HK1171364B - Highly porous, fast-disintegrating solid dosage forms and its way of manufacturing comprising the preparation of a powder and a freezedrying step - Google Patents

Description

Rapidly disintegrating solid dosage form with high porosity and method for the production thereof comprising the steps of producing a powder and freeze-drying

The present application is a divisional application of the patent application entitled "highly porous rapidly disintegrating solid dosage form and process for its preparation comprising the steps of producing a powder and lyophilizing" with application number 200580037071.8, filed on 2005-10-27 (international application number PCT/EP 2005/055591).

Technical Field

The present invention relates to an economical process for preparing a rapidly disintegrating solid dosage form of high porosity by partial freeze-drying, and the dosage form obtained.

Background

Tablet manufacturing techniques involve the preparation of compositions containing active ingredients that are robust, suitable for packaging and handling, and disintegrate in a predictable manner.

Immediate release tablets and rapidly disintegrating tablets are particularly important in the field of orally ingested drugs. Many people are reluctant and/or unable to swallow tablets, capsules or other conventional solid dosage forms. Especially in the case of drugs for pediatric or geriatric patients.

One method suitable for these persons is to use effervescent tablets or granules. However, the use of effervescent tablets requires a preparatory step prior to administration, requiring water and a suitable mixing container. In addition, problems with the preparation and stability of effervescent tablets are often encountered. Another possibility is the use of chewing gums or chewable tablets containing drugs that are absorbed through the mouth (U.S. patent No. 5,225,197). Substantial disadvantages inherent in such delivery systems are that many active pharmaceutical ingredients are not suitable for buccal absorption and many people are unable to chew gums or tablets due to braces, dental treatments, and the like. Furthermore, glues are often difficult to prepare.

Two main processes are currently available to obtain pharmaceutical dosage forms that disintegrate rapidly upon contact with saliva in the oral cavity. These methods are summarized in M.Sugimoto, K.Matsubara, Y.KoidaundM.Kobayashi, pharm.Dev.Technol.6(4), 487-:

(1) the active ingredient is mixed with a water-soluble diluent and compressed on a tablet press with low to moderate pressure. This is a more conventional approach and often does not give the tablets the required tensile strength and reasonable disintegration time. The updated method is OraSolv^TMThe process involves adding microencapsulated pharmaceutical ingredients to the resulting tablet by compression (U.S. Pat. No. 5,178,878). Due to the insufficient mechanical resistance of such tablets in conventional blister packs, such tablets have to be packaged in special packagingPeel-off blister packs. Immediate release tablets have been prepared using suitable crystalline sugar structures under suitable curing conditions (U.S. Pat. No. 5,866,163). U.S. patent No. 6,221,392 discloses a further compressed, rapidly releasable dosage form comprising an active ingredient and a matrix composed of an indirectly compressed filler and a lubricant.

(2) Suspensions are prepared of the active ingredient with suitable excipients. The suspension was dispersed in blister packs and lyophilized (U.S. Pat. No. 4,371,516). This method generally gives tablets with a porous structure, reasonable tensile strength and disintegration time, but is time consuming and requires a costly freeze-drying process. In the terminology ofThe corresponding methods of technical marketing are protected by us patent numbers 4,642,903 and EP 295242. A particular form of this technology is protected in U.S. patent nos. 5,976,577, 6,156,359, 6,413,549, 6,423,342, 6,509,040 and 6,709.669.

The efficacy of the lyophilization process always depends on the physicochemical parameters of the active substance used. International patent application WO97/38679 discloses the replacement of the lyophilization step by conventional drying at room temperature or elevated temperature, and also drying by microwave radiation, but is likewise time-and energy-consuming and is also limited to active substances that survive these conditions. European patent application EP03405901.4 describes a convenient way to overcome these drawbacks.

Disclosure of Invention

Summary of The Invention

The invention relates to a method for producing a rapidly disintegrating solid dosage form, characterised in that one or more structure forming ingredients (dose) in the form of a mixed solid powder are introduced into the cavity of a blister pack or mould, the remaining ingredients are dissolved in the dosed water and added to the powder to form a moist, plasticised (plasticized) mass, frozen to below-20 ℃, and the water is sublimed in high vacuum. In this way, a solid dosage form is obtained having a similar porous structure as is usually obtained with a freeze-drying process, but which process requires much less water, which means considerably less time and less energy. The invention further relates to a dosage form obtained in such a process. The invention relates in particular to rapidly disintegrating pharmaceutical dosage forms for oral use.

Detailed Description

In contrast to the standard freeze-drying processes used in the production of fast-disintegrating solid dosage forms, which are laborious, expensive and energy intensive, the present invention uses a highly economical production process and reasonably new freeze-drying techniques to prepare solid, high porosity fast-disintegrating dosage forms.

In the process of the invention, a structure building component in the form of a solid powder is used. The structure building components, which optionally include tablet fillers and other excipients, are compounds that provide the desired shape and tensile strength to the product, as will be described in detail below. The active ingredient may also be provided in the form of a solid powder, in whole or in part. The remaining compounds to be dissolved in water include the binders, which will be described below, and optionally other excipients, especially those which will be present in molecularly dispersed form. For example, the active ingredient may be dissolved in water.

The freezing step is carried out in a conventional manner. The temperature is below-20 deg.C, such as between-20 deg.C and-50 deg.C, such as around-30 deg.C. The water is sublimed under reduced pressure, e.g. below 6.11mbar (6.11X 10)^-8Pa), e.g. under high vacuum, e.g. at about 1mbar to 0.01mbar (1X 10)^-8To 1x10^-10Pa)。

An optional further step in the process of the invention comprises sealing the blister pack or transferring the resulting product from the mould into a suitable package.

A particular application is in the pharmaceutical field, where the production process is to be applied to oral rapidly disintegrating dosage forms. In this production process, only the active ingredient or the particular component to be combined in molecularly dispersed form will be lyophilized. The resulting new oral dosage form is a shaped, highly porous body, a disk or plate like pharmaceutical tablet or another shaped tablet that rapidly binds water when placed in the mouth, immediately disintegrates and is therefore readily digestible.

The same production process may also be applied to other dosage forms used in veterinary, food or industrial applications. Rapidly disintegrating dosage forms are important in many different fields of application. For example, they can be used in textile washing or dish washing machines and contain detergents and suitable additives. Other applications are, for example, decalcification as bleaching tablets, sanitary tablets, water treatment tablets, denture cleaning tablets, and devices for passing hot water, such as coffee makers, hot water jugs, shower nozzles, and the like.

Another particular application of fast-disintegrating dosage forms is in the food field, for example for coffee, tea, cocoa or milk powder, gravy, soup or other drinks, where the tablets will be dissolved in cold or hot water to reconstitute the original food product, or where the tablets of the edible energy source are placed directly into the mouth without the need for water, e.g. fast energy providers which are consumed and digested during periods of continuous activity such as running, cycling or similar sports.

The novel manufacturing process uses a directed, simplified, partial freeze-drying process that requires a reduced amount of water and no longer has biopharmaceutical or technological disadvantages compared to standard freeze-drying. For example, whereas in standard lyophilization processes, the solution or suspension to be lyophilized typically contains about 10% (w/w) solids and 90% water, or in extreme cases up to 20% solids and 80% water, the production process of the present invention actually uses less than 80% (w/w) water, e.g., between 20% and 70%, preferably between 30% and 40% water. Thus, this production process saves a considerable amount of energy and time. In a standard freeze-drying process, such as that described in U.S. Pat. No. 4,371,516, all components are in the form of an aqueous solution or dispersion and the water is sublimed. However, the present invention uses much less water because the structure building components and optional active ingredients are used in the form of solid powders, i.e. neither aqueous nor aqueous dispersions.

For pharmaceutical applications, the resulting product is preferably in the form of a small disc, column or plate, but may also be referred to as a tablet, although these products do not represent tablets in the usual sense obtainable by compression. When used orally through the mouth, such as when placed on a moist tongue, they rapidly absorb water from saliva, soften, disintegrate immediately, or are easily chewed or crushed with the tongue. For patients who have problems taking standard oral dosage forms, particularly young children and elderly patients, it is a welcome simplification that the pharmaceutical compound is immediately dissolved upon ingestion without the addition of liquid. If it does not dissolve completely, there will be a paste-like substance that is easy to swallow. In this regard, the products of the invention are not fundamentally different from those according to the known artPharmaceutical oral dosage forms prepared by the techniques or related methods.

The new preparation process depends to a large extent on the known conventional freeze-drying methods. As a characterizing aspect of the new technology, the total amount of substance formulated into the desired dosage form is divided into two parts, a liquid part and a solid part, which are dosed separately. In more detail, the production process consists of the following steps: first, the components of the formulation are selected, which do not have to be dissolved and freeze-dried for biopharmaceutical or technical reasons, but can be introduced in solid, powder-like form. These components are intimately mixed. For pharmaceutical oral dosage forms, components suitable for solid handling are specific structural components, for example sugar alcohols such as mannitol or xylitol, sugars such as sucrose, glucose, lactose, fructose, etc. It may also be desirable to incorporate other components which act as fillers or excipients, for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating the osmotic pressure and/or buffers, for example glycine, starch, dicalcium phosphate, microcrystalline cellulose, aroma compounds, dyes and pigments, solid buffers and similar compounds. Fillers are capable of building up a porous structure, supporting rapid disintegration, and preferably have non-hygroscopic characteristics. Such a solid powder mixture may also comprise the active ingredient as long as it is not completely soluble in the aqueous phase or if it is not suitable for biopharmaceutical reasons to incorporate in dissolved form, for example if prolonged activity of the active ingredient is desired.

The liquid part consists of an aqueous solution containing the active ingredient and a binder as main components. Suitable binders selected for this purpose are selected from the usual tablet binders which exhibit good binding properties and also support the structural stability of the lyophilisate (lyophilisate), such as hydrolysed or non-hydrolysed gelatin, polyvinylpyrrolidone (kollidon (r)), cellulose ethers, pregelatinized starches and the like. Small amounts of other excipients, such as preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating the osmotic pressure and/or buffers, may also be dissolved, as far as they are of interest from a biopharmaceutical or technical point of view, in particular surfactants, wetting agents. The optimum, reduced amount of water required is determined from each of the conditions of the preliminary tests. For this purpose, experiments using the solid part of the formulation will be conducted to which an increased amount of the liquid part is added to determine the minimum amount of liquid that produces a uniformly plasticized and thoroughly wetted, moldable mass.

For non-pharmaceutical applications, the choice of structural components, binders and other excipients is of course suitable for the intended use, but the same principle is followed, i.e. the amount of components provided in dissolved form is limited in order to minimize the total amount of water.

In the process of the present invention, the solid portion comprises at least 30%, preferably more than 50%, most preferably more than 75% of the total weight of the components of the solid dosage form, including the water to be sublimed in the process. The less water is needed, the greater the sublimation time and energy savings in the final steps of the process.

The process of the present invention to obtain a highly porous rapidly disintegrating solid dosage form is illustrated in figure 1. The open (white) rings represent the original particles (solid part) of the powdered compound, which are bound together by the components used in liquid form (liquid part), as indicated by the spot areas between the rings. When the liquid fraction containing the dissolved component is added to the solid dosing powder, the liquid enters the remaining open space of the solid, evenly distributed. When cooled and evaporated, lyophilization occurs only in these (speckled) spaces, while the solid, insoluble parts (white) are not directly involved, but are pasted together during freeze-drying. Forming a matrix, wherein the solid powder components can be considered as "bricks" pasted together with "mortar", thus obtaining a solid "brick structure", corresponding to a coated film, aerogel body-like network, wherein the solid "bricks" have a diameter comprised between 0.025mm and 2mm, in particular between 0.1 and 1.5 mm. When such a solid dosage form is used, for example, as a pharmaceutical oral dosage form to be placed on a wet tongue, water (saliva) enters the hollow spaces of the freeze-dried network, almost instantaneously dissolving the components of the initial liquid fraction. Thus, the components of the initial solid powder portion of the matrix are released, and the "brick structure" collapses. The powder particles will then dissolve at a dissolution rate equivalent to their standard solubility.

FIG. 2 shows a micrograph of freeze-dried loperamide, one unit representing 0.01562mm, numbered every tenth unit (i.e., 10 units representing 0.1562 mm); in the upper figure loperamide is described in EP295242Technically produced, uniformly dispersed solids are obtained; in the lower figure loperamide is produced by the process of example 1 of the invention, and proves to be equivalent to the block ("brick") of solid matter characterized by the schematic diagram of figure 1.

In an apparatus suitable for filling, dosing and packaging, e.g. in blister packs, the underlying foil is prepared to accommodate cavities, into which cavities (the lower part of the blister pack) exactly weighed quantities of the respective solid parts and liquid are addedBody part and mixing. This may be done directly in the cavities of the blister foil or in other suitable moulding equipment. The single doses of plasticized and moistened mass thus formed are reintroduced into a standard freeze-drying apparatus, for example for use in a standardTechnical apparatus, freezing to-20 ℃ to-50 ℃. The frozen semi-finished product is further transferred to the high vacuum part of the apparatus, where the residual water is completely or almost completely removed by sublimation.

This new simplified partial freeze-drying process requires only a portion of the total mass to be freeze-dried, which portion needs to be introduced in liquid form for biopharmaceutical or technical reasons. The other components of the formulation, as a rule representing the main part, will only be introduced in solid powder form. This is a more reasonable process for the preparation of a suitably robust, highly porous dosage form that disintegrates already in the presence of small amounts of water and can therefore be easily ingested and swallowed if it is designed for immediate consumption or rapid dissolution in water. The manufacturing process may also be referred to as a containment process because it allows for one-step manufacture of dosage forms using a device to obtain the final package for dispensing from start to finish.

The active ingredient is in particular a drug, but may also be, for example, a vitamin, mineral or dietary supplement. The drug may include, but is not limited to, antacids, analgesics, anti-inflammatory agents, antibiotics, laxatives, appetite suppressants, antiasthmatics, diuretics, antiflatulents, antimigraine agents, antiarrhythmics, antispasmodics, sedatives, antihyperactive agents, tranquilizers, antihistamines, decongestants, beta-blockers, coronary vasodilators, bronchodilators, muscle relaxants, anticoagulants, antiepileptics, antiemetics, hypotensives, sympathomimetics, expectorants, oral antidiabetic agents, hormones, and combinations thereof.

The active pharmaceutical ingredients used in this new manufacturing process may be dissolved, partially dissolved or mixed in the solid state, in pure form or in a specially pretreated form. The active ingredient may be in the form of optical isomers, different crystal modifications of a particular particle size or a particular shape. The pretreated active ingredient is, for example, a coated active ingredient such as microencapsulated or nanocapsule or implanted to perform a specific function, such as enteric coating of the acid sensitive compound, or in a delayed form to control bioavailability over an extended period of time.

Excipients used in the new technology are those from the traditional preparation of oral dosage forms, for example for compressed tablets, such as fillers and structural components, for example sugar alcohols, sugars, cellulose powder, dicalcium phosphate, calcium sulfate, microcrystalline cellulose and the like, but also binders with suitable binding capacity and properties that support the formation of a firm structure of the lyophilisate, for example gelatin, povidone, soluble cellulose ethers and the like. The binder is primarily used to give the formulation a sufficient consistency to avoid breaking of the object when removed from the blister or during handling. Also contemplated as excipients are conventional disintegrants such as starches and super disintegrants, hydrophilic agents (hydrophilizers), solubilizing agents, aroma compounds and sweeteners.

The expression "tablet" as used herein is not limited to a specific size or form of oral dosage form. Tablets may have many different appearances such as traditional dish shapes, but may also be other spherical or ellipsoidal shapes, rods, granules, blocks, rounded cubes, or specific shapes obtained from suitable molds. The size may range from about 1.5mm diameter or 1.5mm extending in the longest direction, so-called microtablets or micropellets, to about 20mm, preferably in the range of 2-10 mm. For non-pharmaceutical use, for example, as a "tablet" for veterinary use containing a food product to be dissolved in water, or as a "tablet" containing a chemical agent for use in a technical process, the size may be much larger, for example up to the size of a golf ball.

As will be readily appreciated from the description of the method of the present invention, this method is less time consuming and less energy consuming than the standard freeze-drying process where the amount of water to be removed by lyophilization is much greater. In another aspect, a tablet-like oral dosage form is obtained having a porous structure similar to that obtained by standard lyophilization processes.

The oral pharmaceutical dosage forms so produced may be immediately packaged in suitable containers for transport and use, such as regular or peel-off (peel-of) blister packs, depending on the nature of the tablet components and their tensile strength.

As a result of the particular preparation process used, the dosage forms of the present invention typically have a density of 200-1000mg/ml, preferably 300-900mg/ml, more preferably 600-900mg/ml or 400-800 mg/ml. This is a much lower density than the density of compressed dosage forms like conventional tablets (having a density above 1000 mg/ml). As a result of its very low density, the dosage form of the present invention disintegrates faster than if the mixture of its components were subjected to compressive forces.

The following examples illustrate the invention but in no way limit its scope.

Detailed Description

Example 1: loperamide rapidly disintegrating tablets, standard active ingredient

Sodium bicarbonate (1.0kg) and peppermint flavor (0.01kg) were mixed with mannitol (244.38kg) in batches (portionbyportion) in a mixer until homogeneous, yielding fraction I as a powder. Gelatin (0.6kg) was dissolved in water (50kg) under mild heat. Aspartame (0.01kg) was added to the solution followed by loperamide hydrochloride (4.0kg) to obtain part II as a solution. In a blister pack device suitable for freeze drying, an accurately weighed portion of powder (part I) is dosed into the cavity of the blister pack lower foil. In the second step, an accurately weighed portion of the solution (part II) was added. The blister foil with the filled cavities is transported to the freezing section of the blister pack device and frozen between-20 ℃ and-50 ℃. After freezing, the water is evaporated (sublimed) in high vacuum. The single portion of the dried tablet of sufficient tensile strength weighed 125 mg. Finally, the blister packs are sealed with a cover foil and further packaged into suitable packages using standard procedures.

Example 2: ibuprofen rapidly disintegrating tablet, sparingly soluble active ingredient

Ibuprofen (20.0kg) and citrus orange flavor powder (0.3kg) were mixed with mannitol (171.6kg) in batches (protionprecipitation) in a mixer until homogeneous, yielding fraction I as a powder. Hydrolyzed gelatin (3.0kg), aspartame (0.1kg) and mannitol (5.0kg) were dissolved in water (50kg) under mild heat to give part II as a solution. In a blister pack device suitable for freeze drying, an accurately weighed portion of powder (part I) is dosed into the cavity of the blister pack lower foil. In the second step, an accurately weighed portion of the solution (part II) was added. A moist plasticized mass is obtained which contains the exact amounts of the components per tablet. The blister foil with filled cavities was further processed as described in example 1 to give single portions of dry tablets of sufficient tensile strength weighing 200 mg.

Example 3: acetylsalicylic acid rapidly disintegrating tablet, stabilizing and coating active ingredient

Acetylsalicylic acid (300.0kg) was stabilized by mixing with an alcoholic solution containing anhydrous citric acid (30.0kg) in ethanol and evaporated to dryness. The stabilized acetylsalicylic acid crystals were then coated with aqueous ethyl cellulose (8%, 125.0kg) ethanol according to standard procedure of a fluidized bed reactor and dried to give approximately 340kg of product. This product was intimately mixed with mannitol (537.0kg), sodium saccharin (sweetener, 1.0kg) and raspberry flavor powder in a mixer by stirring to give part I as a powder. Polyvinylpyrrolidone (8.0kg) and mannitol (10.0kg) were dissolved in deionized water (180kg) under mild heat to give part II as a solution. In a blister pack device suitable for freeze drying, an accurately weighed portion of powder (part I) is dosed into the cavity of the blister pack lower foil. In the second step, an accurately weighed portion of the solution (part II) was added. A moist plasticized mass is obtained which contains the exact amounts of the components per tablet. The blister foil with filled cavities was further processed as described in example 1 to give single portions of dry tablets of sufficient tensile strength weighing 300 mg.

Example 4: rapidly disintegrating tablet of 5-aminosalicylic acid, pre-formed pellets containing active ingredient

Sucrose powder (75kg), corn starch (8kg) and sodium carboxymethyl starch (Vivistar)2.5kg) were mixed intimately until homogeneous. The pre-coated pellets of 5-aminosalicylic acid (100kg) were uniformly distributed in the mixed powder to give a solid fraction I. Gelatin (3kg), mannitol (11kg) and caramel flavourings (0.5kg) were dissolved in water (approximately 60kg) under mild heat to give part II as a solution.

In a blister pack device suitable for freeze-drying, an accurately weighed portion of powder (part I, 1.855g) is dosed into the cavity of the blister pack lower foil. In the second step, an accurately weighed portion of the solution cooled to room temperature (part II, 0.745g) was added. The blister foil with filled cavities containing the thoroughly moistened mass was frozen at-30 ℃. In the next step, the water is sublimated in a high vacuum and the blister pack is sealed with a cover foil. A single dry tablet has sufficient tensile strength and contains 2.0g of product.

Example 5: decalcifying agent

Sodium hexametaphosphate (980g), tetrasodium pyrophosphate (6.0g), polyacrylic acid (0.5g), and sodium metaphosphate (3.5g) were mixed in a mixer with stirring until uniform to obtain fraction I as a powder. Sodium carbonate (10.0g) was dissolved in water (100g) to give a liquid fraction II. The solid powder (part I) is first weighed into the cavity of the blister pack lower foil. Each dose of powder part I was then thoroughly wetted with the measured dose of liquid part II. The blister foil with filled cavities was further processed as described in example 1 to give single portions of dry tablets of sufficient tensile strength weighing 1g, suitable for rapid dissolution in water for decalcification.

Example 6: mint essence

Standard peppermint extract (1.5kg) and mannitol (1.5kg) were mixed using a blender until homogeneous to give part I as a powder. Sucrose (0.3kg) was dissolved in water (0.6kg) as a binder to obtain a liquid fraction II. The solid powder (part I) was dosed in measured amounts into the cavities of the blister pack lower foil and uniformly wetted with the measured dose of part II. The blister foil with filled cavities was further processed as described in example 1 to give single portions of dried tablets of sufficient tensile strength weighing 3g suitable for rapid dissolution in hot water for making mint teas.

Example 7: furosemide

Citric acid (30.0kg) was homogeneously mixed with mannitol (100.0kg) and colloidal silicon dioxide (0.5kg) to give part I as a powder. Furosemide-sodium (50.0kg) was suspended and dissolved as much as possible together with povidone 30(1.5kg), aspartame (0.05) and mannitol (17.95kg) in water (about 70.0-80.0kg) to give liquid fraction II. In a blister pack device suitable for freeze drying, an accurately weighed portion of powder (part I) is dosed into the cavity of the blister pack lower foil. In the second step, an accurately weighed portion of the solution (part II) was added. The blister foil with the filled cavities is transported to the freezing section of the blister pack device and frozen at a temperature between-20 ℃ and-50 ℃. After freezing, the water is evaporated (sublimed) in high vacuum. The weight of a single portion of dried tablet of sufficient tensile strength is 100 mg. The dose of furosemide-sodium is 25 mg/tablet. Finally, the blister packs are sealed with a cover foil and further packaged in suitable packaging using standard procedures.

Example 8: flurbiprofen

Sodium carbonate (30.0kg) was mixed homogeneously with mannitol (50.0kg) and colloidal silicon dioxide (0.3kg) to give part I as a powder. Flurbiprofen-acid (10.0kg) was suspended in a solution of hydrolysed gelatin (1.5kg), sodium saccharin (0.05) and mannitol (28.15kg) in water (approximately 40.0kg) to give a liquid fraction II. In a blister pack device suitable for freeze drying, an accurately weighed portion of powder (part I) is dosed into the cavity of the blister pack lower foil. In the second step, an accurately weighed portion of the solution (part II) was added. The blister foil with the filled cavities is transported to the freezing section of the blister pack device and frozen at a temperature between-20 ℃ and-50 ℃. After freezing, the water is evaporated (sublimed) in high vacuum. The weight of a single portion of the dried tablet of sufficient tensile strength was 70 mg. The single dose of the drug flurbiprofen-acid was 5 mg/tablet. Finally, the blister packs are sealed with a cover foil and further packaged in suitable packaging using standard procedures.

Claims (12)

1.A method of preparing a rapidly disintegrating solid dosage form comprising:

(a) introducing a mixed solid powder formulation comprising one or more structure building components selected from the group consisting of sugar alcohols and sugars into the cavity of a blister pack or a mould,

(b) dosing the remaining ingredients comprising the binder dissolved in water into a cavity containing said powder to form a moist, plasticized mass, wherein the amount of water used is between 20% and 70% (w/w) of the total weight of all ingredients,

(c) freezing to below-20 deg.C, and

(d) the frozen water was sublimed in high vacuum.

2.The process according to claim 1 for the preparation of a rapidly disintegrating solid oral dosage form containing a pharmaceutically active ingredient.

3.The process according to claim 1 for the preparation of a fast-disintegrating solid oral dosage form containing a food product.

4.The method of claim 1, 2 or 3, wherein the structural component further comprises a bulking agent or other excipient.

5.The method according to any one of claims 1-3, wherein the binder is hydrolyzed or non-hydrolyzed gelatin, polyvinylpyrrolidone, cellulose ether or pregelatinized starch.

6.The method of claim 2, wherein the pharmaceutically active ingredient is selected from the group consisting of antacids, analgesics, anti-inflammatory agents, antibiotics, laxatives, appetite suppressants, antiasthmatics, diuretics, antiflatulents, antimigraine agents, antiarrhythmics, antispasmodics, sedatives, antihyperactive agents, tranquilizers, antihistamines, decongestants, β -blockers, coronary vasodilators, bronchodilators, muscle relaxants, anticoagulants, antiepileptics, antiemetics, hypotensives, sympathomimetics, expectorants, oral antidiabetic agents, hormones, and combinations thereof.

7.The method according to claim 6, wherein the pharmaceutically active ingredient is selected from loperamide, ibuprofen, acetylsalicylic acid, 5-aminosalicylic acid, furosemide and flurbiprofen.

8.The method according to claim 6, wherein the pharmaceutically active ingredient is in a pre-treated form.

9.A process according to any one of claims 1 to 3, wherein the solid powder comprises at least 30% (w/w) of the total weight of the solid dosage form components comprising the water to be sublimed in the process.

10.The method according to claim 9, wherein the solid powder comprises at least 50% (w/w) of the total weight of the solid dosage form components comprising the water to be sublimed in the method.

11.The method according to claim 9, wherein the solid powder comprises at least 75% (w/w) of the total weight of the solid dosage form components comprising the water to be sublimed in the method.

12.A method according to any one of claims 1 to 3, wherein the amount of water used is between 30% and 40% (w/w) of the total weight of all components。