United States Patent:   6,027,748

Assignee:  Jagotec AG (Hergiswill, CH)

Filed:  January 6, 1998

Described herein is a particular type of pharmaceutical tablet, for oral use, which is formed by one or more layers, and is specifically designed for controlled release of active principles that present problems of bio-availability linked to absorption in the gastro-intestinal tract, and in particular active principles that present an erratic and unpredictable absorption linked to the presence or absence of food at the level of the stomach and/or of the first portion of the small intestine, the said pharmaceutical form being characterized in that it is completely coated with one or more films of a biocompatible and biodegradable polymeric material.

DESCRIPTION OF THE INVENTION

It has now been unexpectedly found, and this finding forms the subject of the present industrial patent application, that, using precise production technologies that are industrially highly reproducible, it is possible to produce therapeutic systems that do not cause dose dumping and that, above all, enable the problems of variability and unpredictability involved in absorption due to the presence or absence of food in the gastrointestinal tract to be overcome; i.e., a new therapeutic system has been developed and experimented which simultaneously solves the problems linked to dose dumping and those linked to the food effect.

A pharmaceutical form has above all been obtained which presents innovative advantages of safety and therapeutic effectiveness, in that the food effect is completely eliminated; i.e., the absorption of the active principle takes place in a reproducible way either in the presence or in the absence of food.

It has in fact been found, and this finding likewise forms the subject of the present invention, that by applying a film of biocompatible and biodegradable polymeric material on a pharmaceutical form serving as vehicle of the active principle, it is possible to obtain in vivo kinetics of absorption characterized by reduced variability and not influenced by the presence of food (food effect). In addition, it is possible to obtain a delay in the initial phase of release of the active principle, thus avoiding an excessively rapid release (dose dumping) of the active principle.

This result may be highlighted by the determination of the blood plasma levels of the drug obtainable after administration of the new coated tablet, as claimed in the present patent, to healthy volunteers both in fasting conditions and after a standardized meal.

In a typical embodiment (as will be better defined in the examples provided in the present patent application), the new finding has the appearance of a rounded tablet, which contains the active principle. Typically, but not necessarily, the tablet may have one, two, or three layers, one of which serves as vehicle of the drug, whilst the other layer, or the other two layers, have exclusively the function of barriers limiting release, as described and claimed in the U.S. Pat. No. 4,839,177 (1989), and above all in the subsequent U.S. Pat. No. 5,422,123 (1995).

The present invention, however, is characterized by the fact that the aforesaid tablet, which serves as vehicle for the said active principle that presents problems of variability and unpredictability of absorption, undergoes a process of film-coating with a biocompatible and biodegradable, preferably gastro-resistant, polymeric material, using consolidated production processes that guarantee high yield and are altogether acceptable from the pharmaceutical point of view.

A consequence of these characteristics is the total absence of the dose-dumping phenomenon, as well as the possibility of designing therapeutic systems that present release profiles that may be pre-programmed according to the specific therapeutic requirements sought for a given active principle.

The therapeutic form that is the subject of the present patent application consists of a coated tablet containing, in addition to the active principle, suitable excipients. One or more of the said pharmaceutical forms may be contained in capsules of hard gelatine with the aim of vehicling the desired quantities of active principle. The tablets that are the subject of the present patent application are characterized in that they are rounded, so as to facilitate the film-coating process, and in that they have diameters of from 2 to 13 mm, and preferably of from 4 to 10 mm, and a thickness of from 2 to 8 mm, and preferably of from 3 to 6 mm.

One of the characteristics of the tablet of the invention consists in the fact that, in the preparation of the core of the tablet containing the active principle, polymeric substances are used that are capable of modulating (i.e., slowing down and/or speeding up) release of the active principle.

As active principles the following may be employed: steroid anti-inflammatory drugs, such as dexamethasone, hydrocortisone and methylprednisolone, or non-steroidal anti-inflammatory drugs (NSAIDs), such as sodium diclofenac, indomethacin, ibuprofen, ketoprofen, diflunisal, piroxicam, naproxen, flurbiprofen, sodium tolmetin, or sleep-inducing drugs and tranquillizers, such as diazepam, nitrazepam, flurazepam, oxazepam, chlordiazepoxide, medazepam, lorazepam, or active principles for the prevention of attacks of angina, such as nifedipine, nitrendipine, nicardipine, or antihistamine and/or anti-asthmatic drugs, such as ephedrine, terfenadine, theophylline, chlorpheniramine, or antibiotics, such as ampicillin, amoxicillin, cephadrine, their salts or derivatives, and in particular in association with .beta.-lactamase inhibitors, such as clavulanic acid.

The polymer substances used in the preparation of the tablet are chosen in the group comprising hydroxypropylmethyl cellulose with molecular weight of between 1,000 and 4,000,000, hydroxypropyl cellulose with molecular weight of from 2,000 to 2,000,000, carboxyvinyl polymers, polyvinyl alcohols, glucans, scleroglucans, mannans, xanthans, alginic acid and its derivatives, polyanhydrides, polyaminoacids, carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, polyvinyl pyrrolidone, cross-linked polyvinyl pyrrolidone, carboxymethylamide, potassium methacrylate/divinylbenzene copolymer, starches and their derivatives, .beta.-cyclodextrin, dextrin derivatives in general with linear or branched chains, ethyl cellulose, methyl cellulose and cellulose derivatives in general. Said polymer substances are present in a percentage of from 5% to 90% with respect to the total weight of the tablet, and preferably of from 10% to 50%.

Of all the polymers referred to above, there are available on the market various types characterized by different chemico-physical characteristics as well as characteristics regarding solubility and gel formation; in particular, as far as hydroxypropylmethyl cellulose is concerned, various types may be used having different molecular weights (of from 1,000 to 4,000,000) and different degrees of substitution. Said types of hydroxypropylmethyl cellulose present different characteristics, being prevalently erodible or prevalently gellable according to the viscosity and the degree of substitution (DS) that they present in the polymer chain. The adjuvating substances are chosen in the group comprising glyceryl monostearate and its semi-synthetic triglyceride derivatives, semi-synthetic glycerides, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, ethyl alcohol, polyvinyl pyrrolidone, glycerin, ethyl cellulose, methyl cellulose, sodium carboxylmethyl cellulose, magnesium stearate, stearic acid, talcum, sodium benzoate, boric acid, polyoxyethylene glycols, and colloidal silica, as well as other natural or synthetic substances that are well known to those skilled in the sector.

The following substances may moreover be employed: diluents, binders, lubricants, buffering agents, anti-adherent agents, gliding agents, as well as other substances capable of bestowing on the said layer the desired characteristics, as will be illustrated in greater detail by the examples given in the sequel.

The plasticizing substances are chosen from the group comprising hydrogenated castor oil, cetyl alcohol, cetylstearyl alcohol, fatty acids, glycerides and triglycerides as such or variously substituted, and polyoxyethylene glycols and their derivatives having different molecular weights, normally chosen in the 400-6,000,000 range. These have the function of conferring on the formulation the required elasticity and of improving the characteristics of compressibility, adhesion and cohesion.

Finally, excipients may be used that are commonly employed in pharmaceutical techniques, such as mannitol, lactose, sorbitol, xylitol, talcum, magnesium stearate, colloidal silica, as well as glyceryl monostearate, hydrogenated castor oil, waxes, and mono-, bi- and tri-substituted glycerides.

When the aim is to favour the penetration of water and/or aqueous fluids into the layer serving as vehicle of the active principle or core, hydrophilic diluents are introduced, such as mannitol, lactose, starches of various origin, sorbitol, xylitol, or else surfactants, wetting substances and/or substances generally favouring water penetration into the compact are introduced into the formulation.

When, instead, the aim is to slow down the penetration of water and/or aqueous fluids into the layer serving as vehicle of the active principle or core, hydrophobic diluents are introduced, such as glyceryl monostearate, glyceryl behenate, hydrogenated castor oil, waxes, and mono-, bi- and tri-substituted glycerides.

The pharmaceutical tablets of the invention have the advantage of releasing the vehicled active principle in a programmed manner; hence, it is possible to vehicle an appropriate amount of the drug, thus preventing the dose-dumping phenomenon and meeting specific therapeutic requirements by means of the controlled release of the active principle vehicled. In the simplest embodiment, the system appears as a tablet coated with one or more layers, at least one of which contains the active principle suitably vehicled. Alternatively this core could consist of a tablet as described in the U.S. Pat. No. 5,422,123; namely, a system with one or more barriers that limit the portion of the surface of the layer containing the active principle that is exposed to the dissolution means. This portion accounts, on average, for 50-70% of the total surface of the tablet, and it is therefore only from this limited surface that the active principle can be released in the initial phase of contact with the dissolution means after the protection of the coating has been removed.

It should be pointed out that, if the system is one with two barrier layers, the surface from which the active principle is initially released is more limited, and generally accounts for 20-50% of the total area of the pharmaceutical form.

A fundamental characteristic for obtaining the desired therapeutic effect is the fact that on the tablet according to the invention is applied a film of biocompatible and biodegradable polymeric material, or one or more coating films of different compositions may be applied.

For the coating of the tablet, the following materials may be preferably used: polymeric materials, such as derivatives of cellulose (hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and their respective derivatives), polymers of alginic acid and its salts and derivatives, derivatives of acrylic and methacrylic acid, polymers and copolymers of said acids and/or their respective esters, which present different degrees of permeability according to their chemico-physical properties; for example, copolymers synthesized from esters of acrylic and methacrylic acid with a low content of quaternary ammonium groups. The molar ratio of these ammonium groups with respect to the remaining neutral portions of esters of (meth)acrylic acid may range from 1:20 to 1:40, whilst the molecular weight is approximately 150,000.

To obtain gastro-resistance, polymeric materials may be used, such as cellulose acetophthalate, cellulose acetopropionate, cellulose trimellitate, methylvinyl ether-maleic anhydride copolymer, dibutyl phthalate, acrylic and methacrylic polymers and copolymers, having different molecular weights and degrees of solubility depending on their different pH values; for example, anionic-type copolymers consisting of methacrylic acid and methyl ester of methacrylic acid where the ratio between the free carboxyl groups and the esterified groups may range from 1:1 to 1:2, whilst the molecular weight is approximately 135,000.

The said coating is of the gastro-resistant and entero-soluble type, so as to enable activation of the system only after the tablet has reached the duodeno-intestinal tract, or else with pH-dependent solubility, which enables release of the active principle when the pH in the stomach exceeds a given threshold value on account of the presence of food.

Said materials may be applied on the finished pharmaceutical form by means of the classical process of film-coating using said polymers in a solution of organic solvents, but preferably in aqueous dispersion and operating by means of nebulization in a revolving pan or in a fluidized bed.

The said materials may be used in association with other retarding polymers or with the addition of other adjuvants, such as lactose starch, colouring agents, such as iron oxides, opacifying agents, such as talcum and titanium dioxide, and sweeteners. The invention is moreover characterized in that, in the film-coating phase, a plasticizing agent is used, preferably triethyl citrate, diethyl phthalate, diacetin, triacetin, dibutyl phthalate, dibutyl tartrate, tributyl acetate, castor oil, cetyl alcohol, cetylstearyl alcohol, fatty acids, glycerides and triglycerides as such or variously substituted, polyoxyethylene glycols in different percentages with respect to the polymeric material of the coating, but preferably in percentages of between 10% and 20%.

Claim 1 of 15 Claims

1. A pharmaceutical tablet designed for the controlled release of active principles which exhibits a different biological absorption rate in the presence and in the absence of food, which comprises: a core having one or more layers, at least one of which serves as a vehicle for the active principle, while the other layer or layers, selected from the group consisting of erodible, gellable, and erodible and gellable hydrophilic polymers, function as a barrier, being initially impermeable to the passage of the active principle and said tablet being completely coated with one or more films of a biocompatible and biodegradable polymeric material, at least one of said films being of a gastro-resistant and entero-soluble material selected from the group consisting of: cellulose acetophthalate, cellulose acetopropionate, cellulose trimellitate, copolymers of methacrylic and acrylic acids, copolymers of methacrylic acid and methylmethacrylate and methylvinylether-maleic anhydride copolymers.

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