RU2177785C2 - Solid delivery systems for controlled release of included molecules and method for their preparation - Google Patents

Abstract

FIELD: medicine, medicinal forms. SUBSTANCE: method deals with glass-like carriers and transported substance. Carrier is taken out of stabilizing polyole and hydrophobic carbohydrate derivative (HCD). Stabilizing polyole refers to disaccharide, trisaccharide, oligosaccharide and their corresponding saccharine spirits. HCD has got carbohydrate basic chain and, at least, one hydroxyl group substituted by hydrophobic fragment. Transported substance is a pharmaceutical agent or biological modifier. Shape of a solid dosed delivery system is chosen out of press cakes, tablets, disks, films, suppositories, needles, microneedles, particles, microparticles, spheres, microspheres, powders and implanted means. In preference, carrier represents trehalose and transported substance represents cyclosporin A. EFFECT: a glass-like delivery system provides stability of transported substance and its safety with no activity losses due to various delivery types and rates of transported substance. 39 cl, 20 dwg, 6 tbl, 10 ex

Description

 The present invention relates, in general, to solid delivery systems for storing, distributing and controlled release of molecules, and more particularly, to solid dosage delivery systems containing a glassy carrier and transportable substances. Also provided are methods for producing delivery systems and methods for using them.

 Solid delivery systems are useful in a wide range of applications, such as controlled release of labile molecules, in particular biologically active materials such as pharmaceutical agents, enzymes, vaccines, and biological control agents such as fertilizers, pesticides, and pheromones.

 The delivery of biologically active materials in the form of a solid dose to biological tissues, such as mucosal, dermal, ocular, subcutaneous, intradermal and pulmonary, provides several advantages compared to previously known methods, such as local application of fluids, transdermal administration through the so-called "patches" and hypodermic injection. A solid dose can be delivered using direct transdermal delivery of a solid dose, which reduces the risk of infection by eliminating the use of conventional needles and syringes, provides a more accurate dosage than multi-dose vials, and minimizes or eliminates the discomfort that often accompanies hypodermic injection. Several solid metering delivery systems have been developed, including those using transdermal and ballistic delivery agents.

 Local delivery is used for a variety of biologically active materials, such as antibiotics, for wound healing. These local lotions, gels, creams and so on should be applied repeatedly at short intervals to maintain their effectiveness. This is especially difficult in the case of burn wounds and ulcers.

 Medications used to administer transdermally drugs typically include laminate composites with a layer of a drug reservoir and a composite adhered to the skin, that is, a transdermal patch, such as described in US Pat. No. 4,906,463. However, many drugs are unsuitable for transdermal delivery and do not have transdermal rates drug release, for which the ability of such delivery is impeccable.

Subdermal implantable therapeutic systems are also formulated to slowly release certain pharmaceutical agents over an extended period of time, such as months or years. A well-known example is the Norplant ^® for delivery of steroid hormones.

 When a drug is delivered through a permeable membrane, the drug is encapsulated inside a reservoir, which is surrounded by a polymer membrane that limits the rate of release. A drug reservoir may contain either drug particles or a dispersion (or solution) of a solid drug in a liquid or in a dispersion medium such as a matrix. The polymer membrane may be made of a homogeneous or heterogeneous non-porous polymeric material or a microporous or semi-permeable membrane. Encapsulation of a drug reservoir within a polymer membrane can be achieved by pouring, encapsulating, microencapsulating, and other techniques. Implants release drugs by dissolving the drug in the inner core and slowly diffusing through the outer matrix. The drug release from this type of implantable therapeutic system should be relatively constant and highly dependent on the dissolution rate of the drug in the polymer membrane or the diffusion rate through the microporous or semipermeable membrane. The inner core can mainly dissolve after some time, however, the outer matrix does not dissolve in the currently used products.

 The implants are placed subcutaneously by incision of the skin and the forceful introduction of implants between the skin and muscle. At the end of their use, if they are not dissolved, these implants are removed surgically. US Pat. No. 4,244,949 describes an implant that has an inert plastic outer matrix, such as polytetrafluoroethylene. Examples of this type of implantable therapeutic system are the Progestasert IUD and the Ocusert system.

 Other implantable therapeutic systems include drug delivery controlled by diffusion in the matrix. A drug reservoir is formed by homogeneous dispersion of the drug particles in a lipophilic or hydrophilic polymer matrix. Dispersion of the drug particles in the polymer matrix can be achieved by mixing the drug with a viscous liquid polymer or semi-solid polymer at room temperature, followed by cross-linking of the polymer, or by mixing the drug particles with the molten polymer at an elevated temperature. It can also be obtained by dissolving the particles of the drug and / or polymer in an organic solvent, followed by mixing and evaporating the solvent in the form at elevated temperature or in vacuum. The rate of drug release from this type of delivery device is not constant. Examples of this type of implantable therapeutic system are the contraceptive vaginal ring and the Compudose implant. PCT / GB 90/00497 describes slow-release glass systems for the formation of implantable agents. The described implants are biologically adsorbable and do not require surgical removal. However, the introduction is carried out using surgical means. In addition, these devices are strictly limited with respect to the type of biologically active material that can be included, since they must be stable with respect to heat and / or solvent in order to enable inclusion in the delivery vehicle.

 When drug delivery is controlled by dissolving the micro reservoir, the drug reservoir, which is a suspension of drug particles in an aqueous solution of a water-miscible polymer, forms a homogeneous dispersion of a variety of discrete, non-leachable microscopic drug reservoirs in a polymer matrix. Microdispersion can be obtained by using highly efficient dispersion. The release of a drug from this type of drug delivery vehicle follows either the interfacial distribution or the controlled diffusion process in the matrix. An example of this type of drug delivery vehicle is Syncro-Mate-C Implant.

 In the case of molded polymer implants, biologically active materials that cannot withstand organic solvents are not suitable. In the case of systems based on extruded polymer, biologically active materials that cannot withstand the elevated temperatures necessary to form implants are unsuitable for use. In all cases, biologically active materials that are unstable at body temperature, especially for extended periods of time, are unsuitable for use.

 A large set of drugs is designed for administration in the form of aerosols on the mucous membranes, in particular "by inhalation" (nasopharyngeal and pulmonary). Compositions for pharmaceutical administration by inhalation typically include a liquid preparation of a pharmaceutical agent and means for delivering a liquid in the form of an aerosol. US patent 5011678 describes corresponding compositions containing a pharmaceutically active substance, a biocompatible amphiphilic steroid and biocompatible coal (hydrogen / fluorine) propellant. US patent 5006343 describes appropriate compositions containing liposomes, pharmaceutically active substances and a certain amount of alveolar surfactant protein, effectively enhancing the transport of liposomes through the pulmonary surface.

One of the drawbacks of using aerosol preparations is that the content of pharmaceutical agents in aqueous suspensions or solutions can lead to aggregation and loss of activity and bioavailability. Loss of activity can be partially prevented by freezing, however, this limits the use of these drugs. This applies in particular to peptides and hormones. For example, synthetic analogues of gonadotropin releasing hormones (GnRH), such as a nafarelin agonist or a ganirelex antagonist, are designed for potency, increased hydrophobicity, and membrane binding. The compounds are sufficiently hydrophobic in nature for aggregation in an aqueous solution and for the formation of an ordered structure, which increases the viscosity over time. Therefore, the bioavailability in nasal and pulmonary preparations can be very low. The use of powdered preparations overcomes many of these disadvantages. The required particle size in such powders is 0.5-5 microns to achieve deep alveolar deposition during pulmonary delivery. Unfortunately, powders with this particle size tend to adsorb water and stick together, thus reducing the deposition of the powder in the depths of the alveoli. Although powders with a large particle size are suitable for delivery to the nasopharyngeal region, the tendency of the powders to stick together reduces the available surface area of the particle for contact and adsorption through these membranes. Devices that destroy aggregates formed as a result of electrostatic interactions are currently used (for example, Turbohaler ^TM ); however, they do not destroy aggregates caused by moisture. It would be an advantage to have powders that do not absorb moisture and do not stick together, thus increasing the pulmonary concentration of the drug.

 Solid dosage delivery vehicles for ballistic transdermal administration have also been developed. For example, in US Pat. No. 3,948,263, a ballistic implant for animals, consisting of an outer polymer shell surrounding a biologically active material, is described for veterinary use. Similarly, US Pat. No. 4,326,524 describes a “ballistic bullet” for a solid dosage comprising a biologically active material and an inert binder without an outer shell. Delivery is carried out using compressed gas or by explosion. Gelatin-coated implant tranquilizers that carry ballistic bullets are also described in US Pat.

 Ballistic delivery at the cellular level has also been successfully resolved. A general principle of ballistic introduction is the use of the wavefront of a supersonic wave generated by the release of compressed gas to disperse particles contained in an attached chamber. For example, nucleic acids adsorbed on tungsten particles - "micropuli" were successfully delivered to living epidermal cells of plants. See Klein (1987) Nature 327: 70-73. The best monitoring device is a particle delivery gun (PIG). Vain et al. (1993) Plant Cell. Tissue and Organ Culture 33: 237-246.

 Describes devices that shoot ampoules containing drugs using gas pressure. U.S. Patent 4,790,824; and PCT / GB 94/00753. Also described are several devices that inject liquids, US Pat. Nos. 5,312,335 and 4,680,027. There are several existing formulations suitable for ballistic delivery. However, powdered preparations or medicines in their existing form are unsuitable for ballistic administration. Particles of available powder forms are usually irregular, with a spread in size, shape and density. This lack of uniformity leads to deposition and loss of powder on the surface of the skin during administration, as well as to problems with the control and spread of the depth of delivery into the subcutaneous and intradermal tissues.

 Thus, for ballistic delivery, it would be advantageous to create solid drug delivery systems with a given size, shape, density and dissolution rate to provide a more uniform distribution. Additional benefits would be achieved if the carrier form were controllable to facilitate or control penetration through the epidermis and hard layers of the skin. The small size of the delivery system, preferably associated with a high momentum of delivery, would also increase the comfort of administration and reduce (minimize) tissue damage. The production of such a solid dosage delivery system should be such that both the delivery vehicle and the transported substance are not damaged during delivery or their effectiveness is not reduced. In addition, the transported substance must remain stable when it is loaded with or without a carrier, so that administration efficiency can be achieved and storage of the loaded delivery system is facilitated. The production of a solid carrier for metered-dose delivery, its loading with the contained material to obtain a solid metered-dose delivery system, and the introduction of the system should also be relatively simple and economical.

 All references cited herein are hereby incorporated by reference.

 The present invention includes solid glassy delivery vehicles suitable for loading with a wide variety of substances or “transportable substances” to form solid delivery systems. The choice of glassy carriers for delivery is determined by the nature of the charged substances and the desired delivery rate of the charged substance. A wide variety of types and delivery speeds are provided. Preferred tolerable substances, buffers, excipients and additional stabilizers are also provided. Delivery systems may have sizes and shapes corresponding to a variety of administration methods.

 The invention relates to instant soluble metered dose delivery systems containing a stabilizing polyol (SP) and a portable substance. These delivery systems can be prepared in the form of powders with a homogeneous particle size or more in implantable forms.

 The invention further relates to new glassy carriers formed from hydrophobic derivatives of carbohydrates (GPU). These hcp are non-toxic, and the release of portable substances from these systems is highly controlled with respect to the release of portable substances over extended periods of time. Release from GPU-based delivery systems may be affected by devitrification, dissolution, and / or hydrolysis. GPU-based delivery systems are uniquely adapted for the delivery of hydrophobic transportable substances, such as pesticides, pheromones, steroid hormones, peptides, peptide mimetics, antibiotics and other organic medicines, such as synthetic corticosteroids, bronchodilators, and immunomodulators and immunosuppressants like cyclosporin A ( CSA).

 The invention further relates to co-preparations of various glassy carriers for creating new combined delivery systems. Combined delivery systems include GPUs combined with SP and / or other glassy materials that are slowly soluble in water, such as carboxylate, nitrate, and phosphate glasses, to produce solid metered delivery systems with a wide range of new properties.

 The invention relates to solid metered delivery systems for multiphase delivery, including the outer part containing hcp, slowly dissolving in an aqueous solution having a hollow compartment inside, and the inner part located in the compartment, the inner part includes at least one SP and a therapeutically effective amount of at least one transported substance.

 The invention also relates to methods for delivering biologically active materials to create the solid dosage delivery systems described above and introducing the system into biological tissue. Administration may be mucosal, oral, local, subcutaneous, intradermal, intramuscular, intravenous, or by inhalation.

 The invention further relates to methods for producing solid dosage delivery systems. SP and / or GPU, transported substances and any other components are mixed and processed using a wide range of methods, including melt dissolution and subsequent quenching, spray drying, freeze drying, air drying, vacuum drying, fluidized bed drying, coprecipitation and evaporation supercritical fluid. The resulting glass can be heated to soften and can then be extruded, pressed or stretched into solid or hollow fibers. The dried components can 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 supercritical evaporation.

 The present invention further relates to methods for producing delivery systems suitable for the slow release of transportable substances or their release at a variable rate. The methods include combining the transported substances in solid solutions of stabilizing glass-forming polyols and / or hcp and / or other glass-forming substances with dissolution or decomposition rates lower than those of the joint venture, and treating the components as described above. The ratio of materials can be controlled to provide a wide range of values for precisely defined release rates. Co-preparations of SP and / or GPU and other water-soluble and / or biodegradable glasses, plastics, and glass modifiers thus obtained also relate to the present invention.

 Solid dosage systems and methods according to the invention also relate to solid dosage forms, which include fibers, spheres, tablets, discs, particles and needles with a relatively homogeneous size distribution. Carriers can be either microscopic or macroscopic.

 A wide variety of transportable substances are suitable for use in accordance with the present invention, including, but not limited to, diagnostic, therapeutic, prophylactic and other active agents. Delivery systems and methods of their use are provided for a variety of dosage regimens for the delivery of transportable substances and are suitable for a wide range of uses, including agronomic, veterinary and medical applications.

Brief Description of the Figures
Figure 1 is a graph representing a typical particle size distribution of micron powder trehalose glass, suitable for administration by inhalation. Figure 1 is described in example 2.

 Figure 2A is a graph representing a narrow particle size distribution for trehalose glass powder / buffer salt - molecular water pump (MVN).

 Figure 2B is a graph representing the adsorption of water of various powders of glass trehalose, MVN and trehalose, chloride after storage at ambient temperature and various relative humidity.

 Figure 2B represents 51% relative humidity and MVN (■), 80% relative humidity and MVN (I), 51% relative humidity and chloride (□), and 80% relative humidity and chloride (X). Figure 2 is described in example 2.

 Figure 3 is a graph representing a narrow particle size distribution for trehalose glass powder obtained by spray drying in a Lab-Plant-spray spray dryer. Figure 3 is described in example 2.

 Figure 4 is a graph representing a comparison of the particle size distribution form for trehalose glass powders (0.5 M trehalose / 0.5 M calcium lactate) obtained on two different spray dryers (Lab-Plant (□), and Buchi (vertical black -white arrow pointing up), as shown). Figure 4 is described in example 2.

 Figure 5A is a graph representing the stability of horseradish peroxidase with respect to acetone by drying the trehalose enzyme. Average values are presented for situations: without solvent plus trehalose (°), without solvent minus trehalose (•), acetone plus trehalose (square open from the bottom) and acetone minus trehalose (square open from the top).

 Figure 5B is a graph representing the stability of alkaline phosphatase with respect to acetone, carried out by drying an enzyme with trehalose. In Figure 5B, light circles represent exposure without solvent plus trehalose, dark circles represent exposure without solvent minus trehalose, squares (open from below) represent average acetone plus trehalose, and squares (open from above) represent average acetone minus trehalose. Figure 5 is described in example 3.

 Figure 6 is a graph representing the release of MB9 from selected films of metal-carboxylate glass. The squares represent the film of aluminum hexanoate (100-200 microns), where the release is preceded by dissolution of the film. The circles represent a film of calcium neodecanoate (1-2 mm), where the release follows the dissolution of the film. Figure 6 is described in example 7.

 Figure 7 is a graph representing the release rate of the encapsulated dye Acid Blue 129 from the α-D-glucose-acetate-glass disc of α-HPAC). Figure 7 is discussed in example 8.

 Figure 8 is a graph representing the release of MB9 from a disk of trehalose octa acetate glass (TOAC) (6 mm x 2.5 mm) in a PBS solution. Figure 8 is discussed in Example 9.

и чистый РУДА, 4% весовых красителя (вертикальная черно-белая стрелка, направленная вниз). Фигура 9 описывается в примере 9.Figure 9 is a graph representing the release of MB9 from TOAC / ORE (treagalose octaacetate / raffinose sulphate acetate) matrices into deionized water. The various concentrations presented are: 95% TOAC, 0.61% weight dye (□); 75% TOAC, 1.17 weight dye (°); 50% TOAC, 2.09% by weight of the dye (vertical black and white arrow pointing up); pure TOAC, 1.39% by weight of the dye

and pure ORE, 4% by weight of dye (vertical black and white arrow pointing down). Figure 9 is described in example 9.

 Figure 10 is a graph representing the change in Tg as a function of the molar percentage of TOAC in the co-preparations of two hcp. The squares represent trehalose octaacetate / sorbitol hexaacetate (TOAC / GHAC) glass. The circles represent TOAC / ORE glass. The triangles represent trehalose octaacetate / α-glucosapentaacetate (TOAC / α-HPAC) glass. Figure 10 is described in example 9.

 Figure 11 is a graph representing the average percent release of MB9 in PBS from selected TOAC / ORE glass spheres (n = 4). The squares represent 10% ORE. The circles represent 50% ORE. Triangles represent pure ORE. Figure 11 is described in example 9.

 Figure 12 is a graph representing the release of MP9 (1% by weight) from TOAC co-preparations plus 25% SOAC (■) and 25% COAC (•) (n = 5). Figure 12 is described in example 9.

 Figure 13 is a graph representing the release of MB9 (1% by weight) from TOAC / α-GPAC in the following ratios: 90: 10 (■), 75: 25 (•), 50:50 (vertical black and white arrow pointing up ) and 25: 75 (vertical black and white arrow pointing down) (n = 4). Figure 13 is described in example 9.

 Figure 14 is a graph representing the release of MB9 from TOAC (■) and TOAC / TOPR (25% by weight) (•) (n = 5). Figure 14 is described in example 9.

 Figure 15 is a graph representing the release of MB9 (1% by weight) from pure TOAC (■) and TOAC plus XPDO (5%) (•) (n = 5). Figure 15 is described in example 9.

 Figure 16 is a micrograph of a thin film of a co-preparation of glass containing 10% trehalose in TOAC dried from dimethylformamide (DMF). Figure 16 is described in example 10.

 Figure 17 is a micrograph of the co-preparation of Figure 16 at a higher magnification. Figure 17 is described in example 10.

 Figure 18 is a photomicrograph of a co-preparation of glass containing 10 trehaloses in TOAC, with Methyl Green and Oil Red O, drained from DMF. Figure 18 is described in example 10.

 The present invention includes metered solid delivery systems comprising solid dose delivery vehicles and carriers. Delivery systems are prepared to provide precisely defined delivery rates for the transported substances included therein. Delivery systems are particularly suitable for delivering biologically active molecules to animals, including humans.

 The invention also includes methods for the delivery of therapeutic agents, including but not limited to, mucosal, oral, external, subcutaneous and intradermal, intramuscular, intravenous and inhalation.

 The invention also indicates methods for producing delivery systems.

 A “solid dose” as used herein means that the transportable substance included in the carrier is more in liquid form and the solid form is the form used for delivery. Transferred substances are such molecules, macromolecules and a combination of macromolecules, synthetic and natural, and cell fractions, living and dead cells, bacteria and viruses and other active substances included in the carrier; A wide variety of transportable substances are suitable for use in them and are described below. By "effective amount" of a transported substance is meant the amount necessary to provide the desired effect. For example, in a biologically active material, an effective amount is one that elicits the desired physiological response. The carrier is in solid form and is amorphous or glassy in nature. Other additives, buffers, dyes and the like can be included in the delivery system. As used here, the term "carrier" includes all glass-forming substances embodied in the claimed invention. The term "delivery system (s)" includes solid dosage forms containing carriers and carriers. Delivery systems formed from specific carriers, as indicated, are given various names, unless otherwise indicated, the term delivery system defines each of them.

 In one embodiment, the invention relates to solid dose systems with high release rates of transported substances. In this embodiment, the carrier is SP. It has now been found that SPs can be processed to produce powders with a homogeneous particle size distribution in the form of either microspheres or needles. SP can also be processed to obtain macroscopic forms of delivery, suitable for the preparation of implantable funds. A wide variety of dosage forms and methods for preparing dosage forms are described herein. As found, these SPs are, in particular, suitable for use where, in the opposite case, denaturing conditions would make it impossible to prepare solid dosage forms of biologically active materials. In particular, such conditions include elevated temperatures (those above which the biologically active material would otherwise be denatured) and the presence of organic solvents.

 In another embodiment, the invention relates to solid dosage systems with newly defined and controlled release rates of the transported substances. In this embodiment, the carrier is an organic carboxylate glass. As currently discovered, organic carboxylates form stable amorphous carriers by evaporation of the solvent. These organic glasses release the incorporated transported substances at precisely determined speeds, depending on the composition of the carboxylate anion and the metal cation used. Like carriers containing SP, these glasses can be processed either by themselves or with other organic carboxylates and / or SP and / or GPU to obtain powders with a homogeneous particle size distribution in the form of microspheres, needles and / or implantable means obtaining a wide variety of macroscopic forms of delivery.

 In a further embodiment, the invention relates to solid dosage systems with newly defined and controlled release rates of the transported substances. In this embodiment, the carrier is a hydrophobic derivative of a carbohydrate (HCP). As currently discovered, hcp form stable glassy carriers that release transportable substances under aqueous conditions at precisely defined release rates depending on the carbohydrate, hydrophobic moiety (hydrophobic moieties) used to produce carbohydrate derivatives, and degree of branching. Like carriers containing SP, carriers containing hcp can be processed to obtain powders with a homogeneous particle size distribution in the form of either microspheres or needles. GPUs can also be processed to produce a wide variety of microscopic delivery forms.

 Dosage forms and methods for preparing dosage forms are described herein. These delivery systems have been found to be particularly useful where the nature of the transported substance would make it impossible to prepare solid dosage forms, since they provide delivery systems for hydrophobic transportable substances that are difficult either to prepare in dosage form or to produce effective physiological concentrations due to insolubility in aqueous solvents.

 Delivery systems exist in the form of solid solutions, emulsions, suspensions or coacervates of a transportable substance in a solid carrier. The transferred substance is stable at higher temperatures inside the carrier than in itself. The specific temperature stability depends on the medium used. Thus, the components of the delivery systems can be maintained in the form of melts for short periods without damaging the transported substances during processing. Delivery systems can be further processed in the same way and they are resistant to destruction during co-melting with nitrate and / or carboxylate and / or hcp and / or other glass-forming substances.

 The invention further defines co-preparations of various delivery vehicles and delivery systems to create a wide variety of combined delivery vehicles.

 The present invention defines compositions and methods for preparing compositions. Although single forms may be used, more than one carrier, more than one transportable substance, and more than one additive may be provided. Determination of effective amounts of these compounds is the result of the experience of specialists in this field.

Polyol Stabilized Delivery Systems
The invention includes solid dosage delivery systems in which the delivery vehicle contains a stabilizing polyol. They are defined as "joint venture delivery systems." As currently found, SP delivery systems can be processed to obtain a wide variety of solid dosage forms suitable for use, in particular for the therapeutic administration of transportable substances.

 JVs include, but are not limited to, hydrocarbons. As used herein, the term “carbohydrates” includes, but is not limited to, monosaccharides, disaccharides, trisaccharides, oligosaccharides and the corresponding alcohols of these sugars, polysaccharides and chemically modified carbohydrates such as hydroxyethyl starch and sugar copolymers (Ficoll). Both natural and synthetic hydrocarbons are suitable for use here. Synthetic carbohydrates include, but are not limited to, those carbohydrates that have a glycosidic bond substituted with a thiol or carbon bond. Both D and L carbohydrate forms can be used. Carbohydrates can be non-reducing or reducing. Suitable carriers are those in which the carrier can be dried and stored without significant loss of activity due to denaturation, aggregation or other mechanisms. Prevention of loss of activity can be enhanced by the addition of various additives, such as Mallar reaction inhibitors, as described below. The addition of these inhibitors is particularly preferred in combination with reducing carbohydrates.

 Reducing carbohydrates suitable for use in the present invention are carbohydrates known 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, stachyose, sucrose and dextran. Other beneficial carbohydrates include non-reducing glycosides of polyhydroxy compounds selected from sugar alcohols and other straight chain polyalcohols. Sugar alcohol glycosides are preferably monoglycosides, in particular compounds obtained by reducing disaccharides such as lactose, maltose, lactulose and maltulose. The glycoside group is preferably a glucoside or galactoside, and the sugar alcohol is preferably sorbitol (glucitol). Particularly preferred carbohydrates are maltitol (4-O-β-D-glucopyranosyl-D-glucitol), lactitol (4-O-β-D-galactopyranosyl-D-glucitol), palatinite (a mixture of GPS, α-D-glucopyranosyl-1 -> 6-sorbitol and GPM, α-D-glucopyranosyl-1 -> 6-mannitol) and its specific sugar alcohols, GPS and GPM components.

 Preferably, SP is a carbohydrate that exists as a hydrate, including trehalose, lactitol and palatinite. Most preferably, SP is trehalose. It has now surprisingly been found that solid dosage delivery systems containing certain sugar hydrates, like trehalose, lack the “stickiness” or “attachment” of solid dosage forms containing other carbohydrates. Thus, for production, packaging and administration, trehalose is the preferred joint venture.

 Trehalose, (α-D-glucopyranosyl-α-D-glucopyranoside), is a non-reducing disaccharide of natural origin, which was originally found to be associated with the prevention of damage in the absence of moisture in certain plants and animals that can dry without damage and can come to life, when water is attached. Trehalose has been shown to be useful in preventing the denaturation of proteins, viruses, and food when dried. See patents 4891319; 5,149,653; 5,026,566; Blakeley et al. (1990) lancet 336: 854-855; Roser (July 1991) Trends in Food Sci. and Tech. 166-169; Colaco et al. (1992) Biotechnol. Internant, 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 suitable SPs for use herein are described, for example, in WO 91/18091, 87/00196 and US Pat. The solid dosage forms defined by the present invention, as currently discovered, are suitable for direct use as delivery systems for the controlled release of included transportable substances. In addition, these polyols can be used in combination with other amorphous matrices to produce delivery systems that are currently found to have a wide range of release rates and characteristics that are easily and accurately controlled to produce unique solid dosage systems.

 It has now also been discovered that transportable substances, preferably soluble in organic solvents, can be dried in trehalose from a mixture of organic / aqueous solvents to produce co-preparations which are now readily reduced in aqueous solvents. The present invention defines solid dosage systems obtained in this way. The present invention provides methods for producing dried material and compositions obtained therefrom. The transferred substance is dissolved in an organic, aqueous solvent in combination with an effective amount of trehalose, and then dried. This gives a solid solution, emulsion, suspension or coacervate of the transferred substance in trehalose glass, which then readily dissolves in an aqueous solution, giving a finely divided suspension of an insoluble transferred substance. It has now been shown that the CSA immunosuppressant (which is poorly soluble in water and is usually introduced as an oil emulsion) in a solution of trehalose in a mixture of ethanol: water 1: 1 can be dried to obtain a clear glass of trehalose containing CSA. This glass can be ground to obtain a free-flowing powder, which can also be tabletted, which, when added to water, dissolves directly, giving a finely dispersed suspension of CSA in water.

GPU Delivery Systems
The invention further defines solid dose delivery systems in which the carrier contains at least one GPU. They are defined as "GPU delivery systems." GPUs form a separate group of non-toxic derivatives of hydrocarbons suitable for use in the formation of a solid dose carrier. Although many hcp were synthesized, the benefits of light glass formation were not previously reported. Thus, the invention defines the glassy form of these hcp, which are also referred to as an amorphous matrix-forming composition. GPU delivery systems are particularly suitable for use in the controlled, variable or sustained release of transported substances. Any of the portable substances described here can be included in the GPU delivery system.

 As shown here, hcp easily form glass either from quenched melt or from an evaporated organic solvent. GPU can also be processed using the methods described for SP.

В формуле 1 R представляет гидроксильную группу или ее низшее гидрофильное производное, такое как простой или сложный эфир, или любые их функциональные модификации, где хотя бы один R является не гидроксилом, а гидрофобным производным. Соответствующие функциональные модификации включают, но не ограничиваются ими, такие, где атом кислорода замещен гетероатомом, таким как N или S. Степень замещения также может варьироваться и может представлять собой смесь различных производных. Полное замещение гидроксильных групп не является необходимым и предоставляет возможность изменения физических свойств (таких как растворимость) носителя. R может иметь любую длину цепи, начиная с С₂, и может быть линейным, разветвленным, циклическим или модифицированным. Хотя формула 1 изображает дисахаридтрегалозу, любой из углеводов, обсуждаемых здесь, может быть углеводной основной цепью, а положение гликозидной связи и длина цепи сахарида могут быть различными. Обычно практическим диапазоном в терминах стоимости и эффективности синтеза является пентасахарид; однако изобретение не ограничивается сахаридами конкретного типа с конкретной гликозидной связью или длиной цепи. Различные другие аспекты ГПУ не являются ограничивающими. Например, компоненты сахаридов в каждом ГПУ также могут варьироваться, положение и природа гликозидной связи между сахаридами могут быть изменены, и тип замещения может варьироваться внутри ГПУ. Представительным примером ГПУ со смешанным замещением простыми и сложными эфирами является 1-о-октил-β-D-глюкопиранозид 2,3,4,5-тетраацетат:
формула 2

где R представляет собой О₂ССН₃.As used herein, the term “GPU” refers to a wide variety of hydrophobic derivatives of carbohydrates, where at least one hydroxyl group is replaced by a hydrophobic moiety, including, but not limited to, ethers and esters. Numerous examples of the corresponding GPUs and their syntheses are described in Developments in Food Carbohydrate 2 ed. 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. (1993) Tetra. Letts 34: 7767; Khan (1984) Pure & Appl. Chem. 56: 833-844; and Khan et al. (1990) Carb. Res. 198: 275-283. Specific examples of GPUs include, but are not limited to, sorbitol hexaacetate (GHAC), α-glucose pentaacetate (α-HPAC), β-glucose pentaacetate (β-HPAC), 1-O-octyl-β-D-glucose tetraacetate (OHTA), trehalose octaacetate (TOAC), trehalose octapropanoate (TOC), sucrose octa acetate (SOAC), cellobioose octaacetate (RAC), raffinose acetate, sucrose octapropanoate, cellobose-octa-acetoacetate diacetone diacetone diacetone diacetone diacetone diacetone diacetone diacetate An example of an appropriate GPU, where trehalose is a hydrocarbon, is:
Formula 1

In formula 1, R represents a hydroxyl group or its lower hydrophilic derivative, such as an ether or ester, or any functional modifications thereof, where at least one R is not a hydroxyl, but a hydrophobic derivative. Appropriate functional modifications include, but are not limited to, those where the oxygen atom is substituted with a heteroatom, such as N or S. The degree of substitution may also vary and may be a mixture of different derivatives. Complete substitution of hydroxyl groups is not necessary and provides the ability to change the physical properties (such as solubility) of the carrier. R may have any chain length starting from C ₂ , and may be linear, branched, cyclic, or modified. Although Formula 1 depicts disaccharide trihalose, any of the carbohydrates discussed herein may be a carbohydrate backbone, and the position of the glycosidic bond and the chain length of the saccharide may be different. Typically, the pentasaccharide is a practical range in terms of cost and synthesis efficiency; however, the invention is not limited to a particular type of saccharide with a specific glycosidic bond or chain length. Various other aspects of the GPU are not limiting. For example, the saccharide components in each GPU can also vary, the position and nature of the glycosidic linkage between the saccharides can be changed, and the type of substitution can vary within the GPU. A representative example of hcp with mixed substitution of ethers and esters is 1-o-octyl-β-D-glucopyranoside 2,3,4,5-tetraacetate:
formula 2

where R represents O ₂ CCH ₃ .

 The ability to modify the properties of hcp by small changes in the composition makes them unique as carriers of solid doses, especially in comparison with polymer systems, which often depending on the regions of crystallinity change their properties, in particular biological erosion. GPU delivery systems can be designed to have certain (clear) properties, such as release rates of transported substances. Such design can occur by varying the modifications of a particular carbohydrate or by combining a set of different GPUs.

 Pure glasses based on a single hcp have been found to be stable at ambient temperatures and at a humidity of at least 60%. Mixtures of hcp glasses, including certain transportable substances, are, however, unexpectedly stable at ambient temperatures and at humidity up to 95%. Remarkably, the inclusion of even 10% (w / v) of exclusively hygroscopic transported substances, such as synthetic corticosteroid 6α, 9α-difluoro-11β, 21-dihydroxy-16α, 17α-propyl methylene dioxo-4-pregnen-3,20-dione (XPDO), gives hcp glasses that are stable when exposed to relative humidity up to 95% at room temperature for more than one month, while still releasing the transported substances for 5-10 minutes when added to liquid water. An identical effect on the stability of hcp glass was found in TOAC glasses containing 10% (w / v) CSA, included as a transportable substance.

 We have also found at present that the addition of other hcp at the same levels also produces mixed hcp glasses that are equally resistant to devitrification at 95% relative humidity. Thus, TOAC glasses containing 10% (weight / volume) of either HPAA or TOPR demonstrate complete resistance to devitrification at 95% relative humidity. Interestingly, these composite glasses behave differently in liquid water, GPAC / TOAC glass devitrifies from the surface much faster than TOPR / TOAC glass. See figures 13, 14. This ability to set the dissolution rates of composite hcp glasses makes them particularly useful as controlled release delivery vehicles.

 Hcp glass can be formed either by evaporation of the solvent or by quenching the hcp melt. Due to the low softening temperatures of certain hcp glasses, thermally labile transportable substances such as drugs and biological molecules can be incorporated into the hcp melt during processing of the delivery system without decomposition. Surprisingly, these transportable substances exhibit zero order release kinetics when compositions forming an amorphous matrix undergo erosion in an aqueous solution. Release follows the process of devitrification of the surface. GPU delivery systems can be easily modeled into any form, such as those described herein. Such modeling can be carried out by extrusion, casting, and so on, using any method known in the art. GPU delivery vehicles are non-toxic and inert with respect to any substances that may be included in them.

 These GPU delivery systems, when prepared in the form of matrices and / or coatings, undergo heterogeneous surface erosion when they are placed in an aqueous environment. Although not tied to any theory, one of the possible mechanisms of their decomposition begins with the initial devitrification of the surface, since super saturation occurs at the interface with subsequent erosion and / or dissolution of the surface layers at a lower rate. The matrices can be modified by carefully selecting the components to obtain the desired devitrification rates and, therefore, the required release rates of the transported substance, since the devitrified matrix does not provide any barrier to the release of the transported substance.

 GPU melts are excellent solvents for many organic molecules. This makes them especially suitable for use in the delivery of biologically active materials that are otherwise difficult to incorporate into the preparation. More than 20% by weight of organic molecules can be included in the GPU delivery system. It is remarkable that the hcp are inert and do not show any reactive activity with respect to the dissolved molecules or transported substances included in them. As described in more detail below, hcp are suitable for forming a fine suspension of a delivery system SP to obtain complex composite delivery systems.

Multicomponent hcp are synthesized with high purity using established principles of chemical or enzymatic synthesis. GPU and transported substances can be thoroughly mixed together in appropriate molar ratios and melted to transparency. Suitable melting conditions include, but are not limited to, melting in open glass flasks at a temperature between 100 and 150 ^{° C.} for 1-2 minutes. This results in a liquid melt, which can be allowed to cool slightly first, dissolving the transported substance in the melt, if necessary, before quenching to glass, for example by pouring onto a bronze plate or into a metal mold for molded delivery vehicles. In another way, the melt temperature can be carefully controlled, and the transported substances can either be included in the GPU preparation before melting, or mixed in the cooling GPU melt before quenching.

 GPU melts are thermally stable and make it possible to incorporate organic molecules without denaturing or suspending the basic particles, without changing their physical nature. Glass melts can also be used to coat micron-sized particles; this is especially important in the preparation of non-hygroscopic powders containing hygroscopic agents for administration by inhalation of therapeutic agents.

 Alternatively, glassy delivery vehicles can be formed by evaporation of the hcp and the transportable substance, which must be included in the solution in a solvent or in a mixture of solvents. Multicomponent hcp are readily soluble in many organic solvents. Suitable solvents include, but are not limited to, dichloromethane, chloroform, dimethyl sulfoxide (DMSO), dimethylformamide (DMF) and higher alcohols. The nature of the solvent is not important, since it is completely removed during the formation of the delivery system. Preferably, both the component of the hcp and the transportable substance are soluble in the solvent. However, the solvent may dissolve the hcp and allow the suspension of the transferred substance. When the solvent is concentrated, using more suitable hcp, crystallization is not carried out. Instead, an amorphous solid product is formed which is similar in properties to extinguished glass. Again, the transported substances can be easily incorporated either from solution or in the form of a suspension of particles.

The glass transition temperatures of the hcp (Tg) are low, usually lower than 70 ^{° C.} , and, unexpectedly, are not predictable by melting points. Typically, the tendency to crystallize from a cooling melt or with a reducing solvent is low. Both devitrification and melt flow at temperatures close to Tg can be controlled using modifiers such as other sugar derivatives and certain organic active agents. Tables 1 and 2, obtained as described in the examples below, contain data on Tg and melting point for a number of hcp, suitable for use either individually or in composite glass.

 The invention further defines delivery vehicles containing combinations of various hcp, which, as currently found, enable the creation of new delivery vehicles with well-controlled Tg and other physicochemical properties, such as viscosity and resistance to water decomposition.

Combined Delivery Systems
The invention also provides solid dose delivery systems containing GPU and SP, and / or other stacking agents in co-preparations and other combinations. They are defined as “integrated delivery systems”.

 At least two combined delivery systems are obtained by the joint preparation of GPU and SP carriers to obtain delivery systems. In one case, the microspheres of the SP delivery system are suspended in the GPU delivery system. In the second case, the GPU microspheres of the delivery system are suspended in the delivery system. These combined delivery systems enable the release of at least two different transportable substances, one hydrophobic and one hydrophilic, with at least two different release rates.

 Other combined delivery systems form by coating one delivery system with another. For example, an SP delivery system in implantable form could be coated with a layer of GPU or GPU delivery system to provide delayed release of the transported substance in the SP delivery system or sequential release of various transportable substances. It is easy to imagine the variety of such forms. The number of coatings is theoretically unlimited and can be determined by a person skilled in the art.

 Combined delivery systems can also be formed by extruding a hollow cylindrical carrier having a clearance from a carrier or delivery system (SP, GPU or combination) and filling the gap with another delivery system. These compositions are particularly suitable for forming injection or implantation agents.

Other components in delivery systems
Other glass
As discussed below, delivery systems may further comprise at least one physiologically acceptable glass. Suitable glasses include, but are not limited to, carboxylate, phosphate, nitrate, sulfate, bisulfate, hcp, and combinations thereof. Carboxylates were previously used where glasses that slowly dissolve in water were required, as many of them dissolve poorly in water. Such suitable glasses include, but are not limited to, those described in PCT / GB 90/00497. However, the formation of these carboxylate glasses was previously carried out only by quenching the melt. The elevated temperature required for the melting of carboxylates severely limits the carboxylates that can be used to form glassy delivery vehicles, especially in the case of biologically active materials that tend to be thermolabile. The authors have unexpectedly discovered at the present time that carboxylate glasses can be easily formed by evaporation of a solvent containing a glass-forming metal carboxylate and a transportable substance to be included. The invention thus defines methods for preparing carriers and solid dose systems, including dissolving the carboxylate component in a suitable solvent and evaporating the solvent to produce glassy glass. Mixtures of carboxylates can be used as "packaging" mixtures of other glass-forming components to obtain new delivery systems, which are determined using the present invention.

 Delivery systems can also be coated with one or more layers of physiologically acceptable glass having a given dissolution rate. This is especially effective for releasing variable rate transported substances. Further, the composition may include other water-soluble and biodegradable glass-forming substances. Suitable glass-forming substances include, but are not limited to, lactide polymers and lactide / glycolide copolymers, glucuronide polymers and other polyesters, polyorthoesters and polyanhydrides.

Transported substances
Examples of types of transportable substances that can be used in the carrier and in the methods of the present invention include industrial chemicals such as colorants and flavors, and medical or agricultural biologically active materials suitable for in vivo and in vitro use. Suitable biologically active materials include, but are not limited to, pharmaceutical agents, therapeutic and prophylactic agents, and agrochemicals such as pesticides and pheromones.

 Suitable pharmaceutical agents include, but are not limited to, anti-inflammatory drugs, analgesics, anti-arthritis drugs, antispasmodics, antidepressants, antipsychotics, tranquilizers, anxiety drugs, drug antagonists, drugs against Parkinson’s disease, cholinergic agonists, chemotherapeutic drugs, immunosuppressive drugs agents, antibiotic agents, appetite suppressants, antiemetic drugs, anticholinergics, antihistamines agents, antimigraine agents, coronary, cerebral or peripheral vasodilators, hormonal agents, contraceptives, antithrombotic agents, diuretics, antihypertensive agents, vaso-cardiac drugs, opioids, and the like.

 Suitable therapeutic and prophylactic agents include, but are not limited to, any therapeutically effective biological modifier. Such modifiers include, but are not limited to, subcellular compositions, cells, bacteria, viruses and molecules, including, but not limited to, lipids, organics, proteins and peptides (synthetic and natural), peptide mimetics, hormones (peptide, steroid and corticosteroids), D and L polymers of amino acids, oligosaccharides, polysaccharides, nucleotides, oligonucleotides and nucleic acids, including DNA and RNA, protein-nucleic acid hybrids, small molecules and their physiologically active analogues. Further, modifiers can be obtained from natural sources or produced using recombinant or synthetic means and include analogs of agonists and homologs.

 As used herein, the term “protein” also refers to peptides and polypeptides. Such proteins include, but are not limited to, enzymes, biopharmaceuticals, growth hormones, growth factors, insulin, monoclonal antibodies, interferons, interleukins and cytokines.

 Organics include, but are not limited to, pharmaceutically active chemicals. For example, the presented organic includes, but is not limited to, vitamins, neurotransmitters, antimicrobials, antihistamines, analgesics, and immunosuppressants.

 Suitable steroid hormones include, but are not limited to, corticosteroids, estrogen, progesterone, testosterone and their physiologically active analogues. Numerous steroid hormone analogs 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 their analogs, are especially suitable for use in the present invention, since they are not adsorbed transdermally and, with the exception of a few analogs, are destroyed by oral administration by the so-called mechanism of the first passage through the liver.

 As used herein, the term “nucleic acids” includes any therapeutically effective nucleic acids known in the art, including but not limited to DNA, RNA, and physiologically active analogs thereof. Nucleotides can encode single genes or can be any recombinant DNA vector known in the art, including but not limited to plasmids, retroviruses, and adeno-associated viruses. Preferably, the nucleotides are administered in powder form in a solid dosage system.

 Compositions comprising a solid dosage delivery system containing prophylactic biologically active materials and their carriers are further determined by the present invention. Preferred compositions include immunogens, such as for use in vaccines. Preferably, the compositions comprise an immunogenic amount of an immunogen effective either for immunization or for stimulating inoculation.

 Suitable immunogens include, but are not limited to, live and attenuated viruses, nucleotide vectors encoding antigens, bacteria, antigens, antigens plus excipients and haptens associated with carriers. Particularly preferred are immunogens that are effective in eliciting an immune response against diphtheria, tetanus, pertussis, botulism, cholera, dengue fever, hepatitis A, C and D, hemoglobinin bacteria of influenza B, herpes virus, Helicobacterium pylori, influenza, Japanese encephalitis, meninge B and C, measles, mumps, papilloma virus, pneumococcus, polio, rubella, rotavirus, respiratory syncytial virus, shigella, tuberculosis, yellow fever, and combinations thereof.

 Immunogens can also be obtained using molecular biology techniques to obtain recombinant peptides or fusion proteins containing one or more parts of a protein derived from a pathogen. For example, fusion proteins containing an antigen of interest and the B subunit of a cholera toxin have been shown to induce an immune response to an antigen of interest. Sanchez et al. (1989) Proc. Natl. Acad Sci. USA 86: 481-485.

 Preferably, the immunogenic composition contains a certain amount of excipient sufficient to enhance the immune response to the immunogen. Suitable excipients include, but are not limited to, aluminum salts, squalene mixtures (SAF-1), muramyl peptide, saponin derivatives, mycobacterial cell wall preparations, monophosphoryl lipid A, mycolic acid derivatives, non-ionic block copolymer surfactants, Quil A, the cholera toxin B subunit, polyphosphazene and derivatives and immunostimulating complexes (ISCOM), such as those described by Takahashi et al. (1990) Nature 344: 873-875. For veterinary use and production of antibodies in animals, mitogenic components of Freund's excipient can be used.

 As is the case with all immunogenic compositions, immunologically effective amounts of immunogens must be determined empirically. Factors to be considered include immunogenicity, whether the immunogen is complexed or covalently bound to an excipient or a carrier protein or other carrier or not, the route of administration and the number of immunizing doses to be taken. Such factors are known in the field of vaccination, and immunologists have sufficient experience in conducting such determinations without undue experimentation.

 Preferably, if the transferred substance and / or carrier contains carboxyl and amino, imino or guanidino groups, the delivery systems further comprise at least one physiologically acceptable Mallar reaction inhibitor in an amount effective to substantially prevent the condensation of amino groups and reactive carbonyl groups in the composition.

 The Mallard reaction inhibitor may be any of those inhibitors known in the art. The inhibitor is present in an amount sufficient to prevent or substantially prevent the condensation of amino groups and reactive carbonyl groups. Typically, amino groups are present on the biologically active material, and carbonyl groups are present on the hydrocarbon, or vice versa. However, amino and carbonyl groups can be intramolecular, inside either a biological substance or a hydrocarbon. Various classes of compounds are known to exhibit an inhibitory effect on the Mallar reaction and are therefore suitable for use in the compositions described herein. These compounds are usually either competitive or non-competitive inhibitors. Competitive inhibitors include, but are not limited to, amino acid residues (both D and L), combinations of amino acid residues and peptides. Particularly preferred are lysine, arginine, histidine and tryptophan. Lysine and arginine are the most effective. There are many known non-competitive inhibitors. They include, but are not limited to, aminoguanidine and derivatives are 4-hydroxy-5,8-dioxoquinoline derivatives and corresponding Mallar inhibitors, such as those described in EP-A-O-433679.

Dosage forms
In addition to the dosage forms described above, many other dosage forms that are suitable for various uses are provided herein.

 The invention defines delivery systems that are sized and shaped for penetration through the epidermis and are suitable for ballistic delivery. The corresponding carrier size is thus on the order of microns, preferably in the range of 1-5 microns in diameter and 5-150 microns in length, which allows penetration and delivery through the epidermis to subcutaneous and intradermal, intramuscular, intravenous tissues. It is understood that, at this size, the delivery system may macroscopically appear to be in powder form regardless of its configuration at the microscopic level.

Preferred configurations for ballistic delivery systems are microneedles and microfibres. Microfiber production is relatively simple and economical and results in stable delivery systems consisting of a carrier in a glassy form and a transportable substance. Additional stabilizers, buffers, glasses, and polymers can also be added during processing, as described herein. Many of the most labile biomolecules can withstand high temperatures (for example, 60-100 ^o C) after stabilization by drying in trehalose, providing contact of most of their surface with the carrier. Temperatures of 70 ^{° C.} can be maintained for more than a month (Colaco et al. (1992) Bio / Technology 10: 1007-1011), and higher temperatures for shorter periods. The results presented here show that the fluorescent protein picoerythrin dried in trehalose can be stored at 100 ^° C for at least one month without noticeable loss of functional activity. Other carriers provide protection at lower temperatures than trehalose. The maximum temperature of protection should be determined empirically with the help of the experience gained in this field, and without unnecessary experiments.

 Microfibers obtained in accordance with the principles of the present invention have a relatively high aspect ratio, that is, length to diameter, preferably in the range of 1-5 microns in diameter and 5-150 microns in length. This high aspect ratio provides enhanced penetration through the ballistic delivery due to the tendency of microfibers to line up parallel to the barrel of the ballistic microinjector, as described in more detail below. Longer macro fibers can be injected using conventional pulsed ballistic devices or using a trocar. Alternatively, macroscopic glass needles with a sufficient intrinsic length can be directly inserted through the skin for subcutaneous, intradermal or intramuscular administration of a transportable substance.

 Alternative preferred embodiments of the delivery systems include uniform microspheres, preferably with a narrow size distribution. This configuration is particularly useful when enhanced control of the depth of penetration of the delivery system is desired. Such a control would be useful, for example, for intradermal, intramuscular, intravenous delivery of vaccines to the basal layer of the epidermis, in order to introduce antigen near the skin cells of Langerhans to induce optimal immune responses.

 The invention also defines hollow fibers for the delivery of transportable substances. By forcing the hollow preform through a zone furnace, which causes local softening of the glass carrier, thin empty needles can be formed. These needles can be filled with a stabilized compound in the form of a fine powder by introducing a fine powder during the melting and forcing process. Hollow fiber can also be obtained from thermoplastic, organic polymer, and / or hydrocarbon, and / or GPU, which in itself can be quickly or slowly soluble in water and / or biodegradable.

 An alternative embodiment of a delivery carrier in the invention comprises a hollow carrier consisting of glass or plastic that is poorly soluble in water, which fills and optionally covers the delivery systems described herein.

 In another embodiment of the invention, co-preparations of carriers and other poorly water soluble materials are included. For example, co-preparations of carriers with water-soluble glasses, such as phosphate, nitrate or carboxylate glasses, or biodegradable plastics, such as lactide polymers or lactide / glycolide copolymers, will provide a more slowly degradable carrier for slow release of the biologically active material.

Methods of obtaining delivery systems
The invention further indicates methods for producing solid dosage systems. Providing that the exposure time is limited, the transported substances mixed with dry carriers can be heated to soften the glass, which can then be pressed or stretched like a fiber without damaging the product. The fibers can either be squeezed out of the preform, cooled before they are cured, and then wound onto a drum, or they can be drawn through thin holes in a rapidly rotating cylinder that is heated to a temperature above the melting temperature of the carrier. Being initially brittle, these fibers can be easily cut, broken, or cut into short pieces to form long cylindrical rods or needles. By varying the diameter of the resulting fibers, needles can be formed that vary from micro to macro needles, that is, from thicknesses of a few microns to fractions of a millimeter. Cotton candy making machines have been found to be suitable for use with smaller microfibres. Although the optimal conditions for each carrier should be selected empirically, such definitions are quite accessible to specialists in this field.

 Several methods can be used to produce the microspheres of the present invention, depending on the desired use of the delivery vehicles. Suitable methods include, but are not limited to, spray drying, freeze drying, air drying, drying in a vacuum, drying in a fluidized bed, grinding, coprecipitation and evaporation of supercritical fluid. In the case of spray drying, freeze drying, air drying, drying in a vacuum, drying in a fluidized bed and evaporation of a supercritical fluid, components (SP, and / or GPU, and / or other glass-forming substance, transportable substances, buffers and the like) first dissolved or suspended in appropriate solvents. In the case of grinding, the glasses formed from the components either by evaporation of the solvent or by quenching the melt are ground in dried form and processed using a method known in the art. In the case of coprecipitation, the components are mixed under organic conditions and processed as described below.

 Spray drying can be used to load the carrier with a portable substance. The components are mixed under the conditions of an appropriate solvent and dried using precise nozzles, producing exceptionally uniform drops in the drying chamber. Suitable spray drying machines include, but are not limited to, Buchi, NIRO, and Lab-plant spray dryers used according to manufacturers instructions. A number of hydrocarbons are unsuitable for use in spray drying, since the melting points of the hydrocarbons are too low, causing the dried amorphous materials to adhere to the walls of the drying chamber. Typically, hydrocarbons with a melting point lower than the operating temperature of the spray drying chamber are unsuitable for use in spray drying. For example, palatinite and lactitol are unsuitable for use in spray drying under normal conditions. The determination of suitable hydrocarbons can thus be carried out at known melting points or determined empirically. Such definitions are readily available to those skilled in the art.

 An alternative way to obtain microspheres as delivery vehicles in accordance with the present invention is the preparation of a homogeneous emulsion of the aqueous / organic phase of the transferred substance in a solution of the carrier, as in the aqueous phase, and a glass-forming substance in the organic phase, or vice versa. This is followed by drying the emulsion droplets to form a solid solution of a transportable substance and a carrier in an amorphous matrix of a glass-forming substance. In one variation of this method, the emulsion can be formed from a transportable substance in solid solution in a carrier and two different glass-forming substances and / or polymers dissolved together in one solvent or dissolved in two separate solvents. Then, the solvent (s) are removed by evaporation to give two- or multi-walled microspheres. Suitable methods for producing multi-walled microspheres are described, for example, by Pekarek et al. (1994) Nature 367: 258-260 and U.S. Patent 4,861,627.

 The delivery system can also be dried from an organic solution of SP and a hydrophobic transportable substance to form a glass containing a uniformly distributed transportable substance in a solid solution or a finely divided suspension in polyol glass. These glasses can then be ground and / or ground to micron size to obtain microparticles with a uniform predetermined size distribution.

 The transported substance and the carrier can also be coprecipitated to obtain high quality powders. Coprecipitation is carried out by spraying, for example, using an aerosol can, various components and / or polymeric glass-forming substances in a liquid in which not one of them is soluble, such as acetone on ice.

 The invention also defines hollow fibers for the delivery of transportable substances. Thin hollow needles can be formed by forcing a heated hollow preform. They can be made to contain a stabilized compound in the form of a fine powder by introducing a fine powder during the melting and forcing process. Hollow fiber can also be made of thermoplastic, organic polymer, and / or carbohydrate, and / or hcp glass, which alone can be slowly or quickly dissolved in water and / or biodegradable.

 An alternative embodiment of the delivery system of the present invention includes a hollow carrier consisting of glass or plastic that is poorly soluble in water, which is filled and optionally coated with SP and / or GPU glass and a transportable substance. Thin hollow fibers from inorganic or organic glasses slowly dissolving in water can be squeezed out of the hollow preform, and the delivery system ground into fine powder SP can be included in the lumen of the preform and, therefore, the fibers during the process.

 In another embodiment of the present invention, co-preparations of carriers and other water-soluble materials are included. For example, carrier co-preparations with water-soluble glasses, such as phosphate glasses (Pilkington Glass Company), or biodegradable plastics, such as lactide polymers or lactide / glycolide copolymers, will provide a more slowly degradable carrier for slow release of the transported substance. To obtain co-preparations, glass in the form of a fine powder containing a transportable substance can be thoroughly mixed with carboxylate glass in the form of a fine powder and sintered. Alternatively, if the metal carboxylate glass has a lower melting point than the delivery system, the latter can be homogeneously weighed as an encapsulate in the carboxylate glass when quenching the resulting melt. It can be ground to obtain a fine powder with solubilities intermediate between the relatively fast solubility of the carrier and the slow solubility of the carboxylate glass.

 Alternative co-preparations include using a homogeneous suspension of a fine powder of a glassy delivery system incorporated in carboxylate glass by drying from an organic solvent in which the carboxylate is soluble but not an amorphous powder to form a carboxylate glass. It can be ground to produce a fine powder that has a relatively fast dissolving delivery system trapped inside a slowly dissolving carboxylate glass (i.e., comparable to a conventional slow release system). Variable rate release can be achieved either by repeating encapsulation cycles, using glasses with different dissolution rates, or by mixing powders of a number of co-preparations with a desired range of release characteristics. Note that this glass can also be extruded or extended to produce microfibers that could be implants with low release rates. It will be apparent that any drug in the delivery system must be such that it is capable of releasing the transportable substance upon administration, and should not adversely affect the stability of the material being administered.

 As discussed above, glasses of carbohydrate derivatives are also suitable for use herein. Suitable carbohydrate derivatives include, but are not limited to, carbohydrate esters and ethers, imides, water-poorly soluble derivatives and polymers.

 The delivery vehicle may be loaded with a transportable substance by drying a solution of a transportable substance containing a sufficient amount of carrier to form glass upon drying. This drying is achieved by methods known in the art, including, but not limited to, freeze drying, vacuum drying, spray drying, conveyor drying, air drying, or fluidized bed drying. The dried material may be ground to a fine powder before further processing the material with polyol glass or co-preparation.

 Depending on the delivery vehicle used, various dosage regimens may also be achieved. The delivery vehicle of the present invention may be provided for the rapid release of the current dose of the tolerated substance after administration, where the delivery system is readily soluble. Co-preparations of carriers with slowly water-soluble glasses and plastics, such as phosphate, nitrate or carboxylate glasses, and lactide / glycolide, glucuronide or polyhydroxybutyrate plastics and polyesters, can provide slower-dissolving carriers for slower release and longer dosage action. The initial and accelerating effect can also be realized by using a hollow carrier slowly dissolving in water, filled and coated with rapidly dissolving SP and / or GPU glass loaded with a transportable substance. A glass coating loaded with a transportable substance will dissolve quickly, giving the effect of an initial dosage. When a portion of the carrier located on the outer wall dissolves, there will be no dosing effect, but the initial initiating dose will be followed by a reinforcing dose from the inner filling when the outer wall is thinned due to dissolution. This variable rate release regimen is particularly useful for delivering immunogenic compositions. If a multiple variable speed delivery effect is desired, delivery vehicles with any combination of “unloaded” carrier layers and carriers loaded with transportable substances can be designed.

 Delivery of more than one transportable substance can also be achieved using a delivery system consisting of many coatings or carrier layers loaded with various materials or mixtures thereof. The introduction of solid dose delivery systems of the present invention can be used in conjunction with other conventional methods of therapy, or it can be carried out in conjunction with other therapeutic, prophylactic or diagnostic substances.

Delivery Methods
The invention further defines methods for the delivery of solid dosage systems.

 Suitable methods for the delivery of transportable substances include, but are not limited to, local, transdermal, transmucosal, oral, gastrointestinal, subcutaneous, ocular, intramuscular, intravenous methods and administration by inhalation (nasopharyngeal and pulmonary, including transbronchial and transalveolar). Topical administration is carried out, for example, by dressing or bandage having a dispersed delivery system inside, or by directly introducing the delivery system into cuts or open wounds. Creams or ointments having dispersed beads or microspheres of a slow-release delivery system in them are suitable for use, for example, as external ointments or wound filling agents.

 Compositions for transdermal administration are preferably powders of delivery systems in the form of microneedles or beads of the same size. Macroscopic shapes of larger needles and beads for delivery systems are also provided for subcutaneous implantation and extended drug delivery. Particle sizes should be small enough to cause only minimal skin damage upon administration. Powdered forms of delivery systems can be microneedles of about 10-1000 microns in length and 1-150 microns in diameter. Powders can be pre-packaged in single dose, sealed, sterile packaging.

 Suitable methods for transdermal administration include, but are not limited to, direct-stick delivery, ballistic, trocar delivery, and a stream of fluid. For direct injection delivery, macro needles can be precisely formed using methods well known in the field of inorganic glass molding, such as those used in the manufacture of optical fiber. These needles can be contained in a finely formed closed fitted plastic barrel and can be inserted directly through the skin using a plunger. Ballistic administration is preferred because it is relatively painless. Typically, the delivery system is accelerated in a shock wave of helium or other gas and is shot at the epidermis. A suitable ballistic delivery device is described in PCT / GB 94/00753. A suitable device for delivery in a liquid stream is a Medi-ject device (Diabetes Care (1993) 1b, 1479-1484). Such liquid-jet devices are particularly useful for large-sized macro-needle delivery systems, which can also be delivered using conventional pulsed ballistic devices or using a trocar.

 With transdermal administration, the degree of penetration of the delivery systems can be controlled to a certain extent, not only using the ballistic micro-injector described below, but also using the shape and size of the powder particles. For example, when relative uniformity and a lower degree of penetration are desired, microspheres may be more appropriate for the practice of the present invention. When a high degree of penetration is desired, a microneedle configuration may be preferred.

 Since the ratio of sizes (i.e., the ratio of length to diameter) of microneedles is high, they have larger masses than spherical particles with a similar diameter. If they are given an impulse to penetrate the skin “through”, their higher mass will give them a greater impulse at the same speed and they will thus penetrate deeper into the tissue. When randomly oriented microneedles are placed in a laminar gas flow, they themselves will line up in the direction of the air flow, and in a ballistic injector driven by gas, this will allow them to penetrate the skin at right angles to ensure penetration.

 Delivery systems suitable for transmucosal delivery include, but are not limited to, mucoadhesive wafers, films or powders, oral lozenges, pessaries and rings, and other devices for vaginal or cervical delivery.

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

 Compositions suitable for subcutaneous administration include, but are not limited to, various implants. Preferably, the implants are discoid, spherical or cylindrical particles for ease of administration and can provide either quick or slow release. Since the entire implant dissolves in body fluids, removal of the implant is not necessary. In addition, implants do not contain synthetic polymers and are biodegradable.

 Compositions suitable for ocular administration include, but are not limited to, microsphere preparations and macrospheres and saline drops, creams and ointments containing them, and round rods that comfortably fit into the inferior conjunctival arch beyond the lower eyelid.

 Compositions suitable for administration by inhalation include, but are not limited to, powder forms of delivery systems. Preferably, the powders have a particle size of from 0.1 to 10 microns. More preferably, the particle size is from 0.5 to 5 microns. Most preferably, the particle size is from 1 to 4 microns. In particular, for pulmonary administration, the preferred particle size is 2.5-3 microns.

Preferably, the SP powders of the delivery vehicles also contain an effective amount of a physiologically acceptable buffer, a molecular water pump (MVN). MVN is a physiologically acceptable salt that causes the loss of water from the composition, so that at ambient humidity, the pressure of crystallization water vapor is at least 14 mm Hg. Art. (2000 Pa) at 20 ^o C and does not interfere with glass formation in the carrier. An effective amount of MVN is such that, to prevent noticeable sticking, it significantly reduces hygroscopicity, for example, it is a 50% molar fraction of potassium sulfate. Sodium sulfate and calcium lactate are preferred salts, with potassium sulfate being the most preferred.

 Composite GPU delivery systems are particularly suitable for use by inhalation dosage forms. For example, 10% (w / v) α-HPAC / TOAC mixed delivery systems are resistant to 95% relative humidity (RH), but recrystallize upon contact with liquid water and thus release any transportable substances included in them. This is especially important for inhalation powders, as these powders should preferably devitrify and release the transported substances upon reaching the alveolar fluid, rather than in the wet tracheal airways.

 Powder-filled atomizers and vaporizers are also defined by the present invention. There are a variety of devices suitable for use in the delivery of powders by inhalation. See, for example, Lindberg (1993) Summary of Lecture at Management Forum 6-7 December 1993 "Creating the Future for Portable Inhalers". Additional devices suitable for use herein include, but are not limited to, the devices described in WO 9413271, WO 9408552, WO 9309832 and in US patent 5239993.

 The present invention defines a variety of other solid dosage delivery systems. They are suitable for the delivery of a wide variety of non-medical transportable substances. For example, GPU glass, including an agronomic transportable substance, is dry in stock, even in the tropics, but releases pesticide or biological control agents in contact with liquid water on plantation surfaces or in soil. GPU glass, including the enzyme, is useful when added to washing surfactants, since it stabilizes the enzyme even at high humidity, releasing the enzyme directly in contact with water. Numerous other embodiments are defined by the claimed invention and are readily understood by those skilled in the art.

 The following examples are provided to illustrate, but not limit the present invention.

Example 1
Methods for the production of microfiber joint ventures of glassy dosed solid delivery systems.

a) Obtaining SP microfiber
Glasses are obtained by drying 20% solutions of either trehalose, or lactitol, or palatinite, or GPS, including MVN, and 1 mg / ml of the phycoerythrin seaweed fluorescent protein, in vacuum (80 mTorr) for 16 hours. The glasses are ground in a home-made hand coffee mill to produce coarse powder, which is used to fill the rotating head of a Kando K1 Kandy Floss cotton candy machine (UK patent 1533012). Then, the motor is turned on and the powdered sugar glass is heated when the machine is set between 5 and 9. The residence time in the rotating head is 2-10 minutes, and the continuous process is maintained by continuously adding powder to the head.

 The obtained fibers are ground in a home coffee grinder, and the results are presented in Table 3, which shows the average value for the obtained needles. These data show that for all three sugar glasses, lower settings result in smaller microneedles. With trehalose, setting 6 gives microneedles with an average diameter of 15 microns, and setting 9 microneedles with an average diameter of 40 microns. With GPS, setting 9 produces microneedles with an average diameter of 15 microns. Microneedles obtained from glasses containing buffer salts remain dry at ambient temperatures and humidity. Microneedles containing picoerythrin exhibit a delay in biological activity according to fluorescence estimates.

b) Obtaining microfibers based on binary SP / organic composite glasses
Glasses are created by drying a 5: 1: 1 mixture of trehalose, sodium octanoate and water in vacuum (80 mTorr) for 16 hours. The glasses are ground in a home-made hand coffee mill to produce coarse powder, which is used to fill the rotating head of the Kando K1 Kandy Floss cotton candy machine. The motor is then turned on and the powdered binary hydrocarbon / organic glass is heated at settings between 5 and 9. As with pure trehalose glasses, reduced setting values result in smaller microneedles. Binary mixtures for glasses can be selected to produce glasses with significantly different mechanical properties compared to the corresponding pure trehalose glasses. The residence time in the rotating head is again 2-10 minutes, and the continuous process is maintained by continuously adding powder to the head. The results show that scatter in the melting temperatures and dissolution times of the glasses and the resulting physical properties of microfibers can be achieved by varying both the hydrocarbon / organic molecules and their ratios.

Example 2
Methods for producing powdered SP glassy dosage solid delivery systems
a) The inclusion of the active agent in the SP glassy delivery carrier with obtaining micron-sized powders
Glasses are created by drying 20% solutions of either trehalose, or lactitol, or palatinite, or GPM, or GPS, including the equimolar ratio of MVN and protein, by freeze drying in vacuum (80 mTorr) for 16 hours. Glasses are turned into powder using an air-jet mill (Trost). Particle sizes in micron powders are measured using a Malvern Mastersizer laser particle size meter. The results obtained with micron-sized powders obtained from an initial solution of 0.5 M trehalose and 0.5 M calcium lactate show a monodisperse distribution of particles with average particle diameters of 1.1 microns (Figure 1). Powders, including MVN, remain in the form of a loose powder and do not exhibit particle size changes or sticking and absorption of water during prolonged exposure at ambient temperatures and humidity (Figures 2A and 2B).

b) Inclusion of the active agent in the SP glassy delivery carrier to obtain spray dried powders
20% Trehalose solutions containing MVN salts and protein (phycoerythrin) are dried in a Buchi or Lab-plant spray dryer with a pump capacity of 500-550 ml / h and an outlet temperature of 180 ^o C. Particle size is measured using a laser size meter SympaTec particles. Spray dried powders exhibit a monodisperse particle distribution with a sufficiently narrow size distribution peak for efficient use as particles in a powder ballistic device. In the results presented in figure 3, the analysis of particle sizes of powders obtained by spray drying, which are obtained by spray drying a mixture of 0.5 M trehalose and 0.5 M calcium lactate in a Lab-plant spray dryer, shows the average particle diameter in 8.55 microns and illustrates the resulting narrow distribution peak.

 Variation in the average particle size can be achieved by varying either the composition of the mixture to be spray dried or the characteristics of the nozzle of the drying spray assembly used. The results presented in FIG. 4 make it possible to compare the particle size analysis of the powder obtained by spray drying as in FIG. 3 with the powder obtained by spray drying, which is obtained by drying the same mixture in a Buchi spray dryer that uses a different nozzle assembly . The distribution peak shown in FIG. 4 represents an equally narrow range, but the average particle size here is 7.55 microns.

 These data show that particles obtained by various spray drying processes are equally suitable for creating compositions for ballistic delivery. Note that the ability to vary the particle size results in a composition with different penetration characteristics. This is especially important for determining intradermal, intramuscular, intravenous or intramuscular delivery, since penetration is a function of the particle momentum, and distribution is a function of the dispersion of particle sizes.

 c) The inclusion of the active agent in the SP glassy delivery carrier by drying from organic solvents.

 A 50 mg / ml solution of CSA in a 1: 1 ethanol: water mixture containing 20% trehalose is dried in air at ambient temperature to form a clear trehalose glass containing CSA in a solid suspension or solution. The glass is ground to obtain a powder according to the method described in example 1, and maintaining the bulk powder at ambient temperature and humidity. Adding powder to water results in the dissolution of trehalose and the formation of a homogeneous aqueous suspension of CSA.

 d) Inclusion of the active agent in the SP glassy delivery vehicle by coprecipitation.

 20% Trehalose, lactitol, palatinite, GPM or GPS solutions containing MVN and protein (phycoerythrin) are dried by spraying in a chilled bath containing acetone and solid carbon dioxide. The precipitated powders are separated by centrifugation or filtration and dried in air to remove residual solvent. The powders again show a monodisperse particle distribution, and the powders containing the salts of the buffering preparations remain dry at ambient temperatures and humidity.

 e) Obtaining a composite glassy carrier for delivering a solid dose of a hydrophobic active agent in a joint venture by drying from organic solvents.

Two different solvent systems are used to make composite glasses. In the first case, the CSA is dissolved in absolute ethanol, and then an equal volume of water is slowly added, so that the CSA, which precipitates with each addition, is able to re-dissolve. Trehalose is then dissolved in a 50% ethanol solution (v / v) to a final concentration of 50% w / v. Composite glasses are obtained by evaporating the mixed solvent on a burner at 70 ^° C. In the second case, both CSA and trehalose are dissolved in DMF and again composite glass is obtained by evaporation, as described above. In both cases, the result is slightly opalescent glass. Then, water drops are applied to the glass films to study the dissolution and release properties of the glasses.

 The results show that glass behaves completely differently. Glasses made from DMF are water repellent with an apparently hydrophobic surface. They gradually form opaque white spots and accumulations of precipitated CSA where they were in contact with water. Glasses made from 50% ethanol are hydrophilic. They quickly dissolve in water and at the same time release a cloud of very small particles of CSA. The last glass probably contains CSA either as a fine suspension of solid particles, or as a solid solution in trehalose glass, which releases CSA as a precipitate when trehalose dissolves. As such, it presents a very useful dosage form for a CSA with high bioavailability due to its homogeneous and finely divided state after release.

 The different behavior of glasses of the same composition after drying from different solvents suggests an interesting and useful way to provide precise control over the deposition structure of different glasses during evaporation of the solvent. Since CSA is more soluble in DMF than trehalose, composite glasses of 10-20% CSA in trehalose obtained from this solvent tend to create hydrophilic trehalose nuclei with hydrophobic CSA coatings. In contrast, when 50% ethanol is vaporized, an early loss of ethanol at 97% azeotropy causes the release of CSA from the solution surrounded by trehalose syrup, which then solidifies as a continuous phase, resulting in a solid emulsion of CSA in trehalose glass.

Example 3
Protein protection from organic solvent and elevated temperatures by drying in trehalose
a) Protection of horseradish peroxidase and alkaline phosphatase from acetone, carried out by drying in trehalose
0.1 mg / ml horseradish peroxidase solution or 1 mg / ml alkaline phosphatase / 4 mg / ml bovine serum albumin solution is dried in an FTS Systems freezer dryer with or without 50% trehalose. Vacuum drying is used and the mixtures are dried without freezing. Four times add a volume of solvent and allow the solution to evaporate to dryness. The contents are redissolved in 5 milliliters of water and the enzyme activity is evaluated by sequential dilution using a commercial “kit” of reagents. The alkaline phosphatase kit is taken from Sigma Chemical Co. and the horseradish peroxidase kit is taken from Kirkegaard & Perry Laboratories, Inc. As shown in figures 5A and 5B, the enzymes dried with trehalose are more resistant to acetone than the enzymes dried without trehalose.

b) Protection of phycoerythrin from organic solvents by drying in trehalose
400 μg / ml phycoerythrin is freeze dried in a Labconco freeze dryer with or without 20% trehalose. The dried protein powder is exposed to a number of organic solvents for 72 hours. Phycoerythrin remains fluorescent in acetone, acetonitrile, chloroform and methanol. In pyridine, phycoerythrin remains fluorescent for 24-48 hours, but begins to moisturize and loses fluorescence after 72 hours. In dimethyl sulfoxide, the powder solubilizes, but phycoerythrin remains fluorescent.

c) Protection of phycoerythrin from a temperature of 100 ^o With, carried out by drying in trehalose
400 μg / ml phycoerythrin is freeze dried in an FTS dryer with or without 20% trehalose. The dried protein is stored at a temperature of 100 ^o C for one month without loss of functional activity.

Example 4
Preparation of a glassy solid dose delivery system with a transportable substance included in a composite SP and / or GPU and / or carboxylate glass
a) Joint preparation of a glassy dosed solid delivery system from a composite of SP and organic glasses by evaporation
Trehalose microparticles containing MB9 are obtained by spray drying as described in Example 2b. The dried solution contains 0.39 M trehalose, 0.14 M calcium lactate and 0.5% MV9. These particles are coated by adding them to a saturated solution of zinc palmitate (ZnC ₁₆ ) in toluene and cooling from 60 ^° C to 30 ^° C. This deposits a layer of ZnC ₁₆ on the particles, which are then filtered under vacuum to remove excess ZnC ₁₆ , washed with acetone and air dried. The resulting powder remains un-wetted in water for at least three days (particles float in water without immersion or release of MB9 and then dye is slowly released into water). Thus, water-soluble powders without this can be made watertight by coating with metal carboxylates, such as ZnC ₁₆ , to obtain slow release modes. Note that the coating material is most likely in crystalline form and is not glass; therefore, the solid phase in which the transported substances are suspended does not have to be a glassy phase in order to be waterproof.

b) The joint preparation of a glassy dosed solid delivery system of SP glasses containing the active agent and organic glasses by evaporation
Powdered trehalose glass containing phycoerythrin is added to the mixed carboxylate glass, namely, a 1: 1 mixture of sodium octanoate and zinc ethyl hexanoate dissolved in excess chloroform and evaporated in a stream of N ₂ at room temperature to obtain a carboxylate glass containing powdered phycoerythrin in solid or suspensions. Co-prepared glass remains insoluble in water for at least 48 hours. Powdered phycoerythrin remains fluorescent both in the initial organic solution and in the final glass.

 c) Co-preparation of a glassy, dosed solid delivery system from SP glass containing the active agent and organic glass by co-melting.

The previously obtained organic glass obtained by quenching a melt of a 1: 1 mixture of sodium octanoate and zinc ethyl hexanoate is softened at a temperature of 95 ^{° C.} and powdered trehalose glass containing phycoerythrin is added to the melt. The resulting mixture is directly quenched on an aluminum bar pre-cooled to 15 ^° C. A transparent carboxylate glass is formed containing powdered phycoerythrin, which retains its biological functionality, as measured by its fluorescence ability. Varying the nature and relationships of carbohydrate and organic residues in co-prepared glasses results in a glass with a range of slow release characteristics, which is estimated by their differing dissolution times in water.

 d) Joint preparation of a glassy dosed solid delivery system from SP glasses containing an active agent and GPU glass by evaporation.

Delivery systems are prepared by spray drying using a Buchi B-191 spray dryer. Pre-prepared 6 μm particles (0.264 g) from a spray dried trehalose / MB9 dye mixture (1%) are suspended in a solution of TOAC (4 g) and azobenzene (0.029 g) in dichloromethane (100 ml) and dried in a spray dryer at a temperature inlet 40 ^o C. A turbid yellow hydrophobic powder is obtained with TOAC glass, including the yellow dye azobenzene, encapsulating trehalose glass, including the blue dye MB9. The composite delivery vehicle shows the sustained release of the intense water-soluble blue dye MB9 when immersed in an aqueous solution.

 f) Joint preparation of a glassy dosed solid delivery system from SP glasses containing the active agent and plastics by evaporation.

The powdered trehalose glass containing phycoerythrin obtained according to Example 1 is added to a perspex solution dissolved in excess chloroform and evaporated in a stream of N ₂ at room temperature to give a solid perspex block containing powdered phycoerythrin in solid solution. Powdered phycoerythrin remains fluorescent both in the initial organic solution and in the re-formed solid perspex, which is impervious to water even after 4 weeks. Similar results are obtained with polyester dissolved in dichloromethane and with polyurethane dissolved in dimethyl sulfoxide.

Example 5
Making empty needles filled with delivery systems
The end of the trehalose glass tube blank with a central cavity filled with powdered trehalose glass containing phycoerythrin prepared in accordance with Example 1 is melted in a zone furnace and the fiber is spirally pulled onto a metal drum rotating at a constant speed. The resulting hollow fibers contain a compound stabilized with finely divided trehalose powder and can be cut to the desired size. Hollow fiber can also be made from biodegradable thermoplastics, or organics, or hcp, and filled needles can be formed by changing the diameter of the fibers produced, which can vary from micro to macro needles, i.e. from microns to fractions of a millimeter. Hollow needles may be filled with any solid dose carrier described herein.

Example 6
Ballistic delivery of metered solid delivery systems
Powdered glasses are injected into the skin with a jolt at supersonic speeds, using the pressure shock wave generated by the release of compressed gas. The powder is contained in a chamber attached to the wider end of the funnel-shaped cavity, the narrower end of which is attached to a can of compressed gas sealed with a Mylar film, and a supersonic shock wave is generated by breaking the Mylar membrane. Alternatively, a time relay controlled solenoid can be used to control the release of helium, which would allow it to function at lower helium pressures. This is the principle used in the Particle Delivery Gun (PIG) developed by Feiner to transform plant tissues. Vain et al. (1993) Plant Cell Tissue and Organ Culture 33: 237-246.

Example 7
Obtaining solid dosage systems for the delivery of organic glasses by evaporation
a) Preparation of carboxylate solid dosage delivery systems by evaporation of the solvent
Aluminum hexanoate is dissolved in chloroform (0.5 g / 10 ml) together with 1 weight. % finely divided suspension of MB9 as a tracer dye. A thin amorphous film (100-200 μm thick) is formed by pouring silicate glass onto plates and evaporating the solvent in a stream of warm air. The release of the dye into distilled water is observed for 5 hours and is presented in figure 6. The devitrification of these glasses is not observed, and the films remain transparent, although they are discolored, since the dye diffuses from them into the medium.

Amorphous films are also formed from calcium neodecanoate dissolved in chloroform (0.5 g / 10 ml), as described above. The release of dye from these thicker films (1-2 mm thick) into distilled water is again observed for 24 hours and is shown in Figure 6. In contrast to aluminum films, the release of dye from calcium neodecanoate films is accompanied by dissolution of the films, which is observed using atomic adsorption spectroscopy of Ca ²⁺ .

 b) Preparation of composite glassy, solid, metered-dose DP glass delivery systems containing an active agent incorporated into carboxylate glass by evaporation.

 Films of glucose glass, including 1 weight. % MV9, prepared by quenching the melt. These films are coated with thin (100 micron thick) amorphous metal carboxylate films by evaporation from a solution of carboxylate in chloroform (0.5 g / 10 ml). The metal carboxylates used are aluminum hexanoate and octanoate, calcium neodecanoate and magnesium isostearate and magnesium neodecanoate. The dissolution of the films is observed by the release of the dye into distilled water. These delivery systems prolong the release of dye over a period of time ranging from minutes to hours, with the exception of films formed from magnesium isostearate, which extend the release of dye for 10 days.

Example 8
Preparation of GPU solid dosage systems
Several hcp glasses are prepared by melting and quenching. In the following examples, multicomponent GPUs are purchased from Aldrich Chemical with the exception of TCR, which is synthesized by the method described by Akoh et al. (1987). The components form glass with little or no decomposition. Fructose, sucrose and, to a certain extent, glucose melt with marked decomposition or polymerization. An ester such as α-D-glucose pentaacetate is stable at its melting point and forms a clear, colorless glass when quenched. Higher stability of derivatives of ethers and esters is an obvious advantage in the encapsulation of reactive organic materials such as pesticides and biocides.

 GPUs with particularly low melting points form soft waxy glasses after quenching. The NMR spectrum of glassy α-D-glucose pentaacetate was found to be identical to the spectrum of crystallized α-D-glucose pentaacetate.

 Glass formed from β-D-glucose pentaacetate is poorly soluble in water, and a disk (20 mm in diameter and 2.5 mm thick) prepared from this ester and placed in running water loses approximately 33% of its initial weight over 10 days. Another glass disk with similar dimensions is prepared from α-D-glucose pentaacetate and placed in 1 liter of water, which is replaced daily. After 7 days, the glass loses 20% of its original weight. The rate of release of the encapsulated dye Acid Blue from this glass, as shown in Figure 7, is almost constant. The dye release rate is higher on the first day, since the release occurs mainly from the surface of the glass disk.

 Excellent release is obtained by encapsulating several organic substances in glasses. Α-D-glucose pentaacetate glass disks containing 2% w / w of the materials listed in Table 4 are formed by melt and quench, and then milled. Photochrome II is 5-chloro-1,3-dihydro-1,3,3-trimethylspiro [2H-indole-2,3 '- [3H] -naphtha [2,1-b] [1/4] -oxazine .

 The encapsulated materials are extracted with an appropriate solvent, such as methanol or water. The results obtained are presented in Table 4.

 Acid Blue 129 release rates have been found to depend on dissolution rates and glass shapes. The pesticide-like Oxadiazone dissolves easily, without problems, in the melt of this glass at about 15% w / w.

Example 9
Obtaining and release properties of glassy hcp solid dosage delivery systems by quenching from the melt.

a) Obtaining and release properties of simple and composite glassy hcp glasses from the melt
In subsequent experiments, the delivery system is preliminarily prepared either as a homogeneous material or as a mixed composition. This is done by carefully grinding the multicomponent hcp, followed by carefully controlled melting in an oven at a temperature of approximately 120-140 ^o With and in a normal atmosphere with the formation of melts. The melts are quenched to glass by pouring onto the surface of a bronze block. Then this glass is finely ground.

The dye MB9 (1 or 5 wt.%) Is mixed with ground glass before re-melting at 140 ^o C, the melt is quenched with the formation of small glass beads 2.5 mm in diameter, which are used in experiments on controlled release.

The controlled release of the encapsulated dye is observed by suspending three such beads in 25 or 50 ml of deionized water or in a PBS solution at ambient temperatures (27-30 ^° C) or at 37 ^° C, as shown. The media are in a calm state with the exception of periodic mixing and are replaced at regular intervals by fresh media (usually at 72-hour intervals). Both homogeneous hcp glass and composite hcp glass are formed. The obtained hcp composite glasses are presented in Table 5. The dye release is measured using spectrophotometry (λ _max is 516 nm), and the results are presented in figures 8-14. TOAC glass demonstrates the characteristics of the kinetics of the release of zero order. The use of other GPUs as modifiers in composite GPU preparations makes it possible to design glasses designed to obtain the desired release characteristics.

Figure 8 presents the characteristics of the kinetics of the release of zero order TOAC delivery systems. In figure 8, the results were obtained on disks made of TOAC glass (6 mm • 2.5 mm) with dye MV9 uniformly dispersed in them at 2% by weight. The release is controlled at 25 ^{° C.} with gentle stirring and medium changes at regular intervals. Note the linear release of MB9 dye over a period of 55 days. The results presented in figure 8 show that pure glassy hcp delivery system systems give a zero-order release rate of the transported substances. The results presented in figures 9-14, represent the change in the rate of release by changing the ratios of various hcp in the delivery systems, changing the length of the carbohydrate main chain and changing the nature of the derivative on the carbohydrate main chain. In each example, it is clear that the GPU delivery system allows you to have a wide range of release rates that can be selected for a given transportable substance and delivery.

 Figure 9 presents the results obtained when the ratio of two different GPUs in the delivery system varies. The release rate of MB9 from the TOAC / ORE matrices is measured as described for Figure 8. The release rate was found to vary with different preparations, but is directly related to the concentration of the ORE. For example, the highest release rate is observed at 75% TOAC (25% ORE), and the lowest release rate is observed at 95% TOAC. Thus, the release rate from these delivery systems can be easily obtained empirically.

 Figure 10 compares the Tg change of three different hcp co-preparations with different amounts of TOAC. Three different co-drugs, TOAC / SGAC, TOAC / ORE and TOAC / α-HPAC with an increasing molar percentage of TOAC, are investigated. These results indicate that carrier Tg increases directly with the molar percentage of TOAC in those co-preparations that initially have lower values of Tg / TOAC / α — HPAC and TOAC / SGAC.

 Figure 11 compares the percent release of MB9 dye from two different TOAC / RUDA co-preparations and only RUDA. ORE has a two-phase release rate with an initial fast release of approximately 60% of the dye after 5 days and a slow release of a few more percent of the carrier over the next 25 days. The release rate of pure ORE is substantially modified by the presence of TOAC. The drug 50% RUDA exhibits a linear release rate greater than the release rate for 10% of the ore.

 Figure 12 compares the release of MB9 from TOAC co-preparations (75%) with either SOAC or COAC to demonstrate the effect of changes in the carbohydrate backbone. The results show that in this way the release rates can be changed, the TOAC / SOAC co-preparation exhibits an increased release rate compared to the TOAC / SOAC co-preparation.

 Figure 13 compares the release rate of dye MB9 from co-preparations of two components of the hcp with different lengths of the carbohydrate backbone, TOAC and α-GPAC. The release rates are not directly related to the weight percent of TOAC, with 50% TOAC having the lowest release rates, and at 25% having the highest. Again, the speeds are easily determined empirically.

Figure 14 compares the release rate of MB9 dye from two different co-preparations of the hcp components with the same carbohydrate backbones and different derivatives, TOAC and TOPR. The results show that the addition of 25% TOPR to the TOAC delivery system dramatically reduces the rate of release of the transported substance
b) Inclusion of transported substances in GPU by quenching of the melt
The synthetic XPDO corticosteroid (described below) is dissolved in the TOAC melt and quenched to form a glassy solid dosage delivery system. From the point of view of the release of MB9 into aqueous solution, these experiments examine the compatibility of the steroid with glass, the subsequent recovery of the steroid and study the effect that XPDO has on the properties of the formed delivery system in terms of the release of MB 9 into the aqueous solution. TOAC (3.21 g) is pre-melted at 150 ^{° C.} before being quenched to glass. The glass is finely ground with XPDO (0.15 g) before re-melting. The clear melt was quenched again to give an hcp / active agent composite glass. Thermal analysis is performed on a Rheometric Scientific Differential Scanning Calorimeter (DSC) at a heating rate of 10 ^o / min in a nitrogen atmosphere. Receive the following samples:
1. TOAC / XPDO (5 wt.%) - Tg = 50, 6 ^o С
2. TOAC / XPDO (5 wt.%) + MV9 (1 wt.%) - Тg = 50, 9 ^o С
3. TOAC pure - Tg = 50.1 ^o C
4. TOAC / MV9 (2 wt.%) - Tg = 50.3 ^o C
The release characteristics of glassy hcp dosed solid delivery systems are studied by recording the release of MB9 from TOAC / XPDO glasses, as shown in FIG. 15. To analyze the stability of the active agent in glassy hcp solid dosed delivery systems, XPDO is removed from the samples by dissolving the glass in acetonitrile and analyzed by HPLC. There is a complete recovery of the tolerated substance even after storage at 45 ^{° C.} for 4 weeks.

Example 10
Obtaining glassy hcp dosed solid delivery systems by evaporation of the solvent
a) Obtaining hcp glasses by evaporation of the solvent
As described above, TOAC was found to provide a good delivery vehicle by quenching the melt. Such a delivery system has a low melting point and a very slight tendency to recrystallize. Then, a series of experiments were performed on TOAC glasses by evaporation of the solvent on 3 • 1 inch sodium glass plates.

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

Glasses are prepared by evaporating DCM on a set of burners at 65 ^° C from 25% TOAC solutions (50% solutions often precipitate crystals at the end of the pipette). Drying is continued for 2 hours to ensure complete dryness. Homogeneous glasses are obtained by using an Eppendorf type pipette to deliver 100 μl to a glass plate previously placed on a burner, and then removing about 50 μl by using a pipette reverse piston. Glasses are very transparent and adhere to the substrate immediately after preparation, but gradually recrystallize for 1 month at room temperature (Room temp.) And 50-60% relative humidity (OB).

 Trehalose glasses are obtained in a similar way by evaporating water from a 50% trehalose solution, they are transparent immediately after preparation, but gradually recrystallize over a period of several weeks.

 b) Inclusion of the active agent in the hcp glass by evaporation of the solvent; powders suitable for inhalation.

 XPDO is a steroidal anti-inflammatory compound. Chemically, it is 6α, 9α-difluoro-11β, 21-dihydroxy-16α, 17α-propylmethylenedioxy-4-pregnen-3, 20-dione. XPDO crystallizes in the form of spirals that are packed together in needles, leaving long intermolecular empty spaces that attach water molecules like zeolites. This makes the steroid hygroscopic enough to make it difficult to use as a dry powder for inhalation, which is the preferred method of administration. In an amorphous (non-crystalline) form, XPDO is not hygroscopic, but it is chemically unstable. Studies on the stabilization of this compound with trehalose were unsuccessful because it was not possible to obtain a non-hygroscopic powder.

Therefore, XPDO is included in TOAC glass by dissolving both crystalline TOAC and XPDO in DCM and evaporating the solvent at 70 ^° C on a burner. XPDO is used in proportions of 10% and 20% of the total solid product in the final TOAC glass. These glasses are perfectly transparent like water. If stored at 75%, 81%, 90%, and 95% RH for 4 weeks, they do not show any changes in the structure of the glass, such as recrystallization.

 However, when they are placed in liquid water, the glass surface slowly recrystallizes, so that microscopic TOAC pyramidal crystals can be seen under an inverse microscope for 15-30 minutes after adding water. Crystallization gradually continues, and over the next minutes small clusters of typical needle-shaped XPDO crystals appear. Since neither needle-shaped XPDO nor TOAC pyramidal crystals adhere to the glass underneath, they are easily washed off, revealing a fresh glass surface for further slow dissolution. The complete displacement of XPDO from TOAC crystals confirms that this molecule, originally incorporated into the glassy TOAC matrix, is now released into the liquid phase.

c) Release of the active agent in HDC glass by evaporation of the solution; spray dried powders suitable for administration by inhalation
Studies are performed using a synthetic XPDO corticosteroid dissolved in DXM. The solution was spray dried in a Buchi B191 spray dryer using an inlet temperature of 40 ^° C. This results in a fine white powder that contains XPDO in solid solution. XPDOs are included at 20% by weight. The powder is completely amorphous, which is confirmed by thermal analysis (Tg = 46 ^o C).

For analysis, XPDO is extracted from the spray dried powder by dissolving the powder in acetonitrile and then diluting the acetonitrile with sodium phosphate buffer before analysis by HPLC. Samples are collected for XPDO stability studies in preparations obtained by spray drying at 45 ^{° C.} and stored over saturated zinc sulfate (OM is 80-85%).

To release 0.0868 g of spray-dried powder into sodium phosphate buffer, shake in 10 ml of buffer for 1 minute. Then the suspension is filtered through a 0.2 μm filter. When analyzed by HPLC, it is concluded that XPDO is effectively released into the aqueous solution. The bioavailability of the steroid from the delivery system is investigated by immersion in an aqueous solution for a short time. The stability of the steroid in a spray-dried preparation is examined at high humidity and 45 ^{° C.} (both factors are important for successful use in the form of a powder for inhalation). The results show resistance to high humidity, stability in glass, and easy bioavailability in in vitro studies. By HPLC analysis, there was no evidence of decomposition of the spray dried glass powder, even after 4 weeks of storage at 45 ^{° C.} and 85% RH.

 d) Inclusion of transported substances in hcp glasses by evaporation of the solvent; Slow release CSA.

Cyclosporin (CSA, Sandimmune ^© ) is a hydrophobic cyclic peptide used as an immunosuppressive agent, in particular for a patient with transplanted organs. CSA is administered orally or intravenously. For administration, it is dissolved in alcohol. In clinical practice, the levels of this drug in the blood undergo severe fluctuations due to unreliable adsorption in the proximal small intestine (small intestine). This problem can be overcome if the CSA exits at a constant rate for several hours in a form suitable for adsorption.

CSA is introduced into TOAC glass by dissolving both crystalline TOAC and CSA in DCM and evaporating the solvent at 70 ^° C on a burner. CSA is used in proportions of 5%, 10% and 20% of the total solid product in the final TOAC glass. These glasses are completely transparent like water. When stored at 75%, 81%, 90%, and 95% RH for 4 weeks, they do not exhibit changes in the structure of the glass, such as recrystallization. When immersed in water, these glasses behave like XPDO-containing glasses, that is, they slowly recrystallize as separate TOAC and CSA crystals.

 e) Obtaining glassy solid dosage delivery vehicles from composite hcp glasses by evaporation of the solvent.

 In addition to TOAC, two other hydrophobically modified saccharides, α-HPAC and TOPR, are tested in mixtures to create mixed glasses with improved properties.

Mixed glasses of pairs of these hcp are obtained by mixing the crystalline components in various proportions, and then the glasses are obtained either by evaporating the DCM solvent on a burner or by melting at 150 ^{° C.} and quenching on a bronze plate.

 The resulting glasses are tested for their usefulness as controlled release matrices in two ways. First, they are evaluated for their ability to resist devitrification when exposed to high OM and Room. pace. Secondly, they are placed in water or phosphate-buffered saline (PBS) to study their solubility and degradation rate by surface re-crystallization.

 One-component glasses from both α- and β-HPAC can be obtained only by quenching from the melt. When the solvent evaporates, the solutions of these hcp always crystallize. One-component glasses from TOAC and TOPR are easily obtained either by evaporation of the solvent or by quenching, but they are very susceptible to devitrification at high OM, demonstrating the complete recrystallization of thin glass films on microscope wafers and surface recrystallization on quenched disks at OM from 75 % to 95% after exposure overnight. Mixed glasses behave as described in Table 6.

 The results obtained show that the effect of various OMs is very uniform. While pure TOAC and some of the composite glasses crystallize at all OM from 75% to 95%, other composite glasses remain amorphous for all studied OB values.

 Glasses with 10% α-HPAC and 10% TOPR in TOAC and glass with a TOAC: α-HPAC molar ratio of 50:50 are also immersed in water to study their devitrification rate in liquid water rather than in moist air. The first glass recrystallizes within 20-30 minutes, while the second glass forms a small amount of small crystals after 4 hours, while the 50: 50 glass does not change for 4 days, showing unexpectedly low solubility.

 As a carrier for delivering drugs in powder form into the depths of the lungs, glasses with 10% α-HPAC in TOAC show very desirable resistance properties with respect to 95% OM, such as can be found in an inhaler and when air passes, at the same time time with rapid recrystallization in liquid water, such as in a layer of liquid covering the alveoli.

 TOAC glasses with or without 10% or more α-glucosapentaacetate or trehalose octapropanoate or without them provide a range of environmental resistance and dissolution rates, making it possible to construct a controlled release of drugs dispersed in such glasses.

 f) Inclusion of the active agent in composite hcp and / or SP glass with slow release by evaporation of the solvent.

 For maximum benefit, the slow release characteristics of the hcp should be suitable for both hydrophobic and hydrophilic molecules. The former are easily prepared in solid solution in one hcp either by evaporation of the solvent or by direct dissolution in the melt, followed by quenching. Hydrophilic molecules are not directly soluble in hcp.

 Currently, the authors have found a remarkably useful method for incorporating hydrophilic substances with a very uniform and useful distribution in the matrix of the hcp. The method is well illustrated by the use of trehalose as a hydrophilic substance and TOAC as a hydrophobic matrix. Good solvents for both modified and native trehalose are DMF and DMSO. When a solution of 10% trehalose and 90% TOAC in DMF is evaporated to dryness, the result is a glass similar to drizzle or opalescent. Under the microscope, it can be seen that the distribution of spherical glassy microspheres of the same size in a continuous matrix is very uniform (figures 16 and 17). By rough measurement using a ruler in a microscope eyepiece, the size of the microspheres is approximately 4 micrometers in diameter.

 The identity of the two phases is checked by including a small amount of a highly hydrophobic lipid dye, Oil Red O, together with a small amount of hydrophilic dye, Methylene Green in a DMF solution, before producing glass. As expected, the hydrophobic Oil Red O is distributed exclusively in the continuous phase, proving that it is TOAC, while the hydrophilic Methylene Green is distributed exclusively among discrete homogeneous particles, proving that they are trehalose (Figure 18). Composite glass thus obtained consists of a very uniform and stable glass in a glass "solid emulsion" or "solid suspension", rather than in solid solutions, such as those observed for hydrophobic transportable substances XPDO, CSA or dye Oil Red O .

 When the same mixtures of trehalose and TOAC are evaporated from a solution in DMSO, the appearance of the composite glass is different. In this case, the glass is more transparent and the continuous trehalose phase is presented under the microscope in two forms. One form is a very fine dispersion of extremely small trehalose particles uniformly distributed in a continuous matrix. Another form consists of large spherical balls of trehalose concentrated in a cluster in the center of the composite glass.

 Without the desire to be bound by any theory, it seems plausible that the various structures detected reflect differences in the solubility of the two carbohydrates in the solvents used, so that they are precipitated from the solution at different stages of solvent evaporation. Convincing evidence to support this explanation was found in experiments on the production of composite glasses with the opposite orientation, that is, with a hydrophobic transportable substance finely dispersed in a hydrophilic continuous matrix.

g) Toxicity of hcp glass
A saturated solution of TOAC in deionized distilled water (0.42 g in 20 ml) was tested for in vitro toxicity using cells obtained from a Vero African green monkey kidney, either by 10-fold sequential dilution, or by adding TOAC powder to the culture medium tissue. After a week, no toxic effects on the culture were detected and cell division was normal.

 Although the described invention has been described in sufficient detail for purposes of clarity and illustration, for those skilled in the art it is understood that certain changes and modifications may be made. For this reason, the description and examples should not be construed as limiting the scope of the invention, which are set forth using the attached claims.

Claims (39)

 1. The composition, which is a solid dosage delivery system containing a glassy carrier and an effective amount of at least one portable substance, characterized in that the carrier is a carrier in which the portable substance can be stable and stored without loss of activity, selected from stabilizing polyol and a hydrophobic carbohydrate derivative (HCP), wherein the stabilizing polyol is a natural or synthetic carbohydrate selected from the group consisting of disaccharides, tris arides, oligosaccharides and their corresponding sugar alcohols, the hcp has a carbohydrate backbone and at least one hydroxyl group substituted with a hydrophobic moiety, the transferred substance is selected from the group consisting of pharmaceutical agents and biological modifiers, and the solid dosage system form is selected from lozenges tablets, discs, films, suppositories, needles, microneedles, particles, microparticles, spheres, microspheres, powders and implantable agents.  2. The composition according to p. 1, characterized in that it further comprises at least one physiologically acceptable glass selected from the group consisting of carboxylate, nitrate, sulfate, bisulfate and combinations thereof.  3. The composition according to p. 1 or 2, characterized in that the stabilizing polyol is a synthetic carbohydrate selected from compounds that have a glycosidic bond substituted by a thiol or carbon bond. 4. The composition according to p. 1, characterized in that the carbohydrate is selected from the group consisting of trehalose, glucose, maltose, lactose, maltulose, isomaltulose, lactulose, mono-reducing glycosides of polyhydroxy compounds selected from sugar alcohols, other straight chain polyalcohols, raffinose, stachyoses, melesitoses, dextran, sucrose and their sugar alcohols, maltitol, lactitol, palatinite, 2-D-glucopyranosyl-1 _{→ 6-} mannitol and their individual sugar alcohols.  5. The composition according to p. 4, characterized in that the carbohydrate is trehalose.  6. The composition according to p. 1, characterized in that the hcp is a simple or complex ester or their functional modification, where the oxygen atom is replaced by a heteroatom, such as nitrogen or sulfur.  7. The composition according to p. 6, characterized in that the GPU is selected from the group consisting of sorbitol hexaacetate, β-glucose pentaacetate, α-glucose pentaacetate, 1-0-octyl-β-D-glucose tetraacetate, trehalose octaacetate, trehalose octapropanoate sucrose octaacetate, sucrose octapropanoate, cellobiose octaacetate, cellobiose octapropanoate, raffinose undeacetate and raffinose undepropanoate.  8. The composition according to p. 1, characterized in that it further includes at least one stabilizing polyol and at least one GPU.  9. The composition according to any one of paragraphs. 1-8, characterized in that the tolerated substance has increased stability at elevated temperatures or in the presence of organic solvents.  10. The composition according to any one of paragraphs. 1-9, characterized in that the solid dose form is a needle.  11. The composition according to p. 10, characterized in that the needle has a size of 1-50 microns in diameter and 5-150 microns in length.  12. The composition according to p. 10, characterized in that the needle has dimensions of 0.1-4 mm in diameter and 1-30 mm in length.  13. The composition according to p. 1, characterized in that the transferred substance is a pharmaceutical agent selected from the group consisting of anti-inflammatory drugs, analgesics, anti-arthritis drugs, antispasmodics, antidepressants, antipsychotics, tranquilizers, antiemetics, antagonists of drugs, anti-Parkinson’s agents , cholinergic agonists, chemotherapeutic drugs, immunosuppressive agents, antiviral agents, antibiotic agents, appetite suppressants, antiemetics, and anticholinergics, antihistamines, anti-migraine agents, coronary, cerebral or peripheral vasodilators, hormonal agents, contraceptives, antithrombotic agents, diuretics, antihypertensive agents, cardiovascular drugs and opioids.  14. The composition according to p. 11, characterized in that the biological modifier is selected from the group consisting of subcellular compositions, cells, bacteria, viruses and molecules.  15. The composition according to any one of paragraphs. 1-12, characterized in that the transferred substance is selected from the group consisting of lipids, proteins and peptides (synthetic and natural), mimetics of peptides, hormones, polymers of D- and L-amino acids, oligosaccharides, polysaccharides, nucleotides, oligonucleotides and nucleic acids including DNA and RNA, hybrids of proteins and nucleic acids, and small molecules, and their physiologically active analogues.  16. The composition according to p. 15, characterized in that the proteins are selected from the group consisting of enzymes, biomedicals, growth hormones, growth factors, insulin, monoclonal antibodies, interferons, interleukins and cytokines.  17. The composition according to p. 15, characterized in that the hormone is selected from the group consisting of peptides, steroids and corticosteroids.  18. The composition according to p. 17, characterized in that the hormone is a steroid and is selected from the group consisting of estrogen, progesterone, testosterone and their physiologically active analogues.  19. The composition according to p. 15, characterized in that the transferred substance is immunogenic and is selected from the group consisting of live and attenuated viruses, nucleotide vectors encoding antigens, bacteria, antigens, antigens plus excipients and haptens associated with the carrier.  20. The composition according to p. 19, characterized in that the transferred substance is selected from the group consisting of agents that cause an immune response to diphtheria, tetanus, whooping cough, botulism, cholera, dengue fever, hepatitis A, C and D, hemoglobinophilic influenza B bacteria , herpes virus, Helicobacterium pylori, influenza, Japanese encephalitis, meningococci A, B and C, measles, mumps, papilloma virus, pneumococcus, poliomyelitis, rubella, rotavirus, respiratory syncytial virus, Shigella, tuberculosis, yellow fever and their  21. The composition according to p. 19, characterized in that it further comprises an excipient effective in enhancing the immune response to the vaccine.  22. The composition according to p. 21, characterized in that the excipient is selected from the group consisting of aluminum salts, squalene mixtures (SAF-1), muramyl peptide, saponin derivatives, microbacterial cell wall preparations, monophosphoryl lipid A, mycolic acid derivatives, surface active substances based on nonionic block copolymers, Quil A, B subunits of cholera toxin, polyphosphazene and derivatives, immunostimulating complexes and mitogenic components of Freund’s excipient.  23. The composition according to p. 19, characterized in that the carrier is selected from the group consisting of hemocyanin of the mollusk leaf and bovine serum albumin. 24. The composition according to any one of the preceding paragraphs, characterized in that it further comprises a certain amount of at least one physiologically acceptable salt, which is present in an amount sufficient to cause the loss of water from the composition, so that when the humidity is ambient, vapor pressure crystallization water is at least 14 mm Hg. Art. (2000 Pa) at a temperature of 20 ^o C and does not interfere with the formation of glass media ("buffer - molecular water pump, MVN").  25. The composition according to any one of the preceding paragraphs, characterized in that it further comprises at least one physiologically acceptable inhibitor of the Mallar reaction in an amount effective to practically prevent the condensation of amino groups and reactive carbonyl groups in the composition.  26. The composition according to any one of the preceding paragraphs, characterized in that the glass is coated with phosphate glass having a given dissolution rate.  27. The composition according to any one of the preceding paragraphs, characterized in that it further comprises at least one glass selected from the group consisting of lactide and lactide / glycolide copolymers, glucuronide copolymers, other polyesters and polyorthoesters and polyanhydrides.  28. The composition according to p. 1, containing trehalose and a transportable substance, preferably soluble in organic solvents, characterized in that the transportable substance is a solid solution or suspension in trehalose glass and dissolves upon exposure to an aqueous solution, giving a finely divided aqueous dispersion of insoluble transportable substance .  29. The composition according to p. 28, characterized in that the transferred substance is cyclosporin A.  30. The composition according to p. 28, characterized in that it further includes at least one GPU.  31. A method for producing a glassy dosage solid delivery system, characterized in that it comprises the steps of processing at least one first component capable of forming a glassy carrier selected from a stabilizing polyol and a hydrophobic carbohydrate derivative (HCP), and at least , one second component, which must be a portable substance, to obtain their mixture, the formation of the mixture in the desired form, selected from cakes, tablets, discs, films, suppositories, needles, microneedles particles, microparticles, spheres, microspheres, powders and implantable means, while the carrier can be stable in the carrier and can be stored without loss of activity, a carbohydrate, natural or synthetic, selected from the group consisting of disaccharides, is used as a stabilizing polyol, trisaccharides, oligosaccharides and their corresponding sugar alcohols, the hcp has a carbohydrate backbone and at least one hydroxyl group substituted with a hydrophobic moiety, and the transferred substance is selected from ruppa consisting of pharmaceutical agents and biological modifiers.  32. The method according to p. 31, characterized in that the treatment is carried out by melting the first component and incorporating the second component into it, the melt temperature being sufficient for melting the first component and insufficient for substantially inactivating the second component, followed by quenching of the melt.  33. The method according to p. 31, characterized in that the treatment is carried out by drying the mixture formed by the first and second component, heating said mixture and forcing it through a hollow cylindrical shape having a clearance.  34. The method according to p. 33, characterized in that through a hollow cylindrical shape having a lumen, the composition described in any one of paragraphs is pressed through. 1-30.  35. The method according to p. 31, characterized in that the processing and forming stages are carried out by dissolving or suspending the first and second components in a solvent effective in dissolving at least one component and drying the mixture in the form of particles or spheres by spray drying.  36. The method according to p. 35, characterized in that the stage of processing and formation is carried out by dissolving the first and second components in an organic solvent and evaporating the solvent.  37. The method according to p. 35, wherein the processing steps include preparing a homogeneous water-organic emulsion containing the first and second components, removing the organic solvent and coprecipitation of the components.  38. The method according to p. 31, characterized in that the treatment includes suspending the first and second components in a solvent in which they both dissolve, and the formation step involves spraying the solution.  39. The method according to p. 32, characterized in that it includes an additional stage of coating the mixture one or more times. Priority on points:
08/04/1994 - on pp. 1, 2, 8-22, 24-27, 30-39 in terms of the sign of "stabilizing polyol" and PP. 3-5, 28, 29;
08/04/1995 - according to PP. 1, 2, 8-22, 24-27, 30-39 regarding the sign of "GPU" and paragraphs. 6, 7, 23.

Images