Title:  Biconvex rapidly disintegrating dosage forms

United States Patent:  6,224,905

Assignee:  Janssen Pharmaceutica N.V. (BE)

Filed:  December 3, 1998

PCT NO:  PCT/EP97/03065

102(e) Date:  December 3, 1998

PCT PUB. Date:  December 24, 1997

A method for preparing solid rapidly disintegrating dosage forms shaped as biconvex tablets having symmetrical top and bottom surfaces and dosage forms obtainable thereby.

Description of the Invention

The present invention is concerned with a process for the preparation of a solid rapidly disintegrating dosage form comprising a porous network of matrix forming materials, which process comprises:

overfilling a mold with a predetermined amount of an aqueous composition comprising the matrix forming materials so that a convex meniscus is created on top of the mold;

freezing the aqueous composition in the mold; and

removing the solvent from the frozen composition by subjecting it to lyophilization or to solid state dissolution, thus leaving a porous network of matrix forming materials;

characterized in that the shape of the bottom surface of the mold is a mirror-image of the shape of the frozen meniscus on the top, the mirror-plane being parallel to the plane defined by the rim of the mold, thus yielding a dosage form shaped as a biconvex tablet having symmetrical top and bottom surfaces.

The aqueous compositions may be frozen by any conventional cooling process. For example, the aqueous compositions may be frozen by dispensing it into preformed molds corresponding to the size and shape of the desired dosage form and subsequently cooling such molds on refrigerated shelves or in refrigerated chambers. Alternatively, the molds containing the mixture may be passed through a stream of cold gas or vapor, such as liquid nitrogen in a freezing tunnel. In a preferred method of freezing, the composition is passed through a freezing tunnel into which liquid nitrogen is injected, the liquid nitrogen being vaporised and the resulting cold gaseous nitrogen being passed over the composition. Another method for freezing the aqueous compositions in the molds is to surround the molds in dry ice until the aqueous composition is frozen.

The best-known process of removing solvents from frozen solutions or dispersions is lyophilization which involves desolvation of the mixture by sublimation of the solvent under a vacuum. If desired, the frozen compositions may be stored in a cold store before the sublimation process is carried out. The sublimation may be carried out in a freeze drier by subjecting the frozen composition in the mold to reduced pressure and, if desired, controlled application of heat to aid the sublimation. The pressure can be below 4 mmHg (533 Pa), e.g. below 0.3 mmHg (40 Pa), for example 0.1 to 0.2 mmHg (13.3 to 26.6 Pa) or even below 0.05 mmHg (6.7 Pa). The initial temperature in the freeze drier may be, for example, as high as 60^oC. and this temperature can be reduced (e.g. to 40^oC.) as the temperature of the frozen composition increases. Various methods and improvements are described in the references cited at the very beginning of the specification. The frozen compositions also may be removed from the mold prior to lyophilization.

The dosage forms can also be prepared by a solid-state dissolution method of removing solid solvent from frozen samples. In this less conventional method, one or more matrix forming agents are dissolved or dispersed in a first solvent, frozen and subsequently contacted with a second solvent at a temperature at or higher than the solidification point of the second solvent and at a temperature at or lower than the solidification point of the first solvent. The first solvent in the solidified state is substantially miscible with the second solvent, while the matrix forming agent(s) are substantially insoluble in the second solvent. The first solvent is thereby substantially removed from the solidified matrix yielding a solid matrix substantially free of the first solvent. Typically, the first solvent is water and the second ethanol.

The biconvex dosage forms obtainable by the processes according to the present invention can be prepared in a variety of sizes. The volume of the mold is conveniently in the range of 300 to 2,000 mm³ (0.3 to 2 ml) and the volume of the dosage form is in the range of 350 to 2,500 mm³ (0.35 to 2.5 ml). Preferably, the volume of the mold is in the range of 350 to 800 mm³ (0.35 to 0.8 ml) and the volume of the dosage form is in the range of 450 to 1,000 mm³ (0.45 to 1 ml). In other words, the overfill or the volume of the convex meniscus above the mold can be up to 30% of the volume of the mold itself. Generally speaking said overfill will be in the range of from 20% to about 26% of the volume of the mold. Besides the extent of the overfill, the size of the convex meniscus is constrained by the contact angle between the aqueous composition and the material forming the rim of the mold and the surface tension of the aqueous composition. It is important to note that the larger the overfill is, the greater the curvature of the convex surface will be. This, in turn maximizes both the reduction in friability and the improvement of the handling properties.

The maximum depth of the mold is conveniently in the range of 3.4 to 6 mm; or the maximum thickness of the frozen composition in the mold is in the range of 5.0 to 8.5 mm. This maximum distance is the distance measured along the axis perpendicular to the rim of the mold and running through the upmost point of the meniscus on the top of the mold and the downmost point on the bottom of the mold. Lower values are generally not preferred because the resulting dosage forms are so thin that their strength is often insufficient, whereas larger values for the thickness are often undesirable because of the difficulty in effectively removing all solvent from such frozen compositions, especially when using lyophilization for removing the solvent.

The area of the surface defined by the rim of the mold is typically in the range of 100 to 500 mm² and has a rounded shape. The rounded shape contributes to the mechanical strength of the dosage form by reducing its friability. Said rounded shape can be circular, elliptical, oblong, oblate or polygonal, the latter preferably with rounded corners if the internal angle² 90^o.  

The mold can be, for example a depression in a metal plate (e.g. an aluminium plate). The plate may contain more than one depression, each depression being of the size and shape corresponding to the desired size of the shaped article. However, the mold may also be a depression in a sheet of filmic material. The filmic material may contain more than one depression. The filmic material may be similar to that employed in conventional blister packs which are used for packaging pharmaceutical tablets and the like medicament forms. For example, the filmic material may be made of thermoplastic material with the depressions formed by thermo-forming. The preferred filmic material is a talc-filled polypropylene film or a polyvinyl chloride film. Laminates of filmic material such as polyvinyl chloride/polyvinylidene chloride, polyvinyl chloride/poly-tetrafluorethylene or polyvinyl chloride/polyvinylidene chloride/polyethylene may also be used.

Where lyophilization is used, it may be advantageous to freeze the matrix material solution in molds that are coated or lined for easy release of the frozen material. Preferred molds are thermoformed cups made in talc-filled polypropylene sheets, optionally siliconized with a layer of silicone/simethicone baked on the surface(s) which come into contact with the aqueous composition.

The profile and volume of the bottom of the mold can be determined as described hereunder. A first mold having the desired volume and having a flat bottom (parallel to the rim of the mold) with the desired rounded shape is overfilled to the desired extent with the aqueous solution from which the final dosage form is to be prepared. This is processed to a dosage form by freezing and removing the solvent. The volume of the meniscus can be determined by substracting the mold volume from the volume added to the mold, or alternatively by calculating the volume from a number of equations describing the top surface of the meniscus. One such way comprises sectioning the dosage form along one or more symmetry planes, measuring the cross section where said symmetry plane intersects the top surface of the meniscus and determining the equation describing said intersection. As one can safely assume that an ellipse adequately describes such intersections, measurement of the major axis and minor axis readily provides the parameters required for each equation. The equations of the intersections of the top surface of the meniscus with the various symmetry planes (along which the cross sections were made) can then be used to derive the equation describing the top surface of the meniscus, and using art-known integration methods, the volume of the meniscus can then be calculated. With the thus obtained information one can then proceed to calculate how the mold needs to be reshaped in order to yield a biconvex symmetrical dosage form. For example, one can calculate to which extent the depth of the original mold needs to be reduced so that the volume of the mold is reduced by the volume of the meniscus, followed by adding the mirror image of the top meniscus at the bottom of the mold. This procedure secures that the convex bottom has both the shape and the volume of the meniscus on the top which will eventually be used. The data obtained in the calculations are then provided to the manufacturer of the mold so that the convex shaped mold can be shaped in metal.

The aqueous composition may be in a variety of forms such as a solution, a suspension, a dispersion, an emulsion, or a foam. Persons skilled in the art will recognize acceptable methods for preparing each of these. Water is preferably employed as the solvent in the composition which is frozen and desolvated. An additional co-solvent (such as an alcohol) may also be used if it is desired to improve the solubility, dispersability or wettability of any of the ingredients of the composition.

The dosage form comprises a porous network of matrix forming materials comprising:

i) a water-soluble, hydratable gel or foam-forming material,

ii) a rigidifying agent for the gel or foam-forming material, and optionally

iii) one or more amino acids.

Suitable water-soluble, hydratable gel or foam-forming materials include proteinaceous materials such as gelatin, gelatin A, gelatin B, fluid gelatin, modified fluid gelatin, gelatin derivatives, albumin, soy fiber protein, wheat and psyllium seed proteins, potato protein, papain; phospholipids such as coacervate egg lecithin, or lecithin; gums such as acacia, guar, agar, locust bean, xanthan and tragacanth gum; polysaccharides such as alginates, polymannuronic acid, chitosan, carrageenans, dextrans, dextrins, maltrins (maltodextrins), pectins, polygalacturonic acid, microcrystalline cellulose, corn syrup solids, konjac flour, rice flour, wheat gluten; synthetic polymers such as polyvinylpyrrolidone, sodium carboxymethyl-cellulose, sodium starch glycolate, hydroxyethylcellulose; and polypeptide/protein or polysaccharide complexes such as gelatin-acacia complexes, each singly or in combination.

Suitable rigidifying agents include monosaccharides, linear and cyclic oligosaccharides and polysaccharides, e.g. mannitol, xylitol, sorbitol, dextrose, fructose, sucrose, lactose, maltose, galactose, trehalose; cyclic sugars such as cyclodextrins e.g. beta-cyclodextrin and 2-hydroxypropyl-beta-cyclodextrin; dextran, dextrin; and further include inorganic substances such as sodium phosphate, sodium chloride, magnesium aluminum silicates, magnesium trisilicate, natural clays, or a combination thereof. The preferred rigidifying agent is mannitol.

Suitable amino acids have from 2 to 12 carbon atoms, e.g. glycine, L-alanine, L-aspartic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine, L-phenylalanine, or a combination thereof. Glycine is the preferred amino acid. Dosage forms containing glycine as one of the matrix forming components have several advantages: quick dissolution and disintegration in aqueous media, pleasant taste and mouthfeel, nutritional value, low caloric content and noncariogenicity. Of particular importance is the fact that these dosage forms can be produced with minimal cracking or meltback and that they have uniform porosity and adequate strength of handling, i.e. resistance to disintegration or crumbling under normal manufacturing and handling conditions. These latter properties contribute to the feasibility of the post-loading processes whereby active ingredients are loaded onto placebo or unloaded dosage forms.

Preferred matrix forming agents include pharmaceutical grade gelatins, pectins (non-hydrolyzed, partially hydrolyzed or hydrolyzed), glycine and mannitol. A particularly preferred combination of matrix forming agents comprises gelatin, glycine and mannitol.

The percentages and ratios mentioned in the following paragraphs are all by weight.

The solution or dispersion of materials for preparing the matrix can contain from 0.1% to 15% by weight of gel or foam forming material, in particular from 1% to 5% more in particular from 1.2% to 3%. It can further contain from 0.5% to 10%, in particular from 0.8% to 2.5% by weight of amino acid and from 0.5% to 10%, in particular from 1% to 4% of rigidifying agent, the remainder being solvent and secondary components as mentioned hereinafter.

The ratios between these materials may vary within certain ranges. In particular the weight by weight ratio of the total amount of amino acids to that of the water-soluble, hydratable gel or foam-forming material is from 1:1 to 1:3. A preferred ratio is 1.5: 1. The weight by weight ratio of the amount of the water-soluble, hydratable gel or foam-forming material to that of the rigidifying agent is from 2:1 to 1:2. A preferred ratio is 1.5:2.

Typically, the weight by weight ratio of the total amount of non-solvent components to that of the water in the aqueous composition is in the range of about 1:9 to 1:33, in particular from about 1:13 to 1:30, for example about 1:20.

Solid rapidly dissolving dosage forms find many applications, particularly where it is desired to administer, dispense or otherwise utilise an active ingredient in predetermined unit quantities. The active ingredient in particular is a drug substance for human of veterinary use.

The active ingredient used in the solid rapidly dissolving dosage form may be present in a coated form. For example, it may be present in particulate form and the particles of the active ingredient may be coated with an appropriate coating agent so as to protect it from process diluents, the aqueous environment of the suspension or of the oral or other mucosal cavity. or other environmental conditions that would dissolve or deteriorate said active ingredient. These coating materials may be selected from natural or synthetic polymers that are either hydrophilic or hydrophobic in nature or other hydrophobic materials such a fatty acid, glycerides, triglycerides and mixtures thereof. In this way, the taste of the active or bioactive agent may be masked, while at the same time permitting the solid dosage form to dissolve rapidly upon contact with physio-logical diluents. Examples of bitter active ingredients that may be coated in accordance with the present invention include acetaminophen. ibuprofen, chlorpheniramine maleate, pseudo-ephedrine, dextromethorphan, cisapride, domperidone, risperidone. Pharmaceutical applications comprise dosage forms having mucoadhesive properties or designed to deliver a drug at a controlled rate; dosing units designed to deliver drugs in the eye, in vaginal, rectal and other body orifices; solid dosage forms designed to replace liquid formulations; dry medicated preparations for topical application after resolvation (reconstitution); preparation of medicated units or sheets for topical application; preparation of more palatable dosage forms of drugs that exhibit disagreeable organoleptic properties; dosage forms for oral delivery of drugs to persons who have difficulty swallowing tablets or capsules.

Secondary components such as nutrients, vitamins, other active ingredients, sweeteners, flavouring agents, colouring agents, surfactants, preservatives, antioxidants, viscosity enhancers, minerals, diagnostics, fertilizers and insecticides may also be incorporated in the formulation of the dosage form.

The solution or suspension of which the dosage forms are made may further contain the secondary components mentioned before. Xanthan gum or polyacrylic acid polymers and salts thereof (also referred to as carbomers or carboxyvinyl polymers, e.g. Carbopol.TM.) may be added in order to increase viscosity, or to keep the components of the mixture in suspension.

The present invention also provides biconvex, solid rapidly disintegrating dosage forms obtainable by any one of the processes described hereinbefore.

The speed with which the biconvex tablet prepared by the inventive method dis-integrates is dependent entirely or at least in large part on the choice of matrix forming agent(s), their concentration and the solidification/desolvation process conditions. In particular, dosage forms of the size mentioned in the examples described hereinafter, will dissolve or disperse rapidly, for example, in less than about 10 seconds and generally faster e.g. in less than about 5 or even less, e.g. within 1 to 2 seconds.

The dosage forms disperse rapidly in water, e.g. in less than 10 seconds. The disintegration time of a dosage form is determined to check whether it is capable of being disintegrated by water sufficiently rapidly using a standard tablet disintegration apparatus as described in British Pharmacopoeia, 1980, Vol II, Appendix XII A, but with the standard 2.00 mm wire mesh replaced by stainless steel 40 mesh screen. A sample product is placed in a dry tube held above the surface of the water. The apparatus is started and the sample immersed in water at 20^oC. The sample should disperse on the liquid surface and any solid residue should pass through the 40 mesh screen within 10 seconds, preferably within 5 and ideally within 1 to 2 seconds.

Claim 1 of 23 Claims

What is claimed is:

1. A process for the preparation of a solid rapidly disintegrating dosage form comprising a porous network of matrix forming materials, wherein said matrix forming materials comprise

i) a water-soluble, hydratable gel or foam-forming material,

ii) a rigidifying agent for the gel or foam-forming material and optionally

iii) one or more amino acids and

which process comprises:

overfilling a mold with a predetermined amount of an aqueous composition comprising the matrix forming materials so that a convex meniscus is created on top of the mold;

freezing the aqueous composition in the mold; and

removing the solvent from the frozen composition by subjecting it to lyophilization or to solid state dissolution, thus leaving a porous network of matrix forming materials;

characterized in that the shape of the bottom surface of the mold is a mirror-image of the shape of the frozen meniscus on the top, the mirror-plane being parallel to the plane defined by the rim of the mold, thus yielding a dosage form shaped as a biconvex tablet having symmetrical top and bottom surfaces.

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