KR100782897B1 - Indication Method of Rapid Disintegration Type - Google Patents

Abstract

The present invention relates to a method of marking the surface of a rapidly disintegrating solid formulation using non-contact marking techniques such as laser engraving and inkjet printing.

Description

Indication Method of Rapid Disintegration Formulation

The present invention relates to a method of marking on the surface of a rapidly disintegrating solid formulation using non-contact marking techniques such as laser imprinting and inkjet printing.

Rapidly disintegrating solid formulations filled with an amount of active ingredient are known from GB-A-1,548,022 (US-4,305,502). These solid dosage forms comprise a porous network of matrix materials that carry the active ingredient, which matrix material consists of a water soluble or water dispersible carrier material. Solid formulations are prepared by lyophilization or lyophilization of a solvent from a frozen solution or suspension of the matrix material and the active ingredient.

Various improvements have been developed to prepare formulations by lyophilization. GB-A-2,111,423 and US Pat. No. 4,371,516 disclose methods for producing solid formulations which are rapidly disintegrated by water and in which a network of matrix substances carries a certain amount of active ingredient, in particular pharmaceutical substances. Many applications are found for such formulations, particularly where it is necessary to administer, formulate or vice versa the active ingredient in a unit dose. For example, solids which are used in the form of solutions or suspensions, but which are difficult to transport or store in this form or which are harmful to the user, can be added to the aqueous medium to produce the desired solution or suspension containing a certain amount of the active ingredient. Can be converted into a form. In addition, the active ingredient may be a reagent that can be added to a known amount of an aqueous liquid to produce a standardized liquid composition and then used, for example, for chemical analysis. In addition, the active ingredient may be a diagnostic compound that is added to a biological sample (eg blood, urine) to determine the amount of a particular ingredient present in the sample. However, preferably, the active ingredient is a human or veterinary drug substance. Fast dissolving solid drug formulations are particularly suitable for oral administration. When orally administered, they generally disintegrate rapidly within the oral cavity (eg within 1 or 2 seconds) and thus this formulation is a particularly useful means for administering the drug to humans and animals. Such formulations may be used for patients such as humans and animals that are difficult to swallow these conventional formulations as a separate means for conventional tablets, pills or capsules.

US-4,642,903 teaches a process for preparing lyophilized foam formulations using conventional lyophilization techniques to obtain rapid dissolving pharmaceutical formulations.

In WO-93 / 23017, there is a problem inherent to the conventional freeze-drying method, namely the lack of uniform porosity in the freeze-dried product. Uniform porosity in the lyophilized product is important for post-loading placebo or unloaded formulations with active ingredients. WO-93 / 23017 relates to a process for the preparation of formulations which avoids cracking and remelting, which have moderate strength and porosity and which will exhibit a fast dissolution rate.

Other methods of preparing solid formulations that rapidly disintegrate in the oral cavity, namely solid state dissolution techniques, are disclosed in US-5,039,540, US-A-5,215,756, US-A5,330,764 and US-5,298,261.

Solid dosage forms provided by the prior art are used to dispense an amount of the active ingredient. The administration of these products is associated with a number of risks and it is therefore necessary to give them identity. Such risks include, for example, mistakes in the administration of a medicament by a doctor, pharmacist or by an end user, patient. Some agencies have proposed legislation requiring all solid oral formulations to have a code identifying the product and manufacturing license holder.

Besides using distinct colors and formulation forms, these problems can be satisfactorily solved by imprinting in typical solid formulations such as compressed tablets and capsules. Typically, a label or text is printed on the surface of the formulation, such as a company logo or name, a product name, a trademark, or a number indicating the amount of active ingredient in the formulation. A separate solution that can be applied to tablets consists of engraving the tablet surface by compression punching, engraving or engraving. Negative sections can be filled with optically anisotropic materials (e.g. EP-0,060,023 and EP-0,096,982), dry filled with materials of different colors (EP-0,088,556), or wet filled with materials of different colors (EP-0,501,553) Can be emphasized.

The use of broad color and formulation forms also clearly applies to rapid dissolution formulations of solids, including incompressible porous networks of matrix forming materials. However, so far no solution has been proposed to mark such formulations that are imprinted or engraved. Compared with conventional compressed tablets, the reduction in mechanical strength, in particular the compressibility of these formulations, has hindered the application of prior art printing and engraving techniques. These techniques rely on physical contact and pressure between the formulation to transfer the markings to the tablet and the printing mat or stamp.

Currently, a method of marking the surface of a rapidly decaying solid formulation including an uncompressed, porous network of matrix forming material has been studied, in which a readable marking on the surface of the rapidly decaying solid formulation using non-contact marking techniques and / or Or by appending a letter, the previous problem is solved.

The present invention provides two such non-contact display methods, laser engraving and ink jet printing.

According to the first method, lasers are used to corrode marks and / or letters on the surface of the formulation by vaporizing shallow and narrow portions of the surface. It is sufficient to create a shadow on the bone left by the impact laser beam in order to be able to read the markings and / or characters. Since the laser beam typically has very little beam divergence, on the order of a few milliradians, the width of the bone at the surface of the solid formulation can actually be very narrow. Under these circumstances, even very shallow valleys will cast a distinct shadow. Most importantly, since the fast dissolving solid formulations comprise a porous network of matrix forming materials, very little material must be vaporized to achieve the desired goal. This is of great practical value for several reasons. First, the energy input required to vaporize a solid material is proportional to the amount of this material, so less energy will be needed for the vaporization process. In effect, this means that each formulation should only be investigated very briefly, or vice versa, so many formulations can corrode per unit of time. The characteristics of high throughput are the most important for making this display method industrially practical. Secondly, the amount of material removed from the solid dosage form, in particular the amount of active ingredient removed from the solid dosage form, is negligibly small relative to the total dosage. Finally, laser-based methods have the added advantage of not introducing new materials into the formulation, which is a clear advantage in pharmaceutical applications.

The first mode of eroding markings and / or letters on the formulation surface involves passing the laser beam through the desired information, preferably with a metal mask or stencil. The laser beam forms an image of the mask and then is directed onto some surface of the solid formulation to be displayed. Suitable lasers are those designed for industrial display applications and producing short, powerful pulses of light energy, preferably infrared (λ = 1 μm-1 mm), for example carbon dioxide lasers (λ = 10.6 μm), helium -Neon laser (λ = 3.39 μm) or the like. Preferably, a pulsed laser is used at low pulse energy (a few Joules) and at a high repetition rate (eg 20 Hz) to achieve a high display speed (eg 1200 displays / minute) that is industrially practical.

A separate method involves moving the solid formulation to pass a plurality of pulsed laser beams arranged along a single line to create a dot matrix pattern on the surface of the solid formulation.

A third mode of corroding markings and / or letters on the formulation surface involves scanning a laser beam on the formulation surface using a rapidly rotating, computer controlled mirror. In this mode, YAG (yttrium aluminum garnet) or continuous wave carbon dioxide lasers are preferably used to corrode product coat information on the solid formulation surface.

The vaporized portions of the surface comprise decomposed matrix forming materials which are usefully removed by adsorption using known apparatus.

According to a second method, an inkjet printer can be used to print indicia and / or letters by dotting ink droplets on the surface of the formulation. From the knowledge of the inventors, the prior art method of inkjet printing has been applied solely to the display of a product which is substantially water impermeable to ink. Surprisingly, it has been fully demonstrated that inkjet printing can be extended to solid formulations with high porosity.

The ink used to mark the formulation must be dispersed or dissolved in a liquid, volatile carrier, such as water, alcohol, or mixtures thereof. The water based inkjet ink may contain 70 to 90% of water, depending on the ink properties. Because of the droplet size, the solvent evaporates quickly and does not affect the structure of the solid dosage form. The ink may or may not be edible depending on the end use of the formulation. Where the formulation contains human or veterinary drugs, only pharmaceutically acceptable edible inks can be used in the method of the present invention for displaying the formulation by an inkjet printer.

The above methods are particularly useful when the formulation is filled with the active ingredient and shaped as a tablet. These methods are more suitable when the active ingredient is a human or veterinary drug substance and the rapidly disintegrating solid dosage form is a pharmaceutical tablet for oral administration.

The formulation comprises a porous network of the following matrix forming materials:

i) water-soluble, hydratable gels or foam-forming materials,

ii) a curing agent for gels or foam-forming materials, and optionally

iii) one or more amino acids.

Solid formulations are prepared by lyophilizing a freeze mixture of the matrix forming material and solvent or by solid state dissolution techniques. These mixtures may be present in various forms such as solutions, suspensions, dispersions, emulsions, blowing agents. Those skilled in the art will be aware of acceptable methods of making each of these.

Preference is given to using water as the solvent in the composition which is frozen and the solvent is removed. Additional cosolvents (such as alcohols) may also be used if desired to improve the solubility, dispersibility, or hydration of any of the composition components.

Suitable water soluble, hydratable gels or foam-forming materials contain gelatin, gelatin A, gelatin B, fluid gelatin, modified fluid gelatin, gelatin derivatives, albumin, soybean protein, wheat and chafer seed proteins, potato proteins, papain, etc. matter; Phospholipids such as coacervate egg lecithin, or lecithin; Gums such as acacia, guar, agar, locust bean, xanthan and tragacanth gum; Alginate (polymannuronic acid), chitosan, carrageenan, dextran, dextrin, maltrine (maltodextrin), pectin (polygalacuronic acid), microcrystalline cellulose, corn syrup solids, konjac flour, rice flour, wheat Polysaccharides such as gluten; Synthetic polymers such as polyvinylpyrrolidone, sodium carboxymethylcellulose, sodium starch glycolate, hydroxyethylcellulose; And polypeptide / protein or poly-saccharide complexes such as gelatin-acacia complexes, alone or in combination, respectively.

Suitable curing agents include monosaccharides, linear and cyclic oligosaccharides and polysaccharides such as mannitol, xylitol, sorbitol, dextrose, fructose, sucrose, lactose, maltose, galactose, trehalose; Cyclic sugars such as cyclodextrins such as beta-cyclodextrin and 2-hydroxypropyl-beta-cyclodextrin; Dextran, including dextrins; And inorganic materials such as sodium phosphate, sodium chloride, magnesium aluminum silicate, magnesium trisilicate, natural clay, or combinations thereof. Preferred curing agents are mannitol.

Suitable amino acids have 2 to 12 carbon atoms, for example glycine, L-alanine, L-aspartic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine, L-phenylalanine, or Combination. Glycine is the preferred amino acid. Formulations containing glycine as one of the matrix forming ingredients have several advantages: fast dissolution and disintegration in aqueous media, sweet taste and feel, nutritional value, low calorie content and non-causticity. Of particular importance is the fact that these formulations can be prepared with minimal cracking or remelting and that they are homogeneous porosity and suitable handling strength, i.e., resistant to collapse or crushing under normal production and handling conditions. These latter properties contribute to the usefulness of the postfilling process whereby the active ingredient is filled onto a placebo or unfilled formulation.

Preferred matrix formers include pharmaceutical grade gelatin, pectin (not hydrolyzed, partially hydrolyzed or hydrolyzed), glycine and mannitol. Particularly preferred combinations of matrix formers include gelatin, glycine and mannitol.

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

The solution or dispersion of material for preparing the matrix may contain 0.1% to 15% by weight, in particular 1% to 5%, more specifically 1.2% to 3%, of the gel or foam forming material. It may additionally contain 0.5% to 10% amino acids, in particular 0.8% to 2.5% by weight, and 0.5% to 10%, in particular 1% to 4%, of a curing agent, the balance being the solvent and the second component mentioned hereafter.

The ratio between these materials can vary within a certain range. Specifically, the weight ratio of the total amount of amino acids to the weight of the water soluble, water hydratable gel or foam-forming material is 1: 1 to 1: 3. Preferred ratio is 1.5: 1. The weight ratio of the amount of water-soluble, water-soluble gel or foam-forming material to the amount of curing agent is from 2: 1 to 1: 2. Preferred ratio is 1.5: 2.

Typically, the weight ratio of the total amount of nonsolvent component to the total amount of water in the aqueous composition is about 1: 9 to 1:33, especially about 1:13 to 1:30, for example about 1:20.

Fast dissolving solid formulations find many applications, particularly when it is necessary to administer, formulate or vice versa a predetermined amount of active ingredient. The active ingredient is in particular a human or veterinary drug substance.

The active ingredient used in the fast dissolving solid formulations may be in the form of a coating. For example, it may be present in particulate form and the particles of the active ingredient may be coated with a coating suitable to protect the process diluent, suspension or aqueous environment of oral or other mucosal cavities, or other environmental conditions that dissolve or degrade the active ingredient. have. 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 acids, glycerides, triglycerides, and mixtures thereof. In this way, the taste of the active or bioactive agent can be blocked, while at the same time the solid formulation allows for rapid dissolution upon contact with the physiological diluent. Examples of bitter active ingredients that can be coated in accordance with the present invention include acetaminophene, ibuprofen, chlorpheniramine maleate, pseudo-ephedrine, dextrometophan, cisapride, domperidone, risperidone. Pharmaceutical applications include mucoadhesive or formulations designed to degrade the drug at a controlled rate; A dosage unit designed to distribute the drug to the eye, vagina, rectum and other body cavities; Solid dosage forms designed to replace liquid formulations; Dry therapeutic formulations for topical application after resolvation (water ride); Therapeutic unit or sheet formulation for topical application; Preparations of more palatable formulations of drugs that exhibit unpleasant sensory properties; Formulations for oral dispensing of the drug to a person having difficulty in encapsulating a tablet or capsule.

Ingredients such as nutrients, vitamins, other active ingredients, sweeteners, flavors, colorants, surfactants, preservatives, antioxidants, viscosity increasing agents, minerals, diagnostics, fertilizers and pesticides may also be incorporated into the formulations of this formulation. .

The solution or suspension for preparing the formulation may further contain the J ingredient mentioned previously. Xanthan gum or polyacrylic acid polymers and salts thereof (also referred to as carbomer or carboxyvinyl polymers such as Carbopol ^™ ) may be added to increase the viscosity or to maintain the components of the mixture in suspension.

The aqueous composition can be frozen by conventional cooling processes. For example, the mixture may be frozen by dispersing it into a preform mold corresponding to the size and shape of the desired formulation and then cooling the mold on a freezer shelf or in a freezer compartment. Alternatively, the mold containing the mixture can be passed through a cooling gas or vapor, such as a stream of liquefied nitrogen in the refrigeration tunnel. In a preferred method of refrigeration, the composition is passed through a refrigeration tunnel into which liquefied nitrogen is injected, the liquefied nitrogen evaporates and the resulting cooling gaseous nitrogen passes over the composition. Another way to freeze the mixture in the mold is to enclose the mold in dry ice until the mixture is frozen.

The best known method of removing solvent from a frozen solution or dispersion is lyophilization, which includes solvent removal of the mixture by sublimation of the solvent under vacuum. If desired, the frozen composition can be stored in a cold reservoir before the sublimation process is performed. Sublimation can be carried out in a freeze dryer by keeping the refrigeration composition in the mold under reduced pressure and, if necessary, controlling the heat to aid sublimation. The pressure may be 4 mmHg (533 Pa) or less, for example 0.3 mmHg (40 Pa) or less, for example 0.1 to 0.2 mmHg (13.3 to 26.6 Pa) or even 0.05 mmHg (6.7 Pa) or less. The initial temperature in the lyophilizer may be as high as, for example, 60 ° C. and this temperature may decrease as the temperature of the freezing composition increases (eg up to 40 ° C.). Various methods and improvements are described in the references cited immediately preceding the specification. The freezing composition may also be removed from the mold prior to lyophilization.

Formulations can also be prepared by a solid-state dissolution method that removes a solid solvent from a solidified sample. In this conventional method, one or more of the distribution matrix formers are dissolved or dispersed in the first solvent, frozen and then the second solvent is at or above the freezing point of the second solvent and at or below the freezing point of the first solvent. Contact with. The first solvent in the solidified state may be substantially mixed with the second solvent, whereas the matrix former is substantially insoluble in the second solvent. The first solvent is thereby substantially removed from the coagulation matrix to obtain a solid matrix that is substantially free of the first solvent. Typically, the first solvent is water and the second solvent is ethanol.

For example, the mold may be a depression in a metal plate (eg an aluminum plate). The plate may contain one or more depressions, each recessed in size and shape corresponding to the desired size of the molded article. However, the mold may also be a depression in the sheet of film material. The film material may contain one or more depressions. The film material may be similar to that used in conventional blister packaging materials used to package pharmaceutical tablets and similar therapeutic drug forms. For example, the film material may be made of a thermoplastic material with depressions formed by thermoforming. Preferred film materials are talc-filled polypropylene films or polyvinyl chloride films. Laminates of film materials such as polyvinyl chloride / polyvinylidene chloride, polyvinyl chloride / polytetrafluoroethylene or polyvinyl chloride / polyvinylidene chloride / polyethylene may also be used.

When lyophilization is used, it is desirable to freeze the matrix material solution in a coated or lined mold for easy release of the frozen material. Preferred molds are thermoformed cups made of talc-filled polypropylene sheets, optionally siliconized with a layer of baked silicone / simethicone baked on the surface in contact with the aqueous composition.

The formulations may be prepared in a wide range of sizes, ranging from about 0.25 ml or g to 30 ml or g and more. It is useful for large formulations to be prepared by a solid state dissolution process without the long drying time required by lyophilization. Frozen and solvent free formulations may be sized to correspond to the desired size of the two or more formulations. For example, the composition may be frozen in a tray and the solvent may be removed from the frozen composition to produce a slab or sheet of desolvated product that corresponds to a large sized desired product size. The sheet can be broken down to form a product of the desired size and the active ingredient can be backfilled into the broken down product by injecting an amount of a suspension containing the active ingredient. A particular advantage of this separate method lies in the fact that the segmentation of the sheet does not need to be performed exactly as the measurand active ingredient is added to the granular product. In addition, if the infusion suspension does not diffuse excessively through the sheet of the sublimated product, a certain amount of active ingredient can be mixed into the sheet at selected locations on the sheet prior to subdivision, and then the sheet is subdivided to form a formulation containing a certain amount of active ingredient, respectively. To provide.

The present invention also provides a rapidly disintegrating solid dosage form with indications obtainable by any of the methods described above.

The rate at which the labeled tablets produced by the process of the invention disintegrate, depending on the overall, or at least mostly, the choice of matrix former, its concentration, and the solidification / solvent removal process conditions. Specifically, formulations of the sizes mentioned in the examples described below are rapidly dissolved, for example, in less than about 10 seconds and generally faster, for example less than about 5 seconds or even less, for example within 1 to 2 seconds. Will be distributed.

The formulations disperse rapidly in water, for example in less than 10 seconds. The disintegration time of the formulation is described in the literature (British Pharmacopoeia, 1980, Vol II, Appendix XII A), but the formulation is sufficiently modified by water using a standard tablet disintegration device in which a standard 2.00 mm wire mesh is replaced with a stainless steel 40 mesh screen. It is measured by checking whether it can collapse quickly. The sample product is placed in a drying tube placed on the surface of the water. Run the apparatus and immerse the sample in water at 20 ° C. The sample is dispersed on the liquid surface and the solid residue passes through a 40 mesh screen within 10 seconds, preferably within 5 seconds and ideally within 1 to 2 seconds.

Claims (19)

Laser engraved on the surface of the fast disintegrating solid formulation comprising an incompressible, porous network of the matrix forming material prepared by the process comprising the step of lyophilizing the freeze mixture of the matrix forming material and the solvent or performing a solid state dissolution. A method for marking the surface of a rapid disintegrating solid formulation, wherein inkjet printing is used to affix readable marks and / or letters. The method of claim 1, wherein the laser is used to etch marks and / or letters on the formulation surface by vaporizing shallow, narrow surface portions. The method of claim 2, wherein the indicia and / or characters are etched into the formulation surface by passing the laser beam through a precut mask or stencil. The method of claim 2, wherein the formulation is etched past a plurality of pulsed laser beams arranged along a single line, thereby creating a dot matrix pattern on the surface to etch the marks and / or letters on the formulation surface. The method of claim 2, wherein the marking and / or text is etched into the formulation surface by scanning a laser beam over the formulation surface using a rapidly rotating computer controlled mirror. The method of claim 1, wherein the inkjet printer is used to print indicia and / or letters on the formulation surface by spotting ink droplets on the formulation surface. The method of claim 6 wherein the ink is suspended or dissolved in a liquid, volatile carrier. 8. The method of claim 7, wherein the formulation is displayed by an inkjet printer that is dotted with edible ink pharmaceutically acceptable on the surface of the formulation. The method of claim 1, wherein the formulation is filled with an amount of active ingredient and molded as a tablet. The method of claim 9 wherein the active ingredient is a human or veterinary drug substance and the rapidly disintegrating solid dosage form is a pharmaceutical tablet for oral administration. The method of claim 1 wherein the matrix forming material comprises the following materials: i) a water soluble, hydratable gel or foam-forming material, and ii) curing agents for gels or foam-forming materials. The method according to claim 11, wherein the gel or foam-forming material is used alone or in combination, respectively, for gelatin, gelatin A, gelatin B, fluid gelatin, modified fluid gelatin, gelatin derivatives, albumin, soybean fiber protein, wheat and chaff seed protein, potato Protein-containing substances such as proteins and papain; Phospholipids such as coacervate egg lecithin, or lecithin; Gums such as acacia, guar, agar, locust bean, xanthan and tragacanth gum; Alginate (polymannuronic acid), chitosan, carrageenan, dextran, dextrin, maltrine (maltodextrin), pectin (polygalacuronic acid), microcrystalline cellulose, corn syrup solids, konjac flour, rice flour, wheat Polysaccharides such as gluten; Synthetic polymers such as polyvinylpyrrolidone, sodium carboxymethylcellulose, sodium starch glycolate, hydroxyethylcellulose; And a polypeptide / protein or poly-saccharide complex, such as a gelatin-acacia complex. The method of claim 11, wherein the cured material is a monosaccharide, linear or cyclic oligosaccharide, polysaccharide, or inorganic material, or a combination thereof. The method of claim 13, wherein the cured 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, further inorganic material such as sodium phosphate, sodium chloride, magnesium aluminum silicate, magnesium trisilicate, natural clay, or combinations thereof. The method of claim 11, wherein the matrix forming material further contains nutrients, vitamins, other active ingredients, sweeteners, flavors, colorants, surfactants, preservatives, antioxidants, viscosity increasing agents, minerals, diagnostic agents, fertilizers or pesticides. Way. 16. A rapidly disintegrating solid dosage form with easy-to-read markings and / or letters that can be obtained by inkjet printing according to any one of claims 1, 6-14 or 15. The formulation of claim 16 which disintegrates in water at 20 ° C. within 10 seconds. The method of claim 11, wherein the matrix forming material further comprises iii) amino acids. The method of claim 18, wherein the amino acid is glycine, L-aspartic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine, L-phenylalanine, or a combination thereof.