agents, chemotherapeutic agonists, cholinergic agonists, cholinergic agonists, , appetite suppressants, anti-emetics, anticholinergics, antihistamines, anti-migraine agents, coronary, cerebral or peripheral vasodilators, hormonal agents, contraceptives, antithrombotic agents, diuretics, antihypertensive agents, cardiovascular drugs, opioids and other.

Suitable therapeutic and prophylactic agents include, but are not limited to, biologic modifiers, therapeutically effective. Such modifiers include, but are not limited to, subcellular compositions, cells, bacteria, viruses and molecules including, but not limited to, lipids, organic substances, proteins and peptides (synthetic and natural), peptide substitutes, hormones (peptides). , steroids and corticosteroids), polymers of amino acids D and L, oligosaccharides, polysaccharides, nucleotides, oligonucleotides and nucleic acids, including DNA and RNA, nucleic acid-protein hybrids, small molecules and their physiologically active analogues. Further, the modifiers may be derived from natural sources or may be obtained by recombinant or synthetic means and include analogues, agonists and homologues.

The term used by the protein also refers to peptides and polypeptides. Such proteins include, but are not limited to, enzymes, biomedicals, growth hormones, growth factors, insulin, monoclonal antibodies, interferons, interleukins and cytokines.

Organic substances include, but are not limited to, pharmaceutically active chemicals. For example, representative organic substances include, but are not limited to, vitamins, neurotransmitters, antimicrobials, antihistamines, analgesics, and immunosuppressants.

Suitable steroid hormones include, but are not limited to, corticosteroids, estrogen, progesterone, testosterone, and physiologically active analogues thereof. Numerous steroid hormone analogues are known in the art and include, but are not limited to, estradiol, SH-135 and tamoxifen. Many steroid hormones such as progesterone, testosterone and analogues thereof are, in particular, suitable for use in the present invention, as they are not transdermally absorbed and, with the exception of a few analogues, are broken down by oral administration through the so-called first step mechanism. hepatic.

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As used herein, nucleic acids include any therapeutically effective nucleic acids 1 known in the art, including, but not limited to, RNA, RNA and physiologically active analogues thereof. Nucleotides can encode single genes or be any vector 3 known in the field of recombinant RNA including, but not limited to, plasmids, retroviruses and adeno-associated viruses. Preferably, the nucleotides are administered as a powder in the solid dose system.

Compositions comprising solid dose administration systems containing prophylactic bioactive materials and support materials are also contained in the present invention. Preferred compositions include immunogens for use in vaccines. Preferably, the compositions contain an immunogenic amount of immunogen effective for either immunization or amplified inoculation. 11

Suitable immunogens include, but are not limited to, live and attenuated viruses, antigen-encoding nucleotide vectors, bacteria, adjuvant plus antigens, and haptens coupled with 13 support materials. In particular, effective immunogens are preferred in determining an immune response against diphtheria, tetanus, butylene, cholera, dengue disease, hepatitis 15 A, C and E, hemophilic influenza, herpes virus, Helicobacterium pylori, influenza, Japanese encephalitis, meningococcus A. and C, measles, rotavirus, mumps, papi viruses Hon, 17 pneumococci, polio, rubella, rotavirus, syncytial viruses, Shigella disease, tuberculosis, yellow fever and combinations thereof. 19

Immunogens can also be produced by molecular biology methods to obtain recombinant peptides or fusion proteins containing one or more portions of protein derived from a pathogen. For example, fusion proteins containing the antigen of interest and the subunit B of the cholera toxin have been shown to induce an immune response to the antigen of interest, Sanchez et al. (1989) in Proc. Natl. Acad. Sci.,

USA, 86: 481-485. 25

Preferably, the immunogenic composition contains an amount of an adjuvant sufficient to enhance the immune response to the immunogen. Suitable adjuvants include, but are not limited to, aluminum salts, squalene mixtures (SAF-1), muramylpeptides, saponin derivatives, mycobacterial cell wall preparations, monophosphoryl lipid A, mycolic acid derivatives 29, surfactants of nonionic block copolymers, Quil A, cholesterol toxin subunit B, polyphosphazene and derivatives and immunostimulatory complexes (ISCCMs) as described by 31 Takahashi et al. (1990) in Nature 344: 873-875. For veterinary use and for the production of antibodies in animals, mitogenic Freud adjuvant components can be used. 33

Like all immunogenic compositions, immunologically effective quantities need to be determined empirically. Factors to consider include immunogenicity, and the immunogen itself may be complexed or covalently attached to an adjuvant or support protein or other support material, the route of administration and the number of doses of immunization 37 to be administered. Such factors are known in the field of vaccines and to a specialist in immunology, to make such determinations without exaggerated experiments. Preferably, if the active substance and / or the carrier contains amino, imino or guanidino groups, the delivery systems further comprise at least one physiologically acceptable Maillard reaction inhibitor, in an amount effective to substantially prevent condensation of the amino groups and of the reactive carbonyl groups, in the composition. 43

The Maillard reaction inhibitor can be any of those known in the art. The inhibitor is present in an amount sufficient to substantially prevent condensation of the 45 amino groups and the reactive carbonyl groups. Typically, amino groups are present in the bioactive material and carbonyl groups are present in the carbohydrate or vice versa. However, amino 47 and carbonyl groups may be intramolecular, within the biological substance or carbohydrate.

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Various classes of compounds having an inhibitory effect in the Maillard reaction are known and can therefore be used in the compositions described herein. These compounds are generally competitive or non-competitive inhibitors. Competitive inhibitors include, but are not limited to, amino acid residues (together D and L), combinations of amino acid residues and peptides. In particular, lysine, arginine, histidine and tryptophan are preferred. Lysine and arginine are the most effective. There are many non-competitive inhibitors. These include, but are not limited to, aminoguanidine and derivatives, such as 4-hydroxy-5,8-dioxochinoline derivatives and suitable Maillard inhibitors, such as those of EP-A-0433679.

In addition to the dosage forms described above, a variety of other dosage forms suitable for various uses are provided herein.

The present invention relates to administration systems that have sizes and shapes for penetrating the epidermis and are recommended for ballistic administration. The size of the carrier is of the order of microns, preferably in the range of 1-5 μ in diameter and 5-150 μ in length, which allow penetration and administration by epidermis to subcutaneous, intradermal, intramuscular and intravenous tissues. It is appreciated that, at this size, the administration system can appear macroscopically in powder form, not unlike the configuration at the microscopic level.

Preferred configurations of ballistic management systems are microwaves and microfibers. The production of microfibers is relatively simple and economical and results in stable administration systems comprising the carrier in glass form and the active substance. Additional stabilizers, buffers, bottles and polymers may also be added during the process, as will be described below. Many of the most labile biomolecules can withstand high temperatures (for example, 60-100 ”C) when stabilized by drying in trehalose, provided that most of their surface is in contact with the carrier. Temperatures of 70 ° C can be tolerated for more than one month shows (Colaco et al. (1992) in Bio / Technology 10: 1007-1011) and higher temperatures for shorter periods of time. The results presented here show that the dried fluorescent protein phycoerythrin in trehalose can be stored at 100'C for at least one month, without any detectable loss in functional activity. Other carriers provide protection at lower temperatures than trehalose. The maximum temperature of protection must be determined empirically by a person skilled in the art, without further experimentation.

The microfibers prepared in accordance with the principles of the present invention have a high shape ratio, ie the length compared to the diameter, preferably in the range of 1-5 μ in diameter and 5-150 μ in length. This high shape report leads to an increased final penetration in ballistic administration, by the tendency of the microfibers of alignment parallel to the ballistic microinjector cylinder, as described in more detail below. Longer macrofibres can be injected using impact ballistic means, conventional or trocar. Alternatively, macroscopic glass needles of sufficient intrinsic strength can be directly driven into the skin for subcutaneous, intradermal or intramuscular administration of the active substance.

Alternative preferred embodiments of the administration systems include microspheres, preferably with a limited size distribution. This configuration is especially usable, when increased control of the depth of penetration of the administration system is desirable. Such control is usable, for example, for intradermal, intramuscular, intravenous administration of vaccines to the basal layer of the epidermis, to bring the antigen close to the skin's Langerhans cells, for the purpose of inducing optimal immune responses.

The invention also comprises tubular fibers for administration of active substances. By drawing a cylindrical block into an oven that produces the local softening of the glass carrier, fine, tubular needles can be formed. These needles can be filled with a

RO 121407 Β1 stabilized compound in fine powder form by introducing fine powder during the process of melting and drawing. Tubular fiber can also be obtained from organic, thermoplastic and / or carbohydrate and / or HDC polymer which can be slowly or rapidly soluble in water 3 and / or biodegradable.

An alternative embodiment of the carrier agent comprises a tubular carrier agent of a water-soluble or plastic hard glass which is filled and optionally covers the delivery systems described herein. 7 In another embodiment of the invention, co-formulations of carrier agents and other water-soluble materials are included. For example, co-formulations of water-soluble carrier 9 agents such as phosphate, nitrate or carboxylate bottles or biodegradable plastics such as lactide or lactide / glycolide copolymers that will give a heavier erodible carrier 11 for delayed release of bioactive material.

The invention also consists of methods for obtaining solid dose systems. As the exposure time 13 is limited, the active substances mixed in the dry carrier can be heated to fluidize the glass that can be pulled or twisted without harming the product. The fibers may be drawn from a block, cooled for solidification and then drawn into a drum or may be drawn through fine holes into a rapid rotary cylinder, which is heated above the melting point of the carrier. Being inherently fragile, these fibers can be easily cut, broken, crushed or cut into short lengths from long cylindrical rods or needles. By varying the diameter of the fibers produced, needles can be formed, ranging from micro to macro, for example, from a few microns to millimeter fractions. It has been found that sugar wadding devices are suitable for use in the preparation of microfibers of fine diameters. Although the optimal conditions must be determined empirically for each 23 carrier agents, such determinations are within the reach of the specialist.

In order to prepare microspheres, according to the present invention, more than 25 methods may be used depending on the application of the carrier agents. Suitable methods include, but are not limited to, spray drying, freeze drying, air drying, drying under 27 vacuum, fluidized bed drying, milling, co-precipitation and supercritical fluid evaporation. in the case of spray drying, freeze drying, air drying, vacuum drying, fluidized bed drying and evaporation of supercritical fluids, components (SP and / or HDC, and / or other glass-forming products, active substances, buffers, etc.) are primarily 31 dissolved or suspended in suitable solvents. In the case of milling, the bottles formed from the components, either by evaporation of the solvent or by the abrupt cooling of the melt, are crushed in the dry state 33 and processed by any method known in the art. In the case of co-precipitation, the components are mixed in an organic environment and processed as described below. 35

Spray drying can be used to charge the carrier with the active substance. The components are mixed in a suitable solvent medium and dried 37 using precision nozzles to produce extremely uniform drops in a cooling chamber. Suitable spray dryers include, but are not limited to, Buchi, NIRO, APV and Lab-plant spray dryers, 39 which operate according to the manufacturer's instructions. A number of carbohydrates are unsuitable for use in 41 spray drying, as the melting points of carbohydrates are too low and dry amorphous materials are adhered to the walls of the drying chamber. Generally, carbohydrates with a melting point lower than the processing temperature in the spray drying chamber are not suitable for use in spray drying. For example, palatinite and lactitol are not suitable for use in spray drying under conventional conditions. An appropriate carbohydrate determination can thus be made based on known or empirically determined melting points 47. Such determinations are within the reach of the person skilled in the art. 49

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An alternative method for obtaining microspheres as carrier agents according to the present invention is the preparation of a uniform aqueous / organic phase emulsion of the active substance in a solution of carrier agent as an aqueous phase and glass in the organic phase or vice versa. This is followed by drying the emulsion droplets to form a solid solution of the active substance and carrier in an amorphous glass matrix. In a modification of this method, the emulsion may be formed from the active substance in the solid solution in the carrier and two different bottles and / or polymers dissolved together in a solvent or dissolved in two separate solvents. The solvents are then removed by evaporation to obtain double or multi-walled microspheres. Appropriate methods for obtaining multi-walled microspheres are described, for example, in Pekarek et al. (1994) Nature 367: 258-260 and in US 4861627.

The administration system may also be dried from an organic SP solution or a hydrophobic active substance, to form a bottle containing the homogeneous active substance distributed in a solid solution or a fine suspension in a polyol bottle. These bottles can then be ground and / or used to obtain microparticles of defined homogeneous size.

The active substance and carrier may also be co-precipitated to obtain high quality powders. Co-precipitation is carried out by spraying, for example with an air stream, the various components and / or the glass-forming polymeric compounds in a liquid in which they do not dissolve, such as ice-cold acetone.

The invention also relates to tubular fibers for releasing active substances. By pulling from a heated cylindrical block, fine tubular needles can be formed. These can be made to contain a stabilized compound in fine powder form by introducing a fine powder during the melting and firing process. Tubular fiber can also be obtained from an organic polymer, thermoplastic and / or carbohydrate and / or HDC glass which can be slowly or rapidly soluble in water and / or biodegradable.

An alternative embodiment of the carrier agent comprises a tubular carrier comprising a water-soluble glass or plastic material which is filled and optionally coated with an SP and / or HDC bottle and the active substance. Fine tubular fibers of inorganic or organic bottles, hardly soluble in water, can be drawn from a cylindrical block and a SP administration system in the form of fine powder can be incorporated into the lumen of the block and then of the fiber, during the process.

In another embodiment of the invention, co-formulations of carrier agents and other water-soluble materials are included. For example, co-formulations of carrier agents with water-soluble bottles such as phosphate bottles. (Pilkington Glass Company) or biodegradable plastics such as lactide or lactide / glycolide copolymers will give a harder erodible carrier for delayed release of the active substance. In order to obtain the co-formulations, a glass in the form of a fine powder containing the active substance can be intimately mixed with a carboxylate glass in the form of a fine powder and co-sintered.

Alternatively, if a metal carboxylate glass has a lower melting point than the delivery system, the latter may be homogeneously embedded as encapsulated in a carboxylate glass by abruptly cooling the obtained melt. It can be milled to obtain a fine powder, with intermediate solubilities between the relatively rapid solubility of the carrier and the low solubility of the carboxylate glass.

Alternative co-formulations include the use of a homogeneous suspension of a fine powdered glass delivery system, encapsulated in a carboxylate bottle by drying in an organic solvent in which the carboxylate is soluble, but the amorphous powder is not soluble, to form the glass. of carboxylate. It can be sedimented to give a fine powder, which would have the relatively rapid dissolution administration system trapped in a

EN 121407 Β1 slow-dissolving carboxylate glass (for example, comparable to a conventional slow-release system). Intermittent release forms can be obtained either by repeated encapsulation cycles using bottles with different dissolution rates or by mixing a number of 3 co-formulation powders, with the desired range of release characteristics. It should be noted that this glass can also be pulled or twisted to obtain microfibers or slow release microfibers that will be assembled. It is to be appreciated that any formulation of administration system should thus be capable of releasing the active substance after administration and should not have an excessive effect on the stability of the material to be administered.

As discussed above, bottles of carbohydrate derivatives are also 9 suitable for this use. Suitable carbohydrate derivatives include, but are not limited to, esters, ethers, carbohydrate imides and other derivatives and polymers which are highly soluble in the water. The carrier agent can be charged with the active substance by drying a solution of the active substance containing a sufficient amount of carrier agent to form a drying bottle. This drying can be accomplished by any method known in the art, including, but not limited to, freeze drying, vacuum, spray, air, fluidized bed drying. The dry material can be ground into a fine powder form before processing the material with polyol or co-formulation glass. 17

Different dosage schemes are chosen, depending on the carrier, release agent, used.

An administration carrier according to the invention may be provided for rapid release or injection dose of the active substance after administration, when the administration system is readily soluble. Co-formulations of carriers 21 or water-soluble hard plastics, such as phosphate, nitrate or carboxylate and lactide / glycol id, glucuronide or polyhydroxybutyrate bottles and polyesters may contain slower 23 carrier agents for a slower release slow and longer. A priming and amplifying effect may also be achieved by the use of a water-soluble tubular carrier, 25, soluble in water, filled and coated with a rapidly dissolving SP and / or HDC bottle loaded with the active substance. the glass coating charged with the active substance will dissolve rapidly to give the initial dosage effect. It will not be a dosing action when the outer, tubular wall portion of the carrier agent dissolves, but the initial priming dose will be followed by a dose 29 to amplify the inner filling when the outer tubular wall is removed by dissolution. Such an intermittent release format is, in particular, usable for administering immunogenic compositions. If a multiple effect of intermittent release is desired, administration carrier agents can be achieved with any combination of layers of 33 unloaded carrier agents and carrier agents loaded with the active substances.

Administration of more than one active substance may also be accomplished using an administration system consisting of multiple coatings or layers of carrier agent loaded with different materials or mixtures thereof. Administration of solid dose delivery systems 37, according to the present invention, can be used in combination with other conventional therapies and co-administered with other therapeutic, prophylactic or diagnostic substances.

The invention also includes methods for administering solid dose systems. 41

Appropriate administration methods of the active substances include, but are not limited to, topical, transdermal, transmucosal, oral, gastrointestinal, subcutaneous, ocular, intramuscular, intravenous, and inhalation (nasopharyngeal and pulmonary, including transbronchial and transalveolar) methods. Topical administration is, for example, by dressing or using a bandage having a delivery system dispersed therein or by direct administration of the administration system to open incisions or wounds. Creams or ointments having 47 dispersed in them beads or microspheres of the delivery system are suitable for use, for example, as topical ointments or wound dressing agents. 49

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The compositions for transdermal administration are preferably powders of delivery systems in the form of microwaves or microbes of homogeneous size. Needle forms or larger macroscopic balls of the administration systems. They are also presented for subdermal implantation and extended drug delivery. Particle sizes should be small enough to minimize skin damage through administration. The powder forms of the delivery systems can be micro-sized about 10-1000 μ in length and 1-150 μ in diameter. The powders can be pre-packed in a single, sealed, sterile dose form.

Appropriate methods for transdermal administration include, but are not limited to, direct impact, ballistic and liquid jet administration. For direct impact administration, macros can be precisely formed by methods well known in the field of inorganic glass formation, such as those used to produce optical fibers. These needles can be obtained in a precise tubular plastic form and directed into the skin with a plunger. Ballistic administration is preferred as it is relatively painless. In general, the administration system is accelerated by a shock wave of helium or other gas and discharges into the epidermis. A suitable means for ballistic administration is described in PCT / GB 94/00753. A suitable means for liquid jet release is a Medi-ject device (Diabetes Care (1993) 1 b, 1479-1484). Such liquid jet devices are, in particular, usable with larger macro needle release systems, which can also be released by the use of conventional ballistic means or trocar.

In transdermal administration, the penetration degree of the administration system can be controlled at a certain level, not only with the ballistic microinjector described below, but also by the shape and size of the powder particles. For example, when a lower and relatively uniform degree of penetration is desired, the microspheres are indicated for the application of the present invention. When a higher degree of penetration is desired, a micraceous configuration may be preferred.

Due to the fact that the shape ratio (for example, length versus diameter) of the microwaves is large, then they will be larger than the spherical particles with a similar diameter. If they can be impacted by the skin, their larger mass will give them a greater momentum at the same speed and they will penetrate deeper into the tissues. When the randomly oriented microwaves are introduced into a laminar gas stream, they will align themselves in the direction of the fluid and in the gas-powered ballistic injector, thus ensuring skin impact at right angles to ensure penetration.

Suitable administration systems for transmucosal delivery include, but are not limited to, mucoadhesive tapes, films or powders, oral release pills, weights and rings, and other means for vaginal or cervical administration.

Compositions suitable for gastrointestinal administration include, but are not limited to, powders, tablets, capsules and pills, pharmaceutically acceptable for ingestion and suppositories for rectal administration.

Compositions suitable for subcutaneous administration include, but are not limited to, different implants. Preferably, the implants are macroscopic, discoidal, spherical or cylindrical in shape for ease of insertion and can be rapid or slow release. Since the entire implant is dissolved in the body's fluids, removal of the implant is not necessary. In addition, the implants do not contain synthetic polymers and are biodegradable.

Compositions suitable for ocular administration include, but are not limited to, microspheres and macrospheres formulations, and saline drops, creams and ointments, containing round-end rods for application on the lower eyelid to treat conjunctivitis.

Compositions suitable for inhalation administration include, but are not limited to, powder administration systems. Preferably, the powders have a particle size of 0.1 to 10 μm. More preferably, the particle size is 0.5 to 5 μ.

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More preferably, the particle size is 1 to 4 μm. In particular for pulmonary 1 administration, the preferred particle size is 2.5-3 μ.

Preferably, the powders of SP release carriers also contain an effective amount of physiologically acceptable buffer and molecular water (MWPB). A MWPB is a physiologically acceptable salt that performs a loss of water from the composition, 5 so that, at ambient humidity, the vapor pressure of the crystallization water is at least 14 mm Hg (2000 Pa) at 20 ° C and does not interfere with glass forming of the purifying agent. An effective amount of MWPB is that which sufficiently reduces hygroscopicity to prevent substantial agglomeration, for example, a molar ratio of 50% potassium sulphate. Sodium sulphate and calcium lactate are the preferred salts, and potassium sulfate is the most preferred. 11

HDC composite administration systems are particularly useful for inhalation dosage forms. For example, 13 10% GPAC / TOAC mixing systems (w / v) are resistant to 95% relative humidity (RH), but recrystallize from contact with water and thus release any active substances incorporated into them. This is especially important for inhalable powders, as these powders preferably devitrify and release the active substances by finding liquid in the alveoli and not in the tracheal pathways 17.

Atomizers and vaporizers filled with powders are also part of the invention.19

There are a variety of suitable means for use in powder administration by inhalation. See, for example, Lindberg (1993) Summary of Lecture at Management Forum 6-721 dec. 1993 Creating the Future for Portable Inhalers. Additional means suitable for use include, but is not limited to, those described in W09413272, W09408552.23

WO9309832 and US 5239993.

Various other solid dose delivery systems are included in the present invention.25

They are suitable for the administration of a wide variety of non-medical active substances. For example, an HDC bottle, incorporating an active agricultural substance, is itself dried, even in the tropics, but releases pesticide or biological control agents in contact with liquid water on the surfaces of plants or in the soil. An HDC bottle incorporating an enzyme can be used by addition to washing detergents, as it stabilizes the enzyme even at high humidity and releases the enzyme immediately into contact with water. Many other 31 embodiments are part of the present invention and are within the scope of the skilled person to apply them. 33

The invention is illustrated by 10 non-limiting examples.

Example 1. Methods for obtaining vitreous systems for administration of solid 35 microfiber SP dosage

a) Formation of microfibres SP 37

The bottles are formed by drying 20% solutions of either trehalose, lactitol, palatinite or

GP, containing MWPS and 1 mg / ml phycoerythrin, algal protein, fluorescence, under vacuum 39 (80 mTorr), for 16 h. The bottles were crushed in a household coffee grinder to obtain a coarse powder which was used to fill the rotating head of a device for preparing Kando K1 Kandy Floss sugar wool (GB 1533012). The engine was then started and the powder glass was heated by pressing the button between 5 and 9. The dwell time in the 43 rotating head was 2-10 min and a continuous process was maintained through the constant operation of the rotating head. 45

The fibers produced were shredded in a household coffee grinder and the results obtained are presented in table 3, which presents an average of those products. These data indicate that, with all three sugary bottles, reduced element adjustments result in the production of finer diameter microwaves. With trehalose, at regulation 6, microwaves with a 49 were obtained

RO 121407 Β1 average diameter of 15 μm and at adjustment 9, microacids with an average diameter of 40 μm. With GPS, adjustment 9 gives microwaves with an average diameter of 15 μ. The microwaves formed from bottles containing buffer salts remained dry at ambient temperatures and humidity. Microorganisms containing phycoerythrin exhibited a retention of the bilayer activity that was assessed by fluorescence.

Table 3

Micro size analysis Length (pm) Thickness (pm) Average 192.60 43.35 Standard error 12.53 2.33 Median 167.5 37.5 Mode 137.5 47.5 Standard deviation 123.44 22.91 Sample variation 15237.75 524.72 Excess 16,17 2.55 distortion 3.35 1.45 Interval 862.5 115 Minimum 67.5 10 maximum 930 125 The amount 18682.5 4205 calculation 97 97 Safety level (95,000%) 24.57 4.56

b) Formation of glass microfibers from SP / organic binary composites

The bottles were formed by drying a 5: 1: 1 mixture of trehalose, sodium octanoate and water under vacuum (80 mTorr) for 16 h. The bottles were crushed into a household coffee grinder to allow get a coarse powder that was used to fill the rotating head of a Kando K1 Kandy Floss car. The engine was then started and the powdered carbohydrate / organic binary glass was heated with the adjusting element between 5 and 9. As with pure trehalose bottles, reduced adjustments resulted in the production of finer microwave diameters. Binary mixing bottles can be cut to obtain bottles with significantly different tensile properties compared to the corresponding pure trehalose bottles. The stationary time in the rotary head was also 2-10 min and a continuous process was maintained through constant head actuation. The obtained results indicated that the variations of the melting points and dissolution times of the bottles and the resulting physical properties of the microfibers can be achieved by the variation of the carbohydrate / organic molecules and the reports used.

Example 2. Methods for obtaining solid-state powder dosing SP systems

a) incorporation of the active substance into the glassy carrier SP to obtain spent powders

The bottles were formed by drying 20% solutions of trehalose, lactitol, palatinite, GMB or GPS, containing an equimolecular ratio of MWPB and protein, by drying-freezing, under vacuum (80 mTorr), for 16 h. powdered in a jet mill

RO 121407 Β1 aer Trost. The particle size of the spent powders was measured using a Malvern Mastersizer laser particle size determination device. The results obtained with spent powders obtained from an initial solution of 0.5M trehalose and 0.5M calcium lactate 3 showed a distribution of monodisperse particles with average particle diameters of 1.1 μ (Fig. 1). The powders containing MWPB remained free flowing powders and showed no change in particle size or agglomeration and water absorption by prolonged exposure to ambient temperatures and humidity (Fig. 2A and 2B). 7

b) incorporation of active substances into the glass carrier SP to obtain spray-dried powders 9

20% trehalose solutions containing MWPB salts and protein (phycoerythrin) were dried in a Buchi or Lab-Plant spray dryer at a pumping rate of 500-550 ml / h 11 and an inlet temperature of 180 ° C. The particle size was measured using a SympaTec laser particle measuring device. The spray-dried powders showed 13 a distribution of monodisperse particles with a distribution of sufficiently narrow size for efficient use as particles in a ballistic powder device. In the results 15 shown in FIG. 3, particle size analysis of the spray dried powder produced by spray drying a mixture of 0.5M trehalose and 0.5M calcium lactate in a 17 Lab-Plant spray dryer showed an average particle diameter of 8.55 μ and illustrates the distribution of the culmination of a narrow curve obtained. 19

The variation of the average particle size can be achieved by changing either the composition of the mixture to be spray dried or the characteristics of the spray nozzle assembly 21 used with nozzle. The results shown in FIG. 4 shows a comparison of the particle size analysis of the spray-dried powder as in FIG. 3 with a spray-dried powder 23 produced by drying the same mixture on a Buchi spray dryer using a different nozzle assembly. The distribution of the culmination point of the curve shown in fig. 4 shows an equally narrow range, but the average particle size is now 7.55 μ.

These data show that the particles obtained by various spray drying processes are equally suitable for obtaining compositions for ballistic administration. It should be noted that the ability to vary the particle size leads to compositions with different penetration characteristics. This is, in particular, important for determining intradermal, intramuscular, intravenous, or intramuscular administration, since penetration is a function of particle moment 31 and distribution is a function of particle size dispersion.

c) incorporation of the active substance in a glass carrier SP, for administration, 33 by drying from organic solvents

A 50 mg / ml solution of CSA in a 1: 1 ethanol mixture, containing 20% 35 trehalose, was air dried at ambient temperature to form a trehalose bottle, containing CSA in solution or solid suspension. The glass was coated to obtain a powder, 37 according to the method described in Example 1 and a free flowing powder was obtained at room temperature and humidity. By adding the powder to the water it led to the dissolution of trehalose 39 and the formation of an aqueous suspension, uniform by CSA.

d) incorporation of the active substance in a vitreous carrier SP, for administration, 41 by co-precipitation.

20% solutions of trehalose, lactitol, palatinite, GMB or GPS, containing MWPB and 43 protein (phycoerythrin) were spray dried in a freezing bath with acetone-solid carbon dioxide. The precipitated powders were separated by centrifugation or filtration and by air drying the residual solvent was removed. The powders again showed a distribution of monodisperse particles and those containing buffer salts in formulation remained dry at ambient temperatures and humidity.

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e) Formation of a vitreous carrier to administer the solid dose, as a composite, of a hydrophobic active substance in SP, by drying from organic solvents

Two different solvent systems were used to produce the mixed bottles. In the first case, the CSA was dissolved in absolute ethanol and an equal volume of water was slowly added, so that the CSA that precipitated at each addition was allowed to redissolve. Then trehalose was dissolved in a 50% volume / volume solution to a final concentration of 50% weight / volume. The mixed bottles were produced by evaporating the mixed solvent on a hot plate at 70 ° C. In the second case, CSA and trehalose were both dissolved in DMF and again the composite glass was obtained by evaporation as described above. In both cases, a slightly opalescent glass resulted. Water films were dripped onto glass films to study the dissolution and release properties of the bottles.

The results showed that the bottles had a different behavior. The bottles obtained from DMF were waterproof, with an obviously hydrophobic surface. Gradually they became opaque, with agglomerations of CSA precipitate when in contact with water. The bottles made from 50% ethanol were hydrophilic. They dissolved rapidly in water, with the release of a cloud of fine CSA particles. This latter glass appeared with CSA content either in a fine solid suspension or in a solid solution in trehalose glass which released CSA as a precipitate, when trehalose dissolved. Thus, this represents a very usable dosage form for CSA with high bioavailability due to its finely divided and uniform format after release.

The different behavior of the bottles of identical composition after drying of different solvents suggests an interesting and usable process, leading to a precise control over the way of depositing the different bottles during the evaporation of the solvent. Because CSA is more soluble in DMF than it is trehalose, 10-20% CSA composite bottles in trehalose prepared from this solvent tend to have hydrophilic trehalose cores and surface layers of hydrophobic CSA. In contrast, when 50% ethanol is evaporated, the early loss of ethanol in the 97% azeotropic causes CSA to arrive in solution surrounded by a trehalose syrup, which then solidifies as the continuous phase leads to a CSA in solid trehalose glass emulsion.

Example 3. Protecting proteins from the action of an organic solvent and high temperatures, carried out by drying in trehalose

a) Protection of horseradish peroxidases and phosphatase facets the action of acetone by drying in trehalose.

A solution of 0.1 mg / ml horseradish peroxidase or 1 mg / ml alkaline phosphatase / 4mg / ml bovine serum albumin solution was dried in an FTS Systems freezer dryer with or without 50% trehalose. The dryer was used as a vacuum dryer and the mixture was dried without freezing. The volume of solvent was added four times and the solution was allowed to evaporate to dryness. The contents were redissolved in 5 ml of water and the enzymatic activity was evaluated, in serial dilution, with commercial kit reagents. The alkaline phosphatase kit was obtained from Sigma Chemical Co. and horseradish peroxidase were obtained from Kirkegaard & Perry Laboratories, Inc. As shown in FIG. 5A and 5B, the dry enzymes with trehalose were more resistant to acetone than the dry enzymes without trehalose.

b) Protection of phycoerythrin against the action of organic solvents provided by drying in trehalose

A 400 µg / ml phycoerythrin solution was freeze-dried in a Labconco freezer dryer with or without 20% trehalose. The dried protein powder was exposed to a number of organic solvents for 72 h. Phycoerythrin remained fluorescent in acetone, acetonitrile, chloroform and methanol. In pyridine, phycoerythrin remained fluorescent for 24 ... 48 h, but it was moistened and lost fluorescence in 72 h. In dimethylsulfoxide, the powder was solubilized, but phycoerythrin remained fluorescence.

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c) Protection of phycoerythrin at 100 ° C achieved by drying in trehalose 1 A solution of 400 µg / ml phycoerythrin was dried by freezing in an FTS dryer with or without 20% trehalose. The dried protein was kept at 100 ° C for one month, without losing its functional activity.

Example 4. Preparation of the glass solid dose administration system with the active substance 5 incorporated in the SP and / or HDC and / or carboxylate composite

a) Co-formulation of the vitreous system, for the administration of the solid dose of mixed SP 7 and organic bottles, by evaporation

Trehalose microparticles containing MB9 were prepared by spray drying as described in Example 2b. The solution which dried contained 0.39M trehalose and 0.14M calcium lactate and 0.5% MB9. These particles were coated by adding to these 11 a saturated solution of zinc palmitate (ZnC ₁₆ ) in toluene and cooling from 60 ° C to 30 ° C. A layer of ZnC ₁₆ was thus deposited on the particles which were then filtered under vacuum 13 to remove the excess ZnC ₁₆ , washed with acetone and air dried. The resultant powder remained unmixed in water for at least three days (the particles floated in the water without dipping and without releasing MB9 and then slowly released dye into the water). Thus, water soluble powders can become impermeable by coating with metal carboxylates such as ZnC ₁₆ , 17 to obtain slow release forms. It should be noted that the coating material is most probably in crystalline form and not a glass; therefore, the solid phase in which the active substances are suspended, requires not to be in the glass phase to be impermeable to water.

b) Co-formulation of the vitreous SP system, of solid dose administration containing 21 active substances and organic bottles, by evaporation.

A powdered trehalose bottle containing phycoerythrin was added to a 23-carboxylate mixed glass, namely, a 1: 1 mixture of sodium octanoate and zinc ethylhexanoate, dissolved in excess chloroform and evaporated under a stream of N ₂ , to at room temperature, for 25 to obtain a carboxylate glass containing phycoerythrin powder in suspension or solid solution. The co-formulated glass remained insoluble in water for at least 48 h. The phycoerythrin powder remained fluorescent both in the initial organic solution and in the final glass.

c) Co-formulation of the glass system for administering the solid dose of SP 29 bottles containing active substances and organic bottles, by co-melting

A performance organic glass obtained by the sudden cooling of a melting mixture 31

1: 1 of sodium ocatnoate and zinc ethylhexanoate was heated to 95 ° C and a powdered trehalose bottle containing phycoerythritis was added to the melt. The resulting mixture was immediately cooled to 33 on an aluminum block preheated to 15 ° C. A clear carboxylate bottle was formed containing a phycoerythrin powder encapsulated which retained its biological functionality, as determined by its fluorescence ability. By varying the nature and ratios of carbohydrate and organic parts in co-formulated bottles, bottles with a slow release characteristic range of 37, as evaluated after the variable time of dissolution in water, result.

d) Co-formulation of the solid-dose SP administration system containing 39 active substances and HDC bottles by evaporation.

The administration systems were prepared by spray drying using a 41 Buchi B-191 spray dryer. Spray-dried trehalose / MB9 dye (1%) particles 6 pm, 0.264 g preformulated were suspended in a solution of TOAC, 4 g and azobenzene, 43 0.029 g in dichloromethane, 100 ml in a spray dryer at room temperature at the entrance of 40 ° C.

A hydrophobic, yellow, muddy powder was obtained with TOAC glass, incorporating yellow azobenzene dye 45, encapsulating trehalose glass incorporating blue MB9 dye. The mixed carrier carrier delayed the release of the water-soluble blue MB9 dye 47 intensely when immersed in an aqueous solution.

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e) Co-formulation of the solid-dose SP administration system containing active substances and evaporative plastics

A powdered trehalose bottle containing phycoerythrin prepared according to Example 1 was added to a solution of perspex (transparent plastic material prepared by the polymerization of methyl methacrylate) dissolved in an excess of chloroform and evaporated under a stream of N ₂ , at room temperature, to obtain a solid perspex block containing phycoerythrin powder in solid solution. The phycoerythrin powder remained fluorescent both in the initial organic solution and in the reformed solid perspex, which was impermeable to water even after 4 weeks. Similar results were obtained with polyester dissolved in dichloromethane and polyurethane dissolved in dimethylsulfoxide.

Example 5. Preparation of tubular needles filled with administration systems

The end of a trehalose glass cylinder with a central cavity filled with a powdered trehalose glass, containing phycoerythrin, prepared according to Example 1, was melted in a zone furnace and the fiber formed by spiraling into a rotating metal drum, with constant speed. The tubular fibers formed contain finely pulverized trehalose-stabilized compound and can be cut to the desired size. The tubular fiber can also be made of thermoplastic, biodegradable or organic materials or HDC and by varying the diameter of the fibers produced, filled needles can be formed that vary from micro to macro-needles, for example, from microns to until fractions of one millimeter. The tubular needles can be filled with any solid dose carrier described herein.

Example 6. Ballistic administration of solid dose administration systems

The powder bottles were injected into the skin by propulsion at hypersonic speeds using a shock pressure created by the release of compressed gas. The powder was retained in the chamber attached to the wide end of a funnel-shaped cavity to the lower end of which a compressed gas cartridge sealed with a film was attached and the hypersonic shock was generated by rupture of the membrane. Alternatively, a time-adjusted relay-actuated solenoid may be used to control the release of helium, which allows operation at lower helium pressures. This is the principle used in the particle admittance gun (PIG) invented by Finer for the transformation of plant tissues, according to Vain et al. (1993) Plant Cell Tissue and Organ Cuiture 33: 237-246.

Example 7. Preparation of solid dose delivery systems from organic bottles by evaporation

a) Preparation of solid carboxylate dosage carboxylate administration systems by solvent evaporation

Aluminum hexanoate was dissolved in chloroform, 0.5 g / 10 ml, together with a fine suspension of 1% by weight MB9 as a tracer dye. A fine amorphous film, 100 ... 200 µm thick, was formed by pouring on silicate glass slides and evaporating the solvent in a hot air stream. The release of the dye in distilled water was monitored for over 5 hours and is shown in Fig. 6. The devitrification of these bottles was not observed and the films remained transparent, although they were discolored as the dye diffused into the environment.

Amorphous films of calcium neodecanoate dissolved in chloroform, 0.5 g / 10 ml, as described above were also formed. Release of the dye from these thicker films (1 ... 2 nm thick) in distilled water was again monitored for over 24 h as shown in fig. 6. In contrast to the aluminum films, the release of the dye from the calcium neodecanoate films, followed by the dissolution of the films, was monitored by Ca ²⁴ atomic adsorption spectroscopy.

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b) Preparation of vitreous systems, SP-carboxylate composites, for administration of solid dose 1 containing active substances incorporated in the carboxylate glass, by evaporation

Glucose film films incorporating 1% by weight MB9 were formulated by cooling 3 abruptly from the melt. These films were coated with thin, amorphous metal carboxylate films (100 µm thick) by evaporation of the carboxylate solution in chloroform, 0.5 g / 10 ml, 5 The metal carboxylate used was hexanoate and aluminum octanoate, calcium neodecanoate and magnesium isostearate and neodecanoate. The dissolution of the films was monitored by releasing the dye in distilled water. These administration systems delayed the release of the dye in time intervals from minutes to hours, except for those consisting of 9 magnesium isostearates which delayed the release of the dye for 10 days.

Example 8. Preparation of HDC Solid Dose Administration Systems 11

Different HDC bottles were prepared by melting and abrupt cooling. In the following examples, the HDC component was delivered from Aldrich Chemicals except TOPR which was synthesized 13 according to the method described by Akoh et al. (1987). The components formed bottles without decomposing or with low decomposition. Fructose, sucrose and, to a certain extent, glucose, have melted with a high degree of decomposition or polymerization. An ester such as α-D-glucose pentaacetate is stable at its melting point and forms a clear, incoherent glass as soon as it is suddenly cooled. Greater stability of the ether and ester derivatives is clearly in the advantage of encapsulating reactive organic materials such as pesticides and 19 biocides.

HDC substances with low melting points form soft, waxy bottles after 21 have been suddenly cooled. The NMR spectrum of glassy α-D-glucose pentaacetate was found to be identical to that of crystallized α-D-glucose pentaacetate. 2. 3

The glass formed from pentaacetate of β-D-glucose is slightly water soluble and a disc (20 mm diameter and 2.5 mm thick) prepared from this ester and placed in a stream of water 25 has lost about 33% of its weight initial in 10 days. Another glass disk of similar size was prepared from α-D-glucose pentaacetate and placed in 1 L of water, which was replaced daily. After 7 days, the bottle lost 20% of its initial weight. The release rate of the encapsulated Acid Blue dye from this glass, as shown in fig. 7, was 29 was quite constant. The release rate of the dye was higher on the first day because the release occurred largely from the surface of the glass disk. 31

Excellent recoveries were obtained by encapsulating various organic substances in bottles. The α-D-glucose pentaacetate glass disks containing 2% w / w of 33 materials listed in Table 4 were formed by sudden melting and cooling and then crushed.

Photochrome II is 5-chloro-1,3-dihydro-1,3,3-trimethylspyrr [2H] -indole-2,3 '- [3H] -naph [2,1-bj-35 oxazine. The encapsulated materials were extracted into a suitable solvent such as methanol or water. The obtained results are presented in table 4.37

Table 439

Encapsulated material boiling point * C melting point ° C Use Yellow Acid 65 > 300 water soluble dye Acid blue 129 > 300 water soluble dye Dispersion red 1 non-linear 161 Optical material Mordant blue 9 > 300 water soluble dye

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Table 4 (continued)

Encapsulated material boiling point 'C melting point 'C Use Ethyl hexanoate 168 Ethyl octanoate 207 oxadiazon 90 Pesticide azobenzene 293 Veterinary melatonin 117 hormone Photochromic II 183 photochromy

The release rates of Blue Acid 129 were found to be dependent on the dissolution rates and the configuration of the bottles. Pesticide, such as Oxadiazon, was easily dissolved in the melt of this bottle at about 15% w / w, without any problems.

Example 9. Formation and release properties of HDC glass systems for solid dose administration, by abrupt cooling of the melt

a) Formation and release properties of single and composite HDC bottles, melted in the following experiences, the administration system was preformulated, either as a simple material or as a mixed composition. This was achieved by thorough grinding of the component HDC substances together, followed by controlled melting, carefully in an oven, between 120 and 140'C and with normal atmosphere to form melts. The melts were suddenly cooled to glass by pouring over a brass block. This bottle was then finely ground.

The MB9 dye (1 or 5% by weight) was mixed with crushed glass before re-melting at 140 ° C. The melt was suddenly cooled to form small glass spheres (2.5 mm diameter) that were used in controlled release experiments.

The controlled release of the encapsulated dye was monitored by suspending three such spheres in 25 or 50 ml of deionized water or PBS solution at room temperature (27 ... 30'C) or at 37 °, as indicated. The environment was left to rest, periodically agitated and the level was completed at fixed intervals (generally at 72 h intervals). Both HDC and mixed HDC bottles were formed. The formulated HDC mixed bottles are shown in Table 5. The dye release was measured by spectrophotometry (max. 516 nm) and the results are shown in fig. 8 ... 14. TOAC glass has zero order release characteristics. The use of other HDC substances as glass modifiers in HDC composite formulations has resulted in obtaining bottles with desired release characteristics.

Fig. 8 presents the zero order release characteristics for TOAC management systems. in FIG. 8, the results were obtained from TOAC glass discs (6 mm x 2.5 mm) with MB9 dye evenly dispersed at 2% by weight. The release of the active substance was controlled at 25'C with slight agitation and medium changes at regular intervals. Note the linear allure of MB9 dye release over 55 days. The results shown in fig. 8 indicated that a pure glass carrier agent system, HDC, has zero order release rates for the active substances. The results shown in fig. 9-14 shows the variation in the release rates by changing the ratios of different HDC substances in the administration systems, by changing the length of the main carbohydrate chain and by changing the nature of the carbohydrate chain derivative.

In each example it is clear that HDC administration systems allow a wide range of 1 release rates that can be arranged depending on the active substance and its release. 3

Fig. 9 shows the results obtained when the reports of two different HDC substances vary in the administration system. The release rate of MB9 dye was measured from the TOAC / RUDA matrix, as described in Fig. 8. Release rates were found to vary with different formulations, but was not directly related to RUDA concentration. 7

For example, the highest release rate was observed for the composite with 75% TOAC (25% RUDA) and the lowest release rate for the composite with 95% TOAC. Thus, the speed 9 of these management systems can be derived easily and empirically.

Fig. 10 compares the change in Tg of three different HDC co-formulations with 11 TOAC variable quantities. Three different co-formulations were tested, TOAC / SHAC, TOAC / RUDA and TOAC / a-GPAC with the percentage increase, in molar percentage, of TOAC. These results 13 indicated that Tg of the carrier agents directly increases with the molar percentage of TOAC in those co-formulations that initially had a lower Tg of TOAC / a-GPAC and TOAC / SHAC. 15

Fig. 11 compares the release of MB9 dye in percentages of two different co-formulations of TOAC / RUDA and RUDA alone. RUDA presented a biphasic release rate 17 with a fast initial release of about 60% dye over 5 days and a slow rate of several percent more dye over the next 25 days. The release speed of RUDA 19 alone is substantially altered by the presence of TOAC. The 50% RUDA formulation has an almost linear release rate, higher than the 10% RUDA formulation. 21 Fig. 12 compares the release of MB9 dye from co-formulations with TOAC (75%) with SOAC or COAC to demonstrate the effect of variation of the main carbohydrate chain. The results show that the release rates can be varied in this way, the TOAC / COAC co-formulation showed an increased release rate compared to the TOAC / COAC co-formulation. 25

Fig. 13 compares the release rate of MB9 dye from co-formulations of two HDC components of different carbohydrate chain lengths, TOAC and a-GPAC. The 27 release speeds were not directly dependent on the TOAC weight percent with 50% TOAC, having the lowest release speeds and 25%, having the highest speeds. Again, 29 speeds are easily determined empirically.

Fig. 14 compares the release rate of MB9 dye from two different co-formulations 31 of HDC components with the same main carbohydrate chain and different derivatives, TOAC and TOPR. The results indicated that the addition of 25% TOPR to a 33 TOAC administration system dramatically decreases the release rate of the active substance.

Table 5 35

Glass system Weight% MB9 Temperature / 'C reports% 1.TOAC 1 and 5 RT, 37 100 2. WHEEL 1 and 5 RT 100 3. TOAC / SOAC 1 RT 75 (weight) 4. TOAC / a-GPAC 1 RT, 37 75 (weight) 5. TOAC / COAC 1 RT 75 (weight) 6. TOAC / TOPR 1 RT 75 (weight) 7. TOAC / p-GPAC 1 RT 75 (weight) 8. TOAC / a-GPAC 1 RT 90, 75, 50, 25 mol% 9. TOAC / WHEEL 1 RT 90, 75, 50, 25 mol%

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b) incorporation of the active substances into the HDC by abrupt melting cooling

Dissolution of the synthetic corticosteroid XPDO (described below) in a TOAC melt and abrupt cooling were performed to form the glass solid dose administration system. By observing the release of MB9 in aqueous solution, these experiments tested the compatibility of the steroid with the glass, the further recovery of the steroid and the effect of XPDO on the properties of the formed administration system was studied, by observing the release of MB9 in the aqueous solution. TOAC, 3.21 g, was melted at 150 ° C, before being suddenly cooled with glass. The glass was finely ground with XPDO, 0.15 g, before being re-melted. The clear melt was cooled again to obtain a mixed HDC / active glass. The thermal analysis was performed on a calorimeter with differential, scientific, rheometric (DSC) scanning at a heating speed of 107min under a nitrogen atmosphere. The following tests were prepared:

TOAC / XPDO (5% by weight) Tg = 50.6 ° C

TOAC / XPDO (5% by weight) + MB9 (1% by weight) TOAC alone

TOAC / MB9 (2% by weight)

Tg = 50.9 ° C

Tg = 50, r

Tg = 50,3'C

The release characteristics of HDC in vitro solid dose, HDC, in vitro administration systems were studied by monitoring the release of MB9 from TOAC / XPDO bottles as shown in FIG. 15. For the analysis of the stability of the active substance in the HDC glass systems of solid dose administration, XPDO was recovered from the samples by dissolving the glass in acetonitrile and analyzing by HPLC. It was a complete recovery of the active substance even after storage at 45 ° C for 4 weeks.

Example 10. Formation of HDC glass systems for solid dose administration by solvent evaporation

a) Formation of HDC bottles by evaporation of the solvent

As described above, it has been found that TOAC becomes a good carrier for sudden melt release. Such an administration system has a low melting point and very little tendency to recrystallize. A series of experiments were performed on TOAC bottles obtained by evaporation of the solvent on inclined 3x1 glass-soda planes.

Dichloromethane (DCM) and chloroform are standard solvents for TOAC, which is also soluble in other solvents such as acetonitrile. DCM was used for all subsequent experiments.

The bottles were obtained by evaporating DCM on a hot plate at 65 ° C from 25% TOAC solutions (50% of the solutions often deposited crystals on the tip of the pipette). The drying was carried out for 2 hours to ensure complete drying. Uniform bottles were obtained by using an Eppendorf pipette to drop 100 µl on a slide recently placed on a hot plate and then removing about 50 µΙ by using the complete eject volume of the pipette.

The bottles were very clear and adherent when they were first made, but gradually recrystallized after one month at room temperature (RT) and relative humidity 50 ... 60% (RRH).

Similar trehalose bottles obtained by evaporating water from a 50% trehalose solution were very clear when first made, but gradually recrystallized after a few weeks.

b) incorporation of the active substance into HDC bottles by evaporation of the solvent; powders suitable for inhalation

XPDO is a steroid anti-inflammatory compound. Chemically he is 6a, 9a-difluoro-1ip, 21dihydroxy-16a, 17a-propylmethylenedioxy-4-pregnen-3,20-dione. XPDO crystallizes as a bundle of coils together in needles, leaving long, empty, intermolecular spaces that bind water molecules in a manner similar to zeolites. This makes the steroid sufficiently high

RO 121407 Β1 to exclude its use in a dry powder inhaler, which is his preferred method of administration. In amorphous (non-crystalline) form, XPDO is nonhygroscopic, but chemically unstable. Studies on the stabilization of this compound with trehalose have not been successful, 3 so that it was not possible to produce a non-hygroscopic powder.

The XPDO was then incorporated into a TOAC bottle by dissolving both TOAC and 5 crystalline XPDO in DCM and evaporating the solvent to 70'0 on a hot plate. XPDO was used in proportions of 10% and 20% compared to all solids in the final TOAC glass. These 7 bottles were perfectly clear as water and transparent. When stored at RH of 75%, 81%, 90% and 95% for 4 weeks, they showed no change in the glass structure, such as 9 recrystallization.

However, when immersed in liquid water, the surface of the glass slightly recrystallized, so that 11 microscopic pyramidal crystals of TOAC could be seen, at a microscope within 15 ... 30 minutes from the addition of water. The crystallization was slightly progressive and after a few more 13 minutes small bundles of typical needles took the form of XPDO crystals. When no needles such as XPDO crystals or TOAC pyramidal crystals adhering to the 15 base glass were observed, they were lightly washed to produce a fresh glass surface for another easy dissolution. The complete exclusion of XPDO from TOAC crystals allowed this molecule, previously incorporated into the TOAC glass matrix, to now be released into the liquid phase. 19

c) incorporation of the active substance into HDC bottles by solvent evaporation; spray-dried powders suitable for inhalation 21

Studies have been performed using a synthetic corticosteroid XPDO, dissolved in DCM. The solution was spray dried in a Buchi B-191 spray dryer, using an inlet temperature of 40 * C. This resulted in a white, fine, amorphous powder, which contained XPDO in solid solution. XPDO was incorporated at 20% by weight. The powder was completely amorphous, as confirmed by thermal analysis (Tg = 46'C).

For analysis, XPDO was extracted from the spray dried powder, by dissolving the powder in acetonitrile and then diluting acetonitrile with sodium phosphate buffer solution for HPLC analysis. The samples were arranged for the stability test of XPDO in spray-dried formulations 29 at 45 ° C and stored over saturated zinc sulphate (RH 80 ... 85%).

For release into sodium phosphate buffer solution, 0.0868 g of spray-dried powder 31 was stirred in 10 ml of buffer solution for 1 min. The slurry was then filtered through a 0.2 µm filter. Upon HPLC analysis, it was concluded that XPDO was 33 effective being released in aqueous solution. The bioavailability of the steroid in the administration system was tested by immersion in an aqueous solution for a short time. The stability of steroid 35 in spray-dried formulation has been tested at high humidity and at 45 ° C (both factors are important if applying as an inhalant powder must be successful 37). The results indicated a high humidity resistance, glass stability and bioavailability in in vitro tests. No obvious degradation was observed by HPLC analysis 39 in spray-dried glass powder even after 4 weeks at 45 ° C and 85% RH.

d) incorporation of the active substances into HDC bottles by solvent evaporation; 41

Slow release of CSA

Cyclosporine (CSA, Sandimmun) is a hydrophobic cyclic peptide used as an immunosuppressive agent in particular in patients with organ transplants. CSA is administered orally and intravenously. It is dissolved in alcohol for administration. In clinical practice, blood levels 45 under treatment with this drug undergo severe fluctuations, due to unimportant absorption in the small intestine (jejunum). This problem could be avoided if the CSA is released at a constant speed for more than a few hours, in a form suitable for absorption. 49

RO 121407 Β1

The CSA was incorporated into a TOAC glass by dissolving both crystalline TOAC and CSA in DCM and evaporating the solvent at 70 ° C on a hot plate. The CSA was used in proportions of 5%, 10% and 20% compared to the total solids in the final TOAC glass. These bottles were perfectly clear as water and transparent. When stored at RH of 75%, 81%, 90% and 95% for 4 weeks, there was no change in the glass structure such as recrystallization. When immersed in water, these bottles behaved similarly to XPDO-containing bottles, for example, they slowly recrystallized as separate TOAC and CSA crystals.

e) Formation of solid dose administration agents / agents, for mixed HDC bottles by solvent evaporation in addition to TOAC, two other hydrophobic modified saccharides, a-GPAC and TOPR, were studied in mixtures to obtain mixed bottles. , with improved properties.

In vitro mixtures of pairs of HDC substances were produced by mixing the crystalline components in different proportions and then evaporating the DCM solvent on a hot or melting plate at 150 ° C and abruptly cooling on a brass plate.

The resulting bottles were tested for their usefulness as a two-way controlled release matrix. The first was the evaluation of the resistance to devitrification by exposure to high RH at RT. The second consisted of immersion in water or phosphate buffered saline (PBS) to study their solubility and erosion rate by surface recrystallization.

Bottles with a single component of both a- and β-GPAC could only be obtained by abrupt melting cooling. When the solvent was evaporated, the solutions with this HDC component crystallized. Glasses with a single component of TOAC and TOPR were easily produced either by solvent evaporation or by sudden cooling, but were highly susceptible to high RH devitrification, presenting complete recrystallization of thin glass films, under microscope and surface recrystallization. discs suddenly cooled to RH from 75% to 95% after overnight exposure. The blended bottles behaved as described in Table 6.

Table 6

% GPAC % T0AC % TOPR Initial form After RH 24 h 100 Glass Christ ⁺⁺⁺⁺ 10 90 Glass Glass 90 10 Glass Glass 50 50 Glass Glass 90 10 Christ ⁺⁺⁺⁺ ND 80 20 CRISFLOR Christ ⁺⁺⁺⁺ 90 10 Christ ⁺⁺⁺⁺ ND

The results showed that the effect of the different HRs was very uniform. While pure TOAC and some of the composite bottles crystallized at all RHs from 75% to 95%, the other composite bottles remained amorphous at all RHs studied.

The 10% α-GPAC and 10% TOPR bottles in TOAC and the 50:50 molar ratio TOAC: α-GPAC bottles were also immersed in water to examine their rate of devitrification in liquid water rather than in air. wet. The first glass recrystallized in 20 ... 30 min, while the second one developed some very small crystals after 4 h, while the 50:50 glass showed no changes after more than 4 days, surprisingly indicating low solubility.

Claims (22)

Claims 1 1. Particle composition for therapeutic use, suitable for administration by inhalation, characterized in that the particles consist of a solid solution 3 comprising a therapeutic agent and a carbohydrate which forms a vitreous state, superior to a monosaccharide and which is capable of stabilize the agent during drying by spraying and storing, provided that when the therapeutic agent is insulin, the solution does not contain citrate. 7 2. A composition according to claim 1, characterized in that the carbohydrate is selected from disaccharides, trisaccharides and oligosaccharides, corresponding sugars, polysaccharides and chemically modified carbohydrates. 3. A composition according to claim 1, characterized in that the carbohydrate is a non-reducing glycoside of a polyhydroxyl compound selected from sugar alcohols and other linear chain polyalcohols. 13 4. A composition according to claim 1, characterized in that the carbohydrate is trehalose, maltose, lactose, maltulose, isomaltulose, lactulose, raffinose, stachiosis, molasses-toza, dextran, maltitol, lactitol, a / fa-D-glucopyranosyl-1-. 6-sorbitol, α-α-D-glucopyranosyl-1-6 mannitol or palatines. 17 5. A composition according to claim 1, characterized in that the carbohydrate is trehalose. 19 Composition according to any one of the preceding claims, characterized in that the particles have a size from 0.1 to 10 pm.21 Composition according to claim 6, characterized in that the particles have a size from 1 to 4 pm.23 A composition according to any one of the preceding claims, characterized in that the therapeutic agent is a protein or peptide, nucleotide, oligonucleotide or nucleic acid. A composition according to any one of claims 1 to 7, characterized in that the therapeutic agent is an enzyme, growth hormone, growth factor, monoclonal antibody, interferon, interleukin or cytokine. A composition according to any one of claims 1 to 7, characterized in that the therapeutic agent is cyclosporine A, estrogen, progesterone, testosterone, estrra-31 diol, Sh-135 or tamoxifen. A composition according to claim 8, characterized in that the therapeutic agent 33 is insulin. A composition according to any one of the preceding claims, without the limiting condition, characterized in that the particles also comprise a pharmaceutically acceptable carboxylate, nitrate, sulfate or bisulfate glass. 37 Composition according to any one of the preceding claims, without the limiting condition, characterized in that the particles also comprise an inhibitor of the Maillard reaction. 39 Composition according to any one of the preceding claims, without the limiting condition, characterized in that the particles also comprise a buffer of the molecular water pump 41. Composition according to any one of claims 1 to 11, without the limiting condition, characterized in that the particles consist only of a therapeutic agent, a carbohydrate and, optionally, a Maillard reaction inhibitor or a molecular water pump buffer. 45 RO 121407 Β1 16. Particle composition for therapeutic use, suitable for inhalation administration, characterized in that the particles consist of a solid solution comprising a therapeutic agent and a carbohydrate which forms a vitreous state, superior to a monosaccharide, which is amorphous at temperatures. high. A composition according to claim 16, characterized in that the therapeutic agent is a protein. Device for pulmonary delivery of a therapeutic agent, characterized in that the device includes particles defined in any one of claims 1 to 17. The process for obtaining the particles defined in any one of claims 1 to 15, characterized in that it comprises the melting steps of the carbohydrate forming a vitreous state, the incorporation of the therapeutic agent therein, wherein the melting temperature is sufficient to fluidize the carbohydrate, but insufficient. to substantially inactivate the therapeutic agent, melt cooling and grinding the cooled product. Process for obtaining the particles defined in any one of claims 1 to 15, characterized in that it comprises the steps of dissolving or suspending the carbohydrate and the therapeutic agent in a solvent, and drying the resulting solution or suspension, to form the particles. 21. The process according to claim 20, characterized in that the drying comprises the spray drying. Process according to claim 20, characterized in that the drying comprises evaporation of the supercritical fluid.