NO146384B - PROCEDURE FOR THE PREPARATION OF NEW PHARMACEUTICAL DOSAGE FORMS - Google Patents

Description

Until now, those in the pharmaceutical industry knew orally

administered solid unit dosage forms can generally be divided into two main groups, i.e. tablets and capsules.

There are different broad categories of both tablets and

capsules within the subject area such as e.g. those that are coated for the intestine to release the drug in the digestive tract, those that release drugs with different mechanisms over an extended period of time, e.g. effervescent agents, such conventional solid oral dosage forms suffer from a number of disadvantages.

First, conventional solid oral unit dosage forms are disadvantageous in that each contains, mixed with the active ingredient, several different substances called "therapeutically inert or non-toxic pharmaceutical excipients".

Such materials fall under professionally known categories

of diluents, excipients, binders, lubricants, explosives, stabilizers, buffers and preservatives.

Although these materials are known as indispensable

in the pharmaceutical formulation, their use nevertheless poses problems that must be considered from a cost-

point of view, final dimensions and weight of the dosage unit.

In addition, each such filling material must be assessed for

its use with regard to potential incompatibilities with the available drugs. Furthermore, certain of these materials,

e.g. lubricants, cause problems with regard to the bioavailability of the active ingredient. In addition, the presence of such materials must be taken into account in the analytical procedure used to determine the strength etc. of the finished dosage form.

Another primary disadvantage of solid oral unit dosage forms which are known is that the available methods for determinations thereof involve destruction of the dosage form which will only allow the determination of a small proportion of such real progress;

stilted forms. Therefore, it is well known that it can be considerable

deviations within a given batch of such dosage forms as the average dosage, behavior etc. for each batch deviation is determined by analyzes of a relatively small number of samples.

?a.tsv.i.s primarily in 11 ina in sea itself is a disadvantage at tidliapre> known fixed dosage forms from a simple economic point of view due to the rate-wise execution, control and provisions.

According to the present invention, solid dosage units are provided, primarily for oral administration, which can be produced in large numbers at high speeds

by a method that is new in the pharmaceutical industry. Furthermore, they do not suffer from the above-mentioned disadvantages that commonly available solid oral dosage forms, i.e. tablets and capsules, have. This method is very advantageous in that it: eliminates the need for batch equipment which is traditionally recognized to provide continuous ongoing analyzes of the potency as well as ongoing functional assessments of the dosage forms as they are manufactured;

substantially eliminates the need to mix conventional pharmaceutical fillers with the drugs with the exception of lubricants that may be necessary to facilitate powder flow and/or certain other materials beneficial to product performance; and provides pharmaceutically elegant unit dosage forms which can be manufactured as slow-release drugs at the desired rate and which can have a faster release rate than the commercial tablets and capsules now available. In summary gives

dosage forms produced according to the invention guarantees that a greater proportion of a more precisely measured amount of medication will be available at a more precisely controlled time after intake, as is the case with the current commercial units.

The oral unit dosage forms produced according to the present invention are advantageous in several different important ways, primarily in that it is suitable for direct coupled process, under high speed, mainly automated manufacturing operations. In addition, the dosage forms produced by the present invention are also advantageous in that the inherent drug is released for absorption with exceptional uniformity over a large number of dosage units. Furthermore, the dosage units produced according to the invention can be controlled to release medication within a shorter time after administration than is possible with fixed oral dosage forms, i.e. tablets and capsules which are now available. Therefore, the dosage units produced according to the invention provide better consistency both in the content of drugs and in the delivery thereof for absorption.

When considering the state of the art, the following publications are considered, which relate to solid dosage forms and differ remarkably from conventional tablets.

In the U.S. Patent 3,444858 of May 20, 1969 Russell describes a solution for oral administration of drugs consisting of a strip of gelatinous material containing drug where this strip is divided into parts, each of which is connected to the next by easily tearable bands. During use, the tip is simply separated from the strip and placed in the mouth.

Another publication worth mentioning is an article in

New England Journal of Medicine, Volume 289, No. 10 pages

533-5 (1973). This article describes a device by which birth control medication is made possible for women in the People's Republic of China on a very large scale. In this method, a sheet of colored, water-soluble carboxymethylcellulose paper is treated with a solution of progestational and estrogenic material.

The foil is then perforated and cut into strips. The preparation is prepackaged as a strip of 22 "squares" that are torn from the strip and taken daily. This method does not provide protection for drugs in the finished dosage form and therefore suffers from the disadvantages of possible contamination and/or inactivation of drugs as soon as the package is opened. As they are also not completely uniform, such perforated strips can cause uneven tearing by perforations and potentially varying dosage.

• Finally, rna is taken into account. Higuchi et al. U.S. Patent 3,625,214 of December 7. 1971 which describes a dosage form used for controlled, i.e. sustained release

of medication. In principle, the dosage form consists of a drug containing a matrix that is placed on a substrate 'which is then rolled up' into a final "roulade". After administration, drugs are released by gradual erosion of the outer layers • of the substrate and also by diffusion from the sides where the drug is exposed. There is no mention of whether the included dosage forms can be used for high-capacity pharmaceutical production. There is also no statement as to whether they include the dosage forms that can be converted into products with a pharmaceutical elegant finish.

In clear contrast to what appears from the aforementioned publications, the new solid dosage forms are produced according to

present invention completely uniform/suitable for

non-destructive continuous analytical measurements during pharmaceutical manufacturing operations with high capacity mainly free of pharmaceutical filler materials that can interfere with effect, has no exposed drug and has a better consistency for dispensing drug that increases its effectiveness.

The present invention relates to a method for the production of solid pharmaceutical unit dosage forms, during which one or more drugs are applied to a therapeutically inert edible band-shaped carrier material, and the carrier material is processed into a geometric shape of predetermined appearance in which the drug is essentially placed inside by applying a continuous active substance layer to it strip-shaped carrier material in continuous work operations, several strips thus obtained are processed into a form with several layers, which form with several layers is divided into several unit dosage forms and the unit dosage forms are closed so that the drug is arranged completely inside, and during which a non-destructive test, respectively. control of the products obtained in the individual process steps is carried out during production. The unit dosage forms are produced by pharmaceutical production techniques with high capacity which in certain cases use new equipment. The manufacturing process includes repeated non-destructive measurements of the dosage forms to determine the amount of drug to which the fabric is loaded prior to fabrication to thereby determine the strength of the finished dosage unit with physical parameters. pp

The present invention relates to a method for producing solid unit dosage forms primarily for oral intake which are advantageous in many ways compared to previously known solid oral dosage forms, i.e. tablets and capsules. Firstly, the fact that the dosage units manufactured according to the invention are essentially free of conventional pharmaceutical filler materials results in cost savings of raw materials and manufacturing procedure as well as the elimination of potential disadvantages caused by the presence of such materials. A distinction must be made here between the band-shaped material which can be considered as supplementary materials, and materials such as fillers, binders etc. which is mixed with drugs in conventional fixed dosage forms.

In the method according to the invention, the fixed unit do-. sering forms continuously and subjected to constant, non-destructive analytical procedure. This eliminates the need for batch production as it is known today, and a considerable financial saving is achieved and a significantly improved level of quality control with regard to the finished dosage units. The fact that the manufacturing operation, according to the invention, includes devices for "feedback" information from a sample -station to the manufacturing procedures immediately preceding thus gives

constant corrections and adjustments.

Such devices facilitate withdrawal of only a small number of dosage units from any number which may be termed a manufacturing quantity, ie from a positive reading immediately preceding a negative reading to the next following positive reading. Designation and withdrawal of such small quantities of dosage forms thus avoids "poisoning the barrel" and constitutes both a great economic advantage over current pharmaceutical manufacturing processes and a better level of quality control, particularly with regard to the content of active "ingredients" in the finished dosage forms. In normal operation, the dosage form according to the invention is produced by time quantum procedure, i.e. the "quantum" of dosage forms consists of the number produced between two given points in time. This idea is believed to be unprecedented in the pharmaceutical industry. However, it should be noted that some destructive tests are required in any pharmaceutical production method as a control of the effect of the finished product. However, such tests are required to a much lesser extent in the methods according to the present invention than in conventional production methods. More important, however, is the fact that such destructive procedures, i.e. impact measurement.

is carried out continuously with "feed-back" information that constitutes the above-mentioned advantages with regard to non-destructive methods.

Thirdly, solid oral dosage units produced according to the present invention are unique in that they differ from conventional tablets and capsules in appearance, shape, texture, etc. and therefore it is an advantage that they are easy to identify. Moreover, the continuous, non-destructive testing procedures and continuous manufacturing operations of the present invention facilitate packaging of unit dosage forms

continuously in individual containers such as, for example, clear plastic strips of pos. packaging and thereby save costs for processing and equipment..

Fourthly, the accuracy in the production of solid dosage forms according to the present invention, i.e.

the evenness of the deposition of the drug on the cloth and precision in the shaping of the final units, combined with the desirable characteristics of the cloth itself enable the final dosage forms to easily accommodate stringent specifications for size, shape and release of drug.

The dosage forms produced according to the invention also possess excellent stability and can be used on drugs which are known to be adversely affected by moisture. Because in certain embodiments of the present invention, drugs are deposited or placed on the cloth by electrostatic deposition which provides an almost total freedom from moisture which may cause an adverse reaction to take place. Also where dosage forms produced according to the present invention are produced from a

laminate of sheets of cloth Drugs that are known in the pharmaceutical field to be chemically incompatible can be deposited on different foils of cloth. This effectively stabilizes such combination without the necessity of resorting to such economically unappealing measures as coating one or more of such incompatible substances with an insulating material, adding stabilizing supplemental materials to such drugs, incorporating such drugs into separate tablet layers which are then pressed together .

Due to one or both of these methods, i.e. placing a drug on a cloth electrostatically as a dry powder and placing potential incompatible drugs alternately between foils of a laminate, the dosage forms produced according to the invention are advantageously applicable in the administration of effervescent formulations.

The solid oral dosage forms produced according to the present invention are further unique in that the contained drug is completely enclosed within the dosage form at the same time that in most cases the feraine duserinyofonr is applied. ir.tet cover.

This represents a further economic problem

for the dosage forms prepared by the present invention compared to conventional tablets which must be coated to provide

containment of the drug.

The dosage forms produced according to the present invention are primarily intended for oral administration. However, dosage forms suitable for rectal and/or vaginal administration can also be prepared.

Experiments have shown that rectal and vaginal introduction of fasting

dosage forms produced according to the invention have essentially not caused any local irritation.

As mentioned above, the new dosage units produced according to the invention can be formulated or "controlled" to any desired release pattern that includes continuous release. Regardless of release patterns, the dosage units produced according to the invention are characterized by an exceptional release uniformity over a large number of dosage units, e.g. ten thousand or more. Variation in the release rate can be achieved according to the present invention by manipulating a number of factors such as e.g. the thickness of the fabric, the composition of the fabric, the presence of an overcoat or outer seal on the 'fabricated fabric', and how tightly the fabric is manufactured.

For example, a tablecloth. with a high content of sodium carboxymethylcellulose is normally broken down slowly in digestive fluids. Dosage forms that are produced from such cloths by fan-folding, which will be described hereafter, will open or unfold upon contact with digestive fluid and thereby release the drug that is on the inner surfaces of these, very quickly, in fact faster than conventional tablets and capsules that are currently available. If, however, such a fan-folded dosage form were to be sealed on the fold edges with a substance such as e.g. ethyl cellulose, cellulose acetate phthalate or 'zein which would prevent the opening of these in digestive fluids, the drug would become available by gradual erosion of the cloth and thereby provide a constant sustained release of the drug. Since the dosage forms produced according to the present invention are capable of releasing drug at a rate greater than currently available solid dosage forms, i.e. tablets and capsules,

such release represents the preferred embodiment

shape,

The attached drawings are summarized as follows:

Fig. 1 is a block diagram of a complete manufacturing

process indicating points for continuous inspection.

Fig. 2 is a diagrammatic representation of a system capable of carrying out the process depicted in Fig. 1. Fig. 3 is a diagrammatic representation of an arrangement for carrying out the envelope folding technique for dosage form fabrication. Figures 4, 4A and Fig. 5 illustrate rotational molding and lamination techniques for dosage form fabrication.

Figures 6A-6D illustrate closing and sealing

the aspects of the fanfold technique of dosage form fabrication.

Figures 7 and 8 are graphical representations of the

the patterns for active ingredient from the dosage forms according to the invention in comparison with conventional solids

dosage forms, i.e. a capsule.

The cloths that can be used for the application of medication according to the present invention must fulfill a large differentiated number of physical and chemical criteria in order to be used in practice according to the invention. These criteria can be briefly summarized as follows: The cloth must be non-toxic, edible and especially not give any objectionable "feelings" in the mouth. In addition, the cloth must be "destructible preferably by itself or broken down in body fluids and/or enzymes. However, the cloth may be of a non-destructible substance which is readily excreted by the body. The cloth is preferably hydrophilic and falls apart easily

in water. These properties must not be adversely affected and preferably not changed by the pH of the digestion fluids.

The cloth must be completely inert to drugs such as

is placed on this and must not release any substance upon dissolution with digestive fluids which would cause an in situ incompatibility with said drugs.

The cloth must be stable over a long period of time and at high temperatures and relative humidity and generally be a poor medium for the growth of microorganisms.

The cloth must have sufficient strength properties so that the powdered drug (which usually has dielectric properties) can be deposited on it by electrostatic deposition. The cloth must have acceptable processing capabilities and mechanical properties, i.e. it must have sufficient elasticity to be pulled thrown into a thin foil, i.e.

from 0.025 mm to 0.25 mm thickness, it must have good tensile strength and tear strength and it must have the necessary folding strength where needed to withstand certain of the fabrication methods that will be described later.

The cloth surface must make the types of continuous analytical methods described hereafter easy, be able to

beleqces with nulverized drug electrostatically or in some other way oq keep the drug suitable for application.

The cloth must be easily sealable with liquids and/or heat-sealing methods that are already known. The seal must, however, be effective at degrees of humidity and heat which do not adversely affect the drugs present in the dosage forms. In addition, the cloth must have acceptable flammability in order to withstand such sealing operations.

In certain cases, the cloth must possess "memory", i.e. must

have sufficient elasticity so that upon contact with digestive fluids it will very quickly reverse the manufacturing process and "open" and thus release medication for absorption. By "opening" it is meant that, for example, if the dosage form is produced by fan folding, it will open like a bellows, if it is manufactured by rolling up, it will be rolled out.

The cloth must possess other properties such as e.g. having acceptable taste and smell which will be obvious to a person skilled in the art.

As mentioned above, the cloth used in the present invention is preferably water-soluble or water-dispersible. There are two basic mechanisms by which the cloths are used. formulated to self-destruct in contact with water. or digestive fluids. Firstly, the cloth may contain particles of substance such as e.g. casein and gelatin which swells on contact with water, causing the cloth to tear or break. Secondly, the fabric formulation can contain both water-soluble and insoluble components. On contact with water, the soluble components in such a formulation will tend to go into solution and the insoluble components to precipitate, thereby causing the cloth to burst. The latter decomposing agents for the cloth are not as fast as the first-mentioned. Examples of suitable water-soluble ingredients include methylcellulose. Examples of suitable water-insoluble components include ethyl cellulose.

Cloth formulations used by the developer to produce the new dosage forms according to the present invention are of two basic types, i.e. polymers and paper.

The polymeric formulation generally consists of:

a) one or more organic film formers.

b) one or more plasticizers.

c) modifiers, i.e. other ingredients which are optional in certain formulations such as

disintegrants and fillers.

d) one or more volatile solvents.

The paper formulation generally consists of:

a) one or more fiber materials

b) one or more non-fibrosis modifiers, i.e. other ingredients optional" via certain formulations,

eg one or more organic film formers, disintegrants and other fillers.

c) a volatile solvent.

The film-forming compound in the polymeric cloths used in

the present invention consists of one or a mixture of known, non-toxic, organic film formers such as e.g. naturally and chemically modified starches and dextrins, proteins such as gelatin; cellulose derivatives such as sodium carboxymethylcellulose, hydroxypropylmethylcellulose and hydroxyethylcellulose,

other polysaccharides such as pectin, acacia, xanthine gum, guar gum and algin, synthetic as

polyvinylpyrrolidone 097 polyvinyl alcohol • Preferred film formers are hydroxypropyl cellulose and sodium carboxymethyl cellulose. Although the concentration of the film-forming component in the polymeric cloth is not particularly critical *red the method according to the invention, it has been found that between 5% by weight and 95% by weight is preferable with a concentration of from around 40% by weight to 90% by weight % as the most preferred.

The above-mentioned film-forming substances are likewise illustrative of the film-forming component in paper cloth formulation whenever such are present. The preferred film formers in the paper cloth formulations are likewise hydroxypropyl cellulose and sodium carboxymethyl cellulose. The concentration of the film-forming component in the paper cloth formulations is also not considered to be critical. However, when such a component is present to act as a binder or disintegrant for fiber material%, it should not exceed about 40% by weight, preferably at 2% by weight to 20% by weight and preferably from around 4% by weight to 10% by weight -%.

The fiber component in the paper towel formulations

can be any of the commercially available natural or artificial fibers which have been shown to be non-toxic in suitable tests. Examples of such fibers include cotton, linen, cellulose, synthetically modified cellulose, rayon, textured vegetable protein, °9 collagen.

In order to ensure the desired functional duration and mechanical properties, the polymer cloths used contain in practice

an effective amount of a plasticizing ingredient. Such a component may comprise one or more types of the plasticizing group known in the field of pharmaceutical formulation such as e.g. glycerol, polysorbates, e.g. polysorbate 80, polysorbate 60-certain mixtures of mixed mono- and di-glycerides of saturated fatty acids.

It is preferred that such plasticizers can be present in an amount ranging from 1% by weight

to 60% by weight, preferably from 10% to 50% by weight of the fabric.

Both polymer <of>T paper towels may contain one or more disintegrants which are known to be common in the area of disposable paper such as different types of starch serf casein.o<g >gelatin . The cloth will

contains from 0% by weight to 40% by weight, preferably from 5% by weight to 20% by weight of disintegration mioas depending on the fabric formulation.

Furthermore, both types of cloth formulations may contain one or more fillers which can be considered common in the area. Such components include e.g. opaque fillers such as titanium dioxide, chalk, kaolin etc., microcrystalline cellulose, calcium carbonate etc. It should be noted that some of the ingredients mentioned here can work in more than one way, and therefore fall under one of the categories mentioned above. E.g. calcium carbonate can function both as a filler Qg dispersant, certain starches can function as a binder and as a disintegrating agent etc.

In addition, both the polymer and the paper formulations may contain one or more modifying components that affect the electrical, mechanical, optical or permeability properties of the cloths produced from them. Examples of such components would include an electrolyte such as sodium chloride, potassium chloride, etc., surfactants such as dioctyl, sodium sulfosuccinate, etc. The cloth may also contain any components such as pharmaceutically acceptable color reagents, preservatives etc.

Finally, both types of cloth formulations will in most cases contain a volatile solvent, e.g. water, certain organic solvents, e.g. ethyl alcohol or combinations of such solvents, i.e. a hydroalcoholic mixture which is removed during the formulation of the cloth.

Specific examples of polymers including those

f <J let end:

Polymeric films that fall apart in an aqueous environment due to the presence of swelling reagents.

All formulations I-IV are sealable upon application

of heat and pressure. Formulation IV self-destructs in an aqueous environment due to the presence of insoluble polymeric constituents.

Preferred paper formulations include

from 70% by weight to 99% by weight, preferably from 90% by weight to 96% by weight of fiber, i.e. harder or bare wood fibers or mixtures thereof, from 1% by weight to 30% by weight, preferably from 4% by weight to 10% by weight of a disintegrating agent selected from the group consisting of

sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, polyphenylpyrrolidone and guar gum and from

0% by weight to 5% by weight, preferably from 0.% by weight

to 2% by weight of a surfactant such as e.g. poly-

sorbate 80, dioctyl-sodium~sulfosuccinate, sodium-iauryl-sul-

barrel etc., the ability of the above-mentioned substances to function as disintegrants in paper formulations is considered to be surprising

considering that where members of this group are used in paper production, they are present in different quantities and have a different function. Where e.g. sodium carboxymethylcellulose has so far been used in papermaking

ing, it is used in small quantities, i.e. 0.1% by weight or less as a dispersion aid for the fibers when the paper is formed.

In clear contrast, it has been found that when sodium carboxymethyl cellulose or other substances as mentioned above, to-

put in large quantities, i.e. up to 30% by weight > after paper

the cock is formed, but while still wet, will act as disintegrants. The addition time for these substances is critical for their function as disintegration agents. These disintegrants are added as a solution and preferably in

the solvent san used vea £re..stiliiiiy a» the paper tap. ^ ^ found that the above-mentioned disintegrants, when added to the web as described herein, coat the fibers. When the final dosage form is brought into contact with water, the disintegrants swell and thus force the fibers to break the web.

When surface-active agents are present, these serve to

increase the water permeability to disintegrants and thus cause tearing.

The cloths used are formed by progressing

way that is conventional in the field, e.g. the papermaking and filmmaking industries. E.g. the polymeric cloths can be sanded on a suitable substrate, e.g. "rVlar" (polyethylene terephthalate) stainless steel, standard paper etc. The cloths are then dried, e.g. in an air-flow oven. The temperature of the drying air and the length of the drying time depend on the nature of the solvent used,

as is well known. However, most of the cloths covered herein are dried at a temperature between 25° and 105°, preferably between 60° and 90°C.

Another method of forming polymeric webs that is conventional in the art is extrusion. This method is preferred for cloths in which the film-forming component is a modified food starch, hydroxypropyl cellulose or other extrudable polymer. The mechanical features of the extruding process, e.g. the particular equipment used, the extrusion force, shape and temperature in the extruder's opening are considered to be well known in the field and can be varied in a known manner to achieve the physical characteristics of the cloth to be described in the following.

The paper towels are made from wood

to use conventional papermaking machinery such as e.g. Fourdrinier papermaking machines. In all cases, however, the cloth must be uniform in both thickness and width. The cloths are between 0.03 mm to 0.3 mm, preferably from 0.038 mm to 0.123 mm thick. A common width for such tablecloths is 30 cm, although the width of the tablecloth is not particularly critical*

The cloth can be produced in any length. Based on the fact, however, that the new dosage forms produced according to the invention are eminently suitable for production at high speed, the cloths should be produced in large quantities, i.e. 4500 m or more, which can be stored, e.g. on cores or coils.

Reference is made to fig. 1, where the complete process system for the production of different types of dosage forms, which are described herein in large numbers, is shown in block diagram form. Block 10 in fig. 1 represents fabric production from formulations as previously discussed. When the canvas forward- . placed, or shortly thereafter, it undergoes an inspection step (Block 11 in Fig. 1) where various examinations, which may be fully or partially automated, are carried out to ensure the integrity of the cloth, as will be described in more detail below. It should be noted, however, that the inspection of the cloth may take place when the cloth is formed or at any convenient point thereafter, either by means associated with the apparatus which produces the cloth or by other apparatus, and may in fact be carried out elsewhere.

The active ingredient to be placed on the cloth is prepared and stored for use in container devices as is generally illustrated at 22 fig. 2, where the figure illustrates, mainly in schematic form, the various apparatus intended for carrying out the step indicated in fig.l.

The prepared active ingredient is brought to a device generally indicated by 23 fig. 2, where the particle size reduction of the active ingredient and the control indicated at step 12 in FIG. 1 is performed. Although this step will be discussed in more detail later, it is intended via this step 13 and the listed apparatus 23 to provide a uniformity in the flow to enable accurate and uniform placement (Block 14 Fig. 1) of the active ingredient on the cloth, which is illustrated at 24 in fig. 2. It should be noted that the system example shown in fig. 2 carries out the deposition of dry particulate material on the track in a dry state. However, it should be clear that the scope of this invention also includes wet deposition of active ingredient on the track. Fig. 2 also schematically illustrates at 21 the embodiment of the invention in which the web is produced and stored for later use, i.e. the lane inspection step (step 11 in Fig. 1) is carried out, e.g. when the web is removed from the storage roll 20. It is obvious that the inspection can be carried out before the web is recovered and stored, as well as or in addition be carried out where and as indicated in fig. 2 at 21. The special features of the lane inspection are described in more detail below.

On closer consideration of the inspection device 21, the inspection of the unpaved track is carried out by different methods. Holes, blisters and lack of physical cohesion in the fabric can be detected and determined using controlling laser beams and photo detector combination. The system can be used in both transmission and reflection modes. The continuous helium-neon-las<e>rstr<ålen> Kau is fed through the track by a mirror on a galvanometer. The mirror position is controlled electronically so that the position of each defect on the track can be located.

The reflected or transmitted light is detected by a linear photodiode located behind an interference filter to exclude room light (stray light).

The electrical result is used to count the number of de-

fences and determine their size and distribution along the length of the track. This is achieved by analyzing the detector-result signal with a pulse height-width analyser.,

An alternative method capable of inspecting the track at considerably higher track speeds is a parallel arrangement of photodiodes placed across the track. Each photodiode has its own input detector system, and digital unit that enables a low-resolution defect size and position-location unit character is included. The signal result can be developed to give an approximate size distribution and location of the defects on the track.

The physical thickness of the track is measured by a parallel arrangement of track riders mounted in precision carriers. These rollers are in contact with the track, and are connected to transducers. which electronically observes the nosition at at least 1/4000 cm. A similar system of physical thickness can be formed by.pneumat-

ice sensors that hover over the track on a fixed air film.

This system has the advantage that it is not in contact with

the track.

Mass thickness (weight per unit area) or basis weight of the webs - is determined using a non-contacting beta beam or X-ray meter. These systems measure absorb-

tion of beta rays or x-rays passing ,

through the track. This absorption is dependent on the mass density. In an alternative system, the electrical counter-

stand between two contacting track rider electrodes are used to determine the basis weight of tracks of known moisture content...

"On-line" analysis of the moisture content can be measured by one or more of the following methods. First, the high dielectric constant of water allows a sensitive moisture determination by direct microwave absorption and radio frequency dielectric constant sensors. Low-frequency conductivity measurements can also be carried out to measure the degree of moisture in the fabric. Infrared spectrophotometric absorption.

provides a completely independent moisture measurement method. Furthermore, the optical absorption at wavelengths in the region 1 to 2 µm will provide a specific and accurate moisture determination in a spectral range in which the inspected web is relatively transparent.

The web which has passed the inspection device 21 is guided by a suitable roller arrangement which is shown in fig. 2, so that it is fed in the immediate vicinity of the active ingredient deposition apparatus 24, in which active ingredient is placed on the web. The deposition apparatus is immediately followed by device 25 which is schematically shown for "on-line" analysis/inspection, e.g. for uniform content of active ingredient, of the coated web, preferably as a single foil, before the active ingredient has been introduced.

A preferred method for non-destructive "on-line" analysis of active ingredient applied to webs is X-ray absorption. In this method, low-energy X-rays are directed to match the absorption edge of the atoms in the path, sent through the coated path. The absorption of X-rays depends on active ingredient + path absorption. Where the active ingredient is placed on the web by a wet coating process, this analysis method can be used either before or after the drying step.

Since total X-ray absorption originates from the combination of the web and cover that contains the active ingredient, it is necessary--

it is necessary to determine the absorption of the path separately. This is carried out using a beta-ray meter or an infrared spectrophotometer. Increasing sensitivity is achieved for the X-ray measurement of applied active ingredient containing atoms with increasing atomic number. The X-ray source can be tuned by varying the accelerating voltage to match the absorption edge for several atoms of interest.

Reflection or transmission spectrophotometry can thus be used to non-destructively analyze the applied active ingredient "on-line".

Reflectance spectrophotometry is used in the near ultraviolet range to confirm whether an active ingredient is present. This technique can be used with any solid active ingredient with an optical absorption in a suitable wavelength range.

Transmission spectrophotometry can also be used for non-destructive "on-line" analysis of active ingredient coated on webs. A suitable light source, monochromatic element, and detector combination is selected for wavelength regions where the active ingredient is selectively absorbed. This must be in a spectral region where the path itself does not absorb strongly.

Such orbital regions pre-

located in the near infrared and functional group infrared regions of the spectrum. A fast wavelength survey system is used to sweep over a small wavelength range of interest. The signal from the detector is time equalized -^ver several applications to "reduce the noise effects. The signal data

is then processed to give a first-transmission derivative with respect to wavelength for increased sensitivity. This is done in a similar way for other wavelength ranges that are sensitive to other components of the system. Thus, water content, basis weight of the web as well as content of active ingredient can be determined simultaneously.

Another method for analysis of active ingredient application

is molecular fluorescence. Radiation in the ultraviolet or visible range of the spectrum is produced by a suitable filter combination. The fluorescence from the active ingredient is recorded by a broad-band filter-detector combination sc<m><p>asserer<t;i->^iuor.essens_t0ppen/ a blocking filter is used to remove excitation potential. For this method, the detector is preferably a photon counter, which counts individual light contributions and provides high sensitivity and linearity

tet at low levels of illumination. With this method of analysis, precautions must be taken to limit <light.>decomposition of the active ingredient during the excitation irradiation.

The overlaid path can be saved for a time or priority

view is sent directly to fabrication devices (step 16

in fig. 1) and divided into dosage units (step 17, fig, 1)

which devices are illustrated in fig. 2 which

a series of knives 26, to cut the coated web into several infinite strips followed by laminating type fabrication and assembly devices 27, i.e. the infinite strips stack one on top of the other to form an end-

loose stack which is pressed and then formed into units according to the invention as described below.

The unit dosage forms are finished and packed

with suitable equipment (step 18 in fig.-l) illustrated diagram-

tic with 28 and 29 in fig. 2 for subsequent distribution. Appropriate inspection (e.g. at 30 in Fig. 2) is carried out in connection with this step. The purpose of the final

The final inspection of individual dosage units is to determine size, shape, integrity, identity, presence and accuracy of printing and content of active ingredient. All this inspection is done in a non-destructive manner, except for the content of active ingredient. In order to analyze active ingredient content and action characteristics, a statistically representative sample of dosage units is taken from the production warehouse and analyzed destructively both with regard to strength

and effect, i.e. dissolution characteristics by dissolution spectroscopy, which will be discussed later.

An optical inspection system can be used to inspect all the production units for size, shape, integrity, identity and presence and accuracy of printing, the system includes a suitable light source and an array of photo detectors or a T.V. camera. A computer is used to process the signals from the optical system. Suitable algorithms are used to determine the tolerability of the dosage units.

Another method uses a comparison of the sample image

with the default image using an image masking technique.

Another method for 100% inspection used an optical transformation of the image of the dosing unit.

The Fourier transform spectrum, energy spectrum or other suitable transformations are compared with a similar transformation of a standard using a computer.

For the final step, (step 19 fig. 1) 'on-line' analysis for resolution and uniformity of content can be carried out by suitably placed apparatus which is not particularly illustrated, where the apparatus can comprise and/or be controlled by computer or similar central processing or logical devices. A systematic sampling mechanism removes one dosage unit at a time from the end of .production." joint with a speed of 25-125 units per minute, preferably at a rate of 40-60 units per minute. Each unit is subsequently transferred to a conventional automatic weighing device where it is weighed by non-destructive devices, and the information is stored. Systematically selected units are then placed in sequence in a conventional automatic analyzer system. The dosage unit is stirred in a suitable solvent for the active ingredient at an appropriate speed. The amount of active ingredient dissolved at tj minus the amount dissolved at t^ divided by tj-^ is considered the dissolution rate. The appropriate time interval (t^-t^) is preselected and. will vary with individual medications. A suitable time interval can be from 5 seconds to 2 minutes or more. The sample is then continuously stirred for a sufficient time for all the active ingredient to dissolve, after which the solution is analyzed with regard to the content of active ingredient. The amount of active ingredient in this analysis plus the amounts from samples t^ and t are the total present in the dosage form. This information is also recorded and stored. If weight, thickness, dissolution rate and analysis of drug content fall within the previously defined limits, the units are judged to be acceptable. If the reading does not fall within these limits, the units produced from the beginning of the negative assays and the end of the next positive assay are withdrawn for further investigation.

It must be noted in connection with fig. 1 that further measures are carried out for controlling functions sam to be carried out according to this invention aaa to be described later. With regard to the lane inspection step, there is e.g. planned that continuous management inspection of the web is carried out with regard to the web's colour, thickness, continuity, stains and defects of any type. These functions can be taken care of by electronic and/or optical instruments as well as by visual observation.

The inspection of the track includes the actual placement of a "flaqg" (ie a marker) now the track where a fault or defect is detected.

In addition, the equipment can be equipped so that at any time

a defect is detected in the path, a signal is generated, either automatically or during operational control, indicating that

on the path^n some distance downstream exists a defect of

one or another type where the signal will include an identification of the type of defect such as a hole, spot, blister etc.

The device for generating the signal can be the same device that actually marks the path itself. Such apparatus^ is considered e.g. as conventional in substance-manufacturing and substance-injection and can be used under the condition that treatment and inspection of the path in the present case will be carried out in accordance with good manufacturing practice for pharmaceuticals.

In addition vi3, • by the same method or additional conventional inspection device the web thickness is measured. This may take the form of a visual representation comprising an operator or may be a detector device connected to a logic arrangement with upper and lower limits for web thickness, and if the thickness of the web exceeds one of the limits, a signal will also be given and a flag placed on the field as described above. A form of apparatus for providing measurement of thickness of the web May take the form of an X-ray or beta-ray apparatus or similar device for measuring the mass thickness of the web.

In the case of step 13 in fig. 1 with regard to particle reduction and flow control, it is intended that the control functions are carried out as described in the following.

In addition to the fact that the uncoated web itself has been checked with regard to defects and thickness, a similar check is carried out according to the invention after application

of active ingredient(s) on the pitch. E.g. X-ray equipment would again be useful for determining the thickness of the applied web, which thickness, in comparison with the previously determined unapplied web thickness, would enable conclusions to be drawn as to the applied amount of active ingredient on the web. In addition, it can be used

mass control agents to determine the amount of active ingredient applied to the web. It must be understood that carrying out the imposed lane inspection can be carried out by passing the imposed lane back through the same apparatus which carries out the lane inspection in connection with step 11 in fig. 1.

The application system for active ingredient (ref. 14 in fig. 1) is controlled by feedback from "on-line" analysis of active ingredient content on the track. E.g. electrical signals from the "on-line" analyzer (digital) or (analog) are used to analyze active ingredient application (weight of active ingredient per unit area of coated web) in a feedbacK mode

(ref. 15 in Fig. 1) to control the amount of active ingredient placed on the web in the application process. These feedback signals are given, for example, to a minicomputer which produces a correct correction signal for the application process. The application signal causes either an increase or a decrease in the application of the active ingredient to keep the application within a narrow range around the intended value. E.g. Now the active ingredient powder is applied to the dry application process. Thus, the correction signal is used to control the supply rate, and consequently the application of this active ingredient.

In the wet application process, the correction signal can be used e.g. to vary the amount of coating formulation applied to the pitch.

E.g. the opening between the spacer rolls or between a spacer knife and the application roller is varied to change the application of active ingredient. Conversely, in roller coating, the rotational speed of the application roller is varied to change the application of active ingredient. Another control system for wet application is by varying the concentration of active ingredient in the ironing wash. Two liquid formulations containing different concentrations of active ingredient are mixed in the desired proportions to give the correct concentration; the ratio between the two formulations can then be varied to precisely control the application of active ingredient. .The methods for "incorporation" of active ingredient in the new dosage forms constitute a

radical step from the methods for incorporating active ingredients into conventional solid dosage forms, i.e.

tablets, capsules, dragees, suppositories^etc. Destiny them

methods and equipment used in the method according to the invention11 may vary somewhat, the dominant, primary purpose is uniform deposition, i.e. to deposit active ingredient on the moving track surfaces in an exceptionally smooth manner. There are many methods of applying the active ingredient according to the present invention

advantages over the usual production methods used in the pharmaceutical industry.

Considering that the active ingredient is placed on or alternatively on the surface of an edible web which is then shaped to completely incorporate it, there is no need for common pharmaceutical excipients, fillers, preservatives, etc. which is mixed with the active ingredient thereby eliminating a cost, and more importantly, a source of potential intolerance and quality problems. According to the present invention, the web is coated with an even coating of active ingredient and then divided into individual dosage forms by linear or geometric division, which thereby provides a uniform strength of active ingredient over a large number of dosage units, which significantly exceeds the requirements

to..sat forward qanasrnåts which are now accepted in the pharmaceutical industry.

In clear contrast, conventional pharmaceutical manufacturing operations require that the active ingredients, and suitable therapeutic inert pharmaceutical excipients be manufactured in a large quantity, and divided volumetrically for filling into capsules or compression into tablets. By applying the manufacturing methods according to the present invention, it is therefore possible to reduce the amount of excess active ingredient present, to ensure accurate dosage from the currently accepted level, of from 1-5% by weight and thereby effect a significant saving, especially in formulation of very expensive, active substances, e.g. certain hormones and antibiotics. Finally, the method for applying or coating the active ingredient on the track, according to the present invention, allows continuous "on-line" non-destructive examination of the dosage by physical parameters and thereby makes it easier to achieve broad uniformity in terms of the amount of active ingredient over a large number of dosage forms.

The active ingredient can be placed on the track, in either wet or dry form, with the dry form being preferred.

In any case, the active ingredient is placed in a form which enables analysis as will be described later, i.e. in finely divided form. The particle size is in the submicron range, and can therefore be within a narrow size range, from 1 up to 100 jum. Particles in the submicron range have hitherto been considered too fine for the production of pharmaceutical tablets without first being subjected to techniques such as granulation which significantly increase the particle size, and which also lead the excipient material to the active ingredient. The technique according to the invention facilitates the use of such ultrafine particles, without the need to resort to such methods and/or the addition of excipient material. The active ingredient is applied as a very uniform coating to the web where it is moved in an automated manufacturing system.

The preferred method of application of active ingredient

on the track where the active ingredient is in a dry form,

is the electrostatic application of powder dust using techniques well known from certain non-pharmaceutical fields. This method generally requires guiding the path through an electrostatic field in a suitable chamber. Finely distributed active ingredient is introduced into the chamber via, e.g.

an imposed airflow, and is applied to the web as it passes over an oppositely charged roll. Obviously, this is an oversimplification. However, the apparatus required to achieve this result is known in certain non-pharmaceutical

istic fields such as the production of adhesives and adhesive papers. In order for a successful application to take place,

it is obvious that the path must have a strength which enables the attachment of the electric particles to it. Adhesives that may be present in the web formulation to increase the correct electrical properties of this have been discussed previously.

In several cases, it has been found that before electrostatic application of active ingredient powder it is necessary to coat

" the path with a substance that will increase the attachment of the powder to

this. Examples of such substances include carboxymethylcellulose, methylcellulose etc. These party favors

the substances can be applied to the webs in a normal way,

e.g. by adding a solution of a volatile solvent such as water and drying with e.g. heated air. On-

the guiding of a coating on the track to ensure the attachment of the active substance is therefore immediately followed "on-line"

by coating or "charging" the track with active substance.

The adhesive is then activated to bind particles of active

substance to the track. This is done by applying heat,

pressure, humidity or a suitable combination thereof to the coated web. In addition to the electrostatic powder-cloud application method, finely divided active ingredient can be placed on the track in a dry state by electrogas-dynamic powder coating. In this method, particles of active ingredient are electrically charged by being exposed to corona discharges and driven by a gas stream into an electrical iso-

clay chamber.

The web is fed through this chamber on a metal surface which is either grounded or charge<t> with the opposite polarity of the charged particle cloud of active substances. The electric field between these particles and the metal surface attracts them to the track and deposits them on it.

Furthermore, according to the present invention, the active ingredient can be applied to the web in the form of a solution or a suspension of finely divided drug, i.e. a colloidal suspension. The liquid used for these operations can be water, an organic solvent, e.g. ethanol, or aqueous >alcoholic solvent. A preferred method for applying active ingredient in a liquid form to a moving web is electrostatic jet spray deposition. In this method, the active ingredient containing solution or suspension is measured in an apparatus that produces a stream of microdroplets, which are concentrated on a specific area of the web using an electrostatic field of defined area. This method has given very good results where small amounts of active ingredients such as e.g. hormones or enzymes must be introduced. • By small amounts is meant active substance with a usual dosage of less than 1 mg.

In addition to electrostatic jet deposition, certain other coating techniques known in other areas to be useful for coating a substrate with a liquid may be used to apply active ingredient to the web. E.g. paper tap can be passed under a roller which is immersed in a bath of saturating liquid. When the web passes the roller, excess liquid is "wiped" off from the web by another roller, an air stream, a rubber drying edge or a wire-twisted rod, i.e. a wire rod etc. In this case, the solution penetrates to some extent into the web, especially if the solvent used to solubilize or suspend the active ingredient is the same or similar to that used to form the paper tap.

Although it is the purpose of the present invention to deposit the active ingredient on the surface of the web, some penetration into the web may result

either from the use of a volatile liquid carrier for the active ingredient or by the application of heat and/or pressure to the web to seal it. Simple experimentation with these factors, e.g. volatile liquids, will determine the proportion of active substance placed on the web that can be absorbed therein. Once this parameter has been determined, the "on-line" control equipment as described here/ can be adjusted accordingly. Where any significant active substance is absorbed into the web, it is necessary to have an unimposed web, i.e. web without active ingredient for the outer surface of the dosing unit, thus avoiding loss of active ingredient when exposed to damaging factors such as air and moisture. ° .3

As indicated above, one of the obvious advantages of the dosage forms, produced according to the present invention, is that the pharmaceutical active substance can be formulated in a stable dosage form without being mixed with conventional pharmaceutical excipients which are usually present in conventional solid dosage forms, in amounts which far exceeds the amount of active substance. However, it should be understood that small amounts of the aforementioned substances may be necessary to add to the track together with the active substance in accordance with the invention as previously described. Where e.g. the active substance is placed on the track in dry form, a small amount, i.e. from 0% by weight to 10% by weight, preferably from 1/4% by weight to 2% by weight of active substance, of a lubricant is homogeneously mixed with this. The purpose of the lubricant is to facilitate the flow of powdered active substance through the application apparatus. Suitable lubricants include e.g. finely divided silicon preparations such as the colloidal silicon oxide marketed under the trademark "Cap-O-Sil" ~

talc, finely divided starch preparations, e.g. 'bri-Flo"-

It can be assumed that the introduction of a lubricant and the amount thereof will depend on the crystalline structure and flow properties of the active substance. In certain cases, a preservative can be mixed with the active substance. However, where the active substance is applied to the track in dry form, this is usually not necessary. Furthermore, as mentioned above, can

adhesive substances are mixed

with the active substance, when applied in wet form, and where both adhesive and active substance are tolerable together with the same liquid carrier. In certain cases, however, the active substances described above are used, where the active substance is applied to the jan in dry form, in order to increase its attachment to it. In any case, said adhesive substance can be present in from 0% by weight to 100% by weight, preferably from 0% by weight to 30% by weight, based on the weight of said drugs.

The amount of active substance that is carried on the web according to the present invention will vary in accordance with the dosage of said substance, the surface of the web to be applied, the thickness of the coating etc. Further factors affecting the amount of pharmaceutical applied to the track are the application method used, the parameters dictated by the manufacturing process to be described below, and the type and sensitivity of the "on-line" control equipment used. In all cases, however, the amount of active substance applied to the web is such that when the applied web has been prepared and divided into units, each product will contain a therapeutically effective dose thereof. As an example of the latter criteria under which the analysis of the applied unit of the pharmaceutical, is carried out by using spectrophotometry which uses photon counting technique to measure the ultraviolet absorption of the active substance on the web, the thickness of the layer of active substance cannot exceed 0.005 cm . In any case, the amount of active substance applied to the track is always expressed in milligrams or p. per cm path.

This is determined for the entire web surface, although in most cases it is necessary to provide a margin for uncoated web that is to be used to seal the dosage form. The ability of the webs to receive and incorporate active substance is expressed as web conversion factor (WCF) and is calculated by the following formula.

Surface area of track

with finished dosage form

If e.g. the web measuring 15.25 cm x 1.0 cm is exposed to the drug and^manufactured into a dosage form measuring 0.5 cm x 1.0 cm becomes:

The next step in the production of the new dosage forms according to the invention is the forming or manufacturing step. As used herein, the term "manufacturing" indicates reshaping of the web as originally shaped/into a fixed geometric shape of predetermined shape which can be divided into a larger number of unit dosage forms. This step can take place, as is the case in connection with the aforementioned steps, in a continuous manufacturing process at high speed. This step transforms the applied planar web into a shaped geometric shape and generally embeds the active ingredient within a protective layer of web. The formed web is then divided into units and completed by the preparation of pharmaceutical satisfactory unit dosage forms suitable for oral administration. It should be noted that, in a preferred operation, the division into units will occur simultaneously with or immediately after manufacture.

In accordance with the present invention is

there are several different methods of production, among which can be mentioned tube forming by extrusion, forming several ribs by folding over rope. and punch forming. The four main techniques for forming or producing the web coated with active substance are: twist winding, rotary forming, fan folding Qg lamination. These four main techniques are discussed in detail below.

For discussion of the individual manufacturing techniques for the invention in detail, different criteria exist for one

acceptable technique is considered in more detail. The manufacturing or forming technique must be applicable to high-speed manufacturing operations and provide a geometric shape according to exact specifications for uniformity. The process must

be able to completely incorporate the active substance. Finally, the manufacturing or forming process must not place excessive stress on the webs such that they deform or tear and must not remove any significant amount of active substance from the web. All the forming processes discussed below meet these criteria.

The first significant technique to be discussed concerns twist folding of the moving web. It is possibly correct to distinguish between twisted folding and spiral folding, such as e.g. is known in the paper processing industry. In spiral forming, the paper is fed to the spiral folder machine from different rollers where it is usually in rolls that are 1/2 to 2 cm wide. The continuous strips of paper from each roller are rolled around a cylindrical spindle which is provided at one end. The strips are rolled up in such a way that they overlap. An adhesive is applied to each paper strip and the overlapping strips from a continuous spiral as they are twisted around the spindle. The roller thus formed is caused to rotate around the spindle by means of a continuous belt which also forces the roll of paper forward towards the unattached end of the spindle. At the end of the spindle, the thus shaped rudder is cut into the desired lengths by periodic exposure to a knife at high speed. The paper that is reshaped in this way will always have a hole in the middle due to the spindle on which it is shaped. In the twist-folding process there is no spindle and therefore it is not necessary or desirable to have a hole in the center of the shaped rod. It is actually an express purpose of this invention to greatly limit or completely eliminate this hollow center area.

Reference is made to fig. 3 which schematically illustrates an example of twisted folding. In the twisted folding processes in fig. 1 3 the drawn or coated web 61 is passed from a single roller through a system such as, for example. consists of guide wire 62 and roller 63 to sn cutting device 64 which cuts the web crosswise into desired lengths, normally from around 12 to 25 cm in length. The web sections are then fed into a grooved roller arrangement 65 where a grooved roller forms a series fold by pressing the web against a soft rubber roller. As a result of the groove effect, the individual parts of the web are shaped or curled like loosely twisted rolls. The loosely rolled webs coming from the grooved roll arrangement are then passed between a stationary surface and a moving surface where the space between the two surfaces gradually decreases along the movement of the rolled webs. The stationary and moving surfaces can be in the form of two concentric cylinders, one of which is stationary and the other rotates in relation to the stationary cylinder or as shown in fig. 3, they can take the form of a flat fixed plate 67 as a stationary surface and a movable belt 66 as a non-stationary surface. As the section of the web as loosely wound rods passes between the moving and stationary surfaces, they are wound tightly until a solid rod is formed.

By appropriately adjusting the space between the two surfaces, the rod can be rolled tight enough to eliminate every single hole in the middle. However, it should be clear that, if desired, the space can be made such that a hole of the desired size is left in the center of the formed rod.

The rod can be sealed in different ways. First, it has been found that the conventional method of making, e.g. confectionery bars cannot be used in practice with the present invention. In the conventional method, the movable surfaces that come into contact with the web during rod formation are sprayed or coated with water in contact with a large part of the web. The amount of water absorbed by the web, around 18%, is unacceptable for the manufacture of unit dosage forms

because of the possible destructive effect on the adhesion of the drug to the web as well as on the drug itself. Furthermore, rods formed by this conventional process are mostly found to be too tightly sealed to provide good release of drug into the body. According to the present invention, it has been found that by spraying approximately the same portions of the web as in the conventional process with a sufficient amount of fine water spray to merely wet it and rapid drying of the bars after they are formed, produces finished dosage forms possessing good uniformity and drug release rate as well as stability with respect to the active ingredient with the obvious exception of those drugs known in the pharmaceutical formulation field to be very sensitive to moisture.

Second, the rods can be sealed by applying a piece of heat-sealable edible polymer to the free edge of each foil of the webs, or the free edge of each foil is covered with a heat-sealable edible polymer directly after the cut is made from the endless web. Alternatively, a heat-sealable polymer can be used over the entire part of the web either as a separate foil or even coating. Suitable polymeric materials would e.g. comprise a water-soluble polyoxyethylene or cellulose ether derivative containing a plasticizer as described above.

After the rods have been tightly twisted, in such a case it is lined under a heated plate where both heat and pressure on-

is added to provide a seal. E.g. part of a fixed plate 67 could contain a heated part.

Alternatively, the rods can be sealed after forming by

introduction of water or an adhesive to the outer layer.

or the track., Water is preferably used as a sealing

reagent. This method will normally require the presence of sub-

stops in or on the field, e.g. starch or starch derivatives that form a seal by post-

following drying or by applying heat and pressure.

The method illustrated in Fig. 3 for illustrative purposes provides a water spray 68 to contact the outer surface of the endless belt 66 along the lower

rearward portion thereof, so that the belt surface which is brought into contact with the coiled web sections; only retains enough water in the form of droplets to effect a proper sealing of the bars. The water can also now be fed through the tightly rolled rod-

one, e.g. by passing them under a water transfer roller,

a porous jjlate through which a measured amount of water is applied uniformly over the whole length of the rods or a sponge arranged to bring water to the outer surfaces of the rods-

one. The rods could then be brought to pass between an outer portion of the movable and stationary surfaces where pressure or pressure and heat can be applied to provide the complete seal.

This general method of performing a water seal is considered

which is clearly better than known methods, e.g. for shaping confectionery sticks as previously described. With the water filling methods previously described, the total amount of water supplied to each rod is less than that which is filled by known methods.

As a result, the amount of water that must be removed by subsequent drying of the rods is significantly less than that which is generally required by known methods.

The rods thus formed are each as long as the width of the web of the feed roller. This width is usually 20

to 40 cm. After each rod is sealed, it is brought into contact with e.g. ultra sharp knives 69 (fig. 3) via belt 66 where they are divided into units, i.e. the rod is cut to desired lengths. Methods for unit division and finished shaping of these rods into final dosage forms will be discussed in more detail below.

Another forming or fabrication method to be considered is generally called rotational forming. This method can take different specific forms. This method can be considered as belonging to the more generic lamination method, since in this method stacks of webs which are applied with active substance, in endless strips or rod formations, are first produced either by fan forming or lamination, both of which will be discussed in the following. In a specific rotational forming method illustrated in fig, a continuous, relatively thick laminated strip of web 70 coated with active substance is passed between a pair of press rollers 71. The thus continuously formed or pressed laminated rod 72 is passed to a further station, i.e. a rod-forming and densifying station such as consists of one or more spring-loaded stainless steel rollers 73 with a peri-

feri edge which is shaped to transfer the strap in several continuous rods 74 or substantially circular or other desired cross-section. The rods 74, which are thereby shaped into the desired geometric shape, are then passed through a third rotation station where, e.g. one or more pairs of suitably positioned rollers form the bars into individual dosage units. This can be followed by other suitable pressure or finishing operations which will be described in more detail below. It should be noted that the pressing operation can be carried out in the dividing step comprising the third set of rollers 75.

Another example of rotational molding is shown in fig. 5 in which the formed endless stack (strip or bar) 81 is continuously chipped at regular intervals by reciprocating matrix blocks 82 and/or a pair of suitable heated rollers 83 to provide completely rounded corners of the finished dosage units so that the result of the rotary dosage-forming station is a continuous

lig chain of end-joined dosage forms 85. As with all the different methods of rotational forming, the rods thus modified can be passed through press-dg dividing stations, e.g. as represented by the rollers in Fig.5 shown to the right of the rollers 83, all at high speed.

In another closely related rotational forming technique, the continuous stack is fed into a rotary forming and compacting unit consisting, as before, for example, of one or more pairs of stainless steel rollers. The layers of web, which can be made from layers of paper or polymer film, are heated and compressed into a continuous stack. It is preferred that the outer layers of the stack are paper, e.g. to prevent the stack enjiet from sticking to the heated rollers. During this densification operation, the layers of the web are bound together into a unit, which reduces displacement of the layers and splitting of the edges during the following side and end forming operations. Next, the ends of the dosing units are formed by feeding the continuous rectangular stack produced at the densification station into another station, where the ends of the dosing units are formed by a pair of heated rollers which may have forming, transverse knives placed on the roller surfaces . The cut ends of the dosing units are shaped and sealed by the heat from the rollers. The shape of the end knife determines the shape of the ends of the dosing units. The shape of the end cuts is designed to provide a smooth transition with the side cuts of the dosing units which are carried out in the next station.

The sides of the dosing units are formed in the laminated end-shaped, cut material stack with a third pair of heated rollers. These rollers may have angled recesses with raised cutting edges. The shape of the recesses in the roller surfaces gives a desired cross-section of the dosing unit. Heat and pressure applied from the edge-like cutting elements of the rollers seal the sides of the dispenser

the units to a smooth surface.

The rotary pre-mentioned method for dosage unit manufacture which is illustrated in fig. 5 therefore consists of three primary stations, i.e. one. pre-densification station, an end forming and a side forming side station. Each of these stations consists of a set of rollers, preferably up-

heated, through which the continuous path stack is fed. The shape of the outer surface, i.e. the surface of the rollers at each of the stations is different, depending on the particular station and the result to be achieved. Various additional operations such as further cutting, printing or finishing steps can be carried out between or at the three described stations. These operations are described in more detail below.

It should be noted that one or more different stages of the rotational molding method can be provided at the same time^ and one can perform on the endless laminated inforte strap via a single pair of e.g. spring-loaded heated co-operating rollers, all the various above stages, i.e. rod forming, dosage forming, division into units and also printing.

The third example of rotational molding described above leads in itself to an example of combining two or more of the described steps into one. This is illustrated in fig. 4 A

where in the main laminating-pressing and rod-forming step in the above-mentioned third rotational forming method and also the method illustrated in fig. 4, is combined, e.g., by the use of a single pair of heated, pressure rollers and shear rollers (not specifically shown) which simultaneously press the added laminate and érides it into a shape resembling a number of stacked donuts when viewed from the side.

These end-cut parts then quickly become a unit divider that provides the longitudinal cuts that enable the performance of individual dosages. The printing step could e.g. also performed at this last station.

It is also within the idea of the present

invention to prepackage the unit-divided dosage forms directly when they come out of the unit division operation, e.g. by inserting them into bladder strips by equipment that is considered professional.

A third method for forming dosage forms according to the present invention is the fan-folding technique. One could also classify the fan-folding technique as a form of lamination in a general sense. By this method

a path up to, for example, 30 cm wide is first produced to incorporate the active ingredient that has been added to it. This can be done either by first folding the web in half or by laminating two coated webs with the coated surfaces against each other. A stack of more than a pair of laminated webs can be used in this way, the webs e.g. first

'can be formed with a larger width, i.e. up to 60 cm and after lamination is divided to give two or more widths of a dimension described for the fan-folding operation, i.e. from .1 to 15 cm.

After the coated web has first been folded or laminated as described above, it is then passed through furrow rollers where it is furrowed in preparation for the fan-folding operation. The furrow rollers can be powered or not. The web is moved significantly by traction rollers. Furring can e.g. is achieved

by spring loading one of the pairs of furrow rollers. As the web is preferably folded in the direction of the furrings that enter the web material, the furrings can be placed alternately in the upper and lower rollers depending on the desired fan-folding pattern. The furrowed web is then fed into a fan-folding sliding chute with folding blades that begin to gently bend the web at the point of contact and limit both width and overlap so that the web is folded appropriately tightly at the discharge end. At the end of the folding-sliding chute there is a device for pulling the web through the furrows and folding the equipment such as e.g. a pair of stainless steel rollers that are spring-loaded. This serves a dual function i.e. that the web is moved through the folding apparatus and the folded web is compressed into a continuous fixed geometric shape.

The traction means can be combined with means for sealing the track. However, the fan-folded web can be sealed by other methods to be described below. The different paths can be divided into units in different ways such as the rotational forming method described above.

In Figures 6A - 6D, a fan-folding dosage form technique is illustrated in which the originally fan-folded webs 91 are assembled into perforations 92A with cooperating mold in therapeutically inert web structure, preferably consisting of paper designated as the center strap 92. This "charged" center the strap that carries the fan-folded webs becomes so

sandwiched between outer straps of web 93 to form a composite laminated structure. This final composite laminated strap then quickly becomes, for example, a rotary dosage forming unit or station not unlike the unit 83 fig. 5, in which the strap is brought to an appearance as shown in fig. 6B. Finally or at the same time as the step "which is carried out in connection with Fig. 6B, the unit providing step is carried out which provides individual dosages as shown in Fig. 6C. Fig. 6D illustrates in cross-section the dosage form illustrated in 6C. Fig. 6D shows how the fan-shaped webs 91 are completely incorporated and that, for example, the center strap 92 is forced by the stopping process slightly outwards so that some of it is exposed between the edges of the outer straps 93 which are dimensioned thereto.It should be noted that preferably they are outer straps 93 and center strap 92 free of any active ingredient, whereby it is guaranteed that none of the active ingredient will be present on any outer surface of the individual dosage forms.

The fourth main forming method

is the lamination method that is generally stated here earlier. With this method, between 20 and 60

rolls of web first rolled out simultaneously from a multi-coil unwinding stand and then quickly together to give a continuous rod. The 20 to 60 layers of web may all be paper-like material with a suitable coating to enable sealing

in a subsequent step, or they may be a laminate of a paper-like web and a heat-sealable edible polymer web, or they may consist of one or more paper-like webs alternatively interrupted by heat-sealable edible polymer webs . Suitable polymer materials include e.g. a water-soluble polyoxyethylene or cellulose ether derivative containing a plasticizer. Active substance can be applied to any number of lanes. Preferably, the paper webs are coated with an active substance.

An alternative method of stacking the webs required active ingredients to obtain it directly from the application equipment. The width of the track is normally 12 - 25 cm.

The web that is stored on rolls or retrieved from the transfer equipment may initially be several times the final width which is cut to the desired final width as part of the stacking process.

Once the web is first stacked, the resulting continuous bundle is fed to a laminating station. Apparatus which is known from various fields for lining strips of flexible films together and forming a laminate thereof is generally applicable for carrying out this embodiment according to the present invention. As already mentioned, the surface for applying active substance to the web strips or foils will vary depending on e.g. of the method of sealing the lamination. Cutting and finishing of the laminate can also vary in accordance with the invention. E.g. the laminate can be treated as in the rotational forming process described above. However, the laminating station could also consist of a pair of reciprocating matrix plates which form, seal and cut the dosage forms from the continuous feed web stack. A typical matrix plate will have a surface area of approximately 25 cm x 25 cm.

The laminates are in

a special design unique in that they are sealed only at the edges as opposed to each foil being fully

permanently sealed to the neighboring foils. It has unexpectedly been found that suitable dosage forms can be produced from a stack of layers of web in which up to six layers of paper: '•

web is inserted between layers of a web consisting of a heat-sealable polymer by applying heat and pressure to the stack by cutting devices during the division into units. During the unitization operation, the layers of polymeric web in the stack are biased by heat and printed and "spread" to cover and seal the edges of the intervening layers of paper. It is quite obvious that the top and bottom layers of such a laminate must be a polymer. It is preferred that the drug in a paper-polymer web stack is placed on the paper layers in the web. It is quite obvious from the foregoing description that such a laminate which is only peripherally sealed possesses a superior drug release rate compared to a similar stack of webs which are fully laminated.

An alternative method for forming dosages from the web stack is to feed the stack between two rotating rollers that have individual embossing dies on the outside. The dosage units are formed, sealed and cut from the continuous feed web' stack as it passes between such rotating rollers.

Some advantages of pharmaceutical preparations that are achieved by the use of the lamination techniques will be discussed here. First, the lamination techniques provide barriers that facilitate the composition of two or more therapeutically active substances that are incompatible without having to use the addition of stabilizing substances or a special composition technique such as e.g. encapsulation of one or more components. Then e.g. up to 60 layers can be used to form a laminate, this embodiment of the invention is ideally suited for pharmaceutical preparations containing a large number of active substances where there are several possibilities for mutual incompatibilities such as e.g. multivitamin preparations. Furthermore, the insulating effect of the layers in a laminate, and the deposition or application of active substance on the web in a dry state __ make such techniques ideally suited for the supply of effervescent preparations. In such preparations, it is clear that the web material had to be such that it would quickly dissolve or disperse in water. As also indicated above, the application of the active ingredient on the track in a dry state is advantageous where the active substance is adversely affected by moisture.

In further consideration of the laminate process

is it possible-to vary for-

the molding in the different layers within a laminate as well as checking that each layer is coated with active substance. Obviously, the surface of the top and bottom layers of a laminate will be bare, not coated, and vu ,

provide effective incorporation of the active substance. For example it has been found that the inclusion of one or more layers of a starch-based formulation in a cellulose laminate makes the laminate more plastic than increasing the amount of plasticizer in the formulation of the cellulose layers.

With regard to the forming method discussed above, it is preferred to deposit or coat the web with active ingredient in wet form where the forming takes place by the twist winding or fan-folding process. The rotary forming and laminating processes are equally applicable for the deposition of active substance in wet or dry form. as the choice depends on the properties of the active ingredient that is imposed, e.g. the solubility in the special solvent used and stability against moisture.

For practical reasons, division into units cannot be mentioned without also mentioning sealing and without first having mentioned fabrication, as per definition cutting and division into units of the shaped webs could expose some active ingredient on one or more of the outer surfaces. An exception

- for this, would be to have the application operation adapted to deposit active substance at short intervals in contrast

to a continuous application thereof with active substance "point located" and surrounded on all sides by uncoated track.

In light of considerations of the manufacturing equipment and the need to maintain uniformity in the deposition of the coating for "on-line" testing, it is preferred to add active substance continuously to the web in sufficient quantities so that the division operation produces dosage forms that contain a therapeutically effective dosage. In certain of the operations described herein, e.g. the fan-folding process, the outer parts of the web can be left free of active substance to ensure incorporation of active substance and in certain cases provide a surplus of the web that can be used to seal the divided dosage forms.

The cutting of the formed path must be carried out in such a way that it does not deform the path. The cutting operation itself can be performed by stationary or rotating knife blades, by single or two-stage dies or by other conventional methods. To ensure that the manufactured web will not be deformed during the cutting operation, several cuts can be made from different angles. As discussed above under rotational forming, the formed web can also first be carefully folded or shaped to compensate for the distortion that occurs during the high-speed splitting operation.

The forming, imposed path can be divided into units by individual separation, i.e. formation of one unit at a time as by cutting precise lengths from a rod or preferably several units can be formed simultaneously as by cutting a twisted rod into several

dosing units using multiple uniform spaced cutting edges. Another method of forming multiple dosage forms simultaneously would be the use of shaped dies, either single or double and rotary mounted, or reciprocally mounted on plates to cut a single laminated web or a twisted rod structure. The shape of the finished dosage form has an appearance and is such that several shapes will fit into a matrix plate almost without any loss at the edge, such as a rectangle, a square or preferably a hexagon.

The shape of the dosage forms produced from rods can also be determined by the shape of the cuttings. The cutter could e.g. have a rectangular shape with the parallel long sides moderately bent so that the ends of the dosage forms cut from this would be slightly rounded.

However, one must not forget that such lateral support as is required to

avoid twisting and sudden evaporation, must be applied to the manufactured dosage forms during the unit division operation.

Unit splitting and final sealing operations can be combined. Although there are different ways by which the dosage forms can be sealed, the most common is in combination with the unit division operation heat and/or pressure. In addition to making a seal on the closed edges of the dosage form by heating the cutting tool, heat and pressure can be applied through the die to bond the laminate. Furthermore, the application of moisture or a volatile solvent to seal the edge of the twisted rod as mentioned above can be extended to the cutting operation by applying such solvent to the cutting surface. Heat and/or pressure can also be applied at the same time to ensure a proper seal.

The methods by which the unit divided dosage forms produced according to the present invention can be sealed are not unconventional during the processing of plastic 'c and lamination area. These include, in addition to the use of water or other volatile solvents such as e.g. ethanol, methanol and chloroform, application of pressure and heat, application of a separate adhesive, infrared heating, ultrasonic bonding, encapsulation or the combination of two or more of these. A preferred method of sealing dosage forms

is the use of a top cover which can be pre-printed if desired. This can e.g. be a thin layer of edible polymeric material such as hydroxymethyl cellulose,

modified starch and gelatin which are placed on the dosing units from a bath in which the dosing units are immersed. Such layers could be self-sealing as e.g. by suspending a volatile solvent. More preferred methods of effecting a sealing layer on unit divided dosage units are encapsulation and basket sealing.

In the first of these methods, the fixed dosage units are lined between converging layers of flexible film of e.g. gelatin which closes the dosage form as illustrated in fig. 6A. The gelatin film is thus heat-sealed and cut to shape. Apparatus for encapsulating liquid by this method is known in the pharmaceutical industry and such apparatus can easily be adapted to coat new dosage forms.

Another method is basket sealing which can be lined through

with the following two processes. In the first, preformed curves are produced from material such as e.g. gelatin or a cellulose derivative by well-known equipment, e.g. in the area of plastic molding, i.e. injection topping. The unit divided dosage forms are automatically placed in these baskets at high speed and the baskets are then covered with an oversheet which is sealed to the basket by any of the sealing methods herein indicated, preferably ultrasonic welding. The baskets are separated by cutting with a stationary or rotating cutting edge. The walls or preformed basket are usually thicker than the top or seal layer. The sealing layer is, however, sufficiently thick to protect the dosage form, but so that the dosage form will be released from the basket via the sealing layer within a very short time after ingestion, usually within seconds of having ruptured the stomach. Alternatively, the basket can be formed from identical halves which are sealed using a method that has been described here.

An alternative to the basket seal as described above is to form a continuous substrate, web or strap of the material as described above for the basket, and cut holes in it to exactly retain the dosage form,

e.g. fan-shaped dosage forms as illustrated in fig. 6A. In this embodiment, the unit's divided dosage forms are placed in the holes, e.g. by a pin through the hole and another pin on top of the unit's split dosage form to hold it under pressure. The strap is then sealed by supplying a top and bottom layer of similar material, while maintaining pressure on the dosing unit. The thickness of the strap is in no case more than the dosage forms. The strap can, however, be thinner than the dosage form, but not less than around half its thickness. It is preferred that the supporting strap is close or equal in thickness to the dosage form

. of different reasons. Firstly, the sealing film can be as thin as that described above in connection with the curve, as it is not noticeably changed by the sealing operation. Secondly, a thicker substrate web will be less subject to changes during the perforation and unit operations. Thirdly, holes can be made closer together in a thicker strap and thus enable a minimum of play. As soon as the dosage form is placed in the substrate strap and sealed, the strap is again divided into units as described herein. An advantage of both the basket and the under layer strap idea described above is that it is the track material on the outer rafts that does not contain active substance and can be subjected to finishing operations such as e.g. embossing and bevel cutting without risk of loss of active substance. Furthermore, the use of a basket or underlay-strap idea can facilitate the use of different colours'

in the final dosage forms, i.e. by making the substrate, the sealing strips or the dosing units themselves in contrasting colours, which will give a particularly appealing and distinct appearance.

The material to be used for the production of the basket, the center support strap and the sealing films described above must, like the tracks themselves, satisfy certain critical tests. In addition to the obvious pharmaceutical purity criteria, it must have good durability, be non-toxic and compatible with the active substance used, the material must have good surface quality, color and resistance to blackening, structural unity, deformability, dimensional stability and release of active ingredients in water . The preferred substances for this use are hydroxypropyl cellulose and methyl cellulose. A particularly preferred material consists of hydroxypropyl cellulose, a starch or starch derivative as filler or explosive, a plasticizer such as e.g. polyethylene glycol, suitable pigments, e.g. titanium dioxide and an antioxidant such as 2,6-di-tert-butyl-4-methylphenol.

One of the main advantages achieved by the production of the new dosage forms is that it can be carried out "on line"

non-destructive quality control. In the context of the present invention, the term "non-destructive"

meant in a practical sense as opposed to the purely literal definition. This means that the quality control of the new dosage forms is achieved by very fast manufacturing processes with a real loss of less than 1% of the dosage form. As the new dosage forms can be manufactured with a very low standard deviation in dosage, and therefore a manufacturing surplus of less than the standards conventionally accepted in the pharmaceutical industry at the moment, the very small portions of the dosage form lost during testing are effectively almost zero when considers the tolerances of the present manufacturing process in its entirety.

In the manufacture of the new dosage forms produced

according to the present invention, quality assurance of the manufacturing process is obtained, a situation which is new in the pharmaceutical industry. The "on line" testing procedure that provides such assurance must be clearly distinguished from such well-known pharmaceutical quality control procedures as chemical and physical control of components of dosage forms before the manufacture has begun, destructive measurements of solid dosage forms after the manufacturing procedure has ended both for physical characteristics e.g. . op<p>reading rates, incidence of

of cover strip and chemical characteristics such as strength, occurrence of incompatibilities and

physical quality controls of fixed dosage forms such as e.g. manual inspection of two colored capsules to ensure that each has ends with contrasting colors. Such tests, which are well known and commonly practiced in the pharmaceutical industry and described in the official compendiums, have no connection with and do not suggest the "on line" production control which is a critical feature of the fixed dosage forms produced via the invention . It should be noted at the time that certain conventional methods such as e.g. pure quality control and testing of all ingredients for the manufacturing process form an integrating component of the manufacture of the dosage forms.

"On line" quality assurance during the production that follows

, the new dosage forms

is achieved by all such forms described herein beginning with a continuous edible path adaptable to non-destructive testing. First, the web manufacturing itself is controlled with regard to the physical characteristics of the web to ensure that the web is smooth and free of defects. For example, the path can be passed through a resonance

hollowing where a microwave passing through the track is continuously controlled as an indicator of track thickness, "ie as soon as the resonant frequency is determined, changes therein are indicative of changes in track thickness. Other means of controlling track thickness include laser beam refraction, liquid sensing and physical contact sensors.

It is also possible to examine the track with regard to weight per surface unit and defects.

The preferred method before testing the track on weight per surface unit is soft X-ray absorption, e.g. a wavelength of around 4 angstroms. (3-beam absorption using a PM 147 source is also applicable. Web defects such as spots, holes and streaks can be detected by laser beam

rehearsal. Holes in the track can be detected by electrical output

charging methods using equipment that is commercially available.

The methods detailed above are also applicable in cases where the web receives another layer either in the form of one or more further webs or a

firing coating laid on an imposed course. Laser testing is particularly advantageous for the "on line" quality control of .. such coatings.

Another important area of "on line" quality control

is to control it

amount of active substance that is placed on the track and thus the smoothness of the application operation. It must first be remembered that a clear advantage of the method according to the present invention by which the new dosage forms are produced,

is that the active substance is placed on the track in a form that is compatible with the investigation methods to be described

in the following, i.e. in especially fine particle form or as a fine film..

There are different methods for analyzing the uniformity of the deposition of active substance. E.g. a photon counter can be used to measure the ultraviolet absorption of the highly diluted active substance-path system. Mere X-ray absorption using a wavelength of

around 4 angstroms and (3-beam absorption can also be used. Light scattering apparatus is preferred as it is ideally suited

for controlling particle size and concentration in the dust cloud or on the track. The suitable apparatus for such operations is commercially available.

The fabrication, unit breakdown and final steps are as above. described can also be adapted to "on line" examination procedures as described above in connection with the track. Such attempts will naturally include physical

cal parameters for the path after fabrication as dimen-

tion, thickness and uniformity. Similar tests

is carried out on the unit divided dosage forms with regard to form. on evenness. _

The discussion so far has been about means by which the new dosage units are examined not

destructive "on line" during manufacture. Two additional examinations comprise "non-destructive examination".'

In a "first such operation, a tiny part of the track becomes

periodically removed "on line" by cutting with knives, dies, liquid jet<*> or a laser beam. It is expected that the removed part of the web will not destroy the integrity of the web or adversely affect any of the fabrication operations. The sample of the web can be taken before or after the active substance has been applied to it or, in some cases, during early manufacturing steps, e.g. when a few webs have been stacked in a previous lamination or folding operation. The web thus removed is chemically analyzed both with regard to web material and active substance. This analysis is therefore carried out on a quantitative basis, especially with regard to active substance.

In addition to the spot analysis, the finished dosage forms are taken out, and subjected to an "on-line" effectiveness guarantee. Although such measurement is a necessary procedure at the moment for most solid dosage forms marketed in the USA, it is not carried out "on line" during the manufacturing operation as is the case with the present invention. First, it must be remembered that the new dosage forms

are not affected by rate restrictions in the process by which they are produced. A "rate" can therefore be the number of dosage units that fall between two samples that satisfy

the quality specifications, provided that this number does not exceed the test requirements of the "Federal Food and Drug Administration". When the method of nerve acquisition is used less than satisfies such requirements,

can a "batch" of new dosage units as herein required,

be of any ordinary number, i.e. number of units that can be produced from a given production quantity of active substance.

Another special aspect of quality control is the fuse

of the new dosage forms

is that the results of such tests as well as all other "on-line" tests discussed herein can be computerized and used to adjust the parameters during manufacturing

the process. Proceeding in this way, a negative reading of any of the trials signifies the beginning of a series of dosage units that must be isolated and the next following positive result after the corrections have been made automatically ends the series. The dosage units produced between these 2 measurements must therefore be further examined to determine how many conform to the specifications. Where the tests are carried out "on line" on the pitch, e.g. on

the amount of imposed active substance, a negative reading, can be transferred to simultaneously affect two functions. First, the web can be marked with a spot of non-toxic dye, thus making it possible for the production procedure to be temporarily stopped and part of the web to be removed manually. Secondly, the reading through a computer affects an adjustment in the amount of active substance that is placed on the track by either increasing or reducing said amount to satisfy the specifications. When the path passing the measuring unit again meets the specifications, another spot will auto-

matically lined on the track and thus mark the length of the track that does not meet the specifications. Similar opera-

sessions are carried out at each of the "on line" measurement points

With regard to impact analysis, the operation is deemed to

complete samples of finished dosage units and are automatically placed in aliquots of test solution and examined with regard to dissolution rate. The special criteria used to prove the dissolution of unit dosage

the forms will vary with the active substance or substances present therein. E.g. can a sample dosage unit

is added to a suitable solvent and thereby give a solution of the active ingredient. The resulting sample solution can be measured photometrically to determine the concentration of active ingredient as a function of time after the sample unit was placed therein. Other possible indicators that could be measured in the sample solution are changes in pH, colour, heat and chemical reactions. Means where each of these changes can be registered automatically as a function of time are specialist. As soon as the solution information is determined, it can be used through a system such as a computer to perform such adjustments in formulation/unit division, finishing and sealing operations as are required to correct or improve the readings.

The "on line" test methods described herein are in any case applicable to measure the entire track, i.e. device - which measures web thickness. However, in certain cases measuring the entire path may not be feasible from an economic point of view. For example is it possible to measure a small area of the track using a light scattering sensor and further possible to mount two or more sensing devices in close proximity to examine a corresponding number of small widths within a passing track. However, the costs of the necessary equipment to measure the entire track can be prohibitive. When therefore only limited areas of the track can be checked, the measuring equipment can be mounted on means which enable its oscillation transversely across the width of the track. The proportion of the web and therefore finished dosage units that are measured in this way far exceeds any non-destructive measurement method that has so far been carried out in the pharmaceutical industry.

As discussed in various places herein, the final onerations for the finished dosage forms

performed independently or preferably in combination with other operations, e.g. unit division. Finish with regard to the new dosage forms

can be divided into two basic groups, i.e. uniformity of the surface of the dosage form and finish or appearance of the surface thereof.

The smoothness of the surface of the dosage forms

may or may not be a problem depending on

the technique used to divide dosage units

the forms from the continuous stack and whether a sealing operation has been carried out. Where e.g. a laminated stack of webs is cut into a special shape as described above,

small irregularities may occur where the cutting means are fashioned.

There may also be some end or side unevenness from the unit-splitting operation in dosage forms formed by other preferred manufacturing methods. In general, however, the fabrication technique is minimized in the present up-

finding the possibility of such irregularities.

Irregularities as described here can generally be removed

for gentle grinding such as e.g. by subjecting the dosage units to mild reversal action with or without the presence of a mild abrasive substance such as salt crystals. It must be noted, however, that in most cases such treatment must precede pressure operations.

Superficial appearance, i.e. the gloss of the dosage forms

can vary from a weak

polished appearance to a relatively high gloss depending on the technique used and the desired finish. Where sealing techniques such as basket seal or encapsulation methods as indicated above are used, the gloss of the finished surface can be adjusted as desired simply by the choice of material used to form the seal. The same is the case where a cover is used to seal the dosage forms. Where such sealing operations are used, complete removal of unevenness is not normally required as the covering ensures complete continuity of the surface.

The pressure rating is likewise dependent on the fabrication and

the sealing techniques used. Printing can be done on

the path itself at each appropriate point in the entire manufacturing operation. E.g. the outer layer of a laminated dosage form can be pressed for the manufacturing operation, which

part of the unit-splitting operation or also after the unit-splitting has been completed. Dosage forms produced by e.g. twisted winding • can be printed while it is still in continuous rod or stack. Where the dosage forms of the invention are sealed by using a cover, printing is preferably carried out after the cover has been removed, although it is mulia

to press the dosage forms and then add a clear cover. The printing of fixed unit dosage forms for the completion of the preparation is a new idea in the field

'' the pharmaceutical industry.

The choice of a printing method depends on various factors, the most important of which is the physical nature of the substrate to be printed. The choice of a suitable method is also dependent to a certain extent on the place in the overall manufacturing operation where the printing is carried out, i.e.

whether the web is to be printed for fabrication, the finished dosage forms are to be printed or printing will be carried out at an intermediate point, perhaps in combination with other operations such as e.g. unit division. The printing method and the associated equipment can be chosen from among the following: offset and direct printing press, offset engraving, lithography, electrostatic powder engraving, electrostatic net stencil and print-straie. Of course, offset engraving is the most applicable method, although other methods can be used in special cases •

It will be clear from the preceding discussion of finish and printing operations that there are several ways in which the color of the new dosage forms can be varied both in tone and intensity. Firstly, the web material itself can contain a color that can light up in intensity when layers of web are combined during the various manufacturing operations. The color can also be absorbed by a covering or sealing layer. Where the basket or encapsulation methods of sealing are used, two or more contrasting colors may be possible in the obvious design and vary the color of the different parts thereof. The dosage forms produced by lamination can also be made the subject of variations in color by simply varying the color of the webs that are fed into the laminating apparatus.

The new dosage forms are in practice

regardless of the type of active substance for which they serve as a carrier. The terms "active substance", "active ingredient" and "drug" which are considered synonymous in connection with the present invention and which are used interchangeably throughout the present description and can clearly be defined as any substance which will produce a pharmacological effect in the body.

The active substances used can be in free form

or in any non-toxic pharmaceutically acceptable form in which their therapeutic activity is retained.

The amount of active substance or mixtures of substances

to be incorporated into the new dosage forms is normally the amount known to be an effective therapeutic dosage for the particular drug. In general, the amount of active ingredient present in a single dosage form should not exceed approx. 500 mg with an upper practical limit of around 750 mg.

As stated herein, the new dosage forms possess

extremely smooth indication speed which can also be controlled to meet desired specifications. Irrespective of the delivery methods that are therefore available, the dosage forms exhibit

a uniformity of release within a

such a pattern which is better than that shown by conventional . solid dosage forms, e.g. tablets and capsules.

Fig. 7 graphically illustrates the superiority of the release rate for the dosage forms produced according to the invention compared to a conventional solid oral dosage form, i.e. commercial capsules. In the experiment illustrated

in fig. 7, six randomly selected conventional capsules each containing an equal amount of the same active ingredient were each placed in 100 ml of artificial gastric juice, U.S.P. (without ..enzyme) The liquid kept under stirring at 37°C. The liquid in each of the reaction flasks was constantly filtered and circulated through flow cells in a suitable spectrophotometer.

The absorption of the liquids was read at one-minute intervals and the presence of dissolved active ingredient calculated for each reading. In fig. 7, the fastest and slowest dissolved sample from each group is shown and the shaded re-

the council between covers the remaining four tests. With regard to fig. 7 two conclusions quickly arise. Firstly, the new dosage forms produced according to the present invention dissolve much faster than the tried conventional capsules.

Secondly, the variation between six samples of the dosage units produced according to the invention was strikingly smaller than for the conventional capsules examined. These results clearly show the superior release properties which are characteristic of the dosage forms produced according to the present invention.

-5llod level ■- - the curve set up in fig. 8 also compares the new dosage forms produced according to the present invention with commercially available capsules containing the same amount of the same active ingredient. The blood-level curves are theoretically calculated based on two entry rates

in a one-r oms pharmacokinetic model. The blood level curves are based on a theoretical 100% absorption of the amount of active ingredient released from the dosage form at a point in time and are thus proportional to the dissolution rate. The difference in blood-level curves is therefore a function of dissolution rates.

It is clear from the data illustrated in fig. 8

that the dosage forms in the present invention not only reach effective blood levels faster, but maintain a higher blood level of active ingredient than the conventional capsules. The ability to reach a higher level of active ingredient in the blood faster is a clear advantage especially in the administration of certain types of chemotherapeutic reagents, e.g. antibiotics

Claims (9)

1. Method for the production of solid pharmaceutical unit dosage forms, during which one or more drugs are applied to a therapeutically inert edible band-shaped carrier material, and the carrier material is processed into a geometric shape of predetermined appearance in which the drug is essentially placed inside, characterized by the fact that a continuous active substance layer is applied the ribbon-shaped carrier material in continuous work operations, several ribbons thus obtained are processed into a form with several layers, which form with several layers is divided into several unit dosage forms and the unit dosage forms are closed so that the drug is arranged completely inside, and during which a non-destructive test, respectively. control of the products obtained in the individual process steps is carried out during production. 2. Method according to claim 1, characterized in that the fabrication procedure comprises cutting said applied web crosswise to form essentially equal lengths of applied web which can each be divided into a number of unit dosage forms, undulating each length of web to shape this into a loosely twisted roll, tying said loose rolls to a substantially solid rod and cutting the rod transversely into a number of unit dosage forms. 3. Method according to claims 1 and 2, characterized in that a web is used with a composition that can be water-sealed and in which the rods are sealed by contacting the rollers with a sufficient amount of water as a fine spray to moisten them and then the rods are dried . 4. Method according to claim 3, characterized in that the application of water is limited to the place on the surface of the rod where sealing is required. 5. Method according to claim 1, characterized in that a stack of said webs is formed, at least one of which has medication applied to it, cutting of said stack to divide the same into unit dosage forms and at the same time sealing only the edges of the unit dosage forms by adding heat and pressure during the cutting operation. 6. Method according to claim 5, characterized in that the stack of webs comprises at least two layers of webs consisting of a heat-sealable polymer material consisting of an organic film-forming component and a plasticizer for this and at least one layer of a paper material consisting of one or more fiber materials and at least a non-fiber modifying material therefor, the top and bottom layers of the stack being polymeric with the proviso that there are no more than six of the paper material webs distributed between each pair of the polymer material webs in the stack, and said heat and pressure applied to the stack of webs during the cutting operation is sufficient to cause the polymer webs to deform and seal the edges of all intervening layers of paper material webs. 7 . Method according to claim 1, characterized in that a continuous stack of several layers of web is formed and the stack is subjected to pressure in order to condense and shape this into a continuous rod-like first geometric shape, unitarily divide the geometric shape into said number of unit dosage forms and seal the unit dosage - the forms to completely incorporate the drug. 8 . Method according to claim 7, characterized in that said continuous stack of a number of layers of web is formed by laminating a number of webs which are positioned so that the top and bottom surfaces are free of drug. 9 . Method according to claim 1, characterized in that the manufacturing method comprises fan-folding a continuous web structure consisting of at least a couple of layers of web with drug placed on the outer rafts thereof and subjecting said stack to pressure to densify and shape this into a continuous rod-like geometric shape .