The invention relates to the field of oral dosage forms for glipizide.

BACKGROUND OF THE INVENTION The present invention relates to a therapeutic system for the oral administration of glipizide, comprising a compartment for a therapeutically effective amount of the active ingredient alipizide, swelling agents and, optionally, water-soluble substances and to processes for the manufacture of such a system.

Orally administered therapeutic systems for delivering therapeutic amounts of glipizide in a controlled release way are known. They rely on a technology known as"push-pull"system and are disclosed in US Patent Specifications 4,327,725,4,612,008,5,024,843,5,082,668, 5. 091,190,5,545,413,5,591,454. The system can be described as a two-layered tablet surrounded by a semi-permeable membrane and a hole, which allows the body fluids to communicate with the active substance of the tablet. Glipizide can be delivered with this system at therapeutic amounts. US Patent Specification 4,992,278 discloses a system which uses also the osmotic principle but achieves the controlled release of sparingly soluble active ingredients by using a one layer tablet surrounded by a semi-permeable membrane. This

invention discloses the use of said system for carbamazepine, nifedipine and acetylsalicylic acid.

We surprisingly discovered that such a system which is obtained by an inventive selection of specific excipients allows the controlled release of therapeutic amounts ofglipizide similar or even better as compared with those obtained with a two-layered tablet. Also, the simpler design of the tablet as compared with push-pull systems leads to a significant reduction of costs at the manufacture level. It is definitely more cost effective to manufacture a one- layered tablet than a two-layered one.

OBJECTS OF THE INVENTION It is the object of the invention to provide an oral dosage form for glipizide characterized by the controlled release or sustained release of the active agent.

It is yet another object of the invention to provide the controlled release of glipizide, similar or better than the release pattern in a two-layered tablet, by preparing a mono-layer tablet in combination with an inventive selection of specific excipients.

SUMMARY OF THE INVENTION Surprisingly, it was found that a oral dosage form comprising a core consisting essentially of glipizide, a hydrophilic, polymeric swelling agent consisting of a mixture of a vinylpyrrolidone/vinyl acetate copolymer with an ethylene oxide homopolymer, optionally a water-soluble substance for inducing osmosis and, optionally, further pharmaceutically acceptable adjuncts, surrounded by a semi-permeable wall with a hole through said semi- permeable wall connecting said core with the external environment, is effectively delivering glipizide in a controlled or sustained release pattern, after wetting of the dosage form, to the

external environment.

DETAILED DESCRIPTION OF THE INVENTION The present invention, therefore, relates to an oral delivery form adapted to deliver glipizide The therapeutic system according to the invention comprises: (a) core comprising i. glipizide in an amount sufficient to deliver an effective amount thereof over the intended delivery time period and ii. a hydrophillc, polymeric swelling agent consisting of a mixture of a vinylpyrrolidone/vinyl acetate copolymer with an ethylene oxide homopolymer, optionally a water-soluble substance for inducing osmosis and, optionally, further pharmaceutically acceptable adjuncts (b) a casing made of a material that is permeable to water and is impermeable to the components of the core containing glipizide, (c) a hole through said semi-permeable wall connecting said core with the external environment.

The definitions and terms used herein before and hereinafter preferably have the following meanings in the context of the description of the present invention : Within the context of the description of the present invention the term controlled release is defined by the delivery of approximately constant predetermined amounts of the therapeutic agent glipizide within the time period considered (approximate zero order release).

Glipizide is l-cyclohexyl-3-(4-[2-(z-methylpyrazine-2-carboxami dolbenzenesulphonyl) urea

being used as hypo-giycaemic agent. It is administered orally in the treatment of non-insulin dependent diabetes mellitus and has a duration of action of up to 24 hours. The usual initial dose is 2.5 to 5 mg daily given as a single dose 15 to 30 min before breakfast. Dosage may be adjusted at intervals of several days by amounts of 2.5 to 5 mg daily, to a maximum of 40 mg daily. Glipizide is metabolized mainly in the liver and excreted chiefly in the urine, largely as inactive metabolite. (Martindale, The Extra Pharmacopoeia, 31S'Ed). Once-a-day controlled release formulations are designed to deliver up to 10 mg of the active ingredient (Physicians'Desk Reference, 52nid Edition 1998).

The hydrophilic swelling agent contained in the core (a) is a polymer which interacts with water from the aqueous body fluid contained in the gastro-intestinal tract, swells and is able to expand until it reaches a state of equilibrium-The swelling agent is capable of absorbing large quantities of water and of producing the swelling pressure required for the therapeutic system to function.

The hydrophilic, polymeric swelling agent used in the therapeutic system according to the invention consists of a mixture of a vinylpyrrolidone/vinyl acetate copolymer and an ethylene oxide homopolymer. This mixture has the surprising advantage that the pressure produced during swelling does not lead to rupturing of the system and the swelling speed is uniform so that almost constant amounts of active ingredient are released from the system.

The vinylpyrrolidone/vinyl acetate copolymer component preferably has a molecular weight of 60, 000. +/-. 15, 000. The ratio of the monomer vinylpyrrolidone and vinyl acetate, which forms the basis of the copolymer, is preferably approximately 60: 40 (% by weight). The vinylprrolidone/vinyl acetate copolymer has the following properties : purity: 95% (remainder water), insoluble in ether, aliphatic hydrocarbons, readily soluble in water, ethyl and isopropyl alcohol, methylene chloride, glycerin and 1,2-propylene glycol, pH value of a 10% aqueous solution 3-5, viscosity (10% aqueous solution) : 5 mPas, see H.

P. Fiedler, Lexikon der Hitfsstoffe, li. P. Fiedler, Editio Cantor 1982.

Vinylpyrrolidone/vinyl acetate copolymers are known and/or can be manufactured in a manner known per se with any desired mixing ratio of the monomers. The preferred 60 : 40 copolymer is commercially available, for example, under the trade name Kollidon. 0. VA 64 (BASF).

The vinylpyrrolidone/vinyl acetate copolymer is mixed with an ethylene oxide homopolymer having a degree of polymerization of approximately 2.0 x 103-1. 0 x 1 and a corresponding approximate molecular weight of approximately 1.0 x 105-5. 0 x 106 and having the following properties: for a molar weight of approximately 4,000 and above solid wax-like substances. Miscible in any ratio with water and each other. Soluble in methanol, ethaciol, acetone, methylene chloride.

Ethylene oxide homopolymers (polyethylene glycols) are known and are commercially available in various degrees of polymerization, for example under the name Polyox. 0.

(Union Carbide). It is preferable to use Polyox. 0. (coagulant) having a molecular weight of more than 1. 0 x lO6 In a preferred embodiment of the invention a 1: 1 mixture (by weight) of vinylpyrrolidone/vinyl acetate copolymer (commercial form: Kollidon. #. VA 64) and ethylene oxide homopolymer (comjnerda ! form Polyox. #. MW: 5.0 x 106) is used.

The hydrophilic, polymeric swelling agent can be present in the core in parts by weight of approximately 5-80%, based on the total weight of the therapeutic system in question.

The casing (b) made of a material that is permeable to water and impermeable to the

components of the core containing the active ingredient can be in the form of a semi- permeable membrane which is permeable to water but is impermeable to the constituents contained in the core of the form of administration, such as active ingredients, swelling agents, adjuncts etc The polymeric substances described in the literature, for example in U. S. Pat. Nos.

3,916,899 and 3, 977,404, which are not metabolized in the gastro-intestinal tract, that is to say are excreted unchanged, are suitable for the manufacture of the casing made of semi- permeable material. For example, it is possible to use acylated cellulose derivatives (cellulose esters) that are mono-to tri-substituted by acetyl groups or mono-or di-substituted by acetyl groups and substituted by a further acyl radical other than acetyl, for example cellulose acetate, cellulose triacetate, agar acetate, amylose acetate, cellulose acetate ethyl carbamate, cellulose acetate phthalate, cellulose acetate methyl carbamate, cellulose acetate succinate, cellulose acetate dimethylaminoacetate, cellulose acetate ethyl carbonate, cellulose acetate chloroacetate, cellulose acetate ethyl oxalate, cellulose acetate methyl sulphonate, cellulose acetate butyl sulphonate, cellulose acetate propionate, cellulose acetate diethylamino-acetate, cellulose acetate octate, cellulose acetate laurate, cellulose acetate p- toluenesulphonate, cellulose acetate butyrate and other cellulose acetate derivatives. Also suitable as semi-permeable membrane material are hydroxypropylmethyl-cellulose and polymeric epoxides, copolymers of alkylene oxides and alkyl glycidyl ethers, polyglycols or polylactic acid derivatives and further derivatives thereof. It is also possible to use mixtures, such as, for example, of acrylates that are insoluble in water per se (for example the copolymer of acrylic acid ethyl ester and methacrylic acid methyl ester).

Water-soluble substances that are suitable for inducing osmosis are in principle all water- soluble substances acceptable for use in pharmacy, for example the water-soluble adjuncts mentioned in pharmacopoeias or in"Hager"as well as in Remington's Pharmaceutical Science. Especially suitable are pharmaceutically acceptable water-soluble salts of inorganic or organic acids or non-ionic organic substances having an especially high degree of

solubility in water, for example carbohydrates, such as sugar, or amino acids, for example glycine.

Such water-soluble substances for inducing osmosis are, for example, inorganic salts, such as magnesium chloride or sulfate, lithium, sodium or potassium chloride, lithium, sodium or potassium sulfate or sodium or potassium hydro- salts of organic acids, such as sodium or potassium acetate, magnesium succinate, sodium benzoate, sodium citrate or sodium ascorbate, carbohydrates, such as arabinose, ribose or xylose (pentoses), glucose, fructose, galactose or mannose (hexoses), sucrose, maltose or lactose (disaccharides) or raffinose (trisaccharides), sugar alcohols such as mannitol, sorbitol, galactitol, inositol and xylitol, water-soluble amino acids, such as glycine, leucine, alanine or methiorune, urea etc., and mixtures thereof. These water-soluble adjuncts can be present in the core in parts by weight of approximately 0.01-35%, based on the total weight of the therapeutic system in question. Further adjuncts are, for example, plasticizers, which improve the flow properties and the handling of the hydrophilic polymeric material during the manufacture of the core, for example glycerin, triethyl citrate, diethyl phthalate, diethyl sebacate, and the like. The amount of plasticizer added is approximately from 0.01 to 20% by weight, based on the total amount of the therapeutic system.

It is also possible to add surface-active substances, so-called surfactants, in the manufacture of the core, for example anionic surfactants of the alkyl sulfate type, for example sodium, potassium or magnesium n-dodecyl sulphate, n-tetradecyl sulphate, n-hexadecyl sulphate or n-octadecyl sulphate, alkyl ether sulfates, for example sodium, potassium or magnesium n- dodecyloxyethyl sulphate, n-tetradecyloxyethyl sulphate, n-hexadecyl-oxyethyl sulphate or n-octadecyloxyetliyl sulphate or alkanesulphonates, for example sodium, potassium or magnesium n-dodecanesulphonate, n-tetradecanesulphonate, n-hexadecanesulphonate or n- octadecanesulphonate.

Suitable surfactants are, in addition, non-ionic surfactants of the fatty acid/polyhydroxy

alcohol ester type, such as sorbitan monolaurate, oleate, stearate or palmitate, sorbitan tristearate or trioleate, polyoxyethylene adducts of fatty acid/polyhydroxy alcohol esters, such as polyoxyethylene sorbitan monolaurate, oleate, stearate, palmitate, tristearate or trioleate, polyethylene glycol/fatty acid esters, such as polyoxyethyl stearate, polyethylene lcol-400 steacate, polyethylene glycol-2000 stearate, especially ethylene oxide/propylene oxide block polymers of the Pluronic. 0. (BWC) or Synperonic. e). (ICI) type.

Further adjuncts are, for example, pulverulent carrier materials, such as lactose, saccharose, sorbitol, mannitol, starch, for example potato starch, corn starch or amylopectin, or cellulose, especially microcrystalline cellulose.

The expression"passage through the casing (b) for the transport of the constituents contained in the core into the surrounding aqueous body fluid"covers apparatus as well as methods suitable for releasing the active ingredient preparation from the core of the therapeutic system. The expression includes passages, openings, bores, holes and the like through the casing (b), acting as a semi-permeable membrane, which connect the surface of the casing and the core. The passage can be made by mechanical drilling or laser drilling or by decomposing a degradable constituent, for example a gelatin plug, forming a passage in the casing of the therapeutic system. In one embodiment the passage can be formed in response to the hydrostatic pressure acting on the therapeutic system. In another embodiment two or more passages can be made at any desired point in the system. The passage can also be formed by mechanical breaking up of the layers during administration of the system. The passage has a minimal diameter, which is dependent on the particle size of the crystals of active ingredient. The diameter of the passage must be greater than the average length of the glipizide particles. The maximum diameter is likewise fixed approximately. It should not be so large that it allows aqueous body fluid to enter the therapeutic system as a result of convection. A precise description of the manufacture of the passage and the maximum and minimum dimensions thereof is contained in U. S. Pat. Nos. 3,485,770 and 3,916,899 and the associated drawings.

The therapeutic system according to the invention can be of different shapes and can be, for example, round, oval, oblong or cylindrical or the like, and can be of various sizes depending on the amount it contains. The therapeutic system can, furthermore, be transparent, colorless or colored and may carry writing to impart an individual appearance to the product and/or to make it instantly recognizable.

The therapeutic system according to the invention has valuable pharmacological properties and can be used in the peroral administration of an active amount of glipizide. An improvement in the therapeutic effect as compared with that of solid forms of administration customary hitherto, such as tablets and dragees is achieved.

The drug release of the delivery form is explained by the action of water on the water soluble aridlor swelling agents contained in the core of the dosage form thus releasing constant amounts of active agents over the time period considered. The action of water with the water soluble and/or swelling agents results in a build-up of osmotic pressure or swelling pressure or a combination of both. Since the semi-permeable casing (b) is rigid or at least only slightly elastic, the pressure produced by osmosis and swelling can be balanced only by release of the material contained in tie core through the passage (c) in the membrane.

The therapeutic system according to the invention comprises: (a) core comprising i. glipizide in an amount sufficient to deliver an effective amount thereof over the intended delivery time period and ii. a hydrophilic, polymeric swelling agent consisting of a mixture of a vinylpyrrolidone/viny acetate copolymer with an ethylene oxide homopolymer, optionally a

water-soluble substance for inducing osmosis and, optionally, further pharmaceutically acceptable adjuncts (b) a casing made of a material that is permeable to water and is impermeable to the components of the core containing glipizide, (c) a hole through said semi-permeable wall connecting said core with the external environment.

A particularly preferred embodiment of the invention relates to a delivery form comprising (a) a core comprising i. a therapeutic active amount of glipizide between 1 and 100 mg, preferably 2 to 20 mg and ii. a 1: 1 mixture (by weight) of vinyl-pyrrolidoneivinyl acetate copolymer having a molecular weight of 60,000. +-. 15, 000 and a monomer ratio of approximately 60: 40 (% by weight) and ethylene oxide homopolymer having a degree of polymerization of from 2, 000 to 100, 000, sodium or potassium chloride for inducing osmosis and optionally further pharmaceutically acceptable adjuncts (b) a casing made of acylated cellulose, for example cellulose acetate, that is permeable to water and impermeable to the components of the core containing the active ingredient and to the ions contained in body fluids, for example in gastric or intestinal juices; (c) a passage through the casing (b) for the transport of the constituents contained in the core into the surrounding aqueous body fluid.

The present invention relates especially to a therapeutic system for the peroral administration of a therapeutic active amount of glipizide having the compositions indicated in the Examples.

The therapeutic system according to the invention is manufactured in accordance with processes known per se, for example by comminuting the constituents of the core, mixing them with one another, granulating them and compressing them, covering the core with a casing and, where appropriate, making the passage through the casing (a) for the transport of the constituents contained in the core, for example an opening through the semi-permeable membrane. Micronized glipizide is mixed with the constituents forming the core of the form of administration and granulated, for example by mixing the adjuncts, sodium chloride and Polyox. @. with the active ingredient and adding to this mixture a solution of polyvinylpyrrolidone/polyvinyl acetate in an organic solvent or water, removing the solvent and granulating and drying the residue. The granulate is then compressed and punched out into shapes, for example tablet cores, optionally with the addition of glidants, for example magnesium stearate, of conventional shape and size; for example, approximately 5-12 mm in diameter (round shapes) and approximately 4-8 mm (in width) and 10-22 mm (in length- oblong shapes).

All solvents in which copolymers of polyvinylpyrrolidone and polyvinyl acetate are soluble, especially water or lower alkanols, such as methanol, ethanol or isopropanol, are suitable.

The semi-permeable casing can be applied to the core containing the active ingredient by pouring, molding, spraying or by dipping the capsule into the material forming the semi- permeable casing. Another process that can be used to apply the casing is the air suspension procedure. This process comprises suspending and tumbling the materials (capsules or capsule cores) in a stream of air and an agent forming the casing until the casing surrounds and covers the core. The air suspension procedure is described in U. S. Pat. No. 2,799,241 and in J. Am. Pharm. Assoc., Vol. 48, p. 451-459, 1979, and in Volume 49, p. 82 to 84, 1980. An example of other preferred standard processes is the spray pan process, which is described, in Reminoton's Phannaceutical Sciences, 14th Edition, on pages 1686-1687.

The passage in the semi-permeable casing can be produced subsequently by mechanical drilling or using a laser. The following examples illustrate the invention.

Example 1:

Core (mg) Glipizide 2. 5 Microrcrystalline cellulose, Avicel @ 24. 5 Vinylpyrrolidone/vinyl acetate, 60: 40, Kollidone VA 64 90. 0 ! Polyethylene glycol, MW: SxlO, Polyox-Coagulant 90. 0 ; Sodium chloride-90 0- Magnesium stearate 3. 0 Subtotal 300.0 Casing I Cellulose acetate 320 16. 0 Cellulose acetate 398 20. 0 Polyethyleneglycol 2.5 Hydroxypropyl methylcellulose 2.5 Subtotal 41 Total 341.0 Glipizide which is ground to an average particle size of 5 ptm, methylhydroxypropylcellulose and sodium chloride are mixed in a planet mixer. This mixture is granulated with a part of the vinylpyrrolidone/vinyl acetate copolymer dissolved in a methanoUisopropanol mixture.

The mixture is forced through a sieve, and the resulting granules are dried in vacuum.

The dry granulate is mixed with the remainder of the vinylpyrrolidone/vinyl acetate copolymer, microcrystalline cellulose and magnesium stearate. The homogeneous mixture is then compressed to tablets (punch size 10 mm diameter).

The resulting tablet cores are coated in a fluidized bed coater (Aeromatic Strea (D) with an organic lacquer containing the constituents of the casing of the therapeutic system. The coated tablets are dried in a drying oven at 40 °C. for 48 hours. An opening about 750 um in diameter is made in each tablet using a drill or a laser.

Example 2 (Preparation is described in example 1) : Core Core Glipizide 5.0 10. 0 Microcrystalline cellulose, Avicel# 22.0 17. 0 , VinyIpyrrolidone/vinyl acetate, 60: 40, Kollidone VA 6490. 090. 0 Polyethylene glycol, MW : 5x106, Polyox-Coagulant 90.0 90. 0 'Sodium chloride 90. 0 90. 0 magnesium stearate 3. 0 3. 0 Subtotal300. 0300. 0 Casing , Cellulose acetate 320 16. 0 16. 0 Cellulose acetate 398 20.0 20.0 Polyethylene glycol 2. 5 2. 5 Hydroxypropyl methylcellulose 2. 5 2. 5 Subotal 41.0 41.0 Total 341.0 341. 0