HK1158545B - Carbidopa/levodopa gastroretentive drug delivery - Google Patents

Description

Carbidopa/levodopa gastric retention dosing

Cross reference to related patent applications

This application claims priority from U.S. provisional patent application No. 61/046,261 filed on day 4/2008 and 18 and U.S. provisional patent application No. 61/120,051 filed on day 4/2008, and these patent application documents are incorporated herein by reference in their entirety.

Technical Field

The present invention relates to a multi-layered, biodegradable gastroretentive drug formulation (GRDF) for controlled release of an active pharmaceutical agent having a narrow absorption window in the upper gastrointestinal tract, which acts locally in the gastrointestinal tract or has other principles of gastroretentive administration. Further, the present invention describes a multilayered, biodegradable gastroretentive drug formulation for immediate and sustained release of the active agent. The gastroretentive drug formulation of the present invention can be administered orally to a mammal for systemic or local treatment of a pathological condition or pathological deficiency.

Background

Administration of drugs, such as amino acid and nucleic acid analogs, peptide and peptide drugs, various antibiotics, various antiviral drugs, and some other drugs, to mammals delivers the drugs to the gastrointestinal tract and the drugs are absorbed only in specific regions of the gastrointestinal tract, such as the stomach, duodenum, and small intestine, so that only drugs delivered to the vicinity of these regions are absorbed. This phenomenon is often referred to as "Narrow Absorption Window (NAW)". The site of action of various other drugs is located in a specific region of the gastrointestinal tract. In addition, various other drugs (e.g., water-insoluble drugs) have a medicinal principle of gastric retention administration. Furthermore, transit time through each region of the gastrointestinal tract is a highly variable value.

Although the advantages of sustained release technology are applicable to many drugs, controlled release of drugs having a relatively narrow absorption window in the gastrointestinal tract remains a challenge. It is desirable to extend the gastric residence time of these drugs so that the drug is released over an extended period of time to the vicinity of its site of absorption (or action), or in the same manner to other sites in the gastrointestinal tract. Examples of delivery systems that can increase the residence time of the drug are floating low density dosage forms, such as so-called hydrodynamically balanced delivery systems, effervescent systems comprising gas generating materials. Similarly, other delivery Systems have been tried, such as high density formulations and bioadhesive or mucoadhesive formulations that retard upper gastrointestinal delivery by adhering to the intestinal mucosa (Hwang, SJ. et. al., Critical Reviews in Therapeutic Drug Systems, 15 (3): 243-84 (1998); Desai, S.and Bolton, S., Pharmac.Res.10 (9): 1321-25 (1993); Whitehead, L.et. J.ScL., Europan J.Pharm. ScL, 4 (1): S182 (1996); Iannucelli, V.et. al., Intern.J.174: 55-62 (1998); Jimenez-tella Casllanos, NR.et. Druger. J., Dexel. 143. J.; Drug J. 143. 1993); Drug J.143. 1993); Critical J.143. J.1993)).

Controlled Release (CR) drug dosage forms have the following advantages: delivering the target drug over an extended time interval; eliminating the inconvenience and concomitant side effects of repeated daily doses. However, conventional CR drug delivery systems are rarely suitable for drugs having a relatively narrow absorption window in the gastrointestinal tract because their residence time within or beyond the absorption window is shorter than the release time span that is considered beneficial. Accordingly, there is a need in the art for a controlled release pharmaceutical dosage form that provides sustained release of a drug having a relatively narrow absorption window in the gastrointestinal tract. Likewise, in certain instances, it is considered beneficial to rapidly establish therapeutic blood levels and maintain them for a longer period of time, a subject known in the art as a "loading dose," and there is a need in the art for a combination pharmaceutical dosage form that includes an immediate release component and a sustained release component suitable for delivery of a narrow absorption window material. U.S. patent 6,685,962B2, which is incorporated herein by reference, provides a pharmaceutical gastroretentive drug delivery system for the controlled release of active agents in the gastrointestinal tract.

The present invention fills the need in the art for a dosage form that provides sustained release or a combination of immediate and sustained release of a drug having a narrow absorption window in the gastrointestinal tract, or other principles related to gastroretentive administration, by providing a gastroretentive drug dosage form that is also fully biodegradable and has a relatively high loading capacity.

Disclosure of Invention

To further achieve these objects, the present invention provides a biodegradable multi-layered gastroretentive drug formulation for the sustained release of an active agent in the gastrointestinal tract. In another aspect, the present invention provides a biodegradable multi-layered gastroretentive drug formulation that combines immediate and sustained release of an active agent in the gastrointestinal tract.

In one embodiment, a biodegradable, multi-layered gastroretentive drug formulation for the sustained release of an active agent in the stomach and gastrointestinal tract of a patient includes an inner layer comprising an active agent and a degradable polymer that is not immediately soluble in gastric fluid. The inner layer has a first face and an opposite second face. At least one membrane covers the inner layer. The membrane comprises at least one polymer combination of a hydrophilic polymer and a polymer that is insoluble in gastric media, the membrane being hydratable in gastric media. The membrane is secured directly to and covers both sides of the inner layer and has a predetermined length in a planar orientation greater than 20 millimeters, the membrane and inner layer being arranged in an accordion folded orientation sufficiently compact to be placed within a capsule dissolvable in a patient's stomach and simulating gastric media. The membrane and inner layer unfold from the accordion folded orientation to a length of at least 20 millimeters within 30 minutes of exposure to gastric media. The membrane allows passage of gastric media from the environment to the internal layer and allows passage of the active agent from the internal layer through the membrane to the environment.

In another embodiment, a biodegradable, multi-layered gastroretentive drug formulation for the sustained release of an active agent in the gastrointestinal tract comprises an inner layer comprising an active agent and a degradable polymer that is not immediately soluble in gastric fluid. A first membrane and a second membrane cover the inner layer, the membranes including at least one of a polymeric combination of a hydrophilic polymer and a polymer that is insoluble in gastric media, and the membranes being hydratable. The first and second films have a width and length greater than a width and length of the inner layer. The first and second films are ultrasonically welded or otherwise affixed or joined directly together at their edges. The first film is ultrasonically welded to the first side of the inner layer and the second film is ultrasonically welded to the second side of the inner layer. The ultrasonically welded inner layer and the first and second membranes are disposed in a planar orientation for a predetermined length greater than 20 millimeters, the membranes and inner layer being arranged in an accordion folded orientation sufficiently compact to be placed within a capsule dissolvable in the stomach or simulated gastric media. The ultrasonic weld has sufficient mechanical strength and stability to allow the dosage form to remain intact when exposed to gastric fluid.

In yet another embodiment, a biodegradable, multi-layered gastroretentive drug formulation for the sustained release of an active agent in the gastrointestinal tract is disclosed, comprising an inner layer comprising an active agent and a degradable hydrophilic polymer that is not immediately soluble in gastric fluid and a degradable enteric polymer that is substantially insoluble in solutions having a pH of less than 5.5, and optionally a plasticizer. At least one membrane covering the inner layer, the membrane comprising at least one of a polymeric combination of a hydrophilic polymer and a polymer insoluble in gastric media and at least one plasticizer. The membrane swells in the presence of gastric juices. At least one material of each of the inner layer and the membrane can be ultrasonically welded together. The film is directly secured to and covers both sides of the inner layer and has a predetermined length in a planar orientation greater than 20 millimeters. The membrane and inner layer are arranged in an accordion folded orientation sufficiently compacted to be placed within a capsule dissolvable in the stomach or simulated gastric media. The membrane allows passage of gastric media from the environment to the internal layer and allows passage of the active agent from the internal layer through the membrane to the environment. The membrane and inner layer unfold from the accordion folded orientation to a length of at least 20 millimeters within 30 minutes of exposure to gastric media.

In yet another embodiment, a biodegradable, multi-layered gastroretentive drug formulation for the sustained release of an active agent in the gastrointestinal tract comprises an inner layer comprising an active agent and a degradable hydrophilic polymer that is not immediately soluble in gastric fluid and a degradable enteric polymer that is substantially insoluble in solutions having a pH of less than 5.5, and a plasticizer. A first film and a second film cover the inner layer, the films comprising at least one of a polymeric combination of a hydrophilic polymer and a polymer insoluble in gastric media and at least one plasticizer. The membrane swells in the presence of gastric juices. At least one material of each of the inner layer and the membrane can be ultrasonically welded together. The membrane is directly secured to and covers both sides of the inner layer and has a predetermined length in the planar direction greater than 20 millimeters, the membrane and inner layer being arranged in an accordion folded orientation sufficiently compact to be placed within a capsule dissolvable in the stomach. The film and inner layer unfold from the accordion folded orientation to a length of at least 20 millimeters within 30 minutes of exposure to gastric fluid. The first and second films have a length and width greater than a length and width of the inner layer. The first and second films are ultrasonically welded or otherwise adhered or joined directly at their edges. The first membrane is ultrasonically welded to the first face of the inner layer. The second membrane is ultrasonically welded to the second side of the inner layer. The membrane allows passage of gastric media from the environment to the inner layer, and allows passage of the active agent from the inner layer through the membrane to the environment. The ultrasonically welded inner layer and the first and second films have a predetermined length in a planar orientation greater than 20 millimeters. The membrane and inner layer are arranged in an accordion folded orientation that is sufficiently compacted to be placed within a capsule dissolvable in the stomach. The ultrasonic weld has sufficient mechanical strength and stability to maintain the dosage form intact upon exposure to gastric fluid.

In one embodiment, a gastroretentive drug formulation for sustained release of an active agent in the gastrointestinal tract, the gastroretentive drug formulation comprising: i.) an inner layer or compartment comprising an active agent, one or more pharmaceutically acceptable excipients, wherein at least one of said pharmaceutically acceptable excipients is a polymer; ii.) two membranes which together form an envelope around the inner membrane, each membrane comprising at least one polymer combination of a polymer insoluble in gastric fluid and a hydrophilic swelling polymer, and at least one plasticizer; and iii) an optional additional layer covering each outer membrane and comprising a powder or film that prevents the outer membrane from adhering to itself when folded within the capsule.

In various embodiments, a gastroretentive drug formulation for immediate and sustained release of an active agent in the gastrointestinal tract, the gastroretentive drug formulation comprising: i.) an inner layer or compartment comprising an active agent and a polymer; ii.) two membranes which together form an envelope around the inner membrane, each membrane comprising at least one polymer combination of a polymer insoluble in gastric fluid and a hydrophilic swelling polymer, and at least one plasticizer; and iii) one or two layers comprising an active agent and a soluble polymer, said layers for immediate release of said active agent and being attached to the outside of one outer membrane or the outside of both outer membranes or the outside of a portion of an outer membrane. Optionally, an additional layer may cover each immediate release film and include a powder or film that prevents the outer film or Immediate Release (IR) film from adhering to itself when folded within the capsule. In some embodiments, the immediate release film has surface properties that prevent adhesion to itself when folded within the capsule.

In a preferred embodiment, the gastroretentive drug formulation effectively unfolds and maintains its mechanical integrity for more than 24 hours under acidic pH conditions and is completely biodegradable after 3 hours in simulated intestinal fluid.

In one aspect, the polymer in the inner layer is a degradable polymer that is not immediately soluble in gastric fluid. In another aspect, the polymer is a degradable enteric polymer that is substantially insoluble in a solution having a pH of less than 5.5. The invention also concerns mixtures of the polymers described above.

In one embodiment, the enteric polymer in the inner layer is a polymethacrylate copolymer. In various embodiments, the enteric polymer is cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, or hydroxypropyl methylcellulose acetate succinate. In a preferred embodiment, the active agent and polymer are substantially uniformly distributed in the inner layer.

In another embodiment, the composition of the polymer of the outer membrane comprises a gel and hydroxypropyl methylcellulose acetate succinate as the enteric polymer. In one embodiment, the enteric polymer in the outer membrane is a type a polymethacrylate copolymer. In various embodiments, the enteric polymer in the outer film is a type C polymethacrylate copolymer. In further embodiments, the plasticizer in the outer film is propylene glycol.

In a preferred embodiment, the inner layer or compartment, the outer membrane and optionally the additional layer or immediate release layer are sealed by applying ultrasonic welding.

In further embodiments, the inner layer provides at least 50% of the mechanical strength of the overall GRDF when wetted by gastric juices. In a preferred embodiment, the gastroretentive drug formulation reaches its maximum strength within 1 hour of simulated gastric fluid. In another preferred embodiment, the inner layer has a planar accordion geometry that expands to at least 50% of its original length within 30 minutes in the gastric medium.

In one aspect, the gastroretentive drug formulation is completely degraded within 3 hours in simulated intestinal fluid. On the other hand, the gastroretentive drug formulation provides gastric retention for up to 24 hours under low or moderate calorie diet. In yet another aspect, the gastroretentive drug formulation moves within the stomach during gastric retention.

The gastroretentive drug formulation is designed for oral administration and is compressed or folded into a standard size capsule that is easily swallowed. The active ingredient or ingredients are incorporated in the gastroretentive drug formulation as dissolved substances in the formulation, powder, granules, spheroids, granules, microparticles, nanoparticles, multiparticulates, tablets or compositions of microcapsules.

In one aspect, the active agent has a narrow absorption window in the gastrointestinal tract. The active agent may be a therapeutic nucleic acid sequence, a therapeutic protein or peptide, an amino acid analog, a peptide drug, a nucleoside analog, an antibiotic, a therapeutic ion, a vitamin, a bronchodilator, an anti-gout agent, an anti-hypertensive agent, a diuretic, an anti-hyperlipidemia agent, an ACE inhibitor, an anti-neoplastic agent, a histamine (H2) blocker, a bismuth salt, or a synthetic prostaglandin. In one aspect, the active agent is levodopa and a levodopa/carbidopa mixture. Preferred antibiotic agents are selected from the beta-lactam group and the fluoroquinazolinone group.

In another aspect, the active agent is a drug for topical treatment in the gastrointestinal tract, such as: various drugs for the treatment of localized infections, or various drugs for the treatment of various diseases or conditions of the gastrointestinal tract, or various drugs for the treatment of metabolic disorders such as obesity, diabetes, high cholesterol, or various drugs for the treatment of localized cancer or cancer-related diseases. In a preferred aspect, the medicament comprises a serotonin-containing compound and another enteric neuromodulating, poorly absorbed substance, poorly absorbed antibiotic and compound, acting in the liver according to a predominant pharmacological location.

The foregoing general description and the following brief description of the drawings, as well as the detailed description, are exemplary and explanatory and are intended to provide further explanation of the invention as claimed. Other objects, advantages and novel features of the invention will become apparent to those skilled in the art from the following detailed description of the invention.

Drawings

Fig. 1 illustrates one embodiment of a GRDF design showing the overall GRDF and the planar dimensions of the inner layer.

Fig. 2A shows in cross-section (a) a cross-section of a single immediate release layer arranged on top of the outer portion. Fig. 2B shows in cross-section (B) that the immediate release layer covers the entire surface of the GRDF.

Fig. 3 shows the physical dimensions of the GRDF dosage forms illustrated in example 11.

Figure 4 shows the GRDF folded inside the capsule prior to placement of the capsule cap. The folds and their folding geometry can be seen.

Figure 5 provides calculations showing the mechanical properties of GRDF and a membrane cut into dog bone shapes. The photographs labeled 1, 2, 3 show the various stages of mechanical testing of the GRDF after immersion in Simulated Gastric Fluid (SGF). The graph in the upper right corner shows the results expressed in a load-displacement graph, wherein the various stages of the test correspond to the various stages shown in photographs 1, 2, 3, respectively.

Figure 6 shows the design of the anvil (a) and horn (B) of an ultrasonic welder used to join GRDF layers together.

Fig. 7 shows a diagram (a) of ultrasonic welding on a GRDF. The edge lines of the inner layer and the weld range (B) on the cross section providing the GRDF are shown with arrows.

Fig. 8 shows the GRDF after welding.

Figure 9 shows the dissolution profile of a combination of immediate release and controlled release carbidopa/levodopa GRDF.

Fig. 10 and 11 show the results of the measurement of the development of placebo GRDF in acetate buffer and SGF.

FIG. 12 shows gastric retention, IR + for a single dose of GRDF CD/LD75/300mg as described in example 7CR, single doseIR 100/25 mg and Single dose Sinemet25/100mg dose-adjusted carbidopa concentration mean.

FIG. 13 shows the results obtained in example 10 for GRDF CD/LD75/300mg, GRDF CD/LD 50/200mg andleast squares mean concentration of levodopa in blood samples over time with treatment of subjects with IR CD/LD 50/200 mg.

Detailed Description

Definition of

As used herein, "gastroretentive dosage form" refers to a dosage form that has delayed gastric emptying compared to food (or retention in the stomach exceeds retention of food).

"simulated gastric fluid" and "gastric media", and "simulated intestinal fluid" and "intestinal media", used interchangeably herein, refer to the media present in the stomach and intestinal tract, respectively, or to a solution used to simulate its chemical and/or enzymatic environment in vitro. One such medium is described in example 2.

The term "degradable" as used herein means capable of being chemically and/or physically reduced, dissolved or broken down in the body of a patient and over a corresponding period of time.

The phrase "polymer that is not immediately soluble in gastric fluid" as used herein means that the polymer will gradually dissolve during residence in the gastrointestinal tract.

The term "inert" as used herein means that the ingredients within the inner layer or compartment, outer membrane, optional layer and/or immediate release layer do not normally react with or affect the performance of the active ingredient or cause any biological effect upon administration to a subject.

The phrase "extended period of time" as used herein means a period of delivery that lasts from several hours to about 24 hours, typically over 5 hours, and often between 5 hours and 15 hours.

With respect to polymers, the terms "swellable" and "swelling" mean: the polymer is capable of absorbing liquid and expanding when in contact with liquid present in the environment of use.

The terms "active agent" and "drug" are used interchangeably herein to refer to an Active Pharmaceutical Ingredient (API), compound, composition of matter, and mixtures thereof that provides a therapeutic effect or a prophylactic effect.

Reference herein to a "patient" is to a human or non-human mammal that may be in need of receiving a gastroretentive drug formulation of the invention.

As used herein, "treating" or "treatment" refers to obtaining a desired pharmacological or physiological effect. The effect may be prophylactic in terms of: preventing or partially preventing a disease, symptom, or pathological condition, and/or treating a disease in: a partial or complete cure for a disease, disorder, symptom, or adverse effect caused by a pathological condition. Thus, "treatment" encompasses any treatment of a disease in a mammal, particularly a human, including: (a) preventing the occurrence of a pathological state in an individual who may have a predisposition to develop the pathological state but has not yet been diagnosed as having such a pathological state, i.e.: for a subject who may be predisposed to developing a pathological condition but who has not yet experienced or exhibited symptoms of that condition, not developing clinical symptoms of the pathological condition in vivo; (b) inhibition, i.e.: preventing or reducing the development of the pathological condition or its clinical symptoms; or (c) relieving symptoms associated with the pathological condition.

In a prior embodiment, the gastroretentive drug delivery system includes an inner layer and an outer layer. The outer layer is formed from two films which are slightly larger than the inner layer and which are sealed or welded together around their edges and completely surround the inner layer. With the outer layers being bonded and welded together, the outer portion of the inner layer is also welded to the outer layers.

Optionally, in the current embodiment, the gastroretentive drug delivery system includes an inner layer and an outer layer, and the outer layer is formed of two membranes, the membranes being of equal size to the inner layer and sealed or welded together around their edges and the outside of the inner layer. Optionally, the gastric retentive drug delivery system includes an additional layer that is larger than or equal in size to the inner/outer membrane assembly and wraps around the assembly to prevent the membrane from adhering to itself, which layer may be formed from one or more membranes, ultrasonically welded or otherwise attached or affixed to the assembly, and may optionally include an API. The ultrasonically welded or otherwise connected inner and outer layers are folded in an accordion arrangement and placed in the capsule. In some embodiments, the capsule is made from gelatin and hypromellose. The layers are shaped in a substantially elliptical polygonal shape such that they maximally fill the space within the capsule. Once the gel or hypromellose capsule is dissolved in the gastric medium, the inner and outer layers unfold from an accordion folded orientation to a more planar orientation.

Because the gastroretentive drug formulation of the present invention has the ability to withstand gastric motility and mechanical contractions, and thereby release the drug in a controlled manner to its site of absorption and not prematurely enter non-absorbed regions of the gastrointestinal tract, the gastroretentive drug formulation of the present invention significantly improves the absorption and bioavailability of suitable active agents, and in particular improves the absorption and bioavailability of drugs having a narrow absorption window in the gastrointestinal tract. The inventors have found that the gastric retentive drug formulation provides gastric retention of active agents with a narrow absorption window for up to 24 hours under low or moderate calorie diet, unlike other formulations in the art that require high calorie and high fat diets for proper functioning. In addition, administration of these dosage forms to mammals can improve the pharmacokinetic and pharmacodynamic properties of active agents with narrow absorption windows. Because gastroretentive drug dosage forms are fully degradable, they provide a means to administer the appropriate dose of drug without creating non-degradable residues that are not excreted after drug release.

Since the gastroretentive drug formulation incorporates an inner layer having a planar-accordion structure under which all components are completely biodegradable, the gastroretentive drug formulation is stable, completely degradable, and provides effective delivery of various drugs in the gastrointestinal tract. Combining an expanded outer membrane with a substantially non-expanding inner layer having a planar accordion structure allows the inner layer to undergo a process of deployment once the dosage form reaches the stomach, thereby prolonging gastric residence time and preventing the dosage form from emptying before being released in bulk or completely.

Sustained release gastroretentive drug dosage forms

According to a first embodiment of the present invention, a stable, degradable, multi-layered gastroretentive drug formulation for the sustained release of an active agent in the gastrointestinal tract is provided. The gastroretentive drug formulation includes: i.) an inner layer or compartment comprising an active agent, one or more polymers and one or more modifiers, such as plasticizers and/or solubilizers and/or fillers; ii.) two outer membranes, each membrane comprising at least one of a polymeric combination of a hydrophilic polymer and a polymer that is insoluble in gastric media, and at least one plasticizer; and iii) an optional additional layer covering each outer film and comprising a powder or film that prevents the outer film from adhering to itself.

According to another embodiment of the present invention, a degradable multi-layered gastroretentive drug formulation for the sustained release of an active agent can be combined with one or more immediate release layers covering the outer membrane and comprising an active agent, a polymer and optionally other excipients known in the art for the immediate release of an active agent to form a degradable multi-layered gastroretentive drug formulation for the combined immediate and sustained release of an active agent. The gastroretentive drug formulation of the present invention includes an optional additional layer covering each outer membrane and including a powder or film that prevents the outer membrane from adhering to itself. Additional disclosure regarding immediate release and controlled release dosage forms is provided below.

Inner layer

The inner layer or compartment of the gastroretentive drug formulation contains an active agent and a polymer substantially uniformly distributed on the inner layer. The polymer may be: a degradable hydrophilic polymer that is not immediately soluble in gastric fluid, a degradable enteric polymer that is substantially insoluble at a pH of less than 5.5, a hydrophobic polymer, or mixtures thereof. The inner layer may also include acceptable pharmaceutical additives such as plasticizers, humectants, fillers and other additives.

Examples of degradable hydrophilic polymers which are not immediately soluble in gastric fluid suitable for the present invention are hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyethylene oxide and methyl cellulose. Preferably, the enteric polymer is polymethacrylate copolymer, cellulose acetate phthalate, hypromellose acetate succinate or hypromellose phthalate. These polymers are combined with an active agent (e.g., levodopa and/or carbidopa). Exemplary ranges for the active agents and polymers are given in the table below.

Composition (I)	Range in the inner layer
		Carbidopa (Carbodopa)	5％-17％
Levodopa (Levodopa)	40％-65％
		Acrylic resin (Eudragit L100)	10％-35％
Poloxamer407 (Poloxamer407)	7％-19％
		Polyethylene glycol (PEG400)	4％-14％

Preferably, the inner layer has a planar accordion geometry. This geometric feature, together with the above-mentioned polymers in the inner layer or compartment, provides considerable mechanical strength to the inner layer. Preferably, the inner layer has a Young's modulus of about 0.5Kgf/mm²To 15Kgf/mm²Mechanical strength of (2). Preferably, the mechanical strength range may be about 3.0Kgf/mm²To about 10.0Kgf/mm²Or about 3.0Kgf/mm²To about 6.0Kgf/mm². The stress in simulated gastric fluid after 1 hour is about 0.03Kgf/mm²To about 0.6Kgf/mm²Such that the gastroretentive drug formulation reaches its maximum strength within 1 hour of simulated gastric fluid. Alternatively, the stress may range from about 0.05Kgf/mm²To about 0.4Kgf/mm²Or about 0.1Kgf/mm²To about 0.4Kgf/mm²。

The composition of the inner layer may be varied based on the characteristics of the active ingredient being delivered. For example, some active ingredients may be more soluble in some polymers than in others, and may require reformation of the inner layer. In some embodiments, the active ingredient may require the formation of an inner layer that is incapable of providing an effective weld between the inner layer and the outer membrane. In this case, the inner layer may be composed of two or more parts, each of which has a certain function. In one embodiment, the central region (free of welding) may be formulated from a separate film to hold the active ingredient and placed in the central portion and over an inner film, wherein the inner film includes additional portions that support the central portion. The additional portion may then be welded to the outer membrane. In further embodiments, although the inner layer may not be formulated to produce the necessary mechanical strength in the gastric media, at least one additional layer (optionally containing no drug) may be used as a stent, whereupon a formulated drug storage membrane may be placed and welded or otherwise attached or affixed to one or both sides of the stent, the assembly may be welded to the outer membrane or other component of the delivery system.

Outer film

Each outer membrane of the gastroretentive drug formulation comprises at least one polymeric combination of a hydrophilic polymer and a polymer insoluble in gastric media and at least one plasticizer.

Examples of suitable ingredients of the present invention include gelatin, hydroxypropylcellulose, pectin, polyethylene oxide, starch, and zein. Preferably, the hydrophilic polymer is a gel. The amount of gel in each outer membrane is between about 20% and about 45% of the total outer membrane composition, and preferably, between about 25% and about 35% of the total outer membrane composition.

Examples of enteric polymers that may be used in the outer film include hypromellose phthalate, hypromellose acetate succinate, and polymethacrylate copolymers. Preferably, the enteric polymer is a type a polymethacrylate copolymer or a type C polymethacrylate copolymer.

Plasticizers suitable for the present invention include various polyethylene glycols, glycerin, triethyl borate. Preferably, the plasticizer is propylene glycol.

The outer membrane swells in the presence of gastric fluid and completely degrades within 2 hours in simulated intestinal fluid. The combination of the swollen outer film layer with a non-swollen inner layer having a planar accordion geometry allows the inner layer to undergo a deployment process once the dosage form enters the stomach, thereby prolonging residence time in the stomach and preventing the drug-containing dosage form from being excreted before complete release. In one embodiment, the inner layer has an expansion ratio that is less than the expansion ratio of the membrane.

The membrane allows gastric media to pass from the environment to the inner layer and also allows active agents to pass from the inner layer to the environment through the outer membrane.

In some embodiments, such delivery dynamics may be slow and unacceptable. Thus, in some embodiments, one or more apertures may be perforated in the outer membrane to aid in the mass transfer process through the outer membrane. In a preferred embodiment, the apertures are evenly distributed in an area adjacent to the formulated drug layer.

In a preferred embodiment, the outer layer does not contain any active ingredient. In other embodiments, the outer layer comprises one or more active ingredients.

Optional additional layers

The gastroretentive drug formulation of the present invention may further comprise an optional additional layer covering each outer membrane and comprising a powder or film. In some embodiments, it may be found that the outer layers stick together in the capsule and do not properly unfold when the capsule dissolves. In such cases, the optional layer prevents the outer film from sticking to itself and allows the GRDF to properly unfold. In a preferred embodiment, the optional layer comprises at least one powder, and optionally at least one polymer. In other embodiments, the preferred polymer is a fast dissolving film former that may be selected from, but is not limited to: soluble cellulose derivatives, namely: methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose; povidone of various grades; polyvinyl alcohol and its derivatives, namely polyvinyl alcohol polyethylene glycol copolymers (kollicoat ir); soluble gums and others. The film may also include surfactants, plasticizers, and humectants.

Immediate release layer

The present invention also contemplates gastroretentive drug formulations that combine immediate release and controlled release of active agents in the gastrointestinal tract. These dosage forms comprise an inner layer or compartment and at least two outer membranes as described above, and further comprise one or more immediate release layers covering the outer membranes and comprising an active agent and a soluble polymer for immediate release of the active agent. Examples of soluble polymers useful for the immediate release may be selected from: soluble cellulose derivatives, namely: methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose; povidone of various grades; polyvinyl alcohol and its derivatives, namely polyvinyl alcohol polyethylene glycol copolymers (Kollicoat IR); soluble gums and other gums. The film may also contain surfactants, plasticizers, and humectants such as polyethylene glycol, various grades of polysorbate, and sodium lauryl sulfate.

The relative amounts of the polymers may be adjusted based on the solubility of the active ingredient.

Although the inner and outer layers are typically welded together, the immediate release layer typically does not require such a strong connection to the rest of the GRDF device. But rather allows the immediate release dosage form to rapidly dissolve to deliver the targeted drug. The immediate release layer may be affixed to the outside of the GRDF by a compatible solvent, ultrasonic welding, or some other means.

The ability to add an additional immediate release layer is particularly useful in the development of GRDFs. By combining the immediate release profile with the controlled release profile of the present invention, the drug release profile of the target drug can be modified. Thus, the patient may receive both an immediate bolus dose of the drug and an extended delivery of the active agent with the aim of quickly establishing a therapeutic level of the drug and maintaining said therapeutic level for an extended period of time, up to 24 hours.

Also of note is the ability to deliver multiple drugs through the GRDF of the present invention. Embodiments of the present invention are not limited to delivery of a single active agent. Rather, multiple drugs may be formulated and delivered simultaneously. By combining an immediate release layer and a controlled release layer, multiple drugs can be delivered simultaneously according to a specific release profile. For example, the examples provide a combined levodopa/carbidopa release dosage form.

All of the ingredients of the inner layer or compartment, outer membrane, optional layer and/or immediate release layer are pharmaceutically acceptable and inert.

Coating layer

As an additional method of delivering immediate release drugs, a coating may be applied over the drug-containing capsules. When entering the stomach, the coating will immediately allow release of the drug and improve the release profile of the drug. Methods for applying coatings to capsules are well known to those skilled in the art.

Ultrasonic welding

The inner layer or compartment, outer membrane, optional layer and/or immediate release layer may be interconnected by various means. Preferably, they are sealed by applying ultrasonic welding. An example of a device suitable for these purposes is a Dynamic 745 ultrasonic welder (Rinco Ultrasonics), although other devices may be used. The welding effectively seals the inner layer within the outer membrane by welding the outer layers together and also welding the edges of the inner layer to the outer layers. The welding may also effectively connect the layers to each other without the need to seal the entire envelope, which means that welding of the same material is not required if the dosage form is compatible.

Different patterns and times of welding may be used as desired by those skilled in the art. Although the edges of the layers may be welded together, embodiments of the present invention do not weld the central portion of the GRDF device to minimize heating or reaction on the main portion of the inner layer that retains the active agent for controlled release. In some cases, it may be necessary to weld more inner layers depending on the composition of the GRDF.

Capability of GRDF

The gastroretentive drug formulation is designed for oral administration and is compressed or folded into standard size capsules that are easily swallowed. The active ingredient or ingredients are incorporated into the accordion-like pill in the form of a powder, granules, spheroids, particles, microparticles, nanoparticles, multiparticulates, solid solution, tablet or microcapsules. Active agents that may be delivered using gastric retentive drug formulations include those that act at: peripheral nerves, adrenergic receptors, cholinergic receptors, skeletal muscles, the cardiovascular system, smooth muscles, the blood circulation system, climatic sites (synoptic sites), neuroeffector junctures, the endocrine and hormonal systems, the immune system, the reproductive system, the skeletal system, the digestive system, the histamine system, and the central nervous system. Particularly preferred are active agents for the treatment of gastrointestinal disorders including, but not limited to: duodenal ulcer, gastric ulcer, Zollinger-Ellison syndrome, gastroesophageal reflux disease, erosive esophagitis, gastritis, gastric cancer, and stomach spasm. In addition to other conditions known to those skilled in the art that can be delivered via gastric retentive devices, other indications are envisioned, such as cancer, infections and metabolic disorders.

For example, suitable active agents include: proteins, enzymes, enzyme inhibitors, hormones, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, peptides, polypeptides, steroids, hypnotics, sedatives, psychostimulants, tranquilizers, anticonvulsants, antidepressants, muscle relaxants, anti-parkinson agents, analgesics, immunosuppressive agents, anti-inflammatory agents, antihistamines, local anesthetics, muscle contractants, antimicrobials, antimalarials, antivirals, antibiotic agents, bronchodilators, antigout agents, antiobesity agents, antidiabetic agents, antihypercholesterolemic agents, hormonal agents (including: contraceptives), sympathomimetic agents, antihypertensive agents, diuretics, lipid regulating agents, ACE inhibitors, bismuth salts, synthetic prostaglandins, antiandrogenic agents, antiparasitic agents, neoplastic agents, antineoplastic agents, antihyperglycemic agents, hypoglycemic agents, nutritional supplements, Growth supplements, fats, ophthalmic drugs, anti-inflammatory agents, electrolytic agents, and diagnostic agents.

Preferably, the active agent has a narrow absorption window in the gastrointestinal tract. Antiviral, antifungal and antibiotic agents (including sulfonamides, quinolones, penicillins, cephalosporins, aminoglycosides, tetracyclines) are a typical class of drugs for active agents with a narrow absorption window in the gastrointestinal tract. Specific examples of drugs include, but are not limited to: cimetidine, ranitidine, famotidine, nizatidine, zolentine, metronidazole, tinidazole, amoxicillin, clarithromycin, minocycline, tetracycline, somatostatin analogues, and also carbidopa and levodopa.

Furthermore, for example, topically acting active agents are: drugs for the treatment of localized infections, drugs for the treatment of various gastrointestinal diseases and conditions, drugs for the treatment of metabolic disorders, drugs for the treatment of localized cancer or drugs for the treatment of cancer-related diseases. More specifically, in this regard, the active agents of interest are those which must be administered in the inflamed intestine when inflammatory bowel disease occurs, such as metronidazole, vancomycin, budesonide and others, and the very rapid emptying of the inflamed tissue of the active agent reduces its efficacy. These substances may be poorly absorbed systemically, such as vancomycin, or may be incorporated into targeted delivery systems, such as budesonide.

Other drugs that may be formulated in accordance with the present invention include those used in the treatment of Parkinson's disease. Parkinson's Disease (PD), one of the most common neurodegenerative diseases in the elderlyThe slowly progressive clinical symptoms are characterized by resting tremor, bradykinesia, muscle rigidity and gait instability. PD may also be associated with dysphagia, olfactory failure, dysphasia, depression and dementia. The pathogenesis of PD involves the degeneration of dopaminergic neurons within the substantia nigra pars compacta and the consequent loss of the neurotransmitter dopamine within the basal ganglia. Levodopa (LD) (decarboxylation to dopamine by the L-amino acid dopa decarboxylase LD enzyme within the CNS) is therapeutically used to replenish depleted dopamine reservoirs within the brain, since dopamine cannot cross the blood brain barrier. LD is considered the most therapeutically effective drug for the treatment of parkinson's disease. Decarboxylation can also occur in some cases in the nerve terminal region, even before levodopa reaches the brain. Levodopa is therefore usually administered together with an effective L-amino acid dopa decarboxylase inhibitor, such as carbidopa. Inhibiting the decarboxylation of levodopa in the nerve terminal region reduces dopamine formation in the nerve terminal region and reduces the side effects of dopamine production (i.e., orthostatic hypotension, nausea and vomiting), while increasing the bioavailability of levodopa in the CNS. Carbidopa/levodopa are commercially available as a combination product, both as immediate release tablets (e.g.Merck&Co., Inc.) or controlled release tablets (e.g., Sinemet-Merck&Co.，Inc.)。

The plasma half-life of LD in the absence of Carbidopa (CD) is approximately 50 minutes. When CD and LD are administered together, the half-life of LD increases to about 1.5 hours. In the steady-state of the process,the bioavailability of LD tablets of (a) is approximately 99%, which is associated with concomitant administration of carbidopa and LD.

Although LD is the most effective therapeutic agent for the treatment of Parkinson's disease, there is no limitation to the use of LDThere are also problems with the long-term use of drugs. In the early days, PD patients had good LD use and the patients produced a sustained response to each dose of LD. However, over time, the duration of the response decreases after each dose, resulting in a "fade" in which the drug does not function until the next dose reaches therapeutic levels. As the disease progresses, the patient will suffer a longer "OFF" period in which LD does not function. In addition, the disabling side effects of LD therapy are motor disturbances, usually due to peak doses. Both phenomena of progressive drug effect and dyskinesia are believed to be due to pulsatile stimulation of striated dopamine receptors and large differences between the peak and trough levels of dopamine. It would therefore be beneficial to provide sustained rather than pulsatile dopamine stimulation by treatment with controlled release products or by increasing the frequency of dosing. Currently available controlled release LD therapy (Sinemet)) Shows reduced bioavailability and efficacy of LD since LD is absorbed mainly in the upper intestinal tract and a sustained release product that has passed through the absorption area fails to work.

The GRDF dosage forms of the present invention maintain the controlled release of LD, i.e., the controlled release at or above the absorption zone (upper intestinal tract), with minimal peak/trough fluctuations, thereby providing the most beneficial treatment from a efficacy and safety profile standpoint.

The gastroretentive dosage forms of the present invention can conveniently release the active agent in a sustained form or a combination of immediate and sustained form over an extended period of time while maintaining high drug bioavailability over an extended period of time.

The details of the present invention are further illustrated by the following examples, which are provided for illustration only and should not be construed as limiting the scope of the invention. Variations of those embodiments and equivalent embodiments will be apparent to those skilled in the art from the description, drawings and claims disclosed herein.

Gastric retention in low and moderate calorie diets

Gastric retentive drug formulations retain their physical integrity for extended periods of time so that the active agent can be retained in the stomach for up to 24 hours on low or moderate calorie diets. It is advantageous to use a low or medium calorie diet because this is consistent with the patient's normal eating habits and does not require an excessive amount of diet in each GRDF administration. While GRDF can be retained in the stomach for extended periods of time, all components of GRDF are degradable and undergo complete breakdown once they reach the intestinal tract.

The invention is further illustrated by the following examples. The examples are illustrative only and are not intended to limit the invention to the specific embodiments described herein.

Examples

Example 1: ultrasonic welding of GRDF

For welding the film layers of the GRDF, a Dynamic 745 ultrasonic welder from Rinco Ultrasonics was used, using the following parameters:

ultrasonic welding parameters
		Flip-flop	275N
Lift of trigger force	380N/s
		Time of fusion	650ms
Lift of trigger force	600N/s
		Amplitude of vibration	9
Curing force	600N
		Dwell time	600ms

Fig. 6 and 7 show the design of the anvil and horn of an ultrasonic welding machine for welding the film layers of GRDF together. In addition, a cross-sectional view of the weld area is provided. Fig. 8 shows an enlarged picture of a portion of a GRDF ultrasonically welding outer layers to each other to form an envelope surrounding the inner layers. The weld between the edge portion of the inner layer and the outer layer can also be seen.

Example 2: development of GRDF

The following data indicate: the GRDF of the present invention deploys in a short period of time and does not pass through the stomach as quickly before the active ingredient is released and deployed. The following experiments were performed with placebo GRDF first encapsulated and then placed in SGF pH 1.2 or acetate buffer (USP) pH 4.1(USP Apparatus 2, 50 rpm). GRDF was visually checked after 15 minutes. Further, the length of the accordion sheet along its longest dimension was measured after 30 minutes, 60 minutes, and 120 minutes in the medium. A completely flat device has a length of 45 mm. See fig. 10 and 11 for results. The device took 30 minutes to deploy. Visual inspection at 15 minutes showed: the pill has dissolved and the device has expanded to about the same size as seen at 30 minutes.

Example 3: mechanical Properties of GRDF

The mechanical properties of the GRDF and its film layers were tested. The results are shown in FIG. 5. To determine their mechanical properties, intact GRDF and dog-bone cut samples were tested. Values for strain, load, stress and young's modulus are given.

Example 4: degradability of GRDF

The following results show that the GRDF of the present invention biodegrades completely once it enters an environment similar to the intestinal tract. Four GRDF devices were placed in simulated intestinal fluid (USP SIF) and examined every hour for three hours. The device is not first loaded into a pill, but is directly loaded with SIF. After three hours, the device had dissolved.

Example 5: carbidopa-levodopa GRDF dosage form

The inner, outer and immediate release layers of the GRDF made were of the following composition:

example 6: carbidopa-levodopa GRDF release profile

To illustrate the ability of the GRDF to provide both immediate and controlled release of the active ingredient, the release profile of the carbidopa-levodopa GRDF (example 5) described above was determined. Carbidopa and levodopa account for 75mg and 300mg, respectively, of the total amount. Specifically, carbidopa contains 30mg in the immediate release layer and 45mg in the inner layer provided to the patient as a controlled release. For levodopa, there were 100mg in the immediate release layer and 200mg in the inner layer.

The experiment was performed in acetate buffer (USP) pH 4.1, USP apparatus 2 at 50 rpm. As shown in fig. 9, both drugs were released immediately within 1 hour and an extended release was seen for 8 hours.

These experiments show the ability of the GRDF of the present invention to effectively deliver one or more drugs simultaneously. If delivered simultaneously, the drug may be concentrated in the immediate release layer and the controlled release layer to provide the desired release profile and release characteristics in the same system.

Example 7: comparison of the pharmacokinetic Profile and immediate Release of carbidopa/Levodopa GRDF in healthy personsAnd controlled release SinemetPharmacokinetic profile of

Study of

A three-way crossover study was performed in healthy subjects to evaluate the pharmacokinetic profile of single doses of the two GRDF levodopa/carbidopa (LD/CD) dosage forms. GRDF LD/CD (dosage form in example 5) in single dose (containing 300mg of levodopa and 75mg of carbidopa) taken after meal for male healthy people and(containing 100mg of levodopa, 25mg of carbidopa) and Sinemet(containing 200mg of levodopa and 50mg of carbidopa) were compared.

Pharmacokinetic properties of levodopa

The plasma half-life of levodopa in the absence of carbidopa is about 50 minutes. When carbidopa and levodopa are administered together, the half-life of levodopa increases to about 1.5 hours. At steady state, relative to concomitant administration of carbidopa and levodopa,the bioavailability of carbidopa in the tablet is about 99%.

Carbidopa inhibits levodopa decarboxylation in the nerve ending region. It cannot cross the blood brain barrier and affect the metabolism of levodopa within the central nervous system.

Carbidopa reduces the amount of levodopa required to produce a given response by approximately 75%, and when administered with levodopa, increases plasma levels and plasma half-life of levodopa, and reduces dopamine and homovanillic acid in plasma and urine.

In clinical pharmacology studies, the simultaneous administration of two drugs, carbidopa and levodopa, produced a greater ratio of urinary excretion of levodopa to dopamine excretion than the separate administration of the two drugs.

Patients treated with levodopa for parkinson's disease may experience fluctuations in symptoms manifested as terminal relapse, peak movement disorders, and akinesia. The late form of symptom fluctuation (the "on-off" phenomenon) is manifested as an unpredictable swing between activity and immobility. Although the cause of the fluctuation in symptoms is not fully understood, in some patients the fluctuation in symptoms can be attenuated by a treatment regimen that results in stable levodopa plasma levels.

Currently levodopa/carbidopa (Sinemet)) The dosage form provides a controlled release of the ingredients for 4 to 6 hours. However, sustained release products of this combination have a systemic bioavailability (70% to 75%) that is lower than that of immediate release products (99%), and an increase in the daily dose may be required to achieve the same degree of relief. For a total daily dose of 300mg to 400mg of levodopa, typically the initial dose of LD/CD is 100mg of levodopa, 25mg of carbidopa, 3 to 4 times a day.

For the purposes of the study, a total daily dose of 600mg of levodopa was planned using GRDF CD/LD75/300 mg.

Since gastric retention (food retention) can be achieved by eating high fat, high calorie food, the true gastric retention is assessed on healthy people eating low calorie breakfast.

Product(s)

A.Reference product

Product(s)

Administration dosage 25/100(1 tablet)

Immediate release of the active ingredient carbidopa/levodopa

Dosage form tablet

The concentration is 100mg/25mg

Manufacturer MERCK & CO, INC

B.Reference product

Product Sinemet

Administration dosage 50/200(1 tablet)

Controlled release of the active ingredient carbidopa/levodopa

Dosage form tablet

The concentration is 25/100mg

Manufacturer MERCK & CO, INC

C.Reference product

GRDF CD/LD product

Administration dosage 75/300

Controlled release of the active ingredient carbidopa/levodopa

Dosage form capsule

The concentration is 75/300mg

Treatment of

Single-center, open, single-dose, three-way crossover pharmacological study was conducted in 24 male healthy individuals between the ages of 18 and 55. Adult healthy subjects participated in 3 study days with a buffer period of at least 1 week between each study day.

All oral dosage forms were swallowed whole with 240ml of water after a simple breakfast. All healthy subjects were offered a standard meal throughout the study day.

Venous blood samples were taken prior to dosing and the pharmacokinetic properties of the drugs were then frequently compared. Plasma levels of levodopa were analyzed.

The results of the study are shown in figure 12 and the following table.

Results of levodopa

For the log transformed data (Ln) LSmeans is the geometric mean and the ratio is the geometric mean ratio.

AUC＝AUC0-t

MRT ═ average residence time (hours)

DA-indicating parameters Adjusted to 300mg according to Dose (Dose-Adjusted)

CV% -estimated fluctuation parameter in the subject

P < 0.05, blank indicates p > 0.05 (adjusted for multiple pairings comparison)

The results show that: GRDF LD/CD has an extended retention time in the stomach and a controlled release of the active ingredient lasting 5 hours compared to the reference product. GRDF LD/CD provides prolonged release of the active ingredient at a site above its absorption window and improved bioavailability with little fluctuation in plasma levels, thereby providing stable levodopa and carbidopa plasma levels.

It is known that patients treated with levodopa for parkinson's disease may experience fluctuations in symptoms manifested by end-of-dose recurrence, peak-of-dose dyskinesia, and akinesia. These symptoms can be reduced by creating a treatment regimen that stabilizes the plasma levels of levodopa. GRDF LD/CD satisfies the need for an immediate release mechanism in combination with a controlled release mechanism of LD/CD by providing rapid rise and stable levodopa and carbidopa levels, which combination provides stable levodopa and carbidopa levels, resulting in lower daily doses and better patient response and compliance.

Example 8: gastric retention efficacy of GRDF formulations in healthy and Parkinson's patients

To determine the gastric retention efficacy of GRDF dosage forms, various clinical trials of placebo GRDF were conducted using MRI. The drug storage layer of the GRDF studied in these experiments did not contain active ingredients. Instead, the drug storage layer contains iron oxide food color (sicovit black el 72) that is visible in Magnetic Resonance Imaging (MRI).

The results of these MRI studies indicate that: the GRDF dosage forms remained in the stomach for 7 to 13 hours in healthy volunteers, while the GRDF dosage forms remained in the stomach for 7 to 24 hours in parkinson's patients.

Example 9: carbidopa-levodopa GRDF dosage form

Three additional GRDF dosage forms were also prepared.

	mg/GRDF
		Levodopa	200.0
Carbidopa	50.0
		Potassium hydroxide	6.0
Propylene glycol	94.2

Gel (Fish glue)	94.2
		Polyacrylic resin L100-55	23.5
Polyacrylic resin L100	184.4
		Polyacrylic resin S100	47.1
Polyethylene glycol 400	13.1
		Tween 80	11.8
Polyvinylpyrrolidone (Colidyne) 90F	13.7
		Lutrol F127 (Poloxamer407)	89.3
Total amount of	827.3

Example 10: comparing carbidopa/levodopa GRDF immediate and controlled release profile to immediate release profile in healthy subjectsAnd controlled release SinemetPharmacokinetic properties of

Purpose of study

The purpose of this study was to evaluate the best characteristic curve of GRDF CD/LD by: comparing the pharmacokinetic profiles of levodopa and carbidopa after oral single dose of three different controlled release GRDF CD/LD dosage forms with different release profile ranges (example 9) with single dose reference dosage forms: (50/200mg administered as two tablets 25/100mg IR tablets). Additional objectives were to monitor the subject for adverse events during the study and to compare the safety of the test and reference dosage forms.

Design of research

The study was designed as a single-center, randomized, single dose, open, four-way crossover, four-treatment (four-treatment), comparative crossover study. The study included four identical dosing cycles, each cycle including one carbidopa pretreatment day and one study drug dosing day during which a single dose of one of the test dosage forms or the reference drug was taken after a light and medium calorie breakfast. The dosing was followed by pharmacokinetic blood sampling and monitoring for adverse events lasting 24 hours. After a meal, a single dose of GRDF CD/LD (containing 200mg or 300mg of levodopa, 50mg or 75mg of carbidopa) was administered to 24 healthy male people between the ages of 18 and 55 years. And preparing a medical advice type administration table with the total daily dose of the levodopa of 400-600 mg for the GRDF CD/LD. The GRDF CD/LD is formulated to release both of its active ingredients in immediate release and controlled release combinations to provide rapid and stable levodopa levels. Because protein competes with levodopa absorption, this study tested the pharmacokinetic profile of gastric retention controlled release GRDF CD/LD after low protein content, medium to low calorie breakfast.

Product(s)

Test product GRDF CD/LD

The dosage is 75/300mg, or 50/200mg

The active ingredient carbidopa/levodopa, IR + CR

Dosage form capsule

The 75/300mg dose was tested in two dosage forms (a and b) and the 50/200mg dose was tested in one dosage form.

Reference productTablet (carbidopa/levodopa 25/100mg)

Taking 50mg carbidopa and 200mg levodopa (25/100mg two-piece tablet)

Immediate release of the active ingredient carbidopa/levodopa

Dosage form tablet

Manufacturer MERCK & CO, INC

Carbidopa pretreatment

The dosage is 50mg (two tablets) three times a day (-1)

Carbidopa as active ingredient

Dosage form tablet

Manufacturer MERCK & CO, INC

The subjects were randomly assigned to unique treatment groups.

Study procedure

The study drug was swallowed whole with 240ml of water at room temperature. Each subject will experience a buffer period of at least 7 days between each treatment.

To measure the plasma levels of carbidopa and levodopa during each study, 17 consecutive blood samples were taken per subject. Pharmacokinetic data of levodopa were calculated.

Results of levodopa

The results for levodopa were shown in figure 13 and the following graph for 21 volunteers.

90% confidence interval for ratio of least squares geometric means

The results show that gastroretentive controlled release delivery of levodopa produces true controlled release behavior. As expected, both gastroretentive dosage forms showed similar bioavailability, somewhat inferior to the low dose GRDF and the immediate release dosage forms. The mean residence time of the gastroretentive controlled release product is increased by two times or more compared to the immediate release dosage form. There is clearly no proportional relationship between Cmax and dose, and this is consistent with true controlled release behavior.

Example 11: carbidopa-levodopa GRDF dosage form

Two other GRDF formulations were also prepared, with the inner, outer and immediate release layers using the following ingredients:

example 12: carbidopa-levodopa GRDF release profiles

To illustrate the ability of the GRDF to provide both immediate and controlled release of the active ingredient, the release characteristics of both of the above GRDF dosage forms were determined. Carbidopa and levodopa accounted for 50mg and 250mg or 50mg and 375mg, respectively, in total (example 11). Specifically, there is 25mg of carbidopa in the immediate release layer and 25mg of carbidopa in the inner layer provided to the patient in a controlled release manner. For levodopa, 70mg or 100mg in the immediate release layer and 180mg or 275mg in the inner layer.

The experiment was performed in acetate buffer (USP) at pH 4.1(USP Apparatus 2, 50 rmp). The immediate release of both drugs occurred within 1 hour, while the extended release for levodopa of 250mg lasted for 12 hours and the extended release for levodopa of 375mg lasted for 16 hours.

Claims (40)

1. A degradable, multi-layered gastroretentive drug formulation for the sustained release of an active agent in the stomach and gastrointestinal tract of a patient, comprising:

an inner layer comprising an active agent and a degradable polymer composition that is not immediately soluble in gastric media, the inner layer comprising a first face and an opposing second face; and

at least one outer membrane covering the inner layer, the outer membrane comprising at least one polymer combination of a hydrophilic polymer and a polymer that is insoluble in gastric media, the outer membrane hydrating at a greater rate than the inner layer and the outer membrane swelling in the presence of gastric media;

said outer membrane being secured directly to and covering both sides of said inner layer and having a predetermined length in a planar orientation greater than 20 millimeters, said outer and inner membranes being arranged in an accordion folded orientation sufficiently compacted to be disposed within a capsule dissolvable in the stomach;

the outer membrane and inner layer develop sufficient mechanical force to unfold from the original accordion folded orientation to a length of at least 20 mm within 30 minutes of exposure to gastric media,

said outer membrane allowing passage of gastric media from the environment to said inner layer and allowing passage of said active agent from said inner layer through said outer membrane to the environment,

wherein the active agent and the degradable polymer composition are uniformly distributed throughout the inner layer;

wherein the inner layer provides at least 50% of the mechanical strength of the entire gastroretentive drug dosage form when wetted by gastric media;

wherein the active agent is carbidopa and/or levodopa;

the degradable polymer composition which is not immediately dissolved in gastric media is a degradable enteric polymer which is not soluble in a solution with a pH value less than 5.5, and the degradable enteric polymer is any one of polymethacrylate copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate or hydroxypropyl methylcellulose acetate succinate;

wherein the hydrophilic polymer is any one of gel, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, pectin, polyethylene oxide, starch and zein; and

wherein the polymer insoluble in gastric media is an enteric polymer, and the enteric polymer is any one of polymethacrylate copolymer, hypromellose phthalate and hypromellose acetate succinate.

2. The gastroretentive drug formulation of claim 1, wherein the membrane and internal layer expand to a length of at least 20 millimeters within 15 minutes of exposure to gastric media.

3. The gastroretentive drug formulation of claim 1, wherein the mechanical strength of the inner layer is described by young's modulus ranging from 0.5 to 15kgf/mm and the stress of the inner layer after 1 hour in simulated gastric media is 0.03 to 0.6 kgf/mm.

4. The gastroretentive drug formulation of claim 1, wherein the membrane comprises two separate membranes, each membrane being directly joined together along its outer edges, the entire inner layer being located entirely between the membranes, the membranes being secured to the inner layer along a portion of at least one surface of the inner layer.

5. The gastroretentive drug formulation of claim 4, wherein the membranes are joined together by ultrasonic welding.

6. The gastroretentive drug formulation of claim 5, wherein the membrane is ultrasonically welded to the inner layer along the vicinity of the outer edge of the inner layer.

7. The gastroretentive drug formulation of claim 6, wherein the middle of the surface of the inner layer is substantially free of ultrasonic welding.

8. The gastroretentive drug formulation of claim 4, wherein the inner layer and membrane do not require additional adhesive components.

9. A degradable, multi-layered gastroretentive drug formulation for the sustained release of an active agent in the stomach and gastrointestinal tract of a patient, comprising:

an inner layer comprising an active agent and a degradable polymer composition that is not immediately soluble in gastric media, the inner layer comprising a first face and an opposing second face; and

a first membrane and a second membrane covering the inner layer, the membranes comprising at least one polymer combination of a hydrophilic polymer and a polymer that is insoluble in gastric media, the membranes hydrating at a greater rate than the inner layer;

the width and length of the first and second films are greater than the width and length of the inner layer;

the first and second films being ultrasonically welded or otherwise affixed or joined directly together at their edges, the first film being joined to the first face of the inner layer and the second film being joined to the second face of the inner layer;

the inner layer and the first and second films are disposed in a planar orientation for a predetermined length greater than 20 millimeters, the films and inner layer being arranged in an accordion folded orientation sufficiently compacted to be disposed within a capsule dissolvable in the stomach;

the ultrasonic weld has sufficient mechanical strength to leave the dosage form intact when exposed to gastric media;

wherein the active agent is carbidopa and/or levodopa;

the degradable polymer composition which is not immediately dissolved in gastric media is a degradable enteric polymer which is not soluble in a solution with a pH value less than 5.5, and the degradable enteric polymer is any one of polymethacrylate copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate or hydroxypropyl methylcellulose acetate succinate;

wherein the hydrophilic polymer is any one of gel, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, pectin, polyethylene oxide, starch and zein; and

wherein the polymer insoluble in gastric media is an enteric polymer, and the enteric polymer is any one of polymethacrylate copolymer, hypromellose phthalate and hypromellose acetate succinate.

10. The gastroretentive drug formulation of claim 1, wherein the inner layer and first and second outer layers comprise a central portion that is substantially free of ultrasonic welding.

11. The gastroretentive drug formulation of claim 1, wherein the ultrasonic weld performed between the membrane and the inner layer does not penetrate completely through the inner layer.

12. The gastroretentive drug formulation of claim 11, wherein the ultrasonic weld pattern between the membrane and inner layer is discontinuous.

13. The gastroretentive drug formulation of claim 12, wherein ultrasonic welding at the membrane edge forms a skirt region that surrounds but does not occupy the inner layer.

14. The gastroretentive drug formulation of claim 13, wherein the inner layer and first and second outer layers comprise a central portion that is substantially free of ultrasonic welding.

15. The gastroretentive drug formulation of claim 11, wherein the ultrasonically welded inner layer and membrane have a mechanical strength described by young's modulus of 0.05 to 0.4kgf/mm after 1 hour in simulated gastric media.

16. The gastroretentive drug formulation of claim 15, wherein the membrane and internal layer expand to a length of at least 20 millimeters within 15 minutes of exposure to gastric media.

17. The gastroretentive drug formulation of claim 16, wherein the length of the membrane in the planar orientation is at least 30 millimeters.

18. The gastroretentive drug formulation of claim 1, wherein the gastroretentive drug formulation is fully degradable within 3 hours in simulated intestinal fluid.

19. The gastroretentive drug formulation of claim 1, wherein the gastroretentive drug formulation provides gastric retention of an active agent for up to 24 hours in the presence of low or moderate calorie diet in humans.

20. The gastroretentive drug formulation of claim 1, wherein at least one additional layer is affixed to the outer membrane on one or both sides of the gastroretentive drug formulation and the additional layer comprises a drug or combination of drugs and one or more additives selected from: water-soluble polymers, plasticizers, solubilizers for immediate release of the drug in the stomach, disintegrants and glidants.

21. The gastroretentive drug formulation of claim 1, wherein the formulation comprises 250mg of levodopa and 50mg of carbidopa as active agents.

22. The gastroretentive drug formulation of claim 21, wherein 70mg of levodopa and 25mg of carbidopa are formulated as an immediate release component, while the remaining carbidopa and levodopa are released in a controlled release manner over 8 to 10 hours.

23. The gastroretentive drug formulation of claim 1, wherein the formulation comprises 375mg levodopa and 50mg carbidopa as active agents.

24. The gastroretentive drug formulation of claim 23, wherein 100mg of levodopa and 25mg of carbidopa are formulated as immediate release ingredients, while the remaining carbidopa and levodopa are released in a controlled manner over 8 to 10 hours.

25. The gastroretentive drug formulation of claim 1, wherein the internal compartment comprises a layer acting as a strut to increase the mechanical strength of the formulation and to one or both sides of which an additional layer or layers containing an active ingredient or some active and inactive ingredients and intended for the controlled release of the drug are attached, wherein these layers are covered by and sandwiched between two outer membranes according to the above claims.

26. The gastroretentive drug formulation of claim 1, wherein the inner layer and the at least one membrane are effectively unfolded from an accordion folded orientation and stable at acidic pH for up to 24 hours and then completely degraded after 3 hours in simulated intestinal fluid.

27. The gastroretentive drug formulation of claim 1, wherein the inner layer provides at least 50% of the mechanical strength of the welded inner layer and membrane when wetted by gastric media.

28. The gastroretentive drug formulation of claim 1, which is designed for oral administration and is compacted or folded into a standard size capsule that is easy to swallow.

29. The gastroretentive drug formulation of claim 1, wherein the active agent is incorporated in the inner layer in the form of one or more of solid solutions, powders, granules, spheroids, granules, microparticles or microcapsules.

30. The gastroretentive drug formulation of claim 29, wherein the particles are selected from: nanoparticles and multiparticulates.

31. The gastroretentive drug formulation of claim 1, wherein the active agent is levodopa.

32. A biodegradable, multi-layered gastroretentive drug formulation for the sustained release of an active agent in the gastrointestinal tract, comprising:

an inner layer comprising an active agent, a degradable hydrophilic polymer, a degradable enteric polymer that is substantially insoluble at pH values less than 5.5, and a plasticizer, at least one outer membrane covering the inner layer, the inner layer comprising a first face and an opposing second face, the outer membrane comprising at least one of a polymer combination of a hydrophilic polymer and a polymer that is insoluble in gastric media and at least one plasticizer, the at least one outer membrane hydrating at a greater rate than the inner layer, the outer membrane swelling in the presence of gastric media;

one of the materials of each of the inner layer and the outer film may be ultrasonically welded together;

said outer membrane being secured directly to and covering both sides of said inner layer and having a predetermined length greater than 20 mm in a planar orientation, said outer membrane and inner layer being arranged in an accordion folded orientation, sufficiently compacted to be placed within a capsule dissolvable in the stomach, said outer membrane allowing passage of gastric media from the stomach to said inner layer and allowing passage of gastric media and said active agent from said inner layer through said outer membrane to the stomach;

the outer membrane and inner layer generate sufficient mechanical force to unfold from the accordion folded orientation to a length of at least 20 millimeters within 30 minutes of exposure to gastric media,

wherein the active agent and the degradable polymer composition are uniformly distributed throughout the inner layer;

wherein the inner layer provides at least 50% of the mechanical strength of the entire gastroretentive drug dosage form when wetted by gastric media;

wherein the active agent is carbidopa and/or levodopa;

the degradable polymer composition which is not immediately dissolved in gastric media is a degradable enteric polymer which is not soluble in a solution with a pH value less than 5.5, and the degradable enteric polymer is any one of polymethacrylate copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate or hydroxypropyl methylcellulose acetate succinate;

wherein the hydrophilic polymer is any one of gel, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, pectin, polyethylene oxide, starch and zein; and

wherein the polymer insoluble in gastric media is an enteric polymer, and the enteric polymer is any one of polymethacrylate copolymer, hypromellose phthalate and hypromellose acetate succinate.

33. The gastroretentive drug formulation of claim 32, wherein the outer membrane is a gel.

34. The gastroretentive drug formulation of claim 32, wherein the enteric polymer in the outer membrane is selected from one or more types of polymethacrylate USP.

35. The gastroretentive drug formulation of claim 32, wherein the outer membrane comprises propylene glycol as a plasticizer.

36. The gastroretentive drug formulation of claim 33, wherein the amount of gel in the outer membrane is between 20% and 45% of the total composition of the outer membrane.

37. The gastroretentive drug formulation of claim 32, wherein the internal layer has a mechanical strength described in young's modulus of 0.5 to 15kgf/mm and a stress of 0.03 to 0.6kgf/mm after 1 hour in simulated gastric media.

38. The gastroretentive drug formulation of claim 32, wherein the outer membrane swells at a faster rate than the inner layer, causing the accordion folded outer and inner membranes to unfold in gastric media.

39. The gastroretentive drug formulation of claim 38, wherein the outer membrane is tightly affixed or connected to the inner layer to apply a force that causes deployment, the outer membrane swelling at a faster rate than the inner membrane such that the accordion folded outer and inner layers deploy in the gastric medium.

40. A biodegradable, multi-layered gastroretentive drug formulation for the sustained release of an active agent in the gastrointestinal tract, comprising:

an inner layer comprising an active agent, a degradable hydrophilic polymer that is not immediately soluble in gastric media, a degradable enteric polymer that is substantially insoluble at a pH of less than 5.5, and a plasticizer, the inner layer comprising a first face and an opposing second face; and

a first film and a second film covering the inner layer, the films comprising at least one of a polymer combination of a hydrophilic swelling polymer and an enteric polymer and at least one plasticizer, the films hydrating at a greater rate than the inner layer, the films swelling in the presence of gastric media;

one of the respective materials of the inner layer and the membrane can be ultrasonically welded together;

said membrane being secured directly to and covering both sides of said inner layer and having a predetermined length in a planar orientation greater than 20 mm, said membrane and inner layer being arranged in an accordion folded orientation sufficiently compacted to be placed within a capsule dissolvable in the stomach;

the membrane and inner layer generate sufficient mechanical force to unfold from the accordion folded orientation to a length of at least 20 millimeters within 30 minutes of exposure to gastric media;

the width and length of the first and second films are greater than the width and length of the inner layer;

the first and second membranes being ultrasonically welded directly together at their edges, the first membrane being ultrasonically welded to the first face of the inner layer, the second membrane being ultrasonically welded to the second face of the inner layer, the membranes allowing passage of gastric media from the stomach to the inner layer and allowing passage of gastric media and the active agent from the inner layer through the membranes to the stomach;

the inner layer and the first and second films are disposed in a planar orientation for a predetermined length greater than 20 millimeters, the films and inner layer being arranged in an accordion folded orientation sufficiently compacted to be disposed within a capsule dissolvable in the stomach;

the ultrasonic weld has sufficient mechanical strength to remain intact when the dosage form is exposed to gastric media,

wherein the active agent and the degradable polymer composition are uniformly distributed throughout the inner layer;

wherein the inner layer provides at least 50% of the mechanical strength of the entire gastroretentive drug dosage form when wetted by gastric media;

wherein the active agent is carbidopa and/or levodopa;

the degradable polymer composition which is not immediately dissolved in gastric media is a degradable enteric polymer which is not soluble in a solution with a pH value less than 5.5, and the degradable enteric polymer is any one of polymethacrylate copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate or hydroxypropyl methylcellulose acetate succinate;

wherein the hydrophilic polymer is any one of gel, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, pectin, polyethylene oxide, starch and zein; and

wherein the polymer insoluble in gastric media is an enteric polymer, and the enteric polymer is any one of polymethacrylate copolymer, hypromellose phthalate and hypromellose acetate succinate.