FI69243C - FRAMEWORK FOR THE FRAMEWORK OF PHARMACEUTICAL PHARMACEUTICALS - Google Patents

Description

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(51) Kv.lk. * / Lnt.CI. «A 61 K 9/00 FINLAND —FINLAND (21) Patent application - Patentansdkning 763597 (22) Application date - Ansökningsdag 15-12.76 (FI) '' (23) Starting date - Giltighetsdag 15-12./6 (41) Become public - Blivit offentlig 1 &, 06.77

National Board of Patents and Registration Date and date of publication and publication

Patent * och registerstyrelsen '' Ansökan utlagd och utl.skriften publicerad JU.uy.o :? (32) (33) (31) Privilege requested — Begärd priority 15-12.75 15-12.75, 15-12.75, 15-12.75, 15.12.75, 15-12.75, 15-12.75, 15.12.75, 15.12.75, 15.12 .75 USA 640654, 640655, 640610, 6-41068, 640609, 640608, 640612, 640651, 640653, 640652 (71) F. Hoffmann-La Roche & Co. Aktiengesel1schaft, Grenzacherstrasse 124-184, Basel, Switzerland-Switzerland (CH) (72) August Sturzenegger, Essex Fells, New Jersey,

Arthur Roman Mlodozeniec, Montclair, New Jersey,

Edward Solomon Lipinsky, Columbus, Ohio,

Arthur H. Goldberg, Montclair, New Jersey,

William Elmore Gardner, Wyckoff, New Jersey,

Dennis Joseph Dabal, Whippany, New Jersey,

Joseph James Williams, West Caldwell, New Jersey,

Jim Mills Adams, West Caldwell, New Jersey,

Lawrence Samuel White, Ramsey, New Jersey,

Robert Bruce Reif, Grove City, Ohio, USA (74) Oy Koister Ab (54) Method for preparing solid pharmaceutical unit dosage forms - Förfarande för framstäl1 Ning av fasta farmaceutiska enhets-dosformer

The invention relates to a process for the preparation of solid pharmaceutical unit dosage forms, wherein one or more drugs are applied to a therapeutically inert edible carrier material in the form of a strip, and the carrier material is shaped into the desired geometric shape in which the active drug substance is substantially contained therein.

The orally administrable solid unit dosage forms used heretofore in the pharmaceutical industry can generally be divided into two basic forms, i. tablets and capsules. There are several broad groups of capsules and tablets known in the art, such as those coated with an enteric agent to release the drug in the gastrointestinal tract, those that release drugs over a prolonged period of time, effervescent agents, and the like. However, there are numerous disadvantages to these oral dosage forms.

69243

First, conventional solid oral dosage forms are disadvantageous because they all contain, when mixed with the active ingredients, a variety of substances called "therapeutically inert or non-toxic, pharmaceutically acceptable substances." Such classes of materials used in the art include diluents, fillers, binders, lubricants, anti-dispersants, stabilizers, buffers, preservatives, and the like. Although these materials are considered essential for the preparation of pharmaceutical compositions, their use presents difficulties in terms of cost, final unit dose size and weight, and the like. In addition, each such additive must be tested prior to use to determine possible incompatibilities with the drugs used. Further, certain of these materials, i. lubricants may cause difficulties in the bioavailability of the active ingredient. Thus, when using these materials, the effect of the final dosage form must be investigated using analytical methods.

Another main drawback of solid oral unit dosage forms known in the art is that the methods available for their analysis cause the dosage form to be destroyed so that only a small percentage of the products actually prepared can be examined. Thus, it is known in the art that significant variations may occur in a given batch of such dosage forms because the averages of the dosage amount, its effect, etc. for each batch are determined by analyzing a relatively small number of samples.

The batch concept itself is a drawback of prior art solid oral dosage forms in terms of simply batch design, control, and investigation.

The present invention provides solid dosage units primarily for oral use which can be prepared in large quantities at high speeds and, because they are prepared by a method unique to the pharmaceutical industry, do not contain the aforementioned solid oral dosage forms currently in use, i. disadvantages in tablets and capsules. This method is very advantageous because it eliminates the need for 6Q243 batch requirements that are normally required; allows for continuous, in-line analysis to determine efficacy, as well as for on-line efficacy determination of dosage forms during their preparation; makes it possible to eliminate the mixing of conventional pharmaceutical additives with drugs, with the exception of lubricants, which may be required to facilitate the flow of powders and / or certain other materials which have a beneficial effect on the effectiveness of the product; provides pharmaceutically preferred dosage forms that can be prepared to release the drug at any desired rate and that are capable of releasing the drug at a higher rate than currently available commercial tablets and capsules. In summary, the dosage forms of the invention are able to ensure that a higher percentage of the more accurately measured amount of drug is available at a more closely monitored time after ingestion than can be achieved with current commercial units.

Oral unit dosage forms prepared in accordance with the invention are preferred for a number of important reasons, the most important of which is that they are excellently suited for line treatments in high speed, substantially automated manufacturing. Dosage forms prepared in accordance with the invention are further preferred because the drug they contain is exceptionally evenly released from a plurality of dosage units for absorption. In addition, unit dosage forms can be prepared to release the drug in a shorter period of time after ingestion than is possible with currently used solid oral dosage forms, i. tablets and capsules. Thus, the dosage units form a superior combination in terms of both drug concentration and release by absorption.

The following notable publications have been published in the art for solid dosage forms other than conventional tablets. Russel discloses in U.S. Patent 3,444,858 a device for buccal administration of a medicament comprising a strip of drug-containing gelatinous material, the strip being divided into portions, 69,243 each connected to the next by an easily tearable fastening wire. In use, each part is merely separated from the strip and placed in the mouth.

Another publication worth mentioning is an article in the New England Journal of Medicine, Vol. 289, No. 10 (1973) 533-5.

This article presents the way in which a birth control drug is administered on a very large scale to women in the People’s Republic of China. According to this method, a colored, aqueous solution of carboxymethylcellulose paper is treated with a solution of progestational and estrogenic materials.

The sheet is then perforated and cut into strips. The drug is packaged in a strip of 22 "squares" that are torn from the strip and ingested daily. This method does not use encapsulation of the drug in the final dosage form, so the disadvantage is the possibility of contamination and / or ineffectiveness of the drug after opening the package. In addition, because they are not entirely unit doses, these perforated strips may have uneven tearing at the perforations and the possibility of varying dosages.

Finally, mention should be made of the dosage form disclosed by Higuchi et al. In U.S. Patent No. 3,625,214, which is used for controlled, i. delayed release of the drug. The dosage form consists essentially of a drug-containing matrix with a coated substrate which is then wound into a screw to give a final "jelly-screw" appearance. After ingestion, the drug is gradually released from the beginning within the outer layers and also from the sides where the drug is exposed. It is not mentioned whether the disclosed dosage forms can be prepared with a high-performance pharmaceutical device. Furthermore, no mention is made of the way in which the disclosed dosage forms can be converted into pharmaceutically acceptable end products.

Clearly contrary to the teachings of the above publications, the novel fixed dosage units of the present invention are completely uniform, can be tested for damage during high speed pharmaceutical manufacturing steps, are substantially free of pharmaceutical additives that may affect their efficacy, have no exposed drug and have excellent drug release. which improves their efficiency.

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The process according to the invention for preparing solid pharmaceutical unit dosage forms is characterized in that a continuous layer of active compound is applied to the strip carrier material as a continuous process, several strips thus obtained are combined into a multilayer form, the multilayer form is divided into several unit dosage forms, , and wherein, during manufacture, the products obtained from the individual process steps are subjected to an intact test and inspection.

These solid unit dosage forms for oral administration consist essentially of edible paper tissue and / or polymeric materials coated on at least a portion of their surface with one or more substantially no adjuvants, the tissue being made into an edible, pharmaceutically acceptable and cosmetic form. that the drug is not exposed at all. The manufacturing process includes a non-damaging test on the products to determine the amount of drug placed on the carrier material prior to manufacture, whereby the efficacy of the final unit doses is analyzed using physical parameters.

The invention is directed to solid unit dosage forms intended primarily for oral dosage and have several advantages over current solid oral dosage forms, i. compared to tablets and capsules. First, the fact that the dosage units according to the invention substantially do not contain any conventional pharmaceutical additives causes savings in raw materials and manufacturing processes and eliminates any incompatibilities that may result from the presence of these substances. In this connection, it is necessary to distinguish between the tissues according to the invention, which can be considered as additives, and materials, such as fillers, binders and the like, which are mixed with the drugs in conventional solid dosage forms.

Second, because the solid unit dosage forms of the invention are continuously manufactured and subjected to non-damaging analytical procedures on line 69243, the batch preparation requirements currently known are eliminated, resulting in significant economic savings and a substantially better level of quality control over final unit doses. The fact that the manufacturing method according to the invention includes means for feedback of information from the analysis station to the manufacturing step immediately preceding them thus allows in-line corrections and adjustments. These means allow even a small unit dose amount to be removed from each batch, i. removing a negative result from a positive result on either side of it. The labeling and deletion of these small dosage forms avoids "batch rupture" and provides both a great economic advantage over current pharmaceutical manufacturing methods and an excellent level of quality control, especially with respect to the amount of active ingredient contained in the final dosage form. In normal use, the dosage forms according to the invention are prepared according to a time-batch procedure, i. the batch of dosage forms comprises an amount prepared between two given time points.

This concept is assumed to be unique in the pharmaceutical industry. It should be noted, however, that some destructive testing of samples is required in each pharmaceutical process to determine the potency of the final product. However, this experiment requires less material in the process of the invention than in conventional manufacturing methods. More importantly, however, such destructive treatment, i. the potency determination is performed on-line and the information is fed back, thereby achieving the benefits of non-destructive methods outlined above.

Third, the solid oral dosage forms of the invention are unique in that they differ from conventional tablets and capsules in appearance, shape, structure, etc., and thus have the advantage of easy identification. Also in-line test procedures and continuous manufacturing steps allow the unit doses of the invention to be packaged in-line in individual cases, such as clear plastic strips or breakable packaging, thus saving costs in both handling and equipment.

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Fourth, the manufacturing accuracy of the solid dosage forms of the invention, i. the uniformity of drug application to the carrier material and the design accuracy of the final units, combined with the advantageous properties of the carrier material, allow the final dosage forms to easily meet even the most demanding requirements in terms of size, shape, drug release and similar properties. The dosage forms of the invention are also very stable and are suitable for drugs known to be adversely affected by moisture, because in certain embodiments of the invention the drug is placed or applied to the tissue by electrostatic precipitation to achieve near complete moisture removal, which can cause an adverse reaction. Also, if the dosage forms of the invention are made from a laminate of tissue sheets, drugs known in the pharmaceutical art to be chemically incompatible can be applied to alternating tissue layers. This effectively stabilizes such combinations without the need for economically disadvantageous procedures such as coating one or more such incompatible materials with an insulating agent, mixing the stabilizers with these drugs, using these drugs as separate tablet layers, which are then compressed together or similar procedures. Due to either or both of these procedures, i.e. by compounding the drug to the tissue as an electrostatically dry powder and placing any incompatible drugs alternately between the laminate sheets, the dosage forms of the invention are preferably used to administer effervescent preparations.

The solid oral dosage forms of the invention are further unambiguous in that the drug they contain is completely enclosed within the dosage form and yet, in most cases, the actual coating is not applied to the final dosage form. This provides an additional economic advantage to the dosage forms of the invention over conventional tablets that must be coated to encapsulate the drug therein.

Although the dosage forms prepared by the method of the invention are intended primarily for oral use, they are equally suitable for rectal and / or vaginal administration. Modifications to tissue size and to the manufacturing methods described below to obtain dosage forms having the desired shape and size will be apparent to those skilled in the art. Certain changes in tissue composition to obtain the desired type and mode of drug release may also be made. Experiments have shown that rectal or vaginal placement of the solid dosage forms of the present invention does not substantially cause local irritation.

The novel dosage units prepared by the method of the invention may be shaped or "arranged" into any desired donor form, including sustained release. Regardless of the release, the unit doses according to the invention are characterized by an exceptional uniformity of release from a large number of unit doses. i. tens of thousands or more. Variations in the release rate according to the present invention can be achieved by changing several factors, such as the thickness of the tissue, the composition of the tissue, the use of additional edges or by sealing the tissue and changing the density of the tissue, and the like. For example, tissue containing a high proportion of sodium carboxymethylcellulose usually decomposes slowly under the influence of digestive fluids. Dosage forms made from these carrier materials using edge folding, as described below, open or pivot upon contact with digestive fluids, thus releasing the drug placed on their inner surface very rapidly, in fact faster than currently available conventional tablets and capsules. However, if such an edge-turned dosage form is sealed from the bent edges with an agent such as ethylcellulose, cellulose acetate phthalate, or a wall that prevents it from being opened by digestive fluids, the drug is released by the gradual corrosion of the tape, thereby uniformly releasing the drug. Because the dosage forms prepared in accordance with the invention are capable of releasing the drug at a rate significantly greater than currently available solid dosage forms, 6 ° 243 m.p. tablets and capsules, can be achieved, represents such an embodiment of the present invention.

The accompanying drawings are, in essence, as follows:

Figure 1 is a block diagram of the overall manufacturing process showing the points of in-line inspection.

Figure 2 is a schematic representation of a system in which the process shown in Figure 1 may be implemented.

Figure 3 is a schematic representation of an arrangement in which the winding for preparing a dosage form can be made.

Figures 4, 4A and 5 show circulating and laminating procedures for preparing a dosage form.

Figures 6A-6D show the finishing and sealing technique of a fan-forming technique during the preparation of dosage forms.

Figures 7 and 8 are graphical representations of a release formulation of the active ingredient according to the invention compared to a conventional solid dosage form, i. in the capsule.

The tapes that can be used to position the drug in accordance with the present invention must meet a wide variety of physical and chemical requirements in order to be acceptable in the practice of the invention. These requirements can be summarized as follows:

The tape must be non-toxic, edible and, in particular, it must not give an unpleasant "feel" to the mouth. In addition, the tape preferably degrades spontaneously or by body fluids and / or enzymes. However, the tape can be a non-dispersible substance that the body can easily remove. The strip is preferably hydrophilic and easily dispersible in water. These properties must not be adversely affected or altered by the pH of digestive fluids.

The tape must be completely inert to the drug placed on it and must not release any substance in its solution in the digestive fluids that would cause incompatibility with other drugs in situ.

The tape must remain stable for extended periods of time and at elevated temperatures and relative humidity, and generally must be a poor substrate for the growth of microorganisms.

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The tape must have acceptable resistance properties so that powdered drugs (which usually have dielectric properties) can be placed on it by electrostatic precipitation.

The strip must have acceptable machinability and mechanical properties, i.e. it must be flexible enough to be pulled or cast into a thin sheet, i.e. to a thickness of about 0.025 to 0.25 millimeters, its tensile strength and tear strength must be good and it must withstand bending if necessary to withstand the specific manufacturing procedures described below.

The surface of the tape must facilitate the analytical procedures performed in the following line, be electrostatically or otherwise coatable with the powdered drug, and must be preservable and printable.

The tape must be easily sealable using the liquid and heat sealing methods used in the art. However, the seal must be effective when using moisture and temperature levels that do not adversely affect the drug contained in the dosage form. In addition, the flame retardancy of the tape must be sufficient to withstand these sealing treatments.

In some cases, the strips must have a "memory", i.e. it must be flexible enough so that on contact with digestive fluids it very quickly reverses the manufacturing process and "opens", thus releasing the drug for absorption. "Opening" means, for example, that if the dosage form is made by turning it into a fan, it opens like bellows, if it is made by winding it into a helix, it unwinds, etc.

In addition, the tape must have other properties, such as its taste and odor must be acceptable, as will be apparent to those skilled in the art from this presentation.

As mentioned above, the tapes used in the present invention are preferably water-soluble or water-dispersible. The strips of the present invention are made with two basic self-dispersing surfaces in contact with water or digestive fluids. First, the tape may contain ingredients, such as particles of casein, gelatin, or the like, that swell under the action of water, breaking or disintegrating the tape. Second, the tape may contain both water-soluble and water-insoluble ingredients. Upon contact with water, the soluble constituents of such a preparation tend to migrate into solution and the insoluble constituents precipitate therein, thus causing the strip to disintegrate. The latter tape spreading procedure is not as fast as the previous one. Examples of suitable water-soluble ingredients include methylcellulose and the like. Examples of suitable water-insoluble ingredients include ethylcellulose and the like.

The tape compositions used in the preparation of the novel dosage forms of the present invention are of two basic types, i. polymers or paper. The polymer compositions generally contain: a) one or more organic film formers, b) one or more plasticizers, c) modifiers, i. other ingredients in certain compositions, such as dispersants, extenders and the like; d) one or more volatile solvents.

Paper compositions generally contain: a) one or more fibrous materials, b) one or more non-fibrous modifiers, i. any other ingredients that may be present in certain compositions, for example one or more organic film formers, dispersants, extenders, etc.

(c) a volatile substance.

The film-forming compound of the polymer tape of the present invention contains one of the non-toxic organic film-formers known in the art or a mixture of such film-formers, such as natural or chemically modified starches and dextrins, ethylcellulose, proteins such as gelatin, natulelloxone, cellulose derivatives, cellulose other polysaccharides such as pectin, xanthine gum, acacia, guar gum, algin and the like; synthetic agents such as polyvinylpyrrolidone, polyvinyl alcohol and the like. Preferred film formers include hydroxypropylcellulose and sodium carboxymethylcellulose. Although the concentration of the film-forming ingredient in the polymeric tape is not particularly critical in the practice of the present invention, it has been found that a concentration of between about 5% by weight and about 95% by weight is preferred and a concentration of about 40-90% by weight is most preferred.

The aforementioned film-forming agents are equally suitable film-forming ingredients for paper web preparations in the present invention when used. Hydroxypropylcellulose and sodium carboxymethylcellulose are also preferred film formers and paper tape preparations of the present invention. The concentration of the film-forming ingredient in paper tape preparations in the invention is also not critical. However, if these ingredients are present as binders or dispersants for the fibrous material, their content should not exceed 40% by weight and is preferably 2-20% by weight and most preferably about 4-10% by weight.

The fibrous component of the paper tape products of the invention may be any commercially available natural or synthetic fiber which has been found to be non-toxic in appropriate experiments. Examples of these fibers include cotton, flax, cellulose, synthetically modified cellulose, artificial silk, woven plant protein, collagen, and the like.

To ensure the required machinability and mechanical properties, the polymeric tapes used in the practice of the present invention contain an effective amount of plasticizer. These ingredients may include one or more plasticizers known in the pharmaceutical industry, such as glycerin, polysorbates, e.g., polysorbate 80, polysorbate 60, certain mixtures of mono- and diglycerides of saturated fatty acids, and the like.

It is preferred to use such a plasticizer in an amount of from about 1% to about 60% by weight, preferably from about 10% to about 50% by weight of the tape composition.

Both the polymeric and paper webs may contain one or more disintegrants conventionally known to be used in the manufacture of disposable papers, such as various types of starch, casein, gelatin, and the like. The 13 69243 carrier materials of the invention contain from about 0% to about 40% by weight, preferably from about 5% to about 20% by weight of disintegrant, depending on the tape preparation.

Furthermore, both types of tape preparations may contain one or more fillers or extenders conventionally used in the art. These ingredients include, for example, opaque fillers such as titanium dioxide, chalk, porcelain clay and the like, microcrystalline cellulose, calcium carbonate and the like. It should be noted that some of the ingredients mentioned herein may perform more than one function and thus fall into more than one of the above categories. For example, calcium carbonate can act as both an opaque agent and a dispersant, certain starches can act as binders and disintegrants, and so on.

In addition, both polymeric and paper preparations may contain one or more modifying ingredients which affect the electrical, mechanical, optical or transmission properties of the tapes made therefrom. Examples of these ingredients include electrolytes such as sodium chloride, potassium chloride and the like, surfactants such as dioctyl sodium sulfosuccinate and the like. The strips may also contain optional ingredients such as pharmaceutically acceptable colorants, antiseptics, and the like.

Finally, both tape preparations may in most cases contain a volatile solvent, for example water, certain organic solvents, for example ethyl alcohol, or combinations of such solvents, for example a water-alcohol mixture, which is removed during the preparation of the tape.

Examples of film compositions according to the invention are the following: polymeric films which decompose spontaneously in swelling in an aqueous medium: I Ingredient Weight% hydroxypropylmethylcellulose 46.69 acacia 19.44 gelatin, ultra-fine, soluble 32.03 dioctyl sodium sulphosuccinate 14% 69243 I Ingredient% by weight titanium oxide 1.94 lecithin 0.75 100 II purified starch 33.06 carboxyethylcellulose 33.06 propylene glycol 33.06 sodium benzoate 0.55 sorbic acid 0.28 100 III hydroxypropylmethylcellulose 55.19 cellulose acetate phthalate phthalate phthalate phthalate 28.66 propylene glycol 9.87 titanium dioxide 1.52 dioctyl sodium sulfosuccinate 1.52 lecithin 0.24 100 IV hydroxypropyl methylcellulose 64.00 cellulose acetate phthalate 3.10 calcium carbonate 21.74 propylene glycol 9.06 titanium dioxide 0.91 dioctyl dioxide 0.91 dioct 30 100

All preparations I-IV are sealable using heat and pressure. Preparation IV is spontaneously destroyed in an aqueous environment by insoluble polymeric substances.

Preferred paper preparations according to the present invention comprise about 70-99% by weight, preferably about 90-96% by weight of fibrous material, for example hard and soft wood chip fibers or mixtures thereof, about 1-30% by weight, preferably about 4- 10% by weight of a disintegrant such as carboxyethylcellulose, methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone and guar gum and about 0-5% by weight, preferably about 0-2% by weight of a surfactant such as polysorbate 80, dioctyl sodium sulfosuccinate, sodium lauryl sulfate and the like, the ability of the above-mentioned substances to act as disintegrants in paper preparations is surprising given that when used in the manufacture of paper, they are present in different amounts and have different modes of action. For example, while sodium carboxymethylcellulose has heretofore been used in the manufacture of paper, it has been used in small amounts, for example 0.1% by weight or less, to facilitate dispersion of the fibers during paper formation. Clearly in contrast, it has been found that when sodium carboxymethylcellulose or any of the other substances mentioned above are added in large amounts, i. up to about 30% by weight after the formation of the paper web, but when it is still moist, they act as disintegrants, with the timing of their addition being critical for them to act as disintegrants. Disintegrants are preferably added dissolved in the solvent used to make the paper web. It has been found that the above disintegrants when added to the fabric coat the fibers. When the final dosage form comes into contact with water, the disintegrant swells, thus forcing the fibers to break down the tissue. If surfactants are used, they promote the penetration of water into the disintegrant, thus helping to degrade.

The tapes used in accordance with the present invention are manufactured by methods conventionally used in the art, for example in the papermaking and film manufacturing industries. For example, polymer strips can be cast on a suitable substrate such as Mylar film, stainless steel, release paper, and the like. The strips are then dried in a convection oven, for example. The temperature of the drying air and the length of the drying time depend on the nature of the solvent used, as is known in the art. However, most of the strips used herein are dried at temperatures between about 25-105 ° C, preferably between 80-90 ° C.

Another method of making a polymeric strip, which is conventional in the art, is extrusion. This method is recommended for tapes in which the film-forming component is modified food starch, hydroxypropylcellulose or other extrudable polymer. Extrusion details, i.e. the equipment used, the compressive force, the shape of the nozzle and the temperature, are assumed to be known to those skilled in the art and can be varied in a known manner to obtain the physical properties of the strip, as described below.

The paper webs of the present invention are made using conventional papermaking machines, such as a cylindrical paper machine. In all cases, however, the strip must be uniform in both thickness and width. The thicknesses of the strips range from about 0.03 to 0.3 mm, preferably from about 0.038 to 0.123 mm. A suitable width for these strips is 30 cm, although the width of the strip is not particularly critical in the practice of the invention. The lengths of the strips can be arbitrary. However, the novel dosage forms prepared according to the present invention are particularly suitable for preparation at high speeds, so that the strips should be made in large quantities, for example 4500 meters long or longer, which can be stored, for example, on reels.

Figure 1 is a block diagram of an overall process for preparing large amounts of the dosage forms disclosed herein. Block 10 refers to the manufacture of a strip from the above compositions. Once the tape is formed or shortly thereafter, it is subjected to an inspection step (block 11 in Figure 1) in which a series of examinations, which may be partially or completely automatic, are performed to ensure the integrity of the tape, as will be described in more detail later. It should be noted, however, that the inspection of the tape may be performed at the time of tape formation or at some suitable point thereafter, either by means connected to the tape manufacturing device or by some other device, and may in fact be performed at another location.

The active ingredient to be placed on the strip is prepared and stored for use in a container, as generally shown at 22 in Figure 2, which diagrammatically shows schematically various devices suitable for performing the steps shown in Figure 1. The prepared active ingredient is advanced by the arrangement generally shown at 23 in Figure 2, in which the particle size reduction and control of the active ingredient shown in step 12 of Figure 1 is performed. Although this step will be described in more detail later, in this step 69243 and in the device 23 shown, it is intended to provide a uniform flow to obtain an accurate and uniform precipitation of the active ingredient on the strip (block 14 in Figure 1) shown in Figure 24 in Figure 2. It should be noted that with a strip of dry fine material in a dry place. However, it is to be clearly understood that wet deposition of the active ingredient on the tape is also within the scope of this invention. It is shown schematically in point 21 of Figure 2 that in an embodiment of the invention where the tape is manufactured and stored for later use, the tape inspection step (step 11 in Figure 1) is performed, for example, by removing the tape from the storage roll 20. It should also be and storage as well as in addition to it can be performed in Figure 2 at item 21. The details of the tape inspection will be described later.

Using the inspection means 21, the inspection of the uncoated tape can be performed in various ways. Tape holes, defects, and physical integrity can be determined and measured using a combination of a scanning laser beam and a photodetector. The arrangement is used according to both the transmission and the reflection method. The continuous beam of the helium-neon laser is guided across the strip by means of a mirror in the galvanometer. The position of the mirror is adjusted electronically so that the point of each fault on the tape can be detected. The reflected or transmitted light is detected by a linear photodiode located behind the interference filter to eliminate room light (scattered light). The electrical output is used to calculate the number of faults and to determine their size and distribution along the longitudinal direction of the strip.

This is done by analyzing the detector output signal using a pulse-height analyzer.

An alternative method of inspecting the tape at significantly higher tape speeds uses parallel photodiodes positioned transversely of the tape. Each photodiode has its own threshold detection system and digital logic that allow the size and location of a low-resolution fault to be determined. The output signal can be processed to obtain an approximate size distribution and location distribution of the faults in the tape.

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The physical thickness of the strip is measured by means of riders placed on the strip in parallel mounted on precision bearings.

These rollers contact the tape and are connected to relay devices that electronically sense the tape at intervals of at least 2.5 micrometers. A similar arrangement for measuring physical thickness can be made by means of pneumatic sensors floating above the strip in a fixed layer of air. The advantage of this system is that the tape is not touched.

The pulp thickness (weight per unit area) or the basis weight of the strips is determined using a non-contact beta or X-ray measuring device. In these systems, the adsorption of beta rays or X-rays as they pass through the strip is measured.

This absorption is proportional to the thickness of the pulp. In an alternative system, a resistor between two electrodes in contact with the strip can be used to determine the basis weight of the strips when moisture is known.

The moisture content in the line can be measured using one of the following procedures. First, the high dielectric constant of water allows sensitive humidity measurement to be performed using direct microwave absorption and radio frequency dielectric constant meters. Low frequency conductivity measurement can also be used to measure the moisture content of the tape. Infrared spectrometric absorption provides a completely independent moisture measurement method. Furthermore, optical absorption at wavelengths in the range of 1-2 micrometers provides a specific and accurate determination of moisture in the spectral range in which the band under consideration is relatively transparent.

After ignoring the inspection means 21, the belt is guided by means of the suitable roller arrangement shown in Fig. 2 so as to bypass the device 24 to be applied relatively close to the active ingredient, in which the active ingredient is applied to the belt. The applicator is immediately followed by a schematically illustrated device for an in-line analysis / inspection step, in which, for example, the uniformity of the active ingredient content of the coated strip is examined, preferably as a single sheet, before sealing the ingredient.

The preferred method for in-line analysis of the active ingredient applied to the tape is X-ray absorption. In this method, a low-energy X-ray beam, the peak of which is brought into line with the absorption edge of the atoms applied to the tape, is guided through the coated tape. The absorption of X-rays is proportional to the absorption of the active ingredient as well as the tape. If the active ingredient has been applied to the strip by a wet coating method, this method of analysis can be used either before or after the drying step.

Since the total X-ray absorption consists of the absorption of the tape and the coating containing the active ingredient, it is necessary to determine the absorption of the tape separately. This is done with a beta beam measuring device or an infrared spectrophotomer. Improved sensitivity is achieved in X-ray measurement if the precipitated active ingredient contains atoms with increasing atomic numbers. The X-ray source can be tuned by changing the acceleration voltage to correspond to the absorption edge of several of the atoms in question.

Reflection or transmission spectrophotometry can also be used as a non-damaging method of analysis for the precipitated active ingredient in line. Reflection spectrophotometry is used in the near ultraviolet range to determine the rate of application of the active ingredient. This method can be applied to any solid active ingredient having an optical absorption in the appropriate wavelength range.

Permeation spectrophotometry can also be used as an in-line assay method to determine the active ingredient on a strip. A suitable light source, monochromatic moiety and detector combination is selected for the wavelength range in which the active ingredient selectively absorbs. This must be in the spectral range where the band itself does not absorb strongly. Such regions for the bands of the invention fall in the near-infrared region of the spectrum and in the infrared regions of the functional groups. A fast wavelength sweep system is used to sweep the relevant small wavelength range. The signal from the detector is averaged over time during most scans to reduce the effect of noise. The signal values are then processed to obtain the first derivative of the transmission with respect to the wavelength as the sensitivity increases. This is done in the same way for other wavelength ranges to which other components of the system are sensitive. Thus, the water content, the basis weight of the strip and the content of the active ingredient can be determined simultaneously.

Another method for analyzing the amount of active ingredient is molecular fluorescence. The excitation radiation in the ultraviolet or visible region of the spectrum is generated by a suitable filter combination. The fluorescence of the active ingredient is detected by a broadband filter-detector combination adapted to the fluorescence peak; a blocking filter is used to remove the excitation energy. The detector in this method is preferably a photon counter that counts individual light events, giving high sensitivity and linearity at low illumination levels. In this method of analysis care must be taken to limit the photodegradation of the active ingredient by the action of excitation radiation.

The coated tape may be stored for some time or is preferably passed to a manufacturing (step 16 in Figure 1) and sealing step (step 17 in Figure 1) to form unit doses, with suitable equipment shown in Figure 2 as a series of knives 26 for cutting the coated tape into a plurality of continuous strips. the following lamination-type treatments sealing means 27, i. the continuous strips are superimposed to form a continuous pin, which is compressed and finally formed into units according to the invention, as shown below.

The individual dosage forms are then finished and packaged by means of a suitable device (step 18 in Figure 1) schematically shown at 28 and 29 in Figure 2 for distribution. An appropriate check (e.g., at 30 in Figure 2) is performed in connection with this step. The purpose of the final inspection of the individual dosage units is to ascertain their size, shape, uniformity, identity, the presence and accuracy of the printing and the concentration of the active ingredient. All these checks are carried out in such a way that the products are not damaged, except for the determination of the content of the active ingredient. To analyze the concentration and efficacy properties of the active ingredient, a statistically sufficient sample of dosage units is removed from the production line and analyzed for destruction in terms of efficacy and efficacy.

il 21 69243 so. dissolution properties by solution spectrophotometry as follows.

An optical indicating system can be used to inspect all production units for size, shape, uniformity, identity, and the presence and accuracy of printing. The system comprises a suitable light source and an array of photodetectors or a TV camera. A computer is used to process signals received from an optical system. Appropriate algorithms are used to determine the acceptability of unit doses. The second method uses a comparison of the sample pattern to a standard image using an image overlay procedure.

In another, 100% control method, an image conversion of unit doses is generated. The spectrum, power spectrum, or other suitable transform of the Fourier transform is compared to the corresponding standard transform using a computer.

Prior to the finishing step, step 19 (Figure 1) is performed as a line analysis for dissolution and concentration uniformity by means of a suitably arranged device, not shown separately, which may include and / or be controlled by a computer or a similar central control system or logic circuit. The random sampling mechanism periodically removes one unit dose from the end of the production line at a rate of 25-120 units per minute, preferably at a rate of 40-60 units per minute. Each unit is in turn transferred to a conventional automatic weighing device, where it is weighed while the unit remains stable and the information is stored. Randomly selected units are sequentially transferred to a conventional automated analysis system. The unit dose is mixed with a suitable solvent for the active ingredient at a suitable rate. The dissolved amount of the active ingredient at time t ^ - the amount dissolved at time t ^ divided by t ^ - t ^ is the dissolution rate.

The appropriate time interval (t ^ - t ^) is selected in advance and varies for different drugs. A suitable time interval may range from 5 seconds to 2 minutes or more. The sample is then continuously stirred for a sufficient time to dissolve all of the active ingredient, after which the solvent is analyzed to determine the concentration of the active ingredient. The amount of active ingredient obtained in this analysis, as well as the amounts from the samples and t ^, is the total amount of the dosage form. This information is also stored and stored. If the weight, thickness and rate of dissolution of the drug 22 6 9 2 4 3 in the dose are within predetermined limits, the units are found to be useful. If the readings are not within these limits, units prepared from the onset of negative analytical results to the beginning of the next positive analysis are removed for further investigation.

It can be seen from Figure 1 that additional steps are used to monitor the required functions according to the invention, as shown below. For example, the tape inspection step is to perform a continuously monitored inspection of the tape for tape color, thickness, continuity, dirt stains, and defects of all kinds. These inspections may be carried out by electronic and / or optical means as well as by visual inspection.

Inspection of the tape involves placing a "tag" on the tape at a location found to be defective. In addition, the device can be equipped so that when an error in the tape is detected, it is memorized either automatically or by the supervisor indicating that there is some kind of error in the tape at some point ahead, which may include a fault type, such as a hole, black dot, stain, etc.

The device used to generate the note may be, for example, the same device which also performs the affixing of the tag, except that the handling and inspection of the tape may in individual cases be carried out in accordance with good manufacturing practice.

In addition, the thickness of the strip can be measured by means of the same or a conventional additional inspection device. This can be done by a visual inspection by the user or it can be detected by a detector connected to the logical system, using an upper and lower limit for the tape thickness, and if the tape thickness deviates outside these limits, a note is made and a tag is placed on the tape.

One device for measuring the thickness of the tape uses an X-ray or beta ray measuring device or some other similar device to measure the mass thickness of the tape.

In step 13 of Fig. 1, in which particle reduction and flow control are performed, the monitoring is to be performed as follows. According to the invention, despite the fact that the uncoated 23 6 9 2 4 3 tape has been monitored for its defects and thickness, the corresponding monitoring is performed after the tape has been coated with the active ingredient. For example, an X-ray measuring device can again be used to measure the thickness of the coated tape, which thickness, compared to the previously determined thickness of the uncoated tape, allows conclusions to be drawn about the amount of active ingredient applied to the tape. In addition, it is within the scope of the invention to use an actual mass monitoring device to measure the amount of active ingredient applied to the tape. It is to be understood that the inspection of the thickness of the coated tape is performed by guiding the coated tape back through the perforation of the device to perform the tape inspection in step 11 of Figure 1.

The active ingredient delivery system (Reference 14 in Figure 1) is monitored by reconnecting the results of an in-line analysis of the concentration of active ingredient on the tape. For example, when analyzing the electrical signals of an in-line analyzer (digital or analog), the active ingredient concentration (weight of active ingredient per unit area of coated tape) is used for feedback (Reference 15 in Figure 1) to control the amount of active ingredient applied to the tape in the coating process. These feedback signals are fed, for example, to a minimum computer which provides a suitable correction signal for the coating process. The correction signal either increases or decreases the application of the active ingredient so that the concentration is maintained in a narrow range near the optimum point. For example, in a dry application method, the active ingredient powder is fed to an application device. In this case, the correction signal is used to control the feed rate and thus the active ingredient.

In the wet application method, the correction signal can be used, for example, to vary the amount of coating product to be applied to the tape. For example, the gap between the measuring rollers or the measuring knife and the application roller is changed to change the application rate of the active ingredient. In counter-roll coating, the rotational speed of the application roll is changed to change the application rate of the active ingredient. Another procedure for controlling wet application is to change the concentration of the active ingredient in the coating liquid. The two liquid preparations containing different concentrations of the active ingredient are mixed together in the required proportions to obtain the correct concentration. The ratio of the two preparations can then be varied to precisely control the concentration of the active ingredient.

Methods for "adding" an active ingredient to the novel dosage forms of the present invention are fundamentally different from conventional methods for adding active ingredients to solid dosage forms, e.g., tablets, capsules, granules, suppositories, etc. Although the methods and devices used in the method of the invention may vary. . applying the active ingredient to the moving belt exceptionally evenly. The method of application of the active ingredient according to the present invention is unique and has numerous advantages over the manufacturing methods commonly used in the pharmaceutical industry.

Because the active ingredient is applied to at least most of the edible strip, which is then treated to completely seal it, conventional pharmaceutical additives, excipients, preservatives, and the like are not required to be mixed with the active ingredient, saving costs and, more importantly, avoiding potential incompatibilities and quality. According to the present invention, a uniform coating of active ingredient is placed on a strip and then divided into individual portions by dividing it linearly or geometrically, thereby achieving uniform strength of the active ingredient in a number of unit doses, which is considerably better than current pharmaceutical industry requirements. Clearly, conventional pharmaceutical manufacturing methods require the preparation of the active ingredient and suitable therapeutically inert pharmaceutical excipients in large quantities and are divided by volume to fill or compress the capsules into tablets. Thus, using the manufacturing methods of the present invention, it is possible to reduce the amount of excess active ingredient from the currently used 5-10% by weight nominal amount to about 1-5% by weight, thereby achieving significant savings, especially when using very expensive active ingredients, e.g. certain hormones and antibiotics. . Finally, the method of applying the active ingredient to the tape according to the present invention allows continuous, in-line, dose-free inspection of doses by means of physical parameters, thus achieving a very high uniformity of the active ingredient in a large number of doses.

The active ingredient may be applied to the tape either wet or dry, with a dry form being preferred. In both cases, the active ingredient is applied in a form suitable for analysis, as described below, i. a fine. The size of the particles is in the sub-micrometer range and can also be in a very narrow range of 1-100 micrometers. The particles in the submicrometer range have heretofore been considered too small to make pharmaceutical tablets without first undergoing, for example, a granulation treatment, which substantially increases the particle size and also adds an excipient to the active ingredient. The method of the invention uses such ultrafine particles without the need for these procedures and / or the addition of extenders. The active ingredient is deposited as a very uniform coating on the strip as it passes through an automated manufacturing system.

The preferred method of precipitating the active ingredient on a strip when the active ingredient is in the form of a dry powder is electrostatic precipitation of a powder cloud. In general, this method requires passing the strip through an electrostatic field in a suitable chamber. The finely divided active ingredient is introduced into the chamber, for example in a stream of compressed air, whereby it precipitates on the strip as it passes over rollers of opposite charge. This method is used in certain non-pharmaceutical fields, such as in the manufacture of adhesives and adhesive papers. In order to achieve successful precipitation, it is obvious that the resistivity of the strip must be such that the dielectric particles are able to precipitate on it. Additives that can be used in tape preparations to obtain suitable electrical properties for them have been discussed above. In several cases, it has been found that before electrostatic precipitation of the active ingredient powder, it is necessary to coat the strip with a substance which improves the adhesion of the powder to it. Examples of these substances include carboxymethylcellulose, methylcellulose and the like. These adhesion promoters can be applied to the strip 26 69243 in a conventional manner, for example by application as a solution in a volatile solvent such as water and drying, for example, with warm air. After application of the coating which improves the adhesion of the active ingredient to the strip, the coating or "loading" with the active substance is carried out immediately in line. The adhesive is then activated to bind the active agent particles to the tape. This is done by applying heat, pressure, humidity, or a suitable combination of these to the coated tape. In addition to the electrostatic powder cloud precipitation method, the finely divided ingredient can be applied to the strip as a dry powder by means of an electrogas-dynamic powder coating. In this method, the active agent particles are electrically charged using a corona discharge and conducted in a gas stream to an electrically isolated chamber. The strip passes through this chamber on a metallic substrate which is either grounded or charged opposite to the charged cloud of active substance particles. As a result of the electric field between these particles and the metal surface, the particles are transferred to and deposited on the strip.

According to a further present invention, the active ingredient may be deposited on a strip of a solution or suspension of a finely divided drug, for example a colloidal suspension. The liquid used in these procedures may be water, an organic solvent, for example ethanol or a water / alcohol solvent. The preferred method of applying the active ingredient as a liquid to a moving belt is electrostatic spray deposition. In this method, a solution or suspension containing an active ingredient is measured in a device that directs a jet of microprodices that focus on a specific area of the tape when an electrostatic field having a specific area is used. This method has given very good results when small amounts of active ingredient, such as hormones or enzymes, have to be applied to the tape. By small amounts are usually meant amounts of less than one milligram of active ingredient.

In addition to electrostatic spray deposition, certain other coating methods used in other fields, which are suitable for coating a substrate with a liquid substance, are useful for coating a strip with an active ingredient. For example, 11 27 69243 paper webs can be transferred under a roll embedded in a saturated liquid bath. As the strip bypasses the roll, the excess liquid is "wiped" off the strip by means of another roll, an air jet, a rubber wiper melt, a rod on which the wire is wound, i. Using a Meier rod or the like. In this case, the solution penetrates slightly into the tape, especially if the solvent used to dissolve or suspend the active ingredient is the same or similar to that used in the manufacture of the paper tape.

It should be noted that although the present invention is intended to apply the active ingredient to the surface of the strip, some penetration into the strip may occur either by using a volatile liquid carrier for the active ingredient or by applying heat and / or pressure to seal the strip. Simple experiments with these factors, such as volatile liquids, indicate the percentage of active ingredient that is absorbed into the tape by the coating on it. Once this parameter is set, the on-line analyzers can be adjusted accordingly. If a significant amount of active ingredient is absorbed into the tape, it is necessary to use an unloaded tape, i.e. a strip without active ingredient on the outer surface of the dosage unit, thereby preventing loss of active ingredient due to destructive forces such as air and moisture.

As mentioned above, one obvious advantage of the dosage form of the present invention is that the pharmaceutically active agent can be formulated into a stable dosage form without mixing conventional pharmaceutical excipients present in conventional dosage forms in amounts substantially in excess of the amount of active agent. It should be noted, however, that small amounts of inert substances must necessarily be placed on the strips with the active ingredient according to the invention. For example, if the active ingredient is applied to the tape dry, a small amount, for example 0-10% by weight, preferably 0.25-2% by weight of the active ingredient of the glidants may be uniformly mixed therewith. The purpose of the glidant is to facilitate the flow of the powdered active substance through the precipitator. Suitable glidants include, for example, finely divided silicon preparations such as colloidal silicon oxide, sold under the tradename Cag-O-Sil Cabot Corp., Boston, Mass., Talc, finely divided starch preparations such as Driflo, sold by National Starch, Inc. and the like. It can be seen that the addition of the glidant and its amount depend on the crystal structure and flow characteristics of the active substance. In certain cases, preservatives may be mixed with the active ingredient. However, when applying the active substance to the tape dry, this is usually not necessary. It is further within the scope of the invention to mix the adhesives with the active agents, as mentioned above, when applied wet and when both the adhesive and the active agent are compatible with the same liquid carrier. In most cases, however, adhesives are used, as described above, to apply the active agent to the tape to improve dry adhesion. In both cases, the adhesive can be used in an amount of 0 to 100% by weight, preferably about 0 to 30% by weight based on the weight of the drugs.

According to the present invention, the amount of active agent to be applied to the tape varies depending on the dosage amount of the agent, the surface area of the tape to be coated, the thickness of the coating, and so on. Other factors that affect the amount of drug applied to the tape include the delivery mechanism used, the parameters required by the manufacturing method, and the type and sensitivity of the in-line tester used. In all cases, however, the amount of material to be applied to the tape will be such that when the coated tape is prepared and formed into unit doses, each unit obtained will contain a therapeutically effective amount of drug. As an example of the latter requirement, when analyzing the uniformity of drug application by photon counting spectrophotometry to measure the ultraviolet absorption of the active substance of the tape, the coating of the active substance must not be thicker than 0.005 cm. In all cases, the amount of active substance applied to the tape is expressed in milligrams or micrograms per square centimeter per tape. This is determined per total area of the strip, although in most cases it is necessary not to coat the edge area of the strip to seal the doses. The ability of the bands to receive the active agent and form unit doses therefrom in accordance with the present invention

II

29 69243 is expressed by the tape conversion factor (WCF) and is calculated according to the following formula: Drug-covered tape area - = tape conversion

Maximum area of the final dose addition factor

For example, if a drug has been applied to a 15.25 cm x 1.0 cm tape and 0.5 cm x 1.0 cm doses are prepared, it is 15.25 x 1.0 - = 30.5 (tape conversion factor) .

0.5 x 1.0

The next step in preparing the novel dosage forms of the present invention is the forming or assembling step. As used herein, the term "assembling step" is understood to mean the conversion of an initially formed strip into a solid, predetermined geometric shape that can be divided into several portions. This step can be performed, as in the above steps, by a continuous, high-speed manufacturing process. At this stage, the coated flat tape is converted to the shape of a geometric pattern, and generally the active ingredient is sealed with a protective tape coating. The formed strip is then made into unit doses and finished to form pharmaceutically acceptable unit doses suitable for oral administration. It should be noted that, in the recommended procedure, unitization may occur during or immediately after the assembly phase.

The present invention uses a variety of manufacturing methods, including extrusion into hoses, multi-strip fabrication, wrapping, injection molding, and the like. There are four main methods for forming or assembling an active material coated tape: helical winding, twist manufacturing, fan bending, and lamination. These four main principles are set out in detail below.

Before a detailed examination of the individual assembly procedures used in accordance with the invention, various requirements for an acceptable method are set forth. The assembly or shaping procedure must be suitable for high-speed fabrication and give a geometric shape that exactly meets the given uniformity requirements. The method must be able to substantially encapsulate the active ingredient. Finally, in the assembly or shaping process, the strip must not be subjected to excessive stress to deform or tear, nor must a significant amount of active substance be removed from the strip. Each of the formulation procedures presented below meets these requirements.

The first main procedure concerns the helical winding of a moving belt. It may be appropriate to distinguish between helical winding and helical winding, which are used in the paper processing industry, for example. In spiral winding, paper is fed to the spiral winding machine from several rollers, whereby the width of the coils is usually 0.5 to 2 cm. Continuous strips of paper from each roll are wound around a cylindrical mandrel supported at one end. The strips are wound so that they overlap. The glue is applied to each strip of paper and to the overlapping strips of the continuous spiral as they are wound around the mandrel. The roll thus formed is circulated around the mandrel by means of a continuous belt, which also forces the paper roll to move towards the unsupported end of the mandrel. The tube thus formed at the end of the mandrel is cut to the desired length by the intermittent operation of a high-speed knife. The paper thus produced always has a hole due to the spindle around which it is formed. Spindle winding processes do not use a mandrel and thus it is neither necessary nor advantageous to have a hole in the center of the rod formed. In fact, it is an object of the present invention to substantially limit or eliminate this central hollow area.

Figure 3 schematically shows an example of a helical winding. In the helical winding process of Figure 3, the coated or loaded strip 61 is passed from a single roll through a system comprising, for example, a guide wire 62 and a roll 63 belonging to a cutting system 63 which cuts the strip perpendicularly to a desired length, usually about 12-25 cm. The portions of the strip are then fed to a corrugating roll system 65, where the corrugating rollers form a series of corrugations by pushing the strip against a soft rubber roll. As a result of the crimping effect, the individual strips of the strip are formed or twisted into loosely wound coils. As the loosely twisted strips exit the rollable roll arrangement, they are passed between two surfaces, one stationary and the other movable, whereby the distance between the two surfaces gradually decreases along the path of the twisted strips. The stationary and movable surface may consist of two concentric cylinders or, as shown in Fig. 2, a flat fixed plate 67 as a stationary surface and a movable belt 66 as a movable surface. As the strips of tape in loosely wound coils pass between a moving and stationary surface, they twist tightly until a strong rod is formed. By appropriately adjusting the distance between the two surfaces, the rod can be wound tight enough to remove the hole in the central portion. It's natural! take into account that, if desired, the distance can be made so that a hole of the desired diameter remains in the middle of the formed rod.

The rod can be closed in different ways. First, it has been found that conventional methods for making, for example, paper caramel sticks are not suitable for use in the present invention. In the conventional method, moving surfaces that come into contact with the tape when forming the stick are treated or coated with water to bring a large portion of the tape into contact. The amount of water absorbed by the tape, about 18% by weight, is not acceptable in preparing unit doses of the invention due to possible adverse effects on the adhesion of the drug to the tape as well as to the drug itself. Furthermore, rods made by this conventional method have been found for the most part to be too tightly closed to achieve good drug release in the body. In accordance with the present invention, it has been found that spraying a strip of approximately equal size as in a conventional method with a fine amount of water as a fine jet just to moisten it and drying the rods rapidly after manufacture provides unit dosages of acceptable uniformity and adequate drug release rate and active ingredient stability. the pharmaceutical industry is known to be very sensitive to moisture.

Second, the rods can be sealed by using a heat-sealable edible polymer at the end of each strip sheet 32 69243 or by coating the end of each sheet with a heat-sealable edible polymer immediately after cutting from the continuous strip. Alternatively, the heat-sealable polymer can be applied to the entire area of the strip portion, either as a separate sheet or as a flat coating. Suitable polymeric materials include, for example, a water-soluble polyoxyethylene or a cellulose ether derivative containing the plasticizer described above.

Once the bars are twisted tightly, they are allowed to pass as such from under the heated plate, applying both heat and pressure to the bars to seal and seal them. For example, a portion of the solid plate 67 may comprise a heated area.

Alternatively, the rods may be sealed after formation using water or an adhesive in the outer layer (s) of the strip. Preferably, water is used as a barrier agent. Certain substances can also be used in the strip composition or on the surface of the strip, for example starch or starch derivatives, which form a seam during the next drying or when heat and pressure are applied.

According to the method shown in Fig. 3 by way of example, a water jet 68 is used to wet the recirculating portion below the outer surface of the continuous belt 66 so that the surface of the belt in contact with the moving belt contains only enough water as droplets to sufficiently seal the rods. Water can also be fed to tightly wound rods, for example under a wire transfer roller, using a porous water through which a measured amount of water is fed evenly over the entire length of the rods or a sponge to transfer water to the outer surfaces of the rods. The rods must then be guided between a moving and fixed surface portion where pressure or pressure and heat can be applied to achieve complete sealing.

This general method for performing water sealing is clearly superior to known methods for forming, for example, the paper candy sticks described above. Using the water application methods described above, the amount of water obtained by each rod is less than that achievable using known methods. As a result, the amount of water to be removed during the subsequent drying of the rods 33 69243 is considerably less than is usually required in known methods.

The rods thus formed are all as long as the width of the strip obtained from the feed roll. This width is typically 20-40 cm. After sealing each rod, they are brought into contact with, for example, very sharp knives 69 (Fig. 3) by means of a belt 66 and are formed into units, i. the rod is cut into sections of the desired length. The formation of these rods into units and their finalization into final dosage forms will be described in more detail later.

The second forming or assembling method to be processed is commonly referred to as rotational molding. This method involves several distinct forms. This method can be considered to be related to a more general lamination method, in which the active substance-coated strip stacks as continuous strips or rods are initially made by either fan folding or lamination, both methods of which will be described in more detail later. In a particular rotational molding process shown in Figure 4, a continuous, relatively thick, active agent-coated laminated strip 70 is passed through two press rolls 71. The continuous stack of laminate 72 thus formed or compressed is moved to another position, i. a rod forming and sealing station comprising, for example, one or more spring-loaded stainless steel rollers 73, the outer circumference of which is formed so as to form a plurality of continuous rods 74 having a circular cross-section or other desired shape. The rods 74 thus shaped into the desired geometric shape are then passed through a third rotating position where, for example, one or more pairs of suitably arranged rollers form individual portions of the rods. This may be followed by other suitable printing and finishing treatments, as will be explained in more detail later. It should be noted that the printing can be performed in the step of preparing individual batches using the third roll group 75.

Another example of rotational molding is shown in Figure 5, in which the fabricated stack (strip or rod) 81 is intended to continuously form evenly rounded edges into final dosage units by means of oppositely moving compression molds 82 and / or a suitably heated pair of rollers 83 so that the rotating dosing station is a continuous chain consisting of end-to-end unit doses 85. As in all of the rotational molding processes of the invention, the molded rods are thus fed to the printing station and the unit manufacturing station all at high speed.

In another closely related rotational molding process, a continuous stack is fed to a rotary forming and sealing system comprising, as above, for example, one or more pairs of stainless steel rolls. Tape layers made of, for example, paper or polymer film sheets are heated and pressed into a continuous laminate. It is advantageous if the outer layer of the laminate is made of paper to prevent, for example, the laminate installation from focusing on the heated rolls. During this sealing step, the strip layers bond together to form unitary units, which reduces the displacement of the layers and the tearing of the edges in subsequent side and end shaping treatments. Next, the ends of the dosage units are formed by feeding a continuous rectangular laminate from a sealing station to another station where the ends of the unit doses are formed by a pair of heated rollers which may be of the desired pattern and with transversely positioned cutting heads. The cut ends of the dosage forms are shaped and sealed by the heat from the rollers. The shape of the head cutting blades determines the shape of the heads of the unit doses. The sectional shape of the heads is designed to provide a smooth transition to the side sections of the dosage units, which is performed at the next position.

The sides of the dosage units are formed in a laminated, cut stack of material in which the ends are formed by a third pair of heated rollers. These rollers may have annular recesses provided with raised cutting edges. The shape of the recess on the surfaces of the rollers forms the desired cross-section of unit doses. The heat and compression from the brush-like cutting elements of the rollers seal the sides of the unit doses into a flat surface.

The method of manufacturing unit doses in rotary formulation thus shown in Figure 5 thus comprises three main stations, i. pre-sealing station, end shaping station and side shaping station. Each of these 35 69243 stations comprises a group of rolls, preferably heated, through which a continuous stack of strips is conveyed. Exterior surface design, i.e. the surfaces of the rollers in each position, is different depending on the particular position and the desired result. Several additional steps, such as additional cutting, printing, and finishing steps, can be performed between the three positions shown. These functions will be described in more detail later.

It should be noted that it is within the scope of the invention to perform one or more different steps in the rotational molding process simultaneously and in fact to perform on a continuous feed belt with a single pair, e.g. spring loaded, heated, cooperating rollers using all the different steps above, i. bar formation, dose formation, unit dose formation and even printing.

The third example of rotational design presented above is well suited, for example, for combining two or more of the steps shown together into one step. Such is shown in Fig. 4A, in which the lamination pressing and bar forming steps of the substantially third rotary forming method described above and also the method shown in Fig. 4 are combined, for example using one pair of heated pressing and cutting rollers (not specifically shown) simultaneously pressing the laminate feed and cutting it into shape. viewed from the side resembles several interconnected ball rings. These cut ends are then immediately fed to a unit forming device where longitudinal cuts are made to obtain individual doses. For example, the printing step can be performed in this latter step. It is also within the scope of the present invention to package unit doses immediately after the unit forming step, for example by placing them in blister strips by means of a device conventionally used in the art.

A third method of preparing the dosage forms of the present invention is a fan-turning method. The fan-turning procedure can be considered as a form of laminator in the general sense. In this method, for example, a 30 cm wide strip is prepared to close the active ingredient applied to it. This can be done either by initially bending the strip in half or by laminating 36 6 9 2 4 3 two coated strips with the coated sides facing each other. More than one pair of strips laminated in this way can be used, the strips can be made, for example, initially wider, for example up to 60 cm wide, and after lamination can be divided into two or more strips of the size shown in the fan turning process, i. about 1-15 cm wide.

Once the coated tape is initially folded or laminated as described above, it is then passed through drawing rollers, whereby it is drawn to perform the fan-forming step. The drawing rollers may or may not be motor driven. The belt moves mainly by means of traction rollers. The drawing can be performed, for example, by loading one of the drawing rollers with a spring. Since the tape folds mainly in the direction of the drawing plates which press into the tape material, the drawing plates can be placed alternately on the upper and lower rolls according to the desired pattern. The drawn strip then passes into a fan-forming trough with bending plates which gently begin to bend the strip from the point of contact and compress it at width and overlapping points so that the strip is relatively tightly folded at the discharge end. At the end of the bending trough there are means for pulling the strip through the drawing and folding device, such as a pair of spring-loaded rolls of stainless steel. These have a dual function, i.e. the strip passes through a folding device and the folded strip is compressed into a continuous, solid geometric shape. It is, of course, within the scope of the invention to connect the pulling means to the means for closing the strip. The fan-folded tape can be closed by other methods, as shown below. The sealed strip can be formed into units in a number of ways, such as by the rotational molding method described above.

Figures 6A-6D show a method of forming a dosage form into a fan, wherein the initially folded strips 91 are mounted in openings 92A to which they fit in shape in a therapeutically inert strip, preferably paper, referred to as a center strip 92. This "filled" center strip The folded strips are placed, then laminated to form a laminate structure connected between the protective strips 93. This combined, continuous laminated tape is fed, for example, to a rotating dose forming unit or station that does not differ from unit 83 of Figure 5, where the tape acquires the appearance shown in Figure 6B. Finally, or simultaneously with performing the step shown in Figure 6B, single doses are formed to give the unit doses shown in Figure 6C. Fig. 6D shows how the strips 91 folded into a fan are completely closed and that, for example, the central strip 92 is forced to move slightly outwards so that it gets slightly between the protective strips 93 to which it is sealed. It should be noted, however, that the protective strips 93 and the central strip 92 do not contain any active substance, thus ensuring that the active substance is not present on the outer surface of the individual dosage forms.

The fourth main method used in the present invention is the above-mentioned lamination method. In this method, about 20-60 rolls of tape are first unwound simultaneously in a multi-coil unwinding position and then guided together to form a continuous bar. These 20-60 layers of tape may all be of a paper-like material provided with a suitable coating to facilitate sealing in the next step, or they may be a laminate of paper-like tape and an edible, heat-sealable polymer tape and may consist of one or more paper-like tapes alternating with heat-sealable polymer tape. Suitable polymeric materials include, for example, water-soluble polyoxyethylene or a plasticizer-containing cellulose ether derivative. Any number of these strips can be coated with the active substance.

Preferably, the strips of paper composition are coated with an active agent.

An alternative method of superimposing strips of active ingredient is to stack them directly from the precipitator. The width of the strip is usually 12-25 cm. The width of the strip derived from the rollers or derived from the precipitating device may initially be many times the final width and may thus be cut into strips to the desired final width as a step in the stacking process.

The continuous bundle obtained by stacking the strip is passed to the lamination station. Devices known in various fields for joining strips of flexible films together and forming a laminate therefrom are generally useful in this embodiment of the present invention. As already mentioned, the area to which the active substance is applied to the strips or sheets varies, for example, depending on the method of sealing the lamination. The cut and finish of the laminate may also vary in the practice of the invention. For example, the laminates can be treated as in the rotational molding process described above. However, the lamination station must also include a pair of opposing press plates that form, seal, and cut the dosage forms from the continuously fed tape stack. The surface area of a typical press plate may be approximately 25 cm x 25 cm.

Laminates made in accordance with the present invention are unique in one embodiment in that they are seamed only at their edges instead of completely enclosing each sheet in an adjacent sheet. Unexpectedly, it has been found that suitable dosage sizes can be made from a stack of strip sheets with strips of heat sealable polymeric material interposed between the stack of up to six layers of paper strip by applying heat and pressure to the laminate using unit cutting means. During the unit dose forming step, the layers of polymeric tape in the laminate are distorted by heat and pressure, "spreading" to cover and seal the edges of the sheets of paper between them. It is self-evident that the top and bottom layers of such a laminate must be a polymer composition. It is recommended to place the incoming drug on the paper-polymer tape stacks on the layers of the paper tape. It is self-evident from the above presentation that such a laminate, which is closed only at its edges, has a very high release rate of the drug compared to the corresponding strip laminates, which are completely closed.

An alternative method of forming doses from the strip laminate is to pass the laminate between rotating cylinders with individual double cutting blades on the outer surface. Unit doses are formed, sealed and continuously cut from the fed strip laminate as it passes between such rotating cylinders.

39 6 9 2 4 3

Some pharmaceutical manufacturing advantages are achieved using the lamination procedures disclosed herein. First, the lamination process provides barrier layers that facilitate the handling of two or more therapeutically active agents that are incompatible without the need for the addition of stabilizers or special handling techniques, such as encapsulation of one or more ingredients. Since, for example, up to 60 layers can be used to form a laminate, this application of the invention is ideal for pharmaceutical preparations containing a large number of active substances, with several possibilities for their incompatibility, such as in multivitamin preparations. Furthermore, the insulating effect of the laminate layers and the precipitation or application of the active ingredient to the strip in a dry state make these procedures ideally suited for the production of effervescent preparations. In these preparations it should be noted that the composition of the strip must be such that it is readily soluble or dispersible in water. Also, as discussed above, dry application of the active ingredient to the tape is advantageous if the active ingredient is adversely affected by moisture.

Further considering the lamination process of the present invention, it is within the scope of the invention to vary the compositions of the different layers of the laminate as well as whether all the layers are coated with the active substance. Obviously, the top and bottom layers of the laminate, which are exposed, are not coated, thus achieving effective isolation of the active substance. For example, it has been found that placing one or more starch-based layers in a cellulosic laminate provides more softness to the laminate than increasing the amount of plasticizer in the composition of the cellulosic layers.

Considering the above shaping procedure, it is advantageous according to the invention to precipitate or apply the active ingredient to the strip in a wet form, where the shaping is a helical winding or a fan-forming procedure. Circulating and laminating procedures are equally suitable for applying the active agent, either dry or wet, the choice depending on the properties of the active ingredient to be applied, for example solubility in the solvent used, stability to moisture, etc.

For practical reasons, unit formation cannot be performed without sealing at the same time and without first processing the assembly, because, as mentioned above, cutting or forming units from the resulting strips may expose some active ingredient on one or more outer surfaces. An exception to this could be a method of application adapted to precipitate the active ingredient at short intervals as opposed to continuous application, whereby the active ingredient would be "spotted" and surrounded on all sides by an uncoated tape. In view of the manufacturing equipment and the need to maintain the integrity of the coating for in-line testing, it is recommended that the active ingredient be continuously applied to the strip in a sufficient amount so that the unit forming step provides dosage forms containing a therapeutically effective dosage amount. In certain methods disclosed herein, for example, in a fan folding process, the edge regions of the strip may be left free of active agent to ensure closure of the active agent and, in certain cases, to form an excess of tape that can be used to seal unit dosage forms.

The cutting of the formed strip must be performed so that the strip is not deformed. The cutting procedure itself can be performed with stationary and rotating cutting blades, single- or two-stage presses, or by some other conventional method. To ensure that the strip to be processed does not change shape during cutting processing, several cuts can be made from different directions. Also, as described above in connection with the rotational shaping, the produced strip can be slightly wrinkled or toothed to compensate for the deformation that occurs during the high speed unit manufacturing step.

The assembled, coated tape can be formed into units by individual separation, i. by forming one unit at a time, such as by cutting a part of the rod having an exact length, or preferably several units can be formed simultaneously, such as by cutting a helically wound rod into a plurality of dosing units using several evenly spaced cutting blades. Another method of forming a plurality of dosage units at the same time would be to use a mold press mounted either singly, in pairs or as a rotating or reciprocating plate to cut a laminated strip or helically wound rod-like structure. The shape of the final dose is preferably cosmetically pleasing and such that a number of different shapes fit the press plate without substantial loss except in the edge areas where the shape is rectangular, square or preferably hexagonal.

The shape of the dosage units made of bars can also be determined by means of cutters. For example, the cutting device may be rectangular in shape with the parallel sides slightly curved so that the ends cut into the dosage forms are slightly rounded. It should be noted, however, that transverse supports must be used to prevent wrinkling of the prepared dosage form and the formation of burrs therein during the preparation of unit doses.

It is within the scope of the present invention to combine the formation of units and the final sealing step. Although there are numerous ways in which dosage forms can be sealed, the most common combination of unit formation is the use of heat and / or pressure. In addition to closing the different sides of the dosage form by heating the cutting tool, heat and pressure can be applied by means of a press to bond the laminate. Also, the use of moisture and volatile solvent in closing the end of the helical winding rod, as mentioned above, can be extended to the cutting stage by using such a solvent on the cutting surface. Heat and / or pressure can be used simultaneously to obtain a good seal.

The methods by which the unit doses according to the invention can be sealed are not uncommon in the treatment and lamination of plastics. These include, in addition to the use of water or another volatile solvent, such as ethanol, methanol and chloroform, the use of pressure and heat, the use of a separate adhesive, infrared heating, ultrasonic sealing, encapsulation, or the combined use of two or more thereof. The preferred method of sealing the dosage forms of the present invention is, if desired, the use of pre-printed wrappers. These 69243 42 may be, for example, thin films of edible polymeric material, such as hydroxymethylcellulose, modified starch, and gelatin, and the dosage units are coated thereby by immersing the units in baths containing these materials. Such a layer may be self-sealing, such as by removing a volatile solvent. More preferred methods of forming a shell for unit doses of the present invention are encapsulation and use of blister packs.

In the first of these methods, solid dosage units are placed between two converging flexible films, such as gelatin, which seal the dosage forms as shown in Figure 6A. The gelatin film is then heat sealed and cut to the desired shape. A device for encapsulating liquids in this manner is known in the pharmaceutical industry and such a device can be easily adapted to coat the novel dosage forms of the present invention.

Another method is the use of blister packs, which can be done by at least the following two methods. First, preformed blister sheets are made of, for example, gelatin or a cellulose derivative by means of a device well known, for example, in the plastics industry, for example by injection molding. The unit doses are automatically placed in these bubbles at high speed and the bubble sheets are then coated with a shell which is sealed by a suitable sealing procedure for the bubble sheet, preferably by ultrasonic sealing. The bubbles are then separated by a stationary or rotating cutting blade. The walls of the resulting bubbles are usually thicker than the lid or barrier layer. However, the barrier layer is thick enough to protect the dosage form, yet such that the dosage form is released from the bubble relatively soon after ingestion, usually within a few seconds of reaching the stomach. Alternatively, the bubbles may be formed from two identical halves which are sealed, for example, by the methods described above.

An alternative to the above bubble cover is to form a continuous backing strip or strip of the above-mentioned material used in connection with the bubbles and to cut openings in it so that the dosage forms, for example the dosage forms shown in Fig. 6A, fit exactly. In this implementation, the unit doses are placed in the openings using, for example, a stick extending through the opening and another stick on top of the unit dose to hold it in compression. The strip is then sealed by adding base and top layers of similar material while compressing the unit doses. The thickness of the strip is never greater than the thickness of the dosage units. However, the strip may be thinner than the dosage form, but not less than about half of its thickness. It is preferred that the thickness of the backing strip be the same as or close to the thickness of the dosage form for a number of reasons. First, the barrier film can be as thin as that mentioned in connection with the bubble plates because it is not significantly distorted when closed. Second, the thicker backing tape is less prone to distortion when forming openings and preparing unit doses. Third, the openings can be made closer to each other in a thick strip, resulting in less losses. Once the dosage forms have been placed on the backing strip and sealed, the strip is again formed of units as described above. The advantage of both the bubble and backing strip treatments described above is that the outer surface material which does not contain the active substance can be finished using, for example, embossing, beveling and the like without the risk of loss of the active material. The use of bubbles or a backing strip also facilitates the use of different colors in the final dosage form, whereby, for example, by making the backing strip, the sealing strips or the unit doses themselves different colors, a particularly pleasant and different appearance can be achieved.

The material used in the manufacture of the bubbles, the supporting central strip and the barrier films as described above, like the strips themselves, must meet the critical requirements. In addition to the obvious pharmaceutical requirements such as purity, good storability, non-toxicity and compatibility with the active substance used, the surface quality of the material must be good, it must be able to absorb colors and inks, the structure must be uniform, flexible, dimensionally stable and release into water. A preferred composition for this purpose contains hydroxypropylcellulose, starch or a starch derivative as an extender 69243 44 and a disintegrant, a plasticizer such as polyethylene glycol, suitable pigments such as titanium dioxide and an antioxidant such as BHT.

One of the main advantages of the new dosage forms according to the present invention is their suitability for in-line, non-damaging quality control. In the present invention, the term "undamaged" has a practical meaning as opposed to a precise literal meaning. By this is meant that the quality determination of the novel dosage forms of the present invention is performed during the high speed manufacturing steps, whereby the actual loss of the dosage forms is less than 1%. Because the novel dosage forms of the invention can be prepared with a small standard deviation of dosages, the excess required is less than is currently common in the pharmaceutical industry and a very small percentage of doses disappear during inspection and become substantially zero considering the overall tolerances of the present method.

The novel dosage forms of the present invention receive a quality guarantee in the manufacturing process, which is unique in the pharmaceutical industry. This guarantee is based on in-line inspection procedures that clearly differ from known pharmaceutical quality control procedures, such as chemical and physical inspection of batch ingredients prior to manufacturing, inspection of solid dosage forms where samples are destroyed. , the determination of incompatibilities and the like and the physical quality checks of solid dosage forms, such as the visual inspection of two - color capsules to ensure that both ends are different colors. Such experiments, which are accepted and commonly used in the pharmaceutical industry and are set forth in general textbooks, are in no way and are not recommended for use in in-line quality assurance assays that are a characteristic of the solid dosage form of the present invention. It should be noted, however, that certain conventional procedures, such as careful quality control and analysis of all ingredients prior to the manufacturing steps, form an integral part of the preparation of the dosage forms disclosed herein, as is the case with any good pharmaceutical preparation.

The quality guarantee for the manufacture of the novel dosage forms of the present invention arises from the fact that the manufacture of all the forms disclosed herein begins with a continuous edible strip that can be adapted for inspection. First, the manufacture of the tape itself is controlled for the physical properties of the tape to ensure the integrity and flawlessness of the tape. For example, the tape may be passed through a resonant cavity where the microwave energy passing through the tape is continuously monitored to control the thickness of the tape, with changes in the resonant frequency implying changes in the thickness of the tape.

Other methods of tape thickness control include laser beam diffraction, fluid sensing, and sensors that make physical contact. According to the present invention, it is also possible to determine the weight of the unit area of the strip and its defects.

The preferred method for determining the weight of a tape per unit area is to use soft X-ray absorption, for example at a wavelength of about 4 Angstroms. Beta ray absorption using a source of PM 147 is also possible. Tape defects such as dots, holes, and streaks can be detected by an electrical discharge method using commercially available equipment.

The above methods are equally applicable in cases where a second coating is applied to the tape, either as one or more additional tapes or as a protective coating for the coated tape. Laser scanning is particularly advantageous for determining the quality guarantee of these coatings on line.

Another main point for determining in-line quality according to the invention is the control of the amount of active substance applied to the strip and its uniformity during coating. It should be recalled at the outset that a significant advantage of preparing the novel dosage forms of the present invention is that the active agent is applied to the tape in a form suitable for use in the following test methods 69243 46, i. as a fine or fine film.

There are several methods for analyzing the uniformity of an active substance. For example, a photon counter can be used to measure the ultraviolet absorption of a combination of a highly attenuating active agent and a tape. Soft X-ray absorption using a wavelength of about four Angstroms and beta beam absorption can also be used. A light scattering device is recommended as it is ideally suited for monitoring particle size and the concentration of powder cloud on the tape. Suitable devices for this purpose are commercially available.

The above assembly, unit formation, and finishing steps are also suitable for in-line inspections, as described above in connection with the tape. These tests naturally take into account the physical parameters of the strip after its manufacture, such as dimensions, thickness, evenness and the like. Similar tests are also performed with regard to unit dosage forms, uniformity and the like.

Two other tests can be used within the scope of the invention. In the first of these, a small portion of the strip is occasionally removed in line by cutting with knives, presses, liquid jets, or a laser beam. It is intended that the removed portion of the tape does not destroy the integrity of the tape or adversely affect any manufacturing step. The strip sample can be removed before or after application of the active ingredient, in some cases at an early stage of assembly, for example when a few strips have been pre-stacked for lamination or folding treatment. The sample thus removed is analyzed for both the composition of the strip and the active substance.

This analysis is carried out quantitatively for the active ingredient in particular.

In addition to spot analysis, samples of the finished dosage forms are taken and subjected to in-line potency analysis. Although such an analysis is a procedure currently required to be performed for most solid dosage forms marketed in the United States, it is not performed in-line during the manufacturing step as in the present invention. It should first be noted that the dosage forms of the present invention are not hampered by the requirements of the batch due to their manufacturing process. Thus, in accordance with Invention 47 69243, a "batch" may be the number of unit doses between two samples that meet the performance requirements, provided that said number meets the sampling requirements set by the Federal Food and Drug Administration. Because the sampling procedure used in the present invention substantially exceeds these requirements, the "batch" of novel dosage forms used herein may be any suitable number, for example, the number of units that can be prepared from a given batch of active agent.

Another unique feature of the warranty testing of the efficacy of the novel dosage forms of the present invention is that the results of these tests, as well as the results of all in-line tests presented herein, can be computer processed and used to adjust manufacturing process parameters. In doing so, a negative result in one of these tests indicates the start time for those dosage units that need to be removed and the next positive result after corrections automatically decides the deletion of these dosage units. Dosage units prepared between these two tests must then be further examined to determine how many meet the requirements set for them. If the tests are performed in line on the tape, for example with respect to the amount of active substance precipitated, the negative result can be automated to start two operations simultaneously. First, the tape can be marked with a spot of non-toxic color, which allows the production to be temporarily suspended and part of the tape to be removed by hand. Second, the result, via a computer, causes a correction in the amount of active agent applied to the tape, either by increasing or decreasing the amount as instructed. If the tape fed to the analysis unit again meets the requirements, a second spot is automatically made on the tape, thus marking the length of the tape that does not meet the requirements. Corresponding measures are performed at each checkpoint on the line.

To perform the efficacy analysis, random samples are removed from the finished dosage unit and some of them are automatically placed in the analysis solution and the dissolution rate is analyzed. The particular requirements used for the analysis of the dissolution of unit doses vary with the active substance or substances present in them. For example, a sample dosage unit may be added to a suitable solvent to give a solution of the active ingredient. The resulting sample solution can be examined photometrically to determine the active ingredient as a function of time after the sample unit is placed therein. Other possible parameters that can be measured from the sample solution include changes in pH, color, temperature, chemical reaction, and the like. Those skilled in the art are familiar with the means by which each of these changes can be automatically recorded as a function of time. Once the dissolution information is stored, it can be used to make the necessary changes in the system, such as a computer, during the formation, fabrication, finishing, and closure steps to correct or improve the results.

The in-line analysis procedures presented here are in all cases suitable for inspecting the entire strip, for example a device for examining the thickness of the strip. However, in some cases, inspection of the entire tape is not possible for economic reasons. For example, it is possible to analyze a small part of the strip using a light scattering sensor and it is still possible to place two or more measuring devices close to each other to examine a corresponding number of narrow cross-sections of the passing strip. However, the number of devices needed to examine the entire tape may be too large. Thus, if only a limited area of the tape can be examined, the analyzer can be placed in means that allow it to rotate back and forth with respect to the width of the tape. The percentage of tape tested in this way, and thus of finished dosage units, far exceeds the percentage of samples currently tested in the pharmaceutical industry by non-destructive testing procedures.

As mentioned, the finishing treatments of the novel dosage forms according to the invention can be carried out independently of other treatments or, preferably, in connection therewith, for example when forming units. The finishing of the new dosage forms according to the invention can be divided into two basic parts, i. the smoothness of the surface of the dosage form and the finish or appearance of the surface.

The uniformity of the surface of the dosage form according to the invention can be problematic depending on the formation of a unit dose of continuous I! 49 69243 on the procedure used for laminate and whether sealing is performed. For example, if the laminated strip stack is cut to a certain shape, as described above, there may be a small wrinkling at the point where the Cutting Tools meet. Slight wrinkling at the ends and sides may also occur if unit dosage forms are made according to another manufacturing method. In general, however, the assembly methods of the invention minimize the occurrence of such wrinkling.

The above wrinkling can generally be removed by gently rubbing, such as by gently circulating the dosage units in a drum using a potentially weakly abrasive such as salt crystals. It has been found that in most cases such processing must take place before printing.

The appearance of the surface, i.e. the gloss of the dosage forms of the invention may vary from slightly opaque to relatively high gloss depending on the method used and the finish desired. When sealing methods such as bubble sealing and encapsulation methods described above are used, the gloss of the final surface can be adjusted simply by selecting the material used for sealing. The same can be done when using a wrapper to seal the dosage form. If such seal treatments are used, complete removal of the burrs is generally not necessary, as the wrap ensures complete continuity of the surface.

The printing also depends on the assembly and sealing methods used. The printing can be done on the tape itself at a suitable place during manufacture. For example, the outer shell of the laminated dosage form may be printed prior to assembly as part of the unit formation step or even after unit formation. For example, spiral wound dosage forms can be printed while still in a continuous rod or stack. If the dosage forms of the present invention are sealed using a wrapper, printing is preferably performed after wrapping, although it is within the scope of the invention to print on the dosage form and apply a clear wrapper thereafter. The printing of solid dosage forms before their completion is unique in the pharmaceutical industry.

69243 50

The choice of printing method depends on several factors, the most important of which is the nature of the substrate on which the printing is performed. The choice of a suitable method also depends to some extent on the time of the manufacturing process at which the printing is performed, i. whether the strip is printed prior to assembly, whether the final dosage forms are printed, or whether the printing is performed at some suitable intermediate stage, optionally in combination with other steps, such as unit formation. The printing method and suitable equipment can be selected from the following: offset printing and direct letterpress printing, offset gravure printing, lithographic printing, electrostatic powder printing, electrostatic screen printing, inkjet and the like. Of these, offset printing is a first-class choice, although other methods may be used in certain cases, and new printing methods that become available and applicable to the technology disclosed herein may also be used within the scope of the invention.

It is self-evident from the finishing and printing step described above that the color of the new dosage forms according to the invention can be varied both in terms of its shade and strength. First, the tape composition itself may contain a dye, the strength of which increases as the tape layers are joined together during the various manufacturing steps. The toner can also be added to the wrapper or barrier layer. If bubble or encapsulation procedures are used, it may be possible to use two or more colors by adding different colors to different parts. Dosage forms prepared by lamination are also suitable for using different colors by simply changing the color of the strip introduced into the laminator. Other variations of these procedures will be apparent to those skilled in the art.

The types of active substances used in the novel dosage forms according to the invention are practically unlimited. The terms "active ingredient", "active ingredient" and "drug", which may be considered synonymous in the context of the present invention and are used interchangeably in the specification and claims of the application, refer to any region which produces a pharmacological effect in the body. These substances include, for example, the following:

Benzodiazepines such as chlorodiazepoxide, diazepam, flurazepam, oxazepam, chlorosepate and the like. Other compounds in the "benzodiazepines" category have been reported by Garatti, Mussini and Randal in "The Benzodiazepines",

Raven Press 1973;

Other sedatives such as reserpine, thiopropazate and phenothiazine compounds such as perphenazine, chlorpromazine and the like;

Sedatives and hypnotics such as phenolbarbitals, methylpyrloniglutethimide, ethylchlorol, meaqualone and the like;

Psychiatric stimulants such as amitriptyline, imipramine, methylphenidate and the like;

Narcotic and non-narcotic anesthetics such as codeine, levorphanol, morphine, proxifene, pentazocine and the like;

Analgesic and antipyretic agents such as aspirin, phenacetin, salicylamide and the like:

Anti-inflammatory agents such as hydrocortisone, dexamethasone, prednisolone, indomethacin, phenylbutazone and the like;

Antipasmodic / anticholergic agents such as atropine, papaverine, propantheline, zidyclomine, clindinium and the like;

Antihistamine / antiallergic agents such as diphenhydramine, chlorpheniramine, tripelennarine, bromophenamine and the like;

Anti-swelling agents such as phenyl ephedrine, pseudoephedrine and the like;

Diuretics such as chlorothiazide, hydrochlorothiazide, flumethiazide, triamterene, spironolactone and the like;

Nutrients such as vitamins, essential amino acids for humans and the like;

Agents used in the treatment of Parkinson's disease, such as L-DOPA alone and in combination with enhancers, such as 1 N-DL-seryl-N- (2,3,4-trihydroxybenzyl) hydrazinex; 69243

Androgenic steroids such as methyltestosterone and fluoxymesterone;

Progestational agents such as progesterone, etisterone, noretodelrel, norethindrone, medroxyprogesterone and the like;

Estrogens such as estrone, ethinyl estradiol, diethylstilbestrol and the like;

Hormone preparations such as prostaglandins, ACTH and the like;

Antibiotic / anti-inflammatory agents such as penicillins, cephalosporins, tetracycline, chlortetracycline, streptomycin, erythromycin, sulfonamides such as sulfoxazole, sulfadimethoxine, sulfamethoxazole and the like such as nitrofurazone and the like;

Cardiovascular agents such as nitroglycerin, pentaerythritol tetranitrate, isosorbide dinitrate, digitalis preparations such as digoxin and the like;

Antacids / antiflatulents such as aluminum hydroxide, magnesium carbonate, simethicone and the like;

Other therapeutic agents and / or combinations of agents that are considered therapeutically useful in medicine.

The active ingredients used in the present invention may be in free form or in a non-toxic, pharmaceutically acceptable form, thereby delaying their therapeutic effect. For example, the acidic substances may be in the form of esters or salts with pharmaceutically acceptable inorganic bases, such as sodium salt, potassium salt or the like, or with organic bases, such as amines or in quaternary forms. Basic substances can be used as salts of organic acids such as acetates, tartrates and the like. Certain substances, such as ampicillin, may be in the form of their hydrates. In general, any pharmaceutically equivalent form of a particular active agent known to be used in the preparation of pharmaceutical compositions using said agent is useful in the dosage forms of the present invention, limited only by natural incompatibility with the tape material. In the few cases where such a 53 69243 incompatibility occurs, it can be easily detected by a simple experiment.

The amount of active agent or combination of agents to be added to the novel dosage forms of the invention is usually that amount which is known to be a therapeutically effective amount of the particular drug. In general, the amount in a single dosage form should not exceed 500 mg, with a practical upper limit of about 750 mg.

As mentioned above, the release rate of the novel dosage forms of the present invention is very constant and can also be adjusted as desired. Thus, with any form of release, the release rate of the dosage forms of the present invention is consistent with this formulation, and is significantly better than that achievable with current conventional solid dosage forms, e.g., tablets and capsules.

Figure 7 shows graphically the release rate of the dosage forms of the invention compared to conventional solid oral dosage forms, i. commercial tablets. In the experiment shown in Figure 7, six randomly selected conventional capsules, each containing an equal amount of the same active agent, were each transferred to 100 milliliters of artificial digestive fluid U.S.P. (without enzyme). The liquid was kept under stirring at 37 ° C. The liquid in each reaction vessel was continuously filtered and circulated through the flow cells in a suitable spectrophotometer.

The adsorbence of the liquids was measured every one minute and the percentage of dissolved active substance was calculated for each measurement. Figure 7 shows the fastest and slowest dissolving sample from each group, with the other samples hitting the shaded area between them. Looking at Figure 7, two conclusions can be easily drawn.

First, the novel dosage forms of the present invention dissolve significantly faster than conventional capsules tested. Second, the variation between the six dosage units of the present invention was significantly less than between the conventional capsules tested. These results clearly demonstrate the superior uniformity of release characteristic of the novel dosage forms of the present invention.

The blood level curves shown in Figure 8 also compare the novel dosage forms of the present invention with commercially available capsules containing the same amount of active ingredient. Blood level curves have been plotted theoretically based on two feed rates in a one-compartment pharmacokinetic model. Blood level curves are based on a theoretical 100% absorption of the active ingredient released from the dosage form at a given time point and are thus proportional to the rate of dissolution. The difference in blood level curves is thus a function of dissolution rates. It is clear from the curves shown in Figure 8 that the new dosage forms according to the invention not only achieve an effective level in the blood much faster but also achieve higher levels of the active ingredient in the blood than with conventional capsules. The ability to form a higher level of active ingredient in the blood is a clear advantage, especially when administering certain types of chemotherapeutic agents, for example, antibiotics, cardiac active agents, and the like.

Claims (9)

55 69243 A process for the preparation of solid pharmaceutical unit dosage forms, wherein one or more drugs are applied to a therapeutically inert edible carrier material in the form of a strip, and the carrier material is shaped into the desired geometric shape in which the active drug substance is substantially contained therein. as a continuous process, a continuous layer of active compound is applied, several strips thus obtained are combined into a multilayer form, this multilayer form is divided into several unit dosage forms, and the unit dosage forms are sealed so that the drug is completely contained therein. A method according to claim 1, characterized in that it comprises cutting the coated strip transversely to obtain substantially contiguous portions of the coated strip, each of which can be divided into a plurality of unit dosage forms, corrugating each strip portion to form a loosely wound coil, loose winding to form a substantially solid rod and cutting the rod transversely to form a plurality of unit dosage forms. A method according to claim 1, characterized in that a strip is used, the composition of which allows sealing with water and that the rods are closed by contacting the windings with a sufficient amount of water as a fine jet to moisten them and then drying the rods. Method according to Claim 3, characterized in that the wetting with water is limited to the point on the surface of the rod where sealing is desired. A method according to claim 1, characterized in that a stack is formed of strips to which at least one drug has been applied, the stack is cut to divide it into unit dosage forms and simultaneously heat and pressure are applied during the cutting step to close the edges of the unit doses. 56 69243 A method according to claim 5, characterized in that the stack of strips comprises at least two strips of strip consisting of a heat-sealable polymeric composition containing an organic film-forming agent and a plasticizer therefor and at least one layer of paper composition consisting of one or more fibrous materials and at least one non-fibrous modifier therefor, the top and bottom layers of the stack being a polymeric material, provided that no more than six strips of paper composition are interposed between each pair of strips of polymeric composition in the stack and that the heat and pressure to close the edges of the strip of paper composition. A method according to claim 1, characterized in that a continuous stack of several strip layers is formed and pressure is applied to the stack to seal and shape it into a continuous rod-like first geometric shape, the geometric shape is divided into several unit dosage forms and the unit dosage forms are completely enclosed. A method according to claim 7, characterized in that the continuous stack of several strip layers is produced by laminating a plurality of strips arranged so that the upper and lower surfaces are free of drug. A method according to claim 1, characterized in that it comprises folding a continuous strip structure consisting of at least one pair of strip layers on the outer surfaces of which a drug has been applied into a fan and applying pressure to the stack to seal and shape it into a continuous rod-like geometric shape. 69243 57