DK152172B - PROCEDURE FOR PREPARING A SOLID PHARMACEUTICAL UNIT DOSAGE FORM - Google Patents

Description

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The present invention relates to a process for the preparation of solid pharmaceutical unit dosage forms in which one or more medicaments are applied to a therapeutically inert, edible web and the web is formed in a geometric shape of a predetermined shape.

This method is characterized in that a continuous and uniform layer of drug is applied to the web in a continuous working process, several of the resulting webs are formed into a layered form, the layered form is divided into a plurality of unit dosage forms, and the unit dosage forms are sealed in such a way. that the drug is completely enclosed, during the manufacture of a non-destructive examination or quality control of the products obtained in each process step. With the dosage forms, drug release can be obtained which can be controlled as desired and the procedure can be performed in high speed automated equipment.

Orally administered solid unit dosage forms previously known in the pharmaceutical industry can generally be subdivided into two basic forms, namely tablets and capsules. Within this field, various broad categories of both tablets and capsules are known, e.g. those which are enteric coated to release the drug into the intestinal tract, and those which, by various mechanisms, release the drug over a longer period of time or are showers. On the whole, such usual solid oral dosage forms suffer from various disadvantages.

First, conventional solid oral unit dosage forms are disadvantageous in that each contains, in admixture with the active ingredient, several different substances, which are referred to as "therapeutically inert or non-toxic pharmaceutical additives". Such materials fall into the categories of diluents, excipients, binders, lubricants, disintegrants, stabilizers, buffers and preservatives known in the art. Although these substances are considered to be indispensable in pharmaceutical manufacturing, their use nevertheless presents problems which must be solved taking into account costs and the final size and weight of the unit dosage form. Furthermore, any such additive must be examined before use for possible incompatibility with the particular drug. Furthermore, some of these substances, e.g. lubricants, bioavailability issues of the active ingredient. Presence of such substances may 2

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also involved in the analytical technique used to test e.g. the strength of the finished dosage form.

Second, prior art solid oral unit dosage forms have the primary disadvantage that the methods that can be used to study the unit dosage forms involve the destruction of the dosage form, so it is only possible to test a small proportion of the manufactured forms. It is therefore known in the art that there may be significant deviations within a given portion of such dosage forms, as e.g. the average dose and size of each portion deviation is determined by analyzing a relatively small number of samples.

The concept of portioning itself is a disadvantage in the prior art for the preparation of oral solid unit dosage forms solely because of the economic aspects of portion designation, control and assessment.

According to the present invention, solid unit dosage forms, primarily for oral ingestion, are prepared in large numbers at high speed, and since they are prepared by the above-mentioned special process which is unique in the pharmaceutical industry, they do not have the disadvantages mentioned above associated with with available solid oral dosage forms, e.g. tablets and capsules. The method is very advantageous in that it: eliminates the necessity of making portions as they are commonly known; enables continuous on-line analysis for strength as well as on-line assessment of the amount of active material in the dosage forms while they are being prepared; substantially eliminates the need for admixture with conventional pharmaceutical additives and the drug, with the exception of lubricants which may be necessary to facilitate powder flow, and / or certain other substances beneficial to the manufacture of the product; and provides pharmaceutically elegant unit dosage forms which may be administered such that the drug is released at any rate and which may have a faster release rate than usual tablets and capsules. Briefly, it can be said that the dosage forms prepared by the method of the invention ensure that a greater proportion of a more accurately metered drug amount will be available for a more accurately determined period of time after ingestion than in the case of the commercial unit doses used so far.

The method of the invention is advantageous in several important respects, the first being the fact that it can be substantially carried out by

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3 t on-line technology at high speed, essentially by automated processes. In addition, the dosage forms prepared are also advantageous in that the drug contained therein is released for absorption with exceptional uniformity in a large number of dosage units. Furthermore, the dosage units can be prepared such that the drug is released in less time after ingestion than is possible with previously available solid oral dosage forms such as tablets and capsules. The dosage units produced have superior properties, both in drug content and in their release for absorption.

The following publications, which deal with fixed dosage forms different from usual tablets, must be mentioned. U.S. Patent No. 3,444,858 discloses a buccal administration of medicaments comprising a strip of gelatinous material containing the medicament, which strip is divided into sections, each connected to the next by easily tearful strands.

In use, a section is simply separated from the strip and placed in the mouth.

Another publication to be mentioned is an article in the New England Journal of Medicine, Vol. 289, no. 10, pp. 533-535 (1973). This article describes contraceptives made available to women on a very large scale in the People's Republic of China. In the method described, a sheet of colored, water-soluble carboxymethyl cellulose paper is treated with a solution of progestational and estrogenic substances. The sheet is then perforated and cut into strips. The drug is packaged as a strip of 22 "squares" which are torn off the strip and taken daily. This method does not enclose the drug in the final dosage form, thereby causing the disadvantage that once the package is opened, the drug may be contaminated and / or inactivated. Since they are not completely uniform, such perforated strips may tear uniformly into the perforations, which may result in uneven dosing.

Also mentioned is U.S. Patent No. 3,625,214. In this patent, pharmaceutical unit dosage forms with controlled release of active substance are described in which a tissue of edible material is coated with a drug-containing matrix, and this coated material is then rolled into a thin, roulade-like configuration. The patent does not disclose how the drug can be completely enclosed and how the finished unit dosage forms could be prepared by pharmaceutical production.

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4 high capacity onsite equipment. This is true of that described in column 2, lines 65-69 of the patent, as it is evident from the description that the caps in question only protect the ends of the roll, while the transverse edge of the roll is not sealed, thereby exposing a certain amount of the drug. It is clear that the use of such caps is not intended to completely enclose the drug, but on the contrary serves to prevent the release from being uncontrollably from both ends of the roll if these are not closed by caps.

U.S. Patent No. 2,836,291 discloses a process for preparing unit dosage forms in which measured amounts of a liquid, semi-solid or powdered drug are introduced into "pockets" formed between two webs of an edible material, after which the webs are sealed about each of these individual drug dosages so that the individual portions of the drug are completely enclosed in the "pocket" thus formed (cf. claim 5 of said United States patent). The process described in this patent does not in principle differ significantly from the method which has long been used for filling soft gelatin capsules. Thus, the process is solely directed to a manufacturing technique better adapted to an automated work process.

U.S. Patent No. 3,007,848 describes a further development of the method described in U.S. Patent No. 2,836,291. Essentially the same principle is used except for the one shown in FIG. 1 and 2, wherein a thermoplastic material in which a drug is admixed is formed into a web which is then cut into separate unit dosage forms.

These are inserted into "pockets" formed between two webs of an edible material in substantially the same manner as described in U.S. Patent No. 2,836,291.

In contrast, the present invention relates to a completely different principle of manufacture in that, according to the present invention, a drug is applied continuously and in a uniform layer to a web-shaped carrier material. This web, on the surface of which a drug is applied, is then formed into a ready-to-use form whereby the active substance is completely enclosed, i.e. that the web, by layering and sealing, in itself forms an outer surface on which substantially no drug is placed. The main advantage of the new manufacturing method is that it enables a simple fix 5

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measuring the dosage amount by means of a corresponding geometric division of the web, and enabling on-line non-destructive quality control. Nowhere in the above-mentioned United States patents is a continuous application of a drug in a uniform layer to an edible carrier material.

The solid unit dosage forms prepared by the process of the present invention are completely uniform, they can be subjected to non-destructive, on-line analysis during the high capacity pharmaceutical manufacturing operation, are essentially free of pharmaceutical additives which may affect appearance, has no drug uncovered and has superior drug release ability, which enhances this effectiveness.

In the method of the invention, solid unit dosage forms are prepared, primarily for oral administration, comprising a therapeutically inert, edible web of paper and / or polymeric materials on which one or more drugs are applied, in a continuous and uniform layer, to which essentially no pharmaceutical additive is added, which web is formed into a layered form which is divided into a plurality of unit dosage forms which are sealed so that no drug is uncovered. The unit dosage forms are prepared by a high-capacity pharmaceutical manufacturing technique using apparatus which may comprise certain components which are known per se, for example from the paper industry, but which as a whole are considered to be unknown. The manufacturing process comprises means for non-destructive testing of the dosage forms on-line to determine the amount of drug applied to the web prior to formation, thereby determining the strength of the final dosage unit by physical parameters.

The solid unit dosage forms prepared by the method of the invention, which are primarily for oral ingestion, are advantageous in several ways over known solid oral dosage forms, e.g. tablets and capsules. First, the unit dosage forms prepared are substantially free of conventional pharmaceutical additives, thereby saving on raw material costs and manufacturing processes and eliminating any incompatibility caused by such materials. Here, a distinction must be made between the webs which can be considered as additives and materials such as fillers, binders and similar agents which are mixed with the drug in conventional solid dosage forms.

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Secondly, the need for batch lot preparation, as is known today, is eliminated since the solid unit dosage forms of the process of the invention are continuously prepared and subjected to on-line, non-destructive analysis, thereby achieving significant economic savings and substantial savings. improved quality control level for the finished unit doses. The fact that the manufacturing operation of the invention includes means for returning information from a test area to the immediately preceding manufacturing process results in on-line corrections and adjustments. Such agents facilitate the removal of only a small number of unit doses from any number which may be referred to as a manufactured batch, ie. from the positive reading immediately before a negative reading to the next positive reading.

In determining and removing such small amounts of dosage forms, "poisoning of the portion" is avoided and both a great economic advantage over conventional pharmaceutical manufacturing techniques and an improved quality control level are obtained, especially with respect to the content of active ingredients in the final dosage forms. In normal operation, the dosage forms of the invention are prepared by a "time-lot technique", i.e. a "batch" dosage forms constitute the number produced between two times. This concept is believed to be unique in the pharmaceutical industry. However, it is clear that any destructive testing is necessary in any pharmaceutical preparation technique as a control of the amount of active material in the final product. However, such testing is only necessary to a considerably lesser extent in the method of the present invention than in conventional manufacturing operations. However, it is more important that such destructive methods, viz. performance evaluation is carried out on-line with the information returned, thereby obtaining the above-mentioned advantages with regard to the non-destructive technique.

Third, the solid oral unit dosage forms prepared by the method of the present invention are unique in that they differ from usual tablets and capsules in appearance, shape and drug effect, thereby having the advantage of being readily identified. The on-line, non-destructive testing technique and continuous preparation method of the present invention further facilitates the packaging of the unit dosage forms prepared.

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7 on-line in individual containers, e.g. clear plastic strips in blister packs, saving on handling and equipment costs.

Fourth, the accuracy of the preparation according to the invention enables a fixed dosage form, i.e. the uniform and continuous drug application on the web, and the precision in designing the final units, combined with the desired properties in the web itself, that the final dosage forms can easily meet stringent requirements for size, shape and drug release. The dosage forms prepared are also extremely stable and allow the incorporation of drugs which are known to be adversely affected by humidity since, in certain embodiments of the method of the present invention, the drug is disposed on the web electrostatically, thereby providing an almost total absence of moisture which may cause an adverse reaction. In one embodiment of the method according to the invention, the dosage forms are prepared by applying different drugs to at least two of the web layers and placing these layers of different drugs such that at least one web layer is placed between to separate such different drugs. Hereby, drugs which are known to be chemically incompatible in the pharmaceutical art are effectively stabilized without the need to use such economically unattractive agents such as coating one or more of such incompatible substances with an insulating material, admixture of stabilizers for such drugs, incorporating such drugs into separate tablet layers, which are then compressed, and the like. Since one or both of these techniques, i.e. The application of a medicament to the electrostatic pathway as a dry powder and the application of potentially incompatible drugs alternately between path layers, the dosage forms prepared are advantageous in the administration of effervescent compositions.

Furthermore, the solid oral dosage forms prepared are unique in that the drug contained therein is completely enclosed in the dosage form, although in most cases no coating agent per se is applied to the final dosage forms. This results in a further economic benefit to the dosage forms produced over conventional tablets which must be coated to achieve drug exclusion completely.

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While the dosage forms prepared by the method of the invention are primarily intended for oral administration, similarly, dosage forms suitable for rectal and / or vaginal administration may be prepared. Modifications in web size and manufacturing methods, | as described below, for the preparation of dosage forms of the desired size and shape, will be apparent to those skilled in the art. Certain modifications of the web material to obtain the desired type and release pattern of the drug must also be performed.

Studies have shown that rectal and vaginal administration of solid dosage forms according to the invention have produced essentially no local irritation.

As noted above, the novel unit doses may be formulated or "formed" into any desired release pattern, including extended release. Apart from the release pattern, the unit doses produced are peculiar to an exceptional uniformity of release in a large number of unit doses, e.g.

10,000 or more. Variation in the release rate can be obtained according to the invention by changing a number of factors such as the thickness of the web, the composition of the web, the presence of a coating or an outer seal on the web produced and its composition, the density of the web and the like. Eg. For example, a web material with a high content of sodium carboxymethyl cellulose will normally decompose slowly in the stomach fluid. Dosage forms made from such webs by pleating, as described below, will be opened or unfolded upon contact with the gastric fluid, thereby releasing the drug applied to its inner surfaces very quickly, in fact faster than usual tablets and capsules. However, if such pleated dosage forms were to be sealed on the folded edges with a substance such as ethyl cellulose, cellulose acetate phthalate or zein which would prevent it from opening in the gastric fluid, the drug would become available through the gradual degradation of the web, thereby providing a constant, extended drug release. Since the dosage forms prepared by the method of the present invention can release the drug at a rate greater than previously available solid dosage forms, e.g. tablets and capsules, such a release is a preferred embodiment of the present invention.

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The figures can be described as follows;

FIG. 1 is a block diagram of the total manufacturing process showing the points at which On-line inspection is performed.

FIG. 2 is a schematic representation of a system by which the embodiment of FIG. 1 process.

FIG. 3 is a schematic representation of an arrangement for carrying out the unrolling technique for preparing unit doses.

FIG. 4, FIG. 4A and FIG. 5 illustrates the rotational molding and lamination technique of the dosage mold preparation.

FIG. 6A - 6D illustrate the finishing and sealing aspects of the pleating technique in the dosage form preparation.

FIG. 7 and 8 are graphical illustrations of the active ingredient release pattern from the dosage forms of the invention in comparison with a conventional solid dosage form, e.g. a capsule.

Course.

The webs on which drug can be applied in accordance with the present invention must meet a wide variety of physical and chemical requirements. These requirements can be summarized as follows:

The web must be non-toxic, edible and, in particular, not give any unpleasant "feeling" in the mouth. In addition, the web must preferably itself be degraded or degradable in body fluids and / or by enzymes that may be present in these body fluids. However, the web may be of non-degradable substance which is easily eliminated by the body.

The web is preferably hydrophilic and readily degradable in water. These properties must not be offset by the pH of the stomach fluid and should preferably be increased by it.

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The web must be completely inert to the drug applied to it and must not, upon dissolving in the stomach fluid, release any substance which may cause an in situ incompatibility with the drugs.

The web must be stable for a long time and at elevated temperature and relative humidity and generally must be a poor medium for the growth of microorganisms.

The web must have acceptable specific resistance so that powdered drug (usually with dielectric properties) can be applied to it by electrostatic deposition.

The web must have acceptable workability and mechanical properties, ie. it must be sufficiently elastic to be able to be pulled out or cast in a thin layer, ie. between approx. 0.025 and approx. Thickness of 0.25 mm, it must have good tensile strength and tear strength, and it must have acceptable folding strength when needed to withstand certain fabrication methods as described below.

The surface of the web must facilitate the on-line assay methods described below, must be capable of being coated with and retained powdered drug applied electrostatically or otherwise, and must be pressurized on the web.

The web must be easily sealed by liquid or by heat sealing methods known in the art. However, this seal must be effective at humidity levels and temperatures which do not adversely affect the drug in the dosage form. Furthermore, the web must have acceptable ignition properties to withstand such sealing methods.

In some cases, the path may have "memory", ie. it must have sufficient elasticity for it to quickly reverse and "open" the manufacturing process, in contact with stomach fluids, releasing the drug for absorption. By "opening" is meant that if e.g. the dosage form is formed by pleating, then it will open as a bellows, and if the formation is done by coiling in a spiral, it will roll up.

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Finally, the track must have other properties such as acceptable taste and odor, which will be apparent to those skilled in the art from the foregoing.

As noted above, the webs used in the present invention are preferably water-soluble or water-dispersible. There are two basic mechanisms by which the pathways of the present invention are formulated to be autodestructed upon contact with water or gastric fluid. First, the web may contain particles of substances such as casein or gelatin which swell upon contact with water, thereby tearing or breaking the web. Second, the web material may contain both water-soluble and insoluble components. Upon contact with water, the soluble constituents of such material will tend to dissolve and the insoluble constituents will precipitate and the web will tear. The last method of breaking down the track is not as fast as the first. Examples of suitable water-soluble constituents include methyl cellulose. Examples of suitable water-insoluble ingredients include ethyl cellulose.

The web composition used to prepare the novel dosage forms of the method according to the invention is of two basic types, namely polymers and paper.

The polymeric materials generally comprise: a) one or more organic film-forming agents; b) one or more plasticizers; c) modifiers, i. other ingredients, optionally together with certain materials such as disintegrants and diluents; and d) one or more volatile solvents.

The paper materials generally comprise: a) one or more fibrous materials; b) one or more non-fibrous modifiers, i. other materials, optionally together with certain materials such as one or more organic film forming agents, disintegrants and diluents, and c) a volatile solvent.

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The film-forming component of the polymer webs comprises one or a mixture of known, non-toxic organic film-forming agents, e.g. natural and chemically modified starches and dextrins; proteins such as gelatin; Preferred film forming components are hydroxypropyl cellulose and sodium carboxymethyl cellulose. Although the concentration of the film-forming component in the polymer web is not particularly critical in carrying out the process of the invention, it has been found that between 5% by weight and approx. 95% by weight is preferred, especially a concentration of between approx. 40% by weight and approx. 90% by weight.

The above-mentioned film-forming components are also examples of the film-forming components of paper web feeds used in accordance with the invention where these occur. Preferred film forming constituents of the paper web material used in the invention are also hydroxypropyl cellulose and sodium carboxymethyl cellulose. Also, the concentration of the film-forming component in the paper web material is not considered critical in this case. However, when such a component appears to act as a binder or disintegrant in the fibrous material, it should not exceed approx. 40% by weight, and preferably between about. 2% by weight and approx. 20% by weight and in particular between approx. 4% by weight and approx. 10% by weight.

The fibrous component of the paper web material may be any of the commercially available natural or artificial fibers which, by appropriate tests, have been found to be non-toxic.

Examples of such fibers include cotton, flax, cellulose, synthetically modified cellulose, rayon, textured vegetable protein, and collagen.

To ensure the required workability and mechanical properties, the polymer webs used in the practice of the present invention may contain a sufficient amount of a plasticizer.

Such plasticizer may comprise one or more examples from the group of plasticizers known in the pharmaceutical practice, e.g. glycerol

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13, polysorbates such as polysorbate 80 and polysorbate 60 as well as certain mixtures of mixed mono- and diglycerides of saturated fatty acids.

It is preferred that such plasticizers occur in an amount of between about 1% by weight and approx. 60% by weight, preferably between approx. 10% by weight and approx. 50% by weight, based on the web material.

Both polymer and paper webs may contain one or more disintegrants, which are customary in disposable paper materials, e.g. different types of starch, casein and gelantine. The courses may contain from approx. 0 to approx. 40% by weight, preferably from approx. 5 to approx. 20% by weight disintegrant, depending on the web material.

Furthermore, both types of web materials may contain one or more fillers or diluents which are customary in the art. Such components may e.g. may be opacifying fillers such as titanium dioxide, lime or kaolin, microcrystalline cellulose or calcium carbonate. It is to be understood that some of the constituents herein may fulfill more than one purpose and therefore fall within one or more of the above categories. Eg. For example, calcium carbonate can act as both an opacifier and dispersant, and certain starches can act both as binders and as disintegrants.

In addition, both polymer and paper materials may contain one or more modifiers which affect the electrical, mechanical, optical or permeate properties of the webs produced therefrom. Examples of such constituents are an electrolyte such as sodium chloride or potassium chloride and surfactants such as dioctyl sodium sulfosuccinate. The webs may optionally also contain ingredients such as pharmaceutically tolerable dyes and preservatives.

Furthermore, in most cases both types of web materials may contain a volatile solvent, e.g. water, certain organic solvents such as ethyl alcohol or combinations of such solvents, i. a hydroalcoholic mixture which is removed during formulation of the web.

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Specific examples of film materials used in the present invention are:

Polymer films which are decomposed in aqueous environments due to the presence of swelling agents.

Ingredient Weight% I Hydroxypropylmethylcellulose 45.69

Acacia rubber 19.44

Gelatin, extra fine, solubilized 32.08 Dioctyl-sodium sulfosuccinate, 75% aqueous solution 0.09

Titanium Dioxide 1.94

Lecithin 0.75 100 II Refined Starch 33.06

Carboxymethyl cellulose 33.06

Propylene glycol 33.06

Sodium benzoate 0.55

Sorbic Acid 0.28 100 III Hydroxypropylmethylcellulose 55.19

Cellulose Acetate Phthalate 2.99

Corn starch 28.66

Propylene Glycol 9.87

Titanium Dioxide 1.52

Dioctyl-sodium sulfosuccinate 1.52

Lecithin 0.25 100

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IV Hydroxypropylmethylcellulose 64.00

Cellulose acetate phthalate 3.10

Calcium carbonate 21.74

Propylene glycol 9.06

Titanium dioxide 0.91

Dioctyl sodium sulfosuccinate 0.91

Lecithin 0.30 100

All compositions I - IV can be sealed by heat and pressure. Composition IV is auto-degradable in aqueous environments due to the absence of insoluble polymers.

Preferred paper compositions comprise ca. 70 - approx. 99% by weight, preferably approx. 90 - approx. 96% by weight, fiber material, e.g. hardwood fibers or softwood fibers or mixtures thereof, ca. 1 - approx. 30% by weight, preferably approx.

4 - approx. 10% by weight, of is. disintegrant, which may be sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone or guar gum, and ca. 0 approx. 5% by weight, preferably approx. 0 - approx. 2% by weight of a surfactant, e.g. polysorbate 80, dioctyl sodium sulfosuccinate or sodium lauryl sulfate, the ability of the aforementioned agents to act as disintegrants in paper materials must be considered unexpected since substances of this type are used in papermaking in various quantities and have a different function . For example, when sodium carboxymethyl cellulose has previously been used in papermaking, it has been used in small amounts, i. 0.1% or less, to aid in the dispersion of the fibers while the paper is being formed.

In stark contrast to this, it has been found that when sodium carboxymethyl cellulose or the other listed substances are added in large amount, i. up to 30% by weight after the paper web is formed, but while still wet, they can act as disintegrants, and the time of addition of these substances is critical to their function as disintegrants. The disintegrants are added as a solution, preferably in the solvent used to prepare the paper web.

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It has been found that the disintegrants listed above coat the fibers when added to the web as described above. When the final dosage form is brought into contact with water, the disintegrants swell up, forcing the fibers apart to break the web.

When these surfactants are present, they assist in increasing the penetration of water to the disintegrant, thereby promoting tearing. :

The webs used according to the invention are formed by processes known in the art, e.g. in the papermaking and film-making industries. Eg. For example, polymer webs may be molded onto a suitable substrate, "Mylar" (polyethylene terephthalate; cf. Merck Index, 10th edition, no. 7442), stainless steel or slip paper. The webs are then dried, e.g. in an oven with ventilation. The temperature of the drying air and the length of the drying time depend on the nature of the solvent used in a known manner. However, most of the webs described herein are dried at a temperature between about 25 to 105 ° C, preferably between ca. 60 and 90 ° C.

Another known method of forming polymer webs is extrusion. This method is preferred for webs wherein the film-forming component is a modified food starch, hydroxypropyl cellulose or other extrudable polymers. The mechanical parameters of the extrusion process, e.g. the equipment used, the extrusion force, shape and temperature of the orifice, are within the skill of the art and may be varied in known manner to achieve the physical properties described below in the webs.

The paper webs are manufactured using conventional papermaking machinery, e.g. Fourdrinier papermaking machines.

In all cases, however, the web must be uniform in both thickness and width. The courses are between approx. 0.03 and approx.

0.3 mm, preferably between 0.038 and approx. 0.123 mm thick. A convenient width for such webs is 30 cm, although the width of webs is not very critical in carrying out the invention. The webs can be made to any length. Since the dosage forms prepared by the process of the invention are highly suitable for high speed preparation, the webs should be prepared in large quantities, e.g. 5000 m or more, which can be stored on e.g. cores or coils.

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17 In FIG. 1, the overall system for preparing a large number of the various dosage forms described in the present application is shown in block diagram form. Block 10 in FIG. 1 denotes web production from the materials described above. When the web is manufactured, or shortly thereafter, it passes an inspection step (block 11 in Fig. 1) in which various studies, which may be fully or partially automated, are performed to ensure the web's completeness, which is further described below. It should be noted, however, that the examinations of the web may be carried out while the web is being formed, or at any convenient time thereafter, either by means associated with the apparatus on which the web is manufactured, or by any other apparatus; and can in fact be performed in another location.

The active ingredient to be placed on the web is prepared and stored in containers, which is generally illustrated at 22 in FIG.

2, which, mainly in schematic form, illustrates the various apparatus which can be used to perform the steps indicated in FIG. 1. The active ingredient produced is sent to a device generally shown at 23 in FIG. 2, wherein the particle size reduction of the active ingredient and the control thereof is shown at step 13 of FIG. 1. Although this step is dealt with in more detail below, via this step 13 and the suggested apparatus 23, it is sought to induce a uniform flow to allow accurate and even placement (block 14 of Figure 1) of the active ingredient on the web, which is illustrated at 24 in FIG. 2. It should be noted that the system example shown in FIG. 2, indicates only the application of dry particulate material to the web in a dry state. It is to be understood, however, that the scope of the present invention also encompasses wet application of the active ingredient to the web. In FIG. 2 is also illustrated schematically by the embodiment of the invention in which the web is stored for later use, and by 21, where inspection of the web (step 11 of FIG. 1) is carried out, e.g. while the web is taken from the storage roll 20. It is clear that the inspection can be carried out before the web is rolled up and stored, and inspection can also be carried out after, or only after, the storage as indicated by 21 in FIG. 2. The details of the inspection of the track are described in more detail below.

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With regard to inspection means 21, inspection of the uncoated web may be carried out in various ways. Holes, errors and physical uniformity of the path can be assessed and measured using a scanning laser beam and photodetector combination. The system is used in both transmission and reflection designs. The continuous helium-neon laser beam is guided across the path by a mirror on a galvanometer. The mirror position is controlled electronically so that the position of any defect in the path can be determined. The reflected or transmitted light is defective by a linear photodiode placed behind an interference filter to exclude room light (atmospheric light). The electrical signal is used to count the number of defects and determine their size and distribution along the longitudinal direction of the path. This is done by analyzing the detector output with an impulse-height-width analyzer.

Another method that can be used to inspect the web at significantly greater path speeds is a parallel array of photodiodes located across the web. Each photodiode has its own threshold detector system and its digital logic, which enables a high resolution capability for small defect sizes and position-location characterization. The output signal can be processed to provide approximate size distribution and to locate the errors in the path.

The physical thickness of the track is measured by a parallel array of track riders mounted in precision bearings. These rollers touch the web and are connected to transducers that electronically sense the position with accuracy of at least 1/4000 cm. A similar system for measuring physical thickness can be made with pneumatic sensors floating over the web on a stationary air film. This system has the advantage of not touching the track.

Mass thickness (weight / area unit) or base weight of the web is determined by using a non-touching β-ray or X-ray equipment. These systems measure the absorption of β-rays or X-rays by illuminating the web. This absorption is set as a function of the mass thickness. In an alternative system, the electrical resistance is measured between two touching path rider electrodes which can be used to determine the basis weight of the path of known moisture content.

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On-line moisture content analysis can be performed by one or more of the methods listed below. First, the high dielectric constant of water enables fine-sensing moisture determinations by direct microwave absorption and by radio frequency dielectric constant sensors. Low frequency conductivity measurements can also be used to measure moisture in the web. IR Spectrophotometric Absorption is a totally independent moisture measurement method. The optical absorption at wavelengths in the range of 1-2 micrometers can further provide a specific and accurate moisture determination in a spectral region in which the path being inspected is relatively translucent.

After passing the inspection equipment 21, the web is guided by a suitable rolling arrangement shown in FIG. 2 so that it passes close by the apparatus 24 whereby the active ingredient is placed on the web. The annealing apparatus is immediately followed by devices 25, schematically indicated for on-line analysis / inspection e.g. of the uniformity of the active ingredient's coated web, preferably as a single layer, before the active ingredient is included.

A preferred method of non-destructive on-line analysis of the active ingredient placed on the web is X-ray absorption. In this method, low-energy X-rays set at a peak value corresponding to the absorption edge of the atoms located on the path are passed through the coated path. The X-ray absorption is dependent on the absorption of active ingredient plus pathway. If the active ingredient is placed on the web by a wet coating process, this assay method can be used either before or after drying.

Since the total X-ray absorption derives from the combination of web and active ingredient containing coatings, it is necessary to determine the absorption of the web individually. This is done using a β-ray meter or an IR spectrophotometer. Increased sensitivity is obtained for the X-ray measurement of applied active ingredient containing atoms with increasing atomic numbers. By varying the acceleration voltage, the X-ray source can be set to match the absorption edge of many atoms that may be of interest.

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Reflection or transmission spectrophotometry can also be used for on-line non-destructive analysis of the applied active ingredient. Reflection spectrophotometry is used in the near ultraviolet range to determine the amount of active ingredient applied. This technique can be used for any optical active ingredient with optical absorption in a suitable wavelength range.

Transmission spectrophotometry can also be used for non-destructive on-line analysis of active ingredient located on orbits. A suitable light source, a monochromatizing element, and a detector combination are selected for wavelength ranges in which the active ingredient absorbs selectively. This must be in a spectral region where the path itself does not absorb strongly. Such regions for trajectories occur in the near infrared region and in the infrared regions of the spectrum where functional groups absorb. A fast wavelength scanning system is used to review a small wavelength range that may be of interest. Time averaging of the signal from the detector is determined by multiple scans to reduce the noise power. From the signal data, then, the first differential quotient of the transmission with respect to wavelength is calculated for increasing sensitivity. This is done similarly for other wavelength ranges that are sensitive to other components of the system. Thus, the water content, the basis weight of the web and the content of the active ingredient can be determined simultaneously.

Another method for analyzing the applied active ingredient is molecular fluorescence. Pulse radiation in the ultraviolet or visible region of the spectrum is obtained by a suitable filter combination. The fluorescence of the active ingredient is determined by a broadband filter detector - combination corresponding to the fluorescence peak. A blocking filter is used to remove the impulse energy. The detector for this method is preferably a photon counter, which counts individual photo signals, has high sensitivity and linearity at low light levels.

By this method of analysis, it must be ensured that the photodegradation of the active component of the impulse radiation is limited.

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21

The coated web may be stored for a period of time or, preferably, fed directly to the machining (step 16 of FIG. 1) and the division (step 17 of FIG. 1) to form dosage forms; the processing means are illustrated in FIG. 2 as a series of knives 26 for cutting the coated web into several endless strips followed by lamination type splitting means 27, i. the endless strips are stacked on top of one another to form an endless stack which is pressed and finally divided according to the invention as described below.

The divided dosage forms are completed and then packaged in a suitable apparatus (step 18 of FIG. 1), schematically illustrated at 28 and 29 of FIG. 2 for subsequent distribution. Appropriate inspection (for example, 30 in Fig. 2) is performed in connection with this step. The purpose of the final inspection of the individual unit doses is to confirm the size, shape, perfection, identity, appearance and accuracy of the pressure and the content of the active ingredient. All these inspections are performed non-destructively, except for the active ingredient. To analyze for active ingredient content and appearance characteristics, a statistically representative sample of unit doses is removed from the production line and analyzed destructively, both for strength and for properties, e.g. solution properties, by solution-spectrophotometry, which are dealt with below.

An optical scanning system can be used to inspect the size, shape, completeness and presence and accuracy of print of all the produced units. The system includes a suitable light source and a matrix of photo detectors or a TV camera. A computer is used to process the signals from the optical system. Appropriate algorithms are used to determine whether the dosage forms are acceptable. In other methods, a comparison of the sample image with a standard image is used by an image masking technique.

By another method of 100% inspection, an optical transmission of an image of a unit dose is made. The fourier transformed spectrum, the potene transformed spectrum, or other suitable transformations are compared to a similar transformation of a standard by means of a computer.

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22 Before the final step, step 19 (Fig. 1) is performed with on-line analysis for resolution and uniformity of content with a suitable non-illustrated device, which may include and / or be controlled by a computer or similar central governing or logical bodies. A random sampling mechanism removes at a rate of 25 - 120 units / minute, preferably 40 - 60 units / minute, unit doses, one at a time, at the end of the production line. Each unit is individually transferred to a standard automatic weighing device in which it is weighed in a non-destructive manner and the information is stored. The randomly selected units are then placed separately in a conventional automatic assay system. The unit doses are stirred in a suitable solvent for the active ingredient at a suitable rate. The amount of active ingredient that dissolves at time t1 minus the amount that is dissolved at time t1 divided by tj-t1 is the dissolution rate. The time interval in question (tj-t ^) is fixed in advance and may vary depending on the different medications. A suitable time interval can be between 5 seconds and 2 minutes or more. The samples are then stirred continuously for such a long time that the entire active ingredient is dissolved, after which the solvent is analyzed for active ingredient content. The amount of active ingredient in this assay plus the amounts from samples t1 and tj is the total amount present in the dosage form. This information is recorded and stored. If the weight, thickness, dissolution rate, and result of the drug content analysis fall within predetermined limits, the units are judged to be acceptable. If the readings do not fall within these limits, the units made between the time of the negative analysis and the first positive analysis are taken out for further examination.

Referring to FIG. 1, it is noted that further measures have been taken to measure functions performed in accordance with the present invention, as described below. With respect to the lane inspection step, it is envisaged that e.g. Continuous monitoring of the web can be done based on the web color, thickness, continuity, dirt stains and faults of virtually all species. These functions can be performed with electronic and / or optical instruments as well as by visual observation.

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23

The inspection of the track includes a current location of a "mark" on the track when an error or a defect is found. The apparatus must be further equipped such that when a defect is detected on the track, a signal is given, either automatically or under operation control, which shows that there is a fault of some sort on the track a certain distance from it, which signal may include identifying the type of error, e.g. hollow, stain or bladder.

The means for producing the signal may be the same apparatus used per se for marking the web. Such an apparatus must be considered conventional in textile manufacture and inspection, e.g. with the exception that in this case the handling and inspection of the track can be carried out in accordance with good manufacturing practice.

Furthermore, the thickness of the web can be measured immediately or with additional conventional inspection equipment. This may be in the form of a visual signal to an operator, or it may be a measuring apparatus coupled to a logical arrangement with upper and lower boundaries of web thickness, which, if the web thickness exceeds one of the boundaries, will also be induced. a signal and placed a mark on the track as indicated above. One form of apparatus for measuring the thickness of the web may be an X-ray or β-ray meter or similar equipment for measuring the mass thickness of the web.

In the case of step 13 of FIG. 1 with respect to particle size reduction and flow control, it is envisaged that the measurement functions can be performed as described below. In addition, since the uncoated web has itself been examined for errors and thicknesses, similar measurements according to the invention can be foreseen after application of active ingredients to the web.

Eg. X-ray apparatus may also be used here to determine the thickness of the coated web, which thickness, as compared to the previously determined non-coated web thickness, would allow for deduction of the amount of active ingredient disposed on the field. Furthermore, it is within the scope of the present invention to use mass measuring means for use

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tuning the amount of active ingredient placed on the web.

It is to be understood that inspection of the coated web can be carried out by passing the coated web back through the same apparatus, with which at step 11 of FIG. 1, lane survey is performed.

The active ingredient application system (14 in Fig. 1) is controlled by feed-back from the on-line analysis of the active ingredient content on the web. Eg. on-line electrical signals - the analyzer (digital or analog) analyzing the applied amount of active ingredient (the weight of the area of the applied active ingredient path) used in feed-back (reference 15 in Fig. 1) to regulate the amount of active ingredient applied to the web during the application process. This feed-back signal is transmitted e.g. to a minicomputer which produces a suitable correction signal for the application process. The correction signal causes either an increase or a decrease in the amount of active ingredient applied so that the application is kept within a narrow range of the target value. Eg. in the dry application process, the powder of active substance is fed into the application apparatus. Thus, the correction signal is used to control the feed rate and thus the application of active substance.

In the wet application, the correction signal can be used for e.g. to vary the amount of coating composition (consisting of a solution or suspension of finely divided drug) applied to the web. Eg. the aperture is varied between the measuring rollers or between the measuring knife and the feed roll to change the application of active substance. In the reverse roll application, the rotational speed of the application roll is varied to change the application of the active ingredient. Another control method of the wet application is to vary the concentration of the active ingredient in the coating liquid. Two liquid preparations containing different concentrations of active substance are mixed in the conditions necessary to obtain the correct concentration. Therefore, the ratio of the two compositions can be varied to precisely control the application of active ingredient.

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25

Application of drug to the field.

The methods of "incorporating" active ingredient into the dosage forms prepared according to the present invention present a radical change from methods of incorporating active ingredients into usual solid dosage forms, e.g. tablets, capsules, dragees or suppositories. While the methods and equipment used for the various embodiments of the method of the present invention may vary somewhat, the overall objective is continuous and uniform placement, ie. applying active ingredient to the continuous web surface in a continuous and highly uniform manner.

The way in which the active ingredient is incorporated according to the present invention is unique and has several advantages over the manufacturing processes commonly used in the pharmaceutical industry.

Since the active ingredient is placed on the surface of an edible web which is then formed to completely enclose the drug, there is no need to mix the active ingredient with ordinary pharmaceutical excipients, fillers or preservatives, thereby eliminating cost and what is more substantially, a source of potential incompatibility and quality control issues is eliminated. According to the present invention, a continuous and uniform layer of active ingredient is applied to the web, which is then subdivided into individual dosage forms by linear or geometric subdivision, thereby obtaining a uniform strength level of the active ingredient in a large number of unit doses which are substantially superior to the ratio. to the batch requirements accepted in the pharmaceutical industry. In stark contrast thereto, in conventional pharmaceutical manufacturing operations, the active ingredients and suitable therapeutically inert pharmaceutical additives are required to be produced in bulk and subdivided by volume for filling into capsules or for compression into tablets. Therefore, using the method of the present invention, it is possible to reduce the amount of excess active ingredient to ensure the stated dose from the currently accepted level of from 5 to 10

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26 wt% to 1-5 wt%, thereby achieving a considerable saving, especially when very expensive active substances are used, e.g. certain hormones and antibiotics. Further, the method of applying or applying the active substance to the web of the present invention enables continuous, on-line, non-destructive testing of the dose by physical parameters, thereby facilitating the preparation of a large number of dosage forms with superior uniformity in the amount. of active ingredient.

The active ingredient may be applied to the web in either wet or dry form, of which the dry form is preferred. In each case, the active ingredient is applied in a form which can be subjected to analysis as described below, i.e. in finely divided form. The particle size is in the sub-micron range and can therefore be within a narrow size range of 1 to 100 microns. So far, particles in the submicron region have been considered to be too fine for the preparation of pharmaceutical tablets without first being subjected to techniques such as granulation, which significantly increases particle size and which also add diluent to the active substance. The technology of the invention facilitates the use of such ultrafine particles without necessitating the use of such techniques and / or the addition of diluents. The active ingredient is applied as a continuous and very uniform coating to the web while advancing in an automatic manufacturing system.

The preferred method of applying active ingredient to the web when the active ingredient is in dry form is as a powder cloud electrostatically applied using techniques generally known in the art of pharmaceuticals. Generally, by this method it is necessary to guide the path through an electrostatic field in a suitable chamber. Fine particulate active substance is then introduced into the chamber via e.g. a flow of air and applied to the web while passing over an opposite 'charged roller' It is obvious that this is an oversimplification. However, apparatus which can bring about this result is known in certain non-pharmaceutical fields, e.g. in the production of adhesives and adhesive paper. In order for the application to be as optimal as possible, it is clear that the web must have a specific resistance allowing dielectric particles to be placed thereon. Additives which may be present in the web material to enhance the appropriate electrical properties are discussed above. It has been found that

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In some cases, it is necessary to coat the web with a substance which enhances the adhesion of the powder before electrostatic application of the powder with the active ingredient. Examples of such substances are carboxymethyl cellulose and methyl cellulose. These adhesion enhancers can be applied to the web in the usual manner, e.g. by adding a solution in a volatile solvent such as water and drying with e.g. heated air. Application of a coating to the web to ensure adhesion of the active substances is then followed immediately on-line by coating or application of the active substance to the web. The adhesive is then activated to bind the particles of the active substance on the web. This is accomplished by affecting the coated web with heat, pressure, humidity or an appropriate combination thereof.

In addition to the method of electrostatic application of the powder cloud, the active ingredient in finely divided form can be applied to the web in a dry state by electro-gas dynamic powder application. In this method, the particles of the active ingredient are charged electrically by being subjected to corona discharge and blown by a gas stream into an electrically insulated chamber. The web is passed through this chamber on a metallic surface which is either grounded or charged with a polarity opposite to that of the charged cloud of active substance particles. The electric field between these particles and the metallic surface guides them to the web and places them thereon.

According to the present invention, the active ingredient can be applied to the web in the form of a solution or suspension of finely divided drug, e.g. and a colloid suspension. The liquid used for these operations may be water or an organic solvent such as ethanol or a hydroalcoholic solvent. A preferred method of applying active ingredient in liquid form to a continuous web is electrostatic nozzle spraying. In this method, the solution or suspension containing the active ingredient is metered into an apparatus which sprays microdrops which are concentrated on a specific area of the web using an electrostatic field applied to a specific area. This method has produced very good results when applying very small amounts of active ingredient to the web, e.g. hormones or enzymes. By small amounts is meant active substances which are usually dosed in less than 1 mg.

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28

In addition to electrostatic nozzle spraying, various other application techniques known from other areas for applying a substance with a liquid can be used to apply active substance to the web. Eg. For example, a paper web may be passed under a roller immersed in a bath of liquid which saturates the web. As the web passes the roller, excess liquid is "wiped" off the web by another roller, an air stream, a rubber wiper or a rewind rod, ie. and a Meyer rod. In this case, the solution penetrates somewhat into the web, especially if the solvent used to solubilize or suspend the active ingredient is the same or similar to that used to form the paper web.

It is to be understood that while it is an object of the invention to apply the active ingredient to the surface of the web, some penetration may occur in the web either as a result of the use of a volatile liquid carrier for the active ingredient or by applying heat and / or push to the lane to seal this one. Simple trials of these factors, e.g. volatile liquids, the proportion of active substance absorbed therein can be determined. Once this parameter is determined, the on-line testing equipment can then be set. If a significant amount of active substance is absorbed into the web, it is necessary to have uncoated web, ie. pathway without active ingredient, such as outer surface of the unit dose, thereby avoiding loss of active ingredient caused by degrading factors such as air and humidity. This result can be obtained by obvious modifications to the formation process described below.

As stated above, one of the obvious advantages of the dosage forms prepared by the process of the present invention is that pharmaceutical active ingredient can be formulated in a stable dosage form without being mixed with usual pharmaceutical excipients which usually occur in usual solid dosage forms in amounts far exceeding the amount of active substance.

However, it is clear that small amounts of inert substances must necessarily be applied to the web with the active substance of the invention as described above. When the active substance e.g. applied to the web in dry form, a small amount of lubricant, i.e. between approx. 0 and approx. 10% by weight, preferably between approx. 0.25 and approx. 2% by weight, calculated on the active substance, is mixed homogeneously therewith. The purpose of the lubricant is to facilitate

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29 the flow of the powdered active substance through the applicator.

Suitable lubricants are e.g. finely divided silica containing substances such as colloidal silica such as e.g. marketed under the trademark "Cab-O-Sil" ® by Cabot Corp., Boston, Massachussetts, talc and comminuted starch preparations, e.g. DryFl <P ^ from National Starch, Inc. It is clear that the use of a lubricant and the amount thereof depends on the crystalline structure and flow properties of the active substance. In some cases, a preservative may be added to the active substance. However, when the active substance is applied to the web in dry form, this is usually not necessary. It is within the scope of the present invention to mix the above adhesives with the active substance when applied in wet form and where both the adhesive and the active substance are compatible with the same liquid carrier. In most cases, the adhesive is used as described above, where the active substance is applied to the web in dry form, to improve adhesion. In each case, the adhesive must be used in an amount of 0 - approx. 100% by weight, preferably 0 - approx. 30% by weight, based on drug weight.

The amount of active substance applied to the web according to the invention will vary depending on the dosage of this substance, the surface of the coated web and the thickness of the coating. Additional factors affecting the amount of drug applied to the web are the method of application, parameters determined by the manufacturing process as described below, and the type and sensitivity of the on-line test equipment used. In all cases, the amount of active substance applied to the web is of such a size that each resulting unit contains a therapeutically effective dose when the web is formed. As an example of the last criterion in which the analysis of uniformity in drug application is performed using spectrophotometry using photon counting technique to measure the ultraviolet absorption of the active ingredient in the web, the thickness of the active substance layer cannot exceed 0.005 cm. In each case, the amount of active substance placed on the web is always expressed in millimeters or grams per microgram. cm lane. This is determined for the total web surface, although in most cases it is necessary to leave an edge uncoated web used for sealing the dosage form. The ability of the webs to receive and contain active substance according to the present invention is expressed as the conversion factor of the web (WCF) and is calculated according to the following formula:

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30

Path area applied to drug --3 - = ^ - 3 - = - = -: - - = Path conversion factor

The maximum area of the final dosage form

For example, if a web with the dimensions 15.25 cm x 1.0 cm is applied to drug and it is formed into a unit shape with the dimensions 0.5 cm x 1.0 cm, the path conversion factor is 15.25 x 1.0 0.5 X 1.0 = 30'5,

Cutting.

The next step in preparing the dosage forms is the molding or forming step. In the present application, the term "formation" means that the already formed web is transmitted in a fixed geometric shape of predetermined shape, which is divisible into several unit dosage forms. This step can take place, like the steps described above, in a continuous high-speed manufacturing process.

In this step, the coated flat web is transformed into a geometric shape of a particular shape, thereby enclosing the active ingredient in a protective web coating. The formed pathway is subdivided and finalized to form pharmaceutically attractive unit dosage forms suitable for oral administration. In a preferred embodiment, the division occurs simultaneously with or immediately after formation.

in

There are several different embodiments of forming, among which may be mentioned extrusion stretching, multiple rib forming, forming a wrapped rope, or thread pulling. The four basic techniques, rolling, rotating, pleating and laminating, are discussed in detail below.

Before discussing the various fabrication techniques of the invention, an overview of the various criteria for an acceptable technique must be provided. The forming or forming technique must be suitable for high speed manufacturing operations and produce a geometric shape that exactly meets uniformity requirements. In the process, the active substance must be included. The final fabrication or forming process must not strain the web to deform or tear, and no significant amount of active substance may be released from the web. Each of the formation processes discussed below meets these criteria.

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31

The first principle technique to be discussed concerns the rolling of a continuous web. It may be appropriate to distinguish between coiling and coil recovery, such as e.g. is known in the paper processing industry. In spiral recovery, the paper is fed to a spiral recovery machine from multiple rollers, usually in spirals 1/2 to 2 cm wide. The continuous strips of paper from each roller are wound around a cylindrical mandrel supported at one end. The strips are twisted in such a way that they overlap. An adhesive is applied to each paper strip, and the overlapping strips from a continuous coil are then wound around the mandrel. The roll thus formed is caused to rotate about the mandrel by the action of a continuous belt which also forces the roll of paper forward toward the unsupported end of the mandrel. At the end of the mandrel, the thus formed tube is cut to desired lengths by intermittent cutting with a high speed knife. Paper pea shaped in this way will always have a hole in the middle because of the mandrel over which it is formed. In the rolling process, there is no mandrel, so it is not necessary or desirable to have a hole in the center of the fabricated rod. It is an object of the present invention to completely limit or eliminate this central cavity.

Thus, in one embodiment of the method of the invention, the fabrication procedure comprises transverse cutting with medicament to form substantially equal lengths of web, each of which is divisible into several unit dosage forms, each length of web being corrugated to form a loosely wound coil. loosely wound coils are rolled to form a substantially solid rod and this rod is cut across to form multiple unit dosage forms.

Referring to FIG. 3, which illustrates an example of rolling. In the rolling process of FIG. 3, the coated or coated web 61 is passed from a single roller through a system,

DK 152172 B

32 which e.g. comprises guides 62 and guide rollers 63 for a cutting arrangement 64 which cuts the web transversely to the desired lengths, usually between approx. 12 and 25 cm1 in length. The web sections are then fed into a corrugating roller arrangement 65, wherein a corrugated end roller forms a plurality of folds by pressing the web against a soft rubber roller. As a result of the corrugation, the individual web sections are formed or coiled into loosely wound coils. The loosely wound webs from the corrugation roller arrangement are then passed between a fixed surface and a continuous surface, the space between the two surfaces gradually narrowing along the path of the curled webs. The stationary and running surfaces may be in the form of two concentric cylinders, one of which is stationary and the other rotating relative to the stationary cylinder, or, as shown in FIG. 3, they may be in the form of a fixed plate 67 as the stationary surface and a roller belt 66 as the non-stationary surface. As the web sections, as loosely wound rollers, pass between the continuous and stationary surface, they are rolled closer until a solid rod is formed. By appropriately adjusting the space between the two surfaces, the rod can be rolled up so tightly that there is no hole in the middle. Of course, it is clear that the space can also be designed so as to have a hole of the desired size in the center of the rod formed.

The wand can be sealed differently. First, it has been found that conventional manufacturing processes, e.g. for forming rods, cannot be used in the practice of the present invention. By conventional methods, the running surfaces which come into contact with the web during formation of the rod are sprayed or coated with water which comes into contact with a large portion of the web.

The amount of water absorbed by the web, approx. 18% by weight is unacceptable in the preparation of the unit dosage forms because of the possible degrading effect on the adhesion of the drug on the web as well as on the drug itself. Furthermore, the rods produced by the usual technique have been found to be for the most part too tightly enclosed to cause good release of the drug into the body. Therefore, according to the invention, a web with a water-sealable composition is used and the rods are sealed by contacting the coils with a sufficient amount of water in the form of a fine spray to moisten them and then drying the rods.

DK 152172 B Ί 33

This gives the final dosage forms acceptable uniformity and release of the drug as well as stability with respect to the active ingredient, except, of course, of the drugs known in the pharmaceutical practice to be highly sensitive to humidity.

Second, the rods can be sealed by applying a piece of heat-sealable edible polymer to the protruding edge of each web layer, or coating the protruding edge of each layer with a heat-sealable, edible polymer, just after the cut is made from the endless web. Alternatively, a heat-sealable polymer can be applied over the entire web section, either as a single layer or as a uniform coating. Suitable polymeric materials include e.g. a water-soluble polyoxyethylene or cellulose ether derivative containing a plasticizer as described above. After the rods are tightly rolled, in such a case they are brought under a heated plate, where both heat and pressure are applied to effectively seal them. Eg. For example, a portion of the stuck plate 67 may contain a heated section.

Alternatively, after the formation thereof, the rods may be sealed by application of water or an adhesive to the outer layer (s) or web.

Preferably, water is used as a sealant.

This method necessitates the presence of substances in or on the web material, e.g. starches or starch derivatives which may form a seal upon subsequent drying or using heat and pressure.

The FIG. 3 illustrated method shows e.g. a water spray 68 contacts the outer surface of the endless tape 66 on its lower return portion so that the tape surface contacted with the rolled web sections has only sufficient water droplets to effect a sufficient sealing of the rods. The water can also be applied to the tightly wound rods, e.g. by passing them under a water transfer roller, a porous plate through which one

DK 152172B

34 measured quantity of water is applied evenly throughout the length of the rod, or a sponge so arranged as to apply water to the outer surface of the rod. The rods can then be passed between a further section of continuous and stationary surfaces, where pressure or pressure and heat can be applied to cause the finished seal.

This common method of performing a water seal is considered to be clearly superior to known methods for forming e.g. confectionery products as described above. With the water application method described above, the total amount of water supplied to each rod is less than that applied by the known methods.

As a result, the amount of water to be removed by the subsequent drying of the rods is substantially less than that which is generally necessary to remove in known methods. It has been found particularly advantageous to limit the spraying of water to the point of the rod surface where sealing is desired.

The rods thus formed are each as long as the width of the web on the feed roller. This width is typically 20 - 40 cm. After sealing each rod, it is brought into contact with e.g. ultrasound blades 69 (Fig. 3) where they are divided, i.e. the rod is cut to desired lengths. Methods for forming and finalizing these spells for final dosage forms are discussed in more detail below.

Another forming or manufacturing method to be mentioned is generally called rotational formation. This method can take several specific forms. Generally, a stack is formed of the webs of which at least one drug is placed and the stack is cut into unit dosage forms, simultaneously applying heat and pressure to seal only the edges of these unit dosage forms, thereby completely enclosing the drug. For example, the stack may be formed by pleating or lamination, which is discussed below. This stack can be pressurized to compress and mold it into a continuous rod-like geometric shape which can be divided into multiple unit dosage forms which are then sealed to completely enclose the drug. By a specific rotational formation method as illustrated in FIG. 4, a continuous, relatively thick laminated web strip 70 is applied to the active substance between a pair of pressure rollers 71. The continuous thus formed or compressed laminate stack 72

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35 is led to the next station, ie. a rod forming and compressing station, e.g. comprises one or more spring loaded stainless steel rollers 73 having circumferential edges formed to convert the strip into multiple continuous rods 74, of substantially circular or cross-sectional shape. The rods 74 thus formed in the desired geometric shape are then passed through a third rotating station, e.g. one or more pairs of appropriately arranged rollers divide the rods into individual doses. This can be followed by other suitable printing and finishing operations, which are further described below. The pressing operation may be performed in the splitting step using a third roller set 75.

Another example of rotational formation is shown in FIG. 5, wherein the formed endless stack (strip or rod) 81 is continuously provided with grooves at regular intervals by reciprocating press heads 82 and / or pairs of suitable heated rollers 83 to eventually produce rounded corners in the final unit doses, so that the starting product of the rotary dose-forming station is a continuous chain of end-connected dose units 85. As in all the various methods of rotary formation by the method of the invention, the thus-converted rods are passed through printing and splitting stations or subdivisions, all at high speed.

By another closely related rotary forming technique, the continuous stack is fed into a rotary molding and compressing unit which, as above, includes e.g. one or more pairs of stainless steel rollers c The web stack, which can be made of paper layers and polymer films, is heated and compressed into a continuous stack. This stack can be formed by laminating multiple webs arranged so that the top and bottom surfaces are free of drug. It is preferred that the outer layers of the stack be made of paper, e.g. to prevent the stack from sticking to the heated rollers. During the compression operation, the web layers are bonded together to a unit, reducing the offset in the layers and splitting the edges during subsequent side and end forming operations. Then, the ends of the unit boxes are formed by directing the continuous rectangular stack made in the compression step to a next station, where the ends of the unit boxes are formed by a pair of heated roller blades which may have cut, transverse cut-off mechanisms. roll surfaces.

The cut ends of the unit doses are shaped and sealed by the heat from these rollers. The design of the end cutter determines the end shape of the unit doses. The shape of these end cuts is determined such that a smooth transition to the cuts of the side edges of the unit dose is obtained, which is performed in the next step.

The sides of the unit dose are formed in the laminated, end-formed, cut material stack with a third pair of heated rollers. These rollers must have angular recesses with raised cutting edges. The shape of these recesses in the roller surfaces forms the cross section of the desired unit dose. Heat and pressure from the back-like cut-off elements on the rollers seal the sides of the unit doses to a smooth surface.

The rotary forming method for preparing unit doses illustrated in FIG. 5, therefore, comprises three primary stations, namely a pre-compression station, an end-forming station and a side-forming station. Each of these stations consists of a set of rollers, preferably heated, between which the continuous path is conducted. The design of the outer surface, namely the surface of the rollers, is different at each station, depending on the station concerned and the result to be achieved. Various additional operations, e.g. as additional cutting, pressing or finishing steps can be performed between or at the three stations described. These operations are described in more detail below.

It is within the scope of the invention to perform one or more of the different steps of the rotation simultaneously and in effect to perform all the different steps listed above, i.e. rod formation, dose formation, division and even printing, on the endless laminate input strip via a single pair e.g. spring loaded, heated, cooperating rollers.

37

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The third example of rotation formation described above. easily leads to an example of combining two or more of the suggested steps into one. As illustrated in FIG. 4A, wherein substantially the lamination press and the rod forming step of the rotary forming method described above and also the method illustrated in FIG. 4 are combined, e.g. by using a single pair of heated, compressed and cut-off rolls (not specifically shown), which simultaneously compresses the laminate supplied and end-cuts it in a form resembling several stacks of side cakes. These end-cut sections are then immediately directed to a splitting apparatus which performs the longitudinal sections to obtain individual doses. The pressing step may e.g. also performed in this last station. It is also within the scope of the invention to pack the formed unit doses directly as they emerge from the splitting operation, e.g. by inserting them into blister strips in apparatus known in the art.

A third embodiment of the method according to the invention for forming dosage forms is the pleating technique. The pleating technique can also be classified as a form of lamination in the broad sense. In this method, a web of up to e.g. 30 cm wide first so that the active substance placed thereon is enclosed. This can be done either by first folding the web half over or by laminating two coated webs with the coated surfaces facing each other. A stack of more than one pair of webs may be laminated in this way, and the webs may first be formed to a greater width, e.g. up to 60 cm, after which they are laminated, divided into two or more widths to be used for the pleating operation, ie. from approx. 1 to approx. 15 cm.

After the coated web is first folded or laminated as described above, it is passed past notch-forming rollers, where notch is made in preparation for the pleating operation. The engraving rollers may be powdered. The web is driven in principle by pull rollers. The jaw formation can e.g. is performed by spring loading of one of the two love rollers. Since the web is preferably folded in the direction of the notches which are pressed into the web material,

DK 152172 B

38, the notches may be alternately placed on the upper and lower rollers in accordance with the desired pleating pattern. The notched web is then fed into a pleated slit with folding blades, which starts by softly bending the web at the point of contact and narrowing both the width and the overlap so that the web folds appropriately close to the exit point. At the end of the folding slide there is a means for pulling the web through the notch-forming and folding apparatus, e.g. a pair of stainless steel, spring loaded drive rollers. This serves a dual function, namely pulling the web through the folding apparatus and pressing the folded web into a continuous, solid geometric shape.

It is, of course, within the scope of the invention to combine the pulling means with means for sealing the web. However, the pleated web may be otherwise sealed as described below. The sealed web can be divided into units in different ways, e.g. by rotation forming methods as described above.

In FIG. 6A - 6D illustrate a pleated dosage form technique in which initially pleated web 91 is placed in cooperating perforations 92A of a therapeutically inert web structure, preferably of paper, labeled as center strip 92. This "enriched" center strip with the pleated web is then laid between outer web strips 93 to form a composite laminate structure. This composite endless laminated strip is then fed into e.g. a rotary dose-forming unit or station, not unlike unit 83 of FIG. 5, in which the strip is made to accept it in FIG. 6B. Finally, or simultaneously with the step performed in relation to FIG. 6B, the partitioning step is performed to obtain individual doses as shown in FIG. 6C. FIG. 6D illustrates in cross-section the embodiment of FIG. 6C. FIG. 6D shows how the pleated web 91 is completely enclosed and that e.g. the center strip 92 of the casting technique is forced somewhat outwardly so that some of it lies between the edges of the outer strip 93 sealed thereto. The outer strips 93 and the center strip 92 are preferably free of active ingredient, thereby ensuring that none of the active ingredient is present on any outer surface of the individual dosage forms.

DK 152172B

39

The fourth principle forming method encompassed by the present invention is the lamination method suggested above. In this method, between approx. 20 and 60 web rolls are first simultaneously discharged from a multi-coil unwinding stand and then fed in to form a continuous rod. The 20 to 60 web layers may all be of paper-like material with a suitable coating to facilitate sealing in a subsequent step, or they may be a paper-like web laminate and heat sealable edible polymer web, or may consist of one or more paper-like webs, between which are heatable sealable, edible polymer webs. Suitable polymeric materials are e.g. a water-soluble polyoxyethylene or cellulose ether derivative containing a plasticizer. Any number of these paths can be applied to active substance. The paper material is preferably applied to the active substance.

Another method of stacking the webs to which the active ingredient is applied is to conduct them directly from the application apparatus. The width of the web is usually 12 - 25 cm. The web, which is stored in rolls or is fed directly from the applicator, may first be a multiple of the final width which is split into the final desired width as part of the stacking process.

When the web is stacked, the resulting continuous bundle is led into a lamination station. Apparatus known in the art for bringing together strips of flexible film and forming a laminate therefrom are generally used in carrying out a variant of the invention. As stated above, the area of the web strip or sheet on which the active substance is placed will vary depending on the method used for sealing the laminate. The cutting and finishing of the laminate may also vary according to the invention. Eg. For example, laminates can be treated as described above for the rotary forming process. However, the laminating station may also comprise a pair of reciprocating press plates which shape, seal and cut dosage forms of the continuously applied web stack. A typical press plate has a surface of approx. 25 cm x 25 cm.

DK 152172B

In a particular embodiment, the stack of webs comprises at least two web layers consisting of a heat sealable polymeric material comprising an organic film-forming component and a plasticizer therefor and at least one layer of paper material comprising one or more fibrous materials and at least one non-fibrous modifier therefor, wherein the bottom layer of this stack is polymeric. Surprisingly, it has been found that suitable dosage forms can be prepared from a stackable web layer wherein up to six layers of paper webs are disposed between web layers of a heat sealable polymeric material by applying heat and pressure to the stack at the cutting means during partitioning. During the cutting operation, the web stack is applied with sufficient heat and pressure to deform the polymer webs and seal the edges of the intermediate layers of paper material webs.

It is preferred that the drug in a paper-polymer web stack be applied to the paper layers in the web. It is clear from the foregoing that such a laminate sealed on the outer edge alone has a superior release rate of the drug over a similar web stack which is completely laminated.

Another method of forming the dosage forms from the web stack is to allow the stack to pass between rotating cylinders which have separate double cutting mechanisms on the periphery. The unit doses are formed, sealed and cut from the continuously supplied web stack while being passed between such rotating cylinders.

Some advantages of the pharmaceutical manufacturing method are apparent from the lamination technique described herein. First, by the lamination technique, barriers are obtained which facilitate the mixing of two or more therapeutically active substances which are incompatible without the need to resort to the addition of stabilizers or a special manufacturing technique, e.g. encapsulation of one or more components. For example, can be used up to 60 layers in forming the laminate, this embodiment is ideal for pharmaceutical compositions containing a large number of active substances where there are many incompatibilities, e.g. in multivitamin preparations. In addition, the insulating effect of the sheets on the laminate and the application of the active substance to the web in dry form makes such a technique ideal for dispensing effervescent compositions. In such preparations it is clear,

DK 152172B

41 that the web material must be such that it is readily dissolved or dispersed in water. As noted above, the application of the active ingredient to the web in a dry state is advantageous when the active substance is adversely affected by moisture.

Furthermore, within the scope of the lamination process, it is within the scope of the invention to vary the composition of the various layers of the laminate and to regulate whether each layer is coated with active substance. It is to be understood that the surface of the top and bottom layers of a laminate which will face outwards is not coated thereby effectively enclosing the active substance. Eg. It has been found that putting one or more layers of a starch-based material into a cellulose laminate makes the laminate much more soft than increasing the amount of plasticizer in the formulation of the cellulose layers.

With regard to the molding method described above, it is preferred according to the invention to apply or coat the web with active substance in wet form, the molding being carried out by rolling or pleating. The rotational formation and lamination processes are equally good for coating with active substance in wet or dry form, the choice being dependent on the properties of the active ingredient applied, e.g. the solubility of the particular solvent or the moisture resistance.

Division into units.

Of course, the division into units cannot be discussed without also discussing sealing and without first discussing fabrication, as cutting or dividing into units of the formed web per unit. definition may expose some of the active ingredient to one or more of the outer surfaces. In some of the operations described herein, e.g. In the pleating process, the outer edges of the web may optionally be released from active substance to ensure that the active substance is enclosed, and in some cases only a web surplus which can be used to seal the divided dosage forms with.

42

DK 152172 B

The cutting of the formed web must be carried out in such a way that the web is not deformed. The cutting operation itself may be performed by stationary or rotary blade blades, by single or two-stage presses or by other conventional means. In order to ensure that the formed web does not deform during the cutting operation, several sections can be made from different angles. As noted above in connection with rotational formation, the formed web may also first be slightly shrunk or grooved to compensate for the deformation that occurs during the high speed splitting operation.

The formed coated web can be divided into units by individual separation, i.e. forming one unit at a time, e.g. by cutting exact lengths of a rod or, preferably, a plurality of units may be formed simultaneously, e.g. by cutting a coiled rod into a plurality of unit doses using a number of equally spaced cutting tools. Another method of forming multiple unit doses simultaneously is the use of formed presses, either single or double, and placed rotating or arranged reciprocally on plates which cut a laminated web or a rolled rod-like structure. The shape of the final dosage forms should preferably be appealing and such that a number of units fit into a plunger plate with substantially no waste except at the periphery, e.g. a rectangle, a square or, preferably, a hexagon.

In cases where the forming step has led to the formation of a continuous rod-like geometric shape, the splitting step may comprise uniform transverse notch formation in the rod-like geometric form and subsequent cutting of it in the slots to form unit doses. Alternatively, the splitting step may include cutting the longitudinal rod-like geometric shape to form multiple continuous geometric shapes, each of which is divisible into multiple unit doses, and subsequently cutting across each of these continuous geometric shapes at uniform intervals to form individual unit doses. Furthermore, the splitting step may include cutting across the rod-like first geometric shape at uniform intervals, thereby obtaining multiple geometric shapes, each of which can be divided into multiple dosage units, and subsequently cutting these forms longitudinally to form individual dosage units.

DK 152172B

43

The shape of the dosage forms produced from rods can also be determined by the shape of the cutting means. The cutting means may e.g. be of rectangular shape with the parallel slender sides made fashion-steering concave, so that the ends of the dosage forms cut off will be slightly rounded. Other variations are obvious to those skilled in the art.

However, it should be remembered that such lateral support as is necessary to prevent torsion and bloating must be used for the dosage forms produced during the splitting operation.

It is within the scope of the invention to combine the splitting operation and the final sealing operation. Although there are various ways in which the dosage forms can be sealed, the methods most often combined with the splitting operation are heat and / or pressure. In addition to sealing on the cut edges of the dosage mold upon heating of the cutting tool, heat and pressure can be applied through the mold to bond the laminate. Also, moisture or a volatile solvent can be used to seal the forward edges in a rolled state, as stated above in connection with the cutting operation, by applying such solvent to the cutting surface. Heat and / or pressure can also be used at the same time to ensure good sealing.

The methods by which the split unit dosage forms prepared according to the present invention can be sealed are not uncommon in the plastics or lamination technique. These include, in addition to the use of water or other volatile solvents such as ethanol, methanol or chloroform, the application of pressure and heat, a special adhesive, infrared heating, ultrasonic bonding, encapsulation or combinations of two or more of these methods.

A more preferred method of obtaining a sealing layer on the manufactured divided unit doses is encapsulation. In this method, the fixed unit doses are passed between converging layers of flexible film, e.g. gelatin which encloses the dosage form as illustrated in FIG. 6A. The gelatin film is heat sealed and cut into shape. Apparatus for encapsulating liquids in this manner are known in the pharmaceutical industry, and such apparatus can be readily formed to coat the dosage forms prepared by the process of the invention.

DK 152172 B

44

Quality control.

One of the great advantages of the dosage forms produced by the method of the invention is that they can be subjected to on-line, non-destructive quality control. In this specification, the term "non-destructive" is used in its broad, practical scope, contrary to the strictly limited literal definition. This means that quality control of the novel dosage forms is achieved during the manufacturing process at high speed with a current loss of substantially less than 1% of the dosage forms. Since the novel dosage forms can be prepared with a low standard deviation in dose, therefore a manufacturing surplus of less than the standards usually accepted in the pharmaceutical industry, a very small percentage of the dosage forms are lost during the test, in fact none when considered to the tolerances within the currently used progress processes.

The dosage forms produced as a final product have a quality uniformity in the manufacturing process, which is unique in the pharmaceutical industry. The on-line testing procedure which provides such accuracy clearly differs from known pharmaceutical quality control procedures such as chemical and physical control of dosage form ingredients before manufacture begins, destructive testing of solid dosage forms after completion of manufacture, both for physical properties, e.g. . rate of dissolution and occurrence of tire failure, and chemical properties such as strength and incompatibility, as well as physical quality control of the solid dosage forms such as manual inspection of two-color capsules to ensure that each one ends up with different colors. Such tests, which are known and commonly used in the pharmaceutical industry and described in official works, are unrelated to and are not proposed for on-line preparation control which is a critical feature of the preparation of the solid dosage forms of the invention. However, it is clear that certain conventional techniques, e.g. Strict quality control and testing of all ingredients prior to the manufacturing process form part of the preparation of the dosage forms, which is also the case «save any good pharmaceutical manufacturing practice.

DK 152172 B

45

The on-line quality control of the dosage form manufacturing process is based on the fact that all such forms start with a continuous edible web that can be subjected to non-destructive testing. First, the web production itself is examined for physical properties in the web to ensure that the web is uniform and free from defects. Eg. For example, the path may be caused to pass through a cavity resonator where a microwave running through the path continuously monitors the path thickness, i.e. when the resonant frequency is established, changes therein show changes in the path thickness. Other methods for monitoring the thickness of the web include laser beam diffraction, fluid sensor measurement and physical contact sensors. It is also possible according to the invention to measure the weight of the web by weight. area unit and defects.

The preferred method for determining the weight of the web per area unit is soft X-ray absorption, e.g. at wavelengths of approx. 4 Å. Beta ray absorption using a PM 147 source can also be used. Path errors such as voids, holes and siirs can be detected by laser beam scanning. Gaps in the web can be detected by an electric discharge method using commercially available equipment.

The above methods may also be used in cases where an additional coating is applied to the web, either in the form of one or more additional webs, or a protective coating is applied to a coated web. Laser scanning is particularly advantageous in the on-line quality control of such coatings.

Another large area of quality control on-line in accordance with the invention is the monitoring of the amount of active substance applied to the web as well as the uniformity of the coating operation. It should be noted at the outset that a significant advantage of the method of the invention in which the dosage forms are prepared is that the active substance is applied to the web in a form which can be subjected to testing techniques as described below, e.g. in finely divided form or in the form of a fine film.

DK 152172 B in 46

Several methods may be envisaged to investigate the uniformity of application of the active substance. Eg. a photon counter can be used to measure the ultraviolet absorption of the highly attenuating active-substance pathway system. Measurement of soft X-ray absorption using a wavelength of approx. 4 Å and beta-ray absorption can also be used. Light scattering devices are preferred as they are ideally suited for monitoring particle size and concentration in the powder cloud or on the web. Devices that can be used for such operations are commercially available.

The fabrication, division into units and the finishing steps described above may also be subjected to on-line testing procedures as described above in connection with the web. Such tests will, of course, include physical parameters of the web after fabrication such as dimension, thickness and uniformity. Similar tests are also performed on the divided dosage forms in terms of shape and uniformity.

The discussion on this point has centered on bodies with which the unit doses produced are tested non-destructively on-line during manufacture. Two further tests according to the invention are envisaged without departing from the spirit of the term "non-destructive testing".

In the first of such operations, a negligible portion of the web is removed at intervals on-line by cutting with knives, press heads, liquid jets or a laser beam. It is assumed that the amount of web removed does not destroy the whole web or adversely affect any of the manufacturing operations. The web sample may be removed before or after coating with the active substance or, in some cases, during an early fabrication stage, e.g. when few lanes are stacked in an initial lamination or folding operation.

The sample thus removed is chemically analyzed both for web composition and for active substance. This analysis is also performed on a quantitative basis, especially with regard to active substance.

Eel

... DK 152172 B

In addition to this single analysis, the finished dosage forms are tested and subjected to on-line functional control. While such testing is a procedure usually required with most solid dosage forms marketed in the U.S.A., it is not performed on-line during the manufacturing process, as is the case with the present. First, it should be recalled that the novel dosage forms are not subject to batch restrictions due to the process by which they are prepared.

Accordingly, a "batch" according to the invention may be the number of dosage units falling between two samples meeting the functional requirements, provided that this number does not exceed the test requirements of the Federal Food and Drug Administration. Since the test techniques envisaged according to the invention are substantially above such requirements, a "batch" of the unit doses produced can be any convenient number, e.g. the number of units that can be prepared from a given amount of active ingredient produced.

Another unique aspect of testing the dosage forms prepared by the process of the invention is that the results of such tests, as well as of all the other on-line tests mentioned in this specification, can be electronically processed and used to set the parameters of the manufacturing process. . In this way, a negative reading of any of the tests marks the beginning of a portion of unit doses which must be isolated, and the next positive result after the corrections automatically ends the withdrawal. The unit doses produced between these two tests must then be tested further to determine how many meet the specifications. When conducting tests on-line on the track, e.g. on the amount of active substance applied, a negative reading can be automated to produce two effects simultaneously. First folded, the web can be marked with a mark of a non-toxic dye, thereby making it possible to suspend the production procedure temporarily and a web section can be removed manually. Second, the reading, through a computer, can affect an adjustment of the amount of active substance applied to the web to either increase or decrease to conform to the specifications. When the lane passing the test unit again meets the specifications, an additional mark can be automatically applied to the lane, thereby marking the lane length that does not meet the specifications. Similar operations can be established at each of the other online test sites.

48

DK 152172 B

With regard to the function analysis operation, samples taken at random sampling of final unit doses are removed and placed automatically in aliquots of test solution and tested for dissolution rate. The particular criterion used for testing the solution of the unit dosage forms will vary with the active substance (s) present therein. Eg. For example, a sample with a unit dose may be added to a suitable solvent to form a solution of the active ingredient. The resulting test solution can be photometrically examined to determine the concentration of active ingredient as a function of time after placement of the test unit. Other possible indicators that can be measured in the test solution are changes in pH, color, heat and chemical reaction. Means by which each of these changes can be determined automatically as a function of time are within the prior art. When the resolution information is measured, it can be used by a system, e.g. a computer, to make settings in the formation, splitting, finishing, and sealing operations necessary to correct or improve readings.

The on-line test procedures described in this specification can be used in all conditions for testing the entire web, e.g. an apparatus which examines the web thickness. However, in some cases it is not attractive from an economic point of view to examine the entire course. It is e.g. possible to examine a small path area using a light scattering sensor and further possible to mount two or more sensing devices close to each other to examine a similar number of narrow pieces of the path passing. However, the cost of the equipment needed to have the entire track examined can be prohibitive. Therefore, when only limited trajectory areas can be examined, the testing equipment can be mounted on means which make it easier to oscillate over the width of the trajectory. The proportion of the web and thus the final unit doses tested in this way far exceeds any non-destructive test procedure currently used in the pharmaceutical industry.

DK 152172 B

49 Finishing and Imprinting.

As indicated at various locations in this specification, the operations on the dosage forms prepared can be completed independently or, preferably, in combination with other operations, e.g. division into units. Completion in respect of the previously formulated dosage forms can be divided into two different areas, namely the surface uniformity of the dosage form and the surface finish or appearance.

Surface smoothness of the dosage forms may be a problem that depends on the technique used to prepare the dosage forms from a continuous stack and whether a sealing operation has been used. Eg. If a laminated web stack is cut out in a particular shape as described above, a small "flashing" may occur where the cutting members meet. There may also be some end or side flashing from the operation where it is divided into unit dosage forms by other preferred manufacturing methods. However, the manufacturing technique of the present invention generally minimizes the occurrence of such "flashing".

"Flashing" as described above can generally be removed by gentle grinding, e.g. by subjecting the unit doses to mild tumbling with or without the presence of a mild abrasive such as salt crystals.

It is clear that such an operation must be performed before printing.

The surface appearance, ie. The dosage form's gloss may vary from slightly matte to quite glossy, depending on the technique used and the finish desired. Where sealing technique, e.g. encapsulation methods as described above are used, the gloss of the final surface can be adjusted in the desired manner simply by selecting the material used for the seal. The same is true when a coating is used to seal the dosage forms.

When such sealing operations are used, it is usually not necessary to completely remove "flashings" as the coating completely ensures uniformity.

DK 152172 B! 50 The printing operation is similarly dependent on the fabrication and sealing technique used. Printing can be done on the web itself at any point throughout the manufacturing process. Eg. For example, the outer layer in a laminated dosage form can be applied before the fabrication operation, as part of the cutting operation or after the splitting is complete. Dosage forms, e.g. made by winding up can be printed while still in the form of a continuous rod or stack. When the dosage forms prepared are sealed by applying a coating, the printing is preferably carried out after the coating is applied, although it is possible according to the invention to print the dosage form and then apply a clear coating. The printing on the solid unit dosage forms prior to the final formation is considered unique in the pharmaceutical industry.

The choice of printing method depends on various factors, of which the most important is the physical nature of the fabric on which to print. The selection of a suitable method also depends, to a certain extent, on the place in the total manufacturing operation where the printing is carried out, ie. whether the web can be printed before fabrication, whether the finished dosage form can be printed, or whether the printing can be performed at an intermediate stage, perhaps in combination with other operations such as unit splitting. The printing method and apparatus which can be used for this can be selected from the following: offset and direct printed text, offset engraving, lithography, electrostatic powder graphics, electrostatic screen template printing or ink jet. Of these, offset engraving is the preferred one, although other methods may be used in particular cases, and new printing methods which emerge and can be used in the technology described herein are within the scope of the present invention.

It is clear from the foregoing with regard to finishing and printing operations that there are several different ways in which the color of the novel dosage forms can be varied, both in tint and intensity. First, the web material itself may contain a color which can be built up in intensity when several web layers are joined during the various fabrication operations. There can also be-

DK 152172 B

51 reads color by a coating or sealing layer. When encapsulation methods are used, two or more contrasting colors can be used in the obvious utilization of different colors in the different sections. The dosage forms produced by lamination can also be given different color, simply by varying the color of the webs introduced into the lamination apparatus.

Other variations of these techniques are obvious to those skilled in the art.

Active ingredient.

The dosage forms of the process according to the invention have practically no restrictions on the type of active ingredient to which they can be used, the term "active ingredient", "active ingredient" and "drug" are considered synonyms with the present invention. invention and are used interchangeably in the present description and claims and may be defined as any substance capable of eliciting a pharmacological effect in the body. Such substances include, but are not limited to, the following:

Benzodiazepines such as chlorordiazepoxide, diazepam, flurazepam, oxazepam and chlorzepate. Further compounds under the term "benzodiazepines" are described in "The Benzodiazepines" Garattine, Mussini and Randal,

Raven Press 1973, and the information contained herein shall not limit the term

Other tranquilizers such as reserpine, thiopropazate and phenothiazine compounds such as perphenazine and chlorpromazine.

Sedatives and hypnotics such as phenobarbitals, methylprylonone, glutethymiaf etchlorvynol and methaqualon.

Mental stimulants such as amitriptyline, imipramine and methylphenimidate.

Narcotic and non-narcotic analgesics such as codeine, levorphanol, morphine, propoxyphene and pentazocin.

Analgesic antipyretics such as aspirin, phenacetin and salicylamide.

DK 152172 B

52 *

Anti-inflammatory agents such as hydrocortisone, dexamethazone, prednisolone, indomethacin and phenylbutazone.

Antispasmodics / anticholinergics such as atropine, papaverine, propanethelin, dicyclomine and clindinium.

Antihistamine / antiallergics such as diphenhydramine, chlorpheniramine, triplenennamine and brompheniramine.

Decongestants such as phenylephrine and pseudoephedrine.

Diuretics such as chlorothiazide, hydrochlorothiazide, flumethiazide, triamter and spironolactone.

Additives such as vitamins and essential amino acids.

Anti-Parkinson's agents such as L-DOPA alone and in combination with potassium antagonists such as N -DL-Seryl-N - (2,3,4-trihydroxybenzyl) hydrazine.

Androgenic steroids such as methyl testosterone and fluoxymesterone.

Progestational agents such as progesterone, ethisterone, norethynodrel, norethindrone and medroxyprogesterone.

Estrogens such as estrone, ethinyl estradiol and diethylstilbestrol. Hormone products such as prostaglandins and ACTH.

Antibiotics / anti-infectives such as penicillins, cephalcsporins, tetracycline, chlorotetracycline, streptomycin, erythromycin, sulfonamides such as sulfisoxazole, sulfadimethoxine and sulfamethoxazole and other agents such as nitrofurazone and metronidazole.

Cardiovascular agents such as nitroglycerol, pentaerythritol tetra nitrate, isosorbide dinitrate and digitalis preparations such as digoxin.

Antacids / antiflatulents such as aluminum hydroxide, magnesium carbonate and simethicone.

DK 152172 B

53

Other therapeutic agents and / or combinations of agents known in the art to be therapeutically valuable.

The active substances used in the present invention may be in free form or in any non-toxic pharmaceutically tolerable form in which the therapeutic activity is retained. Eg. acidic substances may appear as esters or as salts with pharmaceutically tolerable inorganic bases, e.g. such as the sodium salt or potassium salt, or organic bases, e.g. such as amines or quaternary forms. Basic substances can occur as salts with organic acids, e.g. the acetate or tartrate. Certain substances such as ampicillin may be present in hydrated form. In general, any pharmaceutical equivalent form of a given active substance known in the pharmaceutical preparation for that substance may be used in the dosage forms prepared by the method of the invention, of course, subject to the In the few cases where such incompatibility occurs, it is easily detected by simple tests.

The amount of active substance or combination of substances which can be incorporated into these dosage forms is usually the amount known to be an effective therapeutic dose for the particular drug.

In general, the amount of active ingredient in a single dosage form should not exceed approx. 500 mg with a practical upper limit of approx. 750 mg.

Resolution.

As stated above, the dosage forms have an extremely constant release rate which can also be adjusted to meet specific specifications. Whatever release pattern is envisaged, the dosage forms in question have a release rate that is constant within such limits as are superior to those achieved with conventional solid dosage forms, e.g. tablets and capsules.

DK 15217 2 B.

54 In FIG. 7 illustrates graphically the rate of release of the dosage forms prepared in comparison with a conventional solid oral dosage form, e.g. commercially available capsules. In the embodiment of FIG. In seven illustrated experiments, six randomly taken conventional capsules, respectively, dosage forms prepared according to the invention * each containing an equal amount of the same active ingredient, were placed in 100 ml of artificial gastric fluid U.S.P. (United States Pharmacopoeia) (without enzyme). This liquid was kept at 37 ° C with stirring. The liquid in each reaction flask was constantly filtered and circulated through flow cells in a suitable spectrophotometer.

The absorbance of the fluids was read at one minute intervals and the percentage of dissolved active ingredient was calculated for each reading. In FIG. Figure 7 shows the fastest and slowest dissolving sample in each group, and the shaded area between them covers the remaining four samples. From FIG. 7 can be drawn two conclusions. First, the dosage forms dissolve much faster than "the usual capsules tested. Secondly, the variation within the six samples of the unit doses in question was noticeably less than for the usual capsules tested. These results clearly show the superior release characteristics characteristic of the dosage forms. produced by the method of the invention.

The blood level curves depicted in FIG. 8, also compares the dosage forms with commercially available capsules containing the same amount of the same active ingredient. The blood level curves are drawn theoretically based on two input rates in a one-chamber pharmacokinetic model. The blood level curves are based on a theoretical 100% absorption of the amount of active ingredient released from the dosage form at one point and thus are proportional to the rate of dissolution. The difference in the blood level curves is therefore a function of the dissolution rates.

It is clear from the data illustrated in FIG. 8, that the dosage forms according to the invention according to the invention not only reach the effective blood levels

Claims (12)

A method of preparing solid pharmaceutical unit dosage forms in which one or more medicaments are applied to a therapeutically inert, edible web and the web is formed in a geometric shape of a predetermined shape, characterized in that a continuous and uniform layer of drug is applied to the web in a continuous working process, several of the resulting webs are formed into a layered form, the layered form is divided into a plurality of unit dosage forms, and the unit dosage forms are sealed in such a way that the drug is completely enclosed, during a non-destructive operation. examination or quality control of the products obtained in each process step. A method according to claim 1, characterized in that at least two of the web layers are applied to different drugs and that these layers of different drugs are arranged so that at least one web layer is placed in between to separate such different drugs. Method according to claim 1, characterized in that the fabrication procedure comprises cutting across the web with a medicament for forming substantially equal lengths of the web, each of which is divisible into several unit dosage forms, each length of the web being corrugated to form a loosely wound coil. , the loosely wound coils are rolled to form a substantially solid rod and this rod is cut across to form several unit dosage forms. 56 DK 152172 B Method according to claim 1 or 3, characterized in that a web with a composition which can be sealed with water is used and that the rods are sealed by contacting the spirals with a sufficient amount of water in the form of a fine spray to moisten them and then wipe the rods. Process according to claim 1, 3 or 4, characterized in that the application of water is limited to the point of the surface of the rod where sealing is desired. Method according to claim 1, characterized in that a stack of the webs is formed, of which at least one drug is arranged, that this stack is cut into unit dosage forms, and at the same time as the cutting is applied heat and pressure to seal only the edges. of these unit dosage forms, thereby completely enclosing the drug. Process according to claim 6, characterized in that the stack of webs comprises at least two web layers consisting of a heat sealable polymeric material comprising an organic film forming component and a plasticizer therefor and at least one layer of paper material comprising one or more fibrous materials and at least one non-fibrous modifier. therefore, where the top and bottom layers of this stack are polymeric, with the proviso that no more than six layers of paper material are placed between each pair of polymeric webs in this stack and that the heat and pressure applied to the web stack during the cut operation is sufficient to deform the polymer webs and seal the edges of the intermediate layers of paper material webs. Method according to claim 1, characterized in that a continuous stack of multiple web layers is formed and subjected to pressure to compress and mold it into a continuous rod-like first geometric form, that this geometric form is divided into several unit dosage forms. and these unit dosage forms are sealed to completely enclose the drug. DK 152172B A method according to claim 8, characterized in that splitting steps comprise uniform cross-sectional notch formation in the rod-like first geometric form and subsequent cutting of the geometric form in the notches to form unit doses. Method according to claim 8, characterized in that the partitioning step comprises cutting the rod-like first geometric shape longitudinally to form several continuous geometric shapes, each of which can be divided into several unit doses, and subsequent cutting across each of these. continuous geometric shapes at uniform intervals to form individual unit doses. Method according to claim 8, characterized in that the partitioning step comprises cutting across the rod-like first geometric shape at uniform intervals, thereby obtaining several geometric shapes, each of which can be divided into several dosage units, and subsequently cutting these shapes into along to form individual dosage units. Method according to claim 8, characterized in that the continuous stack of multiple web layers is formed by laminating several webs arranged so that the top and bottom surfaces are free of medicament.