MXPA98010823A - Marking of dosed forms of rapida desintegrac - Google Patents

Abstract

The present invention relates to a method of marking the surface of solid dosage forms of rapid disintegration, using a non-contact marking technique such as laser printing and inkjet printing.

Description

MARKING OF DOSED FORMS OF QUICK DISINTEGRATION FIELD OF THE INVENTION The present invention relates to a method of marking the surface of rapidly disintegrating dosage forms using a non-contact marking technique, such as laser printing and ink jet printing.

BACKGROUND OF THE INVENTION Solid dosage forms of rapid disintegration loaded with a predetermined amount of an active ingredient are known from GB-A-1, 548, 022 (US-4,305,502). These solid dosage forms comprise a porous network of a matrix material carrying an active ingredient, the matrix material consisting of a water-soluble or water-dispersible carrier material. The solid dosage forms are prepared by freeze drying or lyophilization of the solvent of a frozen solution or suspension of the matrix material and the active ingredient. Several improvements have been developed for the preparation of dosage forms by lyophilization. GB-A-2,111,423 and US-4,371,516 disclose methods of this class for preparing solid dosage forms that rapidly disintegrate in water, and in which a network of matrix material carries a predetermined amount of an active ingredient, particularly a pharmaceutical substance. These dosage forms find many applications, particularly when it is desired to administer, dispense or otherwise use an active ingredient in predetermined unit amounts. For example, certain active ingredients that are used in the form of solution or suspension, but which are difficult or dangerous to transport or store in such form, can be converted into a solid form that can be added by the user to an aqueous medium to produce the desired solution or dispersion containing a predetermined amount of the active ingredient. In addition, the active ingredient can be a reagent that can be added to a known amount of aqueous liquid to produce a standardized liquid composition which can then be used, for example, in chemical analysis. In addition, the active ingredient can be a diagnostic compound that has to be added to a biological sample (for example blood, urine) and in this way allows to determine the amount of a particular constituent present in the sample. However, preferably, the active ingredient is a drug substance for human or veterinary use. The solid dosage forms of rapid drug dissolution are particularly suitable for oral administration. When administered orally, they usually disintegrate rapidly in the mouth (e.g., within one or two seconds) and thus the dosage form is a particularly advantageous means of administering drugs to humans and animals. These dosage forms can be used as alternatives to conventional tablets, pills or capsules, particularly for patients (humans and also animals) who have difficulty swallowing these conventional dosage forms. US-4,642,903 teaches a process for preparing a dosage form of freeze-dried foam using conventional lyophilization techniques, which results in rapidly dissolving pharmaceutical dosage forms. O-93/23017 handles an intrinsic problem with conventional lyophilization methods, particularly the lack of uniform porosity in the lyophilized product. Uniform porosity in a lyophilized product is critical for subsequently loading a placebo or a dosage form without loading an active ingredient. WO 93/23017 relates to a method for producing a dosage form which prevents it from cracking and remelting, has adequate potency and porosity, and exhibits rapid dissolution. Other methods for the preparation of solid dosage forms that rapidly disintegrate in the mouth, particularly solid state dissolution techniques, are described in US-5, 039, 540, US-A-5, 215, 756, US-A-5, 330, 764 and US-5,298,261. The solid dosage forms provided by the prior art are used to release predetermined amounts of active ingredients. Since the administration of these products is associated with many risks, there is a need to give them an identity. These risks include, for example, errors in the administration of medicines by physicians, pharmacists or end users, patients. Some regulatory authorities have issued regulations requiring all solid oral dosed forms to carry a code identifying the product and the holder of the manufacturing authorization. In addition to using different colors and dosage forms, this problem can be solved satisfactorily in classical solid dosage forms such as compressed tablets and capsules, by printing. Typically, a mark or text is printed on the surface of the dosage form, for example a logo or company name, a product name, a trademark, or a number indicating the amount of active ingredient in the dosage form. An alternative solution applicable to tablets consists in notching the surface of the same by means of a compression, incision or engraving punching process. The notches can be highlighted by filling with an optically anisotropic substance (eg EP-0,060,023 and EP-0, 096, 982), filling dry with a material having a different color (EP-0,088,556) or wet filling with a material that has a different color (EP-0, 501, 553). The use of different colors and dosed forms is also clearly applied to the rapidly dissolving solid dosage forms comprising an uncompressed porous network of materials forming the matrix. However, until now no solutions have been offered to mark these dosage forms with impressions or notches. The reduced mechanical strength, in particular the compressible nature of these dosed forms, in comparison with conventional compressed tablets, has impeded the application of prior art printing and notching techniques thereto. Said techniques are based on the physical contact and pressure between the dosage form and the printing or stamping mat to transfer the mark to the tablet.

BRIEF DESCRIPTION OF THE INVENTION A method for labeling the surface of rapidly disintegrating solid dosage forms, comprising an uncompressed porous network of matrix forming materials, has now been developed, wherein the above problem is solved by applying readable marks and / or characters to the surface of the matrix. said solid dosage forms of rapid disintegration, using contactless marking techniques. The present invention provides two of these contactless marking methods, particularly laser printing and ink jet printing.

DETAILED DESCRIPTION OF THE INVENTION In accordance with the first method, a laser beam is used to record marks and / or characters on the surface of the dosage form, vaporizing a shallow and narrow portion of the surface. So that the marks and / or characters are legible, it is enough to create a shadow in the valley left by the incident laser beam. Since laser beams typically have a very small beam divergence, typically of the order of a few milliradians, the width of the valley at the surface of the solid metered form can actually be very narrow. Under these circumstances, even a very shallow valley will mold a visible shadow. More importantly, since the rapidly dissolving solid dosage forms comprise a porous network of matrix forming materials, very little material has to be vaporized to achieve the desired objective. This is of great practical value for several reasons. First, since the energy input required to vaporize solid material is proportional to the amount of said material, little energy will be required in the vaporization process. In effect, this means that the individual dosed forms will have to be irradiated only for a very short time, or conversely that a large number of dosed forms can be recorded per unit of time.

This high performance feature is of primary importance to make the marking method industrially viable. Secondly, the amount of material removed from the solid dosage form, in particular the amount of active ingredient removed from it, is very small in relation to the total amount of the dosage form, such that it is negligible. Finally, the method using a laser has the additional advantage of not introducing any new material into the dosage form, which is a distinct advantage in pharmaceutical applications. A first way of engraving the marks and / or characters on the surface of the dosage form comprises passing the laser beam through a dial or stencil, preferably in metal, pre-cut with the desired information. The laser beam forms an image of the dial and is then directed onto the surface of the part to be marked in the solid dosage form. Suitable laser beams are those that have been designed for industrial marking applications and that produce powerful short pulsations of light energy, preferably on the infrared scale (lambda = l μm - 1 mm), for example carbon dioxide laser (lambda = 10.6 μm), helium and neon laser (lambda = 3.39 μm) and the like. Preferably, the driven laser beams are used at a low pulse energy (a few Joules) and at a high repetition rate (e.g., 20 Hz) to achieve a high, industrially viable marking speed (eg, 1200 marks / min). An alternative comprises moving a solid metered form passing through a plurality of driven laser beams disposed along a single line, thus creating dot matrix patterns on the surface of the solid metered form. A third mode of etching the marks and / or characters on the surface of the dosage form comprises sweeping a laser beam on the surface of the dosage form using computer-controlled mirrors of rapid rotation. In this mode, a YAG (yttrium aluminum garnet) or continuous wave carbon dioxide laser is used, preferably for recording product code information on the surface of a solid dosage form. The vaporized portion of the surface comprises degraded matrix forming materials that are conveniently removed by suction using devices known in the art. According to the second method, an ink jet printer can be used to print marks and / or characters on the surface of the dosage form by dot droplets of an ink on said surface. The methods of the prior art for ink jet printing, according to the knowledge of the inventors, have hitherto been applied exclusively to the marking of articles which are substantially impervious to ink. Surprisingly, it has been proven that it is perfectly possible to extend the ink jet printing technology to highly porous solid dosage forms. The ink used to mark dosage forms must be suspended or dissolved in a volatile liquid carrier such as water, alcohol or mixtures thereof. Water-based jet inks can contain 70 to 90% water, depending on the nature of the ink. Due to the size of the small droplets, the solvent evaporates rapidly and does not affect the structure of the solid dosage form. The ink may be edible or inedible, depending on the final use of the dosage form. In case the dosage form comprises a drug for human or veterinary use, obviously only pharmaceutically acceptable edible inks can be used in the present method of labeling the dosage form, by means of an ink jet printer. The above methods are particularly useful when the dosed formula is loaded with an active ingredient and is shaped as a tablet. The methods are particularly suitable when the active ingredient is a drug substance for human or veterinary use and the solid dosage form of rapid disintegration is a pharmaceutical tablet for oral administration. The dosage form comprises a porous network of matrix-forming materials: i) a hydratable gel or water-soluble foam-forming material, ii) a stiffening agent for the gel or foam-forming material, and optionally iii) one or more amino acids . The solid dosage forms are prepared by lyophilization or by a solid state dissolution technique of a frozen mixture of a solvent with the matrix-forming materials. These mixtures can be in a variety of forms such as solutions, suspensions, dispersions, emulsions, foams. The person skilled in the art will recognize acceptable methods for preparing each of these. Water is preferably used as the solvent in the composition that freezes and desolvates. An additional cosolvent (such as an alcohol) can also be used if desired to improve the solubility, dispersibility or wettability of any of the ingredients of the composition. Water-soluble hydratable gel materials or suitable foam formers include protein materials such as gelatin, gelatin A, gelatin B, fluid gelatin, modified fluid gelatin, gelatin derivatives, albumin, soy fiber protein, wheat seed proteins. and Psyllium potato protein, papain; phospholipids such as egg lecithin coacervate or lecithin; gums such as acacia, guar, agar, carob, xanthan and gum tragacanth; polysaccharides such as alginates (polymannuronic acid), chitosan, carrageenans, dextrans, dextrins, maltrins (maltodextrins), pectins (polygalacturonic acid), microcrystalline cellulose, Konjac flour, rice flour, wheat gluten; synthetic polymers such as polyvinyl pyrrolidone, sodium carboxymethyl cellulose, sodium starch glycolate, hydroxyethyl cellulose; and polypeptide / protein complexes or polysaccharides such as gelatin and acacia complexes, each individually or in combination. Suitable stiffening agents include monosaccharides, linear and cyclic oligosaccharides and polysaccharides, for example mannitol, xylitol, sorbitol, dextrose, fructose, sucrose, lactose, maltose, galactose, trehalose; cyclic sugars such as cyclodextrins for example beta-cyclodextrin and 2-hydroxypropyl-beta-cyclodextrin; dextran, dextrin; and also include inorganic substances such as sodium phosphate, sodium chloride, aluminum magnesium silicates, magnesium silicate, natural clays or a combination thereof. The preferred stiffening agent is mannitol. Suitable amino acids have from 2 to 12 carbon atoms, eg. 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. The dosed forms containing glycine as one of the matrix-forming components have some advantages: rapid dissolution and disintegration in aqueous medium, pleasant taste and mouthfeel, nutritional value, low caloric and non-cariogenic content. Of particular importance is the fact that these dosed forms can be produced with minimal cracking or melting and as having uniform porosity and adequate handling strength, i.e., resistance to disintegration or collapse under normal manufacturing and handling conditions. These latter properties contribute to the feasibility of the post-loading processes, by means of which the active ingredients are loaded onto the placebo or unfilled dosage forms. Preferred matrix forming agents include gelatins, pectins (non-hydrolyzed, partially hydrolyzed or hydrolyzed), glycine and pharmaceutical grade mannitol. A particularly preferred combination of matrix forming agents comprises gelatin, glycine and mannitol. The percentages and relationships mentioned in the following paragraphs are all by weight. The solution or dispersion of materials for preparing the matrix may contain from 0.1% to 15% by weight of gel or foam-forming material, in particular from 1% to 5%, particularly from 1.2% to 3%. It may also 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 stiffening agent. The rest being solvent and secondary components as mentioned below. The relationships between these materials can vary within certain scales. In particular, the weight-to-weight ratio of the total amount of amino acids to that of water-soluble hydratable or foamable gel material is from 1: 1 to 1: 3. A preferred ratio is 1.5: 1. The weight to weight ratio of the amount of hydratable gel or water-soluble foam forming material to that of stiffening agent is from 2: 1 to 1: 2. A preferred ratio is 1.5: 2. Typically, the weight-to-weight ratio of the total amount of non-solvent components to that of water in the aqueous composition is in the range of about 1: 9 to 1:33, in particular from 1:13 to 1:30 for example. approximately 1:20. The solid dosage forms of rapid dissolution find many applications, particularly when it is desired to administer, dispense or otherwise use an active ingredient in predetermined unit amounts. The active ingredient in particular is a drug substance for human or veterinary use. The active ingredient used in the solid dosage form of rapid dissolution may be present in 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 to protect it from the process diluents, the aqueous medium of the suspension or the oral cavity or other mucosa, or environmental conditions. environment that could dissolve or deteriorate said active ingredient. These coating materials can be selected from natural or synthetic polymers that are hydrophilic or hydrophobic in nature or other hydrophobic materials such as fatty acid, glycerides, triglycerides and mixtures thereof. In this way, the flavor of the active or bioactive agent can be masked, while at the same time allowing the solid dosage form to dissolve rapidly after its contact with the physiological diluents. Examples of bitter active ingredients that can be coated according to the present invention include acetaminophen, ibuprofen, chlorpheniramine maleate, pseudoephedrine, dextromethorphan, cisapride, domperidone, risperidone. Pharmaceutical applications comprise dosage forms that have mucoadhesive properties or designed to release a drug at a controlled rate; dosage forms designed to release drugs in the eye, in the vaginal, rectal and other orifices of the body; solid dosage forms designed to replace liquid formulations; dried medicinal preparations for topical application after resolvation (reconstitution); preparation of medicinal units or sheets for topical application; preparation of more acceptable dosage forms of drugs exhibiting unpleasant organoleptic properties; dosage forms for oral delivery of drugs to people who have difficulty swallowing tablets or capsules. Secondary components such as nutrients, vitamins, other active ingredients, sweeteners, flavoring agents, coloring agents, surfactants, preservatives, antioxidants, viscosity enhancers, minerals, diagnostic agents, fertilizers, etc. can also be incorporated into the dosage form formulation. insecticides. The solution or suspension from which the dosage forms are made may also contain the above mentioned minor components. Xanthan gum or polyacrylic acid polymers and salts thereof can be added (also referred to as carbomers or carboxyvinyl polymers eg Carbopol ™) to increase the viscosity, or keep the components of the mixture in suspension. The aqueous compositions can be frozen by any conventional cooling method. For example, the mixture can be frozen by dispensing it into preformed molds corresponding to the size and shape of the desired dosage form, and subsequently cooling these molds in refrigerated shelves or in refrigerated chambers. Alternatively, the molds containing the mixture can 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 in which liquid nitrogen is injected, the vaporized liquid nitrogen being, and the resulting cold nitrogen gas passed over the composition. Another method for freezing the mixtures in the molds is to surround the molds on dry ice until the mixture is frozen. The best known procedures for removing solvents from solutions. or frozen dispersions is lyophilization, which involves the desolvation of the mixture by sublimation of the solvent under vacuum. If desired, the frozen compositions can be stored in a cold store before carrying out the sublimation process. Sublimation can be carried out in a freezing dryer by subjecting the frozen composition to the mold under reduced pressure and, if desired, controlled application of heat to assist sublimation. The pressure can be less than 4 mmHg (533 Pa), for example less than 0.3 mmHg (40 Pa) for example 0.1a 0.2 mmHg (13.3 to 26.6 Pa) or even less than 0.05 mmHg (6.7 Pa). The initial temperature in the freezing dryer can be, for example, up to 60 ° C and this temperature can be reduced (eg at 40 ° C) as the temperature of the frozen composition increases. Various methods and improvements are described in the references cited at the beginning of the specification. The frozen compositions can also be removed from the mold prior to lyophilization. The dosed forms can also be prepared by a solid state dissolution method of removing solid solvent from the solidified samples. In this less conventional method, one or more release matrix forming agents are dissolved or dispersed in a first solvent, frozen and subsequently contacted with a second solvent at a temperature equal to or greater than the solidification point of the second solvent and at a temperature equal to 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 agents are substantially insoluble in the second solvent; thereby, the first solvent is substantially removed from the solidified matrix producing a solid matrix substantially free of the first solvent. Typically, the first solvent is water and the second is ethanol. The mold can be, for example, a depression in a metal plate (for example an aluminum plate). The plate may contain more than one depression, each depression being of the size and shape corresponding to the desired size of the article formed. However, the mold can also be a depression in a sheet of film material. The film material may contain more than one depression. The film material may be similar to that used in conventional bubble packages that are used to package pharmaceutical tablets and similar dosage forms. For example, the film material can be made of thermoplastic material with the depressions formed by thermoforming. The preferred film material is a polypropylene film filled with talc or a polyvinyl chloride film. Laminates of film material such as polyvinyl chloride / polyvinyl dichloride can also be used, polyvinyl chloride / polytetrafluoroethylene, polyvinyl chloride / polyvinylidene chloride / polyethylene. When lyophilization is used, it may be desirable to freeze the solution of matrix material in molds that are coated or lined for easy release of the frozen material. Preferred molds are thermoformed cups made of polypropylene sheets filled with talc, optionally siliconized with a silicone / simethicone layer baked on the surface or surfaces that come into contact with the aqueous composition. The dosage forms can be prepared in a wide variety of sizes, ranging from about 0.25 ml or g to 30 ml or g and larger. The large dosage forms can be conveniently prepared by the solid state dissolution process without the long drying times required by lyophilization. The frozen and desolvated dosage forms can be of a size corresponding to the desired size of two or more dosage forms. For example, the composition can be frozen in a tray and the solvent removed from the frozen composition to produce a plate or sheet of desolvated product corresponding in size to the number of desired shaped articles. The sheet can be subdivided to form products of the desired size and the active ingredient can be subsequently loaded onto the subdivided products by injecting a predetermined amount of a suspension comprising said active ingredient. A particular advantage of this alternative resides in the fact that it is not required to carry out the subdivision of the sheet in an exact manner, since a measured quantity of active ingredient is added to the subdivided products. Furthermore, if the injected suspension does not diffuse excessively through the sheet of sublimated product, the sheet can be dosed with the predetermined amount of active ingredient in selected positions on the sheet before subdivision and the sheet subsequently subdivided to form dosed each containing the predetermined amount of active ingredient. The present invention also provides solid dosage forms of marked rapid disintegration which are obtained by one of the methods described hereinabove. The speed with which the labeled tablet prepared by the method of the invention disintegrates is completely dependent, or at least for the most part, on the choice of the matrix forming agents, their concentration and the conditions of the solidification process. / desolvation. In particular, the dosage forms of the size mentioned in the examples described below, will dissolve or disperse rapidly, for example in less than about 10 seconds and usually faster, in less than about 5 seconds or even less, for example in 1 or 2 seconds. The dosed forms are rapidly dispersed in water, for example in less than 10 seconds. The disintegration time of a metered form is determined to check whether it is capable of disintegrating in water fast enough using a standard tablet disintegrating apparatus as described in the British Pharmacopoeia, 1980, Vol II, Appendix XII A, but with the Standard 2.00mm wire mesh replaced with 40 mesh stainless steel screen. A product sample is placed in a dry tube held above the surface of the water. The appliance is turned on and the sample is immersed in water at 20 ° C. The sample must be dispersed in the liquid surface and any solid residue must pass through the 40 mesh screen in 10 seconds, preferably in 5 seconds, and ideally in 1 or 2 seconds.

Claims (10)

NOVELTY OF THE INVENTION CLAIMS

1. A method of marking the surface of fast-disintegrating solid dosage forms comprising a non-compressed porous network of matrix-forming materials, characterized in that readable labels and / or characters are applied to the surface of said fast-disintegrating solid dosage forms, using contactless dialing techniques.

2. A method according to claim 1, characterized in that the non-contact marking techniques comprise laser printing and ink jet printing.

3. A method according to claim 2, characterized in that a laser beam is used to record marks and / or characters on the surface of the dosage form, vaporizing a shallow and narrow portion of the surface.

4. A method according to claim 3, characterized in that the marks and / or characters are recorded on the surface of the dosage form by passing the laser beam through a pre-cut mask or stencil.

5. - A method according to claim 3, characterized in that the marks and / or characters are recorded in the dosage form by moving the dosage form by passing a plurality of laser lasers arranged along a single line, thus creating patterns of dot matrix on the surface.

6. A method according to claim 3, characterized in that the marks and / or characters are recorded on the surface of the dosage form by sweeping a laser beam on the surface of the dosage form, using computer-controlled rapid rotation mirrors.

7. A method according to claim 2, characterized in that an ink jet printer is used to print marks and / or characters on the surface of the dosage form, by tapping droplets of an ink on said surface.

8. A method according to claim 7, characterized in that the ink is suspended or dissolved in a volatile liquid vehicle.

9. A method according to claim 8, characterized in that the dosage form is marked by means of an ink jet printer by stippling droplets of a pharmaceutically acceptable edible ink on the surface of the dosage form.

10. A method according to claim 1, characterized in that the dosage form is loaded with a predetermined amount of an active ingredient and is shaped as a tablet. 11.- A method in accordance with the claim 10, characterized in that the active ingredient is a drug substance for human or veterinary use, and the solid dosage form of rapid disintegration is a pharmaceutical tablet for oral administration. 12. - A method according to claim 1, characterized in that the matrix-forming material comprises: i) a water-soluble hydratable gel or foam-forming material, ii) a stiffening agent for the gel or foam-forming material, and optionally iii) one or more amino acids. 13. - A method in accordance with the claim 12, characterized in that the gel or foam-forming material is a protein material such as gelatin, gelatin A, gelatin B, fluid gelatin, modified fluid gelatin, gelatin derivatives, albumin, soy fiber protein, wheat seed proteins and Psyllium, potato protein, papain; phospholipids such as egg lecithin coacervate or lecithin; gums such as acacia, guar, agar, carob, xanthan and gum tragacanth; polysaccharides such as alginates (polymannuronic acid), chitosan, carrageenans, dextrans, dextrins, maltrins (maltodextrins), pectins (polygalacturonic acid), microcrystalline cellulose, Konjac flour, rice flour, wheat gluten; synthetic polymers such as polyvinyl pyrrolidone, sodium carboxymethyl cellulose, sodium starch glycolate, hydroxyethyl cellulose; and polypeptide / protein complexes or polysaccharides such as gelatin and acacia complexes, each individually or in combination 14. A method according to claim 12, characterized in that the stiffening material is a monosaccharide, linear or cyclic oligosaccharide, a polysaccharide or an inorganic substance, or a combination thereof. 15.- A method in accordance with the claim 14, characterized in that the stiffening material is mannitol, xylitol, sorbitol, dextrose, fructose, sucrose, lactose, maltose, galactose, trehalose; cyclic sugars such as beta-cyclodextrin and 2-hydroxypropyl-beta-cyclodextrin, dextran, dextrin, an inorganic substance such as sodium phosphate, sodium chloride, aluminum magnesium silicate, magnesium trisilicate, a natural clay or a combination of the same. 16. A method according to claim 12, characterized in that the amino acid is glycine, L-aspartic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine, L-phenylalanine, or a combination thereof. 17. A method according to claim 12, characterized in that the matrix-forming materials further comprise nutrients, vitamins, other active ingredients, sweeteners, flavoring agents, coloring agents, surfactants, preservatives, antioxidants, viscosity enhancers, minerals, diagnostic agents, fertilizers or insecticides. 18. A solid dosage form of rapid disintegration with markings and / or legible characters obtained by any of the methods of claims 1 to 17. 19. A dosage form according to claim 18, characterized in that it disintegrates in 10 seconds in water at 20 ° C.