KR20030013460A - Rapidly expanding composition for gastric retention and controlled release of therapeutic agents, and dosage forms including the composition - Google Patents

Abstract

The present invention relates to providing a pharmaceutical composition for use in formulations to be administered orally to a patient. The composition swells upon contact with gastric fluid and promotes the formulation to stay in the stomach for an extended period of time. The present invention also relates to providing pharmaceutical formulations and pharmaceutical compositions containing the active ingredient. This form is used for immediate release or controlled release of the active ingredient. The formulations can be advantageously used to treat Parkinson's disease by levodopa and to treat hyperactivity and attention deficit disorder by methylphenidate.

Description

RAPIDLY EXPANDING COMPOSITION FOR GASTRIC RETENTION AND CONTROLLED RELEASE OF THERAPEUTIC AGENTS, AND DOSAGE FORMS INCLUDING THE COMPOSITION}

After finding a new drug to treat human disease, further studies are conducted to determine whether the drug is most effectively administered to the patient intravenously, transdermally, subcutaneously or orally. It is often preferred to administer the drug orally if the oral route is possible.

Pharmacokinetic studies provide important information on how to obtain optimal therapeutic responses from drugs. For some drugs, maintaining a constant blood flow and tissue concentration throughout the course of treatment may be the most desirable method of treatment. Immediate release of these drugs can raise blood levels to a maximum above the concentration required to elicit the desired response, which may waste the drug and cause or exacerbate toxic side effects.

Many drugs provide better therapies when delivered in a controlled manner. Formulations capable of sustained release or delayed release of the drug are known. In some sustained release formulations, the active ingredient is embedded in the matrix such that it is slowly eroded to release the active ingredient. Other sustained release formulations and delayed release formulations also have a coating. These coatings coated on sustained release formulations may be semipermeable to the drug, thus slowing the release of the drug. Coatings on some conventional delayed release formulations are impermeable to the drug and slowly dissolve in the gastrointestinal fluid, thus delaying the release of the active ingredient until the coating dissolves and allows contact of the drug with the gastrointestinal fluid. However, semipermeable and impermeable coatings and conventional erosive matrices are often ineffective for sustained and delayed release of drugs by site specific absorption.

Many oral medications are easily absorbed by most of the jejunum and duodenum. Most other drugs are easily absorbed through the stomach wall. Few drugs are efficiently absorbed by the colon. The residence time of the above conventional formulations is on average from 1 hour to 3 hours. After a brief stay in the stomach, the bioavailability has a window of about 3 to 5 hours before the formulation reaches the colon. Sustained release or delayed release vehicles that do not stay in the stomach before and during drug release may release a significant portion of the drug after the bioavailability window has elapsed. However, when the formulation remains in the stomach, the active ingredient is released upstream of the small intestine and enters the small intestine in solution, ie, the active ingredient can be readily absorbed. Stomach retention formulations, ie formulations designed to stay in the stomach for extended periods of time, can increase the bioavailability of drugs that are most readily absorbed by the upper gastrointestinal tract.

Another important use of gastric retention formulations is to increase the bioavailability of drugs that are unstable to basic conditions of the intestine. Compositions designed to dissolve upon contact with any aqueous solution dissolve at least partially in the stomach because they reach the stomach before reaching the intestine. However, if the drug is not absorbed very quickly, or if the residence time is increased, some of the drug goes to the intestine. Unstable drugs are at least partially degraded into product compounds which are not absorbed or which, if absorbed, do not exert the desired therapeutic effect. Thus, degradation of base sensitive drugs into the intestine reduces the effectiveness of the formulation and provides an uncontrollable factor that is detrimental to correct administration.

Another important use of gastric retention is to deliver drugs to the active site for the treatment of local disorders of the stomach such as peptic ulcers.

For the reasons mentioned above, pharmaceutical formulation experts are developing methods to increase the residence time of oral formulations in the stomach. One common method is intragastric dilation, wherein dilation of the formulation prevents the formulation from passing through the pylorus. The diameter of the pylorus varies from about 1 cm to about 4 cm per individual, but on average about 2 cm. Inflatable gastric retention formulations are preferably two-dimensional, with a size of 2.5 cm x 2 cm, but should expand the formulation to at least 2 cm x 2 cm to cause gastric retention.

One type of intragastric swelling formulation is a type that prevents the formulation from passing through the pylorus by expanding the formulation to a sufficient size upon contact with gastric fluid using a hydrogel. Examples of such formulations are described in US Pat. No. 4,434,153. This' 153 patent discloses a device for carrying out a therapeutic program after oral administration, which device comprises a matrix consisting of a non-hydrated hydrogel and a plurality of small pills containing the drug dispersed throughout the matrix. Has

As described in Hwang, S. et al., "Gastric Retentive Drug-Delivery Systems", Critical Reviews in Therapeutic Drug Carrier Systems, 1998, 15, 243-284, one of the major problems associated with intragastric expandable hydrogels Is that it may take several hours for the hydrogel to sufficiently hydrate and expand to a sufficient size so that the hydrogel stays in the stomach. Because the non-expandable formulations stay on average about 1 to 3 hours in the stomach, known intumescent formulations, such as those in the patent '153 patent, are passed through the pylorus before they become large enough to block passage. The rate determinant of normal hydrogels is the rate of diffusion of water to the non-surface hydrogel material in the formulation. Since conventional hydrogels do not have high porosity when dried, the transport of water into the hydrogels can be slow. In addition, a low permeability gelatin layer is formed on the representation of the wet hydrogel, which also slows the transport of water into the hydrogel.

One approach to solving the problem of slowed expansion is to develop superporous hydrogels. Superporous hydrogels have a network of small pores with a diameter of at least 100 μm. At such diameters, the pores can rapidly transport water deeply into the microporous hydrogel by capillary action. Water reaches the non-surface hydrogel material and performs the rapid expansion of the superporous hydrogel to the maximum extent possible. Superporous hydrogels are still under development and are not approved by the US Food and Drug Administration for pharmaceutical use. There are also disadvantages in the use of superporous hydrogels, which tend to be structurally weak and some cannot withstand the mechanical stresses of natural shrinkage that drives out of the stomach and into the intestine. Superporous hydrogels tend to disintegrate rapidly into particles that are too small to be retained.

Chen, J. and Park, K. Journal of Controlled Release 2000, 65, 73-82 describe a superporous hydrogel in which the mechanical strength of the hydrogel in the presence of a superdisintegrant is improved by polymerization of the precursor hydrogel monomer. It is described. The polymerization products described in Chen and Park are novel materials having crosslinked networks of interconnecting polyacrylates and for example crosslinked carboxymethyl cellulose sodium. Such interconnecting networks are not expected to have the same physical properties as conventional hydrogels prepared from the same precursor hydrogel monomers.

Another common method for retaining the formulation in the stomach is intragastric suspension, as illustrated in US Pat. Nos. 4,140,755 and 4,167,558. The intragastric suspension system is less dense than gastric juice and thus floats on top of the gastric juice to avoid passage through the pylorus. Such systems generally take one of three forms. A hydrodynamically balanced suspension system includes a capsule consisting of the active ingredient and a hydrogel which, upon contact with water, forms a gelatinous coating and slows the absorption of water. In one such system, the capsule containing the non-hydrated hydrogel and the active ingredient dissolves upon contact with gastric juice. The hydrogel then comes into contact with gastric juice and forms a gelatinous coating on the surface. Gelatin coatings trap the air inside the hydrogel, making the mass rich. In addition, the expansion of the hydrogel makes its density smaller, resulting in greater floatability. Another form of intragastric suspension system is a gas generating system, which produces gas upon contact with water. Gas bubbles trapped in the formulation make the formulation suspended. Another variation on the gastric floating system is a low density core system, where the active ingredient is coated on a low density material, such as inflated rice.

The aforementioned suspension formulations and intumescent formulations are operated by various gastric retention mechanisms with their respective requirements to be effective. Suspension systems must remain suspended while absorbing gastric fluid. The expandable system must be able to expand to a size sufficient to block passage into the intestine, but can still be small enough to be swallowable and unhydrated. The invention includes not only embodiments that expand but also those that expand and generate gas.

There is a particular need for an effective gastric retention system for treating levodoparo Parkinson's disease. Parkinson's disease is a degenerative symptom associated with reduced dopamine concentrations in the basal ganglia region of the brain. This deficiency is considered to be caused by the oxidative degradation of dopamine functional neurons in the black matter. A preferred course of treatment is to restore dopamine levels in the brain by administering levodopa, a metabolic precursor of dopamine that can cross the blood brain barrier, unlike dopamine. Metabolic conversion from levodopa to dopamine is catalyzed by aromatic L-amino acid decarboxylase enzymes. This enzyme is found throughout the body, including gastric juice and intestinal mucosa. Treatment with levodopa alone requires the administration of large doses of the drug due to extracellular metabolism of such enzymes. High concentrations of extracellular dopamine that form form vomiting in some patients. To solve this problem, levodopa is usually administered in combination with inhibitors of aromatic L-amino decarboxylase enzymes, such as carbidopa.

Levodopa mitigates signs of Parkinson's disease by temporarily increasing dopamine levels in the central nervous system, but is not a cure. While the treatment of the disease with levodopa is prolonged, the body is typically less sensitive to the concentration of levodopa in the brain. The system needs to be administered more frequently to suppress the signs of the disease, tremor, muscle stiffness, lack of facial expression and altered gait. As plasma concentrations drop, the recovery of signs of the disease in the so-called "off-state" signals a need for immediate administration of another dose. Unfortunately, there is a time delay from the ingestion of levodopa to the recovery of disease signs to "on-state" inhibition. Active administration of levodopa to avoid off-state signs of stiffness and ataxia can lead to the disabling of so-called reflex motion, called dyskinesia.

From the foregoing, it would be highly desirable if a patient could be administered levodopa as a sustained release oral formulation capable of stabilizing the serum concentration of levodopa. Levodopa / carbidopa are currently marketed as Cinnamet® CR controlled release tablets (DuPont Pharma) which slowly erode and release the active agent. According to Physician's Desk Reference , 54th ed., Tablets use a polymeric drug delivery system. Prolonged inhibition of disease manifestations using these tablets is limited by the mechanism of absorption of levodopa from the gastrointestinal tract. Levodopa is absorbed by an active transport mechanism for amino acids, which is most active in the duodenum region of the small intestine. Thus, sustained release is limited by the passage time of the formulation through the stomach and duodenum, which typically takes only about 3 hours to about 4 hours, although largely dependent on individual differences and depending on nutritional status. The released levodopa is not bioavailable after 3-4 hours of treatment window. The bioavailability of Cinemet® CR controlled release tablets is about 75% of Cinemet's generic release tablets. See Physicians Desk Reference , 54th edition (Medical Economics Co., publisher, 2000).

Another problem in the treatment of Parkinson's disease that could be treated using an improved controlled release levodopa delivery vehicle is the reduction of plasma levodopa concentrations that occur during sleep of the patient. Parkinson's patients usually wake up in the morning and can work comfortably after waiting for the dose to take effect. If Parkinson's disease patients take levodopa in the evening, it would be highly desirable to wake up in the morning without any signs of disease, while the therapeutic effect of the previous dose is maintained. For this purpose, the drug delivery vehicle not only prolongs the release of levodopa over time, but also delays the levodopable release until the early morning hours before the patient wakes up so that the therapeutic effect of the dosage is close to its maximum. It would be ideal if you could wake up.

Therefore, there is a need for a controlled release levodopa oral dosage form that can deliver levodopa to a patient's bloodstream over an extended period of time than is currently possible without relying on frequent dosing schemes and without fluctuations in plasma levodopa concentrations that occur with frequent dosing. exist. There is also a need for improvements in controlled release formulations that improve the bioavailability of levodopa and reduce the frequency of administration.

There is a particular need for a gastric retention system that is effective in the treatment of children with hyperactivity and attention deficit disorders. Methylphenidate, the main drug in the treatment of hyperactivity, has a short half-life in the human body, requiring frequent dosing (drugs every four hours). Therefore, children need to take medication while at school. This is a management problem in that the school must observe whether the child is taking his medicine. Sustained release formulations of methylphenidate have been developed. Methylphenidate is currently commercially available as Ritalin® SR sustained release tablet (Novatis). According to Physician's Desk Reference, 54th ed., Ritalin-SR tablets contain cellulose compounds and povidone. Another sustained release formulation of methylphenidate has been proposed in US Pat. No. 5,874,090. Unfortunately, patients become resistant to sustained high blood levels of methylphenidate, requiring more drugs to suppress their hyperactivity or attention deficit.

US Pat. No. 6,034,101 (and WO 98/14168) discloses methylphenidate formulations designed to overcome the development of resistance in a single dose interval. This formulation delivers methylphenidate in pulses of synergistic intensity (concentration). However, this formulation is not a gastric retention form. Therefore, while the first pulse of drug is released in the stomach, the next pulse is delivered to the jejunum, ileum and / or colon. Methylphenidate is more readily absorbed in the stomach rather than in the intestine. In conclusion, the most powerfully designed pulses are least bioavailable because they are emitted downstream of the stomach. Another formulation for delivering methylphenidate in pulses is described in US Pat. No. 5,837,284. In addition to mismatches between rising dosage profiles and decreasing bioavailability as the formulation passes through the GI tract, these pulsed methods may increase the incidence and severity of side effects (particularly sleep disturbances) with the drug. There are disadvantages.

Allowing a sufficiently long time period without drug between administrations of methylphenidate is a more desirable approach to preventing acute resistance compared to using a synergistic drug profile. However, pulse delivery systems used to deliver methylphenidate over extended periods of time have the same bioavailability issues as pulsed formulations with synergistic profiles. Therefore, there is a need for a gastric retention pulsed delivery system capable of delivering methylphenidate in pulse form while maintaining a constant bioavailability.

There is a clear need for improvements in gastric retention-controlled release techniques, particularly for improved gastric retention formulations of levodopa and methylphenidate.

Cross Reference to Related Application

The present invention relates to the provisional tax application No. 60 / 213,832 filed June 23, 2000, the provisional tax application No. 60 / 217,110 filed July 10, 2000 and the pseudo-tax application filed August 4, 2000 Profit from heading 60 / 223,212 to 35 USC Application filed under 119 (e).

Field of invention

The present invention relates to a gastric retention system administered orally, and to a pharmaceutical dosage form for releasing drugs in the stomach of a patient using the system.

1 is a plot showing blood levels of levodopa and carbidopa over time in Beagle dogs after administration of the delayed release levodopa and carbidopa formulations of the present invention.

Summary and purpose of the invention

We have found a composition that swells rapidly in the gastric juice of a patient, increasing the likelihood that the composition will stay in the stomach for a long time. This composition is a blend of superdisintegrant, tannic acid and one or more hydrogels. This composition is useful in gastric retention formulations because this composition increases the likelihood that the active ingredient contained in the formulation will release in the stomach. The formulations of the present invention rapidly expand at a rate previously unachievable by known expandable hydrogel formulations, but because they do not contain superporous hydrogels, there are no mechanical strength problems associated with superporous hydrogels. Another advantage of using conventional hydrogels in the compositions and formulations of the present invention is that the degradation / erosion rates of these hydrogels are well studied.

The present invention provides a pharmaceutical composition for use as an orally administered drug that swells upon contact with gastric fluid and enhances the retention of the formulation for an extended period of time in the stomach of the patient. The composition comprises about 20 wt% to about 70 wt% of hydrogel, super disintegrant, tannic acid, about 10 wt% to about 75 wt% of superdisintegrant, and about tannic acid, except for any other excipients that may be present. 2 wt% to about 12 wt%.

In one embodiment, the pharmaceutical composition comprises about 10% to about 20% hydroxypropyl methylcellulose ("HPMC"), about 45% to about 50% hydroxypropyl cellulose ("HPC"), sodium From about 25% to about 35% by weight starch glycolate and from about 4% to about 6% by weight tannic acid. A second embodiment of the pharmaceutical composition comprises about 10% to about 30% hydroxypropyl methylcellulose, about 40% to about 60% hydroxypropyl cellulose, about 7% to about 35% sodium croscarmellose. Wt%, tannic acid from about 4 wt% to about 12 wt%. These compositions can expand to five or more volumes in about 15 minutes by absorbing water from gastric juice.

The present invention also provides oral dosage pharmaceutical formulations containing the pharmaceutical composition and the therapeutic agent. The formulations can be used to deliver a therapeutic agent to a patient's stomach in an immediate or controlled release manner. For example, in one formulation, the therapeutic agent is provided as coated particles dispersed in a matrix comprising the pharmaceutical composition of the present invention. This form is well suited for delivering delayed and pulsed therapeutics. In another formulation embodiment, the therapeutic agent is included in a sustained release reservoir embedded in a shell comprising the composition of the present invention. This shell improves the retention of the formulation in the stomach of the patient while the therapeutic agent is continuously released from the reservoir.

The present invention also provides formulations for gastric controlled release of methylphenidate and gastric controlled release of levodopa. These formulations are suitable for addressing the problems with current therapies using these drugs. Accordingly, the present invention provides a method of treating a disease with these and other drugs by administering the formulations and compositions of the present invention.

Detailed description of the invention

"Drug", "active agent", "active ingredient", "therapeutically beneficial drug" and "therapeutic agent" are all used interchangeably herein, and compounds that exhibit a therapeutically beneficial effect in a patient, and the compounds Prodrugs, solvates, molecular complexes, and pharmaceutically acceptable salts and derivatives.

"Gastric fluid" means the endogenous latex medium of the stomach, or simulated gastric juice, including water and secretions. "Mock gastric juice" means any emulsion generally recognized as providing useful substitutes for true gastric juice in experiments designed to evaluate the chemical or biochemical behavior of a substance in the stomach. One such simulated gastric juice is the enzyme-free USP gastric fluid TS. See, United States Pharmacopeia and National Formulary 24/19 p. 2235 (1999). Therefore, in the present specification and claims, "gastric juice" means true gastric or simulated gastric juice.

By "rapid release" is meant a release in which the release of the active ingredient is not significantly delayed by the method of protective coating or embedding in the matrix. Excipients used to achieve immediate release are typically rapidly dissolved or dispersed in gastric juice. "Sustained release" means that the active ingredient is released from the formulation over a longer period of time compared to the time when the same active ingredient equivalent is immediate release from the same dosage in the immediate release formulation. By "delayed release" is meant that there is a time when the formulation is not released after contact with gastric juice or the drug is released at a rate that is not therapeutically effective for the purpose administered to the patient. "Burst release" means release of most active ingredient over a short period of time (typically less than 30 minutes). “Pulsed release” refers to the release of the active ingredient over two or more time periods separated by a period in which the active ingredient is not released or the drug is released at a rate that is not therapeutically effective for the purpose administered to the patient. it means. Ejection release, pulsed release and sustained release are combined with delayed release so that, depending on the profile, the release of the active ingredient is therapeutically effective for the purpose that the active ingredient is not released or the drug is administered to the patient. It can be started after a delay that is released at a slow rate. "Controlled release" means delayed release; Sustained release (including delayed sustained release); Jetted release (including delayed jetted release); Pulsed emission (including delayed pulsed emission); And generic to release other than immediate release.

The present invention provides a gastric retention composition which rapidly expands after contact with gastric juice of a patient. The advantage of this intumescent composition is that it is used as a gastric retention delivery system (“GRDS”) in orally administered pharmaceutical formulations to increase the likelihood of the formulation staying in the stomach for extended periods of time.

After the expandable composition is hydrated and expanded, this causes the solubilized material in the expanded composition to diffuse into the surrounding emulsion environment. Therefore, intumescent compositions are well suited for use in delayed, explosive and / or pulsed release formulations. This expandable composition is also well suited for use with reservoirs designed to deliver drugs with sustained release. The reservoir may be a sustained release core embedded in the expandable composition; A tablet enclosed in a capsule with the expandable composition; Alternatively, the reservoir layer may be one layer in a multilayer structure containing the active ingredient, which is provided with a continuous release of the active ingredient in a sustained manner with other layers containing the intumescent composition. This expandable composition is also well suited for use with sustained release particles having a coating applied to particles that slow down the release of the active ingredient, or with sustained release particles having the active ingredient dispersed in a particle matrix that slows down the release of the active ingredient. . Intumescent compositions can also be used to slow the release of the active ingredient.

The rapid rate of expansion of the composition is clinically relevant. Any expanding gastric retention formulation has a chance to pass through the stomach before it expands sufficiently to retain. If the drug is administered to the patient just before peristalsis, the formulation can pass through the stomach in much less time than the average residence time. After the incompletely expanded formulation has passed into the intestine, further swelling can cause blockage of the patient's intestine for a period of time. In addition, the window of bioavailability may be lost, especially if the active ingredient is very easily absorbed in the stomach or is unstable in basic conditions. The likelihood of passage through the stomach before the expanding formulation is large enough to block passage through the pylorus depends on a number of factors, such as the patient's fasting or food supply and the patient's stomach movements. In the fasted state, conventional oral formulations are removed from the stomach by gastric peristalsis about every 100 minutes. Another factor providing clinical control of the present invention is the relationship between the time required for the formulation to swell and the time taken for removal from the stomach. Therefore, rapid expansion speed is considered to be a great advantage of the present invention.

Another aspect of the invention provides a formulation containing an intumescent composition of the invention. The formulation according to the invention is maintained in the stomach for a long time by swelling and optionally floating of the composition. In embodiments that utilize suspension for improved gastric retention, the formulation contains a substance that foams upon contact with an aqueous or acidic aqueous solution. The expanded composition renders the formulation suspended by trapping a portion of the bubbles produced by the foamable material. Stomach retention causes the active ingredient to be released upstream of the jejunum and duodenum, which are the two regions of the GI tract that most actively absorb multiple drugs. Over time, the expanded formulation becomes particles small enough to decompose or corrode and pass through the pylorus.

Rapid expansion of the compositions and formulations containing them is achieved by a novel combination of hydrogels, superdisintegrants and tannic acid.

Hydrogels are polymers that are hydrophilic or insoluble in water. Under their hydrated conditions, they swell to equilibrium volumes and can elastically deform, but are substantially resistant to plastic deformation. When dry, the hydrogel is structurally hard. Preferred hydrogels of the swelling composition are hydroxypropyl methylcelluloses, which may be used alone or in combination with hydroxypropyl cellulose and / or crosslinked acrylate polymers. The molecular weight of HPMC is about 4000 to about 100,000 a.u., and the viscosity grade is preferably about 8000 mPa · s or less. HPMC is available from Dow Chemical Company under Methocel®.

The molecular weight range of hydroxypropyl cellulose used in the expandable composition is preferably about 80,000 to 1.2 million, more preferably about 1 million to about 1.2 million. HPC is commercially available from Klucel® under Hercules Inc.

Suitable crosslinked acrylate polymers include polyacrylic acid crosslinked with allyl sucrose (commercially available from Carbopol® from BF Goodrich Chemical Limited) and polyacrylic acid crosslinked with divinyl glycol.

Most preferred hydrogels in the present invention are combinations combining hydroxypropyl methylcellulose and hydroxypropyl cellulose in a weight ratio of about 1: 3 to about 5: 3.

The intumescent composition also includes a superdisintegrant. Superdisintegrants are disintegrants which expand upon contact with water. Preferred disintegrants of the present invention expand at least two times their unhydrated volume upon contact with water. Examples of these superdisintegrants include crosslinked carboxymethyl cellulose sodium (alias croscarmellose sodium), sodium starch glycolate and crosslinked polyvinyl pyrrolidone (alias crospovidone). Croscarmellose natrium is marketed as Ac-Do-Sol® by FMC Corporation and by Primelose® by Abebe Corporation. Sodium starch glycolate is marketed by Explotab® at the Fenwest Pharmaceuticals Company and Primogel® by Avebe Corporation. Crospovidone is marketed by Collidone® CL at BASF Corporation and is marketed by Polyplastone® at International Specialty Chemicals Corporation. Most preferred superdisintegrant is croscarmellose sodium.

The expandable composition further comprises tannic acid. Tannic acid, also called tannin, gallotannin, and gallotannic acid, is a natural component of bark and fruits of many trees. The term "tannin" as used herein usually means two groups of compounds, "condensed tannin" and "hydrolyzable tannin". See Merck Index monograph No. 8828 (9th edition, 1976). Hydrolyzable tannins are sugars esterified with at least one (polyhydroxyarene) formic acid. One common polyhydroxyarene formic acid substituent of tannic acid is galloyl (ie, 3,4,5-trihydroxybenzoyl). Another common polyhydroxyarylene formic acid substituent of tannic acid is meta-digal acid. A common sugar moiety of tannic acid is glucose. It is preferable to use USP grade tannic acid.

The expandable composition comprises a hydrogel, preferably hydroxypropyl methylcellulose, and includes other hydrogel polymers, superdisintegrants, and tannic acid, as desired, with preferred amounts of from about 20% to about 70, excluding any other excipients. Wt% hydrogel, about 10 wt% to about 75 wt% superdisintegrant, and about 2 wt% to about 12 wt% tannic acid. Particularly preferred intumescent compositions are compositions comprising from about 30 wt% to about 55 wt% superdisintegrant, about 5 wt% (± 2 wt%) tannic acid, and an amount of hydrogel sufficient to make the total to 100 wt%.

As previously described, the preferred hydrogel for the intumescent composition is hydroxypropyl methylcellulose, which may be used in combination with hydroxypropyl cellulose or crosslinked acrylate polymers as needed. The expandable composition in which a preferred hydrogel is used comprises about 10 wt% to 30 wt% hydroxypropyl methylcellulose, about 40 wt% to about 60 wt% hydroxypropyl cellulose, about 7 wt% to about 35 wt% cross Carmellose sodium and from about 4% to about 12% by weight tannic acid.

Embodiments of a second preferred expandable composition using a preferred hydrogel include from about 10 wt% to about 20 wt% hydroxypropyl methylcellulose, from about 45 wt% to about 50 wt% hydroxypropyl cellulose, from about 25 wt% About 35% sodium starch glycolate and about 4% to about 6% tannic acid by weight.

Hereinafter, within these ranges, preferred formulations of the formulations designed for specific applications are described below. In particular, matrix type formulations for delayed release of levodopa or a mixture of levodopa and carbidopa are provided. Particularly suitable intumescent compositions for the matrix of delayed release levodopa / carbidopa formulations include from about 10 wt% to about 14 wt% HPMC, from about 42 wt% to about 47 wt% HPC, from about 7 wt% to about 12 wt% % Croscarmellose sodium, about 6% to about 9% tannin acid, about 18% to about 22% levodopa and about 3% to about 6% carbidopa and about 0.3% to It contains about 1% by weight tablet lubricant, for example magnesium stearate.

Particularly preferred formulations of the intumescent compositions for use as shells in reservoir formulations of levodopa, levodopa / carbidopa, methylphenitate or alendronate are from about 10% to about 20% by weight HPMC, from about 50% to about 60% Wt% HPC, about 12 wt% to about 25 wt% croscarmellose sodium, about 8 wt% to about 12 wt% tannic acid and about 0.5 wt% to about 1 wt% tablet lubricant, for example stearic acid Contains magnesium.

The novel expandable compositions of the present invention can be prepared conventionally by dry blending, dry granulation or wet granulation.

In the dry granulation process, the composition is blended to dryness and then compressed into slugs or sheets and then ground into compressed granules. Crushing and recompression followed by slugging or roller compaction is believed to cause the hydrogel, superdisintegrant and tannic acid to be present in the granules in the final formulation. In addition, the active ingredients of the drugs can be provided in the granules by blending the intumescent composition with them prior to compression. Alternatively, the active ingredient, hydrogel, superdisintegrant or tannic acid can be added after grinding, such that (or these) component (s) are present outside the granules. The granules can be used to prepare the formulation by any of the methods described below or by any other method.

In the wet granulation process, excipients may be granulated by standard granulation techniques known in the art using a water: alcohol mixture or alcohol as the granulation solvent. The granules are then dried, finely divided and sieved as necessary. Hydrogels, superdisintegrants, tannic acid or the active ingredient may be added to one or more wet granulated ingredients before or after compression, in which case the ingredients added after granulation are extraparticles in the final formulation. After drying, the granules can be prepared by the methods described below or by any other method using granules prepared by wet granulation.

The composition may be compressed according to conventional compression or direct compression techniques. Direct compression produces a more uniform tablet without granules. Thus, hydrogels, superdisintegrants, tannic acid, active ingredient (s) and other certain excipients are blended with the composition directly prior to compression tableting. Such additional excipients which are particularly suitable for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. Suitable uses of these excipients and other excipients in direct compression tableting are known to those skilled in the art and in the art of formulating particular formulations of direct compression tableting.

In some formulations, controlled release of the active ingredient can be provided by applying a coating to the active ingredient. Thus, it will be appreciated that where the aforementioned portions describe the mixing, blending, granulation, compression, etc. of the active ingredient, the active ingredient may already be coated with a coating.

The foregoing is intended to highlight variations of mixing techniques already known in the art. However, the composition can be used with any chemically compatible drug in any method of preparation. Hereinafter, certain novel and therapeutically useful gastric retention formulations are described.

Pharmaceutical formulations of the invention include drug delivery vehicles comprising the active ingredient and the intumescent composition of the invention and any other desired pharmaceutical excipient. The pharmaceutical formulation of the present invention may be maintained in the stomach for at least 3 hours, more preferably at least about 5 hours. The formulations of the present invention may increase in volume by at least about 3 times, at least about 5 times when using the expandable composition according to a preferred embodiment, and at least about 8 times when using the expandable composition according to the most preferred embodiment. Dilation occurs within about 15 minutes when contacted with gastric juice and within about 5 minutes when formulated according to a preferred embodiment.

Further improvement in gastric residence time can be realized by adding effervescent compounds, such as sodium bicarbonate, which produce a gas upon contact with gastric juice. In the dry granulation process, the expandable compound can be introduced into the formulation by blending the expandable compound into the expandable composition before or after primary compression. In the wet granulation process, it may serve as extragranular component after wet granulation. The additional effervescent compound may be a component of the reservoir in the reservoir formulation. The effervescent compound is preferably used at low concentration, ie from about 0.5% to about 5% by weight of the formulation. Examples of effervescent compounds other than sodium bicarbonate include other alkali metal and alkaline earth metal carbonates and bicarbonates.

In addition, mucoadhesive materials may be added to enhance gastric retention of formulations prepared according to the present invention.

Embodiments of one gastric retention formulation can be prepared by compressing the intumescent composition, active ingredient (s) and, if desired, other excipients as powder blends or granules in any tableting equipment known in the pharmaceutical art. Another formulation is a capsule, which may be prepared by filling a conventional capsule shell (eg gelatin) with powder blends, granules or tablets containing the intumescent composition, active ingredient (s) and other excipients as needed.

The formulations of the invention can be prepared in any desired shape. Oval or oval formulations are well maintained even after they have fully expanded. Oval or elliptical formulations preferably have a two-dimensional size of about 4 mm to 10 mm, a three-dimensional size of about 10 mm to 20 mm, more preferably 6 × 6 × 16 mm ± 2 mm.

There are many different types of formulations, and there are many ways to use intumescent compounds in the formulations of the present invention.

The formulation may be of a matrix type wherein the active ingredient (s) are particles that are uniformly dispersed throughout the expandable composition. In the matrix construct, the particles of the active ingredient (s) may be finely divided powders or granules. In addition, the particles may be preformed beads, pills, pellets, microcapsules, microspheres, micro granules, nanocapsules or nanospheres, etc., containing the active ingredient or having the active ingredient on the surface. These premixed particles are dispersed in the matrix.

Pre-blended particles may contain powdered active ingredients in a natural, semisynthetic or synthetic polymer matrix. Representative matrices for the dispersed particles are polysaccharides, agar, agarose, sodium alginate, carrageenan, gum arabic, tragacanth gum, locust bean gum, pectin, amylopectin, gelatin, starch, microcrystalline cellulose and hydrogels. Examples of the particle matrix further include crosslinked gelatin, crosslinked albumin, crosslinked sodium alginate, crosslinked carboxymethylcellulose, crosslinked polyvinyl alcohol and crosslinked chitin, which are disclosed in US Pat. No. 5,007,790.

The active ingredient (s) may be applied to beads, small peels, microspheres, nanospheres and micro granules coated with coated particles, for example ingredient (s) that are impermeable or semipermeable to the active ingredient and / or are slowly dissolved in gastric juice. It may be contained. Coatings can be used that slow the release rate of the active ingredient or delay the release of the active ingredient. The delayed release coating is impermeable to the active ingredient until the coating is degraded by gastric juice. The formulation of the matrix can be formulated with delayed release using the coated particles. The intumescent composition will hold the formulation in the stomach until the delay has elapsed until the drug is released.

The particles are water soluble resins such as arabingalactan, carboxymethylcellulose, gelatin, gum arabic, hydroxyethylcellulose, methylcellulose, polyvinyl alcohol, polyacrylic acid and starch; Water-insoluble resins such as cellulose nitrate, ethyl cellulose such as Ethocel ^™ ; Cellulose nitrate, polyamide, polyethylene, poly (ethylene-vinyl acetate), poly (lactide-co-glycolide), polymethacrylates such as Eudragit ^™ NE, Eudragit ^™ RS, Eudragit ^™ RL, Eudragit ^™ L and Eudragit ^™ S and silicone; Waxes and lipids such as paraffin, carnauba wax, sperm, beeswax, stearyl alcohol stearic acid and glyceryl stearate; And known film coatings such as enteric resins such as cellulose acetate phthalate, polyvinyl acetate and hydroxypropyl methylcellulose acetate. Glyceryl esters can be mixed with waxes already disclosed in US Pat. No. 4,764,380, which is incorporated herein by reference in its entirety. Such coatings include glyceryl distearate, glyceryl tristearate, glyceryl monostearate, glyceryl dipalmitate, glyceryl tripalmitate, glyceryl monolaurate, glyceryl didocosanoate, glyceryl tridoco Sanoate, Glyceryl Monodocosanoate, Glyceryl Monocaprate, Glyceryl Dicaprate, Glyceryl Tricaprate, Glyceryl Monomyristate, Glyceryl Dimyristate, Glyceryl Trimyristate, Glyceryl Monodeseno And triglyceryl esters such as glyceryl didesenoate and glyceryl tridesenoate. Waxes that may be used include beeswax, cetyl palmitate, spermaceti, carnauba wax, cetyl myristate, cetyl palmitate, ceryl cerate, stearyl palmitate, stearyl myristate and lauryl laurate. Particle coatings can also be made with other polymeric coating materials, such as methylcellulose phthalate, poly (alkyl methacrylate), poly (alkyl cyanoacrylate), polyglutaraldehyde, poly (lactide-glycol) Rides) and albumin. Additional coating materials that can be used are disclosed in US Pat. Nos. 4,434,153, 4,721,613, 4,853,229, 2,996,431, 3,139,383 and 4,752,470, which are incorporated herein by reference in their entirety. do.

Particles coated with a delayed release coating can be advantageously used to prepare pulsed release formulations of the active ingredient (s). For example, a patient may deliver a dose of two, three (or more) doses in a pulsed fashion when the patient wishes to take only one dose. Simulating three doses of a drug at a given time, the drug is absorbed by each dose in the stomach or in the upper part of the intestine. Such dosing regimen allows for improved compliance with the dosing schedule and will in many cases lead to improved treatment. Delayed formulations that are not associated with gastric retention will deliver their respective doses to the gastrointestinal tract at other sites, with different absorption profiles for each dose. Such therapies would not be equivalent to administering three doses of the drug at any given time because the drug is absorbed in the stomach or upper intestine at each release. For this purpose, the particles may be provided with coatings of different thicknesses. Alternatively, the particles may be coated with other materials with different dissolution rates in gastric juice.

Gastric fluid rapidly penetrates the intumescent formulation due to the hydrophilicity and porosity of the intumescent composition. Thus, the coated particles are in contact with gastric juice at about the same time regardless of proximity to the outer surface of the formulation. Coating of a proportion of the particles, whether thin or coated with a relatively soluble coating, disintegrates almost simultaneously. This releases the active ingredient (s) from the particles in a short time, ie in a pulsed manner. The second pulse occurs when the coating of particles coated with a thicker coating or a coating of a slower dissolution rate breaks down. The timing and intensity of the pulses can be determined by formulating technicians using knowledge regarding the dissolution rate of the coating material and by selecting the ratio per type of coating particle in a conventional manner to suit the desired pulse intensity.

Pulsed release may be used to deliver one, two or more active ingredients at different times after a patient has swallowed the formulation.

In coated pulsed release formulations, it may be desirable for the core of the particles to be in the form of a mixture with one or more active ingredient (s) or excipients that do not delay release of the active ingredient (s). Even if the core of the particle contains an excipient, for example high molecular weight polyvinyl pyrrolidone, which delays the release of the active ingredient in certain applications, rapid release may occur due to the small volume and relatively large surface area of the particle.

In the hydrated state, the expandable composition of the present invention does not necessarily limit the diffusion of the dissolved active ingredient into the gastric environment. Thus, pulsed release of the active ingredient inside the swollen formulation may result in pulsed release into gastric juice.

The compositions of the present invention are also suitable for retaining the drug in the stomach when the drug is contained in a tablet partially embedded in the expandable composition or attached by an adhesive. Such tablets may exhibit slow release properties that slowly or controlled release the drug in the stomach for extended periods of time. Such tablets may also have delayed pulse emission. The intumescent composition of the present invention will retain its formulation in the stomach until the delay time has elapsed until the drug is released in a jet or pulsed manner. Multi-purpose dosing regimens can be realized in a single dose by attaching or partially embedding a plurality of tablets that delay release in different types each time. For example, a patient may deliver three (or more) doses in a pulsed fashion when only one dose is desired. Three doses of the drug are simulated, such as three doses at a given time, and the drug is absorbed in the stomach at each dose. Such dosing regimen allows for improved compliance with the dosing schedule and will in many cases lead to improved treatment. Delayed formulations that are not associated with gastric retention will deliver their respective doses to the gastrointestinal tract at other sites, with different absorption profiles for each dose. Such therapies will not be equivalent to administering three doses of the drug at any given time because the drug is absorbed in the stomach at each release.

The formulation may be in the form of a reservoir (depot). The reservoir form contains the active ingredient in a reservoir that is embedded in a shell with any desired thickness so that the formulation does not become too large for the patient to swallow. Embedded tablets and tablets with a core are examples of formulations in reservoir form. Reservoir formulations also include capsule forms, multilayer forms, and other forms that separate the active ingredient from the intumescent composition. The reservoir may be completely embedded in the shell of the intumescent composition, or may be partially embedded such that a portion of the surface of the reservoir is exposed. The reservoir may be a tablet enclosed in a capsule with a tablet containing the expandable composition. Products of this type can be prepared using methods known in the art.

The reservoir may be formulated to be immediate or controlled release. The release profile of the formulation may be made similar to the release profile of the reservoir because the hydrated and expanded composition does not necessarily inhibit the diffusion of dissolved material into the stomach environment (even if the reservoir is completely embedded in the expandable composition). Can be. For example, immediate release reservoirs can be prepared by blending the active substance (s) with microcrystalline cellulose, lactose and magnesium stearate and compressing the blend into a compression reservoir. In another example, the sustained release reservoir contains about 5-75% of hydroxypropyl methylcellulose, such as Methocel® K15M, K100LV, K4M, K100M, E4M and E10M, lactose and magnesium stearate. It can be prepared by direct compression with.

The reservoir can also be attached to the expandable composition using an adhesive. The expandable composition is compressed into tablets (“GRDS tablets”). The reservoir deposits adhesive droplets on the GRDS tablet as it leaves the punching station of the tablet press, and the device can be attached by adhesive during manufacture by pushing the reservoir containing the drug, for example another tablet, towards the deposited adhesive using the device. have.

More preferably, the reservoir containing the drug coats the GRDS tablet with an aqueous adhesive that does not adversely affect its swelling and mounts the GRDS tablet and one or more drug reservoir (s) in a gelatin capsule of appropriate size to the gastric site. To the GRDS tablet, wherein the GRDS tablet is in physical contact with the drug reservoir (s) to which it is attached. As water enters the capsule, the adhesive wets and adheres the drug reservoir (s) due to access within the capsule before the GRDS system swells. The tablets remain attached to each other after swelling. Preferred aqueous adhesives for such applications are protein adhesives such as gelatin, egg albumin and casein and their salts and derivatives, and polysaccharide adhesives such as starch, modified starch and other polysaccharide derivatives known in the glue art. . The most preferred adhesive for in situ adhesion of drug reservoirs to GRDS units is sodium caseate, commercially available as Emulac ^™ 50.

The reservoir can be coated with a conventional sustained release coating. Such coating materials include polymethacrylates such as Eudragit ^™ NE, Eudragit ^™ RS, Eudragit ^™ RL, Eudragit ^™ L and Eudragit ^™ S and mixtures of hydrophilic and hydrophobic film formers. Hydrophilic film types include methyl cellulose, hydroxypropyl methylcellulose, cellulose phthalate, cellulose acetate phthalate and polyvinyl alcohol. Hydrophobic film formers include ethyl cellulose, cellulose acetate, hydroxypropyl methylcellulose phthalate, polyvinyl alcohol maleic anhydride copolymer, β-pinene polymer rosin, partially hydrogenated rosin and glycerol esters of rosin. Sustained release coatings may be applied by methods known in the art, such as fluid layers and fan coating techniques.

In addition to immediate or sustained release, the reservoir may be delayed pulsed or delayed sustained release.

The formulations of the present invention may also have a layered structure in which the active substance alone or in admixture with any other excipients forms a layer that is bonded, for example by compression, to another layer containing the expandable composition. The preferred size of the layered formulation is about 14 × 8 mm ± 2 mm. Layered structures can be manufactured using conventional multilayer compression techniques. Layered formulations comprising two or more layers, i.e. a layer comprising an intumescent composition and a layer comprising the active ingredient and any other preferred excipients, retard the active material by coating only the active material containing layer with a conventional coating resistant to gastric juice. Can be released in the mold. Another method of achieving delayed release is to formulate the drug containing layer as a matrix to delay diffusion and erosion or to incorporate the active material into microcapsules or coated beads in the drug containing layer.

One preferred active ingredient for use in the formulations of the present invention is methylphenidate. Particularly preferred formulations for pulse delivery of methylphenidate are the following tablet and capsule formulations.

One preferred pulsed release methylphenidate tablet contains coated particles or multiple coated reservoirs dispersed in a matrix or shell comprising an intumescent composition. In each case, the particles or reservoirs are covered with a suitable coating as described above. In such methylphenidate tablets containing particles, some of the plurality of particles may not be coated for immediate release. The second portion of the particles is preferably coated to release a second pulse (rapid pulse) of methylphenidate about 3 to about 5 hours after the tablet is administered to the patient. There may also be a third portion of the particles coated to be released after about 4 hours with a second pulse. Pulse timing of about 4 hours provides a low methylphenidate concentration interval in the blood that resists the development of acute resistance. In reservoir containing tablets, a number of reservoirs correspond to a certain number of pulses, typically two or three pulses. One of the reservoirs may not be coated for immediate release, while the other is coated to release methylphenidate within the same time range described above with the desired release time from the particles.

Particularly preferred capsule formulations for pulse delivery of methylphenidate contain two tablets (reservoir) containing the coated drug for on-time delay of release. These two tablets contact an coated GRDS tablet with an adhesive such as sodium caseate and an immediate release dose of methylphenidate as its coating. When the capsule enters the stomach, the gelatin capsule dissolves, the adhesive coating on the GRDS is wetted to adhere the drug-containing tablet to the GRDS tablet, release an immediate dosage of methylphenidate, and the GRDS tablet to swell for gastric retention. . All three tablets stay in the stomach for a long time. At predetermined times, such as 4 hours, the second dose is released. The third dose is released at a second predetermined time, such as eight hours.

In the methylphenidate pulsed release capsule, the first tablet is an immediate release formulation and the second tablet may be a delayed release formulation, but both may be released in a delayed form. There will be some delay in release from immediate release tablets due to the time it takes to dissolve the capsule. Immediate release formulations may be tablets prepared as described by any of the methods described above, or by other methods of dispersing methylphenidate as a component of a powder or particles throughout the tablet matrix. It may be desirable for the delayed release tablet to be of the matrix type with a delayed release coating surrounding the tablet. Therefore, such tablets may contain methylphenidate dispersed as a powder or as a component of immediate release particles. Two or more delayed release tablets may be provided in the capsule with different materials or coatings of different thickness to release methylphenidate at different times. The preferred release time for the first delayed release tablet is from about 4 hours to about 5 hours after administration of the drug to the patient. It is preferred that successive delayed release pulses from additional delayed release tablets that can be provided to the capsule occur at intervals of about 4 to about 5 hours.

Whether the pulsed release methylphenidate formulation is a tablet, capsule or other formulation, each pulse preferably releases about 2 to about 15 mg of methylphenidate, more preferably about 5 to about 10 mg of methylphenidate. .

Another preferred active ingredient for use in the formulations of the invention is levodopa in combination with inhibitors of aromatic L-amino decarboxylase enzymes, such as carbidopa, as desired. The most preferred embodiment for treating Parkinson's disease patients is a formulation in which levodopa and carbidopa are uniformly dispersed in the gastrointestinal retention delivery system. The most preferred formulation for GRDS with levodopa and carbidopa evenly mixed in the matrix is from about 10% to about 14% by weight HPMC, from about 42% to about 47% by weight HPC, from about 7% to about 12 wt% croscarmellose sodium, about 6 wt% to about 9 wt% tannic acid, about 18 wt% to about 22 wt% levodopa, about 3 wt% to about 6 wt% carbidopa and as needed From about 0.3 wt% to about 1.0 wt% tablet lubricant, such as magnesium stearate. This formulation is administered every 8 hours and is a clearly improved formulation over current dosing methods.

A second most preferred aspect of treating Parkinson's disease patients is night medication of levodopa that causes the patient to wake up in an "on" state. In this case, slow release tablets of levodopa / carbidopa are embedded in the intumescent composition such that a delay in drug release occurs while the delivery system is in the stomach. For example, slow release tablets based on HPMC as known in the art are inserted into the intumescent composition using a Kilian RUD compression coat apparatus or equivalent. The most preferred formulation for this use is about 10% to about 20% by weight HPMC, about 50% to about 60% by weight HPC, about 12% to about 25% by weight croscarmellose sodium, about 8% by weight To about 12 wt% tannic acid and about 0.5 wt% to about 1 wt% tablet lubricant, such as magnesium stearate. This tablet may be taken at night before sleep and will delay release until early morning, after which the drug will be released slowly.

The levodopa dosage is preferably from about 150 to 250 mg, more preferably about 200 mg, in combination with an amino decarboxylase enzyme inhibitor, if desired, in the most preferred formulation for delivery of levodopa. When carbidopa is used, the carbidopa dosage is preferably present in about 25 to about 100 mg, more preferably about 50 mg in the most preferred formulations for the delivery of levodopa and amino decarboxylase enzyme inhibitors. do.

The formulations of the present invention are useful for the administration of a wide range of active ingredients. The formulations are particularly useful for delayed release, sustained release and pulsed release of drugs with narrow bioavailability windows due to slow or selective absorption by the stomach, duodenum or jejunum. The formulations can be used to administer drugs that are best absorbed through the lining of the stomach, duodenum or jejunum or drugs with local effects at these sites. Drugs intended to have a topical effect in the stomach include antidigestive ulcer drugs, antacids, gastroenteritis and esophagitis therapeutic drugs and drugs that reduce the risk of gastric carcinoma. As mentioned above, the formulations prepared in accordance with the present invention provide a clear therapeutic benefit in the treatment of attention deficit disorder and hyperactivity in children with methylphenidate, in the treatment of Parkinson's disease with levodopa and bone deletion with alendronate and other bisphosphonates. to provide.

Other active ingredients that may be administered with the drug delivery vehicles of the present invention include adrenergic receptor agonists and antagonists; Muscarinic receptor agonists and antagonists; Anticholinesterase formulations; Neuromuscular blockers; Ganglion blockers and stimulants; Sympathetic stimulant drugs; serotonin receptor agonists and antagonists; Central nervous system active drugs such as psychotropic drugs, antipsychotic drugs, antianxiety drugs, antidepressants, anti-mania drugs, anesthetics, hypnotics, sedatives, hallucinogenic drugs, and antipsychotic drugs; Antiepileptic drugs; Antimigraine drugs; Parkinson's disease, Alzheimer's disease and Huntington's disease treatment drugs; painkiller; Sailing material; Antihistamine drugs; H ₁ , H ₂ and H ₃ receptor antagonists; Bradykinin receptor antagonists; fever remedy; Anti-inflammatory agents; NSAID; diuretic; Na ⁺ -Cl ^- inhibitor of simpot; Vasopressin receptor agonists and antagonists; ACE inhibitors; Angiotensin II receptor antagonists; Renin inhibitors; Calcium channel blockers; β-adrenergic receptor antagonists; Antiplatelet agents; Antithrombotic agents; Antihypertensives; Vasodilators; Phosphodiesterase inhibitors; Antiarrhythmic drugs; HMG CoA reductase inhibitors; H +, K + -ATPase inhibitors; Prostaglandins and prostaglandin analogs; laxative; Anticoagulant; Anti-emetic agents; Gastrointestinal motility promoters; Antiparasitic agents such as antimalarial agents, antibacterial agents, therapeutic drugs and parasitic agents of protozoan infections; Antibacterial drugs such as sulfonamides, quinolones, β-lactam antibiotics, aminoglycosides, tetracycline, chloramphenicol and erythromycin; Tuberculosis treatment drugs, leprosy treatment drugs; Antifungal agents; Antiviral agents; Immunomodulators; Hematopoietic agents; Growth factor; vitamin; Mineral; Anticoagulants; Hormones and hormonal antagonists such as antithyroid drugs, estrogens, progestins, androgens, corticosteroids and corticosteroid inhibitors; insulin; Hyperglycemic agents; Calcium absorption inhibitors; Glucocorticoids; Retinoids and heavy metal antagonists. The active ingredient in the formulation may be a pharmaceutically acceptable salt, produck or derivative of the formulation that gives a therapeutic effect to the patient.

In addition to the aforementioned excipients, the drug delivery vehicle may further comprise one or more other excipients that may be added to the vehicle for various purposes. Those skilled in the art will appreciate that certain materials serve one or more purposes in the formulation. For example, some substances are binders that help keep the tablets together after compression, or disintegrants that help break down the tablets when they reach the stomach of the patient. It will also be appreciated that the hydrogels, superdisintegrants and tannic acid of the intumescent composition will serve to perform additional functions in the formulation, which functions may already be known to those skilled in the art.

Diluents increase the volume of solid pharmaceutical product and can be easily handled by patients and managers. Examples of diluents include microcrystalline cellulose (e.g., Avicel®), ultrafine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dexrate, dextrin, dextrose, dibasic calcium phosphate dihydrate Water, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylate (eg Eudragit®), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.

Compressed formulations similar to the formulations of the present invention may include excipients whose function helps to combine the active ingredient with other excipients together. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), sodium carboxymethylcellulose, dextrin, ethyl cellulose, gelatin, glucose, guar gum, hydrogenated vegetable oils, hydroxyethyl cellulose, hydroxypropyl cellulose (Eg Klucel®), hydroxypropyl methylcellulose (eg Methocel®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylate, polyvinylpyrrolidone (eg , Kollidon (registered trademark), Plasdone (registered trademark)), starch, pregelatinized starch, sodium alginate and alginate derivatives, but are not limited to these.

In addition, the rate of degradation of the compressed intragastric formulation of a patient can be controlled by adding a disintegrant or a second superdisintegrant to the formulation in addition to the superdisintegrant of the composition of the present invention. Such further disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (E.g., Kollidon®, Polyplasdone®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polyacrylic potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glucolate ( Explotab® and starch, for example, but are not limited to these.

Glidants can be added to improve the flowability of the solid composition and to improve the accuracy of the dosage. Excipients that can function as glidants include, but are not limited to, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.

When a formulation, such as a tablet, is prepared by compression, the composition may be pressurized from a punch and a die. Some excipients and active ingredients have a tendency to adhere to the surfaces of punches and dies, which causes the product to have recesses or other surface irregularities. Lubricants can be added to the composition to reduce adhesion and to facilitate release of the product from the die. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, Stearic acid, surfactants, talc, waxes and zinc stearate, but are not limited to these.

Flavors and flavor enhancers make the formulation more aesthetic to the patient. Conventional flavoring and flavor enhancers for pharmaceutical products that may be included in the drug delivery vehicles of the present invention include, but are not limited to, maltol, vanillin, ethyl vanillin, menthol, citric acid, ethyl maltol and tartaric acid.

In addition, the formulation may be colored using any pharmaceutically acceptable colorant to improve its appearance and / or to assist the patient in identifying the pharmaceutical product and unit dosage level.

The present invention has been described above with reference to certain preferred embodiments, and the following examples are provided to further illustrate the present invention.

material

The HPMC used was Methocel® K-15PM from Dow Chemical Company. The hydroxypropyl cellulose used was Klucel® HF NF from Hercules, except where otherwise noted. Croscarmellose sodium used was Ac-Di-Sol (registered trademark) of Avebe Corporation. The crosslinked polyacrylic acid was Carbopol® 974P from B. F. Goodrich Chemical Limited. Tannic acid was purchased from Merck. All materials were of drug grade.

Example 1

Manufacture of tablets

The composition of each tablet prepared in Example 1 is summarized in Table 1 below. All compositions include hydroxypropyl methylcellulose, tannic acid, superdisintegrant and 1% magnesium stearate. All excipients except magnesium stearate were mixed simultaneously and thoroughly blended by hand. Thereafter, magnesium stearate was added in an amount of 1% w / w, and the blend was further mixed by hand until the magnesium stearate was uniformly distributed throughout the composition. After determining the amount of each composition required to produce 5 mm thick tablets, this amount was compressed into 5 mm thick tablets in a Manesty f3 single punch tablet press device equipped with a 10 mm diameter punch and die. The weight of the tablets was in the range of 350-400 mg, and each tablet had a hardness in the range of 5-7 KP as tested in the Erweka hardness test apparatus.

Formulation number (% by weight) Excipient One 2 3 4 5 6 7 8 Hydroxypropyl methylcellulose hydroxypropyl cellulose crosslinked polyacrylic acid 23.80.00.0 32.70.00.0 30.30.00.0 23.80.00.0 26.716.00.0 38.519.20.0 34.80.08.7 15.947.60.0 Total hydrogel 23.8 32.7 30.3 23.8 42.7 57.7 43.5 63.5 Sodium Starch Glycolate Cross Carmellose Sodium Tannic Acid 71.40.04.8 65.40.02.0 60.60.09.1 0.071.44.8 53.30.04.0 38.50.03.8 52.20.04.3 31.70.04.8 Total amount 100 100 100 100 100 100 100 100

Dilatancy test

Tablets were added to 40 ml of simulated gastric juice (0.1 M HCl) contained in a 50 ml beaker and maintained at 37 ± 2 ° C. After 15 minutes the tablet was taken out using tweezers and measured with a caliper. Gel strength was qualitatively measured using tweezers.

The results of the swelling test are summarized in Table 2 below. The swelling degree of the hydrogel was improved by the use of croscarmellose sodium or sodium starch glycolate. The formulation may advantageously comprise a mixture of two hydrogel polymers exemplified by the incorporation of hydroxypropyl cellulose and Carbopol® in the formulations of Examples 5, 6 and 8 as required. The most expanded (36-fold) tablets included about 5 wt% tannic acid and croscarmellose sodium as superdisintegrant. The second highest expanded tablet (18 times) also contained about 5 wt% tannic acid, but used sodium starch glycolate as the superdisintegrant. All of these gels (Examples 1 and 4) were qualitatively weak compared to the gels of Examples 5-8. The tablets with the highest performance in terms of high swelling and good mechanical strength were those of Examples 5 and 8, which contain 5% by weight tannic acid and which contain hydroxypropyl methylcellulose and hydroxypropyl cellulose hydrogel polymers. Used.

Formulation number Dilatation ³ burglar One 18.1 middle 2 12.7 middle 3 7.2 middle 4 36.0 middle 5 10.4 Strong 6 2.0 Strong 7 4.5 Strong 8 9.7 Strong ³ Hydrogenated Refining Volume: Dry Refining Volume

Example 2

Swelling Ratio and Swelling Rating of Placebo Formulations

The formulations of Table 3 were prepared by first dry mixing powdered ingredients except magnesium stearate for 5 minutes, then adding magnesium stearate and blending for at least 2 minutes. The formulation was compressed into ovoid tablets of size 17 × 9 × 8.5 mm using a Manesty f3 single punch tablet compressor, where 8.5 refers to the tablet thickness or height of the compressed size.

Formulation of Placebo GRDS ingredient Formulation number (% by weight) 10 11 12 HPMC K15HPC cross carmellose sodium tannate magnesium stearate 164831.93.11 15.747.231.44.71 13.44529.1120.5

The tablets were immersed in 450 ml USP Gastric TS buffer solution (pH = 1.2) without enzymes at 37 ° C. in a USP Type II digestion bath with a paddle set on top of the buffer solution to avoid bumping into the expanding tablet. This solution was stirred at 50 RPM. Tablets were removed from the buffer solution at 15 minutes, 1 hour and 3 hours, slowly absorbed with blotter and dried, and measured using a calibrated caliper. Two main sizes were measured: length and height. The third size extended from 9 mm to about 14 mm in all cases. The measurement results are shown in Table 4 below.

Swelling of Placebo GRDS Tablets in USP Gastric TS Buffer Solution Formulation number 10 11 12 Hours (h) Size (mm × mm) Size (mm × mm) Size (mm × mm) 00.2513 17 × 8.521 × 1521 × 1521 × 15 17 × 8.525 × 2132 × 2432 × 24 17 × 8.525 × 1827 × 1927 × 20

Most swelling occurred within the first 15 minutes. It can be seen that the degree of swelling is largest in compression size. This size expanded from 1.8 to 2.8 times, and in length tablets increased from 1.2 to 1.9 times.

Example 3

Way

Gel strength was measured by the weight required to distort the swollen gel up to 4 mm. The gel was removed from the Gastric TS buffer solution, absorbed with blotter, dried, and placed on the flat side of the toploading scale. The plastic cylinder was placed on the gel and water was slowly added to the cylinder until the gel was compressed down to 4 mm. The weight required for 4 mm distortion was recorded.

Effect of Tannic Acid Content on Gel Strength

The formulation was prepared as in Example 2 with varying amounts of tannic acid. The tablets were compressed and immersed in the simulated digestive fluid as described in Example 2. All tablets swelled at least 25 × 22 mm in 15 minutes. The measurement results of the gel strength are shown in Table 5 below.

Strength of expanded gel as a function of tannic acid content Formulation Tannic Acid (%) Strength (g) 13141516 4.24.767 275190147

When the tannin acid content (%) was increased from 4.2% to 7%, the strength of the swollen gel increased significantly. In experiments not reported in Table 5 above, it was found that increasing the percentage of tannic acid from 7% to 12% resulted in little further increase in gel strength.

Effect of Superdisintegrant Content on Gel Strength

The formulation was prepared as in Example 2 with varying amounts of croscarmellose sodium. The tablets were compressed and immersed in the simulated digestive fluid as described in Example 2. All tablets swelled at least 23 × 18 mm in 15 minutes. The results of the measurement of the tested formulation and gel strength are shown in Table 6 below.

Strength of expanded gel as a function of croscarmellose sodium content ingredient Formulation number (% by weight) 17 18 19 Weight (g) when HPC cross carmellose sodium HPMC K15 magnesium stearate magnesium gel wheels to 4mm 46.63115.55.9190 50261561116 55.921.415.761157

As shown in Table 6 above, decreasing the percentage of superdisintegrant in the formulation tended to increase gel strength.

Example 4

Strength of Expanded Gel of Tablets Containing Levodopa / Carbidopa

Formulations in Table 7 below containing 200 mg of levodopa and 50 mg of carbidopa were prepared as follows. Drug Granules: A 0.75% w / v Klucel LF solution in ethanol was used as the binding solution for a mixture of 4: 1 levodopa: carbidopa. The granulation process was carried out in a Zanchetta Rotolab Wan spot granulator. The granules were dried under reduced pressure in a granulator, or air dried at room temperature with light blocking. The final composition of the granules was levodopa 80.5%, carbidopa 19.9%, Klucel LF 0.6%. Drug granules containing levodopa were prepared in the same manner. Final Composition: 99.4%, 0.6% Klucel FC.

The dry granules were ground to a 0.63 mm sieve and then mixed with other powders and tablets compressed as described in Example 2. The drug granules are uniformly dispersed throughout the intumescent composition. The tablets were swollen and the strength was measured as in Example 3. All formulations swelled at least 25 × 22 mm in 15 minutes. The formulations were tested and the strength of the swollen gel was measured and shown in Table 7 below.

Extended gel strength as a function of croscarmellose sodium content for levodopa / carbidopa GRDS formulations ingredient Formulation (wt%) 20 21 22 23 24 HPMCHPC Cross Carmellose Sodium Tannic Acid Levodopa / Carbidopa Granules Levodopa Granules Magnesium Stearate 12.738.416.87.624.1-0.4 12.743.411.87.624.1-0.4 17.738.411.87.624.1-0.4 12.745.99.37.624.1-0.4 13.448.49.88-200.4 Weight required for 4 mm wheels (g) 100 162 168 282 298

As shown in Table 7, above, lowering the superdisintegrant content in the formulation has a significant effect on tablet strength as seen in placebo formulations. Replacing an amount of croscarmellose with HPC as in Formula No. 21 or HPMC as in Formula No. 22 does not affect gel strength.

Example 5

Release of Drugs Uniformly Dispersed in GRDS Formulations

Formulations or drug granules of other drugs were prepared using a direct compression technique in which the drug was uniformly dispersed in the powder mixture and the tablets were compressed as described in the examples above. Drug release was measured in 900 ml of USP Gastric TS with a USP Type II dissolution apparatus equipped with paddles at baseline at 50 RPM and 37 ° C. Tablets that swell to medium density sometimes hit the paddle during the release experiment. The tablets were hard enough not to deform due to this strike.

Levodopa and carbidopa tablets

The release of drug in Formulations 23 and 24 described above in Example 4 was measured. The cumulative amount of drug released was determined by HPLC using the following conditions.

Column: Merck Lichrosphere 60 RP-Select B Sym 125 × 4 mm

Mobile phase: 94: 4 phosphate buffer solution (pH = 2.3): acetonitrile

Flow rate: 1 ml / min

Detector: UV at 280 nm

Retention time: 5 minutes for levodopa; Carbidopa 13 minutes

Levodopa and carbidopa were released in the GRDS system at the same rate of about 8% per hour. Formulations 23 and 24 provided prolonged controlled release of both drugs. Release data is shown in Table 8 below.

Cumulative release rate of levodopa and carbidopa evenly distributed in GRDS Formulation Number 23 24 Hours (h) Levodopa (%) Carbidopa (%) Levodopa (%) One 9 8.5 11.4 2 21.4 18.1 26.1 3 30.8 26.4 33 4 37.6 33.4 39.1 5 44.5 39.6 --- 6 52.8 53.5 48.8 7 58.1 56.9 --- 8 64 62 54.6 12 --- --- 67.9 18 --- --- 78.5 24 --- --- 92.4

Acetaminophen tablets

Diffusion tablets of acetaminophen were prepared as tablets weighing 1 g at 200 mg and 10 mg doses per tablet. The formulations are shown in Table 9 below.

Formulation of GRDS with Acetaminophen Uniformly Dispersed in Tablets ingredient Formulation (wt%) 25 26 HPMCHPC Cross-Carmellose Sodium Tannic Acid Acetaminophenstearate Magnesium 16.756.315111 13461010201

Drug release was measured in Gastric TS as described above and cumulative drug release was measured by HPLC using the following conditions.

Column: Hypersyl ODS 250 × 4.6 mm, 5 micron

Mobile phase: 75:25 Water: methanol

Flow rate: 1.5 ml / min

Detector: UV at 243 nm

Retention time: 3.5 minutes

The results of drug release are shown in Table 10 below. Here we can see the extended controlled release of soluble drugs.

Cumulative Release Rate of Acetaminophen Uniformly Dispersed in GRDS Hours (h) Release(%) 25 26 123420 11.820.228.034.986.1 16.025.032.639.291.5

Alendronate Tablets

Sodium allandronate monohydrate was dispersed in GRDS at a weight equivalent to 10 mg of alendronic acid per tablet. The formulations are shown in Table 11 below and the release profiles are shown in Table 12 below. Alendronate concentrations were determined by HPLC using the following conditions for FMOC (9-fluoronailmethylchloroformate) derivatives.

Column: Hamilton PRP-1, 250 × 4.1 mm, 5 micron

Mobile phase: 75: 20: 5 citrate + phosphate buffer solution (pH = 8): acetonitrile: methanol

Flow rate: 1.0 ml / min

Detector: UV at 266 nm

Retention time: 5.6 minutes

Preparation of Alendronate Uniformly Dispersed in GRDS ingredient Formulation No. 27 (% by weight) HPMCHPC Cross-Carmel Sodium Sodium Tannate Alendronate Monohydrate Magnesium Stearate 16.756.614101.671

Cumulative Release Rate of Alendronate Uniformly Dispersed in GRDS Hours (h) Release(%) 1235824 2.53.15712.645

Example 6

Release of levodopa and carbidopa from reservoirs embedded in GRDS

275 mg reservoir tablets were prepared containing 200 mg levodopa and 50 mg carbidopa evenly dispersed in the HPC matrix. This reservoir slowly erodes and releases the drug over about 2 hours. This reservoir was embedded in 725 mg of the GRDS formulation of Tablet 13 and compressed into elliptical tablets of size 17 × 9 × 8.5 mm.

ingredient Formulation number 28 (% by weight) HPCHPMC cross carmellose sodium tannate magnesium stearate 50.316.722101

The cumulative release amount of the two drugs is measured in the same manner as in Example 5 and shown in Table 14 below.

Cumulative release rate of levodopa and carbidopa from tablets embedded in GRDS Hours (h) Levodopa (%) Carbidopa (%) 123456 1.123.15.116.469.7 0.91.535.916.973.7

Both drugs are initially delayed in release and after several hours, the two drugs are released similarly. Internal corrosion tablets were designed for short-term controlled release. This example demonstrated the feasibility of administering GRDS levodopa / carbidopa in the evening to deliver delayed stomach in the early morning. In addition, this tablet may be designed to obtain a longer release profile.

Release rate of alledronate from a reservoir partially embedded in GRDS

Two different formulations of the internal tablet of Alendronate, Formulation 29 and Formulation 30, were prepared and embedded in the GRDS formulation, allowing one side of the embedded tablet to be partially exposed to the surface. The GRDS formulations used are shown in Table 15 below.

ingredient GRDS (% by weight) of formulation numbers 29 & 30 HPCHPMC cross carmellose sodium tannate magnesium stearate 57.316.715101

The inner core of Formulation No. 29 was formed by wet granulation of sodium allandronate monohydrate and urea with 50% aqueous ethanol, drying, finely powdered, and mixing this powder with magnesium stearate. The compressed tablets were 5 mm in diameter and the weight of one tablet was 50 mg, which included 11.6 mg of sodium allandronate monohydrate, 37.9 mg of urea and 0.5 mg of magnesium stearate per tablet.

The internal core of Formulation No. 30 mixes the Alendronate salt and Avicel, adds magnesium stearate and then mixes for several minutes, 11.6 mg of sodium allandronate monohydrate, 37.9 mg of Avicel and 0.5 mg of stearic acid per tablet 5 mm diameter 50 mg tablets containing magnesium were again formed by compression.

Release of the alendronate was measured as described in Example 5 and the results of these measurements are shown in Table 16 below. As can be seen from the cumulative release over 21 hours, partially embedded tablets are another means of achieving extended controlled release from the GRDS system in the stomach of the patient.

Cumulative Release Rate of Alendronate from Partially Embedded Tablets Hours (h) Cumulative Release (%) Formulation 29 Formulation 30 1234621 1623.727.831.644.279.6 718314153-

Example 7

In Vivo Release of Levodopa / Carbidopa in Beagle Dogs

Levodopa, an important agent in the treatment of Parkinson's disease, benefits from an extended drug release profile. However, conventional extended release formulations cannot be used for this drug. This is because these drugs are only absorbed in the duodenum and not in the terminal small intestine or colon. The residence time of the drug in the duodenum is very short, such as about a few minutes. Any extended delivery of levodopa must be maintained in the stomach from which the drug will be delivered to the duodenum, the site of absorption. Thus, the gastric retention prolonged delivery vehicle will greatly enhance the efficacy of levodopa in the treatment of Parkinson's disease. In addition, the drug is an excellent indicator of gastric retention. Immediately after the stomach is empty, the drug is no longer absorbed. In addition, levodopa has a short half-life in the blood. All prolonged absorption found in in vivo experiments results in duodenal absorption and gastric retention.

Way

Blood Sampling for Drug Kinetic Assessment

Prior to the study, an appropriate amount (5-10 ml) of whole blood was sieved in dogs to prepare a standard calibration reference curve.

In addition, four labeled Eppendorf microcentrifuge tubes were prepared for each sampling time (ie, 0-12 hour intervals). To each prepared microcentrifuge tube was added 50 μl of water + 300 μl of extraction mixture. This extraction mixture contains 25.5 ml of 70% perchloric acid, 2.5 g sodium metabisulfite, 2.5 g sodium lauryl sulfate, 0.25 g disodium EDTA, 2.5 ml TEA, 50 ml ethanediol and 1.25 g Tween 20 Volume was adjusted with water until the total volume was 500 ml.

In this study, the forelimbs (right or left leg that the animal trainer considered appropriate) were shaved using an electric razor and the area was washed with chlorhexidine swabs. A permanent indwelling polyethylene catheter was inserted into the head vessels of each forelimb using a 23 gauge needle and taped for intact and in place for periodic blood sampling for at least 12 hours. A plastic bonnet was wrapped around each dog's head to prevent the dog's mouth from reaching the catheter site.

At each time point, 2.0 ml of blood was soaked with a syringe and placed in a pre-labeled heparinized test tube. The test tube was shaken strongly by hand. Four aliquots, each containing 250 μl of whole blood, were then pipetted from the test tube and added to one of the four labeled Eppendorf microcentrifuge tubes for that sampling time point.

After the Eppendorf microcentrifuge tube was vortexed, it was immediately transferred to a quick freezer to keep the sample at -70 ° C.

The separator tube was weighed and 25 μl of 1 M Na ₂ HPO ₄ solution containing Na ₂ S ₂ O ₅ (10% w / v) was added to this tube. This tube was then centrifuged at 13000 g at 4 ° C. for about 15 minutes. Supernatant from each sample was filtered through a 0.2 μm syringe-type filter. If sample dilution was required, the residual supernatant was stored frozen at -70 ° C in labeled vials.

HPLC analysis

The concentrations of levodopa and carbidopa in whole blood were measured by electrochemical detection by reverse phase high performance liquid chromatography (RR-HPLC).

HPLC column was Licrosphere 60RP select B, 5 μm, 250 × 4.0 mm (Merck, # 1.50214) [Licrocart 4-4 cartridge 60RP select B, 5 μm, 4.0 × 4.0 mm (Merck, No. 1.50963)]; The injection volume is 10 μl, the sample temperature is 5 ° C. and the flow rate is 1.3 ml / min. The column temperature is 50 ° C. and run for about 10 minutes. Electrochemical detector (Coulochem II 5200-A ESA Huntingdon, UK, Model 5010; analytical cell = model 5021) has potential E ₁ = −350 mV; Potential E ₂ = + 250 mV; Protective potential E = -50 mV; The rise time has a variable of 5 seconds and a gain of -1 ms.

The lower limit of detection (LLD) for levodopa and carbidopa is 12.5 ng / ml.

Experiment

The dog was fasted overnight for at least 12 hours and then given a single mixed meal consisting of solid food and liquid nutrition. 250 mg of a bite-sized commercial Bonzo Feed was measured and placed in a food dish. After the dogs were eaten for 1/2 hour, the dishes were removed. The weight of food left in the dish was measured and the difference from the 250 mg of the original food was recorded as the amount of food consumed. Additionally, 250 calories of liquid nutrition (Ensure®, 237 ml) were injected through the gastroesophageal feeding tube. No additional food was given during the course of the experiment, but water was randomly provided at the tap in the kennel during the experiment.

Within 2 hours after meals, the dogs were waited for catheter insertion and blood samples were drawn at time "0" before "administration." Blood was drawn and samples were manipulated as described above (“blood sampling for drug kinetics evaluation”).

Formulation 23 (Example 4, Table 7) having the following composition was administered after taking a blood sample “before administration” within 2 hours after meals.

ingredient Formulation 23 weight% Weight% (mg) HPMCHPC cross carmellose sodium tannin levodopacarbidopastearate magnesium 12.745.99.37.619.34.80.4 1324769679200504 Total amount 100 1037

After administration of the test component hydrogel, 300 mg of pH adjusted (pH of 2.0) water was administered up through the flexible tube.

Administered every hour up to 12 hours, a blood sample of whole blood (2 ml) was recovered from the catheter and placed in a heparinized glass test tube, from which four aliquots (250 μl) were removed and each aliquot was labeled Eppendorf microcentrifuge. Put into separator tube. After vortexing the microcentrifuge tube for several seconds (Vortex-2 Genie; Scientific Industries Model G-560E), it was immediately placed in a quick freezer and the sample was kept at -70 ° C until analysis.

Four aliquots were prepared and frozen every simplicity. Two samples were then analyzed for levodopa and carbidopa concentrations over several days, and the two remaining aliquots were stored in a deep freezer for further analysis.

result

The results of in vivo release of levodopa / carbidopa are shown in Table 17 below.

In vivo release rate of levodopa / carbidopa in beagle dogs Hours (h) Blood concentration (ng / ml) Levodopa Carbidopa 0123456789101112 0.096.5104.1574.3653.1387.41008.71934.81783.1371.1214.0202.396.5 0032.552.886.375.0119.2337.0661.8226.7145.7174.070.9

The release of the two drugs is delayed and significantly prolonged. For more than six hours levodopa was released at a fairly high concentration, and the peak concentration was delayed, indicating that the delivery system is present in the stomach, releasing the drug for many hours. In addition, the data in Table 17 is shown schematically in FIG. 1.

Example 8

Gastric retention delivery system with inherent external tablet adhesion

One method of obtaining pulsed delivery of the drug in the stomach is to attach a tablet with a predetermined delay to the gastric retention delivery system (GRDS) tablet before disintegrating. This may be accomplished by partial embedding of the tablet in the GRDS matrix, or by attaching the tablet externally to the GRDS. In this example, we have shown the feasibility of such external bonding.

GRDS formulations are shown in Table 13 above in Example 6. The powders except the lubricant were mixed for 5 minutes. Then magnesium stearate was added and the powders were mixed for at least 1 minute. The blend was compressed into a 10 × 7 × 7 mm rectangle (cut ninth) in a Manesty f3 single punch tablet press.

The adhesive solution was prepared as follows. Sodium casein [Emolac (R) 50, 15 g] was dissolved in 100 ml of water by stirring overnight at room temperature. 500 ml of ethanol were added with stirring to obtain an emulsion of 2.5% sodium caseinate in water: ethanol.

The tablets were then coated with an adhesive. The emulsion was spray coated onto tablets in a pan coater at a rate of 4 ml / min, a preparation temperature of 30-40 ° C., and a coating weight of 5-14 mg. The tablets were air dried in a coating pan to give an adhesive coated GRDS tablet.

Placebo tablets based on microcrystalline cellulose were prepared (5 × 5 × 5 mm squares) and coated with Eudragit ™ S to make them impermeable under acidic conditions. Tablets were loaded into gelatin # 00 capsules in a stack with GRDS tablets between two placebo tablets. The contact between tablets was made on the 7 × 7 mm plane of the GRDS tablet perpendicular to the compression axis.

Gelatin capsules were placed in a USP type II dissolution bath at 37 ° C. containing 0.1 N HCl and stirred at 50 RPM. The capsules were dissolved and the three tablet stacks were glued to each other in situ. Within 15 minutes GRDS tablets swelled from 10 × 7 mm to 13 × 22 mm (swelling usually along the compression axis). At the second hour GRDS tablets swell to 14 × 25 mm. Despite swelling, the remaining placebo tablets remained adhered to GRDS in the dissolution bath for at least 12 hours. In order to test the adhesion retention under higher flow rate conditions, the stack was placed in 0.1 N HCl at 37 ° C. in a disintegration test apparatus at a rate of 50 strokes per minute. The flow rate of the tablet phase in the disintegration test apparatus was significantly faster than that in the dissolution test apparatus. The three tablets remained adhered to each other for 10 hours.

Example 9

Timely pulse delivery of methylphenidate

Methylphenidate disintegrating tablets of the formulations shown in Table 18 below were prepared.

ingredient ratio(%) Methylphenidate HPC (Clucell LF) Starch Microcrystalline Cellulose (Avicel) Sodium Starch Glycolate Magnesium Stearate 1052549101

Tablets were prepared as follows. Two parts methylphenidate was added in two parts water, mixed in a Zanchetta Rotolab Wanpot granulator and granulated with one part HPC and five parts starch. The granules were dried at 45 ° C. in a fluidized bed drier and ground to 0.63 mm sieve. The granules were mixed with microcrystalline cellulose and sodium starch glycolate for 5 minutes, magnesium stearate was added and mixed for 1 minute. The blends were each compressed to 5 mm of 100 mg tablets in a Manesty f3 single punch tablet press.

A coating solution having a total weight of 100 g was prepared by dissolving 5 g ethylcellulose, 0.75 g urea and 0.5 g triethyl citrate in ethanol. This solution was sprayed onto the tablets in a pan coater and the tablet layer was maintained at 30-40 ° C. Different weight coatings were sprayed onto the tablets. The delay in ejected drug release in the USP type II dissolution apparatus at 0.1 N HCl at 37 ° C. and 50 RPM was tested. The results of the jet delay as a function of coating level are shown in Table 19 below.

Coating level (mg / tablet) Blowout time (h) 468 2512

Tablets of this type can be adhered to GRDS to effect extended retention in the stomach and spontaneous release of methylphenidate.

While the present invention has been described with reference to some preferred embodiments, other embodiments will become apparent to those skilled in the art in view of the specification and examples. The specification, including examples, is used for illustrative purposes only, and the scope and spirit of the present invention is defined by the claims below.

Claims (112)

A gastric retention vehicle composition for use in oral administration pharmaceutical products containing hydrogels, superdisintegrants, and tannic acid, wherein the volume of the composition is increased about threefold within about 15 minutes of contact with gastric juice. The gastric retention vehicle composition of claim 1, wherein the volume of the composition is increased about 5 times within about 15 minutes of contact with gastric juice. The gastric retention vehicle composition of claim 2, wherein the volume of the composition is increased about 8-fold within about 15 minutes of contact with gastric juice. The gastric retention vehicle composition of claim 1, wherein the volume of the composition is increased about 3 times within about 5 minutes of contact with gastric juice. The gastric retention vehicle composition of claim 1, which is compressed. The gastric retention vehicle composition of claim 1, wherein the hydrogel comprises hydroxypropyl methylcellulose. 7. The gastric retention vehicle composition of claim 6, wherein the hydrogel further comprises hydroxypropyl cellulose. 8. The gastric retention vehicle composition of claim 7, wherein the hydrogel comprises hydroxypropyl methylcellulose and hydroxypropyl cellulose in a weight ratio of about 1: 3 to about 5: 3. The gastric retention vehicle composition of claim 6, wherein the hydrogel further comprises a crosslinked polyacrylate. The gastric retention vehicle composition of claim 9, wherein the crosslinked polyacrylate is a polyacrylic acid polymer crosslinked with allyl sucrose. The gastric retention vehicle composition of claim 1, wherein the superdisintegrant is selected from the group consisting of crosslinked carboxymethylcellulose sodium, sodium starch glycolate and crosslinked polyvinylpyrrolidone. The gastric retention vehicle composition of claim 11, wherein the superdisintegrant is crosslinked carboxymethylcellulose sodium. The gastric retention vehicle composition of claim 11, wherein the superdisintegrant is sodium starch glycolate. The gastric retention vehicle composition of claim 1, wherein the tannic acid is present in an amount from about 2% to about 12% by weight of the total weight of the hydrogel, superdisintegrant, and tannic acid, except for other vehicles that may be present. The gastric retention vehicle composition of claim 1 comprising the components of a) -c) below based on the total weight of hydrogel, superdisintegrant and tannic acid, except for other vehicles that may be present. a) about 20 wt% to about 70 wt% hydrogel, b) about 10% to about 75% by weight of a superdisintegrant, c) about 2 wt% to about 12 wt% tannic acid. The hydrogel of claim 15, wherein the hydrogel is present in an amount sufficient to make about 30% to about 55% by weight of a superdisintegrant, from about 3% to about 7% by weight of tannic acid, and 100% by weight of the total weight. Gastric retention vehicle composition. The method of claim 1, wherein from about 10% to about 30% by weight of hydroxypropylmethyl cellulose, from about 40% to about 60% by weight based on the total weight of the hydrogel, superdisintegrant and tannic acid, excluding any other excipients that may be present A gastric retention vehicle composition comprising hydroxypropyl cellulose, about 7 wt% to about 35 wt% sodium croscarmellose sodium, and about 4 wt% to about 12 wt% tannic acid. The method of claim 1, wherein from about 10% to about 20% by weight of hydroxypropyl methyl cellulose, from about 45% to about 50% by weight, based on the total weight of the hydrogel, superdisintegrant and tannic acid, excluding any other excipients that may be present Gastric retention vehicle composition comprising hydroxypropyl cellulose, about 25% to about 35% by weight sodium starch glycolate and about 4% to about 6% by weight tannic acid. The gastric retention vehicle composition of claim 1, wherein the gastric juice is simulated gastric juice. 20. The gastric retention vehicle composition of claim 19, wherein the simulated gastric juice is prepared by mixing 7 volumes of hydrochloric acid with a sufficient amount of water so that the total volume of the solution is 1000, and the temperature of the simulated gastric juice is 37 ° C. 20. The gastric retention vehicle composition of claim 19, wherein the simulated gastric juice is 0.1M HCl and the temperature of the simulated gastric juice is 37 ° C. A pharmaceutical formulation for oral administration to a patient containing a) a therapeutic agent and b) a gastric retention vehicle composition containing a hydrogel, a superdisintegrant and tannic acid, wherein the gastric retention vehicle composition expands upon contact with gastric fluid so that the formulation Wherein the release of the therapeutic agent from the formulation occurs for the prolonged period of time, and after this prolonged time, the formulation decomposes into fragments of a size so small that the formulation cannot remain in the stomach. Formulation. The pharmaceutical formulation of claim 22, wherein the expansion of the gastric fluid retention vehicle composition causes the formulation to achieve a maximum cross-sectional area of at least about 20 × 20 mm. The dosage form of claim 23, wherein the maximum cross-sectional area is at least about 25 × 20 mm. The pharmaceutical formulation of claim 23, wherein the cross-sectional area of 20 × 20 mm is within about 15 minutes of contact with gastric juice. The pharmaceutical formulation of claim 25, wherein the cross-sectional area of 20 × 20 mm is within about 5 minutes of contact with gastric juice. The pharmaceutical formulation of claim 22, wherein the volume increases about threefold within about 15 minutes of contact with gastric juice. The pharmaceutical formulation of claim 27, wherein the volume increases about 5 times within about 15 minutes of contact with gastric juice. The pharmaceutical formulation of claim 28, wherein the volume increases about 8-fold within about 15 minutes of contact with gastric juice. The pharmaceutical formulation of claim 27, wherein the volume increases about threefold within about 5 minutes of contact with gastric juice. The pharmaceutical formulation of claim 22, wherein the delay time is at least about 4 hours. The pharmaceutical formulation of claim 22, further comprising an effervescent component. 33. The pharmaceutical formulation of claim 32, wherein the foamable component is sodium bicarbonate. 23. The therapeutic agent according to claim 22, wherein the therapeutic agent is selected from the group consisting of levodopa and methylphenitate, which may be combined with amino dicarboxylase enzyme inhibitors selected from the group consisting of carbidopa and benserazide and methylphenidate as needed. Phosphorus Pharmaceutical Formulations. The pharmaceutical formulation of claim 22, which is in tablet form. 36. The pharmaceutical formulation according to claim 35, which is in a multi-layered tablet form. The pharmaceutical formulation of claim 22, which is in capsule form. The pharmaceutical formulation of claim 22, which is in encapsulated tablet form. The pharmaceutical formulation of claim 22, wherein the gastric retention vehicle composition contains the following components of a) -c) based on the total weight of the hydrogel, superdisintegrant and tannic acid, except for other vehicles that may be present. a) about 20 wt% to about 70 wt% hydrogel b) about 10 wt% to about 75 wt% superdisintegrant, and c) about 2 wt% to about 12 wt% tannic acid. A pharmaceutical formulation for releasing a therapeutic agent in a stomach of a patient, a) a gastric retention vehicle comprising a hydrogel, a superdisintegrant and tannic acid, which provides a homogeneous solid matrix, and b) a therapeutic agent dispersed in the matrix, When in contact with gastric fluid, the gastric retention vehicle composition is expanded to facilitate the retention of the formulation for an extended period of time in the stomach of the patient, wherein the release of the therapeutic agent from the formulation occurs in the stomach in the extended period of time. The pharmaceutical formulation of claim 40, wherein the therapeutic agent is dispersed in the matrix as a component in a plurality of particles dispersed in the matrix. 42. The pharmaceutical formulation of claim 41, wherein the particles are selected from the group consisting of compressed granules, beads, pills, pellets, macrocapsules, macarose spheres, micro granules, nanocapsules and nanospheres. The pharmaceutical formulation of claim 41, wherein the particles are coated. The pharmaceutical formulation of claim 43, wherein the particles are coated with a coating that delays the release of the therapeutic agent. 45. The method of claim 44, wherein the particles of the first portion of the plurality of particles are coated with a coating that delays the release of the therapeutic agent for a first time, wherein the second portion of the plurality of particles is the therapeutic agent for a second time longer than the first time. The pharmaceutical formulation is coated with a second coating to delay the release of. The pharmaceutical formulation of claim 43, wherein the particles are coated with a coating that delays the release of the therapeutic agent. The pharmaceutical formulation of claim 41, wherein the first portion of the plurality of particles is uncoated and the second portion of the plurality of particles is coated with a coach to delay release of the therapeutic agent from the particles. The pharmaceutical formulation of claim 40, wherein the therapeutic agent is released in a sustained release manner. The pharmaceutical formulation of claim 48, wherein the therapeutic agent is contained in a plurality of particles having a matrix that slows the release of the therapeutic agent. 49. The pharmaceutical formulation of claim 48, wherein the therapeutic agent is contained in a plurality of particles with a coating that slows down the release of the therapeutic agent. The pharmaceutical formulation of claim 40, further comprising a second therapeutic agent. A pharmaceutical formulation for pulsing one or more therapeutic agents in the stomach of a patient, a) a gastric retention vehicle composition containing a hydrogel, a superdisintegrant, and tannic acid, which provides a homogeneous solid matrix, b) a plurality of first particles dispersed in the matrix and containing the first therapeutic agent, c) a plurality of second particles dispersed in the matrix and containing a second therapeutic agent, impermeable to the second therapeutic agent, dissolved in gastric fluid and coated with a coating that can be degraded by gastric juice after a delay time, The first and second therapeutic agents may be the same or different from each other. Upon contact with gastric fluid, the gastric retention vehicle expands to facilitate the retention of the formulation in the patient's stomach, the first therapeutic agent is released from the plurality of first particles, and after an extended period of time, the coating of the second particle And wherein the second therapeutic agent is released from the plurality of second particles. A pharmaceutical formulation for pulsed release of one or more therapeutic agents in a stomach of a patient, a) a gastric retention vehicle composition that provides a hydrogel, a superdisintegrant, and tannic acid, with a uniform solid matrix, b) a plurality of first particles dispersed in a matrix and containing a first therapeutic agent, impermeable to the first therapeutic agent and dissolved in gastric fluid and coated with a first coating that can be degraded by gastric fluid after a first delay time, and c) a plurality of coatings coated with a second coating that is dispersed in the matrix and contains a second therapeutic agent, impermeable to the second therapeutic agent, soluble in gastric fluid and degradable by gastric fluid after a second delay time longer than the first delay time. Second particles, The first therapeutic agent and the second therapeutic agent may be the same or different, and the first coating and the second coating may also have the same thickness or different, Upon gastric fluid contact, the gastric retention vehicle composition expands to facilitate the retention of the formulation in the patient's stomach, after the first delay time elapses, the first coating degrades, the first therapeutic agent is released from the first particles, and the second time elapses. Thereafter, the second coating is degraded and the second therapeutic agent is released from the second particle. A pharmaceutical formulation for releasing a therapeutic agent in the patient, wherein the shell contains a therapeutic agent and contains a reservoir embedded in a compressed shell containing hydrogel, superdisintegrant, and tannic acid, wherein the shell swells upon contact with gastric fluid Wherein the formulation is allowed to remain for an extended period of time in the stomach, and the therapeutic agent is released from the reservoir within a delay time, after which the shell breaks down into fragments of a size so small that it cannot remain in the stomach. 55. The pharmaceutical formulation of claim 54, wherein the reservoir provides for sustained release of the therapeutic agent. 55. The pharmaceutical formulation of claim 54, wherein the reservoir provides delayed sustained release of the therapeutic agent. 55. The pharmaceutical formulation according to claim 54, wherein the reservoir provides an ejected release of the therapeutic agent. 55. The pharmaceutical formulation of claim 54, wherein the reservoir provides a delayed bursted release of the therapeutic agent. 55. The pharmaceutical formulation of claim 54, wherein the reservoir provides immediate release of the therapeutic agent. 55. The pharmaceutical formulation of claim 54 wherein the reservoir is partially embedded and a portion of the surface of the reservoir is exposed. The pharmaceutical formulation of claim 54, wherein the reservoir is coated. The pharmaceutical formulation of claim 61, wherein the reservoir is coated with a coating that delays release of the therapeutic agent. The pharmaceutical formulation of claim 61, wherein the reservoir is coated with a coating that slows the release of the therapeutic agent. The pharmaceutical formulation of claim 54, wherein the reservoir provides a matrix that slows the release of the therapeutic agent. The pharmaceutical formulation of claim 54 encapsulated. 55. The pharmaceutical formulation of claim 54, wherein the reservoir is a tablet. A pharmaceutical formulation comprising a compressed gastric retention vehicle composition comprising a hydrogel, a superdisintegrant and tannic acid, and a capsule enclosed with a reservoir containing a therapeutic agent bound to the gastric retention vehicle composition compressed by compression or adhesive, comprising: Upon ingestion, the capsule dissolves in the patient's stomach and expands in contact with the water and gastric retention vehicle composition, thereby facilitating reservoir retention for an extended period of time in the patient's stomach, and also causing the therapeutic agent to be released from the reservoir within the delayed time and extended Wherein the compressed gastric retention composition decomposes into fragments that are so small that they cannot remain in the stomach after a predetermined time. The pharmaceutical formulation of claim 67, wherein the reservoir provides a sustained release of the therapeutic agent. The pharmaceutical formulation of claim 67, wherein the reservoir provides a sustained sustained release of the therapeutic agent. 68. The pharmaceutical formulation of claim 67, wherein the reservoir provides a burst release of the therapeutic agent. 68. The pharmaceutical formulation of claim 67, wherein the reservoir provides a delayed bursted release of the therapeutic agent. The pharmaceutical formulation of claim 67, wherein the reservoir provides immediate release of the therapeutic agent. The pharmaceutical formulation of claim 67, wherein the adhesive is applied to a portion of the surface of the gastric retention vehicle composition. The pharmaceutical formulation of claim 67, wherein the adhesive is applied to a portion of the surface of the reservoir. The pharmaceutical formulation of claim 67, wherein the capsule encloses a second reservoir containing a second therapeutic agent. The pharmaceutical formulation of claim 75, wherein the second therapeutic agent of the second reservoir is the same as the therapeutic agent of the reservoir. The pharmaceutical formulation of claim 67, wherein the reservoir is a tablet. 68. The pharmaceutical formulation of claim 67 comprising a capsule encapsulating a first compressive composition comprising a hydrogel, a superdisintegrant and tannic acid and a second compressive composition comprising a therapeutic agent, wherein at least one of the first or second compressive composition An adhesive is applied to some of the surfaces, and upon ingestion by the patient, the capsule dissolves in the stomach of the patient, causing the water to come into contact with the first compressive composition, which causes the capsule to expand and the water to come into contact with the adhesive, The adhesive bonds the first and second compression compositions to each other, the expansion of the first compression composition promotes the retention of the formulation for an extended time in the stomach of the patient, the therapeutic agent is released from the second compression composition within a delay time, Pharmaceutical formulation, wherein said fragment is degraded into very small fragments of such an extent that said prolonged period of time cannot remain in the stomach. a) a first layer containing a therapeutic agent, and b) a second layer bonded to the first layer by compression or by an adhesive, the second layer containing a gastric retention vehicle composition comprising hydrogel, superdisintegrant and tannic acid, When the second layer comes in contact with gastric juice, it expands to promote the formulation's retention in the patient's stomach for an extended period of time, and the therapeutic agent is released from the first layer for an extended period of time, after which the second layer remains in the stomach. A multi-layered pharmaceutical formulation for releasing a therapeutic agent in the stomach of a patient, which is broken down into fragments of an insignificant size. The pharmaceutical composition of claim 79, wherein the therapeutic agent is released from the first layer in a delayed release, erupted release, delayed release, pulsed release, delayed pulsed release, sustained release or delayed sustained release manner. Formulation. 80. The multilayer pharmaceutical formulation of claim 79, wherein the first layer is coated with a nose to delay release of the therapeutic agent. 80. The multilayer pharmaceutical formulation of claim 79, wherein the first layer is coated with a coating that slows the release of the therapeutic agent. A pharmaceutical formulation orally administered to a patient providing sustained gastric release of levodopa, the formulation comprising levodopa, carbidopa or bencerazide, if desired, and combinations thereof, which expand upon contact with gastric fluid. A pharmaceutical formulation comprising a gastric retention vehicle composition comprising tannic acid that causes the formulation to retain in the stomach for at least about 4 hours. 84. The pharmaceutical formulation of claim 83, wherein the levodopa is released in the simulated gastric juice for at least 4 hours. 84. The pharmaceutical formulation of claim 83, wherein the release of levodopa in the simulated gastric juice is delayed for at least 4 hours. A pharmaceutical formulation for providing oral administration to a patient of gastric release of levodopa for an extended time period, comprising about 10% to about 14% by weight of hydroxypropyl methylcellulose, about 42% to about 47% by weight of hydroxy Propyl cellulose, from about 7 wt% to about 12 wt% sodium carmellose sodium, about 6 wt% to about 9 wt% tannic acid, about 18 wt% to about 22 wt% levodopa, about 3 wt% to about 6 A pharmaceutical formulation containing by weight carbidopa and by weight from about 0.3% to about 1% by weight tablet lubricant as needed. 87. The pharmaceutical formulation of claim 86, wherein release of levodopa over the patient's stomach occurs over 8 hours. A pharmaceutical formulation for oral administration to a patient providing gastric release of levodopa, wherein the sustained release storage of levodopa, together with an amino decarboxylase enzyme inhibitor selected from the group consisting of carbidopa and benserazide, as desired As a group, they are embedded in a shell, the shell comprising about 10% to about 20% by weight of hydroxypropyl methylcellulose, about 50% to about 60% by weight of hydroxypropyl cellulose, about 12% to about 25 A pharmaceutical formulation containing, by weight, croscarmellose sodium, about 6% by weight to about 12% by weight tannic acid, and optionally about 0.3% by weight to about 1% by weight tablet lubricant. 89. The pharmaceutical formulation of claim 88, wherein release of levodopa over the patient's stomach is over 8 hours. A pharmaceutical formulation for oral administration to a patient that provides pulsed gastric release of methylphenidate, a) gastric retention vehicle composition containing hydrogel, superdisintegrant and tannic acid, providing a homogeneous solid matrix, b) a plurality of first particles dispersed in the matrix and containing methylphenidate, c) dispersed in a matrix and containing a plurality of second particles impermeable to methylphenidate and containing methylphenidate dissolved in gastric fluid and coated with a coating capable of being degraded by gastric fluid, Wherein the gastric fluid retention vehicle composition expands upon contact with gastric fluid to facilitate retention of the formulation on the patient, and methylphenidate is released from the first particle and after about 3 hours to about 5 hours, The pharmaceutical formulation wherein the coating degrades and methylphenidate is released from the second particle. 91. The method of claim 90, further comprising a plurality of third particles containing methylphenidate dispersed in the matrix and having a coating impermeable to the methylphenyldate and soluble in gastric fluid, wherein the coating is dissolved in gastric fluid And is released from the third particle about 3 to 5 hours after the methylphenidate is released from the second particle. 91. The pharmaceutical formulation of claim 90, wherein the first particles are coated with a coating that delays the release of methylphenidate from these particles. As a pharmaceutical formulation for oral administration to a patient, which provides a pulsed gastric release of methylphenidate: a) gastric retention vehicle composition containing hydrogel, superdisintegrant and tannic acid, b) a first reservoir containing methylphenidate, c) contains methylphenidate, a second reservoir impermeable to methylphenidate and coated with a coating that is soluble in gastric fluid and can be degraded by gastric fluid, Wherein the gastric fluid retention vehicle composition expands upon contact with gastric fluid, thereby facilitating the retention of the dosage form on the patient's stomach and methylatedate is released from the first reservoir and after about 3 hours to about 5 hours, the second particles Wherein the coating is degraded and methylphenidate is released from the second reservoir. 95. The method of claim 93, wherein the third reservoir is coated with a coating that is impermeable to methylphenidate and dissolvable in gastric fluid and can be degraded by gastric fluid, wherein 3 to 5 hours after methylphenidate is released from the second reservoir. The pharmaceutical formulation is released from the third reservoir. 95. The pharmaceutical formulation of claim 93, wherein the first reservoir is coated with a coating that delays the release of methylphenidate in the reservoir. 95. The pharmaceutical formulation of claim 93, wherein the gastric retention vehicle composition and reservoir are encapsulated. A method for treating or converting a disease by administering to a patient or sensitive patient a therapeutically effective amount of a clinically suitable therapeutic agent contained in the pharmaceutical formulation of claim 22. 23. A method of treating this deficiency by administering the pharmaceutical formulation of claim 22 to a patient in need of a treatment for central nervous dopamine deficiency disease, wherein the therapeutic agent is amino dica selected from the group consisting of carbidopa and bengerazide as needed. Levodopa in combination with a reboxylase enzyme inhibitor. In the method of treating this deficiency by administering a pharmaceutical formulation to a patient in need of treatment of central nervous system dopamine deficiency, the pharmaceutical formulation is amino decarboxylase selected from the group consisting of carbidopa and bengerazide as needed. Levotopa in combination with an enzyme inhibitor and releasing levodopa in the stomach of the patient for a period of at least 8 hours. In the method of treating this deficiency by administering a pharmaceutical formulation to a patient in need of treatment of central nervous system dopamine deficiency, the pharmaceutical formulation is amino decarboxylase selected from the group consisting of carbidopa and bengerazide as needed. Wherein the release of a therapeutically effective amount of levodopy, levovopa in combination with an enzyme inhibitor is delayed for at least 4 hours after dosing, after which the patient's gastric leodopa is released. 101. The method of treating central nervous system dopamine deficiency of claim 100, wherein the formulation is administered in the evening or at night. To a patient in need of treatment of hyperactivity or attention deficit disorder, a first dose of methylphenidate is released on the patient's stomach and a second dose of methylphenidate is released from about 3 hours to about 5 hours after the first dose is released. A method of treating hyperactivity or attention deficit disorder by administering to a patient a single formulation containing two or more doses of methylphenidate. 107. The method of claim 102, wherein the formulation contains a third dose of methylphenidate released from about 3 hours to about 5 hours after releasing the second dose. 107. The method of claim 102, wherein there is a delay of about 3 hours to about 5 hours after administration of the formulation before the first dose of methylphenidate is released. 107. The formulation of claim 102, wherein the formulation comprises a homogeneous matrix containing hydrogels, superdisintegrants, and tannic acid, the plurality of particles containing methylphenidate dispersed throughout the matrix, wherein some of the plurality of particles are coated particles. Wherein the coating has a coating that delays the release of methylenedate from and wherein the release from the coated particles is a second dose. 103. The formulation of claim 102, wherein the formulation comprises a gastric retention vehicle composition containing a hydrogel, a superdisintegrant and tannic acid, a first reservoir containing methylphenidate to release methylphenidate at a first dose, and methylpheny at a second dose. A second reservoir containing methylphenidate that releases the date, the reservoir being coated with a coating that delays release of the second dose of methylphenidate for about 3 to about 5 hours after administration of the first dose. How to be. 103. The formulation of claim 102, wherein the formulation comprises a compressed gastric fluid retention vehicle composition comprising a hydrogel, a superdisintegrant, and tannic acid with a methylphenidate coating, and a capsule enclosed with a delayed release reservoir of methylphenidate. Wherein the capsule is dissolved in the stomach of the patient such that the capsule is in contact with the gastric retention vehicle composition. a) combining the hydrogel, superdisintegrant, tannic acid and therapeutic agent, and b) compressing the combination, wherein the preparation of the orally administered pharmaceutical product, wherein the volume of the pharmaceutical product expands rapidly upon gastric fluid contact. 109. The method of claim 108, wherein the volume of the pharmaceutical product is increased about three times within about 15 minutes of contact with gastric juice. 109. The method of claim 109, wherein the volume of the pharmaceutical product is increased about 5 times within about 15 minutes of contact with gastric juice. 109. The method of claim 108, wherein the volume of the pharmaceutical product is increased about 8-fold within about 15 minutes of contact with gastric juice. 109. The method of claim 108, wherein the volume of the pharmaceutical product is increased about three times within about 5 minutes of contact with gastric juice.