Dosage form

The solid oral dosage forms previously known in the pharmaceutical industry, orally taken, can be divided into two basic forms, namely tablets and capsules. A wide range is known for both tablets and capsules, for example those that are coated in accordance with the intestine so that they dissolve in the intestinal tract, those that dissolve by means of various mechanisms over a long period of time, foaming forms and so on. Overall, such conventional solid oral dosage forms have numerous disadvantages.

First, a disadvantage of conventional, solid, oral unit dosage forms is that they contain several different substances mixed with the active ingredient, which are referred to as therapeutically ineffective or non-toxic, pharmaceutical additives. Such substances or materials belong to the known categories such as diluents, extractants, binders, lubricants, disintegrants, stabilizers, ï Tlt / 24.11.I97g

Buffers, preservatives and so on. While it is known that these substances are indispensable in the preparation of pharmaceutical mixtures, their use nevertheless presents problems regarding the cost of the final form and the weight of the dosage unit, and so on. In addition, each additional material must be checked for possible incompatibilities with the existing medication before it is used. Furthermore, certain of these materials, such as lubricants, can cause problems regarding the bioavailability of the active ingredient. Also, the presence of these materials must be taken into account in analytical procedures that test the effectiveness, etc., of the finished dosage form.

A second important disadvantage of the known oral unit dosage forms is that the unit dosage form must be destroyed when tested, which means that only a small percentage of the forms actually manufactured can be tested. It is known that the dosage forms of a batch can vary significantly because of the mean variation within each batch in terms of dosage, properties, etc. is determined by analyzing a relatively small number of samples.

The batch or batch concept itself means a disadvantage of conventional oral, solid dosage forms with regard to the economics of batch construction, control and testing.

The invention has for its object to provide pharmaceutical unit dosage forms which do not have the disadvantages mentioned, which are economically producible, in particular with high effectiveness, and which allow simple quality control.

This object is achieved with fixed dosage units primarily intended for oral administration, which can be produced in large numbers at high speed and which, because they are produced by a process which is unique in the pharmaceutical industry, do not currently have the disadvantages listed above available oral dosage forms, ie tablets and capsules. This method has the following advantages in particular:

It eliminates the need to work with individual batches as has been required up to now; it enables continuous on-line testing for efficacy and on-line testing of dosage forms during their manufacture; it substantially eliminates the need to add conventional pharmaceutical additives to the medication, with the exception of lubricants, which may be required to improve the flow properties of powders and / or other materials that are beneficial to product properties; it permits the production of pharmaceutically advantageous unit dosage forms, which can be designed so that they release the medicament at any desired rate, and with which a release rate which can be achieved above and beyond can be achieved. tablets and capsules. Overall, the dosage forms according to the invention ensure that a larger percentage of a more precisely measured amount of medically active substance is available at a more precisely controlled time after ingestion than is the case with conventional, commercially available units of the Pall.

The oral unit dosage forms of the invention are advantageous in many ways. Probably the most important advantage lies in the fact that they are precisely checked for their quality by on-line processes during their high-speed, essentially automated production. An additional advantage of the dosage forms according to the invention is that the medicament contained in them is released for absorption in a large number of dosage units with extraordinary uniformity. Furthermore, the dosage units according to the invention can be constructed such that their dissolution or Medicinal efficacy begins within a shorter period of time after ingestion than is possible with conventional fixed oral dosage forms, such as tablets and capsules. The dosage units according to the invention thus have excellent properties both in terms of their drug content and in terms of releasing the drug for absorption.

From the prior art, the following publications are worth mentioning, which deal with solid dosage forms which can be distinguished from conventional tablets. U.S. Patent 3,444,858 describes a form intended for oral medication which has a strip of gelatinous material containing the medicament. The strip is divided into individual sections, each with the next by easily tearable tapes or Connections is connected. In use, a section is separated from the strip and pushed into the mouth.

A second publication worth mentioning is an article in the New England Journal of Medicine, vol. 289, no. 10 pp. 533-5 (1973).

This article describes a device by which women in the People's Republic of China have had access to a birth control drug on a large scale. In this process, a colored sheet of water-soluble carboxymethyl cellulose paper is treated with a fabric solution with progesterone and estrogen. The sheet is then perforated and cut into strips. The drug is packaged as a strip of 22 squares that are torn off the strip and taken daily. This method does not hide the drug in the final dosage form and thus has the disadvantage that once the package is opened the drug can become contaminated and / or inactivated. Furthermore, due to the incomplete separation, the perforated strips can be torn off unevenly at the perforations, which can lead to an uneven dosage.

Finally, reference is made to US Pat. No. 3,625,214 which describes a dosage form which is used for a controlled, ie continuously maintained release of medication. This dosage form consists essentially of a drug-containing matrix layered on a substrate which is then spirally wound into a roll. After ingestion, the drug is released by the gradual degradation of the outer substrate and by diffusion from the sides where the exposed drug is located. In U.S. Patent 3,625,214_:there is no information as to whether the dosage forms are suitable for production in large numbers. Furthermore, there is no information on how the dosage forms can be brought into the form of pharmaceutically perfect finished products.

In clear distinction from the teachings of the publications mentioned, the novel, solid dosage forms according to the invention are completely isolated and are suitable for non-destructive, on-line discovery according to the performing analytical test during pharmaceutical production in large quantities, and are essentially free of pharmaceutical additive materials that can adversely affect their properties, do not contain any exposed drug and have an excellent consistency in releasing the drug, which increases their effectiveness.

i

The solid unit dosage forms according to the invention, which are primarily intended for oral ingestion, contain an edible carrier material in the form of a tape made of paper and / or polymeric substances, to which or at least some are applied to the one or more medications, which are essentially do not contain any pharmaceutical additives mixed with them. The tape is brought into an ingestible, pharmaceutically and cosmetically acceptable form and sealed in such a way that no medication is exposed. The unit dosage forms are manufactured at high speed pharmaceutical manufacturing technology, with new devices being used in certain cases. The manufacturing process includes a device for non-destructive on-line testing of the dosage forms in order!

the amount of media applied to the tape before it is processed!

ί kaments and thereby to check the effectiveness of the finished dosage units using physical parameters.

I

As can be seen from the above, the invention is concerned with solid unit dosage forms which are primarily intended for oral ingestion and which have several advantages over conventional oral dosage forms such as tablets and capsules. First of all, the dosage forms according to the invention are essentially free of pharmaceutical additives, which leads to savings in the use of raw materials as well as in production, and eliminates possible incompatibilities which are caused by such additives. Here the difference must be made between the inventive changes which can be considered as additives and materials, such as fillers, binders and the like, which are mixed into the medicament in conventional solid dosage forms.

Second, since the solid unit dosage forms of the present invention are continuously produced and analytically tested online, non-destructively, there is no need for batch production as is currently known, which saves significant costs and significantly improves the quality control of the finished dosage units. The fact that a device is provided in the manufacture of the dosage forms according to the invention, with which information can be transferred back directly from a test station to the previous manufacturing processes, makes online corrections and adjustments possible. Such a device facilitates the removal of only a few dosage units from any number that serves as a production quantity or guideline. The selection and removal of such small amounts of dosage forms in this way eliminates poisoning of the tube and offers both a great economic advantage over conventional pharmaceutical manufacturing processes and better quality control, in particular with regard to the content of active ingredient in the finished dosage forms. The dosage forms according to the invention are normally produced by time-quantity processes, ie a quantity of dosage forms forms a number made between two times. This concept is unique in the pharmaceutical industry. It should be noted, however, that any pharmaceutical manufacturing requires some level of non-destructive testing to test the properties of the finished product.

Such a test is, however, necessary to a considerably lesser extent in the process according to the invention than in conventional production processes. What is more important, however, is the fact that such non-destructive processes, ie property evaluations, are carried out online with information feedback, which leads to the advantages outlined above with regard to the non-destructive processes.

Thirdly, the oral dosage units according to the invention are clearly distinguishable from conventional tablets and capsules in terms of their appearance, shape, texture, etc., as a result of which they can be easily identified. The on-line, non-destructive testing and continuous manufacturing processes of the invention enable on-line packaging of the unit dosage forms of the invention into individual containers such as clear plastic strips or blister packs, thereby saving handling and equipment costs.

Fourthly, the finished dosage forms of the present invention can easily meet tight specifications regarding size, shape, drug release, etc. because the dosage forms are made very precisely, that is, the drug is applied evenly to the belt, and the finished units are formed accurately and the tape has exactly the desired properties. The dosage forms according to the invention have excellent stability. They may also include drugs that are adversely affected by moisture because, in certain embodiments of the invention, the drug is applied to the tape by electrostatic precipitation, which can almost completely avoid moisture that could cause an adverse reaction to occur. Also, if the dosage forms according to the invention are produced from a layering of tape: layers, medicaments which are known to pharmacists as chemically incompatible can be applied to alternating tape bearings. Thus, such a combination can be effectively stabilized without the need to use economically disadvantageous measures, such as coating one or more such incompatible substances with an insulating one

I material, the admixture of stabilizing additive materials' to such medication, the incorporation of such medication in separate

Tablet layers that are then pressed together and the like.

The dosage forms according to the invention can be used for one or both of the measures mentioned for foaming formulations, namely the electrostatic application of a medication to the tape as a dry powder and the alternating arrangement of possibly incompatible medications between layers of a layer arrangement.

The solid oral dosage forms according to the invention are further distinguished by the fact that the medicament contained in them is contained entirely within the dosage form, with no coating as such being applied to the finished dosage form in most cases. This represents an additional economic advantage of the dosage forms according to the invention over conventional tablets which have to be coated so that the medicament is taken up inside.

The dosage forms produced according to the invention are primarily intended for oral administration, but they are also suitable for rectal and / or vaginal use. To produce dosage forms of the desired shape and shape, the dimensions of the band and the manufacturing process can be modified in a suitable manner. A desired release of the medicament can be achieved by certain changes in the composition of the band or the band material. Experiments have shown that rectal and vaginal use of the solid dosage forms according to the invention does not cause local irritation.

The dosage forms according to the invention can be formulated or constructed in such a way that any desired release behavior, including delayed release, is achieved. Irrespective of the respective release properties, the dosage units according to the invention are distinguished by a remarkably uniform release of a large number of dosage units, for example 10,000 or more. A change in the release rate can be achieved according to the invention by changing a number of factors, for example the thickness of the band, the composition of the band, the presence of a covering or external seal on the finished band or its composition, how tightly the band is produced or folded and Shnliches. For example, a band composition is released

.......................... tv .. ......... · λ.

with a lot of sodium carboxymethyl cellulose usually slowly in gastric fluids. Dosage forms made from such bands by fan-shaped folding, as described below, open or unfold upon contact with gastric fluid, thereby releasing the drug applied to their inner surfaces with ease, faster than with conventional tablets and capsules. When such a fan-shaped dosage form is sealed on the folded edges with a substance such as ethyl cellulose, cellulose acetate, phthalate or zein that prevents it from opening in gastric fluids, the drug becomes accessible through gradual breakdown of the tape, resulting in a permanent, sustained support sustained release leads. Because with the dosage forms according to the invention a release of the medication at higher speeds than conventional solid dosage forms such as tablets and capsules is possible, embodiments of the invention with such a rapid release are preferred.

The invention is explained below with reference to schematic drawings, for example and with further details.

They represent:

1 is a block diagram of the entire production with the places of the on-lire test,

2 shows a plant for the production according to FIG. 1,

3 shows a device for performing the tight winding in the manufacture of the dosage form,

4, 4A and. 5 shows the rotary form and layering technique for the manufacture of the dosage form, FIGS. 6A to 6D the finishing and the closure in the manufacture of the dosage forms by fan-shaped folding, and

7 and 8 are curves showing the release of the active ingredient in dosage forms according to the invention in comparison with a conventional solid dosage form, here one

Capsule.

The ribbon

Those used to deposit the medication according to the invention

Tapes must meet numerous physical and past criteria to be useful in the practice of the invention. These criteria can be briefly summarized as follows:

The tape must be non-toxic and edible and must not cause an unfavorable feeling in the mouth. In addition, the band must preferably degrade itself in body fluids and / or enzymes or be decomposable therein. However, the tape can be made of non-decomposable material that is easily excreted by the body. The tape is preferably hydrophilic and easily dissolvable in water. These properties must not be adversely affected by the pH value of the gastric fluid, but should be favored thereby. The tape must be completely neutral for the medication applied to it and, on contact with gastric fluid, must not release any substance that is in situ incompatible with the medicationⁿwould bring about;

The tape must be stable for long periods of time at elevated temperatures and a humid environment and must be a poor medium for the growth of microorganisms;

The tape must have acceptable resistance properties so that powdered medicament (which generally has dielectric properties) can be deposited on it by electrostatic precipitation;

The tape must be perfectly machinable and have suitable mechanical properties, ie it must be sufficiently elastic so that it can be drawn or formed into a thin film (between 0.025 and 0.25 mm thick), it must have good tensile strength and tear strength and it must have acceptable folding durability if it has to withstand certain manufacturing processes, as explained below;

The tape surface must allow the on-line analytical procedures described below, must be capable of being coated and held with powdered medicament that is electrostatically or otherwise applied to it, and must be suitable for printing;

The band must be able to be closed in a simple manner by known liquid or heat-sealing methods. However, the sealing or sealing must already take place in a moisture and heat which does not adversely affect the medicament contained in the dosage form. In addition, the tape must have sufficient flame resistance so that such closing operations are possible.

In certain cases, the tape must have a memory, ie it must have sufficient resilience so that when it comes into contact with gastric fluids it quickly reverses the manufacturing process and opens, thereby releasing the medication for absorption. For example, opening means that the dosage form, when it is made by fan-shaped folding, how a bellows opens, and when it is made by tight winding, develops, etc.;

Finally, the tape must have other properties, such as an acceptable taste and smell, properties that (

the person skilled in the art can be found in the description below.

As stated above, the tapes used according to the invention are preferably water-soluble or water-dispersible. There are two basic mechanisms by which the tapes of the invention are constructed to self-destruct in contact with water or gastric fluid. First, the tape may contain particles of substances such as casein, gelatin, and the like, which swell upon contact with water, causing the tape to tear or break. Second, the tape material can contain water-soluble and insoluble components. Upon contact with water, the soluble components of such a material tend to dissolve, while the insoluble components tend to separate, causing the tape to break. The latter mechanism of breaking the tape is not as fast as the former. Examples of suitable water-soluble components are methyl cellulose and the like. Examples of non-water-soluble components are ethyl cellulose and the like.

The tape formulation or materials used to make the • new dosage forms are two fundamentally different types, polymeric material and paper.

The polymeric formulations generally contain:

a) one or more organic film formers,

b) one or more plasticizers,

c) Modifiers, ie, "other arbitrary components" with certain formulations, such as disintegrants, extenders and the like: - d) one or more volatile solvents.

• The paper compositions generally contain:

a) one or more fibrous materials,

b) one or more non-fibrous modifiers, ie

\ other, arbitrary components with certain

Formulations such as one or more organic films¹ formers, wetting agents, extenders and the like,

c) a volatile solvent.

, The film-forming component of the polymeric tapes contains one or a mixture of known, non-toxic, organic film, formers, such as, for example, natural and chemically modified starch and dextrins, proteins, such as gelatin, cellulose derivatives, such as sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose and the like , other polysaccharides, such as pectin, acacie, xanthin gum, guar gum, algin and the like, plastics such as polyvinylpyrrolidone, Polyvinyl alcohol and the like. Preferred film formers are hydroxypropyl cellulose and sodium carboxymethyl13 cellulose. While the concentration of the film-forming component in the polymeric tape is not critical, a concentration between about 5 and about 95 percent by weight is preferred, most preferably between about 40 and about 90 percent by weight.

The film-forming substances mentioned are also examples of the film-forming substances of the paper tape formulations. Preferred film formers of the paper tape formulations are also hydroxypropyl cellulose and sodium carboxymethyl cellulose. The concentration of the film-forming component in the paper tape formulations is also not critical. However, if such a component is used as a binder or an explosive or Solvent for the fibrous material is used, it should not exceed about 40 wt .-%, preferably between about 2 and about 20 wt .-% and most preferably between about 4 and 10 wt .-%. ·

The fibrous component of the paper tape formulations can be any commercially available natural or artificial fiber,

I which has been shown to be non-toxic in experiments. Examples of such fibers are cotton, linen, cellulose, synthetically modified cellulose, rayon (protected trademark), textured vegetable protein, collagen and the like.

I

In order to maintain the machinability and mechanical properties required, the polymeric BSider used in the practice of the invention contain an effective amount of a plasticizing ingredient. Such an ingredient may contain one or more of the plasticizers known in the pharmaceutical industry, for example glycerin, polysorbates, for example polysorbate 80, polysorbate 60, certain mixtures of mono- and di-glycerides of saturated fatty acids and the like. Such plasticizers are preferably present in an amount between about 1 and 60% by weight, preferably between about 10 and 50% by weight, of the tape material.

Both polymers and paper tapes can contain one or more disintegrants well known in the paper industry, such as various types of starch, casein, gelatin and the like. The tapes according to the invention should contain between about 0 and 40% by weight, preferably between about 5 and 20% by weight, of disintegrant, depending on the tape composition.

Furthermore, the formulations of both types of tape can contain one or more fillers or extenders, as are generally known. Such ingredients contain, for example, opacifying fillers such as titanium dioxide, lime, kaolin and the like, microcrystalline cellulose, calcium carbonate and the like. Some of the components listed may have more than one function and therefore fall under more than one of the categories listed above. For example, calcium carbonate can act as both an opacifier and a dispersant, certain strengths can act as binders and disintegrants, etc.

In addition, both the polymer and paper formulations may contain one or more modifying ingredients that affect the electrical, mechanical, optical, or permeative properties of the tapes made therefrom. Examples of such ingredients include an electrolyte such as sodium chloride, potassium chloride and the like, surface active agents such as dioctylnabrium sulfosuccinate and the like. The tapes can also be ingredients^:, such as pharmaceutically acceptable colorants, preservatives and the like.

Finally, both types of tape formulations mostly contain a volatile solvent, e.g. water, certain organic solvents, e.g. ethyl alcohol, or combinations of such solvents, e.g. a mixture of alcohol and water, which is removed during the manufacture of the tape.

Specific examples of tape compositions or materials according to the invention are given below.

Polymer films or tapes that are. self-destructing in an aqueous environment due to swelling agents are the following:

Component weight%

I hydroxypropylmethyl cellulose 45.69

Acacia 19.44

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

Titanium dioxide 1.94

Lecithin 0.75

100

II Purified starch 33.06

Carboxymethyl cellulose 33.06

Propylene glycol. 33.06

Sodium benzoate 0.55

Sorbic acid 0.28

100

III hydroxypropylmethyl cellulose 55.19

Cellulose acetate phthalate 2.99

Grain size 28.66

Propylene glycol 9.87

Titanium dioxide 1.52

Dioctyl sodium sulfosuccinate 1.52

Lecithin 0.25

100

IV hydroxypropylmethyl cellulose 64.00

Cellulose acetate phthalate 3.10

Calcium carbonate 21.74

Propylene glycol: 9.06

Titanium dioxide 0.91

Dioctyl sodium sulfosuccinate 0.91

Lecithin 0.30

100

The formulations I to IV are sealed by heat and pressure.

. Lockable. Formulation IV self-destructs due to the presence of insoluble polymeric agents in an aqueous environment.

Preferred paper formulations according to the invention contain between about 70 to 99% by weight, preferably between about 90 and 96% by weight of fiber, for example hardwood or softwood fibers or mixtures thereof, between about 1 and about 30% by weight, preferably between about 4 and 10% by weight of a disintegrant which is selected from the group consisting of sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone and guar gum and between about 0 and 5% by weight, preferably between about 0 and 2% by weight of a wetting agent, for example polysorbate 80, dioctyl sodium sulfosuccinate, sodium lauryl sulfate and the like, the ability of the substances mentioned to function as disintegrants in paper formulations is said to be unexpected due to the fact that if members of the Group used in papermaking, they are present in different quantities and fulfill a different function. For example, sodium carboxymethyl cellulose, where it has hitherto been used in papermaking, has been used in small amounts, ie 0.1% by weight or less, to assist in dispersing the fibers in paper formation. In contrast, it has been found that when sodium carboxymethyl cellulose or the other substances listed above in large quantities, ie up to 30% by weight, after the formation of the paper tape, but while it is still wet, can be added as disintegrants, the time i the addition of these substances being critical for their function as disintegrants. The disintegrants are preferably added as a solvent to the solvent used to make the paper tape. It has. it has been found that the above-mentioned disintegrants, when added to the belt as described, cover the fibers. When the finished dosage form comes into contact with water, the disintegrant swells and thus forces the fibers to tear the tape. The wetting agents, when present, act to assist water penetration into the disintegrant and thus promote tape tear.

The tapes used in the present invention are made in a conventional manner, for example, as is common in the paper making and film making industries. For example, the polymeric tapes can be poured onto a suitable substrate, for example Mylar, stainless steel, release paper and the like. The tapes are then dried, for example in a draft oven. The temperature of the dry air and the duration of the drying time depend on the nature of the solvent used, as is known. Most of the foils relevant here, however, are dried at temperatures between about 25 ° and 105 °, preferably between about 60 ° and 90 ° C.

A second method of making polymeric tapes is a conventional extrusion process. This method is preferred for tapes in which the film-sealing component is a modified food starch, hydroxypropyl cellulose or another extrudable polymer. The mechanical details of the extrusion process, such as the device used, the extrusion force, the shape and the temperature of the. Openings are considered to be known to the person skilled in the art and can be modified in a known manner in order to obtain the physical properties of the strips described below.

The paper tapes according to the invention are produced using conventional paper production machines, for example on Fourdrinier-ıhpier machines. In all cases, however, the tape must be uniform both in terms of its thickness and in terms of its width. The tapes are between about 1 and about 10 mils (about 0> 03 to about 0.3 mm), preferably between about 1.5 to 4.5 mils (about 0.038 to about 0.123 mm) thick. A normal width of these tapes is 12 inches (30 cm), although the width of the tape is not particularly critical in the practice of the invention. The tape can be made in any length. Because the dosage forms made according to the invention are very well suited for high speed manufacture, the tapes should be made in large quantities, for example 15,000 feet (4,575 m) or more can be stored on cores or spools.

Referring to Fig. 1, block 10 represents tape manufacture from the above formulations. During manufacture or shortly thereafter, the tape is puffed (block 11 in Fig. 1), with various tests being performed in whole or in part automatically to ensure the integrity of the tape To ensure band, as will be explained in more detail below. The tests of the tape can be carried out at the time the tape is formed or at a suitable later location by devices which cooperate with the tape manufacturing device or by other devices, and can be carried out at any other location.

The active ingredient to be applied to the tape is manufactured and stored for use in containers as indicated generally at 22 in FIG. 2, FIG. 2 showing the various devices for performing the steps shown in FIG. 1 in a highly schematic manner. The prepared active ingredient is fed to an arrangement, indicated generally at 23 in FIG. 2, where the size reduction of the particles of the active ingredient and their testing takes place, as shown in FIG. 1 designated 12. This step is described in more detail below; with the step and the device 23 a uniform flow should be brought about, so that an exact and uniform application (block in FIG. 1) of the active ingredient to the tape is possible, which is denoted by 24 in FIG. 2. It should be noted that the in Fig. 2 plant shown as an example relates to the application of dry, particulate material to the tape in the dry state. The invention also includes wet deposition of the active ingredient on the belt. 21 in FIG. 2 shows that of the invention in which the strip is prepared and stored for later use, ie in which the strip test (stage 11 in FIG. 1) is carried out, for example when the tape is pulled off the storage roll 20. This test can be carried out before the tape is wound up and stored, or can additionally be carried out, as denoted by 21 in FIG. The details of the tape test are described in more detail below

The uncoated strip can be tested in the test device 21 in various ways. Holes, spots and the physical integrity of the tape can be detected and quantified using a scanning laser beam in combination with a photodetector. The system is used in transmission and reflection. The continuous HeliumNeon laser beam is guided over the belt using a mirror attached to a galvanometer. The position of the mirror is electronically controlled so that the position of any defect on the belt can be determined. The reflected or transmitted light is detected by means of a linear photodiode, which is arranged behind an interference filter in order to switch off room (scattered) light. The electrical output signal is used to count the number of defects and to determine their size and distribution along the strip. This is done by analyzing the output signal of the detector with a pulse height width analyzer.

Another method with which the tape can be tested at significantly higher tape speeds uses a parallel arrangement of photodiodes arranged across the tape. Each photodiode has its own threshold detector system and digital logic, which enables the defect size to be characterized with low resolution and the location of the defect. The output signal can be processed to give a possible size distribution and the location of the defects on the tape.

The physical thickness of the tape is measured by means of a parallel arrangement of tape scanning rollers, which are arranged in precision bearings. These rollers touch the tape and are connected to transducers that electronically record the location with an accuracy of at least 0.002 mm (1/10000 inch). A similar device for measuring the thickness can consist of pneumatic sensors floating on the belt on a solid film of air. The advantage of this system is that it does not touch the tape.

The mass thickness (weight per unit area) or the basis weight, I the Bender is made using a non-contact one

Beta-beam or X-ray technology determined. This system measures the absorption of beta rays or X-rays that radiate through the tape. This absorption is related to the mass thickness. In another system, the electrical

Resistance measured between two electrodes touching the tape to determine the basis weight of tapes with a known moisture content.

The on-line analysis of the moisture content can be carried out using one or more of the following methods: First of all, the high dielectric constant of water enables a sensitive measurement of the moisture by direct microwave absorption and by sensors in the radio frequency range for the dielectric constant. Low frequency conductivity measurements can also be used to measure the moisture content of the tape. Spectrophotometric infrared absorption is a completely independent method for measuring the moisture content. Furthermore, the optical absorption at wavelengths in the range of 1 to 2 pm results in a specific and precise moisture measurement in a spectral range in which the band tested is relatively transparent.

The strip that has passed through the testing device 21 is guided by a roller arrangement shown in FIG. 2, so that it moves very close to a device 24 for applying the active component, in which the strip is loaded with active component. The device 24 is followed by a device 25 for Qn-line analysis / testing, for example the uniformity of the content of active ingredient, of the coated tape, the tape preferably being in the form of a single layer before the active ingredient is inside is arranged.

A preferred method for non-destructive on-line analysis of the active, tape-applied component is x-ray absorption. In this method, low-energy X-rays with a frequency peak corresponding to the absorption edge of the atoms deposited on the cbm band are directed through the coated band. The absorption of the X-rays is related to the absorption of the active ingredient plus band. If the active Be: .....

part is applied to the tape by wet coating; this analysis method can be used both before and after cbr drying.

Because the total X-ray absorption results from the combination of tape and the coating containing the active ingredient, it is necessary to determine the absorption by the tape separately. This is done using a beta radiation measurement or an infrared spectrophotometer. The sensitivity can be increased by the X-ray measurement of the deposited active component, which contains atoms of higher atomic numbers. The X-ray source can be adjusted by changing the acceleration voltage according to the absorption edge of many atoms of interest.

Spectrophotometry operating in reflection or transmission can also be used for non-destructive on-line analysis of the deposited active component. Reflecting spectrophotometry is used in the near ultraviolet to determine the level of active ingredient. This technique can be used with any solid active ingredient that has optical absorption in a suitable wavelength range.

Transmission spectrophotometry can also be used for non-destructive on-line analysis of active components applied to tapes. A light source, a monochromatosing element and a detector are selected with respect to the wavelength ranges in which the active ingredient is selectively absorbed. The wavelength range must lie in a spectral range in which the band itself does not absorb strongly. Such ranges are in the near infrared and infrared ranges of the spectrum associated with functional groups in the bands of the present invention.

A fast wavelength scanning system is used to cover a small wavelength range of interest. The output signal of the detector is time-averaged over several samples in order to reduce the effects of the noise. The signal data are then processed further in order to obtain a first derivative of the transmission with respect to the wavelength in order to increase the sensitivity. This is done in a similar way for other wavelength ranges that respond to other components in the system. In this way, the water content, the basic weight of the strip S and the content of active ingredient can be determined at the same time.

Another method for analyzing the load of active ingredient is molecular fluorescence. A suitable filter combination generates excitation radiation in the ultraviolet or visible range of the spectrum. The fluorescence of the active ingredient is measured with a broadband filter-detector combination selected according to the fluorescence tip; A blocking filter is used to switch off the excitation energy.

The detector used in this method is preferably a photon counter that counts individual photo events and enables high sensitivity and linearity in low lighting.

During this analysis, precautionary measures must be taken to limit the photodecomposition of the active ingredient by the excitation radiation.

The coated tape can be stored temporarily or is preferably fed directly to a manufacturing facility (stage 16 in Fig. 1) and a separator (stage 17 in Fig. 1) to manufacture dosage forms. These devices are shown in FIG. 2 as a series of knives 26 for cutting the coated strip into a plurality of endless strips, which are followed by a processing and separating device 27 of the layer type,

- That is, the endless strips are stacked one on top of the other, so that an endless stack is formed, which is pressed and finally separated according to the invention, as will be described below.

The individual dosage forms are then finished and packed in a device (stage 18 in FIG. 1), which is shown schematically in FIG. 2 with 28 and 29, and then distributed

<img file="LU76378A1_D0001.tif" />

to become. An examination is carried out in connection with this working stage (for example 30 in FIG. 2). The purpose of the last check of the individual dosing units is to determine the size, shape, integrity, identity, the presence and the accuracy of a print, and the content of active ingredient. With the exception of the active ingredient content test, this entire test is non-destructive. For the analysis of the content of active ingredient and the characteristic properties, a statistical sample of dosage units is taken from the production line and analyzed with destruction in terms of effectiveness and properties, ie the dissolution properties. This is done by solution spectrophotometry, as described below.

An optical scanning system can be used to inspect all production units for size, shape, integrity, identity and the presence and accuracy of a print. This system contains a source of light and a matrix of photodetectors or a TV camera. A computer is used to process the output signals of the optical system. A suitable algorithm is used to determine the acceptability of the dosing units. Another method works by comparing the sample image with a standard image using an image mask technique. '

Another method for a 100% inspection optically transforms the image of the dosage unit. The transformed Fourier spectrum, energy spectrum, or other suitable transform is compared to a similar transform of a standard using a computer.

Before the finishing stage, stage 19 (FIG. 1) carries out an on-line analysis with regard to the uniformity of the resolution and the content. This analysis is carried out by means of a device, not shown individually, which contains a computer or a similar central processing or logic device and / or can be controlled thereby. A statistical sample r_;

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The ft24 take-up mechanism takes one dosing unit from the end of the production line at a rate of 25 to 120 units per minute, preferably from 40 to 60 units per minute. Each unit is fed sequentially to a conventional automatic weighing device in which it is destroyed by means of a destruction device^egg^^ orr ^ .chtung, is weighed, the associated information is stored. Statistically selected units are then arranged sequentially in a conventional automatic analysis system. The dosing unit is agitated in a solvent for the active ingredient at an appropriate speed. The amount of active resolved at time tj. Component less the amount solved at time t ^ divided by tj - is taken as the solution speed. The appropriate time interval (tj - t ^) is preselected and changes for individual medications. A suitable time interval i

can range from 5 seconds to 2 minutes and more. The sample is then stirred continuously for a period of time sufficient to dissolve all of the active ingredient, after which the solvent is analyzed for active ingredient content. The amount of active ingredient in this analysis plus the amounts from the samples at times t ^ and tj provides the total amount present in the dosage form. 'This information is also recorded and saved. If the weight, thickness, dissolution rate and drug analysis are within predetermined limits, the units are acceptable. If the values ​​are outside these limits, the manufactured units are isolated for further evaluation, starting with the negative analysis and ending with the next positive analysis.

With reference to FIG. 1, it should also be pointed out that the functions or properties described below are additionally monitored according to the invention. The tape check is carried out, for example, continuously on tape color, thickness, connection, dirt stains and defects of any kind. These functions can be carried out by electronic and / or optical instruments or by visual observation.

Checking the tape involves placing a flag on the tape wherever an error or defect is found. In addition, a device can be provided which, whenever a defect is detected on the tape, automatically or under operational control produces a printout which indicates that a defect of a kind is present on the tape at a certain distance in the direction of movement, the printout includes identification of the type of defect, such as a hole, black spot or other defect, etc.

The device for producing the printout can be the same

Device which flags the tape itself.

Such a device is in the manufacture of fabric or

Fabric and testing of the fabric, for example, are common, with the exception that the handling and testing of the tape in the present case would be carried out according to careful manufacturing requirements.

In addition, the same or additional conventional

Tester the strip thickness can be measured. This could be done with a visual display that an operator needs, or could be done in a measuring device that is logically arranged with upper and lower. Limits for the tape thickness would be connected, whereby as soon as the thickness of the tape is outside the limits, a printout is also made and a flag would be arranged on the tape as described above. An embodiment of a device for measuring the thickness of the strip could be a measuring device operating with X-rays or beta rays or a device which is similar to that for measuring the mass thickness of the strip.

1, which relates to the reduction in particle size and the flow control, the following functional monitoring should take place. The unloaded bail itself has already been checked for its thickness and for defects, but according to the invention a similar test is provided after loading the band with active ingredient (s). For example, a measuring device working with X-rays could again be used to measure the thickness of the loaded belt, this thickness compared to the previously measured thickness of the unloaded belt ίϊ

-> 26 !

Infer the amount of active on the tape

Component. In addition, it is within the scope of the invention to provide means for monitoring the actual mass in order to determine the amount of the active ingredient loaded onto the belt. The test of the loaded belt could be done by passing the loaded belt back through the same device that performs the belt test according to stage 11 in FIG. 1.

The device for applying the active ingredient (reference 14 in Fig. 1) is controlled by feedback from the on-line analysis of the active ingredient content on the belt.

I

For example, electrical signals from the on-line analyzer (digital or analog) analyzing the active ingredient load (weight of active ingredient area of ​​the coated tape) are used in a feedback operation (reference 15 of Figure 1) to determine the amount to control the active ingredient applied to the belt during deposition. These feedback signals are fed, for example, to a mini computer, which generates a suitable correction signal for the deposition process. This correction signal either increases or decreases the load with the active component, so that the load remains within a narrow range around the target value. For example, in the case of dry deposition, the powder with the active ingredient is introduced into the deposition device. The correction signal is used here to control the feed rate and in accordance with the loading with active component.

In the case of wet deposits, the correction signal can be used, for example

Change the amount of coating formulation used on the tape. For example, the gap between the metering rollers or between an metering knife and an application roller is changed in order to change the loading with active ingredient. With reverse roller coating, the speed of the application roller is changed to change the loading of the active ingredient. Another means of controlling wet deposition is to change the concentration of the active ingredient in the coating liquid. Two liquid formulations with different concentrations of active ingredient are mixed in the required proportions so that the correct concentration is delivered; the ratio of the two formulations can then be changed for precise control of the loading with active ingredient.

Deposition of the drug on the tape

The methods for introducing the active ingredient into the new dosage forms according to the invention form a radical departure from methods by which active ingredients are introduced into conventional solid dosage forms, for example tablets, capsules, coated tablets, suppositories, etc. The methods and the devices used according to the invention may differ somewhat; the fundamental most important goal, however, is the uniformity of the deposition, ie the active ingredient being applied or deposited on the moving belt surfaces in an extremely uniform manner. The method of applying the active ingredient according to the invention is unique and is associated with numerous advantages over the manufacturing processes used conventionally in the pharmaceutical industry.

Because the active ingredient is deposited on or substantially on the surface of an edible tape, which is then processed to contain all of the active ingredient inside, there is no need to add ordinary pharmaceutical extractants, fillers, preservatives, and the like to the active ingredient. which saves costs and, more importantly, eliminates a source of possible incompatibilities and problems related to quality control. According to the invention, a uniform coating with an active ingredient is applied to the belt. The belt is then divided into individual dosage forms by straight-line or geometric subdivision, which, with a large number of dosage forms, achieves a uniformity in the strength of the active ingredient, which is substantially higher than that with the production in individual batches,

- 2'8 as is currently accepted in the pharmaceutical industry.

In stark contrast to the invention, conventional pharmaceutical manufacturing processes require that the active ingredients and therapeutically neutral pharmaceutical adjunct materials be made in large quantities and then divided volumetrically into capsules for filling or into tablets for compression. When using the production methods according to the invention, it is therefore possible to reduce the amount of excess active ingredient present, which ensures the target dosage, from the currently customary level between 5 to 10% by weight to approximately 1 to 5% by weight, which is a noticeable result Cost savings result in particular when very expensive active substances, for example certain hormones and antibiotics, are processed. Finally, the method according to the invention makes it possible to deposit or unload the active ingredient on the belt, a continuous,^ze^rsTrouble-free on-line testing of the dosage by physical parameters, which favors the maintenance of a high uniformity of the amount of active ingredient in a variety of dosage forms.

The active ingredient can be applied to the tape in wet or dry form, with the dry form being preferred.

In any event, the active ingredient is deposited in a form available for analysis, as will be described below, ie in the form of fine particles. The particle size is in the submicron range and can also be within a narrow size range. range from 1 to 100 microns. Submicron particles have so far been considered too fine for the manufacture of pharmaceutical tablets unless they have previously been subjected to special techniques, for example granulation which significantly increases the particle size and adds extractants to the active ingredient. The technology of the invention favors the use of such ultrafine particles without the need for such techniques and / or the addition of extraction material. The active ingredient is applied to the belt as a very even coating while it is moving in an automated manufacturing system.

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The preferred method by which the active ingredient, when in dry form, is excreted on the belt is the electrostatic precipitation of a powder cloud, in certain non-pharmaceutical sectors. known techniques are used. This process requires the tape to pass through an electrostatic field in a chamber. Fine particulate matter is introduced into the chamber, for example by means of a maintained air flow, and is deposited on the belt as it moves over an oppositely charged roller. While this description is a great simplification that is required to achieve this result, the device is well known in certain non-pharmaceutical fields, such as the manufacture of adhesives and adhesive papers. In order for satisfactory deposition to take place, the tape must have a resistance that allows dielectric particles to be deposited on the tape. Additives that may be present in the tape composition to achieve the correct electrical properties have been discussed above. In many cases it has been found that before electrostatically depositing the powdery active ingredient it is necessary to coat the tape with a substance which promotes the adhesion of the powder to it. Examples of such substances are carboxymethyl cellulose, methyl cellulose and the like. These adhesion-promoting substances can be applied to the tapes in a conventional manner, for example by applying a solution with a volatile solvent, such as water and drying with, for example, heated air. The application of the coating to the tape, which ensures adhesion of the active substance, is then immediately followed by coating or loading of the tape with the active substance. The AdhSsionsmittel then works and binds the particles of the active substance to the Btmd. This is achieved by applying heat, pressure, moisture or a suitable combination of the above measures to the belt. In addition to the process of electrostatic

A powder cloud separator can be applied with an active ingredient in the form of a fine powder on the belt in a dry state by means of electrogas dynamic powder coating. In this method, the particles of the active ingredient are electrically charged by being exposed to a corona discharge and are driven by a gas flow into an electrically insulated chamber. The tape runs through this chamber on a metallic surface that is grounded or charged with the charged cloud of particles of active substance of opposite polarity. The electrical field between the particles and the metallic surface pulls the particles onto the tape unc / deposits them there.

Furthermore, according to the invention, the active ingredient can be applied to the tape in the form of a solution with, a suspension of finely divided medication, ie a colloidal suspension.

The liquid used for this can be water, an organic solvent, for example ethanol or a water-alcoholic solvent. A preferred method after the active ingredient is applied in liquid form to a moving belt is electrostatic spray deposition. In this method, the solution or suspension with the active ingredient is metered into a device which emits a jet of microdroplets concentrated on a specific surface of the belt with the aid of an electrostatic field with a defined area. This method has given very good results when small amounts of active ingredients, such as hormones or enzymes, are to be applied to the tape. Active substances with a normal dose of less than 1 milligram are mentioned in small quantities.

In addition to electrostatic spray deposition, certain other coating techniques can be used to load the tape with active ingredient, which are known in techniques other than suitable for coating a substrate with a liquid. For example, the paper tape can pass under a roller that is immersed in a bath of saturation liquid.

As the belt moves along the roll, the excess liquid is wiped off by means of another roll, an air jet, a rubber wiper stick, a wire-wound stick, ie a Meier stick, or the like. In this case, the

- 31 some solution into the tape, especially if the solvent used to solubilize or suspend the active ingredient is the same as or similar to that used to make the paper tape.

A goal pursued by the invention is to apply the active ingredient to the surface of the tape by using a volatile liquid carrier for the active ingredient or by applying heat to the tape and /

Or pressure when sealing or closing it can penetrate the tape somewhat. Simple experiments with these factors, for example volatile liquids, make it possible to determine the percentage of the active substance applied to the tape that is absorbed in the tape. If this parameter is fixed, the on-line test device described here can be set accordingly. If a noticeable amount of active substance is absorbed in the band, it is necessary to have unloaded band, ie band with no active ingredient, on the outer surface of the dosage unit in order for a loss of active ingredient due to its exposure to destructive forces such as air and moisture , is avoided. Obvious changes in the manufacturing process described later lead to this result.

As already stated, one of the main advantages of the dosage forms according to the invention is that pharmaceutically active substance can be brought into a stable dosage form without the addition of conventional pharmaceutical extracting agents, which are usually present in conventional solid dosage forms in amounts which are more active Substance far exceeded. However, there may be a need for small amounts of neutral substance to be applied to the tapes with the active substance according to the invention. If the active substance is applied to the tape in a dry form, for example

I

32 a small amount, ie from about 0% by weight to about 10% by weight, preferably from about 1/4% by weight to about 2% by weight of the active substance, of a lubricant is homogeneously mixed in purpose ^; this lubricant is to assist the flow of the powdered active substance through the applicator. Suitable lubricants contain, for example, fine, particulate silicon-containing compositions, such as colloidal silica, which is sold under the trade name Cab-O-Sil by Cabot Corp., Boston, Mass., Lime, starch composition in the form of fine particles, for example DriFlo by National Starch, Inc. and the like. The inclusion of a lubricant and its amount depends on the crystal structure and the flow properties of the active substance. In certain cases, a preservative can be added to the active substance. However, when the active substance is applied to the tape in 'dry form, it is generally not necessary. Furthermore, it is within the scope of the invention to mix the above-mentioned adhesive substances with the active substance if it is applied in wet form and the adhesive and active substance is compatible with the same liquid carrier.

In most cases, however, the adhesive substances are used as described above to increase the adhesion of the active substances when they are applied to the tape in a dry form. In any case, the adhesive substance can be present in an amount between 0 and about 100% by weight, preferably between 0 and about 30% by weight, of the medication.

The amount of active substance applied to the tape according to the invention changes according to the dosage of the substance, the covered tape area, the thickness of the coating and the like. Additional factors that influence the amount of the drug applied to the tape are the application method used the manufacturing process to be described below and the type and sensitivity of the on-line test equipment used. In any case, however, the amount of the active substance applied to the belt is such that after the loaded belt has been produced and separated, each form obtained contains a therapeutically effective dosage thereof. As an example of the latter criteria, the thickness of the active substance coating cannot exceed 0.005 cm when the uniform application of the drug is checked spectrophotometrically using photon number technology to measure the ultraviolet absorption of the active substance on the tape. In any case, the amount of active substance applied to the tape will be in milligrams or micrograms per cm^s Band specified. This will be for the whole. Tape area determines, although it is usually necessary to leave an edge of uncoated tape which is used to seal or close the dosage form. The ability of the tapes to absorb active substance according to the invention and to be able to arrange it inside is expressed as a band conversion factor (WCF) and calculated using the following formula:

; surface of the tape exposed to the drug; ---_____________ —— _ = tape conversion factor .maximum FISche of the finished dosage form

For example, if a tape measuring 15.25 cm x 1 cm is exposed to the drug and a dosage form measuring 0.5 cm x 1 cm is made from it, the result is

1525x10 zr-i-χ-_η· ~ - - 30.5 as B-earth conservation factor.

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processing

The next step in the manufacture of the dosage forms according to the invention is the form^-Or processing stage. The term processing here means the conversion of the tape from its initial shape into a fixed geometric shape of a predetermined shape, which can be divided into a plurality of unit dosage forms. This stage, like the stages described above, can proceed in a continuous manufacturing process at high speed. This step transforms the flat loaded belt into a designed geometric shape and generally houses the active component essentially within a protective layer or layer of the belt. The shaped tape is then separated and finished, so that pharmaceutically acceptable unit dosage forms suitable for oral administration are formed. The separation preferably takes place together with or immediately after processing.

According to the invention, there are several different processing methods, among which the extrusion production, the multi-strip forming, the cord formation by winding, the press forming and the like are mentioned. The many basic techniques for shaping or processing the tape covered with active substance are: closed winding, rotary molding, fan-like folding and layering. These four main techniques are explained in more detail below,

Before discussing the individual processing techniques in more detail, the various criteria for an acceptable technique should be summarized. The processing or molding technique should be one with high speed production and result in a geometric shape with high accuracy with regard to uniformity. The method must essentially accommodate the active substance inside the tape. Finally, the processing or shaping process must not exert an unduly high tension on the strips, so that they deform or tear_fand must not remove a noticeable amount of active substance from its place. Each molding process described below meets these criteria.

The first basic technique concerns the closed winding of a moving belt. It may be advantageous to distinguish between closed winding and spiral winding, as is known, for example, in the paper-forming industry. Spiral wrapping involves feeding paper from various reels to a spiral winder, with the paper typically being in 1/2 to 2 cm wide windings. These continuous strips of paper from each roll are wrapped around a cylindrical mandrel that is supported at one end. The strips are wrapped overlapping, an adhesive is applied to each paper strip and the overlapping strips form a continuous spiral as they are wrapped around the mandrel Forces towards the unsupported end of the mandrel. At the end of the mandrel, the tube thus produced is cut into desired lengths by intermittent actuation of a high-speed knife. Paper thus fashioned always has a cavity in its center because of the mandrel on which it is manufactured. When the winding is closed, there is no mandrel, so that a cavity in the center of the rod formed is neither necessary nor desirable. In fact, the invention is expressly intended to severely restrict or completely eliminate this central cavity. /

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An example of closed winding is shown schematically in FIG. The coated or loaded belt 61 is guided by a single roll through the system, which for example guide wires 62 and guide rollers 63 for a cutting or. Separator assembly 64 which cuts the tape transversely into desired lengths, the length of which is typically between about 12 and 25 cm. These pieces of tape are then fed into a corrugating roller arrangement 65, in which a corrugating roller forms a series of folds or sieves by pressing the tape against a soft rubber roller. As a result of this corrugation, the individual pieces of tape are formed into loosely wound windings. The loosely wound tapes that leave the corrugated roller assembly_/then pass between a stationary surface and a moving surface, the distance between the two surfaces ISngs of the movement path of the wound strips gradually decreasing. The stationary and moving surfaces can be formed as two concentric cylinders, one of which is stationary and the other rotates relative to the stationary cylinder, or as shown in Fig. 2 shown, in the form of a flat fixed plate 67 as a stationary surface and a moving belt 66 as a non-stationary surface. When the loosely wound bar pieces move between the moving and the stationary surface, they are tightly wrapped together until a stable bar is formed. By adjusting the distance between the two surfaces, the bar can be wrapped so tightly that each Cavity in its middle is excluded. If necessary, the distance can be adjusted so that a cavity of the desired size remains in the middle of the rod produced.

The rod can be closed or sealed in various ways. First of all, it was found that conventional methods, for example sugar gluing, are not suitable for carrying out the invention. In the conventional method, the moving surfaces that come into contact with the belt during the formation of the rod are sprayed or coated with water so that they touch a large area of ​​the belt. The amount of water absorbed by the tape, approximately $ 18% by weight, is unacceptable in the manufacture of the unit dosage forms of the invention due to the possible adverse effects on the adhesion of the drug to the tape and on the drug itself. Furthermore, it has been found that the rods formed with this conventional method are mostly too tightly sealed for the medication to be released well in the body. Rather, according to the invention, it has been found that spraying approximately the same areas of the tape as in the conventional method with a sufficient amount of a fine water spray, only to moisten the tape, and rapid drying of the bars after their formation results in finished dosage forms which have a satisfactory uniformity and drug release rate, as well as stability with respect to the active ingredient, except for those drugs, which are known to be highly sensitive to moisture in pharmaceutical preparation.

Second, the bars can be sealed by applying a piece of heat-sealable, sealable, edible polymer to the trailing edge of each piece of tape, or coating baron, edible polymer immediately after cutting off the endless tape. A heat-weldable or cross-linkable polymer can also be applied over the entire band piece as a separate layer or as a uniform coating. Suitable polymeric materials are, for example, a water-soluble polyoxyethylene or cellulose ether derivatives with a plasticizer, as described above. In this case, after the bars have been wrapped tightly, they are passed under a heated plate, where they are sealed with the aid of heat and pressure. For example, part of the fixed plate 67 could have a heated area

Once formed, the bars can also be sealed by applying water or an adhesive to the outer layer (s) or tape. Water is preferably used as a sealing agent. This method would require the presence of substances in or on the belt material, such as starches or starch derivatives, which form a seal during subsequent drying or under heat or pressure.

The inFig. 3, as an example, uses a water jet 68 which strikes the outer surface of the endless belt 66 along its lower, returning part, so that the belt surface coming into contact with the rolled band pieces retains sufficient water or water droplets for a perfect sealing of the bars , The water could also be applied to the tightly wound bars, for example, by moving the bars beneath a water application roller, a porous plate by means of which a measured amount of water is applied evenly over the entire length of the bars, or a sponge, the water on the Outside surface of the bar. The bars could then be passed between another part of the moving and stationary surfaces, where^: Pressure or pressure and heat can cause the closure or sealing.

This general method of sealing with the help of water appears to be clearly advantageous over known methods, according to which, as described above, for example sealing with the aid of sugar solution, is clearly advantageous. When applying water according to the above-mentioned methods, the total amount of water is each stick of water applied is smaller than in known processes. As a result, the amount of water removed during the subsequent drying of the bars is considerably smaller than in the known methods.

I

The rods thus made are each as long as the width of the ribbon of the supply roll. A typical width is 20 to cm. After sealing, each bar is moved by means of the belt 66 in contact with, for example, ultra-sharp knives 69 (FIG. 3) where it is separated, ie where the bar is cut into the desired lengths. The processes for separating and finishing these bars into finished dosage forms are explained in more detail below.

A second molding or processing method is generally referred to as turning molding. This procedure can be carried out in various special ways. It is related to a general layering process because it initially produces stacks of active substance loaded tape in arrays of endless strips or bars by fan folding or laminating, as described below. In a special rotary molding process, according to FIG. 4 a continuous, relatively thick, multi-layered strip of ribbon 70 loaded with active substance is passed between a pair of press rolls 71. The thus formed or pressed layered stack 72 is fed to a second station, a rod forming and compacting station, which contains, for example, one or more spring-loaded stainless steel rollers 73 with a circumferential contour so shaped that the strip is shaped into a plurality of continuous rods 74 with a cross-section in shape a wide circle or other desired cross-section is formed. The rods 74 thus shaped in the desired geometric shape are passed through a third turning station, in which, for example, one or more pairs of correspondingly arranged rollers separate the rods into individual cans. This can be followed by printing and finishing steps, which are explained in more detail below. The printing process can take place in the separating stage with the third set of rollers 75.

In the example of a rotary molding shown in FIG. 5, the shaped endless stack (strip or rod) 81 is continuously and reciprocally moved at regular intervals

Stamp blocks 82 and / or a pair of heated rollers 83 are notched or cut so that rounded edges are formed in the finished dosage units, with a continuous chain connected at the ends of the rotating dosage forming station. 85 As is the case with alien or the various methods of rotary shaping according to the invention, the rods modified in this way are passed through printing and separating stations or subassemblies which all work at high speed,

According to another closely related rotary molding technique, the continuous stack is fed to a rotating molding and compacting assembly which contains, for example, one or more pairs of stainless steel rollers. The wall layers, which may consist of layers of paper and polymeric film, are heated and pressed into a continuous stack. The outer layers of the stack are preferably made of paper, for example in order to prevent the stack from sticking to the heated rollers. During this compaction process, the layers of tape are connected to one another, causing the layers to shift and tear at the. Margins is reduced during the subsequent side and final form operations.

The ends of the metering units are then formed by feeding the continuous rectangular stack formed in the compacting station to a second station, in which the ends of the metering units are formed by a pair of heated rollers, which may have blades oriented transversely on their rolling surfaces. The cut ends of the dosage units are shaped and sealed by the heat from the rollers. The design of the end knife determines the shape of the ends of the dosage units. The shape of the end knives is chosen so that there is a smooth transition to the sides of the dosage units which are formed in the next station.

The sides of the metering units are formed in the layered, shaped end, cut, material stack using a third pair of heated rollers. These rollers can have angular grooves with raised cutting edges. The formation of the grooves in the roller surfaces forms a desired metering unit cross section. The heat and pressure exerted by the ridge-like cutting elements of the rollers seal the sides of the dosing units to form a smooth surface.

The rotary molding process for producing the dosing units shown in FIG. 5 therefore consists of three primary stations, a precompression station, a final molding station and a side molding station. Each of these stations consists of a set of rollers, which are preferably heated and through which the continuous stack of belts is guided. The formation of the outer surface, ie the circumferential surface, the rollers is different at each of the stations and depends on the respective station and the desired result. Various additional operations such as additional cutting or separating, printing or finishing steps can be carried out between the three described stations. These processes are described in more detail below.

It is within the scope of the invention to carry out one or more of the various stages of the rotary molding process simultaneously and on the endless history entrance strip with the aid of a single pair of, for example, spring-loaded, heated, cooperating rollers, all of the various stages explained above, i.e. rod formation, dosage formation, separation and even printing perform.

The explained third example of the rotary forming suggests an example according to which two or more of the stages shown are combined into one. This is shown in FIG. 4A, where essentially the stratification and bar forming stages of the third rotary molding process discussed above and also the process of FIG. 4 are combined, for example through the use of a single pair of heated press and cutting rollers (not shown in detail) that simultaneously press and cut the fed layer into a shape that resembles a side view of several pancakes stacked on top of each other. These end-cut parts are then fed to a separating device, in which the longitudinal cuts for producing the individual dosage forms are carried out. The pressure stage, for example, could also take place in this latter station. It is also within the scope of the invention to pack the individualized dosage forms directly as they result from the separating process, for example by using them in blister packs by means of conventional devices.

A third method of making the dosage forms according to the invention is the FScher folding technique. The FScher folding technique could also be classified as a form of layering in the general sense. In this method, a tape of up to, for example, 30 cm width is first processed in such a way that the active ingredient applied is absorbed inside. This can be done by initially folding the tape in half or by layering two coated strips together, with the coated surfaces facing each other. A stack of more than one pair of tapes layered in this way can be used, the tapes initially being made, for example, with a larger width of up to 60 cm and being split after layering so that two or more widths are formed in one dimension, as described for F-folding, ie between about 1 cm and 15 cm.

After the initial folding or stacking of the loaded belt, it is passed between the furrow rollers, where it is furrowed or ribbed in preparation for the fan fold.

The furrow rollers can be driven. Basically, the belt is moved by pull rollers. Furrowing can be done, for example, by one of the pair of furrowing rollers being spring-loaded. Since the band folds preferably in the direction of the furrow rings that press into the band material, the furrow rings can alternate in accordance with the desired Fcher fold pattern in the upper and the lower roller be formed. The furrowed band then moves into a fan folding trough with tongues that begin to gradually bend the band at a point of contact and determine or narrow its width and overlap, so that the band is reasonably tightly folded at the exit end. At the end of the folding trough is a device that pulls the tape through the folding and folding device, such as a pair of spring loaded, stainless steel driven rollers. This has a dual function; the tape is moved through the folding device and the folded tape is compacted into a continuous, solid geometric shape. The pulling device can be combined with the device for closing the band. However, the fan-folded band can be closed by other methods, as will be explained below. The sealed tapes can be separated in different ways, as in the rotary molding process described above.

6A to 6D show a technique for making a fan-shaped dosage form in which the initial fan-shaped strips 91 are arranged in recesses 92A of a suitable size of a therapeutically ineffective band structure, preferably made of paper and designated with central strips 92. This loading¹ The central strip, which supports the fan-folded bands, is then sandwiched between the outer strips 93, so that a composite, layered structure is formed. This composite endless layered strip is then fed, for example, to a rotating dosage form unit or station which is not unlike the unit 83 shown in FIG. 5 where the strip is brought into the form shown in FIG. 6B. Afterwards or simultaneously with the one shown in FIG. 6B, the separation is carried out, which leads to individual doses according to FIG. 6C. FIG. 6D shows the cross section of the dosage form according to FIG. 6C. Fig. 6D shows how the fan-folded tapes 91 are received entirely on the inside and that the central strip 92 is forced outward somewhat by the molding process so that part of it is exposed between the edges of the outer strips 93 which are connected to it , Preferably, the outer strips 93 and 93 contain

Central strip 92 is not an active ingredient, so that it is ensured that no active ingredient is present on an outer surface of the individual dosage forms.

Layers or

The fourth basic molding process is / lamination, which has already been pointed out generally. In this method, between about 20 and 60 reels of tape are first simultaneously unwound from a multi-reel unwind stand and then brought together so that they form a continuous bar.

The 20 to 60 layers of tape can all be made of paper-like material, which is provided with a coating suitable for facilitating the sealing in a later stage. They can also consist of a multi-layer arrangement of paper-like tape and heat-sealable, edible polymeric tape or can consist of one or more paper-like layers between which alternately heat-sealable, edible polymer tapes are inserted. A suitable polymer material is, for example, a water-soluble polyoxyethylene or a cellulose ether derivative with a plasticizer. Any number of tapes can be loaded with active substance. The strips of paper material are preferably loaded with active substance.

In another method for stacking the tapes loaded with active ingredients, they are fed directly from the applicator. The width of the band is usually 12 to 25 cm. The tape, stored on rolls or fed from the applicator, may initially be several times the final width, and is then cut or slit to the desired final width as part of the stacking process.

As soon as the tape is arranged in a stack, the resulting coherent bundle is fed to a layering station. Known devices can be used to implement the invention, which bring together strips of flexible films or tapes and produce a laminate from them. As already explained, the application area of ​​active substance to the tape strips or sheets depends, for example, on the method of sealing the layer body. The laminated body can also be cut and finished differently. For example, layered bodies can be processed in the rotary molding process described above. The layering station could also consist of a pair of reciprocating stamp plates that shape, seal and cut the dosage forms from the: continuously fed stack of tapes, a typical one. The stamp plate would have a surface of approximately 25 x 25 cm.

The layered bodies produced according to the invention are distinguished in a special embodiment in that they are sealed only at the edges and not every layer is completely connected to the adjacent layers. It has unexpectedly been found that satisfactory dosage forms can be made from a stack of tape layers in which up to 6 layers of paper-like tape are interposed between tape layers of a heat sealable polymeric material, in which heat and heat are applied to the stack in the cutter during the separation Pressure is applied During the separation, the polymeric tape layers in the stack are deformed and spread by the heat and the pressure, so that they cover and seal the edges of the intermediate paper tape layers. The top and bottom layer of such a laminated body must consist of polymeric material. In the case of a paper-polymer tape stack, the medicament is preferably applied to the paper layers of the tape. A layered body, which is only closed at its periphery, has a significantly higher drug release rate than a similar stack of tapes, which is completely laminated.

Another method for producing the dosage forms from the stack of tapes is to pass the stack between rotating cylinders, which have individual dual stamps on the outer circumference, in which the dosage units are molded, sealed and cut from the continuously fed stack of tapes, while the stack of tapes rotates between them Cylinders moved through.

The use of layering techniques, as described above, has several advantages in pharmaceutical manufacture. First, the layering technique creates barriers that allow the incorporation of two or more therapeutically active, incompatible substances without the need to add stabilizing substances or using a special mixing technique, such as encapsulating one or more components. Because up to, for example, 60 layers can be used to form a laminate, this embodiment of the invention is ideally suited for pharmaceutical preparations with a large number of active substances, where there is. There are numerous possibilities of incompatibilities, for example with multi-vitamin preparations. Furthermore, the insulating effect of the layers of the layered body and the deposition of the active substance on the tape in the dry state make this technique ideal for the production of foaming preparations the tape material should be such that it easily dissolves or disperses in water, Furthermore, the application of active ingredient to the tape in the dry state is advantageous when the active substance is adversely affected by moisture.

Regarding the stratification, it is further within the scope of the invention to combine the different layers within one

Change layer bodies and control whether each layer is covered with active substance. The surface of the uppermost and lowermost layers of a laminated body that are exposed are not coated, whereby the active substance is absorbed inside. For example, it has been found that an intermediate arrangement of one or more layers of starch-based material in a cellulose-like laminate helps the laminate to have more elasticity than an increase in the amount of plasticizer in the composition of the cellulose layers.

In the shaping process explained above, it is preferred according to the invention to strip the strip with active ingredient in wet form to '-1¹ WTTK.

load if molding is done by tight wrapping or fan-shaped folding. The rotary forming and layering processes are equally suitable for the application of active substance in wet or dry form, the choice depending on the properties of the active ingredient used, for example: the solubility in the specially used solvent, compared to the stability Moisture and the like.

separation

The separation cannot be explained without the closure also being explained and without the processing having been discussed beforehand, because when cutting or separating the shaped strips, an active ingredient could be exposed on one or more of the outer surfaces. An exception to this would only exist if the active substance was applied at short intervals and not continuously during loading, as a result of which the active substance was deposited in spots and surrounded on all sides by an unloaded band. In view of the manufacturing equipment and the need to maintain the integrity of the deposited coating for on-line testing, it is preferred to continuously apply the active substance to the tape in an amount sufficient to form dosage forms with a therapeutically effective dose during the singling process , In certain processes described here, for example the fan-shaped fold, the outer edges of the band can remain free of active substance so that it is actually later taken up inside and in certain cases excess band is formed which can be used to close the individual dosage forms.

The cutting or cutting of the shaped band must be carried out so that the band is not deformed. The cutting process itself can be carried out by stationary or rotating knives in one or two-stage tools or 'with other conventional' methods. In order to. the processed tape is not deformed when it is cut, different cuts can be made at different angles. Also, as explained above in the case of the rotary molding, the shaped strip can initially be slightly crimped or incised so that the deformation is compensated for, which is caused by the high-speed separation.

The formed, loaded belt can be separated by individual separation, ie one unit can be formed by cutting exact lengths from a rod, or, preferably, several units can be formed at the same time, for example by a tightly wound rod using a number evenly cutting edges separated from one another is divided into several dosage units. Another method of making multiple dosage units simultaneously would be to use dies which are single or double and rotatably mounted or reciprocally mounted on plates and which separate egg-layered tape or a tightly wound rod-like structure. The shape of the finished dosage form preferably has a cosmetically acceptable appearance and is such that several such shapes fit into a stamp plate without substantial clearance except for the circumference, such as, for example, a rectangular, square or preferably hexagonal shape.

The shape of the dosage forms made from bars can also be determined by the shape of the knives. The knife, for example, could have a rectangular shape and be slightly curved on its parallel, larger sides, so that the ends of the dosage forms cut with it are approximately rounded. Other changes are known to those skilled in the art. However, it must be taken into account that the processed dosage forms have to be supported laterally during the separation in such a way that the formation of wrinkles or other irregularities is avoided.

The separation and the final closure can be combined. There are numerous possibilities for closing or sealing the dosage forms, the most common way, combined with the separation, is to apply heat and / or pressure. In addition to sealing the trimmed edges of the dosage form by heating the cutting tool, heat and pressure can be applied via the tool used to bind the laminate. The use of moisture or a volatile solvent to seal the trailing edge of the tightly wound rod, which was explained above, can also be extended to the cutting or separating process by applying such a solvent to the cutting surface. Heat and / or pressure can also be applied simultaneously for effective sealing.

The methods by which the individual dosage forms produced according to the invention can be sealed are not uncommon in plastics processing and laminating technology. bräuchlich. They also include the use of water or volatile solvents such as ethanol, methanol and chloroform, the application of pressure and heat, the application of a separate adhesive, infrared heating. Ultrasound binding, encapsulation or combinations of the options mentioned. A preferred method of sealing dosage forms is to use a wrapper that can be printed if necessary. Such an envelope can

I can be, for example, a thin layer of edible, polymeric material, such as hydroxymethyl cellulose, modified starch and gelatin, which is applied to the dosage units in a bath in which the dosage units are immersed. Such a layer could, for example, be self-sealing due to the escape of a volatile solvent. More preferred methods of applying a sealing layer to the individual dosage units are the encapsulation and the pocket seal.

I

In the first of these methods, the fixed dosage units are passed between mutually approaching layers of a flexible film of, for example, gelatin, which surround the dosage forms as shown in FIG. 6A. The gelatin film is then heat sealed and cut to shape,

A device for encapsulating liquids by means of this method is known in the pharmaceutical industry. Such a device can be converted in a simple manner in such a way that the dosage forms can be encapsulated with it.

A second method is the pocket seal, which can be carried out using at least the following two methods.

In the first method, preformed bags made of a material, such as gelatin or a cellulose derivative, are preformed in a device which is known, for example, from plastic molding, ie injection molding. The individual dosage forms are automatically placed in these pockets at high speed and the pockets are then covered by a cover layer which is welded to the pocket by one of the abovementioned joining methods, for example by ultrasonic welding. The pockets are separated from one another by cutting with a stationary or rotating cutting edge. The pre-formed pouch is usually thicker than the top or closed position, but the closed position is of sufficient thickness to protect the dosage form. The thickness of the top layer is such that the dosage form is released from the pocket through the top layer within a short time after ingestion, usually within a few seconds after reaching the stomach. The pocket can also be formed from two identical halves which are connected to one another by the above-mentioned methods.

An alternative to the described pocket seal consists in the production of a continuous carrier tape or strip from a material as described above for the pockets. Holes are punched into this carrier tape which contain the dosage forms, for example, fan-shaped dosage forms according to FIG. 6A_;record exactly. In this embodiment, the individualized dosage forms are placed in the holes, for example by means of a pin through the hole and a second pin on top of the individualized dosage form to keep it under pressure. The strip is then sealed by adding a top and bottom of similar material while maintaining the dosage unit compression. The thickness of the strip is in no case greater than that of the dosage units. However, the strip can be thinner than the dosage form, but not less than about half the thickness. For several reasons, the carrier strip preferably has approximately the thickness of the dosage form. First of all, the sealing film can be as thin as described above in connection with the pocket, because it is not significantly deformed during the sealing or connecting process. Secondly, a thicker carrier tape is less exposed to deformation during perforation and separation. Third, with a thicker strip, the narrower holes can be formed adjacent, which allows for minimal drop. When the dosage form is arranged in the carrier strip and is sealed or closed, the strip is again separated, as described here. An advantage of both the pocket and the carrier strip concept is that there is strip material on the outer surface that contains no active substance and could be subjected to the finishing operations, such as embossing, flattening and the like, without the risk there is a loss of active substance. The use of the pocket or carrier strip concept also facilitates the use of different colors for the finished dosage form, for example by producing the carrier tape, the closure strips or the dosage units themselves in contrasting colors, as a result of which a pleasing and distinctive appearance can be achieved.

This is for the production of the bag, the central carrier strip and the above-mentioned closure

<img file="LU76378A1_D0004.tif" />

pass exact tests. In addition to the obvious

I

- 52 pharmaceutical criteria regarding purity, good durability, non-toxicity and compatibility with the active or active substance used, the material must have good surface quality, color and printing ink receptivity, structural integrity, deformability, dimensional stability and release properties for active ingredient in water. Preferred substances for this use are hydroxypropyl cellulose and methyl cellulose. A particularly preferred composition contains hydroxypropyl cellulose, a starch or a starch derivative as an extender and disintegrant, a plasticizer, for example polyethylene glycol, suitable dyes, for example titanium dioxide and an antioxidant, for example BHT.

QualitStssicherung

One of the greatest advantages achieved with the dosage forms according to the invention is that they are accessible to non-destructive online quality assurance. The term non-destructive is here meant in a practical sense and not exactly literally. This means that the quality control of the dosage forms takes place during the high-speed manufacturing processes, the actual loss being well below. 1% lies. Because dosage forms can be made with a small standard deviation and corresponding to a manufacturing surplus that is below the standard that is currently common in the pharmaceutical industry, the very small percentage of dosage lost during testing becomes essentially zero when considering the overall tolerances of the current manufacturing processes taken into account.

As a finished product, the dosage forms according to the invention have the quality assurance of the manufacturing process, a concept which is outstanding in the pharmaceutical industry. The on-line testing procedures that provide this security are distinctly different from recognized pharmaceutical quality testing procedures, such as chemical and physical control of the components of the dosage form before the start of production, with destruction of testing of the solid dosage forms after completion of the production with regard to physical characteristics , for example solution rates, incidence of the cover and the like, as well as chemical characteristics, such as effectiveness, Presence of incompatibilities and the like and physical quality checks of the fixed¹ Dosage forms such as manual inspection of two-tone capsules. to ensure that each end has contrasting colors. Such tests, which are recognized and generally performed in the pharmaceutical industry and described in the official summaries, have no relation to any

On-line manufacturing control, which is an essential feature of!

solid dosage forms according to the invention, and do not suggest them. Certain conventional methods, such as strict quality control and testing of all components before the manufacturing process, however, form an integral part of the dosage forms described here, so that it is common in any perfect pharmaceutical production. '.

The on-line quality control of the production of the new dosage forms according to the invention is created by the fact that all the forms described here are produced starting from a continuous, edible belt which is accessible to a non-destructive test. First, the tape manufacture itself is monitored for physical tape characteristics to ensure that the tape is smooth and free from defects. For example, the tape can be passed through a resonance cavity in which a microwave passing through the tape continuously monitors the tape thickness, ie, when a resonance frequency is set, its changes indicate changes in the tape thickness. Other options for monitoring the strip thickness are, for example, laser beam scattering, fluid scanning and sensors that are in direct contact. According to the invention, it is also possible to check the basis weight of the belt and defects.

To check the basis weight of the strip, the absorption of soft X-rays is preferred, for example X-rays with a wavelength of about 4 angstroms. Beta radiation absorption using a PM 147 source is also suitable. Tape defects such as spots, holes and streaks can be detected by laser beam scanning. Holes in the tape can also be determined by the electrical discharge method using commercially available equipment.

I

The methods listed above can be used both where the belt receives a second coating in the form of one or more additional belts or where a protective layer is applied to a loaded belt. Laser scanning is particularly advantageous in the on-line quality inspection of such coatings.

A second major field of the on-line quality assurance according to the invention is the checking of the amount of active substance applied to the tape and the checking of the uniformity of the application process. It should be recalled here that a major advantage of the method according to which the dosage forms according to the invention be produced, is that the active substance is applied to the tape in a form, '. the test procedure to be described later is accessible, ie in a finely divided form or as a fine film,

There are various methods for checking the uniformity of the deposition of the active substance. For example, a photon counter can be used to measure the ultraviolet absorption of a highly absorbent active substance-band system. It can also absorb soft X-rays with a

Wavelength of about 4 angstroms and beta radiation absorption are used. A light scattering apparatus is preferred because it is ideally suited for monitoring the particle size and concentration in the powder cloud or on the belt. Devices for such operations are commercially available.

The processing, separating and

Finishing stages are also suitable for on-line tests as described above with regard to the strip. Such tests naturally contain physical parameters of the strip after processing, such as dimensions, thickness, uniformity and the like. Similar tests can be carried out on the individual dosage forms with regard to their shape, uniformity and similar,

So far, the explanation has primarily referred to devices with which the dosage units are checked online and non-destructively during production. Two additional tests are possible within the invention and without departing from the meaning of the term non-destructive testing.

In a first such process, a small portion of the tape is periodically removed online by cutting with knives, stamps, fluid nozzles, or a laser beam. The portion of the tape removed does not destroy the tape integrity or adversely affect any processing operations. The tape sample can be taken before or after the active substance is applied, or, in some cases, during earlier stages of processing, for example when some tape is stacked in a preliminary layering or folding process. The sample taken in this way is chemically analyzed both with regard to the strip material and the active substance. This analysis is also carried out on a quantitative basis, particularly with regard to the active substance.

I

In addition to the stain analysis, samples of the finished dosage forms are taken and subjected to on-line property tests. While such testing is currently required for most solid dosage forms available in the United States, it is not performed on-line during manufacture as in the invention. First of all, it must be remembered that the dosage forms according to the invention are not subject to batch restrictions due to their manufacturing process. A batch of the invention may be the number of dosage units that fall between two property specimens provided the number does not exceed the Federal Food and Drug Administration's sampling requirements. Because the sampling methods considered in connection with the invention greatly exceed such requirements, a batch of dosage units can be any suitable number, for example a number of units that can be made from a given production amount of active substance.

A second special aspect of the property tests of the dosage forms according to the invention is that the results of these tests, like all the other online tests explained here, can be processed in a computer and can be used to set the parameters of the manufacturing process. A negative result of any test thus indicates the start of a manufacturing line of dosage units that need to be isolated and the next positive result after corrections automatically ends that line. The dosage units made between these two tests must then be further tested to determine how many meet the guidelines. Where online tests are carried out on the line, for example with regard to the amount of active substance applied, a negative value can automatically be used to trigger two functions at the same time. First of all, the tape can be marked with a stain, non-toxic dye, which temporarily stops the production and a part of the tape can be removed by hand. Furthermore, reading out via a computer causes the amount of active substance loaded onto the tape to be adjusted in order to increase or decrease the amount so that it corresponds to the specifications. When the tape that passes through the test unit again meets the specifications, a second spot can be automatically applied to the tape, which marks the length of the tape that does not meet the requirements. Similar operations can be carried out at all on-line test sites.

With reference to property analysis, statistical samples of finished dosage units can be taken and automatically placed in any test solution where their dissolution rate is checked. The specific criteria used to check the dissolution of the unit dosage forms depend on the active substance or substances present. For example, a sample dosing unit can be supplied to a suitable solvent, which results in a solution of the active ingredient. The resulting test solution can be scanned photometrically in order to record the concentration of the active ingredient as a function of the time after the test unit has been introduced. Other possible indicators measured in the test solution include changes in pH, color, heat, chemical reaction and the like. Facilities in which these changes can be recorded automatically as a function of time are known to the person skilled in the art.

Once the information regarding the resolution is recorded, it can be used in a system, for example in a computer, for settings of the formation, separation, finishing and sealing processes, as is necessary to correct or improve the measured values.

With the on-line test methods described here, the entire strip can be checked in all cases, for example by means of a device that checks the strip thickness. In certain cases, however, an examination of the entire volume may not be advisable for economic reasons. For example, it is possible to inspect a small band area by means of a light scattering sensor, and it is further possible to install two or more sensing devices in close proximity in order to scan a corresponding number of narrow widths within a continuous band. However, the cost of the equipment required to scan the entire tape can preclude this. Therefore, in cases where only limited strip areas are tested, the test equipment can be installed so that it can be moved back and forth across the width of the rod. The percentage of the tape and according to the finished dosage units that are tested in this way far exceeds any current non-destructive testing methods in the pharmaceutical industry.

Finishing and printing

As already mentioned variously, the finishing processes for the dosage forms can be carried out independently or preferably in combination with other processes, for example the separation. The finishing of the dosage forms can be divided into two basic aspects, namely the uniformity of the surface of the dosage form and the finish or appearance of the surface.

The uniformity of the surface of the dosage forms may or may not be a problem depending on the singulation technique used and whether a capping process is taking place. For example, a small irregularity or margin may be visible where the cutter comes together when a coated stack of tape is cut into a particular shape as described above. An irregularity at the ends or sides can also occur from the separation of the dosage forms produced by the other preferred processing methods. Overall, however, the processing techniques according to the invention minimize the occurrence of such irregularities.

Irregularities described here can be caused by slight

Abrasion are eliminated, for example by subjecting the dosage units to a rolling action with or without the presence of a mild, abrasive substance such as salt crystals. In most cases, this effect must precede printing.

The surface appearance, ie the gloss of the dosage forms,. or matt,. , ,, can be between slightly rough / and high-gloss, depending on the technique used and the desired finish. If sealing techniques, such as bag sealing or encapsulation, are used, the gloss of the finished surface can be adjusted by simply selecting the material used to form the seal. The same applies if an enclosure is used to seal the dosage forms. With such sealing processes, the irregularities generally do not have to be completely eliminated because the covering ensures complete continuity of the surface.

The printing process depends similarly on the processing and sealing technology used. The tape itself can be printed at any point in the entire manufacturing process. For example, the outer layer of a / coated dosage form can be printed before processing as part of the separation process or even after the separation process. Dosage forms produced by tight winding can still be printed in the connected rod or stack. If the dosage forms are sealed by applying a covering, the printing is preferably carried out after the covering has been applied, although the dosage form can also be printed and then a transparent covering can be applied. Printing solid unit dosage forms before they are made or mixed together as is. being considered here is one in the pharmaceutical industry. good concept.

The selection of a printing process depends on several factors, the most important of which is the physical nature of the substrate to be printed. The selection of a suitable method also depends to a certain extent on the point in the entire manufacturing process at which the printing takes place, ie whether the tape is printed before processing, the finished processing. Dosage forms are printed or the printing takes place at an intermediate point, for example in combination with other processes, such as the separation. The printing process and the associated device can be selected from the following: offset or direct character printing, offset engraving, lithography, electrostatic powder engraving, electrostatic screen stencil, ink jet and the like,

Of these, offset engraving is the preferred method, although other methods can be used in special cases and new printing methods, as they become accessible and adaptable to the technology described here, are considered to be within the scope of the invention.

It follows from the previous discussion of the finishing and printing processes that the color of the dosage forms can be changed in a variety of ways, both in terms of hue and in terms of intensity. First of all, the tape material itself can contain a color that can result in an intensity when the tape layers are joined together during the various processing operations. The color can also result from a wrapping or sealing layer. If sealing by means of. Pocket or encapsulation method, two or more contrast colors are possible, in that the color of the different parts is different. The coating forms produced by layering can have different colors in that only the color of the strips fed to the layer device is different. Other modifications to these techniques are known to those skilled in the art,

Active ingredient

The dosage forms according to the invention are not subject to any restrictions with regard to the type of active or active substance for which they serve as carriers. The terms active substance. active ingredient and medicament that are used interchangeably in the context of the invention and are interchangeable throughout the description and claims can be defined as any substance that elicits a pharmacological response in the body. These substances are in no way limiting the following:

The benzodiazepines such as chlordiazepoxide, diazepam, flurazepam, oxazepam, chlorozepate urid-like. Additional substances that come under the name benzodiazepine are mentioned in The Benzodiazepines, Garattini, Mussini and Randal, Raven Press 1973, the content of the publication mentioned being not restrictive.

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

Sedatives and hypnotics such as the phenobarbitals, methylprylon, glutethimide, ethchlorvynol, methaqualon and the like;

mental pathogens such as amitriptyline, imipramine ', methylphenidate and the like;

Narcotic and non-narcotic analgesics such as codeine, levorphanol, morphine, propoxyphene, pentazozin and the like?

Analgesic antipyretics such as aspirin, phenacetin, salizylamide and the like;

Anti-inflammatory agents such as hydrocortisone,

Dexamethazone, prednisolone, indomethacin, phenylbutazone and the like;

, - 62 Antispasmodica / Anticholinergica like. for example atropine, papverine, propantheline, dicyclomine, clindinium and the like;

Antihistamines / antiallergics such as diphenhydramine, chlorpheniramine, tripelenamine, brompheniramine and the like;

Decongestants such as phenylephrine, pseudoephedrine and the like;

Diuretics such as chlorotiazide, hydrochlorothiazide, flumethiazide, triamteren, spironolactone and the like;

nutritional aids such as vitamins, essential amino acids and the like;

Antiparkinsonian agents such as L-DOPA alone and ^;, , 1 2 in combination with potentiators such as N -DL-Seryl-N (2,3,4 “trihydroxybenzyl) hydrazine? '

Androgenic steroids such as methyltestosterone and fluoximesterone;

Progestational agents such as progesterone, ethisterone, norethynodrel, norethinodron, medroxiprogesterone and the like;

estrogens such as oesterone, ethynyl estradiol, diStylstilbesterol and the like; .

Hormonal preparations such as prostaglandin, ACTH and the like;

Antibiotics / anti-infection agents such as the penicillins, cephalophorins, tetracylcines, chlorotetracyclines, streptomycin, erythromycin, sulfonamides such as sulfisoxazole, sulfadimethoxine, sulfamethoxazoles and other agents such as nitrofurazone, metronidazole and Shnlfches;

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

anti-gastric acid / antiflatulent agents such as aluminum hydroxide, magnesium carbonate, simethicone and the like;

other therapeutic agents and / or combinations of such agents, the therapeutic utility of which is known.

The active substances used in connection with the invention can be present in free form or in any non-toxic, pharmaceutically acceptable form in which their therapeutic activity is retained. For example, acidic substances can be present as esters or salts with pharmaceutically acceptable inorganic bases, such as sodium salt, potassium salt and the like, or organic bases, such as amines or quaternary forms. Base substances can be present as salts with organic acids, such as acetate, tartrate and the like. Certain substances, such as ampicillin, may be present in a hydrated form. In general, any pharmaceutically equivalent form of a given active substance that is known in the pharmaceutical preparation for the substance can be used in dosage forms according to the invention, with only the limitation of incompatibility with the tape material. In the few cases where such incompatibilities may exist, these are determined by simple experiments. '

The amount of active substance or combination of substances that must be included in the dosage forms is usually the amount known as the therapeutically effective dosage of the particular drug. In general, the amount of an active ingredient present in a single dosage form should not exceed 500 mg, with a practical upper limit of about 750 mg.

- 64 resolution

As already stated, the dosage forms have an extremely precise release rate which can be adjusted according to the respective requirements. Regardless of which release pattern is considered, the dosage forms according to the invention show: an accuracy of the release rate within such a pattern which is higher than that of conventional solid dosage forms, for example “tablets and capsules”.

7 graphically shows the superiority of the release rate of dosage forms according to the invention compared to a conventional solid oral dosage form, here commercial capsules,

In the experiment shown in FIG. 7, six dosage forms according to the invention and randomly selected conventional capsules / each with the same amount of the same active ingredient in 100 ml of artificial gastric fluid, USP (without enzyme) were introduced. The liquid was kept at 37 ° C with stirring. The liquid in each reaction vessel was constantly filtered and siphoned through flow cells of a spectrophotometer.

The absorbance of the liquids was read at minute intervals and the percentage of active ingredient dissolved was calculated for each reading. In Fig. 7 are the curves for the¹ the fastest and slowest dissolving sample of each group and the shaded area in between covers the remaining four samples. 7 shows two conclusions. First, the dosage forms according to the invention dissolve much faster than the conventional capsules. Secondly, the variation among the six samples of the dosage units according to the invention is considerably less than that among the conventional capsules tested. These results clearly show the improved certainty of release, which is a characteristic property of the dosage forms according to the invention.

<img file="LU76378A1_D0005.tif" />

The blood level curves shown in FIG. 8 also compare the dosage forms according to the invention with conventional capsules containing the same amount of the same active ingredient. The blood level curves are theoretically drawn based on two input rates into a single chamber pharmacokinetic model. The blood level curves are based on a theoretical 100% absorption of the amount of active ingredient released from the dosage form at a time and are therefore proportional to the rate of dissolution. The difference between the blood level curves is therefore a function of the dissolution rates. From Fig. 8th it can be seen that the dosage forms according to the invention not only achieve blood levels which act more quickly but also achieve a higher blood level of the active ingredient than the conventional capsules. The ability to reach a higher blood level of the active ingredient is a significant advantage, particularly with regard to the utilization of certain types of chemotherapeutic agents, for example antibiotics, cardiac muscle active agents and the like.