MX2008004282A - Pharmaceutical dosage forms having immediate release and/orcontrolled release properties - Google Patents

Abstract

The present invention relates generally to pharmaceutical dosage forms comprising:an absorption window active agent;a controlled release component comprising enteric-coated controlled release beads, wherein the enteric-coated release beads comprise at least two pH- sensitive polymer layers. The controlled-release dosage forms provide good bioavailability of absorption window active agents.

Description

PHARMACEUTICAL DOSAGE FORMS THAT HAVE PROPERTIES RELEASE OF IMMEDIATE RELEASE AND / OR CONTROLLED RELEASE Background of the Invention The present invention relates to pharmaceutical drug delivery systems for the controlled release of active agents with absorption window which: (1) have an absorption window in the gastrointestinal tract (ie, they are usually absorbed in the duodenum and / or jejunum); (2) have a treatment site in or near the gastrointestinal tract (eg, stomach and / or duodenum); or (3) they degrade in the colon. The invention also relates to the uses of these controlled release delivery systems in the treatment of various disorders and diseases in mammals. Conventional drug delivery systems, such as immediate-release drug delivery systems, have only limited use for: (1) active agents that have an absorption window in the gastrointestinal tract; (2) active agents that have a treatment site in or near the gastrointestinal tract; and (3) active agents that degrade in the colon. Conventional sustained release dosage forms of such active agents are difficult to formulate because typical sustained release formulations will release such active agents in areas of the Gl tract that do not absorb. suitably such active agents. Yes, it is difficult to formulate such active agents in a controlled release formulation to obtain the benefits of controlled release formulations, such as reducing the frequency of dosing and minimizing peaks and declines in the level of drug plasma. Certain active agents have a window of absorption in the gastrointestinal tract. The absorption of these active agents, such as, for example, baclofen, are site specific. Baclofen is mainly absorbed in the upper gastrointestinal tract (Gl). In addition, the degree of absorption of baclofen is substantially reduced in the lower Gl tract. The absorption can be dose-dependent, which is reduced with increased doses. An improved method of administering an active agent with a limited absorption window, such as baclofen, to a patient would include the delivery of effective amounts of the drug to the upper Gl tract over a prolonged period. In addition, several side effects may be associated with the administration of active agents to mammals, particularly when administered as immediate release dosage forms. For example, side effects of baclofen include nausea, vomiting, diarrhea, dizziness, sedation in daylight, and often less, psychotic states such as depressive mood disorders. In addition, adherence of the patient with a dosage regimen may be suboptimal where frequent doses are required, such as the need to administer a pharmaceutical dosage form three or four times a day. A pharmaceutical dosage form that requires less frequent dosing, such as once or twice a day, will be preferable. In addition, a pharmaceutical dosage form capable of establishing and maintaining stable plasma levels of the active agent over a prolonged period of time may benefit patients by requiring less frequent dosing and / or by minimizing side effects. Several other formulations have been described for active agents having an absorption window. For example, a pharmaceutical dosage form for baclofen that involves adhesive tablets placed in contact with the oral mucosa to deliver the active agent through the mucous membrane. This pharmaceutical dosage form, however, exhibits several known disadvantages associated with the adhesive tablets. In addition, the adhesive tablets provide baclofen to a site considered to be suboptimal for agents related to α-aminobutyric acid (GABA). Other proposed formulations for the active agents that have, an absorption window include dosage forms of matrix exhibiting marked swelling and high dimensional stability in the swollen state to facilitate prolonged gastric residence time. In addition, an osmotic pump-type dosage form for delivering an active agent with an absorption window has been proposed that provides for the continuous administration of the active agent over a prolonged period of time. However, a significant and continuing need remains for suitable pharmaceutical dosage forms to provide sustained release of active agents having an absorption window. In addition, a need remains for pharmaceutical dosage forms for active agents with an absorption window that establish and maintain stable plasma levels of the active agent over a prolonged period of time to achieve less frequent dosing and to minimize side effects. These and other objects are realized by the present invention. Brief Description of the Invention The present invention relates generally to pharmaceutical drug delivery systems for the controlled release of active agents with absorption window which: (1) have an absorption window in the gastrointestinal tract (for example, they are usually absorbed in the stomach and / or small intestine), (2) have a treatment site in or near the gastrointestinal tract (e.g., stomach and / or small intestine); or (3) they degrade in the colon. The invention also relates to the uses of these controlled release delivery systems in the treatment of various disorders and diseases in mammals. Surprisingly it has now been found that the prolonged duration of the active agents with absorption window can be achieved with pharmaceutical dosage forms comprising: (i) an active agent with window of absorption; and (ii) a controlled release component comprising enteric coated controlled release beads, wherein the enteric coated release beads comprise at least two polymer layers sensitive to pH. Preferably, the outer pH sensitive polymer layer is dissolved at a lower pH than the inner pH sensitive polymer layer. Active agents with absorption window suitable for use with the present invention include, but are not limited to: ACE inhibitors, antibiotics, anti-gout agents, anti-hyperlipidemic agents, anti-hypertensive agents, anti-tumor agents, salts of bismuth, bronchodilators, COX-2 inhibitors, diuretic agents, GABA receptor agonists, histamine blockers (H2), nonsteroidal anti-inflammatory agents (NSAIDs), nucleic acid or amino acid derivatives, opioids, peptidomimetic drugs, prostaglandins, therapeutic ions, vitamins or mixtures of any of them. The pharmaceutical dosage forms of the present invention are adapted to provide prolonged in vivo absorption as compared to immediate release active agent formulations. Brief Description of the Drawings Figure 1 is a graph of the dissolution profile in vi tro of a baclofen capsule formulation, 20 mg, prepared according to Example 2, according to the measurements under the USP palette method of 75 rpm in 900 ml of gastric fluid • simulated (pH 1.2) at 37 ° C. Figure 2 is a graph of the in vivo plasma profiles of baclofen tablet formulations according to the protocol described in Example 7. Figure 3 is a graph simulating baclofen plasma levels in a permanent state according to the invention. protocol described in Example 8, wherein (C) represents the 40 mg dosage form of the present invention and (D) represents the immediate release dosage form of 20 mg of reference. Detailed Description of the Invention The present invention relates generally to pharmaceutical drug delivery systems for the controlled release of the active agents with absorption window which: (1) have an absorption window in the gastrointestinal tract (for example, they are usually absorbed in the stomach and / or small intestine); (2) have a treatment site in or near the gastrointestinal tract (e.g., stomach and / or small intestine); or (3) they degrade in the colon. The invention also relates to the uses of these controlled release delivery systems in the treatment of various disorders and diseases in mammals. The present invention relates to pharmaceutical dosage forms comprising: (i) an active agent with window of absorption (that the active agent with window of absorption can include analogs, derivatives, prodrugs or mixtures thereof, as well as a racemic mixture of the active agent with absorption window or a purely optical isomeric mixture of the active agent with absorption window); and (ii) a controlled release component comprising enteric coated controlled release beads, wherein the enteric coated release beads comprise at least two polymer layers sensitive to pH. The enteric coated controlled release beads of the pharmaceutical dosage form comprise a core of the active agent with absorption window, wherein the active agent with absorption window is coated with an inner pH sensitive polymer layer and an outer pH sensitive polymer layer. According to the present embodiment, the core comprises the active agent with absorption window that can be segmented into a sugar sphere. The inner pH sensitive polymer layer adheres to and substantially envelops the core. The outer pH sensitive polymer layer adheres to the polymer layer sensitive to the inner pH and substantially envelopes both the core and the inner pH sensitive polymer layer. Preferably, the outer pH sensitive polymer layer is dissolved at a lower pH than the inner pH sensitive polymer layer. The outer pH responsive layer retards the release of the active agent with absorption window until the pharmaceutical dosage form passes through the stomach and reaches the highest pH environment of the small intestine. At this point the outer pH sensitive layer will dissolve and the inner pH sensitive layer will be exposed. The inner pH sensitive layer, until exposure to the pH environment of the small intestine, will cause sustained release of the active agent with window of absorption. The sustained release and / or absorption of the active agent with absorption window before passage of the form of Pharmaceutical dosage beyond the area of the Gl tract where the active agent with absorption window can be effectively absorbed is controlled by the amount of pH sensitive polymers. In a preferred embodiment, the outer pH responsive layer will dissolve at a pH of about 5, about 5.5, about 6 or about 6.5, and the inner pH sensitive layer will dissolve at a pH of about 5.5, about 6.0, about 6.5 or approximately 7, respectively. The dissolution profile of the present invention can be adapted by adjusting the amount of the pH sensitive polymer inside and / or the pH sensitive polymer used in the formulation. The amount of the pH-sensitive polymer inside and / or the pH-sensitive polymer outside can be measured by various means well known in the art, such as, for example, the percent weight with respect to the enteric coated controlled release count, the thickness of the coating on the enteric coated controlled release count, or the weight percentage with respect to the pharmaceutical dosage form. The outer polymer layer may have a percent by weight with respect to the enteric coated release count of from about 5% to about 50%, from about 10% to about 40% or about 15% by weight. approximately 35%. The inner polymer layer may have one percent by weight with respect to the enteric coated release count of about 5% to about 50%, about 8% to about 40%, about 10% to about 35% or about 20% to approximately 30%. The pharmaceutical dosage form of the present invention may also further comprise an immediate release component. In one embodiment, the immediate release component comprises immediate release accounts. In this embodiment, the immediate release component exhibits an in vi tro dissolution profile in simulated gastric fluid comprising at least about 80% release of the active agent with absorption window after 1 hour. The immediate release component can comprise any suitable amount of active agent with absorption window necessary to produce the desired physiological result. The ratio of the immediate release component to the controlled release component is well known to those of ordinary skill in the art. For example, the ratio of the immediate release component to the controlled release component is from about 1: 4 to about 4: 1, from about 5: 1 to about 1: 5, from about 6: 1 to II about 1: 6, from about 7: 1 to about 1: 7, from about 8: 1 to about 1: 8, from about 9: 1 to about 1: 9, from about 1:10 to about 10: 1, about 1: 3 to about 3: 1 or about 1: 1. In another embodiment, the ratio of the immediate release component to the controlled release component is from about 1: 2 to about 2: 1. It has been found that the formulations of the present invention can allow for less frequent dosing as compared to the immediate release formulations. For example, for patients requiring chronic GABAB agonist therapy, twice daily administration of the formulations of the present invention is bioequivalent to about three times of daily administration of an existing immediate release formulation. This reduced dosing frequency is more convenient for patients and typically leads to better patient compliance. In addition, it reduces the number of peaks and channels in the plasma, which is typically associated with improving efficacy and reducing side effects. Active agents that have an absorption window in the gastrointestinal tract are suitable for use with the pharmaceutical dosage form of the present invention. Examples of such active agents with window Reduced that are suitable for use with the present invention include, but are not limited to: ACE inhibitors, antibiotics, anti-gout agents, anti-hyperlipidemic agents, anti-hypertensive agents, anti-spasm agents, anti-tumor agents, bismuth salts, bronchodilators, COX-2 inhibitors, diuretic agents, GABA receptor agonists, histamine blockers (H2), nonsteroidal anti-inflammatory agents (NSAIDs), nucleic acid or amino acid derivatives, opioids, peptidomimetic drugs, prostaglandins, therapeutic ions, vitamins or mixtures of any of them. ACE inhibitors suitable for the present invention include, but are not limited to: benazepril, captopril, cilazapril, enalapril, fosinopril, ramipril or meclaz of any of these. Amino acid derivatives suitable for the present invention include, but are not limited to: baclofen, gabapentin, levodopa, a-methyldopa, valaciclovir or mixtures of any of these. Antibiotics suitable for the present invention include, but are not limited to: ciprofloxacin, clarithromycin, metronidazole, nitrofurantoin, tetracycline, β-lactam antibiotics, quinolones or mixtures of any of them, β-lactam antibiotics suitable for the present invention include, but are not limited to: amoxicillin, cephalexin or mixtures thereof. Quinolones suitable for the present invention include, but are not limited to: ciprofloxacin, enoxacin, fleroxacin, lomefloxacin, norfloxacin, ofloxacin, pefloxacin or mixtures of any of these. Anti-hypertensive agents suitable for the present invention include, but are not limited to: atenolol, metoprolol or mixtures thereof. As an example, pravastatin is an anti-hyperlipidemic agent suitable for the present invention. Anti-spasmodic agents suitable for the present invention include, but are not limited to: dantrolene, tizanidine or mixtures thereof. Bronchodilators suitable for the present invention include, but are not limited to: albuterol, pirbuterol or mixtures thereof. As an example, furosemide is a suitable diuretic agent for the present invention. The nucleic acid derivatives for the present invention include, but are not limited to: acyclovir, AZT, didanosine or mixtures of any of them. Therapeutic ions suitable for the present invention include, but are not limited to: calcium carbonate, calcium citrate, lithium carbonate, citrate lithium or mixtures of any of them. Vitamins suitable for the present invention include, but are not limited to: ascorbic acid, folic acid, riboflavin, vitamin E, thiamin disulfide or mixtures of any of these. In addition, the pharmaceutical dosage form of the present invention can be used to deliver active agents for local treatment in the gastrointestinal tract. These active agents may be useful for the treatment of, for example, stomach neoplasms (eg, adenocarcinoma of the stomach or gastric lymphoma). Examples of active agents suitable for use with the pharmaceutical dosage form of the present invention and suitable for local treatment in the gastrointestinal tract include, but are not limited to: anti-tumor agents, histamine (H2) blockers, salts of bismuth, prostaglandins, non-steroidal anti-inflammatory agents (NSAIDs), opioids, COX-2 inhibitors or mixtures of any of them. These dosage forms can be used in the treatment of various disorders and diseases in mammals. Anti-tumor agents suitable for the present invention include, but are not limited to: 5-cisplatin, doxorubicin, etoposide, fluorouracil, methotrexate, mitomycin, semustine or mixtures of any of these.

Suitable bismuth salts for the present invention include, but are not limited to: bismuth subcitrate, bismuth subsalicylate or mixtures thereof. Histamine (H 2) blockers suitable for the present invention include, but are not limited to: cimetidine, famotidine, ranitidine or mixtures of any of these. Prostaglandins suitable for the present invention include, but are not limited to: misoprostol, synthetic misoprostol, synthetic prostaglandins or mixtures of any of them. As stated above, the pharmaceutical dosage form of the present invention is also suitable for the active agents which can degrade in the colon. An example of a suitable active agent for the present invention because it degrades in the colon is metoprolol. Additional examples of the active agents suitable for the present invention are: allopurinol, chlorpromazine or mixtures thereof. The pharmaceutical dosage form of the present invention may exhibit an in vitro dissolution profile in the simulated intestinal fluid medium comprising at least about 5% release of the active agent with absorption window after 1 hour, so less about 20% release of active agent with window of absorption after 4 hours and at least about 30% release of active agent with window of absorption after 6 hours. The pharmaceutical dosage forms of the present invention may also exhibit a profile of the in vi tro solution in the simulated gastric fluid / simulated intestinal fluid medium (1 hour of switching) comprising from about 2% to about 90% release of the agent active with absorption window after 1 hour, at least about 30% release of active agent with absorption window after 4 hours and at least about 40% release of active agent with absorption window after 6 hours. Another embodiment of the present invention exhibits an in vivo plasma profile comprising the release of the active agent with average maximum absorption window from about 30 minutes to about 7 hours (preferably from about 1 hour to about 5.5 hours, more preferably from about 90 minutes to about 5.5 hours and even more preferably from about 2 hours to about 5.5 hours) after the administration of a single dose to a rapid patient. In a permanent state, the dosage forms The pharmaceutical compositions of the present invention will achieve a CMIN comparable to that obtained in the permanent state of an immediate-release dosage form at a later time point, which will allow for less frequent dosing. In particular, a pharmaceutical dosage form of the present invention, when administered twice daily, will deliver in the area in average permanent state under the plasma concentration time curve (AUC), maximum plasma concentration (CMAX) and the minimum plasma concentration (CM? N) similar to that of an immediate-release tablet formulation administered three times daily. In an alternate embodiment, the pharmaceutical dosage form of the present invention exhibits a plasma profile in vivo comprising at least 2 hours of active agent concentrations with sustained absorption window at greater than therapeutic levels, after approximately 2 hours after administration to a patient fasting. The pharmaceutical dosage forms of the present invention contain a controlled release component, wherein a controlled release component comprising enteric coated release beads comprise at least two layers of pH sensitive polymer. The enteric coated release beads also they can comprise the active agent with absorption window. The controlled release component exhibits an in vitro dissolution profile in the simulated gastric fluid / simulated intestinal fluid medium (2 hours of switching) comprising less than about 10% release of the active agent with absorption window after 2 hours , at least about 40% release of active agent with window of absorption after 3 hours and at least about 70% release of active agents with window of absorption after 6 hours. Preferably, the controlled release component exhibits an in vitro dissolution profile in the simulated gastric fluid / simulated intestinal fluid medium (2 hours of switching) comprising less than about 10% release of active agent with absorption window after of 2 hours, at least about 50% release of the active agent with window of absorption after 3 hours and at least about 80% of the release of the active agent with window of absorption after 6 hours. Most preferably, the controlled release component exhibits an in vi tro dissolution profile in the simulated gastric fluid / simulated intestinal fluid medium (2 hours of switching) comprising less than about 10% of the active agent release with window of absorption after 2 hours, at least about 60% release of the active agent with active absorption window after 3 hours and at least approximately 90% release of active agent with absorption window after 6 hours. The present invention includes pharmaceutical dosage forms that have both immediate release and controlled release components. In this embodiment, the pharmaceutical dosage form exhibits an in vitro dissolution profile in the simulated gastric fluid / simulated intestinal fluid (2 hours of switching) medium comprising less than about 75% release of active agent with absorption window after 2 hours and at least about 80% release of the active agent with absorption window after 3 hours. Preferably, the pharmaceutical dosage form exhibits an in vitro dissolution profile in the simulated gastric fluid / simulated intestinal fluid (2 hours of switching) medium comprising less than about 65% release of the active agent with absorption window after of 2 hours and at least about 90% release of the active agent with absorption window after 3 hours. Appropriate in vi tro dissolution test methods for the dosage forms of the present invention are known to those skilled in the art and include those described in the Examples herein. The USP palette method refers to the Method of Paddle and basket as described in the United States Pharmacopoeia, Edition XXII (1990). In particular, the USP palette method of 50 rpm or 75 rpm in 900 ml of simulated gastric fluid (SGF) (pH 1.2) or simulated intestinal fluid (SIF) (pH 6.8) at 37 ° C can be used to determine the profiles of dissolution in vi tro in accordance with the present invention. The pharmaceutical dosage forms of the present invention are adapted to allow prolonged absorption of the active agent with absorption window, which allows less frequent administration as compared to the existing immediate release formulations. As used herein, "prolonged absorption" means that the active agent with absorption window is absorbed in vivo, to rapid conditions, over a prolonged period of time. In a preferred embodiment comprising both an immediate release component and a controlled release component, the period of time over which the majority (i.e., 80-90%) of absorption occurs to extend to approximately 7 or 8 hours after the administration of the dosage form. Specifically, the average time period in which at least 80% of the active agent with absorption window is absorbed from the dosage forms of the present invention is greater than 2.5 hours after administration, typically three to 4.5 hours. after the administration. For comparison, the average time period in which at least 80% of the active agent with absorption window is absorbed from existing immediate release formulations is 1.5 to two hours after administration. The period over which an active agent with absorption window is absorbed from a dosage form can be calculated by unconverting using mathematical methods known to those skilled in the art. The total daily dosages of the compounds useful according to this invention administered to a host in single or divided doses are generally in amounts of about 0.01 mg / kg to about 100 mg / kg by weight of the daily body, preferably about 0.05 mg / kg at about 50 mg / kg body weight per day, from about 0.1 mg / kg to about 45 mg / kg body weight per day, from about 0.15 mg / kg to about 40 mg / kg body weight per day, from about 0.2 mg / kg to about 35 mg / kg body weight per day or from about 0.2 mg / kg to about 30 mg / kg body weight per day. However, it must be understood, that the specific dose level for any particular patient will depend on a variety of factors including body weight, general health, gender, diet, time and route of administration, absorption and excretion ratios, combination with other drugs and the severity of the particular disease that is treated. The current dosage levels of the active agent with absorption window in the compositions of the present invention can be varied to obtain an amount of the active agent with absorption window that is effective to obtain a desired therapeutic response for a particular composition and method of administration. . The total daily dose of the active agents useful according to this invention which are administered to a host in individual or divided doses may be in amounts, for example, from about 0.01 mg / kg to about 20 mg / kg in body weight per day and preferably 0.02 to 10 mg / kg / day, from about 0.03 mg / kg to about 15 mg / kg of body weight per day, from about 0.05 mg / kg to about 10 mg / kg of body weight per day or of about 0.1 mg / kg to approximately 5 mg / kg in body weight per day. The preferred dosage range of the active agent with absorption window is between 2.5 mg and 100 mg per dosage form. The dosage forms according to the present invention may contain such amounts or fractions thereof as may be used to constitute the daily dose.

The pharmaceutical dosage form of the present invention (preferably a tablet or capsule, which may contain beads, granules, particles or a mixture thereof) may contain an active agent with absorption window in an amount of about 1 mg to about 1000 mg, from about 1.5 mg to about 500 mg, from about 2 mg to about 250 mg, from about 2.5 mg to about 200 mg, from about 3 mg to about 175 mg, from about 3.5 mg to about 150 mg, of about 4 mg approximately 125 mg, from about 10 mg to about 100 mg, from about 12 mg to about 75 mg, from about 15 mg to about 50 mg, from about 17 mg to about 45 mg, from about 20 mg to about 40 mg , from about 25 mg to about 35 mg and can be used in the treatment of various disorders and diseases in mammals s. In addition, the pharmaceutical dosage form of the present invention may contain an active agent with absorption window in an amount of from about 200 mg to about 1000 mg, from about 300 mg to about 900 mg, from about 400 mg to about 800 mg, from about 450 mg to about 750 mg, of about 500 mg to about 700 mg, from about 550 mg to about 650 mg. Typically, the optimal dosage for a patient will be determined by grinding, whereby the patient is initially given in small doses, which are then gradually increased until the patient reaches the dosage level that achieves maximum therapeutic efficacy with minimal side effects. Among apparent pharmaceutical dosage forms for the skilled person, the solid oral dosage form according to the present invention can be a tablet formulation or a capsule formulation filled with discrete unit or a pouch formulation. The discrete units of the present invention include beads, pellets, pellets, spheroids, particles, tablets, pills, etc. The dosage forms can be made according to methods known in the art. Some preferred methods are described below. Dosage Forms Based on Particle, Immediate Release Particles. The immediate release / controlled release dosage forms of the present invention may also take the form of pharmaceutical particles. The pharmaceutical dosage forms can include immediate release particles in combination with controlled release particles in a sufficient ratio to provide the desired release of the active agents with absorption window. Controlled release particles can be produced by coating the immediate release particles. The term "particle" as used herein means a granule having a diameter of between about 0.01 mm and about 5.0 mm, preferably between about 0.1 mm and about 2.5 mm and more preferably between about 0.5 mm and about 2 mm . The skilled person should appreciate that the particles according to the present invention can have any geometric shape within this size range. While the average for a statistical distribution of the particles falls within the particle sizes listed above, they will be considered to fall within the contemplated scope of the present invention. The particles can assume any standard structure known in pharmaceutical techniques. Such structures include, for example, matrix particles, non-pareil cores having a drug layer and active or inactive cores having multiple layers thereon. A controlled release coating can be added to any of these structures to create a controlled release particle.

The particles can be produced according to any of a number of known methods for making particles. The immediate release particles comprise the active agent with absorption window and a disintegrant. Suitable disintegrants include, for example, starch, low substitution hydroxypropyl cellulose, croscarmellose sodium, carboxymethyl cellulose calcium, hydroxypropyl starch, sodium starch glycolate and macrocrystalline cellulose. In addition to the ingredients mentioned above, the pharmaceutical dosage form may also contain suitable amounts of other materials, for example, diluents, lubricants, binders, granulation aids, colorants, flavors and slip agents which are conventional in the pharmaceutical arts. The amounts of these additional materials are sufficient to provide the desired effect to the desired formulation. A pharmaceutical dosage form incorporating particles may also contain suitable amounts of these other materials such as diluents, lubricants, binders, granulation aids, colorants, flavors and slip agents which are conventional in pharmaceutical techniques in amounts up to about 75% in weight of the particulate, if desired.

In a preferred embodiment, oral dosage forms are prepared to include an effective amount of particles as described above within a capsule. For example, the melt extruded particles can be placed in a gelatin capsule in an amount sufficient to provide an effective controlled release dose when ingested and contacted by the gastric fluid. In another preferred embodiment, a suitable amount of the particles are compressed into an oral tablet using conventional tabletting equipment using standard techniques. The techniques and compositions for making tablets (compressed and molded), capsules (hard and soft gelatin) and the pills are also described in RE INGTON'S PHARMACEUTICAL SCIENCES, Arthur Osol, ed., 1553-93 (1980), incorporated herein by reference. The particles can be made by mixing the relevant ingredients and granulating the mixture. The resulting particles are dried and screened and the particles having the desired size are used for the formulation of the drug. Controlled Release of Enteric Coating. The controlled release of the active agent with absorption window is achieved with coatings of at least two polymers sensitive to pH. The functions of the external pH sensitive polymer as a retarder or coating enteric sustained release delay. Any of the commercially available pH sensitive polymers can be used for each of the two pH sensitive coatings. The active agent with absorption window is minimally or not released in the stomach acidic environment of pH of about 4.5 or less. The active agent with window of absorption should become available when the enteric layer dissolves at the higher pH present in the intestine; after a suitable delay time; or after the unit passes through the stomach. The preferred duration of drug release time is in the range of up to about 7 hours after dosing under fast conditions. Enteric polymers include cellulose acetate phthalate, cellulose acetate trimethylate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, co-polymerized methacrylic acid / methacrylic acid methyl esters such as, for example, known materials under the trade name Eudragit® L12.5, Eudragit® L100, or Eudragit® S12.5, SlOO (Rohm GmbH, Darmstadt, Germany) or similar compounds used to obtain enteric coatings. Aqueous colloidal polymer dispersions or re-dispersions can also be applied, for example, Eudragit® L 30D-55, Eudragit® L100-55, Eudragit® SlOO, Eudragit® preparation 4110D c; Aquateric®, Aquacoat® CPD 30 (FMC Corp.); Kollicoat MAE® 30D and Kollicoat MAE® 30DP (BASF); Eastacryl® 30D (Eastman Chemical, Kingsport, TN). The enteric polymers used in this invention can be modified by mixing with other known coating products that are not pH sensitive. Examples of such coating products include neutral methacrylic acid esters with a small portion of trimethylammonioethyl methacrylate chloride, currently sold under the tradename E Eudragit®, Eudragit® RL, Eudragit RS; a neutral ester dispersion without any of the functional groups, sold under the trade name Eudragit® NE30D and Eudragit® NE30; and other independent pH of coating products. The enteric coating will substantially envelop the controlled release component. The term "substantially wrapped" is intended to define the total or near total closure of a component. Such enclosing preferably includes at least about 80% enclosure, more preferably at least about 90% enclosure, and even more preferably at least about 99% enclosure. In a preferred embodiment, the dosage form is a capsule formulation, the capsule which contains a combination of beads containing the active agent with absorption window in an immediate release formulation and beads containing the active agent with absorption window in an enteric coated controlled release formulation. In this preferred embodiment, the enteric coated controlled release beads contain two pH sensitive layers that control the release rate of the active agent with absorption window. Controlled release beads are prepared by coating the active agent with an absorption window over sugar spheres, then coating the pH-sensitive polymer inside the active agent with an absorption window coated with sugar spheres, after coating the sensitive polymer. External pH on the sugar spheres coated with the active agent with absorption window and the polymer sensitive to internal pH. Preferably, the outer pH sensitive polymer layer will dissolve at a pH of about 5.5 or greater. In an alternating mode, the outer pH sensitive polymer layer will dissolve at a pH of about 3 or higher, at a pH of about 3.5 or higher, at a pH of about 4 or higher, at a pH of about 4.5 or higher, at a pH of about 5 or higher, at a pH of about 5.5 or higher, at a pH of about 6 or higher or at a pH of approximately 6.5 or higher. The inner pH responsive layer functions to provide sustained release of the active agent with window of absorption until the dissolution of the outer-enteric coating. The inner pH sensitive polymer layer will be applied in such an amount that, in combination with the outer pH sensitive polymer layer, the aesthetically coated controlled release component produces better bioavailability of the active agent with absorption window. Preferably, the inner pH sensitive polymer layer will dissolve at a pH of about 6 or higher. In an alternating mode, the inner pH sensitive polymer layer will dissolve at a pH of about 4 or higher, at a pH of about 4.5 or higher, at a pH of about 5 or higher, at a pH of about 5.5 or higher, at a pH of about 6.5 or higher or at a pH of about 7 or higher. Particularly preferred polymers are described in the following Examples. One embodiment of the present invention provides a free flowing formulation comprising the active agent with absorption window. The term "free flow" as used herein, proposes dosage forms that pass through a patient's digestive system without impediment or mechanism at a slow pace. Thus, for example, the term "free flow" will exclude gastric-mass dosage forms, which are designed to reside in the stomach for prolonged periods as in, for example, U.S. Patent No. 5,651,985. The dosage forms according to the present invention may also include a combination of the active agent with absorption window and at least one additional active agent, such as tizanidine, dantrolene, nonsteroidal anti-inflammatory agents (NSAIDs), opioids and inhibitors. of COX-2. The other active agents can be co-formulated into the immediate release-or controlled release components to provide desirable therapeutic effects. The dosage levels of the active agent with absorption window, as well as any active agent to be used in combination with the active agent with absorption window, in the compositions can vary while obtaining an amount of active agent with window of absorption. absorption, and, when used as a combination product, an amount of active ingredient that is effective to obtain a desired therapeutic response for a particular composition and method of administration. One objective of the present invention provides controlled bioavailability of the active agent with window of absorption as desired by health providers Bioavailability refers to the degree to which the therapeutically active drug becomes available in the body after administration. Typically, bioavailability is measured in patients who fasted overnight before dosing with the test preparation. The plasma samples are then taken and analyzed for the plasma concentration of the parent compound and / or its active metabolite. These data can be expressed as CMA, the maximum amount of the active ingredient found in the plasma, or as AUC, the area under the time curve of the plasma concentration. Shargel & Yu, APPLIED BIOPHARMACEUTICS AND PHARMACOKINETICS ch. 10 (3- edtion 1996); see also APPLIED PHARMACOKINETICS: PRINCIPLES OF THERAPEUTIC DRUG MONITORING, - Evans et al., eds. (3rd edition 1992). For example, active agent formulations with absorption window can be used in a comparative bioavailability study in subjects. Subjects fast during the night before drug administration. The plasma samples are then taken at dosing and every hour for twelve hours after dosing and then at sixteen and twenty-four hours after dosing, and analyzed for the ng / ml concentration of active agent with absorption window or metabolites of the same.

As used herein, the term "active agent with window of absorption" refers to those active agents that are absorbed in a particular location of the gastrointestinal tract, will benefit the patient by being absorbed in a particular location of the gastrointestinal tract, or it will be degraded at a different location in the gastrointestinal tract. The active agents with window of absorption differ from active agents that do not have an absorption window and, thus, are absorbed throughout the entire Gl tract. The absorption window could be due to any number of reasons, for example, physiological characteristics of the Gl tract, location of active transport mechanisms by the Gl tract, or pharmacological characteristics and / or absorption of the active agent. For example, certain active agents, such as baclofen, are more readily absorbed in the upper portion of the small intestine and not well absorbed in the large intestine. In a preferred embodiment, the active agent with absorption window is more easily absorbed in the stomach and / or small intestine. In another embodiment, the active agent with absorption window is more easily absorbed in the stomach. In an alternative embodiment, the active agent with window of absorption is more easily absorbed in the small intestine. More preferably, the active agent with absorption window is more easily absorbed in the upper small intestine. In still another embodiment, the active agent with window of absorption is more easily absorbed in the duodenum. Alternatively, the active agent with window of absorption is more easily absorbed in the jejunum. On the other hand, the active agent with window of absorption is absorbed in the ileum. Any active agent that has a therapeutic effect on the gastrointestinal tract, or that has an absorption window in the gastrointestinal tract, or that must be administered to a particular location in the Gl tract, or that is degraded in the colon, different from the referred agents, can be delivered by the pharmaceutical dosage form of the present invention. Such active agents are well known to persons of ordinary skill in the art and can be delivered alone or in combination with other suitable active agents. The term "analogous" means a compound comprising a chemically modified form of a specific compound or class thereof and maintaining the characteristic of pharmaceutical and / or pharmacological activities of the compound or class. The term "derivative" means a chemically modified compound wherein the modification is routinely considered by the ordinary skilled chemist, such as an ester or an amide of an acid, protecting groups, such as a benzyl group for an alcohol or thiol and a tert-butoxycarbonyl group of an amine. The term "prodrug", as used herein, includes any covalently linked carrier that releases a drug of active origin of the present invention in vivo when such a prodrug is administered to a patient. Because prodrugs are known to increase numerous desirable pharmaceutical qualities (i.e., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention can be delivered in the form of a prodrug. The prodrugs of the present invention can be prepared by modifying the functional groups in the compound in such a way that the modifications adhere, either in routine manipulation or in vivo, to the parent compound. The transformation in vivo can be, for example, as the result of some metabolic processes, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulfate ester, or reduction or oxidation of a susceptible functionality. Prodrugs within the scope of the present invention include those compounds wherein a hydroxy, amino or sulfhydryl group is linked to any group which, when the prodrug of the present invention is administered to a mammalian subject, is cleaved to form a free hydroxyl group , free amino or free sulfhydryl, respectively. The functional groups which can be easily transformed, by metabolic cleavage, into a class of groups reactive with the carboxyl group of the compounds of this invention. They include, but are not limited to, such groups as alkanoyl (such as acetyl, propionyl, butyryl, and the like), unsubstituted or substituted aroyl (such as benzoyl and substituted benzoyl), alkoxycarbonyl (such as ethoxycarbonyl), trialkyl (such) as trimethyl- and triethylsilyl), monoesters formed with dicarboxylic acids (such as succinyl) and the like. Because the rest with which the metabolically cleaved groups of the compounds useful according to this invention are cleaved in vivo, the compounds carrying such groups act as prodrugs. The compounds that carry the metabolically cleavable groups have the advantage that they can exhibit better bioavailability as a result of increased solubility and / or absorption rate conferred until the parent compound by virtue of the presence of the metabolically cleavable group. A discussion of prodrugs is provided in the following: DESIGN OF PRODRUGS, H. Bundgaard, ed. (Elsevier, 1985); METHODS IN ENZYMOLOGY, K. Widder et al., Eds., Volume 42, 309-96 (Academic Press 1985); A TEXTBOOK OF DRUG DESIGN AND DEVELOPMENT, Krogsgaard-Larsen & H. Bundgaard, ed., Chapter 5; Design and Applications of Prodrugs, 113-91 (1991); H. Buadgard, Advanced Drug Delivery Reviews, 1-38 (1992); 8 J. PHARM. SCIENCES 285 (1988); N. Nakeya et al., 32 CHEM. PHARM., BULL. 692 (1984); T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, 14 A.C.S. SYMPOSIUM SERIES: BIOREVERSIBLE CARRIERS IN DRUG DESIGN, Ed ard B. Roche, ed. (Am. Pharm. Assoc. &Pergamon Press 1987), each of which is incorporated herein by reference. The term "metabolite" refers to a form of a compound obtained in a human or animal body by the action of the body on the administered form of the compound, for example a demethylated analogue of a compound carrying a methyl group which is obtained in the body after administration of the methylated compound as a result of action by the body on the methylated compound. The metabolites may themselves have biological activity. The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problem or complication commensurate with a reasonable benefit / risk ratio. For example, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds wherein the specified compound is converted to an acid or base salt thereof. Such pharmaceutically acceptable salts include, but are not limited to, mineral salts or organic acid of basic residues such as amines; alkaline or organic salts of acidic residues such as carboxylic acids; and the similar ones. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, of non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the prepared salts of organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroximic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric , toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic and the like. For purposes of the present invention, the term "controlled release" refers to a part or all of a dosage form that can release one or more active pharmaceutical agents over a prolonged period of time (ie, over a period of time). 1 hour), or delay the release of active agent during a prolonged period of time. The characteristics of controlled release (CR) can also be referred to as sustained release (SR), prolonged release (PR), modified release (MR), delayed release (DR) or prolonged release (ER). When used in association with the dissolution profiles discussed herein, the term "controlled release" refers to that portion of a dosage form according to the present invention that delivers active agent for a period of time greater than 1 hour. . "Immediate release" refers to a part or all of a dosage form that immediately releases the active substantially in contact with gastric juices and that results in substantially complete dissolution within about 1 hour. The immediate release (IR) feature can also be referred to as immediate release (IR). When used in association with the dissolution profiles discussed herein, the term "immediate release" refers to that portion of a dosage form according to the present invention that delivers active agent for a period of time less than 1. hour. The term "CMA?" is the concentration of peak blood plasma exhibited by the compositions of the present invention. "TMA?" refers to the time that CMñ? occurs in the plasma concentration-time profile. "CMIN" is the minimum plasma concentration. "C" is the abbreviation for concentration, "T" for time, "max" for maximum and "min" for minimum. The initial peak plasma level refers to the first elevation in the blood plasma level of the active agent and may be followed by one or more additional peaks, one of which may be CMAX. As used herein, "active agent level with average maximum absorption window" refers to the active agent with average absorption window CMñ ?. The plasma concentrations in blood described herein are typically determined through a population of at least 12 subjects. The plasma concentrations in the blood described above can relate to plasma levels after an individual oral administration of the dosage form, or can refer to levels obtained at a permanent state. As used herein, "permanent status" plasma concentrations in the blood refer to plasma levels obtained in the repeated dosing of a drug. until it releases a stable level of absorption and elimination such that the amount of drug in the body is substantially constant. As used herein, the term "patient" means any mammal including humans. The term "effective amount" means a amount of a compound / composition according to the present invention effective in producing the desired therapeutic effect. The term "excipients" refers to pharmacologically inert ingredients that are not active in the body. See HANDBOOK OF PHARMACEUTICAL EXCIPIENTS (Am. Pharm. Ass'n 1986). A person of ordinary skill in the art will recognize that many different excipients can be used in formulations according to the present invention and the list provided herein is not exhaustive. The active agents of the present invention can be mixed with pharmaceutically acceptable carriers, diluents, adjuvants, excipients or vehicles, such as preservatives, fillers, polymers, disintegrating agents, glidants, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, lubricating agents, acidifying agents and dispersing agents, depending on the nature of the mode of administration and dosage forms. Such ingredients, which include pharmaceutically acceptable carriers and excipients, can be used to formulate oral dosage forms. Pharmaceutically acceptable carriers include water, ethanol, polyols, vegetable oils, fats, wax polymers, including gel forming polymers and non-gel forming and suitable mixtures thereof. Examples of excipients include starch, pregelatinized starch, Avicel, lactose, lactose, sodium citrate, calcium carbonate, dicalcium phosphate and lacquer mixture. Examples of disintegrating agents include starch, alginic acids and certain complex silicates. Examples of lubricants include magnesium stearate, sodium lauryl sulfate, talc, as well as high molecular weight polyethylene glycols. "Dosage under fasting conditions" is defined as when the dosage is administered orally with 240 ml of water at room temperature after the subjects are fasted overnight for at least 10 hours. No fluid, except what is given with the administration of drug, will be allowed from 1 hour before the administration of doses until 1 hour after dosing. At 2 hours post-dose, subjects can consume 240 ml of water at room temperature. As used herein and in the claims, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, the reference to a profile is a reference to one or more such profiles, which include equivalents thereof known for those skilled in the art. Different in the operation examples, or where otherwise indicated, all numbers expressing amounts of ingredients or reaction conditions used herein must be understood as modified in all examples by the term "approximately". All patents and other identified publications are incorporated herein by reference for the purposes of describing and disclosing, for example, the methodologies described in such publications that could be used in connection with the present invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as those commonly understood by one of ordinary skill in the art to which this invention pertains. Although any of the known methods, devices and materials can be used in the practice or testing of the invention, preferred methods, devices and materials in this regard are described herein. Without further elaboration, one skilled in the art having the benefit of the foregoing description may use the present invention to the fullest extent. The following examples are illustrative only and do not limit the rest of the description in any way.

EXAMPLES Example 1. Seeds coated with active baclofen.

Povidone (Plasdone K-29 / 32®) is added to purified water and mixed until the povidone dissolves completely. The baclofen is mixed in the previous solution until it is uniformly dispersed. A fluidized bed coating apparatus is then used to coat the sugar spheres with the baclofen suspension to produce active coated seeds. Example 2. Seeds coated with active baclofen.

The hypromellose, Type 2910®, USP (Pharmacoat 606, 6cps) is added to an appropriate amount of purified water and mixed until the Hypromellose is completely dissolved. The baclofen is mixed in the previous solution until it is uniformly dispersed. A fluidized bed coating apparatus is then used to coat the sugar spheres with the baclofen suspension to produce active coated seeds. The dissolution profile of this formulation is shown in Figure 1. Example 3. Granules containing active baclofen.

Mix Baclofen, Starch 1500 (pregelatinized starch) and Avicel PH-102 (microcrystalline cellulose). Load the baclofen mixture into a Hobart mixer and mix to form a uniform mixture. Granulate the mixture with purified water to form a granulate. Dry the granulate in an oven at a temperature of 60 ° C to form granules. Sort the granules using a # 30 mesh screen. Mix the magnesium stearate to form active granules. Example 4 Composition containing baclofen active coated seeds and enteric coated.

The hypromellose, Type 2910, USP is added to an adequate amount of purified water and mixed until the hypromellose is completely dissolved. The baclofen is then mixed in the previous solution until it is uniformly dispersed. The suspension is passed through a # 40 mesh screen in a stainless steel container. The sugar spheres are loaded in a fluid bed coating device with a Wurster insert and heated until the exhaust air temperature reaches 50 ± 5 ° C. The active suspension of the above is sprayed to cover the sugar spheres, which are then dried at a temperature of 60 ± 10 ° C for 5-30 minutes. IR seeds are passed through a # 16 stainless steel screen. The seeds IR acceptable they are collected and mixed with talc, the USP in a tilted cone mixer for one to ten minutes. An enteric solution is prepared by mixing isopropyl alcohol and acetone. Triethyl citrate and methacrylic acid copolymer, type A, are stirred in the mixture until they dissolve completely. The talc is mixed in the previous solution until it is completely dispersed. A fluidized bed coating apparatus is then used to coat the IR seeds prepared as above with the enteric solution to produce enteric coated seeds. The enteric coated seeds are passed through a # 14 mesh stainless steel screen. The acceptable enteric coated seeds are harvested for the second enteric coated layer. A second enteric solution is prepared by mixing purified water and acetone. The triethyl citrate and the methacrylic acid copolymer, type C, are stirred in the mixture until they are completely dissolved. The talc is mixed in the previous solution until it is completely dispersed. A fluidized bed coating apparatus is then used to coat the enteric coated seeds prepared as above with the enteric solution to produce the enteric coated seeds. The enteric coated seeds are passed to through a # 12 mesh stainless steel screen. The acceptable enteric coated seeds are collected and mixed with talcum, the USP in a tilted cone mixer for one to ten minutes. An appropriate amount of IR seeds more. the appropriate amount of enteric coated seeds are encapsulated to produce Baclofen ER capsules. Example 5. Baclofen ER capsules. Baclofen ER capsules having the following formulations were prepared in accordance with the Example 6. Baclofen ER capsules. Baclofen ER capsules having the following composition were prepared according to the method described in Example 10. Capsules were prepared having 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg and 40 mg of baclofen, with different dosing resistances that is directly proportional. Composition of Baclofen ER Capsules 40 mg (Lot RB04042-60A) IR / EC (EC2) = 19: 21 Example 7. Determination of plasma profiles for formulations containing baclofen. A bioavailability study was done on 20 healthy volunteers comparing a 36 mg baclofen formulation prepared according to Example 6, with the exception that the immediate release component contained 12 mg of baclofen and the enteric coated controlled release component contained 24 mg of baclofen and the remaining excipients were adjusted proportionally with the dose. The formulation was compared to a 20 mg immediate release reference tablet (Watson Laboratories, Inc.) under fasted conditions. The test samples were administered orally with 240 ml of room temperature after the subjects were fasted overnight for at least 10 hours. No fluid, except what is given with the administration of drug, is allowed from 1 hour before the administration of doses until 1 hour after dosing. In 2, 6, 8 and 12 hours post-dose, subjects consumed 240 ml of water at room temperature. In addition, subjects consumed 480 ml of fluid with lunch and dinner. Blood samples were taken at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 16 and 24 hours after administration. The results are shown in Figure 2. In addition, Figure 2 shows the simulated blood plasma levels for 30 days. mg of baclofen immediate release, based on the data obtained from administration of the dosage concentration of 20 mg. Example 8. Determination of plasma profiles in permanent state for formulations containing baclofen. Based on the individual dose bioavailability data, the baclofen plasma levels in steady state were calculated by a 40 mg baclofen formulation prepared according to Example 6 administered every 12 hours and a baclofen formulation of 12 mg of immediate release (Watson Laboratories, Inc.) administered every 8 hours. The results are shown in Figure 3 (where (C) represents the 40 mg dosage form of the present invention and (D) represents the immediate release dosage form of 20 mg reference). The results show that, in a permanent state, the 40 mg dosage form of the present invention will reach a CMIN at 12 hours after administration comparable to the CMIN obtained by the immediate release formulation eight hours after administration. Having now fully described this invention, it will be understood by those of ordinary skill in the art that the methods of the present invention can be carried out with a wide range and equivalent of conditions, formulations and other parameters without departing from the scope of the invention or any of the modalities thereof.

Claims (40)

1. REI INDICATIONS 1. A pharmaceutical dosage form, characterized in that it comprises: i. an active agent with absorption window; and ii. a controlled release component comprising enteric coated controlled release beads, wherein the enteric coated release beads comprise at least two pH sensitive polymer layers.
2. 2. The pharmaceutical dosage form according to claim 1, characterized in that the enteric coated controlled release beads comprise a core comprising the active agent with absorption window, wherein the active agent with absorption window is coated with a layer of internal pH sensitive polymer and an outer pH sensitive polymer layer.
3. 3. The pharmaceutical dosage form according to claim 2, characterized in that the outer pH sensitive polymer layer is dissolved at a lower pH than the inner pH sensitive polymer layer.
4. 4. The pharmaceutical dosage form according to claim 2, characterized in that the outer pH sensitive polymer layer is dissolved at a pH of about 5.5 or less and the inner pH sensitive polymer layer is dissolved at a pH of about 6 or higher.
5. 5. The pharmaceutical dosage form according to claim 1, characterized in that it also comprises an immediate release component.
6. 6. The pharmaceutical dosage form according to claim 5, characterized in that the immediate release component comprises immediate release beads.
7. 7. The pharmaceutical dosage form according to claim 1, characterized in that it also comprises a plasticizer.
8. 8. The pharmaceutical dosage form according to claim 7, characterized in that the plasticizer is selected from the group consisting of: 1,2-propylene glycol, acetylated monoglycerides, castor oil, dibutyl sebacate, diethyl phthalate, phthalate esters , polyethylene glycol, propylene glycol, triacetin, tributyl citrate, triethyl citrate or a mixture of any of them.
9. 9. The pharmaceutical dosage form of according to claim 2, characterized in that the outer pH sensitive polymer layer is dissolved at a pH of about 3 or higher.
10. 10. The pharmaceutical dosage form according to claim 9, characterized in that the outer pH sensitive polymer layer is dissolved at a pH of about 4 or higher.
11. 11. The pharmaceutical dosage form according to claim 10, characterized in that the outer pH sensitive polymer layer is dissolved at a pH of about 4.5 or higher.
12. 12. The pharmaceutical dosage form according to claim 11, characterized in that the outer pH sensitive polymer layer is dissolved at a pH of about 5 or higher.
13. 13. The pharmaceutical dosage form according to claim 12, characterized in that the outer pH sensitive polymer layer is dissolved at a pH of about 5.5 or higher.
14. 14. The pharmaceutical dosage form according to claim 13, characterized in that the > The external pH sensitive polymer is dissolved at a pH of about 6 or higher.
15. 15. The pharmaceutical dosage form according to claim 2, characterized in that the The inner pH sensitive polymer layer dissolves at a pH of about 5 or higher.
16. 16. The pharmaceutical dosage form according to claim 15, characterized in that the inner pH sensitive polymer layer is dissolved at a pH of about 5.5 or higher.
17. 17. The pharmaceutical dosage form according to claim 16, characterized in that the inner pH sensitive polymer layer is dissolved at a pH of about 6 or higher.
18. 18. The pharmaceutical dosage form according to claim 17, characterized in that the inner pH sensitive polymer layer is dissolved at a pH of about 6.5 or higher.
19. The pharmaceutical dosage according to claim 2, characterized in that the inner pH sensitive polymer layer and / or the outer pH sensitive polymer layer are comprised of pH sensitive polymers selected from the group consisting of: carboxymethylethylcellulose, phthalate of cellulose acetate, cellulose acetate trimellitate, co-polymerized methacrylic acid, hydroxypropyl methylcellulose phthalate, methacrylic acid and methyl esters, polyvinyl acetate phthalate or a mixture of any of them.
20. 20. The pharmaceutical dosage form of according to claim 19, characterized in that the outer pH sensitive polymer layer comprises co-polymerized methacrylic acid.
21. 21. The pharmaceutical dosage form according to claim 5, characterized in that the ratio of the immediate release component to the controlled release component is from about 1: 4 to about 4: 1.
22. 22. The pharmaceutical dosage form according to claim 21, characterized in that the ratio of the immediate release component to the controlled release component is from about 1: 2 to about 2: 1.
23. 23. The pharmaceutical dosage form according to claim 1, characterized in that the pharmaceutical dosage form is a tablet.
24. 24. The pharmaceutical dosage form according to claim 1, characterized in that the pharmaceutical dosage form is a capsule.
25. 25. The pharmaceutical dosage form according to claim 24, characterized in that the capsule further comprises discrete units selected from the group consisting of beads, granules, particles, tablets or a mixture thereof.
26. 26. The pharmaceutical dosage form of according to claim 1, wherein the active agent with absorption window comprises an ACE inhibitor, an antibiotic, an anti-gout agent, an anti-hyperlipidemic agent, an anti-h'ipertensivo agent, an anti-espasmático agent, an anti-tumor agent, a bismuth salt, a bronchodilator, a COX-2 inhibitor, a diuretic agent, a GABA receptor agonist, a histamine blocker (H2), an anti-inflammatory spheroidal a mixture of any thereof agent (NSAID), a derivative nucleic acid or amino acid, an opioid, a peptidomimetic drug, a prostaglandin, a therapeutic ion, a vitamin or.
27. 27. The pharmaceutical dosage form according to claim 26, wherein the ACE inhibitor is benazepril, captopril, cilazapril, enalapril, fosinopril, ramipril or a mixture of any thereof.
28. 28. The pharmaceutical dosage form according to claim 26, wherein the amino acid sequence or amino acid derivative is baclofen, gabapentin, levodopa,-methyldopa, valaciclovir or a mixture of any thereof.
29. 29. The pharmaceutical dosage form according to claim 1, characterized in that the active agent with absorption window is a mixture racemic
30. 30. The way of. pharmaceutical dosage according to claim 1, characterized in that the active agent with absorption window is an optically pure isomeric mixture.
31. 31. The pharmaceutical dosage form according to claim 1, characterized in that the active agent with absorption window is released in the stomach and small intestine.
32. 32. The pharmaceutical dosage form according to claim 1, characterized in that the active agent with absorption window is released in the stomach.
33. 33. The pharmaceutical dosage form according to claim 1, characterized in that the active agent with absorption window is released in the small intestine.
34. 34. The pharmaceutical dosage form according to claim 33, characterized in that the active agent with absorption window is released in the upper small intestine.
35. 35. The pharmaceutical dosage form according to claim 33, characterized in that the active agent with absorption window is released into the duodenum.
36. 36. The pharmaceutical dosage form according to claim 33, characterized in that active agent with absorption window is released in the jejunum.
37. 37. The pharmaceutical dosage form according to claim 2, wherein the outer polymer layer is present in an amount of about 5 percent weight to about 50 percent by weight relative to the enteric-coated release account.
38. 38. The pharmaceutical dosage form according to claim 37, characterized in that the outer polymer layer is present in an amount of about 15 weight percent to about 35 weight percent with respect to the enteric coated release count.
39. 39. The pharmaceutical dosage form according to claim 2, characterized in that the inner polymer layer is present in an amount of about 5 weight percent to about 50 weight percent with respect to the enteric coated release count.
40. 40. The pharmaceutical dosage form according to claim 39, characterized in that the outer polymer layer is present in an amount of about 20 weight percent to about 30 weight percent with respect to the enteric coated release count.