MX2008009613A - Drug delivery systems comprising weakly basic drugs and organic acids - Google Patents

Abstract

A pharmaceutical dosage form such as a capsule, a conventional or orally disintegrating tablet capable of delivering a nitrogen (N)-containing therapeutic agent having a pKa in the range of from about 5 to 14 into the body in a sustained- released fashion, in order to be suitable for a twice- or once-daily dosing regimen, comprises at least one organic acid, which solubilizes the therapeutic agent the drug prior to releasing it into the hostile intestinal environment wherein said weakly basic drug is practically insoluble. The unit dosage form is composed of a multitude of multicoated particulates (i.e., immediate-release beads, sustained- release beads and/or one or more timed, pulsatile-release bead populations) is designed in such a way that said weakly basic drug and said organic acid do not come into close contact during processing and/or storage for in-situ formation of acid addition compounds while ensuring that the acid is not depleted prior to completion of the drug release.

Description

SYSTEM OF DISTRIBUTION OF DRUGS COMPRISING BASIC DEGREES AND ORGANIC ACID PHARMACOS FIELD OF THE INVENTION The present invention relates to the development of modified release dosage forms comprising one or more populations of pearls of pulsatile, programmed release, of a therapeutic agent that contains nitrogen (N), weak basic having a pKa in the range of about 5 to 14 and a solubility of not more than 200 ug / ml, at a pH of 6.8, and one or more pharmaceutically acceptable organic acids. The dosage form exhibits comparable release profiles of both active and organic acid after a predetermined delay (delay) when the solution was tested by the dissolution methodology of the United States Pharmacopeia (USP) using a two-stage dissolution medium (first 2 hours in 0.1 N HCl followed by the test in a pH regulator at a pH of 6.8). According to another aspect of the invention, the drug distribution systems for target P profiles (pharmacokinetics, i.e. concentration-time in plasma) suitable for a once or twice daily dosing regimen in patients in the need for a medication BACKGROUND OF THE INVENTION Many therapeutic agents are more effective Ref. 195185 when they are available at constant degrees at or near the absorption sites. The absorption of the therapeutic agents thus made generally available results in desired plasma concentrations which lead to maximum efficacy, and minimal toxic side effects. Much effort has been devoted to the development of sophisticated drug distribution systems such as osmotic devices for oral application. However, there are instances where the maintenance of a constant level in the blood of a drug is not desirable. For example, a main goal of chronotherapy for cardiovascular diseases is to distribute the drug at higher concentrations during the time of greatest need, for example, early morning hours, and at lower concentrations when the need is less, for example, at late afternoon and the first hours of sleep. In addition, for an appropriately designed drug distribution system, the administration time is equally important. The only required pharmacokinetic profile can be calculated using computerized stimulation and modeling techniques based on knowledge of pharmacokinetic parameters, solubility, absorption throughout the gastrointestinal tract in the elimination half-life. While the pharmaceutical dosage form orally administered passes through the human digestive tract, the drug should be released from the dosage form and be available in the form of solution at or near the site of absorption from the gastrointestinal (GI) tract to occur. The rate at which the drug is combined with the solution and released from a dosage form is important for the kinetics of drug absorption. The dosage form and therefore the active ingredient are subjected to variable pHs during transit, i.e. variable pH of about 1.2 (stomach pH during fasting but may vary between 1.2 and 4.0, after food consumption) to approximately 7.4 (bile pH: 7.0-7.4 and intestinal pH: from 5 to 7). In addition, the transit time of a dosage form in individual parts of the digestive tract can vary significantly depending on its size and prevailing local conditions. Other factors that influence drug absorption include physicochemical properties of the drug substance itself such as pKa, solubility, crystalline energy, and the specific surface area. The prevailing local conditions that play an important role include the properties of the light content (pH, surface tension, volume, agitation, and ability to regulate the pH) and changes after the ingestion of food. Consequently, it is usually difficult to achieve the release of the drug at constant speeds. The basic and acidic drugs exhibit pH-dependent solubility profiles that vary by more than two orders of magnitude in the physiological pH range. The most difficult candidates to work with are the weak pharmaceutically active basics, which are practically insoluble at a pH higher than 6 and require high doses to be therapeutically effective. After entering the intestinal region, part of the drug released from the dosage form can be precipitated in a hostile pH environment unless the rate of absorption is faster than the rate of drug release. Alternatively, the drug can remain in a state of supersaturated solution facilitated by the presence of bile salts and lecithin in the intestine. A good supersaturation about an order of magnitude greater than that of aqueous solubility has been evident in the prior art. In the case of precipitation, there is evidence of redissolution for absorption in a slower phase. Functional polymer membranes comprising suitable combinations of synthetic polymers such as water-soluble polymers (eg, povidone), insoluble in water (eg, ethylcellulose insoluble at physiological pH), gastrosoluble (e.g.

EPO Eudragit) or enterosoluble (eg, gastric resistant hypromellose phthalate), have been applied in a tablet or granule nucleus comprising the active and one or more solubilizers to achieve drug release at constant rates with limited success . The development of pharmaceutical compositions of highly water-soluble active ingredients has been described as acidic or basic pHs using pharmaceutically acceptable pH regulating acids, pH regulating acid salts, and mixtures thereof, - to provide drug release at substantially constant rates . Organic acids have been used to improve bioavailability, to reduce intra- and intra-subject variability, and to minimize the effect of foods on weak basic pharmaceutical actives. Multiparticulate dosage forms comprising weak basic drugs to provide extended release profiles are also described in the literature. These dosage forms are typically obtained by granulating or coating the drug with one or more organic acids and coating them with a combination of water-soluble and water-insoluble or enteric polymers. Although the release of the drug in this description could be moderately extended, it suffers from two disadvantages, that is, it fails to maintain the profile of the drug. adequate plasma to achieve a once daily and partial dosing regimen to complete the in-form formation of the salt form, thus creating a new chemical entity. Even when the organic acid containing cores that were coated with a sustained-release polymer membrane, the distribution system failed to prolong the release of the acid for a continuous solution and the resulting absorption of the active to provide adequate plasma levels 24 hours later of oral ingestion In addition, many weak basic drugs are known to form salts in the presence of organic acids, especially when dissolved in common solvents for drug coating or during granulation. Even in dosage forms wherein the organic acid and the drug layers are separated by a sustained release membrane (SR), the drug coating formulation contains an organic acid. Accordingly, the active in finished dosage exists in a partially or completely neutralized salt form. This is not an acceptable situation based on regulatory considerations. Regulatory agencies may consider these assets as new drug entities. Thus, there is an unfulfilled need to develop drug delivery systems comprising weak basic drugs with a pKa in the range of about 5 to 14. and require high doses and organic acids in an undisturbed form to release the active ingredients and thus maintain the target plasma concentrations of Cmax and Cmin in order to be suitable for once daily dosing regimens. After extensive investigations, it was surprisingly discovered that this unfulfilled need can be achieved by preventing the organic acid and the weak basic active agent from contacting each other to form a salt during processing and / or in the dosage form during storage. , before discharging it in a dissolving medium in vi tro or before oral administration. This could be achieved through the application of a SR membrane to control the rate of dissolution between the acid layer in the inert nuclei and in the drug layer applied to the nuclei containing acid to isolate these two components and also an SR membrane. and / or TPR (coating with delay) on the IR beads in order to synchronize the release of the acid with that of the drug. BRIEF DESCRIPTION OF THE INVENTION The present invention provides pharmaceutical compositions and methods for creating pulsatile delivery system, which involve the prevention of the weak basic nitrogen (N) -containing therapeutic agent having a pKa in the range of about 5 to 14 (typically soluble in acidic pHs, but poorly to be practically insoluble at neutral and alkaline pH) and elimination of the half-life of about 2 hours or more, and a pharmaceutically acceptable organic acid to be contacted to form an acid addition compound. In addition, the dosage forms described herein provide target drug release profiles through solubilization of the drug prior to release within the hostile intestinal environment when the drug is practically insoluble, thereby improving the likelihood of achieving a concentration. of acceptable plasma of up to 12-24 hours after dosing in order to be suitable for a dosing regimen twice or once daily. Another embodiment of the invention relates to a multiparticulate pharmaceutical composition comprising one or more populations of coated beads containing one or more weak basic nitrogen (N) -containing therapeutic agents and having a pKa in the range of about 5 to 14, solubility of no more than about 200 μg / ml at a pH of 6.8, and a ratio of the optimum optimum dose to solubility at a pH of 6.8 of at least about 100. For example, if the dosage regime for a form of Immediate-release (IR) dosage of a drug with a solubility of 0.5 mg / ml at a pH of 6.8 is 5 mg twice a day, the highest optimal dose is 10 mg once a day and the ratio of the highest optimum dose (mg) to solubility (mg / ml) at a pH at a pH of 6.8 would be 200. The multiparticulate composition prepared according to an aspect of The present invention will comprise nuclei containing organic acid coated with a barrier membrane (eg, SR (sustained release)) wherein the weak basic therapeutic agent with a pKa in the range of about 5 to 14, is coated or covered with a SR membrane and / or a delay membrane such that both the organic acid and the weak basic therapeutic agent exhibit comparable drug release profiles. The multiparticulate compositions prepared according to one aspect of the present invention comprise one or more populations of coated beads that exhibit release profiles of similar compounds of both organic acid and therapeutic agent containing weak basic nitrogen (N) when tested for solution using Apparatus 1 of the United States Pharmacopeia (baskets at 100 rpm) or Apparatus 2 (pallets at 50 rpm) and a 2-step dissolution methodology (test in 700 ml of 0.1 B HCl (hydrochloric acid) for the first 2 hours and then in 900 ml at a pH of 6.8 obtained through the addition of 200 ml of a pH modifier). Another embodiment of the invention relates to a multiparticulate pharmaceutical composition comprising one or more populations of coated beads that exhibit the acid release profile that is particularly slow compared to that of the weak basic active in order to prevent the undissolved active from remaining inside the coated beads. A multiparticulate pharmaceutical composition according to one aspect of the invention comprises populations of beads coated with a weak basic pharmaceutical active with a pKa in the range of about 5 to 14 comprising: a) a core particle containing organic acid (crystal, granule, bead and similar organic acid); b) a barrier or sustained-release membrane in the acid-containing core particle comprising a water-insoluble polymer or a water-insoluble polymer in combination with a water-soluble or enteric polymer forming a pore; c) a weak basic drug coated on a core particle containing acid covered with a barrier and a core particle containing acid covered with a barrier and optionally provided with a protective seal layer to form an immediate release (IR) bead; d) if SR beads are provided, a membrane SR coating on the IR bead comprising a water insoluble polymer or a water insoluble polymer in combination with a water soluble polymer forming an SR bead; and / or e) if programmed pulsatile release (TPR) beads are provided, a delay time coating membrane on the SR coated bead or directly on one. IR bead comprises a combination of water insoluble and enteric polymers to form a TPR bead. The compositions according to the particular aspects of the invention typically exhibit desired or desired release profiles of both the active and the organic acid after a predetermined delay of at least 2 hours when tested for the release of the drug and / or organic acid. used the two-stage dissolution methodologies described above. A pharmaceutical composition of a weak basic nitrogen (N) containing therapeutic agent having a pKa in the range of about 5 to 14, a solubility of no more than about 200 μg / ml at a pH of 6.8, and a from the highest optimum dose to the solubility at a pH of 6.8 of no more than about 100 can be prepared by filling the corresponding bead populations in a hard gelatin capsule or by compressing them into a conventional tablet or in the form of ODT (oral disintegration tablet) according to certain embodiments of the present invention. A pharmaceutical composition of a weak basic therapeutic agent in the form of ODT prepared according to another embodiment of the present invention disintegrates in contact with the saliva in the oral cavity within about 60 seconds forming a suspension that is easy to swallow, soft (without leaving with a sandy or limy taste). The pharmaceutical composition of a weak basic pharmaceutical active in the form of ODT may comprise one or more populations of coated beads with an average particle size of no more than about 400 μ ??, such as taste-concealing microcapsules comprising cores that they contain the drug (crystals, granules, granules, tablets and the like), SR bead and programmed pulsatile release (TRP) bead populations that comprise nuclei containing SR-coated acids. The dissimulation of taste can be achieved through any of the well-known prior art descriptions. The ODT may also include rapidly dispersing microgranules with an average particle size of no more than about 400 um, or in some embodiments no more than about 300 um, comprising a disintegrant (eg, crospovidone, crosslinked polyvinylpyrrolidone) and an alcohol of sugar (for example, mannitol), a saccharide (for example, lactose) or a combination thereof, each having an average particle size of no more than about 30, and, optionally, pharmaceutically acceptable excipients typically used in the ODT formulations, i.e., flavors, a sweetener, coloring agents, and an additional disintegrant. The ODT according to one embodiment exhibits the following properties: 1) disintegrants in contact with the saliva in the oral cavity in about 60 seconds forming a soft, easy-swallow suspension comprising flavor-masking and / or coated particles (beads of SR and / or TPR); 2) taste-masking particles, if present, provide a substantially complete, rapid release of the dose after entry into the stomach (eg, typically greater than about 75% in about 60 minutes); 3) coated particles (SR and / or TPR beads) that provide a prolonged release of the active for continuous absorption along the GI tract. The ODT according to one embodiment comprises taste-masking microparticles that demonstrate an effective taste disguise through the release of no more than 10% in about 3 minutes (the time of longer typical residence anticipated by the ODT in the oral cavity) when the solution was tested in a simulated saliva fluid (pH approximately 6.8) when the release was not more than 50% of the dose in about 30 minutes when the solution was tested on 0.1 N of HC1. According to certain embodiments, the fast-dispersing microgranules and the coated beads (IR, taste simulator, SR beads and / or TPR) of one or more weak basic actives may be present in a weight ratio of approximately 6: 1. at 1: 1, more particularly from about 4: 1 to 2: 1, to achieve a smooth mouthfeel. According to certain other embodiments, coated beads (IR that disguise the flavor, SR beads and / or TPR) of one or more weak basic actives can be coated with a compressible coating (eg, fluid bed covering with a dispersion). Aqueous plasticized ethylcellulose) in order to minimize the fracture of the membrane during compression with rapid dispersion microgranules. A pharmaceutical composition of the weak basic pharmaceutical active in the conventional tablet form according to another embodiment of the present invention, may comprise one or more populations of beads, such as IR beads (crystals, granules, granules, beads and the like), and SR beads and / or TPR beads comprising cores that contain SR coated acid. The pharmaceutical composition of a weak basic pharmaceutical active in the conventional tablet form is disintegrated into the constituent beads (taste masking particles, SR beads and / or coated TPR beads) after oral ingestion in about 10 minutes. The conventional tablet may also include pharmaceutically acceptable excipients typically used in disintegrating tablet formulations such as compressible diluents, fillers, coloring agents and optionally a lubricant. The conventional tablet prepared according to one embodiment exhibits the following properties: 1) disintegration after oral ingestion in about 10 minutes in the IR particles and / or covered particles (beads of SR and / or TPR); 2) IR particles, if present, provide a substantially complete, rapid (eg, greater than about 95%) release of the dose within about 60 minutes, more particularly, within about 30 minutes after entry into the stomach; 3) SR and / or TPR beads that provide a prolonged release of the active for continuous absorption throughout the gastrointestinal (GI) tract. Another embodiment of the invention relates to a multiparticulate pharmaceutical composition comprising one or more populations of coated beads comprising one or more weak basic therapeutic agents having an elimination half-life of approximately 2 hours or more, wherein the active is coated on nuclei containing organic acid covered with SR. The pulsatile delivery system developed in accordance with this aspect of the present invention may comprise populations of IR beads, SR beads and pulsatile release pearls (TPR), programmed. Cores containing SR-coated organic acid are typically prepared through the coating of an organic acid (eg, fumaric acids) on inert particles (e.g., sugar spheres) of a polymeric binder solution and coated with an insoluble polymer at water (for example, ethylcellulose, with a viscosity of about 10 cps) alone or in combination with a water-soluble polymer (for example, polyvinylpyrrolidone, povidone K-25 or polyethylene glycol, PEG 400) or an enteric polymer (e.g. hypromellose phthalate, HPMCP or HP-55). The population of IR beads comprising cores containing SR-coated acid is prepared by coating the drug on SR-coated acid-containing nuclei of a polymeric binder solution and provides a protective seal layer of Opadry Clear or Pharmacoat ™ 603 Pearl populations of SR and TPR are prepared through the coating of IR beads with a water insoluble polymer (e.g., ethylcellulose) alone or in combination with a water soluble polymer (e.g., PVP K-25 or PEG 400) or an enteric polymer (e.g., hypromellose phthalate, HPMCP or HP-55). The IR bead population comprising cores containing SR-coated acid is prepared by coating the drug on SR-coated acid-containing nuclei of a polymeric binder solution and provide a protective seal layer of Opadry Clear. Pearl populations of SR and TPR are prepared through the coating of IR beads with an insoluble polymer (e.g., ethylcellulose) alone or in combination with a water soluble polymer (e.g., PVP-25 or PEG 400). According to one aspect of the invention, each population of SR or TPR beads releases both the drug and the acid at comparable speed, with rapid release or sustained release profiles after a predetermined delay (eg, a delay of up to 10 minutes). hours) after oral administration. The IR beads, if included in the dosage form (conventional capsule or tablet or oral disintegrating tablet, can comprise coating the drug directly on inert nuclei and covering it with a protective seal layer or taste-dissimulating membrane, which form part of the total dose, provides rapid absorption (bolus dose) after the oral administration. Also provided is a method for manufacturing a multiparticulate pharmaceutical composition wherein a distribution system developed in accordance with certain embodiments of the present invention comprises one or more weak basic active pharmaceutical ingredients in amounts sufficient to be administered orally to a patient at a controlled rate. dosing twice or once daily prescribed to provide therapeutic efficacy. The method for manufacturing a multiparticulate pharmaceutical composition according to particular embodiments includes the coating of a pharmaceutically acceptable organic acid such as fumaric acid from a polymeric binder solution on inert particles selected from the group consisting of sugar spheres and cellulose spheres. The coating on the bed or fluid tray can be used to apply the organic acid and the polymeric binder solution. According to other embodiments, the core particles may be crystals, microgranules, granules or beads with a desired particle size distribution containing one or more organic acids. According to certain modalities, the microgranules, the granules in extruded spheres or compressed microtablets comprise one or more acids organic, a polymeric binder, imparting elastic characteristics to dried microgranules, hydrophilic fillers / diluents, and optionally a flavor, sweetener and / or disintegrant. These organic acid containing particles are coated with a SR (sustained release) polymer membrane barrier comprising a water-insoluble polymer (eg, ethylcellulose with an average viscosity of 10 cps) alone or in combination with a soluble polymer at water (for example, polyvinylpyrrolidone or polyethylene glycol) or an enteric polymer (for example, hypromellose phthalate (HPMCP or HP-55)). The water-insoluble and water-soluble or enteric polymers can be present in a weight ratio of about 95: 5 to about 50:50, more particularly about 90:10 to 60:40 and the thickness of the membrane can vary from about 3% to 50%, more particularly about 5% to 30% by weight according to particular embodiments. According to particular embodiments, one or more weak basic drugs are applied on the particles containing barrier coated acid of a polymeric binder solution and also, a protective seal layer with a hydrophilic polymer (e.g., Pharmacoat ™ 603 or Opadry®). Clear) is applied to the beads coated with the drug to produce IR beads. He Organic acid or drug loading depends on the physicochemistry as well as the pharmacological properties of the weak basic assets selected to develop, and the drug and the organic acid may be present in a weight ratio of approximately 5: 1 to 1:10, or more particularly from about 3: 1 to 1: 3 depending on whether the organic acid crystals or the nuclei containing organic acid are used according to certain modalities. According to certain embodiments of the present invention, the IR beads comprise cores that contain barrier coated acid that are coated with a barrier with an SR polymer membrane comprising a water insoluble polymer (e.g., ethylcellulose with an average viscosity). 10 cps) alone or in combination with a water-soluble polymer (e.g., polyvinylpyrrolidone or polyethylene glycol). The water-insoluble and water-soluble polymers can be present in a weight ratio of from about 95: 5 to about 50:50, more particularly from about 90:10 to 60:40 and the thickness of the membrane can vary from about 3. % to 50%, more particularly from about 5% to 30% by weight according to particular modalities. According to other embodiments of the present invention, SR beads comprising coated beads with the drug they are coated with a delayed membrane comprising a combination of a water insoluble polymer (e.g., ethylcellulose with an average viscosity of 10 cps) and an enteric polymer (e.g., hypromellose phthalate (HPMCP or HP-55 )) to produce TPR beads. According to certain other embodiments, the water insoluble and enteric polymers can be present in a weight ratio of about 95: 1 to about 1: 4, more particularly about 3: 1 to 1: 1, and the thickness of the The membrane may vary from about 5% to 60%, more particularly from about 15% to 50% by weight according to particular embodiments. Functional polymeric systems that are applied from aqueous and solvent-based compositions typically contain plasticizers at suitable concentrations. The finished dosage form can be a modified release capsule (MR), a standard (conventional) tablet or an oral disintegration tablet (ODT) comprising a population of spherical and coated beads containing the active substance alone or in combination two or more populations of coated beads to provide objective plasma concentrations suitable for a once-daily dosing regimen. For example, a one-time dosage form of an active with an elimination half-life of approximately 7 hours may contain a mixture of a population of IR beads that allows immediate release, a second population of TPR beads with a lower delay (approximately 3-4 hours), which allows a rapid, delayed release, a third population of pearls from TPR with a longer delay (approximately 7-8 hours), which typically allows a sustained release profile, delayed for approximately 8-12 hours, to maintain acceptable plasma concentrations at 12-24 hours, thus improving safety, therapeutic efficacy and patient acceptance while reducing the cost of treatment. Alternatively, the finished dosage form may comprise a population of IR beads and a second population of TPR beads with a delay of about 7-8 hours followed by a sustained release profile for 10-12 hours. The delay time that can be achieved depends on the composition and the thickness of the barrier coating, as well as the composition and the thickness of the delay time coating. Specific factors that can affect the achievement of twice-daily or once-optimal dosage forms include, but are not limited to, pKa of the therapeutic agent (and its solubility above a pH of 6.0), elimination half-life, and improving the solubility in an aqueous solution of an organic acid selected from the group consisting of acid aspartic acid, citric acid, fumaric acid, maleic acid, oxalic acid, succinic acid, tartaric acid, and the like. According to certain embodiments of the present invention, there is also provided a method for manufacturing a multiparticulate composition comprising a weak nitrogen (N) containing therapeutic agent having a pKa in the range of about 5 to 14, and a solubility of no. more than 200 pg / ml at a pH of 6.8. The method may comprise the steps of: a) Preparing core particles (crystals with a particle size distribution of, 20-500 μm, more particularly 100-300 μm, beads or granules) of one or more pharmaceutically acceptable organic acids; b) coating these acid-containing cores with a water-insoluble polymer or a water-insoluble polymer in combination with a water-soluble or enteric polymer in order to program the release of the acid for a gain weight of about 3% a fifty%; c) coating said therapeutic agent containing weak basic nitrogen (N) of a polymeric binder solution and applying a protective seal layer on the beads coated with the drug to produce IR beads; d) applying a barrier coating (sustained release) of an insoluble polymer to water or a water insoluble polymer in combination with a polymer soluble to water for a weight gain of about 3% to 30% to produce SR beads; e) applying a delay coating (delay) of a combination of water insoluble and enteric polymers at a weight ratio of about 10: 1 to 1: 4 for a weight gain of about 10% to 60% by weight of the coated bead to produce TPR beads; and f) filling in hard gelatin capsules or compressing them into conventional tablets / oral disintegrating tablets (ODT) after mixing with the pharmaceutically acceptable excipients and one or more populations of beads (eg, a combination of IR beads, SR beads and / or TPR beads to a desired ratio). The composition comprising one or more populations of beads (eg, a combination of populations of IR and TPR beads) can exhibit the following properties: a) disintegrants of the composition in contact with saliva in the oral cavity form an easy suspension of swallowing, soft (if in the ODT form) or disintegrating within approximately 10 minutes after oral ingestion (if in the conventional tablet or capsule form); b) IR beads, disguise the taste or not, rapid release of the dose after entry into the stomach (eg, typically greater than about 50%, more particularly greater than about 75%, in about 60 minutes); c) the SR or TPR beads release the drug for a period of about 40 to 20 hours in synchronization with that of the organic acid after a predetermined delay (eg, up to 10 hours) after oral administration; d) the compound drug release profile of the composition is similar to the release of the target drug / plasma concentration profile in vivo in order to be suitable for a dosing regimen of two times or once daily. These and other embodiments, advantages and features of the present invention will become clear when the detailed descriptions and examples are provided in the subsequent sections. BRIEF DESCRIPTION OF THE FIGURES Figure 1A-1D illustrates the solubility profiles of pH for (Fig.lA) Ondansetron hydrochloride, (Fig.lB) Carvedilol, (Fig.lC) Dipyridamole and (Fig.lD) Clonazepam; Figure 2 illustrates a cross-section of the core containing SR-coated organic acid according to one aspect of the invention; Figure 3 illustrates a cross-section of a TPR bead comprising a core containing organic acid SR coated according to a particular aspect of the invention; Figure 4 illustrates the release of fumaric acid from the SR-coated acid crystals coated at different EC-10 / PEG ratios of Example 1; Figure 5 illustrates the dipyridamole release profiles of TPR beads of Example 2E; Figure 6 illustrates the release profiles of the carvedilol TPR beads of Example 5 against Comparative Example 4B; Figure 7 illustrates the release profiles of ondansetron hydrochloride from TPR beads in stability (Example 5); Figure 8 illustrates the release profiles of ondansetron hydrochloride from TPR beads coated at different ratios of EC-10 / HP-55 / TEC to 50% by weight of Example 5; and Figure 9 illustrates the plasma concentration-time profiles of the HC1 test formulations of ondansetron (QD) and Zofran 8 mg (BID) of Example 7. DETAILED DESCRIPTION OF THE INVENTION All documents cited here, in part relevant , are incorporated herein by reference; the citation of any document should not be construed as an admission that it is the prior art with respect to this invention As used herein, as well as in the specific examples thereof, the term "weak basic pharmaceutical active" includes the base, pharmaceutically acceptable salts, polymorphs, stereoisomers, and mixtures thereof. This term, which is more fully defined in the subsequent section, refers to a therapeutic agent containing nitrogen (N) having a pKa in the range of about 5 to 14, more particularly to an agent having a solubility of no more than of 200 ug / ml, at a pH of 6.8. As used herein, the term "immediate release" refers to the release of more than or equal to about 50%, especially if the dissimulation of taste for incorporation into a dosage form of orally disintegrating tablet, preferably greater than about 75%, more preferably greater than about 90%, and according to certain embodiments greater than about 95% of the active within about 2 hours, more particularly, within about 1 hour after administration of the dosage form. The term may also refer to the release of the active from a programmed, pulsatile, release dosage form characterized by an immediate release pulse after the designated delay time.

The term "delay" refers to a period of time wherein less than about 10%, more particularly substantially nothing, of the dose (drug) is released, and a delay of about 2 to 10 hours is achieved by typically coating with a combination of water-insoluble and enteric polymers (for example, ethylcellulose and hypromellose phthalate). Unless otherwise indicated, all percentages and ratios are calculated by weight based on the total composition. A pharmaceutically acceptable or aqueous solvent medium can be used to prepare core particles containing organic acid for the coating of drugs ie, beads containing acid by coating an acid on inert cores (e.g., sugar spheres) or beads of IR through the coating of the drug on nuclei containing acid or directly on sugar spheres of an appropriate polymer binder solution in a fluid bed equipment. An aqueous dispersion of functional polymers, which are available as dispersions or a solvent system for dissolving functional polymers to coat acid-containing beads, IR beads or SR beads, may also be used. Many active pharmaceutical ingredients (API, by its acronym in English) are basic weak in the sense that these assets are free to moderately soluble at acidic pHs, but are poor to practically insoluble at neutral and alkaline pH. Their pKa values are in the range of about 5 to 14. The pH-dependent solubility data for typical basic and weak assets are presented in Figures 1A-1D. For example, the solubility of dipyridamole in 0.1 N HCl (hydrochloric acid) is about 1 mg / ml, while at a pH of 6.8 the solubility is only 30 ug / ml. Although the solubility of carvedilol is similarly dependent on pH and variable, it is not obvious from Figures 1A-1D since it undergoes rapid in situ salt formation with the pH regulating agent such as citric, acetic, and hydrochloric acid and consequently, the observed solubility is that of the salt formed in situ. Table 1 lists the improved solubility of weak basic assets in pH regulators of organic acid. The three different groups can be identified. Group A of assets, as represented by ondansetron hydrochloride, exhibits a dramatic increase in the solubility of weak basic active in pH buffer with a trace of fumaric acid. For example, the solubility of ondansetron of approximately 26 mg / ml in the pH buffer containing only 0.05 mg / ml of fumaric acid remains unchanged after the increase in fumaric acid concentration in the pH regulator to 5 mg / ml. In Group B, represented by dipyridamole, carvedilol and lamotrigine, the solubility of the weak basic drug increases with increasing concentrations of the acid. In Group C, represented by clonazepam, the organic acid has a very limited impact, that is, the improvement in solubility typically accounts for less than about 3 times. For example, the solubilities of clonazepam are approximately 11.6 and 6.9 ug / ml in regulators at a pH of 2.3 and 6.8 containing a higher and lower concentration of fumaric acid, respectively. The specific embodiments of the invention will be described in greater detail with reference to the accompanying Figures 2 and 3. In Figure 2, a core covered with SR 10 comprises a coating of SR 12 applied on a core containing organic acid comprising a layer of pharmaceutically acceptable organic acid in a binder 14 coated on an inert particle core 16. The inert particle core 16, the organic acid coating layer 14 and a SR layer controlling the dissolution rate 12 form the core containing coated organic acid of SR 10. In Figure 3, a representative TPR bead is illustrated. The TPR bead 20 comprises a delay coating 22 applied on a primary SR layer 24, a protective seal layer 26, and a weak basic drug layer 28 applied over a core containing SR 10 coated acid. The weak basic drug is typically applied from a polymeric binder solution. The SR coating sustains the release of the drug while the delayed coating provides the delay (a period of time exhibiting less than about 10%, more particularly substantially nothing, of the released dose). In this way the delayed coating 22, the outer SR coating on the IR beads 24, and the inner SR coating 12 on the acid-containing core together control the release properties of both the drug and the acid from the beads of TPR TABLE 1 Solubilities of Basic Basic Fats in Organic Acids PH concentration of pH of Solubility pH of Solubility of acid start termination of fumaric acid hydrochloride Dipyridamole (mg / ml) of (mg / ml) Qndansetron (mg / ml) 5 2.13 2.01 26.9 2.98 6.24 2.5 2.26 2.14 27.0 3.42 1.80 1 2.48 2.40 26.1 3.68 0.93 0.25 2.79 2.75 26.2 3.88 0.65 0.05 3.19 3.49 26.0 4.33 0.27 0.01 6.64 4.05 26.1 4.71 0.13 0.0025 4.15 4.33 26.1 6.28 0.006 Solubility (mg / ml) Solubility (mg / ml) Solubility (mg / ml) of Carvedilol in Lamotrigine in Clonazepam in Tartaric Acid Tartaric Acid Fumaric Acid pH (mg / ml) pH (mg / ml) pH ( mg / ml) regulatory regulator regulator of pH of pH 2.12 2.51 2. 43 4.48 2, .3 0. .0116 2. 28 1.36 3. 33 1.77 2, .8 0, .0103 2. 54 0.731 4. 36 1.61 3, .2 0. .0096 2. 94 0.508 4. 97 0.488 3, .7 0. .0098 3. 64 0.121 5. 66 0.226 4, .8 0. .0095 . 46 0.105 5. 85 0.197 5, .5 0. .0093 . 90 0.028 6. 50 0.161 6, .2 0. .0072 6, .8 0. .0069 The novelty / usefulness of the formulations developed according to the embodiments of the present invention are described using ondansetron hydrochloride, lamotrigine, dipyridamole, and carvedilol as examples of weak basic nitrogen (N) -containing therapeutic agents having a p a in the range of about 5 to 14 and a solubility of no more than 200 ug / ml, at a pH of 6.8. Ondansetron hydrochloride, a selective serotonin 5-HT3 receptor blocking agent, is an anti-emetic, and anti-vomiting agent. It is moderately soluble in acidic pHs while practically insoluble in a pH of 6.8. Dipyridamole, an antiplatelet agent, is chemically a dipiperidine derivative. It is soluble in dilute acids and practically insoluble in water, neutral and alkaline pH regulators. Carvedilol, a beta-blocker with antiproliferative properties, additional vasodilators, is indicated for the treatment of high blood pressure (HF), coronary artery disease and congestive heart failure. The current commercial formulation of carvedilol is immediate release, and is administered twice daily. The immediate dosage form is rapidly and extensively absorbed after oral administration, with a terminal elimination half-life of between 7 and 10 hours. A once-a-day daily dosage of a carvedilol formulation is commercially desirable, and could simplify the dosage regimen and improve patient acceptance. Carvedilol exists as a racemate and contains a secondary oc-hydroxyl amine, with a pKa of 7.8. This exhibits a predictable aqueous solubility, that is, above a pH of 9, the solubility is less than 1 ug / ml and its solubility increases with a decreasing pH and reaches a level near a pH of 5; its solubility is about 23 ug / ml at a pH of 7 and about 100 ug / ml at a pH of 5. At lower pHs (pH from 1 to 4), the solubility is limited by the solubility of the protonated form of carvedilol or its salt form formed in situ. The salt form of HCl is less soluble than its protonated form itself. Carvedilol is absorbed from the GI tract through transcellular transport. In vivo absorption is decreased within the intestine in the following order: jejunum greater than ileus greater than colon. The highest absorption is achieved in the jejunum at a neutral pH. Since drug dissolution is a rate limiting factor for the absorption of carvedilol in the distal part of the GI tract potentially due to the decrease in solubility. The once-a-day dosage form according to one embodiment could comprise at least two populations of beads-one population of IR beads and another population of TPR beads that comprise organic acid cores coated with SR. Iloperidone is an anti-psychotic agent and Lamotrigine, an anticonvulsant drug, as indicated for the treatment of epilepsy. According to certain embodiments of the present invention, the property of improving the solubility of organic acid pH regulators takes advantage of, and At the same time, the formation in itself of the acid addition compounds is avoided by having an SR coating membrane between the internal organic acid layer and the weak basic drug layer. The SR coating membrane of this form is applied precisely by controlling the release of the organic acid to ensure that no drug is left in the dosage form due to lack of solubilization of the acid in Table TPR. In a modality, the active core of the dosage form of the present invention may comprise an inert particle coated with an organic acid, an SR coating, coated drug (IR beads), an additional barrier or SR coated and / or delayed coated. The amount of organic acid or the loading of the drug in the nucleus will depend on the drug, the dose, its pH-dependent solubility, the improvement in solubility, and the elimination of the half-life. Those skilled in the art will be able to select an appropriate amount of drug / acid to be coated on the core to achieve the desired BID (twice daily) or QD (once daily) dosing regimen. In one embodiment, the inert particle may be a sugar sphere, a cellulose sphere, a sphere of silicon dioxide or the like. Alternatively, organic acid crystals with a desired particle size distribution can function as nuclei, especially for drugs of Group C, and in this case, these crystals are coated membranes to program the release of the acid, which according to certain modalities, is synchronized with that of the drug to ensure the complete release of the drug before the removal of the acid. According to one aspect of the present invention, the core of the dosage form may comprise a crystal of organic acid (eg, fumaric acid) with a desired average particle size or an inert particle such as a sugar sphere coated with an organic acid or a polymer binder solution. Acid-containing organic acid crystals or cores are coated with water-insoluble polymer alone or in combination with a water-soluble or enteric polymer, and the composition and thickness of the SR membrane is optimized in such a way that the release of the acid it is slower or synchronized with the dissolution / release of the drug from the bead, therefore, ensuring that the release of the acid is not complete before the elimination of drug release. In certain aspects of the invention, the acid-containing cores may be in the form of microgranules or granules which can be prepared through rotogranulation, high-shear granulation and extrusion-spheres or compression (as micro-tablets of about 1). -1.5 mm in diameter) of organic acid, a polymeric binder, and optionally fillers / diluents. A weak basic active agent such as carvedilol is coated onto SR-coated fumaric acid-containing beads of a polymeric binder solution (e.g., povidone) and a protective seal layer comprising the hydrophilic polymer such as Opadry® Clear or Pharmacoat 603 (hypromellose 2910; 3 cps) to form IR beads. In one embodiment, the IR beads containing the drug can be coated twice, an internal barrier coating membrane with a water-insoluble polymer (eg, ethylcellulose) only in combination with a water-soluble polymer and a coated membrane delaying a water insoluble polymer in combination with an enteric polymer to produce TPR beads with a delay (delayed start release) of about 1 to 10 hours after oral administration. The insoluble polymer in the water and the enteric polymer may be present in a weight ratio of about 9: 1 to about 1: 4, preferably at a weight ratio of about 2: 1 to 1: 1. The membrane coating typically comprises from about 5 to about 60%, preferably from about 10 to about 50% by weight of the coated beads. According to yet another modality, the IR beads can simply be coated with a combination of insoluble polymer to water and an enteric polymer in the aforementioned amounts. The unit capsule or conventional tablet dosage form according to the present invention may comprise TPR beads alone or in combination with IR beads while the unit ODT may comprise TPR beads alone or in combination with immediate release (IR) beads. flavor. IR beads that do not have a taste-masking membrane will provide rapid release of the weak basic drug into the gastrointestinal tract within about 60 minutes, preferably within 30 minutes after oral administration. If they have a taste dissimulator, these beads exhibit taste dissimulation in the oral cavity and substantially complete release of the weak basic drug in the gastrointestinal tract within about 2 hours, preferably within 1 hour, after oral administration. The TPR beads will release the weak gastric drug for a period of up to about 4-20 hours in the gastrointestinal tract after a delay of approximately 1-10 hours after oral administration. The present invention also provides a method for manufacturing a pharmaceutically elegant multiparticulate dosage form having one or more populations of pulsatile, programmed release beads of one or more weak basic assets comprising cores containing SR-coated organic acid, i.e. series of well-controlled pulses in time such that the active agents and the acid, which are deposited in Well-separated / isolated layers do not contact each other to form acid addition compounds until the dosage form is contacted with a dissolution medium or body fluids after oral ingestion. The dosage form of this produced form exhibits release profiles composed of the active agent and the acid which are comparable, more particularly, the acid release profile is slower than that of the drug such that no drug is left undissolved in the dosage form for lack of organic solubilizing acid. In accordance with one embodiment of the present invention, the method may include the steps of: a. providing a core particle containing organic acid (e.g., an organic acid crystal with a desired particle size distribution or a particle comprising an inert particle (e.g., a sugar sphere, or a cellulose sphere, a silicon dioxide sphere) coated with an organic acid from a polymeric binder solution); b. coat the core particle that contains organic acid with an SR coating membrane consisting of a water-insoluble polymer such as EC-10 (ethylcellulose with an average viscosity of 10 cps) only in combination with a water-soluble polymer (e.g., povidone or PEG 400) or an enteric polymer such as hydroxypropyl methylcellulose phthalate (e.g., HP-55); c. applying a layer of a weak basic drug on a core particle containing SR-coated organic acid to form an IR bead; d. applying a barrier coating membrane on the IR bead with a solution of a water insoluble polymer alone or in combination with a water soluble polymer; and. apply a delayed coating membrane on the SR bead with a solution of a water insoluble polymer in combination with an enteric or a ratio of about 9: 1 to 1: 4 to form a programmed pulsatile release drug particle (TPR bead ). In accordance with certain embodiments of the present invention, the method may include the steps of: i. IR beads dissimulating the taste by coacervating the solvent with a soluble polymer (for example, ethylcellulose with an average viscosity of 100 cps) alone or in combination with a gastrosoluble pore former (for example, calcium carbonate) according to the description of the co-pending US patent application Serial No. 11 / 213,266 filed on August 26, 2005 (US Publication No. 2006/0105038 published on October 18, 2005). May 2006) or through a fluid bed coating with a water-insoluble polymer (eg, ethylcellulose with an average viscosity of 10 cps) alone or in combination with a gastrosoluble polymer (eg, Eudragit E100 or EPO) of according to the description of co-pending US patent application Serial No. 11 / 248,596 filed October 12, 2005 (EUA Publication No. 2006/0078614 published April 13, 2006) or a gastrosoluble pore former (for example, a calcium carbonate) according to the description in co-pending US patent application Serial No. 11 / 256,653 filed October 21, 2005 (EUA Publication No. 2006/0105039 published on October 18, 2005). May of 200 6), the content of the application established in this paragraph is incorporated herein by reference. ii. granulation of a powder mixture of sugar alcohol such as mannitol or a saccharide such as lactose and crospovidone, for example, using the description of co-pending US patent application Serial No. 10 / 827,106 filed on April 19 of 2004 (US Publication No. 2005/0232988 published on October 20 of 2005), the content of which is incorporated herein by reference to produce rapidly dispersing microgranules; iii. mixing one or more populations of TPR beads from step (e) alone or in combination with IR beads with disguised taste from step (i), and / or SR beads from step (d) to a desired ratio to provide a profile plasma once a day, rapidly dispersing microgranules of step (ii) and other pharmaceutically acceptable excipients; and iv. compress the mixture from step (iii) into orally disintegrating tablets comprising the required dose of one or more weak basic drugs, which could rapidly disintegrate in contact with the saliva in the oral cavity forming a suspension that is easy to swallow, smooth and exhibiting a profile of plasma suitable for dosing regimen twice or once daily with reduced incidences of adverse events including non-acceptance. An aqueous medium or a pharmaceutically acceptable solvent can be used to prepare core particles based on inert, coated particles. The type of inert binder that is used to bind the water-soluble organic acid or the weak basic drug to the inert particle or the SR-coated acid-containing core is not critical but usually the water-soluble or alcohol-soluble binder such as polyvinylpyrrolidone (PVP or povidone) or hydroxypropyl can be used. He Binder can be used at any concentration capable of being applied to the inert particle. Typically, the binder is used at a concentration of about 0.5 to 10% by weight. The organic acid or the weak basic drug may preferably be present in this coating formulation in the form of a solution or suspension. The solid content of the drug-coated composition may vary depending on the application but will typically vary from about 5 to 30% by weight depending on the viscosity of the coating formulation and / or the solubility of the drug. According to other embodiments, nuclei containing organic acid can be prepared through rotogranulation, or through granulation followed by extrusion-spherical formation or tabletting into micro-tablets. The organic acid, a binder, and optionally other pharmaceutically acceptable excipients (e.g., diluents / fillers) can be mixed together in a high shear granulator, or a fluid bed granulator, such as the Glatt GPCG granulator, and granulated to form agglomerates. The wet mass can be extruded and formed into spheres to produce spherical particles (granules). The mixture comprises acidic particles, a binder, and optionally a filler / diluent or granules containing the drug may also be tablets in the micro-tablets (approximately 1-1.5 mm in diameter) to produce granules containing organic acid. In these embodiments, the acid content can be as high as 95% by weight based on the total weight of the granulate, extrudate, or compressed core. These acid-containing cores are coated with an SR membrane before coating the drug and subsequent coating with functional polymers. The individual polymer coatings in the nuclei containing acid and IR beads can vary from about 5 to 50% by weight depending on the relative solubility of the organic acid for the active, nature of the active, composition of the barrier layer, and the delay required. In one embodiment, acidic cores can be provided with a barrier layer of a polymer insoluble to plasticized water, such as ethylcellulose (EC10), at about 5-50% by weight to sustain acid release for about 5-20 hours . In certain other embodiments, the other acids may be provided with a barrier layer of a plasticized ethylcellulose and hydroxypropylmethylcellulose phthalate (hypromellose) (HP-55) of about 10-50% by weight while the IR beads are coated with ethylcellulose ( EC-10) at 5-20% by weight to achieve drug release synchronized with that of the acid. In still another embodiment of the present invention, the IR beads may not be provided with any barrier coating, and the external delay coating of EC-10 / HP-55 / plasticizer at about 45. 5/40/14. 5 for a weight gain of about 30-50% by weight which controls the release of the drug after the delay. The composition of the membrane layer and the individual weights of the polymers are important factors to be considered in order to achieve a desired drug / acid release profile and a delay before appreciable drug release. The drug / acid release profiles of IR beads, barrier beads / SR coated and TPR beads can be determined according to the following procedure: The IR Pearl Dissolution Test, disguised or not, is conducted with a Apparatus 1 USP (baskets at 100 rpm) or Apparatus 2 (pallets at 50 rpm) in 900 ml of 0. 1 N of HCl at 37 SC while the dissolution test of SR and TPR beads is conducted in a USP apparatus using a two-stage dissolution medium (first 2 hours in 700 ml of 0.1 N HCl at 37 ° C followed by dissolution test at a pH = 6.8 obtained through the addition of 200 ml of a pH modifier). The release of the drug / acid with time is determined by HPLC in samples taken at selected intervals.

There are instances where the initiation of drug release should be initiated several hours after oral administration to provide an adequate plasma concentration to be appropriate for a dosing regimen of twice daily or once daily, depending on the half-life of the drug. elimination of the asset. According to particular aspects of the invention, drug release may be delayed up to 8-10 hours after oral administration. An individual activated sustained release profile for several hours after oral administration, with or without an immediate release pulse, is provided in accordance with certain embodiments of the present invention. An aqueous medium or a pharmaceutically acceptable solvent can be used to prepare core particles containing organic acid or IR beads containing drug through the coating of the drug on inert cores such as sugar spheres or on cores containing SR-coated acid. . The type of inert binder that is used to bind the soluble organic acid to water with the inert particle or the weak basic drug on SR-coated acid nuclei is not critical, but usually binders soluble in water or alcohol and / or soluble in water are used. acetone. Representative examples of binders include, but are not limited to a, polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPLC), hydroxypropyl cellulose, carboxyalkyl cellulose, polyethylene oxide, polysaccharides such as dextrin, corn starch, which can be dissolved or dispersed in water, alcohol, acetone, or mixtures thereof. same. Binders are typically used at concentrations of about 0.5 to 10% by weight. Representative inert particles used for the acid layers or pharmaceutical active include sugar spheres, cellulose spheres, and silicon dioxide spheres with a suitable particle size distribution (e.g., 20-25 mesh sugar spheres). to form the coated beads for incorporation into a capsule formulation and 60-80 mesh sugar spheres to form coated beads for incorporation into an ODT formulation). Examples of weak basic nitrogen (N) -containing therapeutic agents having a pKa in the range of about 5 to 14 include, but are not limited to, analgesics, anticonvulsants, antidiabetic agents, anti-infective agents, antineoplastic agents, anticancer agents. Parkinsonians, anti-rheumatic agents, cardiovascular agents, stimulants of the CNS (central nervous system), dopamine receptor agonists, anti-emetics, gastrointestinal agents, psychotherapeutic agents, opioid agonists, opioid antagonists, antiepileptic drugs, H2 histamine antagonists, antiasthmatic agents, and musculoskeletal relaxants. Representative pharmaceutically acceptable organic acids that improve the solubility of pharmaceutical actives include citric acid, fumaric acid, malic acid, tartaric acid, succinic acid, oxalic acid, aspartic acid, glutamic acid, and the like. The ratio of organic acid to pharmaceutical active typically ranges from about 5: 1 to 1:10, more particularly about 3: 1 to 1: 3 by weight in some embodiments of the present invention. Representative examples of water-insoluble polymers useful in the invention include ethyl cellulose, polyvinyl acetate (for example Kollicoat SR # 30D from BASF), cellulose acetate, cellulose acetate butyrate, neutral copolymers based on ethylacrylate and methyl methacrylate, copolymers of acrylic and methacrylic acid with quaternary ammonium group such as Eudragit NE, RS and RS30D, RL or RL30D and the like. Representative examples of water-soluble polymers useful in the invention include polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose (HP C), hydroxypropylcellulose (HPC), polyethylene glycol, and the like. Representative examples of enteric polymers useful in the invention include cellulose esters and their derivatives (cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate), polyvinylacetate phthalate, pH-methacrylate-sensitive methacrylic acid copolymers and shellac. These polymers can be used as dispersions of dry or aqueous powder. Some commercially available materials that can be used are methacrylic acid copolymers sold under the tradename Eudragit (L100, S100, L30D) manufactured by Rohn Oharma, Cellacefate (cellulose acetate phthalate) from Eastman Chemical Co. , Aquateric (aqueous dispersion of cellulose acetate phthalate) from FMC Corp. and Aqoat (aqueous dispersion of hydroxypropyl methylcellulose acetate succinate) from Shin Etsu KK The enteric, water-soluble and water-insoluble polymers used in membrane formation they are usually plasticized. Representative examples of plasticizers that can be used to plasticize the membrane include triacetin, tributyl citrate, triethyl citrate, acetyl tri-n-butyl citrate, diethyl phthalate, resinous oil, dibutyl sebacate, mono and diacetyl glycerides ( commercially available Myvacet 9-45), and the like or mixtures thereof. The plasticizer, when used, can comprise about 3 to % by weight and more typically around 10 to 25% by weight based on the polymer. The type of plasticizer and its content depend on the polymer or polymers and the nature of the coating system (eg, based on aqueous or solvent, based on solution or dispersion, and total solids.) In general, it is desirable to prime the surface of the particles coated with the drug before applying the barrier membrane coatings or separating the different membrane layers through the application of a thin hydroxypropyl methylcellulose (HPMC) film (for example, Pharmacoat® 603 or Opadry® Clear). HPMC is typically used, other primers such as hydroxypropylcellulose (HPC) or lower viscosity ethylcellulose can also be used The pharmaceutically active ingredients suitable for incorporation into these time-controlled pulsatile delivery systems include weak basic active pharmaceutical ingredients, derivatives and salts thereof, which are bioactive portions that contain nitrogen having a pKa in the range of about 5 to 14, a solubility of not more than 200 and g / ml, at a pH of 6.8, and an optimum higher dose to solubility ratio at a pH of 6.8 of not less than approximately 100. The drug substance can be selected from the group of chemical entities pharmaceutically acceptable with proven pharmacological activity in humans. Specific examples of weak basic nitrogen (N) -containing therapeutic agents include without limitation: olanzapine, a piperazinyl derivative indicated for the treatment of schizophrenia, ondansetron or ondansetron hydrochloride, a selective serotonin 5-HT3 receptor agonist indicated for prevention of nausea and vomiting associated with chemotherapy or post-operative surgery, dipyridamole, a dipyrimidine derivative indicated for the prevention of post-operative thromboembolic complications of cardiac valve replacement, carvedilol, a beta-adrenergic blocking agent indicated for the treatment of failure cardiac ischemic or cardiomyopathic, lamotrigine, a triazine derivative indicated for epilepsy therapy in adults and pediatric patients, olanzapine or pharmaceutically acceptable salt thereof, a psychotropic agent indicated for the treatment of schizophrenia, quetiapine, a piperazinyl derivative indicated for the tra of bipolar disorders. The membrane coatings can be applied to the core using any of the coating techniques commonly used in the pharmaceutical industry, but the fluid bed coating is particularly useful. The present invention is directed to multi-dose forms, it is said drug products in the form of multiparticulate dosage forms such as hard gelatin capsules or conventional tablets or orally disintegrating tablets compressed using a rotary tablet press, comprising one or more populations of beads for oral administration to provide target PK profiles in patients the need for treatment. Conventional tablets disperse rapidly at the entrance into the stomach while the ODTs disintegrate rapidly in contact with the saliva in the oral cavity forming a smooth suspension of coated beads for easy swallowing. One or more populations of coated beads can be compressed together with suitable excipients in tablets (eg, a binder, a diluent / filler, and a disintegrant for conventional tablets with a fast dispersion granulation can replace the binder-diluent / filler combination in ODT). In addition, compression of the ODT can be achieved using a tablet press equipped with an external lubrication system to lubricate the punches and the dies before compression. The following non-limiting examples illustrate the dosage forms of capsules comprising one or more pulses, each with a predetermined delayed onset and the entire in vitro drug release profile or emission of the plasma concentration profile in vivo. after oral administration of the dosage form, the desired profile should be imitated to achieve maximum therapeutic efficacy to improve patient acceptance and quality of life. Said dosage forms, when administered at the "exact time" or as recommended by the physician, should allow maintaining the concentration of the plasma in the drug at a potentially beneficial level in minimizing the occurrence of side effects associated with the drug.

Cmax O Cmin · Example 1 SR beads of fumaric acid Fumárico acid crystals were charged in 40-80 mesh (3750 g) in a fluid bed coater, Glatt GPCG 5 equipped with a Wurster insert with bottom of 9 inches, 10-inch column length and 16-mm pipe. These acid crystals were coated with a solution (at 6% solids) of 250 g of ethyl cellulose (Ethocel Premium 10 cps, hereinafter referred to as EC-10) and 166.7 g of polyethylene glycol (PEG 400) in a ratio of 60 g. / 40 dissolved in 98/2 acetone / water (6528.3 g) for a weight gain of up to 10% by weight. The processing conditions were as follows: atomization of air pressure: 2.0 bar; nozzle diameter: 1.00 mm; lower distribution plate: B; Spray / stirring interval: 30 s / 3 s; product temperature maintained at 35 + l2C; entrance of air volume: 145-175 cubic feet (4.11-4.96 m3) per minute (cfm) and increased spray speed of approximately 8 to 30 g / min. The fumaric acid crystals were also coated as described above using different ratios of ethylcellulose and PEG. More specifically, the acid crystals were coated with a solution of EC-10 (Ethocel Premium 10 cps) / PEG 400 at a ratio of either 75/25 or 67.5 / 32.5 for a gain weight of up to 10% by weight in each case. Figure 4 shows the fumaric acid release profiles of fumárico crystals coated at different ratios of EC-10 / PEG. B. Barrier Coated Tartaric Acid Crystals Tartaric acid crystals were charged with a 60-100 mesh (900 g) in a fluid bed coater, Glatt GPCG 1 equipped with a 6 inch lower spray Wurster insert (15.24). cm), column length of 6 inches (15.24 cm) and 1 cm from the bottom. These acid crystals were coated with a solution (at 6% solids) of 202.5 g of ethyl cellulose (Ethocel Premium 10 cps) and 22.5 g of triethyl citrate (TEC) for a weight gain of 20%. The processing conditions were as follows: atomization of air pressure: 1.5 bar; diameter of nozzle: 1.00 mm; lower distribution plate: B; product temperature maintained at 33 + 1 SC; air inlet speed 4-5 and increased spray speed of approximately 5 to 8 g / min. After coating, the beads were dried in the unit for 10 minutes to remove excess residual solvent. The release of tartaric acid was too fast. 20% of the crystals coated with SR released 67% of tartaric acid in 1 hour when the solution was tested in 0.1 N of HC1. This coated glass was covered with EC-10 / HP-55 / TEC at a ratio of 60/25/15 dissolved in 95/5 acetone / water for a weight gain of 20%. The release of tartaric acid at 2 and 4 hours from points in time was 66% and 93% respectively when tested by the methodology of a two-stage solution. Example 2: A. Nuclei containing fumaric acid Hydroxypropyl cellulose (Klucel LF, 33.3 g) would be added slowly to 90/10 alcohol / water test SD 3C 190 at 4% solids with rigorous stirring for dissolution and then added slowly fumaric acid (300 g) for dissolution. Glatt GPCG 3 equipped with a Wurster spray insert with a 6"depth (15.24 cm) would be loaded, the 8" split column (20.32 cm) would be loaded with 866.7 g of Sugar Spheres with 25-30 mesh. The spheres of sugar would be coated with the fumaric acid solution while maintaining the product temperature at approximately 33-34 ° C and the velocity of the air intake at approximately 3.5-4.5 m / s. The acid cores would be dried in the unit for 10 minutes to remove residual solvent / moisture and sift through 20-30 separating screen. B. Fumárico Acid Nuclei Coated with SR The above acid nuclei (1080 g) would be coated with a solution (at 7.5% solids) of 108 g of ethylcellulose (BC-10) and 12 g of triethyl citrate (TEC) at a ratio of 90/10 dissolved in 95/5 acetone / water for a weight gain of 10% by weight. C. Acid Cores Covered With SR Comprising Dipiramadol IR Beads Dipirimadol (225 g) was slowly added to an aqueous solution of polyvinylpyrrolidone-29/32 Povidone (25 g) for drug dissolution. SR-coated acid cores would be coated on the Glatt GPCG 3, with the drug solution and the drug-coated beads provided with a protective seal layer of Opadry Clear (about 2% weight gain) to form IR beads. with a drug load of 17.29% by weight. D. SR beads of Dipirimadol Previous IR beads of dipyrimadol (1080 g) would be covered with a barrier (covers with SR) by spraying a solution (7.5% solids) of 90/10 EC-10 / TEC (triethyl citrate) to 5-10% by weight and drying in the Glatt for 10 minutes to eliminate the residual solvent in excess. The dried pearls would be sifted to rule out any duplicates if they were formed. E. Dipyrimadol TPR Beads Dipyrimadol SR Beads (1080 g) with 7% coating from Example 2D would also be coated with a delayed coating membrane of EC-10 / HP-55 (hypromellose phthalate) / TEC (triethyl citrate) at a ratio of 50/35/15 for a weight gain of approximately 20%. The TPR beads would be dried in the Glatt at the same temperature to remove the residual solvent and sieved. Fig. 5 shows the release profiles of fumaric acid from TPR Beads of Dipyridamole. Example 3: A. Nuclei containing fumaric acid Hydroxypropyl cellulose would be slowly added (Klucel LF, 20 g) to 90/10 alcohol / water SD 3C 190 denatured at 4% solids with rigorous stirring for dissolution and then slowly add fumaric acid (200 g) to the solution. Glatt GPCG 3 would be loaded with 780 g of Sugar Spheres with 25-30 mesh. The sugar spheres were coated with the acid solution Fumárico like described in the Example 1. The nuclei of acid would dry in the unit during 10 minutes to delete the residual solvent / humidity and sift through separating screen of 20-30. B. Fumárico Acid Nuclei coated with SR The above acid nuclei (900 g) would be coated with a solution (at 7.5% solids) of 90 g of ethyl cellulose (EC-10) and 10 g of triethyl citrate (TEC) at a ratio of 90/10 dissolved in 95 / 5 acetone / water for a weight gain of 10% by weight. C. IR Beads of Lamotrigine Lamotrigine (162 g) was slowly added to an aqueous solution of Klucel LF (13 g) for drug dissolution. The acid cores coated with SR (900 g) above would be coated in Glatt GPCG 3 with the drug solution, and the drug coated beads were provided with a protective seal layer of Opadry Clear (approximately 2% weight gain) and dried in Glatt to produce IR Pearls. D. Lamotrigine SR beads IR Lamotrigine beads would be coated with barriers through the spraying of a solution (7.5% solids) of 70/30 EC-10 / TEC to 3-5% by weight and dried in Glatt GPCG 3 at the same temperature for 10 minutes to remove excess residual solvent. The dried pearls are They would sift to discard any duplicate if it was formed. E. Lamotrigine TPR beads Lamotrigine SR beads at 5% coating would also be coated with a delayed coating membrane of EC-10 / HP-55 / TEC at a ratio of 42.5 / 42.5 / 15 for a gain of weight of approximately 10-15%. The TPR beads would be dried in Glatt to remove the residual solvent and screened through a 20 mesh molecular sieve. F. MR Lamotrigine capsules, 50 mg: Hard gelatine capsules would be filled with IR beads, SR beads ( 3% coating) and TPR beads (10% coating) at a ratio of 35/40/25. Example 4: A. Barrier-coated tartaric acid crystals Tartaric acid crystals of 60-100 mesh (900 g) were coated in Glatt GPCG 3 with a solution of fumaric acid (90 g) and 10 g of Klucel LF to a ratio of 90/10 dissolved in alcohol / water test SD 3C 190 alcohol / test water denatured at 4% solids and also coated with EC-10 / HP-55 / TEC at a ratio of 65/20/15 dissolved in 95/5 acetone / water at 7.5% solids for a gain of 30% by weight as described in the previous Examples. The coated crystals would dry and they would be screened to discard the duplicates if they were formed, B. Lamotrigine IR Beads Lamotrigine (540 g) was slowly added to an aqueous solution of Klucel LF (60 g) to disperse the drug homogeneously. The acid cores coated with SR (900 g) above would be coated in Glatt GPCG 3 with the drug suspension, and the beads coated with the drug would be provided with a protective seal layer of Opadry Clear for 2% weight gain ) and dried in Glatt to produce IR Pearls. C. Lamotrigine SR beads. IR beads with SR of Lamotrigine (800 g) will be coated by spraying a solution (7.5% solids) of 85/15 EC-10 / TEC for a weight gain of 5-10. %. The SR beads were dried in Glatt at the same temperature for 10 minutes to remove excess residual solvent that would be screened to rule out any duplicates if formed. D. Lamotrigine TPR beads Lamotrigine SR beads would also be coated with a delayed coating membrane of EC-10 / HP-55 / TEC at a ratio of 45/40/15 for a weight gain of approximately 10 -twenty%. E. Lamotrigine MR Capsules, 50 mg: The hard gelatin capsules would be filled with IR beads, SR beads (5% or 10% coating) and TPR beads (10% or 20% coating) at a ratio of 35/40/25. Example 5: A. Nuclei containing fumaric acid Hydroxypropyl cellulose was slowly added (Klucel LF, 33.3 g) to 90/10 alcohol / test water 190 to 4% solids with rigorous stirring for dissolution and then slowly added fumaric acid (300 g) for dissolution. Glatt GPCG 3 was charged with a Wurster sprayer insert with 6"bottom, the 8" split column with 866.7 g of sugar spheres with 60-80 mesh. The sugar spheres were coated with the acid solution Fumárico while maintaining the temperature of the product at approximately 33-34 ° C and the speed of the air intake to approximately 3.5-4.5 m / s. The acid cores were dried in the unit for 10 minutes to remove residual solvent / moisture and sieved through a 40-80 separating screen. A. SR-coated fumaric acid cores The above acid cores (800 g) were coated with a solution (at 7.5% solids) of 180 g of ethylcellulose (EC-10) and 20 g of triethyl citrate (TEC). at a ratio of 90/10 dissolved in 95/5 of acetone / water for a weight gain of 10% to 20%. C. Carvedilol IR beads Hydroxypropyl cellulose (Klucel LF, 77.8 g) was slowly added to purified water (at 6% solids) with rigorous stirring for dissolution and Carvedilol (700 g) was slowly added with stirring to disperse the drug homogeneously. The acid cores covered with SR (900 g) above were coated in Glatt GPCG 3 with the drug dispersion, and the beads coated with the drug were provided with a protective seal layer of Opadry Clear (34.2 g for approximately 2% of gain weight) and dried on Glatt to produce IR Pearls. D. Carvedilol SR beads Carvedilol IR beads (1080 g) would be covered with barrier (SR coated) through the spraying of a solution (7.5% solids) from 90/10 EC-10 / TEC to 5 % by weight and dried in Glatt at the same temperature for 10 minutes to remove residual solvent in excess. The dried pearls would be sifted to rule out duplicate if it was formed. E. Carvedilol TPR beads Carvedilol SR beads would also be coated with a late coating membrane of EC-10 / HP-55 / TEC at a ratio of 50/35/15 for a weight gain of approximately 10 -20% by weight. The TPR beads would be dried in Glatt to remove the residual solvent and sieved through a 20 mesh molecular sieve. Fig. 6 shows the release profiles of TPR beads from carvedilol. F. IR Beads with Sneaky Flavor The IR Beads obtained above would be coated with 50/50 EC-10 / Eudragit E100 dissolved in 48.5 / 24 / 27.5 acetone / DP A / water for a weight gain of about 10-20 % in weigh. G. Rapid dispersion microgranules Rapid dispersion microgranules comprising a sugar alcohol such as mannitol and a disintegrant such as crospovidone were prepared following the procedure described in U.S. Patent Application. co-pending No. 2005/0232988, published on October 20, 2005, the content of which is incorporated herein by reference. D-mannitol (152 kg) was mixed with an average particle size of approximately 20μp? or less (Pearlitol 25 from Roquette, France) with 8 kg of interlaced povidone (Crospovidone XL-10 from ISP) in a high shear granulator (Vector GMX 600) and granulated with purified water (approximately 32 kg) and crushed wet using Quadro's Cornil and dried on tray for an LOD (loss on drying) of less than about 0.8%. The dried granules were screened and the excessively large material was ground to produce rapidly dispersing microgranules with an average particle size in the range of approximately 175-3 OOym. H. ODT of CR Carvedilol Rapidly dispersible microgranules would be mixed with TPR beads, SR beads, simulated flavored IR beads and other pharmaceutically acceptable ingredients, such as flavor, sweetener, and additional disintegrant at a ratio of rapidly dispersible microgranules to 2: 1 carvedilol muliticubierta beads, in a double V shell mixer for a sufficient time to obtain a homogenously distributed mixture for compression. The tablets comprise the simulated flavored pearls, SR Pearls and TPR Pearls at a ratio of 35/40/25 according to carvedilol would be compressed using a production scale tablet press equipped with an external lubrication system at medium hardness of approximately 5-7 kP. ODT MR of Carvedilol, 50 mg, in this way produced would rapidly disintegrate in the oral cavity creating a soft, easy-to-swallow suspension comprising coated carvedilol beads, which would provide a suitable target profile for a once-daily dosing regimen. Example 6: A. Nuclei containing fumaric acid Hydroxypropyl cellulose (Klucel LF, 53.6 g) was added slowly to 90/10 190 alcohol / water test at 4% of solids with rigorous stirring for dissolution and then fumaric acid (482.1 g) was added slowly for dissolution. Glatt GPCG 5 equipped with 9"Wurster bottom spray insert (22.86 cm) was loaded, 10"split column with 3750 g of Sugar Spheres with mesh of 25-30.The sugar spheres were coated with the fumaric acid solution while maintaining the product temperature at approximately 33-35 ° C and a speed The acid cores were dried in the unit for 10 minutes to remove the solvent / residual moisture and sieved through a 40-80 mesh screen. B. Fumedic acid cores coated with SR The above acid cores (3750 g) were coated with a solution (at 7.5% solids) of 177.6 g of ethyl cellulose (EC-10) and 19.7 g of triethyl citrate (TEC) at a ratio of 90/10 dissolved in 95/5 acetone / water for a weight gain of 5% by weight following the procedures described above C. IR beads of Ondansetron Hydrochloride Dehydrated Hydroxypropyl cellulose (Klucel LF, 77.8 g) was slowly added to 50/50 alcohol / test water 190 (4247.4 g alcohol + 4247.4 g of water at 5% solids) with rigorous stirring for dissolution and HC1 was added slowly from ondansetron (402.8 g) with stirring for drug dissolution. The SR-coated acid cores (3500 g) were coated on Glatt GPCG 5 with the drug solution, and the drug-coated beads were provided with a protective seal layer of Pharmacoat 603 (80.5 g for about 2% gain). of weight) and dried in Glatt to produce IR Pearls (batch size: 4028 g). D Ondansetron Hydrochloride SR beads IR beads from Ondansetron Hydrochloride (3500 g) (SR coated) were coated with a barrier by spraying a solution (7.5% solids) of 90/10 EC-10 / TEC at 5% by weight and dried in Glatt at the same temperature for 10 minutes to remove excess residual solvent. The dried pearls were sifted to discard the duplicate if it was formed. E. Ondansetron Hydrochloride TPR Beads The Ondansetron Hydrochloride SR Beads were further coated with a delayed coating membrane of EC-10 / HP-55 / TEC at a ratio of 60.5 / 25 / 14.5 for a gain of weight of 20% to 45% by weight. The TPR Pearls were dried in Glatt to remove the residual solvent and sieved through a 30 mesh molecular sieve. The TPR Pearls packed in sealed induction HDPE bottles were placed on ICH stability guides. Fig. 7 demonstrates the drug release profiles generated in TPR beads in accelerated stability (ie at 40 ° C / 75% RH) for up to 6 months. Table 1 demonstrates that the formulation of the present invention is physically and chemically stable.

Table 1: Stability of multi-coated TPR Beads in sealed induction HDPE bottles Example 7 (Comparative): A. Carvedilol IR Beads Coated in Sugar Spheres Hydroxypropyl cellulose (Klucel LF, 77.8 g) was slowly added to 90/10 alcohol / test water 190 (11667 g of alcohol + 1296 g of water at 6% solids) with rigorous stirring for dissolution and Carvedilol (700 g) was slowly added with stirring for drug dissolution. The Sugar Spheres with mesh of 25-30 (900 g) were coated on Glatt GPCG 3 with the drug solution, and the drug coated beads were provided with a protective seal layer of Opadry Clear (34.2 g for approximately 2% weight gain) and dried on Glatt to produce IR beads (batch size: 1712 g)). B. Carvedilol SR beads Carvedilol IR beads (800 g) would be covered with barrier (SR coated) by spraying a solution (6% solids) of 80/10 EC-10 / TEC to 15% by weight and dried in Glatt for 10 minutes to remove excess residual solvent. Samples were removed at 5%, 7. 5% and 10% are coated. The dried pearls would be sifted to discard the duplicates if it was formed. The solution that tested SR beads coated at 5% and 10% demonstrated the impact of incorporating an organic acid core. C. Diffraction of X-ray Powder X-ray powder diffraction patterns would be generated from fumaric acid, carvedilol, SR-coated fumaric acid beads, Carvedilol IR beads, SR beads, and TPR beads from Example 6. Analysis of these X-ray patterns would show that carvedilol exists in IR and TPR beads in the original crystalline state and not as formate salt. Example 8: A. Nuclei containing fumaric acid The cores containing fumaric acid (at a fumaric acid loading of 5.4% by weight) were prepared by the procedure described above. B. Nuclei Containing SR-Coated Fumaric Acid The above fumaric acid cores (3750 g) were coated with a solution of EC-10 and either PEG 400 (BI) at a ratio of 60/40 or TEC (B.2). ) at a ratio of 90/10 as the plasticizer, dissolved in 98/2 acetone / water (6% solids) for a weight gain of 10%. C. Ondansetron Hydrochloride IR Beads The Ondansetron Hydrochloride IR Beads of BI and B.2 above were prepared as described in Example 3 C. The drug coated beads were provided with a protective seal layer with Pharmacoat 603 (hypromellose 2910; 3 cps) for a weight gain of 2%. D. SR beads of Ondansetron Hydrochloride The IR beads of Ondansetron Hydrochloride (1080 g) were barrier coated (SR coated) by spraying a solution of EC-10 and either PEG 400 (DI) to a ratio of 60/40 or TEC (D.2) at a ratio of 90/10 as the plasticizer, dissolved in 98/2 acetone / water (7.5% solids) for a weight gain of 10% and dried in Glatt at the same temperature for 10 minutes to remove excess residual solvent. The dried pearls were sifted to discard any duplicates if formed. E. Ondansetron Hydrochloride TPR Beads Ondansetron Hydrochloride SR Beads Previous Dl and D.2 were also coated with a late coating membrane of EC-10 / HP-55 / TEC at three ratios of 45.5 / 40 / 14.5 (EI - lot # 1084-066), 50.5 / 35 / 14.5 (E.2 - lot # 1117-025) and 60.5 / 25 / 14.5 (E.3-lot # 1117-044) dissolved in 90/10 acetone / water (7.5% solids) for a gain of up to 50% in weigh. The TPR Beads were dried in Glatt to remove the residual solvent and sieved through a 18 mesh molecular sieve. Fig. 8 shows the release profiles for Ondansetron Hydrochloride from TPR Beads coated with EC-10 / HP - 55 / TEC to three different relationships (EI, E.2 and E.3). More specifically, Fig. 8 shows the release profiles for the following formulations: (1) TPR beads batch # 1084-066 - The coating of EC-10 / HP-55 / TEC at a ratio of 45.5 / 40 / 14.5 50% by weight applied on IR Beads coated with 60/40 EC-10 / PEG 400 at 10% while the IR Beads (5% coated ondansetron / PVP 90/10) comprise fumaric acid cores (4% coated on spheres of acid sugar / Klucel) coated with 60/40 of EC-10 / PEG 400 at 10%. (2) TPR Beads batch # 1117-025 - The EC-10 / HP-55 / TEC coating at a ratio of 50.5 / 35 / 14.5 to 50% by weight applied on IR Beads coated with 90/10 EC- 10 / TEC at 10% while the IR Beads (6% drug coated ondansetron / Klucel LF 90/10) comprise fumaric acid cores (acid / PVP) coated with 90/10 EC-10 / TEC at 10 %. TPR Beads batch # 1117-044 - The EC-10 / HP-55 / TEC coating at a ratio of 60.5 / 25 / 14.5 to 50% by weight applied on IR Beads coated with 90/10 EC-10 / TEC at 10% while the IR Beads (6% coated drug 90/10 ondansetron / Klucel LF) comprise fumaric acid cores (coated in sugar / acid spheres PVP) coated with 90/10 EC-10 / TEC at 10%. Example 9: A. Proof of the Concept of the Formulations of Test Ondansetron Hydrochloride IR beads (PE364EA0001) and TPR Pearls (lot # PE366EA0001 with a 30% delayed coating, lot # PE367EA0001 with 45% delayed coating, and lot # PE368EA0001 with a delayed coating were encapsulated. 50%) at a ratio of 35% / 65% in hard gelatin capsules to produce MR Capsules (modified release), 16 mg (batches # PF380EA0001, batches # PF381EA0001, and batches # PF382EA0001) of QD (dosed once a day) for a pilot bioavailability study in humans compared to Zofran marketed 8 mg (as ondansetron) dosed twice daily (twice daily). B. PK Trial of the Human Concept A 4-arm transition pilot POC study was conducted that included 12 healthy, Caucasian male volunteers aged 18 to 55 years with a 7-day washout period. Each volunteer was dosed with 250 ml of sterile mineral water of the Individual Test Formulation Form A (16 mg) (PF380EA0001), B (PF381EA0001), or C (PF382EA0001 of Example 4) at 8 AM or two Zofran® (8 mg ) at 8 AM and 4:30 PM after adjourning during the night (at least 12 hrs and lunch was served at 11 AM). Blood samples were taken at 0 (pre-dose), 20 min, 40 min, 1 hr, 1.5 hrs, 2 hrs, 3 hrs, 4 hrs, 6 hrs, 8.5 hrs (before the second dose), 9 hrs 10 min, 9.5 hrs, 10 hrs, 10.5s, 11.5 hrs, 12.5 hrs, 14.5 hrs, 17 hrs, 20 hrs, 22 hrs, 24 hrs and 36 hrs. Fig. 9 shows the average plasma concentration-time profiles achieved. The figure demonstrates that the plasma profiles of Test Formulations A (PE280EA0001), B (PE28 IEA0001), and C (PE282EA0001) are those characteristics of sustained release formulations, ie, life Apparent average is signi fi cantly longer than that of Zofran. AUC or Cmax of the Test Formulations do not deviate substantially from that of Zofran (ie, AUC within + -25% and Cmax approximately 70% of Zofran). The current Cmax for Zofran 8 mg was 30 ng / ml compared to the 24 ng / ml predicted while the current Cmax for the IR component was approximately 24 ng / ml when normalized. Approximately 70% of Zofran 8 mg twice daily (dosed twice) was absorbed in 24 hrs. Test Formulations A to C exhibited the expected post-dosing trend to the crossing point at approximately 15-16 hrs; then, Formula C continued to exhibit a lower plasma concentration-time profile against the predicted behavior. Example 10: A. SR-coated Tartaric Acid Crystals Tartaric acid crystals with 60-199 mesh were coated as described in Example 2B. B. Carvedilol IR beads (Drug loading: 40.9% w / w) IR beads would be prepared as described in Example 5. C. SR Pearls from Carvedilol The IR Pearls obtained above would be coated with SR with 90/10 EC-10 / TEC for a weight gain of 5-10%. D. Carvedilol TPR beads Carvedilol coated SR beads with 5% coating would be coated with a delayed cover of EC-10 / HP-55 / TEC at a ratio of 50/35/15 for a weight gain of up to about 30% by weight. E. Carvedilol CR Capsules, 50 mg Hard gelatin capsules would be filled with IR Beads, SR Beads (5% or 10% coating) and TPR Beads (30% rewind) at a ratio of 35/40 / 25. From these demonstrations, it is evident that the incorporation of an organic acid, as the solubilizer for the weak basic drugs exhibits a pH-dependent solubility profile (ie, shows a decrease in solubility at the pH of 6.8 in approximately 2 g. orders of magnitude as compared to its maximum solubility in the GI fluid) and functional acid recovery before applying the pharmaceutically active ingredient has a significant impact on the delay, a desired but complete drug release profile prior to the elimination of the pH regulator. In addition, the pharmaceutically active ingredient remains in an unaltered form in the solid dosage form until it is released by absorption in the GI tract. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (39)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A pharmaceutical multiparticulate dosage form characterized in that it comprises one or more populations of sustained release (SR) beads and / or one or more populations of programmed pulsatile-release beads (TPR) of at least one weak basic drug, wherein the weak basic drug comprises a pharmaceutically acceptable nitrogen-containing (N) -containing therapeutic agent or a pharmaceutically acceptable salt thereof, which has a in the range of about 5 to 14, and a solubility of not more than about 200 ug / ml, at a pH of 6.8; wherein the SR beads comprise organic acid core particles coated with an SR coating, the TPR beads comprise delayed coated organic acid core particles, and the organic acid core particles comprise at least one pharmaceutically acceptable organic acid and the weak basic drug, wherein the weak basic drug and the organic acid do not contact each other. 2. - The pharmaceutical multiparticulate dosage form according to claim 1, characterized in that the ratio of the highest optimum dose for the weak basic drug the solubility of the weak basic drug at a pH of 6.8 is not less than about 100; and the weak basic drug is particularly insoluble. 3. The pharmaceutical multiparticulate dosage form according to claim 1, characterized in that: a) the TPR beads comprise a coating with an external delay comprising a polymer insoluble in water in combination with an enteric polymer arranged on the beads of SR; the coating with external delay provides a delay from about 2 to about 7 hours before the start of the weak basic drug release; b) the SR beads comprise an SR coating (barrier) disposed on the IR beads, the SR coating comprises a water insoluble polymer alone or in combination with a water soluble polymer; c) the IR beads comprise the weak basic drug disposed on coated organic acid core particles (SR); d) the SR coated organic acid core particles comprise an internal barrier coating disposed on the core particles of organic acid, the internal barrier coating comprises a water insoluble polymer alone or in combination with a polymer soluble to water or an enteric polymer; and e) the organic acid core particles comprise at least one pharmaceutically acceptable organic acid that functions as a weak basic drug solubilizer. 4. The pharmaceutical multiparticulate dosage form according to claim 1, characterized in that it is in the form of an orally disintegrating tablet (ODT). 5. The pharmaceutical multiparticulate dosage form according to claim 1, characterized in that: a) the TPR beads comprise an externally delayed coating comprising a water-insoluble polymer in combination with an enteric polymer arranged on the IR beads , coating with internal delay provides a delay from about 2 to about 7 hours before the start of the release of the basic drug deficiency; b) IR beads comprise the weak basic drug disposed on SR-coated organic acid core particles. c) the SR coated organic acid core particles comprise an internal barrier coating disposed on the core particles of organic acid, the internal barrier coating comprises a water insoluble polymer alone or in combination with a water soluble polymer or an enteric polymer; and d) the organic acid core particles comprise at least one pharmaceutically acceptable organic acid. 6. - The pharmaceutical multi-particulate dosage form according to claim 1, characterized in that it comprises a population of IR beads, a first population of TPR beads and a population of SR beads.; or a population of IR beads, a first population of TPR beads, and a second population of TPR beads; where the ratio of the population of beads from IR to the first population of TPR beads to the population of SR beads, or the ratio of the population of beads from IR to the first population of TPR beads to the second population of TPR beads ranges from about 10: 90: 0 to about 40:10:50. 7. - The pharmaceutical multiparticulate dosage form according to claim 1, characterized in that the weak basic drug is selected from the group consisting of analgesics, anticonvulsants, antidiabetic agents, anti-infective agents, anti-neoplastic agents, anti-Parkinsonian agents, anti-drugs - Rheumatic, cardiovascular agents, stimulants of the SNC (central nervous system), dopamine receptor agonists, anti-emetics, gastrointestinal agents, psychotherapeutic agents, opioid agonists, opioid antagonists, anti-epileptic drugs, H2 histamine antagonists, anti-asthmatic agents, and musculoskeletal relaxants. 8. - The pharmaceutical multiparticulate dosage form according to claim 7, characterized in that the weak basic drug is selected from the group consisting of olanzapine, ondansetron, ondansetron hydrochloride, dipyridamole, carvedilol, lamotrigine, olanzapine, quetiapine, pharmaceutically acceptable salts of them, and combinations of these. 9. - The pharmaceutical multiparticulate dosage form according to claim 1, characterized in that the organic acid is selected from the group consisting of citric acid, fumaric acid, malic acid, maleic acid, tartaric acid, succinic acid, oxalic acid, acid aspartic acid, glutamic acid, and mixtures thereof. 10. The pharmaceutical multiparticulate dosage form according to claim 1, characterized in that the ratio of the weak basic drug to the organic acid ranges from about 5: 1 to 1:10 by weight. 11. The pharmaceutical multiparticulate dosage form according to claim 3, characterized in that the organic acid core particles comprise: i. a crystal of organic acid; ii. an inert particle coated with an organic acid and a polymer binder, or iii. a granule or a microtablet comprising the organic acid, a polymer binder and a diluent / filler. 12. - The pharmaceutical multiparticulate dosage form according to claim 11, characterized in that the IR bead comprises a drug layer comprising a weak basic drug and a polymeric binder at a drug to binder ratio of about 85:15 to about 99: 1 the polymeric binder is selected from the group consisting of polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, corn starch, pre-gelatinized starch and mixtures thereof. 13. - The pharmaceutical multiparticulate dosage form according to claim 3, characterized in that the internal barrier coating comprises a water-insoluble polymer alone or a water-insoluble polymer in combination with a water-soluble polymer at an insoluble polymer ratio in water / water soluble polymer of about 9: 1 to 5: 5 wherein the Barrier coating is applied for a weight gain of about 1.5% to 20% by weight based on the weight of the SR coated organic acid core particles. 14. - The pharmaceutical multiparticulate dosage form according to claim 11, characterized in that the water insoluble polymer is selected from the group consisting of ethyl cellulose, cellulose acetate, cellulose acetate butyrate, polyvinyl acetate, neutral copolymers based on ethylacrylate and methyl methacrylate, copolymers of acrylic and methacrylic acid esters and mixtures thereof. 15. - The pharmaceutical multiparticulate dosage form according to claim 11, characterized in that the insoluble polymer is selected from the group consisting of methylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone and polyethylene glycol and mixtures thereof. 16. - The pharmaceutical multiparticulate dosage form according to claim 3, characterized in that the delayed coating comprises a water-insoluble polymer in combination with an enteric polymer or a ratio of about 9: 1 to 1: 3, respectively, for a weight gain of about 10% to 60% by weight based on the weight of the TPR bead. 17. - The pharmaceutical multiparticulate dosage form according to claim 16, characterized in that the enteric polymer is selected from the group consisting of cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinylacetate phthalate, pH-methacrylate-sensitive methacrylic acid copolymers and shellac, derivatives and mixtures of the same. 18. - The pharmaceutical multiparticulate dosage form according to claim 3, characterized in that at least one internal barrier coating and the external delay coating further comprises a plasticizer selected from the group consisting of triacetin, tributyl citrate, triethyl citrate , acetyl tri-n-butyl citrate, diethyl phthalate, dibutyl sebacate, polyethylene glycol, polypropylene glycol, resin oil, mono and diacetyl glycerides and mixtures thereof. 19. - The pharmaceutical multiparticulate dosage form according to claim 3, characterized in that it also comprises IR beads that release no more than about 50% of weak basic drug contained in the IR beads within the first hour after administration oral of the dosage form. 20. - The pharmaceutical multiparticulate dosage form according to claim 3, characterized in that the IR bead comprises the weak basic drug and a polymer binder coated on the inert core. 21. - The pharmaceutical multiparticulate dosage form. according to claim 1, characterized in that it comprises one or more populations of TPR beads, wherein the weak basic drug comprises carvedilol or a pharmaceutically acceptable salt thereof; and each TPR bead population comprises SR-coated organic acid core particles comprising tartaric acid; and the late coating comprises ethylcellulose phthalate and hydroxypropyl methylcellulose at a ratio of about 9: 1 to about 1: 3 for a weight gain of up to about 50%, each population of TPR beads exhibiting after administration of the dosage form a predetermined delay and different release characteristics. 22. The pharmaceutical multiparticulate dosage form according to claim 1, characterized in that it comprises one or more populations of TPR beads, wherein the weak basic drug comprises ondansetron or a pharmaceutically acceptable salt thereof; and each population of TPR beads comprises particles of SR coated organic acid core comprising fumaric acid; and delayed coating of ethyl cellulose phthalate and hydroxypropyl methylcellulose at a ratio of about 9: 1 to about 1: 3 for a weight gain of 60%, each population of TPR beads exhibiting after oral administration of the dosage form a predetermined delay different release characteristics. 23. - The pharmaceutical multiparticulate dosage form according to claim 1, characterized in that it is in the form of an orally disintegrating tablet comprising a population of SR beads and / or one or two populations of TPR beads; wherein each population of SR or TPR beads respectively comprises an outer SR or TPR coating disposed on the beads comprising sustained release coated fumaric acid cores further coated with a weak basic drug. 24. - A method for the preparation of the multiparticulate dosage form according to claim 1, characterized in that it comprises: a. preparing particles of organic acid nuclei comprising at least one pharmaceutically acceptable organic acid. b. prepare acid core particles coated organic SR by coating the organic acid core particles with an SR coating comprising a water-insoluble polymer alone or a water-insoluble polymer in combination with a water-soluble polymer or an enteric polymer or a ratio of about 95%. / 5 to about 50/50 for a weight gain of up to about 20%; c. preparing IR beads (immediate release) by coating a solution comprising the weak basic drug or a pharmaceutically acceptable salt thereof, and a binder polymer, and optionally applying a protective seal layer comprising a water soluble polymer, onto the particles of SR coated organic acid. d. prepare SR beads through a (barrier (SR) coating) of a water insoluble polymer alone or a water soluble polymer, in combination with a water soluble polymer at a ratio of about 95: 5 to about 50: 50 for a weight gain of about 1.5% to about 20% by dry weight of the coated beads; and. prepare TPR beads through the application of an externally delayed coating comprising an insoluble polymer in water in combination with an enteric polymer to the SR beads at a ratio of about 9: 1 to 1: 3 for a gain of weight of about 10% to 60% of the dry weight of the TPR beads; and f. filling a capsule or compressing in an orally disintegrating tablet or tablet, SR beads and / or one or more populations of TPR beads in amounts sufficient to provide a suitable objective pharmacokinetic profile for a once-a-day dosing regimen in patients in need of medication. 25. - The method according to claim 24, characterized in that each coating or application steps comprise the coating or application of a solution in a pharmaceutically acceptable solvent system or an aqueous dispersion. 26. - The method according to claim 24, characterized in that step (f) is comprised of an orally disintegrating tablet, and the method further comprises: i. disguising the flavor of SR beads and / or one or more populations of TPR beads by coacervation of the conventional solvent or through fluid bed coating prior to compression. 27. - The method according to claim 24, wherein the step of compressing orally disintegrating tablets comprises compressing in a tablet press equipped with an external lubrication system to lubricate the dice and punches before compression. 28. The method according to claim 24, characterized in that the pharmaceutical multiparticulate dosage form comprises therapeutically effective amounts of SR beads, and / or one or more populations of TPR beads wherein each of the SR beads and / or one or more populations of TPR beads exhibit different release characteristics and a predetermined delay. 29. - The pharmaceutical multiparticulate dosage form according to claim 1, characterized in that the pharmaceutically acceptable organic acid is not removed from the dosage form until the completion of the release of the weak basic drug when the solution is assayed by the methodology of dissolution of the United States Pharmacopeia (USP) using a two-stage dissolution medium (first two hours in 0.1N HC1 followed by assay in a pH regulator at a pH of 6.8). 30. The pharmaceutical multiparticulate dosage form according to claim 1, characterized in that it also comprises immediate release (IR) beads. 31. The pharmaceutical multiparticulate dosage form according to claim 2, characterized in that it exhibits a pharmacokinetic profile at 24 hours after the appropriate dosage for a once-daily dosing regimen for patients in need thereof. 32. - The pharmaceutical multiparticulate dosage form according to claim 1, characterized in that the ratio of the weak basic drug to the organic acid is within the range of about 5: 1 to about 1:10. 33. - The pharmaceutical multiparticulate dosage form according to claim 4, characterized in that the ODT further comprises fast dispersing microgranules, wherein the rapidly dispersing microgranules comprise a disintegrant and a sugar alcohol or a saccharide or a combination of these , and each of the disintegrant and sugar alcohol or saccharide has an average particle size of no more than about 30 μm. 34. - The pharmaceutical multiparticulate dosage form according to claim 33, characterized in that the rapidly dispersing microgranules have an average particle size of not more than 400 [i. 35. - The pharmaceutical multiparticulate dosage form according to claim 33, characterized in that the ODT has a friability of not more than 1% by weight, and a disintegration time of about 60 seconds or less in contact with saliva. 36.- The pharmaceutical multi-particulate dosage form according to claim 3, characterized in that it comprises TPR beads, wherein the late coating comprises ethylcellulose and hydroxypropylmethyl cellulose. The method according to claim 26, characterized in that it also comprises: ii. providing a compressible coating in the SR beads and / or one or more populations of TPR beads, wherein the compressible coating comprises a plasticizing polymer, and therefore the coating fracture during compression is eliminated / minimized. 38.- The method according to claim 26, characterized in that it also comprises: iii. granulating a sugar alcohol or a saccharide, or a combination thereof, and a disintegrant, each having an average particle size of no more than about 30 μm to produce rapidly dissolving microgranules; iv. mix the SR beads and / or one or more populations of TPR beads with rapidly dispersing microgranules; and V. compress the mixture from step (iv) into orally disintegrating tablets. 39. The method according to claim 38, characterized in that the ratio of SR beads and / or one or more populations of TPR beads to rapidly dispersing microgranules is in the range of about 1: 6 to about 1: 2.