WO2020011945A1

WO2020011945A1 - Floating gastric retentive drug delivery system

Info

Publication number: WO2020011945A1
Application number: PCT/EP2019/068743
Authority: WO
Inventors: Karl G. Wagner; Fabian Josef SIMONS
Original assignee: Rheinische Friedrich-Wilhelms-Universität Bonn
Priority date: 2018-07-11
Filing date: 2019-07-11
Publication date: 2020-01-16
Also published as: EP3820442A1

Abstract

The present invention relates to a floating gastric retentive drug delivery system, which has a density below 1 g/cm3, and which has the form of a closed hollow body, the hollow body being formed from a release sustaining matrix of a polymer component comprising an active ingredient dispersed therein, wherein the hollow body comprises the active ingredient in an amount in a range of ≥ 45 weight % to ≤ 85 weight %, based on a weight of 100 weight % of the hollow body.

Description

Floating gastric retentive drug delivery system

B e s c h r e i b u n g

The present invention relates to a gastroretentive dosage systems, in particular to a floating drug delivery system which remains buoyant for a sufficient period of time in the stomach. Further, the invention relates to the process of preparation thereof.

Due to the ease of administration and patient compliance, the oral route remains the most preferred route of administration. Many drugs of central therapeutic importance, such as levodopa (Parkinson), metformin (diabetes) or gabapentin (neuropathic pain) however have an absorption window in the upper small intestine area. An improvement in pharmacotherapy through a standard retardation over the entire gastrointestinal tract is therefore not possible, and a retardation needs to be achieved by prolonging the gastric residence time. Various approaches of gastro-retention to prolong the gastric residence time are available, such as bioadhesive systems, swelling systems, and floating drug delivery systems. The

mucoadhesive systems are intended to extend the gastric residence time by adhering the drug to the gastric mucous membrane. Swelling systems contain and reach a significantly larger size in the stomach due to swelling or unfolding processes that prolong their time in the gastrointestinal tract. Buoyancy is considered one of the most promising approaches for gastro-retention. Floating drug delivery systems have an apparent density < 1 g/cm³, i.e. less than gastric fluids, and so remain buoyant in the stomach for a prolonged period of time. While the system is floating on the gastric contents, the drug is released slowly at the desired rate from the system. The floating drug systems can further be classified into porous systems, hollow capsule dosage forms, gas generating systems and hydrodynamically balanced systems. The buoyancy of these systems however is attained by the aid of substances responsible to generate the low density. These approaches have in common that an adjuvant additive is necessary to form a gastric retentive system, which at the same time influences the drug release, thus rendering not only formulation development more complex but also the release mechanisms. In addition, more adjuvants lower the drug loading which results in that many systems are usable only for low-dose drugs.

EP 1 513 508 Bl describes a process for producing an oral sustained release drug delivery system for retention in the stomach, the method comprising an extrusion of a mix of hydratable polymer and active ingredient using an extrusion mould designed to provide an extrudate which is a hollow tube, and cutting the extrudate to give sealed tubes.

The gastric retentive dosage forms of the prior art are not satisfactory in every respect and there is a demand for improved gastric retentive dosage forms. The object of the present invention is therefore to provide a floating, gastric retentive drug delivery system, which does not suffer from the above disadvantages.

The object is achieved by a floating gastric retentive drug delivery system according to claim 1, and a method of preparing a floating gastric retentive drug delivery system according to claim 12, and a floating gastric retentive drug delivery system manufactured by the process according to claim 14 and 15. Advantageous embodiments are the subject of the dependent claims. The embodiments may be combined freely unless the context clearly indicates otherwise. Accordingly, a floating, gastric retentive drug delivery system is provided, the floating gastric retentive drug delivery system having a density below 1 g/cm³, and having the form of a closed hollow body, the hollow body being formed from a release sustaining matrix of a polymer component comprising an active ingredient dispersed therein, wherein the hollow body comprises the active ingredient in an amount in a range of > 45 weight% to < 85 weight%, based on a weight of 100 weight% of the hollow body.

It has surprisingly been found that a floating gastric retentive drug delivery system having a high active substance loading can be provided. Advantageously, due to the shape of the hollow cylinder the swimming behavior of the floating gastric retentive drug delivery system is not depending on the properties of mixture of active ingredient and polymer. The floating gastric retentive drug delivery system has an apparent density below 1 g/cm³, i.e. below the density of gastric fluid, and thus floats immediately. The density is provided by the cavity of the closed hollow body. It is a significant advantage that it is possible to vary the release profile of the system without changing the buoyancy. It could be shown that a wide range of release profiles between 1 and 12 hours for the drug metformin with various polymers could be achieved. Further, the matrix-controlled release provides that while maintaining the geometric ratios of the hollow body, the dose of the active ingredient can be varied without varying the release profile. A sustained release over 12 hours in combination with a drug loading of up to 80% could be realized. Due to the flexibly adjustable release profiles, the floating gastric retentive drug delivery system can be used for a variety of drugs.

As used herein, the term“floating drug delivery system” (FDDS) refers to an oral dosage form that is retained in the stomach for a significant period of time, where the drug can be released into an acid pH of the stomach. Floating drug delivery systems have a bulk density less than gastric fluids and so remain buoyant in the stomach without affecting the gastric emptying rate for a prolonged period of time. While the system is floating on the gastric contents, the drug is released slowly at the desired rate from the system. As used herein, the term“gastroretentive” refers to a drug delivery system that provides a prolonged gastric residence time. Several techniques for gastro retentive drug delivery systems (GRDDS) have been developed, such as floating drug delivery systems.

As used herein, the term“sustained release” refers to describe a pharmaceutical dosage form formulated to prolong the release of a therapeutic agent such that its appearance in the systemic circulation is delayed and/or prolonged and its plasma profile is sustained in duration.

As used herein, the term“release sustaining matrix” refers to a matrix that is provided by a polymer component comprising an active ingredient dispersed throughout the polymer matrix providing sustained release of the active ingredient. The closed hollow body formed from the sustained release matrix may be manufactured by extrusion of a powder blend containing the active ingredient, the polymer component and optionally additives, and melt extrusion and further processing using an extrusion mold, or injection moulding or 3D-printing.

Alternatively, the closed hollow body may be formed from a cylindrical hollow body manufactured by extrusion of a powder blend containing active ingredient, polymer component and optionally additives, and separately provided sealing caps or sealing plugs.

As used herein, the term“modified release polymer” refers to a polymer providing delayed and sustained release either alone or in combination.

As used herein, the term“active ingredient” refers to a compound having biological activity, such a therapeutic agent, or being capable of being converted to such compound, e.g. a pro drug.

In embodiments of the floating gastric retentive drug delivery system, the amount of the active ingredient is in a range of > 50 weight% to < 80 weight%, preferably in a range of > 55 weight% to < 75 weight%, based on a weight of 100 weight% of the hollow body. The amount of the active ingredient may be chosen depending on the nature of the active ingredient. Advantageously, a wide range of amounts are possible, and particularly high amounts are usable. The amount of the polymer component thus may be in a range of > 15 weight% to < 55 weight%, preferably in a range of > 20 weight% to < 50 weight%, more preferably in a range of > 25 weight% to < 45 weight%, based on a weight of 100 weight% of the hollow body.

If not specifically denoted otherwise, given % are weight%, and are calculated on the basis of a dry weight of 100 weight% of the closed hollow body.

In embodiments of the floating gastric retentive drug delivery system, the active ingredient is selected from the group comprising metformin, levodopa, pregabalin and/or gabapentin. In a preferred embodiment, the active ingredient is metformin, or a salt, ester, derivative, hydrate and/or solvate thereof. Metformin is the INN name of 1 , 1 -dimethylbiguanide. In a further preferred embodiment, the active ingredient is levodopa, or a salt, ester, derivative, hydrate and/or solvate thereof. Levodopa is the INN name of L-3,4- dihydrophenylalanine. In a further embodiment, the active ingredient is pregabalin, or a salt, ester, derivative, hydrate and/or solvate thereof. Pregabalin is a gamma-aminobutyric acid (GABA) derivative.

Pregabalin is denoted (S ) -3 - (aminomethyl) -5 -methylhexanoic acid according to IUPAC. In a further embodiment, the active ingredient is gabapentin, or a salt, ester, derivative, hydrate and/or solvate thereof. Gabapentin is the INN name of 1 - (aminomethyl)cyclohexaneacetic acid.

The polymer component may comprise a modified release polymer, such as polymers used for hydrophobic sustained release matrixes or enteric coatings, and/or water soluble polymers to modify the release properties. The water soluble and/or low molecular weight polymers are combined with the modified release polymer to achieve different dissolution profiles. The term“polymer for enteric coatings” is a term of the art referring to a polymer which is preferentially soluble in the less acid environment of the intestine relative to the more acid environment of the stomach. Useful enteric polymers for practicing the present invention include cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate, polyvinyl acetate phthalate, polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic mono-ester copolymer, methacrylic acid methylmethacrylate copolymer, methyl acylate-methacrylic acid copolymer, methacrylate - methacrylic acid-octyl acrylate copolymer, and combinations thereof.

The polymer component may comprise a polymer selected from the group comprising cellulose-based polymers, polymers or copolymers of acrylic acid and/or methacrylic acid, a poly(lactide), lipid based polymers, polyethylene oxide (PEO), polyvinyl acetate, polyvinyl acetate phthalate (PVAP), poly(acrylic acid) (Carbomer®), mixtures of polyvinyl acetate and polyvinylpyrrolidone (PVP), and mixtures of these polymers. The cellulose -based polymer may be selected from the group of ethylcellulose (EC), hydroxypropylmethyl cellulose (HPMC), cellulose acetate succinate (CAS), cellulose acetate phthalate (CAP),

hydroxypropylmethylcellulose acetate succinate (HPMC AS) and

hydroxypropylmethylcellulose phthalate (HPMCP).

The polymer or copolymer of acrylic acid and/or methacrylic acid may be selected from the group of methacrylic acid-ethyl acrylate copolymer, methacrylic acid-methyl methacrylate copolymer, ammonio methacrylate copolymer and methyl acrylate, methyl methacrylate and methacrylic acid copolymer. Methacrylic acid-ethyl acrylate copolymer, for example, is available under the brand name Eudragit^® L from Evonik Industries AG, methacrylic acid- methyl methacrylate copolymer as Eudragit^® S, ammonio methacrylate copolymer under the brand name Eudragit^® RS and RL, and methyl acrylate, methyl methacrylate and methacrylic acid copolymer under the brand name Eudragit^® FS. The ammonium groups in the polymers EUDRAGIT^® RL and RS provide pH-independent permeability to the polymers. The EUDRAGIT^® RL and RS polymers enable time controlled release of the active ingredient by pH-independent swelling. The poly(lactide) may be selected from the group of poly(e-caprolactone) (PCL), polyglycolide (PGA), poly(DL-lactide-co-glycolide) (PLGA) and poly(lactide) (PLA). The lipid based polymer may be selected from the group of glyceryl dibehenate, glyceryl distearate and glyceryl monostearate. Preferred is glyceryl dibehenate. Mixtures of polyvinyl acetate and polyvinylpyrrolidone are, for example, available under the brand name Kollidon^® SR.

The term“water-soluble” polymers denotes polymers that dissolve, disperse, or swell in water and thus modify the physical properties of the closed hollow body. The polymer component may comprise a water soluble polymer selected from the group comprising cellulose-based polymers, polyvinyl based polymers, poly (butyl methacrylate, 2-dimethyl aminoethyl methylacrylate), ethylene oxide/propylene oxide copolymer (Poloxamer), polyvinyl alcohol (PVA), polyethylene glycol (PEG), alginates, pectins, guar gum, dextrans, chitosan and starch. For example, POLYOX™ WSR N10 LEO NF is a water soluble PEG with a relatively low molecular weight.

Cellulose -based polymers may be selected from the group of hydroxypropylmethylcellulose acetate succinate (HPMCAS), methylcellulose (MC), hydroxyethylcellulose (HEC), hydroxypropyl cellulose (HPC) and hydroxyethylmethylcellulose (HEMC). Polyvinyl based polymers may be selected from the group of polyvinylpyrrolidone (PVP),

polyvinylpyrrolidone/vinylacetate copolymer (Kollidon^® VA 64), and

polyvinylcaprolactam/polycinyl acetate/polyethylene glycol copolymer.

In embodiments of the floating gastric retentive drug delivery system, the polymer compound comprises:

- in a range of > 10 weight% to < 55 weight% of a polymer or copolymer of acrylic acid and/or methacrylic acid, and - in a range of > 3 weight% to < 40 weight% of a water-soluble polymer selected from the group comprising poly(butyl methacrylate, 2-dimethyl aminoethyl

methylacrylate), ethylene oxide/propylene oxide copolymer (Poloxamer), polyvinyl alcohol (PVA), polyethylenoxide (PEO), polyethylene glycol (PEG) and/or polyvinyl based polymers selected from Polyvinylpyrrolidone (PVP),

polyvinylpyrrolidone/vinylacetate copolymer (Kollidon^® VA 64) and

polyvinylcaprolactam/polyvinyl acetate/polyethylene glycol copolymer, the weight% being based on a weight of 100 weight% of the hollow body.

Floating gastric retentive drug delivery systems on basis of polymers or copolymers of acrylic acid and/or methacrylic acid achieved particularly advantageous release properties.

Preferably, the polymer or copolymer of acrylic acid and/or methacrylic acid is comprised in a range of > 15 weight% to < 50 weight%, more preferably in a range of > 20 weight% to < 45 weight%, and/or the water-soluble polymer is comprised in a range of > 5 weight% to < 35 weight%, more preferably in a range of > 7 weight% to < 30 weight%, the weight% being based on a weight of 100 weight% of the hollow body.

Preferred polymers or copolymers of acrylic acid and/or methacrylic acid are

aminoalkylmethacrylate copolymer such as under the tradename of Eudragit® RS PO, which is a copolymer of ethyl acrylate, methyl methacrylate and a low content of methacrylic acid ester with quaternary ammonium groups. The IUPAC name therefore is poly(ethyl acrylate- co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) 1:2:0.1.

In preferred embodiments, the polymer compound comprises, based on a weight of 100 weight% of the closed hollow body:

in a range of > 10 weight% to < 55 weight%, preferably in a range of > 15 weight% to < 25 weight%, of a polymer or copolymer of acrylic acid and/or methacrylic acid, such as Eudragit® RS PO, and in a range of > 3 weight% to < 40 weight%, preferably in a range of > 5 weight% to < 25 weight%, of a polymer selected from the group comprising poly (butyl

methacrylate, 2-dimethyl aminoethyl methylacrylate), such as Eudragit® E PO, and ethylene oxide/propylene oxide copolymer (Poloxamer).

In further preferred embodiments, the polymer compound comprises, based on a weight of 100 weight% of the closed hollow body:

in a range of > 10 weight% to < 55 weight%, preferably in a range of > 25 weight% to < 45 weight%, of a polymer or copolymer of acrylic acid and/or methacrylic acid, such as Eudragit® RS PO, and

in a range of > 3 weight% to < 40 weight%, preferably in a range of > 5 weight% to < 25 weight%, of polyethylene glycol (PEG).

- in a range of > 10 weight% to < 55 weight% of a polymer selected from the group comprising polyvinyl acetate, polyvinyl acetate phthalate (PVAP), poly (acrylic acid) (Carbomer), cellulose-based polymers preferably ethylcellulose and

hydroxypropylmethyl cellulose, polyethylenoxide (PEO) and a mixture of polyvinyl acetate and polyvinylpyrrolidone (Kollidon® SR), and

- in a range of > 3 weight% to < 40 weight% of a water-soluble polymer selected from the group comprising ethylene oxide/propylene oxide copolymer (Poloxamer), polyvinyl alcohol (PVA), polyethylene glycol (PEG) and/or polyvinyl based polymers selected from polyvinylpyrrolidone (PVP), polyvinylpyrrolidone/vinylacetate copolymer (Kollidon® VA 64) and poly vinylcaprolactam/poly vinyl

acetate/polyethylene glycol copolymer, the weight% being based on a weight of 100 weight% of the hollow body. Preferably, the polymer selected from the group comprising polyvinyl acetate, polyvinyl acetate phthalate (PVAP), poly(acrylic acid) (Carbomer), cellulose-based polymers preferably ethylcellulose and hydroxypropylmethyl cellulose, polyethylenoxide (PEO) and a mixture of polyvinyl acetate and polyvinylpyrrolidone (Kollidon® SR) is comprised in a range of > 15 weight% to < 50 weight%, more preferably in a range of > 20 weight% to < 45 weight%, and/or the water-soluble polymer, preferably polyethylene glycol (PEG), is comprised in a range of > 5 weight% to < 35 weight%, more preferably in a range of > 7 weight% to < 30 weight%, the weight% being based on a weight of 100 weight% of the hollow body.

A preferred sustained release polymer is a mixture of polyvinyl acetate and

polyvinylpyrrolidone, such as available under the brand name Kollidon® SR. A preferred water-soluble polymer is polyethylene glycol (PEG). Particularly floating gastric retentive drug delivery system comprising amounts of active ingredient in a range of > 45 weight% to < 75 weight%, could be manufactured based on a mixture of polyvinyl acetate and

polyvinylpyrrolidone. The polyethylene glycol (PEG) may be comprised in a range of > 5 weight% to < 15 weight%.

In embodiments of the floating gastric retentive drug delivery system, the polymer compound comprises a lipid based polymer selected from the group of glyceryl dibehenate, glyceryl distearate and glyceryl monostearate in a range of > 5 weight% to < 20 weight%, based on a weight of 100 weight% of the hollow body. Preferably, glyceryl dibehenate, glyceryl distearate or glyceryl monostearate is comprised in a range of > 7 weight% to < 18 weight%, more preferably in a range of > 9 weight% to < 15 weight%, based on a weight of 100 weight% of the hollow body.

The floating gastric retentive drug delivery system preferably comprises in a range of > 10 weight% to < 15 weight% of glyceryl dibehenate, glyceryl distearate or glyceryl

monostearate, in a range of > 20 weight% to < 30 weight% of a polymer or copolymer of acrylic acid and/or methacrylic acid and in a range of > 10 weight% to < 20 weight% of a polyvinyl based polymer selected from the group of polyvinylpyrrolidone (PVP), polyvinylpyrrolidone/vinylacetate copolymer (Kollidon® VA 64) and

In further embodiments, the floating gastric retentive drug delivery system may comprise a particularly high amount of the active ingredient and a polymer or copolymer of acrylic acid and/or methacrylic acid. These embodiments preferably are free of a second polymer, such as a water-soluble polymer. In embodiments of the floating gastric retentive drug delivery system the hollow body comprises the active ingredient in an amount in a range of > 50 weight% to < 85 weight% and a polymer or copolymer of acrylic acid and/or methacrylic acid in a range of > 15 weight% to < 50 weight%, based on a weight of 100 weight% of the hollow body. In preferred embodiments, the hollow body comprises in a range of > 60 weight% to < 80 weight%, preferably in a range of > 65 weight% to < 75 weight%, of the active ingredient and/or in a range of > 20 weight% to < 40 weight%, preferably in a range of > 35 weight% to < 25 weight%, of the polymer or copolymer of acrylic acid and/or methacrylic acid, the weight% based on a weight of 100 weight% of the hollow body.

The hollow body may further comprise additives such as plasticisers, glidants, anti-tacking agents and surfactants. A usable anti-tacking agent is talcum. Usable surfactants are sorbitan esters (Span) and Polysorbate (Tween®). The hollow body may comprise plasticisers to ensure the producibility regarding torque overload and/or a glidant to ensure good powder flow properties. Usable plasticisers are selected from the group comprising triethylcitrate, dibutylsebacate, glyceroltributyrate, diacetylated monoglyceride, glycerin, sorbitol, diethyloxalate, diethyl phthalate, diethylmalate, dibutylsuccinate, oleic acid, stearic acid, stearyl alcohol, polyethylenglycol, propylengylcol, ethylene oxide/propylene oxide copolymer (Poloxamer), dibutyltartrate, ethanol, citric acid, carbon dioxide, methyl-, ethyl-,

propylparaben, triacetin and water. Preferred plasticisers are selected from stearyl alcohol, triethylcitrate and polyethylenglycol. A most preferred plasticiser is stearyl alcohol. A preferred glidant is fumed silica (e.g. availbale under the trade name Aerosil®). The hollow body may comprise a plasticiser in a range of > 1 weight% to < 15 weight% and/or a glidant in a range of > 0,2 weight% to < 2 weight%, based on a weight of 100 weight% of the hollow body. Preferably, the hollow body may comprise a plasticiser, preferably stearyl alcohol, in a range of > 2 weight% to < 10 weight%, more preferably in a range of > 2,5 weight% to < 7 weight%, and/or a glidant, preferably fumed silica (Aerosil®), in a range of > 0,5 weight% to

< 2 weight%, more preferably in a range of > 0,5 weight% to < 1 weight%, based on a weight of 100 weight% of the hollow body.

Advantageously, due to the shape of the hollow cylinder the swimming behavior of the floating gastric retentive drug delivery system is not depending on the properties of the mixture of active ingredient and polymer. The floating gastric retentive drug delivery system has an apparent density below 1 g/cm³, and thus swims immediately in the gastric fluid. The apparent density may be lower, for example < 0.99 g/cm³, or < 0.95 g/cm³, or < 0.9 g/cm³, or

< 0.8 g/cm³, or < 0.7 g/cm³, or < 0.5 g/cm³. The density is provided by the cavity of the closed hollow body. It is a significant advantage that it is possible to vary the release profile of the system without changing the buoyancy.

The cavity volume and/or the wall volume of the hollow body may vary. The cavity volume may be in a range of > 2 vol% to < 85 vol% and the wall volume may be in a range of > 15 vol% to < 98 vol%, based on a total volume of the hollow body of 100 vol%.

Advantageously, while maintaining the geometric ratios of the hollow body, the dose of the active ingredient may be varied without varying the release profile.

The hollow body may vary in its dimensions, depending on the ratio of inner to outer diameter, the selected drug loading, the targeted dose and the polymers used. In embodiments, the hollow body has a wall thickness in a range of > 0.3 mm to < 3 mm, preferably in a range of > 0.5 mm to < 2.5 mm, more preferably in a range of > 0.7 mm to < 2 mm, even more preferably in a range of > 1 mm to < 2 mm. The outer diameter of the hollow body may be in a range of > 3 mm to < 10 mm, preferably in a range of > 5 mm to < 9 mm, more preferably in a range of > 6 mm to < 8 mm, and/or the inner diameter may in a range of > 1 mm to < 9 mm, preferably in a range of > 3 mm to < 7 mm, more preferably in a range of > 4 mm to < 6 mm. The length of the hollow body may in a range of > 5 mm to < 26 mm, preferably in a range of > 7 mm to < 21 mm, more preferably in a range of > 10 mm to < 18 mm.

The floating gastric retentive drug delivery comprises a cavity. In embodiments, the cavity gets in contact with a medium surrounding the closed hollow body after a period of floating, such that the medium enters into the cavity and the gastric retentive drug delivery system sinks into the medium. Communication with the surrounding medium may be provided after the closed hollow body opens up to the surrounding medium. Opening may be provided by an opening provided in the hollow body, that may be closed, for example by caps or plugs. The caps and plugs may be formed from a material that may dissolve in the medium, for example in the stomach or gastric environment. Alternatively, caps and plugs may be adhered to the hollow body by means of an adhesiv that may dissolve and thus release the sealing caps and plugs, or the caps and plugs may be releasably pressed on the opening of the hollow body.

The closed hollow body may be formed as a one piece-structure. The closed hollow body may be formed for example by extruding an extrudate in the form of a hollow body, for example in the form of a hollow cylinder, cutting the extrudate into pieces and sealing the ends to give closed hollow bodies. Alternatively, the open ends may be closed by sealing caps or plugs, also denoted stoppers.

Generally, the cavity of a hollow body may be closed by sealing caps or plugs. In

embodiments of the floating gastric retentive drug delivery system, the closed hollow body comprises a hollow body providing a cavity having at least one opening and at least one sealing cap and/or plug for closing the at least one opening. In such embodiments, the closed hollow body may be formed from separately provided components such as a hollow body, for example in the form of a hollow cylinder, and sealing caps or sealing plugs. In particular, caps also are obtainable by dip-coating. Such dip -coating processes are known for manufacturing hard capsules. A suitable template is preferably repeatedly dipped into a polymer solution and the applied polymer forms one or more layers by subsequent drying. Preferably polymers that dissolve in a solvent are usable for dip-coating. Alternatively, caps are obtainable using a template and immersing in polymer melts.

Caps and plugs may be formed in separate processes. Separately manufacturing the components is much easier than forming the closed hollow bodies in one piece. Caps and plugs may be formed for example by tableting, injection moulding or by 3D-printing.

The caps or plugs may be adhered by pressing on or into an opening or may be releasably adhered to an opening, such as by using a polymeric adhesive. Using a water-soluble polymer as adhesive allows that a cap or plug may become detached after the polymer dissolves, for example in the stomach or gastric environment, and the inner volume of the hollow body gets in contact with the surrounding of the hollow body after a certain time.

The sealing caps or plugs can close one or both ends of a hollow cylindrical body. The sealing caps or plugs can be formed using the same or a different polymer component compared to the cylindrical body. This provides a huge advantage in view of amending buoyancy or floatability of the floating gastric retentive drug delivery system. Further, the sealing caps or plugs may comprise the same or a different active ingredient compared to the cylindrical body, or may comprise the active ingredient in the same or a different concentration, or may be free of active ingredient.

In preferred embodiments of the floating gastric retentive drug delivery system, the closed hollow body comprises a cylindrical hollow body, preferably a hollow cylinder, and at least one sealing cap and/or plug for closing one or both ends of the cylindrical hollow body.

Preferably, the cavity of the cylindrical hollow body at both ends is similarly sealed, particularly using sealing caps or plugs. Preferably, both ends are sealed by sealing caps. Caps provide the advantage of better floating capabilities compared to plugs, as no part extends into the hollow body and replaces the air in the cavity that provides buoyancy. Plugs provide the advantage that the plug can have the same outer diameter as the hollow body, since the part extending into the hollow body supports the fastening and no circumferential rim is needed. This provides for easier swallowing and better compliance.

In embodiments wherein the closed hollow body comprises a hollow cylinder and sealing caps and/or plugs for closing the ends, the wall thickness refers to the wall of the hollow cylindrical body, while the caps or plugs may have the same or a different thickness. The wall thickness may in a range of > 0.3 mm to < 3 mm, preferably in a range of > 0.5 mm to < 2.5 mm, more preferably in a range of > 0.7 mm to < 2 mm, even more preferably in a range of >

1 mm to < 2 mm.

The wall of the hollow cylinder and the caps or plugs may be formed from the same or from different polymer components. The polymer component may comprise a modified release polymer, such as polymers used for sustained release matrixes or enteric coatings, such as polymers with pH dependent solubility, a water-soluble polymer, or mixtures thereof. For the polymer components, reference is made to the description above. Further,

polyhydroxyalkanoate (PHA), acrylnitrile butadiene styrene copolymers (ABS), polyethylene (PE), polypropylene (PP) or polycarbonate (PC) may be used.

The sealing caps and/or plugs may be formed from polylactic acid (PLA). In preferred embodiments, the sealing caps and/or plugs are formed from a water-soluble polymer. The water-soluble polymer may be selected from the group comprising cellulose-based polymers, polyvinyl based polymers, poly(butyl methacrylate, 2-dimethyl aminoethyl methylacrylate), ethylene oxide/propylene oxide copolymer (Poloxamer), polyvinyl alcohol (PVA), polyethylene glycol (PEG), alginates, pectins, guar gum, dextrans, chitosan, starch and mixtures thereof. Preferably, the sealing caps and/or plugs may be formed from polyvinyl alcohol. A water-soluble polymer can dissolve in the stomach. Consequently, water can enter the hollow body and floatability of the gastric retentive drug delivery system will be ended. The gastric retentive drug delivery system will sink into the content of the stomach and consequently will be removed from the stomach. This prevents floating gastric retentive drug delivery systems from accumulating in the stomach. This provides a huge advantage in view of pharmacological safety. The selection of a water-soluble cap or plug can provide for a time-controlled dissolving of caps or plugs and thus a time-controlled ending of buoyancy. The water-soluble polymer may be selected to dissolve after a time period of 6 h to 12 h. this has the advantage that a sustained release of the active ingredient with a selected release profile can be provided, before the delivery system can be safely removed.

The sealing caps or plugs may comprise a different active ingredient compared to the hollow cylindrical body. This provides for that at least two or more such as three different active ingredients can be provided in one delivery system. In embodiments, where a different active ingredient in a different polymer matrix is provided, two or more active ingredients can be administered using different time profiles. In these embodiments, the polymer matrix of the caps or plugs comprises or is made from the same or a different polymer compared to the hollow cylindrical body.

In further embodiments, the sealing caps or plugs may comprise the same active ingredient compared to the cylindrical body, preferably in a different concentration. This provides the advantage that the release profile of the ingredient can be varied over time. Using the same polymer component and active ingredient compared to the cylindrical body, but in a different concentration, allows to vary the initial dose of the active ingredient.

In preferred embodiments, the sealing caps and/or plugs are free of active ingredient. Such embodiments provide the significant advantage that the buoyancy of the system may be varied without changing the release profile of the active ingredient. In most preferred embodiments, caps and/or plugs are used for sealing both ends of the hollow body, the sealing caps and/or plugs are free of active ingredient and are manufactured of a water-soluble polymer, particularly dissolving between 6-12 hours, according to the desired release rate.

The present invention is further directed towards a process of manufacturing a floating gastric retentive drug delivery system according to the invention, wherein the closed hollow body is manufactured by a process comprising the steps of:

- compounding of a powder blend containing the active ingredient, the polymer component and optionally additives by melt extrusion, and

- forming the closed hollow body by extrusion using an extrusion die designed to provide an extrudate in the form of a hollow body, cutting and sealing the extrudate to give closed hollow bodies, or by injection moulding or by 3D-printing.

In a first step, a blend of active ingredient, the polymer component and optionally one or more additives is compounded by melt extrusion. In a following step, the compounded blend is processed and a closed hollow body is formed from the compounded blend. The forming can for example be achieved by injection moulding or by 3D-printing. For 3D-printing filaments may be formed from the compounded blend, which can be printed to form a closed hollow body. For injection moulding the compounded blend may be injected into a mould unit.

Preferably, forming of the closed hollow body is achieved by extrusion using an extrusion die designed to provide an extrudate in the form of a hollow body, cutting, and sealing the extrudate to give closed hollow bodies. The blend of active ingredient, the polymer component and optionally one or more additives may be fed, for example by a doser, into an extruder. In the extruder, the powder blend melts due to the effects of heat and shear. The active ingredient is thereby finely dispersed in the polymer matrix. The molten mass can then be passed through a die plate at the end of the extruder. The shape of the die head determines the geometry of the extrudate.

For forming hollow tube extrudates a die with exchangeable components allows the forming of extrudates with variable inner and outer diameter. For example, the outer diameter may be specified by the die plate, and the inner diameter by the die tip. By varying one or both of the diameter of die plate and die tip, the wall thickness of the hollow body can be varied. For example, die plates providing an outer diameter in a range of > 6 mm to < 9 mm, or > 7 mm to < 8 mm, and/or die tips providing an inner diameter in a range of > 3 mm to < 6 mm, or > 4 mm to < 5 mm, may be used.

The hollow tube extrudates can be cut to the desired cylinder lengths. Extrudate strands can for example be cut by a circular saw or a flying saw while the hollow body is still in a semi- molten condition or after reaching ambient temperature. After cutting the cutting edges of the hollow bodies may closed while the hollow body is still in a semi-molten condition.

Alternatively, the open ends of the cut cylinders may be molten and sealed by pressing into a heated round shaped mould, thus providing closed hollow bodies.

The closed hollow body may be manufactured as a one piece-structure. Alternatively, the closed hollow body may be manufactured using separately provided components such as a hollow cylindrical body and sealing caps or sealing plugs. Also in embodiments where sealing caps or sealing plugs are used to close the hollow body, the hollow cylindrical body is manufactured by the steps of compounding of a powder blend containing the active ingredient, the polymer component and optionally additives by melt extrusion, and using an extrusion die designed to provide an extrudate in the form of a hollow body.

In such embodiments, forming the closed hollow body comprises the steps of:

a) cutting the extrudate to give a hollow body, preferably a cylindrical hollow body; b) providing sealing caps or plugs; and c) sealing the hollow body, preferably the cylindrical hollow body, with the sealing caps or plugs.

Caps and plugs may be formed by separate processes. Separately manufacturing the components is easier than forming the closed hollow bodies in one piece. Caps and plugs may be formed for example by tableting, injection moulding or by 3D-printing. The caps or plugs may be adhered by pressing on or into an opening or may be releasably adhered to an opening, such as by using a polymeric adhesive. In embodiments, sealing may be supported by warming the cutting edges of the hollow bodies and pressing the sealing caps or plugs on or in the cutting edges or by moistening the cutting edges with a solvent or a molten polymer as a polymeric binder solution. The solvent may be isopropanol. The molten polymer preferably is the same polymer as used for polymer component of the cylindrical hollow body or the sealing caps or plugs.

The hollow body preferably is in the form of a hollow cylinder. The wall of the cylindrical body and the caps or plugs may be manufactured using the same or different polymer components. The polymer component may comprise a modified release polymer, such as polymers used for hydrophobic sustained release matrixes or enteric coatings and/or water soluble polymers. The sealing caps and/or plugs may be formed from polylactic acid (PLA). Preferably, the sealing caps and/or plugs are formed from a water-soluble polymer, preferably selected from the group comprising cellulose-based polymers, polyvinyl based polymers, poly(butyl methacrylate, 2-dimethyl aminoethyl methylacrylate), ethylene oxide/propylene oxide copolymer (Poloxamer), polyvinyl alcohol (PVA), polyethylene glycol (PEG), alginates, pectins, guar gum, dextrans, chitosan, starch and mixtures thereof. Preferably, the sealing caps and/or plugs are be formed from polyvinyl alcohol. Preferably, the sealing caps and/or plugs are manufactured without active ingredient. The present invention also relates to a floating gastric retentive drug delivery system manufactured by the process according to the invention. For the description of the floating gastric retentive drug delivery system, reference is made to the description above.

The present invention also relates to a floating gastric retentive drug delivery system comprising a hollow body providing a cavity having at least one opening and at least one sealing cap and/or plug for closing the at least one opening. In preferred embodiments, the floating gastric retentive drug delivery system comprises a cylindrical hollow body and at least one sealing cap and/or plug for closing one or both opening ends of the hollow cylindrical body. The cylindrical hollow body may have the form of a hollow cylinder having a cavity. Both ends of the hollow cylinder may be sealed by plugs or caps. The caps or plugs may be adhered by pressing on or into an opening or may be releasably adhered to an opening, such as by a polymeric adhesive. The floating gastric retentive drug delivery system may be manufactured by the process according to the invention. For the description of the floating gastric retentive drug delivery system, caps, plugs and manufacturing process reference is made to the description above.

Unless otherwise defined, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

The Examples, which follow serve to illustrate the invention in more detail but do not constitute a limitation thereof.

The figures show:

Figure 1 the drug release of closed hollow bodies having a drug loading of 50 weight% metformin.

Figure 2 the drug release of closed hollow bodies having a drug loading of 69.5

weight% metformin. Figure 3 the drug release of closed hollow bodies having a drug loading of 80 weight% metformin.

Figure 4 the floating force of closed hollow bodies having a drug loading of 69.5

weight% metformin.

Figure 5 a column diagram of measured density of the open tube extrudates (“open”), the calculated density of closed hollow bodies (“predicted”), and the measured density of the closed hollow bodies (“measured”) of hollow bodies having a drug loading of 69.5 weight% metformin.

Figure 6 a column diagram of measured density of the open tube extrudates (“open”), the calculated density of closed hollow bodies (“predicted”), and the measured density of the closed hollow bodies (“measured”) of hollow bodies having different cavity volumes.

Figure 7 the floating force of closed hollow bodies having different cavity volumes. Figure 8 in figure 8a) shows the scanning electron microscope images of a hollow body before drug release and the figure 8b) after drug release.

Figure 9 the drug release of closed hollow bodies with different the wall thickness. Figure 10 the drug release of closed hollow bodies with different diameter.

Figure 11 the drug release of closed hollow bodies with different cut lengths of the

extrudates, and final drug dosages of 300 mg, 400 mg, 500 mg and 600 mg metformin.

Figure 12 the drug release of closed hollow bodies of coextrudates of metformin in a mixture of Eudragit® and Polyox™ WSR 301.

Figure 13 the drug release of closed hollow bodies of coextrudates of metformin in a mixture of Poylox™ W301 and Poylox™ N10 Leo NF.

Figure 14 the drug release of closed hollow bodies of coextrudates of metformin in

Kollidon® SR and PEG 1500.

Figure 15 the drug release of closed hollow bodies of coextrudates of metformin in

Eudragit® FS and Eudragit® E PO. Figure 16 the drug release of closed hollow bodies having a drug loading of 50 weight% levodopa.

Figure 17 the drug release of closed hollow bodies having a drug loading of 77.5 or 79.5 weight% levodopa.

Figure 18 the drug release of closed hollow bodies having a drug loading of 49.5

weight% gabapentin.

Figure 19 a schematic view of a floating gastric retentive drug delivery system sealed by sealing plugs in Fig. 19 a) and by sealing caps in Fig. 19 b).

Figure 20 the drug release of closed hollow bodies sealed by sealing caps and plugs Figure 21 the floating force of closed hollow bodies sealed by sealing caps and plugs.

The figure 19 a) shows a schematic constructional drawing of a floating gastric retentive drug delivery system 1 comprising a cylindrical hollow body 2 and two plugs 6. The cylindrical hollow body is in the form of a hollow cylinder 2 and has a cavity 8. Both ends of the hollow cylinder 2 are sealed by plugs 6. The figure 19 b) shows a schematic constructional drawing of a floating gastric retentive drug delivery system 1 wherein both ends of the hollow cylinder 2 are sealed by caps 4.

Methods:

Preparation of mixtures of active ingredient and polymer component for extrusion: a) Metformin HC1

The mixtures denoted Met 5-10 and Met 20-22 containing Eudragit Polymers and stearyl alcohol as plasticizer were prepared as follows: Stearyl alcohol flakes were filled into 50 ml stainless steel milling chambers and cooled rapidly with liquid nitrogen. Three milling cycles of 30 seconds each with 30 Hz were performed (Ball mill MM 400; Retsch GmbH, Haan, Germany). The required amounts of Eudragit® RS PO and/or Eudragit® E PO and/or Eudragit® FS 100 and milled stearyl alcohol were weighted into a 540 ml container and mixed in a Turbula blender for 5 minutes with 50 rpm to prepare a pre -blend.

To ensure a homogenous particle size distribution, Metformin was screened with a centrifugal mill (Retsch GmbH, Haan, Germany) through a 500 pm sieve. Aerosil® was

desagglomerated by screening with a 250 pm sieve. Metformin (Metformin HC1, Wanbury Limited, Vashi, India) and Aerosil® 200 Pharma (Evonik Industries AG, Darmstadt,

Germany) were added to the pre -blend and mixed for 10 min with 50 rpm in a Turbula blender to form a final blend. Mixtures Met 1 - 4 and Met 11 were prepared as described above except that stearyl alcohol and Aerosil® were not added to the blend.

Mixtures containing Polyox™ WSR 301 Leo NF and/or Polyox™ WSR N10 Leo NF and/or Eudragit® RS PO, which are in the following denoted Met 12-17, were prepared as follows: The required polymer amounts were weighted into a 540 ml container and mixed in a Turbula blender for 5 minutes with 50 rpm to prepare a pre -blend. To ensure a homogenous particle size, Metformin was screened with a centrifugal mill threw a 500 pm sieve. Aerosil® was desagglomerated by screening with a 250 pm sieve. Metformin and Aerosil® were added to the pre-blend and mixed for 10 min with 50 rpm in a Turbula blender to form a final blend.

Batches containing Kollidon® SR and Polyethylenglycol 1500, which are in the following denoted Met 18-19, were manufactured analogous to the Eudragit® batches. PEG 1500 plates were filled into 50 ml stainless steel milling chambers and cooled rapidly with liquid nitrogen. Three milling cycles (each 30 seconds) with 30 Hz were performed. The required amounts Kollidon® SR and milled PEG 1500 were weighted into a 540 ml container and mixed in a Turbula blender for 5 minutes with 50 rpm to form a pre-blend. To ensure a homogenous particle size, Metformin was screened with a centrifugal mill threw a 500 pm sieve. Aerosil® was desagglomerated by screening with a 250 pm sieve. Metformin and Aerosil® were added to the pre-blend and mixed for 10 min with 50 rpm in a Turbula blender to form a final blend. b) Levodopa Stearyl alcohol flakes were filled into 50 ml stainless steel milling chambers and cooled rapidly with liquid nitrogen. Three milling cycles of 30 seconds each with 30 Hz were performed. The required amounts of Eudragit® RS PO and/or Eudragit® E PO and milled stearyl alcohol were weighted into a 540 ml container and mixed in a Turbula blender for 5 minutes with 50 rpm to form a pre -blend. Aerosil® was desagglomerated by screening with a 250 pm sieve. Levodopa (Swapnroop Drugs & Pharmaceuticals, Maharashtra, India) and Aerosil® were added to the pre-blend and mixed for 10 min with 50 rpm in a Turbula blender to form a final blend. c) Gabapentin

The required amounts of Eudragit® RS PO, Eudragit® E Po and Compritol 888 ATO were weighted into a 540 ml container and mixed in a Turbula blender for 5 minutes with 50 rpm to form a pre -blend. Aerosil® was desagglomerated by screening with a 250 pm sieve.

Gabapentin (Zach System S.p.A, Milan, Italy) and Aerosil® were added to the pre-blend and mixed for 10 min with 50 rpm in a Turbula blender to form a final blend.

Hot melt extrusion and downstream process:

Hot-melt extrusion was performed using a co-rotating 12 mm twin-screw extruder ZE 12 (Three-Tec GmbH, Seen, Switzerland) with a functional length of 25:1 L/D. A tube die was mounted. To assure a constant feeding of the final blend into the extruder, the volumetric feeder was calibrated for each blend (5 point calibration; 2 min for each calibration point). Throughput was kept constant at 2.0 g/min and screw speed was set to 100 rpm for all trials. The temperature profile for extrusion was adjusted on final blend properties in a range of 90°C - l60°C. The tube die was also heated and a support pressure of 0.1 bar was set.

Extrudate strands were cut by a circular saw after reaching room temperature. The cylinder length was depending on the drug load and desired dose of the final dosage form. Open ends of cut cylinders were molten in a temperature range of 110 - 170 °C and sealed by pressing into a heated round shaped mould. Alternatively, separate caps or plugs were manufactured via 3D printing using PLA filaments and the open ends of cut cylinders were heated to 100 °C and sealed with the caps or plugs, or open ends were moistured with isopropanol and caps or plugs were fixed on the open ends.

Calculation of extrusion die configuration:

Final blend true densities were measured (n=l) using an AccuPyc 1330 helium pycnometer (Micromeritics GmbH, Norcross, USA). Twenty purge cycles followed by 25 sample runs were performed until a standard deviation of less than 0.01% was reached. A filling pressure of 136.86 kPa-g and an equilibration rate of 0.0345 kPa-g/min were used for all

measurements.

Based on the final blend true density suitable die settings for extrusion were calculated.

Taking the dose (e.g. 300 mg), the true density of the final blend and a desired density of 0.8 g/cm³ into account, the needed volume of the final dosage form to achieve the density was calculated. Knowing the final volume the ratio of inner to outer diameter, which defines the extrusion die parameters, was calculated.

For a powder density of 1.20 g/cm³, a drug load of 50 weight%, a dose strength of 300 mg and a desired density of 0.80 g/cm³ the calculation was as follows.

1) Mass of the final dosage form

0,3 [g] - 100

m ass [ r] 0.6 [g]

50 [%] (formula 1)

2) Needed total volume of the dosage form

0,75 [cm³]

0.8 g

Lcnr (formula 2)

3) Wall volume of the hollow cylinder 0.8 0.75 [cm³]

Ffoitf) [cm 3 1] _

0.5 [cm³]

1.20

Loir (formula 3)

4) Cavity volume

V (m) [cm³] = 0.75 [cm3]—0.5 [cm³] = 0.25 [cm³] (formula 4)

5) Calculation of the die parameters for a 4 mm inner diameter: a. Length of the cylinder

0.25 [cm³] * 4

lenght [cm] = - -— - = 1.99 [cm]

(0 4 [cm])- * IF (formula 5)

The calculation was based on the cavity volume. During the sealing process of the hollow cylinder, the volume of the cavity is decreasing, whereas the total mass remains constant. Therefore the total density increases. To avoid this, a correction factor was applied to counterbalance volume loss. The correction factor was determined empirically and varied between 0.1 - 0.2 mm depending on the outer diameter of the cylinder. lenght (corr) [cm] = 1.99 [cm] * 2 * 0 1 [cm] = 2.19 [cm] (formula 6) b. Outer diameter 0.6713 [cm] (formula 7)

To achieve a density of 0.8 g/cm³ for the aforementioned preset parameters a die combination of 4 mm inner and 6.7 mm outer diameter was calculated to be applied. As 6, 7, 8 and 9 mm outer diameters were used, the diameter closest to the calculated diameter was selected. In this example a 4 mm / 7 mm inner/outer die setting was used.

Determination of the true density: Final blend and unsealed tube cylinder true densities were measured (n=l) using a AccuPyc 1330 helium pycnometer (Micromeritics GmbH, Norcross, USA). Twenty purge cycles followed by 25 sample runs were performed until a standard deviation of less than 0.01% was reached. A filling pressure of 136.86 kPa-g and an equilibration rate of 0.0345 kPa-g/min were used for all measurements.

Determination of the apparent density:

Apparent densities of sealed tube extrudates (n=3) were analyzed by displacement measurement with a GeoPyc 1360 (Micromeritics GmbH, Norcross, USA). Before each sample analysis a blank measurement was performed. Samples were measured in a 12.7 mm diameter chamber running three cycles with a compression force of 28.0 N. Standard settings for Zero depth (45.5427 mm) and conversion factor (0.1284 cm³/mm) for the 12.7 mm chamber were implemented.

Determination of extrudate dimensions:

Thin discs (n=4) of tube extrudates cross sections were cut. A Canon EOS 700D mounted with an EF-S l8-55mm STM lens was fixed on a tripod to ensure the same working distance for all shots. Pictures were taken with a focal length of 55 mm and aperture priority mode. A millimeter scale was present in all pictures. Based on the scale bar, inner and outer diameters of cut discs were analyzed using ImageJ.

Dissolution test:

Dissolution tests were performed in Ph.Eur. apparatus 1 with 500 ml 0.1 N HC1 at 37 °C +/- 0.5 °C and stirring speed of 50 rpm. All experiments were conducted in triplicate. Samples were taken over a 12 hour period (5, 10, 15, 30, 45, 60, 90, 120, 180, 240, 300, 360, 420, 480, 540, 600, 660, 720 minutes) and analyzed using a UV spectrophotometer. Measurement was performed at 245 nm for Metformin and 290 nm for Levodopa using the first derivative of the absorbance. Gabapentin was quantified by HPLC-UV detection. Determination of floating behavior:

To monitor the floating behavior continuously, an online measurement system was implemented. The basket holder was directly mounted to the load cell of an Extend ED224S analytical balance (Sartorius AG, Gottingen, Germany), thus the resultant weight in vertical direction could be directly measured. The balance was connected via RS232C interface with a computer. Resultant weight was recorded every 30s over a period of 12 hours using a self- programmed Lab VIEW based software. After immersing the basket into a glass vessel filled with 500 ml 0.1 N HC1, which was kept at 37 °C and stirred during the entire measurement with a magnetic bar, the balance was tared. The floating extrudate was directly inserted into the immersed basket.

Example 1

Determination of drug release of floating gastric retentive drug delivery systems comprising metformin

Drug release was tested by dissolution tests of samples comprising 50 weight%, 69.5 weight% or 79.5 weight% metformin as described above. The following table 1 summarises the metformin formulations used and the outer and inner extrusion die diameters. Table 1: Metformin formulations and die diameters

The figure 1 shows the drug release over a time period of 12 hours of the samples Met 1 to Met 4 having a drug loading of 50 weight% metformin. As can be seen in figure 1, by variation of the polymer composition using only Eudragit® E PO (Met 1), mixtures of Eudragit® RS PO and Eudragit® E PO and only Eudragit® RS PO (Met 4), a wide range of release profiles in a range of 1 hour to more than 12 hours could be achieved. It could also be seen that the buoyancy advantageously was not affected by the change in the composition of the wall of the closed hollow bodies.

The figure 2 shows the drug release of the samples Met 5 to Met 9 having a drug loading of 69.5 weight% metformin over 12 hours. As can be seen in figure 2, also with a drug loading of 69.5 weight% a variety of different release profiles was obtained.

The figure 3 shows the drug release of the sample Met 10 having a drug loading of 80 weight% metformin over 12 hours. As can be seen in figure 3, for metformin a maximum drug loading of 80 weight% could be achieved. Significant is that despite the high drug load the buoyancy was maintained and a sufficient retardation over 12 hours was achieved.

Example 2

Determination of buoyancy

The floating behavior of the samples Met 5 to Met 9 as shown in table 1 was determined as described above. The figure 4 shows the floating force of the samples Met 5 to Met 9. As can be seen in the figure 4, the samples floated immediately and maintained buoyancy for over 12 hours. This shows that using the cylindrical shape of the hollow body the release can be changed without affecting the buoyancy. The decoupling of these two parameters offers great flexibility in drug delivery of a floating gastric retentive drug delivery system. Example 3

Determination of the density of the hollow bodies

To achieve the buoyancy of the hollow bodies, their apparent density has to be below 1 g/cm³, i.e. the density of gastric fluid. For this purpose, a cavity volume needs to be chosen for that depending on the powder density after closing of the body sufficient air is trapped in the cavity. To validate the apparent density of the extruded hollow bodies, the calculated density was compared to the measured density of the closed hollow bodies of the samples Met 5 to Met 9 as shown in table 1. The samples represent a series of extrusions with 69.5 weight% drug loading and differ in the ratio of the two polymers Eudragit® RS (water-insoluble) and Eudragit® E (water-soluble). The apparent densities of sealed tube extrudates was determined as described above.

The figure 5 shows a column diagram providing the measured density of the open tube extrudates“open” with a helium pycnometer, the calculated density of closed hollow bodies based on powder density and the specific inner and outer diameter of the extrudate

“predicted”, and the measured density of the closed hollow bodies“measured” with a Geopyc (Micromeritics). The density was determined by the volume difference between two measurements of blank value and sample. The column diagram clearly shows that the density via the manufacturing process can be reduced below 1 g/cm³, so that the hollow bodies are instantly buoyant. Considering the differences between the measured and the predicted values it is clear that the calculation corresponds well to the actual density values.

Example 4

Comparison of buoyancy

The buoyancy of two samples with differing wall thickness achieved by differing inner die diameter was compared. For this the formulation of sample Met 5 was extruded with differing die combinations. The sample Met 5 (7/5) was extruded with a 7 mm outside and a 5 mm inside die diameter and sample Met 5 (7/4) was extruded using a 7 mm outside and a 4 mm inside die diameter.

The figure 6 shows the column diagram providing the measured density of the open tube extrudates (“open”), the calculated density of closed hollow bodies (“predicted”) and the measured density of the closed hollow bodies (“measured”) of the samples Met 5 (7/5) and Met 5 (7/4). As can be seen in the figure 6, due to the larger cavity the 7/5 sample exhibits a much lower apparent density than the 7/4 sample, while the density of the 7/4 sample is scarcely above 1 g/cm³.

The figure 7 shows the floating force of the samples Met 5 (7/5) and Met 5 (7/4). As can be seen in the figure 7, the measurement of buoyancy confirms the results of the density measurements. The sample Met 5 (7/4) is unable to swim as the buoyancy force is

insufficient. The sample Met 5 (7/5), however, floats from the start and maintained buoyancy for 12 hours. These results show the importance of the extrusion die parameters, to provide sufficient buoyancy of the hollow bodies.

Example 5

Determination of wall integrity before and after drug release

To determine the drug release and the wall integrity, thin discs of cross sections of an extrudated body of the sample Met 6 having a drug loading of 69.5 weight% metformin in Eudragit® RS PO and Eudragit E PO as given in table 1 was cut and scanning electron microscope images were taken as described above. After 12 hours of drug release hollow bodies of the sample Met 6 were cut and scanning electron microscope images were taken for comparison.

The figure 8a) shows the scanning electron microscope images of the hollow bodies of sample Met 6 before drug release and the figure 8b) shows the scanning electron microscope images after drug release. Figures 8a) and b) clearly show that the release is a matrix-controlled mechanism. Even after drug release, the matrix scaffold of Eudragit® RS remained intact and no water entered the cavity of the floating gastric retentive drug delivery system. Example 6

Determination of the effects of wall thickness and diameter of the extruded hollow bodies

To determine the effect of wall thickness, samples with identical drug and polymer formulation but increasing wall thickness were prepared by varying the inner die diameter, as summarized in table 2:

Table 2: Metformin formulations and outer and inner extrusion die diameters

Drug release was tested by dissolution tests of the samples as described above. The figure 9 illustrates drug release over 12 hours. It can be seen that increasing the wall thickness reduces the amount of active ingredient released per time. It is assumed that due to an extended diffusion path the active substance needs more time to diffuse through the matrix. The figure 9 shows how important the wall thickness is for the floating gastric retentive drug delivery system.

Further samples with identical drug and polymer formulation and identical wall thickness but increasing diameter were prepared by increasing both die diameters, as summarized in table 3:

Table 3: Metformin formulations and outer and inner extrusion die diameters

Drug release was tested by dissolution tests of the samples as described above. The figure 10 illustrates the drug release over 12 hours. It can be seen that the releases differs only marginally as the diffusion path remains constant. This illustrates that the diameter of the hollow bodies may be varied without affecting the release kinetics, as long as the wall thickness is kept constant.

Example 7

Determination of the effect of the cutting length of the extruded hollow bodies

To determine the effect of the cutting length, samples of the formulation Met 6 as shown in table 1 containing 69.5 weight% metformin and were extruded using a 7/5 die combination. The received bodies differed only in the cut length of the extrudates, whereby a final drug dosage of 300 mg, 400 mg, 500 mg and 600 mg metformin was achieved. Drug release was tested by dissolution tests of the samples as described above.

The figure 11 illustrates the drug release over 12 hours. It can be taken from figure 11 that the release differs only marginally. This differentiates the hollow bodies from state of the art gastric retentive drug delivery system, since in normal matrix systems, e.g. tablets, an increase in the dose at the same time leads to an altered release. Due to the cylindrical shape, the mass/volume ratio can be kept constant, whereby constant release kinetics can be achieved. Changing the dose without affecting the kinetics provides advances in drug development.

Example 8 Determination of metformin Eudragit® RS PO and Polyox™ W301 coextrudates

Closed hollow bodies of coextrudates comprising 50 weight% metformin, and differing amounts of Eudragit® RS PO and Polyox™ W301 or Polyox™ W301 and Polyox™ WSR N10 were manufactured and the drug release properties of the respective polymer components was tested as described above. The following table 4 summarises the metformin formulation compositions.

Table 4: Metformin formulation compositions

The figure 12 illustrates the effect of the coextrudate of the Eudragit® copolymer of ethyl acrylate, methyl methacrylate and a low content of methacrylic acid ester with quaternary ammonium groups with the water-soluble poly(ethylene oxide) polymer Polyox™ WSR 301 of the samples Met 12 to Met 15. As can be seen in the figure 12, the addition of the Polyox™ W301 high molecular weight polyethylene glycol starting at a polymer content of 7.5 weight% lead to an accelerated release. These experiments show that mixtures of Eudragit® RS and PolyoxW30l can cover a wide range of release profiles.

The figure 13 illustrates the effect of the water-soluble poly(ethylene oxide) polymer

Polyox™ WSR 301 Met 17 and a coextrudate of the two water-soluble poly(ethylene oxide) polymers Met 16. As can be seen in the figure 13, the poly(ethylene oxide) polymers can also be used alone as polymer component. Poylox W301 showed a slower release than the mixture of W301 and N10 Leo NF. The lengths of the N10 Leo NF polymer chains are shorter than those of the W301 and therefore cannot effectively retard the release of the active ingredient. However, a combination of both offers further possibilities to control the drug release. It was seen that the pure Polyox™ batches dissolved completely during release.

Example 9

Determination of metformin Kollidon® extrudates

Closed hollow bodies of amounts of 49.5 or 69.5 weight% metformin were extruded with a mixture of Kollidon® SR, a polyvinyl acetate / polyvinyl pyrrolidone copolymer, and polyethylene glycol 1500 (PEG 1500) were manufactured and the drug release properties of the respective polymer components was tested as described above. The following table 5 summarises the metformin formulation compositions.

Table 5: Metformin formulation compositions

The figure 14 shows the drug release of the samples Met 18 and Met 19. As can be seen in the figure 14, the polymer component could be prepared by the method and the formulations showed a sufficient retardation effect and thus also offer a broad scope in formulation development.

Example 10

Determination of Eudragit® FS 100 based extrudates

Eudragit® FS 100 is a methyl acrylate, methyl methacrylate and methacrylic acid copolymer and soluble only above pH 7.2, which is usually used for colon targeting. The polymer was tested in combination with poly(butyl methacrylate, 2-dimethyl aminoethyl methylacrylate) (Eudragit® E PO) in view of the advantage of dissolving after exiting the stomach in the later sections of the intestine. Closed hollow bodies of coextrudates comprising 69.5 weight% metformin and differing amounts of Eudragit® FS and Eudragit® E PO were manufactured and the drug release properties of the respective polymer components was tested as described above. The following table 6 summarises the metformin formulation compositions. In the examples Met 20 to 22 a 7 mm / 5 mm outer/inner die setting was used.

Table 6: Metformin formulation compositions

The figure 15 shows the drug release of the samples Met 20, 21 and 22. As can be seen, the mixture of Eudragit® FS and Eudragit® E PO as polymer component also provides a sufficient retardation.

Example 11

Determination of drug release of floating gastric retentive drug delivery systems comprising levodopa

Drug release was also tested for samples comprising 50 weight%, 77.5 weight% or 79.5 weight% levodopa. The manufacture of the closed hollow bodies and testing of drug release over a time period of 12 hours was performed as described above. The following table 7 summarises the levodopa formulations using Eudragit® RS PO, Eudragit® E PO and several mixtures thereof. For the examples Lev 1 to Lev 13 a 7 mm / 5 mm outer/inner die setting was used.

Table 7: levodopa formulation composition

The figure 16 shows the drug release of the samples Lev 1 to Lev 6 having a drug loading of 50 weight% levodopa. As can be seen in figure 16, the release profiles for levodopa as the active substance show that a combination of Eudragit® RS and Eudragit® E can achieve a wide range of release profiles also for levodopa.

The figure 17 shows the drug release of the samples Lev 7 to Lev 13 having a drug loading of 77.5 or 79.5 weight% levodopa. As can be seen in figure 17, the flexibility in the release profiles is maintained even with an active ingredient loading of nearly 80 weight% levodopa. The data confirm that the floating gastric retentive drug delivery system of the invention is also suitable for other active substances. Example 12

Determination of drug release of floating gastric retentive drug delivery systems comprising gabapentin Drug release was also tested for samples comprising 49.5 weight% gabapentin. The manufacture of the closed hollow bodies and testing of drug release over a time period of 12 hours was performed as described above. For extruding gabapentin loaded hollow bodies, the polymer component comprised Eudragit® RS PO, Eudragit® E PO and glycerol dibehenate (Compritol® 888 ATO) as an additional ingredient. Glycerol dibehenate has both retarding properties and a very low melting point, which allowed the temperature during extrusion to be lowered below 100 °C. This is advantageous for gabapentin as the drug rapidly degrades under heat. The following table 8 summarises the gabapentin formulations. For the examples GBP 1 and GBP 2 a 7 mm / 5 mm outer/inner die setting was used. Table 8: gabapentin formulation composition

The figure 18 shows the drug release of the samples GBP 1 and GBP 2 having a drug loading of 49.5 weight% gabapentin. As can be seen in figure 18, also for gabapentin as the active ingredient a delayed release over 12 hours could be achieved.

Example 13

Determination of drug release and buoyancy of floating gastric retentive drug delivery systems sealed with caps and plugs Drug release and buoyancy was tested for samples using different polymer components comprising 50 weight% metformin and sealed by different methods. The hollow cylindrical bodies were manufactured using an outer die diameter of 7 mm and an inner die diameter of 4 mm using the polymer components comprising 50 weight% metformin given in table 9. The caps and plugs were manufactured from polylactic acid (PLA, Prusament PLA Pearl Mouse, Prusa Research) without metformin using 3D printing.

Samples denoted“M“ were closed by melting the open ends of cut cylinders and pressing into heated round shaped mould. Samples denoted“St/M“ were closed by heating the open ends to 100 °C and pressing plugs on the heated ends. Samples denoted“Ka/LM“ were closed by moistening the open ends with isopropanol and pressing caps on the moistened ends. Samples denoted“St/LM“ were closed by moistening the open ends with isopropanol and pressing plugs on the moistened ends. Samples denoted“Ka/M“ were closed by heating the open ends to 100 °C and pressing caps on the heated ends. The following table 9 summarises the formulations and sealing methods.

Table 9: Metformin formulation composition and sealing methods

The figure 20 shows the drug release over a time period of 12 hours for the samples Met 24 and Met 25 having a drug load of 50 % (w/w) metformin. As can be seen in figure 20, a similar release profile for each formulation in a range of 1 hour to more than 12 hours was achieved, irrespective of the closing method. This shows that sealing the floating gastric retentive drug delivery systems with caps or plugs has no negative impact on drug release.

The figure 21 shows the buoyancy over a time period of 12 hours for the samples Met 23. As can be seen in figure 21, the floating force of the Met 23 samples was comparable for all closing methods. The samples closed by caps showed slightly better floating capacity compared to plugs, which is attributed to the internal parts of the plugs replacing air in the hollow body. This shows that the floating gastric retentive drug delivery systems can be tightly sealed with caps or plugs manufactured from water insoluble polymer.

In summary, the results show that a floating gastric retentive drug delivery system with very high active substance loading can be provided. The results further illustrate that by varying the polymer composition a wide range of release profiles can be achieved. It is a particular advantage of the floating gastric retentive drug delivery system of the invention that changes in the composition of the wall of the closed hollow body will not affect the buoyancy.

Claims

P a t e n t c l a i m s

1. A floating gastric retentive drug delivery system, which has a density below 1 g/cm³, and which has the form of a closed hollow body, the hollow body being formed from a release sustaining matrix of a polymer component comprising an active ingredient dispersed therein, wherein the hollow body comprises the active ingredient in an amount in a range of > 45 weight% to < 85 weigh t%, based on a weight of 100 weight% of the hollow body.

2. The floating gastric retentive drug delivery system according to claim 1, wherein the amount of the active ingredient is in a range of > 50 weight% to < 80 weight%, preferably in a range of > 55 weight% to < 75 weight%, based on a weight of 100 weight% of the hollow body.

3. The floating gastric retentive drug delivery system according to claim 1 or 2, wherein the active ingredient is selected from the group comprising metformin, levodopa, pregabalin and/or gabapentin.

4. The floating gastric retentive drug delivery system according to any one of the

preceding claims, wherein the polymer compound comprises:

- in a range of > 10 weight% to < 55 weight% of a polymer or copolymer of acrylic acid and/or methacrylic acid, and

- in a range of > 3 weight% to < 40 weight% of a water-soluble polymer selected from the group comprising poly(butyl methacrylate, 2-dimethyl aminoethyl

methylacrylate), ethylene oxide/propylene oxide copolymer, polyvinyl alcohol, polyethylenoxide, polyethylene glycol and/or polyvinyl based polymers selected from polyvinylpyrrolidone, polyvinylpyrrolidone/vinylacetate copolymer and

5. The floating gastric retentive drug delivery system according to any one of the preceding claims, wherein the polymer compound comprises:

- in a range of > 10 weight% to < 55 weight% of a polymer selected from the group comprising polyvinyl acetate, polyvinyl acetate phthalate, poly(acrylic acid), cellulose-based polymers preferably ethylcellulose and hydroxypropylmethyl cellulose, polyethylenoxide and a mixture of polyvinyl acetate and

polyvinylpyrrolidone, and

- in a range of > 3 weight% to < 40 weight% of a water-soluble polymer selected from the group comprising ethylene oxide/propylene oxide copolymer, polyvinyl alcohol, polyethylene glycol and/or polyvinyl based polymers selected from

polyvinylpyrrolidone, polyvinylpyrrolidone/vinylacetate copolymer and

6. The floating gastric retentive drug delivery system according to any one of the

preceding claims, wherein the polymer compound comprises a lipid based polymer selected from the group of glyceryl dibehenate, glyceryl distearate and glyceryl monostearate in a range of > 5 weight% to < 20 weight%, based on a weight of 100 weight% of the hollow body.

7. The floating gastric retentive drug delivery system according to any one of the

preceding claims, wherein the hollow body comprises the active ingredient in an amount in a range of > 50 weight% to < 85 weight% and a polymer or copolymer of acrylic acid and/or methacrylic acid in a range of > 15 weight% to < 50 weight%, based on a weight of 100 weight% of the hollow body.

8. The floating gastric retentive drug delivery system according to any one of the preceding claims, wherein the hollow body has a wall thickness in a range of > 0.3 mm to < 3 mm, preferably in a range of > 0.5 mm to < 2.5 mm, more preferably in a range of > 0.7 mm to < 2 mm, even more preferably in a range of > 1 mm to < 2 mm.

9. The floating gastric retentive drug delivery system according to any one of the

preceding claims, wherein the closed hollow body comprises a cavity, which cavity gets in contact with a medium surrounding the closed hollow body after a period of floating, such that the medium enters into the cavity and the gastric retentive drug delivery system sinks into the medium.

10. The floating gastric retentive drug delivery system according to any one of the

preceding claims, wherein the closed hollow body comprises a hollow body (2) providing a cavity having at least one opening and at least one sealing cap (4) and/or plug (6) for closing the at least one opening.

11. The floating gastric retentive drug delivery system according to claim 10, wherein the closed hollow body comprises a cylindrical hollow body (2) and at least one sealing cap (4) and/or plug (6) for closing one or both ends of the cylindrical hollow body (2).

12. A process of manufacturing a floating gastric retentive drug delivery system according to any of claims 1 to 11, wherein the closed hollow body is manufactured by a process comprising the steps of:

13. The process according to claim 12, wherein forming the closed hollow body comprises the steps of:

a) cutting the extrudate to give a cylindrical hollow body (2);

b) providing sealing caps (4) or plugs (6), preferably formed by injection moulding, 3D-printing or tableting; and

c) sealing the cylindrical hollow body (2) with the sealing caps (4) or plugs (6).

14. A floating gastric retentive drug delivery system manufactured by the process

according to claims 12 or 13.

15. A floating gastric retentive drug delivery system, comprising a hollow body (2) providing a cavity having at least one opening and at least one sealing cap (4) and/or plug (6) for closing the at least one opening.