MX2015006399A - Composition for immediate and extended release. - Google Patents

Abstract

The subject invention relates to fast dissolving pharmaceutical compositions comprising an active ingredient for immediate release and further comprising a controlled release dosage form comprising an active ingredient for controlled release.

Description

COMPOSITION FOR IMMEDIATE AND PROLONGED RELEASE FIELD OF THE INVENTION The present invention relates to fast-dissolving pharmaceutical compositions comprising an active ingredient for immediate release and further comprising a controlled release dosage form comprising an active ingredient for controlled release, methods for making them and their use in controlled release. the treatment and prophylaxis of diseases in mammals, particularly in humans.

BACKGROUND OF THE INVENTION Rapidly dissolving pharmaceutical dosage forms which are designed to immediately release an active ingredient in the oral cavity are well known and can be used to deliver a wide variety of drugs (Critical Reviews in Therapeutic Drug Carrier Systems, 21 (6): 433-475 (2004); Seager H. (1998), J. Phar. Pharmacol 50: 375-382; Bandari et al. (January 2008), Asian Journal of Pharmaceutics 2-1D.

In a fast dissolving dosage form, a drug is physically trapped in a matrix composed of a carrier material, for example, mannitol and fish gelatin (EP 1 501 534; EP 1 165 053), modified starch (US 6,509,040), pullulan in combination with an amino acid (EP 1 803 446), maltodextrin in combination with sorbitol (document US 2004/0228919), levan (WO · 2011/120904) or inulin (WO 2011/120903). For the preparation of the fast dissolving dosage form, a solution, suspension or dispersion of the drug and the carrier material can be poured into bubble-type, frozen and then lyophilized bubble cavities.

Controlled release tablets comprising an active ingredient that is released in a controlled manner are also well known in the art and are described for example in US 6, 911, 217, US 2009/0192228, EP 1 781 275 and WO 2007/029087. These controlled release beads have typically been used in the pharmaceutical industry within pharmaceutical capsules (hard gelatin) for oral administration and can be prepared by a wide variety of methods such as stratification, extrusion spheronization, granulation, melt extrusion. hot, spray drying and the like.

Certain diseases and disorders require that a drug be administered in such a way that Immediate release results and another drug is administered in such a way that prolonged release results. Naturally, it would be advantageous if there were two drugs that could be administered in an individual dosage unit which would release one drug in an immediate form and the other in a prolonged manner.

SUMMARY OF THE INVENTION The present invention now provides a formulation that not only comprises a first drug for immediate release trapped in a matrix, but additionally comprises another dosage form trapped within the matrix, the other dosage form is sustained release beads comprising a second drug for prolonged release.

The present invention thus provides a single dose unitary pharmaceutical combination product comprising a lyophilized, melt-like, dissolving or rapidly disintegrating type formulation comprising a first active ingredient for immediate release (IR). ) wherein the rapid dissolution formulation further comprises prolonged release tablets (ER) comprising a second ingredient pharmaceutically active that is released in a controlled manner. Prolonged-release tablets are entrapped or physically integrated into the matrix of the rapid dissolution formulation.

Rapidly dissolving oral pharmaceutical compositions are typically oral lyophilized (also called oral disintegrating tablets or oral dissolution tablets), which comprise a first active ingredient for immediate release (IR) and which further comprise prolonged release (ER) tablets which they comprise a second pharmaceutically active ingredient that is released in a controlled manner.

The extended-release tablets can be formulated by methods known in the art such as stratification, extrusion spheronization, granulation, hot melt extrusion, spray drying and the like.

It has been discovered that the composition of the present invention, which comprises tablets within a rapid dissolution formulation, allows to achieve many unexpected and beneficial technical effects: • Stable release profiles of the first drug and the second drug (active ingredients), ie release profiles which are similar to, substantially identical or identical to those observed in separate compositions comprising only the first drug in an IR formulation and the second drug in an ER formulation, respectively; • A relatively high tensile strength (ie the force required to break a tablet in a three-point bend test) compared to a tabletless composition; • A total weight of the composition which is pharmaceutically acceptable and acceptable from the point of view of a consumer; • A short disintegration / dissolution time of less than 30 seconds; Y • The composition can be prepared by lyophilization with only little, substantially without or without influence on the prolonged release profile of the tablet.

The relatively high tensile strength allows, among other things, to easily remove the composition from its container, typically a bubble-type package, without disintegration and without risk of damaging the dosage form between the fingers. The unit dosage form of the invention can typically be handled in a manner similar to that of a conventional compressed tablet, without disintegration occurring. only on contact with a watery liquid or with saliva inside the mouth.

Notwithstanding this tensile strength, the composition of the invention rapidly disintegrates when in contact with an aqueous medium or with saliva, in particular the composition disintegrates rapidly when orally ingested.

The pharmaceutical composition of the invention can be obtained by sublimating a solvent (for example water), for example in a freeze drying process, from a liquid preparation comprising the first active ingredient, the forming agent (s) ( is) of matrix and controlled release beads (which also comprise a second additional active ingredient) in solution. According to one embodiment, the amounts of unit dosages of the liquid preparation are introduced into depressions and then the sublimation is carried out, to thereby obtain (after sublimation) a pharmaceutical composition in a unit dosage form comprising Two active ingredients, one for immediate release and one for controlled release. The depressions can be those of an open bubble-like package and after the sublimation step (and thus after the formation of the solid unit dosage form of the composition in the depression), a film or thin sheet of sealing metal is placed over the depressions to form a sealed bubble-like package.

In particular, the present invention relates to a pharmaceutical composition comprising an open matrix network comprising a first pharmaceutically active ingredient; one or more matrix forming agents; and controlled release beads comprising a second pharmaceutically active ingredient.

The invention further relates to a process for preparing a pharmaceutical composition comprising sublimating a solvent of a liquid preparation comprising a first pharmaceutically active ingredient, one or more matrix-forming agents, controlled release tablets comprising a second pharmaceutically active ingredient and a solvent The invention also relates to a process for the preparation of a pharmaceutical composition comprising the steps consisting of: (a) preparing a mixture comprising a first active ingredient, controlled release beads comprising a second active ingredient, one or more matrix-forming agents and a solvent; (b) freezing the solution; (c) sublimate the solvent of the frozen solution, wherein the pharmaceutical composition obtained in this manner disintegrates within 30 seconds upon contact with a standardized aqueous medium.

The invention relates to a method for treating overactive bladder, nocturia or a combination thereof in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of a composition wherein the second active ingredient is an antimuscarinic compound. .

The invention relates to a method for treating benign prostatic hyperplasia in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of a composition wherein the second active ingredient is a selective alpha-blocker.

BRIEF DESCRIPTION OF THE DRAWINGS Figure la is a schematic representation of a single dose unitary pharmaceutical combination product of the invention comprising a freeze-dried, fast dissolving, melt-type formulation comprising a first active ingredient for immediate release wherein the dissolution formulation Rapid also comprises prolonged-release tablets comprising a second pharmaceutically active ingredient which is released in a controlled manner.

Figure Ib is a schematic representation of a prolonged-release tablet or bead which is used in the present invention and which comprises: 1: a core 2: an optional interior sealer coating layer 3: a layer containing inner drug 4: an optional exterior sealer coating layer 5: an outer membrane layer and 6: an optional additional polymer layer.

The Figure is a schematic representation of a prolonged-release tablet or bead used in the present invention and comprising a core comprising drug, excipients and optionally controlled-release polymers. The core can optionally be coated with a controlled release polymer.

Figure 2 is a diagram comparing the dissolution profiles of beads (particles) and lyophilized ER of Detrusitol XLMR and tolterodine according to Example 1 in phosphate buffer at pH 6.8 using Apparatus 1 (basket) of the Pharmacopoeia of the United States (USP, for its acronym in English) at 100 rpm.

Figure 3 is a diagram that compares the release of the first active ingredient (desmopressin) and the second active ingredient (tolterodine) from the dosage form of Example 2 in phosphate buffer at pH 6.8 using Apparatus 2 (paddle) of the USP at 50 rpm for desmopressin and the Apparatus 1 (basket) of the USP at 100 rpm for tolterodine.

Figure 4 is a diagram comparing the release of the first active ingredient (desmopressin) and the second active ingredient (tolterodine) from the dosage form of Example 3 in phosphate buffer at pH 6.8 using Apparatus 2 (pallet) from USP at 50 rpm for desmopressin and Apparatus 1 (basket) of the USP at 100 rpm for tolterodine.

Figure 5 is a diagram comparing the release of the first active ingredient (desmopressin) and the second active ingredient (tolterodine) from the dosage form of Example 4 in phosphate buffer at pH 6.8 using Apparatus 2 (pallet) from USP at 50 rpm for desmopressin and Apparatus 1 (basket) of the USP at 100 rpm for tolterodine.

Figure 6 is a diagram comparing the release of the first active ingredient (desmopressin) and the second active ingredient (tolterodine) from the dosage form of Example 5 in phosphate buffer at pH 6.8 using Apparatus 2 (pallet) from USP at 50 rpm for desmopressin and Apparatus 1 (basket) of USP at 100 rpm for tolterodine.

Figure 7 is a diagram comparing the dissolution profiles of beads (particles) and lyophilized ER of Detrusitol XL® and tolterodine according to Example 6 in phosphate buffer at pH 6.8 using Apparatus 1 (basket) of the Pharmacopoeia from the United States (USP) at 100 rpm.

Figure 8 is a diagram comparing the dissolution profiles of beads (particles) and lyophilized ER of Detrusitol XL ^ ® and tolterodine according to Example 7 in phosphate buffer at pH 6.8 using Apparatus 1 (basket) of the United States Pharmacopeia (USP) at 100 rpm.

Figure 9 is a diagram comparing the dissolution profiles of beads (particles) and lyophilized ER of Detrusitol XLMR and tolterodine according to Example 8 in phosphate buffer at pH 6.8 using Apparatus 1 (basket) of the Pharmacopoeia of the United States (USP) at 100 rpm.

Figure 10 is a diagram comparing the release of the first active ingredient (desmopressin) and the second active ingredient (tolterodine) from the dosage form of Example 9 in phosphate buffer at pH 6.8 using Apparatus 2 (pallet) from USP at 50 rpm for desmopressin and Apparatus 1 (basket) of USP at 100 rpm for tolterodine.

Figure 11 is a diagram comparing the release of the first active ingredient (desmopressin) and the second active ingredient (tolterodine) from the dosage form of Example 10 in phosphate buffer at pH 6.8 using Apparatus 2 (pallet) from USP at 50 rpm for desmopressin and Apparatus 1 (basket) of the USP at 100 rpm for tolterodine.

Figure 12 is a diagram comparing the release of the first active ingredient (desmopressin) and the second active ingredient (tolterodine) from the dosage form of Example 11 in phosphate buffer at pH 6.8 using Apparatus 2 (pallet) from USP at 50 rpm for desmopressin and Apparatus 1 (basket) of the USP at 100 rpm for tolterodine.

Figure 13 is a diagram comparing the release of the first active ingredient (desmopressin) and the second active ingredient (tolterodine) from the dosage form of Example 12 in phosphate buffer at pH 6.8 using Apparatus 2 (pallet) from USP at 50 rpm for desmopressin and Apparatus 1 (basket) of the USP at 100 rpm for tolterodine.

Figure 14 is a diagram comparing the release of the first active ingredient (desmopressin) and the second active ingredient (tolterodine) of the dosage form of Example 13 in phosphate buffer at pH 6.8 using Apparatus 2 (paddle) of USP at 50 rpm for desmopressin and Apparatus 1 (basket) of USP at 100 rpm for tolterodine.

Figure 15 is a diagram comparing the release of the first active ingredient (desmopressin) and the second active ingredient (tolterodine) from the dosage form of Example 14 in phosphate buffer at pH 6.8 using Apparatus 2 (pallet) from USP at 50 rpm for desmopressin and Apparatus 1 (basket) of the USP at 100 rpm for tolterodine.

DETAILED DESCRIPTION OF THE INVENTION , An object of the invention is to provide a dosage form comprising two active ingredients, one of which must be released immediately and one in a controlled manner.

The present invention now provides a new orodispersible dosage form comprising two drugs (active ingredients). One of the drugs is released in an immediate way, the other in a controlled manner. The dosage form is a fast dissolving dosage form such as, but not limited to, a melt or lyophilized type unit.

The drug released in a controlled manner is comprised within tablets (beads) which in turn are contained within the rapid dissolution formulation. Despite the presence of the tablets within the fast dissolving dosage form, the composition is stable, the weight of the complete composition is pharmaceutically acceptable and acceptable from the point of view of a consumer and the time of oral dissolution of the Fast dissolving dosage form is still fast.

The terms "drug", "active ingredient" or "pharmaceutically active ingredient" will be used interchangeably in this document.

The term "pharmaceutical composition" and "composition" are used interchangeably herein to refer to a pharmaceutical composition of the invention.

The terms "controlled release tablets" or "tablets" or "controlled release beads" or "beads" or "controlled release particles" or "particles" will be used interchangeably herein.

The controlled release beads can be manufactured by various methods known in the field such as stratification, spheronization by extrusion, granulation, hot melt extrusion, spray drying and so on wherein the second active ingredient is mixed and / or coated with release controlling agents.

When the controlled release beads are made by stratification, the controlled release beads typically contain a pharmaceutically inactive core 1 selected from a water-soluble core, a water-insoluble core and a water-swellable core coated with a layer that it contains interior drug 3 and an outer membrane layer 5 that controls the release of the drug from the inner layer.

Some controlled release beads also comprise a "sealant coating" 2 made of a polymer selected from a substantially water-insoluble polymer and a substantially water-soluble polymer, between the inner core 1 and the inner drug-containing layer 3.

Some controlled release beads also comprise a "sealant coating" 4 made of a polymer selected from substantially water-insoluble polymer and a substantially water-soluble polymer, between the inner drug-containing layer 3 and the outer membrane layer 5.

The controlled release pearls can further contain an additional polymer layer 6 on the outer membrane layer 5.

An object of the invention is to provide controlled release beads, the drug release profile of which is not significantly influenced by lyophilization, thereby making possible the use of those beads within the lyophilized dosage forms of the invention.

The cores are typically made of a water-soluble, water-insoluble or water-swellable material, and can consist of any material that is conventionally used as cores or any other water-soluble, water-insoluble or water-swellable material that can be form in pearls or tablets. For example, the nuclei may be sucrose / starch spheres (NF Sugar Spheres), sucrose crystals, glass or microcrystalline cellulose. In particular, the cores can be water-soluble sugar spheres or water-swellable microcrystalline cellulose cores. The cores can be made, for example, by extrusion and subsequent drying of extruded products of excipients such as microcrystalline cellulose and lactose.

The polymer substantially insoluble in water in the optional sealant coating layers 2 and 4 located (i) between the core 1 and the layer containing interior drug 3 and / or (ii) between the inner drug-containing layer 3 and the outer membrane layer 5 (to control the penetration of water into the core) is generally a film-forming polymer "insoluble in GI fluids" (GI) = gastrointestinal) or "partially insoluble in GI fluids". Non-limiting examples of these polymers are ethyl cellulose, cellulose acetate, cellulose acetate butyrate, polymethacrylates such as ethyl acrylate / methyl methacrylate copolymer (Eudragit NE 30 Dm) and types A and B of sodium methacrylate copolymer. ammonium (Eudragit RL 30 D®1 and Eudragit RS 30 D®), silicone elastomers and mixtures of two or more of them. In a particular modality, the substantially water insoluble polymer of the inner sealant coating layer 2 comprises ethyl cellulose. Occasionally, one or more plasticizers are used together with the polymer. Non-limiting examples of plasticizers include dibutyl sebacate, propylene glycol, triethyl citrate, tributyl citrate, castor oil, acetylated monoglycerides, acetyl triethyl citrate, acetyl butyl citrate, diethyl phthalate, dibutyl phthalate, triacetin, medium chain triglycerides such as fractionated coconut oil and so on.

The water-soluble polymer of the layers of optional sealant coating 2 and 4 may be selected from hydrophilic polymers such as polyvinylpyrrolidone (PVP), polyalkylene glycol such as polyethylene glycol, gelatin, polyvinyl alcohol, starch and derivatives thereof, cellulose derivatives, such as hydroxypropylmethyl cellulose (HPMC), hydroxypropyl- cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethyl hydroxyethyl cellulose, acrylic acid polymers, polymethacrylates and mixtures of two or more thereof.

The inner layer 3 containing the (second) active ingredient can be comprised of the active ingredient (drug) with or without a polymer as a binder. The binder, when used, is usually hydrophilic and can be soluble in water or insoluble in water. Non-limiting examples of polymers that are used in the inner layer containing the active drug are hydrophilic polymers such as polyvinylpyrrolidone (PVP), polyalkylene glycol such as polyethylene glycol, gelatin, polyvinyl alcohol, starch and derivatives thereof, cellulose derivatives, such as hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethylhydroxyethyl cellulose, acrylic acid polymers, polymethacrylates and mixtures of two or more thereof. In a particular embodiment, the inner drug-containing layer 3 comprises hydroxypropylmethyl cellulose as a binding agent. The ratio of the drug to the hydrophilic polymer in the inner layer is usually in the range of 1: 5 to 10: 1 (w / w).

Polymers suitable for use in the outer membrane layer 5 for controlling drug release may be selected from water insoluble polymers or polymers with pH-dependent solubility, such as, for example, ethyl cellulose, hydroxypropylmethyl cellulose phthalate. , cellulose acetate phthalate, cellulose acetate trimellitate, polymethacrylates or mixtures thereof, optionally combined with plasticizers, such as those mentioned above. Optionally, the controlled release layer comprises, in addition to the above polymers, another substance (s) with different solubility characteristics, to adjust the permeability and, thus, the rate of release of the second drug. Exemplary polymers that can be used as a modifier together with, for example, ethyl cellulose include: HPMC, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, polyethylene glycol, polyvinylpyrrolidone (PVP), polyvinyl alcohol, polymers with pH-dependent solubility, such as cellulose acetate phthalate or ammonium methacrylate copolymer and methacrylic acid copolymer, or mixtures thereof. Additives such as sucrose, lactose, pharmaceutical grade surfactants and mixtures of two or more thereof can also be included in the controlled release layer. In a particular embodiment, the outer membrane layer 5 comprises a combination of hydroxypropylmethyl cellulose (HPMC) and ethyl cellulose.

Polymers suitable for use in the optional additional polymer layer 6 on the outer membrane layer 5 are those which can provide an enteric and / or lyoprotective functionality and can be selected from copolymers of methacrylic acid, cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethylethylcellulose, shellac, cellulose ethers (eg, ethylcellulose, hypromellose, hiprolose), PVP, acrylate polymers (e.g., Eudragit NE 30 DMR, Eudragit RL * ®, Eudragit RS *) and mixtures of two or more thereof. These can be coated in the form of solutions or dispersions on the membrane layer exterior 5. Optionally, the lyoprotectant functionality may be prevented from dissolving the outer membrane 5 during lyophilization.

Controlled release beads are prepared by: a) providing a core unit 1 of a material substantially water soluble, insoluble in water or swellable in water; b) optionally applying an inner sealant coating layer 2 of a polymer on the core 1; c) applying on the core 1 or on the inner sealant coating layer 2 an inner layer 3 containing the (second) active ingredient and optionally a polymeric binder; d) optionally applying an outer sealant coating layer 4 of a polymer on the inner layer 3; e) applying on the inner layer 3 or on the outer sealant coating layer 4 an outer membrane layer 5 which is effective for the controlled release of the active ingredient; Y f) optionally applying an additional polymer layer 6 on the outer membrane layer 5.

Stratification operations or Coating is preferably performed by atomizing a solution or dispersion of the respective layer material (s) on the core, for example in a centrifugal coater, coating pan, Granurex * rotary process or fluidized bed coater. , preferably in a fluidized bed coater.

After the coating of the sealant coating and the outer layers, the beads can be "cured", usually in a fluidized bed system or in a tray drying system, for example by heating at a temperature of about 30-80 °. C for approximately 60 minutes.

In one embodiment, the amount of the optional interior sealant coating layer 2 constitutes from about 4% to about 15% (w / w) of the final composition of the beads.

In one embodiment, the amount of the inner layer containing drug 3 constitutes from about 5% to about 25% (w / w) of the final composition of the beads.

In one embodiment, the amount of the optional outer sealant coating layer 4 constitutes from about 1% to about 25% (w / w) of the final composition of the beads.

In one embodiment, the amount of the outer membrane layer 5 constitutes from about 25% to about 55% (w / w) of the final composition of the beads.

In one embodiment, the amount of the optional additional polymer layer 6 constitutes from about 10% to about 35% (w / w) of the final composition of the beads.

When the controlled release tablets are obtained by means of hot melt extrusion, the (second) active ingredient and a controlled release excipient are extruded using a known hot melt extrusion equipment. The resulting extruded products are milled and sieved to obtain the desired fraction. The dried particles of a desired particle size are optionally coated with a controlled release polymer. The particle coating can be made in an appropriate coating equipment, for example, a centrifugal coating machine, a coating tray, a Graijurex® rotary process, a fluidized bed coater and the like.

The controlled release excipient for use in hot melt extrusion can be selected from ethyl cellulose, phthalate hydroxypropylmethyl cellulose, cellulose acetate phthalate, cellulose acetate trimellitate, polymethacrylates, HPMC, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, polyethylene glycol, polyvinyl pyrrolidone (PVP), polyvinyl alcohol, carbomer, poly (lactide) co-glycolide), polyethylene oxide, glyceryl palmitostearate, glyceryl behenate and mixtures of two or more thereof, optionally combined with plasticizers, such as those mentioned above.

When the controlled release beads are obtained by spray drying, the (second) active ingredient and a controlled release polymer dissolve or disperse in a medium. This solution or dispersion is spray-dried and the resulting particles are optionally dried and sieved to obtain the desired particle size.

The controlled release polymers for use in spray drying can be selected from polymers such as, for example, ethyl cellulose, hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, polymethacrylates, HPMC , hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, polyethylene glycol, polyvinyl pyrrolidone (PVP), polyvinyl alcohol and mixtures of two or more thereof, optionally combined with plasticizers, such as those mentioned above.

When the controlled release beads are obtained by means of granulation, the (second) active ingredient is dry mixed with excipients and granulated using a binder solution. The granules are dried and sieved to obtain the desired fraction. Dry granules of the desired particle size can be further coated with a controlled release polymer. Alternatively, the active ingredient and a controlled release excipient are dry blended and granulated using a binder solution. The granules are then dried and sieved to obtain the desired fraction. Dry granules of the desired particle size can optionally be additionally coated with a controlled release polymer.

The granulation process is performed in a granulator such as, but not limited to, a fast mixer granulator, planetary mixer, fluidized bed processor, centrifugal granulator and the like. The coating of granules can be carried out in an appropriate coating equipment such as a centrifugal coating machine, coating tray, rotary process Granurex®, fluidized bed coater and the like.

The controlled release polymers for use in the granulation can be selected from polymers such as, for example, ethyl cellulose, hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, polymethacrylates, HPMC, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, polyethylene glycol, polyvinyl pyrrolidone (PVP), polyvinyl alcohol and mixtures of two or more thereof, optionally combined with plasticizers, such as those mentioned above.

When the controlled release beads are obtained by means of extrusion spheronization, the (second) active ingredient, a filler and optionally a controlled release polymer are dry blended and granulated in a granulator such as a mixer granulator fast, planetary mixer, fluidized bed processor, centrifugal granulator and the like. The wet mass obtained is then extruded and spheronized to form spherical particles. The spherical particles are dried and sieved to obtain the desired fraction. The dried particles of the desired particle size can be additionally coated with optionally with a controlled release polymer. Alternatively, the extruded particles are dried and sieved to obtain the desired fraction. The dried particles of the desired particle size can optionally be additionally coated with a controlled polymer. The particle coating is performed in an appropriate coating equipment, for example, a centrifugal coating machine, coating pan, Granurex ™ rotary process, fluidized bed coater and the like.

The controlled release polymers for use in extrusion-spheronization can be selected from polymers such as, for example, ethyl cellulose, hydroxypropylmethyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, polymethacrylates, HPMC, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, polyethylene glycol, polyvinyl pyrrolidone (PVP). , polyvinyl alcohol and mixtures of two or more thereof, optionally combined with plasticizers, such as those mentioned above.

In one embodiment, the prolonged release profile of the beads used in the present invention is resistant to, ie is not substantially influenced by, the lyophilization process used. for preparing the pharmaceutical composition of the invention.

It should be understood that the term "matrix" indicates a solid carrier medium for an active ingredient. The matrix comprises one or more excipients. The excipients forming the matrix are referred to herein as "matrix forming agents" and each of the agents as "matrix forming people".

It should be understood that the term "an open matrix network" comprises a matrix of water-soluble or water-dispersible carrier material (matrix-forming agent (s)) having interstices dispersed throughout. The matrix disintegrates rapidly on contact with an aqueous medium or with saliva.

Unless defined otherwise, the percentages within the specification and the claims are based on weight (% by weight or w / w).

The matrix forming agent in the composition can be any agent capable of forming a matrix of a water-soluble or water-dispersible carrier material. Non-limiting examples of matrix forming agents are levan, inulin, pullulan, sodium alginate, fish gelatin, beta-dextrin bound (BLD), modified starch, maltodextrin (optionally in combination with sorbitol), acacia gum, hydroxypropyl methylcellulose and / or pectin and any combination of same. In one embodiment, the matrix forming agents are selected from the group consisting of levan, inulin, pullulan, acacia gum, maltodextrin, HPMC, sodium alginate and combinations thereof.

Levan (also called leaven, levulosan, polifructose, polyfructose and polylevulan) is a fructose polymer, C6Hi206. Levan is a polysaccharide with b- (2-> 6) linkages between the fructose rings where the numbers describe the carbon atoms in the fructose ring which are linked and b describes the stereochemical relationship. Levans have also been described as fructans in which the predominant glycosidic linkage between the monomeric units of D-fructofuranoside is b- (2-> 6). Levanes are usually made by microorganisms and do not appear as high molecular weight compounds in plants. Some low molecular weight levans that have a molecular weight of less than 100,000 Daltons may appear on the turf.

It should be understood that "levan" as used herein comprises derived from any source such as but not limited to Aspergillus indicus, Aspergillus versicolor, Acetobacter suboxydans, Achromobacter spp., Actinomycenes sp., Actinomyces viscosus, Aerobacter aerogenes, Aerobacter levanicum. , Aspergillus sydowi, Azotobacter chroococcum, Bacillus polymyxa, Bacillus licheniformis, Bacillus macerans, Bacillus megatherium, Bacillus mesentericus, Bacillus subtilis, Bacillus vulgatus, laevaniformans Corynbacterium, Erwinia herbicola, Gluconobacter oxydans, Leuconostoc mesenteroides, Odontomyces viscosus, Phytobacterium vitrosum, Phytomonas pruni, Pseudomonas fluorescens, Pseudomonas syringae, Pseudomonas prunicola, Rothis dentocariosa, Serratia kiliensis, Steptococcus bovis, Steptococcus mutans, Streptococcus salivarius, Xanthomonas campestris, Xanthomonas pruni, Zymo onas mobilis and so on. In a specific modality, the levan is obtained from the Zymomonas and Bacillus species. In a more specific modality, the levan is obtained from Zymomonas mobilis.

It should be understood that also the levan derivatives (for example as described in WO 98/03184) can be used in place of the levan.

Inulin is a fructose polymer, C6HI206, which typically has a terminal glucose. Inulin is a polysaccharide with b- (2 > 1) linkages between fructose rings where the numbers describe the carbon atoms in the fructose ring which are linked and b describes the stereochemical relationship. Inulins are produced by many types of plants.

It should be understood that inulin as used herein comprises inulin derived from any source such as but not limited to plants that contain high concentrations of inulin which include, but are not limited to, Enula campana (Inula helenium); Dandelion (Taraxacum of fie inale); Ñame Silvestre (Dioscorea spp.); Jerusalem artichokes (Helianthus tuberosus); Chicory (Cichorium intybus); Jicama (Pachyrhizus erosus); Burdock (Arctium lappa); Onion (Allium cepa); Garlic (Allium sativu); Agave (Agave spp.); Yacon (Smallanthus sonchifolius spp.); and Beds (Camassia spp.). In a specific modality, inulin is obtained from Chicory (Cichorium intybus).

One or more secondary matrix forming agents may be present in the composition. Non-limiting examples of sugars, sugar alcohols, monosaccharides, disaccharides, trisaccharides, polysaccharides, proteins, amino acids, gums and the like, which are useful as secondary matrix forming agents, include without limitation, mannitol, trehalose, raffinose, inositol, pullulan, sucrose, lactose, dextrose, erythritol, xylitol, lactitol, maltitol, isomalt, alanine, arginine, threonine, glycine, cistern, serine, histidine, valine, proline, lysine, asparagine, glutamine, ribose, glucose, galactose, fructose, maltose, maltotriose, guar gum, xant no gum, tragacanth gum, veegum, microcrystalline cellulose, sodium carboxymethyl cellulose and so on the style.

Generally, the rest of the formulation can be a matrix. In this way, the percentage of the matrix can approach 100%. The amount of a secondary matrix forming agent that is useful in accordance with the present invention may vary from about 0 to about 30%.

In one embodiment of the invention, the levan is the main matrix forming agent in the composition. In another embodiment, inulin is the principal matrix forming agent. In yet another embodiment, both the levan and the inulin are used in combination as the main matrix forming agents.

In another embodiment, the composition further comprises mannitol or raffinose or trehalose or combinations thereof as secondary matrix forming agent (s) in the open matrix network.

In one embodiment, the levant is the matrix forming agent, which constitutes 10-50% of the complete weight of the composition. In another embodiment, the levan constitutes 20-40% of the complete weight of the composition. In yet another embodiment, the levan constitutes 25-35% of the complete weight of the composition.

In other embodiments, mannitol or trehalose or raffinose or combinations thereof are used as the secondary matrix forming agents, which constitute 10-40% of the complete weight of the composition. In one embodiment, those secondary matrix forming agents constitute 20-30% of the total weight of the composition.

In this manner, a composition of the invention can be one comprising levant as the main matrix forming agent and mannitol or trehalose or raffinose (or combinations thereof) as the secondary matrix forming agent, wherein the levan constitutes 10 - 50% (all% ingredients are w / w, which means that the weight of the mentioned ingredient is out of the weight of all the constituents of the composition combined) and the secondary matrix forming agent constitutes 10-40%, typically 20-30%.

The content of the first active ingredient may be typically (but not exclusively) in the range of 0.01-1% of the complete composition, typically in the range of 0.02-0.2% depending on the nature of the active ingredient. The content of the second active ingredient may typically (but not exclusively) be in the range of 1-50% of the complete composition, typically in the range of 3-10% depending on the nature of the active ingredient. In one embodiment, the active ingredients constitute approximately 4% of the total weight of the composition. In another modality, the Active ingredients constitute approximately 5% of the complete weight of the composition. In still another embodiment, the active ingredients constitute approximately 6% of the total weight of the composition. In other embodiments, the active ingredients constitute 7% of the total weight of the composition. In still other embodiments, the active ingredients constitute 8% of the total weight of the composition.

The term "disintegration" refers to the dissolution or "decomposition" of the matrix with the first drug for immediate release and release or release of the prolonged-release dosage form, such as tablets or beads, allowing them from this way they start to release the second drug, depending on the conditions in the aqueous medium. The disintegration in a standardized aqueous medium is typically within less than 30 seconds and more typically within less than 10 seconds, or even less than 9, 8, 7, 6, 5, 4, 3, 2 or even 1 second.

"Disintegration Time" and "Dissolution time" are used interchangeably in this document and should be understood to mean the time necessary to dissolve or disintegrate the composition of the invention in a standardized aqueous medium.

It must be understood that "oral dissolution time" as used in this document means time necessary to dissolve the composition of the invention in the oral cavity.

It should be understood that "rapid disintegration / dissolution" as used herein comprises the disintegration / dissolution of the composition of the invention in a standardized aqueous medium within 30 seconds, typically within 20, preferably within 10 seconds, or even within 9, 8, 7, 6, 5, 4, 3, 2 or second.

Examples of an aqueous medium as used herein are water or a buffer (for example potassium diacid phosphate, dipotassium acid phosphate, sodium acid phosphate) or artificial saliva as described by Morjaria et al. (May 2004), Dissolution Technologies 12-15. A "standardized aqueous medium" as used herein for the determination of decay time is as defined in the experimental section. The method for determining the decay time is as described in the experimental section.

Saliva as used herein refers to saliva in the oral cavity of a mammal, in particular a human.

It should be understood that "tensile strength" as used in this document is the required strength to break a tablet, which is measured by means of the three-point bend test, where the tablet is subjected to a bending stress (Mohd et al. (2002), Drug r Development and Industrial Pharmacy 28 (7): 809-813).

In one embodiment, a pharmaceutical composition of the invention has a tensile strength in the range of about 0.05 to 2 N / mm2. In another embodiment, a pharmaceutical composition of the invention has a tensile strength in the range of about 0.05 to 0.3 N / mm2. In another modality, a » The pharmaceutical composition of the invention has a tensile strength in the range of about 0.1-0.25 N / mm2. In yet another embodiment, a pharmaceutical composition of the invention has a tensile strength in the range of about 0.11-0.23 N / mm2.

It is contemplated that a pharmaceutical composition of the invention has a rapid disintegration / dissolution rate such that the composition dissolves in a standardized aqueous medium within 30 seconds, typically within 10 seconds.

In one embodiment, a pharmaceutical composition of the invention has a tensile strength in the range of about 0.05-2 N / mm2 and a speed of rapid disintegration / dissolution such that the composition dissolves in a standardized aqueous medium within 30 seconds, typically within 10 seconds.

In another embodiment, a pharmaceutical composition of the invention has a tensile strength in the range of about 0.05-0.3 N / mm2 and a rapid disintegration / dissolution rate such that the composition dissolves in a standardized aqueous medium within 30 seconds. , typically within 10 seconds.

In another embodiment, the invention provides a pharmaceutical composition comprising a first pharmaceutically active ingredient and a second pharmaceutically active ingredient, having a tensile strength ranging from about 0.05-2 N / mm2 and a fast disintegration / dissolution rate such that the composition dissolves in a standardized aqueous medium within 30 seconds, typically within 10 seconds.

In another embodiment, the invention provides a pharmaceutical composition comprising a first pharmaceutically active ingredient and a second pharmaceutically active ingredient, having a tensile strength ranging from about 0.05-0.3 N / mm2 and a fast disintegration / dissolution rate such that the composition Dissolve in a standardized aqueous medium within 30 seconds, typically within 10 seconds.

The open matrix network makes it possible for a liquid to enter the dosage form through the interstices and permeate through its interior. The permeation by aqueous means (such as saliva, water, etc.) exposes the carrier material of both the interior and exterior of the dosage form to the action of aqueous media or saliva whereby the network of the carrier material disintegrates. it dissolves rapidly thereby releasing the first active ingredient and the controlled release tablets into the oral cavity.

The open matrix structure is porous in nature and improves the disintegration of the dosage form as compared to the standard, solid, shaped, pharmaceutical dosage forms such as tablets (granulated and compressed), pills, capsules, suppositories and pessaries. Rapid disintegration results in rapid release of the active ingredient that is comprised in the matrix and also results in the release of controlled release beads which are swallowed / absorbed and which will release their active ingredient in a controlled manner.

The pharmaceutically active ingredients used in the present invention can be any pharmaceutically active ingredient such as a compound of low molecular weight, a peptide, a nucleotide and so on.

The first active ingredient and the second active ingredient may be identical or different from each other. In one modality, they are different from each other.

Non-limiting examples of drugs (active ingredients) which may be comprised in the open matrix network of the present invention and / or may be comprised within the tablets that are comprised within the open matrix network are analgesic, alpha- blockers, anti-allergic, anti asthmatic, (allergic rhinitis, chronic urticaria), anti-inflammatory, antacids, anthelmintics, anti-arrhythmic agents, anti-arthritic, anti-bacterial, anti-anxiety, anti-coagulants, anti-depressants, anti diabetics , anti-diarrheic, anti-diuretic, anti-epileptic, anti-fungal, anti-gout, anti-hypertensive, anti-incontinence, anti-insomnia, anti-malaria, anti-migraine, anti-muscarinic, anti-neoplastic and immunosuppressant, anti-protozoal, anti-rheumatic, anti-rhinitis, anti-spasmodic, anti-thyroid, antiviral, anxiolytic, sedative, hypnotic and neuroleptic, beta-blockers, anti-benign hyperplasia (BHP, for its sigl as in English), cardiac inotropes, corticosteroids, antitussives, cytotoxics, decongestants, diabetic gastric stasis, diuretics, enzymes, anti-parkinsonian, gastro-intestinal, histamine receptor antagonists, infertility, endometriosis, hormone replacement therapy, lipid regulating agents, local anesthetics, neuromuscular agents, nitrates and anti-anginal agents, menstrual disorders, motion sickness, analgesics, anti-nausea, movement disorders, nutritional agents, opioid analgesics, vaccines Oral, proteins, peptides and recombinant drugs, prevention of nausea and vomiting induced by chemotherapy and postoperative, proton pump inhibitors, schizophrenia, sex hormones and contraceptives, epileptic / panic attack disorder, sexual dysfunction (male and female) , spermicides, stimulants that cancel dysfunctions, veterinary medicines and so on.

Specific non-limiting examples of these drugs are: Alpha-Blockers: Tamsulosin Analgesics and anti-inflammatory agents: aspirin, aloxiprine, auranofin, azapropazone, benorilate, diflunisal, etodolac, fenbufen, calcium fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, oxifenbutazone, phenylbutazone, piroxicam, sulindac, paracetamol.

Antacids: aluminum hydroxide, magnesium carbonate, magnesium trisilicate, hydrotalcite, dimethicone.

Anthelmintics: albendazole, befenium hydroxynatodate, cambendazole, dichlorophen, ivermectin, mebendazole, oxamniquine, oxfendazole, oxantel embonate, praziquantel, pyrantel embonate, thiabendazole.

Anti-allergic: des-loratidina, loratidina, Montelukast, Montelukast sodium, Cetirizine, Fexofenadine, Ebastine.

Anti-arrhythmic agents: amiodarone HCl, disopyramide, flecainide acetate, quinidine sulfate.

Antibacterial agents: benetamine-penicillin, cinoxacin, ciprofloxacin HC1, clarithromycin, clofazimine, cloxacillin, demeclocycline, doxycycline, erythromycin, ethionamide, imipenem, nalidixic acid, nitrofurantoin, rifampicin, spiramycin, sulfabenzamide, sulfadoxine, sulfamerazine, sulfacetamide, sulfadiazine, sulfafurazole, sulfamethoxazole, sulfapyridine, tetracycline, trimethoprim.

Anticoagulants: dicoumarol, dipyridamole, nicoumalone, fenindione.

Antidepressants: amoxapine, cyclazindol, HC1 maprotiline, mianserin HCl, nortriptyline HC1, trazodone HC1, trimipramine maleate.

Anti-diabetics: acetohexamide, chlorpropamide, glibenclamide, glielazide, glipizide, tolazamide, tolbutamide.

Antidiarrheals: atropine sulfate, codeine phosphate, co-phenotrope, diphenoxine, loperamide hydrochloride, sufasolazine, mesalazine, olsalazine, corticosteroids, prednisolone.

Anti-diuretics: desmopressin, desmopressin acetate.

Anti-epileptics: beclamide, carbamazepine, clonazepam, ethotoin, methoin, methsuximide, methyphenobarbitone, oxcarbazene, parametadione, phenacemide, phenobarbitone, phenytoin, fensuximide, primidone, sultiam, valproic acid.

Anti-fungal agents: amphotericin, butoconazole nitrate, clotrimazole, econazole nitrate, fluconazole, flucytosine, griseofulvin, itraconazole, ketoconazole, miconazole, natamycin, nystatin, sulconazole nitrate, terbinafine HC1, terconazole, thioconazole, undecenoic acid.

Anti-gout agents: allopurinol probenecid, sulfinpyrazone.

Anti-hypertensive agents: amlopidine, benidipine, darodipine, dilitazem HCl, diazoxide, felodipine, guanabenz acetate, indoramin, isradipine, minoxidil, nicardipine HC1, nifedipine, nimodipine, phenoxybenzamine HC1, prazosin HC1, reserpine, terazosin HC1.

Anti-insomnia: Zolpidem Anti-malaria: amodiaquine, chloroquine, chloroproguanil HC1, halofantrine HC1, mefloquine HC1, proguanil HC1, pyrimethamine, quinine sulfate.

Anti-migraine agents: rizatriptan, dihydroergotamine mesylate, ergotamine tartrate, methysergide maleate, pizotifen maleate, sumatriptan succinate, caffeine.

Anti-muscarinic agents: tolterodine, tolterodine tartrate, oxybutynin, atropine, benzhexol HC1, biperiden, ethopropazine HC1, hioscin-butyl bromide, hyoscyamine, mepenzolate bromide, orphenadrine, oxyphenylcyamin HC1, tropicamide.

Anti-neoplastic agents and Immunosuppressants: aminoglutethimide, amsacrine, azathioprene, busulfan, chlorambucil, cyclosporine, dacarbazine, estramustine, etoposide, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotana, mitozantrone, procarbazine HC1, tamoxifen citrate, testolactone.

Anti-protozoal agents: benznidazole, clioquinol, decoquinate, diiodohydroxyquinoline, diloxanide furcate, dinitolmide, furzolidone, metronidazole, nimorazole, nitrofurazone, ornidazole, tinidazole.

Anti-rheumatic: ibuprofen, aceclofenac, acemetacin, azapropazone, diclofenac sodium, diflunisal, etodolac, ketoprofen, indomethacin, mefenamic acid, naproxen, piroxicam, aspirin, benorilate, auranofin, penicillamine.

Anti-rhinitis, anti-urticaria: Cetirizine, fexofenadin, ebastine, loratidine, montelukast.

Anti-spasmatic: phloroglucinol anhydride Anti-thyroid agents: carbimazole, propylthiouracil.

Antivirals: acyclovir, amantadine hydrochloride, famciclovir, zidovadine, didanosine, zalcitabine, foscarnet sodium.

Anxiolytics, sedatives, hypnotics and neuroleptics: alprazolam, amylobarbitone, barbitone, bentazepam, bromazepam, bromperidol, brotizolam, butobarbitone, carbromal, chlordiazepoxide, chlorpheniramine, chlormethiazole, chlorpromazine, clobazam, clonazepam, clotiazepam, clozapine, diazepam, droperidol, ethinamate, flunanisone, flunitrazepam, fluopromazine, flupenthixol decanoate, fluphenazine decanoate, flurazepam, haloperidol, lorazepam, lormetazepam, medazepam, meprobamate, methaqualone, midazolam, nitrazepam, oxazepam, pentobarbitone, perphenazine-phenylephrine, pimozide, prochlorperazine, pseudoephedrine HCl, sulpride, temazepam, thioridazine, triazolam, zopiclone. b-blockers: acebutolol, alprenolol, atenolol, labetalol, metoprolol, nadolol, oxprenolol, pindolol, propranolol.

Cardiac inotropic agents: amrinone, digitoxin, digoxin, enoximone, lanatoside C, medigoxin.

Corticosteroids: beclomethasone, betamethasone, budesonide, cortisone acetate, deoximetasone, dexamethasone, fludrocortisone acetate, flunisolide, flucortolone, fluticasone propionate, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone.

Expectorants: codeine-dexomethorphan phosphate, guaifenesin, pholcodine, diamorphine, methadone.

Cytotoxic: ifosfamide, chlorambucil, melphalan, busulfan, cytotoxic antibodies, doxorubicin, epirubicin, plicamycin, bleomycin, methotrexate, cytarabine, fludarabine, gencitabine, fluorouracil, mercaptopurine, thioguanine, vincristine, vinblastine, vindesine, etoposide.

Decongestants: pseudoephedrine hydrochloride.

Diuretics: acetazolamide, amiloride, bendrofluazide, bumetañida, clorotiazida, clor alidona, etacrínico acid, frusemida, metolazona, espironolactona, triamtereno.

Enzymes: pancreatin, pepsin, lipase.

Epilepsy: Gabapentin Anti-parkinsonian agents: bromocriptine mesylate, lisuride maleate, selegiline, para-fluoroselegiline, lazabemide, rasagiline, 2-BUMP [N- (2-butyl) -N-methylpropargylamine], M-2-PP [N-methyl- N- (2-pentyl) -propargylamine], MDL-72145 [beta- (fluoromethylene) -3,4-dimethoxy-benzenetanamine], mofegiline, apomorphine, N-propylnoraporphin, cabergoline, metergoline, naxagolide, pergolide, piribedyl, ropinirole, tergurida, quinagolida.

Gastrointestinal agents: bisacodyl, cimetidine, cisapride, diphenoxylate HCl, domperidone, metoclopramide, famotidine, loperamide, mesalazine, nizatidine, esomeprazole, metopimazine, pantoprazole, ondansetron HC1, granisetron, tropisetron, dolasetron, ranitidine HC1, sulfasalazine, Lansoprazole .

Histamine Receptor Antagonists: acrivastine, astemizole, cinnarizine, cielizine, HC1 of cyproheptadine, dimenhydrinate, HC1 of flunarizine, loratadine, HC1 of meclozine, oxatomide, terfenadine, triprolidine.

Hormone replacement therapy: dydrogesterone Hypertension: Enalapril Lactation: Oxytocin, oxytocin agonists Lipid regulating agents: bezafibrate, clofibrate, fenofibrate, gemfibrozil, probucol.

Local anesthetics: amethocaine, amylocaine, benzocaine, bucricaine, bupivacaine, butacaine, butanilicaine butoxicaine, butyl amino cartilaine cartilaine, chloroprocaine, fivecaine, clibucaine chlormecaine, cocaine, cocaine, cyclomethycin, dimetisoquina diperodone, diclocaine, ethyl chloride, ethyl piperidinoacetylaminobenzoate, etidocaine, hexylcaine, isobutamben, ketocaine, lignocaine, mepivacaine, meprilcaine, mirtacaine, octacaine, oxetazain, oxybuprocaine, paretoxicain, pramoxin, prilocaine, procaine, propranocaine, propoxycaine, proxymetacaine, ropivacaine, tolicaine, tricaine, trimecaine, vadocaine.

Dizziness: diphenhydramine Neuro-muscular agents: pyridostigmine.

Nitrates and other anti-anginal agents: amyl nitrate, glyceryl nitrate, isosorbide dinitrate, isosorbide mononitrate, pentaerythritol tetranitrate.

Nutritional agents: beta-carotene, vitamins, such as vitamin A, vitamin B2, vitamin D, vitamin E, vitamin K, minerals.

Opioid analgesics: codeine, dextropropioxifen, diamorphine, dihydrocodeine, meptazinol, methadone, morphine, nalbuphine, pentazocine.

Oral vaccines: to prevent or reduce the symptoms of diseases such as Influenza, Tuberculosis, Meningitis, Hepatitis, Whooping Cough, Polio, Tetanus, Diphtheria, Malaria, Cholera, Herpes, Typhoid, V1H, AIDS, Measles, Lyme Disease, Diarrhea of Travelers, Hepatitis A, B and C, Otitis Media, Dengue Fever, Rabies, Parainfluenza, Rubella, Yellow Fever, Dysentery, Legionnaire's Disease, Toxoplasmosis, Q Fever, Hemorrhagic Fever, Hemorrhagic Fever Junín Virus, Caries, Sickness Chagas, Urinary Tract Infection caused by E. coli, Pneumococcal Disease, Mumps, Chikungunya, Hay Fever, Asthma, Rheumatoid Arthritis, Carcinomas, Coccidiosis, Newcastle Disease, Enzootic Pneumonia, Feline Leukemia, Atrophic Rhinitis, Erysipelas, Foot and Mouth Disease Swine pneumonia or to prevent or reduce the symptoms of diseases caused by Vibrio species, Salmonella species, Bordetella species, Haemophilus species, Toxoplasmosis g Cytomegalovirus, Chlamydia species, Streptococcus species, Norwalk virus, Escherichia coli, Helicobacter pylori, Rotavirus, Neisseria gonorrhae, Neisseria meningitidis, Adenovirus, Epstein Barr virus, Japanese Encephalitis Virus, Pneumocystis carini, Herpes simplex, Clostridia species, Respiratory Syncytial Virus, Klebsiella species, Shigella species, Pseudomonas aeruginosa, Parvovirus, Campylobacter species, Rickettsia species, Varicella zoster, Yersinia species, Ross River Virus, JC virus, Rhodococcus Equi, Moraxella catarrhalis, Borrelia burgdorferi and Pasteurella haemolytica.

Annular dysfunctions: Tamsulosin, trospium chloride, tolterodine, oxybutynin.

Proteins, peptides and recombinant drugs: recombinant hormones and iso-hormones, recombinant cytokines, recombinant plasminogens, TNF receptor fusion protein, monoclonal antibodies, nucleic acids, antisense oligonucleotides, oligonucleotides, glycoproteins and adhesion molecules.

Veterinary Arthritis: Tepoxaline Sex hormones and Contraceptives: clomiphene citrate, danazol, desogestrel, ethinylestradiol, ethinodiol, diacetate, ethinodiol, levonorgestrel, medroxyprogesterone acetate, mestranol, methyltestosterone, norethisterone, norethisterone enanthate, norgestrel, estradiol, conjugated estrogens, dydrogesterone, progesterone, stanozolol, stilboestrol , testosterone, tibolone.

Schizophrenia: Olanzapine, Nicergoline Sexual dysfunction: Cabergoline, oxytocin, tadalafil, sildenafil, vardenafil.

Spermicides: nonoxynol 9.

Stimulants: amphetamines, dexamfetamine, dexfenfluramine, fenfluramine, mazindol, pemoline.

In one embodiment, the first active ingredient is desmopressin or a pharmaceutically acceptable salt thereof, especially desmopressin acetate.

In one embodiment, the second active ingredient (comprised within the controlled release beads) is an antimuscarinic compound. In another embodiment, the second active ingredient is selected from tolterodine ((R) -N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropanamine), the 5-hydroxyethyl metabolite of tolterodine ( (R) -N, N-diisopropyl-3- (2-hydroxy-5-hydroxymethylphenyl) -3-phenylpropanamine), the (S) -enthiomer of tolterodine ((S) -N, N-diisopropyl-3- (2) -hydroxy-5-methylphenyl) -3-phenylpropanamine), the 5-hydroxymethyl metabolite of the (S) -enthiomer of tolterodine ((S) -N, N-diisopropyl-3- (2-hydroxy-5-hydroxymethylphenyl) - 3-phenylpropanamine), the racemate of tolterodine ((R, S) -N, N-diisopropyl-3- (2-hydroxy-5-methylphenyl) -3-phenylpropanamine), its prodrug forms and pharmacologically acceptable salts of the same. In a specific embodiment, the active ingredient is tolterodine or a pharmacologically acceptable salt thereof. In a particular embodiment, the active ingredient is tolterodine tartrate.

In a non-limiting, specific embodiment, the first active ingredient that is comprised in the open matrix network is desmopressin or a pharmaceutically acceptable salt thereof, especially desmopressin acetate, and the second active ingredient that is comprised in the release beads. controlled is tolterodine or a pharmaceutically acceptable salt thereof, especially tolterodine tartrate. The combination of desmopressin acetate and tolterodine tartrate as the first active ingredient and the second active ingredient, respectively, is particularly preferred. In this embodiment, the composition can be used in the treatment of urinary disorders, such as, but not limited to, overactive bladder or overactive bladder with nocturia, particularly in women.

The condition of overactive bladder gives rise to incontinence due to frequency, urgency and / or urinary need. Overactive bladder disorders can also include nocturia, that is, waking up at night to urinate. While overactive bladder is often associated with detrusor muscle instability, bladder function disorders also they may be due to a neuropathy of the central nervous system (detrusor hyperreflexia) that includes spinal cord and brain injuries, such as multiple sclerosis and stroke. Overactive bladder symptoms may also result from, for example, obstruction of bladder outlet in men (usually due to prosthetic hypertrophy), interstitial cystitis, local edema and irritation due to focal bladder cancer, radiation cystitis due to chemotherapy to the pelvis and cystitis.

In one embodiment, the amount of desmopressin acetate in the composition constitutes 0.01-1% w / w and the amount of tolterodine tartrate in the composition constitutes 3 to 10% w / w. In another embodiment, the amount of desmopressin acetate in the composition constitutes 0.02-0.2% w / w and the amount of tolterodine tartrate in the composition constitutes from 3 to 6% w / w.

When tolterodine is the active ingredient in the controlled release bead, the fraction of active ingredient that is released in vitro is preferably not greater than about 40% after 1 hour, from about 35 to about 85% after 3 hours and not it is less than about 65% after 7 hours.

When tolterodine is the active ingredient in the controlled release pearls, the profile of release of tolterodine from the beads (despite their presence within the matrix) will be similar or even identical to the release profile of hard tolterodine capsules commercially available under the trademark DETRUSITOL XI / ®.

In one embodiment, the second active ingredient (which is comprised within the controlled release beads) is a selective alpha-blocker. In another embodiment, the second active ingredient is tamsulosin. { (J¾) -5- (2- { [2- (2-ethoxyphenoxy) ethyl] amino.} Propyl) -2-methoxybenzene-1-sulfonamide), its prodrug forms and pharmacologically acceptable salts thereof. In a specific embodiment, the second active ingredient is tamsulosin hydrochloride.

In a non-limiting, specific embodiment, the first active ingredient that is comprised in the open matrix network is desmopressin or a pharmaceutically acceptable salt thereof, especially desmopressin acetate, and the second active ingredient that is comprised in the release beads. controlled is tamsulosin, or a pharmaceutically acceptable salt thereof, especially tamsulosin hydrochloride. The combination of desmopressin acetate and tamsulosin hydrochloride as the first active ingredient and the second active ingredient, rreessppeeccttiivvaammeennttee ,, ssee prefers particularly. In these modalities, the composition can be used in the treatment of benign prostatic hyperplasia (BPH) in men.

A pharmaceutical dosage form of the invention disintegrates, thereby releasing the active ingredient and the controlled release beads, upon contact with a fluid (an aqueous or salivary medium).

Typically, a pharmaceutical dosage form of the invention is an orodispersible pharmaceutical dosage form which disintegrates in the mouth within 30 seconds, typically 20 seconds or less, preferably 15 seconds or less, more preferably 10 seconds or less and even more preferably within 9, 8, 7, 6, 5, 4, 3, 2 or 1 second.

It should be understood that the term "orodispersible" as used herein comprises a solid dosage form which disintegrates or dissolves in water within (at most) 30 seconds when measured in accordance with Ph. Eur. , section 2.9.1, in water at 37 ° C ± 0.5 ° C.

An appropriate route of administration for the dosage form of the present invention is oral administration, which includes buccal and sublingual administration. In a specific modality, the form of Dosage is administered by the sublingual route. The dosage forms of the invention can also be placed on the tongue, under the tongue and against the cheek or gum.

The pharmaceutical dosage forms of the present invention are adapted to deliver the first active ingredient and the controlled release beads to for example the oral cavity. The first active ingredient can be absorbed through the mucosa at the site of administration, for example the sublingual mucosa, and / or otherwise, in the case of oral administration, from the oral cavity (e.g. buccal and / or gingival mucosa) and / or from the gastrointestinal tract for systemic distribution.

The exact dose and administration regime of the dosage form will necessarily depend on the therapeutic effect that is achieved and may vary with the particular active ingredients, the route of administration and the age and condition of the individual subject to whom the medication is to be administered. . Sometimes patients may be instructed to take two or any other number of unit dosage forms in an individual administration or sometimes only a portion, such as one half or one quarter of the unit dosage form in an individual administration.

The dosage form of the invention achieves a performance balance: tensile strength, stability, uniformity and rapid disintegration. It can be produced by means of a known lyophilized technology. It can be stored (and packed) in blister-type packages but due to its tensile strength, it can also be stored and / or packed in bottles or in bulk. The invention achieves these results in an individual processing step, without the need to resort to multiple steps including granulation.

In addition to the ingredients set forth above, the matrix may also include other excipients (auxiliary agents, complementary agents) such as, but not limited to fillers, thickeners, binding agents, diluents, lubricants, pH adjusting agents, agents protectors, viscosity enhancers, absorption agents by capillary forces, non-effervescent disintegrants, effervescent disintegrants, surfactants, anti-oxidants, wetting agents, dyes, flavoring agents, flavor masking agents, sweeteners, preservatives and so on.

In one embodiment, a composition of the invention can be obtained by sublimating solvent from a liquid preparation comprising a first active ingredient, matrix forming agent (s), controlled release tablets and optionally secondary matrix forming agent (s) in a solvent. Typically, the liquid preparation is placed in a mold, for example in such a way that after the sublimation a solid composition is formed, typically in a dosage unit, inside the mold. The mold can be an open bubble-like package whereby the solid dosage form is formed within the depression of the bubble-type package which is then sealed by a thin film or sheet of sealing metal.

In one embodiment, the process comprises introducing amounts of unit dosages of the preparation into depressions of an open bubble-like package; and then sublimate the preparation to obtain solid dosage forms within the depressions.

Sublimation can be carried out by freeze-drying the liquid preparation comprising the first active ingredient, the matrix-forming agent (s), controlled release beads and optionally the agent (s). (s) secondary matrix former (s) in a solvent. In one embodiment, the solvent is water.

The invention thus discloses a process for preparing the dosage forms of rapid dispersion by lyophilization of a solution, suspension, dispersion or emulsion comprising a combination of a first active ingredient, matrix forming agent (s), controlled release beads and optionally forming agent (s) ) of secondary matrix (s). The fast dispersing dosage form contains a network of the first active ingredient, the matrix-forming agent (s), the controlled release beads and optionally the forming agent (s). secondary matrix (s), the network has been obtained by sublimating solvent from the liquid preparation containing those components.

Typically, an initial preparation comprising a first active ingredient, matrix-forming agent (s), controlled release beads and optionally secondary matrix-forming agent (s) in a solvent is prepared, followed by sublimation. Sublimation can be carried out by freeze-drying the preparation. An early dissolution or release of the second active ingredient during the preparation of the fast dispersing dosage form can be prevented by reducing the contact time between the liquid components and the controlled release beads, for example to a period not greater than 45, 35, 25, 20, 15 or 10 minutes, or no more than 5 minutes.

In a freeze drying process, the preparation (in liquid form) comprising a first active ingredient, matrix-forming agent (s), controlled release beads and any other matrix-forming agent (s) Optional (is) in a solvent is poured into molds. Each mold typically contains a defined amount of this preparation with a defined amount of the first active ingredient and a defined amount of beads. In an alternative embodiment, the controlled release beads are pre-poured into molds in the required amount and optionally are cooled and frozen, and subsequently the liquid form preparation comprising the remaining components of the fast dispersing dosage form is added into the mold. The preparation in the mold is then frozen, for example by passing a gaseous cooling medium over the mold. After the preparation has been frozen, the solvent is sublimated from it. The sublimation is carried out in a freeze dryer. Accordingly, an open matrix network of matrix forming agent (s) optionally together with other matrix forming agent (s) included in the preparation, carrying the first active ingredient. and the pearls, is formed in that way.

The preparation is contained in a mold during the freeze drying process to produce a solid form in any desired configuration. Prior to lyophilization, the mold can be cooled and frozen (for example in a fast freezing tunnel or on the shelves of the freeze dryer), for example using liquid nitrogen or solid carbon dioxide. In one embodiment, the freezing speed is 0.1 to 2 ° C / minute. In another modality, the freezing speed is 0.5 to 1.5 ° C / minute. In yet another embodiment, the freezing speed is 10 to 260 ° C / minute. In another embodiment, the freezing speed is 20 to 260 ° C / minute. In a further embodiment, the freezing speed is 20 to 160 ° C / minute.

After lyophilization, the freeze-dried compositions may be either removed from the mold if desired or stored therein until further use. Typically, each mold is designed in this manner to produce a unit dosage form of the composition. The composition obtained in this way disperses rapidly and disintegrates within at most 30 seconds upon contact with a fluid, typically within less than 10 seconds.

The solvent used in the preparation of the composition of the invention is typically water but may also optionally contain a co-solvent (such as an alcohol for example tert-butyl alcohol).

The liquid preparation from which the composition of the invention is prepared may contain an agent for adjusting the pH which adjusts the pH thereof within the range of 2 to 10, typically 3.5 to 9.5 or 4.5 to 8. The Citric acid and sodium citrate can be used as an agent for adjusting the pH, but others can also be used, including sodium hydroxide, sodium carbonate, hydrochloric acid and malic acid. The non-volatile agents for adjusting the pH will not be removed by freeze drying or other sublimation processes and thus may be present in the final composition.

The mold may comprise a series of cylindrical depressions or other configurations therein, each of a size corresponding to a desired size of a dosage form that is formed.

In one embodiment, the mold is a depression in a sheet or film material. The film material may contain more than one depression. The film material may be similar to that used in conventional bubble-type packaging which is used to pack oral tablets and similar forms of medicine. For example, the film material can be made of thermoplastic material with the depressions formed by means of the thermoforming or cold forming. A polyvinyl chloride film can be used as a film material. Laminated materials made of film material can also be used.

EXAMPLES The invention is further described in the following examples, which are in no way intended to limit the scope of the invention as claimed.

METHODS Method for testing the disintegration time of the matrix This test determines the disintegration time of a composition of the invention in an aqueous medium, which is also an indication of its disintegration time in saliva.

Equipment: Electrolab, Model ED2 SAPO Procedure: The method is followed according to USP 31-NF 26 (General Chapters, <701> Disintegration) and Ph. Eur. 1997 (2.9.1 Disintegration of tablets and capsules). Water is poured into the beaker and kept at 37 ° C ± 0.5 ° C using a water bath. The dosage form is placed in a cage made of copper wire with a diameter of approximately 0.5 mm (± 0.05 mm) and a length of approximately 15 mm. The The cage is then placed inside the shelf assembly basket for the basket and the instrument is turned on. The decay time is observed in seconds.

Dissolution method to test the immediate release of the first active ingredient This test determines the dissolution (%) of the first active ingredient of a composition of the invention in an aqueous medium, which is an indication of the release profile of the first active ingredient.

Equipment: Varian, Model VK7025 Procedure: The method is followed according to USP 32-NF 27 (General Chapters, <711> Dissolution). The dissolution media (0.1 N HCl, phosphate buffer at pH 6.8, acetate buffer at pH 4.5 or 0.5% SLS (sodium lauryl sulfate) in water) are selected based on the active ingredient in the composition. The dissolution bowls are filled with an appropriate volume of media (500 mL or 900 mL) based on the active ingredient in the composition and the temperature of the medium is maintained at 37 ° C ± 0.5 ° C using a water bath. The device used is USP type II (Pallet) and is adjusted to 50 rpm. The samples are removed in 5 minutes, 10 minutes, 15 minutes and 30 minutes. The samples are analyzed chromatographically or by UV, as appropriate, and the% release is calculated.

Dissolution method to test the prolonged release of the second active ingredient This test determines the dissolution (%) of the second active ingredient of a composition of the invention in an aqueous medium, which is an indication of the release profile of the second active ingredient.

Equipment: Varian, Model VK7025 Procedure: The method is followed according to USP 32-NF 27 (General Chapters, <711> Dissolution). The dissolution media (0.1 N HCl, phosphate buffer at pH 6.8, acetate buffer at pH 4.5 or 0.5% SLS in water) are selected based on the active ingredient in the composition. The dissolution bowls are filled with an appropriate volume of media (900 mL) based on the active ingredient in the composition and the temperature of the medium is maintained at 37 ° C ± 0.5 ° C using a water bath. The device used is USP type I (Basket) and is adjusted to 100 rpm. The samples are removed in 1 hour, 2 hours, 3 hours, 5 hours, 7 hours, 9 hours and 12 hours. The samples are analyzed chromatographically or by UV, as appropriate, and the% release is calculated. Method for measuring core particle size This test determines the particle size of the core using standard sieves (BSS, ASTM). Follow the USP Method 35-NF 30 (General Chapters, < 786 > Calculation of Particle Size Distribution by Analytical Screening). The sieves in the range of interest are stacked one on top of the other in ascending degrees of thickness, and the tablets / beads / core particles are placed on the upper sieve. The sieve nest is subjected to a standardized period of agitation and then the weight of the material retained in each sieve is determined exactly.

EXAMPLE 1 Tolterodine ER particles Brief manufacturing procedure: The tolterodine ER particles were prepared in a fluidized bed processor (Wurster coating process). The different components / preparation steps of the ER particles were: to. Inert Core 1: Sugar spheres (Pharm-a-spheres) USP / NF, EP) of a size range of 150-180 mm were selected for the sealant coating, drug stratification and ER coating. b. Sealing coating 2: The Eudragit NE 30 D1® (Colorcon) diluted to a concentration of 20% w / w was used for the first water-insoluble stratification. The dispersion of Eudragit NE 30 D® (the ratio of polymer: talc was 1: 0.5) was atomized on the sugar spheres to obtain a weight gain of 30% w / w. c. Drug Layer 3: An aqueous solution of drug and binding agent was sprayed onto the sugar spheres with sealant coating to a target weight gain of ~ 46% w / w. The ratio of tolterodine tartrate: HPMC 5 cps was 5: 1. d. Extended Release Coating 5: This layer was a combination of Eudragit NE 30 DMR + HPMC 5 cps + Talc; the aqueous dispersion at ~ 20% in w / w of Eudragit NE 30 DMR + HPMC 5 cps (the ratio of Eudragit NE 30 D1®: HPMC 5 cps was 94.34: 5.66, talcum: ~ 43.1% polymer content) was atomized onto the drug-coated particles to obtain an increase in weight of 40% in p / p · and. Healing of the tolterodine ER particles: The tolterodine ER particles were cured for 12 hours at 40 ° C.

Composition of lyophilized: Brief manufacturing procedure for lyophilisates: 1. All excipients were dissolved in purified water to produce the matrix composition. The constitution of the final volume was carried out by means of purified water and the pH was adjusted to pH 4.5 using a 5% w / v citric acid solution 2. Filling of the cavities made of the type packing bubble with an exact content of tolterodine ER particles 3. Filling the matrix solution from step 1 into bubble type packaging cavities containing tolterodine ER particles 4. Freezing of bubble type gaskets filled in a liquid nitrogen tunnel 5. Maintenance of bubble type packages below the freezing temperature until the complete batch freezes 6. Loading of bubble-type frozen packages in a freeze dryer for freeze drying 7. Criterion of evaluation of supervised freeze drying by means of a pressure elevation test 8. Discharge of dried bubble-type packages from the lyophilizer. 9. Sealing of bubble type packaging, followed by printing.

The release of the drug (dissolution profile) from tolterodine from the tolterodine ER particles and lyophilisates from Example 1 and, by comparison, from Detrusitol XL in phosphate buffer at pH 6.8 is shown in Figure 2.

EXAMPLE 2 Tolterodine ER particles Brief Manufacturing Procedure: The tolterodine ER particles were prepared in a fluidized bed processor (Wurster coating process).

The different components / preparation steps of the ER particles were: to. Inert nucleus 1: The sugar spheres (Pharm-a-spheres USP / NF, EP) of a size range of 150-180 mm were selected for the sealant coating, drug stratification and ER coating. b. Sealer coating 2: Surelease® (Colorcon) diluted to a concentration of 15% w / w was used for the first water-insoluble layering. The Surelease * ® dispersion was atomized on the sugar spheres to obtain a weight gain of 30% w / w. c. Drug Layer 3: An aqueous solution of drug and binding agent was sprayed onto the sugar spheres with sealant coating until a target weight gain of -46% w / w. The ratio of tolterodine tartrate: HPMC 5 cps was 5: 1. d. Extended release coating 5: This coating was a combination of Surelease® + HPMC 5 cps. The aqueous dispersion at -15% w / w of Surelease1® + HPMC 5 cps (the ratio of Surelease ™: HPMC 5 cps was 84:16) was atomized onto the drug-coated particles to obtain a 100% weight gain in p / p. and. Healing of the tolterodine ER particles: The tolterodine ER particles were cured for 3 hours at 70 ° C.

Composition of lyophilized: Brief manufacturing procedure for lyophilisates: 1. All the excipients were dissolved in purified water.

The constitution of the final volume was carried out by means of purified water and the pH was adjusted to pH 4.5 using a 5% w / v citric acid solution 2. Filling of the cavities made of bubble type packaging with an exact content of tolterodine ER particles 3. Filling the desmopressin dispersion in bubble type packaging cavities containing tolterodine ER particles 4. Freezing of bubble type gaskets filled in a liquid nitrogen tunnel 5. Maintenance of bubble type packages below the freezing temperature until the complete batch freezes 6. Loading of bubble-type frozen packages in a freeze dryer for freeze drying 7. Criterion of evaluation of the supervised drying by means of a pressure elevation test 8. Discharge of dried bubble-type packages from the lyophilizer. 9. Sealing of bubble type packaging, followed by printing.

The release of the active ingredients of the dosage form of Example 2 in phosphate buffer at pH 6.8 is shown in Figure 3.

EXAMPLE 3 Tolterodine ER particles Brief Manufacturing Procedure: The tolterodine ER particles were prepared in a fluidized bed processor (Wurster coating process).

The different components / preparation steps of the ER particles were: to. Inert Nucleus 1: The sugar spheres (Pharm-a-spheres USP / NF, EP) of a size range of 150-180 mhh were selected for sealer coating, drug stratification and ER coating. b. Sealer coating 2: Surelease ™ (Colorcon) diluted to a concentration of 15% w / w was used for the first water-insoluble layering. The Surelease ™ dispersion was atomized onto the sugar spheres to obtain a weight gain of 30% w / w. c. Drug Layer 3: An aqueous solution of drug and binding agent was sprayed onto the sugar spheres with sealant coating to a target weight gain of ~ 46% w / w. The ratio of tolterodine tartrate: HPMC 5 cps was 5: 1. d. Extended Release Coating 5: This coating was a combination of Surelease1® + HPMC 5 cps. The aqueous dispersion at ~ 15% w / w of Surelease "+ HPMC 5 cps (the ratio of Surelease ^ HPMC 5 cps was 84:16) was atomized on the stratified drug particles. to obtain a weight gain of 100% w / w. and. Healing of the tolterodine ER particles: The tolterodine ER particles were cured for 3 hours at 70 ° C.

Composition of lyophilized: Brief manufacturing procedure for lyophilisates: 1. All the excipients were dissolved in purified water.

The constitution of the final volume was carried out by means of purified water and the pH was adjusted to pH 4.5 using a 5% w / v citric acid solution 2. Filling of the cavities made of bubble type packaging with an exact content of tolterodine ER particles 3. Filling the desmopressin dispersion in bubble type packaging cavities containing particles of Tolterodine ER 4. Freezing of bubble type gaskets filled in a liquid nitrogen tunnel 5. Maintenance of bubble type packages below the freezing temperature until the complete batch freezes 6. Loading of bubble-type frozen packages in a freeze dryer for freeze drying 7. Criterion of evaluation of the supervised drying by means of a pressure elevation test 8. Discharge of dried bubble-type packages from the lyophilizer. 9. Sealing of bubble type packaging, followed by printing.

The release of the active ingredients of the dosage form of Example 3 in phosphate buffer at pH 6.8 is shown in Figure 4.

EXAMPLE 4 Tolterodine ER particles Brief manufacturing procedure: The tolterodine ER particles were prepared in a fluidized bed processor (Wurster coating process).

The different components / preparation steps of the ER particles were: to. Inert nucleus 1: Sugar spheres (Pharm-a-spheres USP / NF, EP) of a size range of 150-180 mm were selected for sealer coating, drug stratification and ER coating. b. Sealer coating 2: Surelease * (Colorcon) diluted to a concentration of 15% w / w was used for the first water-insoluble layering. The Surelease * ® dispersion was atomized on the sugar spheres to obtain a weight gain of 30% w / w. c. Drug layer 3: An aqueous solution of drug and binder agent was sprayed onto the sugar spheres with sealer coating until an objective weight gain of ~ 46% w / w. The ratio of tolterodine tartrate: HPMC 5 cps was 5: 1. d. Extended release coating 5: This layer was a combination of Surelease ™ + HPMC 5 cps. The aqueous dispersion at ~ 15% w / w of Surelease® + HPMC 5 cps (the Surelease ratio rHPMC 5 cps was 84:16) was atomized onto the stratified drug particles to obtain a 100% weight gain in p / p. and. Healing of the tolterodine ER particles: The tolterodine ER particles were cured for 3 hours at 70 ° C.

Composition of lyophilized: Brief manufacturing procedure for lyophilisates: 1. All the excipients were dissolved in purified water.

The constitution of the final volume was carried out by means of purified water and the pH was adjusted to pH 4.5 using a 5% w / v citric acid solution 2. Filling of the cavities made of bubble type packaging with an exact content of tolterodine ER particles 3. Filling the desmopressin dispersion in bubble type packaging cavities containing tolterodine ER particles 4. Freezing of bubble type gaskets filled in a liquid nitrogen tunnel 5. Maintenance of bubble type packages below the freezing temperature until the complete batch freezes 6. Loading of bubble-type frozen packages in a freeze dryer for freeze drying 7. Criterion of evaluation of the supervised drying by means of a pressure elevation test 8. Discharge of dried bubble-type packages from the lyophilizer. 9. Sealing of bubble type packaging, followed by printing.

The release of the active ingredients of the Dosage form of Example 4 in phosphate buffer at pH 6.8 is shown in Figure 5.

EXAMPLE 5 Tolterodine ER particles Brief Manufacturing Procedure: The tolterodine ER particles were prepared in a fluidized bed processor (Wurster coating process).

The different components / preparation steps of the ER particles were: to. Inert nucleus 1: Sugar spheres (Pharm-a-spheres USP / NF, EP) of a size range of 150-180 mm were selected for sealer coating, drug stratification and ER coating. b. Sealer coating 2: Surelease * ® (Colorcon) diluted to a concentration of 15% w / w was used for the first water-insoluble layering. The Surelease1® dispersion was atomized on the sugar spheres to obtain a weight gain of 30% w / w. c. Drug layer 3: An aqueous solution of drug-binding agent was sprayed onto the sugar spheres with sealant coating until a target weight gain of -46% w / w. The ratio of tolterodine tartrate: HPMC 5 cps was 5: 1. d. Extended Release Coating 5: This layer was a combination of Surelease * ® + HPMC 5 cps. Aqueous dispersion at -15% w / w of Surelease * ® + HPMC 5 cps (the ratio of Surelease ™: HPMC 5 cps was 84:16) was atomized on the stratified drug particles to obtain a weight gain of 100% in p / p. and. Healing of the tolterodine ER particles: The tolterodine ER particles were cured for 3 hours at 70 ° C.

Composition of lyophilized: Brief manufacturing procedure for lyophilisates: 1. All the excipients were dissolved in purified water.

The constitution of the final volume was carried out by means of purified water and the pH was adjusted to pH 4.5 using a 5% w / v citric acid solution 2. Filling of the cavities made of bubble type packaging with an exact content of tolterodine ER particles 3. Filling the desmopressin dispersion in bubble type packaging cavities containing tolterodine ER particles 4. Freezing of bubble type gaskets filled in a liquid nitrogen tunnel 5. Maintenance of bubble type packaging under the freezing temperature until the whole batch freezes 6. Loading of bubble-type frozen packages in a freeze dryer for freeze drying 7. Criterion of evaluation of the supervised drying by means of a pressure elevation test 8. Discharge of dried bubble-type packages from the lyophilizer. 9. Sealing of bubble type packaging and followed by printing.

The release of the active ingredients of the dosage form of Example 5 in phosphate buffer at pH 6.8 is shown in Figure 6.

EXAMPLE 6 Tolterodine ER particles Brief manufacturing procedure: The tolterodine ER particles were prepared in a fluidized bed processor (urster coating process).

The different components / preparation steps of the ER particles were: to. Inert Core 1: Sugar spheres (Pharm-a-spheres) USP / NF, EP) from a size range of 106-125 mm were selected for the sealant coating, drug stratification and ER coating. b. Coating sealer 2: Surelease1® (Colorcon) diluted to a concentration of 15% w / w was used for the first insoluble stratification in water. The Surelease ™ dispersion was atomized onto the sugar spheres to obtain a weight gain of 30% w / w.

Drug Layer 3: An aqueous solution of drug and binding agent was sprayed onto the sugar spheres with sealant coating to a target weight gain of ~ 46% w / w. The ratio of tolterodine tartrate: HPMC 5 cps was 5: 1.

Extended release coating 5: This coating was a combination of Surelease® + HPMC 5 cps. Aqueous dispersion at ~ 10% w / w of Surelease1® + HPMC 5 cps (the ratio of Surelease ™: HPMC 5 cps was 84:16) was sprayed onto the drug coated particles to obtain a 120% weight gain in p / p.

Healing of the tolterodine ER particles: The tolterodine ER particles were cured for 3 hours at 70 ° C.

Coating 6: This layer was a combination of Surelease1® + HPMC 5 cps + Eudragit LlOO®. The aqueous dispersion at ~ 15% w / w of Surelease ™: Eudragit L100 ™: HPMC 5 cps 82: 10: 8 was atomized on the tolterodine ER particles to obtain a weight gain of 60% w / w · Healing of tolterodine particles: The coated particles were cured for 3 hours at 70 ° C.

Composition of lyophilized: Brief manufacturing procedure for the lyophilized: 1. All excipients were dissolved in purified water to produce the matrix composition. The constitution of the final volume was carried out by means of purified water and the pH was adjusted to pH 4.5 using a 5% w / v citric acid solution 2. Filling of the cavities made of bubble type packaging with an exact content of tolterodine particles 3. Filling the matrix solution from step 1 into bubble type packaging cavities containing tolterodine particles 4. Freezing of bubble type gaskets filled in a liquid nitrogen tunnel 5. Maintenance of bubble type packaging under the freezing temperature until the whole batch freezes 6. Loading of bubble-type frozen packages in a freeze dryer for freeze drying 7. Criterion of evaluation of the supervised drying by means of a pressure elevation test 8. Discharge of dried bubble-type packages from the lyophilizer. 9. Sealing of bubble type packaging and followed by printing.

The release of the drug (dissolution profile) of tolterodine from the tolterodine ER particles and the lyophilisates of Example 6 and, by comparison, Detrusitol XLMR in phosphate buffer at pH 6.8 is shown in Figure 7.

EXAMPLE 7 Tolterodine ER particles Brief manufacturing procedure: The tolterodine ER particles were prepared in a fluidized bed processor (Wurster coating process).

The different components / preparation steps of the ER particles were: to. Inert core 1: The microcrystalline cellulose spheres (Cellets 175 * ®) of a size range of 150-200 mm were selected for drug stratification and ER coating. b. Drug layer 3: The aqueous dispersion of drug and talc in a binder solution was atomized onto the cores for an objective weight increase of ~ 27% in p / p. The ratio of tolterodine tartrate: HPMC 5 cps was 5: 1. c. Extended Release Coating 5: This coating was a combination of Eudragit NE 30DMR, HPMC 5 cps and talc. The aqueous dispersion of Eudragit NE 300®, HPMC 5 cps and talc was atomized onto the stratified drug particles for a target weight gain of 20% w / w. d. Healing of tolterodine ER particles: The tolterodine ER particles were cured for 24 hours at 40 ° C.

Composition of lyophilized: Brief manufacturing procedure for the lyophilized: 1. All the excipients were dissolved in purified water.

The constitution of the final volume was carried out by means of purified water and the pH was adjusted to pH 4.5 using a 5% w / v citric acid solution 2. Filling of the cavities made of bubble type packaging with an exact content of tolterodine ER particles 3. Filling the matrix solution from step 1 into bubble type packaging cavities containing particles of Tolterodine ER 4. Freezing of bubble type gaskets filled in a liquid nitrogen tunnel 5. Maintenance of bubble type packages below the freezing temperature until the complete batch freezes 6. Loading of bubble-type frozen packages in a freeze dryer for freeze drying 7. Criterion of evaluation of supervised freeze drying by means of a pressure elevation test 8. Discharge of dried bubble-type packages from the lyophilizer. 9. Sealing of bubble type packaging and followed by printing.

The release of the drug (dissolution profile) of tolterodine from the tolterodine ER particles and the lyophilisates of Example 7 and, by comparison, Detrusitol XLMR in phosphate buffer at pH 6.8 is shown in Figure 8.

EXAMPLE 8 Tolterodine ER particles Brief manufacturing procedure: The tolterodine particles were prepared in a fluidized bed processor (Wurster coating process).

The different components / steps of preparation of the particles were: to. Inert core 1: The microcrystalline cellulose spheres (Cellets 175") of a size range of 150-200 mm were selected for drug stratification and ER coating. b. Drug layer 3: The aqueous dispersion of drug and talc in a binder solution was atomized onto the cores for a target weight gain of ~ 27% w / w. The ratio of tolterodine tartrate: HPMC 5 cps was 5: 1. c. Extended Release Coating 5: This coating was a combination of Eudragit NE 30DMR, HPMC 5 cps and talc. The aqueous dispersion of Eudragit NE 30DMR, HPMC 5 cps and talc was atomized onto the stratified drug particles for a target weight gain of 20% w / w. d. Healing of tolterodine ER particles: The tolterodine ER particles were cured for 24 hours at 40 ° C. and. Coating 6: This layer was a combination of Eudragit L 300-55 * ®, talc and triethyl citrate. The aqueous dispersion of Eudragit L 30D-55MR, talc and triethyl citrate was sprayed onto the coated release coated particles for a target weight gain of ~ 20% w / w.

F. Healing of the particles: The particles coated with tolterodine were cured for 2 hours at 40 ° C.

Composition of lyophilized: Brief manufacturing procedure for the lyophilized: 1. All the excipients were dissolved in purified water.

The constitution of the final volume was carried out by means of purified water and the pH was adjusted to pH 4.5 using 5% w / v citric acid solutions. 2. Filling of the cavities made of bubble type packaging with an exact content of tolterodine ER particles 3. Filling the matrix solution from step 1 into bubble type packaging cavities containing tolterodine ER particles. 4. Freezing of bubble type gaskets filled in a liquid nitrogen tunnel 5. Maintenance of bubble type packages below the freezing temperature until the complete batch freezes 6. Loading of bubble-type frozen packages in a freeze dryer for freeze drying 7. Criterion for freeze drying supervised by means of a pressure rise test 8. Discharge of dried bubble-type packages from the lyophilizer. 9. Sealing of bubble type packaging and followed by printing.

The release of the drug (dissolution profile) from tolterodine from the tolterodine ER particles and lyophilized from Example 8 and, by comparison, from Detrusitol XL * ® in phosphate buffer at pH 6.8 is shown in Figure 9.

EXAMPLE 9 Tolterodine ER particles Brief manufacturing procedure: The tolterodine ER particles were prepared in a fluidized bed processor (Wurster coating process).

The different components / preparation steps of the ER particles were: to. Inert core 1: Sugar spheres (Pharm-a-spheres USP / NF, EP) of a size range of 150-180 mm were selected for sealant coating, drug stratification, barrier coating, ER coating and coating Exterior. b. Sealer coating 2: Surelease ™ (Colorcon) diluted to a concentration of 15% w / w was used for the first water-insoluble layering. The Surelease * ® dispersion was atomized onto the sugar spheres to obtain the weight gain of 30% w / w. Drug layer 3: The aqueous solution of drug-binding agent was sprayed onto the sugar spheres with sealant coating for the objective weight gain ~ 46% w / w. The ratio of tolterodine tartrate: HPMC 5 cps was 5: 1.

Outer sealant coating (barrier) 4: The aqueous HPMC solution 5 cps (5% w / v) was sprayed onto the stratified sugar spheres of drug and with sealant coating for target weight gain ~ 10% w / w .

Extended Release Coating 5: This layer was a combination of Eudragit NESOD * ® + HPMC 5 cps + Talc. The aqueous dispersion at ~ 20% w / w of Eudragit NESOD®1 + HPMC 5 cps + Talc (the ratio of Eudragit NE30DMR: HPMC 5 cps; 94.34: 5.66 and Talc is 43.1% of the polymer content) was atomized on the particles stratified with barrier to obtain the weight gain of 40% w / w.

Outer coating 6: This layer was a combination of Eudragit NESOD * ® + Talc. The aqueous dispersion at ~ 20% w / w of Eudragit NE30DMR + Talc (Ratio of Eudragit NE30DMR: Talc, 50:50) was atomized on the stratified particles of ER to obtain the weight increase of 50% in p / p. g. Healing of Tolterodine ER particles: The tolterodine ER particles were cured for 12 hours at 40 ° C.

Composition of lyophilized: Brief Manufacturing Procedure for Lyophilisates: 1. All excipients were dissolved or dispersed in purified water. The constitution of the final volume was carried out by means of purified water and the pH was adjusted to pH 4.5 using 5% w / v citric acid solutions. 2. Filling of the pre-formed cavities of bubble type packaging with an exact content of tolterodine ER particles. 3. Filling the desmopressin dispersion in cavities of bubble type packaging containing tolterodine ER particles. 4. Freezing of bubble type gaskets filled in a liquid nitrogen tunnel. 5. Maintenance of bubble type packages below the freezing temperature until the entire batch freezes. 6. Load the frozen bubble type packages in the freeze dryer for freeze drying. 7. Criterion of evaluation of the supervised drying by means of a pressure elevation test. 8. Discharge of dried bubble-type packages from the lyophilizer. 9. Sealing of bubble type packaging and followed by printing.

The release of the active ingredients of the lyophilized dosage form of Example 9 in phosphate buffer at pH 6.8 is shown in Figure 10.

EXAMPLE 10 Composition of Lyophilized: Brief Manufacturing Procedure for Lyophilisates: 1. All the excipients were dissolved in purified water.

The constitution of the final volume was carried out by means of purified water and the pH was adjusted to pH 4.5 using 5% w / v citric acid solutions. 2. Filling of the pre-formed cavities of bubble type packaging with an exact content of tolterodine ER particles. 3. Filling the desmopressin dispersion in bubble type packaging cavities containing tolterodine ER particles. 4. Freezing of bubble type gaskets filled in a liquid nitrogen tunnel. 5. Maintenance of bubble type packages below the freezing temperature until the entire batch freezes. 6. Load the frozen bubble type packages in the freeze dryer for freeze drying. 7. Evaluation criterion for supervised drying by means of of a pressure rise test. 8. Discharge of dried bubble-type packages from the lyophilizer. 9. Sealing of bubble type packaging and followed by printing.

The release of the active ingredients from the lyophilized dosage form of Example 10 in phosphate buffer at pH 6.8 is shown in Figure 11.

EXAMPLE 11 Composition of Lyophilized: Brief Manufacturing Procedure for Lyophilisates: 1. All the excipients were dissolved in purified water.

The constitution of the final volume was carried out by means of purified water and the pH was adjusted to pH 4.5 using Citric acid solutions at 5% w / v. 2. Filling of the pre-formed cavities of bubble type packaging with an exact content of tolterodine ER particles. 3. Filling the desmopressin dispersion in bubble type packaging cavities containing tolterodine ER particles. 4. Freezing of bubble type gaskets filled in a liquid nitrogen tunnel. 5. Maintenance of bubble type packages below the freezing temperature until the entire batch freezes. 6. Load the frozen bubble type packages in a freeze dryer for freeze drying. 7. Criterion of evaluation of the supervised drying by means of a pressure elevation test. 8. Discharge of dried bubble-type packages from the lyophilizer. 9. Sealing of bubble type packaging and followed by printing.

The release of the active ingredients of the lyophilized dosage form of Example 11 in phosphate buffer at pH 6.8 is shown in Figure 12.

EXAMPLE 12 Composition of Lyophilized: Brief Manufacturing Procedure for Lyophilisates: 1. All the excipients were dissolved in purified water.

The constitution of the final volume was carried out by means of purified water and the pH was adjusted to pH 4.5 using 5% w / v citric acid solutions. 2. Filling of the pre-formed cavities of bubble type packaging with an exact content of tolterodine ER particles. 3. Filling the desmopressin dispersion in bubble type packaging cavities containing tolterodine ER particles. 4. Freezing of bubble type gaskets filled in a liquid nitrogen tunnel. 5. Maintenance of bubble type packaging under the freezing temperature until the entire batch freezes. 6. Load the frozen bubble type packages in the freeze dryer for freeze drying. 7. Criterion of evaluation of the supervised drying by means of a pressure elevation test. 8. Discharge of dried bubble-type packages from the lyophilizer. 9. Sealing of bubble type packaging and followed by printing.

The release of the active ingredients of the lyophilized dosage form of Example 12 in phosphate buffer at pH 6.8 is shown in Figure 13.

EXAMPLE 13 Tolterodine ER particles Brief Manufacturing Procedure: The tolterodine ER particles were prepared in a fluidized bed processor (Wurster coating process).

The different components / preparation steps of the ER particles were: 1. Inert core 1: MCC tablets (Cellets 175 ^) of a size range of 150-200 mm were selected as starting material for drug stratification followed by ER coating. 2. Drug Layer 3: The aqueous dispersion of drug-binding agent was sprayed onto the MCC tablets to target the weight increase ~ 26.58% w / w. The ratio of tolterodine tartrate: HPMC 5 cps was 5: 1. 3. Extended release coating 5: This coating was a combination of Eudragit NE30D® * + HPMC 5 cps + Talc. The aqueous dispersion at -20% w / w of Eudragit NE30D® * + HPMC 5 cps + Talc (Ratio of Eudragit NESOD ^ HPMC 5 cps; 94.34: 5.66 and Talc is 43.1% of the polymer content) was atomized on the particles stratified drug to obtain 20% weight gain in p / p-4. Outer coating 6: This layer was a combination of Eudragit L30055® * + TEC + Talc. The aqueous dispersion at -20% w / w of Eudragit L30 055® * + TEC + Talco (Eudragit L30 D55® *: Talc was 1: 0.5 while TEC was 10% of the actual polymer content Eudragit® *) was atomized on the ER particles to obtain the weight gain of 20% w / w. 5. Healing of Tolterodine ER particles: Tolterodine ER particles were cured for 24 hours at 40 ° C after combining with 2% Talc as the external phase.

Composition of Lyophilized: Brief Manufacturing Procedure for Lyophilisates: 1. All the excipients were dissolved in purified water.

The constitution of the final volume was carried out by means of purified water and the pH was adjusted to pH 4.5 using 5% w / v citric acid solutions. 2. Filling of the pre-formed cavities of bubble type gaskets with an exact content of tolterodine ER particles. 3. Filling the desmopressin dispersion in cavities of bubble type packages containing particles of Tolterodine ER 4. Freezing of bubble type gaskets filled in a liquid nitrogen tunnel. 5. Maintenance of bubble type packages below the freezing temperature until the entire batch freezes. 6. Load the frozen bubble type packages in a freeze dryer for freeze drying. 7. Criterion of evaluation of the supervised drying by means of a pressure elevation test. 8. Discharge of dried bubble-type packages from the lyophilizer. 9. Sealing of bubble type packaging and followed by printing.

The release of the active ingredients of the lyophilized dosage form of Example 13 in phosphate buffer at pH 6.8 is shown in Figure 14.

EXAMPLE 14 Tolterodine ER particles Brief Manufacturing Procedure: The tolterodine ER particles were prepared in a fluidized bed processor (Wurster coating process).

The different components / preparation steps of the ER particles were: 1. Inert core 1: MCC (Cellets 175 ^ ®) tablets of a size range of 150-200 mm were selected as starting material for drug stratification followed by ER coating. 2. Drug Layer 3: The aqueous dispersion of drug-binding agent was sprayed onto the MCC tablets to target the weight increase ~ 26.58% w / w. The ratio of tolterodine tartrate: HPMC 5 cps was 5: 1. 3. Extended Release Coating 5: This layer was a combination of Eudragit NESOD * ® + HPMC 5 cps + Talc. The aqueous dispersion at ~ 20% w / w of Eudragit NE30DMR + HPMC 5 cps + Talc (Ratio of Eudragit NE30DMR: HPMC 5 cps; 94.34: 5.66 and Talc is 43.1% of the polymer content) was atomized on the stratified particles of drug to obtain weight gain of 20% in p / p · 4. Healing of Tolterodine ER particles: Tolterodine ER particles were cured for 24 hours hours at 40 ° C after the combination with 2% Talc as an external phase.

Composition of Lyophilized: Brief Manufacturing Procedure for Lyophilisates: 1. All the excipients were dissolved in purified water.

The constitution of the final volume was carried out by means of purified water and the pH was adjusted to pH 4.5 using 5% w / v citric acid solutions. 2. Filling of the pre-formed cavities of bubble type gaskets with an exact content of tolterodine ER particles. 3. Filling the desmopressin dispersion in cavities of bubble type packages containing particles of Tolterodine ER 4. Freezing filled bubble type gaskets in a tunnel of liquid nitrogen. 5. Maintenance of bubble type packages below the freezing temperature until the entire batch freezes. 6. Load the frozen bubble type packages in a freeze dryer for freeze drying. 7. Criterion of evaluation of the supervised drying by means of a pressure elevation test. 8. Discharge of dried bubble-type packages from the lyophilizer. 9. Sealing of bubble type packaging and followed by printing.

The release of the active ingredients of the lyophilized dosage form of Example 14 in phosphate buffer at pH 6.8 is shown in Figure 15.

Claims (40)

1. CLAIMS 1. A pharmaceutical composition, characterized in that it comprises an open matrix network comprising a first pharmaceutically active ingredient; one or more matrix forming agents; and controlled release beads comprising a second pharmaceutically active ingredient. 2. A pharmaceutical composition according to claim 1, characterized in that one or more of the matrix forming agents are selected from the group consisting of levan, inulin, pullulan, HPMC, maltodextrin, acacia gum, sodium alginate and combinations thereof. 3. A pharmaceutical composition according to claim 1 or 2, characterized in that the open matrix network also comprises mannitol, trehalose and / or raffinose. 4. A pharmaceutical composition according to any of claims 1 to 3, characterized in that it is dissolved in a standardized aqueous medium within 30 seconds. 5. A pharmaceutical composition according to claim 4, characterized in that it is dissolved in a standardized aqueous medium within 10 seconds. 6. A pharmaceutical composition in accordance with any of claims 1 to 5, characterized in that the first pharmaceutically active ingredient is desmopressin acetate. 7. A pharmaceutical composition according to any of claims 1 to 6, characterized in that the controlled release beads comprise a core (1) of an inert water soluble material, insoluble in water or swellable in water having (i) in the core (1) an optional inner sealant coating layer (2) of a polymer substantially water insoluble or substantially water soluble; (ii) an inner drug-containing layer (3) covering the core (1) or an inner sealant coating layer (2) and containing the second active ingredient; and (iii) in the inner drug-containing layer (3) an outer membrane layer (5) of a polymer effective for controlled release of the second active ingredient from the inner drug-containing layer (3). 8. A pharmaceutical composition according to claim 7, characterized in that the core (1) is a sphere of sugar soluble in water. 9. A pharmaceutical composition according to claim 7, characterized in that the core (1) is a core of water-swellable microcrystalline cellulose. 10. A pharmaceutical composition in accordance with any of claims 7 to 9, characterized in that the amount of the inner sealant coating layer (2) constitutes from about 4 to about 15% (w / w) of the controlled release bead. 11. A pharmaceutical composition according to any of claims 7 to 10, characterized in that the amount of the inner drug-containing layer (3) constitutes from about 5 to about 25% (w / w) of the controlled-release bead. 12. A pharmaceutical composition according to any of claims 7 to 11, characterized in that the amount of the outer membrane layer (5) constitutes from about 25 to about 55% (w / w) of the controlled release bead. 13. A pharmaceutical composition according to any of claims 7 to 12, characterized in that the outer membrane layer (5) is coated with an additional polymer layer (6) of a coating with pH-dependent permeability. 14. A pharmaceutical composition according to any of claims 7 to 13, characterized in that the substantially insoluble polymer in water of the inner sealant coating layer (2) comprises ethyl cellulose. 15. A pharmaceutical composition according to any of claims 7 to 14, characterized in that the inner drug-containing layer (3) comprises hydroxypropylmethyl cellulose as the binder. 16. A pharmaceutical composition according to any of claims 7 to 15, characterized in that the outer membrane layer (5) effective for the controlled release of the second active ingredient comprises a combination of hydroxypropylmethyl cellulose and ethyl cellulose. 17. A pharmaceutical composition according to any of claims 1 to 16, characterized in that the second active ingredient is an antimuscarinic compound. 18. A pharmaceutical composition according to claim 17, characterized in that the antimuscarinic compound is selected from tolterodine, the 5-hydroxymethyl metabolite of tolterodine, the (S) -enthiomer of tolterodine, the 5-hydroxymethyl metabolite of the (S) -enthiomer of tolterodine , the tolterodine racemate, its prodrug forms and pharmacologically acceptable salts thereof. 19. A pharmaceutical composition according to claim 18, characterized in that the antimuscarinic compound is tolterodine or a pharmacologically acceptable salt thereof. 20. A pharmaceutical composition according to claim 19, characterized in that the antimuscarinic compound is tolterodine tartrate. 21. A pharmaceutical composition according to claim 20, characterized in that the tartrate fraction of tolterodine that is released in vitro is not greater than about 40% after 1 hour, from about 35 to about 85% after 3 hours and is not less that approximately 65% after 7 hours. 22. A pharmaceutical composition according to any of claims 17 to 21, wherein said composition is for use in the treatment of overactive bladder. -2. 3. A pharmaceutical composition according to any of claims 17 to 21, wherein said composition is for use in the treatment of overactive bladder with nocturia. 24. A pharmaceutical composition according to any of claims 17 to 21, wherein said composition is for use in the treatment of overactive bladder with nocturia in women. 25. A pharmaceutical composition according to any of claims 1 to 16, characterized in that the second active ingredient is a selective alpha-blocker. 26. A pharmaceutical composition according to claim 25, characterized in that the selective α-blocker is tamsulosin, a prodrug form thereof or a pharmaceutically acceptable salt thereof. 27. A pharmaceutical composition according to any of claims 1 to 26, characterized in that it is in an oral dosage form. 28. A pharmaceutical composition according to claim 27, characterized in that it is adapted for sublingual administration. 29. A pharmaceutical composition according to any of claims 1 to 28, characterized in that it can be obtained by: (i) mixing the controlled release beads with a liquid preparation comprising the first active ingredient and one or more matrix forming agents in a solvent to form a mixture; (ii) sublimate the solvent of the mixture. 30. A pharmaceutical composition according to claim 29, characterized in that the Sublimation is carried out by freeze-drying the preparation. 31. A process for preparing a pharmaceutical composition, characterized in that it comprises sublimating a solvent of a liquid preparation comprising a first pharmaceutically active ingredient, one or more matrix-forming agents, controlled release tablets comprising a second pharmaceutically active ingredient and a solvent. 32. A process according to claim 31, characterized in that the sublimation is carried out by freeze-drying the liquid preparation. 33. A process according to claim 31 or 32, characterized in that the solvent is water. 34. A process for the preparation of a pharmaceutical composition, characterized in that it comprises the steps consisting of: (a) preparing a mixture comprising a first active ingredient, controlled release beads comprising a second active ingredient, one or more matrix forming agents and a solvent; (b) freezing the solution; (c) sublimate the solvent of the frozen solution, wherein the pharmaceutical composition obtained in this manner disintegrates within 30 seconds on contact with a standardized aqueous medium. 35. A process according to claim 33, characterized in that the composition disintegrates within 10 seconds upon contact with a standardized aqueous medium. 36. A process according to any of claims 31 to 35, characterized in that the composition is a composition according to any of claims 1 to 28. 37. A pharmaceutical composition according to any of claims 17 to 21 for use in the treatment of overactive bladder, nocturia or a combination thereof in a subject. 38. A pharmaceutical composition according to claim 37, wherein the subject is a woman. 39. A pharmaceutical composition according to claims 25-26 for use in the treatment of benign prosthetic hyperplasia in a subject. 40. A pharmaceutical composition according to claim 39, wherein the subject is a man.